Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Matyas C

PROVIDER: S-EPMC5347963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsMurine models implicate phosphodiesterase 9A (PDE9A) as a nitric oxide-independent regulator of cyclic guanosine monophosphate and promising novel therapeutic target in heart failure (HF) with preserved ejection fraction (HFpEF). This study describes PDE9A expression in endomyocardial biopsies (EMBs) and peripheral blood mononuclear cells (PBMNCs) from patients with different HF phenotypes.Methods and resultsEndomyocardial biopsies and PBMNCs were obtained from patients with HFpEF (n = 24), HF with reduced ejection fraction (n = 22), and inflammatory cardiomyopathy (n = 24) and patients without HF (n = 7). PDE9A expression was increased in EMBs and PBMNCs from patients with HFpEF as compared with other HF phenotypes or subjects without HF. Endomyocardial PDE9A expression in HFpEF correlated with the inflammatory cell count in EMBs, but not with cardiac fibrosis or left ventricular diastolic wall stress. PDE9A expression in PBMNCs was increased in HFpEF patients with higher high-sensitivity C-reactive protein levels and in response to pro-inflammatory stimulation. As a validation cohort, 719 patients with HFpEF and 1106 subjects without HF were identified from the LIFE-Heart study. PDE9A expression in PBMNCs was obtained from array data and displayed an age-dependent distribution. PDE9A levels were elevated and conferred increased risk for HFpEF in middle-aged subjects, but not in elderly HFpEF patients. Following age adjustment, lower PDE9A expression in PBMNCs was associated with worse survival in patients with HFpEF (log-rank test P-value <0.001).ConclusionExpression profiling indicates an up-regulation of endomyocardial PDE9A in different HF phenotypes with the most robust increase in EMBs and PBMNCs from patients with HFpEF. An exclusive risk effect of PDE9A expression on HFpEF in middle-aged patients and an unexpected association with survival calls for further studies to better characterize the role of PDE9A as a treatment target.

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