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Norepinephrine Induces Diastolic Dysfunction in Infarcted Rats
The 11th Annual Scientific Meeting and examined the effects of K201 (JTV519) and diltiazem in this model. Animals were examined in Ca2þ-load for 45 min, NE for 25 min, Ca2þ-load and NE for 25 min after Ca2þ-load (Ca2þ-NE), and vehicle group. The effects of K201 and diltiazem were studied in the Ca2þ-NE group. (each group; n 5 4-6) Hemodynamics and diastolic function were examined using a micromanometer-tipped pressure catheter and Doppler echocardiography. There were no significant changes in LVP and LV-EF among all groups. In the Ca2þ-NE group, a significant increase in LVEDP, and decreased E, Ea and deceleration time (DCT) were found, and NE-induced diastolic contracture (NEIDC) with aortic valve opening occurred in diastole and pulmonary hemorrhage was observed. K201 significantly suppressed the increase in LVEDP and improved Ea and DCT dose-dependently. Diltiazem did not improve DD. NE may be an important factor in development of DD, and K201 may have potential as a cardiac relaxant for treatment of DD.
041 Norepinephrine Induces Diastolic Dysfunction in Infarcted Rats RYUKO MATSUDA, NAOYUKI OHTANI, TAKUO ARIKAWA, SHIGERU TOYODA, HIDEHIKO SUZUKI, NOBORU KANEKO Department of Cardiology and Pheumology, Dokkyo Medical School of Medicine, Mibu, Japan An increased norepinephrine (NE) concentration in heart failure patients indicates a systemically enhanced status of the sympathetic nervous system; however, the involvement of NE in the progression of diastolic heart failure remains unclear. We investigated whether NE induces left ventricular diastolic dysfunction in infarcted rats. The left coronary artery was ligated in male Wistar rats. After 10-13 weeks, hemodynamics were examined before and after administration of NE (40 mg/kg/min) or isoproterenol (0.1 mg/kg/min) for 20 min in post-infarcted and sham-operated animals (each group; n 5 4e6), using a micromanometer-tipped pressure catheter. LVSP and þdP/dt max were significantly elevated after administration of NE in the sham and post-infarcted groups (infarct size; 30 6 13%). The LVDPmin, LVEDP, and -dP/dt max were significantly elevated after NE administration. A positive correlation was observed between the infarct size and LVEDP. However, elevation of LVEDP was not observed following administration of isoproterenol in the post-infarcted group (infarct size; 31 6 5%). These results indicate that NE induces elevation of LVEDP in infarcted rats and that a1-adrenoceptor stimulation, but not b-adrenoceptor stimulation, may aggravate diastolic function following myocardial infarction.
042 SERCA2 Gene Transcription is Regulated by Mitochondrial Transcription Factor, Tfam ATAI WATANABE, MASASHI ARAI, MASAHIKO KURABAYASHI Depertment of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan Background: Mitochondrial (Mt) transcription factor, Tfam, regulates the transcription of genes for Mt enzyme. Our previous study demonstrating the significant correlation between Tfam and SERCA2 mRNA expression in failing heart suggests a hypothesis that Tfam controls the transcription of the SERCA2 gene as well as Mt gene. Methods and Results: The effect of Tfam on the rat SERCA2 gene promoter was examined in the neonatal rat cultured cardiac myocytes. Overexpression of Tfam activated SERCA2 gene transcription by 75% and Tfam siRNA decreased the SERCA2 gene transcription by 30%. Immunofluorescence staining revealed that Tfam localized in the nucleus as well as Mt. ChIP assay disclosed that Tfam bound to the proximal GC-rich region (479 w 2 nt) of the SERCA2 gene. Furthermore, fluorescent correlation spectoscopy supplied another evidence of the specific binding of Tfam with SERCA2 gene promoter. Sp1, a principal transcription factor for GC-rich region, also bound to this region and increased the SERCA2 gene transcription by 85%. Co-transfection of Sp1 and Tam enhanced transcription by 170%. Conclusion: Our data suggest a novel mode of the regulation of SERCA2 gene. Mt transcription factor plays an important role in concert with Sp1 in the regulation of the gene of an ATP-consuming enzyme, SERCA2.
