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A Critical Role of Salusin-beta in Myocardial Ischemia
S172 Journal of Cardiac Failure Vol. 15 No. 7S September 2009 092 Carvedilol Improves Clinical Outcomes in Heart Failure With Preserved Ejection Fraction (HFpEF) as Well as Reduced Ejection Fraction (HFrEF) NAOKO KATO1, KOICHIRO KINUGAWA2, KEIKO KAZUMA1, ATSUSHI YAO2, MASARU HATANO2, TARO SHIGA2, YASUNOBU HIRATA2, RYOZO NAGAI2 1 Department of Adult Nursing, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, 2Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan It has not yet been established how to improve the prognosis of HFpEF, i.e. heart failure with preserved ejection fraction (EF). Purpose: To clarify the differential effects of carvedilol on clinical outcomes and left ventricular EF in HFpEF and heart failure with reduced EF (HFrEF). Methods and Results: A two-year prospective cohort study was conducted on 113 patients with heart failure (74.3% males; mean age 64.4 years) in cardiovascular outpatient clinic of university hospital. HFpEF (EFO 5 50%) and HFrEF (EF ! 50%) were present in 65 (57.5%) and 48 (42.5%) patients. Carvedilol was prescribed 33.9% in HFpEF and 68.8% in HFrEF. Average of daily dose at baseline and the end of follow-up were higher in HFrEF than in HFpEF (7.2 vs. 3.8 mg, P ! 0.01; 10.3 vs. 4.7 mg, P ! 0.01). Two-year cardiac death and/or heart failure hospitalization in HFpEF were relatively lower than those in HFrEF (12.3 vs. 22.9%, P 5 0.15). Carvedilol significantly reduced the cardiac events in HFpEF (P 5 0.03) as well as in HFrEF (P ! 0.01 for linear dose-response). In addition, carvedilol improved left ventricular EF only in HFrEF in a clear dose-dependent manner (P ! 0.01). Conclusions: Our results strongly confirm that the higher dose of carvedilol makes the prognosis better with the higher EF in HFrEF. Besides, our data suggest that carvedilol should also be indicated in HFpEF.
093 Dantrolene Improves Cardiac Contractile Function by Inhibiting SR Ca2D Leak in Failing Hearts HITOSHI UCHINOUMI, MASAFUMI YANO, TAKESHI SUETOMI, XIAOJUAN XU, MAKOTO ONO, HIROKI TATEISHI, SHIGEKI KOBAYASHI, TAKESHI YAMAMOTO, YASUHIRO IKEDA, MASUNORI MATSUZAKI Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine The N-terminal and Central domains of the ryanodine receptor (RyR), harbor many mutations associated with Malignant Hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy type 2. Here, we investigated the effect of dantrolene, a drug generally used to treat MH, on the Ca2þ release and cardiomyocyte function in failing hearts. Sarcoplasmic reticulum (SR) vesicles and cardiomyocytes were isolated from dog LV muscles (normal or rapid ventricular pacing for 4 weeks), for Ca2þ leak, transient, and spark assays. To assess the zipped or unzipped state of the interacting domains, the RyR2 was fluorescently labeled with methylcoumarin acetamido(MCA) in a site-directed manner. The magnitude of domain unzipping (the state of defective inter-domain interaction) of the regulatory domains was determined from the accessibility of the RyR2-bound MCA fluorescence to a large-size fluorescence quencher. In the SR isolated from pacing-induced dog failing hearts, the domain unzipping has already occurred, causing spontaneous Ca2þ leak. Dantrolene suppressed both domain unzipping and the Ca2þ leak. In failing cardiomyocytes, both diastolic Ca2þ sparks and delayed afterdepolarization were frequently observed, but 1 mmol/L dantrolene prevented both events. Dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca2þ leak, in turn improves cardiomyocyte function in failing hearts. Thus, dantrolene may have a potential to treat heart failure, specifically targeting the RyR2.
