心血管科领域文献阅读汇编

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Spinal cord infarction (SCI) is a rare stroke subtype with no established acute treatment guidelines. Thrombolytic therapy has been used empirically based on extrapolation from cerebral stroke protocols, but comparative effectiveness data are lacking. We compared outcomes between standard care and thrombolysis in acute spontaneous SCI. This retrospective cohort study used data from the TriNetX Global Collaborative Network. Adult patients with acute SCI (International Classification of Diseases, Tenth Revision, Clinical Modification code G95.11) were divided into the standard care group (antiplatelet therapy within 48 hours) or the thrombolysis group (alteplase or tenecteplase). Patients who underwent aortic repair procedures were excluded. Propensity score matching (1:1) balanced 68 covariates. The prespecified primary outcome was all-cause mortality; readmission and rehabilitation utilization at 180 days were secondary exploratory outcomes. E values were calculated for the significant association. Of the 965 patients in the standard care cohort and 103 in the thrombolysis cohort, 96 patients in each cohort remained after matching. Standard care was associated with significantly lower mortality (13.5% versus 29.2%; hazard ratio, 0.423 [95% CI, 0.219-0.817]; P=0.008); 180-day survival was 84.27% versus 68.69% (log-rank P=0.008), with an E value of 4.16. Readmission (14.6% versus 16.7%; P=0.669) and rehabilitation utilization (43.8% versus 49.0%; P=0.507) did not differ. The mortality association was consistent in direction across 3 sensitivity analyses. In spontaneous SCI, standard care was associated with significantly lower mortality than thrombolysis, without significant differences in readmission rates or rehabilitation utilization. These hypothesis-generating findings raise concerns about off-label thrombolytic use in SCI and support consideration of conservative management until higher-quality evidence emerges.

Raised inflammatory biomarkers predict an increased short-term risk of recurrent vascular events after stroke or transient ischemic attack, but it is uncertain whether the hazard is maintained thereafter. In the absence of previous population-based studies, we aimed to determine the predictive value of biomarkers for the long-term risk of recurrent stroke in intensively treated patients following transient ischemic attack or stroke. We studied 12 blood biomarkers related to inflammation, neuronal cell damage, and thrombosis soon after transient ischemic attack or stroke in a population-based study (OXVASC [Oxford Vascular Study]; 2002-2011) with follow-up to 2025. We used Cox and negative binomial regressions to assess associations between each log-transformed biomarker (per SD increase) and recurrent stroke (first event and total number), adjusted for age, sex, and baseline vascular risk factors. Of 1292 consecutive patients (mean/SD age, 73.1/13.2 years; 47.8% male), 365 recurrent strokes occurred in 280 patients during 11 336 patient-years. All inflammatory biomarkers were associated with 10-year risk of recurrence, with little impact of adjustment for other risk factors (adjusted incidence rate ratio: IL-6 [interleukin-6], 1.21 [95% CI, 1.04-1.42]; CRP [C-reactive protein], 1.29 [95% CI, 1.11-1.49]; TNFR-1 [tumor necrosis factor receptor-1], 1.24 [95% CI, 1.05-1.46]; and NGAL [neutrophil gelatinase-associated lipocalin], 1.15 [95% CI, 0.99-1.33]). Moreover, number of elevated (top quartile) inflammatory markers was associated with higher burden of recurrence (incidence rate ratio, 1.31 [95% CI, 1.15-1.50]; P<0.001), with no diminution over time (90 days: hazard ratio, 1.24 [95% CI, 0.98-1.57]; 90 days-1 year: 1.24 [95% CI, 0.95-1.62]; 1-5 years: 1.22 [95% CI, 1.01-1.47]; and 5-10 years: 1.34 [95% CI, 1.06-1.68]), and similar associations for transient ischemic attack and minor stroke. Biomarkers related to neuronal cell damage or thrombosis were generally less predictive of recurrent stroke. Inflammatory biomarkers were more predictive of long-term recurrent stroke than neuronal or thrombotic biomarkers, particularly when several inflammatory markers were raised. Predictive value was independent of other vascular risk factors and did not diminish with duration of follow-up, supporting trials of anti-inflammatory strategies for long-term secondary prevention.

Stroke is less common in children than in adults, yet equally devastating. Nevertheless, children with symptoms of acute stroke commonly present to community hospitals or adult stroke centers where experience and institutional protocols for pediatric stroke diagnosis and management may be limited. Despite advances in pediatric stroke awareness and the implementation of stroke pathways in many children's hospitals, significant gaps remain in the timely recognition, diagnosis, and management of pediatric stroke. A key contributing factor is the lack of system-level infrastructure to guide pediatric acute stroke care. This special report examines the challenges and barriers to achieving Pediatric Stroke Readiness at a national level in the United States and presents 5 engagement case studies highlighting efforts to establish processes and networks for pediatric stroke management across diverse care settings. The cases emphasize the development and implementation of systems of care in which pediatric stroke centers collaborate with first responders, community hospitals, and adult stroke centers to improve the delivery of acute stroke care for children. The strategies underscore different engagement approaches and identify opportunities for future research and quality improvement. These case studies also illustrate educational materials and clinical pathways that may serve as resources for others pursuing similar initiatives.

Normobaric hyperoxia (NBO) is a simple neuroprotective strategy that may augment endovascular thrombectomy (EVT) in acute ischemic stroke. We evaluated the safety and preliminary efficacy of NBO plus EVT in patients with large-vessel occlusion presenting 6 to 24 hours after onset. In this phase IIb, randomized, assessor-blinded, controlled trial conducted at 2 academic comprehensive stroke centers in China, patients aged ≥18 years with anterior circulation large-vessel occlusion presenting 6 to 24 hours after acute ischemic stroke onset were assigned 1:1 to EVT+NBO or EVT alone. The NBO group received 100% oxygen via a face mask at 10 L/min for 4 hours, starting before recanalization. The primary end point was early neurological improvement (≥30% reduction in the National Institutes of Health Stroke Scale score at 24 hours). Primary analyses used adjusted regression models controlling for prespecified prognostic covariates. Secondary end points included infarct volume at 24 to 48 hours and the modified Rankin Scale score at 90 days. Safety outcomes were mortality, intracranial hemorrhage, and symptomatic intracranial hemorrhage. Analyses followed the intention-to-treat principle. Early neurological improvement was analyzed using an adjusted binomial regression model, and the 90-day modified Rankin Scale shift was analyzed using an adjusted ordinal logistic regression model, controlling for age, sex, intravenous thrombolysis, and occlusion site. Between October 2021 and October 2023, 324 patients were screened, and 120 were randomly assigned to NBO+EVT or EVT alone (60 patients per group; intention-to-treat population). The median baseline National Institutes of Health Stroke Scale score was 12 (interquartile range [IQR], 8-15) in the NBO+EVT group and 12 (IQR, 9-16) in the EVT-alone group. The median time from stroke onset to randomization was 10.0 hours (IQR, 7.0-14.4) and 9.9 hours (IQR, 8.4-14.8), respectively. The EVT+NBO group demonstrated a significantly higher rate of early neurological improvement compared with EVT alone (35% versus 19%; adjusted odds ratio, 2.86 [95% CI, 1.12-7.45]). The median infarct volume at 24 to 48 hours was significantly smaller in the EVT+NBO group (20.5 [IQR, 13.6-31.8] mL versus 32.3 [IQR, 22.7-44.5] mL; P=0.001). At 90 days, the modified Rankin Scale distribution numerically favored NBO+EVT but was not statistically significant (median modified Rankin Scale, 2 [IQR, 1-3] versus 3 [IQR, 1-4]; adjusted common odds ratio, 1.52 [95% CI, 0.87-2.63]). Mortality, symptomatic intracranial hemorrhage, early neurological deterioration, and recurrent stroke did not differ between groups. In patients with acute ischemic stroke treated 6 to 24 hours after onset, adjunctive NBO with EVT was safe and improved early neurological outcomes and infarct volume, supporting further evaluation in larger trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05128422.

Left ventricular (LV) systolic dysfunction, defined here as reduced LV ejection fraction ≤40% or left wall motion abnormality, is commonly found in patients with ischemic stroke. Although there is an increased risk of incident and recurrent embolic stroke among patients with LV dysfunction without thrombus detected, the data supporting anticoagulation in these patients are limited. In this scientific statement, we summarize the latest evidence regarding the risk of incident and recurrent stroke in patients with LV dysfunction as well as best practice recommendations regarding the management of this population after stroke. We provide a narrative summary and meta-analysis of secondary analyses of randomized clinical trials that evaluated outcomes following anticoagulation versus nonanticoagulation strategies. Whereas anticoagulation is associated with a lower risk of incident stroke in patients with LV dysfunction without thrombus, there remains no net benefit of this strategy over a nonanticoagulant strategy for primary stroke prevention. For patients with stroke and LV dysfunction, anticoagulation may be associated with a lower risk of recurrent stroke and a net benefit when compared with antiplatelet therapy. Anticoagulation treatment decisions in these patients may involve individualized consideration, shared decision-making between patients and healthcare professionals upon discussing risks and benefits, and multidisciplinary collaboration between cardiology and neurology clinicians to optimize cardiac and brain health. As a key modifiable stroke risk factor and therapeutic target, LV dysfunction represents a target for future research.

Stroke rehabilitation research has seen an unprecedented expansion in the volume of randomized controlled trials. This sets the stage for conducting meta-analyses and network meta-analyses, which help compensate for the large number of smaller phase 2 studies. Over half of randomized controlled trials are conducted in the chronic phase when neuroplasticity is reduced, and the timing of the intervention is not directly generalizable to clinical care. Meanwhile, research productivity has plateaued in high-income countries over the past decade. Therapy intensity and dosage are regarded as important to improving recovery, but the optimal intensity and dose are still uncertain. However, timing also matters when it comes to therapy intensity and dosage. Therapy conducted in the chronic phase, when neuroplasticity has declined, requires a much higher dose to have a comparable impact as the same therapy delivered in the acute/subacute phase. More randomized controlled trials are now being conducted in low- and middle-income countries, focusing on different outcome measures and more acute/subacute randomized controlled trials when compared with trials from high-income countries.

Stroke is the third leading cause of death in women and a major driver of disability. Menopause is a universal transition for midlife women, which is accompanied by menstrual cycle changes, hormonal fluctuations, and, for many women, the occurrence of menopausal symptoms. An accumulating body of research underscores the importance of menopause and its features to stroke risk in women, including the type and timing of menopause, endogenous hormone profiles, and menopausal symptoms, including vasomotor symptoms and sleep problems. In addition, menopausal hormone therapy, a leading approach to managing menopausal symptoms, has implications for stroke risk, which varies depending on the menopausal hormone therapy formulation, route of delivery, and the age and health of the recipient, with transdermal menopausal hormone therapy formulations administered to younger midlife women showing a more favorable profile. This review summarizes the data linking menopause and stroke, and offers suggestions to inform clinical decision-making. Knowledge gaps and directions for future research are highlighted.

Despite remarkable advances in stroke management, there is a continued lack of evidence to guide care for the 1 in 3 stroke patients living with disability or dementia (PLWD). To help inform best practices, this study sought to understand how physicians approach the complex issue of determining goals of care for PLWD and what challenges they encounter. In a mixed-methods investigation, we invited physicians involved in stroke care to participate in semistructured interviews and an online survey, enquiring into perspectives on stroke management in PLWD. Interviews were analyzed using an interpretive grounded theory approach. Qualitative findings were triangulated with results from a descriptive analysis of survey items. Of 82 approached physicians, 30 participated in interviews (43% from North America, 77% with ≥10 years of experience; 60% neurologists); of 200 consenting to the survey, 132 completed it (37% from North America, 51% with ≥10 years of experience, 56% neurologists). For both prestroke disability and dementia, survey respondents most frequently indicated severity of the prior condition (87% [95% CI, 80%-91%] and 89% [95% CI, 82%-93%]) and quality of life (88% [95% CI, 82%-93%] and 87% [95% CI, 80%-91%]) as either very or extremely important in decision-making. However, interviewed physicians emphasized uncertainty in evaluating these factors and forming perceptions of patient prognosis and treatment appropriateness. This was attributed to limited reliable information regarding patients' prior well-being and wishes, and paucity of PLWD-specific evidence to guide stroke management. While these ambiguous circumstances appeared to warrant a highly individualized approach to care, physicians also recognized the consequent high risk of biases affecting equity. Physicians encounter profound, multifaceted uncertainty in determining goals of care for PLWD, which may contribute to adverse variability in stroke management. This uncertainty may be eased by routinely documenting patients' baseline well-being and advance healthcare directives in clinical practice and promoting inclusion of PLWD in stroke research, in both contexts, considering patient and family perspectives on quality of life and favorable outcomes.

Complete recanalization of cerebral arteries is strongly associated with good functional outcome in ischemic stroke. We hypothesize that successful recanalization results in better functional outcomes. This is a secondary observational cohort analysis of TEMPO-2 (Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion), a randomized controlled trial comparing tenecteplase with standard of care (control) in minor stroke (National Institutes of Health Stroke Scale score ≤5) with intracranial occlusion/focal perfusion abnormality ≤12 hours of onset. Among those enrolled based on computed tomography angiography with visible occlusion, a follow-up computed tomography angiography was done at 4 to 8 hours after randomization. The primary outcome was return to baseline functional outcomes using the modified Rankin Scale score at 90 days. Safety outcomes included stroke progression (National Institutes of Health Stroke Scale score ≥2 worsening), bleeding events, and mortality. Patients with successful recanalization, defined as revised Arterial Occlusive Lesion score ≥2b/3, were compared with those with unsuccessful recanalization on follow-up computed tomography angiography. Regression analysis was used to assess the association of successful recanalization with outcomes after adjusting for age, sex, baseline stroke severity, and onset-to-randomization time. Of the 886 enrolled patients, 517 (58.3%) with follow-up computed tomography angiography were included. Of these, 178 (34.6%) had successful recanalization (122 [68.5%]: tenecteplase, 56 (31.5%): control), and 336 (65.4%) did not achieve successful recanalization (unsuccessful recanalization; 134: tenecteplase, 202: control). Baseline characteristics were similar between patients with and without successful recanalization. Successful recanalization was significantly associated with the primary outcome as compared with unsuccessful recanalization (adjusted risk ratio, 1.21 [95% CI, 1.07-1.34]). Patients with successful recanalization had significantly lower rates of stroke progression as compared with unsuccessful recanalization (2.8% versus 13.1%, adjusted risk ratio, 0.21 [95% CI, 0.08-0.52]). Multivariable analysis showed that tenecteplase treatment was the strongest independent predictor of successful recanalization (odds ratio, 3.48 [95% CI, 2.33-5.18]). Successful recanalization is a critical determinant of early and 90-day functional recovery in patients with minor stroke with intracranial occlusion, regardless of treatment modality. Tenecteplase significantly increases the odds of achieving successful recanalization compared with standard care. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02398656.

Atrial cardiopathy is an important cause of embolic stroke and a potential cause of cognitive impairment. Increased left atrial volume indexed to body surface area (LAVi) has been widely used as a marker for atrial cardiopathy. However, because physiological remodeling, for example, due to exercise, may also increase LAVi, it lacks specificity. Left atrial to ventricular volume (LA:LV) ratio has been suggested as an improved marker of atrial cardiopathy, allowing detection of imbalanced, pathological atrial remodeling. We investigated if LA:LV ratio is associated with different sequelae of atrial cardiopathy. We analyzed data from 2 cohorts, the population-based UK Biobank cohort (n=38 848) and a cohort of patients with ischemic stroke from the University Hospital Zürich (n=1273). In the UK Biobank cohort, we compared the association of LAVi and LA:LV ratio with risk of incident ischemic stroke or transient ischemic attack ascertained from linked health records, using competing risks survival analysis. We also investigated the association with cognitive function using linear regression models. In the ischemic stroke patient cohort, we compared LAVi and LA:LV ratio for identifying atrial fibrillation/flutter as a cause of stroke. While LAVi was not significantly associated with risk of ischemic stroke/transient ischemic attack (adjusted hazard ratio, 1.11 [95% CI, 0.97-1.26]; P=0.14), a larger LA:LV ratio was (adjusted hazard ratio, 1.15 [95% CI, 1.01-1.30]; P=0.04). Besides, LA:LV ratio was more strongly associated with worse cognitive function. In a stroke patient cohort, LA:LV ratio significantly outperformed LAVi at identifying atrial fibrillation/flutter as underlying cause of ischemic stroke compared with LAVi (area under the receiver operating characteristic curve, 0.856 [95% CI, 0.803-0.908] versus 0.808 [95% CI, 0.750-0.866]; P=0.03). We provide evidence that LA:LV ratio is a strong, novel marker of atrial cardiopathy. Hence, LA:LV ratio has the potential to improve the diagnosis of atrial cardiopathy, facilitating the prophylaxis of ischemic stroke and maintaining brain health.

Magnetic resonance imaging (MRI) is critical for acute stroke triage, but it is time-consuming and often requires contrast injection for perfusion imaging. This study aimed to synthesize T-map perfusion maps from routinely available, noncontrast diffusion-weighted imaging and fluid-attenuated inversion recovery using deep generative models. We hypothesized that relevant perfusion information could be inferred from these modalities to streamline imaging and reduce reliance on dynamic susceptibility contrast perfusion. Acute magnetic resonance imaging data from 355 patients with anterior circulation stroke, including dynamic susceptibility contrast perfusion, were retrospectively collected from 2 European centers (Heidelberg: 2010-2018; Bordeaux: 2021-2022). Six versions of a denoising diffusion probabilistic model and a generative adversarial network architecture were trained to generate synthetic time-to-maximum (T-max) perfusion maps from diffusion-weighted imaging, fluid-attenuated inversion recovery, and infarct core mask as inputs. Performance was assessed by comparing synthetic and ground-truth T-max maps using image similarity metrics. Regions with T-max >6 s were compared using Dice coefficients, and mismatch volume distributions were analyzed. An ablation study quantified the contribution of each input. The best performance was achieved by a denoising diffusion probabilistic model with a 2.5-dimensional architecture using diffusion-weighted imaging, fluid-attenuated inversion recovery, infarct core mask, and a perfusion-weighted loss function. It produced synthetic perfusion T-max maps with high similarity to ground truth under 110 s. The model showed strong spatial overlap for T-max> 6 s regions in internal validation (average Dice, 0.82; SD, 0.08) and external validation (average Dice, 0.59; SD, 0.13), respectively. Synthetic maps closely matched ground truth mismatch distributions, capturing key perfusion patterns. The infarct core mask played a critical role in model performance, alongside diffusion-weighted imaging and fluid-attenuated inversion recovery inputs. We propose a noninvasive, scalable framework to generate synthetic T-max perfusion maps from noncontrast magnetic resonance imaging. This approach could expand access to perfusion data in acute stroke, shorten imaging protocols, and accelerate treatment decisions by eliminating the need for contrast-enhanced acquisition.

Patients surviving spontaneous intracerebral hemorrhage (ICH) who have indications for antithrombotic treatment face increased risks of both hemorrhagic and ischemic events. The aim of STATICH (Study of Antithrombotic Treatment After Intracerebral Haemorrhage) was to assess the safety and efficacy of long-term antithrombotic treatment after ICH. STATICH Antiplatelets (EudraCT 2014-002636-13; Unique identifier: NCT03186729) was a randomized, multicenter, open, blinded end point parallel-group trial, including adults with an indication for antiplatelet treatment to either start or avoid antiplatelet treatment. The target sample size was 500 participants. Patients were allocated 1:1 by a Web-based randomization system and followed for a minimum of 2 years. Outcome assessments were done by personnel blinded to treatment. Participants were not blinded. The primary safety outcome was recurrent symptomatic ICH. The trial was stopped early due to slow recruitment. Sixty-nine patients were included between August 2018 and December 2022: 34 were randomized to start antiplatelet treatment, and 35 were randomized to avoid antiplatelet treatment. No patients were excluded from analyses. The median age was 75 (Q1-Q3, 66-80) years, and 43 (75%) had previous ischemic stroke or transient ischemic attack. Five patients in the start antiplatelet treatment group (15% [95% CI, 6%-31%]), and 1 in the avoid group (3% [95% CI, 0%-18%]) experienced recurrent ICH, while 3 (9% [95% CI, 3%-24%]) and 7 (20% [95% CI, 10%-37%]), respectively, experienced a major ischemic event. A total of 88 serious adverse events and no suspected unexpected serious adverse reactions were registered. There were numerically more recurrent ICHs and fewer ischemic events in patients starting antiplatelet treatment after ICH compared with those avoiding antiplatelet treatment. The slow recruitment might be due to clinicians being certain of the best treatment strategy or patients being too frail to participate. STATICH will contribute to a planned collaborative individual patient-data meta-analysis to resolve this dilemma.

This study aimed to develop a consensus-derived minimum data set for childhood stroke and establish an agreed set of tools to measure key functional outcomes identified as important by childhood stroke survivors and their families. A steering group from Australia and New Zealand comprising rehabilitation clinicians and families with lived experience was established to oversee the modified Delphi process. Online focus groups with parents and young people with lived experience determined key functional outcomes of importance to families throughout rehabilitation. Based on this information, a prospective survey-based modified Delphi process was conducted to reach consensus for an Australasian minimum data set for pediatric stroke rehabilitation. An advisory group comprising specialist rehabilitation clinicians from 9 rehabilitation services across Australia and New Zealand responded to 3 surveys, which aimed to reach consensus on the key functional outcomes that are important to measure, the tools to measure these outcomes, and the time points for measurement. After each survey, the steering group collated and analyzed the data, and confirmed the content of subsequent surveys. Seventy-three participants from 12 rehabilitation disciplines participated. After Survey 3, consensus was reached on the measures for 14 (64%) of 22 functional outcomes in the preschool age band, and 20 (50%) of the 40 potential measures in the school-aged band. The Canadian Occupational Performance Measure was identified as a particularly valuable tool, achieving broad consensus due to its clinical utility, flexibility, and alignment with outcomes of importance to families and clinicians. Agreement on tools to measure other functional outcomes, particularly body function outcomes, reached lower levels of consensus. The agreement on the best measurement tools to be included in a minimum data set represents an important advancement in pediatric stroke rehabilitation research. The current findings provide a foundation for transformative improvements in future research, and in the care of children recovering from stroke.

Variability in poststroke language outcomes remains insufficiently explained by established clinical system neuroscience concepts. This study examined whether damage to neurotransmitter-informed structural networks is associated with poststroke language impairment. Two openly available cohorts of patients with left-hemispheric stroke were analyzed: the Washington Stroke Cohort (St. Louis), including patients after a first symptomatic stroke (acute phase), and the Aphasia Recovery Cohort (South Carolina), focusing on chronic recovery. Language performance was assessed cross-sectionally using either a comprehensive language battery (Washington Stroke Cohort; 1-2 weeks poststroke) or the Western Aphasia Battery-Revised (Aphasia Recovery Cohort; chronic stage). Individual stroke lesion masks were embedded into normative connectomes weighted by positron-emission tomography-derived density maps of 16 neurotransmitter receptors/transporters. Partial least squares regression and adjusted linear regressions (age, sex, lesion volume, and time poststroke) identified predictors of language functioning. Two hundred seventy patients were included. Washington Stroke Cohort (n=44): mean age, 54.2±12.3 years; 45.5% female; median, 12 days poststroke (interquartile range, 10-14). Aphasia Recovery Cohort (n=226): mean age, 57.8±11.2 years; 38.4% female; and median, 721 days poststroke (interquartile range, 403-1765). Across both cohorts, partial least squares analyses converged on a neurochemical profile in which damage to networks related to serotonergic (5-HT1a and 5-HT2a) and dopaminergic (D1) receptor distributions showed the strongest associations with poorer language performance. Damage to 5-HT1a and D1 networks remained significant in fully adjusted models, improving fit over covariate-only models (all PFDR<0.001; Washington Stroke Cohort: ∆AIC5-HT1a=1.77 and ∆AICD1=0.96; Aphasia Recovery Cohort: ∆AIC5-HT1a=25.29 and ∆AICD1=19.96). The disruption of large-scale serotonergic (5-HT1a) and dopaminergic (D1) networks is associated with language impairment in acute to subacute and chronic stroke. Neurotransmitter-related network damage, based on normative positron-emission tomography-derived maps serving as a structural proxy of neurotransmitter systems, explained additional variability beyond clinical variables and lesion burden, providing a neurochemically informed network framework for understanding variability in poststroke aphasia. However, given the indirect nature of the measures, implications for clinical translation and targeted rehabilitation strategies remain preliminary.

Thromboembolism is a common complication after interventional treatment of unruptured intracranial aneurysms. Glycoprotein IIb/IIIa inhibitor tirofiban may reduce thromboembolic complications during neurointerventional therapy for unruptured intracranial aneurysms. We aim to assess the efficacy and safety of prophylactic tirofiban in this clinical setting. In this investigator-initiated, phase 2, prospective, randomized, open-label, blinded end point trial (TEAR [Thromboembolic Events in Endovascular Unruptured Aneurysm Repair]), adults aged 18 years to 80 years with unruptured intracranial aneurysms suitable for neurointerventional therapy were enrolled at 2 comprehensive stroke centers in China. Patients were randomly assigned (1:1) to receive intravenous tirofiban combined with dual antiplatelet therapy or dual antiplatelet therapy alone during endovascular aneurysm repair. The primary outcome was the number and volume of new ischemic lesions on diffusion-weighted imaging within 48 hours postprocedure. Key secondary outcomes included the incidence of symptomatic stroke and hemorrhagic events within 48 hours and at 30 days. Between March 2024 and October 2025, 228 patients were screened; we randomly allocated 192 patients to treatment-one individual did not receive magnetic resonance imaging because of intensive care unit hospitalization before imaging; 191 patients were enrolled (95 in the tirofiban group, 96 in the control group). Median age of the patients was 58 years; 22.0% were men, and 78.0% were women. Adjunctive tirofiban significantly reduced the median volume of new infarcts (48.6 versus 88.2 mm3, P=0.007) and showed a downward trend in the number of new infarction lesions (P=0.046). There were no significant differences between groups in symptomatic stroke, intracranial hemorrhage, or major bleeding rates at either 48 hours or 30 days (all P>0.05). In this randomized, phase 2 trial, prophylactic intravenous tirofiban combined with dual antiplatelet therapy significantly reduced the new postoperative infarct lesions, without increasing hemorrhagic complications and mortality. These findings warrant validation in a multicenter, large-sample trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06238115.

Although the neuroprotective potential of remote ischemic postconditioning (RIPC) has been reported, the efficacy and safety of ultra-early RIPC administered after endovascular treatment (EVT) in patients with acute ischemic stroke remain unclear. This study evaluated the efficacy and safety of ultra-early RIPC in patients with acute ischemic stroke undergoing EVT. The EnTRIPS trial (Endovascular Treatment Combined With Remote Ischemic Postconditioning in Patients With Acute Ischemic Stroke) was a multicenter, randomized, controlled, outcome assessor-blinded, prospective clinical trial. The trial was conducted at 8 hospitals in China between April 12, 2021, and March 26, 2025. Eligible patients were adults with acute ischemic stroke due to large vessel occlusion who presented within 24 hours of symptom onset, underwent EVT, and achieved successful recanalization. A total of 270 eligible patients were randomized within 6 hours after EVT to receive either RIPC plus guideline-based therapy (n=135) or guideline-based therapy alone (n=135). RIPC was administered for 7 days using pneumatic devices consisting of 5 cycles of bilateral upper-arm cuff inflation (5 minutes at 180 mm Hg) followed by deflation (3 minutes). The primary outcome was functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2 (range, 0 [no symptoms] to 6 [death]). Safety outcomes included the incidence of RIPC-related adverse events within 7 days. Among 270 randomized patients, a total of 268 (99.3%) participants completed the trial, including 133 in the RIPC group and 135 in the control group (mean [SD] age, 65.5 [16.8] years; 171 [63.8%] men). At 90 days, functional independence was achieved in 81 (60.9%) patients in the RIPC group and 78 (57.8%) patients in the control group (adjusted risk ratio, 1.07 [95% CI, 0.89-1.30]; P=0.46). RIPC-related adverse events occurred in 10 of 133 (7.5%) patients, and no intervention-related adverse events occurred in the control group. Ultra-early RIPC is safe for patients with acute ischemic stroke treated with EVT, but it does not significantly improve the 90-day functional outcomes. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04581759.

Timely and accurate prediction of poststroke motor outcome is important for efficient rehabilitation planning and resource allocation. Existing bedside models for predicting upper-limb outcome after stroke require further refinement to be effectively implemented in stroke units within the first 72 hours. This study aimed to develop and internally validate a machine learning model to predict the 6-month Action Research Arm Test score using simple clinical tests commonly assessed within the first 3 days poststroke. In 296 first-ever ischemic stroke patients pooled from 4 prospective Dutch cohort studies across 44 centers (2000-2019), we compared the cross-validated prediction performance of multiple eXtreme Gradient Boosting models using different sets of bedside clinical tests to predict the 6-month Action Research Arm Test outcome (0-57). We then selected the model with the minimal predictor set that best balanced bedside feasibility and accuracy and validated it within 72 hours poststroke on a test data set (n=32) from the same cohort using median absolute error as the evaluation metric. A model incorporating Shoulder Abduction from the Motricity Index, voluntary finger extension, Fugl-Meyer Upper Extremity, and total National Institutes of Health Stroke Scale score as bedside tests, showed the best tradeoff between model simplicity and predictive accuracy (median absolute error, 5.9 on the 0-57 score; interquartile range, 2.9-12.9). Our model predicts the 6-month Action Research Arm Test score using a minimal set of bedside clinical tests collected within the first 3 days after stroke, achieving a median absolute error below the Action Research Arm Test minimal clinically important difference of 6 points.

