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Heart failure (HF) remains a pressing health concern, with rising prevalence globally. Subjectivity and ambiguity in the definition of HF and its antecedent stages have limited research, global surveillance, and prevention programs. To address this, several cardiac societies and foundations convened to standardize the definition of HF in 2021 and designated stage B or pre-HF to identify individuals at risk of developing HF. In subsequent years, substantial progress and changes have been made in aspects of preventing HF, improving HF diagnosis and management, and recognizing the importance of the affected individual's voice. Global differences and disparities in HF are better understood, as are causes and comorbidities leading to differences in care, which are also influenced by access to care. This consensus document presents the Second Universal Definition of Heart Failure, aiming to standardize terminology and facilitate a uniform approach for clinicians, researchers, health systems, and policymakers. In this definition, the classification of HF phenotypes moves away from rigid left ventricular ejection fraction cutoffs, instead grouping HF into reduced, preserved, and improved ejection fraction categories to better reflect clinical realities. A universal classification of HF causes is also proposed. The document also addresses the dynamic trajectories of HF-improvement, remission, and recovery-and highlights the impact of social determinants and geographic variation on HF risk and outcomes. By providing a comprehensive, standardized framework for HF definition and classification, this document seeks to improve prevention, early detection, and management of HF worldwide, ultimately enhancing patient care and advancing global cardiovascular health.

Apparent treatment-resistant hypertension (aTRH) is common and associated with adverse outcomes in individuals with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Whether finerenone improves blood pressure (BP) and clinical outcomes in individuals with HFmrEF/HFpEF and aTRH is uncertain. In this pre-specified analysis of the FINEARTS-HF trial, participants were categorized according to baseline BP, with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with ≥3 BP-lowering medications, including a diuretic. Non-resistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under the threshold. Incidence of clinical outcomes and safety events was assessed by baseline hypertension category. Among 6001 participants, 3471 (57.8%) had controlled blood pressure, 1754 (29.2%) had non-resistant hypertension, and 776 (12.9%) had aTRH at baseline. Between baseline and 36 months, finerenone similarly reduced systolic BP across baseline BP categories (Pinteraction = 0.59). Rates of cardiovascular death and total HF events (per 100 person-years) were 17.0 in those with controlled BP, 16.0 in those with non-resistant hypertension, and 13.8 in those with aTRH (Pcomparison = 0.12). Relative treatment benefits of finerenone vs placebo on the primary outcome (Pinteraction = 0.32) and HF-related health status (Pinteraction = 0.22) were consistent across hypertension categories. The safety profile of finerenone vs placebo did not appear to be modified by baseline hypertension category. aTRH was identified in 1-in-8 individuals with HFmrEF/HFpEF in FINEARTS-HF. Finerenone consistently improved clinical outcomes, health status, and blood pressure, including among those with aTRH.

Biventricular pacing (BVP) is the standard for cardiac resynchronization therapy (CRT), particularly in left bundle branch block (LBBB). However, conduction system pacing (CSP) may offer superior outcomes as a physiological alternative. We evaluated the clinical efficacy of CSP compared with BVP as a primary strategy for patients with heart failure indicated for CRT. A systematic review and meta-analysis was conducted using MEDLINE and the Cochrane Library databases. We included randomized controlled trials (RCTs) comparing CSP with BVP in patients with heart failure and a left ventricular ejection fraction below 50%. Pooled estimates were determined using a random-effects model for all outcomes. Twelve RCTs involving 1223 patients were included. CSP significantly improved the echocardiographic response compared with BVP in the overall cohort (odds ratio [OR]: 1.73; 95% confidence interval [CI]: 1.19-2.52) and the LBBB subgroup (OR: 1.74; 95% CI: 1.15-2.62). CSP revealed significant improvements in NYHA functional class (standardized mean difference: -0.27; 95% CI: -0.46 to -0.08) and 6-min walk distance (mean difference: 21.6 m; 95% CI: 8.07 to 35.14). While composite endpoints (OR: 0.59; 95% CI: 0.33 to 1.08) and mortality (OR: 0.90; 95% CI: 0.39 to 2.11) showed trends favoring CSP, neither reached statistical significance. There was no significant difference in procedural crossovers between the groups (OR: 1.24; 95% CI: 0.54 to 2.87). Compared with BVP, CSP improved echocardiographic and functional response in patients requiring CRT. CSP as a primary strategy may be considered in selected patients, but large RCTs with hard clinical endpoints are needed.

Soft robotic cardiac sleeves are an emerging class of non-blood-contact mechanical circulatory support devices designed to augment myocardial function while avoiding direct interaction with blood. Their development addresses important limitations of conventional heart failure therapies and offers a promising strategy for physiological cardiac assistance. This Review examines the pathophysiological basis for sleeve-assisted cardiac support, recent advances in soft robotic technologies, and the key engineering and translational challenges that must be overcome for clinical implementation. Finally, we propose a translational framework to guide the future development of clinically viable soft robotic cardiac sleeves.

Risk prediction is fundamental to pulmonary hypertension (PH) guideline-based care, yet pediatric-specific risk prediction models remain limited, relying primarily on single predictors, expert opinion, or application of adult models to children. The authors developed and externally validated a data-driven 1-year risk prediction model for pediatric PH. Pediatric patients with PH (n=345; World Symposium on Pulmonary Hypertension groups 1 and 3) enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020; 50.4% male; median age, 4.9 years [interquartile range, 1.9-10.3]) were split into training (80%) and test cohorts (20%). The Dutch National Registry for Pulmonary Hypertension in Childhood (n=155 [1993-2020]) and the Spanish Registry of Pediatric Pulmonary Hypertension (n=327 [2009-2023]) were used for external validation. From 176 variables, BorutaSHAP feature selection with random forest identified 16 predictors for a 1-year outcome of time to death, transplant, Potts shunt, or atrial septostomy, modeled using extreme gradient boosting. Performance was assessed with the area under the receiver operating characteristic curve, confusion matrices, calibration, and Kaplan-Meier event-free survival. The final model achieved an area under the receiver operating characteristic curve of 0.90 (0.79-0.97) and 99% (96%-99%) negative predictive value in testing, dividing participants into 3 groups with strong outcome discrimination. External validation showed an area under the receiver operating characteristic curve of 0.76 (Dutch National Registry for Pulmonary Hypertension in Childhood, 0.70-0.81) and 0.77 (Spanish Registry of Pediatric Pulmonary Hypertension, 0.73-0.82) with negative predictive values of 93% (93%-97%) and 96% (93%-97%), respectively. Kaplan-Meier analysis significantly differentiated outcomes by risk group. This multicenter, validated model provides good 1-year risk prediction in pediatric PH across World Symposium on Pulmonary Hypertension groups 1 and 3, providing a robust tool for clinical risk stratification to guide therapy and addressing a gap in pediatric PH care.

Chagas disease (ChD), a neglected cardiovascular condition, affects 7.5 to 10.5 million people worldwide. Opportunistic screening during routine electrocardiography may allow earlier detection of unrecognized infections, enabling timely antiparasitic therapy or optimized cardiac care. This study prospectively evaluated the feasibility and diagnostic accuracy of an artificial intelligence (AI)-enabled ECG model enriched with 3 epidemiological questions (AI-ECG-EPI model) as an opportunistic screening for ChD in endemic regions of Brazil. We conducted a prospective study embedded in the Telehealth Network of Minas Gerais, Brazil, across 107 municipalities in hyperendemic and endemic regions. From October 2023 to September 2024, adults undergoing routine tele-ECGs were eligible. The primary exposure was the output of the AI-ECG-EPI model: all positive individuals and a 3:1 sample of negative individuals were invited for serology (index test-dependent sampling), the reference standard. Weighted analyses (inverse probability) accounted for this sampling design. Diagnostic metrics included sensitivity, specificity, predictive values, likelihood ratios, area under the receiver operating characteristics curve, and area under the precision recall curve. The AI-ECG-EPI model was compared with both an epidemiological questions model and an AI ECG-only model. Among 75 779 eligible ECGs, the AI-ECG-EPI model was available for 59 154 individuals; 6812 (11.5%) screened positive. A total of 7804 selected were invited for serology, and 3509 completed testing (2517 positive; 992 negative). ChD was confirmed in 36.8% of positive and 9.3% of negative individuals. The weighted prevalence of ChD was 12.2%. Sensitivity was 34.3%, specificity 91.6%, harmonic mean of precision and recall score 0.52, and diagnostic odds ratio 5.69. The AI-ECG-EPI model showed higher discrimination than both the epidemiological questions model and AI ECG-only model (area under the receiver operating characteristics curve, 77.6% versus 70.0% and 64.5%, respectively; P<0.001). Precision recall curves showed higher precision across most recall levels. Exploratory analysis suggested improved risk reclassification (net reclassification improvement, 0.503). Performance was higher in women and in individuals with Chagas cardiomyopathy. In this community-based study, an AI-ECG-EPI model integrated into a public telecardiology network enabled feasible opportunistic screening for ChD in primary care. It showed acceptable diagnostic accuracy, with higher discrimination than epidemiological questions and AI ECG-only models, and identified many previously undiagnosed patients in endemic regions, supporting its potential role in scalable screening strategies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02646943.

Heart failure in the perinatal period remains ambiguous in definition and management despite its recognition as a unique disease state. The true incidence and prevalence of heart failure or left ventricular systolic dysfunction during pregnancy and the postpartum period are unknown, although a prevalence as high as 1% to 2% has been reported in the general adult US population. Assessment of heart failure can be challenging in the pregnant or postpartum state, during which symptoms affecting physical function (eg, dyspnea, exercise intolerance, fatigue, and lower-extremity edema) are prevalent because of physiological changes. Delays in the recognition and diagnosis of heart failure during the perinatal period contribute to adverse maternal outcomes, highlighting the need for evidence-based definitions and thresholds, improved diagnostic criteria to aid disease recognition, and effective screening tools. This scientific statement focuses on heart failure with reduced and mildly reduced ejection fraction in the context of pregnancy and the postpartum period, caused by various forms of cardiomyopathy. It addresses challenges related to recognizing heart failure in obstetric patients, outlines established treatment standards, and underscores potential areas for research. To improve the management of preexisting and de novo heart failure in obstetric patients, standardization of disease definitions, specific therapeutic options, implementation of effective screening tools, and interventions to improve maternal health equity are imperative. Future directions include prioritizing the inclusion of pregnant and postpartum individuals in heart failure studies, implementing interventions that facilitate early disease detection, and ensuring the timely initiation of appropriate therapies with the goal of reducing adverse outcomes associated with perinatal heart failure.

G-protein-coupled receptors (GPCRs) represent a compelling intersection of structural biology, systems pharmacology, and clinical medicine. They function as essential molecular regulators of cardiovascular physiology, governing processes from the initiation of cardiac rhythm in the sinoatrial node to the regulation of vascular tone. Their widespread expression in cardiac and vascular tissues, combined with their ability to integrate diverse extracellular signals, positions GPCRs as key regulators of heart rate, contractility, vascular tone, inflammation, and metabolic homeostasis. Recent advances in GPCR structural biology, coupled with mechanistic insights into G-protein- and β-arrestin-mediated signaling mechanisms, underscore their central role in both cardiovascular health and disease. Notably, dysregulation of GPCR signaling has emerged as a unifying mechanism across major cardiovascular diseases (CVDs), contributing to pathological remodeling, impaired contractile function, and maladaptive vascular responses. This review uniquely integrates GPCR structural biology, signaling dynamics, and mechanosensitive and biased signaling mechanisms within the cardiovascular system. We discuss the contributions of class A, class B, and other GPCR families to cardiovascular physiology and pathology emphasizing their relevance to the development of targeted interventions for hypertension, heart failure, arrhythmias, atherosclerosis, and related CVDs. Together, these insights establish a contemporary framework for advancing precision GPCR-directed therapies in CVDs. By framing these developments within a mechanistic and translational context, the review offers a timely and clinically significant resource for both basic researchers and clinicians.

Diabetic vascular complications are a major determinant of poor prognosis in diabetic patients, with their development closely linked to persistent low-grade inflammation. Macrophages, as key regulatory cells in the immune system, undergo significant metabolic reprogramming in the diabetic hyperglycemic microenvironment. This reprogramming involves a coordinated remodeling of key metabolic pathways, including carbohydrate metabolism, lipid metabolism, and amino acid metabolism. This review systematically discusses the classical theories of macrophage polarization and provides an in-depth analysis of how key molecules drive the M1/M2 imbalance. Additionally, it explores the intricate regulatory interactions between the three major metabolic pathways. The metabolic reprogramming-polarization axis is further examined in the context of four typical diabetic vascular complications-diabetic atherosclerosis, diabetic kidney disease, diabetic retinopathy, and diabetic cardiomyopathy-highlighting their specific pathological roles. This work aims to elucidate the theoretical value of this regulatory axis as a central mechanism in diabetic vascular complications and explores its clinical translational potential as a precise therapeutic target. It provides a systematic theoretical foundation and proposes new directions for future research.

Deterioration of transverse-axial tubules (t-tubules) contributes to insufficient excitation-contraction coupling in heart failure, yet the key signals and mechanisms remain unclear. Here, we aimed to identify the signalling pathways that trigger cardiomyocyte t-tubule loss and its underlying cellular process. Adult rat, rabbit, and human ventricular cardiomyocytes and living myocardial slices were exposed to pharmacological activators of protein kinase C (PKC). PKC activation caused rapid t-tubule loss and impaired Ca2+ transients, which were prevented by inhibition of protein kinase D (PKD) or NFκB. RNA sequencing and phosphoprotein analysis showed activation and crosstalk between PKD-, ERK-, and NFκB-dependent pathways, with up-regulation of genes involved in membrane trafficking and endocytosis. Fluorescent dextran uptake assays revealed a clathrin-independent, PI3K- and myosin-I-dependent macropinocytic process whose rate matched the internalization of t-tubule membranes and which was blocked by NFκB inhibition. Constitutive activation of IKK2 in cardiomyocytes of transgenic mice reduced t-tubule density in vivo, confirming that prolonged NFκB activation is sufficient to induce t-tubule remodelling in intact hearts. NFκB inhibition suppressed PKC-induced macropinocytosis also in non-cardiac human cell lines, suggesting that this process represents a conserved cellular response to inflammatory signalling. PKC-PKD-NFκB signalling triggers a macropinocytic form of membrane remodelling that degrades the t-tubule network and impairs excitation-contraction coupling. This identifies a previously unrecognized mechanism linking inflammatory kinase activation to structural and functional decline of cardiomyocytes and suggests that targeting the PKD-NFκB axis could preserve t-tubule integrity and cardiac performance in heart failure.

