Mitochondrial signalling in non-fibrotic dilated cardiomyopathies: aortic regurgitation- and tachycardia-induced heat failure

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Aortic regurgitation- (AI-CM) and tachycardia (T-CM) induced cardiomyopathies share characteristics of left ventricular (LV) remodelling: they are over a long period reversible and non-fibrotic and entail LV dilatation, eccentric hypertrophy and systolic failure. Despite high prevalence and clinical impact of both diseases, underlying signalling processes have not been resolved and are largely underacknowledged. My current work revealed a specific pattern of mitochondrial dysfunctions in T-CM, characterized by enlarged mitochondria shifted towards the intercalated discs, depletion of substrates, and a shift of the mitochondrial redox balance towards a more oxidised state. However, there is no evidence for oxidative stress or relevant fibrosis. These findings contrast characteristic signs of previously reported heart failure aetiologies, such as ischemic, increased afterload, hereditary, and toxic dilated cardiomyopathy, which rather feature increases in NADH and oxidative stress as well as fibrosis and hyperacetylation of the mitochondrial proteome. Of note, I could recently show, that the mitochondrial propensity for calcium-induced mPTP-opening increases in T-CM, giving a hint towards swelling and a potentially relevant signalling via mitochondrial calcium. I hypothesise: (I) Mitochondrial calcium concentration activates the tricarboxylic acid cycle and optimises mitochondrial matrix volume with regard to oxidative phosphorylation capacity. This mechanism partially counteracts mitochondrial dysfunction in T-CM and can be supported by inhibition of the mitochondrial sodium calcium exchanger, offering a new pharmacologic opportunity. (II) T-CM specific mitochondrial dysfunction regulates LV remodelling and hampers excitation-contraction coupling (ECC). (III) These mechanisms are a common pathomechanism in T-CM and AI-CM as examples of non-fibrotic dilated cardiomyopathy. To pinpoint my hypothesis, I link two rare animal models (tachypacing-induced heart failure, interventional aortic valvotomy) to an innovative systems medicine approach, combining current methods of functional metabolic and ECC-evaluation with cellular functional imaging and modern -omics technologies, the later deciphering post-translational signalling. I am going to evaluate specific inhibitors of mitochondrial ion-exchange and ROS-emission for their therapeutic potential in-vitro and in-vivo.