BackgroundSingle ventricle (SV) congenital heart disease is fatal without intervention, and eventual heart failure is a major cause of morbidity and mortality. Although there are no proven medical therapies for the treatment or prevention of heart failure in the SV heart disease population, phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are increasingly used. Although the pulmonary vasculature is the primary target of PDE5i therapy in patients with SV heart disease, the effects of PDE5i on the SV heart disease myocardium remain largely unknown. We sought to determine PDE5 expression and activity in the single right ventricle of SV heart disease patients relative to nonfailing controls and to determine whether PDE5 impacts cardiomyocyte remodeling using a novel serum-based in vitro model.Methods and ResultsPDE5 expression (n=9 nonfailing; n=7 SV heart disease), activity (n=8 nonfailing; n=9 SV heart disease), and localization (n=3 SV heart disease) were determined in explanted human right ventricle myocardium. PDE5 is expressed in SV heart disease cardiomyocytes, and PDE5 protein expression and activity are increased in SV heart disease right ventricle compared with nonfailing right ventricle. Isolated neonatal rat ventricular myocytes were treated for 72 hours with nonfailing or SV heart disease patient serum±sildenafil. Reverse transcription quantitative polymerase chain reaction (n=5 nonfailing; n=12 SV heart disease) and RNA sequencing (n=3 nonfailing; n=3 SV heart disease) were performed on serum-treated neonatal rat ventricular myocytes and demonstrated that treatment with SV heart disease sera results in pathological gene expression changes that are attenuated with PDE5i.ConclusionsPDE5 is increased in failing SV heart disease myocardium, and pathological gene expression changes in SV heart disease serum-treated neonatal rat ventricular myocytes are abrogated by PDE5i. These results suggest that PDE5 represents an intriguing myocardial therapeutic target in this population.

中文翻译：

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磷酸二酯酶-5在单个心室心肌衰竭中升高，并影响体外心肌细胞重塑。

背景单心室（SV）先天性心脏病在没有干预的情况下是致命的，最终的心力衰竭是发病率和死亡率的主要原因。尽管在SV心脏病人群中尚无经证实的治疗或预防心力衰竭的医学疗法，但越来越多地使用西地那非等磷酸二酯酶5抑制剂（PDE5i）。尽管肺血管系统是SV心脏病患者PDE5i治疗的主要目标，但PDE5i对SV心脏病心肌的作用仍然未知。我们试图确定相对于未失败对照的SV心脏病患者右心室中PDE5的表达和活性，并使用新型基于血清的体外模型确定PDE5是否影响心肌细胞重塑。方法和结果确定了移植后的右心室中PDE5的表达（n = 9未失败； n = 7 SV心脏病），活性（n = 8未失败； n = 9 SV心脏病）和定位（n = 3 SV心脏病）。心肌。PDE5在SV心脏病心肌细胞中表达，与未衰竭的右心室相比，PDE5蛋白的表达和活性在SV心脏病右心室中增加。用未失败或SV心脏病患者的血清±西地那非治疗分离的新生大鼠心室心肌细胞72小时。逆转录定量聚合酶链反应（n = 5不失败； n = 12 SV心脏病）和RNA测序（n = 3不失败；在经血清处理的新生大鼠心室肌细胞上进行了n = 3 SV心脏病试验），结果表明SV心脏病血清的治疗导致病理基因表达变化被PDE5i减弱。 PDE5i消除了SV心脏病血清治疗的新生大鼠心室肌细胞中的基因表达变化。这些结果表明，PDE5在该人群中代表了一个引人入胜的心肌治疗靶标。