Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Abstract

AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

Therapeutic benefits of Phosphodiesterase-5 inhibition in chronic heart failure: A meta-analysis

“…Interventional Medicine & Applied Science pathways of sildenafil and related drugs, such as detected in experimental animals, appear to actually be compatible with the hypothesis of a favorable effect by PDE5i on hemodynamic parameters and clinical outcomes of patients with HFpEF [21]. Conversely, with regard to the relatively low efficacy of PDE5i on hemodynamic and spiroergometric parameters, as well as on clinical outcomes in patients with HFpEF, as evidenced by some studies included in our metaanalysis [14,19], this might depend on a possible predominance of the cases of Ipc-PH in these studies.…”

Effects of Anchomanes difformis on Inflammation, Apoptosis, and Organ Toxicity in STZ-Induced Diabetic Cardiomyopathy

“…Also, the loss of insulin sensitivity prevents the utilization of glucose for energy in the cells, thus the body burns fat and muscle as an alternative energy source [46]. Other studies have reported severe weight loss in diabetes mellitus [47,48]. An increase in relative organ weight is indicative of hypertrophy [49].…”

Serum uric acid is associated with incidence of heart failure with preserved ejection fraction and cardiovascular events in patients with arterial hypertension

“…Furthermore, increased activity of this enzyme, which is involved in the reaction of hypoxanthine and xanthine to UA, causes the release of free radicals and increased oxidative stress. Oxidative stress also contributes to the pathogenesis of HFpEF . Several studies have previously examined whether UA‐lowering therapy with xanthine oxidase inhibitor allopurinol or oxypurinol leads to clinical and functional improvement of HF; however, the results are not consistent .…”

“…Oxidative stress also contributes to the pathogenesis of HFpEF. 24,25 Several studies have previously examined whether UA-lowering therapy with xanthine oxidase inhibitor allopurinol or oxypurinol leads to clinical and functional improvement of HF; however, the results are not consistent. [26][27][28][29][30] Cingolani and colleagues 26 indicated that inhibition of xanthine oxidase by oxypurinol in patients with chronic HF decreased UA level and improved LVEF in patients with LVEF ≤40% after 1 month of treatment.…”