Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

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.

Reduction of Major Adverse Cardiovascular Events (MACE) after Bariatric Surgery in Patients with Obesity and Cardiovascular Diseases: A Systematic Review and Meta-Analysis

“…Excess adiposity may also activate RAAS, promoting salt and water retention and vasoconstriction. These mechanisms together with the obesity-induced autonomic nervous system remodeling could facilitate hypertension, cardiac arrhythmias (e.g., AF) and structural remodeling of the heart (i.e., HF) [3,39]. Additionally, excess adiposity could stimulate myocardial fat deposition [3].…”

The Evidence for Sparsentan-Mediated Inhibition of INa and IK(erg): Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor

“…Alternatively, ranolazine, a blocker of late I Na [ 39 , 40 , 41 , 42 ], has been noticeably reported to alleviate contrast-associated acute kidney injury as well as to dilate intrarenal arteries [ 43 , 44 , 45 ]. Sparsentan was also recently demonstrated to improve glomerular blood flow and to augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis [ 14 ]. Therefore, the extent to which its inhibitory actions on ionic currents (e.g., I Na and I K(erg) ) are intimately linked to the reduction in proteinuria in patients with focal segmental glomerulosclerosis remains to be further resolved, although Na + and K + ions do not appear to be osmotically active particles for determination of colloid osmotic pressure.…”

“…Therefore, it is expected to provide meaningful clinical benefits in mitigating proteinuria as well as in improving glomerular filtration rate, although not specifically related to a cardiovascular therapy [ 7 , 8 , 11 , 12 ]. Notably, this compound could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental gloomerulosclerosis [ 14 ].…”

Arterial Hypertension in Aortic Valve Stenosis: A Critical Update

“…The benefits of ARNi are related to the augmentation of peptides degraded by neprilysin, such as natriuretic peptides, and ARB’s simultaneous reduction of angiotensin II’s detrimental effects. They considerably reduced blood pressure more effectively in hypertensive patients than ARBs, alone, with no significant differences in side effects, while, when compared to ACE-I, they generated less bradykinin buildup and angioedema [ 90 ]. They also increased protection against heart functional decline in a pressure unloading animal model according to Li X et al [ 91 ].…”