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Lysosomal destruction of cardiomyocytes in patients with dilated cardiomyopathy
62
Journal of Cardiac Failure Vol. 5 No. 3 Suppl. 2 1999
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P-38
THE CHANGE OF VASCULAR EXTRACELLULAR SUPEROXIDE DISMUTASE IN THE ACUTE AND RECOVERY PHASES OF CONGESTIVE HEART FAILURE
THE PLASMA LEVEL OF DEHYDROEPIANDROSTERONE SULFATE IS DECREASED IN PATIENTS WITH CHRONIC HEART FAILURE: RELATION TO SEVERITY OF HEART FAILURE
Masahatu Miyamoto, Hiromi Tasaki, Yoshitaka Nagai, Shinobu Ued& Masato Tsutsui, Masshiro Okazaki, Yasuhide Nakashim& Tetsuo Adachi 1. the 2nd Int. Med. Univ. Occup. Environ. Health, Kltakyushu 8078555,1Lab.Clin. Pharmaceutics, GifuPharma. Univ.Gifu,Japan
Yasushi Moriyama, Yuji Mizuno, Hiroaki Kawano, Michihiro Yoshimura, Hirofumi Yasue Department of Cardiovascular Medicine, Kumamoto University, Kumamoto 860-8556, Japan
Aim: Oxygen stress is suggested to participate as an aggravating factor in congestive heart failure (CHF). Superoxide is especially focused on the point of inactivation of nifric oxide. This study was undertaken to elucidate whether vascular extracellular superoxide dismutase (EC-SOD), the defending enzyme against superoxide, might change in acute phase a~d recovery phase of CHF. Patlentl and Method=: Twenty patients (male 9, 67.7 48.6y.o.) at acute phase of CHF were enrolled to this study. They were evaluated subjective state (NYHA class), hemodynarnic parameters and blood sampling (EC-SOD, ANP, NOx) at acute phase and at recovery phase. The basal plasma level and heparinreleasable (endothetium-bound) EC-SOD was determined by ELBA (anti-human EC-SOD ab.). Re=ult=: 1) Basal or heparinreleasable EC-SOD were significantly elevated at acute stage (114.34-54.7 or 301.44-142.7 ng/ml) compared to that at recovered stage (92.94-44.7 or 211.94-44.7ng/ml, p=0.028 or p=0.010, respectively). 2) The change of basaJ EC.-SOD in recovery phase was significantly correlated with the decrease of ANP(r=-0.732, p=0.005). 3) No significant change was found in J plasma NOx level between both phase. Conclu=lon:The ' significant change of EC-SOD was recognized in CHF state. Our results suggests that CHF state influences the level of EC-SOD, which might play adefending role in severe CHF state.
P-39
Dehydroepiandorosteron sulfate (DHEAS) decreases with aging. The incidence of heart failure also rises in the elderly population. However, relation between plasma level of DHEAS and heart failure has not been examined. We compared plasma levels of DHEAS between patients with heart failure and age-matched control subjects and assessed its relation to hemodynamic markers, plasma levels of A-type and B-type natriuretic peptide (ANP and BNP). We studied 46 patients (mean + SE age; 61.1+ 1.6 years) with left ventricular dysfunction due to 32 old myocardial infarction and 14 dilated cardiomyopathy, and 37 age-matched control subjects (mean 4. SE age; 59.7+ 1.8 years). Plasma levels of DHEAS, ANP and BNP were measured when diagnostic cardiac catheterization was performed. Plasma levels of DHEAS were significantly lower in patients with heart failure (NYHA I-IV), particularly in patients with NYHA Ill-IV (n=12) than in control subjects (134.14.16.2 pg/dl in control vs. 95.7+7.9 pg/dl in NYHA I-IV; p<0.03 and 68.4 4.11.2 pg/dl in NYHA Ill-IV; p<0.01). Plasma level of DHEAS was significantly correlated with In BNP (r=-0.38, p<0.01), InANP (r=-0.34, p<0.01), left ventricular end diastolic pressure (r=-0.28, p<0.01), left ventricular ejection fraction (r=0.28, p<0.05) and cardiac index (r=0.24, p<0.05) independently of age in all 83 subjects in multivariate regression analysis. In stepwise regression analysis with clinical and hemodynamic data, the plasma level of DHEAS was significantly correlated with age (r=-0.49), In BNP (r=-0.32) and BMI (r=-0.24). These results indicate that plasma level of DHEAS is decreased in }atients with heart failure in proportion to its severity.