Cardiovascular diseases remain the leading cause of global morbidity and mortality, with pathogenesis extending beyond hemodynamic derangements to involve chronic, maladaptive immune-metabolic crosstalk. Macrophage functional identity has evolved beyond the M1/M2 paradigm toward a model of high heterogeneity and dynamic plasticity, wherein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) serves as a pivotal molecular hub. This review systematically delineates the spatiotemporal dynamics and functional duality of TREM2+ macrophages across major cardiovascular conditions, including atherosclerosis, myocardial infarction, heart failure and sepsis-induced cardiomyopathy. It further evaluates the current evidence and limitations of soluble TREM2 (sTREM2) as a candidate biomarker and critically appraises translational strategies targeting this pathway. TREM2 integrates lipid sensing, efferocytosis, metabolic reprogramming, and immune modulation to exert highly context-dependent effects. In early disease stages, TREM2+ macrophages participate in lipid accumulation and inflammation initiation, whereas in later phases, they contribute to plaque stabilization, tissue repair coordination and microenvironmental homeostasis. sTREM2 may serve as a dynamic indicator of macrophage activation and functional transition, but its clinical utility for risk stratification and therapeutic monitoring remains investigational. Translational approaches include agonistic antibodies, small-molecule agonists, gene/RNA-based therapies, and localized delivery systems. However, clinical progress is challenged by profound context dependency, sexual dimorphism, undefined therapeutic windows, and the absence of cardiovascular-specific clinical validation. Future advancement requires integrating multiomics technologies, biomarker-guided trials, and systems biology to move TREM2 from mechanistic insight toward precision cardiovascular immunomodulation.

Inflammation plays a central role in the pathophysiology of heart failure (HF), and contributes to disease progression, morbidity and mortality. However, the relationships between inflammatory cytokines and different HF subtypes are complex, heterogeneous and bidirectional. In this review, we examine inflammatory pathways, biomarker profiles and comorbidities in HF with reduced, mildly reduced and preserved ejection fraction, and summarize evidence on the use of high-sensitivity C-reactive protein as a biomarker for systemic inflammation in HF. We provide insights into emerging methodologies for biomarker discovery in HF, and discuss the use of animal models to elucidate underlying mechanisms and test potential treatment strategies. Finally, we provide an overview of the therapeutic landscape, touching on past challenges and future opportunities for the development of targeted anti-inflammatory therapies in HF.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. A hallmark of HF progression is profound metabolic remodeling accompanied by mitochondrial dysfunction in cardiomyocytes. Impaired mitochondrial oxidative phosphorylation, excessive reactive oxygen species (ROS) production, and disrupted redox homeostasis collectively drive oxidative damage and compromise mitochondrial integrity, ultimately leading to contractile failure, for which no viable strategies currently exist. Although mitochondrial dysfunction is now recognized as a central driver of HF pathogenesis, the upstream molecular regulators that initiate or amplify these defects remain incompletely understood. Here, we identify myocilin as a fibroblast-derived mediator that drives cardiomyocyte mitochondrial dysfunction and ROS production in HF. Myocilin was consistently upregulated in patients with HF and in murine HF models induced by transverse aortic constriction and isoproterenol, and was predominantly expressed in cardiac fibroblasts. In vivo study using male mice showed that myocilin overexpression exacerbated cardiac dysfunction and fibrosis, whereas genetic ablation markedly alleviated pathological remodeling. Using transwell systems and recombinant protein stimulation, we found that fibroblast-derived myocilin impaired mitochondrial function in cardiomyocytes, as evidenced by reduced ATP production, increased ROS, and loss of membrane potential. Mechanistically, myocilin directly interacted with SLC3A2, the heavy chain that pairs with SLC7A11 to form the cystine/glutamate antiporter, on cardiomyocytes and promoted its degradation, thereby impairing cystine uptake. This led to glutathione depletion and redox imbalance, subsequently triggering ferroptosis-associated mitochondrial dysfunction in cardiomyocytes. Collectively, these findings identify a fibroblast-cardiomyocyte signaling axis in which myocilin disrupts cardiomyocyte metabolic homeostasis. Targeting the myocilin-SLC3A2 pathway may represent a potential therapeutic strategy for HF.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with incompletely defined myocardial mechanisms. Here, using a two-hit murine model of cardiometabolic HFpEF induced by high-fat diet and endothelial nitric oxide synthase inhibition, we define a mitochondrial metabolic phenotype characterized by altered substrate handling, redox stress, and S-nitrosylation remodeling. While global proteomic changes were modest, metabolomic profiling revealed selective remodeling of tricarboxylic acid cycle intermediates, increased dicarboxylic acids, and altered redox-associated metabolites, consistent with mitochondrial metabolic and redox imbalance in this experimental setting. S-nitrosylation proteomics demonstrated a highly organized and bidirectional remodeling pattern affecting proteins involved in fatty acid/lipid metabolism, carbohydrate metabolism, mitochondrial energy metabolism, amino acid and organic acid metabolism, nucleotide/co-factor metabolism, and redox defense. Stable isotope tracing showed reduced glucose-derived and increased palmitate-derived acetyl-CoA in HFpEF, whereas Na-βHB reduced palmitate contribution and increased βHB-derived acetyl-CoA without restoring glucose contribution, indicating substrate redistribution and preserved ketone oxidation. Na-βHB supplementation increased oligomycin-sensitive respiration in freshly prepared left ventricular tissue, partially normalized selected TCA-cycle intermediates, reduced mitochondrial ROS and the NADH/NAD+ ratio, restored the GSH/GSSG ratio, and improved diastolic function without altering ejection fraction. Together, these findings define a redox-sensitive mitochondrial metabolic state in the HFD/l-NAME model and identify ketone supplementation as a partial metabolic rescue strategy in this context. At the same time, these findings highlight an important limitation of the murine HFD/l-NAME model, which should be interpreted as an experimental system for studying high-fat-induced cardiometabolic stress rather than as a metabolic equivalent of human HFpEF.

Decidual protein induced by progesterone 1 (DEPP1), also known as DEPP or C10ORF10, was originally identified as a progesterone-induced protein in endometrial stromal cells. Over the past two decades, research has progressively elucidated its involvement in various biological processes such as energy metabolism, redox regulation, and cellular autophagy. Additionally, DEPP1 has been implicated in the pathogenesis of several diseases, including diabetes, atherosclerosis, ischemic cardiomyopathy, breast cancer, and colon cancer. In this review, we systematically summarise the research progress on DEPP1, with particular emphasis on its molecular mechanisms in the crosstalk between oxidative stress and autophagy. Its cellular localization and functional uniqueness are discussed within the context of the classical redox-autophagy regulatory network. Furthermore, key issues in DEPP1 research and its potential translational applications are discussed to provide insights and perspectives for future studies centred on DEPP1.

Liver sinusoidal endothelial cells (LSECs) dysfunction was demonstrated to represent an early and persistent event in chronic heart failure (CHF), preceding congestive hepatopathy and contributing to the pathophysiology of the disease. However, it remains unknown whether classical CHF pharmacotherapy would reverse LSEC defenestration. Herein, we characterised the therapeutic effects of angiotensin-converting enzyme (ACE) inhibitor - perindopril, and sodium-glucose cotransporter 2 (SGLT2) inhibitor - empagliflozin - on the cardiohepatic axis and, in particular, on LSEC defenestration in the murine model of CHF. Untreated 6-month-old Tgαq*44 mice exhibited impaired systolic and diastolic cardiac function, impaired liver perfusion, and LSEC defenestration. Perindopril (2 mg/kg, 8 weeks treatment, 4- to 6-month-old Tgαq*44) significantly improved the left (LV) and right ventricular (RV) systolic function and ameliorated liver perfusion in vivo in Tgαq*44 mice. Perindopril also displayed a pronounced hepatoprotective effect, as evidenced by proteomic analysis of isolated hepatocytes, reduced TBIL, and GGT; however, the number of LSEC fenestrations was unaffected in Tgαq*44 mice treated with perindopril. Empagliflozin (300 mg/kg, 8 weeks treatment, 4- to 6- month-old Tgαq*44) not only significantly improved the LV and RV systolic function and ameliorated liver perfusion, but also improved diastolic cardiac function and significantly reduced defenestration of LSECs. LSEC defenestration was primarily driven by cardiac diastolic dysfunction, not by impaired liver perfusion or hepatocyte function, and was independent of biomarkers of congestive hepatopathy in the murine model of CHF in Tgαq*44 mice. As fully reversed by SGLT2-I, but not by ACE-I, LSEC defenestration arises as a target in the treatment of the cardiohepatic axis in CHF, which is not uniformly improved by CHF pharmacotherapy.

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell-derived cardiomyocytes, we investigated the role of TPM1 isoforms and TPM1's upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.

Although prompt primary percutaneous coronary intervention (PCI) reduces mortality in patients with ST-elevation myocardial infarction (STEMI), the burden of post-infarction heart failure remains considerable and is expected to increase. A major contributory factor is suboptimal myocardial reperfusion, which persists in up to 60% of cases even with timely revascularization. This is largely driven by microvascular obstruction and ischaemia-reperfusion injury, culminating in the no-reflow phenomenon, a critical prognostic factor associated with impaired infarct healing, adverse left ventricular remodelling, and increased risk of heart failure and death. No-reflow is a complex and heterogeneous phenomenon, identifiable through different invasive and noninvasive technologies. When observed post-PCI, after excluding residual epicardial stenosis, it indicates poor microvascular perfusion and necessitates urgent management. Identifying patients at high risk and implementing early targeted interventions are essential to improving outcomes. Pharmacological therapies, including intracoronary adenosine and nitroprusside, have shown unclear benefit in improving microvascular flow. Non-pharmacological strategies, such as ischaemic postconditioning, intracoronary supersaturated oxygen therapy, stent-retriever thrombectomy, and mechanical left ventricular unloading, have demonstrated promise but require further validation in large-scale clinical trials. This clinical consensus statement summarizes current strategies for the prevention and treatment of no-reflow and underscores the need for improved risk stratification and novel microvasculature-targeted therapies. Addressing this persistent and significant unmet clinical need is crucial for improving care for STEMI patients and for mitigating its long-term complications, including heart failure and mortality.

The prevalence of mechanical complications following acute myocardial infarction has steadily declined in recent years owing to advances in prompt coronary revascularization, and they now occur in <1% of acute myocardial infarction cases. Nevertheless, significant haemodynamic impairment may already be present at hospital admission, requiring immediate diagnostic evaluation and urgent intervention. Until recently, surgical repair was the only treatment option, with non-negligible in-hospital mortality rates, particularly among patients with acute cardio-circulatory failure. Advances in transcatheter percutaneous procedures have now introduced alternative treatment strategies, especially for high-risk or inoperable patients. Recurrence of post-acute myocardial infarction mechanical complications, even shortly after the repair of the underlying lesion, has a critical impact on patient outcome and underscores the need for careful monitoring during hospitalization as well as after discharge. The role of concomitant coronary revascularization remains controversial, with variable effects on both early and late outcomes, and warrants further investigation. Temporary mechanical circulatory support has shown encouraging results, either for pre-procedural haemodynamic stabilization ('bridge-to-procedure') or for prophylactic, extended peri-procedural support to facilitate myocardial recovery ('bridge-to-recovery'). Optimal management should be guided by a multidisciplinary Heart Team approach (including Shock Team involvement where appropriate) with integration of palliative care into the decision-making process.

To assess the prevalence of subclinical coronary atherosclerosis and its association with myocardial infarction, death or myocardial infarction, and clinically driven coronary revascularization in asymptomatic women and men in a Danish general population cohort. Asymptomatic women (n = 5710, 57%) and men (n = 4293, 43%) >40 years underwent coronary computed tomography angiography. The primary endpoint was myocardial infarction, while secondary endpoints were death or myocardial infarction combined and clinically driven coronary revascularization. From 40 through to >80 years of age, women had less subclinical coronary atherosclerosis than men (P for gender interaction <.0001), both in persons with and without cardiovascular risk factors. Median follow-up was 6.0 years (interquartile range: 3.9-9.5). In individuals with vs without obstructive subclinical coronary atherosclerosis, the adjusted hazard ratio for having a myocardial infarction was 4.1 (95% confidence interval: 1.5-11) in women and 12 (4.6-34) in men (P for gender interaction = .24). Corresponding hazard ratios for death or myocardial infarction combined were 1.9 (1.3-2.9) and 2.7 (1.9-3.9), respectively (P for gender interaction = .30). Finally, corresponding hazard ratios for clinically driven coronary revascularization were 23 (5.2-106) and 34 (11-106), respectively (P for gender interaction = .35). For the same degree of subclinical coronary atherosclerosis, women may have a lower risk of myocardial infarction than men. These novel findings show that in asymptomatic women and men, the presence of obstructive subclinical coronary atherosclerosis conferred a fourfold and 12-fold risk of myocardial infarction.

To investigate the effect of long-term beta-blocker therapy on physical activity (PA) level after myocardial infarction (MI) in patients without heart failure. The BETAMI trial, randomised patients hospitalised with a MI without heart failure (LVEF ≥40%) to beta-blocker or no beta-blocker. In this pre-planned sub-study PA level was assessed by guideline-recommended PA level (≥30 minutes moderate activity ≥5 days/week) or not and self-reported hours/week with light to moderate and vigorous PA. Between-group differences in PA from baseline before randomisation to 18-months were estimated by linear mixed models. Exploratory analysis assessed treatment effects on a composite of all-cause mortality and major adverse cardiovascular events using Cox proportional hazards model. Of the 2867 randomised patients, 2185 (76%) responded to the PA questions and were included in this analysis. Mean age was 62.5 (SD 10.1) years, 20.6% were women. No differences in guideline-recommended PA level or mean hours of light to moderate and vigorous PA were reported between the beta-blocker and non-beta-blocker group at baseline or during 18-months follow-up. At 12-month follow-up, 37.0% in the beta-blocker group and 36.7% in the no beta-blocker group reported guideline-recommended PA level (OR 0.97, 95% CI 0.69-1.37). Exploratory, hypothesis-generating analyses did not demonstrate a statistically significant interaction (p for interaction = 0.06) between treatment assignment and baseline PA level for recurrent clinical events. Beta-blocker therapy did not result in a change in PA level in post-MI patients without heart failure during the 18 months follow-up.

