Spatial distribution of blood flow predicts metabolic phenotypes and electrophysiological properties in the heart

Abstract

High resolution analysis (300 μl) reveals a temporally stable, patchy pattern of perfusion in the LV free wall. Low flow areas (LowF) receive <60% of the average flow and display decreased energy turnover and enhanced fatty acid content, while the mechanism of this spatial heterogeneity is unknown. Lipid profile analysis of canine LowF showed an elevated triglyceride content (+212%) when compared to High flow samples (HighF). In LowF, mRNA expression of PPARα was reduced to ¼ and the same was true for 5 key enzymes or transporters in lipid metabolism (p<0.05 – 0.001), suggesting preferential glycolysis in LowF. Potassium ion channel expression also displayed flow-related differences, with enhanced expression of ERG (3.5-fold, p<0.001) and KChIP2 (2.1-fold) in LowF, mediating resp. governing IKr and Ito. Model analysis predicted a shorter local APD in LowF, which was confirmed by epicardial mapping of local QT intervals. This revealed a patchy, temporally stable pattern and a QT prolongation upon ERG blockade predominantly in areas of short basal QT (p<0.01). In short QT areas, ERG expression was increased and basal perfusion decreased. Thus, within the apparently homogenous left ventricular wall, distinct metabolic and electrophysiological phenotypes exist. In LowF, both downregulation of fatty acid oxidation and APD shortening will reduce O2 consumption in these regions and may thus partially explain the spatial heterogeneity of perfusion. Supported by DFG.