• cardiomyopathy disease
• Coronary circulation
• Obesity
• Type 2 diabetes

Background: Obesity and diabetes are characterized by profound changes in cardiac metabolism with a net prevalence of fatty acid oxidation over glucose metabolism, with structural and functional alteration in mitochondria resulting in excessive production of free radicals. Enhanced released of reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA) leading to a vicious cycle in which mitochondrial dysfunction sustains and increases mtDNA breakage and cellular damage. Because mitochondrial DNA plays a key role in the production of ATP necessary for the generation of cardiac work (MVO2), we have hypothesized that mitochondrial dysfunction (by the means of mt-DNA damage) causes coronary microvascular dysfunction, impairs coronary metabolic dilation, and induces myocardial ischemia.
Methods and Results: Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN, n=10) and obese fatty (ZOF, n=10) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Consistently, mitochondrial respiration and ROS production were altered in ZOF as compared to ZLN; and were associated with mitochondrial DNA damage. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repairing of mtDNA damage restored mitochondrial function and metabolic dilation and reduced ROS production in ZOF (n=10). Whereas, induction of mtDNA damage in ZLN (n=10) reduced mitochondrial function, increased ROS production, and attenuated coronary metabolic dilation. Proper coronary metabolic dilation was associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; but myocytes from rats with impaired dilation released only H2O2. In rats with mtDNA damage, impaired coronary metabolic dilation induced severe tissue hypoxia, impaired cardiac diastolic and systolic function.
Conclusions: All together these data demonstrate that mitochondrial function plays a seminal role in connecting myocardial blood flow to cardiac metabolism. The integrity mtDNA plays a key role in this connection and may be responsible for the development of the diabetes and obesity related cardiomyopathy.