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Risk Stratification in Patients with Chronic Heart Failure using Cardiac Sympathetic Imaging with MIBG
S138 Journal of Cardiac Failure Vol. 20 No. 10S October 2014 interventions might reduce the risk of cardiac death, propose acceptable therapeutic option, and improve a quality of life in the heart failure patients. If we intend to know the start point of the one-way deterioration, we have to catch the upstream of terminal phenotype. We have to catch the upstream of increasing fibrosis, the upstream of cell death, and, therefore, the upstream of gene expression changes. As the accumulating stress for gene expression can affect the epigenetic status and chromatin structure, we hypothesized that progression of heart failure might related to alter chromatin structure in cardiomyocytes’ nuclei. Thus we aimed to design the pathophysiological study making a quantitative evaluation of the chromate in structure. In the present study we established the original method for automatic calculation of nucleic chromatin structure by electron microscopic analysis. We could clearly distinguish which group can avoid VAD implantation within 12 months after the biopsy in iDCM patients. We would like to discuss about the importance of the evaluation of chromatin structures for early prediction of poor outcome in patients with iDCM.
Epigenetic Therapy as a Potential Novel Treatment for Chronic Heart Failure RURI KANEDA, TOMOHIKO ONO, KEIICHI FUKUDA Department of Cardiology, Keio University School of Medicine The evidences for a role of epigenetic regulation in the development of hypertrophy, contractility, energymetabolism, and fibrosis in the heart have been recently reported. On the treatment, HDAC inhibitors have been focused as valuable drugs for heart disease. We previously demonstrated that the distribution of H3K9me3 in the failing heart is quite different from that in control hearts both in animal models and clinical heart specimens. Therefore we focused on this heart failure-specific histone modification and investigated the prognostic efficacy of administering a histone H3K9 methyltransferase inhibitor, Chaetocin, to Dahl salt-sensitive rats, an animal model of heart failure. Chaetocin has delayed the timing of transition from cardiac hypertrophy to heart failure and prolonged survival term in the animal model. The mitochondrial dysfunction was improved with inhibitor use in the failing heart. In ChIP-seq analysis, at 7,326 loci associated with repetitive elements, including regions neighboring mitochondrial genes, heart failure caused an increase in H3K9me3 alignments and a corresponding reduction with inhibitor use. At only 21 loci, heart failure was associated with a reduction in H3K9me3 alignments, and an increase with inhibitor use. These data suggest that excessive heterochromatinization of repetitive elements in the failing heart might impair pumping function via silencing of mitochondrial genes. H3K9 methyltransferase inhibitor may have promise as a novel therapy for chronic heart failure.
Symposium 9 Immunomodulatory Therapy for Patients with Refractory Heart Failure due to Dilated Cardiomyopathy TSUTOMU YOSHIKAWA1, AKIYASU BABA2, HITONOBU TOMOIKE1 1 Sakakibara Heart Institute, Fuchu, Japan, 2Cardiology, Kitasato Institute Hospital Autoimmune abnormalities appear to be one of the predominant underlying disorders, as well as genetic abnormalities and acquired infection for the development of dilated cardiomyopathy (DCM). Various antimyocardial antibodies are detected in the serum of patients with DCM. Recent findings have suggested that at least some of them are directly related to the pathophysiology of DCM. Immunoadsorption technique (IA) is one of the potentially promising therapeutic measures to remove these autoantibodies. As a proof of concept study, IA therapy was conducted in 16 patients with DCM (NYHA functional class III/IV, mean ejection fraction 182%) using a IgG-3 subclass-specific tryptophan column. Study subjects had autoantibodies directed against either b1-adrenergic or M2-muscarinic receptors. IA was performed for 1.5 hours each session, and repeated 3 to 5 times. IgG-3 subclass was removed to greater extent than other subclass as expected. Left ventricular ejection fraction measured by radionuclide ventriculography significantly increased over the 3 months after completion of IA. Clinical trial comparing 5 times sessions and 10 times sessions has been completed, and awaits analyzing dataset. Conclusions: Our initial experience demonstrated safety and short-term efficacy of IA using a novel IgG3-specific tryptophan column for patients with advanced heart failure due to DCM. This therapy may be one of the options to rescue refractory heart failure due to DCM.