Myocardial infarction necessitates rapid and ultrasensitive point-of-care detection of cardiac troponin I (cTnI). In this work, we develop a HEAzyme-enabled interfacial electrocatalytic transduction strategy integrated with CHA-CRISPR/Cas12a amplification framework for ultrasensitive electrochemical detection of cTnI. Capitalizing on the cocktail effect and carbon-shell confinement, HEAzyme amplifies the electrochemical response by catalyzing the redox reaction of surface-confined methylene blue. Target recognition initiates CHA, generating abundant DNA activators for Cas12a trans-cleavage. The synergistic integration of molecular cascade amplification and interfacial electrocatalysis enables a limit of detection of 0.21 fg/mL across a broad linear range from 1 fg/mL to 100 pg/mL. It exhibits good selectivity, maintains good stability within 7 days (RSD = 3.9%), and shows good batch-to-batch reproducibility in different batches (RSD = 3.44 and 5.8% for intra and inter-batch, respectively). This work establishes an effective strategy for integrating CRISPR-based molecular amplification with HEAzyme-enabled interfacial electrocatalytic transduction, providing a promising electrochemical platform for point-of-care diagnosis of myocardial infarction.

The cardiovascular benefits of eicosapentaenoic acid ethyl ester (EPA-E) in MACE reduction might extend beyond its triglyceride (TG)-lowering effects. However, the mechanism behind remains unknown. This study investigated whether EPA-E exerts cardioprotection in the setting of myocardial infarction (MI). Hypertriglyceridaemia (HTG) was induced in male rats by a high-sucrose diet (>175 mg·dL-1; baseline). Hypertriglyceridaemia rats were administered for 2 weeks high-dose EPA-E supplementation (HTG + EPA-E; n = 21) or placebo (HTG; n = 27) in combination with the diet. A control diet group (CD; n = 15) was included. After 2 weeks, MI was induced by transient coronary ligation and animals were sacrificed 24 h thereafter for infarct size, molecular, histological, and -omic analyses. Echocardiography was performed. HTG + EPA-E animals displayed lower circulating TG levels and better cardiac function as compared to HTG group. HTG + EPA-E animals showed smaller infarcts (P < 0.05 vs both groups), and MI-related mortality was 29% in EPA-E-treated animals (reaching levels comparable to those of the CD group), whereas it was 56% in HTG animals (P = 0.07). No correlation was observed between circulating TG levels and MI-related infarct size or mortality. Cardiac function was similarly deteriorated in all animals post-MI. Eicosapentaenoic acid ethyl ester treatment was associated with lower TG-related cardiolipotoxicity, apoptosis, fibrosis, oxidative stress, pro-inflammatory cell recruitment and less mitochondrial dysfunction in the infarcted heart. EPA-E treatment favoured a pro-resolving response and improved metabolomic and lipidomic profiles both systemically and in the infarcted heart. Eicosapentaenoic acid ethyl ester treatment exerts direct cardioprotective effects and ameliorates cardiac metabolic and lipidomic signatures after MI regardless of its circulating TG-lowering effects.

The complex phytochemical composition of Traditional Chinese Medicines (TCM) like Ligusticum chuanxiong offers multi-target therapeutic potential, yet their intracellular mechanisms remain largely undefined due to a lack of suitable investigative tools. We report a mitochondria-targeted nanoformulation (NSCE) created by loading Chuanxiong extract (CE) into amino-functionalized mesoporous silica nanoparticles (NS). We show that the adsorbed extract components unexpectedly confer mitochondrial tropism to the simple amino-functionalized silica nanoparticles, a function not inherent to the unmodified carrier. In vitro, NSCE selectively localizes to the mitochondria of cardiomyocyte, mitigating oxidative stress and dysfunction more effectively than free CE. In a rat model of ischemia/reperfusion injury, intramyocardial NSCE injection reduces infarct size and improves cardiac function. Mechanistically, NSCE synergistically modulates p53 and PI3K/AKT pathways to suppress apoptosis and oxidative stress, an action linked to its delivery of 52 identified bioactive constituents. This work introduces a paradigm where a complex herbal extract can functionalize a simple nanocarrier for organelle-specific delivery, offering a tractable strategy to dissect and harness the multitarget pharmacology of traditional medicines.

Injectable hydrogels capable of responding to pathological microenvironmental cues represent a promising therapeutic strategy for myocardial infarction (MI). However, existing systems that can simultaneously regulate metabolic abnormalities and drive multi-pathway for diabetic MI repair remain scarce. To address this, a glucose/reactive oxygen species (ROS)-dual responsive injectable hydrogel was developed with stimulus-responsive release properties and complementary multi-target therapeutic functions. The hydrogel exhibited favorable injectability and tissue adhesion, allowing stable retention at the injury site. In vitro studies demonstrated that the glucose-sensitive component enabled controlled puerarin release, while the ROS-sensitive segment showed nitric oxide (NO)-generating capability. When applied in vivo, the hydrogel system significantly reduced local ROS levels and promoted angiogenic responses in the infarcted myocardium. Importantly, the hydrogel improves cardiomyocyte energy supply and metabolic homeostasis by enhancing mitochondrial function and regulating glucose-lipid metabolic balance. Consequently, this combined approach significantly improved both vascular regeneration and myocardial repair in diabetic rats post-MI. This work provides a novel and effective strategy for the multifunctional treatment of diabetic myocardial injury and highlights the potential of smart responsive hydrogels in managing metabolic cardiovascular disorders.

Vascular endothelial cells play a crucial role in maintaining the structural integrity and microcirculatory function of the coronary microvasculature. Endothelial dysfunction, a critical pathological process in various cardiovascular diseases including myocardial infarction (MI), leads to reduced myocardial blood flow due to a lack of nitric oxide gas inside blood vessel walls that ultimately causes inflammation, thrombosis and coronary artery obstruction. Therefore, the identification of molecular mechanisms that protect against endothelial cell injury is necessary for effective MI treatment. In this study, we identified a novel interaction between TEK receptor tyrosine kinase (TEK) and signal transducer and activator of transcription 3 (STAT3), promoting the phosphorylation and nuclear translocation of STAT3. In particular, the upregulation of STAT3 and p-STAT3 could be prevented by inhibiting the binding of STAT3 to TEK using specific STAT3 domain inhibitors. Additionally, chromatin immunoprecipitation (ChIP) analysis revealed that STAT3 acts as a transcription factor, binding to the promoter region of lysyl oxidase (LOX) and LOX propeptide (LOX-PP) and inhibiting their transcription. Notably, excessive LOX-PP has been shown to induce endothelial cell injury, leading to reduced nitric oxide synthesis, increased permeability, and impaired functionality in terms of proliferation, migration, and tube formation. These novel findings reveal a new mechanism of endothelial cell injury after myocardial ischemia and may offer new insights for developing future therapeutic approaches.

Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored. To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay. We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)-mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)-POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)-driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI. This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

Although medically tailored groceries (MTG) hold promise to improve food and nutrition security and health among patients with diet-related illnesses and social needs, few randomized trials have been performed. We enrolled 460 Medicaid-insured adults with type 2 diabetes and elevated hemoglobin A1c (HbA1c) between November 2021 and July 2022 in a randomized controlled trial of MTG in southern California. Eligibility was based on at least 2 HbA1c measurements ≥7.5% in the past year. Participants were randomized 1:1:1 to usual-care (N=153), lower-dose MTG (N=153), or higher-dose MTG (N=154) for 6 months, with the prespecified primary assessment comparing the combined MTG groups with control. MTG was provided as weekly home deliveries of healthy produce, scaled to household size ($100 to $170 per month for the lower dose and $135 to $210 per month for the higher dose), along with matched recipes and telenutrition counseling. The primary outcome was a change in HbA1c at 6 months. Secondary outcomes included changes in food security and nutrition security, measured by surveys, and hypertension and body mass index, measured during clinical care encounters; evaluation of dose-response comparing the lower-dose and higher-dose arms; and effects in key population subgroups. At baseline, mean (SD) age was 59.2 (13.2) years, 284 (64.8%) were women, 373 (85.2%) reported Hispanic ethnicity, 254 (58%) reported food insecurity, and mean (SD) HbA1c was 9.40 (1.53). Among intervention participants, 244 (83.3%) reported eating most or all food provided, and 63 (21.5%) engaged in telenutrition counseling. Compared with baseline, HbA1c declined by 0.66 points in the intervention and 0.25 points in the control group, a treatment difference of -0.40 points (95% CI, -0.73, -0.08; P=0.016). Higher-dose and lower-dose MTG produced similar reductions. Odds of food security and nutrition security increased by 2.12 (95% CI, 1.13, 3.99; P=0.020) and 3.65 (95% CI, 1.84, 7.25; P<0.001), respectively. Hypertension and body mass index did not significantly change. Results were consistent in prespecified subgroup analyses by sex, education, baseline food security, baseline nutrition security, and baseline HbA1c level. Findings were similar in analyses adjusting for baseline demographics, food insecurity, nutrition insecurity, self-reported health, comorbidities, and medication changes. In this randomized trial among Medicaid-insured, racially/ethnically diverse patients with type 2 diabetes, MTG lowered HbA1c and improved food and nutrition security. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05407376.

High intakes of fructose-containing sugars among children and adolescents is implicated in obesity and related comorbidities, including hypertension. However, sugar-sweetened beverages (SSBs), fruit juices, and whole fruit have different nutritional profiles and matrices, which may confer different effects on blood pressure. GUTS (Growing Up Today Study) is a longitudinal cohort of 25 749 individuals (55% female) drawn from 2 enrollment waves, GUTS 1 (n=16 875; baseline 1996) and GUTS II (n=10 918; baseline 2004), followed up prospectively through 2021 (mean age at enrollment, 12 years; mean age at end of follow-up, 36 years). Participants provided updated information on lifestyle, health status, and habitual diet through validated food frequency questionnaires every 1 to 4 years. We conducted multivariable adjusted Cox proportional hazards regression models to estimate the associations of total fructose and SSB, fruit juice, and whole fruit intake (cumulative averages) with incident hypertension (hazard ratios [HRs] and 95% CIs), adjusting for major diet and lifestyle factors. We also modeled substitutions of SSBs or fruit juice with whole fruit, milk, and water. During up to 25 years of follow-up, 1625 participants (6.3%) reported a hypertension diagnosis. Total fructose intake was not associated with incident hypertension (highest versus lowest quintile HR, 1.07 [95% CI, 0.92, 1.25]; Ptrend<0.001). However, participants with the highest intake of SSBs (≥2 servings/d versus <3 servings/week) and fruit juice (≥1.5 servings/d versus <1 serving/wk) had a higher risk of hypertension (HR, 1.52 [95% CI, 1.27, 1.83]; Ptrend<0.001 and HR, 1.35 [95% CI, 1.06, 1.71]; Ptrend=0.018, respectively). In contrast, whole fruit was not associated with hypertension (highest versus lowest category HR, 0.79 [95% CI, 0.59, 1.05]; Ptrend=0.08). Replacing 1 serving/d of SSB with milk, water, or whole fruit was associated with a 13% (95% CI, 5%, 20%), 9% (95% CI, 3%, 15%), and 22% (95% CI, 11%, 31%) lower risk of hypertension, respectively. In addition, replacing fruit juice with whole fruit was associated with a 19% (95% CI, 3%, 32%) lower risk of hypertension. SSB and fruit juice intakes were positively associated with a higher risk of hypertension independently of overall diet quality, physical activity, and other factors. Our findings support public health guidelines to limit the overconsumption of SSBs and fruit juice starting in childhood to protect against the development of hypertension.

Hypertensive disorders of pregnancy (HDP) are primary antecedents of maternal cardiovascular morbidity during and after pregnancy. Despite evidence that 24-hour movement behaviours, including moderate-to-vigorous and light-intensity physical activity (MVPA, LPA), sedentary behaviour (SED) and sleep, relate to cardiovascular disease risk, associations with HDP are unknown. This study identified optimal 24-hour behavioural compositions across pregnancy associated with lower HDP risk. The Pregnancy 24/7 cohort study (N=500) quantified 24-hour movement behaviours in each trimester (100-126, 200-226 and 320-346 weeks gestation) and examined associations with HDP. Participants were enrolled between 2021-2024 from three US study sites. Movement behaviours were quantified from 7-day × 24-hour monitor wear using the activPAL3 micro (MVPA, LPA and SED) and Actiwatch Spectrum Plus (sleep). HDP (gestational hypertension and pre-eclampsia) was abstracted from medical records. Compositional binomial regression models predicted HDP risk based on isometric log-ratio transformation of 24-hour movement behaviours. Optimal overlapping behavioural compositions were identified by aggregating up to three repeated assessments of 24-hour data. Among 470 participants with complete data, 86 (18.3%) developed HDP. The optimal overlapping daily composition (0-5th percentile) associated with the lowest HDP risk (7.2%) consisted of 5.9 (5.5-6.6) hours SED, 7.9 (6.4-8.9) hours LPA, 7 (2-22) minutes MVPA and 10.1 (8.5-11.3) hours sleep. Risk increased exponentially among participants with more than 10 hours/day of SED or less than 5 hours/day of LPA. SED and LPA were the strongest modifiable predictors of HDP, independent of trimester. These findings inform behavioural intervention targets to reduce the risk of HDP.

