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Paracrine Mechanism
The 10th Annual Scientific Meeting Methods: This study group comprised 9 consecutive patients with AMI underwent successful coronary reperfusion therapy. HMW complex of adiponectin level and high sensitive c-reactive protein(HsCRP) were measured at 1 month after onset by using enzyme-linked immunosorbent assay, and compared with the change of LV volume determined by left ventriculography. Results: HMW complex of adiponectin levels did not correlate with the HsCRP. HMW complexes of adiponectin levels was significantly associated with Delta EDVI(12 months-1 month)(r5-81, p!0.01). There was no relationship between HsCRP and Delta EDVI(12 months-1 months). Conclusions: HMW complexes of adiponectin levels at 1 month after onset was related to increase in LV volume after AMI. These finding suggested that HMW complex of adiponectin at 1 month might be useful predictor of LV remodeling at the chronic phase after MI.
1048 Association of Hyperadiponectinemia with Severity of Ventricular Dysfunction in Congestive Heart Failure TOMOHIRO NAKAMURA1, HIROSHI FUNAYAMA1, NORIFUMI KUBO1, TAKANORI YASU1, SAN-E ISHIKAWA2, SHIN-ICHI MOMOMURA1 1 Cardiovascular Division, Jichi Medical University Omiya Medical Center, Saitama, Japan, 2Department of Integrated Medicine 1, Jichi Medical University Omiya Medical Center, Saitama, Japan Background: Adiponectin, which is a collagen-like plasma protein produced by adipose tissue, has anti-atherogenic and anti-inflammatory effects. We determined plasma adiponectin levels in patients with congestive heart failure (CHF). Methods and Results: Ninety patients with congestive heart failure and twenty control subjects were enrolled. Plasma adiponectin, tumor necrosis factor (TNF)-a, brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adiponectin levels were significantly increased according to the severity of NYHA classes in the patients with CHF; control: 6.261.0; NYHA I: 8.561.9, NYHA II: 12.062.2, NYHA III: 13.062.7, NYHA IV: 14.962.7 ug/ml (p50.0008). Plasma adiponectin levels correlated positively with BNP (r50.40, p50.0002) and TNFa (r50.49, p50.0001), and correlated negatively with cardiac index (r5-0.27, p50.05). In 24 of 46 patients of NYHA III and IV groups, according to the prompt improvement in cardiac function, both levels of plasma adiponectin and BNP were significantly reduced (p!0.0001). Conclusions: The present study shows that plasma adiponectin levels are increased according to the severity of CHF. These results may indicate that augmented release of adiponectin is involved in the pathogenesis of CHF. Further study will be necessary to elucidate the exact role of adiponectin in CHF.
1049 Increased Stearoyl-CoA Desaturase-1 Expression in Obese Rat Heart Contributes to Myocardial Lipid Accumulation and Metabolic Abnormalities HIROKI MATSUI1, TOMOYUKI YOKOYAMA2, DAISUKE IIJIMA2, KENICHI SEKIGUCHI1, MIKI YAMAZAKI1, TATSUYA ISO1, MASASHI ARAI1, MASAHIKO KURABAYASHI1 1 Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan, 2Department of Laboratory Sciences, Gunma University School of Health Sciences, Maebashi, Japan Purpose: Human obesity is associated with abnormal accumulation of neutral lipid within metabolic organs and eventually leads to impaired function. Recent studies suggest that lipogenic gene, stearoyl-CoA deaturase-1 (SCD1), is up-regulated in skeletal muscle from obese humans. Although SCD1 is expressed in the heart, SCD1 involvement in cardiovascular disease is poorly understood. We therefore examined the expression of SCD1 in obese rat heart. Method and Result: Obesity rat model was induced by a sucrose-rich diet (50%) for 1 to 6 months. Control was fed a standard diet. Compared with control, sucrose-rich diet rats showed significant accumulation of visceral fat, and hyperinsulinemia, increased plasma free fatty acid, and hypertriglycemia. SCD1 mRNA and protein expression was significantly increased in rat heart after sucrose-rich diet. Other lipid biosynthesis genes were similar between two groups. Next, we confirmed that SCD1 mRNA expression was induced in neonatal rat cardiac myocytes by the exposure of high concentration of glucose, insulin or palmitic acid. Furthermore, SCD1 overexpression significantly increased accumulation of triglyceride in myocytes and decreased fatty acid oxidation. Conclusion: Our results demonstrated for the first time that SCD1 expression was up-regulated in obese rat heart and SCD1-overexpression led to excessive lipid accumulation and deterioration of fatty acid oxidation. Thus, these studies can clarify to the novel mechanism for the progression of heart failure in obese patients.
