Primary Pulmonary Arterial Hypertension Research Articles

New drugs: Ambrisentan, temsirolimus, and eculizumab

Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition that results from restricted blood flow to the lungs due to the constriction of smooth muscle cells in the pulmonary vascular system. Symptoms include shortness of breath, fatigue, chest pain, dizziness, and fainting, and, over time, the right ventricle is unable to sustain adequate pulmonary blood flow without incurring damage that leads to heart failure. The condition occurs as primary PAH, which is not associated with other clinical disorders, or as secondary PAH, which develops as a complication of conditions such as scleroderma, systemic lupus erythematosus, and mixed connective tissue disorders and from use of appetite suppressants. If PAH is not treated, the median survival time after diagnosis may be as short as 3 years. PAH affects approximately 100,000 people in the United States.

DHEA treatment of pulmonary hypertension: New insights into a complex mechanism

See article by Oka et al. [5] (pages 377–387) in this issue . Pulmonary arterial hypertension (PAHT) is an implacable killer. Patients developing PAHT present a survival rate of 40% after 36 months [1]. This deadly pathology remains actually an orphan in terms of long-term treatment and affects more than 100,000 patients in the United States and Europe, with an annual incidence estimated at 2 new cases for primary PAHT and 8 new cases for secondary PAHT per million individuals per year. Pulmonary hypertension is classified into two main categories. The causes of primary PAHT remain largely unknown, but new studies have identified a gene located on chromosome 2 coding for bone morphogenetic protein receptor I (BMPR2), which belongs to the transforming growth factor β type-II receptor family, and inhibits cell growth. A mutation responsible for 6% of primary PAHT induces an abnormal response of the vascular endothelium to injury, leading to cancerous-like proliferation of endothelial cells [2]. Secondary PAHT has many causes that may vary from a prophylaxis reaction [3] to potassium current alterations like the decrease of Kv1.5 subunit expression in smooth muscle cells (SMC) induced by consumption of anorectic agents. … dubuis_e{at}yahoo.fr

Low-dose oral sildenafil for patients with pulmonary hypertension: a cost-effective solution in countries with limited resources

Pulmonary arterial hypertension, both primary and secondary, continues to pose a therapeutic problem. In this study, we evaluate the efficacy and safety of a low-dose of oral sildenafil in 10 patients with pulmonary arterial hypertension. We administered a single daily dose of 0.5 milligrams per kilogram of sildenafil for 3 months to 10 patients with pulmonary arterial hypertension. Their average age was 26.8 years. Diagnoses were primary pulmonary arterial hypertension in 3 patients, and secondary pulmonary arterial hypertension due to congenital cardiac disease in the remaining 7 patients. Outcome measures included the clinical state, the mean pulmonary arterial pressure, and the indexed pulmonary vascular resistance; the latter two assessed at the beginning and at the end of the treatment period by cardiac catheterization. We also analysed the cost of the treatment. Oral treatment was well tolerated, and resulted in an improvement of the functional capacity in 9 of the 10 patients. Pulmonary arterial pressure decreased from 70 to 60 millimetres of mercury (p equal to 0.05), and indexed pulmonary vascular resistance decreased from 21.8 to 15.8 Wood units per square metre (p equal to 0.006). The mean cost per patient for 3 months on oral treatment with sildenafil was 120.99 American dollars. A low dose of 0.5 milligrams per kilogram per day of oral sildenafil, instead of 1 to 4 milligrams per kilogram per day, provided early clinical and haemodynamic improvements, and proved less expensive. Additional experience is now required to define more reliably the true long-term benefits of this therapy.

Mutations of activin-receptor-like kinase 1 (ALK-1) are not found in patients with pulmonary hypertension and underlying connective tissue disease

Pulmonary arterial hypertension is a recognized clinical component of systemic autoimmune diseases, especially systemic sclerosis. Mutations in the bone morphogenetic protein receptor 2 gene reported in sporadic and familial primary pulmonary arterial hypertension have failed to be detected in patients with either scleroderma spectrum disease or underlying connective tissue diseases. Activin receptor-like kinase 1 (ALK-1) gene has recently been linked to the pathogenesis of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, which has some resemblance with the CREST syndrome. The presence of mutations in the ALK-1 gene in ten patients with underlying connective tissue diseases was investigated.

