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The Clinical Efficacy of Three Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension
The 21st Annual Scientific Meeting
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JHFS
S65
effects for elderly patients with residual valvular heart disease. Further prospective case experiences should be required to select suitable candidates for long-term TLV use.
clusion: PAC is useful in the prediction of cardiac event in PH-LHD in HFpEF, but not in HFrEF.
O57-1
O57-4
The Assessment of Right Ventricular Function by Right Ventricular Stroke Work Index in Patients with Pre-Capillary Pulmonary Hypertension Tatsuro Ibe, Hiroshi Wada, Yusuke Ugata, Yousuke Taniguchi, Kenichi Sakakura, Hideo Fujita, Shin-Ichi Momomura; Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
The Clinical Efficacy of Three Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension Hisataka Maki1, Masaru Hatano2, Shun Minatsuki1, Eisuke Amiya1, Yumiko Hosoya1, Issei Komuro1; 1The Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan; 2The Therapeutic Strategy for Severe Heart Failure, The University of Tokyo, Tokyo, Japan
Background: Long-term outcomes of pre-capillary pulmonary hypertension (PH) have been improved. However, morbidity and mortality are still high because of right-sided heart failure (HF). Right-sided HF is closely related to right ventricular (RV) function such as RV stroke work index (RVSWI). The aim of this study was to compare clinical characteristics between low RVSWI and high RVSWI, and to investigate the association between low RVSWI and long-term outcomes in patients with precapillary PH. Methods: We included patients admitted to diagnose and evaluate PH by right heart catheterization between 2007 and 2015. Patients with pre-capillary PH were divided into 2 groups according to the median value of RVSWI (low RVSWI group: RVSWI < 19.7 gm/m2/beat; high RVSWI group: RVSWI > 19.7 gm/m2/beat). Multivariate Cox regression analysis were applied to investigate whether the low RVSWI were associated with HF death or HF readmission in patients with pre-capillary PH. Results: A total of 36 patients with pre-capillary PH were allocated into the low RVSWI group (n = 18) and high RVSWI group (n = 18). The low RVSWI group was significantly associated with HF death or HF readmission compared to the high RVSWI group even after adjusting for confounding factors (hazard ratio: 9.80 [95% CI: 1.15 to 83.85], P = .04). Conclusions: Lower RVSWI was significantly associated with HF death or HF readmission in patients with pre-capillary PH.
O57-2 Riociguat Ameliorates Right Ventricular Function Assessed by Two-dimensional Speckle Tracking Echocardiography in Patients with Pulmonary Hypertension Mitsushige Murata1, Takashi Kawakami2, Masaharu Kataoka2, Takashi Kohno2, Yuji Itabashi2, Keiichi Fukuda2; 1Department of Laboratory Medicine, School of Medicine, Keio University, Tokyo, Japan; 2Department of Cardiology, School of Medicine Background: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Although riociguat significantly improves hemodynamics and exercise capacity in patients with CTEPH, the effect of riociguat on RV function has not been fully established. This study aimed to investigate the effect of riociguat on right ventricular (RV) function assessed by echocardiography. Methods: We studied 27 patients with PAH or CTEPH. RV function was assessed before and after administration of riociguat using conventional echocardiographic parameters such as RV diameter (RVD), tricuspid annular plain systolic excursion (TAPSE), RV S’, and RV fractional area change (RVFAC). We also used two-dimensional speckle-tracking echocardiography to investigate RV strain. Results: Riociguat significantly reduced pulmonary arterial systolic pressure (PASP). RV remodeling assessed by RV diameter and RV area was ameliorated after riociguat administration. Furthermore, RVFAC, and RV global longitudinal strain (RVGLS) were also significantly improved, and were correlated with PASP, while RV S’ and TAPSE were not. Furthermore, ANCOVA analysis revealed that RVGLS after riociguat administration was significantly better than that before administration even under the same PASP, implicating the improvement of RV contractile function by riociguat, regardless of RV loading. Conclusions: Riociguat not only improved the hemodynamics in patients with PAH and CTEPH, but also ameliorated RV remodeling and function.
