Time Of Pulmonary Arterial Hypertension Diagnosis Research Articles

Effects of beta blockers on outcome in patients with PAH with and without comorbid conditions: a Multicenter Prospective Cohort Study (BNP-PL)

Abstract Background The current guidelines do not recommend the use of beta-blockers (BB) in patients with pulmonary arterial hypertension (PAH) unless necessitated by comorbidities. However, the evidence regarding the role of BB in PAH is contradictory. This study investigates the effects of BB on clinical outcomes in patients newly diagnosed with PAH, stratified by the presence of cardiovascular comorbidities that justify their use. Methods We analyzed data from 806 patients newly diagnosed with PAH, who were prospectively enrolled from March 1, 2018, to August 31, 2023, in the multicentre registry, Database of Pulmonary Hypertension in the Polish population (BNP-PL). The primary endpoints were all-cause mortality and a composite of hospitalization due to right heart exacerbation, syncope, or death. The follow-up period for these patients extended until August 31, 2023. Comorbidities in the study group that indicated the need for BB therapy included hypertension, significant arrhythmia, and coronary artery disease. In the Cox regression analysis, the association between BB use and the predefined endpoints was adjusted for age, baseline European Society of Cardiology risk score, and upfront therapy. Results Among the 806 patients, BBs were administered to 469 (58.2%) at the time of PAH diagnosis. In the entire cohort, BB therapy was linked to increased all-cause mortality (29.6% vs 21.4%; p=0.005, Fig 1.A) and a higher incidence of the composite endpoint (34.1% vs 22.6%; p<0.0001, Fig 1.B). The Number Needed to Harm (NNH) for BB treatment, regarding mortality and the composite endpoint, were 12.1 and 8.7, respectively. In patients without comorbidities, BB use significantly raised the risk of both all-cause mortality (Hazard Ratio [HR] 1.81, 95% Confidence Interval [CI]: 1.01-3.15) and the composite endpoint (HR 1.85, 95% CI 1.09-3.14), after adjustments for age, baseline three-strata PAH mortality risk, and upfront therapy. However, in patients with at least one comorbidity, BB therapy showed a neutral effect on both outcomes. Across the whole group, the use of nonselective BB was associated with a higher risk of the composite endpoint (HR 1.78, 95% CI 1.13-2.82, p=0.01) compared to selective β1 agents, although this did not extend to all-cause mortality (HR 1.34, 95% CI 0.79-2.25, p=0.28). Conclusion BBs, particularly nonselective, pose significant risks in patients with PAH who lack comorbidities that justify their use.

Prognostic Significance of Proteomics-Discovered Circulating Inflammatory Biomarkers in Patients With Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH. Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats). In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

Smoking history and pulmonary arterial hypertension: Demographics, onset, and outcomes.

Smoking prevalence and its association with pulmonary arterial hypertension (PAH) outcomes have not been described in patients in the United States. Using the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence, demographics, and outcomes in ever- versus never-smokers with PAH were determined. Ever-smoking status was more prevalent in males (61.7%) than in females (42.9%) enrolled in REVEAL. Ever-smokers were older than never-smokers at the time of PAH diagnosis and REVEAL enrollment. The time to first hospitalization, transplant-free survival, and survival did not differ between ever- and never-smokers overall; however, in newly diagnosed males, ever-smoking was associated with earlier death (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1-3.0; p=0.0199), the composite of transplant or death (HR 2.2, 95% CI 1.4-3.6; p=0.0008), and first hospitalization (HR 1.8, 95% CI 1.2-2.7; p=0.0063), though smoking exposure (pack-years) did not differ between newly and previously diagnosed males. REVEAL PAH data demonstrate that smoking prevalence in male PAH patients is disproportionate. The prevalence of cigarette smoking was significantly higher in males than females enrolled in REVEAL. Ever-smoking status was associated with increased age at PAH diagnosis and, in newly diagnosed male PAH patients, earlier time to hospitalization and shorter survival after PAH diagnosis.

Cytokines as prognostic biomarkers in pulmonary arterial hypertension.

Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH. This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients. Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort. The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.

