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Pharmacological Treatment in Patients with Heart Failure: Upstream Therapy
S126 Journal of Cardiac Failure Vol. 17 No. 9S September 2011
Symposium 2 S2-1 Arrhythmogenic Ion-Channel Remodeling in Heart Failure and Upstream Approach HARUAKI NAKAYA Department of Pharmacology, Chiba University Graduate School of Medicine Class I antiarrhythmic drugs with Na+ channel blocking action cannot be readily used for the treatment of various arrhythmias associated with heart failure because the antiarrhthmic drugs may worsen cardiac function. In failing hearts ion-channel remodeling, such as downregulation of K+ channels and connexin 43, upregulation of Na+-Ca2+ exchanger and HCN channels, and instability of Ca2+ release channels in sarcoplasmic reticulum, can be observed. These electrophysiological abnormalities can produce severe ventricular tachyarrhythmias through reentrant and automatic mechanisms. Neurohumoral factors such as renin-angiotensin system, endothelin system and sympathetic nervous system play an important role in the establishment of the ion-channel remodeling. Upstream approach with blockade of the neurohumoral factors may prevent lethal ventricular arrhythmias. In congestive heart failure atrial tissues are expanded and susceptibility to atrial fibrillation is increased. Control of neurohumoral factors may be also beneficial for the prevention of atrial fibrillation. Recently it has been suggested that inflammatory mechanisms may be also involved in not only the deterioration of heart failure but also induction of atrial fibrillation and ventricular tachyarrhythmias. Drugs with anti-inflammatory action, including the antiarrhythmic drug amiodarone, may be effective for the treatment of arrhythmias associated with heart failure. Current perspective of upstream approach to preventing atrial and ventricular arrhythmias associated with heart failure will be discussed.
S2-2 Heart Failure and Atrial Fibrillation: Basic Aspects KUNIHIRO NISHIDA, HIROSHI INOUE Second Department of Internal Medicine, University of Toyama, Toyama, Japan Atrial fibrillation (AF) is the most frequently encountered sustained tachyarrhythmia in clinical practice and is related to significant morbidity and mortality. Although its pathophysiology has been investigated extensively, many questions still remain unanswered. Congestive heart failure (CHF) is one of the most common clinical causes of AF. A canine model of CHF-related AF has been intensively studied to understand the pathophysiology. Atrial structural remodelling contributes importantly to the arrhythmogenic substrate and interstitial fibrosis plays a central role by interfering with local conduction and stabilizing reentry. Increased content of tissue angiotensin II and enhanced expression of phosphorylated MAPKs precede the remodelling process. TGF-b1 also is one of important atrial profibrotic mediators. Experimental CHF causes substantially more fibrosis in atria than in ventricles, partially due to the different TGF-b1 expression between the chambers. However, atrial fibroblasts per se show consistently greater proliferation responses than ventricular fibroblasts for a range of growth factors. Mice with TGF-b1 and ACE overexpression as well show selective atrial fibrosis and AF, without significant ventricular dysfunction or fibrosis. Several pharmacologic agents, such as enalapril, simvastatin, and PUFAs, can suppress atrial structural remodelling and AF promotion by interfering those pathways. These experimental studies have provided important insights into the mechanisms governing the arrhythmia and have allowed for the development of novel therapeutic approaches.
S2-3 Pharmacological Treatment in Patients with Heart Failure: Upstream Therapy TAKANORI IKEDA Department of Cardiovascular Medicine, Toho University Medical Center, Tokyo, Japan Treatments for atrial fibrillation (AF) with ACEIs, ARBs, and statins have been mainly referred to as upstream therapy. Experimental and clinical studies have demonstrated that these drugs decrease the incidence of AF. An overview of clinical trials including the LIFE and CHARM suggests that ACEIs or ARBs may reduce the occurrence and recurrence of AF. The results showed a role of these drugs for the initial or recurrent AF associated with heart failure (HF). The inhibitions of the renin-angiotensin-aldosterone system by these drugs decrease atrial pressure, reduce the frequency of atrial premature beats, and reduce fibrosis. The meta-analyses have shown a significant 30-48% reduction in risk of AF associated with ACEI and ARB therapies. An overview of clinical studies with statins demonstrated that statin therapy reduce the incidence of AF in the post-operative state - this effect not observed in the setting of HF. Recently, the GISSI-AF, demonstrated no effect of valsartan on the primary endpoint of time to first AF recurrence compared with placebo. The preliminary results of the J-RHYTHM II in patients with hypertension
and paroxysmal AF showed no benefit of treatment with candesartan compared with amlodipine on the frequency and duration of AF recurrence. In this Symposium, I will summarize current status of upstream therapy for the primary and secondary prevention of AF in patients with HF.
