Abstract 17217: Impaired Coupling of Myocardial Blood Flow to Cardiac Work Leads to Cardiac Dysfunction

Abstract

The heart is highly dependent on a continuous supply of oxygen from the coronary circulation to meet its metabolic requirements. There are many mechanisms that contribute to the regulation of coronary blood flow, including redox and oxygen sensing voltage-gated potassium channels. These channels are expressed in coronary smooth muscle cells and appear to couple cardiac work to myocardial blood flow; specifically, we found reduced levels of flow per unit of cardiac work in mice null for the redox sensing Kv1.5 channel (Kv1.5 -/- ) compared to wild types (WT). Accordingly, we hypothesized that Kv1.5 -/- mice, with impaired coronary metabolic dilation, would gradually develop cardiac pump dysfunction due to inadequate perfusion which would lead to microareas of hypoxia, then to apoptosis, to diffuse fibrosis and finally cardiac dysfunction. Methods: Kv1.5 -/- male mice (n=8) and WT (n=6) were used for this study. For cardiac function measurements, transthoracic echocardiography was performed under sevoflurane anesthesia at 4, 8 and 12 months. After echocardiography, animals recovered and measurements were repeated at 8 and 12 months of age. As shown in the diagram, at 4 months of age, %EF is 13% lower in Kv 1.5 -/- mice compared to WT animals (P<0.05). In Kv 1.5 -/- mice at 8 and 12 months, %EF was 20% and 23% lower, respectively, compared to WT animals (P<0.05). Although the E/A ratio, a measure of diastolic function, did not show a significant decline in the Kv1.5 -/- mice compared to WT, there was a trend towards diastolic dysfunction. Hypoxyprobe staining (to label protein adducts produced by severe hypoxia) revealed microareas of hypoxia in hearts from the Kv1.5 -/- mice, but no such areas in WT. Also, Kv1.5 -/- mice show much more collagen deposition in the myocardium than WT. Based on these data, we conclude that alteration in the coupling of myocardial blood flow to cardiac work can lead to cardiac systolic and diastolic dysfunction