The importance of patient perspectives in pulmonary hypertension.

The assessment of objective measurement of cardiopulmonary status has helped us achieve better clinical outcomes for patients and develop new therapies through to the point of market access; however, patient surveys indicate that more can be done to improve holistic care and patient engagement. In this multidisciplinary review, we examine how clinical teams can acknowledge and embrace the individual patient's perspective, and thus improve the care for individual patients suffering from pulmonary hypertension by cultivating the importance and relevance of health-related quality of life in direct clinical care. At the individual level, patients should be provided with access to accredited specialist centres which provide a multidisciplinary approach where there is a culture focused on narrative medicine, quality of life, shared decision making and timely access to palliative care, and where there is participation in education. On a larger scale, we call for the development, expansion and promotion of patient associations to support patients and carers, lobby for access to best care and treatments, and provide input into the development of clinical trials and registries, focusing on the patients' perspective.

Validation of two predictive models for survival in pulmonary arterial hypertension.

The French Pulmonary Hypertension Network (FPHN) registry and the Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) have developed predictive models for survival in pulmonary arterial hypertension (PAH). In this collaboration, we assess the external validity (or generalisability) of the FPHN ItinérAIR-HTAP predictive equation and the REVEAL risk score calculator. Validation cohorts approximated the eligibility criteria defined for each model. The REVEAL cohort comprised 292 treatment-naïve, adult patients diagnosed <1 year prior to enrolment with idiopathic, familial or anorexigen-induced PAH. The FPHN cohort comprised 1737 patients with group 1 PAH. Application of FPHN parameters to REVEAL and REVEAL risk scores to FPHN demonstrated estimated hazard ratios that were consistent between studies and had high probabilities of concordance (hazard ratios of 0.72, 95% CI 0.64-0.80, and 0.73, 95% CI 0.70-0.77, respectively). The REVEAL risk score calculator and FPHN ItinérAIR-HTAP predictive equation showed good discrimination and calibration for prediction of survival in the FPHN and REVEAL cohorts, respectively, suggesting prognostic generalisability in geographically different PAH populations. Once prospectively validated, these may become valuable tools in clinical practice.

Hemodynamic ranges during daily activities and exercise testing in patients with pulmonary arterial hypertension.

BACKGROUND: In patients with pulmonary arterial hypertension (PAH) the relationship between hemodynamic impairment experienced during daily activity and that during exercise testing is not known. METHODS AND RESULTS: Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary arterial (MPAP) pressures. Before starting a new PAH treatment (baseline) and after 12 weeks on treatment, a 6-minute walk test (6MWT) and a maximal walk test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT. Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24 hours. One week of AMBs were averaged for each patient before each exercise test. Mean age was 54 ±18 years, 9 were female, and all were in World Health Organization functional class III. At baseline, RVSP and MPAP increased, respectively, 136 ± 49% and 164 ± 49% during AMB, 63 ± 26% and 79 ± 30% during MAXWT, and 59 ± 32% and 69 ± 33% during 6MWT. There was no difference in pressure change at 12 weeks. CONCLUSIONS: Changes in RV and PA pressures during exercise tests were relatively small compared with the range seen during ambulatory conditions.

[Pulmonary arterial hypertension: epidemiology and registries]. / Pulmoner arter hipertansiyonu: Epidemiyoloji ve kayitlar.

Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases. (J Am Coil Cardiol 2013;62:D51-9) ©2013 by the American College of Cardiology Foundation.

[Updated treatment algorithm of pulmonary arterial hypertension]. / Pulmoner arter hipertansiyonunun güncel tedavi algoritmasi.

The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. (J Am Coll Cardiol 2013;62:D60-72) ©2013 by the American College of Cardiology Foundation.

Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. METHODS AND RESULTS: We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m(2), respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts (P=0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P=0.087) and lower brain natriuretic peptide (P=0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. CONCLUSION: Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00370214.

Diagnostic dilemmas in pulmonary hypertension.

Dilemmas persist in the screening, assessment, and follow-up of patients with pulmonary hypertension, relating to issues of whom and how to screen, how to resolve ambiguities in the clinical classification of patients with multiple potential substrates of pulmonary vascular disease, how to interpret test results, how to integrate multiple clinical parameters into a global diagnosis, how to use ambiguous test results, how to determine disease severity and prognosis, and how to monitor patients on treatment. This article describes how to incorporate available information into the diagnostic process, and where lack of concrete data should impose caution in patient management.

Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).

BACKGROUND: Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. METHODS AND RESULTS: Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. CONCLUSIONS: We identified key predictors of survival based on the patient's most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.

