Non-communicable diseases (NCDs) account for 70% of global mortality and are responsible for over 38 million deaths annually, with cardiovascular disease (CVD) constituting most of these fatalities. While traditional risk factors for CVD have long been recognized, there is growing evidence that a rising prevalence of ubiquitous environmental risk factors (ERFs) may play an increasingly significant role in the genesis and rising prevalence of NCDs. ERFs include many interconnected anthropogenic exposures with cumulative compound health impacts, including air pollution, noise exposure, artificial light at night, plastic pollution, chemical pollution and the various effects of climate change, such as heat extremes, desert storms, floods and wildfires. Urbanization has intensified the impact of many ERFs and created intense exposure environments, highlighting the urgency and the opportunity to address these for maximum public health benefit. Impactful intervention often requires regulatory and policy-driven efforts addressing the genesis of exposures and minimizes their health impact, particularly in vulnerable populations who may contribute the least but may be impacted the most. Solutions must involve the development of resiliency and adaptation measures to a changing world, where the probability of sudden catastrophic and cascading events is much more likely. Political will and international cooperation are essential in establishing and enforcing regulations that promote cleaner air and water, quieter and natural biodiverse environments, and sustainable infrastructure in urban, and rural medical facilities. Integration of planetary and environmental health into cardiovascular care will be vital in reducing the burden of NCDs globally. By addressing the root causes of environmental stressors, it is possible to reduce the incidence of CVDs and promote healthier, just and sustainable societies.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM.METHODS:We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning.RESULTS:We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels.CONCLUSIONS:This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.

Background:Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives:We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods:Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results:Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 ± 5.0 vs. 20.0 ± 4.4mm, P <0.01) and indexed LV mass (81.9 ± 26.0 vs. 71.7 ± 13.3g/m 2 , P <0.001). Of the former, MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 ± 5.2 vs. 20.9 ± 4.5mm, P <0.01) but lower LV ejection fraction (63.1 ± 8.4 vs. 65.3 ± 8.4%, P <0.001). Findings remained significant after covariate adjustment and meta-analysis. 23 (∼1%) patients had >1 disease-linked variants with only 3 (∼0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions:In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity. Condensed Abstract:Prior studies of genotype-phenotype correlations in hypertrophic cardiomyopathy have produced inconsistent findings. In the largest study to date with CMR imaging, we identified significant correlations between disease phenotypes and genotype subgroups of sarcomeric variant-positive patients from the NHLBI Hypertrophic Cardiomyopathy Registry. Patients with disease-linked MYBPC3 variants had greater hypertrophy and lower ejection fraction than those with MYH7 variants but also less incidence of clinical outcomes. Patients with multiple variants were strikingly rare (∼1% of all patients). Ultimately, we discovered phenotypic differences that characterize rare genotype subgroups and resolved prior discrepancies through systematic review and meta-analysis.

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.

BACKGROUND:Cardiovascular magnetic resonance (CMR) accurately measures left ventricular (LV) ejection fraction (EF) and late gadolinium enhancement (LGE), but is not commonly used for diastolic function. This study combined unsupervised machine learning and diastolic function with cine imaging to identify prognostic groups. METHODS:CMR studies from 391 patients with LVEF ≥50%, and no LGE were included. Using LV cine diastolic time-volume curves, early peak filling rate (E-PFR) indexed to stroke volume index (SVI), early to late diastolic filling ratio (E/A) ratio, and deceleration time (Decelt) were measured, along with left atrial volume index (LAVI) and LV mass index (LVMI). K-means clustering grouped individuals using only these parameters. Primary outcome was a composite of heart failure or ventricular arrhythmia admission, heart transplant, mechanical support, and cardiac death. RESULTS:Median follow-up was 5 years with 30 events. Three clusters were identified with event rates of 2.6% (group 1), 8.5% (group 2), and 17.2% (group 3). Time-volume curves demonstrated a triphasic pattern with group 2 having lower E-PFR (6.5 vs 9.7 and 8.4 SVI/s for groups 1 and 3, respectively, p < 0.001), lower E/A (1.2 vs 2.4 and 1.9 for groups 1 and 3, respectively, p < 0.001), and longer Decelt (223 vs 79 and 105 ms for groups 1 and 3, respectively, p < 0.001). Group 3 had increased remodeling based on higher LAVI (51.4 vs 26.6 and 27.5 mL/m2 for groups 1 and 2, respectively, p < 0.001) and LVMI (78.7 vs 48.7 and 50.6 g/m2 for groups 1 and 2, respectively, p < 0.001). Compared to group 1, groups 2 and 3 had hazard ratios (HR) of 3.21 (95% confidence interval [CI] 1.06-9.68, p = 0.038) and 2.52 (95% CI 1.06-4.47, p = 0.002) for events, respectively. Adjusting for comorbidities, only group 3 had a significant HR of 2.55 (95% CI 1.42-4.57, p = 0.002) compared to group 1. CONCLUSION:CMR cine-derived diastolic parameters can add prognostic value despite normal EF and absence of LGE.