Recent studies have demonstrated a greater prevalence of coronary atherosclerosis in male masters endurance athletes, but the underlying contributors remain unclear. We explored the relationship between occult resting and exercise-induced hypertension with coronary atherosclerosis characteristics. 198 male masters endurance athletes with a low Framingham risk score (<10%) and no clinical diagnosis of hypertension underwent 24-hour ambulatory blood pressure (ABP) monitoring and exercise BP assessment. Coronary CT angiography assessed coronary artery calcification (CAC) score, luminal stenosis and high-risk plaque features. Seventy-eight (39%) athletes were hypertensive on ABP monitoring and 93 (47%) demonstrated a hypertensive response to exercise. A CAC score of 1-99 Agatston units (AU), 100-399 AU and ≥400 AU was present in 94 (47%), 32 (16%) and 15 (8%) athletes, respectively. Twenty-four (12%) athletes had coronary stenoses >50%. Sixty-two athletes (31%) had calcified plaque, 32 (16%) had mixed plaque, 2 (1%) had non-calcified plaque and 26 (13%) had markers of high-risk plaque. Hypertension on ABP monitoring was significantly associated with a CAC score ≥100 AU (OR: 2.56; 1.08 to 6.04) and coronary stenosis >50% (OR: 2.92; 1.17 to 7.33). A hypertensive response to exercise was significantly associated with coronary stenosis >50% (OR: 4.72; 1.65 to 13.5) and the presence of high-risk plaque (OR: 3.27; 1.27 to 8.43). Masters male endurance athletes have a high prevalence of occult hypertension, which is associated with high-risk features of coronary atherosclerosis. Both ambulatory and exercise-induced hypertension are associated with a higher prevalence of atherosclerotic coronary artery disease in male endurance athletes. Early identification and timely clinical management of this classic cardiovascular disease risk factor may reduce the burden of coronary atherosclerosis in athletes.

Male breast cancer is a rare but increasingly recognized disease with limited data on modifiable risk factors. Specifically, it is not known if the inverse association between cardiorespiratory fitness (CRF) and breast cancer risk reported in women is similar to the association between CRF and breast cancer in men. The study aimed to evaluate the association between CRF and the incidence of male breast cancer in a large, nationally representative cohort of U.S. Veterans. We analyzed data from 777,618 male Veterans who completed an exercise treadmill testing (ETT) between 1999 and 2024 within the Veterans Health Administration and had no evidence of breast cancer prior to the ETT. CRF was expressed in peak metabolic equivalents (METs). The cohort was categorized into 4 age-adjusted CRF categories based on the peak METs achieved. The primary outcome was incident male breast cancer, ascertained through the Veterans Affairs Computerized Patient Record System. Cox proportional hazards models were used to estimate hazard ratios (HRs) for breast cancer incidence across CRF categories, adjusted for age, race, body mass index, hypertension, diabetes (T2DM), chronic kidney disease, smoking, and alcohol use. Over a median follow-up of 10.7 years 518 men were diagnosed with breast cancer. After multivariable adjustment, age (HR = 1.24, 95% confidence interval (95%CI): 1.14-1.36) per decade, chronic kidney disease (HR = 2.13; 95%CI:1.41-3.23), hypertension (HR = 1.57; 95%CI: 1.28-1.92), T2DM (HR = 1.24; 95%CI: 1.02-1.51), and poor CRF (HR = 1.69; 95%CI: 1.24-2.30) were the strongest predictors of breast cancer. Compared to patients in the lowest CRF category, breast cancer risk was 41% lower for individuals in the highest CRF quartile (HR = 0.59; 95%CI: 0.44-0.81). Higher CRF was independently associated with a substantially lower risk of breast cancer in men. These findings suggest that CRF may represent a modifiable risk factor in the prevention of male breast cancer, underscoring the broader importance of physical fitness in reducing cancer risk across sexes.

The association of gestational diabetes mellitus (GDM) subtypes with maternal cardiometabolic health is not known. We examined whether GDM subtypes were differentially associated with cardiometabolic health 10-14 years after delivery. We used data from the prospective Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study. The exposure was GDM subtype (insulin deficient, insulin resistant, mixed defect, unclassified). The outcomes were prediabetes or diabetes and, secondarily, hypertension, dyslipidemia, metabolic syndrome, and predicted cardiovascular disease. Of 4,693 women, 3.0% had insulin-deficient, 9.0% insulin-resistant, 1.6% mixed-defect, and 0.7% unclassified GDM. Compared with no GDM, all GDM subtypes except unclassified were associated with higher risk of prediabetes or diabetes (adjusted risk ratios 2.14-2.88), metabolic syndrome, and predicted cardiovascular disease. Only insulin-resistant GDM was associated with dyslipidemia. All GDM subtypes were associated with an increased risk of prediabetes or diabetes, metabolic syndrome, and high predicted cardiovascular disease 10-14 years after delivery.

Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular diseases, yet the molecular pathways linking dietary sodium to immune activation and hypertension remain poorly defined. We previously demonstrated that sodium entry into antigen-presenting cells via the ENaC (epithelial sodium channel) promotes inflammation and salt-sensitivity of blood pressure. AP-1 (activator protein-1; c-FOS, FOSB, c-JUN, JUNB, JUND) regulates inflammatory signaling, but its role in salt-sensitivity of blood pressure has not been elucidated. We hypothesized that high salt drives AP-1-mediated inflammatory activation in antigen-presenting cells, contributing to immune dysfunction and hypertension. Using SV129 salt-sensitive mice, we assessed blood pressure responses and profiled immune cell phenotypes under normal- and high-salt conditions by flow cytometry. RNA-seq was performed on human monocytes exposed to high salt in vitro. In a clinical study, we enrolled prehypertensive subjects and performed an inpatient salt-loading/depletion protocol to characterize AP-1 gene expression signatures in salt-sensitive versus salt-resistant individuals. To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(KbDb)null (IA)null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration. High salt robustly induced AP-1 gene expression in murine monocytes. In humans, salt-sensitive but not salt-resistant subjects exhibited concordant increases in AP-1 gene expression and blood pressure during salt loading. PBMCs from salt-sensitive individuals promoted greater tissue infiltration, AP-1 activation, and immune-mediated renal and vascular dysfunction in humanized mice compared with PBMCs from salt-resistant individuals. Strikingly, pretreatment of salt-sensitive PBMCs with T5224 abrogated these effects, preserving normal renal and vascular function despite high-salt exposure. These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension.

The Cre/loxP recombination system is the main tool for cell type-specific lineage tracing and gene targeting. Currently available smooth muscle cell (SMC)-specific Cre mouse lines show off-target activity outside the SMC lineage and are unable to distinguish among arterial SMCs (ASMCs), venous SMCs, and nonvascular SMCs (NVSMCs). These limitations prevent ASMC- and NVSMC-specific gene targeting, which is required to characterize the role of SMCs in different organs and diseases. To achieve precise manipulation of ASMCs in vivo, we combined alleles for Cspg4-Dre and rox-Stop-containing Acta2-CreER (Acta2-rox-CreER), generating a mouse line with Cre activity exclusively in ASMCs. RNA sequencing of fluorescence-activated cell sorting-isolated ASMCs was used to reveal differences in ASMCs among multiple organs. To specifically target and characterize NVSMCs in different organs, a combination of Chrm2-Dre and Acta2-rox-CreER was used. Disease-specific transcriptional changes of pulmonary ASMCs and NVSMCs were determined in the Sugen 5416/hypoxia model of pulmonary arterial hypertension. Usefulness for functional studies was assessed by inactivation of the genes for the splicing factors RBPMS (RNA-binding protein with multiple splicing) and RBPMS2 (RNA-binding protein with multiple splicing 2) in ASMCs. Intersectional genetic approaches using Cspg4-Dre and Acta2-rox-CreER mouse lines specifically targeted ASMCs within various organs. A combination of Chrm2-Dre with Acta2-rox-CreER achieved specific targeting of NVSMCs. Transcriptomic profiling revealed distinct gene expression signatures in ASMCs of different organs, indicating organ-dependent transcriptional adaptation of ASMCs. Transcriptional differences among NVSMCs were found in the lung, intestine, and bladder. Activation of distinct pathways was uncovered in pulmonary ASMCs and bronchial SMCs after induction of pulmonary arterial hypertension. Inactivation of Rbpms and Rbpms2 in ASMCs increased thickness of the muscular layer in pulmonary arteries, whereas inactivation in all SMCs abolished the contractile phenotype of NVSMCs in the intestine. The successful generation of mouse lines specifically targeting different subtypes of SMCs enhances specificity, allowing distinction between vascular and nonvascular effects of diseased SMCs. The identification of vessel bed-specific gene signatures will pave the way for specific manipulation of SMCs in distinct diseased organs, such as the lung in pulmonary arterial hypertension.

Surgical myectomy (SM), performed to relieve dynamic left ventricular outflow tract obstruction in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, provides improved quality of life and symptoms and excellent long-term survival. Guidelines recommend SM in symptomatic oHCM patients refractory to optimal medical therapy. We sought to assess whether SM in patients with fewer symptoms at initial referral is associated with improved long-term outcomes in oHCM. Baseline symptom burden at the time of referral emerged as a powerful prognostic discriminator among 3546 HCM patients undergoing SM. Our findings suggest that earlier surgical referral before advanced decompensation may be associated with more favourable long-term outcomes. Women were more likely to present with advanced symptoms and had higher adjusted risk. These results underscore the need to determine whether a proactive therapeutic strategy, including an earlier intervention, can modify long-term survival in oHCM.

Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would attenuate cardiac ischemic injury. Using a mouse model of ischemia-reperfusion (I/R), we found in mice with systemic deletion of Ffar4 (Ffar4KO), loss of Ffar4 impaired the recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. The transcriptome analysis identified the downregulation of several metabolic pathways suggesting impaired mitochondrial function in the infarcted Ffar4KO myocardium. Mechanistically, basal mitochondrial function and morphology were impaired in cardiac myocytes from Ffar4KO mice corroborating the results of the transcriptome analysis. Interestingly, phosphodiesterase 6c (Pde6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 in vivo and activation of Ffar4 in cardiac myocytes in vitro attenuated ischemic/hypoxic injury respectively. Our results define a novel protective role for Ffar4 in cardiac myocytes to attenuate systolic dysfunction and prevent ischemic cardiomyopathy post I/R by preserving mitochondrial function and activating cGMP signaling.

Variants in PRKAG2 cause hypertrophic cardiomyopathy and conduction disturbances. Although prior studies associated PRKAG2-related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained. We aimed to uncover how PRKAG2 variants induce myocyte hypertrophy and electrical changes during early cardiac development. We generated transgenic zebrafish expressing wild-type or pathogenic variant Prkag2 under a myocardium-specific promoter, Tg(cmcl2:Prkag2WT) (TgWT) and Tg(cmcl2: Prkag2R299Q) (TgR299Q), respectively, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts. TgR299Q fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes. Cardiomyocyte glycogen was elevated in adult but not embryonic hearts. Despite the absence of glycogen accumulation at 6 days post-fertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations, compared to TgWT and wild-type (Tübingen/AB [TuAB]). We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q. Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament. NCX (Na+/Ca2+ exchanger) inhibition increased Ca2+ duration and diastolic Ca2+ in TgWT but not TgR299Q hearts, indicating reduced free cytosolic Ca2+ for NCX-mediated extrusion in TgR299Q. These findings suggest that enhanced AMPKγ2-myosin interaction may promote myofilament Ca2+ retention, thereby prolonging Ca2+ transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPKγ2-myosin interaction in TgR299Q hearts, and both mavacamten and vmhcl knockdown rescued the early electrophysiological abnormalities. The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation. Enhanced interactions between AMPKγ2 and myosin contributed to these early changes. Our study revealed a novel link between cellular energy sensing and contractile machinery, with therapeutic potential for modulating contractile function in cardiomyopathies.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes characterized by myocardial dysfunction and inflammatory cell death. While apoptosis repressor with caspase recruitment domain (ARC) is a known inhibitor of apoptosis, its potential role in regulating pyroptosis, a critical driver of diabetic cardiac injury-remains unexplored. In this study, we identified ARC as a potent endogenous suppressor of cardiomyocyte pyroptosis that is pathologically depleted in models of diabetes. Our findings demonstrated that overexpression of ARC, both in vitro and in diabetic mouse models, significantly alleviates high glucose-induced cardiomyocyte pyroptosis and cardiac dysfunction. We revealed that mechanistically, ARC binds to the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) via its CARD domain, thereby sequestering ASC and preventing NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly. However, under hyperglycemic conditions, we found that ARC undergoes aberrant O-GlcNAcylation at the Ser-104 residue. This modification destabilizes ARC by promoting its ubiquitin-proteasomal degradation, which subsequently releases ASC to trigger NLRP3-mediated pyroptosis. Furthermore, pharmacological inhibition of O-GlcNAcylation or restoration of ARC levels effectively rescued cardiomyocytes from pyroptotic death. In summary, our study elucidated a novel pathogenic "glucose-O-GlcNAc-ARC-pyroptosis" axis in DCM, revealing that hyperglycemia-induced O-GlcNAcylation compromises the protective function of ARC. These findings suggest that targeting the O-GlcNAc-ARC interaction represents a promising therapeutic strategy for diabetic cardiomyopathy.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined. Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide. Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress. Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.

LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic disorder characterized by conduction disease, malignant arrhythmias, myocardial fibrosis, and heart failure. Although LMNA mutations have traditionally been associated with cardiomyocyte-intrinsic defects, the mechanisms driving fibrotic remodelling remain incompletely understood. Spatial transcriptomics and integrated single-nuclei multiomics were performed on explanted human LMNA-DCM hearts to define endothelial transcriptional and epigenomic states associated with fibrosis. Patient-specific induced pluripotent stem cell-derived endothelial cells, engineered cardiac organoids, and the LMNAH222P/H222P mouse model were used to investigate RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT). Genetic and pharmacological RUNX1 inhibition strategies were evaluated in vitro and in vivo. Endothelial populations exhibiting EndoMT-associated transcriptional and epigenomic signatures were identified in human LMNA-DCM hearts. LMNA induced pluripotent stem cell-derived endothelial cells demonstrated endothelial dysfunction, mesenchymal gene activation, and epigenetic activation of RUNX1 following loss of LMNA-mediated repression. Genetic RUNX1 deletion restored endothelial identity, reversed EndoMT-associated transcriptional programmes, and normalized chromatin accessibility at endothelial regulatory loci. In multicellular cardiac organoids, endothelial RUNX1 activation impaired endothelial-cardiomyocyte signalling and cardiomyocyte contractile function, whereas endothelial-specific RUNX1 deletion restored endothelial and myocardial function. Pharmacological RUNX1 inhibition with Ro24-7429 similarly improved endothelial and cardiomyocyte function in vitro and reduced myocardial fibrosis while preserving cardiac function in LMNAH222P/H222P mice, including after disease onset. RUNX1-driven EndoMT represents a central mechanism linking LMNA mutations to fibrotic remodelling in LMNA cardiomyopathy. These findings support endothelial transcriptional reprogramming and RUNX1 signalling as potential therapeutic targets in fibrotic cardiomyopathy.

Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD. CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins. Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.

In acute ischemic stroke due to medium vessel occlusion, the relative effectiveness of intravenous thrombolysis (IVT) and endovascular therapy (EVT) remains controversial, and treatment benefits may vary across patients. We evaluated the interaction between thrombus perviousness and treatment modality on 90-day functional outcome in patients with medium vessel occlusion. This single-center retrospective cohort study analyzed 255 patients with imaging-confirmed medium vessel occlusion treated at a stroke center in China between 2018 and 2024 (154 IVT and 101 EVT with or without prior IVT). Thrombus perviousness was quantified using the thrombus perviousness index (TPI) from noncontrast computed tomography and computed tomography angiography. Multivariable logistic regression and inverse probability of treatment weighting evaluated the TPI-by-treatment interaction for 90-day functional independence (modified Rankin Scale score ≤2). Sensitivity analyses used alternative weighting strategies and a surrogate thrombus perviousness measure. The 90-day functional independence rate was similar between the IVT and EVT groups (51.9% versus 51.5%; P=0.96), and TPI was not independently associated with outcome. In the inverse probability of treatment weighting-weighted model, a significant interaction between TPI and treatment modality was observed (interaction odds ratio, 0.37 [95% CI, 0.24-0.56]; P<0.001). Higher TPI was associated with a greater likelihood of functional independence in IVT-treated patients (odds ratio per 0.05-unit increase, 1.73 [95% CI, 1.19-2.53]; P=0.005), but lower odds in EVT-treated patients (odds ratio, 0.65 [95% CI, 0.49-0.87]; P=0.003). Exploratory analyses in the IVT subgroup revealed a continuous increase in functional independence as TPI increased, without a stable cutoff. Rates of symptomatic intracranial hemorrhage and 90-day mortality did not differ between groups, and TPI was not associated with hemorrhage risk. In medium vessel occlusion, thrombus perviousness was associated with treatment outcomes, with higher perviousness favoring IVT-related benefits, whereas the use of EVT may be relatively advantageous in patients with low-perviousness thrombi.

Suboptimal clinical outcomes are common after ischemic stroke with large vessel occlusion despite current reperfusion treatment with intravenous thrombolysis and mechanical thrombectomy. Targeting residual distal arterial and microvascular occlusions with intraarterial thrombolysis has recently gained substantial interest as an adjunct to improve cerebral tissue perfusion. While recent trials provide promise in selected patients with anterior-circulation stroke, further high-quality, large-scale studies and pooled individual-patient analyses are needed. This review summarizes the evolving role of intraarterial thrombolysis over the past 3 decades and projects potential developments.

In patients with atherosclerotic internal carotid artery stenosis, the risk of subsequent ischaemic stroke is higher in those presenting with a cerebral transient ischaemic attack (TIA) than in those with amaurosis fugax (AFX; transient monocular blindness). While AFX is associated with more stable histological characteristics, the underlying molecular mechanisms remain unclear. We hypothesized that biological processes and gene expression profiles in carotid plaques of patients with AFX differ from those with cerebral TIA and stroke. We analysed carotid plaques from 2508 patients undergoing endarterectomy between 2002 and 2022. Bulk RNA sequencing (RNA-seq) was performed on 1088 plaques (136 asymptomatic, 179 AFX, 481 TIA, 292 stroke). Single-cell RNA-seq from 46 previously profiled plaques was used to identify cell-specific transcriptomic signatures. Mass spectrometry-based proteomics (n = 189) and targeted plasma proteomics (n = 1291) were used to validate the molecular differences. AFX plaques showed fewer lipid-rich cores than those from cerebral TIA [odds ratio (95% CI): 1.41 (1.03-1.94)] or stroke [1.42 (1.01-1.99)]. RNA-seq identified 408 differentially expressed genes (DEGs) between AFX and TIA and 463 between AFX and stroke (FDR < 0.1), while AFX and asymptomatic plaques showed only 10 DEGs. AFX plaques were enriched for vascular smooth muscle cell signatures and extracellular matrix remodelling, while cerebral TIA and stroke plaques exhibited macrophage-driven inflammatory molecular signatures. These transcriptomic differences were confirmed by plaque proteomic analyses. In parallel, circulating proteomic profiling revealed higher levels of inflammatory and thrombo-inflammatory markers in cerebral TIA and stroke compared with AFX. AFX plaques exhibit stable, SMC-dominant molecular signatures that differ markedly from the macrophage-driven inflammatory profiles of cerebral TIA and stroke plaques. These findings support AFX as a biologically distinct entity with potential implications for risk stratification and personalized treatment.

Multi-omics allows for the systematic analysis of molecular information for each biological layer, while also posing the challenge of extracting valuable insights from exponentially growing multi-omics data. Here, we present a roadmap for multi-omics integrated analysis using a least absolute shrinkage and selection operator (LASSO) strategy. In this study, one novel purified safflower polysaccharide (SP1) was successfully obtained. The main chain of the polysaccharide was →4)-α-D-GalpA. Infarct size measurements and histopathology analysis results revealed the significant neuroprotective effects of SP1 in rats with middle cerebral artery occlusion/reperfusion (MCAO/R). Combined transcriptomic and metabolomic analyses identified 341 differentially expressed genes and 317 metabolites altered by SP1 treatment. Ultimately, the Galnt15 gene associated with the neuroprotective effect of SP1 was further identified using the LASSO regression approach. Mechanistically, SP1 upregulated PI3K, AKT, and p-AKT, while downregulating TNF-α, NF-κB p65, p38, and p-p38, indicating that SP1 suppressed inflammation via the p38 MAPK and PI3K/AKT pathways. Molecular docking and dynamics simulation confirmed the high affinity and stability between SP1 and Galnt15. Our study provides a novel strategy to decipher the neuroprotective mechanism of SP1, which may become an effective treatment for ischemic stroke.

The coupled impairment of the cerebrovascular network and the glymphatic system is a critical pathological feature of stroke. However, comprehensively assessing this dual-pathway damage remains a significant clinical challenge. Current clinical MRI contrast agents are fundamentally limited by single-modality contrast, restricted sequence compatibility, and safety concerns, falling short of multi-parametric evaluation at clinical 3.0 T magnetic fields. To address this gap, we propose an integrated multi-sequence MRI strategy enabled by a highly translatable, bovine serum albumin (BSA)-templated Fe3O4 nanoprobe (MS-Fe3O4-Nanoagents). Rather than employing complex nanoarchitectures, we utilized a minimalist biomimetic co-precipitation approach to yield ultrasmall Fe3O4 cores (∼4.5 nm) with an optimized hydrated diameter (∼20 nm). The BSA shell creates a hydrophilic, exchange-rich interface that modulates the rotational motion of water protons, achieving a balanced T1-T2 dual-modal contrast profile (r1 = 11, r2 = 59, and r2* = 131 mM-1 s-1 at 3.0 T) with an optimal r2/r1 ratio. Phantom and in vivo MRI confirmed that the administration of MS-Fe3O4-Nanoagents robustly drives multi-sequence signal modulation-enhancing T1-weighted/mapping signals while effectively attenuating T2/SWI signals. In rat models of ischemic and hemorrhagic stroke, the versatile compatibility of this nanoprobe significantly amplified the signal-to-noise ratio and spatial resolution across multiple sequences. This capability enabled the dynamic and quantitative mapping of venous hemodynamics, microbleeds, blood-brain barrier (BBB) disruption, and delayed glymphatic clearance without the need for sequence-specific contrast agents. By repurposing a biocompatible nanomaterial into a unified multi-sequence platform, this study provides a robust diagnostic tool for the precise prognostic evaluation and therapeutic monitoring of complex post-stroke injuries.

Development of nanomedicines that can cross blood-brain barrier (BBB) for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Here, we report a hydroxylated poly(amidoamine) dendrimer-based delivery system co-loaded with the immunomodulator fibronectin (FN) protein and the antioxidant neuroprotective drug edaravone (EDV) to tackle IS. We show that generation 5 (G5) poly(amidoamine) dendrimers partially functionalized with phenylboronic acid (PBA) and fully terminated with glycidol hydroxyl groups are able to co-load FN/EDV to form G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes (NCs). The GOPFE exhibits a uniform particle size of 122.2 nm, satisfactory colloidal stability, pH/reactive oxygen species (ROS) dual-sensitive drug release behavior and favorable cytocompatibility. Benefiting from FN-mediated active targeting, the GOPFE can be efficiently internalized by microglia and neuronal cells and can cross BBB to selectively accumulate in cerebral inflammatory lesion due to the abundant dendrimer terminal hydroxyl groups and the FN-derived targeting capability. Mechanistically, the GOPFE effectively suppresses oxygen-glucose deprivation-triggered ROS overproduction, restrains excessive neuroinflammation, and ultimately alleviates neuronal apoptosis. In an IS rat model, the GOPFE preferentially accumulates in ischemic lesion, markedly reduces cerebral infarct volume, facilitates neurological functional recovery, and ameliorates ischemic BBB damage via FN-mediated angiogenesis effect. Moreover, the GOPFE orchestrates inflammatory and immune homeostasis, mitigates neuroinflammatory cascades, and attenuates neuronal damage, thereby executing comprehensive multi-target neuroprotection. Hence, the developed GOPFE NCs may hold a great promise as a targeted therapeutic nanomedicine for IS and other inflammation-related cerebrovascular diseases. STATEMENT OF SIGNIFICANCE: Development of blood-brain barrier (BBB)-crossing nanomedicines for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Herein, we design a hydroxylated phenylboronic acid (PBA)-functionalized PAMAM dendrimer of G5.N(Gly)OH-PBA (GOP) to co-load fibronectin (FN) and edaravone (EDV) for neuroprotection by reducing oxidative stress and modulating the inflammatory microenvironment in IS. The obtained G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes can cross BBB to target inflammatory lesions due to the dendrimer surface hydroxyl groups and FN-mediated recognition. In the tMCAO/R rat model of IS, GOPFE presents desired biosafety and potent synergistic therapeutic efficacy of FN and EDV to markedly reduce cerebral infarct volume, relieve oxidative stress, rescue neurons from apoptosis, promote cerebral angiogenesis, and alleviate excessive neuroinflammation for high-efficiency synergistic therapy of IS.

While inflammation and (auto-)immunity are modifiers of atherosclerosis, immunological determinants of cardiovascular risk beyond the established inflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) remain incompletely defined in humans. This exploratory proof-of-concept study aimed to detect immunological signals enriched in patients with increased cardiovascular risk. A nested case-control study was performed within the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, a single-centre prospective study of 3316 patients. Forty-four individuals with and without angiographically confirmed coronary artery disease (CAD) and defined survival status were selected for comprehensive immunophenotyping employing bulk RNA, single-cell RNA (scRNA), single-cell T-cell receptor sequencing, mass cytometry, spatial imaging, and cytokine secretion in blood immune cells. Multi-omics factor analysis was applied to identify shared transcriptional programmes. Readouts were tested for their association with CAD status and cardiovascular mortality and validated in two independent cohorts. The integrated analysis strategy revealed immunological signals not detectable with conventional biomarkers, including a prominent signature of cellular proliferation, linked to activation, memory formation, clonal expansion, interferon signalling, and cytokine secretion in T cells. Cell types and transcriptional programmes associated with CAD status and poor long-term survival were identified. These associations were independent of established inflammatory markers, hsCRP and IL-6 that originated from myeloid cells. Key findings were replicated across independent cohorts using 136 scRNA sequencing datasets. Cellular proliferation was confirmed by protein validation in atherosclerotic plaques, and signatures were evaluated as stratification tools to predict short-term outcomes in acute coronary syndromes. Multi-omic profiling of blood immune cells revealed novel immune signatures associated with CAD, short- and long-term cardiovascular disease outcomes that are independent of systemic inflammation and may be used as risk stratification tools in the future.

Inflammasome activation has emerged as a promising therapeutic target to reduce residual cardiovascular (CV) risk in patients on guideline lipid-lowering therapy. IL-1β and IL-6 have been intensively studied, whereas the role of the inflammasome-related cytokine IL-18 has gained less attention. Here we aimed to assess the associations of IL-18 with risk of coronary events and severity of atherosclerosis. The study included 4742 participants participating in a prospective Swedish Malmö Diet and Cancer (MDC) cohort study, 54 219 general population participants in the UK Biobank, and 1500 participants with Type 2 diabetes and/or known CV disease in the European multicentre SUMMIT VIP imaging study. Plasma levels of IL-18 were analysed using proximity extension assay and atherosclerosis by carotid ultrasound. The incidence of MI and CV death was registered during a 23-year follow-up for the MDC cohort and for a 15-year follow-up for the UK Biobank cohort. There were 617 cases of MI and 644 CV deaths in the MDC cohort and 2454 cases of MI and 1537 CV deaths in the UK Biobank cohort. Elevated IL-18 was associated with an increased risk of MI and CV death independent of hsCRP and IL-6 in both cohorts. In Cox proportional hazards regression models, this association was independent of major CV risk factors in the UK Biobank but not in the MDC cohort. IL-18 did not provide clinically meaningful risk reclassification in the UK Biobank cohort. The association of IL-18 with carotid atherosclerosis in the SUMMIT VIP cohort was weaker than that of IL-6. IL-18 is independently associated with risk of MI and CV death in the general population but does not improve clinical risk stratification. Targeting IL-18 directly or through inflammasome inhibition represents a promising approach for treatment of residual inflammatory risk in high-risk atherosclerosis patients that merits to be evaluated in future randomized clinical trials.

