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Novel Selective EP4 Receptor Agonists Restore the Intracellular Ca2+ Handling and the Cardiomyocyte Function in Heart Failure
The 17th Annual Scientific Meeting
O-077 The Efficacy of Tolvaptan in Acute Heart Failure with Nephrosis TAIKI SAKAGUCHI, TETSUO FURUKAWA, KAZUYA SHINOUCHI, HIROYUKI MIURA, KOICHI MIYAZAKI, GO HAMANO, MASAO KOIDE, HARUHIKO ABE, KEIJI HIROOKA, YOSHIO YASUMURA Department of Cardiology, Osaka National Hospital Backgrounds: Diuretic responsiveness in patients with nephrotic syndrome is limited in using loop diuretics. We studied the effects of Tolvaptan (TLV) in acute heart failure (AHF) patients with nephrotic syndrome who showed diuretic resistance. Methods: Six AHF patients with nephrotic syndrome were enrolled. They were basically treated with the following conventional therapies for heart failure. All patients received intravenous Carperitide (ANP) and loop diuretics, and four of them received serum concentrated albumin additionally. TLV was prescribed after conventional therapeutic interventions. The maximal urine output per day during three days after TLV administration (maxUO) was compared with the urine output of the day before TLV administration (preUO). Difference in body weight (DBW) during one week before and after TLV administration was also calculated. Results: By the intervention only using the conventional therapies, two patients showed sufficient improvement though their serum creatinine level had increased during the period, one patient was not able to stabilize without Furosemide continuous infusion, and three patients were not stabilized. After the prescription of TLV, five patients were stabilized. MaxUO (22996615mL) was larger than preUO (14506415mL), and DBW increased from 0.962.6kg to 2.461.8kg. Conclusions: TLV may be a useful therapeutic option for AHF patients with nephrotic syndrome who show diuretic resistance.
O-078 The Impact of b-blocker Selectivity on Respiratory Function and Outcomes in Congestive Heart Failure Patients with Chronic Obstructive Pulmonary Disease ERITO FURUSE1, YOSHIAKI KUBOTA1, JYUNNSUKE SHIBUYA1, ISAMU FUKUIZUMI1, AYA YOSHINAGA1, KOUJI MURAI1, MASATOMO YOSHIKAWA1, KUNIYA ASAI1, NAOKI SATO2, WATARU SHIMIZU1 1 Cardiovascular Medicine, Nippon Medical School Hospital, 2Cardiovascular Medicine, Nippon Medical School Musashi Kosugi Hospital Background: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with congestive heart failure (CHF). b-blocker use, which is the standard treatment for CHF, has been usually avoided in patients with COPD. The aim of this study was to evaluate the impact of b-blocker selectivity on respiratory function and long-term outcomes in CHF patients with COPD. Methods: We retrospectively analyzed 40 patients (77.4 6 8.0 years, male 89.1 %) with CHF and COPD who had history of hospitalization at our institute and received b-blockers between January 2009 and June 2012. Carvedilol was used in 27 patients(groupA), and bisoprolol was used in 13 patients(groupB). Primary outcome was changes in respiratory function, and secondary outcome was hospitalization rates for CHF or COPD exacerbation. Results: The mean follow-up period was 15.3 months. Baseline characteristics including respiratory function were similar between two groups. There was no significant change in respiratory function (FEV1.0%) of each group (group A: FEV1.0% 74.9624.2%/72.1624.7%, P50.65, group B: FEV1.0% 71.4613.1%/ 62.7619.7%, P50.28) after b-blocker. The number of exacerbations of CHF/COPD was greater in group A than group B (48.1 % vs. 15.6 %, respectively, p50.045). Conclusion: Our results suggest that bisoprolol lower the COPD or CHF exacerbation without affecting the respiratory function compared with carvedilol.
O-079 Carvedilol Reduces Mortality in Elderly Patients with Heart Failure Regardless of Left Ventricular Ejection Fraction KENSAKU YAMADA, YOSHIHARU KINUGASA, KIYOTAKA YANAGIHARA, MASAYUKI HIRAI, MASAHIKO KATO, KAZUHIRO YAMAMOTO Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University Previous clinical trials have proven beneficial effects of beta-blockers in patients with heart failure (HF) with reduced ejection fraction. However, those studies excluded elderly patients from the subjects or included only a small number of them. We assessed whether beta-blocker treatment with carvedilol improves survival in elderly patients with HF regardless of left ventricular ejection fraction (LVEF). We retrospectively analyzed a total of 189 patients aged older than 75 years who were hospitalized with HF from January 2004 to December 2010. Of these, 84 patients (44%) had been treated with carvedilol at discharge. Patients treated with carvedilol were younger, were less likely to have chronic obstructive pulmonary disease, and had lower LVEF compared with those without carvedilol (all p!0.05). During the median follow-up of 2.5 years after discharge, 92 patients died, and carvedilol
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significantly decreased all-cause mortality in this cohort (p!0.01). Furthermore, a beneficial effect on outcome was found in patients with reduced (LVEF #40%) and preserved (LVEF O40%) EF (p!0.05). Even after adjustment for covariates, carvedilol remained an independent predictor of survival in patients of both groups (p!0.05) Carvedilol may improve survival of Japanese elderly patients with HF regardless of LVEF.
