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Depression is an independent predictor of hospitalization in outpatients with heart failure
S148 Journal of Cardiac Failure Vol. 14 No. 7S September 2008
YIA Competitions (Clinical/Basic) YIA-C-1 High serum level of neopterin is a risk factor of patients with heart failure TOSHIKI SASAKI1, YASUCHIKA TAKEISHI2, TETSURO SHISHIDO1, SATOSHI SUZUKI1, TATSURO KITAHARA1, SHIGEHIKO KATOH1, MITSUNORI ISHINO1, YO KOYAMA3, TETSU WATANABE1, ISAO KUBOTA1 1 Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan, 2Fukushima Medical University, Fukushima, Japan, 3Ishinomaki red cross hospital, Ishinomaki, Japan Background: Neopterin is produced by activated monocytes/macrophages, and serum neopterin concentration reflects the level of oxidative stress. We investigated whether serum neopterin is a risk factor for heart failure. Methods and Results: Serum neopterin concentration was measured in 198 patients with heart failure and 62 control subjects. Patients were prospectively followed during a median follow-up period of 745 days with end points of cardiac death or rehospitalization due to progressive heart failure. Serum concentration of neopterin was significantly higher in New York Heart Association (NYHA) Class III/IV patients than in NYHA class I/II patients (P ! 0.001). In the multivariate Cox analysis, serum neopterin concentration was an independent risk factor for cardiac events (P ! 0.01). Conclusions: Serum neopterin concentration predicts adverse clinical outcomes in patients with heart failure.
YIA-C-3 Mechanisms of Reduction of Mitral Regurgitation by Cardiac Resynchronization Therapy: by Analysis of Left Ventricular Morphology KENSUKE MATSUMOTO, TEISHI KAJIYA, TAKATOSHI HAYASHI, YASUYO TANIGUCHI, SHINICHIROU YAMADA, KAZUO MIZUTANI, SACHIYO IWATA, AKIRA SHIMANE, KATSUNORI OKAJIMA, YASUE OKA Department of Cardiology, Himeji Cardiovascular Center, Himeji, Japan Purpose: It’s well known the mechanism of functional mitral regurgitation(MR) is geometric distortion of the mitral apparatus by left ventricular(LV) dilatation, which increases leaflet tethering and restricts closure. The purpose of this study is to assess the relationship between LV morphologic change and reduction of MR after cardiac resynchronization therapy(CRT). Methods: We studied 46 non-ischemic cardiomyopathy patients, and 29 normal controls. Echocardiography was used to assess the severity of MR, LV shape, mitral valve morphology, and displacement of papillary muscles(PM). Results: In patients, LV shape was more spherical (sphericity index: 1.55 6 0.25 vs. 1.93 6 0.25 p ! 0.001), anterior PM shifted posteriorly (PM angle; the angle between anterior PM and posterior interventricular groove: 151.6 6 19.4 vs. 176.7 6 15.1 p ! 0.001), and mitral leaflets were more tethered (tethering area: 1.66 6 0.56 vs. 0.43 6 0.06 cm2 p ! 0.001) than that of normal controls. However at 6 months after CRT, sphericity index (1.51 6 0.20 to 1.89 6 0.40 p ! 0.001) and PM angle (146.6 6 16.5 to 167.7 6 17.7 p ! 0.001) increased significantly. Moreover tethering area (1.63 6 0.72 to 1.03 6 0.77 cm2 p ! 0.001), and MR jet area (28.7 6 16.1 to 16.1 6 19.3% of LA area p ! 0.01) were reduced in responder. Indeed, tethering area correlated with sphericity index (r5-0.39 p ! 0.001), and PM angle (r5 0.29 p ! 0.01). Conclusions: CRT reduced the subvalvar traction by changing the shape of LV and restored displaced anterior PM toward original position. These morphological change contributes to the reduction of functional MR in patients treated with CRT.
