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Immunomodulatory Effects of Inhibitory G-protein Signals Antagonism in Experimental Autoimmune Myocarditis
The 10th Annual Scientific Meeting of the therapy with pimobendan. We examined the effect of combination therapy of oral beta-blocker and pimobendan in these patients. Methods and Results: Between April 2001 and March 2004, 51 patients were hospitalized due to CHF and administration of pimobendan was newly introduced (1.25 to 2.5mg/day, mean 2.360.4mg/day). Twenty-four patients were re-hospitalized for worsening of CHF after 9613 months. Combination therapy of oral beta-blocker (carvedilol, 1.25 to 10mg/day, mean 2.562.7mg/day) and pimobendan (same dose before re-hospitalization) was performed in 10 out of these 24 patients (8167 years old, 5 patients with old myocardial infarction, 3 patients with hypertensive heart disease, and 2 patients with valvular heart disease). After the combination therapy, betablocker was discontinued in 2 patients due to bradycardia, but remaining 8 patients did not show any worsening of CHF for longer follow up periods than those before combination therapy (363 months vs. 14614 months). Conclusions: There is a possibility that the combination therapy of oral beta-blocker and pimobendan in CHF patients provides a more favorable long-term effect on the prevention of recurrent CHF than the therapy with pimobendan alone.
1058 Immunomodulatory Effects of Inhibitory G-protein Signals Antagonism in Experimental Autoimmune Myocarditis TSUTOMU OSAKA, TAKAYUKI INOMATA, HIRONARI NAKANO, MOTOTSUGU NISHII, HISAHITO SHINAGAWA, ICHIROU TAKEUCHI, TOSIMI KOITABASHI, HITOSHI TAKEHANA, TOHRU IZUMI Department of Cardio-angiology, Kitasato University School of Medicine, Kanagawa, Japan Background: The direct effect of beta-adrenergic stimulation on myocardial inflammation has not been fully investigated. Different signaling pathways concerning Gprotein between beta1- and beta2-AR stimulations. Gi-protein may have a key role for the different immunomodulation between beta1/2-AR signals. Objectives: To investigate the role of pertussis toxin (PTX), inhibitory G (Gi)-protein-selective antagonist, for modulating the disease severity of experimental autoimmune myocarditis (EAM). Method and Results: A single injection of PTX in vivo (4 ug/rat) exacerbated active EAM induced by myosin-immunization (aEAM) in the induction phase (macroscopic score (MS): 3.860.6 vs. 2.560.9 (vehicle), P!0.01) but ameliorated aEAM in the effector phase (MS: 0.960.9 vs. 3.260.6 (vehicle), P!0.01) or myocarditogenicT-cell-transferred myocarditis (tEAM) (MS:0.460.7 vs. 3.260.8 (vehicle), P!0.01). Myocardial IFN-gamma and IL-10 expression were significantly decreased in the 4 ug-PTX group, proportionally with the disease severity of myocarditis. Furthermore, incubation of myocarditogenic-T cell with PTX (1000 ng/ml) just before the transfer also ameliorated EAM (MS: 1.560.9 vs. 3.160.5 (vehicle), P!0.01). IFN-gamma and IL-10 expression, however, did not alter in PTX-treated T cells. Conclusion: PTX ameliorates EAM in the effector phase partly through the direct immunomodulation of myocarditogenic T cells except the suppression of cytokine expression.
1059 The Characteristics of Patients with Acutely Decompensated Heart Failure Who are Difficult to Withdraw the Use of Natriuretic Peptide KIYOSHI KUME, HIDEAKI KATAIWA, KENICHI KOMUKAI, MASAKI YAMATO, NORIKO SASAKI, HIROYOSHI YAMAMOTO, KEIJI HIROOKA, YUKIHIRO KORETSUNE, HIDEO KUSUOKA, YOSHIO YASUMURA Division of Cardiology, National Hospital Organization Osaka National Hospital, Osaka, Japan The way how and when we withdraw the intravenous use of human atrial natriuretic peptide(hANP) is empirical in patients with acutely decompensated heart failure(AHF). We studied the characteristics of the patients who are difficult to withdraw the use of hANP. Methods: Thirty-eight patients with AHF were enrolled who were treated with hANP. We tried to withdraw the use of hANP when the improvement of pulmonary hypertension lasted and urine volume was obtained enough. We studied the characteristics of the patients who needed to use hANP for longer than 7 days in spite of our AHF therapeutic regimen. Results: Eleven patients among 38 patients needed to use hANP for longer than 7 days. These patients were categorized into 3 groups. The first group(n53) had giant left atrium(LA)(about 70mm). Pulmonary hypertension deteriorated after the cessation of hANP, and improved when started again. The second group(n54) showed organic mitral regurgitation(MR) which was the main mechanism for AHF. Despite the difficulties to withdraw hANP in these two groups, they were good responders to hANP in respect of the pulmonary arterial pressure reduction and urine volume response. The third group(n54) accompanied with severe anemia, low albuminemia, or severely depressed cardiac function.