S2-4 Treatment of Heart Failure by Eliminating Atrial Fibrillation used Catheter Ablation Guided Solely by Complex Fractionated Atrial Electrogram Mapping NAOYA OKETANI1, HITOSHI ICHIKI1, YASUHISA IRIKI1, HIDEKI OKUI1, SANEMASA ISHIDA1, RYUICHI MAENOSONO2, MASAAKI MIYATA1, SHUICHI HAMASAKI1, KOONLAWEE NADEMANEE3, CHUWA TEI1 1 Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 2Clinical Laboratory Unit, Kagoshima University Hospital, 3Pacific Rim EP Research Institute The treatment of heart failure (HF) is still challenging, even though there are a lot of strategies such as drugs, drips, and devices. Atrial fibrillation (AF) and HF often coexist, and worsen each other. Almost all the antiarrhythmic drugs except amiodarone could be harmful to HF. In general, rate control is better than rhythm control using antiarrhythmic drugs in the treatment of the patients who have AF and HF. But it is obviously that sinus rhythm is better than AF in the patients with HF without using antiarrhythmic drugs. Then we’d like to show the powerful ablation of AF with heart failure, complex fractionated atrial electrogram (CFAE) ablation. There are some patients who have AF and low ejection fraction, even though the heart rate is well controlled. Bi-ventricular pacing device occasionally with ablating atrioventricular node could be one of the choices, but if the ejection fraction is improved by eliminating AF using catheter ablation, that would be better. And the patients who have hypertrophic cardiomyopathy and AF are also very symptomatic. Then we will show some challenging cases of AF coexisting structural heart disease.
S2-5 Ventricular Tachyarrhythmias Associated with Congestive Heart Failure (Therapeutic Roles of Antiarrhythmic Drugs and Catheter Ablation) MASAOMI CHINUSH1, HIROSHI FURUSHIMA2, DAISUKE IZUMI2, KENICHI IIJIMA2, YOSHIFUSA AIZAWA2 1 School of Health Science, Niigata University School of Medicine, 2First Department of Internal Medicine, Niigata University School of Medicine Implantable cardioverter defibrillator (ICD) plays a primary therapeutic role for sustained ventricular tachyarrhythmia (VTA), but supplemental treatment with antiarrhythmic drugs and/or radiofrequency catheter ablation (RFCA) is required to minimize the shock delivery from ICD. Since class I antiarrhythmic drugs worsen the mortality rate of congestive heart failure (CHF) patients, class III antiarrhythmic drugs and/or bepridil are selected for reentrant monomorphic ventricular tachycardia (mVT). However, it is usually difficult to predict the long-term efficacy of the drugs at the beginning of the therapy. Our results of pharmacological therapy are; (1) electrophysiological study-based drug selection was useful in predicting long-term drug efficacy, (2) sotalol or bepridl was more effective in VTA associated with ischemic rather than non-ischemic cadiomyopathy. We determined the target site of RF application from the results of substrate mapping and activation/entrainment mapping. RF current was initially applied to the essential part of the arrhythmogenic substrate, but long linear RF application was required in some patients. Once the clinically documented VTs were successfully ablated, long-term therapeutic efficacy is expected. Recently, VTA originating from the epicardial myocardium can be ablated. Cardiac dysfunction can be improved after suppression of frequent VTA.In patients with CHF, appropriate management of VTA is important in order to prevent sudden cardiac death, and improve cardiac function and quality of life.
