Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction

Abstract

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 + current were observed in aldosterone‐treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db +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.

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF

“… 30 Similarly, in mouse models of HFpEF, empagliflozin pre-incubation (4 h) but not acute treatment (3 min) was not only capable of reducing late I Na but also cellular proarrhythmia in ventricular cardiomyocytes in a CaMKII-dependent manner. 59 , 60 …”

A systematic comparison of machine learning algorithms to develop and validate prediction model to predict heart failure risk in middle-aged and elderly patients with periodontitis (NHANES 2009 to 2014)

“…Many studies have also reported the effect of diabetes on heart failure. [54][55][56] Research has revealed that cardiometabolic damage is directly related to how diabetes affects heart failure. [57] Based on this, Halting the progression of diabetes is crucial for lowering the risk of heart failure.…”

Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

“…Comorbidities frequently associated with HFpEF are as follows: metabolic syndrome or its components (obesity, diabetes mellitus, hypertension), atrial fibrillation, diseases of the respiratory system (chronic obstructive pulmonary disease and sleep-disordered breathing), kidney disease, and anemia [37][38][39][40][41][42][43][44][45]. Glucose metabolism disorders and aldosterone excess favor both cardiac structural damage (cardiac hypertrophy and fibrosis leading to diastolic dysfunction and high ventricular filling pressures) and extracardiac comorbidities associated with HFpEF (diabetes mellitus with marked insulin resistance, severe obesity, vascular dysfunction, and pulmonary hypertension) [46]. There are recent data that show that excess accumulation of adipose tissue at the epicardial level is a risk factor for HFpEF.…”