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：
8860501
负责人：
Shelley Deanne Miyamoto
金额：
$ 50.99万
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/8860501
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 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 connectin effective therapy experience genetic approach heart function hemodynamics improved in vivo infancy inhibitor/antagonist mature animal new therapeutic target novel phosphodiesterase V pressure prevent primary pulmonary hypertension protein expression public health relevance 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（由申请人提供）：单心室先天性心脏病 (SV) 是心血管死亡的主要原因，婴儿期心脏移植的适应症包括一系列由缺氧和单心室循环缺陷定义的紫绀型先天性心脏畸形。在不进行干预的情况下，SV 普遍致命，尽管医学和手术治疗取得了进步，但目前 SV 的 1 年生存率仅为 68.7%。心室可以是形态学上的右心室 (RV)、左心室 (LV) 或混合形态，单个 RV 病变的结果最差，可能是由于当单个 RV 充当体循环和肺循环的唯一泵时，RV 承受增加的后负荷的能力存在固有限制。毫无疑问，右心室衰竭既是这些患者死亡的常见原因，也是心脏移植的指征。目前尚无经过验证的治疗 SV 心力衰竭的疗法，需要确定针对衰竭 SV 的靶向疗法以改善病情。结果磷酸二酯酶5。抑制剂 (PDE5i)，如西地那非，因其已被证明的血管舒张作用而被用于治疗儿童原发性肺动脉高压。在过去的几年中，PDE5i 在 SV HF 患者中的使用急剧增加，目的是降低肺动脉高压。通过小系列 SV 超声检查发现，血管阻力、增加肺静脉回流至心脏以及随后改善心输出量与血流动力学、运动耐量和心肌功能的改善相关。虽然 SV 患者的既定治疗目标是肺血管床，但在成人和心力衰竭动物模型中，越来越多的证据表明 PDE5i 对心肌重塑和功能作用具有有益作用。与衰竭 SV 的后负荷减少、直接心肌效应或两者的组合相关的研究尚不清楚。该提议的中心假设是 PDE5i 对 SV 具有直接心肌效应，导致心脏增强。功能、对 cGMP 调节的信号通路的影响和改变的肌节蛋白磷酸化由于在易受伤害的儿科人群体内进行研究存在困难，当前的应用利用正在进行的外植人类心脏组织库和细胞培养模型来解决特定目标，我们将分析 PDE5i 对肌原纤维力学和肌节磷酸化以及外植 SV 心脏小梁中力产生的影响。目前的应用将是首次。确定 PDE5i 对移植的儿科 SV 心脏的心肌影响，并开始将分子研究结果与功能相关联。最后，我们将使用药理学和遗传学方法研究 PDE5i 对新生大鼠心室肌细胞 (NRVM) 的细胞内影响。