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Effect of Insulin Resistance Modulator on Exercise Tolerance
The 11th Annual Scientific Meeting
031 Albuminuria is an Independent Predictor for the Onset of Heart Failure TOSHIE SEGAWA1, TOSHIYUKI ONODA2, KOUZOU TANNO2, KAZUYOSHI ITAI2, KIYOMI SAKATA2, KAZUKO KAWAMURA3, YOUKO TONARI3, MOTOYUKI NAKAMURA1 1 Second Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 2Department of Preventive Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 3Iwate Health Service Association, Morioka, Japan Background: Albuminuria is associated with increased risk of cardiovascular disease events and mortality in certain high-risk groups such as patients with diabetes and hypertension. However, the relationship between urinary albumin and congestive heart failure events is not established in the Japanese general population. Method: We have measured the albumin to creatinine ratio (UACR) in 8,139 participants (mean age 63) who attended Iwate-KENCO study. After exclusion of subjects with a cardiovascular history and age below 40 and over 80 years, a multivariate Cox regression analysis was performed to analyze the relationship between UACR and the onset of congestive heart failure events in 7,995 subjects. Results: During a mean follow-up of 3.6 years, 29 congestive heart failure events were occurred in the participants (men 5 15 and women 5 14). Compared with participants in the lowest UACR quartile (median 5.1 mg/mg$Cre in men and 6.8 mg/ mg$Cre in women), those in the highest quartile (median 55.8 mg/mg$Cre in men and 50.0 mg/mg$Cre in women) were at increased risk of incident heart failure (hazard ratio, 5.7:95% CI, 1.26 to 26.0) after adjustment for classical cardiovascular risk factors. Conclusion: Elevated UACR is a useful independent predictor for future onset of cardiovascular events in our general population.
032 Losartan Inhibits Proliferation and Inflammation of Uric Acid-stimulated Vascular Smooth Muscle Cells by Modulation of Uric Acid Transporter SEOK MIN KANG1, WOOCHUL CHANG2, SOYEON LIM2, HEESANG SONG2, YANGSOO JANG1, NAMSIK CHUNG1, KI-CHUL HWANG2 1 Yonsei University Medical College, Cardiology, Seoul, Korea, 2Yonsei Cardiovascular Research Institute, Seoul, Korea Purpose: Among angiotensin II receptor blocker (ARB), only losartan lowers serum uric acid (UA) compared with other ARBs. Recent study showed that UA causes vascular smooth muscle cell (VSMC) proliferation by entering cells via uric acid transporter (UAT). In this study, we examined whether losartan could inhibit UAstimulated proliferative and inflammatory signaling by modulation of UAT in rat aortic VSMCs. Methods and Results: Following 24 hours incubation of UA, proliferation of VSMCs was increased dose-dependently with a peak at concentration (80 mg/ml) of UA. Losartan inhibited UA-stimulated cell proliferation in dose-dependent manner with an IC50 value of about 100 mM. UA significantly activated p38 and ERKs as well as expression of COX-2 and MCP-1 production, while losartan dramatically attenuated p38, ERKs activation, COX-2 and MCP-1 production. In 80 mg/ml of UA-stimulated VSMCs, losartan (100 mM) significantly attenuated the expression of UAT. Conclusion: The present study is a first demonstration of the effect of losartan on UAT in the VSMCs. Our data suggest that losartan has anti-proliferative and anti-inflammatory activity by modulation of UAT in UA-stimulated VSMCs. Therefore, losartan would have a beneficial effect on the vasculature in hyperuricemic condition of heart failure.
033 Relation Between Monocyte Chemoattractant Protein-1 Levels and Systolic Dysfunction with Hypertrophic Cardiomyopathy JUN IWASAKI1, KAZUFUMI NAKAMURA1, YOICHI NAKAMURA2, HIROMI MATSUBARA3, NOBUHIRO NISHII1, KIMIKAZU BANBA1, MASATO MURAKAMI1, KEIKO OHTA-OGO1, AYA MIURA1, DAIJI MIURA1, SATOSHI NAGASE1, SATORU SAKURAGI1, KENGO KUSANO1, TOHRU OHE1 1 Department of Cardiovascular Medicine, Okayama University, Okayama, Japan, 2 Division of Cardiology, Ehime Prefectural Central Hospital, Matsuyama, Japan, 3 Division of Cardiology, National Hospital Organization, Okayama Medical Center, Okayama, Japan Purpose: We measured circulating monocyte chemoattractant protein-1 (MCP-1) in patients with hypertrophic cardiomyopathy (HCM), and tested whether the levels were correlated with left ventricular (LV) dysfunction.
