Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Annayya R Aroor,Annayya R Aroor,Juan Carlos Lopez-Alvarenga,Guido Lastra,Guido Lastra,Guanghong Jia,Guanghong Jia,Nitin Das,Srinivas Mummidi,Javad Habibi,Javad Habibi,Vincent G Demarco,Vincent G Demarco,Bysani Chandrasekar,Bysani Chandrasekar

doi:10.1186/s12933-021-01270-1

Abstract

ObjectiveCardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy.MethodsSixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.ResultsSac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD.ConclusionsThese studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Highlights

Heart failure (HF) with normal or preserved ejection fraction (HFpEF) represents a unique pathophysiological phenotype which is distinct from HF with reduced ejection fraction (HFrEF)
Aroor et al Cardiovasc Diabetol (2021) 20:80 but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated diastolic dysfunction (DD)
These studies suggest that sac/val is superior to val in reversing obesity-associated DD

Summary

Introduction

Heart failure (HF) with normal or preserved ejection fraction (HFpEF) represents a unique pathophysiological phenotype which is distinct from HF with reduced ejection fraction (HFrEF). There are no evidence-based therapies to treat HFpEF, and therapeutic strategies are urgently needed to improve cardiovascular outcomes, including DD [10] In this regard, dysregulation of the natriuretic peptide (NP) system and inappropriate activation of the Renin– Angiotensin–Aldosterone System (RAAS) contribute to the development of obesity-associated DD in the absence of significant impairment in EF, a marker of systolic dysfunction [13,14,15,16,17,18]. Inhibition of the RAAS system is considered as one of the therapeutic options for the management of DD, the long-term administration of angiotensin receptor blockers (ARBs) is associated with aldosterone escape [14, 15] To circumvent these side-effects, a new class of drug containing the combination of sacubitril, a neprilysin inhibitor that blocks the degradation of NPs, and valsartan, an ARB, is increasingly recognized as an ideal combination to manage HFrEF [16, 17]. The rationale for combining valsartan with sacubitril is to overcome the deleterious effects of sacubitril-induced Ang II accumulation [12, 18,19,20]

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Conclusion