O57-3 Pulmonary Arterial Capacitance Predicts Clinical Outcome in the Patients with PH-LHD with Preserved Ejection Fraction Yoshihiro Dohi1, Yasuki Kihara2; 1Department of Cardiology, Kure Kyosai Hospital, Hiroshima, Japan; 2Department of Cardiovascular Medicine, Hiroshima University graduate School of Biomedical and Health Science, Hirosima, Japan Background: In the patients with heart failure, pulmonary hypertension has important impact on clinical outcome. Little is known about the predictors of pulmonary hypertension related to left heart disease (PH-LHD) with preserved (HFpEF) and reduced ejection fraction (HFpEF). Purpose: The aim of this study is to investigate the predictor of PH-LHD in both of HFrEF and HFpEF. Methods and Results: We conducted retrospective review in 243 patients with PH-LHD. The end-points were defined as hospitalization due to heart failure and/or cardiac death. The cut-off value of PAC (3.42 ml/ mmHg) was obtained using receiver operating characteristic curve. On multivariate analysis, among age, gender, estimated glomerular filtration rate, hemoglobin, only PAC was a significant predictor of cardiac events in the HFpEF (HR 1.91, 95% CI 1.07– 3.62, P = .0285). In contrast, PAC was not a predictor of cardiac events in the HFrEF (HR 1.76, 95% CI 0.59–7.59, P = .340). Kaplan-Meier analysis revealed the low PAC group was a significantly lower rate of cardiac events compared to the high PAC group (log-rank P = .0251) in the HFpEF, whereas there is no difference in the HFrEF. Con-
Introduction: Endothelin is a key molecule for exacerbating pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Currently, three endothelin receptor antagonists (ERAs), bosentan, ambrisentan and macitentan are available and they improved hemodynamics, exercise capacity and prognosis of PAH patients. These three ERAs have different receptor affinity to two endothelin receptors (ERA/ERB), however, little is known about the difference in hemodynamic effect among these drugs. Objective: To compare the hemodynamic effects of three ERAs in PAH patients. Methods: Forty-two PAH patients who were treated with ERA (16 bosentan, 13 ambrisentan, 13 macitentan) were retrospectively examined. All patients received right heart catheterization before and after ERA introduction. Results: All three ERAs successfully improved hemodynamic parameters such as mean pulmonary arterial pressure (mPAP), cardiac index and pulmonary vascular resistance (PVR). Mean follow-up period was 208 ± 236 days between two hemodynamic examinations. The magnitude of mPAP decrease in ambrisentan and macitentan were significantly greater than that in bosentan [−8.8 ± 8.4 mmHg(ambrisentan), −5.9 ± 4.2 mmHg(macitentan) vs −2.1 ± 5.0 mmHg(bosentan), P < .05]. The magnitude of PVR decrease in ambrisentan was significantly greater than that in bosentan and macitentan [−338 ± 179dynescm−5 (ambrisentan) vs −161 ± 240dynescm−5 (bosentan), −142 ± 96 dynescm-5 (macitentan), P < .05]. Conclusion: Compared with bosentan, ambrisentan and macitentan strongly improved hemodynamic parameters in PAH patients. Ambrisentan and macitantan have stronger affinity to ERA than bosentan, which may influence the power to dilate pulmonary vessels.
