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A Protective Role of Brain-derived Neurotrophic Factor in Cardiac Remodeling After Myocardial Infarction
S62 Journal of Cardiac Failure Vol. 13 No. 6 Suppl. 2007 did not attenuate EAM. The COX-2 inhibitor altered Th1/Th2 cytokine balance and inhibited cell proliferation in vitro. Conclusion: The COX-2 inhibitor suppresses the development of EAM. COX-2 regulation is promising for treating acute myocarditis.
176 MRI Findings in Non-ischemic Heart Failure NAOKI TOKITA1, TAKAYUKI INOMATA2, TOHRU IZUMI2 1 Department of Radiology, Kitasato University School of Medicine, Sagamihara, Japan, 2Department of Cardiology, Kitasato University School of Medicine, Sagamihara, Japan Purpose: Some of causes of non-ischemic heart failure are myocarditis or cardiac sarcoidosis characterized with microscopical cell infiltrating into the myocardium. Cardiac MRI is non-invasive method, and it can offer to make a diagnosis of infiltrative foci in organs. The purpose of this study is to compare MRI with and the pathological findings of the sample of myocardium. Method: Serial thirty-two patients (male, 22; female, 10) were examined MRI in T2 weighed (T2WI), and gadolinium delayed enhanced (DE) images. A positive finding of T2WI was defined as high intensity with more than 5 mm depth from epicardium. 67 Ga-citrate scintigraphy and myocardial biopsy in posterior wall were also done as a marker of infiltration. Result: Eight in 32 had positive infiltration foci in myocardium. Four in the 8 patients with infiltration foci had positive finding inT2WI at posterior wall. We found out 2 patients with positive uptake of 67Ga and typical high intensity in T2WI. Moreover, the high intensity decreased in according with the improvement of heart failure, but DE in the two were remained even one month after the first investigation of MRI. Conclusion: Cardiac MRI is a useful noninvasive method as a marker of infiltration in non-ischemic heart failure.
177 A Protective Role of Brain-derived Neurotrophic Factor in Cardiac Remodeling After Myocardial Infarction SHO OKADA, TOHRU MINAMINO, HARUHIRO TOKO, YOSUKE KAYAMA, ISSEI KOMURO Department of Cardiology, Chiba University Graduate School of Medicine, Chiba, Japan Brain-derived neurotrophic factor (BDNF) was originally found to have neurotrophic functions during embryonic development. Prior studies showed that BDNF and its receptor TrkB were expressed in the heart, and that BDNF induced neovascularization in response to hypoxic stimuli. This suggests the association of BDNF with cardiovascular physiology. Here we show a cardioprotective function of BDNF after ischemic injury. Endothelial cells and cardiomyocytes expressed BDNF in the heart, and the expression was markedly decreased after myocardial infarction (MI). To examine the effect of BDNF on the MI heart, we treated the MI mice with BDNF and analyzed cardiac function 2 weeks later. Echocardiography revealed better contractility and smaller ventricular size in the BDNF-treated group compared with the control. BDNF treatment inhibited death of cardiomyocytes but it did not promote neovascularization in the MI heart. We also found that BDNF treatment increased survival signals in cultured cardiomyocytes. Conversely, conditional deletion of BDNF led to impaired systolic function and promoted cardiac remodeling after MI. These results disclose a protective role of BDNF in cardiac remodeling after MI and suggest that BDNF may exert its beneficial effect by a direct action on cardiomyocytes.