Adverse pregnancy outcomes (APOs) are increasingly recognized as early indicators of maternal cardiovascular risk. However, their associations with nontraumatic subarachnoid hemorrhage (SAH) remain poorly understood. We conducted a nationwide cohort study of 1 785 088 primiparous women in the Swedish Medical Birth Register between 1973 and 2014, followed from first birth through December 31, 2023. APOs included hypertensive disorders of pregnancy, gestational diabetes, placental abruption, preterm birth, abnormal fetal growth, and stillbirth. SAH was the primary outcome, with aortic aneurysm rupture or dissection and spontaneous coronary artery dissection as secondary outcomes. Hazard ratios (HRs) and 95% CIs were estimated using Cox regression, adjusting for calendar year, parity, maternal sociodemographic characteristics, and psychiatric disorders, with sibling analyses to account for shared familial and genetic factors. Mean maternal age was 28.2 years, and abnormal fetal growth was the most common APO category. Over up to 50 years, 759 722 (42.6%) women experienced at least 1 APO; there were 5751 (0.32%) events of SAH. Women with APOs had increased risks of SAH compared with those without, particularly after placental abruption (HR, 1.62 [95% CI, 1.29-2.04]), hypertensive disorders of pregnancy (HR, 1.58 [95% CI, 1.41-1.77]), gestational diabetes (HR, 1.40 [95% CI, 1.04-1.90]), preterm birth (HR, 1.35 [95% CI, 1.24-1.47]), and small for gestational age (HR, 1.34 [95% CI, 1.26-1.43]). The associations were consistent in sibship analyses. The excess SAH risk was greatest in the first years after delivery and attenuated over time. Increased risks of aortic aneurysm rupture or dissection were observed after hypertensive disorders of pregnancy, preterm birth, and severely large for gestational age (HRs ranged from 1.43 to 1.66), whereas associations with spontaneous coronary artery dissection differed in direction. APOs were associated with increased maternal risk of SAH, with variation by the timing, severity, and accumulation of pregnancy complications, suggesting underlying vascular vulnerability.

Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non-ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. We included 3919 patients (median age, 74 [interquartile range (IQR), 63-82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3-12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0-15.1]; P<0.001). Median additional scan time was 6 minutes (IQR, 5-7) for ECG-gated and 13 seconds (IQR, 12-61) for non-ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6-4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1-2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2-2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7-2.5]). Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. URL: https://www.clinicaltrials.gov; Unique identifier: NCT07165093.

We evaluated the efficacy of the Stroke Riskometer mobile phone application to change the Life's Simple 7 risk factor score in a primary prevention population at 6 months postrandomization. This phase III, prospective, outcome assessor-blinded, 2-arm randomized controlled trial in Australia and New Zealand recruited participants from August 2021 to January 2024. Inclusion criteria: age ≥35 and ≤75 years; ≥2 risk factors; smartphone ownership; and no cardiovascular disease history. The intervention group was given access to the application; the usual care group received one email with generic risk factor information. The primary outcome was the mean between-group difference in Life's Simple 7 (score 0 [poor] to 14 [ideal], comprising blood pressure, cholesterol, glucose, body mass index, smoking, and physical activity and diet) from baseline to 6 months postrandomization. Secondary outcomes were between-group changes in individual Life's Simple 7 items. Analyses were performed using intention-to-treat principles with ANCOVA and linear mixed models to examine differences between groups, with prespecified per-protocol and subgroup analyses. We randomized 862 participants (mean±SD age, 58±11 years; 63% women; 74% White). At 6 months postrandomization in intention-to-treat analyses, the mean difference between usual care (n=433) and intervention (n=429) groups in the change in Life's Simple 7 score from baseline was 0.03 ([95% CI, -0.19 to 0.25]; P=0.788). Per-protocol analyses (n=320 usual care; n=276 intervention) were similar (mean difference in change, 0.20 [95% CI, -0.04 to 0.43]; P=0.106). Compared with usual care in intention-to-treat analyses, the intervention group had a nonsignificant increase in metabolic equivalent of task (metabolic equivalent of task) minutes per week of physical activity (313.42 [95% CI, -2.80 to 629.65]; P=0.052), with no differences in other Life's Simple 7 items. Among a general population aged 35 years to 75 years with ≥2 stroke risk factors, there was no evidence that having access to the application changed overall Life's Simple 7 scores at 6-month follow-up. Participants in the intervention group did have a nonsignificant increase in physical activity, compared with the usual care group, after 6 months, but not in other individual risk factors. URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12621000211864.

Intensive blood pressure (BP) lowering after successful reperfusion has resulted in short-term harm in acute ischemic stroke. However, it remains unclear whether these adverse effects persist over the long term. The OPTIMAL-BP (Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control) was a phase 3, multicenter, prospective, open-label, blinded end point, randomized controlled trial with 19 centers throughout South Korea. Patients who underwent endovascular thrombectomy for acute ischemic stroke caused by large vessel occlusion, achieved successful reperfusion of the occluded artery, and exhibited elevated BP (systolic BP ≥140 mm Hg) on 2 measurements obtained 2 minutes apart within 2 hours after recanalization were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg) or conventional management (systolic BP target, 140-180 mm Hg) for 24 hours after enrollment. This study was a 1-year follow-up extension of the OPTIMAL-BP. The primary outcomes were a modified Rankin Scale score of 0 to 2 at 1 year, indicating functional independence and all-cause mortality within 1 year. Adjusted odds ratios were estimated using multivariable logistic regression models adjusting for age, sex, onset-to-randomization time, and baseline National Institutes of Health Stroke Scale. Among 306 randomized patients, 294 (96.1%) completed the 1-year follow-up. In the intention-to-treat analysis, functional independence at 1 year was numerically lower in the intensive BP management group than in the conventional group (40.5% versus 52.7%; adjusted odds ratios, 0.59 [95% CI, 0.34-1.00]; P=0.051). Consistent findings were observed in the per-protocol analysis (41.1% versus 54.7%; adjusted odds ratios, 0.56 [95% CI, 0.32-0.97]; P=0.040). One-year mortality and distribution of modified Rankin Scale changes from 3 months to 1 year did not differ between groups. Intensive BP lowering targeting a systolic BP of <140 mm Hg resulted in worse functional outcomes at 1 year compared with conventional BP management. These randomized data suggest that early postthrombectomy BP management has durable effects on recovery and support current recommendations against intensive BP lowering. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04205305.

Following successful large-vessel recanalization via endovascular thrombectomy (EVT) for acute ischemic stroke (AIS), some patients experience a complication known as no-reflow, defined by persistent microvascular hypoperfusion that undermines tissue recovery and worsens clinical outcomes. Although prompt identification is crucial, standard clinical practice relies on perfusion magnetic resonance imaging (MRI) within 24 hours post-procedure, delaying intervention. In this work, we introduce the first-ever machine learning (ML) framework to predict no-reflow immediately after EVT by leveraging previously unexplored intra-procedural digital subtraction angiography (DSA) sequences and clinical variables. Our retrospective analysis included AIS patients treated at UCLA Medical Center (2011-2024) who achieved favorable mTICI scores (2c or 3) and underwent pre- and post-procedure MRI. No-reflow was defined as a $\gt {15}\%$ reduction in relative cerebral blood volume or flow within the infarct core compared to the contralateral hemisphere. From DSA sequences (anteroposterior and lateral views), we extracted statistical and temporal perfusion features from the target downstream territory to train ML classifiers for predicting no-reflow. Our preliminary results demonstrate that this novel method outperformed a clinical-features baseline (AUROC: 0.9330 vs. 0.7768 ( ${p} = {0}.{006}$ )), suggesting that real-time DSA perfusion dynamics may encode clinically relevant information related to microvascular integrity. This approach establishes a preliminary foundation for immediate, accurate no-reflow prediction, enabling clinicians to proactively manage high-risk patients without reliance on delayed imaging, though it warrants validation in larger, independent cohorts.

Previously, a conditional probability model was developed to determine which transport method, drip and ship (transport to the primary stroke center for thrombolysis and then transfer to an endovascular therapy center) or mothership (direct transport to an endovascular therapy center), predicts the best outcomes for patients with suspected acute ischemic stroke. We compare and validate the conditional probability model based on the RACECAT (Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory). Regional and individual level comparisons were performed by applying the conditional probability model to predict the best transport method compared with actual transport and outcomes. The primary outcome was the modified Rankin Scale score at 90 days. Ordinal logistic regression was used to assess the influence of matching transport methods on 90-day modified Rankin Scale outcomes. Subanalysis was performed to evaluate outcomes of patients with hemorrhagic stroke. The conditional probability model was highly consistent with the RACECAT result overall: transport method outcomes were similar. Two-thirds (66.1%) of Catalonia was predicted to have near equivalent outcomes for drip and ship compared with mothership. Drip and ship best predicted transport in larger areas in the daytime, and mothership for larger areas in the night. There was no significant difference in 90-day modified Rankin Scale outcomes between patients with matching versus mismatched transport methods (odds ratio, 1.13 [95% CI, 0.93-1.37]). Patients with hemorrhagic stroke had worse outcomes in those predicted and randomized to mothership versus those predicted to mothership and randomized to drip and ship (odds ratio, 3.53 [95% CI, 1.12-11.12]). The conditional probability model for stroke transport successfully predicted the RACECAT clinical trial results, showing no difference in outcomes between drip and ship and mothership transport methods. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02795962.

The concept of vascular neurology-specific education was launched nearly 50 years ago in response to a growing understanding of the pathophysiology of stroke. The vascular neurology field, and the training required to support its growth and evolution, has been heavily influenced by a simultaneously increasing breadth of knowledge in approaches to clinical management of stroke. There are increasing numbers of vascular neurology fellows each academic year, yet we continue to experience shortages in clinical coverage for patients with vascular neurological conditions. Here, we review the origins of vascular neurology training and current challenges in sustaining educational programs. We then propose action items to help shape the future of vascular neurology education.

Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Over the past 2 decades, transcranial direct current stimulation has attracted substantial interest as an adjunctive strategy to enhance poststroke motor recovery. In addition to its potential neuromodulatory effects on motor cortical networks, transcranial direct current stimulation devices are low-cost, easy to use, and compatible with concurrent rehabilitation. Yet, despite its promise, several barriers hinder translation into routine clinical practice, including neutral results from several recently completed multicenter trials, such as TRANSPORT2 (Transcranial Direct Current Stimulation for Post-Stroke Motor Recovery). Moving forward, progress will depend on addressing issues in 3 broad domains: device-related (stimulation parameters and montage), disease-related (patient characteristics and timing), and trial design (outcomes, analytical approaches, adjunctive therapy, and trial infrastructure). In this topical review, we critically examine these challenges and outline strategies to refine transcranial direct current stimulation application, with the goal of more effectively leveraging its neuromodulation properties to promote neuroplasticity and enhance motor recovery after stroke.

Randomized evidence suggests that the association of intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) may be time-dependent. We evaluated whether treatment timing modifies the association of IVT+EVT versus EVT alone with short-term in-hospital outcomes. We conducted a multinational observational registry cohort study using RES-Q (Registry of Stroke Care Quality) data (2022-2024) from 38 countries. Among 3132 eligible anterior-circulation large-vessel occlusion patients treated with EVT, 3009 comprised the analytic cohort (IVT+EVT or EVT alone). The primary outcome was the ordinal modified Rankin Scale (mRS) score at discharge; secondary outcomes were the mRS score 0 to 2 at discharge and in-hospital survival. Time strata were ≤100, >100 to 150, >150 to 255, and >255 minutes. Confounding was addressed with stabilized inverse probability of treatment weighting (weights truncated at 10) using a propensity score including arrival mode, admission location/department, vascular risk factors (hypertension, diabetes, hyperlipidemia, atrial fibrillation, prior stroke, smoking), imaging type, and baseline National Institutes of Health Stroke Scale score. For EVT-only patients, onset-to-needle time was predicted only to assign time strata. The mean age was 69.2 years (SD, 13.2), and 45.6% were female. Treatment-by-time interaction was significant for ordinal discharge mRS score (P=0.002) and mRS score 0 to 2 at discharge (P=0.02). IVT+EVT was associated with better outcomes in the earliest treatment windows: at ≤100 minutes, ordinal mRS score odds ratio (OR) 1.99 (95% CI, 1.49-2.63), in-hospital survival OR, 1.81 (95% CI, 1.13-2.92), and mRS score 0 to 2 OR, 1.76 (95% CI, 1.24-2.51); at >100 to 150 minutes, ordinal mRS score OR, 1.58 (95% CI, 1.21-2.06) and mRS score 0 to 2 OR, 1.64 (95% CI, 1.16-2.31). Associations were attenuated beyond 150 minutes. In routine practice, early IVT before EVT was most consistently associated with improved discharge outcomes.

The "2026 Guideline for the Early Management of Patients With AIS" replaces the "2018 Guidelines for the Early Management of Patients With AIS" and the 2019 update to reflect recent advances in evidence. This updated guideline is intended to provide a comprehensive, up-to-date, evidence-based set of recommendations, advising management from prehospital evaluation through acute treatment and early in-hospital management of complications and initiation of early secondary prevention measures. The intended audience includes prehospital care professionals, physicians, allied health professionals, and hospital administrators. A search for literature derived from research principally involving human subjects, published in English since the last AIS guideline in 2018 and the 2019 update, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between September and December 2024. Additional high impact studies and articles published through March 2025 were added later, where appropriate. This guideline represents the most current and comprehensive evidence available in AIS care. Key updates include the incorporation of new evidence related to thrombolytic choice and eligibility, determination of eligibility for endovascular thrombectomy, and management of hyperglycemia and dysphagia; a focused consideration of the pediatric population; and modification of the approach to thrombolysis contraindications. Although this guideline reflects significant advances, it also highlights gaps in knowledge and underscores the urgent need for continued research to further refine and improve treatment strategies.

Non-traditional lipid parameters demonstrate cardiovascular predictive value, yet their interaction with inflammatory markers in stroke risk assessment remains understudied. This research investigated their independent and combined effects on stroke risk in a nationally representative cohort, while comparing their predictive capability with traditional lipid parameters. The study cohort comprised 9,236 individuals aged ≥45 years, derived from the China Health and Retirement Longitudinal Study (CHARLS), with self-reported stroke as the primary outcome. Non-traditional lipid parameters were combined with High-sensitivity C-reactive protein (hs-CRP) to create lipid-inflammatory indices. Cox proportional hazards models and restricted cubic spline regression assessed stroke risk associations. Mediation analysis examined relationships between hs-CRP, lipid parameters, and stroke. During the 7-year follow-up, 664 participants developed stroke. The incidence of stroke increased with increasing quartiles of non-traditional lipid parameters. In fully adjusted models, participants with higher baseline and cumulative levels of non-traditional lipid parameters had the highest risk of stroke, with consistent results across non-traditional lipid inflammation parameters, especially in AIP-CRP (HR = 1.98, 95 % CI: 1.56-2.50). Non-traditional lipid inflammation parameters showed better predictive ability compared with individual parameters, and the results remained robust in subgroup and sensitivity analyses. Mediation analysis established bidirectional mediating effects between non-traditional lipid parameters, hs-CRP, and stroke risk. Non-traditional lipid parameters are significantly associated with increased stroke risk in middle-aged and older Chinese adults, with combined lipid-inflammatory markers demonstrating superior predictive value. These findings underscore the importance of integrating both non-traditional lipid parameters and inflammatory markers for comprehensive stroke risk assessment.

Matching brain stimulation to the brain's natural rhythms can drive plasticity, yet this principle has rarely been tested in humans. We targeted the cerebellum, a key hub for motor coordination and learning, using a rhythm-tuned protocol that pairs theta-frequency transcranial alternating current stimulation with intermittent theta-burst stimulation to engage plasticity of cerebello-cortical circuits. In young healthy adults, this pairing enhanced fine motor control and hand dexterity, with gains closely tracking physiological markers of cerebellar-driven plasticity. Applying the same approach in chronic stroke survivors yielded parallel behavioral and neural gains, demonstrating preserved rhythm-plasticity coupling despite injury. Control experiments confirmed both frequency specificity and site specificity, underscoring the mechanistic precision of the intervention. By linking theta-frequency cerebellar stimulation to circuit-level and functional outcomes, these findings establish a biologically grounded framework for targeted neurorehabilitation. Rhythm-specific cerebellar stimulation provides a scalable strategy for enhancing plasticity and improving motor function across movement disorders and motor impairments.

Despite significant progress in hospital quality initiatives and the organization of regional stroke systems of care, a significant gap persists between the number of patients eligible for acute ischemic stroke reperfusion therapies and those who receive them in a timely manner. This gap reflects persistent delays and variability across the prehospital and interhospital phases of care, from prehospital dispatch and field assessment to destination selection and interhospital transfer workflows. This expert narrative review synthesizes current evidence on acute stroke systems of care, with a particular focus on prehospital identification of stroke, destination decision-making for suspected large-vessel occlusion, and interhospital transfer for patients requiring endovascular thrombectomy. Key processes, including prehospital response and scene times, destination decision-making, and door-in-door-out metrics, are examined to illustrate how system-level bottlenecks affect access to and outcomes of reperfusion therapies. Emerging and novel technologies are also described, including mobile stroke units, blood-based biomarkers for prehospital stroke diagnosis, portable neuroimaging modalities, physiological and device-based detection systems, and cross-cutting tools such as telestroke, all aimed at shifting accurate diagnosis and treatment decisions earlier in the stroke care pathway.

Increasing experimental and clinical evidence indicates activation of cellular programs resembling senescence and senescence-associated secretory phenotype signaling after stroke. However, a central challenge is definitional: in injured brain tissue, many senescence-associated features overlap with acute stress responses, transient cell-cycle perturbations, and reactive glial or vascular programs, complicating interpretation across models, time points, and cell types. Here, we synthesize the literature using a cell-type-resolved framework spanning acute, subacute, and chronic stroke phases across major neurovascular and immune compartments. Rather than treating senescence as a binary fate, we conceptualize post-stroke senescence-associated biology as a dynamic continuum, in which ischemia-reperfusion stress engages multiple senescence-related domains, only a subset of which may stabilize into durable cell senescence. Accordingly, we emphasize convergent multi-domain evidence with spatial and cell identity resolution, and cautious use of the term "senescence-like" during early injury. Finally, we discuss translational implications through a timing- and safety-aware perspective, arguing that modulation of maladaptive secretory outputs may be superior to cell-elimination strategies in early post-stroke windows. We highlight key biological and clinical uncertainties-including blood-brain barrier dynamics, hemorrhagic and infectious risk, and interference with endogenous repair-that define critical risk gates for evaluating senescence-targeting approaches after stroke.

Brain aneurysms are a cerebrovascular disease that results in a severe type of stroke. The cell-specific molecular pathology underlying their formation and rupture is unknown. Here we profile 227,663 neurovascular cells, including 52,946 aneurysmal cells, from a total of 14 adult human brain aneurysms and 11 control vessels. Our atlas of human brain aneurysms, as well as cell-resolution spatial transcriptomics, revealed that pathological cerebrovascular remodeling occurs with the loss of structurally supportive smooth muscle cells and the emergence of activated perivascular fibroblasts, which re-populate the vascular wall and express multiple genes linked to aneurysm risk. Fibrotic changes coincide with fibroblast-myeloid cell signaling pathways and an influx of specialized macrophages that are rarely detected in non-aneurysmal cerebrovasculature and that express destabilizing vascular cell programs. Thus, we reveal an unrecognized interplay between cerebrovascular fibrosis and myeloid inflammation during disease progression, substantially advancing our understanding of the cellular drivers and mechanisms underlying this devastating cerebrovascular disease that will inform translational development.

Over half of pediatric stroke survivors have permanent cognitive deficits, which can emerge late after stroke. Mechanisms of cognitive decline after pediatric stroke may differ from those in adults because children's strokes occur while brain and immune development are still ongoing. We therefore aimed to develop a pediatric mouse model of infarct-induced delayed cognitive decline to define age-related differences in immune responses compared with adults. Male and female C57BL/6J mice were randomized to stroke or sham surgery at 28 days old to model stroke in late childhood. We used permanent distal middle cerebral artery occlusion followed by 60 minutes of hypoxia to induce an ischemic cortical stroke. Juvenile mice underwent behavioral testing at 1 and 7 weeks after surgery using Barnes maze and Novel Object Recognition tests. We quantified stroke size, atrophy, and neuroinflammation at 3 days and 7 weeks after surgery in juvenile and adult mice using immunostaining. One week after surgery, juvenile stroke and sham mice performed comparably on cognitive testing. However, by 7 weeks after surgery, stroke mice of both sexes performed significantly worse on reversal learning with the Barnes maze. Histologically, juvenile mice had greater innate immune activation at sites of secondary neurodegeneration in the corpus callosum, corticospinal tract, and thalamus at 3 days after stroke, while adults had greater chronic innate immune activity at these sites 7 weeks after stroke. In a model of childhood ischemic stroke, juvenile mice of both sexes developed an emerging cognitive deficit analogous to that seen in pediatric stroke survivors. It was associated with chronic neuroinflammation in uninjured subcortical structures that undergo secondary neurodegeneration. Our results suggest that infarct-induced neurodegeneration occurs after stroke in juvenile mice, and that there are age-related divergent trajectories in the innate immune response to stroke at sites of secondary neurodegeneration.

Aldose reductase (AR) is involved in the pathogenesis of ischemic stroke; however, the mechanisms are not well understood. This study aimed to evaluate the role and underlying mechanisms of AR inhibition in ischemic stroke. We found that microglial neuroinflammatory responses to oxygen glucose deprivation/reperfusion (OGD/R) were attenuated by either sorbinil-mediated AR inhibition or AR knockdown. Sorbinil (5-20 μM) attenuated OGD/R-induced endoplasmic reticulum (ER) stress and downstream c-Jun N-terminal kinase (JNK) activation in microglia. Further analysis revealed that sorbinil suppressed microglial autophagic hyperactivation, reduced nuclear receptor coactivator 4 expression, and elevated ferritin heavy chain (FTH1) levels. This effect was accompanied by diminished FTH1 colocalization with lysosomes and decreased intracellular iron (Fe2+) concentrations. Critically, FTH1 knockdown attenuated the inhibitory effect of sorbinil on Fe2+ and interlenkin-1β in microglia. Furthermore, sorbinil mitigated OGD/R-triggered oxidative stress in microglia. Moreover, sorbinil had similar effects on microglia exposed to thapsigargin-induced ER stress. Notably, the protective efficacy of sorbinil was attenuated by the pharmacological activation of JNK. In a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, sorbinil (4, 8, and 16 mg/kg; i.p.) ameliorated neurological deficits and decreased the volume of cerebral infraction in MCAO/R model mice. This suppression coincided with attenuated neuroinflammation and the activation of ER stress and ferritinophagy in MCAO/R model mice. Overall, this study reveals a novel role of AR inhibition in regulating microglial ER stress-ferritinophagy signaling during cerebral ischemia. AR represents a promising therapeutic target for mitigating cerebral ischemia‒reperfusion injury.

We previously reported that transcription factor EB (TFEB) plays a crucial role in regulating the ischemic stroke (IS)-mediated dynamic changes of autophagic flux. Protein phosphatase 3 (PPP3) may regulate the transcriptional activity of TFEB. However, the main isoform of the PPP3 catalytic subunit (PPP3C) involved in TFEB activation, the PPP3-binding site in TFEB, and the upstream regulatory mechanism of PPP3 activation after cerebral ischemia are still unknown. Here, we show that the interaction between TFEB and PPP3 catalytic subunit B (PPP3CB), but not PPP3CA, is strengthened after IS. Knockdown of PPP3CB, but not PPP3CA, significantly inhibited the oxygen glucose deprivation (OGD)-induced increase in the transcriptional activity of TFEB, blocked autophagic flux, and exacerbated neuronal death. Furthermore, the YLAVP peptide, which blocks the LxVP motif-binding site of PPP3C, repressed TFEB transcriptional activity and autophagic flux, and exacerbated neuronal death after OGD. Treatment with ML-SI1, which inhibits the lysosomal calcium channel MCOLN1, blocked the OGD-induced enhancement of TFEB transcriptional activity and autophagic flux, and further aggravated neuronal death. These effects were partly reversed by the MCOLN1 agonist ML-SA1. The PPP3 inhibitor cyclosporin A (CsA) abolished the ML-SA1-induced TFEB transcriptional activation and reduced neuronal death. Our findings identify for the first time that MCOLN1-mediated-PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia. The LxVP motif is required for the interaction between PPP3 and TFEB in response to OGD. This study provides an in-depth insight into the mechanisms underlying TFEB-mediated activation of autophagic flux following IS. Schematic diagram showing how MCOLN1-mediated activation of PPP3CB reduces neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia.

Neural functional impairment following stroke is strongly linked to the loss of white matter (WM) integrity, a process critically dependent on the successful differentiation of oligodendrocyte precursor cells (OPCs). Given that hyperhomocysteine (HHcy) aggravates stroke prognosis, we hypothesized that it impairs OPCs differentiation during the recovery period. Using in vivo (MCAO) and in vitro (OGD/R) models, we showed that HHcy hinders functional recovery, impairs OPC differentiation, and compromises WM integrity. Mechanistically, HHcy acts by upregulating tumor necrosis factor-α (TNF-α), which subsequently promotes the nuclear translocation of protein arginine deiminase 4 (PAD4). This leads to the upregulation of nucleosomal citrullinated histone 3 (CitH3) and the subsequent downregulation of myelin regulatory factor (MyRF), resulting in the observed inhibition of OPCs differentiation. Crucially, pharmacological inhibition of PAD4 using the pharmacological inhibitor YW3-56 effectively promoted OPCs differentiation and enhanced WM repair after ischemic stroke. Therefore, our findings identify the TNF-α/PAD4 pathway as a novel therapeutic target for reversing HHcy-induced white matter impairment and improving neurological outcomes after stroke.

Blood-brain barrier (BBB) disruption is found in many acute and chronic inflammatory encephalopathies. Timely restoration of BBB integrity is essential for controlling disease progression, especially in ischemic stroke. While various brain-targeting strategies have been developed, achieving precise BBB-targeting and sustained retention at the BBB to enable faster and more effective repair remains a significant challenge. In this study, a biomimetic strategy is developed to enhance inflamed BBB-targeting gene delivery using cationic hybrid nanovesicles derived from mesenchymal stem cell (MSC) membranes, named P(ML). The combined contributions of the positive surface charge and the biological targeting capability inherent to MSC membranes enable the precise inflamed BBB-targeting of P(ML). In vitro and in vivo studies demonstrated that P(ML) efficiently accumulated in ischemic brain regions, and exhibited precise retention at inflamed BBB, rather than a diffuse distribution within the whole brain. Additionally, P(ML) showed efficient nucleic acid delivery capability. When loaded with siRNA targeting p66Shc, a protein involved in endothelial dysfunction, P(ML) exhibited significant protective effects on the injured BBB in animal models. This biomimetic P(ML) nanocarrier platform represents a promising strategy for inflamed BBB-targeting gene delivery, offering potential therapeutic applications for ischemic stroke and other BBB-related disorders.

As stroke is the leading cause of long-term disability in the elderly, effective pharmacological therapies for neurorestoration remain an unmet clinical need. RXR (retinoid X receptor) signaling regulates inflammation and tissue repair, but the downstream repair processes linking RXR activation to stroke recovery in the aged central nervous system remain incompletely defined. We used aged mice to test the hypotheses that (1) pharmacological RXR stimulation with the brain-penetrant pan-RXR agonist bexarotene boosts poststroke recovery and (2) myeloid cell-specific RXR signaling facilitates white matter repair and underlies the therapeutic effects of bexarotene. Permanent focal cerebral ischemia was induced in 18- to 22-month-old C57BL/6 male and female mice by distal middle cerebral artery occlusion. Pharmacological RXR activation and genetic ablation were achieved by poststroke bexarotene administration and generation of myeloid cell-specific RXR conditional knockout mice, respectively. Functional (sensorimotor and cognitive performance) and structural measures of central nervous system recovery were assessed up to 35 days after stroke. Poststroke treatment with bexarotene (5-10 mg/kg) improved sensorimotor performance in the rotarod, foot fault, and adhesive removal tests and alleviated cognitive deficits in the Morris water maze and passive avoidance tests. Bexarotene improved white matter integrity at 35 days after distal middle cerebral artery occlusion, without impacting white matter at 3 days or preventing gray matter atrophy at chronic injury stages. Bexarotene also suppressed immune cell infiltration and proinflammatory cytokine production, enhanced inflammation-resolving efferocytosis, promoted long-term oligodendrogenesis and angiogenesis, and fostered a prorepair central nervous system microenvironment. Accordingly, stroke outcomes were markedly worsened in aged RXR conditional knockout mice compared with age-matched wild-type mice, and the functional and white matter benefits of bexarotene were blocked in RXR conditional knockout mice. Myeloid RXR signaling promotes long-term stroke recovery in aged mice of both sexes and engages anti-inflammatory and prorepair mechanisms. Bexarotene warrants further evaluation as a potential neurorestorative therapy for stroke.

