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.
Diastolic dysfunction is highly prevalent in the elderly and contributes to reduced quality of life and survival in this population. Experimental data suggest a possible role for testosterone therapy to reverse diastolic dysfunction and the overall goal of the proposed T1 Translational proposal is to resolve the barriers to the use of testosterone 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 testosterone for treatment of age-related diastlic dysfunction.