Pulmonary Hypertension In Systemic Sclerosis Research Articles

Lung Density and Pulmonary Artery Diameter are Predictors of Pulmonary Hypertension in Systemic Sclerosis.

The aim was to evaluate computed tomography (CT)-measured pulmonary artery diameter (PAD) and lung density as predictors of pulmonary hypertension (PH) in subjects with systemic sclerosis (SSc). We compared these PAD values with normal values and between SSc subgroups with PH and/or interstitial lung disease (ILD). We investigated whether PAD predicts PH and whether lung densitometry, by using the 85th percentile density value (Perc85) as a measure for ILD, can predict PH. PAD and Perc85 were measured in axial CT scans and compared between 54 SSc and 76 control subjects. Four SSc subgroups were defined on the basis of PH (systolic PA pressure ≥35 mm Hg) and/or ILD (fibrosis score ≥7): PH-/ILD-, PH-/ILD+, PH+/ILD-, and PH+/ILD+. The association of PAD with age, body mass index, Perc85, lung function, and hemodynamic measures was investigated using univariate correlation along with the predictive value of these measures with respect to PH. PAD in SSc was larger than that in controls (30.1±4.9 vs. 26.9±2.7 mm, P<0.001). PH+ patients showed increased PAD compared with PH- patients (34.2±4.2 vs. 28.6±4.3 mm, P<0.001), where PH+/ILD+ subjects showed the widest diameter (34.6±4.1 mm). In SSc patients, hemodynamic measures, age, body mass index, Perc85, and lung function correlated with PAD. PAD was best explained by Perc85, together with age (R=0.358). PAD best predicted PH (AUC, 0.877; P<0.001), and PAD≥30.7 mm showed 80% sensitivity and 87% specificity. Perc85 also predicted PH (AUC, 0.733; P=0.024). In subjects with SSc, lung density and PAD are CT markers, each with predictive value for PH.

Combined measurement of carbon monoxide and nitric oxide lung transfer does not improve the identification of pulmonary hypertension in systemic sclerosis

Screening is important to determine whether patients with systemic sclerosis (SSc) have pulmonary hypertension because earlier pulmonary hypertension treatment can improve survival in these patients. Although decreased transfer factor of the lung for carbon monoxide (TLCO) is currently considered the best pulmonary function test for screening for pulmonary hypertension in SSc, small series have suggested that partitioning TLCO into membrane conductance (diffusing capacity) for carbon monoxide (DMCO) and alveolar capillary blood volume (VC) through combined measurement of TLCO and transfer factor of the lung for nitric oxide (TLNO) is more effective to identify pulmonary hypertension in SSc patients compared with TLCO alone. Here, the objective was to determine whether combined TLCO-TLNO partitioned with recently refined equations could more accurately detect pulmonary hypertension than TLCO alone in SSc.For that purpose, 572 unselected consecutive SSc patients were retrospectively recruited in seven French centres.Pulmonary hypertension was diagnosed with right heart catheterisation in 58 patients. TLCO, TLNO and VC were all lower in SSc patients with pulmonary hypertension than in SSc patients without pulmonary hypertension. The area under the receiver operating characteristic curve for the presence of pulmonary hypertension was equivalent for TLCO (0.82, 95% CI 0.79-0.85) and TLNO (0.80, 95% CI 0.76-0.83), but lower for VC (0.75, 95% CI 0.71-0.78) and DMCO (0.66, 95% CI 0.62-0.70).Compared with TLCO alone, combined TLCO-TLNO does not add capability to detect pulmonary hypertension in unselected SSc patients.

Pulmonary Hypertension Complicating Connective Tissue Disease.

Pulmonary hypertension (PH) may complicate connective tissue disease (CTD; particularly systemic sclerosis [scleroderma]), and is associated with increased mortality. More than 70% of cases of PH complicating CTD occur in patients with systemic sclerosis (SSc), which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of SSc-related deaths. “Isolated” PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy in improving CTD-PH outcomes is under investigation, as prognosis and responsiveness to therapy appear to be worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients who fail medical therapy.