YIA-C-4 Sympathetic Cardiorenal Interaction Becomes Exaggerated When Cardiac and Renal Functions are Both Deteriorated YOSHITAKA ODA1, SHUJI JOHO1, TADAKAZU HIRAI1, HIDETSUGU ASANOI2, HIROSHI INOUE1 1 The Second Department of Internal Medicine, University of Toyama, Toyama, Japan, 2Imizu City Hospital
YIA-C-2 Short-term experience of immunoadsorption therapy for refractory heart failure due to dilated cardiomyopathy YUJI NAGATOMO1, AKIYASU BABA2, YASUO KURITA3, IWAO TOSHIAKI MONKAWA5, TAKASHI MATSUBARA3, NAKAMURA4, YASUHISA WAKABAYASHI2, SATOSHI OGAWA1, MAKOTO AKAISHI2, TSUTOMU YOSHIKAWA1 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Kitasato Institute Hospital, 3Hiratsuka Municipal Hospital, 4Hino Municipal Hospital, 5Nephrology, Keio University School of Medicine Background: Dilated cardiomyopathy (DCM) is the predominant cause of end-stage heart failure (HF) in Japan. Autoimmune disorder is one of the features characterizing DCM. Some autoantibodies play a role in mediating myocardial damage. Immunoadsorption technique (IA) is the promising therapeutic measures to remove these autoantibodies. The goal of this study is to determine if the IA has beneficial effect on cardiac function in patients with severe HF. Methods and Results: IA was conducted in 17 patients with DCM (age 53 6 3, male 8, NYHA III/IV, EF 18 6 2%), who were refractory to conventional therapy. Study subjects had autoantibodies against either b1-adrenergic or M2-muscarinic receptors screened by ELISA. All cases completed IA without any complications. We confirmed autoantibody titers for b1-adrenergic and M2-muscarinic receptors decreased or became undetectable after IA. Plasma BNP levels were significantly decreased after IA (from 884 6 181 pg/ml to 520 6 128 pg/ml, p 5 0.002). Plasma inflammatory cytokines including interleukin-6 and TNF-a showed no change after each session of IA. Six minutes walk distance was increased (313 6 39 m to 360 6 29 m, p 5 0.01). LVEF measured by radionuclide ventriculography tended to increase 3e6 months after IA (from 18 6 2% to 21 6 2%, p 5 0.08). Conclusions: Our initial experience demonstrated safety and efficacy of IA for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.
Objective: The pathophysiology of the cardiorenal interaction remains poorly understood. We tested the hypothesis that renal insufficiency (RI) and cardiac dysfunction would contribute to the elevated sympathetic activity in patients with heart failure. Methods: In 79 patients with heart failure (ejection fraction (EF)!0.45), the resting muscle nerve sympathetic activity (MSNA), plasma norepinephrine (NE), brain natriuretic peptide (BNP) were determined. Estimated glomerular filtration rates (eGFR) less than 60 ml/min/1.73 m2 measured by simplified Modification of Diet in Renal Disease equation for Japanese was used to identify RI. Results: Although NE and BNP were comparable between RI group (n 5 30, eGFR 45 6 10) and no RI group (n 5 49, eGFR 76 6 10), MSNA was higher in RI group (burst rate, 54 6 14 versus 46 6 14 bursts/minute, p ! 0.05; burst incidence, 77 6 19 versus 68 6 18 bursts/ 100beats, p ! 0.05). For patients with preserved EF (O or 5 0.30), MSNA was similar between those with and without RI, while for patients with low EF (!0.30), MSNA was significantly higher in those with RI than in those without RI (burst rate, 62 6 10 versus 49 6 15 bursts/minute, p ! 0.01; burst incidence, 88 6 12 versus 68 6 18 bursts/100beats, p ! 0.01). The difference of MSNA between patients with low EF and with preserved EF was significantly greater in RI group than in no RI group (interaction, p ! 0.05). Conclusions: These findings suggest that sympathetic cardiorenal interaction might become exaggerated when cardiac and renal functions are both deteriorated.