178 Rare Gene Mutations are a Common Cause of Pediatric Cardiac Hypertrophy HIROYUKI MORITA1, JON G. SEIDMAN2, CHRISTINE E. SEIDMAN2, JEFFREY A. TOWBIN3, RYOZO NAGAI1 1 Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan, 2 Department of Genetics, Harvard Medical School, Boston, USA, 3Department of Medicine, Baylor College of Medicine, Houston, USA In childhood, ‘‘unexplained’’ cardiac hypertrophy without family history presents frequently and has a poor prognosis. In contrast to the familial HCM, which is clearly established as a genetic disorder, this ‘‘unexplained’’ pediatric cardiac hypertrophy
without family history has been recognized as even a non-genetic disorder and its cause remains to be solved. We hypothesized that the mutations in sarcomere protein genes or PRKAG2 might be responsible for the idiopathic cardiac hypertrophy in the childhood. In 55 pediatric patients with idiopathic cardiac hypertrophy from NHLBI pediatric cohort study, DNA sequences of 8 sarcomere protein genes (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, MYL2, MYL3, ACTC) and PRKAG2 were determined. We identified 26 disease-causing mutations in 55 individuals (26/55 5 47.2%; 95%CI 33.7-61.2%). The further genetic analysis of family members demonstrated sporadic hypertrophy is not necessarily caused by de novo mutations. The idiopathic cardiac hypertrophy observed in childhood is no longer ‘‘idiopathic’’. Single gene defects (sarcomere protein gene or PRKAG2) were shown to account for approximately half of the cases. Additional investigation will clarify the etiology and underlying mechanism, thereby providing an opportunity to improve the therapeutic strategy.
179 Utility of 64-Slice Computed Tomography Compared with Invasive Left Ventriculogram for Quantitative 4-Dimensional Volumetric Analysis of Left Ventricle KOKI NAKAMURA1, NOBUSADA FUNABASHI1, MASAE UEHARA1, KAZUSHI SUZUKI2, MAKOTO TERAO2, KENJI OKUBO1, YUZURU MITA2, FUMIAKI MAEDA2, ISSEI KOMURO1 1 Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan, 2Awa Medical Association Hospital, Tateyama, Japan Purpose: To elucidate the usefulness of CT in evaluating left ventricular (LV) volumes and ejection fraction (EF), we compared 64-slice CT with conventional left ventriculography (CLVG). Method: 71 subjects underwent ECG-gated enhanced CT. End-diastolic volume (EDV) and end-systolic volume (ESV) of LV were selected in 20 phases of R-R interval of ECG; in CLVG these parameters were calculated from the right anterior oblique 30-degree projection. Result: Correlation coefficients between CT and CLVG for EDV, ESV, SV, and EF were 0.76, 0.90, 0.55, and 0.84, respectively. In 35 subjects without apical asynergy of LV wall motion, correlation coefficients were 0.77, 0.91, 0.63, and 0.87 respectively; in 36 subjects, with apical asynergy, those were 0.75, 0.88, 0.50, and 0.74, respectively. The limits of agreement of all parameters were wider in subjects with apical asynergy than without. Conclusion: There was good correlation for all parameters estimated by CT and those by CLVG, but CT tended to overestimate ESV and underestimate EF. In subjects with apical asynergy, estimates of EF were less correlated and the limits of agreement of all parameters were wider than in those without. These discrepancies may come from the capability of CT to estimate LV wall asynergy 3-dimensionally and more accurately.
180 CCN1 Protects Cardiac Myocytes from Oxidative Stress Via b1 Integrin-Akt Pathway YOSHINORI YOSHIDA1, MAKOTO TANAKA2, TORU KITA1 1 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 2Department of Social Service, Kyoto University Hospital, Kyoto, Japan CCN1/Cyr61 is a secreted matricellular protein, mediating angiogenesis and cell survival. Although CCN1 expression is induced in cardiac myocytes under ischemia, its function in the heart is totally unknown. In this study, we investigated effect of CCN1 on survival of cardiac myocytes under oxidative stress and examined a signal transduction pathway downstream of CCN1. CCN1 bound to cardiac myocytes in a dosedependent, saturable manner. Inactivation of b1 integrin inhibited binding with CCN1, indicating that CCN1 bound to cardiac myocytes via b1 integrin. Knockdown of endogenous CCN1 decreased the number of surviving cells under oxidative stress, while pretreatment with recombinant CCN1 significantly increased the number of surviving cells. Furthermore, treatment of cardiac myocytes with CCN1 induced phosphorylation of Akt and ERK. Inactivation of b1 integrin inhibited CCN1-induced phosphorylation of these kinases and abolished the protective effect of CCN1. Moreover, pretreatment of cells with wortmannin completely blocked the effect of CCN1, indicating that the protective effect of CCN1 was mainly mediated by activation of Akt. The anti-apoptotic effect of CCN1 on cardiac myocytes together with its proangiogenic property could be beneficial in the treatment of ischemic heart disease.
