Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.
Highlights
Academic Editors: Selin Gencer and Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Department of Physiology and Pharmacology, State University of New York (SUNY) Downstate Health
The Effects of ARNI on Atrial Arrhythmias In HF patients with reduced ejection fraction (HFrEF) patients with cardiac implantable electronic devices (CIEDs), two studies have suggested a lower recurrence of atrial arrhythmias, reduced atrial arrhythmia burden and fewer ventricular extrasystoles in patients with non-permanent atrial fibrillation (AF) treated with sacubitril/valsartan [38,39]
In PARADIGM-heart failure (HF), the incidence of de novo AF in HFrEF patients receiving sacubitril/valsartan (3%) did not differ from those who received enalapril [16], whereas in HF patients with preserved ejection fraction (HFpEF) patients (PARAGON-HF), sacubitril/valsartan modestly increased the incidence of new-onset AF in women, a non-significant trend in the opposite direction was observed in men [27]
Summary
Pharmacological agents increasing the level of circulating natriuretic peptides (NPs) have been proposed for the management of cardiovascular diseases. Several pharmacological interventions have been explored to preserve or increase the level of NPs to counterbalance excessive RAAS and SNS activation in cardiovascular diseases. These include the administration of exogenous NPs (e.g., nesiritide and carperitide) and the inhibition of neprilysin-mediated NP degradation (e.g., with racecadotril, candoxatrilat, ecadotril, candoxatril or sacubitril) [3]. The combination of ACEi and neprilysin inhibitors effectively lowered angiotensin II level and blood pressure in hypertensive patients but facilitated a higher incidence of bradykinin accumulation-promoted angioedema [9], making the combination of ACEi/neprilysin inhibitor unfavorable. ARNI (i.e., an ARB combined with a neprilysin inhibitor) has shown multiple positive effects in numerous cardiovascular diseases
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