094 Blood Pressure Decline has no Effect for Survival and Cardiac Protection After Myocardial Infarction in the Condition of Renal Failure MASAHITO OGAWA1,2, JUN-ICHI SUZUKI1,2, TAKAAKI HAGA1, KIYOSHI TAKAYAMA3, MITSUAKI ISOBE1 1 Departments of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 2Departments of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3NB Health Laboratory, Saitama, Japan Background: Although the activity of renin angitensin system (RAS) is a key factor in the pathophysiology of heart failure and renal disease, the activity has not yet been elucidated in the condition of renal failure. Thus, the purpose of this study was to clarify the role of RAS using cardio-renal syndrome model. Methods: For weeks after subtotal nephrectomy, myocardial ischemia was induced by a coronary artery ligation. The mice were assigned randomly into treatment groups, administrated by orally injection of hydralazine hydrochloride (30 mg/kg). Results: Blood pressure
decline was observed in the group of hydralazine compared to the vehicle treatment. Many mice were dead during this observation period in vehicle treatment group, also hydralazine treatment mice showed comparable survival rate to vehicle treated mice. Echocardiogram demonstrated that hydralazine treatment did not improve left ventricular ejection fraction. Increase of renin activity observed nephrectomyzed mice compared to the normal mice in plasma. Conclusion: Although blood pressure well known that contribute development of heart failure and renal failure, hydlarazine did not significantly improve survival rate and cardiac remodeling after myocardial infarction. These results suggested that renin angiotensin system has the role of modulator heart failure without increase of blood pressure after myocardial infarction in condition of renal failure.
095 Clinical Significance of Systemic Vascular Resistance in Acute Decompensated Heart Failure TOMOHIRO MIZUTANI, TAKAYUKI INOMATA, TOMOYOSHI YANAGISAWA, EMI MAEKAWA, TAKASHI NARUKE, ICHIROU TAKEUCHI, TORU IZUMI Department of Cardio-angiology, Kitasato University, School of Medicine Background: Although structural and functional changes in peripheral vasculature are involved in the progression of heart failure (HF), there have been few reports investigating systemic vascular resistance in relation to the prognosis of acute decompensated HF. Methods & Results: Forty-nine Consecutive patients (71.6 years of age, 34 males) admitted to our intensive care unit due to HF exacerbation in 200608 with pulmonary catheter monitoring were investigated. The patients were divided into 2 groups according to the systemic vascular resistance index (SVRI) at hospitalization by the median value of 1929 dynes sec/cm5/m2.Although the clinical profile at admission including left ventricular ejection fraction, plasma BNP, cardiac index and pulmonary artery wedge pressure did not differ between the groups, a previous history of HF hospitalization was less in the high SVRI group (H) compared with the low (L) (0.1 6 0.5 vs. 0.6 6 0.7 times, p 5 0.039). During the initial 24-hour follow-up, SVRI was somewhat increased in L, but not in H (delta SVRI: þ577 vs. -48 dynes sec/cm5/m2, p 5 0.001) regardless of the administration of vasodilators. Conclusion: An initially low but then later increased SVRI level during management of acute decompensated HF using vasodilators may be a helpful indicator for predicting a poor prognosis.
096 A Critical Role of Salusin-beta in Myocardial Ischemia AYAKO NAGASHIMA1, TAKUYA NAKAJIMA1, MASAHITO OGAWA2, JUNICHI SUZUKI2, MASAYOSHI SHICHIRI3, MITSUAKI ISOBE1 1 Department of Cardiovascular Medicine, Tokyo Medial and Dental University, Tokyo, Japan, 2Department of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3Department of Endocrinology, Tokyo Medical and Dental University, Tokyo, Japan Backgrounds: A bioactive peptide Salusin-beta is known to have hemodynamic and mitogenic activities. It also stimulates proliferation of vascular smooth muscle cells and fibroblasts and regulates myocardial growth and hypertrophy, and macrophage foam cell formation. However, little is known about the effect of salusins in myocardial remodeling after myocardial infarction (MI). Methods and Results: MI models of rats were created by LAD ligation for 4 weeks. Immunohistochemical staining showed the enhanced expression of salusin-beta in the macrophages around myocardial ischemic area. Administration of anti-salusin-beta antibody (10 micro L/day, i.p.) to MI model animals significantly improved left ventricular ejection fraction on day 7 and day 28, respectively, compared to the control animals. Anti-salusin-beta therapy prevented mean blood pressure decline on day 7 and day 14. Conclusion: These results demonstrate the critical role of salusin-beta in the development of MI. The inhibition of endogenous salusin-beta may be useful to suppress ventricular remodeling after myocardial ischemia.