Red blood cell distribution width as a potential predictor of survival of pulmonary arterial hypertension associated with primary Sjogren\u2019s syndrome: a retrospective cohort study

Pulmonary arterial hypertension (PAH) is a severe complication and leading cause of mortality in patients with primary Sjogren’s syndrome (pSS). This study was to investigate the overall survival rates and the utility of red blood cell distribution width (RDW) as a potential prognostic factor of pSS-PAH. This cohort study retrospectively enrolled 55 patients with pSS-PAH who were followed up at the Department of Rheumatology of Peking Union Medical College Hospital (PUMCH) between August 2007 and May 2017. The patients were stratified according to the level of RDW (≤ 15.0 and > 15.0%). Baseline demographics, laboratory results, pulmonary function conditions, hemodynamic assessments, and treatment regimens were analyzed. Cox proportional hazards regression analysis was used to identify whether RDW level is a factor related to adverse outcome. A total of 55 patients were recruited, with an average age of 38.9 ± 9.3 years. Fifty-four were female (98.2%), and the average duration at the time of PAH diagnosis was 25.5 ± 33.2 months. Higher RDW levels were found in patients who deceased in follow-up (13.8 ± 2.6 vs 16.5 ± 1.6%, p = 0.003) and with higher NYHA classes (13.8 ± 1.8 vs 16.5 ± 2.9%, p < 0.001). Patients with RDW > 15% had a significantly worse overall survival than patients with RDW ≤ 15% (3-year survival rate 59.5 vs. 88.7% log-rank p = 0.015). Cox regression analysis identified RDW > 15% as a prognostic factor for adverse outcome (HR 1.786, 95% CI 1.137–2.803, p = 0.012). RDW can serve as a potential negative prognostic factor of pSS-PAH.

CCL21 as a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis.

Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19-CCL21 axis in patients with SSc-related PAH. Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted. CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39-10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12-10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001). CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.

Prevalence of primary Sjögren's syndrome in patients undergoing evaluation for pulmonary arterial hypertension.

BackgroundThe prevalence of pulmonary arterial hypertension (PAH) in primary Sjögren’s syndrome (SS) had been reported to be rare. However, recent studies using echocardiography as a screening method showed conflicting results, and the true prevalence is still unclear. Since diagnosing primary SS is difficult because of its heterogeneous nature, a number of patients with primary-SS-associated PAH may be misdiagnosed with idiopathic PAH, losing their chance to undergo immunosuppressive therapy. Therefore, we sought to elucidate the prevalence of primary SS among patients who initially present with PAH.MethodsFrom our prospective institutional PAH database, 40 consecutive patients without any obvious cause of PAH at the time of PAH diagnosis were identified. We retrospectively evaluated the prevalence of primary SS diagnosed during or after the initial assessment of PAH.ResultsDuring the initial assessment, one patient was diagnosed with primary-SS-associated PAH. Among the 25 patients who were initially diagnosed with idiopathic PAH, five were diagnosed with primary SS during their course of the disease. Of the five patients, three had key signs suggesting primary SS and were probably underdiagnosed at the time of initial evaluation. The remaining two patients, who were finally diagnosed with primary SS, did not have any specific signs suggesting primary SS at the time of initial evaluation but showed positive conversion of their autoantibodies during the course of PAH.ConclusionThe prevalence of primary-SS-associated PAH may be relatively high among patients who undergo initial evaluation for PAH. Furthermore, primary-SS-associated PAH may be underdiagnosed with routine evaluation for the primary cause of PAH. Clinicians should pay specific attention and carefully evaluate the possibility of primary SS in patients with PAH.

Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension

Objective: To identify circulating angiogenic and inflammatory biomarkers with potential in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc), and in early diagnosis and determination of treatment response in PAH.Method: Plasma samples were taken at the time of PAH diagnosis and at treatment follow-up after a median (interquartile range) of 4 months (3–9.8 months) in idiopathic (n = 9) and SSc-associated PAH (n = 11). In patients with SSc-associated PAH, plasma samples had also been gathered a median of 2 years (0.8–3 years) before PAH diagnosis (n = 10). Additional plasma samples were retrieved at two time-points separated by a median of 12 years (10–13 years) from SSc patients who did not develop PAH (n = 10) and from controls (n = 8). Angiogenic and inflammatory biomarkers were analysed by multiplex immunoassays.Results: Plasma levels of placenta growth factor (PlGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and tumour necrosis factor-α (TNF-α) were higher (p < 0.05) in SSc patients who later developed PAH than in those who did not. Plasma vascular endothelial growth factor (VEGF)-D increased (p < 0.05) in SSc patients as PAH developed. Plasma levels of PlGF, VEGF-A, VEGF-D, sVEGFR-1, interleukin-6, and TNF-α were higher (p < 0.05) in PAH than controls. There were no significant differences in circulating biomarkers between idiopathic and SSc-associated PAH. Plasma sVEGFR-1 decreased (p < 0.05) after initiating PAH-targeted treatments.Conclusions: Plasma levels of PlGF, sVEGFR-1, TNF-α, and VEGF-D have potential in screening for SSc-associated PAH. Plasma sVEGFR-1 may be a biomarker of treatment response.

Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity.