Left ventricular structural assessment is fundamental in heart failure (HF). However, the independent prognostic value of left ventricular size beyond its association with ejection fraction remains poorly defined in real-world, large-scale populations. To investigate the association between left ventricular dimension and mortality risk within a large, nationwide cohort with HF. This was a nationwide cohort study using data from the Chinese Cardiovascular Association Database-Heart Failure Center Registry. Patients were enrolled from January 1, 2018, to May 31, 2022. The multicenter study involved 723 centers across 31 provincial-level administrative regions in mainland China. The study included patients hospitalized with HF. Patients were categorized into groups with a small, normal, or large left ventricle (LV) according to American Society of Echocardiography criteria for LV end-diastolic diameter (LVEDD). Data analysis was conducted from March to June 2025. LVEDD measured by echocardiography. The primary and secondary end points were all-cause mortality and cardiovascular mortality, respectively. A total of 273 921 patients (median [IQR] age, 71.0 [62.0-79.0] years; 161 589 male [59.0%]) hospitalized with HF were included in this study. A significant U-shaped association was found between LVEDD and both all-cause and cardiovascular mortality (P for nonlinearity <.001). Both a small LV (adjusted HR [aHR], 1.32; 95% CI, 1.28-1.37; P < .001) and a large LV (aHR, 1.38; 95% CI, 1.35-1.40; P < .001) were independently associated with elevated all-cause mortality. Sex-specific optimal LVEDD thresholds were identified (47 mm for male patients, 43 mm for female patients), with each 1-mm deviation associated with a significant increase in mortality risk. These findings were consistent across prespecified subgroups and were further corroborated by analysis of LVEDD indexed to body surface area and by extensive sensitivity analyses, including competing risk models and complete-case analyses. This large-scale study established that a U-shaped association exists between LVEDD and mortality in HF, suggesting that both abnormally small and abnormally large ventricles signify high risk, likely through distinct mechanisms. These findings support the integration of LV size assessment into routine risk stratification to guide personalized management.

Aging is associated with increases in pulmonary pressure related to concomitant age-associated left ventricular remodeling, diastolic dysfunction, and declines in pulmonary function. Little is known regarding morphological changes in the pulmonary arterial vasculature underlying these associations. Our aim was to determine the associations between pulmonary vascular arterial remodeling, reflected in distal pruning and proximal dilation, and cardiac structure and function, pulmonary pressure, and functional outcomes. Among 2275 participants in the community-based Atherosclerosis Risk in Communities study (ARIC) who underwent echocardiography and noncontrast cardiac computed tomography at study visit 7 (2018-2019), we quantified the fraction of total pulmonary vascular area comprised of arterial vessels with cross-sectional area <5 mm2 (aBV5/aTBV) and arterial vessels with cross-sectional area >10 mm2 (aBVg10/aTBV) using a validated image processing approach. We assessed the associations of aBV5/aTBV and aBVg10/aTBV with echocardiographic measures of cardiac structure and function and pulmonary artery systolic pressure using multivariable linear regression models adjusted for demographics and cardiovascular risk factors. We also evaluated associations of pulmonary vascular arterial remodeling metrics with circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide), self-reported dyspnea, and incident heart failure. Mean age was 80±4 years, 61% were women, 22% reported Black race, and mean left ventricular ejection fraction was 64±7%. Mean aBV5/aTBV was 0.30±0.08, and aBVg10/aTBV was 0.45±0.09. Lower aBV5/aTBV, reflecting greater distal pruning, and higher aBVg10/aTBV, reflecting greater proximal dilation, were both associated with greater left ventricular remodeling, worse diastolic function, and worse systolic function. Lower aBV5/aTBV and higher aBVg10/aTBV demonstrated nonlinear associations with greater pulmonary artery systolic pressure. Both lower aBV5/aTBV and higher aBVg10/aTBV were associated with higher circulating NT-proBNP and greater odds of moderate to severe dyspnea. Higher aBVg10/aTBV, in particular, was associated with greater risk of incident heart failure over a 4-year follow-up with a hazard ratio of 1.25 (95% CI, 1.03-1.51) per one SD in aBVg10/TBV. Among older adults, pulmonary vascular arterial remodeling is associated with greater left ventricular remodeling, worse diastolic and systolic dysfunction, greater pulmonary artery systolic pressure, greater odds of significant dyspnea, and greater risk of heart failure development. Our findings clarify the morphologic changes in the pulmonary vasculature that link cardiac dysfunction to higher pulmonary pressure in late life and may appear before symptomatology.

Heart failure prevalence is increasing and has a disproportionate burden on older adults. Older adults, however, may encounter unique challenges in accessing and navigating comprehensive disease-modifying, guideline-directed therapies, thus limiting use among those at highest risk of cardiovascular death or worsening heart failure. Care of the older adult with heart failure requires tailored treatment plans to overcome barriers to effective therapies in this population. This scientific statement reviews the literature on care optimization for older adults (≥65 years of age) living with heart failure and highlights strategies for clinicians who aim to deliver patient-centered, evidenced-based heart failure care in the context of common comorbidities seen in older adults. We discuss the consistent treatment effect and safety profiles of guideline-directed therapies for heart failure in older adults and how to manage multimorbidity, polypharmacy, frailty, and social needs using a shared decision-making framework. In consideration of the complexity of heart failure care of the older adult, we highlight a structured framework for therapeutic considerations in the context of benefit-to-risk ratio, multimorbidity, and social needs. We offer practical guidance on the care of older adults with advanced comorbidities who may not have been adequately represented in landmark trials. We also consider implementation strategies, health services interventions, and supportive tools that may foster optimal care in older adults with heart failure. This work is aimed at informing the practice of clinicians and health systems alike to improve outcomes and to reduce the morbidity of heart failure in older adults.

Heart failure (HF) is a common complication of diabetes, associated with a high mortality rate and a substantial healthcare burden. Residual HF risk persists despite achieving current treatment targets, suggesting a role for additional mechanisms beyond conventional risk factors. We sought to prospectively assess HF incidence and independent risk factors in individuals with new-onset diabetes. We used a prospective inception cohort (ANDIS, n=19,892) that included all individuals with newly diagnosed diabetes from southern Sweden between 2008 and 2021. Baseline clinical, biochemical and questionnaire data were linked to the Region Scania Care Database to obtain data on cardiovascular events and to the National Diabetes Registry to gather further data on cardiovascular risk factors that were not collected in the ANDIS study protocol. All-cause HF included all cases of HF regardless of underlying aetiology, whereas non-ischaemic HF was defined as HF occurring in individuals without prior acute myocardial infarction at baseline or during follow-up before the HF diagnosis. Cardiovascular disease incidence was estimated using the Kaplan-Meier method, and the associations with risk factors and incident HF were assessed using Cox proportional hazards regression. The median age of the overall population was 62.5 years (IQR 52.6-70.3), while the median age among individuals who developed incident all-cause HF was 69.8 years (IQR 62.7-76.7). A total of 819 individuals (4.1%) with prevalent HF were excluded. During up to 14 years of follow-up (median 5.0), the cumulative incidence of HF was 4.8%, exceeding that of myocardial infarction (3.0%). No individuals with type 1 diabetes developed HF, but the incidence was similar across those with type 2 diabetes, latent autoimmune diabetes in adults, and secondary diabetes. A lower eGFR and higher HOMA2-IR, were associated with increased risk of all-cause and non-ischaemic HF, independently of the presence of conventional risk factors. Insulin resistance predicted all-cause HF independently of the established SCORE2-Diabetes risk score. The hazard ratio (HR) per 1 SD increase in HOMA2-IR was highest in the low-risk group (HR 1.89; 95% CI 1.02, 3.48; p=4.3 × 10-2), with concordant results observed for non-ischaemic HF. The HF incidence was high, with approximately 1 in 20 individuals developing HF within 5 years after diagnosis of diabetes other than type 1, highlighting a notably high risk of developing HF soon after diabetes diagnosis. Beyond conventional risk factors, higher HOMA2-IR and lower renal function, but not hyperglycaemia or autoantibodies, were independent risk factors for HF. Measuring HOMA2-IR also provided prognostic information in addition to that provided by the SCORE2-Diabetes risk score, supporting its value in HF risk stratification.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome encompassing hypertensive left ventricular remodelling with diastolic dysfunction and systemic inflammation-driven endothelial dysfunction, with possible contributions from visceral adipose tissue-associated metabolic and proinflammatory alterations. However, conventional key risk factors for HFpEF, including advanced age, female sex, obesity, diabetes, and chronic kidney disease, are closely associated with mineralocorticoid receptor (MR) overactivation through several under-recognized mechanisms, i.e. renin-independent aldosterone excess, cortisol dysregulation, and ligand-independent activation. MR overactivation promotes myocardial hypertrophy and fibrosis, vascular remodelling, and systemic inflammation, all of which are hallmark features of HFpEF. Among patients with HFpEF, the steroidal MR antagonist (MRA) spironolactone has been suggested to reduce the risk of HF-related events, while the non-steroidal MRA finerenone has significantly reduced the primary composite of total worsening HF events and cardiovascular death. Across subgroups suggestive of MR overactivation, MRA therapy has shown generally consistent efficacy and safety, although greater adiposity may be associated with greater MRA efficacy. Given the continuum of MR activation across HF stages, early therapeutic intervention targeting MR overactivation may mitigate the risk of HFpEF development and progression. Furthermore, aldosterone synthase inhibitors and MR modulators, which also attenuate MR overactivation, are being evaluated for HFpEF prevention and treatment. This paper presents the mechanistic pathways linking MR overactivation to HFpEF and highlights the potential benefits of mitigating MR activation for its prevention and treatment, calling for renewed consideration of treatment strategies in clinical practice and trial design.

Environmental exposures are increasingly recognized as modifiable risk factors for heart failure (HF), yet the roles of residential green space, blue space, and natural environments in cardiac structural/functional remodelling and HF development remain underexplored. We aimed to prospectively evaluate associations between residential green space, blue space, and natural environment exposure with incident HF and cardiac morpho-functional phenotypes. We analyzed 437 429 UK Biobank participants free of baseline HF, who were enrolled between 2006 and 2010. Residential green space, blue space, and natural environment were quantified as land coverage percentages within 300-m and 1000-m buffers. Incident HF was ascertained via linked health records. Cox proportional regression models adjusted for sociodemographic, lifestyle, clinical, polygenic risk score, and air pollution covariates assessed HF risk. Cardiac magnetic resonance (CMR) imaging data from the UK Biobank data was analyzed for associations with ventricular/atrial structure and function. During the median follow-up duration of 13.9 (IQR: 13.1, 14.5) years, 16 564 incident HF cases were identified. Within a 1000-m buffer, higher exposure to green space (HR 0.87, 95% CI 0.82-0.92), blue space (HR 0.77, 95% CI 0.75-0.80), and natural environment (HR 0.85, 95% CI 0.80-0.90) (for 3rd vs. 1st tertile) was consistently associated with a reduced risk of HF. Similar trends were observed for the 300-m buffer, with comparable protective associations for green space, blue space, and natural environment. In CMR analyses, higher green space exposure correlated with reduced odds of concentric remodelling (OR 0.72, 95% CI 0.54-0.96), eccentric hypertrophy (OR 0.66, 95% CI 0.55-0.79), and concentric hypertrophy (OR 0.29, 95% CI 0.13-0.63) within 1000-m buffers. For blue space (within the 1000-m buffer), higher exposure showed a reduced odds of (OR 0.73, 95% CI 0.59-0.90) and concentric hypertrophy (OR 0.43, 95% CI, 0.25-0.76). Natural environment exposure within a 1000-m buffer demonstrated attenuation of adverse remodelling comparable to green space effects. Residential exposure to green space, blue space, and natural environments is associated with lower HF incidence and healthier cardiac phenotypes, independent of genetic predisposition and air pollution. Green space demonstrates the most robust cardioprotective effects.

Cardiovascular disease (CVD) is a leading global cause of mortality. Environmental factors are increasingly recognized as influential determinants of cardiovascular health. Nevertheless, a finer-grained understanding of the effects of the built environment remains crucial for comprehending CVD. We sought to investigate the relationship between built environment features, including residential greenspace and sidewalks, and cardiovascular risk using street-level imagery and deep learning techniques. This study employed Google Street View (GSV) imagery and deep learning techniques to analyse built environment features around residences in relation to major adverse cardiovascular events (MACE) risk. Data from a Northeast Ohio cohort were utilized. Various covariates, including socioeconomic and environmental factors, were incorporated in Cox proportional hazards models. Of 49 887 individuals included, 2083 experienced MACE over a median follow-up of 26.86 months. Higher tree-sky index and sidewalk presence were associated with reduced MACE risk [hazard ratio (HR) = 0.95, 95% confidence interval (CI): 0.91-0.99, and HR = 0.91, 95% CI: 0.87-0.96, respectively], even after adjusting for demographic, socioeconomic, environmental, and clinical factors. Visible vertical greenspace and sidewalks, as discerned from street-level images using deep learning, demonstrated potential associations with cardiovascular risk. This innovative approach highlights the potential of deep learning to analyse built environments at scale, offering new avenues for public health research. Future research is needed to validate these associations and better understand the underlying mechanisms. This study examined how features of the built environment, such as greenspace and walkability, influence cardiovascular health by analysing Google Street View images using advanced deep learning techniques.Higher levels of greenspace (tree-sky index) around residences were associated with a 5% lower risk of major adverse cardiovascular events.Walkable neighbourhoods (pavement index) were linked to a 9% reduction in cardiovascular risk, independently of greenspace.

International clinical practice guidelines recommend discontinuing sodium-glucose cotransporter-2 inhibitors (SGLT2i) 3-4 days before surgery to prevent euglycemic diabetic ketoacidosis, chiefly on the basis of case reports/series. Whether SGLT2i discontinuation may increase the risk of postoperative cardiovascular complications is unclear. In a secondary analysis of the Basel-PMI (NCT02573532) and PMI-Vital (NCT05866874) prospective cohort studies in major noncardiac surgery, the exposure of interest was continuing, or stopping, SGLT2i in participants receiving chronic SGLT2i therapy. The primary outcome was an ordinal composite of acute heart failure hospitalisation and cardiovascular death within 90 days of surgery, adjusting for prespecified covariates. Secondary outcomes included the incidence of euglycemic diabetic ketoacidosis within 7 days. Among 451 study participants receiving SGLT2i (mean age 72 (range: 47-86) yr; 22% women), 404/451 (89.6%) had diabetes mellitus, and 166/451 (36.9%) had chronic heart failure. SGLT2i were discontinued before surgery in 393/451 (87.1%) participants (39.2% for 1 day, 34.4% for 2 days, 13.5% for ≥3 days). Cardiovascular complications occurred in 1/58 (1.7%) participants who continued SGLT2i, compared with 10/177 (5.7%) stopping for 1 day, 13/155 (8.4%) stopping for 2 days and 7/61 (11.5%) stopping for ≥3 days (P=0.011; adjusted odds ratio: 1.58 [95% confidence interval: 1.08-2.30] per discontinued day). Euglycemic diabetic ketoacidosis occurred in 1/451 participants after SGLT2i discontinuation. Perioperative SGLT2i discontinuation was associated with a substantially increased risk of 90-day cardiac complications. This suggests potential harm in current guideline recommendations; randomised controlled trials are needed to confirm these findings. NCT02573532, NCT05866874.

Heart failure and chronic liver disease account for substantial morbidity and mortality worldwide. Both conditions share common risk factors and a bidirectional pathophysiology, and the coexistence of both conditions is expected to increase over time. Management of coexisting heart failure and liver disease is challenged by the under-representation of participants with liver disease in landmark heart failure clinical trials, impaired hemodynamics at advanced stages of liver disease, altered drug metabolism, and higher risk of adverse events than portended by either condition alone. Moreover, diagnostic pitfalls might be encountered in relation to assessing the primary etiologies driving the disease process, estimating the degree of liver fibrosis, and differentiating primary liver disease from heart failure-related liver congestion particularly, given the complex interplay between sinusoidal pressure, congestion, and structural fibrosis. Cardiovascular-hepatic cross-thematic research, clinical education, and health care services could optimize management and patient outcomes. The purpose of the current review is to (i) highlight the growing epidemiology of concurrent heart failure-liver disease; (ii) provide diagnostic clues for liver disease and an approach for interpreting liver marker abnormalities amongst heart failure patients; (iii) describe the main therapeutic strategies in real-world clinical settings; and (iv) discuss current gaps in knowledge and future directions. This update on the framework of the heart failure-liver disease overlap phenomenon can inform clinical care policies and facilitate novel research in the field.

Urinary proteomic profiling (UPP) provides insights in disease mechanisms and origin of symptoms. Using UPP, this study aimed at deepening insight in the biology of exercise tolerance. In the HOMAGE trial, 268 patients at risk of heart failure underwent the incremental shuttle walk test (SWT) and UPP by capillary electrophoresis coupled with mass spectrometry at baseline (discovery) and the 9-month final visit (replication). Sequencing of 1498 urinary peptides identified 170 non-collagen and 40 collagen-derived proteins. Ten exercise-related variables, including heart rate and blood pressure responses, symptoms and walking distance were summarised into a single factor, higher values indicating exercise intolerance. In exploratory analyses, exercise intolerance was related to the UPP, first in linear and logistic regression models, considering one peptide at a time, and next by elastic net regression considering the peptides retained in the previous step. Replicated proteins were subjected to pathway analysis. Twenty-nine non-collagen and 31 collagen-derived peptides were associated with reduced exercise capacity with correction for multiple testing. In elastic net regression, exercise intolerance was in >50% of 1000 bootstrap runs associated with the non-collagen proteins FXYD2, GAPDH, HBB, KCNB1, MB, MYOCD, SECTM1, SNX9, TACC3, TMSB4X, and TTN and with collagens COL5A1, COL6A1, COL11A2, and COL28A1. Enriched pathways involved oxygen homoeostasis, oxidative stress regulation, metabolic and developmental processes, and muscle biology. In HOMAGE patients, UPP identified parent proteins regulating exercise endurance, which are involved in oxygenation, vascular and muscle structure and function, maintenance of the circulating volume, and protection against oxidative stress. European Union.

The CASTLE-HTx trial (NCT04649801) showed that the combination of catheter ablation and guideline-directed medical therapy (GDMT) was associated with a lower likelihood of a composite of death from any cause, implantation of a left-ventricular assist device (LVAD), or heart transplantation (HTx) in patients with end-stage heart failure (HF) and atrial fibrillation (AF). This is an ancillary analysis with the generalized pairwise comparison methodology of the main outcomes of CASTLE-HTx. In CASTLE-HTX, 194 patients were randomized to catheter ablation and GDMT (n = 97) or medical therapy alone (n = 97). The first hierarchical outcome was a composite of (1) death from any cause, (2) urgent HTx, (3) implantation of an LVAD, and (4) frequency of hospitalizations for worsening HF. Secondary analysis also included AF burden and left-ventricular ejection fraction improvement. Treatment effects are reported as net treatment benefit (NTB) and win odds, with corresponding confidence intervals (CIs). Patients randomized to ablation had more wins with respect to death from any cause (28.4%/12.4%), HTx (4.3%/2.1%), LVAD implantation (4.2%/0.6%), and hospitalizations for worsening HF (24.8%/11.3%). 61.6% of pairs favoured ablation, 26.4% medical therapy, and 12.0% were tied. This resulted in a restricted NTB at 3 years of 35.3% (95% CI, 19.8-49.0, P < .001) favouring ablation (win odds: 2.09; 95% CI, 1.49-2.92). In the secondary analysis, 67.0% of pairs favoured ablation against 28.6% of pairs favouring medical therapy. The restricted NTB was 38.4% (95% CI, 22.8-52.0, P < .001) in favour of ablation (win odds: 2.25; 95% CI, 1.59-3.17). This pairwise analysis of CASTLE-HTx confirms the clinical benefits of early catheter ablation in addition to GDMT among AF patients in end-stage HF. The treatment benefit was primarily driven by mortality and HF hospitalizations.

Target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, have been associated with lower risks of death and kidney failure (KF) in patients with heart failure with reduced ejection fraction (HFrEF). We examined these associations in heart failure with preserved ejection fraction (HFpEF). Among 96,473 Veterans with HFpEF (EF ≥ 50%) newly initiated on ACEIs (2000-2018), 32,728 received target doses recommended for HFrEF. Propensity scores for receiving target-dose ACEIs were used to assemble an outcome-blinded matched cohort of 61,160 patients (target-dose, n=30,580), balanced on 76 baseline characteristics. Outcomes were 5-year all-cause mortality, incident KF, and HF hospitalization. Compared with below-target-dose ACEIs, target-dose ACEIs were associated with a lower KF risk (HR, 0.89; 95% CI, 0.83-0.97), no mortality difference (HR, 0.99; 95% CI, 0.97-1.02), and a higher risk of HF hospitalization (HR, 1.08; 95% CI, 1.04-1.12). Among 16,735 patients with chronic kidney disease (CKD; eGFR 15-59 mL/min/1.73 m2), target-dose ACEIs were associated with a lower risk of KF (HR, 0.82; 95% CI, 0.75-0.90) and mortality (HR, 0.93; 95% CI, 0.89-0.96) without a higher HF hospitalization risk (HR, 0.95; 95% CI, 0.90-1.01). Each association differed significantly from those in patients with eGFR ≥ 60 mL/min/1.73 m2 (interaction p<0.001). In HFpEF, target-dose ACEIs were associated with a lower risk of KF, a higher risk of HF hospitalization, and no association with mortality. These associations were consistently more favorable in the subgroup with CKD. These findings underscore the importance of evaluating treatment strategies within biologically coherent HFpEF phenotypes.

Cardiac remodeling drives heart failure (HF), yet microstructural drivers in human tissue remain poorly defined due to the limited resolution of clinical imaging. This study sought to quantitatively assess cardiomyocyte morphometry and its relationship with clinical phenotypes. We developed MyoSAM, a deep learning framework for quantitative morphometric characterization of H&E-stained whole-slide images (N = 334 patients). Cardiomyocyte size was quantified using the Myocyte Maximum Inscribed Circle (MMIC) radius, along with measures of nuclear size and perinuclear-halo size, interstitial and macrodomain stromal fractions. Independent associations between these histologic features and clinical variables were assessed using multivariable regression and patient-level linear mixed-effects models to account for clustering of cellular measurements within individuals.MMIC radius was the strongest histological predictor of left ventricular mass index (LVMI; p < 0.001) and was positively correlated with clinical HF (Pearson's r = 0.77, p < 0.001). In severe coronary artery disease (CAD), the association between LVMI and MMIC radius was significantly attenuated (p = 0.001), indicating that myocyte hypertrophy was diminished despite increased mass; instead, remodeling shifted toward greater interstitial stromal expansion (p = 0.025). Males exhibited larger MMIC radii than females (FC 1.08, p = 0.003). Distinct etiology-specific signatures emerged: anthracycline-treated hearts showed large MMIC radii and perinuclear halos with minimal stroma, while non-ischemic cardiomyopathy exhibited the greatest nuclear enlargement and stromal macrodomain expansion. Computational pathology enables high-resolution characterization of myocardial remodeling, revealing distinct microstructural phenotypes across sex, coronary disease burden, and HF etiology that may improve cardiac phenotyping and risk stratification.

Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.

Heart failure (HF) represents the final stage of cardiovascular disease progression, characterized by high morbidity and mortality. Pressure overload in HF activates the PI3K/AKT pathway, and prolonged activation leads to pathological cardiac hypertrophy. However, the mechanism underlying sustained PI3K/AKT activation in pressure overload-induced HF remains unclear. In this study, we demonstrate that miR-203 overexpression in transgenic mice counteracts cardiac dysfunction and pathological remodeling in HF, whereas miR-203 downregulation exacerbates HF. At the cellular level, miR-203 overexpression significantly reduces Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and injury, while miR-203 knockdown aggravates these effects. Mechanistically, miR-203 binds to the 3' untranslated region (3'UTR) of insulin-like growth factor binding protein 5 (IGFBP5) mRNA, inhibiting IGFBP5 protein expression, thereby suppressing PI3K/AKT signaling and mitigating cardiomyocyte hypertrophy. Furthermore, we demonstrate that fibronectin-1 (FN1) is a critical functional partner for IGFBP5, as knockdown of FN1 attenuates IGFBP5-induced PI3K/AKT activation and hypertrophy. This study is the first to elucidate the role and mechanism of miR-203 in regulating pressure overload-induced HF, offering a potential genetic tool for HF therapy.

Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]-AMP [adenosine monophosphate] synthase)-STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood. We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47-amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of Stmp1 (Stmp1-KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of Stmp1-KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9-mediated gene restoration in the Stmp1-KO mouse. STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of Stmp1 in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to Stmp1 loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS-STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type Stmp1 or STING inhibition significantly rescued cardiac function in vivo. Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.

Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na+/H+ and Ca2+) cycling underlies reduced cardiac contractility. The mechanisms linking myocardial stress to this ion dysregulation remain incompletely understood. Although the metabolic transcription factor SREBP1 (sterol regulatory element-binding protein 1) remodels cardiac metabolism, its role in HFrEF without metabolic comorbidities, particularly regarding ion handling, remains undefined. Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for SREBP1 transactivation of sodium-hydrogen exchanger 3 (NHE3). Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebf1f/f) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebp1a or shRNA against Slc9a3, driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. SREBP1 was activated in human hearts with HFrEF because of dilated cardiomyopathy, but without diabetes or hyperlipidemia, and in TAC-induced HFrEF mouse hearts. Srebp1a-Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in Srebp1a-Tg mice, confirmed by NHE3 upregulation in TAC hearts and human failing hearts. ChIP-seq, ChIP, and promoter reporter assay demonstrated direct transcriptional regulation of SLC9A3 (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from Srebp1a-Tg mice or those underwent TAC, whereas cardiomyocyte-specific Srebf1 knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of Srebf1 or Slc9a3 restored calcium handling and improved cardiac function in TAC mice. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebf1f/f mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na+ and Ca2+ overload. SREBP1 directly transactivates cardiac NHE3 during the progression of HFrEF, leading to dysregulated calcium handling and impaired contractility, revealing a novel, noncanonical role for SREBP1 in the pathophysiology of heart failure and offering a potential new therapeutic target.

Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.Abbreviations AcAc: acetoacetic acid; BHB: β-hydroxybutyrate; CMA: chaperone-mediated autophagy; COL1: collagen type I; COL3: collagen type III; ECM: extracellular matrix; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCAR2: hydroxycarboxylic acid receptor 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; HF: heart failure; HK2: hexokinase 2; IVRT: isovolumic relaxation time; KD: ketogenic diet; LAMP2A: lysosome associated membrane protein 2A; LBP:Lycium barbarumpolysaccharide; PKM/PKM2: pyruvate kinase M1/2; SHMT2: serine hydroxymethyltransferase 2; VIM: vimentin.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.

While previous studies have characterized the impact of nonlinearity, anisotropy, and viscoelasticity on myocardial mechanics, calcium itself has been thought to primarily affect the active, not passive, mechanics. Recent experimental studies, however, have demonstrated that calcium has a tremendous effect on the passive viscoelasticity of myocardial tissues. This has significant implications for the mechanics of the beating heart, as calcium cycling would imply dynamic changes in the passive function of the heart and could contribute to elevated stiffening in conditions such as diastolic heart failure. In this study, we aim to extend recently developed fractional viscoelastic constitutive models to incorporate this calcium-sensitive response. We show that the effect of calcium on the passive mechanical response requires additional Maxwell arms in the viscoelastic form. The effect of calcium appears to induce a pure viscoelastic response with a first-order exponential decay, characterized by a fast time constant of ∼2.17s. We find that this form captured the passive mechanical response at all calcium levels. This calcium dependence appears as a pure scaling factor in the form of a Hill curve and can elevate passive mechanics by 6-fold in mouse trabeculae. This model will enable more accurate computational models of the heart that incorporate the effects of calcium on passive mechanics. Statement of Significance: Previous studies on the passive mechanics of myocardium have often ignored the effects of calcium, assuming it primarily affects the active response. However, recent experiments have demonstrated a tremendous effect on passive viscoelasticity. This has significant implications, as calcium cycling would imply a dynamic change in passive function and could contribute to elevated stiffness in conditions such as diastolic heart failure. In this study, we show that the effect of calcium can be modeled with an additional Maxwell arm in a fractional viscoelastic model. Calcium induces a pure viscoelastic response with a first-order exponential decay (∼2.17s). The dependence on concentration appears as a scaling factor in the form of a Hill curve and can elevate passive mechanics by sixfold.

Heart failure (HF) is characterized by a severe disruption of myocardial energy metabolism, with mitochondrial dysfunction standing as a central pathological feature. However, the upstream regulatory mechanisms that drive metabolic remodeling, particularly across distinct HF phenotypes, remain inadequately defined. Mounting evidence reveals that, beyond their metabolic role, mitochondria act as central signaling hubs. This review proposes that dysfunctional mitochondrial-organelle crosstalk is a critical upstream initiator of the metabolic dyshomeostasis observed in HF. We analyze how such inter-organelle crosstalk regulates cardiac metabolism in health and deteriorates with aging and disease. A key focus is elucidating the phenotype-specific metabolic reprogramming in HF with reduced and preserved ejection fraction, tracing their differential traits to distinct alterations in inter-organelle signaling. We further dissect this self-perpetuating vicious cycle: communication defects trigger metabolic dysfunction, which in turn erodes inter-organelle communication, thereby accelerating disease progression. We evaluate technologies and propose that restoring the mitochondrial-subcellular interface offers a novel therapeutic strategy to correct the core metabolic disturbance in HF.

