Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload

Abstract

Aims Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin-angiotensin-aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF). Methods and results Sprague-Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks. Sac/val reduced left ventricular weight by 11% compared with vehicle (P = 0.01) and 9% compared with valsartan alone (P = 0.04). Only valsartan reduced blood pressure compared with sham (P = 0.02). Longitudinal early diastolic strain rate was preserved in sac/val compared with sham, while it was reduced by 23% in vehicle (P = 0.03) and 24% in valsartan (P = 0.02). Diastolic dysfunction, measured by E/e'SR, increased by 68% in vehicle (P < 0.01) and 80% in valsartan alone (P < 0.001), while sac/val showed no increase. Neither sac/val nor valsartan prevented interstitial fibrosis. Although ejection fraction was preserved, we observed mild systolic dysfunction, with vehicle showing a 28% decrease in longitudinal strain (P < 0.01). Neither sac/val nor valsartan treatment improved this dysfunction. Conclusions In a model of HFpEF induced by cardiac pressure overload, sac/val reduced hypertrophy compared with valsartan alone and ameliorated diastolic dysfunction. These effects were independent of blood pressure. Early systolic dysfunction was not affected, supporting the notion that sac/val has the largest potential in conditions characterized by reduced ejection fraction. Observed anti-hypertrophic effects in preserved ejection fraction implicate potential benefit of sac/val in the clinical setting of hypertrophic remodelling and impaired diastolic function.

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Tashiro et al (2020) exhibited that the fewest hypertrophic changes-interventricular septum thickness diameter, left ventricular posterior wall thickness diameter and cardiomyocyte cross-sectional area-took place in the sacubutril/ valsartan-treated mice treated with Ang II, despite the similar blood pressure-lowering effect of sacubitril/valsartan, enalapril, and valsartan (Tashiro et al, 2020). A similar finding was also noted in a rat model of heart failure with preserved ejection Frontiers in Pharmacology frontiersin.org fraction (HFpEF) (Nordén et al, 2021). In the study, sacubitril/ valsartan had no significant effect on mean arterial pressure in the rats exposed to cardiac pressure overload, as opposed to reduced effect by valsartan.…”

“…In the study, sacubitril/valsartan had no significant effect on mean arterial pressure in the rats exposed to cardiac pressure overload, as opposed to reduced effect by valsartan. However, the left ventricular weight of the former group was significantly lower than the latter and vehicle-treated groups ( Nordén et al, 2021 ). The findings of both studies suggest that sacubitril/valsartan provides a direct cardioprotection against hypertrophic changes.…”

“…The beneficial effects of sacubitril/valsartan were also demonstrated in animal models. Its administration has resulted in decreased heart weight to body weight ratio in spontaneous hypertensive rats and in rats with induced cardiac hypertrophy ( Chang et al, 2019 ; Zhao et al, 2019 ; Nordén et al, 2021 ). It inhibited left ventricular hypertrophy in various models of cardiac hypertrophy, which was confirmed echocardiographically and histologically.…”

Sacubitril/valsartan (LCZ696) ameliorates hyperthyroid-induced cardiac hypertrophy in male rats through modulation of miR-377, let-7 b, autophagy, and fibrotic signaling pathways

“…Treatment with SAC and/or VAL significantly reduced the inflammatory response as indicated by reversal of these marker changes, consistent with previous studies reporting that LCZ696 ameliorated diabetic cardiomyopathy by inhibiting cardiac inflammatory and oxidative stress 21 . Further, LCZ696 induced substantial improvements beyond those produced by valsartan alone 22 .…”

Effects of sacubitril/valsartan in ESRD patients undergoing hemodialysis with HFpEF

“…Left ventricular remodeling is another central feature in the pathophysiology of HFpEF ( 33 ). The incidence of left ventricular hypertrophy in patients with hemodialysis is as high as 75% ( 34 ).…”