Chronic Thromboembolic Pulmonary Arterial Hypertension Research Articles

Efficacy and safety of riociguat in the treatment of chronic thromboembolic pulmonary arterial hypertension: A meta-analysis.

Background:Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH.Methods:Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test.Results:Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = −0.24, 95%CI −0.35 to −0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = −0.31, 95%CI −0.51 to −0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=−0.23, 95%CI −0.42 to −0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = −0.24, 95%CI −0.61 to −0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed.Conclusions:We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.

How to deal with chronic thromboembolic pulmonary arterial hypertension (CTEPH) during the COVID-19 pandemic: Too many gray zones to be considered

How to deal with chronic thromboembolic pulmonary arterial hypertension (CTEPH) during the COVID-19 pandemic: Too many gray zones to be considered

Shift in transcriptional landscape of human right ventricle in chronic thromboembolic pulmonary arterial hypertension

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a sub group of pulmonary hypertension (PH). CTEPH is characterized by the existence of thromboemboli and vascular remodeling in pulmonary vessels. The effect of increase in pulmonary artery pressures causes right ventricle (RV) hypertrophy and dilatation and finally leads to right heart failure and death. Surgical intervention in operable patients makes the CTEPH as an only curable and unique form of ph. Pulmonary endarterectomy (PEA) is the surgical procedure to remove the thromboembolic clots from the pulmonary vasculature, which restores RV function back to normal with significant improvements in cardiovascular magnetic resonance. Purpose The aim of this study is to use transcriptomic profiling to identify signaling pathways, master regulators, and potentially new biomarkers that specifically indicate the effect of PEA on the RV of patients with chronic thromboembolic pulmonary hypertension. Results RNA -sequencing (RNA-seq) was performed on RV biopsies obtained from CTEPH patients at PEA baseline (before PEA surgery) and the results were compared with those from RV biopsies obtained during follow-up evaluation. Bioinformatic analysis of RNA-seq data identified 2799 genes (n=14, −0.585 ≤ Log2 fold change ≥0.585, FDR ≤0.05) differentially regulated between the PEA baseline and follow-up sample groups. The great number of genes (2799) differentially expressed after PEA surgery in CTEPH patients confirms a major shift in the transcriptional landscape of RV in these patients. To further identify potential biomarker candidates from the large pool of 2799 differentially expressed genes (DEGs), extensive bioinformatic analysis of different data sets shortlisted 250 DEGs that were functionally associated with cardiovascular development or disease. The findings of this study reveal prominent transcriptional changes that occur in response to PEA. Gene ontology enrichment and pathway analysis confirmed altered regulation of hypoxia-inducible factor 1 (HIF-1) signaling, advanced glycation end products and their receptors (AGE-RAGE), mitogen-activated protein kinase (MAPK) signaling, hippo signaling, the Janus kinase/ signal transducers and activators of transcription (Jak-STAT) signaling pathway, and proteoglycans after PEA compared with before PEA. Conclusion Comparison of the results of RNA-seq analysis of RV biopsies of CTEPH patients, pre and post PEA, revealed a major shift in the transcriptional landscape of these patients after reducing the pressure overload of the RV by PEA. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation (DFG)

The enigmatic challenge: secondary pulmonary arterial hypertension due to partial anomalous pulmonary venous return in a young woman

Background: Pulmonary arterial hypertension (PAH) involves many different clinical conditions and has an important impact on the right ventricular (RV) function and patient’s prognosis. Some of these conditions can be potentially curable, for example, congenital heart disease that could be surgically repaired. Case Presentation: We present a case of 41-year-old woman with a progressive shortness of breath, without evident explication. First, she was suspected to have chronic thromboembolic PAH, which was not confirmed by clinical and imaging data. Even arrhythmogenic RV cardiomyopathy was suspected according to the data obtained from the first cardiac magnetic resonance (CMR) imaging. However, due to a step-up in oxygen saturation during the right heart catheterization (RHC), the presence of rare congenital heart disease, such as partial anomalous of pulmonary venous return (PAPVR), was suspected and then confirmed by the repeated CMR. Conclusions: PAPVR is a rare congenital heart disease that could be suspected during the RHC and represents a potentially curable cause of PAH.