Ageing is the strongest risk factor for heart failure, yet the molecular mechanisms underlying cardiomyocyte (CM) ageing remain unclear. We aimed to map the transcriptomic and epigenomic landscape of CM ageing and to test whether DNA hypermethylation is a causal driver of diastolic dysfunction. We performed single-nucleus multiomics (concurrent snRNA-seq and snATAC-seq) on 4- and 28-month-old ventricular myocardium of C57BL/6J mice. Aged CMs showed widespread chromatin remodelling, with 28,324 regions having greater accessibility compared to only 2 with reduced accessibility. 1963 genes were differentially expressed in aged ventricular CMs, with 78.5% neighbouring differentially accessible regions. Promoter accessibility positively associated with expression. Reduced-representation bisulphite sequencing of ventricular CM nuclei identified 1422 regions associated with genes that were hypermethylated in aged CMs, compared to only 167 that were hypomethylated. CpG hypermethylation inversely correlated with differential gene expression. Multi-omic integration revealed ageing signatures shared across cell types, and identified the long non-coding RNA Gm12381 as a CM-selective ageing marker. To test whether DNA hypermethylation is associated with ageing phenotypes, we used cardiotropic MyoAAV to overexpress Dnmt3a in adult hearts. Dnmt3a overexpression induced CM hypermethylation, causing cardiac hypertrophy and diastolic dysfunction, key ageing phenotypes, and altering the transcriptome profile toward that of aged CMs. Gain of chromatin accessibility and CpG hypermethylation associated with transcriptomic reprogramming characterize CM ageing. Experimental elevation of DNA methylation is sufficient to induce diastolic dysfunction and hypertrophy, supporting DNMT3A-mediated hypermethylation as a mechanistic driver. Further work should test whether attenuating methylation prevents or reverses age-related cardiac dysfunction.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by vascular remodeling, abnormal vasoconstriction of small lung arteries, and right heart failure. Hypoxia causes vascular damage, leading to vessel stenosis or occlusion by aberrant endothelial cells, hypertrophy of the tunica media, and thrombus formation. But the precise molecular mechanisms underlying the pathology of PH have been uncertain. To investigate the pathogenic role of Myl (myosin light chain) 9/12 in PH, we utilized the Sugen/hypoxia mouse model, generated by administration of the VEGF (vascular endothelial growth factor) receptor inhibitor SU5416 under hypoxic conditions (10% O2). Lung tissues of patients with PH and human lung microvascular endothelial cells were used to examine their endothelial changes. Platelet-specific Myl9-deficient mice were generated to determine the contribution of platelet-derived Myl9 to the development of PH. The therapeutic efficacy of the anti-Myl9/12 antibody was evaluated by hemodynamics, histological analyses, and single-cell RNA sequencing. Furthermore, serum MYL9, MYL12A, and MYL12B levels were measured in patients with PH and analyzed for clinical correlation. We identified microthrombi containing Myl9/12 in both patients with PH and the PH mouse model. Platelet-derived Myl9 partially contributed to PH development by promoting cellular infiltration. Furthermore, hypoxia upregulated the expression of Myl9/12 through EPAS1 (endothelial PAS domain protein 1) in proliferated lung vascular endothelial cells and induced the release of Myl9/12 into the extracellular space. Anti-Myl9/12 antibody treatment attenuated PH in the mouse model by reducing microthrombus formation, inflammatory cell infiltration, tissue hypoxia, and vascular remodeling. The established PH in Sugen/hypoxia mice was also attenuated by the treatment with anti-Myl9/12 antibody. Moreover, serum levels of Myl9 but not MYL12A or MYL12B levels reflected the severity of PH in patients. These findings reveal that Myl9/12 play a pathogenic role in developing vascular lesions of PH and could be a new therapeutic target for PH.

This narrative review aims to critically summarize available data on the association between adult acromegaly and metabolic dysfunction-associated steatotic liver disease (MASLD), with a particular focus on clinical associations and treatment implications. From a pathophysiological perspective, growth hormone (GH) may improve hepatic steatosis, inflammation, and fibrosis by acting directly on hepatocytes and indirectly (through insulin-like growth factor-1) on hepatic stellate cells, thereby inducing their senescence. Nonetheless, GH excess may also favor the development of hepatocellular carcinoma, possibly through mechanisms unrelated to hepatic fibrosis. From a clinical perspective, individuals with acromegaly have low rates of hepatic steatosis and visceral adipose tissue (VAT), but high insulin resistance (IR), which contradicts the generally observed positive association between IR and VAT or hepatic steatosis. By contrast, limited data do not support lower rates of hepatic fibrosis in acromegaly, possibly because GH excess is controlled after diagnosis. From a therapeutic perspective, published evidence, derived mainly from case series, suggests that surgical or pharmacological management of acromegaly increases hepatic steatosis and VAT, despite decreasing IR. However, the long-term effect of acromegaly control on hepatic inflammation and fibrosis remains largely unknown. Acromegaly is associated with IR, type 2 diabetes mellitus, hypertension and cardiovascular disease; however, acromegaly is inversely associated with VAT and MASLD. Further mechanistic and clinical studies are warranted to better elucidate the intriguing association between acromegaly and MASLD.

Binary classification of adverse pregnancy outcomes (APOs) may obscure differences in women's long-term cardiovascular disease (CVD) mortality. CVD mortality was therefore evaluated considering APO sequence and lifetime parity. A total of 1 001 409 women with complete pregnancy histories were identified from the Medical Birth Registry of Norway (1967-2020) and linked to the Norwegian Cause of Death Registry for premature CVD mortality (≤70 years). Pregnancy histories were categorized by lifetime parity (1 vs ≥2) and APO sequence (first vs later) for composite APO, and APO recurrence type (same vs different) for individual APOs-preeclampsia, gestational hypertension, preterm delivery, perinatal loss, small for gestational age, placental abruption-multiparous women without APOs as reference, compared with binary classification (APO presence vs absence). Hazard ratios (HRs) were estimated using Cox proportional hazards models. For composite APOs, women with APOs in first pregnancy and no further pregnancies had the highest CVD mortality [adjusted HR (aHR) 3.30, 95% confidence interval (CI) 2.97-3.66], followed by those with APOs in both first and later pregnancies (aHR 2.41, 95% CI 2.16-2.69). Women with APOs in later pregnancies only (aHR 1.65, 95% CI 1.50-1.81) and women with only one pregnancy without complications (aHR 1.83, 95% CI 1.69-1.97) had moderate CVD mortality. Women with APOs in first pregnancy followed by uncomplicated pregnancies (aHR 1.39, 95% CI 1.27-1.53) had the lowest CVD mortality. Binary classification indicated an overall 1.73-fold higher CVD mortality (95% CI 1.64-1.84). Similar patterns were observed across individual APOs. Considering APO sequence across complete pregnancy histories provides more detailed CVD information than binary classification.

GIM/FP/GP: [Formula: see text] Cardiology: [Formula: see text].

Intake of ultra-processed food (UPF) is positively associated with arterial hypertension; however, the association with specific markers of ultra-processing (MUPs) has not been assessed so far. This exploratory prospective cohort study included 101 560 non-hypertensive UK Biobank participants who completed at least one 24-h dietary recall (Oxford WebQ). Intake of UPFs and specific MUPs was assessed by matching up to 10 commercial products to each Oxford WebQ item. The ingredient lists of these products contained 37 specific MUPs grouped into nine MUP categories. Cox proportional hazards regression models assessed arterial hypertension in relation to intake of foods containing these MUP categories and specific MUPs, modelled with penalized cubic splines as a percentage of total food intake (%TFI). The hazard ratio (HR) nadir was defined as the minimum HR along the %TFI axis and was rescaled to 1. Over a median follow-up period of 10.5 years, 7633 hypertension cases appeared. Positive associations with hypertension risk were found for foods containing the MUP categories flavour, colouring agent, sweetener, and varieties of sugar with HRs and corresponding 95% confidence intervals observed relative to the HR nadir: flavour [40% vs 8%TFI; HR (95% confidence interval) 1.37 (1.22-1.54)], colouring agent [20% vs 0%TFI; 1.55 (1.36-1.77)], sweetener [20% vs 0%TFI; 1.42 (1.31-1.55)], and varieties of sugar [10% vs 0%TFI; 1.19 (1.11-1.27)]. Intake of foods containing flavour enhancer, processing aid, modified oil, protein source, and added fibre showed no significant associations. Among specific MUPs, increasing amounts of foods containing acesulfame, aspartame, erythritol, saccharin, sucralose, xylitol, bulking agent, dextrose, fructose, hydrolysed protein, and whey protein were significantly and positively associated with hypertension risk, whereas a negative correlation was observed for firming agent, foaming agent, and glazing agent. Only some MUP categories, i.e. flavour, colouring agent, sweetener, and varieties of sugar, are positively linked to incident arterial hypertension. These are prime candidates for UPF reduction strategies and mechanistic studies.

Up to half of patients switch or discontinue antihypertensive medications within the first year, but underlying mechanisms remain elusive. This study aimed to identify genetic predictors of antihypertensive medication use trajectories within the first year. Using longitudinal medication data from >400 000 genotyped antihypertensive medication users across three cohorts (FinnGen, the UK Biobank, and the Estonian Biobank), short-term antihypertensive medication use trajectories were classified as Continue, Switch, or Discontinue. Genome-wide association studies were performed across five medication classes. In total, 14 genome-wide significant loci were identified for switching from angiotensin-converting enzyme inhibitors (ACEI) and dihydropyridine calcium channel blockers (dCCB) to other antihypertensive medications. For ACEI switching, evidence converged on the neurotensin-NTSR1 pathway, including a 320-fold Finnish-enriched protective missense variant in the neurotensin receptor gene NTSR1 (rs148569146 [G301R], odds ratio [OR] 0.49, P = 3.3 × 10-43) and a variant near RASSF9 (rs181941187, OR = 0.74, P = 1.2 × 10-49) tagging the neurotensin gene NTS. In drug-gene interaction analyses, NTSR1 G301R was associated with reduced ACEI-induced cough risk (OR 0.39, P = 8.1 × 10-4). The dCCB switching locus at CYP3A43 was in near-complete linkage (r2 = 0.99) with the functional CYP3A4*22 allele (rs35599367, OR 1.23, P = 6.1 × 10-10). A polygenic risk score (PRS) for ACEI switching predicted two-fold ACEI cough risk in the top 10% PRS compared with the middle 20% in an independent sample of the Estonian Biobank. These findings extend the bradykinin hypothesis of ACEI-induced cough by implicating neurotensin-NTSR1 signalling, pinpoint CYP3A4*22 as a novel functional predictor of dCCB switching with potential for genotype-guided prescribing, and validate medication use trajectories as a framework for pharmacogenetic discovery.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, and the burden is particularly severe in low-income and middle-income countries. Although traditional risk factors such as hypertension, dyslipidemia, diabetes, and smoking have been well established, new research evidence indicates that inflammation, environmental exposure, psychological and social stress, gut microbiota, and genetic susceptibility play a crucial role in shaping the risk profile of CVDs. This review comprehensively summarizes the epidemiology, pathophysiological mechanisms, screening strategies, prevention, and treatment interventions of CVDs throughout the disease development process. Special emphasis is placed on the integration of multiomics methods, artificial intelligence (AI), and digital health technologies (including wearable devices and AI-enhanced electrocardiograms), which are transforming risk prediction and personalized prevention approaches. We also summarize current preclinical and clinical evidence, including ongoing trials, and discuss implementation differences in different socioeconomic environments. Despite significant progress, there are still many challenges in translating new biomarkers and technologies into scalable and equitable clinical applications. This review identifies key knowledge gaps and proposes future directions toward precision cardiovascular medicine, aiming to combine mechanistic insights with practical applications, ultimately reducing the burden of CVDs globally.

The optimal mean arterial pressure (MAP) target in high-risk hypertensive patients undergoing major abdominal surgery remains unclear. The HISTAP trial evaluated whether targeting an intraoperative MAP ≥ 80 compared with ≥ 65 mmHg reduces postoperative organ dysfunction and 30-day mortality, in this population. HISTAP was a multicenter, randomized trial conducted at 18 Italian centers between March 2023 and April 2025. The study included patients aged ≥ 60 years with chronic hypertension requiring home therapy, undergoing elective major abdominal surgery and having at least one additional high-risk criterion. The intraoperative MAP was targeted to ≥ 80 mmHg (Treatment group) or ≥ 65 mmHg (Control group). The primary outcome was a composite endpoint including postoperative mortality and at least one major organ dysfunction. Of 636 randomized patients, 6 were excluded since surgery was canceled after randomization, 630 completed the trial and were included in the intention-to-treat analysis (median age, 74 years [IQR, 69-79]). Mean intraoperative MAP was 77 ± 7 mmHg in the Control group and 88 ± 9 mmHg in the Treatment group. The primary composite outcome occurred in 48.9% of patients in the Control group versus 38.1% of patients in the Treatment group (relative risk, 0.78; 95% CI 0.65-0.93; P = 0.006). Acute kidney injury was significantly less frequent in the Treatment group (23.5 vs. 33.7%; P = 0.005). Among hypertensive patients receiving continuous hemodynamic monitoring and protocolized fluid therapy at increased postoperative risk undergoing major abdominal surgery, targeting an intraoperative MAP ≥ 80 mmHg, compared with ≥ 65 mmHg, reduced major organ dysfunction, primarily due to fewer mild-to-moderate acute kidney injuries. The HISTAP trial has been registered at ClinicalTrials.gov, NCT05637606 (Date of registration: 24 November 2022).

Accurate understanding of long-term risks after living kidney donation is critical to inform evidence-based policies for donor candidate evaluation and selection. To determine whether apolipoprotein L1 gene (APOL1) polymorphisms were associated with worse kidney function after living kidney donation. This retrospective cohort study included all living US kidney donors who donated from January 2000 to December 2008, whose contact information was obtained from the Scientific Registry of Transplant Recipients. After using online search tools to update addresses and telephone numbers, Black and White US living kidney donors who donated during this period were invited to participate. Enrolled study participants had home-based research visits conducted by a subcontract agency between March 2020 and March 2024. Final data analysis was conducted from April 2024 until February 2026. APOL1 polymorphisms and race. The primary outcome was an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2 by serum creatinine at the time of home-based research visits. Additional outcomes were an eGFR of less than 60 mL/min/1.73 m2, urinary albumin-creatinine levels of 30 or greater or 300 or greater mg/g, and hypertension. A total of 445 Black kidney donors (295 female individuals [66%]; mean [SD] age, 38 [10] years) and 208 White kidney donors (141 female individuals [68%]; mean [SD] age, 44 [10] years) were enrolled. Sixty-eight Black donors (15.3%) had APOL1 high-risk genotypes (G1/G1, G2/G2, or G1/G2). Home-based research study visits occurred a median (IQR) of 18.5 (16.9-20.5) years after donation. Forty-six of all participants (7.0%) were noted to have an eGFR of less than 45 mL/min/1.73 m2. Black kidney donors with APOL1 high-risk genotypes had a higher risk of developing an eGFR of less than 45 mL/min/1.73 m2 than Black kidney donors without APOL1 high-risk genotypes (relative risk, 2.31; 95% CI, 1.16-4.61; P = .02) (after adjustment for predonation eGFR: relative risk, 1.91; 95% CI, 0.90-4.03; P = .09). The study found that the APOL1 genotype is a risk factor for reduced kidney function postdonation. These results suggest that all Black individuals who are living donor candidates in the US should undergo APOL1 genotyping for better risk stratification.

A previous epidemiological study showed that higher total serum arsenic levels were associated with an increased risk of hypertension. However, the specific arsenic species contributing to arsenic-induced hypertension remains unknown. Speciation analysis of arsenic in serum samples is technically challenging. Therefore, this cross-sectional study investigated the associations between fasting urinary levels of total arsenic and four speciated arsenic species and the prevalence of hypertension among 2,676 Japanese residents, one of the world's leading fish-consuming populations. A follow-up animal study was conducted to corroborate these epidemiological findings. Consistent with the serum findings, total urinary arsenic levels were positively associated with the prevalence of hypertension. Unlike dimethylarsinate, monomethylarsinate, and inorganic arsenic, arsenobetaine, an organic arsenic species considered non-toxic, was consistently associated with the prevalence of hypertension independent of sodium exposure in both univariate and multivariate models. This association remained robust in a Bayesian kernel machine regression model accounting for combined exposure to the four arsenic species. Causal mediation analysis further suggested that higher fish meat consumption may promote arsenobetaine-mediated hypertension and that increased urinary arsenobetaine is associated with hypertension-mediated cardiovascular diseases. Correspondingly, a 4-week oral exposure to an estimated human-equivalent dose of arsenobetaine, but not dimethylarsinate, increased blood pressure in mice. This human and animal study is the first to suggest that increased exposure to arsenobetaine, which is linked to fish meat consumption, increases the risk of hypertension. Given the global increase in fish consumption, arsenobetaine ingestion may be an emerging international cardiovascular health concern.

Quality metrics with financial incentives are widely used, but their impact on clinical care and patient health remains challenging to isolate. To evaluate the association of a physician-facing quality metric and financial incentive for hypertension control (blood pressure <140/90 mm Hg) with clinical decisions and health outcomes. This quasi-experimental difference-in-differences study in a large US health system compared changes in outcomes at practices that did vs those that did not adopt the financial incentive before (2021) vs after (2022-2023) adoption. Participants included patients with previously diagnosed hypertension, aged 18 to 85 years, with encounters at eligible primary care practices. Data were analyzed from January 2024 to September 2025. Patient exposure to the financial incentive was determined by which practice delivered their care. Initial and final systolic blood pressure at the primary care encounter and number of measurements, antihypertensive prescriptions and dose adjustments, and hospitalizations for incident stroke or acute coronary syndrome (ACS). The study included 334 364 patients with hypertension (mean [SD] age, 64.9 [12.6] years; 53.3% female) and their 770 907 encounters at 103 primary care practices. In January 2022, the hypertension control financial incentive was introduced in physician contracts for 63 of these practices. In the overall population of patients with hypertension, the financial incentive was associated with an increased probability of blood pressure remeasurement (by 1.9 [95% CI, 0.7-3.1] percentage points [pp]; P = .002) with no statistically significant change in hypertension control, medication outcomes, or cardiovascular hospitalizations. For the subgroup of patients with marginally high blood pressure (defined as initial systolic blood pressure of 140-145 mm Hg), the financial incentive was associated with an increased probability (by 4.1 [95% CI, 2.1-6.0] pp; P < .001) that blood pressure was documented as controlled, subsequent to an increased probability of blood pressure remeasurement (by 5.6 [95% CI, 2.9-8.3] pp; P < .001). The probability of an existing antihypertensive medication dose being increased was reduced (-1.1 [95% CI, -2.0 to -3.0] pp; P = .01), and the 3-month risk of hospitalization for stroke or ACS increased (by 0.25 [95% CI, 0.07-0.44] pp; P = .005), with excess risk growing to 0.52 pp (95% CI, 0.17-0.87 pp; P = .008) pp at 1 year. This study's findings suggest that the addition a quality metric and financial incentive to physicians' contracts in a large health system had little impact on measured outcomes in the overall population of patients with hypertension. For patients with marginally high blood pressure, the incentive was associated with increased documented hypertension control because of selective remeasurement of blood pressure, decreased medication adjustments, and increased cardiovascular hospitalizations.

Hypertension manifests with striking sex-based disparities in prevalence, pathophysiology, and therapeutic outcomes, necessitating the reappraisal of current management paradigms. For example, men exhibit higher blood pressure (BP) in early adulthood, while post-menopausal women suffer from accelerated cardiovascular risk owing to estrogen depletion, endothelial dysfunction, and distinct aging trajectories. Moreover, the renin-angiotensin-aldosterone system (RAAS) operates rather divergently: testosterone upregulates vasoconstrictive angiotensin II type 1 receptors in men, whereas estrogen enhances nitric oxide bioavailability and modulates angiotensin II type 2 receptor in premenopausal women. These hormonal influences extend to cardiovascular aging, as women develop greater arterial stiffness post-menopause, predisposing them to heart failure with preserved ejection fraction. Conversely, men demonstrate higher endothelial dysfunction and cardiomyocyte apoptosis. Furthermore, sex-specific pharmacokinetic profiles (e.g., renal clearance, hepatic metabolism) and pharmacodynamic responses to antihypertensives underscore the inadequacy of uniform treatment strategies. This is demonstrated in women by the observed reduced efficacy of angiotensin-converting enzymes inhibitors, but superior blood pressure control using diuretics. Men, however, respond more robustly to beta blockers. Emerging evidence highlights epigenetic modifiers, including X-chromosome-linked microRNAs (miRNAs) and sex-hormone-driven transcriptional regulators, as pivotal mediators of vascular tone and drug metabolism disparities. Despite these insights, clinical guidelines remain relatively inadequately stratified by sex, perpetuating suboptimal outcomes. This review synthesizes molecular, physiologic, and pharmacotherapeutic axes of sexual dimorphism in hypertension. It also advocates for precision medicine approaches that integrate hormonal status, aging-related vascular remodeling, and genetic polymorphisms. Addressing these physiological paradigms promises to bridge the translational gap between bench and bedside, ultimately mitigating the global burden of hypertensive disease, while mitigating shortcomings in sex-based antihypertensive management.

Non-cirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology, such as idiopathic portal hypertension (IPH), non-cirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia, leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF. The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.

Ethnic disparities in the incidence of type 2 diabetes mellitus are well documented in multiethnic urban populations, but the contributions of migration status and mental health are less well understood. This study used a large dataset from primary care centres in South London that is unique in that it includes migration-related information together with information on mental and physical health comorbidities. We aimed to assess how migration status and mental health contribute to longitudinal associations of ethnicity and type 2 diabetes risk in a multiethnic urban population. We conducted a longitudinal cohort study (2012-2019) of approximately 340,000 adults without baseline type 2 diabetes. Cox proportional hazards models were applied with sequential adjustments: first for age and sex; second, adding migration status (country of birth being UK or not); and third, further adding mental health conditions (depression, anxiety, severe mental illness), physical health factors (BMI, hypertension and other macrovascular diseases) and area-level deprivation. This approach allowed us to examine whether ethnic differences in the incidence of type 2 diabetes persist after accounting for additional factors. South Asian, Black African and Black Caribbean groups had 2-3-fold higher type 2 diabetes risks compared with White British individuals, which were only partially explained by socioeconomic and clinical factors. Being born outside the UK increased type 2 diabetes risk by 29% across all ethnic groups. Depression/anxiety and severe mental illness were associated with a higher risk of type 2 diabetes. No statistical evidence of strong interactions between these factors was obtained. Ethnicity, migration status and mental health conditions were each independently associated with type 2 diabetes risk, and ethnic disparities persisted after adjustment. The lack of evidence for interactions suggests that migration- and mental health-related mechanisms may operate similarly across ethnic groups rather than amplifying or mitigating existing disparities in type 2 diabetes rates. Efforts to reduce diabetes inequalities will require both support for post‑migration challenges and addressing of the broader structural and environmental determinants underlying persistent ethnic disparities.

To investigate the incidence of perimetric glaucoma and the effectiveness of interventions in eyes with pseudoexfoliation syndrome (PXF) with and without ocular hypertension (OHTN). Retrospective cohort study. Eyes with documented PXF between 2016 and 2023 at a tertiary referral hospital. We applied 2 natural-language processing models to identify patients with pseudoexfoliation and confirmed PXF status through chart review. Glaucoma incidence was defined using consecutive Humphrey visual field (HVF) tests with positive results for glaucoma labelled by PyGlaucoMetrics (https://github.com/Mousamoradi/PyGlaucoMetrics), which use validated algorithms to estimate glaucoma probability from reproducible HVF data. We estimated the cumulative incidence of perimetric glaucoma using the Kaplan-Meier method and a multivariable Cox regression model to identify factors associated with glaucoma incidence. Outcomes of procedural interventions were evaluated. Glaucoma incidence rates. Among 485 eyes from 369 patients, the 4-year cumulative incidence of perimetric glaucoma was 26.5% (95% confidence interval [CI], 20.7%-32.0%) in eyes without OHTN and 37.5% (95% CI, 24.3%-48.4%) in those with OHTN (P = 0.005, log-rank test). Factors associated with incident glaucoma were older age (hazard ratio [HR], 1.39 per 5 years [95% CI, 1.19-1.62]), OHTN (HR, 2.18 [95% CI, 1.39-3.42]), higher cup-to-disc ratio (CDR; HR, 1.17 per 0.1-higher CDR [95% CI, 1.04-1.31]), and phakia (HR, 1.94 [95% CI, 1.13-3.34]). During follow-up, incident OHTN was observed in 14.6% of eyes with PXF without baseline OHTN. However, 87.3% of eyes that demonstrated glaucoma had no documented OHTN, based on measured intraocular pressure (IOP) at any office visit. Standalone lens extraction reduced the mean ± standard deviation (SD) IOP from 15.8 ± 2.5 mmHg with 0.40 ± 0.78 medications before surgery to 12.9 ± 2.7 mmHg with 0.28 ± 0.57 medications at 1 year postoperatively. More than one-fourth of eyes with documented PXF without OHTN and more than one-third of those with OHTN demonstrated perimetric glaucoma within 4 years. Older age, OHTN, higher CDR, and phakia were associated with incident glaucoma. Nearly 90% of eyes with normal baseline IOP that later demonstrated glaucoma had no documented OHTN at any office visit. Standalone lens extraction reduced IOP by 3 mmHg at 1 year postopertively. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Hypertension (HTN) is a major risk factor for cardiovascular diseases, with chronic low-grade inflammation emerging as a critical contributor to its development and target organ damage. Emerging evidence implies gut microbiota in blood pressure regulation. However, the long-term impact of patient-derived gut dysbiosis on the chronic progression of HTN remains insufficiently characterized. This study aimed to determine how HTN-associated gut microbiota contributes to sustained blood pressure elevation and target organ damage during long-term colonization, and to elucidate underlying immune-metabolic mechanisms using multi-omics analyses. Fecal microbiota from hypertensive patients or normotensive controls were transplanted into germ-free mice, followed by continuous monitoring for 10 weeks to mimic the long-term adaptive remodeling of humanized microbiota within the host. Temporal dynamics of gut microbiota were assessed by 16S rRNA sequencing. Integrated metabolomic and transcriptomic analyses were performed on intestinal, cardiac, fecal, and serum samples. FMT from hypertensive patients induced sustained systolic blood pressure elevation and structural damage in target organs. HTN-FMT mice exhibited reduced microbial diversity and a dysbiotic signature characterized by enrichment of pro-inflammatory taxa and depletion of beneficial commensals. Metabolomic profiling revealed marked disturbances in polyunsaturated fatty acids metabolism. These metabolic alterations were accompanied by enhanced CD4⁺ T cell activation, elevated systemic inflammatory cytokines, and concordant enrichment of interleukin-17 signaling pathways in both intestinal and myocardial transcriptomes. These findings reveal interactions among gut dysbiosis, metabolic imbalance, and immune activation during long-term colonization with HTN-associated microbiota, underscoring the central role of the gut-immune axis in the chronic progression of hypertensive target organ injury.

Replacing sodium chloride (NaCl) with potassium chloride (KCl) is a worldwide sodium reduction strategy, yet bitterness and astringency from KCl affects salt flavor. To address this challenge, a coating technique utilizing starch and the derivatives on KCl via fluidized bed granulation was developed to mask bitterness and astringency in low-sodium salt formulation. Results indicated that the soluble and pre-gelatinized starch coating effectively modulated the interfacial release kinetics, significantly slowing the diffusion and burst release of K+ ions, thereby attenuating their oral bitterness perception. A novel low-sodium salt (NovLSS) was formulated by blending coated KCl (30%) with NaCl (70%). In a mouse model of high-salt diet-induced hypertension, NovLSS reduced the total serum sodium levels and high sodium related adverse syndromes, preventing the blood pressure rise and associated renal injury. Besides, NovLSS also modulated the gut microbiota balance, protected the intestinal barrier, produced short-chain fatty acids, and suppressed the inflammation. Collectively, this study presented a synergistic strategy of starch-based interfacial engineering and controlled-release technology to develop a NovLSS with dual functions of flavor masking and health promotion, exhibiting great potential for sodium reduced functional foods.

Innate and adaptive immune cells play important roles in the pathogenesis of hypertension. B cells play a crucial role in mammalian adaptive immunity via processing antigens and producing antibodies. However, whether B cells and immunoglobulins are involved in regulating blood pressure in hypertension remains unclear. We aimed to reveal the protective role and the potential immunoregulatory mechanisms of B1a cells in hypertension. Wild-type and CD19 knockout (CD19-/-) mice received angiotensin II (Ang II) to induce hypertension. Blood pressure measured by radiotelemetry and tail cuff. Vascular damage was assessed by histology and immunofluorescence. Immune cells were analyzed by flow cytometry. Adoptive transfer of different B-cell subsets was performed. In vitro cocultures examined B1a cell effects on CD4+T cells. We found that the frequency of B1a cells was reduced in the blood and peritoneal cavity in wild-type mice after Ang II infusion. We showed that CD19-/- male mice, which exhibit a marked reduction in B1a cells, largely exacerbated the elevation of both systolic and diastolic blood pressures after Ang II treatment compared with wild type. Vascular dysfunction and damage, including CD4+T cells and macrophage accumulation, aortic structural remodeling, and fibrosis, were worse in CD19-/- male mice compared with wild-type male mice in response to Ang II. Adoptive transfer of B1a cells, but not B2 cells, protected against Ang II-induced hypertension and vascular damage. The serum level of IgM was reduced in CD19-/- mice but increased after transferring with B1a cells. In vitro, B1a cells and natural IgM inhibited the activation and IFNγ (interferon gamma) production of CD4+T cells. Furthermore, transferring B1a cells deficient in the secretion of IgM blocked the protective effects in response to Ang II infusion. Our data demonstrated that B1a cells play a protective role in the development of hypertension via producing natural IgM and inhibiting IFNγ production by CD4+T cells.