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043 Mild Depression Predicts Future Cardiovascular Complications in Patients with Heart Failure TAKAHIRO KOMORI, KAZUO EGUCHI, HIDENORI TOMIZAWA, SATOSHI HOSHIDE, JOUJI ISHIKAWA, KAZUYUKI SHIMADA, KAZUOMI KARIO Division of Cardiology, Jichi Medical University School of Medicine, Shimotsuke, Japan Background: Depression in patients with heart failure (HF) was associated with adverse prognosis, especially in the severely depressed. However, it is not clearly shown mild depression is the risk of future incidence of cardiovascular disease (CVD). Methods: We studied 117 patients with HF (age, 67 6 11 years; male sex, 62%). Center for Epidemiological Studies-Depression (CES-D), ambulatory blood pressure (BP) monitoring, and blood test were performed just before leaving hospital. Incident CVD, defined as either ischemic heart disease, stroke, recurrent HF, renal failure fatal arrhythmia, peripheral artery disease, or cardiac death, were followed for 18 6 9 months. Cox proportional hazard model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of depression-associated risk for CVD. Results: There were 42 (37.8%) incident CVD during the follow-up. In univariate analysis, CES-D was significantly associated with glycemic control and diuretics use, but not with BNP or others. With multivariate Cox regression analysis, CESD (HR 5 1.09, 95%CI 5 1.03e1.15, p 5 0.002) was a predictor of incident CVD, independent of other confounding factors. Conclusions: Even though it is mild, depression is a significant risk factor for future incidence of CVD in patients with HF.
044 Effect of Combination Therapy with bFGF and G-CSF on Angiogenesis and Cardiac Function in Myocardial Ischemia KOHTARO YOSHIDA, NAOHIKO KOBAYASHI, TOMOYUKI OHNO, HIROMICHI FUKUSHIMA, TAKEAKI HONDA, HIROAKI MATSUOKA Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Japan Purpose: The present study investigated whether the simultaneous application of bFGF and G-CSF improves angiogenesis and cardiac function in myocardial ischemia. Method: The infarcted beagles were randomized into the following 4 groups: (1) vehicle group, (2) bFGF group: gelatin hydrogel microspheres containing 100 mg of bFGF injected into the border zone of infarcted area, (3) GCSF group: administered G-CSF (10 mg/kg/day) intra muscular in beagle of consecutive 5 days, and (4) bFGFþGCSF group: (2) plus (3). Four weeks later, end-systolic elastance (Ees) was measured, and immunohistochemistry were measured for angiogenesis. Result: At 4 weeks, bFGF or GCSF decreased infarct sizes, increased capillary density, and improved Ees compared to vehicle-group. Moreover, combination therapy with bFGF and GCSF shows to enhance angiogenesis and ameliorates cardiac function compared with bFGF or GCSF alone. In addition, in bFGFþGCSF, eNOS mRNA was upregulated, and NAD(P)H oxidase p22 phox, p47 phox mRNA was suppressed compared to bFGF or GCSF alone. Conclusion: These results suggest that enhancing cardioprotective effects of combination therapy with bFGF and G-CSF may be mediated in part by inducing eNOS production and suppressing oxidative stress in myocardial ischemia.