PRM101 - THE COST BURDEN OF CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION IN RUSSIAN FEDERATION

Evaluation of the economic burden of the chronic thromboembolic pulmonary arterial hypertension (CTEPH) in Russia was the aim of current work. Study was based on data derived from CTEPH patient registry (10 clinical centers). Study was based on data derived from CTEPH patient registry (10 clinical centers). Methods of descriptive statistics were used in analysis of clinical data. Bootstrapping was applied for estimation of average costs per patient/year. Analysis included direct costs (medical costs: outpatient visits, hospital admissions, emergency, PAH-specific therapy, concomitant therapy; non-medical costs: pension due to disability, payments to patients on sick-leave) and indirect costs (loss of GDP) were calculated. CTEPH patients (n=113) aged 54.6±13.95 years, and 59.3% were women. Duration from first symptoms to the confirmation of diagnosis of CTEPH was 2.58±5.21 years on average. Most of the patients (55%) were in able-bodied age and about a half of patients had a disability. Mean number of outpatient visits and inpatient visits were 1.97±1.65 and 1.01±1.36 per patient/year, respectively. About 54% of patients applied PAH-specific therapy, moreover 46% patients had interruptions of PAH-specific therapy (58.4±66.3 days). The mean annual total costs were 805,901 RUB/11,060 EUR per patient (73.3% PAH-specific therapy, 10.3% inpatient costs, 0.3% outpatient costs, 2.7% concomitant therapy, 5.3% non-medical costs, 8.6% loss of GDP). The overall burden of CTEPH in Russia for total projected CTEPH population (approximately 470 patients) was estimated as 378,579,946 RUB/ 5,195,723 EUR per year. Current study demonstrated that, in overall, the economic burden of CTEPH is lower than costs for other widespread cardiovascular diseases due to rarity of CTEPH. The registry is a valuable tool for studying costs associated with disease and in the identification of problems in health care framework for rare diseases.

Lapatinib impact on pulmonary hypertension.

160 Background: Pulmonary Arterial Hypertension (PAH) and cancer share growth factor and protein kinase signaling pathways that result in smooth muscle cell proliferation and vasculopathy. A number of tyrosine kinase inhibitors (TKI) have been developed for the treatment of cancer, and some of these like Imatinib have been investigated in PAH. There is little known about the impact of other TKI on the pulmonary vasculature. After reporting a case of lapatinib-induced PAH that reversed after withdrawal of the drug, we investigated the association of lapatinib with the development of PAH in our institution. Methods: A retrospective chart review was conducted, in accordance with IRB protocol, of all patients treated with lapatinib over the past five years at our institution. Patients who had undergone 2-D echocardiogram both prior to and after treatment were included in the analysis. Systolic Pulmonary Artery Pressures (PASP), right-sided chamber dilation and function, TAPSE were each evaluated. Through chart review, patients were evaluated in terms of risk factors for non-Group 1 PAH. A Wilcoxon signed-rank sum test was used to compare the changes in PASP before and after the initiation of lapatinib. Results: A total of 27 patients were found to have 2-D echo done before and after starting treatment with lapatinib. All patients had normal PASP before starting treatment. Eight patients developed elevated PASP following treatment. Two patients had evidence of left-sided heart disease felt to contribute to their elevated pressures, while the remaining 6 patients had no evidence for Group 2 (associated with left heart disease), 3 (associated with lung disease or hypoxemia) or chronic thromboembolic PAH. Right heart catheterization was available in one patient, confirming the diagnosis of PAH. The median pre-treatment and post treatment PASP in those 6 patients was 29.5 mmHg and 65.5 mmHg respectively (N=6; p = 0.03). Conclusions: Lapatinib is a TKI with a selective inhibition to EGFR and HER2, approved by FDA in 2007 as a second line agent in advanced breast cancer. Given the potential of TKIs as anti-proliferative agents in PAH, a number are currently under study, but little is yet known. This is the first study in the literature to show that PAH is a potential side effect of lapatinib.

Osteopontin Lung Expression Is a Marker of Disease Severity in Pulmonary Arterial Hypertension

