Testosterone Therapy for Diastolic Function Recovery in Hypogonadal Elderly

描述(申请人提供)：与心脏老化相关的一些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的显著发病率和死亡率。对于舒张期功能障碍，目前尚缺乏有效的治疗方法，而且大多数药理学试验都显示没有疗效或疗效不大。生物可利用的睾酮(T)水平在第四个十年后逐渐下降，有趣的是，在相同的年龄范围内，舒张期功能障碍的患病率增加。因此，流行病学和实验数据表明，T水平下降与舒张期功能障碍恶化之间可能存在关联。生物可利用T缺乏可能导致和/或加重与年龄相关的舒张期功能障碍。因此，T细胞替换术可能为缓解老年患者的舒张期功能障碍提供了一个有吸引力的选择。我们通过证明性腺切除大鼠在替代T治疗后逆转的异常的整体舒张期功能(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。这些数据证实了T疗法治疗舒张期功能障碍的潜在有利效果，从而为T疗法在老年人中的应用提供了一个新的适应症，这将解决一个非常普遍的临床问题。我们确定了临床使用的两个关键障碍 T对舒张期功能障碍的缓解作用：1)对舒张期恢复的最佳T剂量缺乏了解。我们的临床和实验数据表明，中等剂量比低剂量更有效，2)缺乏跟踪舒张期功能变化的成像生物标志物。我们通过超声心动图对局部和全球舒张期力学的广泛研究表明，早期舒张期应变率是一个潜在的生物标志物。建议的T1翻译方案的总体目标是成功解决这些障碍，并为开发T作为治疗老年人舒张期功能障碍的新疗法奠定基础。根据这一建议进行的工作将为T治疗年龄相关的舒张性功能障碍的临床试验奠定基础。具体目标1：确定性腺功能低下的老年男性患者缓解整体和局部舒张期功能障碍的最佳T替代剂量。我们将比较安慰剂和2剂T在性腺功能低下的老年男性中的治疗6个月(目的是将T水平恢复到低水平和中等正常范围)。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期应变率将有所改善。具体目的2：建立一种准确、灵敏的能够监测舒张期功能动态细微变化的成像生物标志物(S)。我们假设早期舒张期应变率将显示局部和整体舒张期力学的间歇性变化。这一建议是基于来自人类受试者和实验模型的大量初步数据，这些数据支持使用T逆转性腺功能低下的老年人的舒张期功能障碍。

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.