The Prognostic Value of Pulmonary Vascular Capacitance Determined by Doppler Echocardiography in Patients with Pulmonary Arterial Hypertension

We sought to determine if a novel measurement of pulmonary vascular (PV) capacitance (PVCAP) by Doppler echocardiography predicts all-cause mortality in patients with primary pulmonary arterial (PA) hypertension (PPAH). The prognosis of patients with PPAH is variable and has been difficult to predict using clinical or hemodynamic parameters. PVCAP is a measure of the workload on the right ventricle (RV) and we recently have shown that PVCAP determined by cardiac catheterization is a strong predictor of survival. This same hemodynamic information to calculate PVCAP can be derived from Doppler echocardiography. Therefore, the purpose of this study was to determine if PVCAP from noninvasive Doppler echocardiography would be a useful measure of survival in patients with PPAH. We analyzed clinical and hemodynamic variables on all patients with PPAH who had a right heart catheterization and echocardiogram from January to December 1999. Because capacitance is directly proportional to stroke volume and inversely proportional to PA pulse pressure, PVCAP was defined as stroke volume/pulse pressure. PVCAP was derived noninvasively from a comprehensive 2-dimensional and Doppler echocardiogram. Using the peak systolic tricuspid regurgitation velocity and the end-diastolic pulmonary regurgitation velocity, the modified Bernoulli equation was used to calculate the PA systolic and diastolic pressures, respectively. Stroke volume was obtained using the volumetric flow through the left ventricular outflow tract. PVCAP was then analyzed as a predictor of mortality, adjusting for other known modifiers of risk. In all, 54 patients (13 men) were studied with a mean age of 44 +/- 11 years, ejection fraction of 62 +/- 11%, and RV systolic pressure of 90 +/- 21 mm Hg. In all, 24% were in World Health Organization (WHO) class II, 52% in class III, and 24% in class IV. During follow-up of 1498 +/- 108 days, 12 patients died. The strongest noninvasive predictor of mortality was PVCAP (risk ratio 3.0/mL/mm Hg decrease in PVCAP, 95% confidence interval 1.2-8.0, P = .0212). WHO class, RV index of myocardial performance, RV systolic pressure, and RV ejection time were weaker predictors. PVCAP was also a stronger predictor of mortality than invasively determined PV resistance, right atrial pressure, and mean PA pressure. In multivariate analysis, PVCAP was the only noninvasive predictor of mortality. In quartile analysis the lowest PVCAP quartile had a 4-year mortality of 39% whereas the highest PVCAP had a mortality of 7%. The novel measure of PVCAP, as determined by Doppler echocardiography, is a strong noninvasive predictor of mortality in patients with PPAH and adds prognostic value to conventional risk markers.

Bosentan for treatment of pulmonary arterial hypertension (I)

Evaluation of: McLaughlin VV., Sitbon O., Badesch DB. et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur. Respir. J. 25, 244–249 (2005). Primary pulmonary hypertension is a rare life-threatening form of pulmonary arterial hypertension. Several pharmacologic classes have recently become available for primary pulmonary hypertension treatment – prostacyclin and prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase inhibitors. Bosentan (Tracleer®) is an oral dual-endothelin receptor antagonist approved in Europe and North America for the treatment of pulmonary arterial hypertension. Several studies focused on the efficacy and safety of bosentan as an add-on or first-line therapy in primary pulmonary hypertension and pulmonary arterial hypertension related with connective tissue diseases. The current study assesses the impact of first-line bosentan therapy on the survival of primary pulmonary hypertension patients, compares it with a predicte...

Beneficial Effect of Oral Sildenafil Therapy on Childhood Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH. After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278+/-114 to 443+/-107 m over 6 months (P=0.02), and at 12 months, the distance walked was 432+/-156 m (P=0.005). A plateau was reached between 6 and 12 months (P=0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg (P=0.014). Median pulmonary vascular resistance decreased from 15 Wood units m2 (range, 9 to 42) to 12 Wood Units m2 (range, 5 to 29) (P=0.024). Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.

Hypertension artérielle pulmonaire en anesthésie–réanimation

Objective. – To review the perioperative anaesthetic management of pulmonary arterial hypertension. Data sources. – Extraction from Pubmed ® database of French and English articles on the perioperative anaesthetic management of pulmonary hypertension for 9 years. Data selection. – The collected articles were reviewed and selected according their quality and originality. The more recent data were selected. Data synthesis. – Pulmonary arterial hypertension is classically divided in primary and secondary. Primary pulmonary hypertension (familial and sporadic) is relatively severe and rare. Muscularization of the terminal portion of the pulmonary vascular arterial tree, caused by smooth muscle cell hyperplasia is the first change. Pulmonary arterial hypertension linked with disorders of the respiratory system and hypoxemia or pulmonary venous hypertension including mitral valve disease and chronic left ventricular dysfunction are often associated with high morbidity and mortality. The main consequence of pulmonary hypertension development is the occurrence of right-sided circulatory failure. A better understanding of disease pathophysiology will contribute to the development of new therapies increasing then the prognosis of these patients. The management of primary pulmonary hypertension or secondary pulmonary arterial hypertension is a challenge for the anaesthesiologist because the risk of right ventricular failure is markedly increased.

