Author + information
- Received November 8, 2017
- Revision received January 14, 2018
- Accepted January 15, 2018
- Published online July 30, 2018.
- aBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- bWake Forest School of Medicine, Internal Medicine/Cardiology, Winston Salem, North Carolina
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, Texas 75226.
Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The 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. Inhibitors of aldosterone, neprilysin, and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 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. 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 physicians might finally have a phenotype of HFpEF that they can understand and treat.
Dr. Packer has recently consulted for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Celyad, Daiichi-Sankyo, Gilead, NovoNordisk, Novartis, Relypsa, Sanofi, Takeda, and ZS Pharma. Dr. Kitzman has recently received research funding from Novartis, Bayer, and St. Lukes’ Hospital; served as a consultant to Abbvie, Bayer, Corvia Medical, ResMed, AstraZeneca, Boehringer Ingelheim, St. Luke’s Hospital, and DCRI; holds stock in Gilead; and has consulted for Relypsa.
- Received November 8, 2017.
- Revision received January 14, 2018.
- Accepted January 15, 2018.
- 2018 American College of Cardiology Foundation
- Central Illustration
- Clinical and Physiological Characteristics of Obesity-Related HFpEF
- Mineralocorticoid Receptor Antagonists in Obesity-Related HFpEF
- Inhibition of Neprilysin and Sodium-Glucose Transporter-2 in Obesity-Related HFpEF
- Implications for Clinical Trials and Clinical Practice