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1050 Adipocyte-derived Serotonin Regulates Adipocyte Differentiation Via an Autocrine/Paracrine Mechanism KOH ONO1, TAKAHIRO HORIE1, YUKIKO ABE2, TERUHISA KAWAMURA2, AKIRA SHIMATSU2, KOJI HASEGAWA2, TORU KITA1 1 Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan, 2Division of Translational Research, Kyoto Medical Center, Kyoto, Japan Differentiation of preadipocytes into mature adipocyte is closely associated with the expression of adipocyte-specific genes that are deeply involved in metabolic syndrome. Therefore, it is critical to elucidate precise molecular mechanisms that mediate adipocyte differentiation. To identify genes required for differentiation of 3T3-L1 preadipocytes into mature adipocytes, we introduced a poly A trap retroviral vector we have constructed into 3T3-L1 cells. Using this approach, we discovered that tryptophan hydroxylase 1 (TPH1), a rate-limiting enzyme for the production of serotonin, was required for adipocyte differentiation. In a TPH1-disrupted clone of 3T3-L1 preadipocytes, differentiation rate into mature adipocyte was clearly reduced compared with wild-type clones. Endogenous TPH1 gene expression and serotonin concentration increased after induction of differentiation in wild-type 3T3-L1 cells. Depletion of 5-hydroxy-triptophan by administrating a TPH inhibitor, p-chlorophenylalanine, dose dependently inhibited the differentiation. Treatment of wild-type 3T3-L1 cells with serotoin activated Akt and ERK, peaked at 5 minutes after the treatment, and induced their differentiation. Serotonin also enhanced glucose uptake. We also analyzed the effect of TPH1 on adipocyte differentiation using TPH-/- mice. As expected, differentiation was significantly impaired in preadipocytes prepared from TPH-/- mice compared to those from wild-type mice. These results provide a novel evidence for serotonin as an autocrine/paracrine factor involved in the regulation of adipocyte differentiation.
1051 Effects of Long-term, Very-low-dose Pimobendan for Patients with Diastolic Heart Failure HAMAOKA MAMORU, TATSUYA SASAKI Division of Cardiology, Osaka Koseinenkin Hospital Purpose: To investigate the effects of long-term, very-low-dose pimobendan on patients with diastolic heart failure. Methods: Twenty-four patients with diastolic heart failure (NYHA II, LVEFO50%) with ACEI and/or ARB were randomly divided into 2 groups: Group P (n513) who were additionally given 1.25 mg/day of pimobendan and Group N (n511) who were not given pimobendan. The end-points were cardiac death or heart failure hospitalization. Other medications were reduced or increased if necessary. Results: The mean LVEF was 61.5%, the mean LVDd was 45.3 mm and the mean BNP was 283.8 pg/mL before the study. Patients’ characteristics and the parameters did not differ in both groups. The mean follow-up period was 41.5 month (6-60 months). Cardiac death was 1 case in earth groups, and heart failure hospitalization was 1 case (8%) in Group P and 4 cases (36%) in Group N. The addition of diuretics for volume control was 3 case (23%) in Group P and 8 cases (72%) in Group N (p!0.05). Kaplan-Meier analysis showed that Group P had significantly fewer cardiac events (the end-points or addition of diuretics) compared with Group N (p!0.05). Conclusions: Long-term, very-low-dose pimobendan for patients with diastolic heart failure was suggested to be useful.
