OP.5C.05] INCREASED RHO KINASE ACTIVITY IN DIALYSIS AND STAGE 3–4 CHRONIC KIDNEY DISEASE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

Abstract

Objective: Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human model opposite to hypertension such as Bartter's/Gitelman's syndromes patients, its downregulation associates with lack of CV remodeling. Information on ROCK activation-LVH link in CKD and DP is lacking. Design and method: Mononuclear cells (PBMCs) MYPT-1 phosphorylation, a marker of ROCK activity, and the effect of fasudil (500 and 1000 uM), a ROCK inhibitor, on MYPT-1 phosphorylation were assessed in 23 DP 42 and 75 years, 16 males and 7 females, 13 stage 3–4 CKD, 8 males and 5 females, 45–70 years and 30 healthy subjects (HS), 31–65 years, 20 males and 10 females, by Western blot. LV mass was assessed by M-mode echocardiography. Results: DP and CKD had higher MYPT-1 phosphorylation compared to HS (p < 0.001 and p = 0.003). Fasudil (500 and 1000 uM) reduced MYPT-1 phosphorylation in DP (p < 0,01). DP had higher LV mass than CKD (p < 0.001). MYPT-1 phosphorylation was higher in patients with LVH (p = 0.009) and correlated with LV mass both in DP and CKD with LVH (p < 0.001 and p = 0.006, respectively). Conclusions: This study provides evidence linking the activation of ROCK, as reflected by the increased phosphorylation state of MYPT-1, to cardiac hypertrophy in dialysis and stage 3–4 CKD patients, a human clinical population at high risk for cardiovascular morbidity and mortality. The results of this study join those provided in another high risk for cardiovascular disease patients such as hypertensive patients and receive indirect support from data provided by a human model opposite to hypertension and type II diabetic patients identifying ROCK activation as a potential LVH marker and providing further rationale for ROCK activation inhibition as target of therapy in patients at high risk for cardiovascular disease such as CKD, dialysis, hypertensive and diabetic patients.