P-40
CLINICAL IMPLICATIONSOF SERUMLEVELSOF SOLUBLEFAS (SFAS) AND SOLUBLEFAS LIGAND(SFASL)MOLECULESINACUTEMYOCARDITIS
LYSOSOMAL DESTRUCTION OF CARDIOMYOCYTES IN PATIENTS WITH DILATED CARDIOMYOPATHY
Koichi Fuse, MakotoKodama,Yuji Okura, MasahiroIto,Satoru Hirono, Kiminori Kato,YoshifusaAizawa, The FirstDepartmentof Internal Medicine,NiigataUniversitySchoolof Medicine, Niigata951-8510, Japan
Hiroaki Shimomura, Fumio Terasaki, Tetsuya Hayashi, Makota Okabe, Haruhiro Toko, Yuzo Hirota, Yasushi Kitaura, Keishiro Kawamura Third Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
We focused on roles ofsFas and sFasL moleculesas a serological markerto )redict prognosisof patientswith acutemyocarditis.In this report,we measured serum levels of the two moleculesin patientswith myocarditis,and compared serum levels of the molecules with the clinical manifestations. Sere were correctedfrom 18 patientswith myocarditis(GroupA), 37 with non-myocarditis Group B) and eight normal volunteers (Group C). The sFas and sFasL concentrationswere measured by the ELISA technique. TNF- a levels were also measured. The mean serum sFas and sFasL level in Group A was significantly higher than those of Group B or those of Group C (Table). The serum levels of sFas and sFasL in patients with fulrninant myocarditis who required mechanicalcirculatorysupport systemduring the acute phase were significantly higher than those from patients with non-fulminant myocardifis. Among the patients with fulminant myocarditis, the fatal cases exhibited significantlyhigher levels of sFas moleculesthan the survivors. In fatal cases, serum sFas levels Increased progressivelyor maintained at high level until death. In contrast,the levels were gradually decreasedlinking to the clinical improvementin some patientswith non-fatal myocarditis.Although serum sFas levelstended to be reducedby steroidpulse therapy,its effectwas transientand the levelswere re-increasedin the patientswith severemyocarditis.SerumTNFa levelsshowed no significantcorrelation with the severityand prognosisof the disease.Thus,increasesof serum sFasand sFasLlevelswere observed in 3afientswith myocarditis. The sFas and sFasL levels appear to be a good serological markerto predictseverityand prognosisof myocarditis. Table GroupA Group B Group C sFas (ng/ml) 7.9±2.4 *t 2.9-+0.2 1.9_+0.1 sFasL(pg/ml) 444_+81.1 1 4 5 - + 1 5 150_+43 StatisticallysignificantdifferencebetweenGroupA and B*, between GroupA and C 1.
In failing hearts cardiomyocytes are degenerated and decrease in number. But the precise mechanism causing cardiomyocyte degeneration is unclear. We presume that lysosomal destruction after autophagy is an important mechanism for cardiomyocyte degeneration in failing hearts, because it has been reported that lysosomal activity increased under stress such as ischemia. Left ventricular myocardium resected from the patients with dilated cardiomyopathy (DCM) by partial left ventriculectomy were examined with immunohistochemistry for ubiquitin and lysosomal enzyme (cathepsin D), since intracellular organelles are lysosomally degraded via autophagocytosis after ubiquitination. Under light microscopic observation cardiomyocytes showed marked scarcity and prominent vacuolation in cardiomyocytes, where many granular structures were scattered. Atrophic cardiomyocytes were observed adjacent to marked interstitial fibrosis. Immunohistochemically, cathepsin D and ubiquitin were positive in granular structures among scarcity and vacuolation in cardiomyocytes and in atrophic cardiomyocytes. It might be possible that increased lysosomal function relate to degeneration of damaged organelles in failing hearts. Additionally, our data indicated that autophagocytosis and lysosomal function possibly have impact on progressive destruction of degenerated cardiomyocytes. It is concluded that the lysosomal destruction via ubiquitination and autophagocytosis is presumably suicidal mechanism of cardiomyocytes, which play an important role in DCM hearts.
