Patients with sickle cell disease underwent ECG with assessment of tricuspid valve regurgitant jet velocity (TRJV) to screen for pulmonary hypertension, followed by right heart catheterization if the TRJV was 2.5 m per second or more. Prevalence was 27% on the basis of ECG criteria but only 6% on the basis of catheterization. In several studies, pulmonary hypertension, particularly pulmonary arterial hypertension, has been reported as a frequent complication of sickle cell disease. 1 – 4 Pulmonary arterial hypertension is characterized by the presence of precapillary pulmonary hypertension in the absence of left-sided heart disease, lung disease, or chronic thromboembolism. On histopathological analysis, pulmonary arterial hypertension is characterized by the proliferation of medial smooth-muscle cells and endothelial cells in the small pulmonary arteries. 5 Pulmonary arterial hypertension may be idiopathic, heritable, or associated with other disorders, such as connective tissue diseases and congenital heart disease. 6 In the updated classification of pulmonary hypertension, sickle cell disease appears . . .
Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertenslon (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.
Chronic thromboembolic pulmonary hypertension is believed to be rare after an episode of acute pulmonary embolism. This study showed that the incidence of this serious complication was nearly 4 percent — substantially higher than previously reported — and was associated with previous pulmonary embolism, large perfusion defects, and an idiopathic presentation. Possible approaches to prevention are discussed. The incidence of this serious complication was nearly 4 percent. Chronic pulmonary hypertension is considered a relatively rare complication of pulmonary embolism but is associated with considerable morbidity and mortality. 1 – 3 It is commonly believed that symptoms become manifest only several years after the initial episode of pulmonary embolism. However, the true frequency (estimated at 0.1 percent among patients who survive a pulmonary embolism) and timing are not well established, and there is limited documentation concerning predisposing factors that could be addressed in an effort to prevent this feared complication. It has been hypothesized that in situ thrombosis and pulmonary arteriopathy are common causes of vascular occlusion leading to chronic . . .
Fibrosing mediastinitis is caused by a proliferation of fibrous tissue in the mediastinum with encasement of mediastinal viscera and compression of mediastinal bronchovascular structures. Pulmonary hypertension (PH) is a severe complication of fibrosing mediastinitis caused by extrinsic compression of the pulmonary arteries and/or veins.We have conducted a retrospective observational study reviewing clinical, functional, hemodynamic, radiological characteristics, and outcome of 27 consecutive cases of PH associated with fibrosing mediastinitis diagnosed between 2003 and 2014 at the French Referral Centre for PH.Fourteen men and 13 women with a median age of 60 years (range 18-84) had PH confirmed on right heart catheterization. The causes of fibrosing mediastinitis were sarcoidosis (n=13), tuberculosis-infection confirmed or suspected (n=9), mediastinal irradiation (n=2), and idiopathic (n=3). Sixteen patients (59%) were in NYHA functional class III and IV. Right heart catheterization confirmed moderate to severe PH with a median mean pulmonary artery pressure of 42 mm Hg (range 27-90) and a median cardiac index of 2.8 L/min/m(2) (range 1.6-4.3). Precapillary PH was found in 22 patients, postcapillary PH in 2, and combined postcapillary and precapillary PH in 3. Severe extrinsic compression of pulmonary arteries (>60% reduction in diameter) was evidenced in 2, 8, and 12 patients at the main, lobar, or segmental levels, respectively. Fourteen patients had at least one severe pulmonary venous compression with associated pleural effusion in 6 of them. PAH therapy was initiated in 7 patients and corticosteroid therapy (0.5-1mg/kg/day) was initiated in 3 patients with sarcoidosis, with 9 other being already on low-dose corticosteroids. At 1-year follow-up, 3 patients had died and among the 21 patients evaluated, 3 deteriorated, 14 were stable, and only 4 patients with sarcoidosis improved (4 receiving corticosteroids and 1 receiving corticosteroids and PAH therapy). Survival was 88%, 73%, and 56% at 1, 3, and 5 years, respectively.We found no clear clinical improvement with the use of specific PAH therapy. Corticosteroid therapy may be associated with clinical improvement, in some patients with fibrosing mediastinitis due to sarcoidosis. Although never performed for this indication, lung transplantation may be proposed in eligible patients with severe PH and fibrosing mediastinitis.
Pulmonary hypertension (PH) is relatively common in connective tissue diseases. However, few studies have focused on the pulmonary hypertension (PH) associated with polymyositis (PM). Our aim is to investigate the prevalence of PH and determine the associated factors for PH in patients with PM. Multicenter study of 61 patients with PM underwent evaluation including general information, physical examination, laboratory indictors, thoracic high-resolution CT (HRCT) imaging, and transthoracic echocardiography (TTE). TTE was performed to estimate the pulmonary arterial pressure. PH was defined as resting systolic pulmonary artery pressure (sPAP) ≥40 mmHg. PH was identified in ten patients (16.39 %) who had few cardiopulmonary symptoms. PM patients with PH had higher prevalence of interstitial lung disease (ILD) and pericardial effusion (PE) compared with patients without PH (18 vs. 11.5 %, p = 0.005; 11.5 vs. 9.8 %, p = 0.004; respectively). After controlling for age, gender, and potential factors, ILD and PE were independently associated with PH in patients with PM in multivariate analysis (OR = 8.193, 95 % CI 1.241–54.084, p = 0.029; OR = 8.265, 95 % CI 1.298–52.084, p = 0.025; respectively). Depending on TTE, the possible prevalence of PH was 16.39 % in patients with PM. Both ILD and PE may contribute to the development of PH in PM.
