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Tolvaptan-vasopressin Antagonist
The 10th Annual Scientific Meeting
Symposium 1 Tolvaptan-vasopressin Antagonist MIHAI GHEORGHIADE Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois The neurohormone arginine vasopressin (AVP) is a promising target in the treatment of heart failure because AVP promotes congestion and hyponatremia, each of which is associated with poor outcomes. Diuretics are standard therapy for heart failure, but have several limitations, including worsening renal function and hyponatremia. Blocking AVP leads to effective aquaresis, improvements in hemodynamics and renal function parameters, weight loss, and normalization of serum sodium, without changes in blood pressure or heart rate. In placebo-controlled trials in the inpatient and outpatient setting, the AVP receptor antagonist tolvaptan reduced body weight and edema and normalized serum sodium in patients with heart failure.
JHFS
S147
Prevention of development of symptomatic HF in subjects with asymptomatic LV dysfunction or merely at increased risk will also be a priority. Finally, targeting of co-morbidities is a potentially fruitful area of research and this is currently being explored for hyponatraemia, anaemia, and diabetes mellitus. Neurohormonal and/or cytokine profiling together with assessment for gene polymorphisms may help delineate patients more appropriately for a specific pharmacological therapy in the future. A huge range of pharmacological targets have been proposed for exploration including additional neurohormonal systems, inter-cardiac cell signaling pathways, broadbased immune inhibitory approaches and other novel targets.
Symposium 1 Symposium 1 The Role of Aldosterone Blockade in Post-MI Heart Failure PRAKASH DEEDWANIA UCSF School of Medicine, San Francisco, CA, USA Aldosterone is an important mediator of the renin-angiotensin-aldosterone system (RAAS) and plays a major role in the pathophysiology of cardiovascular disease as well as regulation of fluid and electrolyte balance. In experimental models, aldosterone has been shown to promote endothelial dysfunction, induce vascular inflammation, myocardial ischemia and necrosis, increase collagen synthesis in cardiac fibroblasts, contribute to plasminogen activator inhibitor-1 regulation, decrease baroreceptor sensitivity and reflex function, block myocardial uptake of norepinephrine, increase oxidative stress, and stimulate cardiomyocyte apoptosis. Experimental data as well as clinical research has shown that aldosterone stimulates myocardial fibrosis and promotes LV remodeling post-MI. Moreover, therapy with ACE inhibitors or angiotension receptor blockers cannot adequately suppress these harmful effects of aldosterone. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that selective aldosterone blockade with eplerenone significantly reduced mortality and morbidity when used in addition to standard therapy, including ACE inhibitors or ARBs and b-blockers, in patients with AMI complicated by LVSD and heart failure. The benefits of eplerenone on all-cause mortality and sudden cardiac death in EPHESUS were observed within 30 days of randomization, indicating the benefit of early initiation of treatment with eplerenone post-infarction, in addition to standard therapy. Recent ACC/ AHA and the HFSA guidelines have recommended the use of eplerenone in post-MI HF patients. Incorporation of eplerenone use into hospital critical pathways, and dissemination of information regarding patient selection, drug administration and monitoring of serum potassium are important steps to encourage increased utilization of this therapy in clinical practice.
Chymase Inhibitor in the Treatment of Heart Failure HIDENORI URATA Fukuoka University Chikushi Hospital, Chikushino, Japan Renin-angiotensin-aldosterone system (RAAS) is deeply involved in the development of heart failure from the early to end stage. Several large clinical trials provided clear evidence for the beneficial effect of the blockers of RAAS in the treatment of heart failure. Recent official guidelines for the treatment of heart failure stated that ACE inhibitor is the first choice drug. Recent clinical trials also showed the equivalent effect of angiotensin receptor blocker (ARB) to ACE inhibitor, but this was not superior. On the other hand, the beneficial effect of an aldosterone blocker spironolactone or eplerenone has been shown in the treatment of heart failure. The results of those clinical trials indicate that suppression of RAAS is a key issue in the treatment of heart failure. Our basic and clinical research showed the significance of another angiotensin II-forming enzyme chymase in the pathological development of heart failure. Effects of chymase inhibitor on the post-myocardial infarction (MI) and/or the following heart failure models have been shown. The monotherapy with chymase inhibitor in such animal model showed the beneficial effect. Furthermore, the combination therapy with chymase and ACE inhibitors further improved the survival rate both in hamster MI and heart failure models. Thus, chymase inhibitor is a promising future drug in the treatment of both ischemia and non-ischemia induced hear failure.
