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Many studies in mice have demonstrated that cardiac-specific innate immune signaling pathways can be reprogrammed to modulate inflammation in response to myocardial injury and improve outcomes. While the echocardiography standard parameters of left ventricular (LV) ejection fraction, fractional shortening, and end-diastolic diameter, and others, are used to assess cardiac function, their dependency on loading conditions somewhat limit their utility in completely reflecting the contractile function and global cardiovascular efficiency of the heart. A true measure of global cardiovascular efficiency should include of the interaction between the ventricle and the aorta (ventriculo-vascular coupling, VVC) as well as measures of aortic impedance and pulse wave velocity. We measured cardiac Doppler velocities, blood pressures, along with VVC, aortic impedance, and pulse wave velocity to evaluate global cardiac function in mouse model of cardiac-restricted low levels TRAF2 overexpression that conferred cytoprotection in the heart. While previous studies reported that response to myocardial infraction and reperfusion was improved in the TRAF2 overexpressed mice, we found that TRAF2 mice had significantly lower cardiac systolic velocities and accelerations, diastolic atrial velocity, lower aortic pressures and rate-pressure product, lower LV contractility and relaxation, and lower stroke work when compared to littermate control mice. Also, we found significantly longer aortic ejection time, isovolumic contraction and relaxation times, and significantly higher mitral early/atrial ratio, myocardial performance index, and ventricular vascular coupling in the TRAF2 overexpression mice compared to their littermate controls. We found no significant differences in the aortic impedance and pulse wave velocity. While the reported tolerance to ischemic insults in TRAF2 overexpression mice may suggest enhanced cardiac reserve, our results indicate a diminished cardiac function in these mice.

Cardiac disease remains a significant cause of death among humans and therapies to treat the disease are lacking. Importantly, heart failure has also been linked to factors including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress 1, which are all factors the mitochondria plays a role in. Critically, mitochondria break down across aging and heart also decrease in efficiency in aging. Key factors implicated in mitochondria morphology, such as the mitochondrial contact site and cristae organizing system (MICOS), and its role across aging remains to be seen in cardiac muscle. To better understand the relationship between mitochondria in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the 3D networks in cardiac muscle samples of mice at aging intervals. In studying cristae, the inner folds of mitochondria, we observed a loss of morphology across aging. This mimicked what was observed upon CRISPR/Cas9 knockdown of Mitofilin, Chchd3, Chchd6 (some members of the MICOS complex) and Opa1 which showed poorer quality cristae and fragmented mitochondria, while mitochondria length and volume decreased. We are the first to examine mitochondria changes in cardiac muscle across aging. In combination, these data suggest that, in the heart, loss of the MICOS complex may be implicated in the loss of function in mitochondria that is seen across aging.