Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2024-10-16 DOI:10.1016/j.bcp.2024.116571

Sandra Moraña-Fernández , Xocas Vázquez-Abuín , Alana Aragón-Herrera , Laura Anido-Varela , Javier García-Seara , Óscar Otero-García , Diego Rodríguez-Penas , Manuel Campos-Toimil , Manuel Otero-Santiago , Alexandre Rodrigues , Alexandre Gonçalves , Juliana Pereira Morais , Inês N. Alves , Cláudia Sousa-Mendes , Inês Falcão-Pires , José Ramón González-Juanatey , Sandra Feijóo-Bandín , Francisca Lago

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Abstract

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

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在大鼠射血分数保留型心力衰竭模型中使用沙库比妥/缬沙坦对心脏代谢的影响

PARADIGM-HF 试验取得的良好结果促使萨库比特利/缬沙坦（SAC/VAL）作为射血分数降低型心力衰竭（HFrEF）患者的首选治疗药物获得批准。此外，还对射血分数保留型心力衰竭（HFpEF）患者进行了 SAC/VAL 治疗效果的研究，虽然观察到纽约心脏协会（NYHA）分级、心力衰竭住院率和心血管死亡人数有所改善，但这些结果并不令人乐观。然而，由于对高频心衰疗法的需求，SAC/VAL 作为一种替代治疗方法获得了批准，尽管还需要进一步的研究。我们的目的是利用高频心衰的临床前模型--扎克脂肪和自发性高血压（ZSF1）大鼠，阐明为期 9 周的 SAC/VAL 治疗对心脏功能和代谢的影响。我们发现，SAC/VAL 能明显改善舒张功能参数，并调节运动时的呼吸商。体内外研究显示，SAC/VAL 治疗可显著降低心脏、肝脏、脾脏和内脏脂肪重量；心脏肥大和纤维化百分比；肝脏脂质浸润以及循环中胆固醇和钠的水平。此外，SAC/VAL 还能降低甘油磷脂、胆固醇和胆固醇酯，同时提高心脏组织中甘油三酯的水平。总之，SAC/VAL 治疗可改善舒张功能和肝功能、呼吸代谢、降低高胆固醇血症、心脏纤维化和肥大，并能调节心脏代谢轮廓。我们的研究结果或许能进一步揭示 SAC/VAL 治疗对肥胖高频心衰患者的疗效。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.