Testosterone Therapy for Diastolic Function Recovery in Hypogonadal Elderly

睾酮疗法恢复性腺功能减退老年人的舒张功能

• 批准号: 8510799
• 负责人: THEODORE P ABRAHAM
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510799
• 关键词: 3 year old; Address; Age; Aging; Baltimore; Bioavailable; Biological Markers; Blinded; Calcium; Clinical; Clinical Trials; Communities; Coronary; Data; Development; Diabetes Mellitus; Diastolic heart failure; Dose; Echocardiography; Elderly; Enrollment; Epidemiology; Evaluation; Experimental Models; Foundations; Functional disorder; Glare; Goals; Health Care Costs; Heart; Heart failure; Human; Hypertension; Image; Knowledge; Longitudinal Studies; Measures; Mechanics; Mediating; Monitor; Morbidity - disease rate; Muscle; Myocardial; Normal Range; Odds Ratio; Pathologic; Patient Selection; Patients; Pattern; Placebo Control; Placebos; Population; Prevalence; Quality of life; Randomized; Rattus; Recovery; Recovery of Function; Relaxation; Resolution; Role; Selection Bias; Staging; Testing; Testosterone; Time; Tissues; Work; age related; base; effective therapy; falls; human subject; improved; indexing; male; men; mortality; novel; public health relevance; restoration; tau Proteins

DESCRIPTION (provided by applicant): Several functional and pathologic changes associated with the aging heart result in impaired myocardial relaxation causing significant morbidity and mortality from diastolic heart failure in the elderly. There is a glaring lack of effective therapy for diastolic dysfunction and most pharmacologic trials have shown none or very modest benefits. Bioavailable testosterone (T) levels decline progressively after the 4th decade and interestingly the prevalence of diastolic dysfunction increases across the same age range. Thus, epidemiologic and experimental data suggest a possible association between decreasing T levels and worsening diastolic dysfunction. It is possible that bioavailable T deficiency contributes to the development and/or exacerbation of age-related diastolic dysfunction. Therefore, T replacement may offer an attractive option to alleviate diastolic dysfunction in the elderly. We have confirmed the above proposed relationship by demonstrating development of abnormal global diastolic function (by invasively-measured time constant of relaxation; tau) in gonadectomized rats that was reversed after replacement T therapy. These data corroborate the potential favorable effects of T therapy for treatment of diastolic dysfunction thus introducing a novel indication for use of T therapy in the elderly that would address a highly prevalent clinical problem. We identify two key barriers to the clinical use of T for alleviation of diastolic dysfunction: 1) the lack of knowledge of the optimal T dose for diastolic recovery. Our clinical and experimental data suggest a moderate, rather than low dose, would be more effective, and 2) absence of an imaging biomarker that will track changes in diastolic function. Our extensive work in regional and global diastolic mechanics by echocardiography suggest early diastolic strain rate as a potential biomarker. The overall goal of the proposed T1 Translational proposal is to successfully resolve these barriers and lay the foundation to develop T as a novel therapy for diastolic dysfunction in elderly humans. The work conducted under this proposal will set the stage for a clinical trial of T for treatment of age-related diastolic dysfunction. Specific Aim 1: To determine the optimal T replacement dose in hypogonadal elderly males that will alleviate global and regional diastolic dysfunction. We will compare placebo to 2 doses of T in hypogonadal elderly males (with the aim of restoring T levels to low versus moderate normal ranges) treated for 6 months. We hypothesize that regional and global diastolic strain rate will improve in the moderate T replacement group compared to low T replacement and placebo groups. Specific Aim 2: To establish an accurate and sensitive imaging biomarker(s) able to monitor dynamic subtle changes in diastolic function. We hypothesize that early diastolic strain rate will demonstrate interval changes in regional and global diastolic mechanics. This proposal develops on substantial preliminary data from human subjects and experimental models that support the use of T for reversal of diastolic dysfunction in the hypogonadal elderly.

描述（由申请人提供）：与衰老心脏相关的几种功能和病理变化导致心肌松弛受损，导致老年人舒张性心力衰竭导致明显的发病率和死亡率。缺乏有效的舒张功能障碍治疗，大多数药理学试验都没有表现出任何或非常适中的好处。在第四个十年后，生物利用可利用的睾丸激素（T）水平逐渐下降，有趣的是，舒张功能障碍的患病率在同一年龄范围内增加。因此，流行病学和实验数据表明降低t水平与舒张功能障碍的恶化之间可能存在关联。可生物利用的T缺乏有助于与年龄相关的舒张功能障碍的发展和/或加剧。因此，T替换可能会提供一个有吸引力的选择，以减轻老年人的舒张功能障碍。我们已经通过证明异常的全球舒张功能的发展（通过在替换T疗法后逆转的性腺大鼠中的浸润时间常数； tau）证实了上述关系。这些数据证实了T疗法对治疗舒张功能障碍的潜在有利作用，因此引入了在老年人中使用T疗法的新颖指示，这将解决高度普遍的临床问题。我们确定临床使用的两个关键障碍 减轻舒张功能障碍的T的T：1）缺乏对舒张期恢复最佳剂量的知识。我们的临床和实验数据表明，中等而不是低剂量将更有效，2）缺乏会跟踪舒张功能变化的成像生物标志物。我们通过超声心动图在区域和全球舒张压方面的广泛工作表明，早期的舒张期应变率是潜在的生物标志物。拟议的T1翻译建议的总体目标是成功解决这些障碍，并为T奠定基础，以作为老年人类舒张功能障碍的新型疗法。根据该提案进行的工作将为T治疗与年龄相关的舒张功能障碍的T临床试验奠定基础。具体目的1：确定可减轻全球和区域舒张功能障碍的性雄性的最佳T替代剂量。我们将比较安慰剂与雄性雄性的2剂T剂量（目的是将T水平恢复到低于中度正常范围），治疗了6个月。我们假设与低T替换和安慰剂组相比，中等T替换组的区域和全球舒张压将提高。具体目标2：建立能够监视舒张功能动态微妙变化的精确和敏感的成像生物标志物。我们假设早期的舒张期应变率将证明区域和全球舒张压的间隔变化。该提案基于人类受试者的大量初步数据和实验模型，这些数据支持t在肌张力障碍的老年人中逆转舒张期功能障碍。