Current Status of Heart Transplantation in Japan KOICHIRO KINUGAWA The Department of Therapeutic Strategy for Heart Failure, The University of Tokyo, Tokyo, Japan Heart transplantation (HTx) and durable ventricular assist device (VAD) are options to improve long-term survival of stage D heart failure patients. VAD can extend patients’ survival with considerable improvement of qualityof life, but there is some limitation for patients with VAD implantation in terms of daily life. In this regard, HTx is the only therapeutic tool to restore virtually normal daily life. However, in Japan there are severe donor shortage even after the amendment of organ transplant law since 2010. If the current number of annual donors continues, total status 1 patients on waiting list might be more than 300 in several years, and as a result waiting period must be over 7 years. I will discuss how to manage stage D HF patients with mechanical assist device in such a tough situation, and also would like to propose to limit HTx eligibility with expansion of VAD indication.
Risk Stratification in Patients with Chronic Heart Failure using Cardiac Sympathetic Imaging with MIBG TAKAHISA YAMADA, SHUNSUKE TAMAKI, MASATAKE FUKUNAMI Division of Cardiology, Osaka General Medical Center Despite recent advances in pharmacolocigal and nonpharmacological treatment, mortality and morbidity remains high in patients with chronic heart failure (CHF). The risk stratification by predicting poor outcomes in patients with CHF can help physicians guide therapy. In CHF, cardiac sympathetic nerve overactivity contributes to the progression of the disease and is associated with poor outcomes. Cardiac MIBG sicntigraphy is the only one of an imaging tool to estimate cardiac adrenergic nerve function, and provides valuable information about the evaluation of CHF severity, the monitoring of clinical course and response to therapy, and prognosis. The prediction of sudden cardiac death (SCD) remains an important goal in CHF patients. We previously reported that cardiac MIBG imaging could be useful for the prediction of SCD in CHF patients and that MIBG imaging would also be a powerful predictor of SCD, compared with electrocardiographic parameters such as signal-averaged ECG, heart rate variability and QT dispersion. Furthermore, the combination of MIBG imaging and the clinical risk score such as Seattle Heart Failure Model could identify the subset at higher risk of poor outcomes in CHF patients. Recently, the large-scaled multicenter studies have provided the validation of the independent prognostic value of cardiac MIBG imaging in assessment of CHF patients. Cardiac MIBG imaging is re-confirmed to be a useful tool to risk stratify CHF patients.
Management of Arrhythmias in Severe Heart Failure TSUYOSHI SHIGA Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan The treatment goals for patients with severe heart failure are to improve prognosis and quality of life. Sudden cardiac death (SCD), which is primarily caused by ventricular tachycardia (VT)/fibrillation (VF), accounts for approximately one-third of all deaths in heart failure patients. Therefore, the prevention of VT/VF is a key issue in the treatment of these patients. Immediate defibrillation by DC shocks is mandatory for the treatment of VT/VF associated with serious hemodynamic deterioration. If arrhythmia persists after several DC shocks, amiodarone or nifekalant is given intravenously. Atrial fibrillation (AF) frequently occurs in patients with severe heart failure. It is recognized that AF leads to clinical deterioration and, even worse, heart failure. AF also increases the risk of mortality and morbidity in heart failure patients. Persistent AF in hemodynamically unstable patients should be promptly cardioverted. Amiodarone appear to be effective for the strategy of maintenance of sinus rhythm in heart failure patients with AF. The mechanisms of arrhythmias associated with heart failure are complex and heterogeneous; they include functional and structural remodeling, as well as neurohormonal activation. Basic drug therapy, beta-blockers and angiotensin-converting enzyme inhibitors, and antiarrhythmics such as amiodarone prevent arrhythmias and SCD. Recently, there has been much progress with the catheter ablation technique, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices, which are now useful in selected patients.
Symposium 10 Diagnosis and Management of Takotsubo Cardiomyopathy SATOSHI KURISU, YASUKI KIHARA Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan Takotsubo cardiomyopathy has become accepted worldwide as a distinct clinical entity since the first report by Sato et al in 1990. Takotsubo cardiomyopathy usually occurs in postmenopausal elderly women, and is characterized by chest symptoms, electrocardiographic changes and transient left ventricular apical wall motion abnormalities after emotional or physical stress. In the clinical setting, takotsubo cardiomyopathy is an important disease which should be differentiated from acute myocardial infarction promptly for the appropriate management. Left ventricular apical wall motion abnormalities are usually resolved during a period of days to weeks, and the prognosis is generally favorable. However, several acute complications have been reported such as congestive heart failure, cardiac rupture, left ventricular apical thrombosis or arrhythmias. Monitoring clinical course is essential to prevent or treat acute complications. Several possible mechanisms including multivessel coronary artery spasm, coronarymicrovascular dysfunction and catecholamine toxicity have been proposed to explain takotsubo cardiomyopathy, but its pathophysiology is not well understood. It is necessary to clarify the precisepathophysiology for establishing the optimal management of takotsubo cardiomyopathy. We will summarize the current knowledge on the diagnosis and management of takotsubo cardiomyopathy.
