Clinical and therapeutic implications of fibrosis in hypertrophic cardiomyopathy

肥厚型心肌病纤维化的临床和治疗意义

• 批准号: 7489824
• 负责人: Martin S Maron
• 金额: $ 14.24万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489824
• 关键词: 3-Dimensional; Age; Aldosterone; Aldosterone Antagonists; Area; Arrhythmia; Cardiac; Cardiology; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Cicatrix; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Collaborations; Collagen; Coronary artery; Data; Disease; Disease Marker; Echocardiography; End Point; Environment; Exercise; Exercise stress test; Fibrosis; Functional disorder; Gender; Generations; Genetic; Heart Diseases; Heart failure; Hour; Hypertrophic Cardiomyopathy; Image; Ischemia; Laboratories; Left Ventricular Mass; Left Ventricular Remodeling; Left ventricular structure; Life; Magnetic Resonance Imaging; Measurement; Measures; Mediator of activation protein; Medical center; Mentors; Metabolic; Metabolism; Methods; Mineralocorticoid Receptor; Mineralocorticoids; Minnesota; Molecular; Monitor; Myocardial; Myocardium; Natural History; New England; Outcome; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Placebos; Population; Population Control; Production; Questionnaires; Randomized; Research Institute; Research Personnel; Resolution; Risk; Role; Serum Markers; Spironolactone; Symptoms; Testing; Therapeutic; Tissues; Ursidae Family; Ventricular Arrhythmia; abstracting; cardiovascular risk factor; clinically relevant; clinically significant; cohort; double-blind placebo controlled trial; experience; follow-up; improved; in vivo; indexing; insight; interstitial; mortality; mouse model; novel; programs; prospective; skills; sudden cardiac death

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)

描述（由申请人提供）： 该提案的主要目标是发展Martin Maron博士的科学和临床研究技能，使他成为独立的临床研究者。Tufts-New England Medical Center的肥厚型心肌病（HCM）中心、分子心脏病学研究所（MCRI）、先进的心脏成像部门和超声心动图实验室将为Maron博士提供一个适当的环境，以研究醛固酮拮抗剂药物是否可以有利地改变HCM患者心肌纤维化的程度，从而改善疾病的临床和形态学标志物。通过与临床导师James Udelson博士以及其他经验丰富的科学和临床研究者的广泛网络合作，Maron博士将获得成熟成为独立临床研究者所需的技能。HCM是最常见的遗传性心肌病，仍然是年轻人心脏性猝死的主要原因，也是任何年龄心力衰竭症状和死亡的重要原因。在HCM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，也是产生室性心律失常的病灶。血清胶原周转标志物已被证明可靠地反映了各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显示在某些病理性心血管状态下减少心肌中纤维组织形成，其中醛固酮产生增加。在HCM中，醛固酮的产生被上调，并与心肌纤维化的形成有关。因此，本提案的具体目的是：1）评估基线时胶原蛋白周转的血清标志物，并将这些发现与各种临床和形态学疾病参数相关联; 2）检查醛固酮拮抗剂螺内酯治疗12个月对纤维化程度的影响，如通过胶原蛋白周转的血清标志物以及临床和形态学疾病参数的变化所测量的。本研究结果将为探讨原发性遗传性心肌病心肌纤维化的临床意义提供重要的参考。螺内酯减少纤维化和改善临床病程的证明将为更大规模的多中心临床试验提供合理性，以评估这种新疗法改善HCM患者的临床结局。 (End摘要）