O-080 Efficacy and Limitations of Oral Inotropic Agents for the Treatment of Chronic Heart Failure: A Single Center Cross-sectional Observational Study EIICHIRO OKA1, KOJI MURAI1, ISAMU FUKUIZUMI1, KUNIYA ASAI1, YOSHIHIKO SEINO2, WATARU SHIMIZU1 1 Cardiology, Nippon Medical School, 2Cardiology, Nippon Medical School ChibaHokusoh Hospital Background: The heart failure guideline in Japan has stated the necessity of investigating the role of oral inotropic agents in patients with chronic heart failure (CHF), which are clinically available only in Japan. Methods: A total of 1,846 consecutive patients with heart failure (mean: 69.5 years old, 1,279 males) treated at our institute from November 2009 to August 2010 were investigated retrospectively. Thirty-one patients (1.84%) who had taken oral inotropic agents (pimobendan 27, docarpamine 6, and denopamine 4) were extracted for this study, and the efficacy and limitations of the treatments were analyzed. Results: Following the oral inotropic treatment, the NYHA functional class (P50.017), cardiothoracic ratio (P50.002) and B-type natriuretic peptide levels (P50.011) were significantly improved, and the number of emergency room (ER) visits (P!0.001) and hospitalizations (P!0.001) were significantly reduced. The non-surviving patients (N57/31, 22.6%) were significantly older (P50.02) and tended to have a larger cardiothoracic ratio (P50.084) compared with the survivors. An absence of concomitant beta-blocker therapy was significantly associated with a worse prognosis (one-year mortality 2/21 versus 5/10, log rank, P50.011). Conclusion: Oral inotropic agents brought about improvements in the clinical parameters of CHF and a reduction in ER visits and hospitalizations. However, concomitant beta-blocker therapy should be considered for patients receiving the oral inotropic treatment.
O-081 Novel Selective EP4 Receptor Agonists Restore the Intracellular Ca2+ Handling and the Cardiomyocyte Function in Heart Failure WAKAKO MURAKAMI, SHIGEKI KOBAYASHI, TAKEKI MYOREN, SHIGEHIKO NISHIMURA, TAKAYOSHI KATO, MASAKAZU FUKUDA, SHINICHI OKUDA, TETSURO ODA, TAKESHI YAMAMOTO, MASAFUMI YANO Division of Cardiology, Department of Medicine and Clinica, Yamaguchi University Graduate School of Medicine Background: Prostaglandin E2 (PGE2) has four receptor subtypes, EP1-EP4. EP4 is reported to be a dominant receptor subtype expressed in cardiac tissue. However, the precise role of EP4 receptor in heart failure has not yet been elucidated. Here, we investigated the effect of selective EP4 agonists the intracellular Ca2+ handling and the cardiomyocyte function in normal and failing cardiomyocytes. Methods: Cardiomyocytes were isolated from the left ventricles (LV) of normal dog and heart failure model by 4-week’s rapid pacing. Then, we investigated the effect of the various concentrations of selective EP4 agonists, Ono 4232 and Ono 437 (Ono pharmaceutical Co., Ltd.), on intracellular Ca2+ transient and cell shortening in intact normal and failing cardiomyocytes. Results: In normal cardiomyocytes, Ono 4232 and Ono 437, have no appreciable effect on peak intracellular Ca transient (% pCaT) and peak cell shortening (%CS) at each dose (1nM, 10nM, 100nM, 1000nM). In failing cardiomyocytes, however, both Ono 4232 and Ono 437 significantly increased % pCaT and % CS at 10nM. Conclusion: These results suggest that selective EP4 receptor agonists improve cardiac function by the correction of abnormal intracellular Ca2+ handling. Therefore, use of a selective EP4 agonist may become a new strategy for the treatment for heart failure.