Targeted Combination Therapy for the Treatment of Primary Pulmonary Arterial Hypertension

Introduction: The treatment of severe primary pulmonary arterial hypertension (PAH) aims to avoid deterioration with the necessity of lung transplantation or continuous administration of pulmonary vasodilators, or even to reverse the course.

Investigation of Second Genetic Hits at the BMPR2 Locus as a Modulator of Disease Progression in Familial Pulmonary Arterial Hypertension

Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression. To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients. Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.

Tadalafil in Primary Pulmonary Arterial Hypertension

Letters2 November 2004Tadalafil in Primary Pulmonary Arterial HypertensionEmiliano Antonio Palmieri, MD, Flora Affuso, MD, Serafino Fazio, MD, and Danilo Lembo, MDEmiliano Antonio Palmieri, MDFrom University Federico II Medical School, 80131 Naples, Italy, and Eli Lilly, 50019 Florence, Italy.Search for more papers by this author, Flora Affuso, MDFrom University Federico II Medical School, 80131 Naples, Italy, and Eli Lilly, 50019 Florence, Italy.Search for more papers by this author, Serafino Fazio, MDFrom University Federico II Medical School, 80131 Naples, Italy, and Eli Lilly, 50019 Florence, Italy.Search for more papers by this author, and Danilo Lembo, MDFrom University Federico II Medical School, 80131 Naples, Italy, and Eli Lilly, 50019 Florence, Italy.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-141-9-200411020-00033 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Background: Sildenafil, a short-acting phosphodiesterase-5 inhibitor (1), is safe and may benefit patients with primary pulmonary arterial hypertension (2-8). However, it requires many daily administrations. We describe a patient with end-stage primary pulmonary arterial hypertension who improved while taking tadalafil, a long-acting phosphodiesterase-5 inhibitor (9).Case Report: A 72-year-old woman was hospitalized for progressive cardiopulmonary failure. Five years earlier, primary pulmonary arterial hypertension was diagnosed and the patient was hospitalized for hydropic decompensation and hypoxemia. Since then, she had been receiving permanent oxygen therapy and had also taken digoxin, amlodipine, furosemide, potassium canrenoate, and acenocoumarol.At the ...

Soluble CD40 ligand in pulmonary arterial hypertension: possible pathogenic role of the interaction between platelets and endothelial cells.

Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH. Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells. Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

Modulation of B-Type Natriuretic Peptide with Epoprostenol in Pulmonary Arterial Hypertension

Background: B-type natriuretic peptide (BNP) levels are elevated in pulmonary arterial hypertension (PAH), in response to right ventricular wall stress. To overcome limitations of invasive testing for evaluation of therapeutic responsiveness, we examined the utility of early modulation of BNP levels as a surrogate marker for predicting efficacy of response to epoprostenol therapy. Methods: In 20 PAH patients eligible for epoprostenol therapy, we measured serial BNP levels (pretreatment and at 3 months post initiation of therapy). The primary endpoint of this prospective study was to evaluate the relationship between early change (0-3 months) in BNP (absolute and relative reduction) and PAH related clinical events (hospitalizations and deaths). Additionally, the predictive power of this biomarker was also assessed in the context of clinical indices (functional class, 6 minute walk test), structural parameters (echocardiographic variables) and invasive hemodynamics by catheterization. Results: Twenty patients (50±14 years, 60% primary PAH, 80% female, 50% Caucasian) were enrolled. The baseline BNP level in this cohort was 828±217 pg/ml. A total of 25 hospitalizations and 1 death occurred in nine patients during follow-up period of 10.3±2.8 months. BNP levels between the event-free group (Group A) demonstrated significantly greater absolute and relative decreases from baseline compared with patients with clinical events (Group B). A decrease in BNP level of ≥50% was strongly associated with event-free survival on epoprostenol (p=0.0003). BNP modulation was the only independent predictor of response to epoprostenol in the context of clinical, echocardiographic and invasive hemodynamic variables analyzed.Baseline BNPBNP at 3 MonthsChange in BNP% Change in BNPGroup A (n=11)1090±372288±92− 801±301− 70Group B (n=9)510±135610±121+ 101±137+ 11p Value0.070.040.020.005BNP in pg/ml

Role of the cardiologist: clinical aspects of managing erectile dysfunction.

