Myocardial Effects of PDE5 Inhibition in Single Ventricle Heart Disease

PDE5 抑制对单心室心脏病的心肌影响

基本信息

批准号：
9033944
负责人：
Shelley Deanne Miyamoto
金额：
$ 49.18万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033944
关键词：
Address Adrenergic Receptor Adult Animal Model Blood Circulation Cardiac Cardiac Myocytes Cardiac Output Cardiovascular system Cause of Death Cell Culture Techniques Cessation of life Child Childhood Clinical Clinical Trials Common Ventricle Congenital Abnormality Congenital Heart Defects Consensus Cyclic AMP-Dependent Protein Kinases Cyclic GMP Data Defect Diagnosis Down-Regulation Enalapril Exercise Tolerance Failure Gene Expression Profile Generations Genetic Goals Guidelines Health Heart Heart Diseases Heart Transplantation Heart failure Human Hypoxia Infant Intention Intervention Kinetics Lead Left ventricular structure Lesion Lung Mechanics Mediating Medical Methods MicroRNAs Modeling Molecular Morphology Muscle Cells Myocardial Myocardium Myofibrils Myosin ATPase Neonatal Operative Surgical Procedures Outcome Pathologic Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylation Placebos Population Property Protein Isoforms Proteins Pulmonary Circulation Pulmonary Vascular Resistance Pulmonary artery structure Pump Rattus Relaxation Research Right ventricular structure Risk Sarcomeres Series Signal Pathway Signal Transduction Single ventricle congenital heart disease Stress Survival Rate Tissue Banking Tissue Banks Troponin I Venous Ventricular Ventricular Remodeling Vulnerable Populations base carvedilol congenital heart disorder connectin effective therapy experience genetic approach heart function hemodynamics improved improved outcome in vivo infancy inhibitor/antagonist mature animal new therapeutic target novel therapeutics phosphodiesterase V pressure prevent primary pulmonary hypertension protein expression response sildenafil targeted treatment therapeutic target trend vascular bed

项目摘要

DESCRIPTION (provided by applicant): Single ventricle congenital heart disease (SV) is the leading cause of cardiovascular death and indication for heart transplantation in infancy. SV comprises a spectrum of cyanotic congenital cardiac malformations that are defined by hypoxia and a univentricular circulation. These defects are universally fatal without intervention and despite advances in medical and surgical therapies, the 1-year survival for SV in the current era is only 68.7%. While the single ventricle can be a morphologic right ventricle (RV), left ventricle (LV) or of mixed morphology, it is the single RV lesions that have the worst outcome, presumably due to inherent limitations in the RV's ability to tolerate increased afterload. When a single RV serves as the sole pump to both the systemic and pulmonary circulations, not surprisingly, failure of the RV is both a common cause of death and indication for heart transplant in these patients. There are currently no proven therapies for SV heart failure and identification of targeted therapies specific to the failing SV are needed in order to improve outcomes. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are used for the treatment of primary pulmonary hypertension in children due to their proven vasodilatory effects. Over the past few years, use of PDE5i in those with SV HF has increased dramatically with the intention of lowering pulmonary vascular resistance, increasing pulmonary venous return to the heart and subsequently improving cardiac output. Sildenafil has been associated with improved hemodynamics, exercise tolerance and myocardial function by echo in small series of SV patients. While the stated target of therapy in SV patients is the pulmonary vascular bed, there is increasing evidence in adults and animal models of HF that PDE5i has beneficial myocardial remodeling and functional effects. Whether the beneficial effects of PDE5i in the SV population specifically are related to afterload reduction of the failing SV, direct myocardial effects or a combination of both is unknown. The central hypothesis of this proposal is that PDE5i has direct myocardial effects in SV that result in augmented cardiac function, effects on cGMP-regulated signaling pathways and altered sarcomeric protein phosphorylation. Due to difficulties performing research in the vulnerable pediatric population in vivo, the current application utilize an ongoing explanted human heart tissue bank and a cell culture model to address the specific aims, thereby minimizing risk to children. We will analyze the effect of PDE5i on myofibril mechanics and sarcomere phosphorylation as well as force generation in trabeculae from explanted SV hearts. The current application will be the first to determine myocardial effects of PDE5i in explanted pediatric SV hearts and begin to correlate molecular findings with function. Finally, we will use pharmacologic and genetic methods to investigate the intracellular effects of PDE5i in neonatal rat ventricular myocytes (NRVMs).

描述（由应用提供）：单通气先天性心脏病（SV）是心血管死亡和婴儿心脏移植的指示的主要原因。 SV包括一系列由缺氧和普遍循环定义的氰基先天性心脏畸形。这些缺陷是普遍致命的，没有干预和医疗和手术疗法的目的地进展，当前时代的SV生存率仅为68.7％。虽然单个心室可以是左心室的形态右心室（RV）（LV）或混合形态，它的结果是最差的单一RV病变，大概是由于RV耐受后负荷增加的能力的继承局限性。当单个RV用作系统性和肺部循环的唯一泵时，RV的失败既是死亡的常见原因，又是这些患者心脏移植的常见原因。目前，为了改善结果，目前尚无对SV心力衰竭和鉴定针对失败SV的靶向疗法的识别的疗法。磷酸酯酶5抑制剂（PDE5I），例如硅酸盐，由于其经过证实的血管舒张作用，用于治疗儿童原发性肺动脉高压。在过去的几年中，在具有SV HF的患者中使用PDE5I急剧增加，目的是降低肺血管耐药性，增加肺静脉恢复到心脏，然后改善心输出量。 Sildenafil在小组SV患者中回声的血液动力学，运动耐受性和心肌功能的改善相关。尽管SV患者的治疗靶标是肺血管床，但在HF的成人和动物模型中，PDE5i具有有益的心肌重塑和功能作用，有越来越多的证据表明。 PDE5I在SV人群中的有益作用是否与减少失败的SV，直接心肌效应或两者的组合有关。该提议的中心假设是PDE5I在SV中具有直接的心肌作用，从而导致心脏功能增强，对CGMP调节的信号通路的影响和改变的肌蛋白蛋白磷酸化。由于难以在体内进行脆弱的儿科人群进行研究，目前的应用利用了正在进行的人类心脏组织库和细胞培养模型来解决特定目标，从而最大程度地降低了对儿童的风险。我们将分析PDE5I对肌纤维力学和SARCome磷酸化的影响，以及从外植体SV心脏中的小梁中产生的力。当前的应用将是第一个确定PDE5I在外植的小儿SV心脏中的心肌效应，并开始将分子发现与功能相关联。最后，我们将使用药物和遗传方法研究新生大鼠心室心肌细胞（NRVM）中PDE5I的细胞内作用。