The evolving landscape of combination therapy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressively fatal disease, and the goal in treatment is to prevent disease progression. The standard of care often involves medications from multiple therapeutic classes, and there has been significant interest both in the choice of agent as well as the timing of initiation. There is a growing body of support for starting multiple medications at the time of diagnosis, or 'upfront ', rather than using sequential addition to prevent clinical deterioration.

Right atrial pressure/pulmonary artery wedge pressure ratio: A more specific predictor of survival in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables. METHODS: We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center. RESULTS: Cohort 1 (n = 847) and Cohort 2 (n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 (p = 0.0001) and 1.35, respectively (p < 0.0001), and was the most consistently predictive hemodynamic variable across the 2 cohorts. These results remain valid even when adjusted for other covariables in multivariable regression models. CONCLUSIONS: The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models.

Early Diagnosis of Pulmonary Arterial Hypertension: A Plea for Help.

Pulmonary arterial hypertension is a devastating, progressive, and fatal disease. When diagnosed, evaluated, and treated early, patients can expect important decreases in disease progression, improvement in quality of life, and improvement in survival rates. Sadly, the disorder is often allowed to progress to New York Heart Association Functional Class or WHO functional class III or IV status before practitioners on the front lines think of the diagnosis or refer to a pulmonary hypertension center. This is a plea to all licensed care providers for more expedient evaluation and treatment of these unfortunate patients.

Lupus-Associated Pulmonary Arterial Hypertension: Variable Course and Importance of Prompt Recognition.

We describe a critically ill young woman with systemic lupus erythematosus (SLE) presenting with circulatory shock, multiorgan dysfunction, and elevated right-sided heart pressures. She was found to have recurrent acute severe pulmonary arterial hypertension (PAH) in the setting of an SLE flare. Our report highlights the variable course that SLE-associated PAH can take in the same patient and the implications of this for instituting the most effective treatment approach with each episode. This report also highlights the potential for SLE-associated PAH to present with life-threatening symptoms requiring critical care level interventions. We also describe evidence-based therapies, which can result in significant improvement in symptoms, function, and long-term outcomes.

Macitentan for the treatment of pulmonary arterial hypertension.

Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug-drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.

Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report.

OBJECTIVE: Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. METHODS: This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. RESULTS: Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. CONCLUSIONS: Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Unresolved pulmonary embolism leading to a diagnosis of pulmonary artery sarcoma.

Pulmonary artery sarcomas (PAS) are rare tumors with a poor prognosis. They are often misdiagnosed as pulmonary embolism (PE) leading to futile anticoagulation treatment and delay in proper diagnosis. We present a case of a patient who was initially misdiagnosed and anticoagulated for presumed pulmonary embolism. Progressive symptoms and additional imaging led to the diagnosis of intimal pulmonary artery sarcoma for which he underwent surgical resection. This case serves as a reminder to consider pulmonary artery sarcoma in the differential diagnosis of patients with dyspnea and filling defects on CT pulmonary angiogram offering the potential for resection prior to metastasis.

Meningoencephalitis due to Gemella haemolysans.

Gemella haemolysans is an uncommon but described cause of invasive disease in humans. We report a case of meningitis due to G. haemolysans that did not grow in cerebrospinal fluid culture, demonstrating a potential role for direct 16S rRNA gene PCR and sequencing in culture-negative cerebrospinal fluid when bacterial meningitis is suspected.

Diagnosis of pulmonary arterial hypertension.

Accurate diagnosis of pulmonary arterial hypertension can be challenging and often requires a high index of clinical suspicion. Use of a variety of noninvasive tests can help define the population of patients in whom invasive cardiac catheterization should be pursued. An understanding of the historical, physical exam, electrocardiographic, radiographic, and echocardiographic clues in the diagnosis is important. A ventilation-perfusion scan and careful assessment for left-to-right shunting are mandatory to avoid missing reasons for pulmonary hypertension that may require nonpharmacologic management. Right heart, and sometimes concomitant left heart, catheterization is required to establish the diagnosis and distinguish pulmonary arterial from pulmonary venous hypertension.

Standard nonspecific therapies in the management of pulmonary arterial hypertension.

Recent advances in pulmonary arterial hypertension (PAH) research have created a new era of PAH-specific therapies. Although these therapeutics have revolutionized PAH therapy, their innovation was predated by supportive but nonspecific medical therapies adapted from their use in more common cardiopulmonary diseases. These therapies include oxygen therapy, diuretics, digoxin, anticoagulation, and high-dose calcium channel blockers. Expert opinion continues to support the use of adjunct therapies based on current pathologic understandings of PAH combined with some evidence extrapolated from small studies. This article discusses why these therapies continue to play an important role in the treatment of patients with PAH.

IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension.

