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JS5-5 Heart Failure Therapy that Targets Nuclear Signaling Pathway in Cardiomyocytes
Joint Session 5: APSC ISCHF Joint Session: Cardiomyopathy and Heart Failure: Update determination of the causative mechanisms leading to the phenotype and severity of disease. In addition, work has been performed in an attempt to correlate the genetic and mechanistic defects with clinical expression of disease (socall genotype-phenotype correlations). These issues will be the topic of this lecture. JS5-2 Treatment of Viral and Autoreactive Inflammatory Cardiomyopathy Bernhard Maisch. Philipps-Universitaet, Marburg, Germany Viral infections of the heart often resolve spontaneously. When they lead to cardiac damage viral cardiomyopathy or inflammatory viral cardiomyopathy develops. The most frequent cardiotropic virus detected by PCR in endomyocardial biopsies of pts with myocarditis is Parvo B19 (30%); entero-, adeno-, cytomegalo-, Epstein-Barr, influenza and herpes humanus 6 or hepatitis C viruses, Borrelia burgdorferi and Chlamydia are rare (<5%) in Europe. The most frequent form of dilated cardiomyopathy with inflammation (DCMi) is the virus negative, autoreactive myocarditis. Most inflammatory forms demand specific treatment beyond conventional heart failure therapy. In entero-, adeno- and cytomegaloviral myocarditis ivIg or interferon eradicate both inflammation and the viral genome. In Parvo B19 positive DCMi iv Ig eradicates inflammation in all, but the virus only in 1/3 of the biopsies*. In the in the BICC trial b-interferon was effective only when all viral forms were analysed together, but failed when only Parvo B19 DCMi was analysed. In undefined myocarditis the American Myocarditis Trial (1996) did not show benefit from immunosuppression, but recent studies in autoreactive myocarditis demonstrated elimination of inflammation by azathioprin and prednisone in giant cell myocarditis, eosinophilic myocarditis, acute and chronic non-viral myocarditis. The RCT ESETCID trial showed that the benefit is seen best in the long term follow-up of patients. JS5-3 Variant Types of Stress-Induced Cardiomyopathy Kee-Sik Kim. Daegu Catholic University, Daegu, Korea Stress-induced Cardiomyopathy (SICMP) is characterized as transient apical ballooning of left ventricle (LV) after severe mental or physical stress. Recently, variant type of SICMP, inverted Takotsubo pattern of disease is increasing with wall motion abnormalty in basal and/or mid-ventricular myocardium, but with sparing of LV apex. This type of SICMP frequently found in patients with subarachnoid hemorrhage. The pathogenesis of variant form was known as similar with apical ballooning type. We evaluate the clinical and echocardiographic features of stress-induced apical ballooning and non-apical ballooning. During nine-year period (1999 2007), 61 patients were clinically diagnosed as stress-induced cardiomyopathy. We analyzed 60 patients who fulfilled the following criteria: (1) regional WMA, (2) absence of obstructive coronary disease corresponding to region of WMA and (3) absence of recent head trauma, intracranial hemorrhage, pheochromocytoma, and known cardiomyopathies. Forty-four patients showed typical apical WMA, and 16 showed non-apical WMA. The patients with apical WMA (A group) were more frequently complained chest pain than patients with non-apical WMA (N group). The patients in A group had more diabetes. However, serious complications including cardiogenic shock, pulmonary edema and arrhythmia were more frequent in N group. However, the ratio of E/Em was higher in A group. In
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conclusion, stress-induced non-apical ballooning might have different features in patient’s characteristics, complications and echocardiographic parameter compared with typical apical ballooning. JS5-4 Advances in the Noninvasive and Immunohistological Diagnosis of Myocarditis Leslie T. Cooper Jr.. Professor of Medicine, Mayo Clinic College of Medicine Consultant, Cardiovascular Diseases, Mayo Clinic, USA The diagnosis of myocarditis is frequently missed because of nonspecific findings on physical examination, poor performance of most noninvasive diagnostic tests and the perceived risks of endomyocardial biopsy (EMB). The sensitivity of the EKG for myocarditis is low at 47%; however, the presence of Q waves or left bundle branch block is associated with higher rates of death or transplantation. Reduced left and right ventricular function are also associated with higher risk. Troponin-I has high specificity (89%) but limited sensitivity (34%) for myocarditis. High serum levels of Fas ligand and interleukin-10 predict increased mortality. Cardiac magnetic resonance is increasingly used to diagnose myocarditis and to guide endomyocardial biopsy. Recent consensus guidelines suggest that combined T2 and T1 weighted images have the best combination of sensitivity (67%) and specificity (91%). EMB is useful to exclude giant cell myocarditis or necrotizing eosinophilic myocarditis in patients with acute cardiomyopathy, and hemodynamic compromise, ventricular arrhythmias, high grade heart block, or who fail to respond to usual care. Diagnostic