O57-5 Clinical Features of the Systemic Sclerosis Associated Pulmonary Arterial Hypertension with Left Heart Disease Hiromu Yanagisawa1, Hideyuki Kinoshita2, Kouichirou Kuwahara3, Hajime Yoshifuji4, Kenji Moriuti1, Hideaki Inazumi1, Naritatsu Saitou1, Yasuaki Nakagawa1, Kou Ono1, Takeshi Kimura1; 1Department of Cardiovascular Medicine, Kyoto University Graduated School of Medcine; 2Department of Community Medicine Supporting System, Kyoto University Graduated School of Medicine; 3Department of Cardiovascular Medcine, Shinshu University School of Medcine; 4Department of Rheumatology and Clinical Immunology, Graduated School of Medcine, Kyoto University Left heart disease (LHD) is common in systemic sclerosis (SSc). Although LHD is supposed to associate with increased mortality, there was little data as to the LHD in the patients with pulmonary arterial hypertension (PAH) associated with SSc. 25 patients with PAH associated with SSc were retrospectively evaluated. 15 out of 25 patients had LHD, which was defined as TDI-e’ (sep) <6 cm/s, left ventricular hypertrophy, valvular heart disease or ischemic heart disease. No patients showed LV systolic dysfunction. LHD group showed advanced age. In the hemodynamic parameter before PAH targeted therapy, LHD group showed lower cardiac index (CI) and higher pulmonary vascular resistance (PVR) compared with non-LHD group. All of the patients were treated with PAH targeted therapy, and the number of PAH targeted therapy was not different in two groups. Although mPAP and PVR were decreased after PAH targeted therapy in both groups, LHD group showed higher mPAP and PVR than non-LHD group. However, prognostic parameters such as survival rate, hospitalization, and frequency of pulmonary edema were not different between two groups. Our data suggested that LHD showed no impact to the prognosis in the PAH patients with SSc, in spite of the high frequency of LHD in PAH patients associated with SSc, and the poor improvement in hemodynamic parameters with the PAH targeted therapy.
O57-6 Acute Effects of Inhaled Iloprost in Pulmonary Arterial Hypertension Patients with Lung Disease Munekazu Tanaka1, Hideyuki Kinoshita1,2, Hiromu Yanagisawa1, Kenji Moriuchi1, Hideaki Inazumi1, Naritatsu Saito1, Yasuaki Nakagawa1, Koichiro Kuwahara3, Koh Ono1, Takeshi Kimura1; 1Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department of Community Medicine Supporting System, Kyoto University Graduate School of Medicine, Kyoto, Japan; 3Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan Although there were no evidence from RCTs suggesting pulmonary arterial hypertension (PAH) targeted therapy improved outcome, some studies suggested beneficial effect of inhaled iloprost in patients with suspected PAH in addition to their lung disease. The purpose of this study is to clarify the acute effect of inhaled iloprost on PAH patients with lung disease.8 patients with suspected PAH and lung disease (connective tissue disease-associated interstitial lung disease 4, CPFE 2, COPD 1, IPF 1) were un-
•
JHFS
S65
effects for elderly patients with residual valvular heart disease. Further prospective case experiences should be required to select suitable candidates for long-term TLV use.
clusion: PAC is useful in the prediction of cardiac event in PH-LHD in HFpEF, but not in HFrEF.
O57-1
O57-4
The Assessment of Right Ventricular Function by Right Ventricular Stroke Work Index in Patients with Pre-Capillary Pulmonary Hypertension Tatsuro Ibe, Hiroshi Wada, Yusuke Ugata, Yousuke Taniguchi, Kenichi Sakakura, Hideo Fujita, Shin-Ichi Momomura; Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
The Clinical Efficacy of Three Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension Hisataka Maki1, Masaru Hatano2, Shun Minatsuki1, Eisuke Amiya1, Yumiko Hosoya1, Issei Komuro1; 1The Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan; 2The Therapeutic Strategy for Severe Heart Failure, The University of Tokyo, Tokyo, Japan
Background: Long-term outcomes of pre-capillary pulmonary hypertension (PH) have been improved. However, morbidity and mortality are still high because of right-sided heart failure (HF). Right-sided HF is closely related to right ventricular (RV) function such as RV stroke work index (RVSWI). The aim of this study was to compare clinical characteristics between low RVSWI and high RVSWI, and to investigate the association between low RVSWI and long-term outcomes in patients with precapillary PH. Methods: We included patients admitted to diagnose and evaluate PH by right heart catheterization between 2007 and 2015. Patients with pre-capillary PH were divided into 2 groups according to the median value of RVSWI (low RVSWI group: RVSWI < 19.7 gm/m2/beat; high RVSWI group: RVSWI > 19.7 gm/m2/beat). Multivariate Cox regression analysis were applied to investigate whether the low RVSWI were associated with HF death or HF readmission in patients with pre-capillary PH. Results: A total of 36 patients with pre-capillary PH were allocated into the low RVSWI group (n = 18) and high RVSWI group (n = 18). The low RVSWI group was significantly associated with HF death or HF readmission compared to the high RVSWI group even after adjusting for confounding factors (hazard ratio: 9.80 [95% CI: 1.15 to 83.85], P = .04). Conclusions: Lower RVSWI was significantly associated with HF death or HF readmission in patients with pre-capillary PH.
