Mátyás Csaba, Németh Balázs T, Oláh Attila, Török Marianna, Ruppert Mihály, Kellermayer Dalma, Barta Bálint A, Szabó Gábor, Kökény Gábor, Horváth Eszter M, Bódi Beáta, Papp Zoltán, Merkely Béla, Radovits Tamás
Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Városmajor u. 68, 1122, Budapest, Hungary.
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
Eur J Heart Fail. 2017 Mar;19(3):326-336. doi: 10.1002/ejhf.711. Epub 2016 Dec 19.
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.
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.
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.
射血分数保留的心力衰竭（HFpEF）具有巨大的流行病学负担。环磷酸鸟苷（cGMP）信号通路在HFpEF中的病理生理作用已得到深入研究。cGMP水平升高已被证明在包括糖尿病性心肌病在内的各种心血管疾病中发挥心脏保护作用。我们研究了磷酸二酯酶-5A（PDE5A）抑制剂伐地那非长期预防性应用对糖尿病性心肌病相关HFpEF的影响。
将Zucker糖尿病肥胖（ZDF）大鼠作为HFpEF模型，ZDF瘦大鼠作为对照。动物在7至32周龄时口服给予载体或10mg/kg体重的伐地那非。在第32周通过左心室（LV）压力-容积分析和超声心动图评估心脏功能、形态。进行心肌细胞力测量。检测cGMP信号通路、硝基氧化应激、细胞凋亡、心肌肥大和纤维化的关键标志物。ZDF动物表现出舒张功能障碍（左心室/心肌细胞僵硬度增加、左心室舒张时间延长）、收缩功能保留、心肌cGMP水平降低以及蛋白激酶G（PKG）活性受损、硝基氧化应激增加、心肌细胞凋亡增强以及心肌肥大和纤维化重塑。伐地那非通过维持舒张功能（降低左心室/心肌细胞僵硬度和左心室舒张时间）、恢复cGMP水平和PKG激活、降低细胞凋亡以及减轻硝基氧化应激、心肌肥大和纤维化重塑，有效预防了HFpEF的发展。
我们报告伐地那非成功预防了糖尿病相关HFpEF的发展。因此，PDE5A抑制作为一种预防方法可能是管理糖尿病HFpEF患者的一个有前景的选择。