YIA-C-5 Depression is an independent predictor of hospitalization in outpatients with heart failure NAOKO KATO1, KOICHIRO KINUGAWA2, NAOMI ITO3, ATSUSHI YAO2, MASARU HATANO2, KEIKO KAZUMA1 1 Department of Adult Nursing, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Cardiovascular Medicine, Graduate School
The 12th Annual Scientific Meeting of Medicine, The University of Tokyo, Tokyo, Japan, 3Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Purpose: We aimed to investigate the prevalence of depression and its contribution to hospitalization, independent of other clinical data, in outpatients with heart failure (HF). Methods: We conducted a one-year prospective survey of 109 outpatients diagnosed with HF. Depression symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). A CES-D score O 5 16 indicated the presence of depressive symptoms. Differences in hospitalization were evaluated with the logrank test, following which the Cox proportional hazard analysis was used to assess the association between depression and hospitalization. Results: At baseline, the mean age was 65.2 years (SD 615.3 years) and the median brain natriuretic peptide (BNP) level was 77.5 pg/mL. Of 109 patients, 30 had depressive symptoms (CES-D score O 5 16). Compared to patients with no depressive symptoms (CES-D score !16), depressed patients demonstrated higher one-year hospitalization rate (8.5% vs. 29.6%; P 5 0.006). In the Cox proportional hazard model for multivariate analysis, adjusted for age, BNP level, previous hospitalization for HF, and use of b-blockers, depressive symptoms remained significantly associated with increased rate of HF hospitalization (hazard ratio, 5.14; 95% confidence interval, 1.57e16.9; P 5 0.007) Conclusions: Depression is an independent predictor of hospitalization in outpatients with HF. Future studies are required to evaluate whether an intervention for depression can reduce hospitalization in these patients.
YIA-B-1 Cardiac 12-lipoxygenase is critically involved in heart failure YOSUKE KAYAMA1, TOHRU MINAMINO1, HARUHIRO TOKO1, MASAYA SAKAMOTO2, HIDEHISA TAKAHASHI1, ISSEI KOMURO1 1 Department of Cardiovascular Science and Medicine Chiba University Graduate School of Medicine, Chiba, Japan, 2Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of Dahl salt-sensitive rats using DNA chip technique. We found that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade which metabolizes eicosanoid. Until recently, 12-LOX is reported to play an important role in atherogenesis, diabetes and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice (Tg) that overexpress 12-LOX only in cardiomyocytes. Echocardiography showed that 12-LOX Tg developed systolic dysfunction from 16 weeks old. Histological analysis revealed that overexpression of 12-LOX induced cardiac fibrosis, which was associated with infiltration of macrophages. Furthermore, expression of MCP-1 was markedly upregulated in the heart of 12-LOX Tg, whereas inhibition of this upregulation by the MCP-1 inhibitor 7ND significantly attenuated infiltration of macrophages as well as improving systolic dysfunction of 12-LOX Tg. Likewise, disruption of 12-LOX significantly reduced infiltration of macrophages, thereby inhibiting cardiac remodeling after myocardial infarction. These results suggest that cardiac 12-LOX is critically involved in the generation of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of heart failure.
YIA-B-2 Activation of L-serine biosynthesis is indispensable for hormetic effects of aldehydes in the heart JIN ENDO1, MOTOAKI SANO2, TAKAHARU KATAYAMA1, TAKESHI ADACHI3, KENTARO HAYASHIDA1, SHINSUKE YUASA1, SHINJI MAKINO2, MAKOTO SUEMATSU3, KEIICHI FUKUDA2, SATOSHI OGAWAI1 1 Cardiology Division, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, 2Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo, Japan, 3 Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Tokyo, Japan Introduction: Increased levels of lipid peroxidation-derived aldehydes are present in the myocardium in patients with ischemic heart disease and heart failure. This study was designed to investigate the molecular mechanism and functional significance of stress-response to aldehydes in the heart. Methods and Results: We developed mouse model of aldehydes-accumulation at increasing rates by interfering aldehydes detoxification using transgenic over-expression of Aldh2*2. DNA microarray analysis revealed that genes that encode enzymes involved in biosynthesis of amino acids that provide precursors for glutathione, particularly 3-phosphoglycerate dehydrogenase (Phgdh), the first step-catalyzing enzymes in the three-step conversion of serine biosynthesis from glycolytic metabolites, were highly induced in Aldh2*2 transgenic hearts. In cultured cardiomyocytes, adenovirus-mediated over-expression of Aldh2*2
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up-regulated Phgdh expression and increased intracellular glutathione levels, thereby enhancing the tolerance to anoxia-reoxygenation injury. SiRNA-mediated knockdown of Phgdh reduced intracellular glutathione levels and canceled stress-resistant phenotype in the Aldh2*2-expressing cardiomyocytes. The expression of Phgdh was increased in the peri-infarcted area followed by ischemia-reperfusion injury concomitant with the increased levels of aldehydes. The heart from Aldh2*2 transgenic mice contained higher levels of glutathione and exhibited enhanced tolerance to ischemiareperfusion injury, while cardiac-specific knockout of Phgdh rendered the heart vulnerable to ischemia-reperfusion injury. Conclusion: Induction of Phgdh as a stress response to aldehydes confers upon hearts favorable tolerance to oxidative stress via maintenance of high levels of glutathione.