1052 Losartan Improved Insulin Resistance in Patients with Congestive Heart Failure KAZUHIDE OGINO1, MASAHIKO KATO1, YOSHIYUKI FURUSE1, KATSUNORI ISHIDA1, KIYOTAKA YANAGIHARA1, OSAMU IGAWA1, ICHIRO HISATOME2, CHIAKI SHIGEMASA1 1 Department of Cardiovascular Medicine, Tottori University Hospital, Yonago, Japan, 2Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medicine, Yonago, Japan Background: Angiotensin II receptor blockers have beneficial effects on glucose metabolism and renal function. On the other hand, insulin resistance and renal dysfunction are often observed in patients with congestive heart failure (CHF). Thus, we evaluated the effects of losartan on glucose metabolism and renal function in CHF patients. Methods: In a randomized crossover double-blind design, the effects of losartan (16 weeks) on glucose profiles and renal function as well as on cardiac performance and lipid profiles were evaluated in 10 CHF patients. Results: Left ventricular ejection fraction by echocardiography was increased with losartan (placebo: 36.862.7 %, losartan: 41.663.2 %) and plasma BNP level was decreased with losartan (placebo: 123.7627.4 pg/ml, losartan: 87.4623.0 pg/ml),
1048 Association of Hyperadiponectinemia with Severity of Ventricular Dysfunction in Congestive Heart Failure TOMOHIRO NAKAMURA1, HIROSHI FUNAYAMA1, NORIFUMI KUBO1, TAKANORI YASU1, SAN-E ISHIKAWA2, SHIN-ICHI MOMOMURA1 1 Cardiovascular Division, Jichi Medical University Omiya Medical Center, Saitama, Japan, 2Department of Integrated Medicine 1, Jichi Medical University Omiya Medical Center, Saitama, Japan Background: Adiponectin, which is a collagen-like plasma protein produced by adipose tissue, has anti-atherogenic and anti-inflammatory effects. We determined plasma adiponectin levels in patients with congestive heart failure (CHF). Methods and Results: Ninety patients with congestive heart failure and twenty control subjects were enrolled. Plasma adiponectin, tumor necrosis factor (TNF)-a, brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adiponectin levels were significantly increased according to the severity of NYHA classes in the patients with CHF; control: 6.261.0; NYHA I: 8.561.9, NYHA II: 12.062.2, NYHA III: 13.062.7, NYHA IV: 14.962.7 ug/ml (p50.0008). Plasma adiponectin levels correlated positively with BNP (r50.40, p50.0002) and TNFa (r50.49, p50.0001), and correlated negatively with cardiac index (r5-0.27, p50.05). In 24 of 46 patients of NYHA III and IV groups, according to the prompt improvement in cardiac function, both levels of plasma adiponectin and BNP were significantly reduced (p!0.0001). Conclusions: The present study shows that plasma adiponectin levels are increased according to the severity of CHF. These results may indicate that augmented release of adiponectin is involved in the pathogenesis of CHF. Further study will be necessary to elucidate the exact role of adiponectin in CHF.
1049 Increased Stearoyl-CoA Desaturase-1 Expression in Obese Rat Heart Contributes to Myocardial Lipid Accumulation and Metabolic Abnormalities HIROKI MATSUI1, TOMOYUKI YOKOYAMA2, DAISUKE IIJIMA2, KENICHI SEKIGUCHI1, MIKI YAMAZAKI1, TATSUYA ISO1, MASASHI ARAI1, MASAHIKO KURABAYASHI1 1 Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan, 2Department of Laboratory Sciences, Gunma University School of Health Sciences, Maebashi, Japan Purpose: Human obesity is associated with abnormal accumulation of neutral lipid within metabolic organs and eventually leads to impaired function. Recent studies suggest that lipogenic gene, stearoyl-CoA deaturase-1 (SCD1), is up-regulated in skeletal muscle from obese humans. Although SCD1 is expressed in the heart, SCD1 involvement in cardiovascular disease is poorly understood. We therefore examined the expression of SCD1 in obese rat heart. Method and Result: Obesity rat model was induced by a sucrose-rich diet (50%) for 1 to 6 months. Control was fed a standard diet. Compared with control, sucrose-rich diet rats showed significant accumulation of visceral fat, and hyperinsulinemia, increased plasma free fatty acid, and hypertriglycemia. SCD1 mRNA and protein expression was significantly increased in rat heart after sucrose-rich diet. Other lipid biosynthesis genes were similar between two groups. Next, we confirmed that SCD1 mRNA expression was induced in neonatal rat cardiac myocytes by the exposure of high concentration of glucose, insulin or palmitic acid. Furthermore, SCD1 overexpression significantly increased accumulation of triglyceride in myocytes and decreased fatty acid oxidation. Conclusion: Our results demonstrated for the first time that SCD1 expression was up-regulated in obese rat heart and SCD1-overexpression led to excessive lipid accumulation and deterioration of fatty acid oxidation. Thus, these studies can clarify to the novel mechanism for the progression of heart failure in obese patients.