Published data suggest that coexisting interstitial lung disease (ILD) has an impact on mortality in patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), but there is scarce knowledge if this is reflected by hemodynamics, exercise capacity, autoantibody profile, or pulmonary function. In this partially retrospective study, 27 SSc-PAH patients were compared to 24 SSc-PAH patients with coexisting ILD respecting to survival, pulmonary function, hemodynamics, exercise capacity, and laboratory parameters. Survival was significantly worse in SSc-PAH-ILD patients than in SSc patients with isolated PAH (1, 5, and 10-year survival rates 86, 54, and 54% versus 96, 92, and 82%, p=0.013). Compared to isolated SSc-PAH patients, patients with SSc-PAH-ILD revealed lower forced expiratory volume after 1s (FEV1) values at the time of PAH diagnosis as well as 1 and 2years later (p=0.002) without significant decrease in the PAH course in both groups. At PAH diagnosis, diffusion capacity for carbon monoxide (DLCO) values were lower in the ILD-PAH group. Coexisting ILD was not associated with lower exercise capacity, different FEV1/forced vital capacity (FVC) ratio, higher WHO functional class, or reduced hemodynamics. Higher levels of antibodies against angiotensin and endothelin receptors predict mortality in all SSc-PAH patients but could not differentiate between PAH patients with and without ILD. Our study confirmed an impact of ILD on mortality in SSc-PAH patients. Pulmonary function parameters can be used to distinguish PAH from PAH-ILD. The higher mortality rate cannot be explained by differences in hemodynamics, exercise capacity, or autoantibody levels. Mechanisms of mortality remain to be studied.

Pregnancy in pulmonary arterial hypertension.

Despite advanced therapies, maternal mortality in women with pulmonary arterial hypertension (PAH) remains high in pregnancy and is especially high during the post-partum period. However, recent data indicates that morbidity and mortality during pregnancy and after birth have improved for PAH patients. The current European Society of Cardiology/European Respiratory Society guidelines recommend that women with PAH should not become pregnant. Therefore, the risks associated with pregnancy must be emphasised and counselling offered to women at the time of PAH diagnosis and to women with PAH who become pregnant. Early termination should be discussed. Women who choose to continue with their pregnancy should be treated at specialised pulmonary hypertension centres with experience in managing PAH during and after pregnancy.

Congenital heart disease‐associated pulmonary arterial hypertension: preliminary results from a novel registry

Pulmonary arterial hypertension (PAH) frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific PAH therapies for PAH prompted formation of a national Australian and New Zealand registry in 2010 to document the incidence, demographics, presentation and outcomes for these patients. This multicentre, prospective, web-based registry enrols patients with CHD-associated PAH being followed in a tertiary centre. The inclusion criteria stipulated patient age ≥16 years, a measured mean pulmonary arterial pressure >25 mmHg at rest or echocardiographical evidence of PAH or a diagnosis of Eisenmenger syndrome, and followed since 1 January 2000. A single observer collected standardised data during a series of site visits. Of the first 50 patients enrolled, 30 (60%) were female. The mean age (standard deviation (SD)) at the time of PAH diagnosis or confirmation in an adult centre was 27.23 (10.07) years, and 32 (64%) patients are currently aged >30 years. Fourteen (28%) patients were in World Health Organization Functional Class II and 36 (72%) in Class III at the time of diagnosis. Forty-seven of 50 (94%) had congenital systemic-pulmonary shunts, and 36 (72%) never underwent intervention. Thirteen (26%) had Down syndrome. Confirmation of PAH by recent cardiac catheterisation was available in 30 (60%) subjects. During follow up, a total of 32 (64%) patients received a PAH-specific therapy. CHD associated with PAH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical course and long-term outcomes for these patients.

Screening for pulmonary arterial hypertension in patients with systemic sclerosis: Clinical characteristics at diagnosis and long‐term survival

