High-energy phosphate metabolism and creatine kinase in failing hearts: A new porcine model

Background - This study aimed to create a pig model of heart failure secondary to severe aortic stenosis and to examine the relationship between the alterations in myocardial high-energy phosphate (HEP) metabolism and protein expression of creatine kinase (CK) isoforms. Methods and Results - Sixteen pigs with left ventricular hypertrophy (LVH) secondary to ascending aortic banding and 10 normal pigs (N) were studied. Myocardial protein levels of CK isoforms (Western blot), HEP levels, and CK kinetics (³¹p MR spectroscopy) were measured under basal conditions. Nine of the 16 animals with LVH developed congestive heart failure (CHF), as evidenced by ascites (100 to 2000 mL). 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±0.36 in hearts with CHF (P<0.01 versus LVH). Right ventricle weight/body weight ratio and LV end-diastolic pressure were significantly higher in hearts with CHF (each P<0.01 versus N or LVH). Myocardial phosphocreatine/ATP ratios and the CK forward flux rates were decreased in LVH hearts, most severely in hearts with CHF. CK-M/β-actin ratios were 2.21±12 (N), 1.69±0.15 (LVH), and 1.39±0.27 (CHF, P<0.05 versus N). CK-mitochondria (CK-Mt)/β-actin ratios were 1.40±0.09 (N), 1.24±0.09 (LVH), and 1.02±0.08 (CHF, P<0.05 versus N or LVH). The severity of the reduction of CK flux rate was linearly related to the severity of the decrease of CK-Mt/β-actin (r=0.68, P<0.01). Conclusions - In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.