Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive disease caused by the deposition of transthyretin 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 endpoints versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular (CV) outcomes and in those with pre-existing CV disease (CVD) is not well elucidated.

The presence of microvascular obstruction (MVO) following reperfusion with percutaneous coronary intervention (PCI) in the setting of ST-segment elevation myocardial infarction (STEMI) portends a poor prognosis. MVO is associated with adverse left-ventricular (LV) remodeling (1), increased major adverse cardiac events and mortality (2). MVO may arise from both intravascular and extravascular mechanisms including distal embolization of thrombus and microvascular dysfunction as well as compression of the microcirculation from interstitial edema as a consequence of ischemia-reperfusion injury. The gold standard for detecting MVO is gadolinium-based cardiac MRI (CMR) which is expensive, time consuming and not universally available at STEMI centers. Identifying MVO is clinically important to help identify high-risk patients who may require intensive medical therapy. Detecting MVO without CMR can provide valuable insight into the outcomes of clinical trials by identifying those high-risk patients who may be more likely to benefit from novel therapeutics.

Cardiac allograft vasculopathy (CAV) is an important cause of mortality after heart transplantation (HT). Dyslipidemia is a major contributor to the development of CAV. The safety and effectiveness of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition to lower cholesterol and prevent CAV early after HT is not well-established.

Background: Mavacamten has been shown to improve cardiac function and symptoms in patients with symptomatic (New York Heart Association [NYHA] class II-III) obstructive hypertrophic cardiomyopathy (HCM). Clinical studies suggest 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 mavaCamten ObservationaL evIdence Global cOnsortium in HCM study (COLLIGO-HCM). Methods: Patient-level data recorded between April 2022 and February 2025 at 7 sites across 5 countries were extracted. Adult patients with a diagnosis of HCM from 2018 onwards were eligible for inclusion if they had ≥1 mavacamten prescription after the date of diagnosis. Patients were categorized based on background therapy status during mavacamten treatment: mavacamten monotherapy or mavacamten with background therapy (down-titration or no dose modification). Results: Overall, 278 patients were included and received mavacamten (mavacamten monotherapy, n=88; mavacamten with background therapy, n=190). At month 9, most patients achieved ≥1 NYHA class improvement from baseline (mavacamten monotherapy, 60.0%; mavacamten with background therapy, 61.0%). Improvements in resting and Valsalva left ventricular outflow tract gradients from baseline to month 9 were observed in both subgroups; mean left ventricular ejection fraction (LVEF) through month 9 remained ≥62.0% with mavacamten monotherapy and ≥61.4% with mavacamten with background therapy. Two patients in the mavacamten monotherapy subgroup and one patient in the mavacamten with background therapy subgroup permanently discontinued treatment owing to LVEF <50%. Conclusions: Mavacamten monotherapy was associated with improvements in cardiac function and symptoms, and positive benefits to the risk profile over a 9-month follow-up period; this was consistent with improvements observed in patients treated with mavacamten with background therapy.

Background: Heart failure with reduced ejection fraction (HFrEF) guideline-directed medical therapy (GDMT) remains underutilized, particularly in socioeconomically disadvantaged populations. It has been proposed that the use of combination pills (polypills) may facilitate prescribing of GDMT and increase adherence. Understanding patient perspectives on implementation barriers and facilitators to the use of polypills is needed for developing effective strategies. Methods: A convergent, parallel, mixed-methods study was conducted with participants who participated in a Phase II randomized controlled trial of an HFrEF polypill (POLY-HF; NCT04633005) in Dallas, Texas. Six focus groups were conducted with participants from both polypill and usual care arms, followed by brief surveys. Qualitative data were analyzed using directed content analysis organized by a socioecological framework to identify barriers and facilitators across individual, interpersonal, and systems levels. Descriptive statistics characterized medication burden and polypill preferences. Results: Study participants (n=41) included trial participants (n=36, mean 53 years, 53% Black race, 39% Hispanic) and caregivers (n=5). Quantitative data revealed substantial medication burden, with 58% taking ≥6 medications and 50.0% reporting missed doses, primarily due to forgetting (44%). 88.6% expressed interest in a polypill approach, and 83% believed it would improve adherence. Qualitative analysis identified multi-level implementation barriers and facilitators. Individual-level barriers included pill size concerns and uncertainty about polypill contents, while facilitators encompassed reduced pill burden, psychological benefits of taking fewer medications, and perceived health improvements. Interpersonal facilitators included caregiver enthusiasm for simplified medication management and strong provider trust. Systems level barriers centered on cost concerns, while institutional trust facilitated acceptance. Mixed-methods integration revealed convergent findings. Quantitative medication burden aligned with qualitative themes of regimen complexity, while high quantitative interest in polypills was contextualized by practical implementation considerations regarding formulation and delivery. Conclusions: In socioeconomically disadvantaged patients with HFrEF, a polypill strategy demonstrated strong patient acceptability, supporting further implementation research.