Background Pulmonary hypertension (PHT) lacks community prevalence and outcome data. Objective To characterise minimum ‘indicative’ prevalences and mortality data for all forms of PHT in a selected population with an elevated estimated pulmonary artery systolic pressure (ePASP) on echocardiography. Design Observational cohort study. Setting Residents of Armadale and the surrounding region in Western Australia (population 165 450) referred to our unit for transthoracic echocardiography between January 2003 and December 2009. Results Overall, 10 314 individuals (6.2% of the surrounding population) had 15 633 echo studies performed. Of these, 3320 patients (32%) had insufficient TR to ePASP and 936 individuals (9.1%, 95% CI 8.6% to 9.7%) had PHT, defined as, ePASP>40 mm Hg. The minimum ‘indicative’ prevalence for all forms of PHT is 326 cases/100 000 inhabitants of the local population, with left heart disease-associated PHT being the commonest cause (250 cases/100 000). 15 cases of pulmonary arterial hypertension/100 000 inhabitants were identified and an additional 144 individuals (15%) with no identified cause for their PHT. The mean time to death for those with ePASP >40 mm Hg, calculated from the first recorded ePASP, was 4.1 years (95% CI 3.9 to 4.3). PHT increased mortality whatever the underlying cause, but patients with PHT from left heart disease had the worst prognosis and those with idiopathic pulmonary arterial hypertension receiving disease-specific treatment the best prognosis. Risk of death increased with PHT severity: severe pulmonary hypertension shortened the lifespan by an average of 1.1 years compared with mild pulmonary hypertension. Conclusions In this cohort, PHT was common and deadly. Left heart disease was the most common cause and had the worst prognosis and treated pulmonary arterial hypertension had the best prognosis.
Background Pulmonary hypertension (PH) is a severe progressive disease. Though five subgroups are recognised, reports on survival focus mainly on pulmonary arterial hypertension (PAH). Methods Long-term transplant-free survival, and its determinants, were investigated in patients with PH (diagnosed by right heart catheterization) within a prospective registry at a single referral center in Giessen, Germany. Results In total, 2067 patients were enrolled (PAH, 685 patients [33.1%]; pulmonary venous hypertension, 307 patients [14.9%]; PH due to lung diseases (LD-PH), 546 patients [26.4%; mainly interstitial lung disease and chronic obstructive pulmonary disease]; chronic thromboembolic PH, 459 patients [22.2%]; PH owing to miscellaneous/unknown causes, 70 patients [3.4%]). Median follow-up was 37 months. Differences in transplant-free survival between etiological groups were highly significant ( p < 0.001), with 1-, 3-, and 5-year survival rates of 88.2%, 72.2%, and 59.4%, respectively, for those with PAH compared with 79.5%, 52.7%, and 38.1%, respectively, for patients with LD-PH. Patients’ age, sex, and 6-minute walk distance (6MWD), but not New York Heart Association (NYHA) functional class, associated significantly with survival across all PH subtypes in multivariate Cox regression analyses. Conclusions This is the largest reported single-center PH cohort. Some parameters used in clinical practice do not independently predict survival. Age, sex, and 6MWD outperformed NYHA functional class in predicting survival across all etiologic groups.
Objective Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. In many patients hemodynamics are normalized early after surgical intervention. However, the effect of residual pulmonary hypertension on postoperative clinical status and survival is unknown. Methods Data were collected prospectively on all patients who underwent pulmonary endarterectomy in a continuous national series between 1997 and December 2007. Postoperatively, patients underwent scheduled reinvestigation, including functional testing and right heart catheterization, at 3 months after the operation. They were divided into 2 groups based on mean pulmonary artery pressure: group 1, less than 30 mm Hg; group 2, 30 mm Hg or greater. Results Three hundred fourteen patients underwent pulmonary endarterectomy, survived to hospital discharge, and completed the 3-month follow-up period. At 3 months after pulmonary endarterectomy, there was a significant reduction in mean pulmonary artery pressure for the whole cohort (48 ± 12 to 26 ± 10 mm Hg, P < .001). However, 31% of the patients had residual pulmonary hypertension. Group 1 patients enjoyed significantly better exercise capacity and improved symptoms compared with group 2 patients. In addition, there were significantly fewer patients receiving targeted medical therapy in group 1 versus group 2 (0% vs 25%, P < .001). Conditional survival after discharge from the hospital for the whole cohort was 90.0% at 5 years and was not different between groups (90.3% for group 1 vs 89.9% for group 2, P = .36). Conclusions For patients undergoing pulmonary endarterectomy, survival after hospital discharge is excellent. Residual pulmonary hypertension significantly compromised symptom status and functional capacity but did not appear to adversely affect medium-term survival. The effect of targeted medical therapy in patients with residual pulmonary hypertension after pulmonary endarterectomy needs to be evaluated further.
Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation(1,2). PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension(3). PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission(4). Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.
Background Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response. Methods We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response. Results Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics. Conclusions mPAWP 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.