O-082 Population Pharmacokinetics Analysis and Proposed Dosing Regimen for Optimizing Serum Digoxin Concentration in Adult Patients TOSHIAKI KOMATSU1, MAMI MORITA1, TAKAYUKI INOMATA2, KOICHIRO ATSUDA1,3 1 Department of Pharmacy, Kitasato University Hospital, 2Department of CardioAngiology, Kitasato University School of Medicine, 3School of Pharmacy, Kitasato University Background: Although digoxin has been utilized even now as an option for heart failure management, its narrow therapeutic window makes it difficult to judge the therapeutic efficacy and to minimize the risk of toxicity. Methods & Results: We
O-077 The Efficacy of Tolvaptan in Acute Heart Failure with Nephrosis TAIKI SAKAGUCHI, TETSUO FURUKAWA, KAZUYA SHINOUCHI, HIROYUKI MIURA, KOICHI MIYAZAKI, GO HAMANO, MASAO KOIDE, HARUHIKO ABE, KEIJI HIROOKA, YOSHIO YASUMURA Department of Cardiology, Osaka National Hospital Backgrounds: Diuretic responsiveness in patients with nephrotic syndrome is limited in using loop diuretics. We studied the effects of Tolvaptan (TLV) in acute heart failure (AHF) patients with nephrotic syndrome who showed diuretic resistance. Methods: Six AHF patients with nephrotic syndrome were enrolled. They were basically treated with the following conventional therapies for heart failure. All patients received intravenous Carperitide (ANP) and loop diuretics, and four of them received serum concentrated albumin additionally. TLV was prescribed after conventional therapeutic interventions. The maximal urine output per day during three days after TLV administration (maxUO) was compared with the urine output of the day before TLV administration (preUO). Difference in body weight (DBW) during one week before and after TLV administration was also calculated. Results: By the intervention only using the conventional therapies, two patients showed sufficient improvement though their serum creatinine level had increased during the period, one patient was not able to stabilize without Furosemide continuous infusion, and three patients were not stabilized. After the prescription of TLV, five patients were stabilized. MaxUO (22996615mL) was larger than preUO (14506415mL), and DBW increased from 0.962.6kg to 2.461.8kg. Conclusions: TLV may be a useful therapeutic option for AHF patients with nephrotic syndrome who show diuretic resistance.
O-078 The Impact of b-blocker Selectivity on Respiratory Function and Outcomes in Congestive Heart Failure Patients with Chronic Obstructive Pulmonary Disease ERITO FURUSE1, YOSHIAKI KUBOTA1, JYUNNSUKE SHIBUYA1, ISAMU FUKUIZUMI1, AYA YOSHINAGA1, KOUJI MURAI1, MASATOMO YOSHIKAWA1, KUNIYA ASAI1, NAOKI SATO2, WATARU SHIMIZU1 1 Cardiovascular Medicine, Nippon Medical School Hospital, 2Cardiovascular Medicine, Nippon Medical School Musashi Kosugi Hospital Background: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with congestive heart failure (CHF). b-blocker use, which is the standard treatment for CHF, has been usually avoided in patients with COPD. The aim of this study was to evaluate the impact of b-blocker selectivity on respiratory function and long-term outcomes in CHF patients with COPD. Methods: We retrospectively analyzed 40 patients (77.4 6 8.0 years, male 89.1 %) with CHF and COPD who had history of hospitalization at our institute and received b-blockers between January 2009 and June 2012. Carvedilol was used in 27 patients(groupA), and bisoprolol was used in 13 patients(groupB). Primary outcome was changes in respiratory function, and secondary outcome was hospitalization rates for CHF or COPD exacerbation. Results: The mean follow-up period was 15.3 months. Baseline characteristics including respiratory function were similar between two groups. There was no significant change in respiratory function (FEV1.0%) of each group (group A: FEV1.0% 74.9624.2%/72.1624.7%, P50.65, group B: FEV1.0% 71.4613.1%/ 62.7619.7%, P50.28) after b-blocker. The number of exacerbations of CHF/COPD was greater in group A than group B (48.1 % vs. 15.6 %, respectively, p50.045). Conclusion: Our results suggest that bisoprolol lower the COPD or CHF exacerbation without affecting the respiratory function compared with carvedilol.
O-079 Carvedilol Reduces Mortality in Elderly Patients with Heart Failure Regardless of Left Ventricular Ejection Fraction KENSAKU YAMADA, YOSHIHARU KINUGASA, KIYOTAKA YANAGIHARA, MASAYUKI HIRAI, MASAHIKO KATO, KAZUHIRO YAMAMOTO Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University Previous clinical trials have proven beneficial effects of beta-blockers in patients with heart failure (HF) with reduced ejection fraction. However, those studies excluded elderly patients from the subjects or included only a small number of them. We assessed whether beta-blocker treatment with carvedilol improves survival in elderly patients with HF regardless of left ventricular ejection fraction (LVEF). We retrospectively analyzed a total of 189 patients aged older than 75 years who were hospitalized with HF from January 2004 to December 2010. Of these, 84 patients (44%) had been treated with carvedilol at discharge. Patients treated with carvedilol were younger, were less likely to have chronic obstructive pulmonary disease, and had lower LVEF compared with those without carvedilol (all p!0.05). During the median follow-up of 2.5 years after discharge, 92 patients died, and carvedilol
JHFS
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significantly decreased all-cause mortality in this cohort (p!0.01). Furthermore, a beneficial effect on outcome was found in patients with reduced (LVEF #40%) and preserved (LVEF O40%) EF (p!0.05). Even after adjustment for covariates, carvedilol remained an independent predictor of survival in patients of both groups (p!0.05) Carvedilol may improve survival of Japanese elderly patients with HF regardless of LVEF.