YIA-B-3 Development of E-NTPDase gene eluting stent that prevents subacute in-stent thrombosis without antiplatelet drugs YASUHIRO TAKEMOTO1, HIROYUKI KAWATA1, KEIICHI IMAGAWA1, TSUNENARI SOEDA1, SATOSHI SOMEKAWA1, SHIRO UEMURA1, MASANORI MATSUMOTO2, YOSHIHIRO FUJIMURA2, YASUHIKO TABATA3, YOSHIHIKO SAITO1 1 First Department of Internal Medicine, Nara Medical University, Nara, Japan, 2 Blood Transfusion Medicine, Nara Medical University, Nara, Japan, 3Department of Biomaterials, Field of Tissue Engineering, Kyoto University, Kyoto, Japan Backgrounds: Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP to AMP, thereby inhibiting platelet aggregation. We investigated whether human placental E-NTPDase (hE-NTPDase) gene transfer by the cationized gelatin-coated stent (GCS) into injured artery could prevent subacute stent thrombosis. Methods and Results: 52 rabbits underwent the repeated balloon injury of femoral artery (FA) at 4-week intervals. The rabbits were divided into four groups: bare metal stent (BMS) group, GCS group, Lac Z gene eluting stent group, and hENTPDase gene eluting stent (hE-NTPDase stent) group. Immediately after the second injury, the stents were implanted into injured FA. Continuous Doppler and angiogram on day 3 and 7 revealed that the patency rate of the stent implanted FA was significantly higher in hE-NTPDase stent group than in other 3 groups (100% vs 17 to 50% p ! 0.05). Although E-NTPDase mRNA expression was dramatically reduced in injured FA, the expression of E-NTPDase mRNA and protein were preserved only in hE-NTPDase stent group on day 3 and 7. Additionally, NTPDase activity in the stent implanted FA was significantly higher in hE-NTPDase stent group than in BMS group (p ! 0.05). Histological examination revealed the occlusion of the stent implanted FA with platelet-rich thrombus in BMS and GCS groups but not in hE-NTPDase stent group.Conclusion: E-NTPDase gene eluting stent can completely prevent subacute thrombosis in injured artery without antiplatelet drugs.
YIA-B-4 Functional Significance and Morphological Characterization of StarvationInduced Autophagy in the Adult Heart HIROMITSU KANAMORI1, GENZOU TAKEMURA2, RUMI MARUYAMA2, KAZUKO GOTO2, RYUKO RI2, MITSURU SEISHIMA1, SHINYA MINATOGUCHI2, HISAYOSHI FUJIWARA3 1 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 2The second Department of Internal Medicine, Gifu University School of Medicine, 3Hyogo Prefectual Amagasaki Hospital The functional significance and detailed morphological characteristics of starvationinduced autophagy in the adult heart remain largely unknown. We exposed mice to starvation up to 3 days to induce autophagy. Under electron microscopy, intracellular electron-dense and homogenous vacuoles appeared in cardiomyocytes as early as 12 hours after starvation. These vacuoles were found to be lysosomes by enzyme histocytochemistry. At the later starvation phase, typical autophagolysosomes that contain intracellular organelles (e.g., mitochondria) were frequently recognized easily. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased along with the starvation interval. Next, we inhibited the autophagy using bafilomycin A1 (BafA1; 0.3 mg/kg/day, i.p.). Treatment with BafA1 did not affect cardiac function in the normally fed mice. In the mice starved for 3 days, however, cardiac function was markedly depressed by the treatment with BafA1 and a significant left ventricular dilatation was seen. There was no TUNEL positive cardiomyocyte in both fed and starved mice. The cardiomyocytes were occupied with accumulated vacuoles and the myocardial ATP content was severely decreased in the mice; both might have contributed to cardiac dysfunction. BafA1 increased myocardial expression of cathepsin D and ubiquitin while decreased that of LC3-II in starved mice. In conclusion, our findings indicate autophagy play a critical role in maintenance of cardiac function in the adult heart during starvation.
