Systemic Sclerosis-related Pulmonary Hypertension Research Articles

Bosentan effect on echocardiographic systolic pulmonary arterial pressure in systemic sclerosis-related pulmonary hypertension: a systematic review and metanalysis.

Bosentan is a dual endothelin receptor antagonist approved for the treatment of SSc digital ulcers (DU) and pulmonary arterial hypertension (PAH). Systolic pulmonary arterial pressure (sPAP) is a relevant parameter for the follow-up and prognosis of SSc-PAH. The therapeutic magnitude of bosentan in SSc-PAH is not fully understood, thus we aim to establish the degree of sPAP reduction in bosentan treated SSc-PAH patients. We performed a systematic literature review in three databases from January 2000 to June 2023, involving sPAP measurement at transthoracic echocardiography of SSc patients before and after starting bosentan. Following the study quality assessment and data extraction, we performed random-effects meta-analysis and Egger's test for publication bias. Stratified analysis was performed for mono-/combination therapy, follow up duration (≤1 year), indication for bosentan therapy (PAH or DU/mixed). In the 11 selected manuscripts, sPAP mean difference before and after bosentan therapy was - 5.63mmHg (CI95% -9.79 to -1.48, p=0.0078). In stratified analysis, sPAP mean was significantly different before and after bosentan therapy only for studies considering < 1 year of follow-up (p=0.0020), monotherapy (p=0.0140) and the strict indication for PAH (p=0.0002). Bosentan significantly decreases sPAP, a relevant prognostic marker, especially in overt SSc-PAH. However, bosentan did not decrease sPAP when started for DU/mixed indication nor for follow-up>1 year. The burden of publication bias was significant. Therefore, further studies are required to assess bosentan's haemodynamic effect in high-risk patients for SSc-PAH.

Role of Left Ventricular Dysfunction in Systemic Sclerosis-Related Pulmonary Hypertension

In systemic sclerosis (SSc), pulmonary hypertension remains a significant cause of morbidity and mortality. Although conventionally classified as group 1 pulmonary arterial hypertension, systemic sclerosis-related pulmonary hypertension (SSc-PH) is a heterogeneous disease. The contribution of left-sided cardiac disease in SSc-PH remains poorly understood. How often does left ventricular (LV) dysfunction occur in SSc among patients undergoing right heart catheterization and how does coexistent LV dysfunction with SSc-PH affect all-cause mortality in this patient population? We conducted a retrospective, observational study of 165 patients with SSc who underwent both echocardiography and right heart catheterization. LV dysfunction was identified using LV global longitudinal strain (GLS) on speckle-tracking echocardiography based on a defined threshold of >-18%. SSc-PH was defined by a mean pulmonary artery pressure > 20mmHg. Among patients with SSc who have undergone right heart catheterization, LV dysfunction occurred in 74.2%with SSc-PH and 51.2%without SSc-PH. The median survival of patients with SSc-PH and LV dysfunction was 67.9 (95%CI, 38.3-102.0) months, with a hazard ratio of 12.64 (95%CI, 1.73-92.60) for all-cause mortality when adjusted for age, sex, SSc disease duration, and FVC compared with patients with SSc without pulmonary hypertension with normal LV function. LV dysfunction is common in SSc-PH. Patients with SSc-PH and LV dysfunction by LV GLS have increased all-cause mortality. This suggests that LV GLS may be helpful in identifying underlying LV dysfunction and in risk assessment of patients with SSc-PH.

A Clinical Decision Tool for Risk Stratifying Patients with Systemic Sclerosis-Related Pulmonary Hypertension.

We devised a scoring system to identify patients with systemic sclerosis (SSc) at risk for pulmonary hypertension (PH) and predict all-cause mortality. Using 7 variables obtained via pulmonary function testing, echocardiography, and computed tomographic chest imaging, we applied the score to a retrospective cohort of 117 patients with SSc. There were 60 (51.3%) who were diagnosed with PH by right heart catheterization. Using a scoring threshold ≥ 0, our decision tool predicted PH with a sensitivity, specificity, and accuracy of 0.87 (95% CI 0.75, 0.94), 0.74 (95% CI 0.60, 0.84), and 0.80 (95% CI 0.72, 0.87), respectively. When adjusted for age at PH diagnosis, sex, and receipt of pulmonary arterial vasodilators, each one-point score increase was associated with an adjusted HR of 1.19 (95% CI 1.05, 1.34) for all-cause mortality. With further validation in external cohorts, our simplified clinical decision tool may better streamline earlier detection of PH in SSc.

