Is the cardioprotective effect of LCZ696 linked to increased cardiac regeneration?

Abstract

LCZ696 treatment reduces the mortality and the risk of hospitalization of patients with hypertension or heart failure with a preserved ejection fraction by 20%. The LCZ696 molecule associates both an angiotensin receptor blocker (valsartan) and an inhibitor of neprilysin (NEP, sacubitril). NEP is an endopeptidase able to degrade several factors such as the natriuretic peptides, angiotensin II, bradykinin, endothelin-1. Despite the cardioprotective effect of LCZ696, its exact mechanism in the heart is not elucidated yet. The aim of this project is to determine whether a part of the cardioprotective effect of this treatment is due to the stimulation of heart regeneration. For this purpose, myocardial infarction was induced in 8–10 weeks-old C57BL/6 mice by ligature of the left anterior descending coronary artery. Mice were treated or not with LCZ696 (at 6 or 60 mg/kg) given by oral gavage once per day and sacrificed 10 days after surgery. For all mice, BrdU (1 mg/ml) was added to drinking water 1 day after surgery and during all the treatment period. The effect of the treatment on heart function, cardiomyocyte proliferation and neovascularization was evaluated. High dose of LCZ696 increases the ejection fraction (+23%) and the fractional shortening (+14%) of infarcted hearts. Heart remodeling (the percentage of increase of the left ventricular diameter) was decreased in systole (−49%). At the cellular level, the number of BrdU+ cardiomyocytes was increased with both doses of LCZ696 (+110% in the infarcted and border zone and + 216% in the remote zone for 6 mg/kg LCZ696). The total number of cardiomyocytes was also increased in the infarcted and border zone (+105%) and in the remote zone (+156%). In contrast, neovascularization measured after CD31 staining didn’t differ between groups. Understanding the cellular mechanisms underlying the beneficial effects of LCZ696 in patients suffering from chronic heart failure is crucial for its further clinical use.