Left Ventricular Noncompaction Cardiomyopathy in Adult JUN KOYAMA, MASATOSHI MINAMISAWA, AYAKO OKADA, HIROHIKO MOTOKI, YUUJI SHIBA, ATSUSHI IZAWA, YUSUKE MIYASHITA, UICHI IKEDA Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan Background: Prognostic impact of regression of left ventricular noncompaction appearance after optimal treatment in adult patients with left ventricular
Epigenetic Therapy as a Potential Novel Treatment for Chronic Heart Failure RURI KANEDA, TOMOHIKO ONO, KEIICHI FUKUDA Department of Cardiology, Keio University School of Medicine The evidences for a role of epigenetic regulation in the development of hypertrophy, contractility, energymetabolism, and fibrosis in the heart have been recently reported. On the treatment, HDAC inhibitors have been focused as valuable drugs for heart disease. We previously demonstrated that the distribution of H3K9me3 in the failing heart is quite different from that in control hearts both in animal models and clinical heart specimens. Therefore we focused on this heart failure-specific histone modification and investigated the prognostic efficacy of administering a histone H3K9 methyltransferase inhibitor, Chaetocin, to Dahl salt-sensitive rats, an animal model of heart failure. Chaetocin has delayed the timing of transition from cardiac hypertrophy to heart failure and prolonged survival term in the animal model. The mitochondrial dysfunction was improved with inhibitor use in the failing heart. In ChIP-seq analysis, at 7,326 loci associated with repetitive elements, including regions neighboring mitochondrial genes, heart failure caused an increase in H3K9me3 alignments and a corresponding reduction with inhibitor use. At only 21 loci, heart failure was associated with a reduction in H3K9me3 alignments, and an increase with inhibitor use. These data suggest that excessive heterochromatinization of repetitive elements in the failing heart might impair pumping function via silencing of mitochondrial genes. H3K9 methyltransferase inhibitor may have promise as a novel therapy for chronic heart failure.
Symposium 9 Immunomodulatory Therapy for Patients with Refractory Heart Failure due to Dilated Cardiomyopathy TSUTOMU YOSHIKAWA1, AKIYASU BABA2, HITONOBU TOMOIKE1 1 Sakakibara Heart Institute, Fuchu, Japan, 2Cardiology, Kitasato Institute Hospital Autoimmune abnormalities appear to be one of the predominant underlying disorders, as well as genetic abnormalities and acquired infection for the development of dilated cardiomyopathy (DCM). Various antimyocardial antibodies are detected in the serum of patients with DCM. Recent findings have suggested that at least some of them are directly related to the pathophysiology of DCM. Immunoadsorption technique (IA) is one of the potentially promising therapeutic measures to remove these autoantibodies. As a proof of concept study, IA therapy was conducted in 16 patients with DCM (NYHA functional class III/IV, mean ejection fraction 182%) using a IgG-3 subclass-specific tryptophan column. Study subjects had autoantibodies directed against either b1-adrenergic or M2-muscarinic receptors. IA was performed for 1.5 hours each session, and repeated 3 to 5 times. IgG-3 subclass was removed to greater extent than other subclass as expected. Left ventricular ejection fraction measured by radionuclide ventriculography significantly increased over the 3 months after completion of IA. Clinical trial comparing 5 times sessions and 10 times sessions has been completed, and awaits analyzing dataset. Conclusions: Our initial experience demonstrated safety and short-term efficacy of IA using a novel IgG3-specific tryptophan column for patients with advanced heart failure due to DCM. This therapy may be one of the options to rescue refractory heart failure due to DCM.
Current Status of Heart Transplantation in Japan KOICHIRO KINUGAWA The Department of Therapeutic Strategy for Heart Failure, The University of Tokyo, Tokyo, Japan Heart transplantation (HTx) and durable ventricular assist device (VAD) are options to improve long-term survival of stage D heart failure patients. VAD can extend patients’ survival with considerable improvement of qualityof life, but there is some limitation for patients with VAD implantation in terms of daily life. In this regard, HTx is the only therapeutic tool to restore virtually normal daily life. However, in Japan there are severe donor shortage even after the amendment of organ transplant law since 2010. If the current number of annual donors continues, total status 1 patients on waiting list might be more than 300 in several years, and as a result waiting period must be over 7 years. I will discuss how to manage stage D HF patients with mechanical assist device in such a tough situation, and also would like to propose to limit HTx eligibility with expansion of VAD indication.