Background: DM1 is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA form toxic hairpins that sequester the muscle blind-like (MBNL) family of splicing factors. This disrupts tissue alternative splicing landscape, triggering multisystemic manifestations - myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurologic disturbances. While impaired mitochondrial function has been reported in brain, skeletal muscle, and fibroblasts of DM1 patients, 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. Methods: Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides (ASO) to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. Results: DM1 induced a multi-state decrease in oxygen consumption rate (OCR) with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor (Mff, encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. ASO-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild type HL-1 cardiomyocytes. Conclusions: Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.

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.

Background: Over the past decade, balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) 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. Methods: This prospective multicenter registry enrolled 1202 consecutive patients with CTEPH who underwent BPA at 44 hospitals between April 2018 and March 2023. We assessed the efficacy and safety of BPA and survival rates, comparing high- and low-volume hospitals based on the BPA center definition (≥ 50 procedures per year) from the 7th World Symposium on Pulmonary Hypertension. Results: A total of 5207 procedures were performed. Thirty-five low-volume hospitals (79.5%) performed 40.8% of all BPA procedures. BPA significantly improved symptoms, clinical parameters, and hemodynamics (55.6% reduction in pulmonary vascular resistance), with 0.2% periprocedural BPA-related mortality. Severe lung injury (0.3%), balloon overdilatation (0.67%), and mechanical ventilation (0.3%) were less common in high-volume hospitals than in low-volume hospitals (1.3%, 1.7%, and 1.5%, respectively; P < 0.001). In the Kaplan-Meier analysis, the survival rate of all patients at 3 years was 94.7% (95% confidence interval: 92.5-96.3%). Multivariable Cox regression analysis showed an increased mortality risk with higher right atrial pressure, and high-volume hospitals were associated with a reduced mortality risk. Conclusions: This nationwide registry demonstrated the outcomes of contemporary BPA in patients with CTEPH. No significant differences were observed in efficacy and periprocedural mortality between low- and high-volume hospitals. However, the significantly lower rate of severe complications in high-volume hospitals indicates that BPA may be safer in high-volume hospitals.

Observational studies have suggested that sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with a lower risk of atrial fibrillation (AF) recurrence after catheter ablation in AF patients with concomitant diabetes, heart failure or chronic kidney disease. However, no randomized trial to date has tested whether SGLT2i reduces AF recurrence post-ablation in patients without established indications. We therefore investigated the effect of dapagliflozin on the prevention of early recurrence of AF after catheter ablation in patients without current indications for SGLT2i.

Background: Women with obstructive hypertrophic cardiomyopathy (oHCM) often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown. Methods: We performed a pre-specified subgroup analysis of sex differences in the doubleblind, randomized-controlled SEQUOIA-HCM trial of aficamten versus placebo in patients with oHCM. Baseline characteristics were compared using t-test for continuous variables and C2 test for categorical variables. Prespecified primary (change in peak oxygen uptake, pVO2) and secondary end points from baseline to end of treatment (week 24) were analyzed using linear regression models, adjusted for baseline values, beta-blocker use, and exercise mode. Results: Of the 282 participants, women (n=115) were older (64 years-old in women vs. 56 years-old in men), had lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), higher NT-proBNP levels, and lower pVO2 at baseline. Women had smaller left ventricular (LV) chamber sizes, higher E/e' ratios, and higher LV outflow tract (LVOT) gradients. At 24 weeks, there was a significant treatment-related increase in pVO2 in women (+1.5, [+0.7 to +2.4] and men (+2.0 [+0.9 to +3.0])). Both women and men had significant treatment-related decreases in LVOT gradients at rest and with Valsalva, with no sex-bytreatment interaction at week 24 (p-interaction ³ 0.13). There was a significant improvement in KCCQ-CSS in women (11 [6 to 15]) and men (6 [2 to 9], p-interaction = 0.08). Women had a greater reduction in lateral E/e' ratio (p-interaction = 0.01). The geometric mean proportional reduction in NT-proBNP were similar in women and men (p-interaction = 0.10). Conclusions: Women enrolled in SEQUOIA-HCM were older with worse baseline health status, higher NT-proBNP, and higher LVOT gradients compared to men. Despite these differences, both men and women derived significant benefits in the primary and secondary end points following treatment with aficamten.