Although previous literature suggests that interleukin (IL)-13, a T-helper type 2 cell effector cytokine, might be involved in the pathogenesis of pulmonary hypertension (PH), direct proof is lacking. Furthermore, a potential mechanism underlying IL-13-induced PH has never been explored. This study's goal was to investigate the role and mechanism of IL-13 in the pathogenesis of PH. Lung-specific IL-13-overexpressing transgenic (Tg) mice were examined for hemodynamic changes and pulmonary vascular remodeling. IL-13 Tg mice spontaneously developed PH phenotype by the age of 2 mo with increased expression and activity of arginase 2 (Arg2). The role of Arg2 in the development of IL-13-stimulated PH was further investigated using Arg2 and IL-13 receptor α2 (Rα2) null mutant mice and the small-interfering RNA (siRNA)-silencing approach in vivo and in vitro, respectively. IL-13-stimulated medial thickening of pulmonary arteries and right ventricle systolic pressure were significantly decreased in the IL-13 Tg mice with Arg2 null mutation. On the other hand, the production of nitric oxide was further increased in the lungs of these mice. In our in vitro evaluations, the recombinant IL-13 treatment significantly enhanced the proliferation of human pulmonary artery smooth muscle cells in an Arg2-dependent manner. The IL-13-stimulated cellular proliferation and the expression of Arg2 in hpaSMC were markedly decreased with IL-13Rα2 siRNA silencing. Our studies demonstrate that IL-13 contributes to the development of PH via an IL-13Rα2-Arg2-dependent pathway. The intervention of this pathway could be a potential therapeutic target in pulmonary arterial hypertension.

Targeted approaches to the treatment of pulmonary hypertension.

Pulmonary arterial hypertension is a progressive and incurable disease. Over the past two decades, significant advances have been made in understanding and thus managing this disease. Multiple therapeutic options are currently available and optimizing the treatment of pulmonary arterial hypertension has become complex. Patients who meet the American College of Chest Physicians criteria for vasoresponsiveness can be safely and effectively treated with high-dose calcium channel blockers but require close follow up to assure durability of response. Patients with World Health Organization (WHO) functional class IV status and those with determinants of high risk for progression and death should be treated with an infused prostanoid agent without delay. These patients should also be referred early after stabilization for transplant evaluation. Patients with WHO functional class II status benefit from early initiation of oral therapies. Those with WHO functional class III status and lower determinants of risk for progression may receive treatment with one or more oral or inhaled agents, though many experts would advise early use of infused prostanoids for these patients as well.

Pregnancy and pulmonary hypertension.

When pulmonary hypertension (PH) occurs in pregnancy, physiologic stress can overwhelm an already strained right ventricle resulting in right ventricular failure and death. Mortality remains unacceptably high (25%-30%). Patients with PH should be counseled to avoid pregnancy. This article discusses the physiologic changes of pregnancy that make it difficult for patients with PH, the pitfalls of transthoracic echocardiography in diagnosing PH in pregnancy, and the historical data regarding mortality. The causes of development of PH during pregnancy are discussed, and the limited data on management of patients with PH who choose to carry their pregnancy to term are reviewed.

Chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension is one of the few forms of pulmonary hypertension that is surgically curable. It is likely underdiagnosed and must be considered in every patient presenting with pulmonary hypertension to avoid missing the opportunity to cure these patients. This article discusses the epidemiology, risk factors, natural history, diagnosis, and preoperative evaluation of patients with this disorder. Also covered are putative mechanisms for the conversion of acute emboli into fibrosed thrombembolic residua. Mechanical obstruction of the central pulmonary vasculature is rarely the sole cause of the pulmonary hypertension, and a discussion of the small vessel arteriopathy present in these patients is offered. Technical aspects of pulmonary endartectomy and the data supporting its role are discussed, as are the limited data on pulmonary arterial hypertension specific medical therapies for patients deemed noncandidates for the operation.

Hemothorax due to rupture of pulmonary arteriovenous malformation: an interventional emergency.

Spontaneous hemothorax as a result of a ruptured pulmonary arteriovenous malformation (PAVM) is a life-threatening event and requires immediate interventional therapy. We present two patients who survived following emergent embolization. Definitive thoracentesis was delayed until embolization was performed. The tamponade provided by the hemothorax may have prevented exsanguination, suggesting to us that drainage of blood from the pleural space should be delayed until the PAVM has been treated. Hemorrhage from a PAVM may be the first manifestation of hereditary hemorrhagic telangiectasia. Genetic testing and screening for other family members should be considered.

Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism.

Various treatments approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH) target three of the many pathways implicated in the development of PAH: prostacyclin-, endothelin-1 (ET-1)-, and nitric oxide-mediated pathways. The objectives of this manuscript are to provide background information on the role of ET-1 in the pathogenesis of PAH, to provide theoretical considerations for the advantages and disadvantages of dual vs single endothelin receptor antagonists (ERAs) for the management of PAH, and to describe the clinical study results from randomized, double-blind, placebo-controlled trials for the various ERAs. ET receptors (ET(A) and ET(B)) have different densities and distributions throughout the body and are dynamically regulated, such that blockade of ET(A) and ET(B) receptors may have different results in normal vs pathological conditions. Although differences in biological effects can be found in studies of isolated cells, blood vessels and animal models, clinical treatment studies have not identified clear differences in efficacy among the various ERAs. The main differences appear to be in safety profiles, with a greater frequency of serum liver function abnormalities occurring with the available dual ET(A)/ET(B) antagonist, and possibly higher rates of peripheral edema noted with selective ET(A) agents. Head-to-head studies will be necessary to resolve the question of whether single vs dual blockade produces better clinical results with fewer side effects in patients with PAH.