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Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Importance Only modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia’s often paroxysmal nature and individuals’ disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF. Observations The National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF. Conclusions and Relevance Workshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.

Introduction: Whether echocardiographic (echo) markers of left ventricular (LV) remodeling and diastolic dysfunction contribute incremental and independent prognostic information to clinical risk markers in patients (Pts) with coronary artery disease and severe LV systolic dysfunction is unclear. We sought to determine which echo variables provide the greatest prognostic value in the Surgical Treatment for Ischemic Heart Failure (STICH) population. Methods: Pts enrolled in STICH for whom transmitral Doppler (E/A ratio) was available on a baseline echo interpreted by an echo core laboratory blinded to treatment and outcomes formed the analysis cohort. Comprehensive datasets to account for missing echo data were created by multiple imputation and the impact on all-cause mortality was determined with the Cox’s regression model. Results: E/A ratio could be measured in 1511 of the 2136 Pts enrolled in STICH. Amongst markers of diastolic dysfunction, E/A ratio was the most significant predictor of mortality (χ 2 41.05, p <0.001) with a non-linear, u-shaped, relationship. Mortality was lowest with E/A ratio = 1.0, and increased for E/A ratio <0.6 and >1.0 up to 2.3, beyond which there was no further increase in risk. The combination of larger LV end-systolic volume index (LVESVI), low or high E/A ratio, and mitral regurgitation severity grade, had highly significant incremental negative effects on mortality (χ 2 69.65, p<0.001) when added to a multivariable model with clinical risk markers. Overall, creatinine (χ 2 30.00, p <0.001), followed by LVESVI (χ 2 27.26, p<0.001), age, and E/A ratio (χ 2 12.46, p<0.001) were among the most significant predictors of mortality and accounted for 74% of the total prognostic information. LVESVI and E/A ratio were stronger predictors of poor prognosis than New York Heart Association (NYHA) functional class, hemoglobin, diabetes, stroke, or atrial fibrillation. Conclusions: Echo markers of advanced LV remodeling and diastolic dysfunction add incremental prognostic value to clinical risk markers and are more predictive of poor prognosis than advanced NYHA functional class or anemia. LVESVI and E/A ratio outperformed other echo markers and should be considered standard in assessing risk in Pts with ischemic LV dysfunction.

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute’s virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

Abstract Aims: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.Methods and Results: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A <0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A <0.6 and >1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke.Conclusions: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.