Pulmonary hypertension in systemic sclerosis: different phenotypes.

Pulmonary hypertension (PH) is a frequent and severe complication of systemic sclerosis (SSc). PH in SSc is highly heterogeneous because of the various clinical phenotypes of SSc itself and because the mechanisms of PH can vary from one patient to another. PH in SSc may be due to vasculopathy of the small pulmonary arteries (group 1; pulmonary arterial hypertension), interstitial lung disease (group 3; PH due to lung disease or chronic hypoxia) or myocardial fibrosis leading to left ventricular systolic or diastolic dysfunction (group 2; PH due to chronic left-heart disease). Pulmonary veno-occlusive disease is not uncommon in SSc and may also cause PH in some patients (group 1'). There is a high prevalence of each of these conditions in SSc and, as such, it may be difficult to determine the dominant cause of PH in a particular patient. However, careful phenotyping of PH in SSc is important as the therapy required for each of these underlying conditions is very different. In this review, we will decipher the different phenotypes of SSc-PH.

Non-Group 1 Pulmonary Hypertension Associated With Systemic Sclerosis: An Under-studied Patient Population

Background: Systemic sclerosis (SSc) is a heterogeneous disorder that results in multiorgan dysfunction. The most common pulmonary manifestations are pulmonary hypertension (PH) and interstitial lung disease (ILD). Systemic sclerosis may be complicated by World Health Organization (WHO) Group 1 PH (SSc-PAH), which is the most well-studied subtype. The PH associated with SSc may also be secondary to underlying left heart disease (SSc-PH-LHD) or ILD (SSc-PH-ILD), and these subgroups are classified as WHO Group 2 and Group 3 PH, respectively. These non-WHO Group 1 PH subsets are notoriously under-studied. Available data suggest that the impact of PH-specific therapy in SSc-PH-LHD and SSc-PH-ILD is limited and survival is poor despite attempted treatment. Implication for clinicians: Most research and clinical trials surrounding PH in SSc have thus far focused on WHO Group 1 SSc-PAH. There are limited data surrounding therapeutic options for WHO Group 2 (SSc-PH-LHD) and Group 3 PH (SSc-PH-ILD) phenotypes. This review aims to summarize and consolidate the data surrounding these 2 distinct clinical phenotypes and to emphasize the available prognostic and treatment considerations. Conclusions: Given the unique pathophysiology, prognostic implications, and poor response to treatment of WHO Group 2 and 3 SSc-PH phenotypes, there is an overwhelming need for more data to best understand optimal management strategies. The focus should be individual patient-level prognostication, how and when to initiate and manage PH-specific therapy, and appropriate triage with regard to the timing of lung (or heart-lung) transplantation.

Exercise echocardiography for the assessment of pulmonary hypertension in systemic sclerosis: a systematic review.