Symposium 1 Improvements of Glucose Tolerance as a New Target of Chronic Heart Failure -Roles of Insulin-sensitizing Agents or Alpha-glucosidase InhibitorsMASAFUMI KITAKAZE, JIYOONG KIM, MASANORI ASAKURA, SOICHIRO KITAKURA, HITONOBU TOMOIKE Cardiovascular Division, National Cardiovascular Center, Suita, Japan
Symposium 1 New Pharmacological Strategies for Heart Failure HENRY KRUM NHMRC Centre of Clinical Research Excellence in Therapeutics, Dept. of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia There has been an explosion of pharmacological research into novel targets that have been elucidated based on an improved understanding of the pathophysiological mechanisms underlying the heart failure disease process. New pharmacological targets will therefore continue to be explored, although the approach of taking on an ‘‘all-comers’’ heart failure patient population may have to be carefully reviewed in light of recent unsuccessful trials. Better matching of patient to the pharmacological target being perturbated may yield improved outcomes and substantive incremental benefits. Furthermore, there may well be a shift away from studies of systolic chronic heart failure towards areas where there is an even greater unmet clinical need, eg. diastolic heart failure, acute decompensated heart failure.
Chronic heart failure (CHF) is a leading cause of death worldwide, and we need to develop another strategy on the top of standardized treatment of CHF. We employed the data-mining methods(DMM) for the large-scale clinical data to identify the novel drugs. In 2000 CHF patients, we performed the decision tree analysis, and revealed that alpha-glucosidase inhibitors are effective for CHF in addition to beta-blockers, ACEI or ARB. Therefore, we investigated the prevalence of the impairment of glucose metabolism, and found 27.3 and 50.9% were suffered from diabetes mellitus (DM) and impaired glucose tolerance (IGT), respectively (control subjects (7.8 and 14.4%). In the animal experiments, we found that IGT is generated in the pathophysiology of CHF produced by aortic banding in mice, myocardial infarction in rats or rapid pacing in dogs, and that either insulin-sensitizing agents such as pioglitazone and metoformine or alpha-glucosidase inhibitors such as voglibose, acarbose or miglitol improve the pathophysiology of CHF. Furthermore, we found that voglibose for 52 weeks decreased left ventricular dimension, the values of NYHA and plasma BNP levels, and improved cardiac function in 30 CHF patients. We conclude that abnormal glucose tolerance is generated in CHF patients, and that its correction using insulinsensitizing agents or alpha-glucosidase inhibitors improve the severity of CHF. DMM is a useful method to seek valid new treatment of CHF.
Symposium 1 Tolvaptan-vasopressin Antagonist MIHAI GHEORGHIADE Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois The neurohormone arginine vasopressin (AVP) is a promising target in the treatment of heart failure because AVP promotes congestion and hyponatremia, each of which is associated with poor outcomes. Diuretics are standard therapy for heart failure, but have several limitations, including worsening renal function and hyponatremia. Blocking AVP leads to effective aquaresis, improvements in hemodynamics and renal function parameters, weight loss, and normalization of serum sodium, without changes in blood pressure or heart rate. In placebo-controlled trials in the inpatient and outpatient setting, the AVP receptor antagonist tolvaptan reduced body weight and edema and normalized serum sodium in patients with heart failure.
JHFS
S147
Prevention of development of symptomatic HF in subjects with asymptomatic LV dysfunction or merely at increased risk will also be a priority. Finally, targeting of co-morbidities is a potentially fruitful area of research and this is currently being explored for hyponatraemia, anaemia, and diabetes mellitus. Neurohormonal and/or cytokine profiling together with assessment for gene polymorphisms may help delineate patients more appropriately for a specific pharmacological therapy in the future. A huge range of pharmacological targets have been proposed for exploration including additional neurohormonal systems, inter-cardiac cell signaling pathways, broadbased immune inhibitory approaches and other novel targets.
Symposium 1 Symposium 1 The Role of Aldosterone Blockade in Post-MI Heart Failure PRAKASH DEEDWANIA UCSF School of Medicine, San Francisco, CA, USA Aldosterone is an important mediator of the renin-angiotensin-aldosterone system (RAAS) and plays a major role in the pathophysiology of cardiovascular disease as well as regulation of fluid and electrolyte balance. In experimental models, aldosterone has been shown to promote endothelial dysfunction, induce vascular inflammation, myocardial ischemia and necrosis, increase collagen synthesis in cardiac fibroblasts, contribute to plasminogen activator inhibitor-1 regulation, decrease baroreceptor sensitivity and reflex function, block myocardial uptake of norepinephrine, increase oxidative stress, and stimulate cardiomyocyte apoptosis. Experimental data as well as clinical research has shown that aldosterone stimulates myocardial fibrosis and promotes LV remodeling post-MI. Moreover, therapy with ACE inhibitors or angiotension receptor blockers cannot adequately suppress these harmful effects of aldosterone. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that selective aldosterone blockade with eplerenone significantly reduced mortality and morbidity when used in addition to standard therapy, including ACE inhibitors or ARBs and b-blockers, in patients with AMI complicated by LVSD and heart failure. The benefits of eplerenone on all-cause mortality and sudden cardiac death in EPHESUS were observed within 30 days of randomization, indicating the benefit of early initiation of treatment with eplerenone post-infarction, in addition to standard therapy. Recent ACC/ AHA and the HFSA guidelines have recommended the use of eplerenone in post-MI HF patients. Incorporation of eplerenone use into hospital critical pathways, and dissemination of information regarding patient selection, drug administration and monitoring of serum potassium are important steps to encourage increased utilization of this therapy in clinical practice.
