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S6-1 The Role of Endothelial Progenitor Cells in Atherosclerosis and Cardiovascular Diseases
Symposia receptor (RyR), with a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. Here, we report both propranolol (PL) and 1,4-benzothiazepine derivative :k201(JTV519) restore cardiac and SR functions, commonly mediated through stabilization of RyR and hence sealing Ca2+ leak. SR vesicles were isolated from dog LV muscles {normal; 4-weeks rapid RV pacing with or without K201 or PL}. Cardiac function was similarly improved in chronic treatment with either K201(+) or PL(+), as compared with untreated (4weeks-paced) group. Spontaneous SR Ca2+ leak was found in untreated failing SR. K201 acutely inhibited this Ca2+ leak in failing SR. Chronic administration of either K201 or PL prevented the partial loss of FKBP12.6 from RyR and the spontaneous Ca2+ leak in failing SR. In the untreated group, RyR was PKA- hyperphosphorylated, whereas it was reversed both in K201 (+) and in PL(+). In conclusion, both K201 and PL commonly correct the defective channel gating of RyR, thereby improving cardiac function. Symposium 6. Heart Failure 6: The Role of Cardiac Remodeling in Cardiac Hypertrophy and Heart Failure S6-1 The Role of Endothelial Progenitor Cells in Atherosclerosis and Cardiovascular Diseases Shing-Jong Lin, Po-Hsun Huang, Jaw-Wen Chen. Division of Cardiology, Taipei Veterans General Hospital; Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan Atherosclerosis is a systemic inflammatory disease of arterial wall and initiated by endothelial damage. Endothelium integrity is maintained by neighboring endothelial cells which migrate and proliferate to restore the injured endothelium. However, the injured endothelial monolayer may also be regenerated partly by circulating bone marrow-derived endothelial progenitor cells (EPCs). These circulating EPCs are mobilized endogenously triggered by tissue ischemia or exogenously by cytokine stimulation. Clinical studies demonstrated that levels of circulating EPCs are associated with vascular endothelial function and cardiovascular risk factors. Aging, hypertension, diabetes mellitus, and hypercholesterolemia have been shown to exert detrimental effects on EPC number and function. Reduced levels of circulating EPCs independently predict atherosclerotic disease progression and development of cardiovascular events. There are several ways to increase levels of circulating EPCs and improve their function by pharmacological strategies and lifestyle modification. Animal and clinical studies of cell therapy have shown that transplantation of autologous EPCs or other cellular pools enriched with vascular progenitors is feasible in both coronary and peripheral atherosclerotic diseases. Our studies have demonstrated that high glucose impairs early and late EPCs by modifying nitric oxide-related but not oxidative stress-mediated mechanisms. MMP-9 is essential for EPCs in ischemia-induced angiogenesis. Statins and red wine intake may increase the number and function of EPCs. S6-2 Antifibrotic Strategies in the Treatment of Cardiac Hypertrophy and Heart Failure Henry Krum. Centre of Cardiovascular Research & Education in Therapeutics, Dept of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia Pathological deposition of extracellular matrix material (fibrosis) is a critical component of the remodelling process
S17 that follows cardiac injury or inflammation. Fibrosis is also an important pathophysiological accompaniment to the cardiac hypertrophy that is often a precursor to diastolic dysfunction and failure. Remodelling is a dynamic process with excessive deposition of matrix material but also activation of enzymes that break down this material (matrix metalloproteases). These in turn are controlled by tissue inhibitors of matrix proteases. The drivers of pathological fibrosis are becoming well known. Central to this process appears to be activation of important growth factors and pro-inflammatory cytokines, critically transforming growth factor b1. A number of effective heart failure therapies work at least in part via inhibition of excessive extracellular matrix deposition. These include ACE inhibitors, angiotensinreceptor blockers, aldosterone receptor blockers and betablockers; angiotensin II and noradrenaline are major profibrotic stimuli. However, despite the significant clinical advances achieved with these agents blocking the renin angiotensin-aldosterone and sympathetic nervous systems, there remains an unacceptably high morbidity and mortality in heart failure, and the need for novel agents is great. Drugs have been developed that specifically target the process of fibrosis, usually by interfering with the synthesis or downstream functionality of transforming growth factor b1. Such drugs include perfenidone, tranilast and connective tissue growth factor inhibitors. Our group have modified tranilast using SAR to improve efficacy and reduce organ specific adverse effects. In vitro studies of cardiac fibroblasts confirm a