BackgroundPulmonary arterial hypertension (PAH) complicates the course of systemic sclerosis (SSc) and is associated with poor prognosis. The elevation of systolic pulmonary arterial pressure (sPAP) during exercise in patients with SSc with normal resting haemodynamics may anticipate the development of PAH. Exercise echocardiography (ExEcho) has been proposed as a useful technique to identify exercise-induced increases in sPAP, but it is unclear how to clinically interpret these findings. In this systematic review, we summarize the available evidence on the role of exercise echocardiography to estimate exercise-induced elevations in pulmonary and left heart filling pressures in patients with systemic sclerosis.MethodsWe conducted a systematic review of the literature using MEDLINE, Cochrane Library and Web of Knowledge, using the vocabulary terms: (‘systemic sclerosis’ OR ‘scleroderma’) AND (‘exercise echocardiography’) AND (‘pulmonary hypertension’). Studies including patients with SSc without a prior diagnosis of PAH, and subjected to exercise echocardiography were included. All searches were limited to English and were augmented by review of bibliographic references from the included studies. The quality of evidence was assessed by the Effective Public Health Practice Project system.ResultsWe identified 15 studies enrolling 1242 patients, who were mostly middle-aged and female. Several exercise methods were used (cycloergometer, treadmill and Master’s two step), with different protocols and positions (supine, semi-supine, upright); definition of a positive test also varied widely. Resting estimated sPAP levels varied from 18 to 35 mm Hg, all in the normal range. The weighted means for estimated sPAP were 22.2 ± 2.9 mmHg at rest and 43.0 ± 4.3 mmHg on exercise; more than half of the studies reported mean exercise sPAP ≥40 mmHg. The assessment of left ventricular diastolic function on peak exercise was reported in a minority of studies; however, when assessed, surrogate variables of left ventricular (LV) diastolic dysfunction were associated with higher sPAP on exercise.ConclusionsWe found very high heterogeneity in the methods, the protocols and the estimated sPAP response to exercise. LV diastolic dysfunction was common and was associated with greater elevation of sPAP on exercise.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1051-9) contains supplementary material, which is available to authorized users.

Right atrial morphology and function in patients with systemic sclerosis compared to healthy controls: a two-dimensional strain study.

Enlargement and dysfunction of the right atrium might be an early sign for pulmonary hypertension in systemic sclerosis (SSc). This is the first study to analyse right atrial morphology and function in SSc patients compared to healthy controls by speckle-tracking two-dimensional strain echocardiography (2DSE) at rest and during exercise. Furthermore, right atrial function was correlated with further clinical findings. Adult patients with SSc for >3years (n = 90) and 55 age- and gender-matched healthy controls underwent a panel of non-invasive assessments including transthoracic echocardiography, pulsed Doppler myocardial imaging and 2DSE at rest and during exercise. Furthermore, serological tests and high-resolution chest computed tomography were performed. SSc patients showed significant impairment of right atrial function and the right atrial enlargement, measured by 2DSE at rest and during exercise compared to controls (both p < 0.001). These findings were more evident in SSc patients with pulmonary fibrosis (p < 0.001) and in patients with high pulmonary artery systolic pressures (PAPs) during exercise. In the SSC patients, right atrial lateral strain was significantly associated with PAPs during effort, right atrial area, left ventricle stroke volume and inferior vena cava diameter using multivariable analysis. The findings of this study suggest that a high proportion of SSc patients reveal right atrial dysfunction even without manifest pulmonary hypertension. Impaired right atrial function occurred mostly in patients with pulmonary fibrosis and/or elevated PAPs during exercise, was independently associated with prognostic factors and may therefore be useful for risk stratification. Further studies are needed to analyse if right atrial dysfunction assessed by 2DSE may help to improve early diagnosis of pulmonary hypertension.

Serum levels of interleukin-18-binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro-inflammatory cytokines to the development of SSc, but the role of interleukin (IL)-18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL-18-binding protein isoform a (IL-18BPa), a soluble decoy receptor for IL-18, by enzyme-linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL-18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL-18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL-18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL-18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL-18BPa levels with erythrocyte sedimentation rate and C-reactive protein were noted. These results suggest that the inhibition of IL-18 signaling by IL-18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.

Can Exercise Echocardiography Predict the Development of Pulmonary Hypertension in Systemic Sclerosis?

Can Exercise Echocardiography Predict the Development of Pulmonary Hypertension in Systemic Sclerosis?

Influence of pulmonary vascular reserve on exercise-induced pulmonary hypertension in patients with systemic sclerosis.