Journal of Cardiac Failure Vol. 5 No. 3 Suppl. 2 1999
P-37
P-38
THE CHANGE OF VASCULAR EXTRACELLULAR SUPEROXIDE DISMUTASE IN THE ACUTE AND RECOVERY PHASES OF CONGESTIVE HEART FAILURE
THE PLASMA LEVEL OF DEHYDROEPIANDROSTERONE SULFATE IS DECREASED IN PATIENTS WITH CHRONIC HEART FAILURE: RELATION TO SEVERITY OF HEART FAILURE
Masahatu Miyamoto, Hiromi Tasaki, Yoshitaka Nagai, Shinobu Ued& Masato Tsutsui, Masshiro Okazaki, Yasuhide Nakashim& Tetsuo Adachi 1. the 2nd Int. Med. Univ. Occup. Environ. Health, Kltakyushu 8078555,1Lab.Clin. Pharmaceutics, GifuPharma. Univ.Gifu,Japan
Yasushi Moriyama, Yuji Mizuno, Hiroaki Kawano, Michihiro Yoshimura, Hirofumi Yasue Department of Cardiovascular Medicine, Kumamoto University, Kumamoto 860-8556, Japan
Aim: Oxygen stress is suggested to participate as an aggravating factor in congestive heart failure (CHF). Superoxide is especially focused on the point of inactivation of nifric oxide. This study was undertaken to elucidate whether vascular extracellular superoxide dismutase (EC-SOD), the defending enzyme against superoxide, might change in acute phase a~d recovery phase of CHF. Patlentl and Method=: Twenty patients (male 9, 67.7 48.6y.o.) at acute phase of CHF were enrolled to this study. They were evaluated subjective state (NYHA class), hemodynarnic parameters and blood sampling (EC-SOD, ANP, NOx) at acute phase and at recovery phase. The basal plasma level and heparinreleasable (endothetium-bound) EC-SOD was determined by ELBA (anti-human EC-SOD ab.). Re=ult=: 1) Basal or heparinreleasable EC-SOD were significantly elevated at acute stage (114.34-54.7 or 301.44-142.7 ng/ml) compared to that at recovered stage (92.94-44.7 or 211.94-44.7ng/ml, p=0.028 or p=0.010, respectively). 2) The change of basaJ EC.-SOD in recovery phase was significantly correlated with the decrease of ANP(r=-0.732, p=0.005). 3) No significant change was found in J plasma NOx level between both phase. Conclu=lon:The ' significant change of EC-SOD was recognized in CHF state. Our results suggests that CHF state influences the level of EC-SOD, which might play adefending role in severe CHF state.
P-39
Dehydroepiandorosteron sulfate (DHEAS) decreases with aging. The incidence of heart failure also rises in the elderly population. However, relation between plasma level of DHEAS and heart failure has not been examined. We compared plasma levels of DHEAS between patients with heart failure and age-matched control subjects and assessed its relation to hemodynamic markers, plasma levels of A-type and B-type natriuretic peptide (ANP and BNP). We studied 46 patients (mean + SE age; 61.1+ 1.6 years) with left ventricular dysfunction due to 32 old myocardial infarction and 14 dilated cardiomyopathy, and 37 age-matched control subjects (mean 4. SE age; 59.7+ 1.8 years). Plasma levels of DHEAS, ANP and BNP were measured when diagnostic cardiac catheterization was performed. Plasma levels of DHEAS were significantly lower in patients with heart failure (NYHA I-IV), particularly in patients with NYHA Ill-IV (n=12) than in control subjects (134.14.16.2 pg/dl in control vs. 95.7+7.9 pg/dl in NYHA I-IV; p<0.03 and 68.4 4.11.2 pg/dl in NYHA Ill-IV; p<0.01). Plasma level of DHEAS was significantly correlated with In BNP (r=-0.38, p<0.01), InANP (r=-0.34, p<0.01), left ventricular end diastolic pressure (r=-0.28, p<0.01), left ventricular ejection fraction (r=0.28, p<0.05) and cardiac index (r=0.24, p<0.05) independently of age in all 83 subjects in multivariate regression analysis. In stepwise regression analysis with clinical and hemodynamic data, the plasma level of DHEAS was significantly correlated with age (r=-0.49), In BNP (r=-0.32) and BMI (r=-0.24). These results indicate that plasma level of DHEAS is decreased in }atients with heart failure in proportion to its severity.