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Conclusions: Special attention must be paid for the withdrawal of hANP in patients with giant LA, organic severe MR, and severely depressed cardiac function.
1060 Effects of Low Dose of Human Atrial Natriuretic Peptide on Hemodynamics During Tachycardia in Patients with Heart Failure NAOKI FUJIMOTO1, KATSUYA ONISHI2, KAORU DOHI1, MASAKI TANABE1, TAKESHI TAKAMURA1, TAIRO KURITA1, TAKASHI TANIGAWA1, MASAAKI ITO1, NAOKI ISAKA1 1 Department of Cardiology, Mie University Graduate School of Medicine, 2 Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine Background: Low dose of human atrial natriuretic peptide (hANP) has favorable effects on hemodynamics and cardiac function in patients with heart failure (HF). However, whether hANP improves hemodynamical deterioration induced by tachycardia in HF has been unclear. Methods: To examine the effects of low dose of hANP on hemodynamics during tachycardia, a conductance catheter with microtip-manometer was used to measure left ventricular (LV) function and hemodynamics in 7 patients (6269 yrs) with dilated cardiomyopathy (average BNP: 452 pg/dl). Hemodynamic measurements before hANP were performed before and during atrial pacing which increased heart rate by 40 beats/min. Then, low dose of hANP (0.01 microgram/kg/min) was infused, and the measurements were repeated in a similar way. Results: Before pacing, heart rate, end-diastolic volume, end-systolic pressure and total systemic resistance were similar before and during hANP. The time constant of LV relaxation (Tau) was significantly shortened (64624 vs. 57624 ms) and end-diastolic pressure was decreased by hANP infusion. During atrial pacing, hANP significantly shortened the time to peak LV force (257624 vs. 245625 ms), leading to the significant shortened Tau (56622 vs. 48623 ms). Conclusions: Low dose of hANP significantly improved LV relaxation, and this effect was preserved during tachycardia.
1061 Sustained Effects of Carperitide, an Atrial Natriuretic Peptide, on Left Ventricle Diastolic Filling and Inflammatory Cytokines in Idiopathic Dilated Cardiomyopathy MAHOTO KATO, KAZUHIKO HASHIMURA, KAZUO KOMAMURA, MASAFUMI KITAKAZE National Cardiovascular Center, Osaka, Japan Purpose: We sought to investigate if carperitide, human atrial natriuretic peptide, have positive effects on diastolic filling and inflammatory cytokines in patients with idiopathic dilated cardiomyopathy (DCM). Method: Low dose of carperitide was administered to 30 patients (NYHA 2-3, 59619 years) for 96 hours. We measured echocardiographic parameters and brain natriuretic peptide (BNP), inflammatory cytokines, before, immediately after and one week after the administration. Results: The values of Ea and interleukin-10 increased. Whereas, E/Ea, serum levels of BNP, tumor necrosis factor-alpha, interleukin-6 and high sensitivity C-reactive protein were decreased. Even one week after the termination, all these parameters remained almost unchanged.
1058 Immunomodulatory Effects of Inhibitory G-protein Signals Antagonism in Experimental Autoimmune Myocarditis TSUTOMU OSAKA, TAKAYUKI INOMATA, HIRONARI NAKANO, MOTOTSUGU NISHII, HISAHITO SHINAGAWA, ICHIROU TAKEUCHI, TOSIMI KOITABASHI, HITOSHI TAKEHANA, TOHRU IZUMI Department of Cardio-angiology, Kitasato University School of Medicine, Kanagawa, Japan Background: The direct effect of beta-adrenergic stimulation on myocardial inflammation has not been fully investigated. Different signaling pathways concerning Gprotein between beta1- and beta2-AR stimulations. Gi-protein may have a key role for the different immunomodulation between beta1/2-AR signals. Objectives: To investigate the role of pertussis toxin (PTX), inhibitory G (Gi)-protein-selective antagonist, for modulating the disease severity of experimental autoimmune myocarditis (EAM). Method and Results: A single injection of PTX in vivo (4 ug/rat) exacerbated active EAM induced by myosin-immunization (aEAM) in the induction phase (macroscopic score (MS): 3.860.6 vs. 2.560.9 (vehicle), P!0.01) but ameliorated aEAM in the effector phase (MS: 0.960.9 vs. 3.260.6 (vehicle), P!0.01) or myocarditogenicT-cell-transferred myocarditis (tEAM) (MS:0.460.7 vs. 3.260.8 (vehicle), P!0.01). Myocardial IFN-gamma and IL-10 expression were significantly decreased in the 4 ug-PTX group, proportionally with the disease severity of myocarditis. Furthermore, incubation of myocarditogenic-T cell with PTX (1000 ng/ml) just before the transfer also ameliorated EAM (MS: 1.560.9 vs. 3.160.5 (vehicle), P!0.01). IFN-gamma and IL-10 expression, however, did not alter in PTX-treated T cells. Conclusion: PTX ameliorates EAM in the effector phase partly through the direct immunomodulation of myocarditogenic T cells except the suppression of cytokine expression.