YIA Competitions (Clinical/Basic) YIA-C-1 High serum level of neopterin is a risk factor of patients with heart failure TOSHIKI SASAKI1, YASUCHIKA TAKEISHI2, TETSURO SHISHIDO1, SATOSHI SUZUKI1, TATSURO KITAHARA1, SHIGEHIKO KATOH1, MITSUNORI ISHINO1, YO KOYAMA3, TETSU WATANABE1, ISAO KUBOTA1 1 Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan, 2Fukushima Medical University, Fukushima, Japan, 3Ishinomaki red cross hospital, Ishinomaki, Japan Background: Neopterin is produced by activated monocytes/macrophages, and serum neopterin concentration reflects the level of oxidative stress. We investigated whether serum neopterin is a risk factor for heart failure. Methods and Results: Serum neopterin concentration was measured in 198 patients with heart failure and 62 control subjects. Patients were prospectively followed during a median follow-up period of 745 days with end points of cardiac death or rehospitalization due to progressive heart failure. Serum concentration of neopterin was significantly higher in New York Heart Association (NYHA) Class III/IV patients than in NYHA class I/II patients (P ! 0.001). In the multivariate Cox analysis, serum neopterin concentration was an independent risk factor for cardiac events (P ! 0.01). Conclusions: Serum neopterin concentration predicts adverse clinical outcomes in patients with heart failure.
YIA-C-3 Mechanisms of Reduction of Mitral Regurgitation by Cardiac Resynchronization Therapy: by Analysis of Left Ventricular Morphology KENSUKE MATSUMOTO, TEISHI KAJIYA, TAKATOSHI HAYASHI, YASUYO TANIGUCHI, SHINICHIROU YAMADA, KAZUO MIZUTANI, SACHIYO IWATA, AKIRA SHIMANE, KATSUNORI OKAJIMA, YASUE OKA Department of Cardiology, Himeji Cardiovascular Center, Himeji, Japan Purpose: It’s well known the mechanism of functional mitral regurgitation(MR) is geometric distortion of the mitral apparatus by left ventricular(LV) dilatation, which increases leaflet tethering and restricts closure. The purpose of this study is to assess the relationship between LV morphologic change and reduction of MR after cardiac resynchronization therapy(CRT). Methods: We studied 46 non-ischemic cardiomyopathy patients, and 29 normal controls. Echocardiography was used to assess the severity of MR, LV shape, mitral valve morphology, and displacement of papillary muscles(PM). Results: In patients, LV shape was more spherical (sphericity index: 1.55 6 0.25 vs. 1.93 6 0.25 p ! 0.001), anterior PM shifted posteriorly (PM angle; the angle between anterior PM and posterior interventricular groove: 151.6 6 19.4 vs. 176.7 6 15.1 p ! 0.001), and mitral leaflets were more tethered (tethering area: 1.66 6 0.56 vs. 0.43 6 0.06 cm2 p ! 0.001) than that of normal controls. However at 6 months after CRT, sphericity index (1.51 6 0.20 to 1.89 6 0.40 p ! 0.001) and PM angle (146.6 6 16.5 to 167.7 6 17.7 p ! 0.001) increased significantly. Moreover tethering area (1.63 6 0.72 to 1.03 6 0.77 cm2 p ! 0.001), and MR jet area (28.7 6 16.1 to 16.1 6 19.3% of LA area p ! 0.01) were reduced in responder. Indeed, tethering area correlated with sphericity index (r5-0.39 p ! 0.001), and PM angle (r5 0.29 p ! 0.01). Conclusions: CRT reduced the subvalvar traction by changing the shape of LV and restored displaced anterior PM toward original position. These morphological change contributes to the reduction of functional MR in patients treated with CRT.
