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Torasemide, a Novel Loop Diuretic Reduces the Progression of Myocarditis to Dilated Cardiomyopathy
S172 Journal of Cardiac Failure Vol. 12 No. 8 Suppl. 2006 although they were not significant. Total cholesterol, LDL-cholesterol, triglyceride or HDL-cholesterol level was not changed with losartan. On the other hand, serum insulin (placebo: 11.261.6 mU/ml, losartan: 6.360.8 mU/ml, p!0.05) and HOMA-IR (placebo: 3.160.5, losartan: 1.760.3, p!0.05) were significantly improved with losartan while fasting plasma glucose was not changed. Serum Cr level was not changed with losartan, however, urine albumin/gCr tended to be decreased with losartan (placebo, 48.7619.5 mg/gCr, losartan: 11.264.8 mg/gCr, p!0.1). Conclusion: Losartan improved insulin resistance in patients with CHF.
1053 Torasemide, a Novel Loop Diuretic Reduces the Progression of Myocarditis to Dilated Cardiomyopathy PUNNIYAKOTI THANIKACHALAM, KENICHI WATANABE, MEILEI MA, PARAS PRAKASH Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan Purpose: Torasemide is a new loop diuretic that combines the effects of furosemide and spironolactone. The purpose of the study was to investigate the long-term effects of torasemide; on metabolic and neurohumoral parameters in a rat model of myosin induced dilated cardiomyopathy. Methods: Twenty-eight days after immunization with pig cardiac myosin, rats were received torasemide (0.3 mg/kg, 3 mg/kg and 10 mg/kg) or vehicle; age-matched normal rats were also used in the study. Metabolic caging studies and electrolyte analysis were carried out. Hemodynamic and echocardiographic analysis was performed to assess the myocardial function. Western Immunoblotting and immunohistochemistry were carried out to assess the protein levels, Evaluation of myocardial fibrosis, and Ang II level in serum were conducted. Results: Diuresis was increased dose dependently by torasemide. The urinary potassium and sodium excretion was decreased and increased respectively. Myocardial functional parameters were significantly improved by torasemide treatment in dose dependent manner. Area of fibrosis, myocardial protein levels of TGF-beta1, aldosterone synthase was lowered, serum level of Ang II was increased dose dependently and was improved sarcoplasmic reticulum Caþ2 ATPase2 protein level with torasemide treatment. Conclusion: Our findings suggest that torasemide treatment ameliorates the progression of cardiac remodeling in rats with heart failure.
1054 Presence of Autoantibody against b1-adrenergic Receptors is Associated with Amelioration of Cardiac Function During b-blocker Therapy for Congestive Heart Failure YUJI NAGATOMO1, TSUTOMU YOSHIKAWA1, TAKASHI KOHNO1, AKIHIRO YOSHIZAWA2, AKIYASU BABA3, TOSHIHISA ANZAI1, TOMOMI MEGURO4, TORU SATO1, SATOSHI OGAWA1 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan, 3 Kitasato Institute Hospital, Tokyo, Japan, 4Tokyo Electoric Power Company Hospital, Tokyo, Japan Background: Autoimmune disorder is one of the features characterizing congestive heart failure(CHF). Autoantibody against b1-adrenergic receptors exerts agonist-like action and elicits persistent myocardial damage and from our previous studies, b-blockers might affect biological actions of the autoantibody. We attempted to determine the significance of the presence of the autoantibody in patients with CHF who received b-blockers. Methods: Eighty-two CHF patients(NYHA class II 63, III 18, IV 1, IDC, 63, IHD, 16, VHD, 3) were enrolled. They were randomly assigned to metoprolol group (n538) and carvedilol group (n544), and received b-blocker therapy for 16 weeks. Sera were collected and presence or absence of the antibody was determined using ELISA. Results: Autoantibody was found to be positive in 15(18%, P). Etiologies of CHF and agents they received were also similar between P and N. Change in LVEDD from baseline value tended to be larger in P than N(-0.560.5 cm vs-0.260.4 cm, p50.09). Change in LVESD was significantly larger in P than N(-0.960.8 cm vs. -0.460.6 cm, p50.02). Change in LVEF measured by radionuclide ventriculography was greater in P than N(þ16612% vs. þ969%, p50.02). Change in plasma BNP level was also larger in P than N(-64.76126.5 pg/ml vs. -19.66218.9 pg/ml, p50.02). Conclusions: Our data suggest that b-blocker therapy is more effective in alleviating cardiac dysfunction and reversing remodeling in patients with autoantibody against b1-adrenergic receptors.
