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舒张受损，从而导致老年人舒张性心力衰竭的显着发病率和死亡率。明显缺乏治疗舒张功能障碍的有效疗法，并且大多数药理学试验没有显示任何益处或效果非常有限。生物可利用的睾酮 (T) 水平在 4 岁以后逐渐下降，有趣的是，在同一年龄范围内，舒张功能障碍的患病率有所增加。因此，流行病学和实验数据表明 T 水平降低与舒张功能障碍恶化之间可能存在关联。生物可利用 T 缺乏可能会导致与年龄相关的舒张功能障碍的发生和/或恶化。因此，T 替代可能为缓解老年人舒张功能障碍提供有吸引力的选择。我们通过证明性腺切除大鼠中异常的整体舒张功能（通过侵入性测量的松弛时间常数；tau）的发展证实了上述提出的关系，并且在替代 T 疗法后得到了逆转。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，从而为老年人使用 T 疗法提供了新的适应症，可以解决高度普遍的临床问题。我们确定了临床使用的两个关键障碍 缓解舒张功能障碍的 T 剂量：1) 缺乏舒张恢复最佳 T 剂量的知识。我们的临床和实验数据表明，中等剂量比低剂量更有效，并且2）缺乏追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整体舒张力学方面进行的广泛工作表明早期舒张应变率是一个潜在的生物标志物。 T1 转化提案的总体目标是成功解决这些障碍，并为将 T 开发为治疗老年人舒张功能障碍的新型疗法奠定基础。根据该提案进行的工作将为 T 用于治疗与年龄相关的舒张功能障碍的临床试验奠定基础。具体目标 1：确定性腺功能减退老年男性的最佳 T 替代剂量，以缓解整体和区域舒张功能障碍。我们将在性腺功能减退的老年男性中比较安慰剂和 2 剂 T 治疗 6 个月（目的是将 T 水平恢复到低与中等正常范围）。我们假设与低 T 替代组和安慰剂组相比，中度 T 替代组的局部和整体舒张应变率将会改善。具体目标 2：建立准确、灵敏的成像生物标志物，能够监测舒张功能的动态细微变化。我们假设早期舒张应变率将表现出区域和整体舒张力学的间隔变化。该提案以人类受试者和实验模型的大量初步数据为基础，支持使用 T 来逆转性腺功能减退老年人的舒张功能障碍。