Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction

• Published in: Journal of the American Heart Association 2022-12, Vol.11 (23), p.e027164-e027164
• Main Authors: Hegyi, Bence, Mira Hernandez, Juliana, Ko, Christopher Y, Hong, Junyoung, Shen, Erin Y, Spencer, Emily R, Smoliarchuk, Daria, Navedo, Manuel F, Bers, Donald M, Bossuyt, Julie
• Format: Article
• Language: English
• Subjects: Aldosterone; Animals; arrhythmia; diabetes; Diabetes Mellitus, Type 2; Heart Failure - drug therapy; HFpEF; Humans; Mice; mineralocorticoid; Original Research; SGLT2 inhibitor; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.122.027164

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 mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca 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 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 alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na current were observed in aldosterone-treated mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the +aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.