Background The impact of COVID-19 in hypertrophic cardiomyopathy (HCM), particularly in the post-vaccine era, remains incompletely understood. We evaluated whether pre-existing cardiovascular magnetic resonance (CMR) phenotypes are associated with COVID-19 outcomes and recovery. Methods In 1704 participants from the international HCM Registry with prior CMR phenotyping, COVID-19 infection and outcomes were assessed using patient-reported questionnaires. Associations between baseline CMR features and hospitalisation or impaired recovery (≥3 months) were evaluated using multivariable logistic regression. Results Among 767 participants with reported COVID-19 infection (mean age 49±11 years), 4% required hospitalisation, 19% reported impaired recovery at ≥3 months and 2 (0.26%) non-cardiac deaths occurred. Persistent symptoms were common particularly fatigue (67%) and dyspnoea (33%). After adjustment, adverse CMR features, including hypertrophy, fibrosis (late gadolinium enhancement) and extracellular volume, were not associated with hospitalisation or impaired recovery. Female sex and younger age were associated with persistent symptoms. Conclusions In this large HCM cohort, COVID-19 was associated with a substantial burden of persistent symptoms, but pre-existing CMR phenotype was not associated with adverse outcomes. These findings suggest that baseline structural disease severity may not identify patients at higher risk of post-COVID-19 complications, although results should be interpreted in the context of self-reported outcomes and limited event rates.

BACKGROUND:The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide decreased risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Women outnumber men with HFpEF, and there are sexual dimorphisms in the relationships between body fat and pathophysiology that could influence response to tirzepatide. OBJECTIVES:This study aims to compare baseline characteristics and effects of tirzepatide on primary and other endpoints in women and men with obesity-related HFpEF. METHODS:In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein, and body weight at 52 weeks. Baseline characteristics and effects of tirzepatide on primary and secondary endpoints were contrasted by sex. RESULTS:Compared with men (n = 338, 46.2%), women with obesity-related HFpEF (n = 393, 53.8%) had greater BMI, waist to height ratio (WHtR), symptom severity (higher NYHA functional class, lower KCCQ-CSS), and poorer exercise capacity (lower 6MWD), whereas men had greater left ventricular remodeling and paracardiac fat. Greater baseline BMI or WHtR were correlated with lower KCCQ-CSS and 6MWD in women and men, with no interaction, but higher WHtR was associated with poorer kidney function exclusively in women (interaction P = 0.043). The effect of tirzepatide on the risk of worsening HF or cardiovascular death did not differ in women and men (HR: 0.66 and 0.61, respectively, interaction P = 0.81), with no heterogeneity of effect on KCCQ-CSS at 52 weeks (8.1- and 5.5-point placebo-corrected improvement, respectively, interaction P = 0.43) or 6MWD (18 m and 15 m placebo-corrected improvement, respectively, interaction P = 0.76). Among patients randomized to tirzepatide, decreases in body weight on treatment were more strongly associated with improvements in KCCQ-CSS in women than men (interaction P = 0.0058). CONCLUSIONS:Compared with men, women with obesity-related HFpEF have greater adiposity, symptom severity, and poorer exercise capacity but lower left ventricular mass and paracardiac fat deposition. Despite these differences, tirzepatide resulted in consistent benefits across multiple domains of HF severity that did not differ by sex. (A Study of Tirzepatide [LY3291876] in Participation With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity [SUMMIT]; NCT04847557).

Non-communicable diseases (NCDs) account for 70% of global mortality and are responsible for over 38 million deaths annually, with cardiovascular disease (CVD) constituting most of these fatalities. While traditional risk factors for CVD have long been recognized, there is growing evidence that a rising prevalence of ubiquitous environmental risk factors (ERFs) may play an increasingly significant role in the genesis and rising prevalence of NCDs. ERFs include many interconnected anthropogenic exposures with cumulative compound health impacts, including air pollution, noise exposure, artificial light at night, plastic pollution, chemical pollution and the various effects of climate change, such as heat extremes, desert storms, floods and wildfires. Urbanization has intensified the impact of many ERFs and created intense exposure environments, highlighting the urgency and the opportunity to address these for maximum public health benefit. Impactful intervention often requires regulatory and policy-driven efforts addressing the genesis of exposures and minimizes their health impact, particularly in vulnerable populations who may contribute the least but may be impacted the most. Solutions must involve the development of resiliency and adaptation measures to a changing world, where the probability of sudden catastrophic and cascading events is much more likely. Political will and international cooperation are essential in establishing and enforcing regulations that promote cleaner air and water, quieter and natural biodiverse environments, and sustainable infrastructure in urban, and rural medical facilities. Integration of planetary and environmental health into cardiovascular care will be vital in reducing the burden of NCDs globally. By addressing the root causes of environmental stressors, it is possible to reduce the incidence of CVDs and promote healthier, just and sustainable societies.

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.