BACKGROUND: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. METHODS AND RESULTS: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. CONCLUSIONS: Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Thrombocytopenia independently predicts death in idiopathic PAH.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive vascular disorder with a high mortality. Clinical experience and small case series suggest thrombocytopenia may be frequent in this population and associated with a poor prognosis. We sought to estimate the prevalence of thrombocytopenia in patients with PAH and characterize its association with disease characteristics and patient outcome. METHODS: Single center cohort study of 714 incident adult patients with Group 1 PH who were evaluated for baseline platelet count at the time of diagnosis. Pts were stratified into three groups: normal platelet count (>150 × 109/L), Grade 1 thrombocytopenia (75-149 × 109/L) and Grade 2-4 thrombocytopenia (<75 × 109/L). RESULTS: The median platelet count was 209 × 109/L (IQR 163, 264). There were 572 (80%) pts without thrombocytopenia, 107 (15%) with Grade 1 and 35 (5%) with Grade 2-4 thrombocytopenia. The median pt age was 55 years (IQR 44-65) with no difference between platelet groups (p = 0.85). Men were more likely to have thrombocytopenia (62, 34%) than women (80, 15%, p < 0.0001). Thrombocytopenia was frequent with portopulmonary PAH (84%) as opposed to idiopathic PAH (iPAH; 14%) or connective tissue disease associated PAH (12%). Platelet counts were not associated with functional class symptoms, the degree of right ventricular enlargement or dysfunction or tricuspid regurgitation by echocardiography. Invasive hemodynamics of right atrial pressure, mean pulmonary artery pressure and pulmonary vascular resistance were also similar between platelet groups. Thrombocytopenia was associated with higher mortality in iPAH patients (age- and sex-adjusted 5 year mortality [HR 1.95 (1.20, 3.08) p = 0.008] but not in other etiology groups. In a multivariate model of iPAH patients (adjusted for age, sex, DLCO, PVR, creatinine and 6MW distance) thrombocytopenia was most predictive of 5-year mortality [HR 1.68 (1.32, 2.12), p < 0.0001]. CONCLUSION: Thrombocytopenia in the context of iPAH portends a poor prognosis and is a simple independent factor to consider in judging severity of disease.

Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies.

BACKGROUND: Pulmonary arterial hypertension is a progressive, fatal disease. Published treatment guidelines recommend treatment escalation on the basis of regular patient assessment with the goal of achieving or maintaining low-risk status. Various strategies are available to determine risk status. This analysis describes an update of the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator (REVEAL 2.0) and compares it with recently published European Society of Cardiology/Respiratory Society guideline-derived risk assessment strategies. METHODS: A subpopulation from the US-based registry REVEAL that survived ≥ 1 year postenrollment (baseline for this cohort) was analyzed. For REVEAL 2.0, point values and cutpoints were reassessed, and new variables were evaluated. The Kaplan-Meier method was used to estimate survival at 12 months postbaseline; discrimination was quantified using the c-statistic. Mortality estimates and discrimination were compared between REVEAL 2.0 and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and French Pulmonary Hypertension Registry (FPHR) risk assessment strategies. For this comparison, a three-category REVEAL 2.0 score was computed in which patients were classified as low-, intermediate-, or high-risk. RESULTS: REVEAL 2.0 demonstrated similar discrimination as the original calculator in this subpopulation (c-statistic = 0.76 vs 0.74), provided excellent separation of risk among the risk categories, and predicted clinical worsening as well as mortality in patients who were followed ≥ 1 year. The REVEAL 2.0 three-category score had greater discrimination (c-statistic = 0.73) than COMPERA (c-statistic = 0.62) or FPHR (c-statistic = 0.64). Compared with REVEAL 2.0, COMPERA and FPHR both underestimated and overestimated risk. CONCLUSIONS: REVEAL 2.0 demonstrates greater risk discrimination than the COMPERA and FPHR risk assessment strategies in patients enrolled in REVEAL. After external validation, the REVEAL 2.0 calculator can assist clinicians and patients in making informed treatment decisions on the basis of individual risk profiles. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00370214; URL: www.clinicaltrials.gov.

The prognostic significance of tricuspid valve regurgitation in pulmonary arterial hypertension.