097 A Pivotal Role of Plasminogen Activator Inhibitor-1 in Myocardial Ischemia TAKUYA NAKAJIMA1, AYAKO NAGASHIMA1, MASAHITO OGAWA2, JUNICHI SUZUKI2, SUSUMU MUTO3, YOICHI YAMAGUCHI3, AKIKO ITAI3, MITSUAKI ISOBE1 1 Department of Cardiovascular Medicine, Tokyo Medial and Dental University, Tokyo, Japan, 2Department of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3Institute of Medicinal Molecular Design Background: Plasminogen activator inhibitor-1 (PAI-1) is known to affect cardiac ventricular remodeling because migration of inflammatory cells and attenuation of
093 Dantrolene Improves Cardiac Contractile Function by Inhibiting SR Ca2D Leak in Failing Hearts HITOSHI UCHINOUMI, MASAFUMI YANO, TAKESHI SUETOMI, XIAOJUAN XU, MAKOTO ONO, HIROKI TATEISHI, SHIGEKI KOBAYASHI, TAKESHI YAMAMOTO, YASUHIRO IKEDA, MASUNORI MATSUZAKI Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine The N-terminal and Central domains of the ryanodine receptor (RyR), harbor many mutations associated with Malignant Hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy type 2. Here, we investigated the effect of dantrolene, a drug generally used to treat MH, on the Ca2þ release and cardiomyocyte function in failing hearts. Sarcoplasmic reticulum (SR) vesicles and cardiomyocytes were isolated from dog LV muscles (normal or rapid ventricular pacing for 4 weeks), for Ca2þ leak, transient, and spark assays. To assess the zipped or unzipped state of the interacting domains, the RyR2 was fluorescently labeled with methylcoumarin acetamido(MCA) in a site-directed manner. The magnitude of domain unzipping (the state of defective inter-domain interaction) of the regulatory domains was determined from the accessibility of the RyR2-bound MCA fluorescence to a large-size fluorescence quencher. In the SR isolated from pacing-induced dog failing hearts, the domain unzipping has already occurred, causing spontaneous Ca2þ leak. Dantrolene suppressed both domain unzipping and the Ca2þ leak. In failing cardiomyocytes, both diastolic Ca2þ sparks and delayed afterdepolarization were frequently observed, but 1 mmol/L dantrolene prevented both events. Dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca2þ leak, in turn improves cardiomyocyte function in failing hearts. Thus, dantrolene may have a potential to treat heart failure, specifically targeting the RyR2.
094 Blood Pressure Decline has no Effect for Survival and Cardiac Protection After Myocardial Infarction in the Condition of Renal Failure MASAHITO OGAWA1,2, JUN-ICHI SUZUKI1,2, TAKAAKI HAGA1, KIYOSHI TAKAYAMA3, MITSUAKI ISOBE1 1 Departments of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 2Departments of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3NB Health Laboratory, Saitama, Japan Background: Although the activity of renin angitensin system (RAS) is a key factor in the pathophysiology of heart failure and renal disease, the activity has not yet been elucidated in the condition of renal failure. Thus, the purpose of this study was to clarify the role of RAS using cardio-renal syndrome model. Methods: For weeks after subtotal nephrectomy, myocardial ischemia was induced by a coronary artery ligation. The mice were assigned randomly into treatment groups, administrated by orally injection of hydralazine hydrochloride (30 mg/kg). Results: Blood pressure
decline was observed in the group of hydralazine compared to the vehicle treatment. Many mice were dead during this observation period in vehicle treatment group, also hydralazine treatment mice showed comparable survival rate to vehicle treated mice. Echocardiogram demonstrated that hydralazine treatment did not improve left ventricular ejection fraction. Increase of renin activity observed nephrectomyzed mice compared to the normal mice in plasma. Conclusion: Although blood pressure well known that contribute development of heart failure and renal failure, hydlarazine did not significantly improve survival rate and cardiac remodeling after myocardial infarction. These results suggested that renin angiotensin system has the role of modulator heart failure without increase of blood pressure after myocardial infarction in condition of renal failure.
