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Mitral Valve Repair for Medically Refractory Functional Mitral Regurgitation in Patients with End-stage Renal Disease and Advanced Heart Failure
S152 Journal of Cardiac Failure Vol. 18 No. 10S October 2012 was not increased by nephrectomy. The nephrectomy-induced deterioration of endothelium-dependent relaxation and eNOS phosphorylation was abolished in TG mice. In cultured human endothelial cells, agonist-induced phosphorylations of eNOS and the upstream kinases, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-related kinase (ERK) 1/2 phosphorylation, but not Akt, were decreased by ADMA at concentrations less than that of L-arginine in the media. Conclusions: Elevated circulating ADMA is the cause, not an epiphenomenon, of endothelial dysfunction in CKD. Inhibition of the CaMKII- and ERK-mediated eNOS phosphorylation may be a novel mechanism by which ADMA impairs eNOS function.
O-020 Cystatin C is Superior to Creatinine-based Estimated Glomerular Filtration Rate for Predicting Prognosis of Heart Failure Patients with Low-body Weight YUYA MATSUE, AKIRA MIZUKAMI, WATARU NAGAHORI, MASAKAZU OHNO, MAKOTO SUZUKI, AKIHIKO MATSUMURA, YUJI HASHIMOTO Department of Cardiology, Kameda Medical Center, Chiba, Japan Background: Although creatinine-based estimation of glomerular filtration rate (Cre-eGFR) is a powerful predictor of prognosis in heart failure (HF) patients, this measure is affected by non-renal factors, such as age, gender, and lean muscle mass. Cystatin-C emerged as novel marker of renal function, and may overcome these limitations. Given that HF leads to body weight loss, so-called cardiac cachexia, we hypothesized that Cystatin-C would be stronger predictor of prognosis especially for low-body weight HF patients. Methods: We enrolled 171 admitted HF patients, and all patients were followed-up for major adverse cerebrovascular events (MACEs). The predictive abilities for MACEs of Cre-eGFR and Cys-C were compared by area under the ROC curve (AUC). In addition to all-cohort analysis, patients were divided into two groups according to median body mass index (BMI) of each gender. Results: At baseline, the median CreGFR and Cystatin-C were 49.5 (IQR: 39.5-64.1 ml/min./1.73m2) and 1.44 (IQR: 1.02-1.81 mg/l), respectively. There were 47 MACEs during follow-up for 2956181 days. The AUCs of Cre-eGFR and Cystatin-C did not significantly different in all-cohort (0.72 vs 0.68, P50.21) and higher-BMI group (0.68 vs 0.71, P50.43). However, the AUC of Cystatin-C for prognosis was superior in lowerBMI group (0.78 vs 0.65, P50.03). Conclusions: Cystatin-C was superior to CreeGFR for providing prognostic information especially in low-body weight HF patients.
O-021 Indoxyl Sulfate, a Uremic Toxin, Exaggerates Cardiac Connective Tissue Growth Factor Expression MASARU OBOKATA, NORIMICHI KOITABASHI, MASASHI ARAI, MASAHIKO KURABAYASHI Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan Background: Uremic cardiomyopathy contributes substantially to the higher mortality in patients with chronic kidney disease (CKD). Connective tissue growth factor (CTGF) is a cytokine, which contributes pathogenesis of cardiac fibrosis. However, the role of CTGF expression in uremic cardiomyopathy is unknown. Indoxyl sulfate (IS), a protein metabolite concentrated in the serum of CKD patients, is considered as a uremic toxin and may play a role for the cardiovascular insult. Methods and Results: We tested cardiac CTGF expression in a rat model of CKD, 5/6-nephrectomized (5/6N) model. CTGF expression was markedly increased in cardiac tissues of 5/6N model. CTGF expression levels were correlated with cardiac fibrosis. To examine the role of uremic toxin on CKD-induced CTGF expression in heart, we performed in vitro experiments using cultured cardiomyocytes (CM) and fibroblasts (CF) isolated from neonatal rat hearts. A uremic toxin, IS, did not showed significant effect on CTGF expression in both CM and CF. However, in the presence of transforming growth factor beta (TGFb), a potent inducer of CTGF, IS dose-dependently increased CTGF expression in CF but not in CM. Conclusion: CTGF expression was increased in a model of uremic cardiomyopathy. IS has a boosted effect on TGFb-induced CTGF expression in CF. These results suggest that IS contributes a pathogenesis of uremic cardiomyopathy through exaggeration of cardiac CTGF gene expression.
