Beneficial effects of riociguat on hemodynamic responses to exercise in CTEPH patients after balloon pulmonary angioplasty - A randomized controlled study.

BACKGROUND: Although balloon pulmonary angioplasty (BPA) improves symptoms and pulmonary hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH), the effects of riociguat on hemodynamics and exercise capacity in patients after BPA remain to be elucidated. METHODS AND RESULTS: This study was a single-center, prospective, randomized, open-label trial. From November 2015 to November 2018, we prospectively examined 21 patients with CTEPH (65 ± 9 years old, M/F 2/19) who showed hemodynamic improvement with mean pulmonary arterial pressure (mPAP) < 30 mmHg after BPA without any vasodilators. We performed hemodynamic evaluation and expired gas analysis both at rest and during exercise in supine position using cycle ergometer. After right heart catheterization during exercise, they were randomly assigned to 2 groups with minimized method, using age, sex, and resting mPAP; riociguat (N = 10) and control (N = 11) groups. After 6 months, exercise capacity evaluated by 6-min walk distance and cardiopulmonary exercise testing, and resting hemodynamic parameters were comparable in both groups. However, cardiac output (CO) (6.0 ± 1.7-7.4 ± 1.6, P < 0.01) and pulmonary vascular resistance (4.8 ± 1.8-3.2 ± 0.7 Wood units, P = 0.02) at peak workload were significantly improved in the riociguat group as compared with the control group. The slope of linearized mPAP-CO relationship was significantly decreased in the riociguat group [14.5 (7.8, 14.7) to 6.41 (5.1, 11.4), P < 0.01] but not in the control group. CONCLUSIONS: These results indicate that riociguat exerts beneficial effects on hemodynamic response to exercise in CTEPH patients even after hemodynamic improvement by BPA.

Current status of long-term prognosis among all subtypes of pulmonary hypertension in Japan.

BACKGROUND: In the current era of treatment of pulmonary hypertension (PH) in Japan, combination therapy has been frequently used thanks to the medical insurance system. Additionally, pulmonary balloon angioplasty (BPA) is widely performed for chronic thromboembolic PH (CTEPH). METHODS: To elucidate the long-term prognosis and the prognostic factors among all five subtypes of PH in this new era, we examined the current status of management of PH from November 2012 to April 2016 in the multicenter registry by the Japanese Pulmonary Circulation Society. RESULTS: Among 1253 consecutive patients registered from 20 PH centers in Japan, we analyzed 997 patients with mean pulmonary arterial pressure ≥ 25 mmHg by right heart catheterization. Transplant-free survival at 5 years in pulmonary arterial hypertension (PAH), PH due to left-heart disease, PH due to lung diseases, CTEPH, and miscellaneous PH were 74.0, 69.3, 63.7, 92.0, and 55.3%, respectively. Of note, 32% of PAH patients were treated with double combination therapy and 42% of those with triple combination therapy, and 66% of CTEPH patients with BPA. Although PAH patients with triple combination therapy had worse hemodynamic parameters than those with other medications, triple combination therapy showed the best prognosis. BPA in CTEPH improved survival even when adjusted for the key background factors. CONCLUSIONS: In the current era of PH treatment in Japan, the five-year transplant-free survival rate in this study was 74% for PAH and 92% for CTEPH, in which active combination medical therapy for PAH and higher performance rate of BPA for CTEPH may be involved.

Cyclophilin A as a biomarker for the therapeutic effect of balloon angioplasty in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed. METHODS: In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia. RESULTS: CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p< 0.05) and were linearly correlated with mean pulmonary arterial pressure (r=0.50, p = 0.0003) and pulmonary vascular resistance (r=0.32, p= 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p< 0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35pg/mL) and normal (<35pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p< 0.05). In contrast, BNP decreased only in patients with higher BNP (p< 0.05). Also, CyPA decreased both in patients with lower (<25 kg/m2) and higher (≥25kg/m2) body mass index (BMI) at baseline (both p<0.05), whereas BPA tended to reduce BNP in patients with lower BMI (p = 0.12) but not in those with higher BMI (p = 0.55). CONCLUSIONS: CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI.