O57-2 Riociguat Ameliorates Right Ventricular Function Assessed by Two-dimensional Speckle Tracking Echocardiography in Patients with Pulmonary Hypertension Mitsushige Murata1, Takashi Kawakami2, Masaharu Kataoka2, Takashi Kohno2, Yuji Itabashi2, Keiichi Fukuda2; 1Department of Laboratory Medicine, School of Medicine, Keio University, Tokyo, Japan; 2Department of Cardiology, School of Medicine Background: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Although riociguat significantly improves hemodynamics and exercise capacity in patients with CTEPH, the effect of riociguat on RV function has not been fully established. This study aimed to investigate the effect of riociguat on right ventricular (RV) function assessed by echocardiography. Methods: We studied 27 patients with PAH or CTEPH. RV function was assessed before and after administration of riociguat using conventional echocardiographic parameters such as RV diameter (RVD), tricuspid annular plain systolic excursion (TAPSE), RV S’, and RV fractional area change (RVFAC). We also used two-dimensional speckle-tracking echocardiography to investigate RV strain. Results: Riociguat significantly reduced pulmonary arterial systolic pressure (PASP). RV remodeling assessed by RV diameter and RV area was ameliorated after riociguat administration. Furthermore, RVFAC, and RV global longitudinal strain (RVGLS) were also significantly improved, and were correlated with PASP, while RV S’ and TAPSE were not. Furthermore, ANCOVA analysis revealed that RVGLS after riociguat administration was significantly better than that before administration even under the same PASP, implicating the improvement of RV contractile function by riociguat, regardless of RV loading. Conclusions: Riociguat not only improved the hemodynamics in patients with PAH and CTEPH, but also ameliorated RV remodeling and function.
O57-3 Pulmonary Arterial Capacitance Predicts Clinical Outcome in the Patients with PH-LHD with Preserved Ejection Fraction Yoshihiro Dohi1, Yasuki Kihara2; 1Department of Cardiology, Kure Kyosai Hospital, Hiroshima, Japan; 2Department of Cardiovascular Medicine, Hiroshima University graduate School of Biomedical and Health Science, Hirosima, Japan Background: In the patients with heart failure, pulmonary hypertension has important impact on clinical outcome. Little is known about the predictors of pulmonary hypertension related to left heart disease (PH-LHD) with preserved (HFpEF) and reduced ejection fraction (HFpEF). Purpose: The aim of this study is to investigate the predictor of PH-LHD in both of HFrEF and HFpEF. Methods and Results: We conducted retrospective review in 243 patients with PH-LHD. The end-points were defined as hospitalization due to heart failure and/or cardiac death. The cut-off value of PAC (3.42 ml/ mmHg) was obtained using receiver operating characteristic curve. On multivariate analysis, among age, gender, estimated glomerular filtration rate, hemoglobin, only PAC was a significant predictor of cardiac events in the HFpEF (HR 1.91, 95% CI 1.07– 3.62, P = .0285). In contrast, PAC was not a predictor of cardiac events in the HFrEF (HR 1.76, 95% CI 0.59–7.59, P = .340). Kaplan-Meier analysis revealed the low PAC group was a significantly lower rate of cardiac events compared to the high PAC group (log-rank P = .0251) in the HFpEF, whereas there is no difference in the HFrEF. Con-
Introduction: Endothelin is a key molecule for exacerbating pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Currently, three endothelin receptor antagonists (ERAs), bosentan, ambrisentan and macitentan are available and they improved hemodynamics, exercise capacity and prognosis of PAH patients. These three ERAs have different receptor affinity to two endothelin receptors (ERA/ERB), however, little is known about the difference in hemodynamic effect among these drugs. Objective: To compare the hemodynamic effects of three ERAs in PAH patients. Methods: Forty-two PAH patients who were treated with ERA (16 bosentan, 13 ambrisentan, 13 macitentan) were retrospectively examined. All patients received right heart catheterization before and after ERA introduction. Results: All three ERAs successfully improved hemodynamic parameters such as mean pulmonary arterial pressure (mPAP), cardiac index and pulmonary vascular resistance (PVR). Mean follow-up period was 208 ± 236 days between two hemodynamic examinations. The magnitude of mPAP decrease in ambrisentan and macitentan were significantly greater than that in bosentan [−8.8 ± 8.4 mmHg(ambrisentan), −5.9 ± 4.2 mmHg(macitentan) vs −2.1 ± 5.0 mmHg(bosentan), P < .05]. The magnitude of PVR decrease in ambrisentan was significantly greater than that in bosentan and macitentan [−338 ± 179dynescm−5 (ambrisentan) vs −161 ± 240dynescm−5 (bosentan), −142 ± 96 dynescm-5 (macitentan), P < .05]. Conclusion: Compared with bosentan, ambrisentan and macitentan strongly improved hemodynamic parameters in PAH patients. Ambrisentan and macitantan have stronger affinity to ERA than bosentan, which may influence the power to dilate pulmonary vessels.
