Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH.

Pathogenic variants in ALPK3 (α-protein kinase 3), an atypical α‑kinase acting as a sarcomeric M-band scaffold, cause cardiomyopathy with severity linked to zygosity. We present a comprehensive review with systematic curation of peer-reviewed clinical and experimental reports through June 9, 2025, encompassing 156 patient-level variants and all published preclinical models. Biallelic loss-of-function variants lead to severe, often lethal cardiomyopathy with prenatal or early onset presentation and extracardiac involvement. Heterozygous protein-truncating variants, defined as nonsense or frameshift (resulting from insertion/deletion events or splicing mutations), explain ≈1% to 4% of adult hypertrophic cardiomyopathy, often with apical/septal hypertrophy, right ventricular involvement, fibrosis, and risk of progression. ALPK3 lacks catalytic activity and maintains sarcomeric proteostasis by scaffolding MYOMs (myomesins), MuRF (muscle ring-finger protein) E3 ligases, and SQSTM1 (sequestosome-1)/p62. Loss of this scaffolding function displaces MYOMs, drives thick‑filament protein aggregation, and precipitates severe contractile dysfunction in human induced pluripotent stem cell-derived cardiomyocytes and multiple mouse models. Therapeutic proof‑of‑concept has now been achieved on 2 fronts: (1) pharmacological correction of sarcomeric hypercontractility with the myosin inhibitor mavacamten and (2) durable phenotypic rescue in global knockout mice using an adeno-associated virus-delivered miniALPK3 gene‑replacement construct. Together, these data position ALPK3 cardiomyopathy as a compelling target for precision medicine. Early genetic diagnosis, genotype-tailored surveillance, and focused development of gene-replacement or editing strategies, potentially combined with modulators of the ALPK3-MuRF proteostatic axis, offer a realistic path to disease-modifying therapy for this once enigmatic condition.

Drug-coated balloons (DCBs) are now a Food and Drug Administration-approved treatment option for the management of in-stent restenosis (ISR) based on superior outcomes compared with plain old balloon angioplasty (POBA) alone. However, the efficacy of DCB compared with drug-eluting stent (DES; repeat stenting) for ISR is uncertain, with prior studies showing inferiority of DCB. We aimed to compare the outcomes of DES, DCB, or POBA in patients with coronary ISR.

The role of cardiac magnetic resonance (CMR) quantification of tricuspid regurgitation (TR) to identify high-risk patients with TR remains poorly defined. The aim of this study was to assess the prognostic relevance of TR quantification and of its consequences by CMR in a large real-world cohort.

Cardiorespiratory fitness is an integrative measure of cardiometabolic health and predictor of survival, yet little is known about its molecular underpinnings. Small molecule metabolites and lipids are increasingly recognized as exercise-stimulated signaling molecules and candidate molecular transducers of cardiorespiratory fitness.

Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis.

The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against a range of hospitalization end points versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular outcomes and in those with pre-existing cardiovascular disease (CVD) is not well elucidated.

Cardiac allograft vasculopathy is an important cause of mortality after heart transplantation (HT). Dyslipidemia is a major contributor to the development of cardiac allograft vasculopathy. The safety and effectiveness of proprotein convertase subtilisin/kexin 9 inhibition to lower cholesterol and to prevent cardiac allograft vasculopathy early after HT are not well established.

Mavacamten has been shown to improve cardiac function and symptoms in patients with symptomatic (New York Heart Association class II-III) obstructive hypertrophic cardiomyopathy (HCM). Clinical studies suggest that mavacamten monotherapy is efficacious and has a favorable safety profile, but limited evidence exists regarding monotherapy in real-world studies. This analysis aimed to describe the effectiveness and safety outcomes of mavacamten monotherapy in the real-world COLLIGO-HCM study (Mavacamten ObservationaL Evidence Global Consortium in Hypertrophic Cardiomyopathy).

Myotonic dystrophy type 1 (DM1) is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA forms toxic hairpins that sequester the MBNL (muscle blind-like) family of splicing factors. This disrupts the tissue alternative splicing landscape, triggering multisystemic manifestations-myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurological disturbances. Although impaired mitochondrial function has been reported in the brain, skeletal muscle, and fibroblasts of patients with DM1, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects.

The rapid development and integration of artificial intelligence (AI), including predictive, generative, and emerging agentic tools, into cardiovascular and stroke care is outpacing traditional evaluation frameworks and the generation of robust clinical evidence. This science advisory addresses the urgent need for pragmatic, risk-proportionate approaches to the evaluation and monitoring of health care AI. AI implementation practices often rely on real-world or anecdotal evidence, with considerable variability in local validation, bias assessment, and postdeployment monitoring. Several evaluation frameworks exist, but they can be difficult to operationalize, especially outside of well-resourced health systems. We propose and discuss evaluation across 3 phases: predeployment, implementation, and postdeployment. We also provide 4 pragmatic guiding principles for health systems that are beginning to set up AI governance processes, including strategic alignment, ethical evaluation, usefulness and effectiveness evaluation, and financial performance, to inform health system selection, validation, deployment, and actionable monitoring of AI tools. The American Heart Association's extensive hospital and volunteer network and commitment to evidence-based practice position it as a trusted leader in advancing responsible AI governance. By grounding evaluation and monitoring in these principles, this science advisory aims to ensure that AI adoption in health care is safe, effective, equitable, and sustainable, ultimately improving patient outcomes and supporting high-quality AI-enabled care.