Exercise-induced pulmonary hypertension (PH) is considered as an early preclinical functional phase of resting PH in systemic sclerosis (SSc). In this study, we investigated the prevalence of exercise-induced PH in patients with SSc and evaluated the influence of pulmonary vascular reserve on exercise-induced PH. This prospective study included 568 SSc patients. The patients with interstitial lung disease and those with left ventricular dysfunction were excluded (n = 50); finally, 518 patients underwent simple exercise echocardiography using a Master's two-step. Systolic pulmonary artery pressure (SPAP), the ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') and pulmonary vascular resistance (PVR) were measured before and after exercise. ΔPVR (the difference between rest and post) was used for the assessment of pulmonary vascular reserve. All patients were stratified into the no exercise-induced PH (SPAP <50 mmHg) or exercise-induced PH (SPAP ≥50 mmHg, n = 133) group. Of the study patients, 27% patients were identified as having exercise-induced PH. ΔPVR was higher in the exercise-induced PH than no exercise-induced PH group (0.2 ± 0.3 vs. 0.4 ± 0.4WU, P < 0.0001). A weak correlation was found between postexercise SPAP and postexercise E/e' (r = 0.31, P < 0.0001), whereas a strong correlation was found between postexercise SPAP and postexercise PVR (r = 0.62, P < 0.0001). The analyzed data demonstrated that ΔPVR was independently associated with exercise-induced PH (odds ratio, 3.435; 95% CI, 1.013-11.650, P = 0.033). The present study demonstrated that exercise-induced PH was common in patients with SSc. Exercise-induced PH might be closely associated with the factors affecting reduced pulmonary vascular reserve in patients with SSc.

FRI0510 Good Detection of Early Pulmonary Hypertension Using Exercise Doppler Echocardiography in Patients with Connective Tissue Diseases and Its Comparison with Other Screening Tool

BackgroundExercise Doppler echocardiography helps to select patients who need right-sided heart catheterization (RHC) [1]. We introduced a formula for estimating mean pulmonary arterial pressure (mPAP) using it for connective tissue...

Left heart disease: a frequent cause of early pulmonary hypertension in systemic sclerosis, unrelated to elevated NT-proBNP levels or overt cardiac fibrosis but associated with increased levels of MR-proANP and MR-proADM: retrospective analysis of a French Canadian cohort

Objectives: Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH.Method: A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM).Results: The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH.Conclusions: Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Relevance of partitioning DLCO to detect pulmonary hypertension in systemic sclerosis.

We investigated whether partitioning DLCO into membrane conductance for CO (DmCO) and pulmonary capillary blood volume (Vcap) was helpful in suspecting precapillary pulmonary (arterial) hypertension (P(A)H) in systemic sclerosis (SSc) patients with or without interstitial lung disease (ILD). We included 63 SSc patients with isolated PAH (n=6), isolated ILD (n=19), association of both (n=12) or without PAH and ILD (n=26). Partitioning of DLCO was performed by the combined DLNO/DLCO method. DLCO, DmCO and Vcap were equally reduced in patients with isolated PAH and patients with isolated ILD but Vcap/alveolar volume (VA) ratio was significantly lower in the isolated PAH group. In patients without ILD, DLCO, DmCO, Vcap and Vcap/VA ratio were reduced in patients with isolated PAH when compared to patients without PAH and both Vcap/VA and DLCO had the highest AUC to detect PAH. In patients with ILD, Vcap had the highest AUC and performed better than DLCO to detect PH in this subgroup. In conclusion, Vcap/VA was lower in PAH than in ILD in SSC whereas DLCO was not different. Vcap/VA ratio and DLCO had similar high performance to detect PAH in patients without ILD. Vcap had better AUC than DLCO, DmCO and FVC/DLCO ratio to detect PH in SSC patients with ILD. These results suggest that partitioning of DLCO might be of interest to detect P(A)H in SSC patients with or without ILD.

OP0160 Evaluation of Non-Invasive Tests as an Early Diagnostic Screen for Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis

BackgroundPulmonary arterial hypertension (PAH) affects 5-15% of all systemic sclerosis (SSc) patients and is associated with up to 30% mortality at 3 years. Early diagnosis improves the outcomes of PAH....