YIA-C-4 Sympathetic Cardiorenal Interaction Becomes Exaggerated When Cardiac and Renal Functions are Both Deteriorated YOSHITAKA ODA1, SHUJI JOHO1, TADAKAZU HIRAI1, HIDETSUGU ASANOI2, HIROSHI INOUE1 1 The Second Department of Internal Medicine, University of Toyama, Toyama, Japan, 2Imizu City Hospital
YIA-C-2 Short-term experience of immunoadsorption therapy for refractory heart failure due to dilated cardiomyopathy YUJI NAGATOMO1, AKIYASU BABA2, YASUO KURITA3, IWAO TOSHIAKI MONKAWA5, TAKASHI MATSUBARA3, NAKAMURA4, YASUHISA WAKABAYASHI2, SATOSHI OGAWA1, MAKOTO AKAISHI2, TSUTOMU YOSHIKAWA1 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Kitasato Institute Hospital, 3Hiratsuka Municipal Hospital, 4Hino Municipal Hospital, 5Nephrology, Keio University School of Medicine Background: Dilated cardiomyopathy (DCM) is the predominant cause of end-stage heart failure (HF) in Japan. Autoimmune disorder is one of the features characterizing DCM. Some autoantibodies play a role in mediating myocardial damage. Immunoadsorption technique (IA) is the promising therapeutic measures to remove these autoantibodies. The goal of this study is to determine if the IA has beneficial effect on cardiac function in patients with severe HF. Methods and Results: IA was conducted in 17 patients with DCM (age 53 6 3, male 8, NYHA III/IV, EF 18 6 2%), who were refractory to conventional therapy. Study subjects had autoantibodies against either b1-adrenergic or M2-muscarinic receptors screened by ELISA. All cases completed IA without any complications. We confirmed autoantibody titers for b1-adrenergic and M2-muscarinic receptors decreased or became undetectable after IA. Plasma BNP levels were significantly decreased after IA (from 884 6 181 pg/ml to 520 6 128 pg/ml, p 5 0.002). Plasma inflammatory cytokines including interleukin-6 and TNF-a showed no change after each session of IA. Six minutes walk distance was increased (313 6 39 m to 360 6 29 m, p 5 0.01). LVEF measured by radionuclide ventriculography tended to increase 3e6 months after IA (from 18 6 2% to 21 6 2%, p 5 0.08). Conclusions: Our initial experience demonstrated safety and efficacy of IA for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.
Objective: The pathophysiology of the cardiorenal interaction remains poorly understood. We tested the hypothesis that renal insufficiency (RI) and cardiac dysfunction would contribute to the elevated sympathetic activity in patients with heart failure. Methods: In 79 patients with heart failure (ejection fraction (EF)!0.45), the resting muscle nerve sympathetic activity (MSNA), plasma norepinephrine (NE), brain natriuretic peptide (BNP) were determined. Estimated glomerular filtration rates (eGFR) less than 60 ml/min/1.73 m2 measured by simplified Modification of Diet in Renal Disease equation for Japanese was used to identify RI. Results: Although NE and BNP were comparable between RI group (n 5 30, eGFR 45 6 10) and no RI group (n 5 49, eGFR 76 6 10), MSNA was higher in RI group (burst rate, 54 6 14 versus 46 6 14 bursts/minute, p ! 0.05; burst incidence, 77 6 19 versus 68 6 18 bursts/ 100beats, p ! 0.05). For patients with preserved EF (O or 5 0.30), MSNA was similar between those with and without RI, while for patients with low EF (!0.30), MSNA was significantly higher in those with RI than in those without RI (burst rate, 62 6 10 versus 49 6 15 bursts/minute, p ! 0.01; burst incidence, 88 6 12 versus 68 6 18 bursts/100beats, p ! 0.01). The difference of MSNA between patients with low EF and with preserved EF was significantly greater in RI group than in no RI group (interaction, p ! 0.05). Conclusions: These findings suggest that sympathetic cardiorenal interaction might become exaggerated when cardiac and renal functions are both deteriorated.