Emergency myelopoiesis by bone marrow hematopoietic stem and progenitor cells (HSPCs) exacerbates disease pathology in various chronic diseases, including myocardial infarction (MI) and atherosclerosis. However, the mechanisms triggering myelopoiesis in the bone marrow after a distant organ injury, such as MI, remain unknown.

Risk stratification of patients with chest pain has traditionally focused on identifying obstructive coronary artery disease (CAD). Using this traditional approach, many symptomatic individuals are found to have nonobstructive CAD. The 2021 American Heart Association/American College of Cardiology/American Society of Echocardiography/American College of Chest Physicians/Society for Academic Emergency Medicine/Society of Cardiovascular Computed Tomography/Society for Cardiovascular Magnetic Resonance chest pain guideline widened the scope of cardiac computed coronary angiography, resulting in increased identification of patients with nonobstructive CAD. In addition, recent advances in artificial intelligence solutions, hardware, and software have allowed identification of microvascular disease and introduced new risk categories within nonobstructive CAD with a risk continuum between primary and secondary prevention. There is thus a growing need for care teams to remain current on the diagnosis, risk stratification, and management of patients with nonobstructive CAD. Whereas only a subset of patients with chest pain are found to have true angina despite nonobstructive CAD, underlying nonobstructive CAD warrants attention. Medical management of nonobstructive CAD plays an essential role in plaque stabilization and regression to decrease the risk of acute coronary syndromes. New pharmacologic therapies and noninvasive plaque evaluation raise the potential for plaque-driven medical interventions. However, data in patients with chest pain who are found to have nonobstructive CAD are limited, and, in clinical practice, multiple factors lead to missed opportunities for precision therapies, with proven disparities in care. We review the current evidence on risk stratification for nonobstructive CAD and discuss its implications and medical management options.

Cardiac rehabilitation (CR) reduces morbidity and mortality among individuals with heart disease. Although the COVID-19 pandemic disrupted health services, its impact on CR participation remains poorly understood-especially among commercially insured populations, for whom CR utilization trends are poorly documented.

Over the past decade, balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension has shown improved outcomes with procedural refinement in expert hospitals with high procedural volume. Whether the outcomes of BPA are reproducible in hospitals with limited procedural volumes remains unknown. The Japan BPA registry was designed to assess the outcomes of contemporary BPA from a nationwide perspective, including hospitals with low treatment volume.

Observational studies have suggested that SGLT2 (sodium-glucose cotransporter 2) inhibitors are associated with a lower risk of atrial fibrillation (AF) recurrence after catheter ablation in patients with AF with concomitant diabetes, heart failure, or chronic kidney disease. However, no randomized trial to date has tested whether SGLT2 inhibitors reduce AF recurrence after ablation in patients without established indications. We therefore investigated the effect of dapagliflozin on prevention of early recurrence of AF after catheter ablation in patients without current indications for SGLT2 inhibitors.

Women with obstructive hypertrophic cardiomyopathy often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown.

Targeted, digital recruitment strategies such as tailored websites using motivational themes may improve recruitment in clinical trials, but their effectiveness remains unclear. We hypothesized that themes emphasizing community well-being, personal health benefits, or access to perks would increase engagement and prescreening sign-ups compared with a standard contribution to science message in a clinical trial focused on Black adults.

Proteins linked to heritable coronary heart disease (CHD) could uncover new pathophysiological mechanisms of atherosclerosis. We report on the protein profile associated with a family history of early-onset CHD and whether the relation between proteins and coronary atherosclerotic burden differs according to family history status, as well as inferences from Mendelian randomization.

Current guidelines recommend a stepwise strategy to achieve low-density lipoprotein cholesterol (LDL-C) goals after acute coronary syndrome (ACS). Earlier intensive strategies based on a combination of lipid-lowering therapies (LLTs) could be useful from the onset of ACS. However, the role of bempedoic acid in ACS, particularly when combined with high-intensity statins and ezetimibe, remains uncertain. The aim of ES-BempedACS (Efficacy and Security of Bempedoic Acid in Acute Coronary Syndrome) was to compare the efficacy and safety of triple LLT (high-dose, high-intensity statin+ezetimibe+bempedoic acid) versus standard of care (high-dose, high-intensity statin+ezetimibe) after ACS.