THU0469 Analysis of 111 Patients with Connective Tissue Disease-Associated (CTD) Pulmonary Arterial Hypertension (PAH) Among 2584 Patients with CTD

BackgroundConnective tissue disease (CTD) is a type of autoimmune disease that affects many organs and tissues. The most common manifestations in the lungs include interstitial lung disease, pulmonary arterial hypertension...

AB0826 Hyperuricemic patients with systemic sclerosis do not present higher incidence of pulmonary hypertension but have worse echocardiographic parameters

BackgroundUric acid (UA) serum levels are increased in conditions that affect the oxidative metabolism. Several studies have demonstrated increased UA levels in patients with pulmonary hypertension (PH) and its relation...

Epidemiology and Risk Factors for Pulmonary Hypertension in Systemic Sclerosis

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and excessive collagen production leading to fibrosis of the skin and internal organs. SSc patients are at risk of developing pulmonary hypertension (PH), a debilitating, progressive condition of the pulmonary vasculature that leads to right heart failure and death. This review is an updated summary of the epidemiology and risk factors for PH in SSc. We describe the current literature examining the incidence, prevalence, and demographic and clinical risk factors associated with PH in SSc. We also discuss classical and novel autoantibodies and potential biomarkers that may be helpful in the assessment of risk and prognosis of PH in SSc patients. The ultimate objective in understanding the risk of developing PH in SSc is early diagnosis and early initiation of appropriate therapy with the hope for improved outcomes for patients with SSc-PH.

Brief Report: Effect of ambrisentan treatment on exercise‐induced pulmonary hypertension in systemic sclerosis: A prospective single‐center, open‐label pilot study

Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

Clinical and echocardiographic correlations of exercise-induced pulmonary hypertension in systemic sclerosis: A multicenter study

Patients with systemic sclerosis (SSc) are at risk for developing pulmonary hypertension, which is associated with a poor prognosis. Exercise Doppler echocardiography enables the identification of exercise-induced increase in pulmonary artery systolic pressure (PASP) and may provide a thorough noninvasive hemodynamic evaluation. The aim of this study was to evaluate the clinical and echocardiographic determinants of exercise-induced increase in PASP in a large population of patients with SSc. We selected 164 patients with SSc (age 58 ± 13 years, 91% female) with normal resting PASP (<40 mm Hg) who underwent a comprehensive 2-dimensional and Doppler echocardiography and graded bicycle semisupine exercise Doppler echocardiography. Pulmonary artery systolic pressure, cardiac output, and pulmonary vascular resistance (PVR) were estimated noninvasively. Cutoff values of PASP ≥50 mm Hg and PVR ≥3.0 Wood Units at peak exercise were considered a significant exercise-induced increase in PASP and PVR, respectively. Sixty-nine (42%) patients showed a significant exercise-induced increase in PASP. Among them, peak PVR ≥3 Wood Units was present only in 11% of patients, about 5% of the total population. Univariate analysis showed that age, presence of interstitial lung disease, and both right and left diastolic dysfunction are predictors of peak PASP ≥50 mm Hg, but none of these parameters predict elevated peak PVR. Exercise-induced increase in PASP occurs in almost one-half of patients with SSc with normal resting PASP. Peak exercise PASP is affected by age, interstitial lung disease, and right and left ventricular diastolic dysfunction and, only in 5% of the patients, is associated with an increase in PVR during exercise, suggesting heterogeneity of the mechanisms underlying exercise-induced pulmonary hypertension in SSc.

Could the Cochin risk prediction score be applied in daily practice to predict pulmonary hypertension in systemic sclerosis? Comment on the article by Meune et al

Could the Cochin risk prediction score be applied in daily practice to predict pulmonary hypertension in systemic sclerosis? Comment on the article by Meune et al