JHFS
S33
Method: Circulating MCP-1 was measured by enzyme immunoassay in 26 patients with HCM and 19 control subjects. Cardiac function was evaluated by 2-dimensional echocardiography and cardiac catheterization. Result: HCM patients had significantly elevated levels of MCP-1 (HCM: 309 6 30 vs. control: 179 6 8 pg/mL, P ! 0.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than in patients without systolic dysfunction (P ! 0.05), and were also significantly higher than in patients with outflow obstruction (P ! 0.05). MCP-1 levels were correlated with fractional shortening (r 5 0.401, P ! 0.05) and correlated with LV end-diastolic pressure (r 5 0.579, P ! 0.01). Furthermore, immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from patients with HCM. Conclusion: MCP-1 levels were elevated in patients with HCM, and the levels were correlated with LV dysfunction. MCP-1 is involved in the progression of heart failure in patients with HCM.
034 Two Successful Cases of Liver Transplantation with Portopulmonary Hypertension Under Epoprostenol Infusion SATOMI KONNO, TAKUYA KISHI, GEORGE KOIKE, KENJI SUNAGAWA Department of Cardiology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Portopulmonary hypertension (PPHTN) is defined as increased mean pulmonary arterial pressure (mPAP) O 25 mmHg with portal hypertension. It is considered that liver transplantation (LT) with severe PPHTN is contraindicated due to increased risk of right-side heart failure (RSHF). Recently, epoprostenol for PPHTN were reported to lower mPAP. However, the standard method of epoprostenol therapy for LT with PPHTN has not been established. Here, we report 2 cases of successful living donor LT (LDLT) in patients with PPHTN treated with epoprostenol. First case was 58-year-old female with end-stage liver cirrhosis (ESLC) due to chronic hepatitis C. She had PPHTN (mPAP 5 46 mmHg). Epoprostenol was started and increased to 21 ng/kg/min, and mPAP was lowered to 33 mmHg. She underwent LDLT without RSHF. After LT, epoprostenol was gradually decreased, and finally terminated. Second case was 20-year-old female with ESLC due to primary biliary cirrhosis. She had PPHTN (mPAP 5 49 mmHg). Epoprostenol was started and increased to 30 ng/kg/ min. Her mPAP was lowered to 43 mmHg, and cardiac index was increased from 3.6 to 4.1 L/min/M2. She underwent LDLT without RSHF. However, epoprostenol was not able to be decreased. Epoprostenol is a useful therapy for LDLT with PPHTN, and standard procedure should be established.
035 Effect of Insulin Resistance Modulator on Exercise Tolerance HITOSHI ADACHI, JUN MURAKAMI, SHIGERU OSHIMA, TANIGUCHI Gunma Prefectural Cardiovascular Center, Maebashi, Japan
KOICHI
Purpose: Insulin resistance is recently reported to deteriorate diastolic function due to, in part, impairing the calcium handling. Therefore, it is hypothesized that cardiac function would be improved by insulin sensitizer. Cardiac function during exercise is a more sensitive indicator of cardiac function than that at rest. Hereby, we studied the effect of insulin resistance modulator on cardiac function during exercise in subjects with insulin resistance. Method: Thirteen heart disease subjects were enrolled. Blood sampling and cardiopulmonary exercise test were performed to determine insulin resistance using HOMA-R method and cardiac function during exercise. After taking the Pioglitazone (30 mg/day) for 3 months, HOMA-R and cardiac function during exercise were evaluated again. Results: No subjects showed worsening of heart failure or exacerbation of pedal edema. HOMA-R was improved from 3.8 6 1.6 to 2.5 6 1.8 (p ! 0.05). Peak oxygen pulse improved from 10.5 6 3.0 mL/beat to 11.3 6 2.6 (p ! 0.01). Peak oxygen uptake also improved significantly (p ! 0.01) form 19.7 6 3.0 mL/min/kg to 21.7 6 3.6. Conclusion: Pioglitazone, one of the insulin resistance modulator, improved cardiac function during exercise.
