Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis

INTRODUCTION: Pulmonary arterial hypertension (PAH) is the most common cause of scleroderma-related deaths. New medications for PAH patients make it necessary to identify patients with high risk factors for PAH. This study looks at the use of an exercise echocardiogram in identifying patients who may have PAH and may be candidates for early therapeutic intervention. METHODS: This study included 54 scleroderma patients with symptoms suggesting they were at risk for pulmonary hypertension, including dyspnea on exertion, diffusing capacity of the lung for carbon monoxide (Dlco)<60% of predicted, FVC<70% of predicted, percentage of predicted FVC/percentage of predicted Dlco (FVC%/Dlco%) ratio>1.6, or resting right ventricular systolic pressure (RVSP)>35 mm Hg. The exercise echocardiogram protocol involved the standard Bruce stress echocardiogram protocol with remeasurement of the RVSP within 1 min of stopping exercise. A positive exercise test result was defined as an increase of at least 20 mm Hg in the RVSP with exercise. Right-heart catheterization with exercise was performed in those with a positive exercise test result. RESULTS: Resting mean RVSP was 34.5 mm Hg, which increased to 51.4 mm Hg with exercise; 44% had at a positive exercise test result, which correlated with a low Dlco, high FVC%/Dlco% ratio (p<0.001), a positive anti-centromere antibody, and RVSP>35 mm Hg (p<0.05). PAH was confirmed by right-heart catheterization in 81% of patients: 19% at rest and 62% of patients with exercise. CONCLUSIONS: Exercise-induced pulmonary hypertension is a common finding in patients at high risk for PAH. This may be a sensitive way to identify patients with early PAH. Long-term follow-up and early treatment should be studied in these patients.     

Sustained success of therapy with inhaled iloprost for severe pulmonary arterial hypertension associated with systemic sclerosis and pulmonary fibrosis

CASE REPORT: We report here the case of a woman with diffuse cutaneous systemic sclerosis with pulmonary involvement and severe (WHO functional class III) pulmonary arterial hypertension (PAH) and recurrent cardiac decompensation. The simultaneous presence of primary biliary cirrhosis with markedly elevated transaminase levels constituted a contraindication for bosentan, which would otherwise have been the first-line treatment for PAH. The patient was therefore treated with inhaled iloprost. DISCUSSION: Once inhaled iloprost therapy had been started, we promptly noted a definite and sustained improvement in physical exercise capacity and normalisation of haemodynamic variables. In cases where bosentan is contraindicated, inhaled iloprost is an effective alternative for the treatment of severe PAH.     

Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension

Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension Lung disease is present in most of the patients with systemic sclerosis and is now the most important cause of mortality. Interstitial lung disease and pulmonary hypertension are, so far, the main disorders found and both are difficult to detect at the earliest stages. However, diagnostic tools such as immunological test, lung function test, high resolution CT, bronchoalveolar lavage, echocardiography, right-side cardiac catheterization, or lung biopsy are necessary to accurately evaluate the clinical status and allow to improve the management organ-specific ad hoc. Progress in immunological and vascular therapies as well as other emergence drugs offer new expectations to scleroderma patients.     

Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis

Pulmonary arterial hypertension (PAH) is the major complication of systemic sclerosis (SSc) and the main cause of morbi-mortality. It is important to find predictors for this vascular problem. The objective of this study was to determine the serum levels of different biomarkers in patients with SSc and secondary PAH and to compare them with those of healthy control subjects to define their potential role as predictors of PAH. Cross-section study in which 20 patients with SSc were included. PAH was diagnosed by echocardiogram. The optical densities of endoglin (Eng), endothelin-1 (ET-1), platelet-derived growth factor (PDGF), tumoral necrosis factor alpha (TNF-α), Transforming growth factor beta 2 (TGF-β2) and Interleukin 8 (IL-8) were measured in 20 patients with SSc and 20 healthy controls matched by sex. The differences found between the group of patients with PAH and the control group were (mean or median and range): ET-1 (0.20; 0.10–0.35 vs. 0.16; 0.10–0.24; P = 0.0276), IL-8 (195.7; 45.5–504 vs. 118.9; 23–299.5; P = 0.0364), TNF-α (0.70; 0.50–0.96 vs. 0.48; 0.38–0.65; P = 1 × 10⁻⁸) and Eng (0.95; 0.57–1.72 vs. 0.75; 0.57–0.89; P = 0.0028). A correlation was found between the progression of the disease and the development of Raynaud’s phenomenon (Rho: 0.67 and P = 0.0011), ET-1 and Eng (Rho: 0.53 and P = 0.0196), and between IL-8 and Eng (Rho: 0.68 and P = 0.0019). In conclusions, the elevation of the serum levels of Eng and ET-1 could represent a useful tool as PAH biomarkers. Nevertheless, the diagnostic value of these markers needs to be determined by prospective studies. Drs. P. Coral-Alvarado and G. Quintana contributed equally to this work and both should be considered as first authors.     

Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis

STUDY OBJECTIVES: The goal of this study was to determine whether the survival of patients with pulmonary hypertension related to systemic sclerosis (SScPH) was different from that of patients with other forms of pulmonary arterial hypertension. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS: Our cohort was composed of 33 patients with pulmonary hypertension that is sporadic, familial, or related to anorexigen use (PPH) and 22 patients with SScPH who underwent initial pulmonary artery catheterization and vasodilator study at our center between January 1997 and June 2001. Measurements and results: Patients with SScPH had somewhat lower percentage of predicted lung volumes than patients with PPH (total lung capacity, 80% vs 92%; p = 0.06) and had lower percentage of predicted diffusion capacity of the lung for carbon monoxide (42% vs 68%; p = 0.0002). Right atrial pressure, pulmonary artery pressure, and cardiac index were similar between the groups. Patients with SScPH and PPH were treated with usual medical therapies, such as digoxin, warfarin, and continuous IV epoprostenol. Despite these similarities, the risk of death in patients with SScPH was higher than in patients with PPH (unadjusted hazard ratio, 2.9; 95% confidence interval, 1.1 to 7.8; p = 0.03). This increased risk appeared to persist after adjustment for a variety of demographic, hemodynamic, or treatment variables. CONCLUSIONS: Despite having similar hemodynamics, patients with SScPH have a higher risk of death than patients with PPH. Future studies of the mechanism and therapy of pulmonary arterial hypertension should focus on the distinctions between the different forms of this disease.     

High incidence of pulmonary arterial hypertension in systemic sclerosis patients with anti-centriole autoantibodies

Abstract

Systemic sclerosis (SSc)-related autoantibodies are useful tools in identifying clinically homogenous subsets of patients and predicting their prognosis. In this report, we described five SSc patients with anti-centriole antibodies. All five patients were females and had digital ulcers/gangrene. Four of five (80%) patients had pulmonary arterial hypertension (PAH). None of the five patients had active pulmonary fibrosis or developed renal crisis. Anti-centriole antibodies may be a marker for PAH and digital ulcers/gangrene.     

Pulmonary arterial hypertension associated with systemic sclerosis in the Czech Republic

Background  

Systemic sclerosis (SSc) is an important cause of pulmonary arterial hypertension (PAH), with an estimated prevalence of 7.85–26.7%.     

Pulmonary hypertension in patients with idiopathic pulmonary fibrosis

STUDY OBJECTIVES: To determine the impact on survival and clinical correlates of pulmonary hypertension (PH) occurring in patients with idiopathic pulmonary fibrosis (IPF). DESIGN: Retrospective study. SETTING: Tertiary care, referral medical center. PATIENTS: Among 487 consecutive patients with IPF, we identified 136 patients who underwent transthoracic echocardiography within 3 months of their initial evaluation at our institution. Patients with left ventricular dysfunction, valvular heart disease, incomplete follow-up, and those in whom pulmonary artery pressures could not be assessed were excluded; the remaining 88 patients were included in this study. Correlations were performed between echocardiographic measures of PH and clinical variables including survival. MEASUREMENTS AND RESULTS: The mean (+/- SD) estimated systolic pulmonary artery pressure (SPAP) for the 88 patients was 48 +/- 16 mm Hg (range, 28 to 116 mm Hg). Among pulmonary function parameters, SPAP correlated best with diffusing capacity of the lung for carbon monoxide (D(LCO)), to which it was inversely related. For survival analysis, patients were stratified into three groups: < or = 35 mm Hg (14 patients), 36 to 50 mm Hg (47 patients), and > 50 mm Hg (27 patients). Using the Kaplan-Meier method, the median survival rates for these three groups were 4.8 years, 4.1 years, and 0.7 years, respectively. Those patients with SPAP > 50 mm Hg had significantly worse survival compared to other subgroups (p = 0.009). CONCLUSION: In patients with IPF, PH correlates inversely with D(LCO) and has a significant adverse impact on survival, particularly when SPAP is > 50 mm Hg.     

Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis

Background

Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc.

Methods and results

We prospectively enrolled 63 patients with SSc (age 54 ± 3 years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mm Hg and EIPH as sPAP > 50 mm Hg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP) = 1.9 + 1.24 × left ventricular (LV) E/e′ and pulmonary vascular resistance (PVR) = (mPAP–LAP) / LV cardiac output (CO) and slope of mPAP–LVCO relationship = changes in mPAP / changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mm Hg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p = 0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mm Hg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP–LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mm Hg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β = 3.1 ± 0.8; p = 0.001) and exercise PVR (β = 7.9 ± 1.7; p = 0.0001) were independent determinants of exercise sPAP.

Conclusion

EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR.     