The "obesity paradox" suggests lower cardiovascular risk at higher body mass index (BMI) after myocardial infarction (MI), but whether it reflects true protection or methodological bias is unclear. From the nationwide SWEDEHEART registry, patients hospitalised with MI from 2010-2021 were included. BMI at admission was modelled both as a continuous variable using restricted cubic splines and categorised into 6 groups, with 20 to <25 kg/m2 as reference. The primary outcome was major adverse cardiovascular events (MACE), a composite of recurrent MI, stroke, heart failure hospitalisation, or cardiovascular death. Cox regression models estimated the BMI associated with lowest risk and HRs for categorical BMI groups. Adjustments included sociodemographic factors, smoking, and comorbidities not attributed to obesity. Mediation analyses assessed the roles of diabetes, hypertension, and prior cardiovascular disease. In 173 617 patients, the mean age was 71.0 years, 66.7% were men, and mean BMI was 27.1 kg/m2. During a median follow-up of 3.3 years, 36.5% experienced MACE. BMI had a U-shaped association with MACE, with the lowest risk at BMI 25.1 kg/m2. The adjusted HR (95% CI) for MACE was 0.99 (0.97-1.01) for overweight and 1.17 (1.14-1.20) for obesity class I, increasing across higher obesity classes. Excess risk was largely mediated by diabetes, hypertension, and prior cardiovascular disease. Obesity was associated with increased risk of MACE, partly mediated by obesity-related risk factors. The findings suggest that previously reported "obesity paradoxes" may reflect differences in confounder adjustment, handling of mediators, patient populations, and survivor bias.

The life expectancy of adult patients with congenital heart disease (ACHD) has improved, thus shifting the research focus towards age-related comorbidities to continue to improve patient outcomes. This study aimed to investigate all-cause mortality and recurrent acute myocardial infarction (AMI) in adults with and without congenital heart disease. A nationwide case control study was conducted between 2000 and 2022. Patients with ACHD (n = 214) and controls (n = 275 377) who experienced their first AMI were identified. Of these, each patient (n = 213) with ACHD was matched with 10 controls (n = 2092) based on age, sex, hypertension, diabetes, hyperlipidaemia, and history of percutaneous coronary intervention or coronary artery bypass grafting. Mortality and recurrent AMI were assessed using unadjusted and adjusted Cox regression for matching and other clinical covariates. Patients with ACHD were younger (58 ± 14 years) than controls (70 ± 12 years) before the matching (P < .001). The mean follow-up time was 6.5 and 7.3 years for patients with ACHD and controls, respectively. There was no significant difference in mortality or recurrent AMI rates at 1 year between patients with ACHD and matched controls. The mortality rate was higher in ACHD at 10 years of follow-up (hazard ratio 1.4, 95% confidence interval 1.0-1.9) but did not remain after adjustment. This study suggests that survival rates and the incidence of recurrent AMI in ACHD patients are similar to those of controls. Since patients with ACHD share similar cardiovascular risk factors as the general population, promoting healthy lifestyles and proactive risk management is crucial to mitigate acquired heart disease.

This study investigates the effect of urban heat island exposure on clinically significant cardiovascular disease (CVD) and how this relationship changes when accounting for other environmental and social factors. We used publicly available data from California urban areas on a census tract-level, including surface urban heat island intensity (SUHII), acute myocardial infarction (AMI) event rate, fine particulate matter pollution (PM2.5), the Normalized Difference Vegetation Index (NDVI), racial and ethnic group percentages, and the Social Vulnerability Index (SVI). We created models to explore how these variables affect the predicted AMI event rate. We created census tract-level bivariate choropleth maps of urban areas in California counties. The models predict that residents in urban census tracts with median and high SUHII exposure have a 17 and 22% increased AMI event rate, respectively, compared with residents living in census tracts with low SUHII exposure. Increasing PM2.5 and SVI were associated with increasing predicted AMI event rates. Urban census tracts with a higher percentage of individuals who were identified as Hispanic, Black, and American Indian had higher predicted AMI event rates. This study highlights the intersection of SUHII, AMI events, and various environmental and social factors within urban areas on a census tract-level. It emphasizes the need to implement mitigation strategies to decrease the urban heat island effect, which may reduce the rate of heat-related AMI events.

Contrast-free myocardial infarction (MI) segmentation is essential for mitigating the health risks associated with contrast agents (CAs) in clinical diagnostics. However, existing approaches are limited by their reliance on strictly paired CINE sequences and contrast-enhanced images, which are often difficult to obtain because patient conditions and imaging protocols often cause inter-modality slice misalignments. Therefore, we propose MTMS, the first label-free training and contrast-free MI segmentation model, enabling effective training without requiring paired datasets. Notably, MTMS is the first framework to incorporate cardiac biomechanical knowledge into contrast-free MI segmentation through a self-supervised paradigm. It leverages dual upstream guidance, combining pseudo-label generation from biomechanical cues with structural for segmentation, and achieves self-supervised learning via iterative pseudo-label refinement. MTMS includes three synergistic modules, Upstream 1: Spatiotemporal Structural Evolution Module that encodes myocardial structure transitions by guided-perturbation modeling of inter-frame morphological divergence, enabling explicit extraction of deformation trajectories critical for infarct localization; Upstream 2: Cardiac Mechanics-Driven Analysis Module that estimates myocardial stress responses by diffeomorphic motion fields and strain energy formulation, enabling generation of physiologically consistent pseudo-labels that reflect regional mechanical dysfunction; Downstream: Dual-Domain Interaction Module that combines structural and biomechanical cues by prototype-guided semantic fusion, enabling consistent and physiologically grounded delineation of infarct boundaries. On 370 clinical cases, MTMS achieves a Dice of 0.698 and HD95 of 19.634, surpassing seven state-of-the-art methods by up to 0.30 in Dice and over 107.392 in HD95. These results demonstrate the potential of MTMS to advance the development of contrast-free MI segmentation. Code is available at https://github.com/wrsssss/mtms.

Late reperfusion therapy (LRT; ≥ 3 h post-MI) reduces the risk of ventricular rupture following myocardial infarction (MI), yet the mechanisms behind this protection remain unclear. We hypothesized that LRT alters the biomechanical properties of the infarct borderzone and to investigate this, we utilized laser micrometry, planar biaxial testing, and quantitative polarized light imaging (QPLI) to quantify spatial variations in the geometric, mechanical, and structural properties of the left ventricle extracellular matrix (LV ECM) in adult male Sprague-Dawley rats. Rats received permanent occlusion (PO), LRT, or a sham surgery and tissue was collected 1-day post-MI, during the inflammatory phase of healing. LRT generated larger infarct borderzones (border-to-core area PO: 0.735 ± 0.3; LRT: 1.15 ± 0.3; p = 0.04). Infarct core and borderzone stiffness was reduced post-MI, and LRT samples exhibited smoother, more consistent stiffness gradients between infarct core and remote regions than PO samples. In general, infarcted LV ECM was thicker and more spatially variable than sham, but less stiff. Additionally, QPLI revealed decreased collagen fiber alignment in infarct cores relative to borders, though this did not differ between PO and LRT groups. Exploratory second harmonic generation imaging revealed more gradual, consistent transitions in collagen fiber alignment throughout LRT LV ECM, although this was limited to one sample from each group. Ultimately, these results further justify LRT and may inform future therapies aimed at spatially modulating post-MI tissue mechanics to improve patient outcomes. STATEMENT OF SIGNIFICANCE: Myocardial infarctions (MI) initially weaken the heart wall and, in severe cases, can lead to ventricular rupture, a life-threatening complication. Late reperfusion therapy (LRT), in which blood flow is restored 3+ hours post-MI, reduces rupture risk, but how it protects the heart remains unclear. Here, we combine full-field imaging and mechanical testing to reveal that LRT broadens the infarct borderzone and smooths gradients in stiffness and thickness. This previously unrecognized mechanical "smoothing" likely reduces stress concentrations that drive rupture. By establishing how LRT reshapes regional properties in the heart, our findings not only provide a mechanistic basis for LRT's benefits, but may also inform the design of spatially-conscious biomaterials and therapies to improve patient outcomes post-MI.

Inducing adult cardiomyocyte proliferation to repair the infarcted heart remains a major therapeutic challenge. While metabolic reprogramming is known to drive regeneration, the specific organelle-level mechanisms governing this process, particularly the crosstalk between mitochondria and lipid droplets (LDs), remain elusive. Here, we identify Heat Shock Cognate 71 kDa Protein (Hsc70) as a critical physiological "metabolic brake" that maintains adult cardiomyocytes in a terminally differentiated state and suppresses cell cycle re-entry by tethering mitochondria to LDs via Mitofusin 2 (Mfn2). Using Ginsenoside Rb2, a bioactive small molecule identified from a clinically effective formula (Shuangshen Ningxin), we demonstrate that Rb2 directly binds to Hsc70 (KD ≈ 32 µM) and disrupts the Hsc70-Mfn2 interaction. This disruption pharmacologically uncouples the remaining mitochondria-LD contacts to f release this physiological barrier, restores metabolic homeostasis, and reactivates cardiomyocyte proliferation in myocardial infarction (MI) rats. Crucially, these regenerative effects were abrogated by AAV9-mediated Hsc70 overexpression, confirming Hsc70 as the non-redundant therapeutic target. Furthermore, a retrospective analysis of 60 patients treated with the Rb2-containing intervention showed significantly improved cardiac outcomes, highlighting the broad cardioprotective and clinical utility of this therapeutic strategy. Our findings reveal a fundamental mechanism linking organelle dynamics to tissue regeneration and highlight Hsc70 as a druggable target for heart failure treatment.

Persimmon leaves (PL) are agricultural and forestry by-products rich in flavonoids with diverse pharmacological activities. To fully exploit their medicinal value, we established an optimized integrated process combining ultrasound-assisted extraction (UAE) and resin purification to efficiently prepare persimmon leaf flavonoids (PLF) with high content and purity. The chemical composition of PLF was comprehensively characterized by ultra performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) and high performance liquid chromatography (HPLC). Furthermore, in vitro cell and in vivo rat models were employed to evaluate the activity and underlying mechanism of PLF against MIRI. Preliminary results showed that the content and purity of PLF prepared by the proposed process were significantly higher than those of crude PLF (C-PLF) obtained by conventional reflux extraction. The total flavonoid content (TFC) and mass fraction of total flavonoids in PL (TFPL) were 48.54 ± 0.86 mg/g and 87.78 ± 1.61%, respectively. In addition, in vitro pharmacological revealed that PLF exhibited significantly stronger anti-oxidative stress activity than C-PLF. Four monomeric compounds, namely hyperoside, isoquercitrin, kaempferol-3-O-galactoside and astragalin, exerted synergistic effects. In vivo animal experiments demonstrated that PLF alleviated myocardial infarction and oxidative stress injury in MIRI rats, and exerted cardioprotective effects by regulating oxidation-related proteins. At present, there are few studies on high-quality PLF worldwide. This study not only verified the high efficiency of UAE in flavonoid preparation, but also proved that high-purity PLF possesses prominent advantages against MIRI. The results provide a theoretical basis for the comprehensive development and utilization of PL resources.

Myocardial infarction (MI) remains a leading cause of cardiovascular-related morbidity and mortality worldwide. Its primary pathophysiological cascade involves the ischemic and hypoxic necrosis of cardiomyocytes (CMs), the degradation of the extracellular matrix (ECM), and the subsequent formation of fibrotic scar, which collectively drive the progression toward terminal heart failure. Current clinical interventions, which predominantly include pharmacotherapy, device implantation and reperfusion strategies, are largely palliative and mainly focus on restoring blood perfusion or alleviating symptoms. Consequently, they fail to fundamentally reverse the permanent loss of functional CMs and the structural devastation of the ECM post-MI. In recent years, hydrogels have emerged as highly promising platforms for myocardial tissue repair and regeneration, owing to their excellent biocompatibility, tunable mechanical properties, inherent biodegradability, and highly biomimetic three-dimensional (3D) network architectures. This review systematically summarizes recent advances in hydrogel engineering for MI repair, analyzing these systems from the dual perspectives of material composition and functional mechanisms. First, we highlight the design strategies underlying major material platforms, including stimuli-responsive systems, cell-engineered platforms and RNA/miRNA-loaded hydrogels. Second, we elucidate the mechanistic roles of hydrogels in myocardial repair, emphasizing mechanical support, microenvironmental modulation, and multifunctional integration. Finally, we critically evaluate the translational barriers facing hydrogel-based therapies and outline prospective future directions. Ultimately, this review aims to provide critical insights and a strategic roadmap for the fundamental research and clinical translation of hydrogels in cardiovascular regenerative medicine. STATEMENT OF SIGNIFICANCE.

Ischemic heart disease, particularly myocardial infarction (MI), is a leading cause of global mortality, and the resulting myocardial fibrosis significantly impairs cardiac function, contributing to heart failure. Despite considerable efforts, effective therapeutic interventions for reversing myocardial fibrosis and restoring heart function remain elusive. Recent studies highlight the crucial role of metabolic reprogramming in the activation of cardiac fibroblasts (CFs) and their transformation into myofibroblasts, which drive fibrosis. Gastrodin (GAS), a phenolic glycoside derived from Gastrodia elata, has demonstrated promising anti-fibrotic and metabolic regulatory effects; however, its clinical application has been limited by poor pharmacokinetic properties and lack of targeted delivery. Here, we designed an intrapericardial (iPC) injection nanocomposite hydrogel incorporating FAP-targeted CAR-T cell membrane-coated GAS nanoparticles (FAP-CAR T CM@PPA-G NPs) within a pH/ROS-responsive CP/PCPD hydrogel. This innovative system achieves specific targeting of FAP-positive myofibroblasts, on-demand release of GAS triggered by pathological ROS and pH changes, and effective inhibition of fibrosis by modulating the KLF2/CREB5/HIF-1α/PFKFB3 metabolic axis. Our findings not only provide a novel therapeutic platform for post-MI fibrosis treatment but also elucidate the mechanistic basis of GAS's anti-fibrotic effects. This strategy offers significant promise for advancing the clinical translation of GAS-based therapies for myocardial fibrosis and heart failure.

The enzyme activity of redox-related selenoproteins is impaired post-tissue injury or inflammation, exacerbating oxidative stress and apoptosis. In this study, we present a strategy using selenotrisulfide (STS) to enhance the selenium content and restore selenoprotein-like activity in vivo via thiol-exchange reactions. The exact mass-to-charge ratio (m/z) change was observed at cysteine residue sites by liquid chromatography-mass spectroscopy (LC-MS), demonstrating the feasibility of the thiol-exchange reaction and the modification of selenium with proteins. Compared to the traditional selenium sources such as sodium selenite (Na2SeO3), L-selenomethionine (SeMet) and L-selenocysteine ((Sec)2), STS exhibited superior antioxidative and therapeutic efficacy by augmenting selenium levels and oxidoreductase-like activities in vitro and in vivo. Proteomic analysis revealed that STS could better improve myocardial contraction and regulate glucolipid metabolism to enhance energy supply and cardiac repair. Furthermore, the core-shell nanofibrous ZPB@STS patch significantly contributed to lower inflammatory response, less cell death and collagen deposition, and stronger cardiac contraction through the cooperative interaction of selenium-regulation from STS and mechanical support from the elastomeric polyurethane fibrous patch.

Myocardial ischemia reperfusion injury (MIRI) remains a major challenge in the treatment of acute myocardial infarction, as restoration of coronary blood flow often fails to prevent progressive cardiomyocyte loss, adverse ventricular remodeling, and heart failure. The pathological complexity of ischemia reperfusion injury, involving oxidative stress, inflammatory amplification, microvascular dysfunction, and multiple forms of regulated cell death, has limited the clinical success of conventional single target therapies. Stem cell-based approaches offer unique cardioprotective and immunomodulatory potential but are hampered by poor cell survival, limited engraftment, and safety concerns in the hostile post reperfusion microenvironment. Recent advances in nanotechnology have enabled the development of stem cell based nanotherapeutics that overcome these limitations by enhancing targeting, stability, and functional control. This review summarizes the key mechanisms underlying MIRI and critically evaluates emerging stem cell based nanotherapeutic strategies, including nanosystem empowered stem cell therapies, stem cell derived nanovesicles, and stem cell biomimetic nanotherapeutics. By integrating mechanistic insights with engineering innovations, these approaches provide a systems level solution to the multifaceted pathology of ischemia reperfusion injury and hold promise for advancing precision therapies for ischemic heart disease.

Periodontitis and myocardial infarction (MI), the leading cause of mortality worldwide, represent globally prevalent inflammatory diseases with bidirectional pathophysiological links. Despite the urgent demand for non-invasive strategies capable of alleviating local periodontal destruction while mitigating associated systemic cardiovascular complications, no integrated treatment modality currently exists. To address this challenge, a protein-loaded antibacterial hydrogel, thiolated chitosan/AMP-PEG-maleimide (C1.5P4/BMP-2), with novel sustained protein release properties was developed. This hydrogel features an interconnected microporous architecture that: (1) enables high-efficiency BMP-2 protein encapsulation, (2) preserves protein bioactivity while ensuring sustained release, thereby addressing the recognized challenge of hydrogel-based protein delivery, (3) confers potent antibacterial properties, (4) facilitates remote cardiac function improvement by resolving periodontal inflammation. In murine models, locally, it attenuated alveolar bone loss (2-fold greater bone regeneration vs controls) while systemically improving post-MI cardiac function (75.6% higher ejection fraction). Mechanistically, the hydrogel's protein-protective microenvironment synergized with its antimicrobial action selectively inhibiting Gram-negative (G-) anaerobic pathogens (primary periodontal culprits) while enriching Gram-positive (G+) commensals, regulating biofilm G-/G+ ratio. Concomitantly, this dual action modulates the oral-cardiac inflammatory axis, specifically downregulating B2 cell/TNF-α signaling to mitigate systemic inflammation associated with MI. Collectively, this study presents a novel non-invasive protein-stabilizing hydrogel that addresses periodontitis-MI comorbidity through sustained osteogenic factor delivery coupled with microbiome-immune modulation.

Epicardial delivery of therapies has the potential to prevent adverse remodeling and promote in situ regeneration after myocardial infarction (MI) but further optimization of bioagent dosing and transport to heart muscle is required to maximize their therapeutic potential. Replenishable reservoir systems have enabled localized bioagent delivery to the epicardial surface but therapy transport from these systems is constrained by semipermeable membranes and fibrous capsule formation. Our approach to improved therapy delivery from epicardial reservoir systems is multi-pronged. First, we introduce a membrane-free reservoir system by incorporating a gelatin scaffold into a flexible polymer implant to promote direct integration with the epicardial surface and act as a replenishable depot to encourage myocardial-directed transport. Next, we perform in vitro and ex vivo validations and multi-scale computational simulations to characterize biomaterial, tissue, and organ-level transport of therapy, considering both native tissue architecture, and the effect of blood vessel clearance. As an in vivo use case of our system, we investigated the functional effect of multi-dose regimens of human follistatin-like 1 protein (FSTL1) in a rat model of myocardial infarction (MI). Groups receiving multiple doses of FSTL1 show increased cardiac performance (ejection fraction and fractional shortening), and decreased chamber stiffness 28 days after MI. Multi-dosing increases ventricular wall thickness and reduces infarct size. We demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone. Finally, we establish a computational and experimental framework for patient-specific modeling to optimize implant parameters such as reservoir size and shape, infarct location, and dosing regimens, with a vision for clinical-imaging guided bioagent delivery strategies that can be modified on a per-patient, therapy-specific basis to optimize dosing regimens of various bioagents. This study highlights the potential for integrating personalized computational models with replenishable delivery systems to improve bioagent transport from biomaterials and enhance post-MI therapeutic outcomes.

Stem-cell-based cardiac repair holds promise for the infarcted myocardium, yet the in vivo molecular behavior of transplanted cells is poorly understood. Using time series spatial transcriptomics, we profiled human pluripotent stem-cell-derived cardiovascular progenitors engrafted into a pig model. We show that the engrafted cardiovascular progenitors progressively upregulated genes associated with cardiac maturation, oxidative metabolism, calcium handling and fibrosis resolution. Cell-cell communication analysis identified Midkine (MDK), secreted by the human xenograft, as a key regulator of host neovascularization. We validated this using immunohistochemistry, lentiviral MDK overexpression and functional assays that demonstrated enhanced endothelial cell migration and increased CD31+ vascular density in vivo. A publicly available interactive Shiny atlas of spatial and temporal transcriptomic data from myocardial infarction pig hearts with human xenografts is provided. These findings advance mechanistic understanding of stem-cell-mediated cardiac repair and identify MDK as a tractable target for therapeutic angiogenesis in ischemic heart disease.

Myocardial infarction (MI) triggers a complex and dynamic immune response involving both innate and adaptive immune cells. Among these, macrophages (Mφ), neutrophils, dendritic cells, and mast cells play essential roles in inflammation, tissue repair, and cardiac remodeling. Although inflammation is necessary for clearing necrotic tissue, dysregulated immune responses can exacerbate injury and lead to adverse cardiac outcomes. A comprehensive understanding of immune cell heterogeneity and functions in MI is critical for developing targeted therapeutic strategies. This review aims to systematically summarize the origins, phenotypic diversity, and functional roles of major immune cell populations involved in MI, with a particular focus on Mφs and neutrophils. It further seeks to evaluate emerging therapeutic strategies targeting these immune cells to improve cardiac repair and clinical outcomes following MI. Recent advances highlight the remarkable heterogeneity and plasticity of cardiac immune cells. Mφs, derived from both resident and monocyte-origin populations, exhibit dynamic phenotypic transitions across inflammatory, proliferative, and reparative phases of MI. CCR2⁺ Mφs primarily drive inflammation, whereas CCR2⁻ subsets contribute to tissue repair and angiogenesis. Neutrophils, as early responders, not only mediate acute inflammation through degranulation and neutrophil extracellular trap formation but also participate in resolution and remodeling processes. Importantly, emerging evidence challenges the traditional dichotomy of pro- and anti-inflammatory phases, revealing overlapping and context-dependent immune functions. Novel therapeutic approaches, including modulation of Mφ polarization, inhibition of excessive neutrophil activation, and targeting specific signaling pathways (e.g., C-C motif chemokine receptor type 2/ligand type 2 (CCR2/CCL2), NOD-like receptor family pyrin domain containing 3 (NLRP3)), demonstrate promising preclinical and clinical potential. Collectively, these findings underscore the importance of precise immune modulation rather than broad immunosuppression in MI treatment, paving the way for more effective and personalized therapeutic strategies.

Over the past decades, the approach to cardiomyopathies has deeply evolved. It has progressively transitioned from one predominantly based on clinical evaluation and conventional imaging towards an integrated and multidimensional approach that incorporates advanced imaging techniques, tissue characterization, and comprehensive genetic testing. In this perspective, the current classification of cardiomyopathies, from the European Society of Cardiology, has introduced the new entity of non-dilated left ventricular cardiomyopathy (NDLVC) that encompasses a spectrum of diseases from hypokinetic non-dilated forms [formerly called dilated cardiomyopathies (DCMs)] to non-hypokinetic non-dilated forms, characterized by left ventricular scar (previously called arrhythmogenic cardiomyopathies). However, the pivotal principle of the new classification is that the phenotype should be considered the starting point of a dynamic diagnostic pathway rather than its ultimate definition. Contemporary evaluation of patients with DCM and NDLVC requires a longitudinal and integrative perspective in which clinical features, imaging markers, and molecular data converge to refine disease characterization. Stated that, several aspects warrant further refinement. Arrhythmic risk stratification of DCM and NDLVC remains incompletely delineated, reflecting the complex and heterogeneous nature of the underlying arrhythmogenic substrate and its variable expression across different stages of the diseases. In addition, a proportion of patients remain genetically elusive despite extensive testing, underscoring the need for deeper molecular insights. At the same time, the expanding recognition of genotype-positive/phenotype-negative individuals introduces clinical scenarios that are not yet fully delineated, particularly with regard to surveillance strategies and preventive decision-making. This review paper aims to provide a structured and evidence-informed framework to guide personalized management of DCM and NDLVC, starting from the phenotype towards precision medicine.

Left ventricular (LV) hypertrabeculation, formerly termed LV noncompaction, is a heterogeneous myocardial entity linked to adverse cardiovascular outcomes. This study evaluated embolic risk in patients with dilated cardiomyopathy (DCM) according to the presence of hypertrabeculation and examined its prevalence and prognostic relevance across DCM genotypes. Clinical data from 1160 patients with DCM evaluated by cardiac magnetic resonance imaging and genetic testing (n=997 [86%]) were collected from 22 international centers. End points included embolic events, advanced heart failure events, and major ventricular arrhythmias. LV hypertrabeculation was identified in 354 patients (30.5%) by fractal analysis and in 343 (29.7%) according to Petersen criteria, with good concordance. After a median follow-up of 5.1 years (interquartile range, 2.8-7.4), embolic events occurred in 37 patients (3.2%), advanced heart failure in 62 (5.3%), and major ventricular arrhythmias in 136 (11.7%). Hypertrabeculation was not associated with increased embolic risk (hazard ratio, 1.5 [95% CI, 0.75-3.00]), even among patients in sinus rhythm with LV ejection fraction ≤40% (hazard ratio, 1.89 [95% CI, 0.7-5.5]). In contrast, atrial fibrillation and reduced LV ejection fraction were associated with embolic events (both P<0.01). LV hypertrabeculation was not associated with an increased risk of major ventricular arrhythmias or advanced heart failure; genotype, LV ejection fraction, and late gadolinium enhancement emerged as the main predictors of adverse outcomes. The prevalence of LV hypertrabeculation varied across genotypes, with the highest prevalence observed in patients with sequence variants in motor sarcomeric genes (58%), TTN (38%), and genotype-negative status (33%), and the lowest prevalence observed among those with variants in cytoskeletal/Z-disk (7%) and nuclear envelope (5%) genes. Hypertrabeculation was not associated with adverse outcomes within any genotype. Although LV hypertrabeculation is common in DCM, it is not associated with worse outcomes and should not prompt differential clinical management. The embolic risk in patients with DCM and hypertrabeculation is low, including in those with reduced LV ejection fraction without atrial fibrillation, and does not support prophylactic anticoagulation in these patients.

Treatment with aficamten in patients with obstructive hypertrophic cardiomyopathy (oHCM) led to significant improvements in patient-reported outcomes (PROs) in the pivotal SEQUOIA-HCM trial over 24 weeks, but its longer-term impact has not been described. The aim of this study was to describe the long-term effects of aficamten across multiple PROs in FOREST-HCM, an open-label extension study. Participants with oHCM completing an aficamten trial were offered enrollment in FOREST-HCM. The Kansas City Cardiomyopathy Questionnaire (KCCQ), Seattle Angina Questionnaire 7-item (S), EuroQol Five-Dimensional Questionnaire (EQ-5D-5L) index, and visual analogue scale (VAS) were administered at baseline and at weeks 12, 24, 36, and 48. Associations among PROs and clinical markers of oHCM severity were assessed with Spearman correlation coefficients.A total of 172 participants (mean age 60.4 [SD ±13.1] years; 45.3% female) completed 48 weeks of follow up as of August 31, 2024, and were included. Significant improvements in all PROs were observed by week 12 and sustained through week 48. At 48 weeks, mean KCCQ-OSS improved by 18.8 (16.9-20.6) points, (P < 0.001, with the largest gains in the KCCQ Quality of Life domain (25.8 points [23.2-28.5; P < 0.001]). S-Summary Scores increased by 17.2 (15.1-19.4; p < 0.001), and EQ-5D-5L index and VAS scores improved by 0.11 and 12.7 points, respectively (p < 0.001). Improvements in PROs were significantly correlated with important clinical measures of oHCM. Aficamten resulted in sustained improvements across multiple health status dimensions, which also correlated with clinical markers of oHCM severity.

In parallel with diagnostic advances and awareness of cardiac amyloidosis (CA) in aging populations, frailty is increasingly observed in CA. However, the relationship between the frailty and CA remains poorly characterized owing to limited studies that have defined frailty a priori. We performed a meta-analysis to characterize the impact of frailty on clinical and functional patient outcomes in CA. Systematic review of four electronic databases was performed for all studies reporting frailty prevalence, functional and clinical endpoints in patients with CA from January 2015 to April 2026 (CRD420251152212). Frailty was classified based on individual study scoring systems. The primary outcome of interest was all-cause mortality, expressed as pooled hazard (HR) or risk ratios (RR) with 95% confidence intervals (CI) using inverse-variance random-effects models. Other outcomes included hospitalizations, quality of life, functional status (6-min walk distance [6MWD]), and prescription of disease modifying treatment. Heterogeneity was summarized using the I2 statistic; study quality was rated with the Newcastle-Ottawa Scale; and certainty of evidence was graded using the GRADE framework. Leave-one-out sensitivity analyses and visual funnel plots were performed where applicable. Fifteen studies with a total of 5048 patients, predominantly (>95%) with transthyretin amyloid cardiomyopathy (ATTR-CM), were included. The prevalence of frailty ranged between 6.7% and 75% across studies with a pooled mean of 33.9% (826/2435 frail). Pooling 2141 patients with outcomes available, both pre-frailty (RR 2.22, 95% CI 1.37-3.60, p < 0.01) and frailty (RR 3.93, 95% CI 2.09-7.40, p < 0.01) significantly associated with increased risks of all-cause mortality after adjustment for age and frailty assessment tool. 6MWD, a functional surrogate of frailty, predicted poorer outcomes both using baseline 6MWD (<350/300 m: HR 2.22, 95% CI 1.15-4.31, p = 0.02) and 1-year interval change in 6MWD (>35 reduction: HR 1.80, 95% CI 1.52-2.14; >5% reduction: HR 1.89, 95% CI 1.60-2.23; both p < 0.01). Beyond mortality, frailty also predicted increased risk of functional decline, poorer quality of life, and reduced prescription of disease-modifying treatment. Patients with ATTR-CM and frailty have higher mortality risk, poorer functional outcomes and reduced prescription of disease-modifying treatment compared to those without frailty. Findings were consistent across frailty instruments and sensitivity analyses, supporting the incorporation of routine frailty assessment and 6MWD into clinical management of ATTR amyloidosis. None.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with diverse prognosis. The underlying mechanisms remain unknown, resulting in limited risk stratification and therapeutic strategies. This study aimed to elucidate molecular subtypes of HCM through integrated proteogenomic analysis and explore subtype-specific therapeutic strategies. We conducted an integrated proteogenomic analysis of 132 patients with HCM using myocardial samples, incorporating whole-exome sequencing, RNA sequencing, and proteomics. Unsupervised clustering was used to identify HCM subtypes, which were validated in heart tissues and human induced pluripotent stem cell-derived cardiomyocytes from 2 independent HCM subsets. Subtype-specific signatures and pathways were explored, and their causal link with HCM pathogenesis was established by genetic evidence. A subtype-specific drug was screened using in silico drug prediction, followed by in vitro and in vivo therapeutic effect assessments. Integrated multi-omics analysis identified 2 proteome-based molecular subtypes, severe and mild. We identified 550 subtype-signature proteins, and enrichment analysis based on which revealed that the reduction in fatty acid metabolism and oxidative phosphorylation pathways in HCM versus healthy controls was predominantly driven by the severe subtype, with more severe clinical characteristics and poorer prognosis compared with the mild subtype. Validation in independent cohorts confirmed the robustness of the proteomic subtypes and their association with clinical severity. Additionally, key proteins in fatty acid oxidation and oxidative phosphorylation exhibited consistent expression differences among healthy controls and 2 HCM subtypes. Furthermore, genetic evidence established a causal link between reduced fatty acid oxidation and HCM pathogenesis. Baicalin, identified as a fatty acid oxidation facilitator, improved metabolic and hypertrophic phenotypes in severe subtype human induced pluripotent stem cell-derived cardiomyocytes and Myh6R404Q/+ mice. Our analysis demonstrates the metabolic heterogeneity of HCM and enables the development of risk stratification and subtype-specific therapeutic strategies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03076580.