031 Albuminuria is an Independent Predictor for the Onset of Heart Failure TOSHIE SEGAWA1, TOSHIYUKI ONODA2, KOUZOU TANNO2, KAZUYOSHI ITAI2, KIYOMI SAKATA2, KAZUKO KAWAMURA3, YOUKO TONARI3, MOTOYUKI NAKAMURA1 1 Second Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 2Department of Preventive Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 3Iwate Health Service Association, Morioka, Japan Background: Albuminuria is associated with increased risk of cardiovascular disease events and mortality in certain high-risk groups such as patients with diabetes and hypertension. However, the relationship between urinary albumin and congestive heart failure events is not established in the Japanese general population. Method: We have measured the albumin to creatinine ratio (UACR) in 8,139 participants (mean age 63) who attended Iwate-KENCO study. After exclusion of subjects with a cardiovascular history and age below 40 and over 80 years, a multivariate Cox regression analysis was performed to analyze the relationship between UACR and the onset of congestive heart failure events in 7,995 subjects. Results: During a mean follow-up of 3.6 years, 29 congestive heart failure events were occurred in the participants (men 5 15 and women 5 14). Compared with participants in the lowest UACR quartile (median 5.1 mg/mg$Cre in men and 6.8 mg/ mg$Cre in women), those in the highest quartile (median 55.8 mg/mg$Cre in men and 50.0 mg/mg$Cre in women) were at increased risk of incident heart failure (hazard ratio, 5.7:95% CI, 1.26 to 26.0) after adjustment for classical cardiovascular risk factors. Conclusion: Elevated UACR is a useful independent predictor for future onset of cardiovascular events in our general population.
032 Losartan Inhibits Proliferation and Inflammation of Uric Acid-stimulated Vascular Smooth Muscle Cells by Modulation of Uric Acid Transporter SEOK MIN KANG1, WOOCHUL CHANG2, SOYEON LIM2, HEESANG SONG2, YANGSOO JANG1, NAMSIK CHUNG1, KI-CHUL HWANG2 1 Yonsei University Medical College, Cardiology, Seoul, Korea, 2Yonsei Cardiovascular Research Institute, Seoul, Korea Purpose: Among angiotensin II receptor blocker (ARB), only losartan lowers serum uric acid (UA) compared with other ARBs. Recent study showed that UA causes vascular smooth muscle cell (VSMC) proliferation by entering cells via uric acid transporter (UAT). In this study, we examined whether losartan could inhibit UAstimulated proliferative and inflammatory signaling by modulation of UAT in rat aortic VSMCs. Methods and Results: Following 24 hours incubation of UA, proliferation of VSMCs was increased dose-dependently with a peak at concentration (80 mg/ml) of UA. Losartan inhibited UA-stimulated cell proliferation in dose-dependent manner with an IC50 value of about 100 mM. UA significantly activated p38 and ERKs as well as expression of COX-2 and MCP-1 production, while losartan dramatically attenuated p38, ERKs activation, COX-2 and MCP-1 production. In 80 mg/ml of UA-stimulated VSMCs, losartan (100 mM) significantly attenuated the expression of UAT. Conclusion: The present study is a first demonstration of the effect of losartan on UAT in the VSMCs. Our data suggest that losartan has anti-proliferative and anti-inflammatory activity by modulation of UAT in UA-stimulated VSMCs. Therefore, losartan would have a beneficial effect on the vasculature in hyperuricemic condition of heart failure.
033 Relation Between Monocyte Chemoattractant Protein-1 Levels and Systolic Dysfunction with Hypertrophic Cardiomyopathy JUN IWASAKI1, KAZUFUMI NAKAMURA1, YOICHI NAKAMURA2, HIROMI MATSUBARA3, NOBUHIRO NISHII1, KIMIKAZU BANBA1, MASATO MURAKAMI1, KEIKO OHTA-OGO1, AYA MIURA1, DAIJI MIURA1, SATOSHI NAGASE1, SATORU SAKURAGI1, KENGO KUSANO1, TOHRU OHE1 1 Department of Cardiovascular Medicine, Okayama University, Okayama, Japan, 2 Division of Cardiology, Ehime Prefectural Central Hospital, Matsuyama, Japan, 3 Division of Cardiology, National Hospital Organization, Okayama Medical Center, Okayama, Japan Purpose: We measured circulating monocyte chemoattractant protein-1 (MCP-1) in patients with hypertrophic cardiomyopathy (HCM), and tested whether the levels were correlated with left ventricular (LV) dysfunction.
