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Aims  Heart 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 results  Zucker 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.    Conclusions  We 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.

european journal of heart failure

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