JHFS
S171
1050 Adipocyte-derived Serotonin Regulates Adipocyte Differentiation Via an Autocrine/Paracrine Mechanism KOH ONO1, TAKAHIRO HORIE1, YUKIKO ABE2, TERUHISA KAWAMURA2, AKIRA SHIMATSU2, KOJI HASEGAWA2, TORU KITA1 1 Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan, 2Division of Translational Research, Kyoto Medical Center, Kyoto, Japan Differentiation of preadipocytes into mature adipocyte is closely associated with the expression of adipocyte-specific genes that are deeply involved in metabolic syndrome. Therefore, it is critical to elucidate precise molecular mechanisms that mediate adipocyte differentiation. To identify genes required for differentiation of 3T3-L1 preadipocytes into mature adipocytes, we introduced a poly A trap retroviral vector we have constructed into 3T3-L1 cells. Using this approach, we discovered that tryptophan hydroxylase 1 (TPH1), a rate-limiting enzyme for the production of serotonin, was required for adipocyte differentiation. In a TPH1-disrupted clone of 3T3-L1 preadipocytes, differentiation rate into mature adipocyte was clearly reduced compared with wild-type clones. Endogenous TPH1 gene expression and serotonin concentration increased after induction of differentiation in wild-type 3T3-L1 cells. Depletion of 5-hydroxy-triptophan by administrating a TPH inhibitor, p-chlorophenylalanine, dose dependently inhibited the differentiation. Treatment of wild-type 3T3-L1 cells with serotoin activated Akt and ERK, peaked at 5 minutes after the treatment, and induced their differentiation. Serotonin also enhanced glucose uptake. We also analyzed the effect of TPH1 on adipocyte differentiation using TPH-/- mice. As expected, differentiation was significantly impaired in preadipocytes prepared from TPH-/- mice compared to those from wild-type mice. These results provide a novel evidence for serotonin as an autocrine/paracrine factor involved in the regulation of adipocyte differentiation.
1051 Effects of Long-term, Very-low-dose Pimobendan for Patients with Diastolic Heart Failure HAMAOKA MAMORU, TATSUYA SASAKI Division of Cardiology, Osaka Koseinenkin Hospital Purpose: To investigate the effects of long-term, very-low-dose pimobendan on patients with diastolic heart failure. Methods: Twenty-four patients with diastolic heart failure (NYHA II, LVEFO50%) with ACEI and/or ARB were randomly divided into 2 groups: Group P (n513) who were additionally given 1.25 mg/day of pimobendan and Group N (n511) who were not given pimobendan. The end-points were cardiac death or heart failure hospitalization. Other medications were reduced or increased if necessary. Results: The mean LVEF was 61.5%, the mean LVDd was 45.3 mm and the mean BNP was 283.8 pg/mL before the study. Patients’ characteristics and the parameters did not differ in both groups. The mean follow-up period was 41.5 month (6-60 months). Cardiac death was 1 case in earth groups, and heart failure hospitalization was 1 case (8%) in Group P and 4 cases (36%) in Group N. The addition of diuretics for volume control was 3 case (23%) in Group P and 8 cases (72%) in Group N (p!0.05). Kaplan-Meier analysis showed that Group P had significantly fewer cardiac events (the end-points or addition of diuretics) compared with Group N (p!0.05). Conclusions: Long-term, very-low-dose pimobendan for patients with diastolic heart failure was suggested to be useful.
1052 Losartan Improved Insulin Resistance in Patients with Congestive Heart Failure KAZUHIDE OGINO1, MASAHIKO KATO1, YOSHIYUKI FURUSE1, KATSUNORI ISHIDA1, KIYOTAKA YANAGIHARA1, OSAMU IGAWA1, ICHIRO HISATOME2, CHIAKI SHIGEMASA1 1 Department of Cardiovascular Medicine, Tottori University Hospital, Yonago, Japan, 2Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medicine, Yonago, Japan Background: Angiotensin II receptor blockers have beneficial effects on glucose metabolism and renal function. On the other hand, insulin resistance and renal dysfunction are often observed in patients with congestive heart failure (CHF). Thus, we evaluated the effects of losartan on glucose metabolism and renal function in CHF patients. Methods: In a randomized crossover double-blind design, the effects of losartan (16 weeks) on glucose profiles and renal function as well as on cardiac performance and lipid profiles were evaluated in 10 CHF patients. Results: Left ventricular ejection fraction by echocardiography was increased with losartan (placebo: 36.862.7 %, losartan: 41.663.2 %) and plasma BNP level was decreased with losartan (placebo: 123.7627.4 pg/ml, losartan: 87.4623.0 pg/ml),