The gut microbiota is a modulator of cardiometabolic disease. Circulating imidazole propionate (ImP) is a microbiota-derived proatherogenic amino acid metabolite modulating the inflammatory response of myeloid cells, endothelial function, and glucose metabolism. This study examined the prognostic value of ImP in patients with coronary artery disease (CAD). Circulating ImP levels were measured in independent prospective cohorts of patients with acute coronary syndrome (ACS; Swiss ACS cohort n = 4787, Swiss cardiac magnetic resonance imaging cohort n = 150, German ACS cohort n = 1428) and chronic coronary syndrome (CCS; German CCS cohort n = 701). Major adverse cardiovascular events (MACE), defined as the first occurrence of a composite of death, non-fatal myocardial infarction, or non-fatal stroke after admission, were the primary endpoint. Cox models, accounting for established risk factors including the gut-derived cardiovascular risk factor trimethylamine N-oxide, were used to evaluate the predictive value of ImP. Circulating ImP was associated with more advanced CAD and with cardiometabolic characteristics including diabetes and elevated high-sensitivity C-reactive protein. High ImP was an independent predictor of MACE [Swiss ACS cohort: hazard ratio (HR) per log2 increase 1.22, 95% confidence interval (CI) 1.10-1.35, P < .001; German ACS cohort: HR 2.34, 95% CI 1.46-3.76, P < .001; German CCS cohort: HR 1.32, 95% CI 1.13-1.53, P < .001)] and of mortality (Swiss ACS cohort: HR 1.34, 95% CI 1.17-1.54, P < .001; German ACS cohort: HR 2.38, 95% CI 1.48-3.82, P < .001; German CCS cohort: HR 1.50, 95% CI 1.14-1.98, P = .004) after adjustment for established risk factors. Imidazole propionate provided predictive value beyond trimethylamine N-oxide (Swiss ACS cohort: HR 1.30, 95% CI 1.05-1.61, P = .014; German CCS cohort: HR 1.31, 95% CI 1.12-1.53, P = .001). Gut microbiota-derived ImP predicted MACE in patients with CAD independently of traditional risk factors and holds promise as a therapeutic target. Imidazole propionate may refine risk stratification for personalized secondary prevention strategies.

Coronary revascularization can be achieved via coronary artery bypass (CABG) or percutaneous coronary intervention (PCI). CABG is associated with higher peri-procedural complications and longer recovery periods but greater long-term reduction in recurrent cardiac events compared to PCI. The preferred revascularization modality depends on various clinical and anatomic factors. In general, CABG is preferable for patients with complex coronary artery disease, especially in cases of concomitant diabetes or reduced left ventricular ejection fraction. Meanwhile, PCI is preferred in patients with less extensive disease or those at high surgical risk. However, patient preference should be a key part of the treatment decision. The majority of randomized evidence is based on primarily White, non-elderly male populations from high-income countries. More robust evidence is urgently needed for patients that are female, older, non-White, and from low- or middle-income countries. In this review, we summarize the current evidence for CABG and PCI, discuss the optimal revascularization strategies for different patient populations, and highlight future directions and knowledge gaps in the field of coronary revascularization.

To determine whether soluble urokinase plasminogen activator receptor (suPAR) is modified by randomized diabetes and revascularization strategies in patients with type 2 diabetes and coronary artery disease and whether combined suPAR and hs-CRP classification refines residual cardiovascular risk stratification. In this ancillary analysis of Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D), we measured plasma suPAR and hs-CRP at baseline (n = 2,277) and 1 year (landmark cohort, n = 1,978). The primary outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Associations were assessed using sequentially adjusted Cox models. Over 1 year, suPAR was not reduced by diabetes (insulin sensitizing vs. insulin provision) or cardiac (revascularization vs. medical therapy) treatment strategies (median 2.96-3.15 ng/mL; all-treatment arm P ≥ 0.75), while hs-CRP declined substantially (median 2.07-1.30 mg/L). suPAR independently predicted the composite outcome (adjusted hazard ratio [HR] 1.40 per SD; 95% CI 1.27-1.55), unattenuated after hs-CRP adjustment. In an exploratory analysis, suPAR modified the diabetes treatment effect (P-interaction = 0.005), with insulin provision associated with worse outcomes in the highest suPAR tertile (HR 1.33; 95% CI 1.03-1.72). Baseline suPAR predicted risk in participants whose hs-CRP normalized (HR 1.45; 95% CI 1.04-2.03). Joint classification revealed a threefold gradient in event rates (7.1% to 21.6%), with elevated suPAR conferring excess risk even after hs-CRP normalization. Over 1 year, suPAR was unmodified by diabetes or revascularization strategies in BARI 2D despite intensive guideline-directed medical optimization, in contrast to hs-CRP, which declined substantially. Combined suPAR and hs-CRP classification produced a graded risk hierarchy that hs-CRP normalization alone did not resolve.

In patients on long-term oral anticoagulation (OAC), the optimal antithrombotic strategy in the setting of concomitant chronic coronary syndrome (CCS) remains unclear. We therefore performed a systematic review and meta-analysis of randomized controlled trials comparing OAC monotherapy versus OAC plus single antiplatelet therapy (combination therapy) in patients with CCS and any indication for long-term OAC.. We systematically searched PubMed/MEDLINE and Embase through February 2026 to identify trials randomizing CCS patients with an indication for long-term OAC to OAC monotherapy vs. combination therapy. Net adverse clinical events (NACE) were defined as primary composite endpoint. Key secondary outcomes included major adverse cardiovascular events (MACE), major bleeding, and major or clinically relevant non-major bleeding. Hazard ratios (HRs) were pooled using Bayesian random-effects models. Six (6) randomized trials met the inclusion criteria. Five (5) contributed to quantitative synthesis of primary and main secondary outcome measures (5,777 participants). OAC monotherapy significantly reduced NACE (HR 0.61, 95% CrI 0.43-0.85), major bleeding (HR 0.47, 95% CrI 0.30-0.71) and major or clinically relevant non-major bleeding (HR 0.47, 95% CrI 0.31-0.66) compared to combination therapy. No significant differences were observed for MACE (HR 0.83, 95% CrI 0.60-1.18), cardiovascular death (HR 0.70, 95% CrI 0.44-1.13), all-cause death, unplanned revascularisation, myocardial infarction and ischemic stroke. Prespecified subgroup analyses for NACE and MACE outcomes detected a signal of lower risk of MACE with direct oral anticoagulant monotherapy compared to monotherapy with vitamin K antagonists (p=0.02). In CCS patients on OAC, OAC monotherapy reduces bleeding events compared to combination therapy, without clear evidence of a concomitant increase in ischemic risk.

Age-specific elevation in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, previously termed "heart stress (HS)," has been associated with adverse cardiovascular disease (CVD) outcomes. Yet, HS status, as defined by longitudinal changes in NT-proBNP concentrations, may improve risk assessment for CVD and mortality in older adults. To evaluate HS status on the basis of 3-year changes in NT-proBNP concentrations with risk for total CVD and all-cause mortality in community-dwelling older adults free of prior CVD. Observational study. The ASPREE (ASPirin in Reducing Events in the Elderly) trial and subsequent observational extension (ASPREE-XT). 8454 participants (mean age, 78.0 years at year 3; 52.9% women) without prior CVD who had NT-proBNP measured at trial enrollment and year 3. Heart stress status, based on changes in NT-proBNP concentrations from enrollment to year 3, was examined in 4 categories: persistently HS-free, HS remission, incident HS, or sustained HS. The 2 coprimary outcomes were total CVD (nonfatal myocardial infarction, fatal or nonfatal stroke, coronary heart disease death, or heart failure hospitalization) and all-cause mortality. Over a median follow-up of 8.0 years, 818 CVD events and 1584 deaths occurred. At year 8, compared with the persistently HS-free category, the adjusted absolute risks (ARs) for total CVD were increased by 7.4% (95% CI, 4.8% to 10.0%) for incident HS and 6.7% (CI, 4.3% to 9.0%) for sustained HS; adjusted ARs were also increased for all-cause mortality by 6.1% (CI, 3.7% to 8.5%) for incident HS and 7.5% (CI, 5.2% to 9.8%) for sustained HS. The HS remission category had similar adjusted ARs to those of the persistently HS-free group. Observational design and predominantly White participants. Heart stress status based on longitudinal changes in NT-proBNP concentration may improve risk stratification of CVD and mortality. None.

Recent European and American dyslipidemia guideline updates mark a relevant shift in preventive cardiology. The 2025 ESC/EAS focused update and the 2026 ACC/AHA guideline share the same biological premise: low-density lipoprotein cholesterol and other apolipoprotein B-containing lipoproteins are causal drivers of atherosclerotic cardiovascular disease, and cardiovascular benefit depends on earlier, deeper, and sustained reduction of atherogenic burden. Their main differences lie in how prevention is organized in clinical practice. The European framework places greater emphasis on the explicit linkage between risk categories, predefined low-density lipoprotein cholesterol goals, and treatment escalation. The American framework gives greater operational weight to lifetime risk, coronary artery calcium, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), treatment burden, and shared decision-making more directly into treatment selection. These differences influence patient classification, treatment intensity, and incorporation of non-statin therapies, particularly in borderline-risk primary prevention, subclinical atherosclerosis, and patients requiring combination therapy beyond statins. At the same time, both documents converge on key principles: reduced tolerance for prolonged exposure to atherogenic lipoproteins, broader use of combination lipid-lowering therapy, earlier intensification after acute coronary syndromes and in very high-risk settings, and selective use of biomarkers and imaging to refine prevention. Together, they offer complementary models of contemporary lipid management.

Global Vhl knockout results in vascular defects and early lethality, limiting our knowledge of VHL (von Hippel-Lindau)/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia pathway has been implicated in cardiovascular diseases (CVDs) characterized by inflammation and vascular remodeling, such as atherosclerosis, but its involvement in Kawasaki disease (KD) remains unknown. Coronary artery dilation and vessel rupture are the most serious complications of KD. However, the molecular mechanisms underlying these cardiac events are not fully understood. We investigated the role of the VHL/HIF pathway in cardiovascular pathology and its relevance to KD. We generated a novel mouse model with genetic hyperactivation of the hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts. We characterized the model using echocardiography, magnetic resonance imaging, histology, and molecular profiling. In parallel, we examined cardiac tissues from patients with KD with fatal coronary aneurysms for evidence of HIF signaling and inflammation using immunohistochemistry. Mice with conditional deletion of Vhl in the Wt1 (Wilms tumor 1) lineage developed normally but exhibited cardiomegaly, vascular abnormalities, progressive coronary artery dilation, pericardial hemorrhage, and systemic inflammation shortly after birth. Histologic analysis revealed coronary arteritis, elastin breaks, vascular remodeling, smooth muscle cell loss, perivascular fibrosis, and frequent intracoronary thrombus formation. In addition, vascular calcification, severe cardiac inflammation, and interstitial hemorrhages were observed, culminating in sudden death between 15 and 20 weeks of age, likely due to vessel rupture. Cardiac transcriptomic profiling identified dysregulated expression of genes involved in extracellular matrix organization, epithelial-mesenchymal transition, angiogenesis, inflammation, coagulation, and calcification, indicating compromised vascular stability and increased remodeling in Vhl conditional knockout mice. Simultaneous deletion of Hif2a rescued both the cardiovascular abnormalities and transcriptomic profile observed in Vhl conditional knockout mice, implicating Hif2 (hypoxia-inducible factor 2) as a key mediator. Human KD cardiac samples showed expression of HIF2 in coronary lesions and surrounding inflammatory infiltrates, confirming hypoxia pathway activation in severe KD. Our findings establish HIF2 as a central driver of coronary inflammation, vascular remodeling, and thrombotic complications resembling those observed in severe KD. The Vhl/Wt1 conditional knockout mouse model recapitulates key cardiovascular features of KD and offers a valuable platform for mechanistic studies and therapeutic exploration.

Phthalate esters (PAEs) in wastewater treatment plants (WWTPs) are drawing increasing attention due to their potential ecological risks to surrounding ecosystems. Comprehensive characterization of PAE structures is a prerequisite for subsequent environmental impacts, which could hardly be accomplished using the traditional target or suspect method. Here, we developed a specific fragment-based screening method of PAEs based on GC-EI&PCI-Orbitrap MS, where the protonated phthalic anhydride ion (C8H5O3+, m/z 149.02332) was selected as the specific fragment. In wastewater and sludge samples collected from a typical municipal WWTP (Zhejiang Province, eastern China), 16 novel PAEs and five previously reported PAEs were discovered. Total PAE concentration in the influent reached 74,787 ng/L, with novel PAEs accounting for 62.05%. In A2O+MBR-dominated biological treatment units, 85.47-100.00% of PAEs were removed through sludge adsorption, resulting in ∑PAEs sludge concentrations as high as 177,659 μg/kg. Calculated log-transformed sediment-water partitioning coefficients (log Kd) of PAEs showed the positive correlation with the hydrophobicity and molecular weight. Compared with traditional PAEs, novel PAEs were more hydrophobic and exhibited higher ecological risks in both effluent and sludges. Overall, this study provides an effective tool for broad-spectrum screening PAEs in complicated environmental samples and highlights the occurrence and ecological risks of novel PAEs with non-negligible significance.