176 MRI Findings in Non-ischemic Heart Failure NAOKI TOKITA1, TAKAYUKI INOMATA2, TOHRU IZUMI2 1 Department of Radiology, Kitasato University School of Medicine, Sagamihara, Japan, 2Department of Cardiology, Kitasato University School of Medicine, Sagamihara, Japan Purpose: Some of causes of non-ischemic heart failure are myocarditis or cardiac sarcoidosis characterized with microscopical cell infiltrating into the myocardium. Cardiac MRI is non-invasive method, and it can offer to make a diagnosis of infiltrative foci in organs. The purpose of this study is to compare MRI with and the pathological findings of the sample of myocardium. Method: Serial thirty-two patients (male, 22; female, 10) were examined MRI in T2 weighed (T2WI), and gadolinium delayed enhanced (DE) images. A positive finding of T2WI was defined as high intensity with more than 5 mm depth from epicardium. 67 Ga-citrate scintigraphy and myocardial biopsy in posterior wall were also done as a marker of infiltration. Result: Eight in 32 had positive infiltration foci in myocardium. Four in the 8 patients with infiltration foci had positive finding inT2WI at posterior wall. We found out 2 patients with positive uptake of 67Ga and typical high intensity in T2WI. Moreover, the high intensity decreased in according with the improvement of heart failure, but DE in the two were remained even one month after the first investigation of MRI. Conclusion: Cardiac MRI is a useful noninvasive method as a marker of infiltration in non-ischemic heart failure.
177 A Protective Role of Brain-derived Neurotrophic Factor in Cardiac Remodeling After Myocardial Infarction SHO OKADA, TOHRU MINAMINO, HARUHIRO TOKO, YOSUKE KAYAMA, ISSEI KOMURO Department of Cardiology, Chiba University Graduate School of Medicine, Chiba, Japan Brain-derived neurotrophic factor (BDNF) was originally found to have neurotrophic functions during embryonic development. Prior studies showed that BDNF and its receptor TrkB were expressed in the heart, and that BDNF induced neovascularization in response to hypoxic stimuli. This suggests the association of BDNF with cardiovascular physiology. Here we show a cardioprotective function of BDNF after ischemic injury. Endothelial cells and cardiomyocytes expressed BDNF in the heart, and the expression was markedly decreased after myocardial infarction (MI). To examine the effect of BDNF on the MI heart, we treated the MI mice with BDNF and analyzed cardiac function 2 weeks later. Echocardiography revealed better contractility and smaller ventricular size in the BDNF-treated group compared with the control. BDNF treatment inhibited death of cardiomyocytes but it did not promote neovascularization in the MI heart. We also found that BDNF treatment increased survival signals in cultured cardiomyocytes. Conversely, conditional deletion of BDNF led to impaired systolic function and promoted cardiac remodeling after MI. These results disclose a protective role of BDNF in cardiac remodeling after MI and suggest that BDNF may exert its beneficial effect by a direct action on cardiomyocytes.
178 Rare Gene Mutations are a Common Cause of Pediatric Cardiac Hypertrophy HIROYUKI MORITA1, JON G. SEIDMAN2, CHRISTINE E. SEIDMAN2, JEFFREY A. TOWBIN3, RYOZO NAGAI1 1 Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan, 2 Department of Genetics, Harvard Medical School, Boston, USA, 3Department of Medicine, Baylor College of Medicine, Houston, USA In childhood, ‘‘unexplained’’ cardiac hypertrophy without family history presents frequently and has a poor prognosis. In contrast to the familial HCM, which is clearly established as a genetic disorder, this ‘‘unexplained’’ pediatric cardiac hypertrophy
without family history has been recognized as even a non-genetic disorder and its cause remains to be solved. We hypothesized that the mutations in sarcomere protein genes or PRKAG2 might be responsible for the idiopathic cardiac hypertrophy in the childhood. In 55 pediatric patients with idiopathic cardiac hypertrophy from NHLBI pediatric cohort study, DNA sequences of 8 sarcomere protein genes (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, MYL2, MYL3, ACTC) and PRKAG2 were determined. We identified 26 disease-causing mutations in 55 individuals (26/55 5 47.2%; 95%CI 33.7-61.2%). The further genetic analysis of family members demonstrated sporadic hypertrophy is not necessarily caused by de novo mutations. The idiopathic cardiac hypertrophy observed in childhood is no longer ‘‘idiopathic’’. Single gene defects (sarcomere protein gene or PRKAG2) were shown to account for approximately half of the cases. Additional investigation will clarify the etiology and underlying mechanism, thereby providing an opportunity to improve the therapeutic strategy.