Risk Stratification in Patients with Chronic Heart Failure using Cardiac Sympathetic Imaging with MIBG TAKAHISA YAMADA, SHUNSUKE TAMAKI, MASATAKE FUKUNAMI Division of Cardiology, Osaka General Medical Center Despite recent advances in pharmacolocigal and nonpharmacological treatment, mortality and morbidity remains high in patients with chronic heart failure (CHF). The risk stratification by predicting poor outcomes in patients with CHF can help physicians guide therapy. In CHF, cardiac sympathetic nerve overactivity contributes to the progression of the disease and is associated with poor outcomes. Cardiac MIBG sicntigraphy is the only one of an imaging tool to estimate cardiac adrenergic nerve function, and provides valuable information about the evaluation of CHF severity, the monitoring of clinical course and response to therapy, and prognosis. The prediction of sudden cardiac death (SCD) remains an important goal in CHF patients. We previously reported that cardiac MIBG imaging could be useful for the prediction of SCD in CHF patients and that MIBG imaging would also be a powerful predictor of SCD, compared with electrocardiographic parameters such as signal-averaged ECG, heart rate variability and QT dispersion. Furthermore, the combination of MIBG imaging and the clinical risk score such as Seattle Heart Failure Model could identify the subset at higher risk of poor outcomes in CHF patients. Recently, the large-scaled multicenter studies have provided the validation of the independent prognostic value of cardiac MIBG imaging in assessment of CHF patients. Cardiac MIBG imaging is re-confirmed to be a useful tool to risk stratify CHF patients.
Management of Arrhythmias in Severe Heart Failure TSUYOSHI SHIGA Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan The treatment goals for patients with severe heart failure are to improve prognosis and quality of life. Sudden cardiac death (SCD), which is primarily caused by ventricular tachycardia (VT)/fibrillation (VF), accounts for approximately one-third of all deaths in heart failure patients. Therefore, the prevention of VT/VF is a key issue in the treatment of these patients. Immediate defibrillation by DC shocks is mandatory for the treatment of VT/VF associated with serious hemodynamic deterioration. If arrhythmia persists after several DC shocks, amiodarone or nifekalant is given intravenously. Atrial fibrillation (AF) frequently occurs in patients with severe heart failure. It is recognized that AF leads to clinical deterioration and, even worse, heart failure. AF also increases the risk of mortality and morbidity in heart failure patients. Persistent AF in hemodynamically unstable patients should be promptly cardioverted. Amiodarone appear to be effective for the strategy of maintenance of sinus rhythm in heart failure patients with AF. The mechanisms of arrhythmias associated with heart failure are complex and heterogeneous; they include functional and structural remodeling, as well as neurohormonal activation. Basic drug therapy, beta-blockers and angiotensin-converting enzyme inhibitors, and antiarrhythmics such as amiodarone prevent arrhythmias and SCD. Recently, there has been much progress with the catheter ablation technique, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices, which are now useful in selected patients.
Symposium 10 Diagnosis and Management of Takotsubo Cardiomyopathy SATOSHI KURISU, YASUKI KIHARA Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan Takotsubo cardiomyopathy has become accepted worldwide as a distinct clinical entity since the first report by Sato et al in 1990. Takotsubo cardiomyopathy usually occurs in postmenopausal elderly women, and is characterized by chest symptoms, electrocardiographic changes and transient left ventricular apical wall motion abnormalities after emotional or physical stress. In the clinical setting, takotsubo cardiomyopathy is an important disease which should be differentiated from acute myocardial infarction promptly for the appropriate management. Left ventricular apical wall motion abnormalities are usually resolved during a period of days to weeks, and the prognosis is generally favorable. However, several acute complications have been reported such as congestive heart failure, cardiac rupture, left ventricular apical thrombosis or arrhythmias. Monitoring clinical course is essential to prevent or treat acute complications. Several possible mechanisms including multivessel coronary artery spasm, coronarymicrovascular dysfunction and catecholamine toxicity have been proposed to explain takotsubo cardiomyopathy, but its pathophysiology is not well understood. It is necessary to clarify the precisepathophysiology for establishing the optimal management of takotsubo cardiomyopathy. We will summarize the current knowledge on the diagnosis and management of takotsubo cardiomyopathy.
Left Ventricular Noncompaction Cardiomyopathy in Adult JUN KOYAMA, MASATOSHI MINAMISAWA, AYAKO OKADA, HIROHIKO MOTOKI, YUUJI SHIBA, ATSUSHI IZAWA, YUSUKE MIYASHITA, UICHI IKEDA Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan Background: Prognostic impact of regression of left ventricular noncompaction appearance after optimal treatment in adult patients with left ventricular