Bosentan ameliorated exercise-induced pulmonary arterial hypertension complicated with systemic sclerosis

Pulmonary arterial hypertension (PAH) is a frequent complication in patients with systemic sclerosis. Bosentan is used in patients with symptomatic PAH; however, it has not been established whether or not bosentan ameliorates the progression of PAH in patients with no PAH-related symptoms. We present a case of systemic sclerosis with no PAH-related symptoms in which bosentan ameliorated exercise-induced PAH evaluated by 6-minute walk stress echocardiography, brachial flow-mediated dilation, and skin temperature of hands and feet. The results suggest that administration of bosentan in patients with early-stage PAH ameliorates pulmonary arterial vasodilatation through improvement of endothelial function.     

Infliximab treatment in a patient with systemic sclerosis associated with lung fibrosis and pulmonary hypertension

This is the first report of the efficacy of anti-TNFalpha treatment in a patient with lung fibrosis and pulmonary hypertension associated with advanced systemic sclerosis, refractory to conventional therapies. The patient was treated with infliximab (5 mg/kg) and methotrexate (10 mg/week) for 1 year. After 6 months of therapy, the echocardiogram showed a reduction in pulmonary pressure, confirmed after 1 year. During treatment, the patient's quality of life improved significantly and high-resolution computed tomography of the chest, lung function tests and blood gas analysis remained stable. After 1 year, the patient decided to stop infliximab therapy (for family reasons related to the distance to our hospital). Lung function tests, pulmonary arterial pressures and blood gas analysis progressively worsened and the patient died 11 months later. Few open-label studies have been conducted on the efficacy of anti-TNFalpha therapy in patients with systemic sclerosis. Here we report our experience in a case of systemic sclerosis complicated by pulmonary fibrosis and hypertension. Infliximab treatment seemed effective, suggesting that controlled randomized trials to evaluate infliximab efficacy in these patients and to compare infliximab with other anti-TNFalpha treatments would be worthwhile.     

Pulmonary thromboembolism in congenital heart defects with severe pulmonary arterial hypertension

IntroductionCongenital heart defect (CHD) with shunt can lead to severe, even irreversible pulmonary arterial hypertension (PAH); in extreme form to Eisenmenger syndrome (ES). Despite relatively good long-term survival, these patients often suffer from cyanosis and multisystemic dysfunction, where pulmonary artery thrombosis can be a potentially fatal complication. Together with bleeding these are the most frequent causes of non-cardiac death in patients with severe PAH due to CHD.Patients and methodsProspective study of 40 patients with severe PAH due to CHD (28 female/12 male, median age 41.5 years) was performed, with the aim to analyze the presence of pulmonary artery thrombosis and correlating anatomical and laboratory risk factors.ResultsPrevious thrombosis and/or thromboembolic event was found in 7 patients (17.5%). Significant differences in cyanotic vs non-cyanotic patients were in red blood count parameters: median hemoglobin level 195 vs 141 (p<0.0001), median erythrocytes count 6.62 vs 4.88×10¹²/l (p<0.0001), median hematocrit 0.58 vs 0.44 (p<0.0001). Laboratory findings causing increased risk for thrombosis were increased thrombocytes aggregation in 15 patients (37.5%), hypercoagulation in 5 patients (12.5%) and endothelial dysfunction in 8 patients (20%). Anatomical risk factor—severe pulmonary artery dilatation (>40 mm in female and >45 mm in male) was found in 19 patients (51.4%).ConclusionsPatients with severe PAH due to CHD represent a high-risk group for pulmonary artery thrombosis with morphological and flow pathology combined with secondary erythrocytosis and coagulation abnormalities. A relatively high incidence of platelet hyperaggregability shown in our study would propose that aspirin therapy might be considered in some highly selected patients with severe PAH due to CHD. Further studies though are needed to support this data.     

Pulmonary hypertension associated with systemic sclerosis

Pulmonary hypertension is a rare but well known life-threatening complication of scleroderma and particularly in its limited variant, the CREST syndrome (Calcification, Raynaud phenomenon, Esophageal dysmotility, Sclerodactily, Telangiectasia). The aim of this article is to analyze the available literature and to report the experience of a center for pulmonary vascular diseases. Dyspnea is the main symptom and is frequently severe. Echocardiography is an excellent tool to detect pulmonary hypertension. However, right-heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension and to test vasoreactivity with a potent vasodilator such as nitric oxide. Hemodynamic parameters are less severe in patients with connective tissue diseases perhaps because of an earlier diagnosis. A significant lower proportion of patients presents an acute vasodilator response suggesting an early constitution of irreversible pulmonary vascular lesions. Continuous intravenous epoprostenol therapy seems to be less effective as compared with patients with primitive pulmonary hypertension and does not improve survival. In our experience, immunosuppressive therapy does not improve hemodynamic or clinical data. Novel therapies including oral, sub-cutaneous or inhaled stable prostacyclin analogues and endothelin receptor antagonists are currently evaluated in large placebo-controlled trials.