Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies.
ABSTRACT Pulmonary arterial hypertension (PAH), which is a subset of pulmonary hypertension, is a group of diseases distinguished by vascular remodeling of the small pulmonary arteries with associated elevated pulmonary arterial pressure and right ventricular failure. This progressive and sometimes fatal disease occurs as an idiopathic disease or as a component of other disease states. Estimates of the incidence of PAH have varied from 5 to 52 cases/1 million population. Symptoms begin with shortness of breath with exertion and progress to dyspnea with normal activities and, finally, dyspnea at rest. Untreated patients with PAH have a 1-, 3-, and 5-year survival rate of 68%, 48%, and 34%, respectively. Treated, the survival rates improve to 91% to 97% after 1 year and 84% to 91% after 2 years. The current definition of PAH consists of 3 specific hemodynamic assessments confirmed by right heart catheterization findings. One of several important pathophysiologic mechanisms involved in PAH is pulmonary vascular remodeling, which is caused by endothelial and smooth muscle cell hyperproliferation. This is coincident with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide and prostacyclin, which further impedes proper vasomotor tone, among other effects. Prostacyclin therapies augment the decreased prostacyclin levels in patients with PAH. The currently approved prostacyclins for the treatment of PAH include epoprostenol, iloprost, and treprostinil. Among the 3 medications, the delivery options include intravenous infusion, subcutaneous infusion, and inhaled formulations. Epoprostenol has been shown to have a positive effect on survival in patients with PAH. All prostacyclins have demonstrated improvements in functional class, exercise tolerance, and hemodynamics in patients with PAH. Intravenously and subcutaneously administered formulations of prostacyclins require continuous infusion pump administration, which presents clinical challenges for both the patient and the care provider. Dosing must be individualized and also presents a clinical challenge. Inhaled formulations seem efficacious in moderately symptomatic patients with PAH and might be appropriate when combined with an oral medication. Combination therapies are commonly used in clinical practice, with the decision to do so based on randomized controlled trial data and case study evidence. The present report provides an overview of PAH, the scientific rationale for treatment with prostacyclin therapy, and the benefits and risks of prostacyclin therapy, both as monotherapy and combined with other medications approved for the treatment of PAH.
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ABSTRACT: The extent to which pulmonary arterial hypertension (PAH) experts share common practice patterns that are in alignment with published expert consensus recommendations is unknown. Our objective was to characterize the clinical management strategies used by an international cohort of self-identified PAH experts. A 32-item questionnaire composed mainly of rank order or Likert scale questions was distributed via the Internet (August 5, 2013, through January 20, 2014) to four international pulmonary vascular disease organizations. The survey respondents (N = 105) were field experts reporting 11.6 ± 8.7 years of PAH experience. Likert scale responses (1 = disagree, 7 = agree) were 3.0-5.0, indicating a disparity in opinions, for 78% of questions. Respondent (dis)agreement scores were 4.4 ± 2.2 for use of expert recommendations to determine catheterization timing in PAH. For PAH patients without cardiogenic shock or known vasoreactivity status, the most and least preferred first-line therapies (1 = most preferred, 5 = least preferred) were phosphodiesterase type 5 inhibitors (PDE-Vi) and subcutaneous prostacyclin analogues, respectively (1.4 ± 0.8 vs. 4.0 ± 1.1; P < 0.05). Compared with US-practicing clinicians (N = 46), non-US-practicing clinicians (N = 57) favored collaboration between cardiology and pulmonary medicine for clinical decision making (1 = disagree, 7 = agree; 3.1 ± 2.2 vs. 4.8 ± 2.2; P < 0.0001) and PDE-Vi (6.5% vs. 22.4%) as first-line therapy for PAH patients with cardiogenic shock but were less likely to perform vasoreactivity testing in patients with lung disease-induced pulmonary hypertension (4.3 ± 2.1 vs. 2.2 ± 1.6; P < 0.0001). In conclusion, practice patterns among PAH experts diverge from consensus recommendations and differ by practice location, suggesting that opportunity may exist to improve care quality for this highly morbid cardiopulmonary disease.09/2014; 4(3):441-51. DOI:10.1086/677357
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ABSTRACT: The pulmonary endothelium represents a heterogeneous cell monolayer covering the luminal surface of the entire lung vasculature. As such, this cell layer lies at a critical interface between the blood, airways, and lung parenchyma, and must act as a selective barrier between these diverse compartments. Lung endothelial cells are able to produce and secrete mediators, display surface receptor, and cellular adhesion molecules, and metabolize circulating hormones to influence vasomotor tone, both local and systemic inflammation, and coagulation functions. In this review, we will explore the role of the pulmonary endothelium in each of these systems, highlighting key regulatory functions of the pulmonary endothelial cell, as well as novel aspects of the pulmonary endothelium in contrast to the systemic cell type. The interactions between pulmonary endothelial cells and both leukocytes and platelets will be discussed in detail, and wherever possible, elements of endothelial control over physiological and pathophysiological processes will be examined. © 2015 American Physiological Society. Compr Physiol 5: 531-559, 2015.03/2015; 5(2-2):531-559. DOI:10.1002/cphy.c140024
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ABSTRACT: Severe portopulmonary hypertension (PPHT) is considered a contraindication for liver transplantation (LT) because of the associated high mortality and poor prognosis. We report the case of a 57-year-old cirrhotic woman with severe PPHT (mean pulmonary artery pressure [mPAP] > 65 mmHg), who underwent a successful living donor LT. Intra-operative use of inhaled iloprost, milrinone, dobutamine, and postoperative use of inhaled nitric oxide and oral sildenafil failed to lower the pulmonary artery pressure (PAP). The patient responded only to nitroglycerin and drainage of massive ascites. Meticulous intra-operative volume control, which included minimizing blood loss and subsequent transfusion, was carried out. The use of vasopressors, which may have elevated the PAP, was strictly restricted. Intra-operative PAP did not show an increase, and the hemodynamics was maintained within relatively normal range, compared to the preoperative state. The patient was discharged without any complications or related symptoms.