1055 Adrenoceptor a1B and Norepinephrine Transporter Polymorphisms are Associated with the Response to b-blockers in Patients with Dilated Cardiomyopathy HIROSHI OKAMOTO1, SHINPEI NONEN2, YASUSHI FUJIO2, YASUHIKO TAKEMOTO3, MINORU YOSHIYAMA3, TOMOYUKI HAMAGUCHI4, YUTAKA MATSUI1, JUNICHI YOSHIKAWA3, AKIRA KITABATAKE1, JUNICHI AZUMA2 1 Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan, 2Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 3Department of Internal Medicine and Cardiology, Osaka City University School of Medicine, 4 Osaka Prefectural Medical Center for Respiratory and Allergic Diseases Background: Recent clinical trials have demonstrated that b-blockers decrease the mortality in patients with heart failure (CHF). Approximately 60-70% of CHF patients exhibit the improvement of left ventricular function in response to b-blockers. Aim: To address this inter-individual variability of the response to b-blockers, we investigated the associations between the response and genetic polymorphisms in 16 genes related to adrenergic system. Methods: Patients with dilated cardiomyopathy (n580) were genotyping by PCR. Good responders were defined as the improvement of left ventricular fractional shortening (LVFS) by 5%, examined by echocardiography. Multivariate logistic regression analysis with adjustment for age, sex, LVFS and NYHA class at pre-administration was performed to evaluate associations between the response to b-blockers and each polymorphisms. Results: Baseline LVFS and NYHA class were different between responders and non-responders. Adrenoceptor a1B G549A (non-responders; GG 53.3%, GA 37.8%, AA 15.4%, p50.005) and norepinephrine transporter (NET) T182C (nonresponders; 25.9%, TC 39.0%, CC 75.0%, p50.007) were associated with response to b-blockers. The risk for non-responders was scored according to the formula for prediction of response. Eighty-one pTT ercents of patients with more than 0.5 were found to be non-responders, while 78% of the remainders were responders. Conclusion: a1B (G549A) and NET (T182C) polymorphisms are independent predictors of the response to b-blockers. These pharmacogenomic findings may be helpful in individualized medicine of b-blockers in CHF.
1056 Usefulness of Bisoprolol for Chronic Heart Failure: A Comparative Study with Carvedilol KENJI MIYAGISHIMA, SHINYA HIRAMITSU, KAZUMASA MORI, HISASHI KIMURA, SHIGERU KATO, YASUCHIKA KATO, MASATSUGU OHTSUKI, MASATSUGU IWASE, SHIN-ICHIRO MORIMOTO, HITOSHI HISHIDA Division of Cardiology, Department of Internal Medicine, Fyjita Health University Purpose: Three types of beta-blocker have been confirmed to be useful for chronic heart failure, carvedilol, bisoprolol, and metoprolol. But we can use only carvedilol in Japan. Here, we compared the usefulness of bisoprolol, which has beta 1 selectivity, with that of carvedilol. Subjects and Method: 738 cases who were admitted to our hospital because of worsening chronic heart failure during the 5-year period from January, 2000 to December, 2004 were focused on. They were divided into a group receiving bisoprolol (108 cases: male567, mean age 67.5612.1 years, mean LVEF536.5613.2%) and a control group receiving carvedilol (274 cases: male5183, mean age 66.1615.0 years, mean LVEF535.5613.9%), and their clinical findings and outcome were investigated. Results: No significant differences were noted on admission between the two groups in clinical findings such as NYHA class, Killip classification, LVEF, BNP, renal function, or serum Hemoglobin. Moreover, in a study using Kaplan-Meier curves no significant difference was found between the groups in the convalescent phase outcome (P50.614). Conclusion: The outcome of the bisoprolol group was equivalent to that of the carvedilol group, confirming the usefulness of this agent for chronic heart failure in Japanes.
