Study of Therapeutic Impact of Extracorporeal Shock Wave on Left Ventricular Dysfunction Caused by Contracture of Left Anterior Descending Coronary Artery in Mini-Pigs with Preexisting Advanced Chronic Kidney Disease

Original Hypothesis: This study will test the hypothesis that extracorporeal shock wave (ECSW) therapy effectively improves ischemia-induced left ventricular dysfunction in mini-pig with setting of severe chronic kidney disease (CKD). Background: Chronic kidney disease (CKD) of different etiologies is a growing epidemic that contributes to high morbidity and mortality in hospitalized patients. Despite the state-of-the-art therapeutic modality and advanced pharmaceutical strategy, progressive deterioration of renal function is frequently observed. On the other hand, coronary artery disease (CAD) which remains the leading cause of death worldwide, is quite frequently observed in those CKD patients. These co-existent diseases, called cardiorenal disease (CRD), always mutually affect each others. Finally, the renal function would deteriorate quickly into the end stage, especially in a situation of inadequate blood perfusion due to ischemia-related left ventricular (LV) dysfunction, called end-state renal disease (ESRD). The ESRD, in return, affects the CAD to deteriorate rapidly and propagate into the difficultly treated features, including (1) heavy calcification lesion, (2) diffuse disease lesion not only in the epicardial vessels but also in distal small vessels, (3) side branches and capillary networks, so called "end-stage CAD". Thus, ESRD and end-stage CAD patients who have angina/heart failure are always refractory to medication usually non candidate for coronary artery intervention [either percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG)]. These patients actually are still waiting for new therapeutic modality to resolve their problem. Growing data from both experimental studies and clinical trials have shown that extracorporeal shock wave (ECSW) therapy effectively improved ischemia-related cardiovascular dysfunction through the underlying mechanisms of upregulating vascular endothelia growth factor (VEGF) and enhancing angiogenesis. However, whether ECSW therapy is also effective on improving the ischemia-related LV dysfunction in setting of advanced stage of CKD (i.e., ＞ stage IV) remains unclear. Aim of the Study: Basic on the requirement of developing a new therapeutic option for patients with CKD and end-stage CAD and the effective treatment of ECSW for ischemia-related organ dysfunction, this proposal will utilize a CKD (by right nephrectomy + 2/3 ligation of left kidney) + ischemia-related LV dysfunction (i.e., by constriction of left anterior descending artery by ring) model in mini-pig to investigate the impact of ECSW therapy for improving the mini-pig heart function and to determine the underlying mechanism of such a strategic treatment. Specific Targets in the Current Proposal 1) To test the impact of ECSW on enhancing angiogenesis and endothelial cell (EC) proliferation in conditions of with and without uremic toxic substance stimulation 2) To test whether ECSW induces angiogenesis through PI3K-Akt-eNOS-VEGF signaling pathway?---in vitro study with and without specific inhibitors 3) To test whether ECSW therapy enhances eNOS gene expression and NO production is through integrity endothelial cells or smooth muscle?---animal model study by denudated endothelial cells of SD rat carotid artery 4) To create an animal model of coexistent chronic kidney disease and ischemic cardiomyopathy 5) To measure the impact of CKD on left ventricular (LV) remodeling and deterioration of LV function 6) To assess the therapeutic impact of ECSW on improving the ischemia-related LV dysfunction in the setting of CKD in mini-pig experimental model

Project ID:PC10408-2544
External Project ID:MOST104-2314-B182-055