Testosterone Therapy for Diastolic Function Recovery in Hypogonadal Elderly

描述（由申请人提供）：与心脏老化相关的一些功能和病理变化导致心肌舒张受损，导致老年人舒张性心力衰竭的显著发病率和死亡率。舒张功能障碍的有效治疗明显缺乏，大多数药理试验显示没有或非常有限的益处。生物可利用睾酮(T)水平在40岁后逐渐下降，有趣的是，舒张功能障碍的患病率在同一年龄段增加。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。生物可利用性T缺乏可能导致与年龄相关的舒张功能障碍的发生和/或加重。因此，T置换术可能是缓解老年人舒张功能障碍的一个有吸引力的选择。我们已经证实了上述提出的关系，通过证明在替代T治疗后，在去性腺细胞的大鼠中出现的异常整体舒张功能的发展（通过侵入性测量的松弛时间常数；tau）得到逆转。这些数据证实了T疗法治疗舒张功能障碍的潜在有利作用，从而为老年人使用T疗法引入了一个新的适应症，这将解决一个高度普遍的临床问题。我们确定了临床应用的两个主要障碍

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.