S2-6 The role of CRT for Cardiac Arrhythmia of Heart Failure Patients TAKESHI MITSUHASHI Division of Cardiovascular Medicine, Jichi Medical University, Tochigi, Japan Cardiac resynchronization therapy (CRT) reduces mortality and improves heart failure symptoms, quality of life and many neurohumoral factors. Furthermore left ventricular function improves gradually accompanied with left ventricular volume reduction (structural reverse remodeling). Some investigators reported CRT also improves many ion channel currents, such as potassium, sodium and calcium and the sensitivity of beta receptor (electrical reverse remodeling). These favorable effects of CRT could be expected to modify ventricular and atrial arrhythmias in heart failure patients.On the other hand epicardial pacing would make QT interval long and QT dispersion large. There were a few reports about the provocation of torsades de
Symposium 2 S2-1 Arrhythmogenic Ion-Channel Remodeling in Heart Failure and Upstream Approach HARUAKI NAKAYA Department of Pharmacology, Chiba University Graduate School of Medicine Class I antiarrhythmic drugs with Na+ channel blocking action cannot be readily used for the treatment of various arrhythmias associated with heart failure because the antiarrhthmic drugs may worsen cardiac function. In failing hearts ion-channel remodeling, such as downregulation of K+ channels and connexin 43, upregulation of Na+-Ca2+ exchanger and HCN channels, and instability of Ca2+ release channels in sarcoplasmic reticulum, can be observed. These electrophysiological abnormalities can produce severe ventricular tachyarrhythmias through reentrant and automatic mechanisms. Neurohumoral factors such as renin-angiotensin system, endothelin system and sympathetic nervous system play an important role in the establishment of the ion-channel remodeling. Upstream approach with blockade of the neurohumoral factors may prevent lethal ventricular arrhythmias. In congestive heart failure atrial tissues are expanded and susceptibility to atrial fibrillation is increased. Control of neurohumoral factors may be also beneficial for the prevention of atrial fibrillation. Recently it has been suggested that inflammatory mechanisms may be also involved in not only the deterioration of heart failure but also induction of atrial fibrillation and ventricular tachyarrhythmias. Drugs with anti-inflammatory action, including the antiarrhythmic drug amiodarone, may be effective for the treatment of arrhythmias associated with heart failure. Current perspective of upstream approach to preventing atrial and ventricular arrhythmias associated with heart failure will be discussed.
S2-2 Heart Failure and Atrial Fibrillation: Basic Aspects KUNIHIRO NISHIDA, HIROSHI INOUE Second Department of Internal Medicine, University of Toyama, Toyama, Japan Atrial fibrillation (AF) is the most frequently encountered sustained tachyarrhythmia in clinical practice and is related to significant morbidity and mortality. Although its pathophysiology has been investigated extensively, many questions still remain unanswered. Congestive heart failure (CHF) is one of the most common clinical causes of AF. A canine model of CHF-related AF has been intensively studied to understand the pathophysiology. Atrial structural remodelling contributes importantly to the arrhythmogenic substrate and interstitial fibrosis plays a central role by interfering with local conduction and stabilizing reentry. Increased content of tissue angiotensin II and enhanced expression of phosphorylated MAPKs precede the remodelling process. TGF-b1 also is one of important atrial profibrotic mediators. Experimental CHF causes substantially more fibrosis in atria than in ventricles, partially due to the different TGF-b1 expression between the chambers. However, atrial fibroblasts per se show consistently greater proliferation responses than ventricular fibroblasts for a range of growth factors. Mice with TGF-b1 and ACE overexpression as well show selective atrial fibrosis and AF, without significant ventricular dysfunction or fibrosis. Several pharmacologic agents, such as enalapril, simvastatin, and PUFAs, can suppress atrial structural remodelling and AF promotion by interfering those pathways. These experimental studies have provided important insights into the mechanisms governing the arrhythmia and have allowed for the development of novel therapeutic approaches.
S2-3 Pharmacological Treatment in Patients with Heart Failure: Upstream Therapy TAKANORI IKEDA Department of Cardiovascular Medicine, Toho University Medical Center, Tokyo, Japan Treatments for atrial fibrillation (AF) with ACEIs, ARBs, and statins have been mainly referred to as upstream therapy. Experimental and clinical studies have demonstrated that these drugs decrease the incidence of AF. An overview of clinical trials including the LIFE and CHARM suggests that ACEIs or ARBs may reduce the occurrence and recurrence of AF. The results showed a role of these drugs for the initial or recurrent AF associated with heart failure (HF). The inhibitions of the renin-angiotensin-aldosterone system by these drugs decrease atrial pressure, reduce the frequency of atrial premature beats, and reduce fibrosis. The meta-analyses have shown a significant 30-48% reduction in risk of AF associated with ACEI and ARB therapies. An overview of clinical studies with statins demonstrated that statin therapy reduce the incidence of AF in the post-operative state - this effect not observed in the setting of HF. Recently, the GISSI-AF, demonstrated no effect of valsartan on the primary endpoint of time to first AF recurrence compared with placebo. The preliminary results of the J-RHYTHM II in patients with hypertension
and paroxysmal AF showed no benefit of treatment with candesartan compared with amlodipine on the frequency and duration of AF recurrence. In this Symposium, I will summarize current status of upstream therapy for the primary and secondary prevention of AF in patients with HF.