Deubiquitinating enzymes (DUBs) are critically involved in diabetic cardiomyopathy (DCM), yet the function of OTU domain-containing protein 7B (OTUD7b), a recently identified DUB, in DCM remains unknown. Here, we identified that OTUD7b expression was significantly elevated in cardiomyocytes from both type 1 and type 2 diabetic mouse hearts. Cardiomyocyte-specific deletion of OTUD7b ameliorated cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice, without affecting systemic hyperglycemia. Mechanistically, combining ubiquitinome and interactome analyses, we identified transforming growth factor β-activated kinase 1 (TAK1) as a direct substrate of OTUD7b in cardiomyocytes. Under diabetic conditions, OTUD7b binds to TAK1 via its zinc finger domain and catalyzes K48-linked deubiquitination at the K346 of TAK1, thereby enhancing TAK1 protein stability. This OTUD7b-mediated stabilization increased the levels of both TAK1 and p-TAK1, which led to hyperactivation of the TAK1-MAPK (JNK/p38) axis, subsequently promoting extrinsic apoptosis and inflammatory responses in cardiomyocytes. Crucially, cardiomyocyte-specific reconstitution of a deubiquitination-resistant TAK1-K346R mutant in diabetic mice completely abolished the cardioprotective effects of OTUD7b deficiency, confirming that OTUD7b drives DCM primarily through deubiquitinating TAK1 at K346. Taken together, our study unveils a novel OTUD7b-TAK1 axis in cardiomyocytes driving diabetic heart injury and positions OTUD7b as a promising therapeutic target for DCM.

Myocardial hypertrophy is a critical pathological basis for the progression of numerous cardiovascular diseases towards heart failure. Programmed cell death (PCD) including apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis, play a pivotal role in both the initiation and advancement of myocardial hypertrophy. These processes contribute to myocardial cell damage and hypertrophy through the induction of oxidative stress, inflammatory responses, and other associated pathways. Natural products, which encompass a range of dietary components and possess medicinal properties, have emerged as a promising area for the treatment of myocardial hypertrophy, due to their multi-pathway and low-toxicity profiles. These natural products systematically inhibit myocardial cell apoptosis, modulate the autophagy pathway and dynamically regulate its activation and inhibition states, restoring myocardial cell homeostasis, regulate pyroptosis by inhibiting the activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, as well as the cleavage and activation of Gasdermin D (GSDMD). Furthermore, they suppress ferroptosis through regulation of iron metabolism, reducing free iron accumulation, enhancing antioxidant defenses, and inhibiting lipid peroxidation. Additionally, they inhibit necroptosis by modulating the key execution molecules involved in this process, ultimately delay the progression of myocardial hypertrophy. Thus, natural products that target PCD offer innovative concepts and potential candidate molecules for the prevention and treatment of myocardial hypertrophy in the context of drug development.

Receptor-interacting protein kinases (RIPKs) are a family of serine/threonine kinases that regulate innate immunity, inflammation, and several modalities of regulated cell death, and are increasingly implicated in cardiovascular disease. Increasing evidence suggests that dysregulated RIPK signaling contributes to cardiomyocyte injury, fibrosis, maladaptive remodeling, mitochondrial dysfunction, and inflammatory amplification in multiple cardiac pathologies. While the roles of RIPK1 and RIPK3 in necroptosis are well recognized, recent studies indicate broader and more complex role in heart disease, including broader non-canonical functions involving mitochondrial regulation, oxidative stress, inflammasome activation, and metabolic remodeling. RIPK2 is emerging as a significant but underrecognized modulator of sterile cardiac inflammation and pathological remodeling. Similarly, RIPK4 has recently been associated with oxidative stress responses and ferroptosis, although direct cardiac evidence remains limited. This review provides an updated overview of RIPK1-RIPK4 signaling within the framework of cardiovascular disease, emphasizing both canonical necroptotic and non-canonical signaling mechanisms. We discuss the involvement of RIPKs in myocardial ischemia/reperfusion injury, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, myocarditis, and doxorubicin-induced cardiotoxicity. We further summarize current and emerging therapeutic strategies targeting RIPKs, including small-molecule inhibitors, natural compounds, and endogenous regulators approaches. Finally, we highlight major knowledge gaps and translational challenges, including isoform-specific functions, temporal dynamics of RIPK activation, safety considerations, and the clinical translation of preclinical findings.

Cardiac fibrosis is a defining pathological feature of diabetic cardiomyopathy (DCM), and excessive activation of cardiac fibroblasts plays a critical role in regulating cardiomyocyte function through paracrine signaling. CCN1 (cellular communication network factor 1), an extracellular matrix protein involved in intercellular communication, has been suggested to influence cardiac remodeling, although its specific impact on cardiomyocytes in DCM has remained unclear. In this study, we found that CCN1 expression was markedly elevated in cardiac tissues from DCM mouse models and in insulin-resistant cell models, with fibroblasts serving as the primary source. Proteomic analysis and co-culture experiments demonstrated that CCN1 suppressed cardiomyocyte macroautophagy/autophagy. To determine its role in vivo, we generated fibroblast-specific ccn1 knockout mice and established a DCM model, demonstrating that ccn1 deletion ameliorated cardiac dysfunction and restored autophagic activity. We further identified ITGAV-ITGB1/integrin αvβ1 as the receptor mediating CCN1 signaling in cardiomyocytes. Molecular dynamics simulations and co-immunoprecipitation experiments confirmed that CCN1 engaged ITGAV-ITGB1/integrin αvβ1 through its cysteine-knot-containing (CT) domain. Mechanistically, this interaction activated the downstream PTK2/FAK-MTOR signaling pathway, leading to inhibition of cardiomyocyte autophagy. Together, these findings reveal a previously unrecognized fibroblast-cardiomyocyte signaling axis in which fibroblast-derived CCN1 drives DCM progression by suppressing autophagy through ITGAV-ITGB1/integrin αvβ1-dependent signaling. This work provides mechanistic insight into the pathogenesis of DCM and identifies CCN1 as a potential therapeutic target for mitigating disease onset and progression.Abbreviations: AAV9: adeno-associated virus serotype 9; ADGRE1/EMR1/F4/80: adhesion G protein-coupled receptor E1; BafA1: bafilomycin A1; BSA: bovine serum albumin; C8: compound 8; CCN1: cellular communication network factor 1; CF: cardiac fibroblast; CSA: cross-sectional area; DCM: diabetic cardiomyopathy; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; ELISA: enzyme-linked immunosorbent assay; HE: hematoxylin and eosin; HFD: high-fat diet; HG: high glucose; IR: insulin resistance; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MD: molecular dynamics; MTOR: mechanistic target of rapamycin kinase; NRCM: neonatal rat cardiomyocyte; PDGFRA: platelet derived growth factor receptor alpha; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; PTK2/FAK: protein tyrosine kinase 2; PTPRC/CD45: protein tyrosine phosphatase receptor type C; RPS6KB1: ribosomal protein S6 kinase B1; S100A4/FSP1: S100 calcium binding protein A4; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; WGA: wheat germ agglutinin.

Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), and ultimately promoted ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM. A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes ferroptosis. Created with Figdraw.com.

Cardiomyopathies frequently arise from rare, highly penetrant coding variants with variable clinical expressivity. Genome-wide association studies (GWAS) suggest significant polygenic contributions to cardiovascular diseases, including cardiomyopathy. Most GWAS loci map to poorly conserved noncoding regions, requiring human genome context for experimental validation. We created engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes and primary cardiac fibroblasts. We assayed single-cell gene expression and chromatin accessibility to generate comprehensive genome-wide regulatory maps. Open chromatin regions were integrated with chromatin contact information and used to fine-map cardiomyopathy GWAS single-nucleotide polymorphisms. Single-nucleotide polymorphisms and their associated open chromatin regions were assessed using reporter assays, genome editing, and expression profiling. EHT Single-cell RNA-seq recapitulated major cardiac cell types, with advanced cardiomyocyte maturation compared with monolayer human induced pluripotent stem cell cardiomyocytes. More than 400 000 open chromatin regions were resolved to cell types and assayed for transcription factor motifs. Functional fine-mapping of GWAS loci prioritized 5817 variants, and reporter assays validated allele-specific enhancer activity. We identified an intergenic chr3p25.1 locus harboring significant GWAS signals from both dilated cardiomyopathy and left ventricular ejection fraction. Several of these variants lie in open chromatin regions participating in long-range chromatin interactions with SLC6A6 and GRIP2. Haplotype-resolved and synthetic reporter assays confirmed enhancer activity and narrowed candidate single-nucleotide polymorphisms. CRISPR-deletion of this region reduced expression of both SLC6A6 and GRIP2, indicating the enhancer regulates the expression of multiple genes. EHTs with the enhancer deletion displayed markedly reduced contractile function, confirming that this enhancer region contributes to myocardial function. EHTs are an experimentally tractable platform for testing the function of noncoding variants as modifiers of cardiomyopathy. Variants fine-mapped from cardiomyopathies using EHT regulatory maps have functional consequences and provide a set of prioritized sites to advance the study of polygenic heart failure.

Pathological cardiac remodeling and afterload-induced increases in energy demand contribute to heart failure (HF). Lysosome-assisted processes, such as autophagy, coupled with alterations in mitochondrial oxidative capacity, are critical regulators of this response. Furthermore, the lysosome is a hub for multiple signaling pathways governing hypertrophic growth. TFEB (transcription factor EB) has emerged as a key regulator of lysosomal genes and mitochondrial function in multiple tissues, especially in response to external stress. Leveraging a cardiomyocyte-specific TFEB knockout mouse (CTKO), pressure overload was induced by transverse aortic constriction (TAC) to elucidate the role of TFEB under hypertrophic stress conditions. Echocardiography was employed to assess cardiac function, and hearts were subsequently harvested for transcriptomic, proteomic, and metabolomic analyses. To glean further insight into the molecular mechanisms involved, we studied neonatal rat ventricular myocytes exposed to phenylephrine, an in vitro model of cardiomyocyte hypertrophy. We report that TFEB is rapidly activated and translocates to the nucleus in cardiomyocytes exposed to hypertrophic stress conditions, triggering a lysosomal gene program independent of autophagy gene changes. At baseline, contractile function measured by echocardiography appeared normal in these mice compared with their Cre-negative littermates. However, in pressure-overload stress induced by TAC, CTKO mice manifested an amplified hypertrophic response, leading rapidly to HF. Unlike WT hearts, CTKO hearts failed to increase lysosomal capacity after TAC. They manifested an increase in the steady-state levels of autophagosome-associated proteins, such as LC3II and p62, as well as accumulation of ubiquitinated proteins, suggesting a defect in protein turnover. Interestingly, CTKO mice harbored altered mitochondrial structure, reduced oxidative capacity, and reduced abundance of peroxisome PGC-1α-b (proliferator-activated receptor-1 alpha-b). Furthermore, CTKO hearts manifested reduced expression of key enzymes within metabolic pathways essential for normal myocardial metabolism, including fatty acid metabolism, carbon metabolism, and branched-chain amino acid metabolism. Surprisingly, AMPK (AMP-activated protein kinase) signaling, while normal at baseline, was significantly decreased in CTKO hearts after TAC. This reliance on TFEB for growth trigger-induced AMPK signaling was also observed in vitro in cells exposed to phenylephrine, as were the antihypertrophic effects of TFEB activation, supporting a direct role of TFEB in this process. Finally, we report that exogenous activation of AMPK in the absence of TFEB can completely rescue the exacerbated hypertrophic response both in vitro and in vivo, independent of lysosomal function. Notably, blunting of the hypertrophic response did not impact the decreased contractile function observed in TAC-treated CTKO mice, highlighting the importance of TFEB in regulating mitochondrial function in response to stress. Our findings demonstrate that TFEB antagonizes pathological hypertrophic cardiac remodeling through upregulation of lysosomal capacity, maintaining mitochondrial energetic function, and promoting AMPK signaling.

Elevated Lp(a) is an independent, causal, genetic cardiovascular disease risk factor that is associated with the progression of high-risk coronary plaques. Risk of atherosclerotic cardiovascular disease (ASCVD)-related conditions, which are among the leading causes of death worldwide, may persist in individuals with elevated Lp(a), even in the presence of at-target, guideline recommended-low-density lipoprotein-cholesterol levels. The prevalence of premature ASCVD, often defined as an ASCVD event occurring in men <55 years old and in women <65 years old, is increasing, and several studies support Lp(a) playing a significant role in the development of premature ASCVD. Despite recognition of Lp(a) as a genetic risk factor for ASCVD and recommendations for universal Lp(a) testing in multiple clinical guidelines, Lp(a) testing occurs infrequently in clinical practice. In this review, we examine the role of elevated Lp(a) in premature cardiovascular events, including premature myocardial infarction, stroke, and peripheral arterial disease. We discuss the potential benefit of universal Lp(a) testing in the context of primary prevention to enable personalised risk assessment and to identify high-risk patients who may benefit from early and targeted management. Further, we evaluate ongoing systems initiatives aiming to a) address barriers to the adoption of universal Lp(a) screening, and b) enable the initiation of CV risk management for the prevention of premature ASCVD. Finally, we highlight the importance Lp(a) testing may play in secondary prevention, focusing on cascade screening for elevated Lp(a) in relatives of affected individuals.

Climate change is intensifying the occurrence and intensity of hot weather that is associated with cardiovascular health risks and disengagement from physical activity. To help promote safe and continued engagement with physical activity despite a warming climate, we aimed to map existing recommendations for physical activity in hot weather that are specific to adults living with cardiovascular disease. We conducted a scoping review of MEDLINE, Web of Science, and SPORTDiscus, supplemented by cross-referencing and grey literature. Sources were included if they reported temperature thresholds or behavioural recommendations for physical activity in hot weather for adults (≥18 years). Data on source characteristics, target populations, temperature thresholds, and specific guidelines or suggested behaviours were extracted. Of 32 included sources, 24 reported at least one temperature above which physical activity should be limited. The most frequently covered themes were preventive recommendations (100%; 20 different recommendations), symptoms (81%; most cited being heat stroke and exhaustion), heat-related risk factors (56%), and treatments (53%). No source mentioned adverse cardiac events as possible health risks. Of the 20 sources highlighting populations at greater risk when exercising in the heat, 12 mentioned individuals with cardiovascular disease. However, no specific recommendations for this population were retrieved. Few sources acknowledge that adults living with cardiovascular disease are at greater health risks during physical activity in hot weather, and specific recommendations for this population are absent. These gaps highlight a need to develop recommendations tailored to adults living with cardiovascular disease.

Just as my seniors nurtured me, I have continued to nurture those who come after me. Through my role as an intermediary, many of my mentors' knowledge and experience have been passed down to numerous mentees. I cannot be grateful enough to my workplaces, which brought together so many highly motivated mentees and allowed me to meet them. "One only half dies who leaves an image of themself in their mentees"; many poets have conveyed similar messages. Cultivating the next generation of leaders in stroke medicine, a field that continues to make remarkable strides, is undoubtedly one of our most important missions.

Neurological complications are common in critical illness and are increasingly recognized as major contributors to morbidity, mortality, and long-term disability among patients admitted to an intensive care unit (ICU). Even in the absence of a primary neurological diagnosis, systemic critical illness can exert substantial physiological stress on the brain through hypoxemia, hemodynamic instability, inflammation, and metabolic derangements. Delirium, stroke, seizures, and neuromuscular disorders represent frequent neurological manifestations of multi-organ dysfunction and are associated with prolonged ICU stay, persistent cognitive deficits, and impaired neuropsychological and functional recovery. Recognition of modifiable risk factors has led to targeted strategies such as standardized delirium screening, judicious sedative use, and mitigation of environmental contributors including immobility, sleep disruption, and sensory impairment. However, variability in definitions, surveillance practices, and outcome measures limits precise estimation of the true burden and may contribute to ongoing underrecognition. In addition, an incomplete understanding of the mechanisms of neurological injury and recovery involving the brain, peripheral nerves, and skeletal muscle further hinders progress in this field. This review synthesizes current evidence on the epidemiology, phenotypes, and risk factors of neurological complications in critical illness, highlighting key knowledge gaps and the current limitations in causal inference and therapeutic evidence, and identifying priorities for future research.

Clonal hematopoiesis of indeterminate potential (CHIP) describes the proliferation of blood cell clones that carry driver mutations, such as DNA methyltransferase 3 alpha (DNMT3A), ten-eleven translocation 2 (TET2), additional sex combs like 1 (ASXL1), and Janus kinase 2 (JAK2), without leading to any obvious malignancy. Its occurrence rate is age-related and associated with cardiovascular and immune aging. In prospective cohort studies, CHIP substantially elevated the risk of myocardial infarction, stroke, and heart failure, with a relative risk increase ranging from 1.4 to 2.0-fold. Furthermore, a larger clone size, as indicated by the variant allele fraction (VAF), is correlated with a heightened risk. Both experimental and human evidence support the association of proinflammatory myeloid reprogramming with the loss of ten-eleven translocation 2 (TET2)/DNA methyltransferase 3 alpha (DNMT3A), NOD-like receptor family pyrin domain-containing 3 (NLRP3), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) signaling, as well as endothelial dysfunction and atherothrombosis. However, the effect sizes vary depending on the specific gene, tissue, and context, and residual confounding remains a concern. This paper reviews the epidemiology and pathophysiology of the disease, its clinical utility, including indications for testing, interpretation of variants, VAF levels, and the added value to conventional risk models and treatment methods, such as cytokine- and mutation-based approaches. Priority areas include genotype- and VAF-stratified trials that focus on outcomes relevant to aging and are rigorously monitored for their safety. Overall, CHIP is associated with somatic mosaicism, inflammaging, and aging of the cardiovascular and immune systems, although significant questions regarding causation and actionability remain unresolved.

To assess the effect of a population-wide implementation of intermittently scanned continuous glucose monitoring (isCGM) on hospitalization rates and trends, length of stay, and inpatient health care costs among adults with insulin-treated type 2 diabetes (T2D). This population-based, longitudinal, quasi-experimental cohort study included adults with T2D taking multiple daily insulin injections who initiated publicly funded isCGM between April 2022 and December 2023. Hospitalizations for acute diabetes-related complications (diabetic ketoacidosis, hyperglycemic hyperosmolar state, simple hyperglycemia, and hypoglycemia) and cardiovascular complications (myocardial infarction, stroke, and major lower-extremity amputation) were identified using ICD-10 codes. Incidence rates and rate ratios (RRs) were estimated using Poisson models. Interrupted time series analyses were used to estimate counterfactual trends. Among 15,413 participants, the mean follow-up was 22.5 ± 4.6 months before and 19.1 ± 4.4 months after isCGM initiation. Mean HbA1c decreased from 8.09 to 7.65% (mean difference -0.44 [95% CI -0.47 to -0.42]). Diabetes-related hospitalization rates decreased from 74.6 to 27.5 per 10,000 person-years (RR 0.37 [95% CI 0.28-0.49]). Cardiovascular hospitalization rates remained stable (228.8 vs. 215.8 per 10,000 person-years; RR 0.94 [0.84-1.06]). Interrupted time series analyses showed a change in cardiovascular admission rates after isCGM initiation relative to the preintervention trend. Median length of stay decreased from 4 (interquartile range 5) to 3 (4) days. Total inpatient costs decreased by $3,806,776.90 (-$955,186.70 per 10,000 person-years). In this real-world study, implementation of isCGM among insulin-treated adults with T2D was associated with substantial reductions in acute diabetes-related hospitalizations, shorter hospital stays, lower health care costs, and changes in cardiovascular hospitalization trends.

COVID-19 vaccines were previously shown to reduce risk of major adverse cardiovascular events (MACEs). Whether the 2024-2025 COVID-19 vaccine continues to reduce COVID-19-associated MACEs in the context of evolving variants and widespread population immunity is unknown. To determine whether the 2024-2025 COVID-19 vaccine is associated with reduced risk of COVID-19-associated MACE. This cohort study was a target-trial emulation using US Department of Veterans Affairs (VA) electronic health records. Participants were veterans with vaccination encounters between September 3, 2024, and December 31, 2024. Same-day coadministration of the 2024-2025 COVID-19 and influenza vaccines vs influenza vaccine alone. Composite end point of COVID-19-associated MACE, defined as COVID-19-associated cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Secondary outcomes included all-cause MACE, hospitalization, and death. Vaccine effectiveness (VE), calculated as 1 minus the risk ratio, and risk difference were estimated at 8 months using inverse probability weighting. Among 1 039 659 participants who received influenza vaccine (mean [SD] age, 70.1 [12.4] years; 954 341 [91.8%] men), 349 085 received COVID-19 vaccine and 690 574 did not. At 8 months, the COVID-19 vaccine was associated with lower risk of COVID-19-associated MACE (VE, 37.7% [95% CI, 18.2%-54.9%]; risk difference per 10 000 persons, 2.0 [95% CI, 0.9-3.7]). VE for COVID-19-associated MACE was statistically significant only in individuals older than 75 years (VE, 50.7% [95% CI, 31.8%-65.6%]), a group that also experienced the largest absolute risk reduction (5.5 fewer events per 10 000 individuals). No statistically significant vaccine effectiveness was observed among those younger than 65 years or aged 65 to 75 years. While VE for COVID-19-associated MACE on the relative scale was statistically significant across subgroups of participants with and without comorbid health conditions, the absolute benefit was consistently and substantially greater for individuals with the comorbid health condition. Secondary analyses of all-cause MACE, all-cause hospitalization, and all-cause death suggested substantially larger absolute risk reductions (risk difference for all-cause MACE, 23.7 [95% CI, 14.1 to 34.7]). In this cohort study, receipt of the 2024-2025 COVID-19 vaccine was associated with reduced risk of COVID-19-associated MACE, with reductions most prominent in those 75 years or older and those with comorbidities. While the reduction in COVID-19-associated MACE was modest, the substantially larger reduction in all-cause MACE suggests that the vaccine's protective association extends to the hidden burden of undetected SARS-CoV-2 and its sequelae.

This study aimed to evaluate whether achieving a minimum of 15% weight loss early after type 2 diabetes diagnosis was associated with subsequent lower risks of developing macrovascular and microvascular complications. Using U.K. primary care data from Clinical Practice Research Datalink Aurum linked to hospital and mortality data, we conducted a cohort study (2000-2024) of adults with obesity and type 2 diabetes. Individuals with ≥15% weight loss within 2 years of type 2 diabetes diagnosis were propensity score matched 1:4 to control subjects maintaining a stable weight (<2% weight change). Cumulative incidence rates were determined, and time to first macrovascular (myocardial infarction, stroke, angina, peripheral arterial disease) and microvascular (chronic kidney disease, retinopathy, neuropathy) events was analyzed using Cox proportional hazards regression. The matched cohort included 14,496 individuals with ≥15% weight loss and 57,984 control subjects. Compared with control subjects, the weight loss group had significantly lower risk of first macrovascular (hazard ratio 0.86, 95% CI 0.81-0.91) and microvascular (hazard ratio 0.90, 95% CI 0.86-0.94) events. Individually, significantly lower risks were observed for myocardial infarction, angina, chronic kidney disease, and retinopathy. The weight loss group also demonstrated better glycemic and blood pressure levels, despite fewer medications. Achieving ≥15% weight loss early in type 2 diabetes was associated with clinically meaningful lower risks for macro- and microvascular complications and better glycemic control compared with stable weight. These real-world findings support prioritizing early, substantial weight reduction as a core therapeutic strategy to improve glycemic control and prevent end-organ damage.

Perioperative bleeding is common. Evidence for tranexamic acid (TXA) in urology remains limited and conflicting, and major urologic guidelines provide no recommendations. In an a priori planned analysis, we evaluated TXA among patients undergoing urologic surgery in POISE-3. POISE-3 was an international randomized trial of patients undergoing surgery with bleeding and cardiovascular risk factors. Participants received TXA (1 g intravenous bolus at surgery start and end) or placebo. The primary efficacy outcome was a 30-day bleeding composite (life-threatening/major/critical organ), and the primary safety outcome was a 30-day thrombosis composite (myocardial injury after noncardiac surgery [MINS], nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism [VTE]). Among 1124 urologic participants (556 TXA and 568 placebo), 489 had laparoscopic/robotic, 360 open, 244 transurethral, and 31 percutaneous surgery. The composite bleeding outcome occurred in 45 (8.1%) with TXA and in 62 (10.9%) with placebo (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.50-1.07). Major bleeding occurred in 34 (6.1%) with TXA and in 54 (9.5%) with placebo (HR = 0.63, 95% CI = 0.41-0.97). The composite safety outcome occurred in 67 (12.1%) with TXA and in 62 (10.9%) with placebo (HR = 1.12, 95% CI = 0.79-1.58; MINS: 62 vs 58; strokes: 2 vs 2; VTEs: 3 vs 3). We identified no interactions by surgical approach, cancer status, or recent antithrombotic usage. Patient-important thrombotic events were few, limiting precision for stroke and VTE estimates. TXA reduced major bleeding and supports perioperative use in urologic surgery, especially when the bleeding risk is high.

Gastrointestinal bleeding (GIB) is common in patients with cardiovascular (CV) disease, but a complete understanding of subsequent outcomes is unknown. We assessed outcomes after GIB in patients with CV disease. INTERBLEED is an international multicenter prospective study comparing adults with CV disease (coronary or peripheral arterial disease, heart failure, atrial fibrillation, cerebrovascular disease, or venous thromboembolic disease) with GIB to those without. Outcomes included major adverse cardiovascular events (MACE; myocardial infarction, stroke, or CV-related death), all-cause death, and recurrent GIB at 12 months. Multivariable regression modelling yielded odds ratios (ORs) with 95% confidence intervals (CIs), and reverse Kaplan-Meier curves were created. A total of 3814 patients were enrolled: 1612 patients with GIB and 2202 without. On multivariable analyses, patients with CV disease experiencing GIB were more likely to die within 12 months (OR, 2.29; 95% CI, 1.24-4.19). GIB was associated with recurrent GIB (OR, 4.28; 95% CI, 2.80-6.53) but not MACE. However, resumption of antithrombotic therapy between 4 and 7 days (OR, 0.37; 95% CI, 0.17-0.83) or 8 and 30 days (OR, 0.37; 95% CI, 0.17-0.81) after GIB were associated with lower odds of MACE within 12 months compared with discontinuation or lack of resumption within 60 days. Any antithrombotic use after enrollment was associated with lower all-cause death (OR, 0.45; 95% CI, 0.28-0.71). Neither antithrombotic use nor early resumption was associated with higher odds of recurrent GIB. GIB in patients with CV disease is independently associated with subsequent morbidity and mortality. Patterns in antithrombotic resumption were associated with outcomes. Further research into optimal antithrombotic management after GIB is essential.

Aging is a fundamental driver of cardiovascular and cerebrovascular comorbidities, yet the mechanisms linking aging to concurrent heart and brain diseases remain incompletely understood. The neurovascular interface (NVI) refers to the structural and functional interface through which neural, vascular, and extracellular-matrix signals interact. In the CNS, this concept substantially overlaps with the classical neurovascular unit, whereas in the heart it refers to an emerging heart tissue-specific interface involving coronary microvessels, vascular cells, autonomic and sensory nerve fibers, cardiomyocytes, and extracellular-matrix components. Although direct experimental evidence that aging affects cardiovascular and cerebrovascular comorbidity through NVI is still accumulating, current evidence suggests that aging may disrupt shared neurovascular features. These changes are associated with hypertension, cerebral small vessel disease, heart failure, and related disorders. Moreover, genetic variants may act as susceptibility modifiers of neurovascular aging - from NOS3 regulating vascular tone to ADRB1 and COMT affecting autonomic balance. These variants are associated with cardiovascular and cerebrovascular disease risk and may represent upstream molecular determinants through which genetic susceptibility and aging-related stressors converge to alter NVI integrity and promote cardiovascular-cerebrovascular comorbidity. This review synthesizes current evidence on the structural and functional basis of the NVI, discusses how aging may disrupt its integrity, and evaluates its potential role as an integrative framework linking aging-related vascular, neural, inflammatory, and extracellular-matrix alterations to cardiovascular-cerebrovascular comorbidity. We also outline potential integrated strategies that may preserve interface function, including lifestyle interventions, senolytics, and gene-guided precision medicine.