095 Clinical Significance of Systemic Vascular Resistance in Acute Decompensated Heart Failure TOMOHIRO MIZUTANI, TAKAYUKI INOMATA, TOMOYOSHI YANAGISAWA, EMI MAEKAWA, TAKASHI NARUKE, ICHIROU TAKEUCHI, TORU IZUMI Department of Cardio-angiology, Kitasato University, School of Medicine Background: Although structural and functional changes in peripheral vasculature are involved in the progression of heart failure (HF), there have been few reports investigating systemic vascular resistance in relation to the prognosis of acute decompensated HF. Methods & Results: Forty-nine Consecutive patients (71.6 years of age, 34 males) admitted to our intensive care unit due to HF exacerbation in 200608 with pulmonary catheter monitoring were investigated. The patients were divided into 2 groups according to the systemic vascular resistance index (SVRI) at hospitalization by the median value of 1929 dynes sec/cm5/m2.Although the clinical profile at admission including left ventricular ejection fraction, plasma BNP, cardiac index and pulmonary artery wedge pressure did not differ between the groups, a previous history of HF hospitalization was less in the high SVRI group (H) compared with the low (L) (0.1 6 0.5 vs. 0.6 6 0.7 times, p 5 0.039). During the initial 24-hour follow-up, SVRI was somewhat increased in L, but not in H (delta SVRI: þ577 vs. -48 dynes sec/cm5/m2, p 5 0.001) regardless of the administration of vasodilators. Conclusion: An initially low but then later increased SVRI level during management of acute decompensated HF using vasodilators may be a helpful indicator for predicting a poor prognosis.
096 A Critical Role of Salusin-beta in Myocardial Ischemia AYAKO NAGASHIMA1, TAKUYA NAKAJIMA1, MASAHITO OGAWA2, JUNICHI SUZUKI2, MASAYOSHI SHICHIRI3, MITSUAKI ISOBE1 1 Department of Cardiovascular Medicine, Tokyo Medial and Dental University, Tokyo, Japan, 2Department of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3Department of Endocrinology, Tokyo Medical and Dental University, Tokyo, Japan Backgrounds: A bioactive peptide Salusin-beta is known to have hemodynamic and mitogenic activities. It also stimulates proliferation of vascular smooth muscle cells and fibroblasts and regulates myocardial growth and hypertrophy, and macrophage foam cell formation. However, little is known about the effect of salusins in myocardial remodeling after myocardial infarction (MI). Methods and Results: MI models of rats were created by LAD ligation for 4 weeks. Immunohistochemical staining showed the enhanced expression of salusin-beta in the macrophages around myocardial ischemic area. Administration of anti-salusin-beta antibody (10 micro L/day, i.p.) to MI model animals significantly improved left ventricular ejection fraction on day 7 and day 28, respectively, compared to the control animals. Anti-salusin-beta therapy prevented mean blood pressure decline on day 7 and day 14. Conclusion: These results demonstrate the critical role of salusin-beta in the development of MI. The inhibition of endogenous salusin-beta may be useful to suppress ventricular remodeling after myocardial ischemia.
097 A Pivotal Role of Plasminogen Activator Inhibitor-1 in Myocardial Ischemia TAKUYA NAKAJIMA1, AYAKO NAGASHIMA1, MASAHITO OGAWA2, JUNICHI SUZUKI2, SUSUMU MUTO3, YOICHI YAMAGUCHI3, AKIKO ITAI3, MITSUAKI ISOBE1 1 Department of Cardiovascular Medicine, Tokyo Medial and Dental University, Tokyo, Japan, 2Department of Advanced Clinical Science and Therapeutics, University of Tokyo, Tokyo, Japan, 3Institute of Medicinal Molecular Design Background: Plasminogen activator inhibitor-1 (PAI-1) is known to affect cardiac ventricular remodeling because migration of inflammatory cells and attenuation of