179 Utility of 64-Slice Computed Tomography Compared with Invasive Left Ventriculogram for Quantitative 4-Dimensional Volumetric Analysis of Left Ventricle KOKI NAKAMURA1, NOBUSADA FUNABASHI1, MASAE UEHARA1, KAZUSHI SUZUKI2, MAKOTO TERAO2, KENJI OKUBO1, YUZURU MITA2, FUMIAKI MAEDA2, ISSEI KOMURO1 1 Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan, 2Awa Medical Association Hospital, Tateyama, Japan Purpose: To elucidate the usefulness of CT in evaluating left ventricular (LV) volumes and ejection fraction (EF), we compared 64-slice CT with conventional left ventriculography (CLVG). Method: 71 subjects underwent ECG-gated enhanced CT. End-diastolic volume (EDV) and end-systolic volume (ESV) of LV were selected in 20 phases of R-R interval of ECG; in CLVG these parameters were calculated from the right anterior oblique 30-degree projection. Result: Correlation coefficients between CT and CLVG for EDV, ESV, SV, and EF were 0.76, 0.90, 0.55, and 0.84, respectively. In 35 subjects without apical asynergy of LV wall motion, correlation coefficients were 0.77, 0.91, 0.63, and 0.87 respectively; in 36 subjects, with apical asynergy, those were 0.75, 0.88, 0.50, and 0.74, respectively. The limits of agreement of all parameters were wider in subjects with apical asynergy than without. Conclusion: There was good correlation for all parameters estimated by CT and those by CLVG, but CT tended to overestimate ESV and underestimate EF. In subjects with apical asynergy, estimates of EF were less correlated and the limits of agreement of all parameters were wider than in those without. These discrepancies may come from the capability of CT to estimate LV wall asynergy 3-dimensionally and more accurately.
180 CCN1 Protects Cardiac Myocytes from Oxidative Stress Via b1 Integrin-Akt Pathway YOSHINORI YOSHIDA1, MAKOTO TANAKA2, TORU KITA1 1 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 2Department of Social Service, Kyoto University Hospital, Kyoto, Japan CCN1/Cyr61 is a secreted matricellular protein, mediating angiogenesis and cell survival. Although CCN1 expression is induced in cardiac myocytes under ischemia, its function in the heart is totally unknown. In this study, we investigated effect of CCN1 on survival of cardiac myocytes under oxidative stress and examined a signal transduction pathway downstream of CCN1. CCN1 bound to cardiac myocytes in a dosedependent, saturable manner. Inactivation of b1 integrin inhibited binding with CCN1, indicating that CCN1 bound to cardiac myocytes via b1 integrin. Knockdown of endogenous CCN1 decreased the number of surviving cells under oxidative stress, while pretreatment with recombinant CCN1 significantly increased the number of surviving cells. Furthermore, treatment of cardiac myocytes with CCN1 induced phosphorylation of Akt and ERK. Inactivation of b1 integrin inhibited CCN1-induced phosphorylation of these kinases and abolished the protective effect of CCN1. Moreover, pretreatment of cells with wortmannin completely blocked the effect of CCN1, indicating that the protective effect of CCN1 was mainly mediated by activation of Akt. The anti-apoptotic effect of CCN1 on cardiac myocytes together with its proangiogenic property could be beneficial in the treatment of ischemic heart disease.