The following are key points to remember from this review article about obesity-related heart failure with a preserved ejection fraction (HFpEF) and rationale for combining aldosterone, neprilysin, and sodium-glucose cotransporter-2 (SGLT2) inhibitors:

1. Obesity-related HFpEF is an important phenotype present in the community, especially in people with metabolic disorders such as dyslipidemia and diabetes.
2. Individuals with this phenotype exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular dysfunction with myocardial and pericardial fibrosis.
3. The increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to HF, even though systolic ejection is not impaired.
4. The clinical features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin.
5. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis.
6. Current evidence is consistent with the hypothesis that obesity-related HFpEF is a distinct phenotype that may result from augmented mineralocorticoid signaling and overactivity of neprilysin, together with increased effects of other adipocytokines.
7. Inhibitors of aldosterone, neprilysin, and SGLT2 may ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines.
8. All three classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors, and is being further tested in an ongoing large-scale trial of neprilysin inhibition.
9. Recognition of the contribution of adipocytes to the systemic and cardiovascular derangements of HF, especially in obesity-related HFpEF, represents an important conceptual breakthrough.
10. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that clinicians might have a type of HFpEF that they can understand and treat.

Keywords: Adipocytes, Adipokines, Aldosterone, Diabetes Mellitus, Dyslipidemias, Heart Failure, Inflammation, Intra-Abdominal Fat, Metabolic Syndrome, Mineralocorticoids, Mineralocorticoid Receptor Antagonists, Neprilysin, Obesity, Plasma Volume, Primary Prevention, Sodium-Glucose Transporter 2, Stroke Volume

< Back to Listings