045 Effect of Combination Therapy with Bone-marrow Mononuclear Cell Implantation and Eplerenone on Angiogenesis and Cardiac Performance in Myocardial Ischemia KOHTARO YOSHIDA, NAOHIKO KOBAYASHI, HIROMICHI FUKUSHIMA, TAKEAKI HONDA, TOMOYUKI OHNO, HIROAKI MATSUOKA Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Japan Purpose: The purpose of the present study was to investigate whether combination therapy with MNCs and eplerenone shows to enhance angiogenesis and ameliorates cardiac function compared with MNCs alone in a canine model of chronic myocardial infarction. Method: Immediately after aspiration of BM, a model of chronic myocardial ischemia was created by left anterior descending coronary artery (LAD) ligation in adult beagles, and then BM-MNCs or medium alone (control) was injected into the LAD risk area. Moreover, eplerenone was administered by orally (50 mg/kg/day) in combination therapy with BM-MNCs and eplerenone. Four weeks later, end-systolic
041 Norepinephrine Induces Diastolic Dysfunction in Infarcted Rats RYUKO MATSUDA, NAOYUKI OHTANI, TAKUO ARIKAWA, SHIGERU TOYODA, HIDEHIKO SUZUKI, NOBORU KANEKO Department of Cardiology and Pheumology, Dokkyo Medical School of Medicine, Mibu, Japan An increased norepinephrine (NE) concentration in heart failure patients indicates a systemically enhanced status of the sympathetic nervous system; however, the involvement of NE in the progression of diastolic heart failure remains unclear. We investigated whether NE induces left ventricular diastolic dysfunction in infarcted rats. The left coronary artery was ligated in male Wistar rats. After 10-13 weeks, hemodynamics were examined before and after administration of NE (40 mg/kg/min) or isoproterenol (0.1 mg/kg/min) for 20 min in post-infarcted and sham-operated animals (each group; n 5 4e6), using a micromanometer-tipped pressure catheter. LVSP and þdP/dt max were significantly elevated after administration of NE in the sham and post-infarcted groups (infarct size; 30 6 13%). The LVDPmin, LVEDP, and -dP/dt max were significantly elevated after NE administration. A positive correlation was observed between the infarct size and LVEDP. However, elevation of LVEDP was not observed following administration of isoproterenol in the post-infarcted group (infarct size; 31 6 5%). These results indicate that NE induces elevation of LVEDP in infarcted rats and that a1-adrenoceptor stimulation, but not b-adrenoceptor stimulation, may aggravate diastolic function following myocardial infarction.
042 SERCA2 Gene Transcription is Regulated by Mitochondrial Transcription Factor, Tfam ATAI WATANABE, MASASHI ARAI, MASAHIKO KURABAYASHI Depertment of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan Background: Mitochondrial (Mt) transcription factor, Tfam, regulates the transcription of genes for Mt enzyme. Our previous study demonstrating the significant correlation between Tfam and SERCA2 mRNA expression in failing heart suggests a hypothesis that Tfam controls the transcription of the SERCA2 gene as well as Mt gene. Methods and Results: The effect of Tfam on the rat SERCA2 gene promoter was examined in the neonatal rat cultured cardiac myocytes. Overexpression of Tfam activated SERCA2 gene transcription by 75% and Tfam siRNA decreased the SERCA2 gene transcription by 30%. Immunofluorescence staining revealed that Tfam localized in the nucleus as well as Mt. ChIP assay disclosed that Tfam bound to the proximal GC-rich region (479 w 2 nt) of the SERCA2 gene. Furthermore, fluorescent correlation spectoscopy supplied another evidence of the specific binding of Tfam with SERCA2 gene promoter. Sp1, a principal transcription factor for GC-rich region, also bound to this region and increased the SERCA2 gene transcription by 85%. Co-transfection of Sp1 and Tam enhanced transcription by 170%. Conclusion: Our data suggest a novel mode of the regulation of SERCA2 gene. Mt transcription factor plays an important role in concert with Sp1 in the regulation of the gene of an ATP-consuming enzyme, SERCA2.