Background: Targeted, digital recruitment strategies like 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 pre-screening sign-ups compared to a standard contribution to science message in a clinical trial focused on Black adults. Methods: We implemented A/B testing of website themes for recruitment in GoFresh, a randomized trial testing the DASH diet intervention on blood pressure among Black adults. Website themes were derived from pre-developed motivational categories and included: (1) contribution to science (control group), (2) community well-being, (3) personal blood pressure improvement (4) access to perks (groceries or cash). A/B randomization directed visitors to a theme randomly between June and December 2024. Using an open-source web analytics platform, we captured data on two primary outcomes: 1) sign-up rate defined as the proportion of unique visitors who completed the trial's pre-screening form; and 2) engagement defined as (a) mean pageviews per session and (b) mean time spent on site per session. We compared themes using Welch's t-tests with statistical significance assessed as two-tailed p<0.05. Results: Among 11,484 visitors over 6 months, the themes of community well-being (13.8%), personal blood pressure improvement (14.1%), and access to perks (13.1%) all attracted higher sign-up rates than contribution to science (11.1%) (p<0.05 for all comparisons). All alternative themes also led to significantly higher mean pageviews compared to the contribution to science theme (p<0.05 for all comparisons) while mean time on site was similar across all themes (range: 52 to 55 seconds with p>0.05 for all comparisons). There were no statistical differences noted across the three alternative motivational themes for these outcomes. Conclusions: Tailored websites with digital messages emphasizing community well-being, personal health benefits, and access to perks significantly improved engagement and prescreening sign-up rates, demonstrating that they may enhance recruitment within cardiovascular research. Registration: Unique Identifiers: NCT05393232, NCT05121337; URL: https://clinicaltrials.gov.

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.

Congenital long-QT syndrome is most often associated with pathogenic variants in KCNQ1 encoding the pore-forming voltage-gated potassium channel subunit of the slow delayed rectifier current (IKs). Generation of IKs requires assembly of KCNQ1 with an auxiliary subunit encoded by KCNE1, which is also associated with long-QT syndrome, but the causality of autosomal dominant disease is disputed. By contrast, KCNE1 is an accepted cause of recessive Jervell and Lange-Nielson syndrome type 2 (JLN2). The functional consequences of most KCNE1 variants have not been determined, and the population prevalence of JLN2 is unknown.

Lp(a) (lipoprotein [a]) and coronary artery calcium score (CACS) are independently associated with atherosclerotic cardiovascular disease (ASCVD) risk. This study aimed to investigate sex-specific prognostic differences between Lp(a) and CACS in ASCVD risk.

Calmodulinopathies are very rare genetic disorders associated with a high risk for sudden cardiac death. Disease-causing variants in 1 of the 3 identical CALM genes cause severe forms of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or idiopathic ventricular fibrillation, and there are many open questions concerning management and underlying mechanisms. What is currently known depends largely on the initial publications from the International Calmodulinopathy Registry. However, progress is delayed because the accrual of patients in the International Calmodulinopathy Registry is slow. As we did long ago for long QT syndrome, this is a call for action, requesting doctors all over the world to enroll even their isolated cases in the registry. This is the only way to obtain, for an adequate number of patients, the data necessary to define the spectrum of clinical manifestations and the genotype-phenotype correlation essential for an improved risk stratification and best therapeutic management. If you are willing to contribute, please contact us.