Takahiko Kiyooka

Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage

Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) 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. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. 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. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.

PHYSIOMIC APPROACH TO BIOMECHANICS OF CORONARY MICROCIRCULATION

The recently proposed Physiome is considered as a powerful successor to the Genome. The definition of Physiome is the quantitative description of the physiological dynamics or functions of the intact organism. The physiome includes integration of knowledge through functional modules of hierarchical system elements of biological systems, and modeling. Biomechanics will offer potent tools to promote the Physiome. By using modern microvisualization technology with physiomic model, this manuscript introduces our physiomic approach to coronary microcirculation which supplies oxygen and nutrients to heart muscles; 1. Mechanical interaction between coronary blood flow and cardiac contraction, and 2. Capillary network and its function.

A case of vasospastic angina in which the ergonovine provocation test with intracoronary isosorbide dinitrate and nicorandil was effective in the diagnosis of microvascular spasm.

A 60-year-old man was admitted with early morning angina while at rest. Coronary angiogram revealed no organic lesions; therefore, a spasm provocation test with ergonovine was performed. Administration of intracoronary ergonovine induced total occlusion of the right coronary artery. The induced total occlusion improved but coronary flow velocity remained severely reduced and chest discomfort with ST-T changes in ECG remained in spite of repeated administration of isosorbide dinitrate (ISDN). Intracoronary administration of nicorandil following ISDN alleviated the chest discomfort, normalized the ST-T change in ECG, and improved the coronary flow. This suggested that microvascular spasm and the epicardial spasm were not relieved by ISDN but by nicorandil. Intracoronary nicorandil injection following ISDN administration may be useful for the diagnosis of microvascular spasm in the ergonovine provocation test.

Celsior preserves cardiac mechano-energetics better than University of Wisconsin solution by preventing oxidative stress

OBJECTIVES Identity of the optimal heart preservation solution remains unknown. Because oxidative stress contributes to contractile failure in the ischaemic/reperfused myocardium and the main characteristic of Celsior is its antioxidant effect, it is important to elucidate the relationship between the inhibitory effect on oxidative stress and cardiac mechano-energetics. We therefore evaluated the efficacy of Celsior from both aspects by comparison with the University of Wisconsin solution (UWS). METHODS We used 18 excised cross-circulated canine hearts. Excised hearts were preserved with UWS (n = 6) or Celsior (n = 6) for 3 h at 4 °C; the remaining six served as controls. Hearts were then cross-circulated and rewarmed. The end-systolic pressure-volume ratio (LV Emax) and the ventricular pressure-volume area, which is a measure of total mechanical energy, were assessed after reperfusion. Biopsies were taken from the endocardium after excising the heart, before reperfusion, after reperfusion and 4 h after reperfusion to assess the inhibitory effect of each agent on oxidative stress. Endo-myocardial biopsy samples were studied immunohistochemically for expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. RESULTS Emax in the UWS group was significantly smaller than in the control group, whereas the Emax in the Celsior group was preserved. Oxygen cost of Emax in the UWS group was significantly higher than in the Celsior group. Myocardial HNE-modified protein levels increased gradually, both under preservation and after reperfusion in the UWS group. Myocardial HNE-modified protein levels in the Celsior group were lower, mainly before and 4 h after reperfusion compared with the UWS group. CONCLUSIONS Celsior may maintain cardiac contractility and conserve oxygen cost by inhibiting oxidative stress.