JHFS
S35
043 Mild Depression Predicts Future Cardiovascular Complications in Patients with Heart Failure TAKAHIRO KOMORI, KAZUO EGUCHI, HIDENORI TOMIZAWA, SATOSHI HOSHIDE, JOUJI ISHIKAWA, KAZUYUKI SHIMADA, KAZUOMI KARIO Division of Cardiology, Jichi Medical University School of Medicine, Shimotsuke, Japan Background: Depression in patients with heart failure (HF) was associated with adverse prognosis, especially in the severely depressed. However, it is not clearly shown mild depression is the risk of future incidence of cardiovascular disease (CVD). Methods: We studied 117 patients with HF (age, 67 6 11 years; male sex, 62%). Center for Epidemiological Studies-Depression (CES-D), ambulatory blood pressure (BP) monitoring, and blood test were performed just before leaving hospital. Incident CVD, defined as either ischemic heart disease, stroke, recurrent HF, renal failure fatal arrhythmia, peripheral artery disease, or cardiac death, were followed for 18 6 9 months. Cox proportional hazard model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of depression-associated risk for CVD. Results: There were 42 (37.8%) incident CVD during the follow-up. In univariate analysis, CES-D was significantly associated with glycemic control and diuretics use, but not with BNP or others. With multivariate Cox regression analysis, CESD (HR 5 1.09, 95%CI 5 1.03e1.15, p 5 0.002) was a predictor of incident CVD, independent of other confounding factors. Conclusions: Even though it is mild, depression is a significant risk factor for future incidence of CVD in patients with HF.
044 Effect of Combination Therapy with bFGF and G-CSF on Angiogenesis and Cardiac Function in Myocardial Ischemia KOHTARO YOSHIDA, NAOHIKO KOBAYASHI, TOMOYUKI OHNO, HIROMICHI FUKUSHIMA, TAKEAKI HONDA, HIROAKI MATSUOKA Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Japan Purpose: The present study investigated whether the simultaneous application of bFGF and G-CSF improves angiogenesis and cardiac function in myocardial ischemia. Method: The infarcted beagles were randomized into the following 4 groups: (1) vehicle group, (2) bFGF group: gelatin hydrogel microspheres containing 100 mg of bFGF injected into the border zone of infarcted area, (3) GCSF group: administered G-CSF (10 mg/kg/day) intra muscular in beagle of consecutive 5 days, and (4) bFGFþGCSF group: (2) plus (3). Four weeks later, end-systolic elastance (Ees) was measured, and immunohistochemistry were measured for angiogenesis. Result: At 4 weeks, bFGF or GCSF decreased infarct sizes, increased capillary density, and improved Ees compared to vehicle-group. Moreover, combination therapy with bFGF and GCSF shows to enhance angiogenesis and ameliorates cardiac function compared with bFGF or GCSF alone. In addition, in bFGFþGCSF, eNOS mRNA was upregulated, and NAD(P)H oxidase p22 phox, p47 phox mRNA was suppressed compared to bFGF or GCSF alone. Conclusion: These results suggest that enhancing cardioprotective effects of combination therapy with bFGF and G-CSF may be mediated in part by inducing eNOS production and suppressing oxidative stress in myocardial ischemia.
045 Effect of Combination Therapy with Bone-marrow Mononuclear Cell Implantation and Eplerenone on Angiogenesis and Cardiac Performance in Myocardial Ischemia KOHTARO YOSHIDA, NAOHIKO KOBAYASHI, HIROMICHI FUKUSHIMA, TAKEAKI HONDA, TOMOYUKI OHNO, HIROAKI MATSUOKA Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Japan Purpose: The purpose of the present study was to investigate whether combination therapy with MNCs and eplerenone shows to enhance angiogenesis and ameliorates cardiac function compared with MNCs alone in a canine model of chronic myocardial infarction. Method: Immediately after aspiration of BM, a model of chronic myocardial ischemia was created by left anterior descending coronary artery (LAD) ligation in adult beagles, and then BM-MNCs or medium alone (control) was injected into the LAD risk area. Moreover, eplerenone was administered by orally (50 mg/kg/day) in combination therapy with BM-MNCs and eplerenone. Four weeks later, end-systolic