O-022 Relationship Between Bone Metabolism and Cardiorenal Syndrome KEISUKE KIDA, NORIO SUZUKI, YOSHIHIRO J. AKASHI, FUMIHIKO MIYAKE Department of Cardiology, St. Marianna University School of Medicine, Kawasaki, Japan Background: Osteoporosis is increasing as a result of the aging society in Japan, which has gained broad attention in the various fields. This study investigated bone quality markers and its association with the severity of chronic heart failure (CHF) and chronic kidney disease (CKD). Methods: Seventy elderly CHF and CKD patients were stratified into the following 4 groups: A, patients with estimated glomerular filtration rate (eGFR) O60 and New York
Heart Association classification (NYHA) I (n511); B, patients with eGFR!60 and NYHA I (n512); C, patients with eGFRO60 and NYHA II-III (n511); D, patients with eGFR!60 and NYHA II-III (n536). A bone densitometer (PRODIGY, GE) utilizing dual energy X-ray absorptiometry measured bone mineral density (BMD) and % Young Adult Mean (YAM). Blood samples were collected for assessing bone quality markers (homocysteine and pentosidine). Results: Osteoporosis accounted for 18% (A), 42% (B), 27% (C), and 28% (D) in each group. BMD or %YAM did not significantly differ between the 4 groups. However, homocysteine and pentosidine were significantly higher in group D (16.967.4nmoL/mL and 0.05060.050mg/m) than the other groups (A, 8.162.2nmoL/mL and 0.02360.008mg/mL; B, 10.763.8nmoL/mL and 0.02460.008mg/mL; C, 11.863.5nmoL/mL and 0.02760.009mg/mL, p!0.01 and p!0.05). Conclusion: This study result demonstrated the usefulness of bone quality markers to identify disease severity in elderly patients with severe CHF and CKD.
O-023 Prediction of Responder and Influence for Cardio-Renal Interaction by Tolvaptan in Patients with Chronic Heart Failure MUNEYUKI KADOTA1, TAKAYUKI ISE1, TAKASHI IWASE1, MASASHI AKAIKE2, KOJI YAMAGUCHI1, YOSHIO TAKETANI1, HIROTSUGU YAMADA1, TETSUZO WAKATSUKI1, TAKESHI SOEKI1, MASATAKA SATA1 1 Department of Cardiovascular Medicine, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan, 2Medical Education, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan Background and Purpose: Conventional diuretics are known to adversely affect cordio-renal interactions, such as activation of the renin-angiotensin-aldosterone system, or worsen renal function. However, the effects of tolvaptan of cardio-renal interactions and the prediction in response to tolvaptan are not well known. Method: We evaluated 19 chronic heart failure patients, who recieved therapy with 15mg/day tolvaptan instead of conventional diuretic drugs and examined the symptoms, laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a decrease in body weight by more than 3kg in 2weeks and an increase in urine volume by 500 ml/day compared with that before tolvaptan administration. Result: The New York Heart Association function class and brain natriuretic peptide levels were significantly improved in the responder group (p!0.05), without worsening of the renal function including serum creatinine, urea nitrogen, uric acid levels. Urine osmolality before administration of tolvaptan was significantly higher in the responder group compared with the non-responder group (P!0.05), and had declined significantly after tolvaptan administration in the responder group (P!0.05). Furthermore, in both groups, no significant changes were observed in plasma renin activity and aldosterone concentration after tolvaptan administration. Conclusion: Treatment with tolvaptan could prevent adverse cardio-renal interactions in chronic heart failure patients. Additionally, monitoring of urine osmolality may be useful in predicting the response to tolvaptan.