Emphysema and interstitial lung disease in systemic sclerosis-related pulmonary hypertension

Pulmonary hypertension (PH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc) [ [1] Steen V.D. Medsger T.A. Changes in causes of death in systemic sclerosis, 1972-2002. Ann. Rheum. Dis. 2007 Feb 2; 66 (PMCID: PMC1955114): 940-944 Crossref PubMed Scopus (1174) Google Scholar ]. Patients with SSc-PH and concomitant interstitial lung disease (ILD) have worse clinical outcomes compared to those with SSc-PH, alone [ 2 Chauvelot L. Gamondes D. Berthiller J. Nieves A. Renard S. Catella-Chatron J. Ahmad K. Bertoletti L. Camara B. Gomez E. Launay D. Montani D. Mornex J.F. Prévot G. Sanchez O. Schott A.M. Subtil F. Traclet J. Turquier S. Zeghmar S. Habib G. Reynaud-Gaubert M. Humbert M. Cottin V. Hemodynamic response to treatment and outcomes in pulmonary hypertension associated with interstitial lung disease versus pulmonary arterial hypertension in systemic sclerosis: data from a study identifying prognostic factors in pulmonary hypertension associated with interstitial lung disease. Arthritis Rheumatol Hoboken NJ. 2021 Feb; 73 (PMID: 32892515): 295-304 Google Scholar , 3 Le Pavec J. Girgis R.E. Lechtzin N. Mathai S.C. Launay D. Hummers L.K. Zaiman A. Sitbon O. Simonneau G. Humbert M. Hassoun P.M. Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum. 2011 Aug; 63 (PMID: 21538327): 2456-2464 Crossref PubMed Scopus (102) Google Scholar , 4 Mathai S.C. Hummers L.K. Champion H.C. Wigley F.M. Zaiman A. Hassoun P.M. Girgis R.E. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum. 2009 Feb; 60 (PMID: 19180517): 569-577 Crossref PubMed Scopus (208) Google Scholar ]. In patients with increasing ILD severity, as assessed by forced vital capacity (FVC), there is a trend toward increased all-cause mortality [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ]. Common in restrictive lung diseases including ILD [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ], reduced FVC also occur in obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), which can also affect SSc patients. To date, little is known about the impact of concurrent obstructive lung disease in SSc-PH which may both confound FVC on pulmonary function testing (PFT) used as a marker for ILD severity [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ], and its contribution to overall mortality [ [6] Koo B.S. Park K.Y. Lee H.J. Kim H.J. Ahn H.S. Yim S.Y. Jun J.B. Effect of combined pulmonary fibrosis and emphysema on patients with connective tissue diseases and systemic sclerosis: a systematic review and meta-analysis. Arthritis Res. Ther. 2021 Apr 6; 23 (PMCID: PMC8022385): 100 Crossref Scopus (4) Google Scholar , [7] Ariani A. Silva M. Bravi E. Parisi S. Saracco M. De Gennaro F. Caimmi C. Girelli F. De Santis M. Volpe A. Lumetti F. Hax V. Bredemeier M. Alfieri V. Santilli D. Bodini F.C. Lucchini G. Mozzani F. Seletti V. Bacchini E. Arrigoni E. Giuggioli D. Chakr R. Idolazzi L. Bertorelli G. Imberti D. Michieletti E. Paolazzi G. Fusaro E. Chetta A.A. Scirè C.A. Sverzellati N. Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis. RMD Open. 2019; 5 (PMCID: PMC6397433)e000820 Crossref Scopus (14) Google Scholar ]. Our goal in this study was to characterize the impact of FVC on clinical outcomes in SSc-PH when adjusted for radiologic ILD/emphysema. We hypothesized that FVC decline in any hypoxic lung disease, regardless of etiology, was associated with increased transplant-free, all-cause mortality in SSc-PH.

Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15mmHg on right heart catheterization. Patients with PAWP ≤ 8mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

Prognostic Value of Cardiac Axis Deviation in Systemic Sclerosis-Related Pulmonary Hypertension.

