High-energy phosphate metabolism and creatine kinase in failing hearts - Anew porcine model

Background-This study aimed to create a pig model of heart failure secondar y to severe aortic stenosis and to examine the relationship between the alt erations in myocardial high-energy phosphate (HEP) metabolism and protein e xpression of creatine kinase (CK) isoforms. Methods and Results-Sixteen pigs with left ventricular hypertrophy (LVH) se condary to ascending aortic banding and 10 normal pigs (N) were studied. My ocardial protein levels of CK isoforms (Western blot), HEP levels, and CK k inetics (P-31 MR spectroscopy) were measured under basal conditions. Nine o f the 16 animals with LVH developed congestive heart failure (CHF), as evid enced by ascites (100 to 2000 mt). LV weight/body weight ratio (g/kg) was 2 .18 +/-0.15 in N hearts, 3.04 +/-0.14 in hearts with LVH (P<0.01), and 4.23 <plus/minus>0.36 in hearts with CHF (P<0.01 versus LVH). Right ventricle we ight/body weight ratio and LV end-diastolic pressure were significantly hig her in hearts with CHF (each P<0.01 versus N or LVH). Myocardial phosphocre atine/ATP ratios and the CK forward flux rates were decreased in LVH hearts , most severely in hearts with CHF. CK-M/beta -actin ratios were 2.21 +/- 1 2 (N), 1.69 +/-0.15 (LVH), and 1.39 +/-0.27 (CHF, P<0.05 versus N). CK-mito chondria (CK-Mt)/<beta>-actin ratios were 1.40 +/-0.09 (N), 1.24 +/-0.09 (L VH), and 1.02 +/-0.08 (CHF, P<0.05 versus N or LVH). The severity of the re duction of CK flux rate was linearly related to the severity of the decreas e of CK-Mt/<beta>-actin (r=0.68, P<0.01). Conclusions-In this new model of heart failure/hypertrophy, the abnormal my ocardial HEP metabolism is related to the decreased CK-Mt protein level, wh ich in turn is related to the severity of the hypertrophy.