Background: Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous ...transluminal pulmonary angioplasty (PTPA). Methods and Results: We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls. Conclusions: PTPA is a promising therapeutic option for distal-type CTEPH. (Circ J 2012; 76: 485-488)
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.
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.
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.
Background:It remains to be determined whether balloon pulmonary angioplasty (BPA) improves biventricular cardiac functions and pulmonary flow in patients with chronic thromboembolic pulmonary ...hypertension (CTEPH).Methods and Results:We enrolled 30 consecutive patients with inoperable CTEPH who underwent BPA, and carried out serial cardiac magnetic resonance imaging (CMR; M/F, 9/21; median age, 65.2 years). No patient died during the treatment or follow-up period. BPA significantly improved WHO functional class (III/IV, 83.0 to 4.0%), 6-min walking distance (330.2±168.7 to 467.3±114.4 m), mean pulmonary artery pressure (40.8±10.7 to 23.2±4.94 mmHg), pulmonary vascular resistance (9.26±4.19 to 3.35±1.40 WU) and cardiac index (2.19±0.64 to 2.50±0.57 L·min·m2; all P<0.01). CMR also showed improvement of right ventricular (RV) ejection fraction (EF; 41.3±12.4 to 50.7±8.64%), left ventricular (LV) end-diastolic volume index (72.1±14.0 to 81.6±18.6 ml/m2) and LV stroke volume index (41.0±9.25 to 47.8±12.3 ml/m2; all P<0.01). There was a significant correlation between change in RVEF and LVEF (Pearson’s r=0.45, P=0.01). Average velocity in the main pulmonary artery was also significantly improved (7.50±2.43 to 9.79±2.92 cm/s, P<0.01).Conclusions:BPA improves biventricular functions and pulmonary flow in patients with inoperable CTEPH. (Circ J 2016; 80: 1470–1477)
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).
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.
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.
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.
•The five-year transplant-free survival rate was 74% for PAH and 92% for CTEPH.•Triple combination therapy showed better survival than other treatments in PAH.•Balloon angioplasty was an effective procedure to improve prognosis in CTEPH.
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.
To determine the role of endothelial AMPK in the development of PAH.
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.
These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.
Background:Pulmonary arterial hypertension with systemic dysfunctions, including metabolic disorders and renal dysfunction, has a poor prognosis. However, it remains to be elucidated whether chronic ...thromboembolic pulmonary hypertension (CTEPH) is also associated with systemic dysfunctions, and if so, whether balloon pulmonary angioplasty (BPA) improves them.Methods and Results:Fifty-five consecutive patients who underwent BPA from March 2012 to December 2014 for systemic dysfunctions, including glycemic control, lipid profiles, renal and vascular function, and nutritional status were examined. The analyses were performed before and after BPA (mean, 3.5 sessions/patient) and changes in hemodynamic parameters were compared. The average follow-up period was 474±245 days. Baseline prevalence of hypertension, diabetes mellitus, dyslipidemia and advanced chronic kidney disease was 58, 7, 33 and 36%, respectively. BPA caused marked hemodynamic improvements in the CTEPH patients. Importantly, BPA also significantly improved dysglycemia (fasting blood sugar, hemoglobin A1c and homeostatic assessment model of insulin resistance), renal (creatinine and estimated glomerular filtration rate) and vascular (cardio-ankle vascular index) functions and nutritional status (albumin, cholesterols, and body mass index). Importantly, there were positive correlations between the degrees of the hemodynamic improvements and those of other improvements.Conclusions:These results indicate that BPA may exert multiple beneficial effects in CTEPH patients, not only in terms of hemodynamics but also in other systemic functions, with positive correlations among them. (Circ J 2016; 80: 980–988)
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 2319, 27 mmHg, P<0.01), pulmonary vascular resistance (517 389, 696 to 268 239, 345 dyne/s/cm5) 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(r2=0.26, P<0.01) and SaO2(r2=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)
Background: It remains to be elucidated whether brain activity is altered in takotsubo cardiomyopathy. Methods and Results: We measured cerebral blood flow (CBF) in 3 consecutive patients with ...takotsubo cardiomyopathy using 99mTc ethyl cysteinate dimmer single photon-emission computed tomography (SPECT) in the acute and chronic phases. In all patients, CBF was significantly increased in the hippocampus, brainstem and basal ganglia and significantly decreased in the prefrontal cortex in the acute phase, which changes subsided in the chronic phase with full recovery of cardiac wall motion. Conclusions: These results provide the first direct evidence for brain activation in takotsubo cardiomyopathy. (Circ J 2014; 78: 256–258)
Plasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and ...late-onset Fabry disease in males and females.
Between 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively.
Of 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml–1) and low α-Gal A activity (≤4.0 nmol h–1 ml–1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance).
Plasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.
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