Chymase Inhibitor in the Treatment of Heart Failure HIDENORI URATA Fukuoka University Chikushi Hospital, Chikushino, Japan Renin-angiotensin-aldosterone system (RAAS) is deeply involved in the development of heart failure from the early to end stage. Several large clinical trials provided clear evidence for the beneficial effect of the blockers of RAAS in the treatment of heart failure. Recent official guidelines for the treatment of heart failure stated that ACE inhibitor is the first choice drug. Recent clinical trials also showed the equivalent effect of angiotensin receptor blocker (ARB) to ACE inhibitor, but this was not superior. On the other hand, the beneficial effect of an aldosterone blocker spironolactone or eplerenone has been shown in the treatment of heart failure. The results of those clinical trials indicate that suppression of RAAS is a key issue in the treatment of heart failure. Our basic and clinical research showed the significance of another angiotensin II-forming enzyme chymase in the pathological development of heart failure. Effects of chymase inhibitor on the post-myocardial infarction (MI) and/or the following heart failure models have been shown. The monotherapy with chymase inhibitor in such animal model showed the beneficial effect. Furthermore, the combination therapy with chymase and ACE inhibitors further improved the survival rate both in hamster MI and heart failure models. Thus, chymase inhibitor is a promising future drug in the treatment of both ischemia and non-ischemia induced hear failure.
Symposium 1 Improvements of Glucose Tolerance as a New Target of Chronic Heart Failure -Roles of Insulin-sensitizing Agents or Alpha-glucosidase InhibitorsMASAFUMI KITAKAZE, JIYOONG KIM, MASANORI ASAKURA, SOICHIRO KITAKURA, HITONOBU TOMOIKE Cardiovascular Division, National Cardiovascular Center, Suita, Japan
Symposium 1 New Pharmacological Strategies for Heart Failure HENRY KRUM NHMRC Centre of Clinical Research Excellence in Therapeutics, Dept. of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia There has been an explosion of pharmacological research into novel targets that have been elucidated based on an improved understanding of the pathophysiological mechanisms underlying the heart failure disease process. New pharmacological targets will therefore continue to be explored, although the approach of taking on an ‘‘all-comers’’ heart failure patient population may have to be carefully reviewed in light of recent unsuccessful trials. Better matching of patient to the pharmacological target being perturbated may yield improved outcomes and substantive incremental benefits. Furthermore, there may well be a shift away from studies of systolic chronic heart failure towards areas where there is an even greater unmet clinical need, eg. diastolic heart failure, acute decompensated heart failure.
Chronic heart failure (CHF) is a leading cause of death worldwide, and we need to develop another strategy on the top of standardized treatment of CHF. We employed the data-mining methods(DMM) for the large-scale clinical data to identify the novel drugs. In 2000 CHF patients, we performed the decision tree analysis, and revealed that alpha-glucosidase inhibitors are effective for CHF in addition to beta-blockers, ACEI or ARB. Therefore, we investigated the prevalence of the impairment of glucose metabolism, and found 27.3 and 50.9% were suffered from diabetes mellitus (DM) and impaired glucose tolerance (IGT), respectively (control subjects (7.8 and 14.4%). In the animal experiments, we found that IGT is generated in the pathophysiology of CHF produced by aortic banding in mice, myocardial infarction in rats or rapid pacing in dogs, and that either insulin-sensitizing agents such as pioglitazone and metoformine or alpha-glucosidase inhibitors such as voglibose, acarbose or miglitol improve the pathophysiology of CHF. Furthermore, we found that voglibose for 52 weeks decreased left ventricular dimension, the values of NYHA and plasma BNP levels, and improved cardiac function in 30 CHF patients. We conclude that abnormal glucose tolerance is generated in CHF patients, and that its correction using insulinsensitizing agents or alpha-glucosidase inhibitors improve the severity of CHF. DMM is a useful method to seek valid new treatment of CHF.