INTRODUCTION: Tricuspid valve regurgitation (TR) is a frequent finding in patients with pulmonary arterial hypertension (PAH). However, its prognostic significance and relation to PAH, while suspected, are poorly understood. We assessed 727 consecutive patients with newly diagnosed PAH who underwent transthoracic echocardiographic evaluation of tricuspid valve function. OBJECTIVES: The study objective was to determine the association of TR presence and severity with patient characteristics, pulmonary artery hemodynamics and outcome. METHODS: Consecutive patients with newly diagnosed PAH (N = 727 with group 1 pulmonary hypertension) underwent transthoracic echocardiographic evaluation of tricuspid valve function at diagnosis. The primary study end point was all-cause mortality or lung transplantation. RESULTS: In this population, 702 patients (96.5%) had TR; in 165 patients (23%), TR was severe. Compared with those with no or mild TR by echocardiography criteria, patients with severe TR had shorter mean (SD) 6-minute walk distances (285 [125] m vs 360 [121] m; P = .02) and higher levels of B-type natriuretic peptide (695 [672] pg/dL vs 328 [300] pg/dL; P < .05). Severe TR was associated with greater right atrial dilatation (91% vs 47%; P = .004) and right ventricular (RV) dilatation (92% vs 51%; P = .008), greater right atrial pressure (mean [SD] 15 [7] mm Hg vs 10 [6] mm Hg; P < .001) and lower cardiac index (mean [SD], 2.2 [0.7] L/min/m2 vs 2.8 [0.9] L/min/m2; P < .001). Severe TR was strongly predictive of greater 5-year mortality risk after adjustment for age, sex, functional class, 6-minute walk distance, diffusing capacity, RV size and pulmonary vascular resistance index (adjusted hazard ratio, 1.83; 95% CI, 1.38-2.41; P < .001). CONCLUSIONS: Severe TR was a significant predictor of long-term mortality rate in PAH, and TR severity correlated with PAH severity.

Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry.

BACKGROUND: Plasma brain natriuretic peptide (BNP) level is a prognostic biomarker in pulmonary arterial hypertension (PAH). Its impact on long-term overall survival (OS) was investigated in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL), a 5-year observational, multicenter, US registry of patients with PAH. METHODS: Patients were ≥ 18 years of age, met right heart catheterization criteria at rest, had World Health Organization group I PAH, and had BNP measurement at enrollment. Optimal BNP threshold was obtained via receiver operating characteristic curve analysis. OS was compared in patients with low (≤ 340 pg/mL) vs high (> 340 pg/mL) BNP at baseline; changes between baseline and last assessment were also examined. Patients were categorized based on baseline (low or high) and follow-up (low or high) BNP values; hazard ratios (HRs) for OS were estimated and compared using Cox regression. RESULTS: Overall, 1,426 patients were analyzed. Mortality risk was significantly higher in patients with baseline high vs low BNP (HR, 3.6; 95% CI, 3.0-4.2). BNP change analysis at ≤ 1 year postenrollment demonstrated that the low-low group had the lowest and the high-high group had the highest 5-year mortality risk (HR, 0.23; 95% CI, 0.19-0.27). Changes in BNP score also correlated with change of risk of death. CONCLUSIONS: Baseline BNP threshold of 340 pg/mL strongly predicted survival up to 5 years in patients with PAH. A BNP reduction at 1 year since enrollment was associated with decreased mortality risk, whereas an increase in BNP at 1 year was associated with an increased mortality risk, supporting BNP as a surrogate marker of PAH survival.

Use of supplemental oxygen in patients with pulmonary arterial hypertension in REVEAL.

BACKGROUND: Supplemental low-flow oxygen is recommended by treatment guidelines as supportive therapy for patients with pulmonary arterial hypertension (PAH), based largely on expert opinion. Reduced diffusing capacity of lung carbon monoxide (DLCO) is associated with increased mortality in PAH. Reduced DLCO is also associated with relative hypoxemia, making the effects of supplemental oxygen use of particular interest in this sub-population. METHODS: Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by presence or absence of supplemental oxygen use and by degree of DLCO reduction. Kaplan-Meier survival estimates were calculated by group. RESULTS: Of 3,046 patients, 57% used supplemental oxygen and 43% did not. Supplemental oxygen users had worse prognostic factors and more PAH-specific medication use. Of the 424 patients with severe DLCO reduction (<40% of predicted), 76% used oxygen and 24% did not. Patients with severe DLCO reduction who used supplemental oxygen had a significantly lower risk of all-cause mortality than those who did not (hazard ratio 0.56; 95% confidence interval 0.39 to 0.83; p = 0.0033). This was true for newly diagnosed and previously diagnosed patients. There was no relationship between oxygen use and outcomes in patients with no, mild, or moderate DLCO reduction. CONCLUSIONS: In this observational study, the risk of death was significantly lower for patients with severe DLCO reduction who received supplemental oxygen compared with those who did not. A randomized trial is warranted to further investigate the relationship between supplemental oxygen use and outcomes in PAH.

Impact of declining renal function on outcomes in pulmonary arterial hypertension: A REVEAL registry analysis.