1057 Effect of Combination Therapy of Oral Beta-blocker and Pimobendan in Patients with Congestive Heart Failure YUYA AOYAMA, HIDEYUKI HARA, MICHIRO KIRYU, DAISUKE SATO, HIROSHI ITO Department of Internal Medicine/Cardiology, Numazu City Hospital, Numazu, Japan Background: It is known that pimobendan acutely reduces cardiac overload in patients with congestive heart failure (CHF), and induces beneficial systemic hemodynamic effect. However, there are some patients who suffered recurrent CHF in spite
1053 Torasemide, a Novel Loop Diuretic Reduces the Progression of Myocarditis to Dilated Cardiomyopathy PUNNIYAKOTI THANIKACHALAM, KENICHI WATANABE, MEILEI MA, PARAS PRAKASH Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan Purpose: Torasemide is a new loop diuretic that combines the effects of furosemide and spironolactone. The purpose of the study was to investigate the long-term effects of torasemide; on metabolic and neurohumoral parameters in a rat model of myosin induced dilated cardiomyopathy. Methods: Twenty-eight days after immunization with pig cardiac myosin, rats were received torasemide (0.3 mg/kg, 3 mg/kg and 10 mg/kg) or vehicle; age-matched normal rats were also used in the study. Metabolic caging studies and electrolyte analysis were carried out. Hemodynamic and echocardiographic analysis was performed to assess the myocardial function. Western Immunoblotting and immunohistochemistry were carried out to assess the protein levels, Evaluation of myocardial fibrosis, and Ang II level in serum were conducted. Results: Diuresis was increased dose dependently by torasemide. The urinary potassium and sodium excretion was decreased and increased respectively. Myocardial functional parameters were significantly improved by torasemide treatment in dose dependent manner. Area of fibrosis, myocardial protein levels of TGF-beta1, aldosterone synthase was lowered, serum level of Ang II was increased dose dependently and was improved sarcoplasmic reticulum Caþ2 ATPase2 protein level with torasemide treatment. Conclusion: Our findings suggest that torasemide treatment ameliorates the progression of cardiac remodeling in rats with heart failure.
1054 Presence of Autoantibody against b1-adrenergic Receptors is Associated with Amelioration of Cardiac Function During b-blocker Therapy for Congestive Heart Failure YUJI NAGATOMO1, TSUTOMU YOSHIKAWA1, TAKASHI KOHNO1, AKIHIRO YOSHIZAWA2, AKIYASU BABA3, TOSHIHISA ANZAI1, TOMOMI MEGURO4, TORU SATO1, SATOSHI OGAWA1 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan, 3 Kitasato Institute Hospital, Tokyo, Japan, 4Tokyo Electoric Power Company Hospital, Tokyo, Japan Background: Autoimmune disorder is one of the features characterizing congestive heart failure(CHF). Autoantibody against b1-adrenergic receptors exerts agonist-like action and elicits persistent myocardial damage and from our previous studies, b-blockers might affect biological actions of the autoantibody. We attempted to determine the significance of the presence of the autoantibody in patients with CHF who received b-blockers. Methods: Eighty-two CHF patients(NYHA class II 63, III 18, IV 1, IDC, 63, IHD, 16, VHD, 3) were enrolled. They were randomly assigned to metoprolol group (n538) and carvedilol group (n544), and received b-blocker therapy for 16 weeks. Sera were collected and presence or absence of the antibody was determined using ELISA. Results: Autoantibody was found to be positive in 15(18%, P). Etiologies of CHF and agents they received were also similar between P and N. Change in LVEDD from baseline value tended to be larger in P than N(-0.560.5 cm vs-0.260.4 cm, p50.09). Change in LVESD was significantly larger in P than N(-0.960.8 cm vs. -0.460.6 cm, p50.02). Change in LVEF measured by radionuclide ventriculography was greater in P than N(þ16612% vs. þ969%, p50.02). Change in plasma BNP level was also larger in P than N(-64.76126.5 pg/ml vs. -19.66218.9 pg/ml, p50.02). Conclusions: Our data suggest that b-blocker therapy is more effective in alleviating cardiac dysfunction and reversing remodeling in patients with autoantibody against b1-adrenergic receptors.