Motor imagery (MI) is a popular noninvasive brain computer interface (BCI) paradigm, yet its decoding accuracy remains hindered by the inherent nonstationarity and low signal-to-noise ratio of electroencephalogram (EEG) signals. Current decoding frameworks often fail to fully exploit the intricate spatial-temporal dependencies, leading to suboptimal feature representation and the omission of latent discriminative cues. To address these challenges, we introduce a deep neural network-powered multifaceted strategy (DPMS-Net) model, a novel approach that employs dynamic convolution to unearth effective discriminative cues across multiple dimensions, including the temporal, spatial, and frequency domains. This model synergizes channel and temporal attention mechanisms to adeptly capture the salient features of EEG signals across diverse spatial-temporal dimensions, thereby mitigating the risk of omitting critical information. Furthermore, we introduce a spectral-domain analysis component that unearths subtle oscillatory signatures hidden within the EEG spectrum, providing enriched evidence for classification. We evaluated the performance of DPMS-Net on two publicly available datasets and a self-collected dataset from stroke patients. On the BCI Competition IV 2a and BCI Competition IV 2b datasets, DPMS-Net achieved subject-dependent classification accuracies of 83.93% and 88.38%, respectively, alongside subject-independent classification accuracies of 65.88% and 76.01%. In the stroke patient dataset, DPMS-Net attained a subject-dependent classification accuracy of 67.67% and a subject-independent classification accuracy of 57.58%. Experimental results indicate that DPMS-Net possesses efficient decoding capabilities and robust stability, reflecting its potential for deployment in neurorehabilitation BCI systems.

In the relationship between periodontitis and coronary heart disease (CHD), the mechanistic role of subclinical atherosclerosis remains incompletely understood. This study examines whether subclinical atherosclerosis mediates the periodontitis-incident CHD association; how a specific periodontitis phenotype modifies subclinical coronary atherosclerosis; and whether periodontitis is associated with epicardial adipose tissue (EAT) attenuation as a marker of inflammation. Data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) were linked to national registers for dental data and CHD incidence. Coronary atherosclerosis was quantified using coronary artery calcium scores (CACS) and segment involvement scores (SIS). EAT characteristics were derived from non-contrast cardiac computed tomography. Associations between severe periodontitis and incident CHD events were examined using multivariable regression models, and mediation by CACS and SIS was explored. Among 29 056 SCAPIS participants, severe periodontitis was present in 6% (n = 1809) and was associated with severe CACS [≥301, odds ratio (OR) 1.69, 95% confidence interval (CI) 1.39-2.06] and severe SIS (>4 segments, OR 1.40, 95% CI 1.17-1.67), with the strongest associations among individuals without concomitant dental caries. Moreover, periodontitis was associated with lower EAT attenuation (β = -0.27 HU, 95% CI -0.48 to -0.05) and a 42% higher risk of incident CHD events (hazard ratio 1.42, 95% CI 1.03-1.97), which was partially mediated by coronary atherosclerosis. Severe periodontitis is positively associated with subclinical coronary atherosclerosis, EAT alterations reflecting inflammatory activity, and CHD event incidence. These results position periodontitis as a marker of increased coronary risk, warranting targeted cardiovascular risk assessment.

Coronary artery stenosis is a leading cause of cardiovascular disease, diagnosed by analyzing the coronary arteries from multiple angiography views. Although numerous deep-learning models have been proposed for stenosis detection from a single angiography view, their performance heavily relies on expensive view-level annotations, which are often not readily available in hospital systems. Moreover, these models fail to capture the temporal dynamics and dependencies among multiple views, which are crucial for clinical diagnosis. To address this, we propose SegmentMIL, a transformer-based multi-view multiple-instance learning framework for patient-level stenosis classification. Trained on a real-world clinical dataset, using patient-level supervision and without any view-level annotations, SegmentMIL jointly predicts the presence of stenosis and localizes the affected anatomical region, distinguishing between the right and left coronary arteries and their respective segments. SegmentMIL obtains high performance on internal and external evaluations and outperforms both view-level models and classical MIL baselines, underscoring its potential as a clinically viable and scalable solution for coronary stenosis diagnosis. Our code is available at https://github.com/NikolaCenic/mil-stenosis.

This prespecified analysis of Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke (VESALIUS-CV) evaluated the efficacy of the PCSK9 inhibitor evolocumab for preventing first cardiovascular events in patients with high-risk diabetes. VESALIUS-CV randomized patients with high-risk diabetes (microvascular disease, insulin use, or duration ≥10 years) or qualifying atherosclerosis, but no prior myocardial infarction (MI) or stroke, and LDL cholesterol (LDL-C) ≥90 mg/dL to evolocumab 140 mg or matching placebo every 2 weeks. The dual primary end points were a composite of coronary heart disease death, MI or ischemic stroke (three-point major adverse cardiovascular event [3P-MACE]) and 3P-MACE plus ischemia-driven arterial revascularization (four-point [4P]-MACE). Of the 6,002 patients with high-risk diabetes, 67% were on a high-intensity statin and 24% were on a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) at baseline. The median LDL-C at 48 weeks was 47 mg/dL and 109 mg/dL in the evolocumab and placebo arms, respectively (P < 0.0001). After a median follow-up of 4.6 years, evolocumab decreased the relative rates of 3P-MACE and 4P-MACE by 29% (hazard ratio [HR] 0.71; 95% CI 0.59, 0.86; P = 0.0004) and 21% (HR 0.79; 95% CI 0.69, 0.91; P = 0.0013), respectively. These findings were consistent regardless of the presence or absence of qualifying atherosclerosis, baseline LDL-C, statin intensity, and SGLT2i or GLP-1RA use (Pint > 0.05 for each). The porportion of patients with all-cause death was 8.8% vs. 11.0% in the evolocumab versus placebo arms (HR 0.79; 95% CI 0.67, 0.93). Evolocumab reduced the rate of cardiovascular events in patients with high-risk diabetes, regardless of the presence or absence of qualifying atherosclerosis and background use of other cardioprotective agents.

Coronary artery disease often develops silently before myocardial infarction, and current risk-based prevention pathways miss some individuals with clinically important disease, particularly those without standard modifiable cardiovascular risk factors. High-sensitivity cardiac troponin I is a blood biomarker of low-level myocardial injury, but its relationship to silent coronary atherosclerosis remains incompletely understood. Here we show, in 1,613 adults undergoing coronary computed tomography (CT) imaging, that low-level high-sensitivity cardiac troponin I is associated with clinically actionable coronary disease, defined by coronary calcium score ≥100, and with quantitative CT markers of plaque burden. A threshold of 2.3 ng l-1 enriched for actionable disease, especially in individuals without standard risk factors. Normalizing troponin for myocardial mass, age and renal function improved prediction and provided mechanistic insight into baseline troponin elevation in chronic coronary syndromes. A two-stage strategy using troponin before CT imaging increased diagnostic yield and reduced the number of scans required. Prospective validation is warranted before clinical implementation.

Cardiovascular diseases (CVDs) involve complex, interrelated pathologies such as oxidative stress, inflammation, endothelial dysfunction, platelet aggregation, and dyslipidemia, for which single-target drugs remain constrained. As a multicomponent herbal medicine, Ginkgo biloba L. (G. biloba) contains diverse bioactive constituents, primarily flavonoids (e.g., quercetin, kaempferol, isorhamnetin, ginkgetin, and isoginkgetin) and ginkgolides (e.g., ginkgolide A, B, C, and J), which are proposed to exert synergistic effects against the multifaceted pathology of CVDs. This review systematically summarizes the pharmacokinetic characteristics and pharmacodynamic mechanisms of the major bioactive components in G. biloba, highlighting distinct mechanistic axes of Nrf2-mediated antioxidant defense, platelet-activating factor (PAF) receptor antagonism, and inflammasome inhibition. These preclinical findings collectively suggest the therapeutic potential of G. biloba extracts (GbE) for atherosclerosis, stable and unstable angina, myocardial infarction, heart failure, obesity-related and diabetic cardiomyopathy, as well as diabetic nephropathy, retinopathy, and non-alcoholic fatty liver disease. However, the clinical evidence remains limited and inconsistent, and G. biloba has not been established as a standard therapy for CVDs. This review evaluates the current clinical evidence and combination therapeutic strategies, aiming to provide a reference for the design of future clinical trials.

Atherosclerosis is the primary underlying cause of coronary artery disease. LMOD1 is a coronary artery disease risk gene whose role in coronary artery pathophysiology is unknown. Whole-body loss of Lmod1 causes a lethal neonatal visceral myopathy in mice, necessitating unique approaches for the study of vascular smooth muscle cell (VSMC) phenotypes. Control mice (Lmod1WT carrying a Cre recombinase allele) and VSMC-restricted Lmod1 knockout mice (Lmod1SMKO) were subjected to various atherogenic regimens. Atherosclerosis and LMOD1 (leiomodin 1) expression in mouse and human coronary arteries were assessed by histopathology and confocal immunofluorescence microscopy. Coronary arteries from Lmod1WT and Lmod1SMKO mice were analyzed with assorted stains and antibodies, immunogold lineage tracing, and spatial metabolomics. Aortic smooth muscle cells from Lmod1WT and Lmod1SMKO mice were subjected to lipid loading with or without lentivirus carrying wild-type or actin nucleation-deficient Lmod1 (Lmod1ND. Mice harboring an intronic deletion of Lmod1 or Lmod1ND were engineered using clustered regularly interspaced short palindromic repeats. A lethal neonatal visceral myopathy occurred in Lmod1SMKO mice using Myh11-CreERT2, prohibiting further investigation. In contrast, Lmod1SMKO mice generated with Itga8-CreERT2 survived and were therefore used in all subsequent studies. Under atherogenic conditions, Lmod1SMKO mice displayed little vascular disease in several organs but developed diffuse, occlusive coronary atherosclerosis with fibrous caps. No such disease was observed in Lmod1WT mice. Time-course studies documented lipid insudation and VSMC migration into the intima of coronary arteries of Lmod1SMKO mice as early as 8 days after the regimen. Immunogold lineage tracing revealed that 46% of coronary plaque cells were of VSMC origin. Spatial metabolomics uncovered multiple lipid species within coronary atheromata of Lmod1SMKO mice. In vitro studies demonstrated elevated lipid accumulation in Lmod1SMKO VSMCs, which was rescued by viral-mediated Lmod1WT or Lmod1ND expression. An intronic deletion of Lmod1, comprising a conserved orthologous sequence where the single nucleotide variant associated with coronary artery disease exists, showed attenuated LMOD1 expression. Heterozygous Lmod1SMKO mice, with a comparable reduction in LMOD1, displayed no coronary artery disease. Similarly, VSMC-restricted expression of Lmod1ND resulted in negligible coronary atherosclerosis. Under atherogenic conditions, Lmod1SMKO mice present with rapid-onset coronary atherosclerosis. LMOD1 safeguards coronary homeostasis, apparently in an actin nucleation-independent manner.

Coronary microvascular dysfunction (CMD) is a key contributor to myocardial ischemia and cardiovascular diseases. It is characterized by abnormalities of the coronary microvasculature, leading to impaired myocardial perfusion. Although CMD has a high prevalence in patients with nonobstructive coronary artery disease and is associated with adverse cardiovascular events, its pathogenesis has not yet been fully elucidated. Current diagnostic approaches combine noninvasive and invasive methods, but there remains a lack of effective targeted therapies. This review discusses the epidemiology, pathophysiology, diagnostic strategies, and treatment options for CMD, with a particular focus on the protective role of the neuregulin-1 (NRG-1)/v-erb-b2 erythroblastic leukemia viral oncogene homolog B (ErbB) signaling pathway. We initially outline how the NRG-1/ErbB pathway affects endothelial function, ventricular remodeling, oxidative stress, and myocardial angiogenesis, highlighting its potential as a therapeutic target. In addition, we explore emerging evidence that traditional Chinese medicine (TCM) interventions may regulate the NRG-1/ErbB axis to improve microvascular function and cardiac outcomes. Overall, this review deepens our understanding of the mechanisms underlying CMD and provides new avenues for integrated precision therapies, including TCM, with the aim of improving clinical management and prognosis in patients with CMD.

Targeting plaque macrophages with siRNA is a promising therapeutic strategy for atherosclerosis, but effective in vivo delivery remains a major challenge. Here, we introduce a therapeutic platform based on a novel ionizable lipid derived from a Calixsalan macrocycle. This lipid enables the formulation of macrophage-targeted lipid nanoparticles (LNPs) for potent siRNA delivery. We validated this platform by targeting Trem2, a receptor implicated in atherogenesis. Our study also reveals that circulating soluble Trem2 (sTrem2) is an independent clinical predictor of coronary artery disease. Mechanistically, we show that macrophage promotes vascular smooth muscle cells proliferation and migration via secretion of PDGF-BB in a KLF4-dependent manner. In an atherosclerotic mouse model, intravenous administration of our targeted LNPs successfully silenced macrophage Trem2, suppressed pro-atherogenic pathways, and significantly attenuated plaque burden. This work establishes Trem2 silencing as a viable therapeutic strategy and presents a new, rationally designed macrocyclic lipid platform for targeted nucleic acid delivery.

Accurate correspondence matching in coronary angiography images is crucial for reconstructing 3D coronary artery structures, which is essential for precise diagnosis and treatment planning of coronary artery disease (CAD). Traditional matching methods for natural images often fail to generalize to X-ray images due to inherent differences such as lack of texture, lower contrast, and overlapping structures, compounded by insufficient training data. To address these challenges, we propose a novel pipeline that generates realistic paired coronary angiography images using a diffusion model conditioned on 2D projections of 3D reconstructed meshes from Coronary Computed Tomography Angiography (CCTA), providing high-quality synthetic data for training. Additionally, we employ large-scale image foundation models to guide feature aggregation, enhancing correspondence matching accuracy by focusing on semantically relevant regions and keypoints. Our approach demonstrates superior matching performance on synthetic datasets and effectively generalizes to real-world datasets, offering a practical solution for this task. Furthermore, our work investigates the efficacy of different foundation models in correspondence matching, providing novel insights into leveraging advanced image foundation models for medical imaging applications.

Coronary artery disease (CAD) is a major global cause of morbidity and mortality, and population ageing is reshaping its clinical phenotype, disease trajectory, and therapeutic complexity. Chronological age alone cannot explain the heterogeneity of CAD outcomes in older individuals, highlighting the need to integrate biological ageing into cardiovascular disease research and management. Cellular senescence, characterised by stable cell-cycle arrest, metabolic reprogramming, and acquisition of a senescence-associated secretory phenotype (SASP), provides a mechanistic bridge between ageing and CAD. Senescent endothelial cells, vascular smooth muscle cells, immune cells, fibroblasts, and cardiomyocytes contribute to endothelial dysfunction, chronic inflammation, plaque instability, impaired myocardial stress tolerance, and adverse remodelling. Conversely, CAD-related stressors, including atherosclerotic injury, disturbed flow, myocardial ischaemia and ischaemia-reperfusion injury, can induce local senescence programmes and propagate inflammatory or extracellular-vesicle-mediated signalling beyond the initial injury site. However, whether CAD directly accelerates whole-organism biological ageing remains less established. In this review, we examine cellular senescence as a bidirectional but context-dependent interface between ageing and CAD. We summarise cell-type-specific senescence programmes in vascular and myocardial compartments, compare the strength of evidence for major molecular pathways, and discuss senescence-targeted therapies. We emphasise that senolytic and senomorphic strategies remain largely preclinical in cardiovascular disease and that their translation will require careful attention to disease stage, treatment timing, cell specificity and patient stratification. This framework may help refine ageing-informed approaches to CAD prevention, diagnosis and therapy.

Atherosclerosis is a chronic disease of the arterial wall driven by complex interactions between vascular, immune, and stromal cells. For decades, our understanding of plaque biology relied on bulk assays that masked the underlying cellular heterogeneity. The development of single-cell and spatial genomics now enables the dissection of these multicellular systems with unprecedented granularity. These technologies have revealed the dynamic nature of vascular smooth muscle and endothelial cells, providing a framework to link genetic risk to specific transcriptional programs and cellular phenotypes. Single-cell RNA sequencing and single-cell epigenome sequencing (single-cell assay for transposase-accessible chromatin with sequencing) have redefined vascular cell biology, revealing intermediate phenotypic states and transcriptional regulators of disease progression. Recent advances in spatially resolved transcriptomics have begun to link these molecular profiles to their anatomic context within the plaque microenvironment, informing on cell-cell signaling pathways. Integrating genetic risk with single-cell data is illuminating how noncoding variants converge on specific vascular cell types and gene-regulatory networks. In this review, we summarize key technological advances in single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics. Furthermore, we highlight recent biological discoveries and discuss emerging approaches, particularly clustered regularly interspaced short palindromic repeats perturbation-based single-cell methods, which are poised to bridge causal genetics and functional vascular biology in atherosclerosis.

Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%-35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%-7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%-28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

To date, limited evidence has assessed the relationships of long-term exposures to PM2.5 constituents and greenness with AF incidence. This study aimed to examine the association between these exposures and incident AF, and further assess the joint effects of genetic susceptibility. PM2.5 constituents and greenness were estimated around the residence of 411 364 UK adults. Time-varying Cox models were used to examine these associations. The polygenic risk score (PRS) assessed genetic susceptibility to AF and explore the joint effect between genes and exposures. The hazard ratios (HRs) [95% confidence intervals (CIs)] of AF for per interquartile range increase in elemental carbon (EC), organic matter (OM), ammonium (NH4+), nitrate (NO3-), sulfate (SO42-), NDVI300m, NDVI500m, NDVI1000m, and NDVI1500m were 1.05 (1.03, 1.07), 1.06 (1.04, 1.08), 1.07 (1.05, 1.10), 1.05 (1.03, 1.07), 1.06 (1.04, 1.09), 0.97 (0.95, 0.99), 0.96 (0.94, 0.98), 0.95 (0.94, 0.97), and 0.95 (0.93, 0.97), respectively. Among PM2.5 constituents, SO42- (43.8%) was the main contributor to AF in the mixture model. Mediation analyses found that negative association between greenness and AF risk was partially mediated by mitigating exposure to PM2.5 constituents. Moreover, there were additive interactions between EC, OM, NH4+, NO3-, SO42-, and NDVI1500m and PRS. Joint effect revealed that participants with a high PRS and high PM2.5 constituents or low greenness had the highest risk of incident AF, with HRs ranging from 3.14 (2.93, 3.37) to 3.26 (3.04, 3.51). Long-term exposure to PM2.5 constituents was positively associated with the incidence of AF, whereas greenness was inversely associated with it.

The life-course joint effects of specific fine particulate matter (PM2.5) components and genetic susceptibility on the progression from atrial fibrillation (AF) to heart failure (HF) remain uncertain. We aimed to investigate these associations for both incident AF and its subsequent progression to HF. In this prospective study of 464 541 UK Biobank participants, we estimated life-course residential exposures to PM2.5 and its key components-including elemental carbon (EC), organic carbon (OC), ammonium (NH₄⁺), nitrate (NO₃⁻), and sulfate (SO₄²⁻)-using a validated spatiotemporal model, and constructed a polygenic risk score for AF and HF. We used Cox models to assess non-linear associations and gene-environment (G × E) interactions on both additive and multiplicative scales and quantile-based g-computation to evaluate mixture effects. During follow-up for a median 12.3-years (IQR: 11.70, 13.23), 27 655 participants (mean age 56.5, SD 8.1; 54.8 female) developed AF, with 12.3% progressing to HF. Life-course exposure to components such as EC was associated with increased risks for both incident AF (HR per 1-SD increase: 1.03; 95% CI: 1.02, 1.04) and progression to HF (HR: 1.04; 95% CI: 1.01, 1.08), often with non-linear threshold effects. We also identified a stage-dependent G × E interaction, shifting from a significant multiplicative interaction for incident AF to an additive interaction for the progression to HF, with a relative excess risk due to interaction of up to 0.46. Our findings highlight that minimizing cumulative pollution exposure is crucial for preventing incident AF and subsequent HF, especially in genetically susceptible individuals, guiding precision prevention strategies.

Gout is an emerging cardiovascular risk factor. We aimed to assess whether gout is associated with an increased risk of stroke in patients with atrial fibrillation (AF). The nationwide registry-linkage FinACAF study (Finnish Anticoagulation in Atrial Fibrillation) included all patients with AF in Finland between 2007 and 2018 from all levels of care. Based on diagnosis codes and pharmacy claims data, the association of gout and urate-lowering therapy with the incidence of ischemic stroke was assessed. We identified 229 565 patients with new-onset AF (50.0% female; mean age, 72.7 years; mean follow-up, 4.0 years), of whom 6 910 (3.0%) had a history of gout. A total of 16 296 (7.1%) patients experienced an ischemic stroke. Gout was associated with higher stroke rates in both unadjusted and adjusted analyses (incidence rate ratio, 1.35 [95% CI, 1.22-1.49] and incidence rate ratio, 1.12 [95% CI, 1.02-1.24], respectively). Analyses restricted to follow-up without anticoagulation yielded consistent results with slightly higher point estimates (incidence rate ratio, 1.88 [95% CI, 1.63-2.17] unadjusted; incidence rate ratio 1.26 [95% CI, 1.09-1.46] adjusted). In patients with gout and AF, time-dependent exposure to urate-lowering therapy was associated with a 30% lower stroke rate. Nonanticoagulated crude stroke rates were 1.5, 1.0, and 4.8 per 100 patient-years for gout patients with CHA2DS2-VA scores of 0, 1, and ≥2, respectively. Gout is an important risk factor for ischemic stroke in patients with AF, and considering gout could improve stroke risk stratification. Urate-lowering therapy was associated with reduced stroke risk, suggesting that gout is a modifiable risk factor in patients with AF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04645537.

Benzo[a]pyrene (BaP), an air pollution-related polycyclic aromatic hydrocarbon, may intersect with molecular pathways relevant to atrial fibrillation (AF), but this relationship remains unclear. To examine whether predicted BaP targets overlap with molecular and cellular remodeling features in human AF-related atrial datasets. Five AF microarray datasets and one single-cell RNA sequencing (scRNA-seq) dataset were analyzed. Differential expression and weighted gene co-expression network analysis (WGCNA) defined AF-associated key genes directly observed from human AF transcriptomic datasets. BaP predicted targets were computationally obtained using ChEMBL, Similarity Ensemble Approach (SEA), and PharmMapper; their overlap with AF-associated key genes defined inferred BaP-AF candidate targets for Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Machine learning (ML) with SHapley Additive exPlanations (SHAP) prioritized hub genes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), docking, and single-cell analyses assessed immune patterns, structural plausibility, and cellular context. Eighteen inferred BaP-AF candidate targets were identified by overlapping AF-associated key genes with BaP predicted targets, and these candidates were enriched in oxidative stress/inflammation and transforming growth factor-beta (TGF-β)-related remodeling pathways. Elastic Net yielded a final hub-gene signature (PPP3CA, ERBB4, PSAP, LAMP1, PPARA, HSP90AB1, TGFBR1, KCNA5). AF exhibited increased neutrophils and reduced M2 macrophages/T follicular helper (Tfh) cells. Single-cell analyses of AF-related human atrial tissue localized the hub genes to major cell populations and revealed AF-associated immune expansion and fibroblast-centered TGF-β signaling, dominated by TGFB1-(TGFBR1 + TGFBR2), rather than directly measuring BaP-induced single-cell remodeling.scTenifoldKnk-based TGFBR1 virtual knockout highlighted perturbations (ABCA8, CD9, IFI44L, BGN). These findings nominate a testable hypothesis that BaP-related target perturbations may intersect with TGFBR1-associated fibroblast remodeling in AF. Future studies should evaluate this hypothesis in exposure-relevant atrial cell models through controlled BaP exposure and TGFBR1 gain- or loss-of-function experiments, followed by in vivo validation of fibroblast activation and atrial remodeling.

Adults with repaired tetralogy of Fallot (TOF) face long-term risks of ventricular tachycardia (VT) and sudden cardiac death (SCD). There is no consensus on arrhythmia management during surgical pulmonary valve replacement (PVR). This study assessed whether pre-operative electrophysiological (EP) testing with targeted intraoperative cryoablation of identified anatomical isthmuses during PVR is associated with a reduction in post-operative VT inducibility and long-term risk of clinical VT/SCD. In this prospective multicentre cohort study, consecutive adults with TOF undergoing surgical PVR (2005-22) underwent standardized pre-operative EP studies. Surgical ablation strategy (EP-guided vs empiric) was at the discretion of the treating team. Post-operative EP studies assessed residual inducibility; clinical VT/SCD were evaluated during follow-up. Among 204 patients (age 35.5 ± 13.1 years, 43.1% female), 91 (45.1%) had inducible VT. Among those undergoing surgical ablation, post-operative VT was non-inducible in 74.1% with EP-guided vs 15.0% with empiric ablation [adjusted odds ratio 20.4, 95% confidence interval (CI) 4.5-91.8, P < .0001]. Persistent post-operative inducibility was associated with increased hazard of VT/SCD compared to patients without inducible VT pre-operatively [adjusted hazard ratio (HR) 5.3, 95% CI 1.8-16.0, P = .003], over a median 10.2-year follow-up. Compared to patients without inducible VT pre-operatively, empiric ablation was associated with a significantly higher hazard of VT/SCD (HR 5.2, 95% CI 1.6-16.5, P = .005), whereas EP-guided ablation was not (HR 2.8, 95% CI 0.8-10.3, P = .228). In adults with repaired TOF undergoing PVR, inducible VT is common. An EP-guided surgical strategy is associated with greater post-operative non-inducibility and improved long-term arrhythmic outcomes compared with empiric ablation.

This study investigates the clinical course and long-term outcomes of adults with subvalvular aortic stenosis (SAS). Adults with SAS, prospectively registered in the Dutch Congenital Cor Vitia (CONCOR) registry between 2001-2019, were included. All-cause mortality, SAS (re-) operation, and cardiovascular events, including arrhythmias, heart failure, (re-)operation for aortic regurgitation (AR), were assessed. Longitudinal changes in echocardiographic peak velocity, interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPW) were analysed using linear mixed-effects models. Differences in the history of SAS repair (operated/unoperated patients), isolated/non-isolated SAS, and sex were explored. Overall, 312 patients were included [age: 26.0 (interquartile range, IQR: 20.0-35.3) years, 68.3% history of SAS repair] with a median follow-up of 16 (IQR: 10-20) years (4423 patient-years). Unadjusted survival at 15 years was lower in the operated group compared to the unoperated group (P = .009) and no significant differences were observed between sexes (P = .083) or isolated/non-isolated SAS (P = .810). The cumulative incidence of (re-)operation for AR at 15 years was 7.6% (95% CI 4.7%-11.0%). The hazard of SAS repair during follow-up was higher in the unoperated group compared to the operated group [HR 0.2 (95% CI 0.1-0.5), P < .001], after correction for covariates. Peak velocity progression was 0.1 m/s (P = .357) during the first period and 0.3 m/s (P = .032) during the second (after ±10 years). No patient showed fast progression (≥0.3 m/s/year) in peak velocity. At baseline no evidence of left ventricular hypertrophy was observed, following IVST/LVPW criteria. Survival of adult SAS patients with a history of SAS repair was substantially lower compared to the unoperated group, reflecting a potentially more severe SAS phenotype. Nevertheless, long-term clinical event rates were considerable. SAS remained stable, suggesting less echocardiographic follow-up may suffice, particularly in mild phenotypes without AR. Additionally, follow-up should focus on the clinical sequelae of SAS.

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized in the general population, but the prevalence among adults with congenital heart disease (ACHD) is not well described. The study aimed to determine the prevalence, characteristics, and hospitalization burden of HFpEF among ACHD patients. Using the electronic medical files, a retrospective, multicentre cohort study was conducted including 4507 ACHD patients with biventricular heart physiology and systemic left ventricle followed at the ACHD centres in Eastern Denmark. Heart failure with preserved ejection fraction was defined as preserved left ventricular ejection fraction (LVEF ≥ 50%) with diuretics use, combined with elevated N-terminal pro-B-type natriuretic peptide and/or echocardiographic signs of HFpEF. Among 4507 ACHD patients, 86% had a preserved LVEF. Heart failure with preserved ejection fraction was identified in 13%, with high prevalence across all ACHD severities (13%, 12%, and 18% in mild, moderate, and severe). Compared with patients with normal left ventricular function, HFpEF patients were older {median age: 60 [interquartile range (IQR) 47-70] vs 41 [IQR 29-56] years, P < .001}, had more comorbidities {age-adjusted odds ratio for diabetes: 15.60 [95% confidence interval (CI) 12.39-19.70]; obesity: 1.48 [95% CI 1.17-1.87], and atrial fibrillation 4.58 [95% CI 2.22-9.88]}, and experienced almost five-fold higher rate of cardiovascular hospitalization [incidence rate ratio 4.6 (95% CI 4.2-5.1), P < .0001]. Despite this, only 4.0% had a heart failure diagnosis, and 5.8% were treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Heart failure with preserved ejection fraction is highly prevalent among ACHD patients, regardless of ACHD severity. It is associated with an increased burden of cardiovascular risk factors and hospitalizations. Despite this, only a minority received SGLT2 inhibitors. These findings emphasize the need for increased awareness of HFpEF in the ACHD population.