dose-dependent direct anti-fibrotic effect with the agent FT-011 (Fibrotech Therapeutics). Studies looking at remodelling post myocardial infarction with FT-011 have demonstrated reduced fibrosis together with improvements in LV structure and function. We have also demonstrated a beneficial effect on parameters of diastolic function with the FT-011 compound in a diabetic diastolic HF model (heterozygous ren-2 diabetes). In summary, fibrosis is emerging as a key target in the management of cardiac hypertrophy and heart failure. Direct anti-fibrotic agents may be of therapeutic benefit in this regard, and potentially of additive clinical benefit to existing agents. S6-3 Remodeling Process After Acute Myocardial Infarction and its Pathophysiologic Mechanisms Byung-Hee Oh. Seoul National University College of Medicine, Korea Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure. The extent of remodeling has been linked to the size of the infarct, adequacy of myocardial reperfusion, and the control of loading conditions. The remodeling includes dilatation, hypertrophy, dyssynchrony, and scar formation. The post-infarct remodeling can be divided into early and late response, with the former occurring in the first 3 days after the MI and the latter occurring more than 3 days after the MI. Early remodeling is mainly due to infarct expansion, occurred in the infarct and peri-infarct zones. Late remodeling includes changes in the geometry and size of the entire left ventricle including the healthy myocardium. Emerging evidence suggests that neurohormonal activation plays an important role. Blockade of renin angiotensin system by ACEIs, ARBs and recently direct renin inhibitor appear to reduce remodeling.
S17 that follows cardiac injury or inflammation. Fibrosis is also an important pathophysiological accompaniment to the cardiac hypertrophy that is often a precursor to diastolic dysfunction and failure. Remodelling is a dynamic process with excessive deposition of matrix material but also activation of enzymes that break down this material (matrix metalloproteases). These in turn are controlled by tissue inhibitors of matrix proteases. The drivers of pathological fibrosis are becoming well known. Central to this process appears to be activation of important growth factors and pro-inflammatory cytokines, critically transforming growth factor b1. A number of effective heart failure therapies work at least in part via inhibition of excessive extracellular matrix deposition. These include ACE inhibitors, angiotensinreceptor blockers, aldosterone receptor blockers and betablockers; angiotensin II and noradrenaline are major profibrotic stimuli. However, despite the significant clinical advances achieved with these agents blocking the renin angiotensin-aldosterone and sympathetic nervous systems, there remains an unacceptably high morbidity and mortality in heart failure, and the need for novel agents is great. Drugs have been developed that specifically target the process of fibrosis, usually by interfering with the synthesis or downstream functionality of transforming growth factor b1. Such drugs include perfenidone, tranilast and connective tissue growth factor inhibitors. Our group have modified tranilast using SAR to improve efficacy and reduce organ specific adverse effects. In vitro studies of cardiac fibroblasts confirm a dose-dependent direct anti-fibrotic effect with the agent FT-011 (Fibrotech Therapeutics). Studies looking at remodelling post myocardial infarction with FT-011 have demonstrated reduced fibrosis together with improvements in LV structure and function. We have also demonstrated a beneficial effect on parameters of diastolic function with the FT-011 compound in a diabetic diastolic HF model (heterozygous ren-2 diabetes). In summary, fibrosis is emerging as a key target in the management of cardiac hypertrophy and heart failure. Direct anti-fibrotic agents may be of therapeutic benefit in this regard, and potentially of additive clinical benefit to existing agents. S6-3 Remodeling Process After Acute Myocardial Infarction and its Pathophysiologic Mechanisms Byung-Hee Oh. Seoul National University College of Medicine, Korea Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure. The extent of remodeling has been linked to the size of the infarct, adequacy of myocardial reperfusion, and the control of loading conditions. The remodeling includes dilatation, hypertrophy, dyssynchrony, and scar formation. The post-infarct remodeling can be divided into early and late response, with the former occurring in the first 3 days after the MI and the latter occurring more than 3 days after the MI. Early remodeling is mainly due to infarct expansion, occurred in the infarct and peri-infarct zones. Late remodeling includes changes in the geometry and size of the entire left ventricle including the healthy myocardium. Emerging evidence suggests that neurohormonal activation plays an important role. Blockade of renin angiotensin system by ACEIs, ARBs and recently direct renin inhibitor appear to reduce remodeling.