Purpose Osteopontin (OPN) is a pleiotropic cytokine involved in the proliferation of pulmonary artery smooth muscle cells (PASMCs). OPN is upregulated in the lungs of patients with pulmonary arterial hypertension (PAH) associated with pulmonary fibrosis (WHO group III), suggesting that the lung is a source of OPN. We hypothesized that OPN lung expression is elevated in WHO group I PAH and is correlated to hemodynamics. Methods and Materials Microarray analysis (Affymetrix R ) was performed after RNA was extracted from explanted lungs in 15 patients with PAH (6 idiopathic PAH, 4 connective tissue disease, 4 congenital heart disease, 1 chronic thromboembolic PAH) who underwent lung transplantation (LTx) and 11 normal controls (normal lung tissue surrounding cancer resections). Pulmonary artery pressures (PAPs) were recorded intra-operatively immediately before starting LTx: average mPAP was 39±11 mmHg, wedge pressure 7±5, pulmonary vascular resistance 701±208 dym.sec.cm- 5 . Serum OPN levels were measured in 28 subjects with PAH and 5 subjects with normal PAPs. Results OPN was among the top 5 upregulated genes in over 34,000 genes analyzed in PAH compared to normal controls (fold change 3.64, false discovery rate p =0.0007, Mann Whitney). OPN expression was similar and equally high in different types of PAH ( p =n.s., ANOVA). A significant correlation was observed between mPAP and OPN gene expression ( r =0.79, p =0.0004). Ingenuity pathway analysis showed that the OPN gene was included in biologically relevant functions and networks (angiogenesis, cancer, cell death). OPN serum levels were not significantly different in subjects with and without PAH. Conclusions In the lungs of patients with severe PAH who failed medical therapy and underwent LTx, OPN is highly expressed and the level of expression is significantly correlated with disease severity. OPN may play an important role in the pathogenesis of PAH, driving an uncontrolled proliferation of PASMCs. Supported by ENTELLIGENCE Young Investigator Award Program.

慢性血栓塞栓性肺高血圧症における超低体温間歇的循環停止法の成績

慢性血栓塞栓性肺高血圧症における超低体温間歇的循環停止法の成績

Inhaled treprostinil: a therapeutic review

Pulmonary arterial hypertension (PAH) is a life-threatening disease which, if untreated, leads to right ventricular failure and often death. Several effective therapies are now available for PAH, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. The prostacyclin analog treprostinil has proven efficacious when delivered by subcutaneous or intravenous infusion, and most recently by inhalation. Inhaled treprostinil has been shown to be 64%–72% bioavailable in healthy volunteers. Pilot clinical studies have elucidated the acute hemodynamic effects and relative pulmonary selectivity of this agent, as well as established target dosing in PAH and nonoperable chronic thromboembolic PAH. Likewise, chronically administered inhaled treprostinil resulted in clinical and hemodynamic improvement. Both pilot studies confirmed a satisfactory safety profile in patients with PAH. The pivotal Phase III trial, TRIUMPH-I, demonstrated the efficacy and safety of inhaled treprostinil (target dose of 54 μg four times daily) in PAH patients added to background therapies of bosentan or sildenafil, as assessed by improvements in the primary endpoint, peak six-minute walk distance (median placebo-corrected treatment effect of 20 m), as well as select secondary endpoints. Inhaled treprostinil is approved by the US Food and Drug Administration for patients with World Health Organization Group I PAH to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association functional class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension

Pulmonary endothelium plays an important role in the mechanism of pulmonary arterial hypertension (PAH). However, there is only a few data regarding the systemic endothelium in this syndrome. This study focused on the systemic endothelial involvement in PAH. Endothelial function was evaluated in 54 patients with idiopathic (n=28), scleroderma-associated (n=10), chronic thromboembolic (n=7), or Eisenmenger (n=9) PAH and 21 controls (13 healthy; eight scleroderma and normal pulmonary pressure). All underwent clinical evaluation, pulmonary assessment, echocardiography, and pulmonary cardiac stress test. Endothelial function was evaluated by measuring the forearm blood flow dilatation response to brachial arterial occlusion by a non-invasive plethysmograph, yielding a peripheral arterial tone (PAT) ratio. The PAT ratio was significantly lower (p<0.05) than healthy controls in all patients except the Eisenmenger group (control: 2.20+/-0.25; idiopathic 1.84+/-0.51; scleroderma 1.66+/-0.66; thromboembolic 1.89+/-0.32; Eisenmenger 2.17+/-0.62). The impaired hyperemic response significantly correlated with disease severity, as measured by NYHA classification (r=-0.210, p=0.035), pulmonary pressure (r=-0.228, p=0.035), 6 min walking distance (r=0.215, p=0.047), and oxygen desaturation on effort (r=0.207, p=0.038). Mean systolic pulmonary pressure among patients was 54-99 mmHg. A systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic thromboembolic PAH that is correlated with disease severity.

