Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction

作者：Bence Hegyi, Juliana Mira Hernández, Christopher Y. Ko, Junyoung Hong, Erin Y. Shen, Emily R. Spencer, Daria Smoliarchuk, Manuel F. Navedo, Donald M. Bers, Julie Bossuyt · 发表于：Journal of the American Heart Association · 年份：2022 · DOI：10.1161/jaha.122.027164 · 被引用次数：33 · 研究领域：Heart Failure Treatment and Management、Diabetes Treatment and Management、Cardiovascular Function and Risk Factors

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor–deficient db/db mice with a 4‐week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca 2+ handling, and electrophysiology. The sodium‐glucose cotransporter‐2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B‐type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca 2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short‐term variability, delayed afterdepolarizations), and enhanced late Na + curren...