1059 The Characteristics of Patients with Acutely Decompensated Heart Failure Who are Difficult to Withdraw the Use of Natriuretic Peptide KIYOSHI KUME, HIDEAKI KATAIWA, KENICHI KOMUKAI, MASAKI YAMATO, NORIKO SASAKI, HIROYOSHI YAMAMOTO, KEIJI HIROOKA, YUKIHIRO KORETSUNE, HIDEO KUSUOKA, YOSHIO YASUMURA Division of Cardiology, National Hospital Organization Osaka National Hospital, Osaka, Japan The way how and when we withdraw the intravenous use of human atrial natriuretic peptide(hANP) is empirical in patients with acutely decompensated heart failure(AHF). We studied the characteristics of the patients who are difficult to withdraw the use of hANP. Methods: Thirty-eight patients with AHF were enrolled who were treated with hANP. We tried to withdraw the use of hANP when the improvement of pulmonary hypertension lasted and urine volume was obtained enough. We studied the characteristics of the patients who needed to use hANP for longer than 7 days in spite of our AHF therapeutic regimen. Results: Eleven patients among 38 patients needed to use hANP for longer than 7 days. These patients were categorized into 3 groups. The first group(n53) had giant left atrium(LA)(about 70mm). Pulmonary hypertension deteriorated after the cessation of hANP, and improved when started again. The second group(n54) showed organic mitral regurgitation(MR) which was the main mechanism for AHF. Despite the difficulties to withdraw hANP in these two groups, they were good responders to hANP in respect of the pulmonary arterial pressure reduction and urine volume response. The third group(n54) accompanied with severe anemia, low albuminemia, or severely depressed cardiac function.
JHFS
S173
Conclusions: Special attention must be paid for the withdrawal of hANP in patients with giant LA, organic severe MR, and severely depressed cardiac function.
1060 Effects of Low Dose of Human Atrial Natriuretic Peptide on Hemodynamics During Tachycardia in Patients with Heart Failure NAOKI FUJIMOTO1, KATSUYA ONISHI2, KAORU DOHI1, MASAKI TANABE1, TAKESHI TAKAMURA1, TAIRO KURITA1, TAKASHI TANIGAWA1, MASAAKI ITO1, NAOKI ISAKA1 1 Department of Cardiology, Mie University Graduate School of Medicine, 2 Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine Background: Low dose of human atrial natriuretic peptide (hANP) has favorable effects on hemodynamics and cardiac function in patients with heart failure (HF). However, whether hANP improves hemodynamical deterioration induced by tachycardia in HF has been unclear. Methods: To examine the effects of low dose of hANP on hemodynamics during tachycardia, a conductance catheter with microtip-manometer was used to measure left ventricular (LV) function and hemodynamics in 7 patients (6269 yrs) with dilated cardiomyopathy (average BNP: 452 pg/dl). Hemodynamic measurements before hANP were performed before and during atrial pacing which increased heart rate by 40 beats/min. Then, low dose of hANP (0.01 microgram/kg/min) was infused, and the measurements were repeated in a similar way. Results: Before pacing, heart rate, end-diastolic volume, end-systolic pressure and total systemic resistance were similar before and during hANP. The time constant of LV relaxation (Tau) was significantly shortened (64624 vs. 57624 ms) and end-diastolic pressure was decreased by hANP infusion. During atrial pacing, hANP significantly shortened the time to peak LV force (257624 vs. 245625 ms), leading to the significant shortened Tau (56622 vs. 48623 ms). Conclusions: Low dose of hANP significantly improved LV relaxation, and this effect was preserved during tachycardia.
1061 Sustained Effects of Carperitide, an Atrial Natriuretic Peptide, on Left Ventricle Diastolic Filling and Inflammatory Cytokines in Idiopathic Dilated Cardiomyopathy MAHOTO KATO, KAZUHIKO HASHIMURA, KAZUO KOMAMURA, MASAFUMI KITAKAZE National Cardiovascular Center, Osaka, Japan Purpose: We sought to investigate if carperitide, human atrial natriuretic peptide, have positive effects on diastolic filling and inflammatory cytokines in patients with idiopathic dilated cardiomyopathy (DCM). Method: Low dose of carperitide was administered to 30 patients (NYHA 2-3, 59619 years) for 96 hours. We measured echocardiographic parameters and brain natriuretic peptide (BNP), inflammatory cytokines, before, immediately after and one week after the administration. Results: The values of Ea and interleukin-10 increased. Whereas, E/Ea, serum levels of BNP, tumor necrosis factor-alpha, interleukin-6 and high sensitivity C-reactive protein were decreased. Even one week after the termination, all these parameters remained almost unchanged.