Mechanism of angiotensin receptor-neprilysin inhibitor in suppression of ventricular arrhythmia.

Abstract

BACKGROUND:

The mechanisms underlying angiotensin receptor-neprilysin inhibitor (ARNi) suppression of ventricular arrhythmia (VA) are unclear. This study aimed to investigate the mechanism of ARNi-related suppression of VA in a heart failure (HF) model.

METHODS:

New Zealand white rabbits (n = 6 per group) were assigned to normal, HF [4 weeks of left ascending artery (LAD) ligation], angiotensin receptor blocker (ARB, valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation), and ARNi (sacubitril at 34 mg/kg/day and valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation) groups. Experiments involving echocardiogram, optical mapping, histological of trichrome stain and immunostain, and flow cytometry were performed.

RESULTS:

HF group had larger left ventricular (LV) internal dimensions in diastole and systole, and lower LV ejection fraction and fractional shortening than normal, ARB, and ARNi groups. HF group had a prolonged action potential duration (APD) and decreased conduction velocity (CV), which was mitigated in ARB and ARNi groups. HF group had a prolonged QRS duration, QT and QTc intervals, which was reversed in ARB and ARNi groups. HF group had a steeper maximum slope of APD restitutions, which was attenuated in normal, ARB, and ARNi groups. HF group had increased number of phase singularities (PSs) and VA inducibility than normal, ARB, and ARNi groups. A higher content of fibrosis was found in HF group than that in normal, ARB, and ARNi groups. Compared to ARB group, ARNi had a lower context of fibrosis. HF group had more peripheral blood CD4+ and CD8+ cells count than normal, ARB, and ARNi group.

CONCLUSIONS:

In a rabbit model of ischemic HF, ventricular arrhythmogenesis could be suppressed by ARNi treatment. This appears to be mediated by reversing changes in the APD, CV, maximum slope of the APDR, PSs, fibrosis, and inflammation.

• Authors: Yung-Nan Tsai, Wen-Han Cheng, Yao-Ting Chang, Ya-Wen Hsiao, Ting-Yung Chang, Yu-Cheng Hsieh, Yenn-Jiang Lin, Li-Wei Lo, Tze-Fan Chao, Ming-Jen Kuo, Satoshi Higa, Shih-Lin Chang, Shih-Ann Chen
• Journal: Journal of cardiology (J Cardiol) Vol. 78 Issue 4 Pg. 275-284 (10 2021) ISSN: 1876-4738 [Electronic] Netherlands
• PMID: 34059408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Receptors, Angiotensin
• Tetrazoles
• Neprilysin

Topics

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Animals
• Arrhythmias, Cardiac (drug therapy, etiology, prevention & control)
• Heart Failure (drug therapy)
• Neprilysin
• Rabbits
• Receptors, Angiotensin
• Stroke Volume
• Tetrazoles (pharmacology)
• Treatment Outcome