O57-5 Clinical Features of the Systemic Sclerosis Associated Pulmonary Arterial Hypertension with Left Heart Disease Hiromu Yanagisawa1, Hideyuki Kinoshita2, Kouichirou Kuwahara3, Hajime Yoshifuji4, Kenji Moriuti1, Hideaki Inazumi1, Naritatsu Saitou1, Yasuaki Nakagawa1, Kou Ono1, Takeshi Kimura1; 1Department of Cardiovascular Medicine, Kyoto University Graduated School of Medcine; 2Department of Community Medicine Supporting System, Kyoto University Graduated School of Medicine; 3Department of Cardiovascular Medcine, Shinshu University School of Medcine; 4Department of Rheumatology and Clinical Immunology, Graduated School of Medcine, Kyoto University Left heart disease (LHD) is common in systemic sclerosis (SSc). Although LHD is supposed to associate with increased mortality, there was little data as to the LHD in the patients with pulmonary arterial hypertension (PAH) associated with SSc. 25 patients with PAH associated with SSc were retrospectively evaluated. 15 out of 25 patients had LHD, which was defined as TDI-e’ (sep) <6 cm/s, left ventricular hypertrophy, valvular heart disease or ischemic heart disease. No patients showed LV systolic dysfunction. LHD group showed advanced age. In the hemodynamic parameter before PAH targeted therapy, LHD group showed lower cardiac index (CI) and higher pulmonary vascular resistance (PVR) compared with non-LHD group. All of the patients were treated with PAH targeted therapy, and the number of PAH targeted therapy was not different in two groups. Although mPAP and PVR were decreased after PAH targeted therapy in both groups, LHD group showed higher mPAP and PVR than non-LHD group. However, prognostic parameters such as survival rate, hospitalization, and frequency of pulmonary edema were not different between two groups. Our data suggested that LHD showed no impact to the prognosis in the PAH patients with SSc, in spite of the high frequency of LHD in PAH patients associated with SSc, and the poor improvement in hemodynamic parameters with the PAH targeted therapy.
O57-6 Acute Effects of Inhaled Iloprost in Pulmonary Arterial Hypertension Patients with Lung Disease Munekazu Tanaka1, Hideyuki Kinoshita1,2, Hiromu Yanagisawa1, Kenji Moriuchi1, Hideaki Inazumi1, Naritatsu Saito1, Yasuaki Nakagawa1, Koichiro Kuwahara3, Koh Ono1, Takeshi Kimura1; 1Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department of Community Medicine Supporting System, Kyoto University Graduate School of Medicine, Kyoto, Japan; 3Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan Although there were no evidence from RCTs suggesting pulmonary arterial hypertension (PAH) targeted therapy improved outcome, some studies suggested beneficial effect of inhaled iloprost in patients with suspected PAH in addition to their lung disease. The purpose of this study is to clarify the acute effect of inhaled iloprost on PAH patients with lung disease.8 patients with suspected PAH and lung disease (connective tissue disease-associated interstitial lung disease 4, CPFE 2, COPD 1, IPF 1) were un-