YIA-C-5 Depression is an independent predictor of hospitalization in outpatients with heart failure NAOKO KATO1, KOICHIRO KINUGAWA2, NAOMI ITO3, ATSUSHI YAO2, MASARU HATANO2, KEIKO KAZUMA1 1 Department of Adult Nursing, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Cardiovascular Medicine, Graduate School
The 12th Annual Scientific Meeting of Medicine, The University of Tokyo, Tokyo, Japan, 3Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Purpose: We aimed to investigate the prevalence of depression and its contribution to hospitalization, independent of other clinical data, in outpatients with heart failure (HF). Methods: We conducted a one-year prospective survey of 109 outpatients diagnosed with HF. Depression symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). A CES-D score O 5 16 indicated the presence of depressive symptoms. Differences in hospitalization were evaluated with the logrank test, following which the Cox proportional hazard analysis was used to assess the association between depression and hospitalization. Results: At baseline, the mean age was 65.2 years (SD 615.3 years) and the median brain natriuretic peptide (BNP) level was 77.5 pg/mL. Of 109 patients, 30 had depressive symptoms (CES-D score O 5 16). Compared to patients with no depressive symptoms (CES-D score !16), depressed patients demonstrated higher one-year hospitalization rate (8.5% vs. 29.6%; P 5 0.006). In the Cox proportional hazard model for multivariate analysis, adjusted for age, BNP level, previous hospitalization for HF, and use of b-blockers, depressive symptoms remained significantly associated with increased rate of HF hospitalization (hazard ratio, 5.14; 95% confidence interval, 1.57e16.9; P 5 0.007) Conclusions: Depression is an independent predictor of hospitalization in outpatients with HF. Future studies are required to evaluate whether an intervention for depression can reduce hospitalization in these patients.
YIA-B-1 Cardiac 12-lipoxygenase is critically involved in heart failure YOSUKE KAYAMA1, TOHRU MINAMINO1, HARUHIRO TOKO1, MASAYA SAKAMOTO2, HIDEHISA TAKAHASHI1, ISSEI KOMURO1 1 Department of Cardiovascular Science and Medicine Chiba University Graduate School of Medicine, Chiba, Japan, 2Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of Dahl salt-sensitive rats using DNA chip technique. We found that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade which metabolizes eicosanoid. Until recently, 12-LOX is reported to play an important role in atherogenesis, diabetes and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice (Tg) that overexpress 12-LOX only in cardiomyocytes. Echocardiography showed that 12-LOX Tg developed systolic dysfunction from 16 weeks old. Histological analysis revealed that overexpression of 12-LOX induced cardiac fibrosis, which was associated with infiltration of macrophages. Furthermore, expression of MCP-1 was markedly upregulated in the heart of 12-LOX Tg, whereas inhibition of this upregulation by the MCP-1 inhibitor 7ND significantly attenuated infiltration of macrophages as well as improving systolic dysfunction of 12-LOX Tg. Likewise, disruption of 12-LOX significantly reduced infiltration of macrophages, thereby inhibiting cardiac remodeling after myocardial infarction. These results suggest that cardiac 12-LOX is critically involved in the generation of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of heart failure.
YIA-B-2 Activation of L-serine biosynthesis is indispensable for hormetic effects of aldehydes in the heart JIN ENDO1, MOTOAKI SANO2, TAKAHARU KATAYAMA1, TAKESHI ADACHI3, KENTARO HAYASHIDA1, SHINSUKE YUASA1, SHINJI MAKINO2, MAKOTO SUEMATSU3, KEIICHI FUKUDA2, SATOSHI OGAWAI1 1 Cardiology Division, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, 2Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo, Japan, 3 Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Tokyo, Japan Introduction: Increased levels of lipid peroxidation-derived aldehydes are present in the myocardium in patients with ischemic heart disease and heart failure. This study was designed to investigate the molecular mechanism and functional significance of stress-response to aldehydes in the heart. Methods and Results: We developed mouse model of aldehydes-accumulation at increasing rates by interfering aldehydes detoxification using transgenic over-expression of Aldh2*2. DNA microarray analysis revealed that genes that encode enzymes involved in biosynthesis of amino acids that provide precursors for glutathione, particularly 3-phosphoglycerate dehydrogenase (Phgdh), the first step-catalyzing enzymes in the three-step conversion of serine biosynthesis from glycolytic metabolites, were highly induced in Aldh2*2 transgenic hearts. In cultured cardiomyocytes, adenovirus-mediated over-expression of Aldh2*2
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up-regulated Phgdh expression and increased intracellular glutathione levels, thereby enhancing the tolerance to anoxia-reoxygenation injury. SiRNA-mediated knockdown of Phgdh reduced intracellular glutathione levels and canceled stress-resistant phenotype in the Aldh2*2-expressing cardiomyocytes. The expression of Phgdh was increased in the peri-infarcted area followed by ischemia-reperfusion injury concomitant with the increased levels of aldehydes. The heart from Aldh2*2 transgenic mice contained higher levels of glutathione and exhibited enhanced tolerance to ischemiareperfusion injury, while cardiac-specific knockout of Phgdh rendered the heart vulnerable to ischemia-reperfusion injury. Conclusion: Induction of Phgdh as a stress response to aldehydes confers upon hearts favorable tolerance to oxidative stress via maintenance of high levels of glutathione.
