Clinical and therapeutic implications of fibrosis in hypertrophic cardiomyopathy

描述(由申请人提供)： 这项提议的主要目的是发展马丁·马龙博士的科学和临床研究技能，使他可能成为一名独立的临床研究员。塔夫茨-新英格兰医学中心的肥厚型心肌病(HCM)中心、分子心脏学研究所(MCRI)、先进的心脏成像科和超声心动图实验室将为Maron博士提供一个合适的环境，在其中研究醛固酮拮抗剂是否可以有利地改变肥厚型心肌病患者的心肌纤维化程度，从而改善疾病的临床和形态标志物。通过与临床导师James Udelson博士的合作，以及由其他经验丰富的科学和临床研究人员组成的广泛网络，Maron博士将获得成长为独立临床调查员所需的技能。肥厚性心肌病是最常见的遗传性心肌病，仍然是年轻人心源性猝死的主要原因，也是任何年龄心力衰竭症状和死亡的重要原因。在肥厚性心肌病中，涉及心肌纤维化的左心室病理性重构可能是心功能不全的主要原因，也是室性心律失常的发生的核心。血清胶原代谢标志物已被证明能可靠地反映多种心血管疾病中心肌纤维化的程度。此外，醛固酮拮抗剂药物已被证明在某些病理性心血管状态下减少心肌纤维组织的形成，在这种状态下，醛固酮产生增加。在肥厚性心肌病中，醛固酮的产生被上调，并与心肌纤维化的形成有关。因此，这项建议的具体目的是：1)评估基线时的血清胶原周转标志物，并将这些发现与各种临床和形态疾病参数相关联；2)检查用醛固酮拮抗剂螺内酯治疗12个月后，通过血清胶原周转标志物以及临床和形态疾病参数的变化来衡量纤维化程度的效果。这项研究的结果将为这种原发遗传性心肌病心肌纤维化的临床意义提供重要的见解。螺内酯可减少纤维化，改善临床病程，这将为更大规模的多中心临床试验提供理论依据，以评估这一新疗法改善肥厚性心肌病患者的临床结果。(摘要结束)

DESCRIPTION (provided by applicant): The main objective of this proposal is to develop the scientific and clinical research skills of Dr. Martin Maron, so that he may become an independent clinical investigator. The hypertrophic cardiomyopathy (HCM) center, Molecular Cardiology Research Institute (MCRI), advanced cardiac imaging department and echocardiographic laboratory at Tufts-New England Medical Center will provide Dr. Maron with an appropriate environment in which to study whether an aldosterone antagonist drug can favorable alter the magnitude of myocardial fibrosis in patients with HCM and thereby improve clinical and morphologic markers of disease. Through collaboration with the clinical mentor, Dr. James Udelson, as well as an extensive network of other experienced scientific and clinical investigators, Dr. Maron will acquire the skills necessary to mature into an independent clinical investigator. HCM is the most common genetic cardiomyopathy and remains the leading cause of sudden cardiac death in young people and an important cause of heart failure symptoms and death at any age. In HCM, pathological remodeling of the left ventricle involving myocardial fibrosis is likely a major contributor to cardiac dysfunction and also a nidus for the generation of ventricular arrhythmias. Serum markers of collagen turnover have been shown to reliably reflect the magnitude of myocardial fibrosis in a variety of cardiovascular diseases. In addition, aldosterone antagonist drugs have been shown to decrease fibrous tissue formation in the myocardium in certain pathologic cardiovascular states in which aldosterone production is increased. In HCM, aldosterone production is up-regulated and has been implicated in the formation of myocardial fibrosis. Therefore, the specific aims of this proposal are to: 1) assess serum markers of collagen turnover at baseline and correlate these findings with a variety of clinical and morphologic disease parameters 2) examine the effects of a 12-month treatment with the aldosterone antagonist spironolactone on magnitude of fibrosis as measured by serum markers of collagen turnover as well as changes in clinical and morphologic disease parameters. The results of this proposal will offer important insights into the clinical significance of myocardial fibrosis in this primary genetic cardiomyopathy. The demonstration that spironolactone decreases fibrosis and improves clinical course would provide the rational for a larger multicenter clinical trial evaluating this novel therapy for improving clinical outcome in patients with HCM. (End of Abstract)