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

Abstract

Objective Cardiac 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. Methods Sixteen-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. Results Sac/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. Conclusions These 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.

Association Between Arterial Stiffness and Heart Failure With Preserved Ejection Fraction

“…Sacubitril/Valsartan (LCZ696) is a new superstar in the management of heart failure and hypertension. Two recently-released independent studies showed that sacubitril/valsartan inhibits the progress of diastolic dysfunction and arterial stiffness to HFpEF in rat models ( 44 , 45 ). However, clinical trials are needed to verify the effects of sacubitril/valsartan on HFpEF patients.…”

"<i>Primum non nocere</i> (First, do no harm)". Case report

“…Избранная тактика ведения пациентки была нацелена в первую очередь на улучшение диастолической функции миокарда и, следовательно, предупреждение значимой объемной перегрузки ЛП и малого круга кровообращения при нагрузке и пароксизмах ФП, что сопровождалось развитием отека легких. В последние годы были проведены многочисленные исследования и опубликован ряд работ, свидетельствующих о способности как комбинации валсартана/сакубитрила [3,4], так и ингибиторов натрий-глюкозного котранспортера 2 типа [5,6] подавлять синтез провоспалительных цитокинов, угнетать окислительный стресс, восстанавливать эндотелиальную функцию, ионный и энергетический гомеостаз кардиомиоци-тов и фосфорилирование саркомерных белков, что нормализует механизм мышечного сокращения и приводит к уменьшению выраженности гипертрофии, интрамурального фиброза и ригидности миокарда с улучшением диастолической функции.…”

Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies

“…One of the early pathological abnormalities in DCM is diastolic dysfunction, which occurs when the heart is unable to relax and fill with blood properly [ 27 , 28 ]. This dysfunction is associated with diabetes-induced changes in cardiac lipid accumulation and calcium homeostasis, leading to ventricular stiffness and impaired relaxation.…”