YIA-B-3 Development of E-NTPDase gene eluting stent that prevents subacute in-stent thrombosis without antiplatelet drugs YASUHIRO TAKEMOTO1, HIROYUKI KAWATA1, KEIICHI IMAGAWA1, TSUNENARI SOEDA1, SATOSHI SOMEKAWA1, SHIRO UEMURA1, MASANORI MATSUMOTO2, YOSHIHIRO FUJIMURA2, YASUHIKO TABATA3, YOSHIHIKO SAITO1 1 First Department of Internal Medicine, Nara Medical University, Nara, Japan, 2 Blood Transfusion Medicine, Nara Medical University, Nara, Japan, 3Department of Biomaterials, Field of Tissue Engineering, Kyoto University, Kyoto, Japan Backgrounds: Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP to AMP, thereby inhibiting platelet aggregation. We investigated whether human placental E-NTPDase (hE-NTPDase) gene transfer by the cationized gelatin-coated stent (GCS) into injured artery could prevent subacute stent thrombosis. Methods and Results: 52 rabbits underwent the repeated balloon injury of femoral artery (FA) at 4-week intervals. The rabbits were divided into four groups: bare metal stent (BMS) group, GCS group, Lac Z gene eluting stent group, and hENTPDase gene eluting stent (hE-NTPDase stent) group. Immediately after the second injury, the stents were implanted into injured FA. Continuous Doppler and angiogram on day 3 and 7 revealed that the patency rate of the stent implanted FA was significantly higher in hE-NTPDase stent group than in other 3 groups (100% vs 17 to 50% p ! 0.05). Although E-NTPDase mRNA expression was dramatically reduced in injured FA, the expression of E-NTPDase mRNA and protein were preserved only in hE-NTPDase stent group on day 3 and 7. Additionally, NTPDase activity in the stent implanted FA was significantly higher in hE-NTPDase stent group than in BMS group (p ! 0.05). Histological examination revealed the occlusion of the stent implanted FA with platelet-rich thrombus in BMS and GCS groups but not in hE-NTPDase stent group.Conclusion: E-NTPDase gene eluting stent can completely prevent subacute thrombosis in injured artery without antiplatelet drugs.
YIA-B-4 Functional Significance and Morphological Characterization of StarvationInduced Autophagy in the Adult Heart HIROMITSU KANAMORI1, GENZOU TAKEMURA2, RUMI MARUYAMA2, KAZUKO GOTO2, RYUKO RI2, MITSURU SEISHIMA1, SHINYA MINATOGUCHI2, HISAYOSHI FUJIWARA3 1 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 2The second Department of Internal Medicine, Gifu University School of Medicine, 3Hyogo Prefectual Amagasaki Hospital The functional significance and detailed morphological characteristics of starvationinduced autophagy in the adult heart remain largely unknown. We exposed mice to starvation up to 3 days to induce autophagy. Under electron microscopy, intracellular electron-dense and homogenous vacuoles appeared in cardiomyocytes as early as 12 hours after starvation. These vacuoles were found to be lysosomes by enzyme histocytochemistry. At the later starvation phase, typical autophagolysosomes that contain intracellular organelles (e.g., mitochondria) were frequently recognized easily. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased along with the starvation interval. Next, we inhibited the autophagy using bafilomycin A1 (BafA1; 0.3 mg/kg/day, i.p.). Treatment with BafA1 did not affect cardiac function in the normally fed mice. In the mice starved for 3 days, however, cardiac function was markedly depressed by the treatment with BafA1 and a significant left ventricular dilatation was seen. There was no TUNEL positive cardiomyocyte in both fed and starved mice. The cardiomyocytes were occupied with accumulated vacuoles and the myocardial ATP content was severely decreased in the mice; both might have contributed to cardiac dysfunction. BafA1 increased myocardial expression of cathepsin D and ubiquitin while decreased that of LC3-II in starved mice. In conclusion, our findings indicate autophagy play a critical role in maintenance of cardiac function in the adult heart during starvation.