O-024 Mitral Valve Repair for Medically Refractory Functional Mitral Regurgitation in Patients with End-stage Renal Disease and Advanced Heart Failure SATOSHI KAINUMA1, KAZUHIRO TANIGUCHI2, KOICHI TODA1, TOSHIHIRO FUNATSU2, SHIGERU MIYAGAWA1, HARUHIKO KONDOH2, TAKAFUMI MASAI4, MITSURU OHISHI3, YOSHIKI SAWA1 1 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Japan, 2Department of Cardiovascular Surgery, Japan Labor Health and Welfare Organization Osaka Rosai Hospital, Sakai, Japan, 3Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan, 4Osaka Cardiovascular Group, Suita, Japan Background: Information regarding patient selection for mitral valve (MV) repair for chronic kidney disease (CKD) or end-stage renal disease with severe heart failure (HF), as well as outcome is limited. Methods: We classified 208 patients with advanced HF symptoms undergoing MV repair for functional mitral regurgitation (MR) into 3 groups: estimated glomerular filtration rate (eGFR) O30 mL/min/ 1.73m2 (control group, n5144); eGFR !30 mL/min/1.73m2, not dependent on hemodialysis (CKD group, n545), and hemodialysis (HD group, n519; preoperative hemodialysis duration 83692 months). Follow-up was completed with a mean duration of 49625 months. Results: Postoperative (1 month) cardiac catheterization showed that LV end-systolic volume index decreased from 109638 to 79641, 103631 to 81631, and 123640 to 76634 ml/m2, in the control, CKD, and HD groups, respectively. LV end-diastolic pressure decreased, while cardiac index increased in all groups, with no intergroup differences for those postoperative values. Freedom from mortality and HF readmission at 5 years was 1867% in CKD (p! 0.0001 vs. control, p50.01 vs. HD), and 64612% in HD (p51 vs. control), as compared with 5265% in the control group. Conclusions: MV repair for medically refractory functional MR yielded improvements in LV function and hemodynamics, irrespective of preoperative renal function status. The HD patients showed favorable late outcome in terms of freedom from mortality and readmission for HF, as compared to those with CKD.
O-020 Cystatin C is Superior to Creatinine-based Estimated Glomerular Filtration Rate for Predicting Prognosis of Heart Failure Patients with Low-body Weight YUYA MATSUE, AKIRA MIZUKAMI, WATARU NAGAHORI, MASAKAZU OHNO, MAKOTO SUZUKI, AKIHIKO MATSUMURA, YUJI HASHIMOTO Department of Cardiology, Kameda Medical Center, Chiba, Japan Background: Although creatinine-based estimation of glomerular filtration rate (Cre-eGFR) is a powerful predictor of prognosis in heart failure (HF) patients, this measure is affected by non-renal factors, such as age, gender, and lean muscle mass. Cystatin-C emerged as novel marker of renal function, and may overcome these limitations. Given that HF leads to body weight loss, so-called cardiac cachexia, we hypothesized that Cystatin-C would be stronger predictor of prognosis especially for low-body weight HF patients. Methods: We enrolled 171 admitted HF patients, and all patients were followed-up for major adverse cerebrovascular events (MACEs). The predictive abilities for MACEs of Cre-eGFR and Cys-C were compared by area under the ROC curve (AUC). In addition to all-cohort analysis, patients were divided into two groups according to median body mass index (BMI) of each gender. Results: At baseline, the median CreGFR and Cystatin-C were 49.5 (IQR: 39.5-64.1 ml/min./1.73m2) and 1.44 (IQR: 1.02-1.81 mg/l), respectively. There were 47 MACEs during follow-up for 2956181 days. The AUCs of Cre-eGFR and Cystatin-C did not significantly different in all-cohort (0.72 vs 0.68, P50.21) and higher-BMI group (0.68 vs 0.71, P50.43). However, the AUC of Cystatin-C for prognosis was superior in lowerBMI group (0.78 vs 0.65, P50.03). Conclusions: Cystatin-C was superior to CreeGFR for providing prognostic information especially in low-body weight HF patients.