S2-4 Treatment of Heart Failure by Eliminating Atrial Fibrillation used Catheter Ablation Guided Solely by Complex Fractionated Atrial Electrogram Mapping NAOYA OKETANI1, HITOSHI ICHIKI1, YASUHISA IRIKI1, HIDEKI OKUI1, SANEMASA ISHIDA1, RYUICHI MAENOSONO2, MASAAKI MIYATA1, SHUICHI HAMASAKI1, KOONLAWEE NADEMANEE3, CHUWA TEI1 1 Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 2Clinical Laboratory Unit, Kagoshima University Hospital, 3Pacific Rim EP Research Institute The treatment of heart failure (HF) is still challenging, even though there are a lot of strategies such as drugs, drips, and devices. Atrial fibrillation (AF) and HF often coexist, and worsen each other. Almost all the antiarrhythmic drugs except amiodarone could be harmful to HF. In general, rate control is better than rhythm control using antiarrhythmic drugs in the treatment of the patients who have AF and HF. But it is obviously that sinus rhythm is better than AF in the patients with HF without using antiarrhythmic drugs. Then we’d like to show the powerful ablation of AF with heart failure, complex fractionated atrial electrogram (CFAE) ablation. There are some patients who have AF and low ejection fraction, even though the heart rate is well controlled. Bi-ventricular pacing device occasionally with ablating atrioventricular node could be one of the choices, but if the ejection fraction is improved by eliminating AF using catheter ablation, that would be better. And the patients who have hypertrophic cardiomyopathy and AF are also very symptomatic. Then we will show some challenging cases of AF coexisting structural heart disease.
S2-5 Ventricular Tachyarrhythmias Associated with Congestive Heart Failure (Therapeutic Roles of Antiarrhythmic Drugs and Catheter Ablation) MASAOMI CHINUSH1, HIROSHI FURUSHIMA2, DAISUKE IZUMI2, KENICHI IIJIMA2, YOSHIFUSA AIZAWA2 1 School of Health Science, Niigata University School of Medicine, 2First Department of Internal Medicine, Niigata University School of Medicine Implantable cardioverter defibrillator (ICD) plays a primary therapeutic role for sustained ventricular tachyarrhythmia (VTA), but supplemental treatment with antiarrhythmic drugs and/or radiofrequency catheter ablation (RFCA) is required to minimize the shock delivery from ICD. Since class I antiarrhythmic drugs worsen the mortality rate of congestive heart failure (CHF) patients, class III antiarrhythmic drugs and/or bepridil are selected for reentrant monomorphic ventricular tachycardia (mVT). However, it is usually difficult to predict the long-term efficacy of the drugs at the beginning of the therapy. Our results of pharmacological therapy are; (1) electrophysiological study-based drug selection was useful in predicting long-term drug efficacy, (2) sotalol or bepridl was more effective in VTA associated with ischemic rather than non-ischemic cadiomyopathy. We determined the target site of RF application from the results of substrate mapping and activation/entrainment mapping. RF current was initially applied to the essential part of the arrhythmogenic substrate, but long linear RF application was required in some patients. Once the clinically documented VTs were successfully ablated, long-term therapeutic efficacy is expected. Recently, VTA originating from the epicardial myocardium can be ablated. Cardiac dysfunction can be improved after suppression of frequent VTA.In patients with CHF, appropriate management of VTA is important in order to prevent sudden cardiac death, and improve cardiac function and quality of life.
S2-6 The role of CRT for Cardiac Arrhythmia of Heart Failure Patients TAKESHI MITSUHASHI Division of Cardiovascular Medicine, Jichi Medical University, Tochigi, Japan Cardiac resynchronization therapy (CRT) reduces mortality and improves heart failure symptoms, quality of life and many neurohumoral factors. Furthermore left ventricular function improves gradually accompanied with left ventricular volume reduction (structural reverse remodeling). Some investigators reported CRT also improves many ion channel currents, such as potassium, sodium and calcium and the sensitivity of beta receptor (electrical reverse remodeling). These favorable effects of CRT could be expected to modify ventricular and atrial arrhythmias in heart failure patients.On the other hand epicardial pacing would make QT interval long and QT dispersion large. There were a few reports about the provocation of torsades de