Systemic sclerosis-related pulmonary hypertension (SSc-PH) is a common complication of SSc associated with accelerated mortality. The present study was undertaken to investigate whether cardiac axis deviation indicates abnormalities in cardiac function allowing for prognostication of disease severity and mortality. This was a retrospective study in which electrocardiograms (ECGs) were reviewed for cardiac axis deviation and their association with echocardiography and cardiopulmonary hemodynamics on right-sided heart catheterization. The primary outcome observed was all-cause mortality from the time of PH diagnosis. ECG results were reviewed from 169 patients with SSc-PH. Right axis deviation (RAD) and left axis deviation (LAD) occurred in 28.4% and 30.8% of patients with SSc-PH, respectively. Compared to those without RAD, patients with RAD exhibited predominantly right-sided cardiac disease on echocardiography and increased PH severity by cardiopulmonary hemodynamics including a greater mean ± SD pulmonary artery pressure (42.0 ± 12.5 mm Hg versus 29.8 ± 7.0 mm Hg) and mean± SD pulmonary vascular resistance (645.6 ± 443.2 dynes · seconds/cm5 versus 286.3 ± 167.7 dynes · seconds/cm5 ). LAD was associated with predominantly left-sided cardiac disease on echocardiography but was not associated with PH severity on cardiopulmonary hemodynamics. Both RAD (hazard ratio 10.36 [95% confidence interval 4.90-21.93], P < 0.001) and LAD (hazard ratio 2.94 [95% confidence interval 1.53-5.68], P = 0.001) were associated with an increased hazard for all-cause mortality. RAD and LAD reflect structural cardiac abnormalities and are associated with poor prognosis in patients with SSc-PH. These findings support the importance of electrocardiography, an inexpensive, widely available noninvasive test, in risk stratification.

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO) were included as discovery cohort (n = 69) and duplication cohort (n = 36) for screening hub genes by weighted gene co-expression network analysis (WGCNA). Furthermore, an independent validation cohort (n = 40), including healthy controls, SSc and SSc-PAH patients, was used for further validation by quantitative real-time polymerase chain reaction. The results showed that four key genes, including IFIT2, IFIT3, RSAD2, and PARP14, may serve as potential biomarkers in SSc-PAH. Also, they could be independent risk factors for SSc-PAH. In conclusion, the four key genes can be expected to become the potential therapeutic targets and early biomarkers for accurate therapy and diagnosis of SSc-PAH in the future, which also provides promising insights into the pathogenesis of SSc-PAH at the molecular level.

SAT0320 Coexistence of Left Heart Diseases is Common among Patients with Connective Tissue Diseases-Associated Pulmonary Arterial Hypertension

BackgroundThe cause of connective tissue diseases-associated pulmonary hypertension (CTD-PH) includes left heart disease and interstitial lung disease (ILD) as well as pulmonary arterial hypertension (PAH). Careful differential diagnosis of them...

SAT0192 High Frequency of Left-Sided Heart Diseases as an Important Cause of Pulmonary Hypertension in Connective Tissue Diseases

BackgroundPulmonary hypertension (PH) is one of the fatal complications in the connective tissue disease (CTD).(1) CTD-associated pulmonary hypertension (CTD-PH) is sometimes associated with left heart disease and interstitial lung disease...

Systemic Sclerosis-Related Pulmonary Hypertension: Unique Characteristics and Future Treatment Targets

Pulmonary arterial hypertension (PAH) is a severe vascular complication of connective tissue diseases. In the context of systemic sclerosis (SSc), PAH is a devastating disease with a dramatic impact on prognosis and survival. Despite advances in early diagnosis and the development of new targeted treatments, SSc-related pulmonary arterial hypertension (SScPAH) represents the leading cause of death in SSc patients with reported poorer response in therapy and worse prognosis compared with idiopathic PAH. Recent findings indicate that factors accounting for these differences may include cardiac involvement, pronounced autoimmune and inflammatory response and pulmonary venous vasculature remodeling. Deeper understanding of the underlying pathogenic mechanisms of pulmonary vascular disorders in SScPAH may lead to novel therapeutic strategies which are currently under investigation and may improve the outcome of these patients, for whom our therapeutic armamentarium is not effective enough. In this article we attempt to critically analyze the factors contributing to the unique phenotype of SScPAH focusing on future challenges for the design of novel targeted treatments which may alter the natural history of the disease.