O-021 Indoxyl Sulfate, a Uremic Toxin, Exaggerates Cardiac Connective Tissue Growth Factor Expression MASARU OBOKATA, NORIMICHI KOITABASHI, MASASHI ARAI, MASAHIKO KURABAYASHI Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan Background: Uremic cardiomyopathy contributes substantially to the higher mortality in patients with chronic kidney disease (CKD). Connective tissue growth factor (CTGF) is a cytokine, which contributes pathogenesis of cardiac fibrosis. However, the role of CTGF expression in uremic cardiomyopathy is unknown. Indoxyl sulfate (IS), a protein metabolite concentrated in the serum of CKD patients, is considered as a uremic toxin and may play a role for the cardiovascular insult. Methods and Results: We tested cardiac CTGF expression in a rat model of CKD, 5/6-nephrectomized (5/6N) model. CTGF expression was markedly increased in cardiac tissues of 5/6N model. CTGF expression levels were correlated with cardiac fibrosis. To examine the role of uremic toxin on CKD-induced CTGF expression in heart, we performed in vitro experiments using cultured cardiomyocytes (CM) and fibroblasts (CF) isolated from neonatal rat hearts. A uremic toxin, IS, did not showed significant effect on CTGF expression in both CM and CF. However, in the presence of transforming growth factor beta (TGFb), a potent inducer of CTGF, IS dose-dependently increased CTGF expression in CF but not in CM. Conclusion: CTGF expression was increased in a model of uremic cardiomyopathy. IS has a boosted effect on TGFb-induced CTGF expression in CF. These results suggest that IS contributes a pathogenesis of uremic cardiomyopathy through exaggeration of cardiac CTGF gene expression.
O-022 Relationship Between Bone Metabolism and Cardiorenal Syndrome KEISUKE KIDA, NORIO SUZUKI, YOSHIHIRO J. AKASHI, FUMIHIKO MIYAKE Department of Cardiology, St. Marianna University School of Medicine, Kawasaki, Japan Background: Osteoporosis is increasing as a result of the aging society in Japan, which has gained broad attention in the various fields. This study investigated bone quality markers and its association with the severity of chronic heart failure (CHF) and chronic kidney disease (CKD). Methods: Seventy elderly CHF and CKD patients were stratified into the following 4 groups: A, patients with estimated glomerular filtration rate (eGFR) O60 and New York
Heart Association classification (NYHA) I (n511); B, patients with eGFR!60 and NYHA I (n512); C, patients with eGFRO60 and NYHA II-III (n511); D, patients with eGFR!60 and NYHA II-III (n536). A bone densitometer (PRODIGY, GE) utilizing dual energy X-ray absorptiometry measured bone mineral density (BMD) and % Young Adult Mean (YAM). Blood samples were collected for assessing bone quality markers (homocysteine and pentosidine). Results: Osteoporosis accounted for 18% (A), 42% (B), 27% (C), and 28% (D) in each group. BMD or %YAM did not significantly differ between the 4 groups. However, homocysteine and pentosidine were significantly higher in group D (16.967.4nmoL/mL and 0.05060.050mg/m) than the other groups (A, 8.162.2nmoL/mL and 0.02360.008mg/mL; B, 10.763.8nmoL/mL and 0.02460.008mg/mL; C, 11.863.5nmoL/mL and 0.02760.009mg/mL, p!0.01 and p!0.05). Conclusion: This study result demonstrated the usefulness of bone quality markers to identify disease severity in elderly patients with severe CHF and CKD.
