Abstract 18543: Impaired Coronary Metabolic Dilation Leads to Heart Failure During Pressure Overload
The coupling of myocardial blood flow to cardiac work (metabolic dilation) is critical for proper cardiac function. If this coupling is altered, the imbalance could lead micro-areas of hypoxia, ischemia, and fibrosis culminating in heart failure. Accordingly we hypothesized, that when subjected to an extreme metabolic challenge (pressure overload), insufficient dilation of the coronary circulation leads to micro-areas of ischemia and infarction (diffuse fibrosis) and compromised cardiac function. To test this, we studied cardiac function and pathology in Wild Type (WT) and Kv1.5-/- mice, which have impaired metabolic dilation. To impose a metabolic challenge, transaortic constriction (TAC) was done in Kv1.5-/- male (n=12), female (n=12) and WT (n=12) mice. TAC increased mean aortic pressure from 98±5 to 142±8 mmHg. Transthoracic echocardiography was performed for evaluation of cardiac function at 7, 28 days after TAC. Masson’s Trichrome and Hypoxyprobe (HP) staining was done at day 28 for evaluation myocardial fibrosis and areas of hypoxia, respectively. After TAC survival rate of Kv 1.5-/- females was lower (P<0.05) than in males and WT (Panel A). Ejection fraction (EF) was lower (P<0.05) in Kv1.5-/- (male and female) than WT at all times after TAC (Panel B). In WT, EF was decreased 7 days after TAC, but the reduction was moderate compared to Kv 1.5-/-. After 28 days of TAC, myocardial fibrosis was markedly higher in Kv1.5-/- compared to WT (Panel C). In Kv1.5-/-, fibrosis was in endocardial and perivascular regions, but in WT it was transmural and less developed. HP and DAPI (to locate nuclei) revealed that the number of cells positive for hypoxyprobe was 222% greater in Kv1.5-/- than in WT, suggesting impaired oxygen delivery. Taken together, we conclude that the absence of Kv1.5 channels, which uncouples myocardial blood flow from cardiac work, compromises coronary and cardiac adaptations to TAC leading to diffuse ischemia, micro-areas of infarction and heart failure. .
- © 2012 by American Heart Association, Inc.