Pulmonary arterial hypertension (PAH) is a severe, life-limiting complication of systemic sclerosis (SSc). Guidelines recommend early detection and management of SSc-PAH. However, little is known about the impact of detection programs on patients with SSc-PAH. This study was undertaken to assess the clinical characteristics of patients with SSc-PAH at diagnosis and their long-term outcomes. Two incident cohorts of patients with SSc-PAH from the same management era (2002/2003) were studied. The first cohort (designated the routine practice cohort) included consecutive adult patients with symptomatic SSc in whom a diagnosis of PAH was made by right-sided heart catheterization (RHC) at the time of recruitment into the French PAH Registry. The second cohort (designated the detection cohort) comprised consecutive patients with SSc who entered a systematic PAH detection program and were subsequently found to have PAH on RHC. Clinical characteristics at diagnosis of PAH and subsequent 8-year mortality were compared between the cohorts. There were 16 patients in each cohort. At the time of PAH diagnosis, patients in the detection cohort had less advanced pulmonary vascular disease compared with patients in the routine practice cohort, as evidenced by more patients being in New York Heart Association class I and class II, a lower mean pulmonary artery pressure and pulmonary vascular resistance index, and a higher cardiac output. Patients in the detection cohort were less likely to receive diuretics and warfarin, but there was no difference in exposure to PAH-specific therapies between the cohorts. The 1-, 3-, 5-, and 8-year survival rates were 75%, 31%, 25%, and 17%, respectively, in the routine practice cohort compared with 100%, 81%, 73%, and 64%, respectively, in the detection cohort (P = 0.0037). Compared with patients in routine clinical practice, PAH detection programs in SSc are able to identify patients with milder forms of the disease, allowing earlier management.

The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH

ObjectiveThe objective of this report is to compare baseline, management and survival characteristics in idiopathic pulmonary arterial hypertension (IPAH) with systemic sclerosis-associated pulmonary arterial hypertension (SSc-APAH) using data from the...

The Demographics of Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: Results from a National Registry

Background: Pulmonary arterial hypertension (PAH) frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific PAH therapies for PAH prompted formation of a national ANZ registry in 2010 to document the incidence, demographics, presentation and outcomes for these patients. Methods: This multicentre, prospective, web-based registry enrolls patients with CHD associated PAH being followed in a tertiary centre. The inclusion criteria stipulated patient age >16 years, a measured mPAP >25 mmHg at rest or echocardiographic evidence of PAH or a diagnosis of Eisenmenger syndrome, and followed since 1/1/2000. A single observer collected standardised data during a series of site visits. Results: Hundred and thirty-seven patients (61.3% females) have so far been enrolled. The mean age (SD) at the time of PAH diagnosis or confirmation in an adult centre was 28.3 (6.7) years and 41 (29.9%) patients were aged >30 years at this time. The mean duration of follow-up is 8.0 (4.4) years. Thirty-eight (27.7%) patients were in WHO functional Class II and 96 (70.1%) in Class III at the time of diagnosis. One hundred and thirty-four out of 137 (97.8%) had congenital systemic-pulmonary shunts and 97 (70.8%) never underwent intervention. Forty-three (31.4%) had Down's syndrome. Confirmation of PAH by recent cardiac catheterisation was available in 90 (65.7%) subjects. During follow-up a total of 19 (13.9%) patients died or underwent transplantation. Conclusions: CHD associated with PAH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical course and long-term outcomes for these patients.

Prognosis of Pulmonary Arterial Hypertension

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …

Is Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?

Pulmonary arterial hypertension (PAH) is a frequent cause of morbidity and mortality in patients with systemic sclerosis (SSc). PAH is generally considered to be a late complication of limited cutaneous SSc. This study identified and investigated a subset of SSc patients with early-onset PAH. Clinical and hemodynamic data at the time of diagnosis were collected retrospectively for 78 consecutive patients with PAH associated with SSc. PAH diagnosed within 5 years of the first non-Raynaud phenomenon symptom of SSc was considered to be an early-onset complication. PAH diagnosed > 5 years following SSc diagnosis was considered to be a late complication. PAH occurred a mean (+/- SD) duration of 6.3 +/- 6.6 years after the diagnosis of SSc (median delay, 4.0 years; 95% CI, 2.88 to 6.0 years). Early-onset PAH was diagnosed in 43 patients (55.1%), and late-onset PAH was diagnosed in 35 patients (44.9%). Patients with early-onset PAH were older at SSc diagnosis than patients with late-onset PAH (mean age, 58.0 +/- 12.5 vs 46.6 +/- 12.9 years, respectively; p = 0.0002). No differences in age at the time of PAH diagnosis, or in SSc subtype (limited vs diffuse; anticentromere vs anti-Scl70 antibodies), were observed between onset subgroups. At diagnosis, early-onset PAH was more severe than late-onset PAH, with a lower cardiac index (2.4 +/- 0.6 vs 2.8 +/- 0.6 L/min/m(2), respectively; p = 0.005) and greater total pulmonary resistance (1,708 +/- 777 vs 1,341 +/- 530 dyne x s x cm(-5)/m(2), respectively; p = 0.02). Mortality at 3 and 5 years was comparable between subgroups. In contrast to the expected scenario, early-onset PAH occurred in approximately half of SSc patients. Early-onset PAH was as frequent among patients with diffuse SSc as those with limited SSc. Annual screening for PAH should be implemented immediately after SSc diagnosis for all patients.