JHFS
S33
Method: Circulating MCP-1 was measured by enzyme immunoassay in 26 patients with HCM and 19 control subjects. Cardiac function was evaluated by 2-dimensional echocardiography and cardiac catheterization. Result: HCM patients had significantly elevated levels of MCP-1 (HCM: 309 6 30 vs. control: 179 6 8 pg/mL, P ! 0.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than in patients without systolic dysfunction (P ! 0.05), and were also significantly higher than in patients with outflow obstruction (P ! 0.05). MCP-1 levels were correlated with fractional shortening (r 5 0.401, P ! 0.05) and correlated with LV end-diastolic pressure (r 5 0.579, P ! 0.01). Furthermore, immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from patients with HCM. Conclusion: MCP-1 levels were elevated in patients with HCM, and the levels were correlated with LV dysfunction. MCP-1 is involved in the progression of heart failure in patients with HCM.
034 Two Successful Cases of Liver Transplantation with Portopulmonary Hypertension Under Epoprostenol Infusion SATOMI KONNO, TAKUYA KISHI, GEORGE KOIKE, KENJI SUNAGAWA Department of Cardiology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Portopulmonary hypertension (PPHTN) is defined as increased mean pulmonary arterial pressure (mPAP) O 25 mmHg with portal hypertension. It is considered that liver transplantation (LT) with severe PPHTN is contraindicated due to increased risk of right-side heart failure (RSHF). Recently, epoprostenol for PPHTN were reported to lower mPAP. However, the standard method of epoprostenol therapy for LT with PPHTN has not been established. Here, we report 2 cases of successful living donor LT (LDLT) in patients with PPHTN treated with epoprostenol. First case was 58-year-old female with end-stage liver cirrhosis (ESLC) due to chronic hepatitis C. She had PPHTN (mPAP 5 46 mmHg). Epoprostenol was started and increased to 21 ng/kg/min, and mPAP was lowered to 33 mmHg. She underwent LDLT without RSHF. After LT, epoprostenol was gradually decreased, and finally terminated. Second case was 20-year-old female with ESLC due to primary biliary cirrhosis. She had PPHTN (mPAP 5 49 mmHg). Epoprostenol was started and increased to 30 ng/kg/ min. Her mPAP was lowered to 43 mmHg, and cardiac index was increased from 3.6 to 4.1 L/min/M2. She underwent LDLT without RSHF. However, epoprostenol was not able to be decreased. Epoprostenol is a useful therapy for LDLT with PPHTN, and standard procedure should be established.
035 Effect of Insulin Resistance Modulator on Exercise Tolerance HITOSHI ADACHI, JUN MURAKAMI, SHIGERU OSHIMA, TANIGUCHI Gunma Prefectural Cardiovascular Center, Maebashi, Japan
KOICHI
Purpose: Insulin resistance is recently reported to deteriorate diastolic function due to, in part, impairing the calcium handling. Therefore, it is hypothesized that cardiac function would be improved by insulin sensitizer. Cardiac function during exercise is a more sensitive indicator of cardiac function than that at rest. Hereby, we studied the effect of insulin resistance modulator on cardiac function during exercise in subjects with insulin resistance. Method: Thirteen heart disease subjects were enrolled. Blood sampling and cardiopulmonary exercise test were performed to determine insulin resistance using HOMA-R method and cardiac function during exercise. After taking the Pioglitazone (30 mg/day) for 3 months, HOMA-R and cardiac function during exercise were evaluated again. Results: No subjects showed worsening of heart failure or exacerbation of pedal edema. HOMA-R was improved from 3.8 6 1.6 to 2.5 6 1.8 (p ! 0.05). Peak oxygen pulse improved from 10.5 6 3.0 mL/beat to 11.3 6 2.6 (p ! 0.01). Peak oxygen uptake also improved significantly (p ! 0.01) form 19.7 6 3.0 mL/min/kg to 21.7 6 3.6. Conclusion: Pioglitazone, one of the insulin resistance modulator, improved cardiac function during exercise.