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH). The prognosis of PVOD patients remains poor, since no effective medical therapy is yet available. Imatinib is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor and is expected as a treatment option for pulmonary arterial hypertension (PAH). Recently, it has been reported that imatinib improved functional capacity of a patient with PVOD. We here report a patient with suspected PVOD who has been successfully treated with imatinib and is alive for 6 years after diagnosis. A 57-year-old woman was admitted to a hospital for severe dyspnea. Echocardiography suggested the presence of PH, because tricuspid regurgitation pressure gradient was elevated. The patient was then transferred to our hospital by an ambulance ahead of schedule due to fever and worsening dyspnea. Because the patient had no left heart disease, we diagnosed that she had PAH associated with severe right heart failure. We immediately started treatment with nitric oxide (NO) for her severe hypoxia; however, it caused pulmonary edema. We suspected PVOD from CT characteristics and pulmonary edema after PAH-targeted vasodilator therapy, and then started oral imatinib treatment. In response to imatinib, her pulmonary edema gradually improved. Since then, the patient has been alive for 6 years with imatinib and pulmonary vasodilators. At present, lung transplantation is the only effective therapy for PVOD with limited availability. We therefore propose that imatinib may be a treatment option for PVOD and a bridge to lung transplantation.

Clinical Diversity in Patients with Anderson-fabry Disease with the R301Q Mutation.

Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A (α-GAL A). We herein report 10 cases of AFD in 5 families (3 men and 7 women) that were found to have a specific common mutation in R301Q [G-to-A transition in exon 6 (codon 301) resulting in the replacement of a glutamine with an arginine residue]. We evaluated their clinical characteristics, residual enzymatic activity, and plasma concentrations of globotriaosylsphingosine (Lyso-Gb3). Although all 10 cases had cardiac and renal manifestations in common, their clinical manifestations were markedly divergent despite the same genetic abnormality.

Effects of Hepatitis C Virus Antibody-Positivity on Cardiac Function and Long-Term Prognosis in Patients With Adult Congenital Heart Disease.

It was reported that hepatitis C virus (HCV) antibody-positivity adversely affects cardiac function. As the screening for HCV began in 1992, we hypothesized that HCV antibody-positive rate would be high in adult congenital heart disease (ACHD) patients who underwent heart surgery before 1992 and adversely affected cardiac function and long-term prognosis. We retrospectively enrolled 243 ACHD patients (mean age 25.9 years) who underwent cardiac surgery before 1992 and visited our hospital from 1995 to 2015. We compared clinical characteristics including cardiac function and long-term prognosis between HCV antibody-positive (n = 48) and antibody-negative (n = 195) patients. The composite end point (CEP) included cardiac death, heart failure hospitalization, lethal ventricular arrhythmias, and cardiac reoperation. The prevalence of reduced systemic ventricular ejection fraction <50% was significantly higher in the HCV antibody-positive group compared with the HCV antibody-negative group (17 vs 5.4%, p = 0.014). During a mean follow-up period of 10.1 years (interquartile range 6 to 14 years), the CEP was noted in 51 patients. Kaplan-Meier analysis showed the HCV antibody-positive group had significantly poor event-free survival than the HCV antibody-negative group (log-rank, p = 0.002). In contrast, HCV ribonucleic acid-positivity was not a significant predictor of the CEP in the HCV antibody-positive group (log-rank, p = 0.442). Furthermore, the HCV antibody-positivity was significantly associated with the CEP in both univariable and multivariable Cox regression models (hazard ratio 2.37, 95% confident interval 1.32 to 4.15, p = 0.005 and 1.96, 1.06 to 3.63, p = 0.032, respectively). In conclusion, these results suggest that more attention should be paid to HCV antibody-positivity in the management of ACHD patients.

Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension.

It is widely known that the incidence of pulmonary arterial hypertension (PAH) is higher in female, whereas prognosis is poorer in male patients. However, sex differences in hemodynamic response to and long-term prognosis with PAH-targeted treatment in the modern era remain to be fully elucidated. We examined the long-term prognosis of 129 consecutive PAH patients (34 males and 95 females) diagnosed in our hospital from April 1999 to October 2014, and assessed hemodynamic changes in response to PAH-targeted therapy. Female patients had better 5-year survival compared with male patients (74.0 vs. 53.4%, P = 0.003); however, higher age quartiles in females were associated with poor outcome. Follow-up examination after medical treatment showed significant decreases in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary arterial capacitance (PAC) in both sexes (both P < 0.05), whereas only females had a significant improvement in right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP), cardiac index, and mixed venous oxygen saturation (SvO2) (all P < 0.05). Baseline age significantly correlated with the hemodynamic changes only in female patients; particularly, there were significant sex interactions in RVEDP and RAP (both P < 0.10). The multivariable analysis showed that SvO2 at baseline and mPAP and SvO2 at follow-up were significant prognostic factors in males, whereas the changes in mPAP, PVR, and PAC and use of endothelin-receptor antagonist in females. These results indicate that female PAH patients have better long-term prognosis than males, for which better improvements of right ventricular functions and hemodynamics may be involved.

The Efficacy of a Genetic Analysis of the BMPR2 Gene in a Patient with Severe Pulmonary Arterial Hypertension and an Atrial Septal Defect Treated with Bilateral Lung Transplantation.

Severe pulmonary arterial hypertension (PAH) rarely develops in children with an atrial septal defect (ASD), even those with a large defect. We herein report the case of a 27-year-old man with a moderate-sized secundum ASD and right ventricular failure due to severe PAH, which developed in his early teens. He was diagnosed as having a genetic mutation of the bone morphogenetic protein receptor-2 (BMPR2) gene and was successfully treated with bilateral lung transplantation with ASD path closure. In patients with congenital heart disease, a genetic analysis may provide information about the lifetime risk of developing PAH.

Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.

AIMS: Although balloon pulmonary angioplasty (BPA) improves haemodynamics and short-term prognosis in patients with inoperable chronic thrombo-embolic pulmonary hypertension (CTEPH), the long-term effects of BPA, and procedure-related complications remain to be fully elucidated. METHODS AND RESULTS: From July 2009 to October 2016, we performed a total of 424 BPA sessions in 84 consecutive patients with inoperable CTEPH. We used 3D reconstructed computed tomography to determine target lesions of pulmonary arteries and optical computed tomography to select balloon size, if needed. In 77 patients (92%) who completed the BPA treatment [65 ± 14 (SD) years-old, male/female 14/63], haemodynamics and exercise capacity were examined at 6 months after last BPA and in the chronic phase [>12 months after first BPA, 31 (20, 41) months]. The BPA treatment significantly improved mean pulmonary arterial pressure (38 ± 10 to 25 ± 6 mmHg), pulmonary vascular resistance (7.3 ± 3.2 to 3.8 ± 1.0 Wood units), and 6-minute walk distance (380 ± 138 to 486 ± 112 m) (all P < 0.01), and the improvements persisted throughout the follow-up period (43 ± 27 months) (N = 53). In the 424 sessions, haemoptysis was noted in 60 sessions (14%), and non-invasive positive pressure ventilation (NPPV) was used to treat haemoptysis and/or hypoxemia in 33 sessions (8%). Furthermore, 5-year survival was 98.4% (only one patient died of colon cancer) with no peri-procedural death. CONCLUSION: These results indicate that BPA improves haemodynamics and exercise capacity in inoperable CTEPH patients with acceptable complication rate and that the beneficial haemodynamic effects of BPA persist for years with resultant good long-term prognosis.