O-023 Prediction of Responder and Influence for Cardio-Renal Interaction by Tolvaptan in Patients with Chronic Heart Failure MUNEYUKI KADOTA1, TAKAYUKI ISE1, TAKASHI IWASE1, MASASHI AKAIKE2, KOJI YAMAGUCHI1, YOSHIO TAKETANI1, HIROTSUGU YAMADA1, TETSUZO WAKATSUKI1, TAKESHI SOEKI1, MASATAKA SATA1 1 Department of Cardiovascular Medicine, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan, 2Medical Education, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan Background and Purpose: Conventional diuretics are known to adversely affect cordio-renal interactions, such as activation of the renin-angiotensin-aldosterone system, or worsen renal function. However, the effects of tolvaptan of cardio-renal interactions and the prediction in response to tolvaptan are not well known. Method: We evaluated 19 chronic heart failure patients, who recieved therapy with 15mg/day tolvaptan instead of conventional diuretic drugs and examined the symptoms, laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a decrease in body weight by more than 3kg in 2weeks and an increase in urine volume by 500 ml/day compared with that before tolvaptan administration. Result: The New York Heart Association function class and brain natriuretic peptide levels were significantly improved in the responder group (p!0.05), without worsening of the renal function including serum creatinine, urea nitrogen, uric acid levels. Urine osmolality before administration of tolvaptan was significantly higher in the responder group compared with the non-responder group (P!0.05), and had declined significantly after tolvaptan administration in the responder group (P!0.05). Furthermore, in both groups, no significant changes were observed in plasma renin activity and aldosterone concentration after tolvaptan administration. Conclusion: Treatment with tolvaptan could prevent adverse cardio-renal interactions in chronic heart failure patients. Additionally, monitoring of urine osmolality may be useful in predicting the response to tolvaptan.
O-024 Mitral Valve Repair for Medically Refractory Functional Mitral Regurgitation in Patients with End-stage Renal Disease and Advanced Heart Failure SATOSHI KAINUMA1, KAZUHIRO TANIGUCHI2, KOICHI TODA1, TOSHIHIRO FUNATSU2, SHIGERU MIYAGAWA1, HARUHIKO KONDOH2, TAKAFUMI MASAI4, MITSURU OHISHI3, YOSHIKI SAWA1 1 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Japan, 2Department of Cardiovascular Surgery, Japan Labor Health and Welfare Organization Osaka Rosai Hospital, Sakai, Japan, 3Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan, 4Osaka Cardiovascular Group, Suita, Japan Background: Information regarding patient selection for mitral valve (MV) repair for chronic kidney disease (CKD) or end-stage renal disease with severe heart failure (HF), as well as outcome is limited. Methods: We classified 208 patients with advanced HF symptoms undergoing MV repair for functional mitral regurgitation (MR) into 3 groups: estimated glomerular filtration rate (eGFR) O30 mL/min/ 1.73m2 (control group, n5144); eGFR !30 mL/min/1.73m2, not dependent on hemodialysis (CKD group, n545), and hemodialysis (HD group, n519; preoperative hemodialysis duration 83692 months). Follow-up was completed with a mean duration of 49625 months. Results: Postoperative (1 month) cardiac catheterization showed that LV end-systolic volume index decreased from 109638 to 79641, 103631 to 81631, and 123640 to 76634 ml/m2, in the control, CKD, and HD groups, respectively. LV end-diastolic pressure decreased, while cardiac index increased in all groups, with no intergroup differences for those postoperative values. Freedom from mortality and HF readmission at 5 years was 1867% in CKD (p! 0.0001 vs. control, p50.01 vs. HD), and 64612% in HD (p51 vs. control), as compared with 5265% in the control group. Conclusions: MV repair for medically refractory functional MR yielded improvements in LV function and hemodynamics, irrespective of preoperative renal function status. The HD patients showed favorable late outcome in terms of freedom from mortality and readmission for HF, as compared to those with CKD.