Concomitant use of antiseizure medications (ASMs) and direct oral anticoagulants (DOACs) is common in epilepsy, but comparative safety data remain limited. To compare risks of thromboembolic events, major bleeding, and all-cause mortality across commonly used ASMs in adults with epilepsy receiving DOACs. This was a retrospective cohort study emulating a target trial for each ASM group against an active comparator; 1:1 propensity score matching in 4 cohorts emulated randomization to estimate the per-protocol outcome of sustained ASM monotherapy. Participant data were acquired from the TriNetX Global Collaborative Network, a federated, deidentified electronic health record platform of 165 health care organizations internationally. Included in the study were adults 18 years or older with epilepsy. Individuals were excluded if there was evidence of recent use of vitamin K antagonists (VKAs) or strong non-ASM cytochrome P450 3A4/P-glycoprotein modulators and if there was a history of major vascular events in the prior year. Participant follow-up began at a prespecified 90-day landmark. Data were analyzed January to March 2026. ASM monotherapy with levetiracetam, valproate, moderate enzyme-inducing ASMs, or strong enzyme-inducing ASMs (eg, carbamazepine, phenytoin), each vs lamotrigine or lacosamide (1 pooled reference group of patients taking either drug; hereafter referred to as lamotrigine/lacosamide). The primary outcomes included primary thromboembolic composite (ischemic stroke, myocardial infarction, pulmonary or systemic/peripheral embolism), major bleeding, and all-cause mortality. Sensitivity analyses included patients treated with VKAs. Of 2.29 million adults (≥18 years) with epilepsy, 40 932 were DOAC eligible, 26 962 had DOAC-ASM overlap within 6 months, 10 209 were monotherapy eligible, and 9529 initiators formed the analytic cohort. Among 9529 initiators (mean [SD] age, 63 [18] years; 4869 female [51%]), there were 5473 (57%) taking levetiracetam, 1395 (15%) taking strong enzyme-inducing ASMs, 1006 (11%) taking valproate, and 382 (4%) taking moderate enzyme-inducing ASMs. In matched analyses vs lamotrigine/lacosamide, levetiracetam was associated with higher thromboembolic risk (hazard ratio [HR], 1.98; 95% CI, 1.37-2.87) and higher all-cause mortality (HR, 1.60; 95% CI, 1.23-2.08), with comparable major bleeding. Strong enzyme-inducing ASMs were associated with higher thromboembolic risk (HR, 1.55; 95% CI, 1.02-2.36) but lower major bleeding (HR, 0.62; 95% CI, 0.46-0.83). Valproate was associated with higher mortality (HR, 1.49; 95% CI, 1.09-2.04) and higher intracranial major bleeding (HR, 3.01; 95% CI, 1.45-6.26). Approximately 28% of thromboembolic events were potentially preventable under a lamotrigine/lacosamide reference. In VKA-treated adults, thromboembolic risks were near null. Results suggest that in adults with epilepsy who are treated with DOACs, ASM selection was associated with distinct thromboembolic, bleeding, and mortality risks, supporting ASM choice as a modifiable contributor to clinical outcomes.

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are proven effective in atherosclerotic cardiovascular disease (ASCVD), but real-world evidence for proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) monoclonal antibodies (mAb) remains limited. This study evaluated their impact in patients with ASCVD without prior ischaemic events. Patients initiating PCSK9i mAb from January 2016 to December 2022 were identified in the Optum Research Database. A 1:2 propensity score-matched comparator cohort of PCSK9i non-initiators was developed. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal ischaemic stroke, or all-cause mortality. Key outcomes from the parametric G-formula were 5-year event rates, relative risk reduction (RRR) and absolute risk reduction (ARR), with intention-to-treat (ITT) analysis. Additional outcomes for PCSK9i mAb initiators included absolute and percent LDL-C reduction from baseline. Overall, 19 670 patients met selection criteria (6545 PCSK9i mAb initiators; 13 125 non-initiators). Baseline characteristics were well-balanced. Under ITT, estimated 5-year event rates were 17.5% [95% confidence interval (CI) 15.5%, 19.5%] with PCSK9i mAb vs 25.4% (95% CI 23.6%, 27.1%) without PCSK9i, yielding a RRR of 30.9% and ARR of 7.8%. Individual endpoints showed RRRs of 28.3% for myocardial infarction (P < .0001), 26.4% for ischaemic stroke (P = .02), and 28.5% for all-cause mortality (P < .0001). Among initiators, mean baseline and follow-up LDL-C were 117.8 and 54.7 mg/dL (on-treatment analysis), respectively, representing an absolute reduction of 63.1 mg/dL and percent reduction of 53.6%. In ASCVD patients without prior events in clinical practice, PCSK9i mAb treatment was associated with lower ischaemic event and mortality rates.

The optimal timing of adjunctive vasopressin after norepinephrine escalation in septic shock remains uncertain. We emulated a target trial comparing ultra-early vasopressin initiation within 0-3 h with early initiation within > 3-6 h after the norepinephrine infusion rate reached 0.25 μg/kg/min or higher. We emulated a target trial using electronic health record databases (MIMIC-IV 2008-2022 and eICU-CRD 2014-2015). Adults with septic shock who reached the norepinephrine threshold before vasopressin use were eligible. We used the clone-censor-weight method to estimate cumulative incidence curves under the ultra-early and early initiation strategies and compared them via the weighted Cox model. Among 3810 eligible patients, after cloning, 744 clones adhered to the ultra-early strategy and 293 clones adhered to the early strategy. The weighted 28-day mortality risk was 48.1% under the ultra-early strategy and 53.0% under the early strategy (risk difference, - 5.0 percentage points; 95% confidence interval [CI] - 6.8 to - 3.2), with a restricted mean survival time difference of 1.58 days (95% CI 1.21-1.92) and a hazard ratio (HR) of 0.82 (95% CI 0.78-0.85). Ultra-early initiation was associated with lower renal replacement therapy (HR, 0.68; 95% CI 0.63-0.74), continuous renal replacement therapy (HR, 0.61; 95% CI 0.55-0.68), and medically treated arrhythmia (HR, 0.91; 95% CI 0.83-0.99), but not with lower acute kidney injury. Among adults with septic shock whose norepinephrine infusion reached 0.25 μg/kg/min or higher before vasopressin use, vasopressin initiation within 0-3 h was associated with lower 28-day mortality than initiation within > 3-6 h.

Single-nucleotide polymorphisms (SNPs) from distinct linkage blocks in the chromosomal region 4q25 (rs1448818, rs2200733, and rs10033464) are associated with increased risk of atrial fibrillation (AF), but their impact on cardiomyocyte and atrial function remains elusive. Here, we tested the hypothesis that these SNPs have differential effects on calcium homeostasis that may afford SNP-specific targets and help explain their impact on atrial function. Analysis of 391 008 individuals from the UK biobank revealed that the three risk alleles increased incident AF during 10-year period in a dose-dependent manner and that genetic and clinical risk was additive for the rs2200733 risk variant. Analyses of PITX2C mRNA expression in human atrial tissue showed that the rs2200733 risk variant increased PITX2C expression. Moreover, patch-clamp analyses in human atrial myocytes from 66 patients without AF revealed that L-type calcium current (ICaL) was significantly reduced in carriers of the rs1448818 risk allele only. In contrast, the transient inward current (ITI) frequency was significantly higher in carriers of rs2200733 or rs10033464 risk alleles only. This concurred with increased sarcoplasmic reticulum calcium load in those with the rs10033464 risk allele, while myocytes with the rs2200733 risk allele had increased ryanodine receptor 2 phosphorylation at Ser2808 (n = 119) and displayed pronounced beat-to-beat alternation when paced. Finally, linear regression analyses of cardiac magnetic resonance imaging data from 39 391 individuals in the UK biobank without AF showed that beta-values for minimal and maximal left atrial volume were increased and active ejection fraction decreased in carriers of rs1448818 or rs2200733 risk alleles but preserved in individuals with the rs10033464 risk allele. Distinct 4q25 risk SNPs produce differential alterations in intracellular calcium homeostasis that may help understand their impact on atrial function or rhythm. Moreover, the findings suggest that genotype-tailored strategies aiming to restore ICaL density may be effective for rs1448818, while attenuation of spontaneous calcium release may be suitable for rs2200733 or rs10033464 variants.

Use of non-vitamin K oral anticoagulants (NOACs) is associated with reduced dementia risk in patients with atrial fibrillation (AF), but their impact on cognitive function and clinical outcomes in AF patients with Alzheimer's disease (AD) remains unclear. Based on the Swedish Registry for Cognitive/Dementia Disorders, individuals with incident AD during May 2007-December 2020 and pre-existing AF were identified. Anticoagulant use at baseline was categorized as non-use, warfarin, or NOACs. Inverse probability of treatment weighting was employed to balance covariates. Mixed-effects models were used to assess the association between anticoagulant use and cognitive decline measured by the Mini-Mental State Examination (MMSE). Cox proportional hazards models were used to examine risks of all-cause mortality, ischaemic stroke/systemic embolism, major bleeding, and fracture. Among 7308 eligible individuals (3341 non-users, 2277 warfarin users, and 1690 NOAC users), NOAC users exhibited significantly slower cognitive decline compared to non-users (difference in MMSE scores β = 0.23 points/year, 95% confidence interval [CI] 0.11-0.36) and warfarin users (β = 0.21 points/year, 95% CI 0.10-0.33). Compared to non-use of anticoagulants, NOAC use was associated with significantly lower rates of mortality (hazard ratio [HR] 0.81; 95% CI 0.72-0.91), ischaemic stroke/systemic embolism (HR 0.66; 95% CI 0.53-0.82), and fracture (HR 0.79; 95% CI 0.64-0.97), without an increased rate of major bleeding (HR 1.05; 95% CI 0.84-1.32); in contrast, warfarin use was associated with significantly lower rates of mortality (HR 0.88; 95% CI 0.80-0.97) and ischaemic stroke/systemic embolism (HR 0.85; 95% CI 0.72-1.00), but a higher rate of major bleeding (HR 1.31; 95% CI 1.09-1.56). Compared to warfarin, NOAC use was associated with lower rates of ischaemic stroke/systemic embolism (HR 0.78; 95% CI 0.62-0.98) and major bleeding (HR 0.80; 95% CI 0.64-1.01), and non-significant reductions in mortality and fracture. In patients with AF and AD, NOAC use was associated with modestly slower cognitive decline and more favourable effectiveness and safety profiles, compared to warfarin or no anticoagulation.

Whether direct oral anticoagulants (DOACs) are a safe and effective alternative to warfarin in patients with atrial fibrillation and mitral stenosis (AF-MS) remains controversial. To evaluate the effectiveness and safety of DOACs versus warfarin in patients with AF-MS. Observational cohort study using target trial emulation. Population-wide insurance claims data in Taiwan. Patients diagnosed with AF-MS and prescribed either DOACs or warfarin between 1 January 2011 and 31 December 2021 were included in the study. DOACs or warfarin. Absolute risk differences (RDs) and risk ratios (RRs) at 1 year and 5 years of follow-up for ischemic stroke, systemic embolism, composite stroke, myocardial infarction (MI), intracranial hemorrhage, gastrointestinal bleeding, bleeding at other critical sites, and all-cause death. Compared with warfarin, DOACs were associated with an increased risk for ischemic stroke (RD, 4.97 percentage points [95% CI, 1.27 to 8.57 percentage points]; RR, 1.22 [CI, 1.05 to 1.41]) and composite stroke (RD, 5.56 percentage points [CI, 1.77 to 8.97 percentage points]; RR, 1.23 [CI, 1.07 to 1.42]) and a decreased risk for MI (RD, -1.61 percentage points [CI, -3.17 to -0.03 percentage points]; RR, 0.61 [CI, 0.37 to 0.99]) at the 1-year follow-up. Rivaroxaban increased the risk for ischemic stroke during both short- and long-term follow-up periods. The 2 groups did not differ in risks for bleeding or all-cause death. Limited sample size, lack of detailed information on MS severity, and lack of international normalized ratio measurements. In Asian patients with AF-MS, DOACs were associated with an increased 1-year risk for stroke but a decreased risk for MI compared with warfarin. Research Grants Council of Hong Kong.

Inflammation is associated with atrial fibrillation (AF), but its precise impact on the long-term progression of the AF substrate, also called atrial cardiomyopathy (ACM), remains debated. Human atria specimens were used for spatial transcriptomic, histology, epicardial progenitor cell (EPDCs) culture and immunofluorescence. Atria removed from B6J mice fed a high fat diet (HFD) were evaluated at 2 and 4 months of diet with single-cell RNA sequencing, microscopy and flow cytometer. Lyve1-resident macrophages deficient and CCR2 (C-C chemokine receptor type 2) knockout mice and their wild type littermates were evaluated in terms of ACM, cardiac structure, metabolic diseases, histology, immune cells characterization and key molecular markers. Olink assay was performed to screen plasma samples and the cellular secretome for various cytokines. Primary THP1-derived macrophages were cocultured with EPDCs and evaluated for myofibroblast differentiation. Macrophage subpopulations were mainly confined in the EAT of human atria. In a mouse model of obesity and ACM, macrophage recruitment was associated with atrial adiposity. In addition, Lyve1+-resident and CCR2+ monocyte-derived macrophages were identified in obese mouse atria. Depleting Lyve1+-macrophages in mice prevented early fat expansion and led to myocardial dystrophy, while CCR2+-macrophage depletion prevented fibro-fatty remodeling, atrial dilation, and AF. These data highlight the pivotal role of macrophages in atrial adiposity, in particular that of Lyve1+-macrophages during adipose tissue expansion.

To characterise the non-linear joint dose-response relationship of accelerometer-measured moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF, estimated as maximal oxygen uptake (VO₂max)) with incident cardiovascular disease (CVD), and to assess causal consistency using Mendelian randomisation (MR). We conducted a cohort study in the UK Biobank using accelerometer data linked to hospital and death registries. A Cox generalised additive model characterised the joint MVPA-CRF association with incident CVD (atrial fibrillation, myocardial infarction, heart failure (HF) and stroke), adjusting for confounders. We derived a fitness-stratified matrix quantifying the weekly MVPA minutes associated with prespecified relative hazard reductions. Complementary two-sample MR analyses leveraged genome-wide association study summary statistics for device-measured physical activity (PA) traits and CRF to assess potential causal effects on cardiovascular outcomes. Among 17 088 participants, 1233 incident CVD events occurred over a median follow-up of 7.85 years (IQR, 7.39-8.27). A significant non-linear interaction between MVPA and CRF was observed (p<0.001). Meeting the 150 min/week guideline yielded a modest ~8%-9% risk reduction across fitness levels, whereas achieving a >30% risk reduction required threefold to fourfold higher volumes (~560-610 min/week). Residual analysis indicated that fitness beyond what MVPA and covariates predicted retained a modest protective association with CVD risk (HR, 0.98 per 1 mL/kg/min; 95% CI 0.97 to 0.99; p<0.001). In MR analyses, genetically proxied higher CRF was associated with lower HF risk (OR, 0.79; 95% CI 0.63 to 0.99), whereas genetic evidence for PA traits was weaker and less consistent. Current MVPA guidelines provide a universal but modest safety margin, whereas optimal cardiovascular protection may require substantially higher activity volumes. The fitness-stratified prescription matrix offers quantitative behavioural targets, and genetic findings reinforce the independent importance of CRF in cardiovascular risk reduction.