Raised LIGHT Levels in Pulmonary Arterial Hypertension

Thrombus formation and inflammation are involved in the pathogenesis of pulmonary arterial hypertension (PAH), and LIGHT (Lymphotoxin-like Inducible protein that competes with Glycoprotein D for Herpesvirus entry mediator on T lymphocytes) has been shown to promote vascular inflammation. We sought to investigate the role of the tumor necrosis factor superfamily ligand LIGHT in the pathogenesis of PAH. We studied 73 patients with severe PAH and 10 control subjects. LIGHT and pro- and antithrombotic markers were assessed by enzyme immunoassays. (1) Patients with idiopathic PAH (n = 21), patients with PAH related to risk factors or associated conditions (n = 31), and those with chronic thromboembolic PAH (n = 21) all had raised serum levels of LIGHT compared with control subjects (n = 10). (2) LIGHT levels in femoral artery were significantly related to mortality in the patients with PAH. (3) Immunostaining of LIGHT and its receptors was seen in alveolar macrophages, vascular smooth muscle cells, and endothelial cells in lungs from patients with PAH. (4) Thirteen patients received prostacyclin infusion (3 mo), and all showed hemodynamic improvement, accompanied by decreased LIGHT levels. (5) Prostacyclin abolished the release of LIGHT from activated platelets in vitro, suggesting that the decrease in LIGHT during prostacyclin therapy could involve direct effects on platelets. (6) LIGHT increased tissue factor and plasminogen activator inhibitor type 1 and decreased thrombomodulin levels in endothelial cells, inducing a prothrombotic state in these cells. Our findings suggest prothrombotic effects of LIGHT in PAH involving endothelium-related mechanisms, potentially contributing to the progression of this disorder.

Treatment of pulmonary arterial hypertension in pregnancy

The treatment of pulmonary arterial hypertension (PAH) in pregnancy is reviewed. PAH is a disease characterized by narrowing of the pulmonary arteries and increased vascular resistance. Women with PAH should avoid becoming pregnant, as the physiological, cardiovascular, and pulmonary changes that occur during pregnancy can exacerbate the condition. However, several viable treatment options are available to improve the outcomes in this patient population, including inhaled nitric oxide, calcium-channel blockers, targeted pulmonary vasodilators, and sildenafil. Epoprostenol, a naturally occurring prostaglandin and vasodilator, is a pregnancy category B drug. Reproductive studies in rats and rabbits have found no impaired fertility or fetal harm at 2.5-4.8 times the recommended human dosage of epoprostenol. Most of the published case reports describe initiating epoprostenol 2-4 ng/kg/min i.v. several weeks before or near the time of delivery. Iloprost is a pregnancy category C drug but has demonstrated benefit in pregnant patients with PAH, with no congenital abnormalities and no postpartum maternal or infant mortality reported. Sildenafil causes vasodilation of the pulmonary vascular bed and vasodilation in the systemic circulation. Two case reports have described the successful treatment with sildenafil, a pregnancy category B drug, of pregnant patients with PAH. Patients with idiopathic PAH or chronic thromboembolic PAH should receive full-dose subcutaneous low-molecular-weight heparin therapy instead of warfarin for bleeding prophylaxis during pregnancy. Targeted pulmonary vasodilators are viable treatment options for pregnant patients with PAH. Early recognition and management of worsening symptoms are essential to improve outcomes for both the mother and infant.

The Role of p38 Mitogen-Activated Protein Kinase in Hypoxia-Induced Vascular Cell Proliferation: An Interspecies Comparison

I nflammation may play a central role in the pathogenesis of pulmonary arterial hypertension (PAH). Levels of interleukin (IL)-6, IL-1, C-reactive protein, regulated on activation normal T cells expressed and secreted (RANTES), and fractalkine are increased in the serum and lungs of PAH patients. Scleroderma, lupus, mixed connective tissue disease, Castleman disease, HIV, and polyneuropathy/organomegaly/endocrinopathy/M protein/skin changes (POEMS syndrome) are associated with increased IL-6 and PAH. IL-6 may play a pathogenic role through inflammation, cellular proliferation, interaction with bone morphogenetic protein pathways, decreasing prostacyclin levels, and induction of the production of other mediators such as serotonin, endothelin (ET)-1 and vascular endothelial growth factor. Experimental models of pulmonary hypertension (PH), including hypoxia and monocrotaline, are associated with increased IL-6 levels. Previous studies have found right ventricular hypertrophy (RVH) in rats treated with recombinant human IL-6. This was associated with evidence of vascular thrombosis and may be a model of chronic thromboembolic PAH. We hypothesized that IL-6 would cause PH in mice and that IL-6 may potentiate the development of PH following chronic hypoxia in mice. Methods/Results Male C57BL/6 mice (weight, 25 g) were treated with daily subcutaneous injections of 200 g/kg recombinant murine IL-6 and saline solution, and exposed to normoxia or hypobaric hypoxia for 14 days. The animals were killed and right ventricular pressure and RVH were measured. IL-6-treated mice had increased right ventricular pressure (p 0.08) and RVH (p 0.05) in normoxia compared to those treated with saline solution. There was no evidence of lung inflammation or vascular thrombosis. During hypoxia, treatment with IL-6 further augmented the increase in RVH compared to treatment with saline solution and this was associated with a greater increase in both IL-6 and ET-1 messages as determined by quantitative polymerase chain reaction.