Congenital heart defects (CHD) aggregate in families, but recurrence patterns across kinships and generations remain incompletely understood. In light of improved survival and diagnostic precision, updated population-based estimates are needed. This study aimed to investigate familial recurrence patterns of CHD among relatives using nationwide Swedish register data. A retrospective, population-based case-control study was conducted, including 51 778 individuals with CHD born between 1987 and 2017 and 522 543 matched controls. Relatives (parents, full siblings, half-siblings, and offspring) were identified through linkage to national health and population registers. Logistic regression with robust standard errors clustered on maternal ID was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Dose-response relationships, kinship-specific associations, and interactions with maternal comorbidities (diabetes, hypertension, and obesity) were explored. Among individuals with at least one affected relative, the OR for CHD was 2.71 (95% CI 2.60-2.83), increasing with each additional affected relative (OR per relative 2.55; 95% CI 2.46-2.64). Recurrence was strongest for mothers (OR 3.12), full siblings (OR 3.22), and offspring (OR 3.18) and lower for fathers and half-siblings. A dose-response was observed by number of affected siblings and offspring. The association between maternal CHD and CHD in index individuals was not explained by maternal comorbidities. Congenital heart defect in a relative (parent, full or half-siblings, or offspring) is associated with CHD in the index individual, with recurrence patterns varying by kinship and number of affected relatives. These findings may inform genetic counselling and reproductive planning.

Cardiovascular disease is the leading cause of death in women, yet significant disparities persist in diagnosis, treatment, and research representation. This clinical consensus statement outlines the rationale and framework for establishing women's heart centres (WHCs) in Europe. Women's heart centres are proposed as hub-and-spoke reference networks embedded within existing cardiovascular systems, delivering multidisciplinary, sex-sensitive care across the life course. The document defines referral pathways, operational standards, and core and advanced training competencies in women's cardiovascular health. Key domains include ischaemia/myocardial infarction with non-obstructive coronary arteries, cardio-obstetrics, cardio-oncology, autoimmune disease, mental health, and cardiac rehabilitation. Implementation strategies emphasize scalable models, integration with primary care, telemedicine, quality improvement, and research engagement. Although long-term outcome data remain limited, available evidence suggests improved diagnostic precision, risk factor control, and patient-reported outcomes. Establishing WHC offers a structured approach to reduce inequities and strengthen cardiovascular care for women across Europe.

Discoid lupus erythematosus (DLE) is associated with systemic inflammation and increased cardiovascular disease risk. Hydroxychloroquine (HCQ) has cardioprotective effects in systemic lupus, but its impact in isolated DLE is unknown. To evaluate whether HCQ initiation in adults with isolated DLE is associated with lower 5-year cardiometabolic and cardiovascular risk. We conducted a single-center retrospective cohort study of 106 adults with isolated DLE and a multi-institutional TriNetX cohort study (2260 propensity-matched pairs). Patients were categorized as HCQ users or HCQ naïve. Outcomes included 5-year incidence of hypertension, hyperlipidemia, diabetes, coronary artery disease (CAD), peripheral arterial disease (PAD), angina, myocardial infarction, stroke, and major adverse cardiovascular events. Multivariable logistic regression and matched risk ratios were used. In the single-center cohort, HCQ use was associated with significantly lower odds of hyperlipidemia, PAD, angina, and CAD, regardless of DLE extent. In TriNetX, HCQ use was associated with significantly reduced risk of hypertension, hyperlipidemia, diabetes, CAD, and stroke. Retrospective design, residual confounding, reliance on ICD-10 coding, and limited assessment of disease activity. HCQ initiation in isolated DLE within our institution and the TriNetX database was associated with lower 5-year cardiometabolic and atherosclerotic risk, supporting its early use for potential cardiovascular risk mitigation.

The predictive value of preoperative resting ECGs for cardiovascular events after noncardiac surgery is unclear. This study evaluated whether incorporating conventional ECG features or the output of a deep-learning algorithm for ECG waveform analysis (PreOpNet) improves risk prediction beyond established clinical risk scores. We conducted a secondary analysis of two prospective cohorts of patients undergoing major noncardiac surgery in China between 2019 and 2023. Eight prespecified conventional ECG features were extracted from ECG reports, and raw ECG waveforms were analysed using PreOpNet. The primary outcome was a composite of any cardiovascular events within 30 days after surgery; the secondary outcome was major adverse cardiac events (MACEs). We built nested logistic regression models based on clinical risk scores, with or without ECG findings. Predictive performance was evaluated using area under the receiver-operating-characteristic curve (AUC), risk reclassification metrics, and decision curve analyses. Among 6080 patients, 733 (12.1%) experienced postoperative cardiovascular events and 174 (2.9%) had MACEs. Adding conventional ECG features (ΔAUC 0.035) or PreOpNet (ΔAUC 0.032) to the Revised Cardiac Risk Index improved model discrimination modestly. When added to the Gupta Perioperative Myocardial Infarction or Cardiac Arrest risk score, both approaches yielded minimal gains (ΔAUC 0.010 for conventional ECG features; 0.006 for PreOpNet). Risk reclassification and decision curve analyses had limited incremental predictive value. Preoperative ECG findings, assessed by including conventional waveform features and the PreOpNet algorithm, provide limited incremental predictive value for cardiovascular risk assessment before noncardiac surgery.

Decompensated cirrhosis is associated with cirrhosis-associated immune dysfunction (CAID), predisposing patients to bacterial infections and poor outcomes. The mechanisms driving CAID remain incompletely understood. To examine whether portal hypertension (PH) is a key upstream driver of CAID and whether its reduction by transjugular intrahepatic portosystemic shunt (TIPS) reverses immune dysfunction. In a prospective cohort study, patients undergoing TIPS (n=75) and controls with compensated cirrhosis (n=15) were included. Plasma markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation were measured in controls and longitudinally before and after TIPS. The effects of patient sera from different stages of cirrhosis on healthy donor-derived monocytes were assessed in vitro. Bulk RNA sequencing was performed on patient monocytes. Immunological findings were correlated with clinical outcomes, which were also validated in an external prospective cohort and a retrospective multicentre cohort of 1180 patients. Patients with decompensated cirrhosis showed elevated markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation compared with compensated controls. These markers significantly decreased after TIPS. Sera from decompensated patients, but not from post-TIPS patients, induced anti-inflammatory markers (MER Tyrosine Kinase (MERTK), CD163) and suppressed interleukin 6 secretion in monocytes in vitro. Transcriptomic analysis identified an anti-inflammatory monocyte signature in decompensated cirrhosis that resolved after TIPS. CAID improvement occurred only in patients with ascites resolution and was associated with fewer bacterial infections. PH is a central driver of CAID in decompensated cirrhosis. Its reduction by TIPS restores gut barrier integrity, reduces inflammation and re-establishes immune homeostasis.

Recent awareness that metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition in individuals with type 2 diabetes and carries a significant risk of cirrhosis and extrahepatic disease has called for an examination of its relationship with diabetes-related complications. MASLD, especially at-risk steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]) with significant fibrosis ≥F2, shares many metabolic abnormalities with type 2 diabetes, including insulin resistance, gluco- and lipotoxicity, chronic subclinical inflammation and mitochondrial impairment. In addition, many cross-sectional and longitudinal observational studies suggest an association between MASLD and micro- and macrovascular complications of type 1 and type 2 diabetes. However, a causal pathogenic relationship has been difficult to confirm given the overlap of cardiometabolic risk factors (CMRFs) in MASLD and type 2 diabetes. Complicating matters further, most of the available evidence has significant limitations. These include shortcomings in participant selection, heterogeneity in study design, use of diagnostic tools with low sensitivity for liver disease and diabetes-related complications, inadequate control for alcohol consumption or CMRFs, and lack of repeat measurements during longitudinal studies. Nevertheless, current evidence suggests that MASLD is a 'risk enhancer' for both micro- and macrovascular disease in diabetes, rather than an independent risk factor. Here, we review the underlying mechanistic pathways and clinical evidence that appear to link both conditions and identify knowledge gaps in need of future research. Until more robust evidence emerges, we hope that a greater awareness about the link between MASLD and diabetes-related micro- and macrovascular complications will prompt clinicians to educate their patients and peers on the potentially heightened health risks of MASLD and encourage clinicians to take a more proactive approach to risk stratification and intervention.

Obesity and associated metabolic disorders are major drivers of cardiovascular disease worldwide. Bile acids are now recognized as endocrine signaling molecules that coordinate metabolic, immune, and cardiovascular homeostasis, extending their traditional role in intestinal lipid absorption. They act through several membrane and nuclear receptors, including farnesoid X receptor and Takeda G protein-coupled receptor 5. Through these pathways, bile acids regulate glucose and lipid metabolism, energy expenditure, inflammation, and vascular tone across multiple organs, such as the liver, gut, adipose tissue, and heart. Altered bile acid pool composition and impaired receptor signaling contribute to the development of obesity, insulin resistance, atherosclerosis, and heart failure. Conversely, pharmacological modulation of bile acid signaling pathways has shown therapeutic potential. Agonists targeting farnesoid X receptor or Takeda G protein-coupled receptor 5 agonists, as well as hydrophilic bile acid derivatives, improve metabolic flexibility, endothelial function, and cardioprotection in experimental and clinical studies. This review summarizes the multifaceted roles of bile acids in inter-organ communication and highlights their emerging potential as therapeutic targets in cardiometabolic disease.

Cardiac aging is a fundamental contributor to heart failure, arrhythmias, impaired stress tolerance, and reduced cardiovascular resilience in the elderly. While intrinsic myocardial aging has been widely examined, the systemic mechanisms driving age-related cardiac decline are not fully understood. Circulating extracellular vesicles (EVs) have emerged as key mediators of intercellular and inter-organ communication, transferring proteins, lipids, and nucleic acids that modify the phenotypes of recipient cells. Growing evidence indicates that EVs originating from cardiovascular cells as well as distant organs, including the liver, kidney, adipose tissue, lung, and intestine, participate in cardiac aging by influencing senescence-associated signaling, chronic inflammation, mitochondrial and metabolic dysfunction, fibrosis, microvascular remodeling, and contractile function. In this review, we outline the biological basis of circulating EVs in cardiac aging, describe their cellular and inter-organ sources, and examine how they promote progressive myocardial remodeling. We also consider their potential as biomarkers for cardiac aging and age-related heart disease, along with emerging therapeutic strategies such as blocking pathogenic EV signals, using reparative or engineered EVs, and implementing systemic interventions that modulate EV-mediated communication. Key translational challenges are highlighted, including EV heterogeneity, low tissue specificity, methodological inconsistencies, and the need to distinguish physiological cardiac aging from accelerated aging and age-related cardiovascular disease, as EV profiles may reflect systemic comorbidities rather than intrinsic cardiac aging. A deeper understanding of systemic EV crosstalk may offer new insights into the aging heart and support more precise methods for risk stratification, monitoring, and intervention.

Climate change represents an escalating global health crisis that profoundly influences the risk factors for cardiovascular disease (CVD). Human-driven alterations in climate-including rising ambient temperatures, more frequent and severe heatwaves, air pollution, and extreme weather events-directly and indirectly exacerbate hypertension, diabetes, hyperlipidaemia, and physical inactivity. Exposure to high temperatures and pollution promotes vascular dysfunction, inflammation, and oxidative stress, leading to worsened blood pressure control, dysglycaemia, and disrupted lipid metabolism. Extreme weather events, floods, and wildfires trigger acute spikes in cardiovascular events through dehydration, myocardial ischaemia, and arrhythmias, while also disrupting healthcare delivery and medication adherence. Moreover, climate-driven changes in food systems and nutritional quality exacerbate unhealthy dietary behaviours, further amplifying cardiometabolic risk. Vulnerable populations-including older adults, racial and ethnic minorities, and those of lower socioeconomic status-bear a disproportionate burden of these effects. Mitigating the cardiovascular consequences of climate change requires integrated approaches that incorporate climate-sensitive risk stratification, targeted education of patients and clinicians, and adaptive health system responses. Primary care physicians play a central role in delivering anticipatory guidance and equitable care to at-risk individuals. This review synthesizes evidence linking climate change with CVD risk profiles. It outlines clinical and public health strategies to strengthen climate resilience in cardiovascular medicine.

Cardiovascular disease, the leading cause of death worldwide, imposing an enormous economic burden on society. Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, contains two tandem deacetylase domains. Recent study reported that the first deacetylase domain of HDAC6 exerts E3 ligase activity. It is known that HDAC6 participates in a variety of cellular activities including microtubule stability, epithelial homeostasis and autophagy by modulating its specific non-histone substrates. However, the role of HDAC6 and its selective inhibitors in cardiovascular disease remains unclear. In this paper, we focus on the role of HDAC6 in the heart, as well as in the progression of cardiovascular disease including heart failure, cardiomyopathy, cardiotoxicity and myocardial infarction. We find that the expression of HDAC6 is elevated in various cardiovascular diseases, suggesting that HDAC6 may act as a biomarker for cardiovascular disease. We further discuss the potential of depletion of Hdac6 or the application of its selective inhibitors in disease prevention and treatment. Elucidation of these issues indicate that HDAC6 and its selective inhibitors might act as potential therapeutic targets for cardiovascular disease.

This study assessed the relationship between air pollution exposure, fine particulate matter ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2), and coronary calcium score (CCS) in a cohort of 60-75-year-old men from the Danish Cardiovascular Screening Trials (DANCAVAS). A total of 12 301 participants were included. Residential and novel workplace address spanning up to 40 years was geocoded. Air pollution exposure was modelled using the Danish Eulerian Hemisphere model (DEHM)/Urban Background Model (UBM)/AirGIS system. Median PM2.5 exposure was 13.7 µg/m3 (interquartile range [IQR]: 13.2-14.1). The median NO2 exposure was 16.3 µg/m3 (IQR: 14.7-18.4). The median CCS was 99 (IQR: 8-410). The primary outcome was CCS ≥ 100, secondary outcomes included CCS ≥ 400 and ordinal-scaled CCS (0, 1-99, 100-399, 400-999, and >999). Binary logistic regression analyses revealed no significant associations; however, generalized ordinal logistic regression analysis of CCS indicated that PM2.5 exposure was associated with coronary artery calcification (CAC) presence (CCS = 0 vs. CCS ≥ 1) with an adjusted odds ratio = 1.11 (95% confidence interval: 1.04-1.18) per 1 µg/m3 increase in PM2.5. No associations were observed for higher CAC categories. The findings for NO2 were non-significant. Addition of workplace exposure showed only moderate changes in effect estimates. Exposure to PM2.5 was modestly associated with the presence of CAC, particularly when combining residential and workplace exposures. No consistent associations were observed with NO2 or advanced stages of calcification. Findings suggest that long-term ambient PM2.5 exposure may contribute to early subclinical atherosclerotic changes; however, modest effect sizes and lack of association with CAC severity call for cautious interpretation.

Antiplatelet medications are overprescribed in patients taking direct oral anticoagulants (DOACs), increasing their risk of major bleeding. The utility of potentially scalable antithrombotic stewardship approaches remains unknown. To evaluate a multicomponent antithrombotic stewardship initiative to reduce unnecessary antiplatelet use in patients prescribed DOACs. This quality improvement study used retrospective multiperiod comparative interrupted-time-series analysis from July 2020 to July 2023 to compare intervention and control sites. Participants were adults prescribed DOACs in the ambulatory setting. The interventions occurred in 7 Veterans Health Administration (VHA) health systems, while 128 other VHA health systems served as controls. Data were analyzed from July 2023 to March 2026. In stage 1, lasting 9 months, intervention sites implemented educational outreach to clinicians and patients and changes to the electronic health record system. In stage 2, lasting 16 months, a clinical pharmacist-facing electronic flag identifying patients receiving antiplatelet therapy was added to a widely used electronic dashboard. Monthly site-level percentage of patients prescribed antiplatelet medications. The summary measure was the difference in the semiannual change in the outcome for intervention compared with control sites, controlling for preintervention trends. Subgroup analyses were performed based on antiplatelet indication. This study found that preintervention antiplatelet use in patients prescribed DOACs was 26.1% (95% CI, 26.0%-26.1%) in the 7 intervention sites (27 588 patients; 704 females [2.6%]) and 30.1% (95% CI, 30.0%-30.2%) in 128 control sites (253 085 patients; 6481 females [2.6%]). Antiplatelet use decreased faster by an absolute -0.58 (95% CI, -0.95 to -0.22) percentage points (pp) per 6 months for intervention compared with control sites after the 2 interventions had been implemented. The initial set of interventions was associated with an absolute -0.29 (95% CI, -0.61 to 0.04) pp change per 6 months and later augmentation with the electronic flag was associated with an absolute -0.29 (95% CI, -0.61 to 0.03) pp change per 6 months. The combined interventions were associated with the greatest reduction in the subgroup of patients with stable coronary artery disease (absolute -2.1 [95% CI, -3.0 to -1.2] pp per 6 months, equivalent to a -5.5% additional change compared with the baseline prevalence in this group), for whom antiplatelet deimplementation is likely appropriate. This study found that the combined interventions were associated with a clinically meaningful reduction in potentially harmful combination antithrombotic therapy. The initial educational outreach and changes to the electronic health record and later augmentation with the electronic flag had additive effects, highlighting the importance of multilevel interventions to speed adoption of evidence-based antithrombotic prescribing.

The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision-making, ultimately improving patient safety while supporting innovation in cancer therapeutics.

Macrophage-driven inflammation plays a critical role in the progression of acute myocardial infarction (AMI). This study revealed that USP7 expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Furthermore, in a mouse model of myocardial infarction (MI), after AMI cardiac inflammation was suppressed by macrophage-specific USP7 knockout. Mechanistically, USP7 directly interacted with STING and suppressed its K63-linked ubiquitination at residue K289, thereby preventing STING degradation via the endosomal sorting complex required for transport (ESCRT)-lysosomal pathway and enhancing STING-mediated inflammatory signaling. The cardioprotective effects of USP7 ablation were abrogated by STING overexpression. Moreover, pharmacological inhibition of USP7 or adenovirus-mediated knockdown of USP7 similarly attenuated AMI-induced cardiac injury and inflammation in mice. These findings identify USP7 as a novel deubiquitinating enzyme that regulates STING ubiquitination and degradation via the ESCRT pathway, thus establishing USP7 as a critical regulator of macrophage inflammatory responses in AMI.

Fine particulate matter (PM2.5) is a well-recognized environmental pollutant increasingly implicated in the pathogenesis of cardiovascular disease (CVD). Whilst numerous studies have established its deleterious effects, incongruencies in the magnitude, dose-response gradients, and modifying factors across systematic reviews (SRs) and meta-analyses (MAs) have limited translational clarity. Per the PRISMA guidelines, we conducted an umbrella review of SRs and MAs examining the association between PM2.5 exposure and cardiovascular morbidity, mortality, or intermediate biomarkers in human populations. Searches were performed across PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Google Scholar up to June 2025. The methodological quality of included reviews was appraised using AMSTAR 2 and ROBIS. Thirty-eight SRs and MAs met eligibility criteria, encompassing data from diverse geographic regions and demographic settings. Cumulative evidence demonstrates a robust association between both short- and long-term PM2.5 exposure and elevated cardiovascular risk, including myocardial infarction [relative risk (RR): 1.02, 95% confidence interval (CI): 1.01-1.03], stroke (RR: 1.011, 95% CI: 1.010-1.012), heart failure (RR: 1.018, 95% CI: 1.011-1.025), arrhythmia (RR: 1.015, 95% CI: 1.006-1.024), and cardiovascular mortality. Several reviews identified dose-dependent relationships, with increased risk observed even at PM2.5 concentrations below current WHO standards (5 µg/m3 annual mean; 15 µg/m3 24 h mean), US national air quality standards (12 µg/m3 annual mean; 35 µg/m3 24 h mean), and Indian national air quality standards (40 µg/m3 annual mean; 60 µg/m3 24 h mean), have also been associated with increased cardiovascular risk. Subgroup analyses highlighted increased susceptibility among older adults, individuals with pre-existing CVD, and populations in low- and middle-income countries. Whilst most reviews were rated as moderate-to-high quality, methodological heterogeneity in exposure assessment and under-representation of data from South Asia and sub-Saharan Africa remain key limitations. This umbrella review consolidates high-level evidence linking PM2.5 exposure to a broad spectrum of adverse cardiovascular outcomes. The findings underline the urgent need to tighten global air quality regulations, prioritize vulnerable populations, and advance mechanistic and regional research to inform tailored policy interventions.

Compliance matching of tissue engineered vascular grafts (TEVGs) is a promising technique to combat common failure modes seen clinically in small diameter vascular procedures like coronary artery bypass grafting (CABG). However, despite the influence of sex on vascular response to injury, the role of biological sex on the success of TEVG innovations such as compliance matching, namely in long-term remodeling, has been understudied. In this study we fabricated compliance matched TEVGs (CM TEVGs) and hypocompliant TEVGs (Hypo TEVGs) by adjusting the thicknesses of a high polyester urethane urea (PEUU) containing layer (80:20 PEUU:Gelatin) and a low PEUU containing layer (20:80 PEUU:Gelatin). All grafts were implanted into the abdominal aorta of both male and female Sprague Dawley rats (n = 4) as interposition grafts for 6 months and monitored using in vivo ultrasound. Upon explant, key outcomes of long-term remodeling were assessed via immunohistochemistry, multiphoton imaging, and qRT-PCR. CM TEVGs were confirmed to be compliance matched to native aorta both in vitro and in vivo upon implant. After remodeling, CM TEVGs had increased degradation and decreased calcification compared to Hypo TEVGs. CM TEVGs had increased mature VSMC genes (Acta2, Myh11, Cnn1) in males and decreased macrophage presence (CD68) in females. Independent of graft type, females had increased intimal thickening, decreased luminal presence of mature VSMCs, and increased fibrillar collagen deposition compared to males in both CM and Hypo TEVGs. Our results suggest that long-term remodeling outcomes in response to compliance matching are dependent on biological sex at both the tissue and cellular level.

Cardiotoxicity remains the leading driver of drug attrition; however, its prediction remains suboptimal when conventional hERG assays and animal models are used. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a human-relevant alternative that aligns with the CiPA initiative and ICH E14/S7B guidelines. This study validated an integrated platform that combines high-purity hiPSC-CMs with Artificial Intelligence (AI) to enhance the accuracy of predicting drug-induced proarrhythmic risk. Phenotypic characterization of the hiPSC-CMs demonstrated high cardiac differentiation efficiency (cTnT +  > 95%) and a predominant ventricular-like identity (MLC-2 V + , 78-84%), ensuring biological relevance for ventricular arrhythmia assessment. Electrophysiological data from 28 CiPA reference compounds were collected via Multielectrode Array (MEA) to train multiple machine learning models. The Artificial Neural Network outperformed the other architectures, achieving a superior ROC-AUC of 0.982. The utility of the platform was evaluated using 12 anticancer agents. Although most drugs showed dose-dependent reductions in impedance-based viability, four compounds (Idarubicin, Erlotinib, Sunitinib, Cyclophosphamide) did not exhibit overt structural cytotoxicity. However, MEA analysis revealed significant functional perturbations, including FPDcF prolongation, in sunitinib- and erlotinib-treated samples after long-term treatment. The AI model subsequently classified these two agents as high-to-intermediate risk for Torsades de Pointes (TdP), thereby quantifying their time-dependent proarrhythmic liabilities. These findings show the platform's ability to detect hidden functional cardiotoxicity, often missed by standard viability assays. The AI-hiPSC-CM system offers a high-throughput, early-stage safety screening tool that bridges in vitro data and clinical outcomes with a standardized risk assessment framework.

The brain vasculature comprises diverse specialized cells that are essential for brain function, yet their spatial organization remains poorly understood. Here, we construct a comprehensive cerebrovascular cell atlas encompassing 314,535 transcriptomes that captures the arteriovenous axis and defines consensus cell states. We then perform spatial transcriptomics to map 1,529,740 cells across the human temporal cortex and hippocampus, uncovering stereotyped micro-communities termed vascular cell ensembles. These ensembles comprise specialized subsets of endothelial cells, mural cells, fibroblasts, and perivascular macrophages that align with the arteriovenous architecture to coordinate segment-specific functions, such as neurovascular coupling, blood-brain barrier transport, and immune surveillance. By overlaying genetic risk and pharmacologic reactivity, we identify ensemble-specific susceptibilities and candidate therapeutic targets across neurological diseases, including small vessel disease and stroke. This study provides a resource to dissect the spatial and functional logic underlying human cerebrovascular biology and establishes a blueprint for decoding neurological disease susceptibility and therapeutic response.

Diabetic cardiomyopathy, a severe complication of diabetes, is marked by mitochondrial dysfunction, metabolic inflammation, and progressive cardiac impairment. Although STING (stimulator of interferon genes) is well recognized as a central mediator of innate immunity, its noncanonical role in metabolic regulation and mitochondrial dynamics in the diabetic heart remains largely unexplored. To elucidate the role of STING in diabetic cardiac remodeling, we used single-cell RNA sequencing, echocardiography, and transmission electron microscopy in both genetic (db/db) and chemically induced (high-fat diet [HFD] plus streptozotocin, HFD/streptozotocin) diabetic mouse models. STING knockout mice and primary neonatal mouse cardiomyocytes were used for mechanistic investigations and functional validation. Mitochondrial respiration and glycolytic flux were assessed using Seahorse extracellular flux analysis. Posttranslational modifications of STING, including S-palmitoylation and S-sulfhydration, were evaluated via acyl-biotin exchange and biotin-switch assays, respectively. ENO1 (enolase 1) enzymatic activity was measured in vitro to assess glycolytic reprogramming. Furthermore, 13C-glucose tracing-based targeted metabolomics was performed to quantify cardiac metabolic flux in db/db mice. Glycolytic metabolites, including lactate and pyruvate, were quantified in cardiac tissues and cultured cardiomyocytes to assess glycolytic activity. Exposure to high-palmitate conditions induced mitochondrial DNA leakage, thereby activating the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway in cardiomyocytes. Mechanistically, STING underwent aberrant translocation to mitochondria, where it interacted with the outer membrane protein TOM (translocase of outer mitochondrial membrane) 40 to impair mitochondrial protein import and disrupt mitochondrial homeostasis. In addition, mitochondrial STING functioned as a scaffold to recruit and activate the glycolytic enzyme ENO1, thereby enhancing its enzymatic activity, accelerating glycolytic flux, and promoting lactate accumulation in diabetic cardiac tissues. Notably, diabetes-associated depletion of endogenous hydrogen sulfide reduced S-sulfhydration of STING at Cys88/91 (cysteine residues 88 and 91 of STING), facilitating its S-palmitoylation and mitochondrial localization. Genetic ablation of STING or pharmacological restoration of hydrogen sulfide levels with GYY4137, a slow-releasing hydrogen sulfide donor, effectively rescued mitochondrial dysfunction, decreased lactate overproduction, and preserved cardiac contractile performance in diabetic mice. These findings identify STING as a spatial immunometabolic modulator that bridges mitochondrial dysfunction with metabolic imbalance in diabetic cardiomyopathy. Enhancing STING S-sulfhydration or targeting its palmitoylation through hydrogen sulfide-based interventions represents a promising therapeutic strategy for the treatment of diabetic cardiomyopathy.

Whether prior pars plana vitrectomy (PPV) independently increases the risk of cystoid macular edema (CME) following cataract surgery remains unknown. To evaluate associations between prior PPV and incidence of CME after cataract surgery. This retrospective cohort study was conducted using the TriNetX US Network, a multicenter federated electronic health record network from December 2005 to December 2025 including academic and community hospitals in the US. Adults aged 18 years or older who underwent cataract surgery were categorized into those with vs those without a history of PPV (≥6 months prior to cataract surgery), excluding those with preexisting CME or risk factors for CME. Data were analyzed from December 2025 through January 2026. History of PPV performed more than 6 months prior to cataract surgery. The primary outcome was the incidence of CME within 30 to 90 days postoperatively, identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. Risk ratios (RR) were used to compare outcomes. Propensity score matching was performed for demographic and clinical covariates (age, sex, race, hypertension, hyperlipidemia, diabetes, myopia, retinal detachment [RD] history). After propensity score matching with 615 983 patients undergoing cataract surgery, 7422 patients had a prior PPV. After propensity score matching, among patients with prior PPV, mean (SD) age was 62.0 (11.6) years, and 3623 patients (49.5%) were female; among the non-PPV group, mean (SD) age was 61.9 (12.2) years, and 3625 patients (49.5%) were female. Among 14 636 patients representing 7318 propensity score-matched pairs, CME occurred in 336 of 7318 patients with prior PPV (4.59%) compared with 90 of 7318 non-PPV controls (1.23%) (difference, 3.36%; 95% CI, 2.82%-3.90%; RR, 3.73; 95% CI, 2.97-4.70; P < .001). Elevated CME risk persisted in subgroup analyses evaluating prior PPV for RD (5.65% vs 1.22%; absolute difference, 4.43%; 95% CI, 3.48%-5.38%; RR, 4.62; 95% CI, 3.20-6.67; P < .001), as well as those for non-RD indications (3.99% vs 1.23%; absolute difference, 2.76%; 95% CI, 2.06%-3.48%; RR, 3.26; 95% CI, 2.36-4.50; P < .001). Furthermore, after excluding patients with intraoperative and postoperative complications of cataract surgery, the prior PPV group was still found to have a higher risk of CME (4.59% vs 1.26%; absolute difference, 3.32%; 95% CI, 2.77%-3.88%; RR, 3.63; 95% CI, 2.88-4.58; P < .001). Results of this cohort study suggest that eyes with vs without prior PPV have higher incidences of postoperative CME. However, numerous limitations, including dependence on coding-based diagnoses and lack of visual acuity outcomes, preclude determining the role of prophylaxis or monitoring for CME in vitrectomized eyes undergoing cataract extraction.