The Neurohormonal Overactivity Syndrome in Heart Failure

Abstract

Heart failure (HF) is categorized arbitrarily based on the left ventricular ejection fraction (LVEF) in HF with reduced (HFrEF; LVEF < 40%), mildly reduced (HFmrEF; LVEF 40−49%), or preserved ejection fraction (HFpEF; LVEF ≥ 50%). In this opinion paper, based on (patho)physiological considerations, we contend that the neurohormonal overactivity syndrome (NOHS), which is present in all symptomatic HF patients irrespective of their LVEF, not only contributes to the development of signs and symptoms but it is also a major determinant of patients’ outcomes. In this regard, NHOS is the only currently available treatment target in HF and should be combatted in most patients with the combined use of diuretics and neurohormonal inhibitors (β-blockers, angiotensin receptor-neprilysin inhibitor/angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid antagonists, and sodium-glucose co-transporter 2 inhibitors). Unfortunately, despite the advances in therapeutics, HF mortality remains high. Probably machine learning approaches could better assess the multiple and higher-dimension interactions leading to the HF syndrome and define clusters of HF treatment efficacy.

Keywords: heart failure; neurohormonal; overactivity; sodium glucose co-transporter 2 inhibitors; syndrome.

Figure 1

Sympathetic and renin-angiotensin-aldosterone system activation across ejection fraction categories and their prognostic impact. Aldo, aldosterone; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NE, norepinephrine NT-proBNP, N-terminal fraction of pro-B-type natriuretic peptide PRA, plasma renin activity. Adapted with permission from Ref. [8]. © 2019 Elsevier B.V.

Figure 2

A complex interplay between risk factors (coronary artery disease, hypertension, obesity, and others), comorbidities (atrial fibrillation, diabetes mellitus, chronic kidney disease, depression, pulmonary diseases, sleep-disordered breathing, anemia, and others), and disease modifiers (sex, genes, and others) leads to cardiac damage manifested by a spectrum of phenotypes. Diverse heart failure (HF) phenotypes converge to the neurohormonal overactivity syndrome (NOHS). Treatment with diuretics and neurohormonal inhibitors (β-blockers, angiotensin receptor-neprilysin inhibitor (ARNI)/angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), mineralocorticoid antagonists (MRAs), and sodium-glucose co-transporter 2 inhibitors (SGLT-2i)) is the only currently available treatment to combat NHOS and, therefore, decrease morbidity and mortality in most HF patients.