Comparative and Combinatorial Effects of Resveratrol and Sacubitril/Valsartan alongside Valsartan on Cardiac Remodeling and Dysfunction in MI-Induced Rats

Abstract

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.

The impact of Sacubitril/Valsartan on cardiac fibrosis early after myocardial infarction in hypertensive rats

“…Some clinical trials also indicated the emerging role of Sacubitril/Valsartan in MI patients. Many preclinical experiments have confirmed the cardioprotective role of Sacubitril/Valsartan in MI and explored the underlying mechanisms [14][15][16][17]. In rabbit MI models, Sacubitril/Valsartan treatment offered better short-term and long-term benefits of preventing left ventricular dysfunction compared with valsartan [18].…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…Together with ACEI, ARNI sacubitril/valsartan suppresses cardiac dysfunction and fibrosis via the downregulation of TGF-β1, BNP, α-SMA, vimentin ( Liu et al, 2021b ). Furthermore, valsartan and sacubitril/valsartan prevent adverse remodeling in MI rats by reducing oxidative stress, inflammation, and fibrosis ( Raj et al, 2021 ). In MI with hypertensive rats model, the mineralocorticoid receptor antagonist (MRA) spironolactone reduces CFs, MFs, and macrophages infiltration in the heart and kidney ( Leader et al, 2021 ); however, it also binds other steroid receptors (e.g., progesterone and androgen receptors) causing side effects (e.g., gynecomastia and galactorrhea) ( Weldon and Brown, 2019 ).…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Oxidative stress and inflammation are the culprits in almost all diseases including heart failure. Sacubitril/valsartan mitigates oxidative stress and inflammation in vivo ( Yang et al, 2019 ; Raj et al, 2021 ) and in vitro ( Peng et al, 2020 ) models of heart failure as well as in patients with the disease ( Acanfora et al, 2020 ; Bunsawat et al, 2021 ; Pang et al, 2021 ). The drug diminished production of intracellular reactive oxygen species (ROS), oxidative products such as malondialdehyde, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukins IL-6 and IL-1β) in the models.…”

“…Therapy with sacubitril/valsartan was shown to improve Tei index (Gokhroo et al, 2021) and global longitudinal strain in heart failure patients (Valentim Gonçalves et al, 2019;Valentim Gonçalves et al, 2020a;Mirić et al, 2021). In addition, sacubitril/valsartan improves fractional shortening, cardiac output, loaddependent indices of left ventricular contractility (dp/dt max ), and relaxation (dp/dt min ) in animal heart failure models (Maslov et al, 2019b;Ge et al, 2020;Liu Y. et al, 2021;Raj et al, 2021) (Table 2). Combination therapy of sacubitril/valsartan therapy with SGLT2 inhibitors-originally developed as anti-diabetic drugs-has shown additional benefits in patients with diabetic cardiomyopathy (Kim et al, 2021;Karabulut et al, 2022).…”