Mechanisms Underlying Takotsubo Syndrome

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Our proposal tests the overarching hypothesis that regional differences in coronary regulation cause micro- areas of ischemia in the apex of the heart and induce Takotsubo Syndrome. We posit that the level of ischemia in the ballooning area is not sufficient to produce cell death, but enough of a decrease to invoke an adaptive program of “myocardial hibernation,” confined to area of ballooning, where the decrease in flow leads to a decrease in cardiac function. The consequence of apical hibernation is a restoration of the match between myocardial blood flow and function as the reduced apical function matches the lower myocardial blood flow, resolving the ischemia. The “benefit” of this hibernation is to prevent irreversible injury, i.e., necrosis. To determine if these hypotheses are correct, we have incorporated a multidisciplinary approach that will not only provide a comprehensive mechanistic analysis of TTS (Aim 1), but will also determine if increasing blood flow in the apex of the heart exerts a salubrious effect in TTS (Aim 2). Within this context, we propose two aims: Specific Aim 1. To determine if Takotsubo Syndrome is caused by impaired flow regulation in the apical regions of the heart leading to micro-areas of myocardial ischemia and a down-regulation of function. Furthermore, we will determine if the ischemia is abated when function downregulates to match the reduced flow. This aim will be tested by the following hypotheses: Hypothesis 1. Vasoactive reactions to vasodilators and vasoconstrictors are different in coronary arterioles from the apex and base of the heart. Hypothesis 2. During the initial development of TTS, the apex of the heart is ischemic. Hypothesis 3. During the stage of TTS characterized by apical ballooning, the downregulation of both cardiac function and myocardial blood flow in the apex eliminates myocardial ischemia and produces apical hibernation. The second specific aim proposes to determine if improving myocardial blood flow (MBF) will induce recovery of metabolic and molecular changes induced during Takotsubo Syndrome. This will be tested in the following hypothesis using two independent mechanisms to increase blood flow: Hypothesis 4. Increasing MBF in the area of ballooning prevents or restores cardiac, coronary, and metabolic dysfunction. This application builds upon the expertise and technological capability of research teams at Northeast Ohio Medical University and Cornell University to decipher mechanisms underlying Takotsubo Syndrome, and to determine whether coronary vasodilation rescues the abnormalities associated with this syndrome. A comprehensive, interdisciplinary approach is imbedded in the experimental plan to include measurements of myocardial blood flow (echocardiography) tissue metabolism and (mass spectrometry), gene expression (RNA seq, RT-PCR), protein expression and phosphorylation (Western blotting) and cardiac myocyte hypoxia using cardiac myocyte specific hypoxia fate- mapping.