P-40
CLINICAL IMPLICATIONSOF SERUMLEVELSOF SOLUBLEFAS (SFAS) AND SOLUBLEFAS LIGAND(SFASL)MOLECULESINACUTEMYOCARDITIS
LYSOSOMAL DESTRUCTION OF CARDIOMYOCYTES IN PATIENTS WITH DILATED CARDIOMYOPATHY
Koichi Fuse, MakotoKodama,Yuji Okura, MasahiroIto,Satoru Hirono, Kiminori Kato,YoshifusaAizawa, The FirstDepartmentof Internal Medicine,NiigataUniversitySchoolof Medicine, Niigata951-8510, Japan
Hiroaki Shimomura, Fumio Terasaki, Tetsuya Hayashi, Makota Okabe, Haruhiro Toko, Yuzo Hirota, Yasushi Kitaura, Keishiro Kawamura Third Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
We focused on roles ofsFas and sFasL moleculesas a serological markerto )redict prognosisof patientswith acutemyocarditis.In this report,we measured serum levels of the two moleculesin patientswith myocarditis,and compared serum levels of the molecules with the clinical manifestations. Sere were correctedfrom 18 patientswith myocarditis(GroupA), 37 with non-myocarditis Group B) and eight normal volunteers (Group C). The sFas and sFasL concentrationswere measured by the ELISA technique. TNF- a levels were also measured. The mean serum sFas and sFasL level in Group A was significantly higher than those of Group B or those of Group C (Table). The serum levels of sFas and sFasL in patients with fulrninant myocarditis who required mechanicalcirculatorysupport systemduring the acute phase were significantly higher than those from patients with non-fulminant myocardifis. Among the patients with fulminant myocarditis, the fatal cases exhibited significantlyhigher levels of sFas moleculesthan the survivors. In fatal cases, serum sFas levels Increased progressivelyor maintained at high level until death. In contrast,the levels were gradually decreasedlinking to the clinical improvementin some patientswith non-fatal myocarditis.Although serum sFas levelstended to be reducedby steroidpulse therapy,its effectwas transientand the levelswere re-increasedin the patientswith severemyocarditis.SerumTNFa levelsshowed no significantcorrelation with the severityand prognosisof the disease.Thus,increasesof serum sFasand sFasLlevelswere observed in 3afientswith myocarditis. The sFas and sFasL levels appear to be a good serological markerto predictseverityand prognosisof myocarditis. Table GroupA Group B Group C sFas (ng/ml) 7.9±2.4 *t 2.9-+0.2 1.9_+0.1 sFasL(pg/ml) 444_+81.1 1 4 5 - + 1 5 150_+43 StatisticallysignificantdifferencebetweenGroupA and B*, between GroupA and C 1.
In failing hearts cardiomyocytes are degenerated and decrease in number. But the precise mechanism causing cardiomyocyte degeneration is unclear. We presume that lysosomal destruction after autophagy is an important mechanism for cardiomyocyte degeneration in failing hearts, because it has been reported that lysosomal activity increased under stress such as ischemia. Left ventricular myocardium resected from the patients with dilated cardiomyopathy (DCM) by partial left ventriculectomy were examined with immunohistochemistry for ubiquitin and lysosomal enzyme (cathepsin D), since intracellular organelles are lysosomally degraded via autophagocytosis after ubiquitination. Under light microscopic observation cardiomyocytes showed marked scarcity and prominent vacuolation in cardiomyocytes, where many granular structures were scattered. Atrophic cardiomyocytes were observed adjacent to marked interstitial fibrosis. Immunohistochemically, cathepsin D and ubiquitin were positive in granular structures among scarcity and vacuolation in cardiomyocytes and in atrophic cardiomyocytes. It might be possible that increased lysosomal function relate to degeneration of damaged organelles in failing hearts. Additionally, our data indicated that autophagocytosis and lysosomal function possibly have impact on progressive destruction of degenerated cardiomyocytes. It is concluded that the lysosomal destruction via ubiquitination and autophagocytosis is presumably suicidal mechanism of cardiomyocytes, which play an important role in DCM hearts.