Effects of Balloon Pulmonary Angioplasty on Oxygenation in Patients With Chronic Thromboembolic Pulmonary Hypertension　- Importance of Intrapulmonary Shunt.

BACKGROUND: Although balloon pulmonary angioplasty (BPA) improves the hemodynamics and prognosis of patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), the mechanisms of improvement in oxygenation remain to be elucidated. METHODS AND RESULTS: From August 2013 to May 2015, we performed a total of 113 BPA procedures in 24 patients with inoperable CTEPH (mean 4.7 procedures per patient). Median age was 70 [60, 74] years and 18 were female (75%). We examined hemodynamics, respiratory functions, and intrapulmonary shunt before and after the BPA procedure. Mean pulmonary arterial pressure (37 [28, 45] to 23[19, 27] mmHg, P<0.01), pulmonary vascular resistance (517 [389, 696] to 268 [239, 345] dyne/s/cm(5)) and 6-min walk distance (390 [286, 484] to 490 [411, 617] m, P<0.01) were significantly improved after BPA therapy. Furthermore, arterial oxygen partial pressure (PaO2, 54.8 [50.0, 60.8] to 65.2 [60.6, 73.2] %, P<0.01) and intrapulmonary shunt (23.4±6.0% to 19.3±5.0%, P<0.01) were also significantly ameliorated. In the multivariate analysis, decrease in intrapulmonary shunt after BPA was significantly correlated with improvement of both PaO2(r(2)=0.26, P<0.01) and SaO2(r(2)=0.49, P<0.01) after BPA. CONCLUSIONS: These results indicated that BPA improved not only pulmonary hemodynamics but also oxygenation with a resultant decrease in intrapulmonary shunt. (Circ J 2016; 80: 2227-2234).

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice.

RATIONALE: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. OBJECTIVE: To determine the role of endothelial AMPK in the development of PAH. METHODS AND RESULTS: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK(-/-)), which were exposed to hypoxia. Under normoxic condition, eAMPK(-/-) mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPK(flox/flox)). In contrast, development of hypoxia-induced PH was accelerated in eAMPK(-/-) mice compared with controls. Furthermore, the exacerbation of PH in eAMPK(-/-) mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. CONCLUSIONS: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.

Different postprandial lipid metabolism and insulin resistance between non-diabetic patients with and without coronary artery disease.

BACKGROUND: Postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis. Diabetes mellitus (DM) has an impact on lipid metabolism, however, little is known about the relationship between the postprandial lipid and glucose metabolism in normoglycemic patients with coronary artery disease (CAD). METHODS: To compare the postprandial lipid and glucose metabolism in normoglycemic patients with and without CAD, a total of 36 normoglycemic patients: 19 patients with stable CAD (CAD group, age 60.2±11.3 years) and 17 patients without CAD (Non-CAD group, age 60.4±9.6 years) were loaded with a high-fat and high-glucose test meal, and the changes in serum level of the lipid and glucose parameters were monitored before and 0, 2, 4, and 6h later. RESULTS: In the Non-CAD group, postprandial serum levels of triglycerides (TG) and remnant-like particle cholesterol increased significantly and reached peak levels at the 4th hour and decreased significantly at the 6th hour of observation, whereas those levels in CAD group kept rising during 6h of observation. Although there was no significant difference in the area under the curves (AUCs) for the postprandial plasma glucose levels between CAD and Non-CAD group, the AUCs for the postprandial plasma insulin and C-peptide levels were significantly higher in the CAD group than in the Non-CAD group. The AUCs for postprandial TG levels showed good correlation with those for postprandial plasma insulin and C-peptide levels (insulin: r=0.455, p<0.005; C-peptide: r=0.462, p<0.05). CONCLUSIONS: These findings suggest that postprandial hyperlipidemia and hyperinsulinemia may have a close relationship in CAD patients without DM and might play an important role in the development of atherosclerosis even before the onset of diabetes.