Obesity-Related Heart Failure With Preserved Ejection Fraction
- Packer M, Kitzman DW.
- Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2. JACC Heart Fail 2018;6:633-639.
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:
- Obesity-related HFpEF is an important phenotype present in the community, especially in people with metabolic disorders such as dyslipidemia and diabetes.
- 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.
- The increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to HF, even though systolic ejection is not impaired.
- 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.
- The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis.
- 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.
- 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.
- 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.
- Recognition of the contribution of adipocytes to the systemic and cardiovascular derangements of HF, especially in obesity-related HFpEF, represents an important conceptual breakthrough.
- 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 X, Mineralocorticoids, Mineralocorticoid Receptor Antagonists, Neprilysin, Obesity, Plasma Volume, Primary Prevention, Sodium-Glucose Transporter 2, Stroke Volume
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