criteria based on immunoperoxidase staining have greater sensitivity, and unlike the Dallas criteria, may have prognostic value in acute lymphocytic myocarditis. In adults, the risk of death from right ventricular EMB when performed with a modified Cordis bioptome by experienced operators is less than 1:2500. JS5-5 Heart Failure Therapy that Targets Nuclear Signaling Pathway in Cardiomyocytes Koji Hasegawa. Director, Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Japan Signals activated by increased hemodynamic overload to the heart finally reach nuclei of cardiac myocytes, change patterns of gene expression and cause their maladaptive hypertrophy. Nuclear acetylation controlled by histone deacetylases and an intrinsic histone acetyltransferase, p300, is a critical event during this process. However, a pharmacological heart failure therapy that targets this nuclear pathway has yet to be established. A cellpermeable natural compound, curcumin, is a polyphenol that is responsible for the yellow color of Indian curry spice turmeric, and commonly used as a health-food diet. In addition, curcumin possesses HAT inhibitory activity with specificity for p300/CBP. We show here that the acetylated form of GATA4, one of the hypertrophy-responsive transcription factors, and p300/GATA4 complex markedly increased in hypertensive hearts in vivo. Curcumin reversed myocyte hypertrophy both in vitro and in vivo by at least two mechanisms: inhibiting nuclear acetylation and disrupting the p300/GATA4 complex. Furthermore, curcumin treatment almost completely prevented the deterioration of systolic function in two different rat models of heart failure, hypertension and myocardial infarction. Thus, a nontoxic dietary compound, curcumin, will provide a novel therapeutic strategy for heart failure in humans.
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conclusion, stress-induced non-apical ballooning might have different features in patient’s characteristics, complications and echocardiographic parameter compared with typical apical ballooning. JS5-4 Advances in the Noninvasive and Immunohistological Diagnosis of Myocarditis Leslie T. Cooper Jr.. Professor of Medicine, Mayo Clinic College of Medicine Consultant, Cardiovascular Diseases, Mayo Clinic, USA The diagnosis of myocarditis is frequently missed because of nonspecific findings on physical examination, poor performance of most noninvasive diagnostic tests and the perceived risks of endomyocardial biopsy (EMB). The sensitivity of the EKG for myocarditis is low at 47%; however, the presence of Q waves or left bundle branch block is associated with higher rates of death or transplantation. Reduced left and right ventricular function are also associated with higher risk. Troponin-I has high specificity (89%) but limited sensitivity (34%) for myocarditis. High serum levels of Fas ligand and interleukin-10 predict increased mortality. Cardiac magnetic resonance is increasingly used to diagnose myocarditis and to guide endomyocardial biopsy. Recent consensus guidelines suggest that combined T2 and T1 weighted images have the best combination of sensitivity (67%) and specificity (91%). EMB is useful to exclude giant cell myocarditis or necrotizing eosinophilic myocarditis in patients with acute cardiomyopathy, and hemodynamic compromise, ventricular arrhythmias, high grade heart block, or who fail to respond to usual care. Diagnostic criteria based on immunoperoxidase staining have greater sensitivity, and unlike the Dallas criteria, may have prognostic value in acute lymphocytic myocarditis. In adults, the risk of death from right ventricular EMB when performed with a modified Cordis bioptome by experienced operators is less than 1:2500. JS5-5 Heart Failure Therapy that Targets Nuclear Signaling Pathway in Cardiomyocytes Koji Hasegawa. Director, Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Japan Signals activated by increased hemodynamic overload to the heart finally reach nuclei of cardiac myocytes, change patterns of gene expression and cause their maladaptive hypertrophy. Nuclear acetylation controlled by histone deacetylases and an intrinsic histone acetyltransferase, p300, is a critical event during this process. However, a pharmacological heart failure therapy that targets this nuclear pathway has yet to be established. A cellpermeable natural compound, curcumin, is a polyphenol that is responsible for the yellow color of Indian curry spice turmeric, and commonly used as a health-food diet. In addition, curcumin possesses HAT inhibitory activity with specificity for p300/CBP. We show here that the acetylated form of GATA4, one of the hypertrophy-responsive transcription factors, and p300/GATA4 complex markedly increased in hypertensive hearts in vivo. Curcumin reversed myocyte hypertrophy both in vitro and in vivo by at least two mechanisms: inhibiting nuclear acetylation and disrupting the p300/GATA4 complex. Furthermore, curcumin treatment almost completely prevented the deterioration of systolic function in two different rat models of heart failure, hypertension and myocardial infarction. Thus, a nontoxic dietary compound, curcumin, will provide a novel therapeutic strategy for heart failure in humans.