Erectile dysfunction (ED) is often a marker for serious underlying cardiovascular disease (CVD), and cardiologists are increasingly involved in the care of men with ED. It is important to ask specifically about ED when evaluating men with CVD, since they may be embarrassed to volunteer this information. During the clinical workup, it is also important to check for contributing factors to ED such as diabetes, depression, stress, alcohol abuse, and cardiovascular risk factors. Patients should be advised that many treatment options are available for ED, including the phosphodiesterase type 5 (PDE5) inhibitors. The PDE5 inhibitors are safe and effective in most patients with CVD, including those taking multiple antihypertensive drugs. Furthermore, they have no deleterious effect on exercise capacity, heart rate, or extent of exercise-induced ischemia. In the future, the PDE5 inhibitors may have a role in reducing pulmonary hypertension in persons with primary pulmonary arterial hypertension (PAH) or congestive heart failure. The one major precaution for men taking PDE5 inhibitors is to avoid concomitant administration of therapeutic and recreational nitrate preparations. Patients with chest pain suggestive of a heart attack need to inform emergency room (ER) personnel if they are taking a PDE5 inhibitor. Similarly, before giving nitrates, ER personnel need to ask patients if they have used PDE5 inhibitors. Nitrates should not be given for at least 24 h after a patient uses sildenafil or vardenafil and at least 48 h after a patient uses tadalafil.

Long term outcome of bosentan treatment in primary pulmonary hypertension (PPH) and pulmonary arterial hypertension associated with the scleroderma spectrum of diseases (PAH-SSD)

transplantation (LTx). In asthma and LTx BOS (Zheng JHLT 1999:18: 231) increased submucosal vascularity has been shown to contribute to airflow limitation. Vascularity has 2 components: sprouting angiogenesis(more vessels) and microvascular enlargement(larger vessels). We hypothesise that the lack of bronchial arterial reanastomosis at the time of transplant may stimulate angiogenesis and be a risk factor for subsequent BOS. Aim: To determine the components and time course in relation to BOS of post-LTx airway vasculature Methods: 27 initially stable(BOS 0) LTx recipients were recruited at 148 80 days post-LTx and followed over 3 years. 8 remained stable and 19 developed BOS. 9 normal controls were also recruited. Airway vasculature was examined immunohistochemically in endobronchial biopsies(EBB) with mouse antihuman collagenIV antibody, quantified by computer image analyser, expressed as average vessel size m, vessel number/mm of lamina propria and overall %vascularity. Demographic, clinical and EBB findings were statistically analysed. Results: There was significant increased baseline vessel size and vascularity, but not vessel numbers in both stable and BOS LTx compared to normals.

TRACLEER® (bosentan), for the treatment of pulmonary arterial hypertension (PAH) - 6 month quality of life data

Bosentan (TRACLEER®), has demonstrated efficacy in pulmonary arterial hypertension (PAH) in placebo-controlled trials and extends the time before clinical worsening. This multicentre, open-label, single-arm Australian study was designed to assess the efficacy and safety of bosentan in patients with primary PAH (PPH) and PAH due to connective tissue disease, and to measure quality of life changes (SF36 and AQOL) with treatment. Bosentan oral therapy was commenced at 62.5mg bid for 4 weeks, increasing to a 125mg bid maintenance dose.

Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a life-threatening disorder that refers to a group of diseases characterized by an abnormal elevation of the blood pressure within the pulmonary circulation due to a vasculopathy of the pulmonary microcirculation (1). If left untreated, the overall prognosis of pulmonary arterial hypertension is poor, with a 5-year survival rate of 34%. The most common cause of death is progressive right-sided heart failure (2). There is no pharmacologic cure for pulmonary arterial hypertension, and a team approach is required for the proper care of these patients (3). Treatment is directed at improving clinical symptoms, increasing exercise tolerance and extending survival. Until just a few years ago, standard treatment options for the treatment of pulmonary arterial hypertension were limited and included coumarin derivatives, calcium channel blockers, diuretics, digoxin and oxygen supplementation (4). In the last decade, the therapeutic options for pulmonary arterial hypertension have made considerable advances. In at least three major randomized controlled trials, the continuous intravenous infusion of epoprostenol, a synthetic salt of prostacyclin with potent vasodilatory ability, has been shown to improve exercise tolerance, hemodynamics, survival and quality of life in patients with New York Heart Association (NYHA) functional classes III and IV with either primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma (5-9). Epoprostenol has now become a mainstay therapy in the long-term treatment of primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma. Nevertheless, epoprostenol is far from an ideal form of therapy. Issues such as the short half-life of the drug, need for continuous central intravenous access and significant side effects have led to the development of more stable prostacyclin analogues as alternative therapies for primary pulmonary hypertension. These alternative therapies include iloprost (inhaled delivery) and treprostinil (subcutaneous delivery). As a result, the Food and Drug Administration (FDA) recently approved treprostinil for the treatment of pulmonary arterial hypertension in patients with NYHA classes II-IV. This review will offer a discussion of the basic pharmacology of treprostinil, its similarities to and differences from epoprostenol, the animal studies as well as the initial investigational studies leading to its FDA approval, and clinical uses of the drug alone or in combination with newer therapies directed at pulmonary arterial hypertension developed over the last decade.

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT

Primary pulmonary arterial hypertension is a rare lethal disease that typically presents radiographically with enlarged central pulmonary arteries, pruning of the peripheral vasculature, and cardiomegaly but clear lung fields. Although it is a disease of unknown etiology, primary PAH has been associated with anorexigen use. We present a case of pulmonary arterial hypertension in a woman with a history of fenfluramine and phentermine use who presented with diffuse micronodules on computed tomography scan. Lung biopsy confirmed the micronodules were radiographic manifestations of extensive diffuse plexogenic arterial lesions. This report represents an unusual radiographic presentation of anorexigen related pulmonary arterial hypertension, and to our knowledge, the first case reported as presenting with diffuse micronodules on high resolution computed tomography scan.

Pulmonary Arterial Hypertension in Systemic Sclerosis

It is increasingly recognized that significant pulmonary arterial hypertension (PAH) develops in more than 15% of patients with systemic sclerosis (SSc). As this complication of SSc may occur even in the absence of overt interstitial lung disease (isolated PAH), it has been likened to primary PAH and is attributable to intrinsic vascular pathology that is the hallmark of SSc. Deregulated activity of mediators controlling vasomotor tone has been implicated, and levels of endothelin-1 (ET-1) are elevated in the circulation and in the lungs. By causing enhanced vasoconstriction, vascular endothelial cell proliferation, smooth muscle hypertrophy, and irreversible vascular remodeling in the lungs, ET-1 appears to play a significant role in the pathogenesis of SSc-associated PAH. Although patients with the limited cutaneous form of SSc are more likely to develop PAH than those with the diffuse form, the true prevalence of PAH in SSc, and the risk factors for its development, are not yet known. Because the prognosis of patients with SSc-associated PAH is substantially worse than that of patients without this complication, intensive efforts are underway to develop sensitive screening strategies and effective treatments. Serial evaluation of SSc patients with Doppler echocardiography appears to be prudent. Antibodies against the centromere or fibrillarin proteins may be useful in identifying those patients with SSc at highest risk for developing PAH. The US FDA has approved a number of novel treatments, including long-acting oral ET-1 receptor antagonists such as bosentan and short-acting parenteral prostacyclin analogs, such as epoprostenol, for PAH. In particular, bosentan appear to be well tolerated, and short-term therapy results in improved exercise tolerance, improved hemodynamics, and possibly improved survival in patients with advanced PAH. These agents may be used alone, or possibly in combination with prostacyclin analogs. Therapeutic agents that modulate the synthesis of nitric oxide, and additional agents targeting the ET-1 signaling system are under preclinical development. Although the large-scale clinical trials that resulted in obtaining FDA approval for these agents were generally carried out in patients with primary PAH, it appears that patients with SSc-associated PAH respond similarly. Therefore, it is reasonable to conclude that ET-1 receptor antagonists and parenteral prostacyclin analogs should be used in SSc patients with moderate to severe PAH. The efficacy of these agents for treating patients with PAH who also experience significant interstitial lung disease, as occurs in many SSc patients, remains unknown. Additional important unresolved issues relate to the long-term efficacy of ET-1 receptor antagonists, and their effects on survival and progression of PAH. Additionally, it is not yet clear if early intervention for SSc patients with mild PAH is beneficial.

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT

Primary Pulmonary Arterial Hypertension Presenting as Diffuse Micronodules on CT