BACKGROUND: Renal dysfunction is associated with abnormal cardiopulmonary hemodynamics, in-hospital death and poor survival in patients with pulmonary arterial hypertension (PAH), and thus it may be a prognostic biomarker. In our analysis we assess the relationship between change in estimated glomerular filtration rate (eGFR) and outcomes in PAH patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). METHODS: Overall 2,368 patients were classified into chronic kidney disease (CKD) stages based on baseline eGFR: normal or Stages 1 or 2 (n = 1,699); Stage 3a (n = 399); Stage 3b (n = 196); and Stages 4 or 5 (n = 74). We evaluated the relationship between baseline CKD stage and survival, as well as the composite end-point of survival and freedom from all-cause hospitalization. The relationships between change in eGFR at ≥1 year and these clinical end-points were also evaluated. RESULTS: Patients with a ≥10% decline in eGFR from baseline over ≥1 year had a significantly increased risk of death (hazard ratio 1.66; p < 0.0001) and the composite of all-cause hospitalization and death (hazard ratio 1.33; p = 0.002). This decline predicted survival independently of changes in 6-minute walk distance and functional class. However, a ≥10% increase in eGFR was not significantly associated with either end-point. CONCLUSION: In REVEAL, a ≥10% decline in eGFR over ≥1 year independently predicted poorer survival. Thus, eGFR may be a simple and economical biomarker in PAH.

Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension.

BACKGROUND: Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-beta type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. METHODS AND RESULTS: We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. CONCLUSIONS: Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Pulmonary hypertension in patients with interstitial lung diseases.

Pulmonary hypertension (PH) in patients with interstitial lung diseases (ILDs) is not well recognized and can occur in the absence of advanced pulmonary dysfunction or hypoxemia. To address this topic, we identified relevant studies in the English language by searching the MEDLINE database (1966 to November 2006) and by individually reviewing the references of identified articles. Connective tissue disease-related ILD, sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary Langerhans cell histiocytosis are the ILDs most commonly associated with PH. Pulmonary hypertension is an underrecognized complication in patients with ILDs and can adversely affect symptoms, functional capacity, and survival. Pulmonary hypertension can arise in patients with ILDs through various mechanisms, Including pulmonary vasoconstriction and vascular remodeling, vascular destruction associated with progressive parenchymal fibrosis, vascular inflammation, perivascular fibrosis, and thrombotic angiopathy. Diagnosis of PH in these patients requires a high index of suspicion because the clinical presentation tends to be nonspecific, particularly in the presence of an underlying parenchymal lung disease. Doppler echocardiography is an essential tool in the evaluation of suspected PH and allows ready recognition of cardiac causes. Right heart catheterization is needed to confirm the presence of PH, assess its severity, and guide therapy. Management of PH in patients with ILDs is guided by identification of the underlying mechanism and the clinical context. An increasing number of available pharmacologic agents in the treatment of PH allow possible treatment of PH in some patients with ILDs. Whether specific treatment of PH in these patients favorably alters functional capacity or outcome needs to be determined.

Unexplained pulmonary hypertension in elderly patients.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) preferentially affects young women. However, a subset of patients with IPAH is elderly. Our objective was to compare elderly (age >/= 65 years) vs younger persons with unexplained pulmonary hypertension (PH) and a presumptive diagnosis of IPAH. METHODS: Clinical, echocardiographic, hemodynamic, and survival data were collected on consecutive patients with suspected IPAH after evaluation in a large tertiary center PH clinic. RESULTS: Of 197 patients (mean age +/- SD, 52 +/- 16 years; 80% female), 48 patients (24%) were elderly. Elderly and younger patients had similar symptom severity, systolic pulmonary artery (PA) pressure (82.7 +/- 20.3 mm Hg vs 86.9 +/- 18.8 mm Hg, respectively; p = 0.21), and severity of right ventricular enlargement and dysfunction. Elderly patients had higher pulmonary capillary wedge pressure (PCWP) [15.3 +/- 7.3 mm Hg vs 11.1 +/- 5.3 mm Hg; p < 0.0001] and more frequently failed (56%) to meet hemodynamic criteria for IPAH (PH with PCWP < 15 mm Hg) than did younger patients (19%). Elderly patients also had higher systemic systolic (p < 0.0001) and pulse (p < 0.0001) pressures and more cardiovascular disease. Among those patients with normal PCWP, elderly patients had worse survival than young patients (p = 0.007). Among those patients with elevated PCWP, elderly patients had lower PA pressures (p = 0.04) and better survival (p = 0.02). CONCLUSIONS: Elderly patients with clinically suspected IPAH often fail to meet hemodynamic criteria for IPAH due to elevated PCWP. Studies to define the proper diagnostic strategy and the safety and efficacy of pulmonary vasodilators in elderly patients with unexplained PH are needed.