Clinical Characteristics and Survival in Systemic Sclerosis-Related Pulmonary Hypertension Associated With Interstitial Lung Disease

Pulmonary hypertension (PH) complicating systemic sclerosis (SSc)-related interstitial lung disease (ILD) is usually associated with a poor prognosis. However, data are either lacking or scarce on prognostic factors in this condition. The objectives of this study were to compare the survival of patients with ILD-associated PH (PH-ILD) or pulmonary arterial hypertension (PAH) and to determine whether the severity of PH has prognostic value in SSc-associated PH-ILD. Consecutive patients with SSc and PH-ILD (n = 47) or PAH (n = 50) confirmed by right-sided heart catheterization were included in a cross-sectional analysis. PH was classified as mild (mean pulmonary arterial pressure [mPAP] ≤ 35 mm Hg) or moderate to severe (mPAP > 35 mm Hg). As compared with patients with PAH, subjects with PH-ILD were younger, were more frequently men with a history of smoking, had more frequently diffuse SSc, less frequently anticentromere antibodies, and a lower FVC/diffusing capacity of lung for carbon monoxide (DLCO) ratio. They had a worse prognosis than patients with PAH (3-year survival of 47% vs 71%, respectively; P = .07). Patients with mild PH-ILD had similar poor outcomes when compared with those with moderate to severe PH-ILD. Pericardial effusion (hazard ratio [HR], 2.44; P = .04) and lower DLCO (HR, 0.96; P = .01) were the only independent factors predictive of a poor survival in the PH-ILD group. Patients with SSc with PH-ILD had a different phenotype and a worse prognosis than those with SSc and PAH. Lower DLCO and presence of pericardial effusion were predictive of a poor outcome in PH-ILD, whereas mPAP seemed to have no prognostic significance.

Systemic sclerosis–related pulmonary hypertension associated with interstitial lung disease: Impact of pulmonary arterial hypertension therapies

Precapillary pulmonary hypertension (PH) is an important cause of death in patients with systemic sclerosis (SSc). It can occur in isolation (pulmonary arterial hypertension [PAH]) or in association with interstitial lung disease (ILD). Importantly, the outcomes and efficacy of PAH therapies in patients with SSc-related PH complicating ILD (PH-ILD) remain unknown. This study was undertaken to evaluate our experience with PH-ILD with regard to the efficacy and safety of PAH therapies in this patient cohort. We conducted a retrospective analysis of consecutive SSc patients from 2 large referral centers who had PH-ILD confirmed by right-sided heart catheterization and who received targeted PAH therapies. World Health Organization (WHO) functional class, 6-minute walk distance, and hemodynamic parameters were assessed at baseline and after a mean ± SD of 7.7 ± 6.2 months of treatment for PAH. Kaplan-Meier and Cox proportional hazards models were used to analyze survival and to identify prognostic factors. Seventy patients were included in the study. No significant changes were observed in WHO functional class, 6-minute walk distance, or hemodynamic parameters after therapy. The 1-, 2-, and 3-year survival estimates were 71%, 39%, and 21%, respectively. In the multivariate model, worsening oxygenation during followup and reduced renal function were the only significant risk factors for death. This study represents the largest series to date in which the impact of PAH therapies in SSc-related PH-ILD was examined. In this cohort, PAH therapies were associated with no clear benefits. Deterioration in oxygenation was an important determinant of long-term survival. Prospective clinical trials focusing on this group of patients are warranted.

Neurohormonal activation in patients with systemic sclerosis-related pulmonary arterial hypertension

Systemic sclerosis (SSc) is a connective tissue disease, which may lead to pulmonary artery hypertension (PAH). N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biologic marker for the diagnosis and treatment of congestive heart failure. The aim of our study was to investigate the potential role of the plasma NT-proBNP assay in the assessment of functional status and right heart performance in systemic sclerosis-related pulmonary hypertension (SScPAH). Systolic pulmonary artery pressure (sPAP) assessed by echocardiography, six-minute walk test (SMWT) and plasma NT-proBNP levels were recorded from 45 SSc patients. Mean value of NT-proBNP for SSc patients with PAH ( n = 14) was 691.7 ± 325.7 fmol/L compared to 417.4 ± 167.1 fmol/L for patients without PAH ( n = 31) ( p = 0.0007). In SSc patients we found a statistically significant correlation between NT-proBNP values and sPAP ( r = 0.32, p = 0.03). Amongst SScPAH patients, NT-proBNP values were significantly correlated with sPAP ( r = 0.73, p = 0.003) and inversely correlated with the SMWT ( r = − 0.60, p = 0.02). These results suggest NT-proBNP as a useful additional biological tool in the evaluation and management of SScPAH patients.

Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension

Objectives: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population. Methods: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH). Results: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation ( P<0.05) between N-T proBNP values and (i) mean pulmonary artery pressure ( r=0.53), (ii) right ventricular end diastolic pressure ( r=0.59) and (iii) pulmonary vascular resistance ( r=0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0. Conclusions: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.