Abstract 4029: Decreased Rho Kinase (ROCK) Activity by Angiotensin Converting Enzyme Inhibitor (ACEi) is Associated With Improved Left Ventricular Function in Patients With Heart Failure
Background: Heart failure (HF) is associated with decreased cardiac contractility and ventricular remodeling, features which are partially reversed by angiotensin converting enzyme inhibitors (ACEi). Since Rho kinase (ROCK) mediates cellular contraction through effects on the actin cytoskeleton and is an important regulator of cardiac fibrosis, we hypothesize that ACEi may improve heart function through inhibition of ROCK activity.
Methods and Results: We enrolled 30 consecutive HF subjects (average age: 52.7±8.2, 60% male in gender, NYHA class 3.2±1.1), with impaired left ventricular ejection fraction (LVEF) of less than 40% by echocardiography (average LVEF=32.1±8.2%), and age- and sex-matched 30 subjects with preserved LVEF function (average LVEF=65.4±9.4%) as the control group. ROCK activity was determined in peripheral leukocytes using a phospho-specific antibody for myosin binding subunit (MBS). Compared with the control group, the subjects with impaired LVEF have higher ROCK activity (phospho-MBS/total-MBS ratio: 0.83±0.38 vs. 0.36±0.23, p=0.01). After correcting the risk factors between groups, including severity of coronary artery disease, hypertension, diabetes mellitus and smoking behavior, we found a tendency between the higher ROCK activity and reduced LVEF (R2=0.381, p=0.06). Treatment with ACEi, enalapril, decreased ROCK activity (0.50±0.33), improved LVEF (40.4±6.2%) and NYHA class (2.1±1.3) (p<0.05 for all compared to baseline). ROCK activity, LVEF, and NYHA class was unaffected by ACEi treatment in control subjects (p>0.05 for all). The improvement in LVEF and NYHA class in HF subjects correlated with the reduction in ROCK activity and improvement in NYHA class (R2=0.35 and 0.31, respectively, p=0.04 for both), but did not correlate with changes in high sensitivity-C reactive protein, or the reduction in systolic blood pressure (p>0.05 for both).
Conclusion: These findings indicate that ROCK activity is elevated in HF subjects and that improvements in LVEF and NYHA class by ACEi are correlated with decrease in ROCK activity. The reduction in ROCK activity by ACEi was independent of changes in inflammation and blood pressure, suggesting that ROCK activity may be a novel marker of HF and its response to therapy with ACEi.