Derangements in adrenergic–adipokine signalling establish a neurohormonal basis for obesity‐related heart failure with a preserved ejection fraction

Abstract

Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

“…Interestingly, the biological actions of the SGLT2 inhibitors evaluated in the EMPEROR‐Preserved Trial can be regarded as opposite to those of leptin, whereas other ongoing trials are evaluating the efficacy of inhibitors of aldosterone and neprilysin . The totality of evidence from these trials may establish a neurohormonal basis for the treatment of HFpEF in a manner that parallels that which exists for patients with HFrEF …”

Highlights in heart failure

“…Identification of specific phenotypes may be helpful. [146][147][148] Drugs blocking these pathways might therefore be beneficial also in this HFpEF phenotype. These patients have specific characteristics, such as an increase in epicardial fat, total heart volume, and right ventricular filling pressure.…”

“…Among them, that of the patients with obesity-related HFpEF represents a large subgroup. [147][148][149][150] 143,144 Increased epicardial fat volume is positively correlated with markers of myocardial injury.…”

The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction

“…If additional studies confirm that dysfunctional expansion of epicardial adipocytes contribute to structural and functional derangements of the underlying ventricular myocardium, then epicardial adipose tissue may become an important therapeutic target in the management of patients with HFpEF. Aldosterone can promote the accumulation and inflammation of epicardial fat, and mineralocorticoid receptor antagonists reduce obesity‐related adipose tissue inflammation and may have benefits in obesity‐related HFpEF . Natriuretic peptide receptor signalling has anti‐adipogenic effects and ameliorates adipocyte inflammation, and levels of natriuretic peptides are inversely related to epicardial fat thickness .…”

“…Aldosterone can promote the accumulation and inflammation of epicardial fat, 13 and mineralocorticoid receptor antagonists reduce obesity-related adipose tissue inflammation and may have benefits in obesity-related HFpEF. 2,14 Natriuretic peptide receptor signalling has anti-adipogenic effects and ameliorates adipocyte inflammation, and levels of natriuretic peptides are inversely related to epicardial fat thickness. 15 These relationships may explain the favourable effects of neprilysin inhibition on cardiac remodelling in HFpEF.…”