The growing global emphasis on health consciousness has significantly increased demand for traditional and complementary medicine products, including functional foods, nutraceuicals, and medicine and food homologous substances (MFHs). The rising prevalence of chronic diseases and the shift toward preventive healthcare have accelerated this market expansion. Although MFHs have been applied for hundreds of years in traditional healthcare systems, contemporary research faces a critical knowledge gap in the systematic organization of scientific evidence. This review systematically summarizes the major bioactive compounds and extraction methods of MFHs with therapeutic potential against MetS. It further discusses the molecular mechanisms underlying their effects on hypertension, hyperglycemia, dyslipidemia, and hyperuricemia, while highlighting current challenges related to safety and clinical translation. MFHs contain diverse bioactive constituents, including polysaccharides, saponins, flavonoids, polyphenols, alkaloids, and terpenoids, which exert beneficial effects on multiple components of MetS through the regulation of oxidative stress, inflammation, energy metabolism, and other signaling pathways. Conventional and emerging extraction technologies have improved the recovery and utilization of these compounds, supporting their applications in functional foods, nutraceuticals, and therapeutic products. Despite promising preclinical evidence, further studies are required to standardize extraction processes, validate efficacy and safety, and strengthen clinical evidence to facilitate the development and application of MFHs in MetS prevention and management.

Platelets are central to hemostasis and thrombosis. Excessive platelet activation contributes to arterial thrombotic events, including myocardial infarction, ischemic stroke, and complications of peripheral artery disease, whereas excessive platelet inhibition increases bleeding risk. Antiplatelet therapy remains a cornerstone of secondary prevention in atherosclerotic and thrombotic cardiovascular diseases, yet current treatment paradigms do not fully account for biological heterogeneity in platelet function, including differences related to sex, age, hormonal status, and disease context. This state-of-the-art review examines current antiplatelet strategies, fundamental mechanisms of signal transduction, clinical indications, and limitations of preclinical and clinical studies, with a focus on sex-specific considerations and opportunities for personalized antiplatelet therapy. Aspirin and P2Y12 receptor antagonists are widely used for secondary prevention. However, women have been underrepresented in many pivotal clinical trials, limiting the precision of sex-specific estimates of efficacy and bleeding risk. In parallel, commonly used preclinical models often fail to recapitulate the physiological conditions in which platelets interact with the vasculature, leukocytes, and soluble factors. Emerging therapeutic approaches seek to refine platelet inhibition by targeting pathways that reduce thrombotic risk while preserving hemostasis. Advancing antiplatelet therapy will require integration of mechanistic platelet biology with diverse clinical trial populations, standardized platelet phenotyping, and disease-specific approaches that account for how platelet function is altered across health and vascular disease.

Mitochondrial heteroplasmy represents a fundamental determinant of mitochondrial function and disease, yet its consequences vary across different tissues. Although mitotic tissues possess mechanisms, such as cell division and mitochondrial turnover, to dilute or remove deleterious variants, postmitotic tissues lack this renewal capacity and are disproportionately vulnerable. Neuromuscular and neurodegenerative disorders have illustrated the impact of heteroplasmic mutations, but the (postmitotic) heart remains underexplored. Current reliance on blood-derived samples provides only an indirect view of cardiac heteroplasmy, highlighting the need for alternative approaches, such as endomyocardial biopsies and human induced pluripotent stem cell-derived cardiomyocytes. Expanding cardiac-focused research is essential for identification, clarifying pathogenesis, improving risk stratification, and guiding patient monitoring. Emerging therapies, including mitochondrial transplantation and mitochondrial-targeted DNA editing, demonstrate potential to modulate heteroplasmy and restore equilibrium. Integrating these strategies with precision medicine will be vital for addressing tissue-specific vulnerabilities. Ultimately, bridging the gap in cardiac heteroplasmy research will be critical for translating basic mitochondrial biology into meaningful clinical advances.

Carbon dioxide (CO2) can regulate blood flow and is applied therapeutically in intensive care units to treat brain injury, as well as in balneotherapy for peripheral arterial disease (PAD) and diabetic angiopathy; however, its mode of action remains unclear. The vasoactive CO2 effects were tested in arteries of healthy C57BL/6J mice, hypertensive apolipoprotein E-deficient mice, and soluble guanylyl cyclase (sGC) knockout mice in a small vessel myograph with and without pharmacologically intervening in endothelium- and/or vascular smooth muscle-mediated vasodilation. CO2-based near-infrared spectroscopy (NIRS-CO2) was developed to assess vasoreactivity of the skin microcirculation to CO2 in healthy individuals, PAD and coronary artery disease (CAD) patients, and was compared with flow-mediated dilation (FMD). We identified CO2 as a triple vasodilator mimicking the actions of endothelium-derived relaxing factor (nitric oxide, NO), endothelium-derived hyperpolarization factor, and direct myogenic vasodilators. CO2 engaged endothelial NO/sGC, endothelial small-/intermediate-conductance calcium-activated potassium channels (SKCa/IKCa), and myogenic voltage-gated (KV) and IKCa potassium channels, respectively, acting as a triple vasodilator. CO2-evoked vasodilator responses were blunted and delayed in diseased human and murine arteries. In the human cohort, the NIRS-CO2-derived time-to-intersection of the HbO2 and HHb curves, capturing the delay phenotype, showed a strong association with PAD/CAD status and, in exploratory analyses, also distinguished young individuals with cardiovascular risk factors, supporting NIRS-CO2 as a physiological readout that integrates endothelial and myogenic components of microvascular reactivity. Duration and extent of CO2 vasodilation were coupled to tissue metabolism through vascular carbonic anhydrases (CAs), providing a mechanism for vasculometabolic coupling and one for clinically approved CA inhibitors. NIRS-CO2 provides a feasible readout of CO2-evoked microvascular responsiveness and shows disease-associated alterations in our PAD/CAD cohort. Larger studies will validate generalizability across vasculopathies and clarify the relative contributions of NO-sGC vs. K+ channel-linked mechanisms for future therapeutic translation.

Metabolic syndrome (MetS) includes obesity, insulin resistance, hypertension, and dyslipidemia. While androgen deprivation therapy (ADT) is associated with an increased risk of dyslipidemia, adiposity, and MetS, evidence is limited on the occurrence and timing of metabolic dysfunction among men receiving concurrent androgen receptor pathway inhibitor (ARPI) therapy and whether patterns vary by age. To characterize the occurrence and rate of MetS during the first year following initiation of ADT-ARPI, examine associations with age and ARPI type, and evaluate component metabolic outcomes (secondary end points). This retrospective cohort study of adult patients from January 2014 to September 2025 with up to 12 months of follow-up per person used data from a national, deidentified health record dataset (Epic Cosmos) and included patients with prostate cancer who initiated treatment with ADT-ARPI (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) without evidence of MetS or its components before treatment. Data were analyzed between October 2025 and January 2026 (further analyses were done with revisions through May 2026). Concurrent ADT and ARPI use, with index date defined as the first date of overlap between therapies. New-onset MetS during the 12 months following the index date. Secondary outcomes included individual metabolic abnormalities. The cohort included 16 924 men with prostate cancer (mean [SD] age, 73.1 [9.1] y; 509 [3.0%] Asian individuals, 912 [5.4%] Hispanic individuals, 3562 [21.0%] non-Hispanic Black individuals, and 11 083 [65.5%] non-Hispanic White individuals). Medical ADT use predominated, and enzalutamide was the most frequently used ARPI. During the first year following initiation of concurrent ADT and ARPI therapy, the cumulative incidence of metabolic syndrome increased steadily, reaching nearly 40%, and varied by age group. Hypertension was the most frequently documented component outcome. Metabolic associations varied by age, with the highest incidence of metabolic syndrome among patients aged 70 to 79 years (51.7 events per 1000 person-months; 95% CI, 50.7-53.9). Heterogeneity in metabolic outcomes by ARPI type was observed in exploratory analyses. This study found that while ARPIs are standard of care for advanced prostate cancer, metabolic abnormalities were frequently documented shortly after initiation of concurrent ADT and ARPI therapy. This suggests that monitoring should extend beyond cancer-specific outcomes to include early detection of metabolic dysfunction, ideally through multidisciplinary care. The early burden of metabolic abnormalities highlights the need to evaluate scalable interventions addressing cardiometabolic risk in men with prostate cancer.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by extracellular myocardial ATTR amyloid infiltration. Vutrisiran, an RNA interference therapeutic that suppresses hepatic TTR production, met its primary end point in the HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) trial. Multiparametric cardiovascular magnetic resonance (CMR) imaging provides high-fidelity structural and functional assessment, including tissue characterization metrics, namely extracellular volume (ECV) mapping, that can track cardiac amyloid load. To analyze the association between treatment with vutrisiran and changes in cardiac structure, function, and amyloid burden by CMR imaging. This was a retrospective post hoc analysis of CMR data from participants in the UK HELIOS-B trial. This was a single-center study conducted at the UK National Amyloidosis Centre (NAC). The study population comprised participants from the HELIOS-B trial at the NAC who underwent CMR imaging at baseline and 1-, 2-, and 3-year time points as part of routine clinical care. Study data were analyzed March to April 2025. CMR imaging during the HELIOS-B trial between April 2020 and August 2024. CMR parameters of cardiac structure, volumetrics, function, and amyloid burden were assessed. Amyloid regression and progression were defined as absolute reductions and increases in ECV of 5% or greater, respectively. Analysis was blinded to treatment allocation. Changes in CMR parameters between baseline and follow-up were evaluated; a mixed-model analysis was used to assess treatment effect. Sensitivity analyses were conducted using the last observation carried forward. A total of 43 patients (mean [SD] age, 75.0 [5.7] years, 41 male [95.3%]) underwent baseline CMR imaging (21 [48.8%] received vutrisiran; 22 [51.2%] received placebo). Thirty-nine patients (21 received vutrisiran, 18 received placebo), 26 (14 received vutrisiran, 12 received placebo), and 17 (9 received vutrisiran, 8 received placebo) underwent 1-, 2-, and 3-year CMR imaging, respectively. Baseline parameters were comparable between groups. No patients received background tafamidis. Treatment with vutrisiran was associated with statistically significant and directionally favorable changes in biventricular ejection fractions (left ventricular ejection fraction least-squares mean difference, 19.18%; 95% CI, 11.76%-26.60%; P < .001; right ventricular ejection fraction, 16.28%; 95% CI, 9.58%-22.97%; P < .001) and stroke volumes (left ventricular stroke volume, 27.82 mL; 95% CI, 13.40-42.23 mL; P < .001; right ventricular stroke volume, 23.69 mL; 95% CI, 8.06-39.32 mL; P = .003), as well as reductions in left ventricular mass (-23.58 g; 95% CI, -38.78 to -8.39 g; P = .002) and ECV (-6.56%; 95% CI, -10.10% to -3.01%; P < .001). At 36 months, amyloid regression was observed in 2 of 9 patients (22%) taking vutrisiran, and no patients receiving placebo experienced regression. Conversely, 5 of 8 patients (63%) receiving placebo demonstrated progression vs 1 of 9 patients (11%) taking vutrisiran. Results of this selected ATTR-CM cohort study show that treatment with vutrisiran was associated with favorable changes in parameters relating to cardiac structure, function, and amyloid burden.

To improve survival of patients at risk of sudden cardiac death, subcutaneous implantable cardioverter defibrillators (S-ICDs) require optimal implant positioning for effective shocks. Defibrillation (DF) testing is recommended but carries serious risks. The PRAETORIAN score predicts defibrillation outcomes on the basis of chest X-ray. The PRAETORIAN-DFT (Prospective Randomized Comparative Trial of Subcutaneous Implantable Cardioverter Defibrillator Implantation With and Without Defibrillation Testing) trial evaluated whether omission of DF testing guided by the PRAETORIAN score is noninferior for first-shock efficacy. In this multinational trial, S-ICD patients from 37 centers were randomized to DF testing or no DF testing. In the No-DF testing group, the PRAETORIAN score was evaluated before discharge. The primary end point was failed first shock for spontaneous ventricular arrhythmias, as a surrogate for defibrillation success, tested for noninferiority with a 3% absolute risk margin. Secondary end points included mortality, potential DF testing-related complications, and S-ICD revisions. The included 965 patients (No-DF testing, n=483; DF testing, n=482) were followed for a median of 41 months. Failed first shock for spontaneous ventricular arrhythmia occurred in 1.7% of the No-DF testing group versus 2.3% of the DF testing group (-0.6% [95% CI, -2.6 to 1.4], P<0.001). There were no significant differences in all-cause mortality (hazard ratio [HR], 0.9 [95% CI, 0.6-1.4]) or arrhythmic death (HR, 0.4 [95% CI, 0.04-3.4]). Potential DF testing-related complications occurred in 1.7% in the DF testing group. Postoperative S-ICD revisions due to inadequate positioning were identical between groups (n=2 each). PRAETORIAN score-guided omission of DF testing after S-ICD implantation did not increase the risk of failed first shocks for spontaneous ventricular arrhythmias and reduced procedural risk without increasing S-ICD revisions. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03495297.

Despite many advances in the last 75 years in the fight against cardiovascular disease mortality, it remains the leading cause of death worldwide. Despite improved therapeutic approaches, cardiovascular disease remains the leading cause of death worldwide. Mounting evidence suggests that restricting food intake to a limited period in the day or extending periods of fasting may be a lifestyle intervention that reduces progression of cardiovascular disease. Various protocols for time-restricted feeding paradigms suggest significant benefits throughout the cardiovascular system. Despite some limitations to their use, the general mechanisms is thought to revolve around circadian alignment of cellular and organ function with behavioral and environmental patterns. Here we review recent evidence in a rapidly expanding field that strives to understand how timing of food intake regulates circadian physiology of cardiovascular systems focusing on heart, vascular, and neuroendocrine physiology. We review both preclinical and clinical reports showing how timed feeding may alter organ function in both health and disease.