In situ central pulmonary artery thrombosis in primary pulmonary hypertension

A rare case of extensive in situ central pulmonary artery thrombosis in primary pulmonary hypertension (PPH) is presented. The differentiation from chronic thromboembolic pulmonary arterial hypertension (CTEPH) is of paramount importance because of different therapeutic strategies. In this case, the presence of mural thrombus in the central pulmonary arteries on computed tomography made the distinction difficult. However, the possibility of in situ thrombosis was suggested on the basis of absence of other findings of CTEPH (abrupt narrowing/truncation of segmental arteries, variation in size of segmental vessels, arterial webs, mosaic attenuation, pulmonary infarcts, and dilated bronchial arteries), and this was confirmed on final pathology.

Pulmonary Arterial Hypertension: Diagnosis with Fast Perfusion MR Imaging and High-Spatial-Resolution MR Angiography—Preliminary Experience

To determine prospectively the accuracy of a magnetic resonance (MR) perfusion imaging and MR angiography protocol for differentiation of chronic thromboembolic pulmonary arterial hypertension (CTEPH) and primary pulmonary hypertension (PPH) by using parallel acquisition techniques. The study was approved by the institution's internal review board, and all patients gave written consent prior to participation. A total of 29 patients (16 women; mean age, 54 years +/- 17 [+/- standard deviation]; 13 men; mean age, 57 years +/- 15) with known pulmonary hypertension were examined with a 1.5-T MR imager. MR perfusion imaging (temporal resolution, 1.1 seconds per phase) and MR angiography (matrix, 512; voxel size, 1.0 x 0.7 x 1.6 mm) were performed with parallel acquisition techniques. Dynamic perfusion images and reformatted three-dimensional MR angiograms were analyzed for occlusive and nonocclusive changes of the pulmonary arteries, including perfusion defects, caliber irregularities, and intravascular thrombi. MR perfusion imaging results were compared with those of radionuclide perfusion scintigraphy, and MR angiography results were compared with those of digital subtraction angiography (DSA) and/or contrast material-enhanced multi-detector row computed tomography (CT). Sensitivity, specificity, and diagnostic accuracy of MR perfusion imaging and MR angiography were calculated. Receiver operator characteristic analyses were performed to compare the diagnostic value of MR angiography, MR perfusion imaging, and both modalities combined. For MR angiography and MR perfusion imaging, kappa values were used to assess interobserver agreement. A correct diagnosis was made in 26 (90%) of 29 patients by using this comprehensive MR imaging protocol. Results of MR perfusion imaging demonstrated 79% agreement (ie, identical diagnosis on a per-patient basis) with those of perfusion scintigraphy, and results of MR angiography demonstrated 86% agreement with those of DSA and/or CT angiography. Interobserver agreement was good for both MR perfusion imaging and MR angiography (kappa = 0.63 and 0.70, respectively). The combination of fast MR perfusion imaging and high-spatial-resolution MR angiography with parallel acquisition techniques enables the differentiation of PPH from CTEPH with high accuracy.

Chronic thromboembolic pulmonary arterial hypertension: correlation of postoperative results of thromboendarterectomy with preoperative helical contrast-enhanced computed tomography.

Pulmonary thromboendarterectomy is the treatment of choice for patients with chronic thromboembolic pulmonary arterial hypertension (CTEPH). Some patients do poorly after this procedure and may be better candidates for heart-lung transplant. The purpose of this study was to correlate preoperative findings on helical contrast-enhanced computed tomography (CT) with surgical outcome. Thirty-seven patients (mean age 52.9, range 22-71) who underwent pulmonary thromboendarterectomy and had preoperative helical contrast-enhanced CT followed by High Resolution CT (HRCT) scans were included in the study. The CTs were evaluated for the presence of central and segmental disease and for the presence of mosaic perfusion pattern. The presence of central disease, as well as the presence of segmental disease, correlated negatively with the postoperative mean pulmonary arterial pressure [r(c) = -0.401, P = 0.015, r(s) = -0.38, P = 0.024)] and the pulmonary vascular resistance [(r(c) = -0.37, P = 0.027, r(s) = -0.39, P = 0.019]. No correlation was found between the clinical variables and the presence of mosaic perfusion pattern. Patients with CTEPH and evidence of chronic PE in the central or segmental pulmonary arteries have a better clinical outcome after pulmonary thromboendarterectomy than patients without these findings. The presence of mosaic perfusion pattern is not helpful in predicting postoperative outcome.