Daily Cardiology Research Analysis

IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIP

BACKGROUND: Right ventricular (RV) dysfunction is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of GP130 (glycoprotein-130) signaling with the small molecule SC144 improves RV function in rodent RV dysfunction via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy and molecular effects in a translational large animal model of RV dysfunction are unknown. METHODS: Four-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144, n=5] or vehicle [PAB-Veh, n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac magnetic resonance imaging quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type-specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue and serum. Quantitative proteomics examined RV mitochondrial protein regulation. Confocal microscopy evaluated alterations in cardiomyocyte size, macrophage abundances, capillary density, and pericyte/endothelial cell localization patterns. RESULTS: SC144 significantly improved RV ejection fraction (control: 60±4%; PAB-Veh: 22±10%; PAB-SC144: 37±6%) without altering RV afterload. Single-nucleus RNA sequencing demonstrated that PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared with control, and many of these changes were blunted by SC144. Immunohistochemistry validated the reduction in RV macrophage infiltration by SC144. Both transcriptomics and proteomics approaches demonstrated that SC144 combatted the downregulation of cardiomyocyte metabolic genes/proteins induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 (mammalian target of rapamycin complex 1) activation. Correspondingly, SC144 rebalanced the RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed that SC144 restored fatty acid metabolism. Finally, CellChat analysis, cardiomyocyte RNAseq analysis, and histological examination suggested SC144 rebalanced pericyte-endothelial cell interactions and blunted cardiomyocyte HIF1 (hypoxia-induced factor 1) activation. CONCLUSIONS: GP130 antagonism blunts RV immune cell infiltration, reduces proinflammatory gene programs in macrophages and lymphocytes, rebalances autophagy, and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte homeostasis to mitigate cardiomyocyte hypoxia and ultimately augments RV function.

IMPORTANCE: Positive health outcomes of a high cardiovascular health (CVH) score have been demonstrated largely with single CVH assessments in midlife, whereas the association of cumulative CVH during young adulthood with premature cardiovascular disease (CVD) and particularly kidney outcomes remains unclear. OBJECTIVE: To examine the association of cumulative CVH from 30 to 40 years of age with the risk of CVD and kidney events in midlife. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used Korean National Health Insurance health screening and claims data on adults aged 40 years without prior CVD or chronic kidney disease (CKD). Data were analyzed from May 1, 2024, to April 30, 2025. EXPOSURE: Ten-year cumulative CVH score, calculated as the area under the CVH score curve from 30 to 40 years of age (range, 0-100 per visit; cumulative range, 0-1000 points × years), based on the American Heart Association's Life's Essential 8 construct. MAIN OUTCOMES AND MEASURES: The primary outcomes were CVD events (myocardial infarction, ischemic stroke, heart failure, or cardiovascular death) and kidney events (incident CKD, kidney replacement therapy, or kidney-related death) after 40 years of age among participants. RESULTS: Among 241 924 adults (78.1% male [n = 188 871]; all aged 40 years) with 3 or more examination visits (at 30 and 40 years of age and ≥1 visits in between; median number of visits, 8 [IQR, 6-10]), 2748 CVD events and 2085 kidney events occurred over a median follow-up of 9.2 years (IQR, 8.4-10.1). The highest quintile (quintile 5 [Q5]; ≥735 points × years) of cumulative CVH from 30 to 40 years of age was associated with a very low incidence of CVD (0.05% per year; adjusted hazard ratio [HR], 0.27 [95% CI, 0.22-0.32] vs Q1) and kidney events (0.05% per year; adjusted HR, 0.25 [95% CI, 0.21-0.31] vs Q1) in midlife. Each 100-point × year higher cumulative CVH (eg, 10-point higher CVH score × 10 years) was associated with a 34% lower hazard of CVD events and a 35% lower hazard of kidney events. The associations were similar by sex and for event subtypes and remained significant after adjustment for CVH score at 40 years of age or the slope of CVH change. CONCLUSIONS AND RELEVANCE: These findings suggest that a higher cumulative CVH score from 30 to 40 years of age was associated with markedly lower risks of CVD and kidney events in midlife, highlighting the importance of sustained primordial prevention efforts throughout early life.