In this trial, 261 patients with chronic thromboembolic pulmonary hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 16 weeks, riociguat had significantly improved the 6-minute walk distance and pulmonary vascular resistance. Chronic thromboembolic pulmonary hypertension is characterized by obstruction of the pulmonary vasculature by residual organized thrombi, 1 leading to increased pulmonary vascular resistance, progressive pulmonary hypertension, and right ventricular failure. 2 , 3 Patients with chronic thromboembolic pulmonary hypertension have a poor prognosis unless they receive treatment early. 4 Pulmonary endarterectomy is the standard treatment for chronic thromboembolic pulmonary hypertension and is the only potentially curative treatment. 5 However, surgery is not an option for all patients; some patients are ineligible for surgery owing to the occlusion of distal vessels or coexisting conditions, some decline surgery, and some do not have access to expert surgical . . .
SUMMARY POINTS Pulmonary hypertension has many causes so prognoses and treatments vary The condition is diagnosed by systematically evaluating the breathless patient and screening patients at high risk Patients at high risk of severe and treatable pulmonary hypertension include those with systemic sclerosis, portal hypertension, congenital heart disease, and previous pulmonary embolism Specialist centres provide access to tailored investigative and treatment pathways and support networks for patients Patients with severe pulmonary hypertension can deteriorate rapidly—do not delay referral to perform specialist investigations Only selected patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension benefit from interventions directed at pulmonary vasculature; for most patients treatment is aimed at the underlying condition
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 . . .
The number of effective, long-term treatments for pulmonary hypertension is limited. In this double-blind, randomized trial, an aerosolized form of iloprost, a stable analogue of the pulmonary vasodilator prostacyclin, was assessed over a 12-week period. Iloprost had a beneficial effect on the combined end point of the distance walked in six minutes and an improvement in the New York Heart Association functional class. A continuous infusion of prostacyclin was the first therapy shown to reduce mortality in a controlled study of patients with severe pulmonary hypertension. 1 However, its use is associated with a number of serious drawbacks. The lack of pulmonary selectivity results in systemic side effects, tolerance leads to progressive increases in the dose, and there may be recurrent infections of the intravenous catheter. 2 As an alternative, inhaled nitric oxide possesses pulmonary selectivity, but it is less potent than prostacyclin in the pulmonary vasculature. 3 , 4 Moreover, an interruption in the inhalation of continuous nitric oxide may cause rebound pulmonary hypertension. 5 , 6 Designed . . .
Summary Background Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. Methods Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients' physicians according to the individual's health-care needs. Findings 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m−2 ). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3–12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right-heart function. Interpretation TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies. Funding Actelion Pharmaceuticals.
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 . . .
Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon disease that is the most serious complication associated with unresolved pulmonary embolism. This disease has several risk factors, but no familial pattern has been described. Few thrombophilic conditions have been reported to increase risk of CTEPH, and none of the hereditary thrombophilias causes this disease. The reason CTEPH develops in some patients after pulmonary embolism remains unknown. We describe a 54-year-old woman and her maternal aunt who both underwent pulmonary thromboendarterectomy for CTEPH. This represents the first description of familial CTEPH.
Pulmonary arterial hypertension is a progressive, symptomatic, and ultimately fatal disorder for which substantial advances in treatment have been made during the past decade. Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Despite progress in treatment, obstacles remain that impede the achievement of optimal outcomes. The current article provides an overview of the pathobiologic mechanisms of pulmonary arterial hypertension, including genetic substrates and molecular and cellular mechanisms, and describes the clinical manifestations and classification of pulmonary arterial hypertension. The article also reviews established approaches to evaluation and treatment, with emphasis on the appropriate application of calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. In addition, the authors discuss unresolved issues that may complicate patient management, such as the clinical importance of mild or exercise-related pulmonary arterial hypertension, and they identify avenues by which treatment may advance in the future through the use of combination treatment, outcomes assessment, and exploration of alternative pharmacologic strategies.