O-080 Efficacy and Limitations of Oral Inotropic Agents for the Treatment of Chronic Heart Failure: A Single Center Cross-sectional Observational Study EIICHIRO OKA1, KOJI MURAI1, ISAMU FUKUIZUMI1, KUNIYA ASAI1, YOSHIHIKO SEINO2, WATARU SHIMIZU1 1 Cardiology, Nippon Medical School, 2Cardiology, Nippon Medical School ChibaHokusoh Hospital Background: The heart failure guideline in Japan has stated the necessity of investigating the role of oral inotropic agents in patients with chronic heart failure (CHF), which are clinically available only in Japan. Methods: A total of 1,846 consecutive patients with heart failure (mean: 69.5 years old, 1,279 males) treated at our institute from November 2009 to August 2010 were investigated retrospectively. Thirty-one patients (1.84%) who had taken oral inotropic agents (pimobendan 27, docarpamine 6, and denopamine 4) were extracted for this study, and the efficacy and limitations of the treatments were analyzed. Results: Following the oral inotropic treatment, the NYHA functional class (P50.017), cardiothoracic ratio (P50.002) and B-type natriuretic peptide levels (P50.011) were significantly improved, and the number of emergency room (ER) visits (P!0.001) and hospitalizations (P!0.001) were significantly reduced. The non-surviving patients (N57/31, 22.6%) were significantly older (P50.02) and tended to have a larger cardiothoracic ratio (P50.084) compared with the survivors. An absence of concomitant beta-blocker therapy was significantly associated with a worse prognosis (one-year mortality 2/21 versus 5/10, log rank, P50.011). Conclusion: Oral inotropic agents brought about improvements in the clinical parameters of CHF and a reduction in ER visits and hospitalizations. However, concomitant beta-blocker therapy should be considered for patients receiving the oral inotropic treatment.
O-081 Novel Selective EP4 Receptor Agonists Restore the Intracellular Ca2+ Handling and the Cardiomyocyte Function in Heart Failure WAKAKO MURAKAMI, SHIGEKI KOBAYASHI, TAKEKI MYOREN, SHIGEHIKO NISHIMURA, TAKAYOSHI KATO, MASAKAZU FUKUDA, SHINICHI OKUDA, TETSURO ODA, TAKESHI YAMAMOTO, MASAFUMI YANO Division of Cardiology, Department of Medicine and Clinica, Yamaguchi University Graduate School of Medicine Background: Prostaglandin E2 (PGE2) has four receptor subtypes, EP1-EP4. EP4 is reported to be a dominant receptor subtype expressed in cardiac tissue. However, the precise role of EP4 receptor in heart failure has not yet been elucidated. Here, we investigated the effect of selective EP4 agonists the intracellular Ca2+ handling and the cardiomyocyte function in normal and failing cardiomyocytes. Methods: Cardiomyocytes were isolated from the left ventricles (LV) of normal dog and heart failure model by 4-week’s rapid pacing. Then, we investigated the effect of the various concentrations of selective EP4 agonists, Ono 4232 and Ono 437 (Ono pharmaceutical Co., Ltd.), on intracellular Ca2+ transient and cell shortening in intact normal and failing cardiomyocytes. Results: In normal cardiomyocytes, Ono 4232 and Ono 437, have no appreciable effect on peak intracellular Ca transient (% pCaT) and peak cell shortening (%CS) at each dose (1nM, 10nM, 100nM, 1000nM). In failing cardiomyocytes, however, both Ono 4232 and Ono 437 significantly increased % pCaT and % CS at 10nM. Conclusion: These results suggest that selective EP4 receptor agonists improve cardiac function by the correction of abnormal intracellular Ca2+ handling. Therefore, use of a selective EP4 agonist may become a new strategy for the treatment for heart failure.
O-082 Population Pharmacokinetics Analysis and Proposed Dosing Regimen for Optimizing Serum Digoxin Concentration in Adult Patients TOSHIAKI KOMATSU1, MAMI MORITA1, TAKAYUKI INOMATA2, KOICHIRO ATSUDA1,3 1 Department of Pharmacy, Kitasato University Hospital, 2Department of CardioAngiology, Kitasato University School of Medicine, 3School of Pharmacy, Kitasato University Background: Although digoxin has been utilized even now as an option for heart failure management, its narrow therapeutic window makes it difficult to judge the therapeutic efficacy and to minimize the risk of toxicity. Methods & Results: We