1055 Adrenoceptor a1B and Norepinephrine Transporter Polymorphisms are Associated with the Response to b-blockers in Patients with Dilated Cardiomyopathy HIROSHI OKAMOTO1, SHINPEI NONEN2, YASUSHI FUJIO2, YASUHIKO TAKEMOTO3, MINORU YOSHIYAMA3, TOMOYUKI HAMAGUCHI4, YUTAKA MATSUI1, JUNICHI YOSHIKAWA3, AKIRA KITABATAKE1, JUNICHI AZUMA2 1 Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan, 2Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 3Department of Internal Medicine and Cardiology, Osaka City University School of Medicine, 4 Osaka Prefectural Medical Center for Respiratory and Allergic Diseases Background: Recent clinical trials have demonstrated that b-blockers decrease the mortality in patients with heart failure (CHF). Approximately 60-70% of CHF patients exhibit the improvement of left ventricular function in response to b-blockers. Aim: To address this inter-individual variability of the response to b-blockers, we investigated the associations between the response and genetic polymorphisms in 16 genes related to adrenergic system. Methods: Patients with dilated cardiomyopathy (n580) were genotyping by PCR. Good responders were defined as the improvement of left ventricular fractional shortening (LVFS) by 5%, examined by echocardiography. Multivariate logistic regression analysis with adjustment for age, sex, LVFS and NYHA class at pre-administration was performed to evaluate associations between the response to b-blockers and each polymorphisms. Results: Baseline LVFS and NYHA class were different between responders and non-responders. Adrenoceptor a1B G549A (non-responders; GG 53.3%, GA 37.8%, AA 15.4%, p50.005) and norepinephrine transporter (NET) T182C (nonresponders; 25.9%, TC 39.0%, CC 75.0%, p50.007) were associated with response to b-blockers. The risk for non-responders was scored according to the formula for prediction of response. Eighty-one pTT ercents of patients with more than 0.5 were found to be non-responders, while 78% of the remainders were responders. Conclusion: a1B (G549A) and NET (T182C) polymorphisms are independent predictors of the response to b-blockers. These pharmacogenomic findings may be helpful in individualized medicine of b-blockers in CHF.
1056 Usefulness of Bisoprolol for Chronic Heart Failure: A Comparative Study with Carvedilol KENJI MIYAGISHIMA, SHINYA HIRAMITSU, KAZUMASA MORI, HISASHI KIMURA, SHIGERU KATO, YASUCHIKA KATO, MASATSUGU OHTSUKI, MASATSUGU IWASE, SHIN-ICHIRO MORIMOTO, HITOSHI HISHIDA Division of Cardiology, Department of Internal Medicine, Fyjita Health University Purpose: Three types of beta-blocker have been confirmed to be useful for chronic heart failure, carvedilol, bisoprolol, and metoprolol. But we can use only carvedilol in Japan. Here, we compared the usefulness of bisoprolol, which has beta 1 selectivity, with that of carvedilol. Subjects and Method: 738 cases who were admitted to our hospital because of worsening chronic heart failure during the 5-year period from January, 2000 to December, 2004 were focused on. They were divided into a group receiving bisoprolol (108 cases: male567, mean age 67.5612.1 years, mean LVEF536.5613.2%) and a control group receiving carvedilol (274 cases: male5183, mean age 66.1615.0 years, mean LVEF535.5613.9%), and their clinical findings and outcome were investigated. Results: No significant differences were noted on admission between the two groups in clinical findings such as NYHA class, Killip classification, LVEF, BNP, renal function, or serum Hemoglobin. Moreover, in a study using Kaplan-Meier curves no significant difference was found between the groups in the convalescent phase outcome (P50.614). Conclusion: The outcome of the bisoprolol group was equivalent to that of the carvedilol group, confirming the usefulness of this agent for chronic heart failure in Japanes.
1057 Effect of Combination Therapy of Oral Beta-blocker and Pimobendan in Patients with Congestive Heart Failure YUYA AOYAMA, HIDEYUKI HARA, MICHIRO KIRYU, DAISUKE SATO, HIROSHI ITO Department of Internal Medicine/Cardiology, Numazu City Hospital, Numazu, Japan Background: It is known that pimobendan acutely reduces cardiac overload in patients with congestive heart failure (CHF), and induces beneficial systemic hemodynamic effect. However, there are some patients who suffered recurrent CHF in spite