Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement

OBJECTIVE: To determine whether there are factors, such as the diffusing capacity for carbon monoxide (DLCO) or pulmonary artery pressure (PAP) on echocardiogram, that can predict the development of pulmonary hypertension (PHT) in patients with limited scleroderma. METHODS: Using the large Pittsburgh Scleroderma Databank, 106 patients who had the diagnosis of PHT after January 1, 1982, were matched with 106 controls by scleroderma subtype, age, sex, race, disease duration, and the mean time to the diagnosis of PHT after the initial Pittsburgh visit. Autoantibodies, vascular features, use of calcium channel blockers, extent of pulmonary function, and echocardiogram findings were determined at any time prior to the diagnosis of PHT (or prior to the matched time in controls). RESULTS: Patients with PHT had a mean DLCO of 52% of predicted at an average of 4.5 years prior to the diagnosis of PHT. This was markedly decreased compared with the values in controls, whose mean DLCO was 81% of predicted (P < 0.0001). The estimated mean PAP on echocardiogram was only slightly higher in the PHT patients compared with controls (34 mm Hg versus 29 mm Hg; P not significant). Nineteen PHT patients had 4 serial measurements of the DLCO during the 15 years prior to the diagnosis of PHT. The initial mean DLCO was 80% of predicted, which decreased in a linear manner to a mean of 35% of predicted at the time of diagnosis of PHT, whereas the value in controls remained at approximately 80% of predicted (P < 0.0001). PHT patients had more severe Raynaud's phenomenon and more severe digital tip ulcers, but they used calcium channel blockers significantly less frequently (37% versus 61% of controls; P < 0.01). The predominance of nucleolar autoantibodies and the absence of anti-Scl 70 antibody were associated with PHT. CONCLUSION: A decreasing DLCO is an excellent predictor of the subsequent development of isolated PHT in limited scleroderma. The DLCO may be significantly decreased for many years prior to the diagnosis of PHT. The presence of autoantibodies and the PAP may also be helpful predictors. The long-term use of calcium channel blockers may be protective, but newer agents that are more effective in treating PHT may also be helpful in altering the natural history of this serious complication in limited scleroderma.     

Comparison of different measures of diffusing capacity for carbon monoxide (DLCO) in systemic sclerosis

In systemic sclerosis (SSc), impaired diffusing capacity for carbon monoxide (DLCO) can indicate interstitial lung disease (ILD), pulmonary hypertension (PH), and/or other disease manifestations, including anemia. We undertook this study to compare the various measures of DLCO in the setting of a complex disease like SSc. We analyzed the pulmonary function tests of a cohort of SSc subjects, as a whole and among subjects with isolated PH and ILD separately. Associations were assessed using Spearman correlation coefficients, Student’s t tests, and F tests by one-way ANOVA. P values <0.05 were considered statistically significant. This study included 225 subjects (mean age, 57 years; 88 % women; mean disease duration, 9.6 years; 32 % with diffuse disease, 44 % with ILD, and 17 % with PH). Mean percent predicted DLCO values were 75 % for DLCOsb and 83 % for DLCOrb. Adjustment for alveolar volume (VA) resulted in near normalization of both DLCOsb/VAsb (91 %) and DLCOrb/VArb (91 %). Subjects with ILD had significantly lower DLCOsb but not DLCOsb/VAsb, whereas those with PH had significantly lower DLCOsb and DLCOsb/VAsb. Among the various measures of DLCO, DLCOsb had the strongest and most consistent associations with clinical outcomes of interest. Adjusting for alveolar volume dampened the associations except with PH, with which DLCOsb/VAsb was more strongly associated than DLCOsb. Low DLCOsb is the most sensitive measure to detect abnormalities in gas exchange in SSc but reflects both parenchymal lung disease and pulmonary vascular disease. Low DLCOsb/VAsb is more specific for pulmonary vascular disease and should be the preferred measure of gas exchange in SSc.     

Prevalence of exercise pulmonary arterial hypertension in scleroderma

Pulmonary arterial hypertension (PAH) is a complication of scleroderma (systemic sclerosis, SSc); as soon as PAH develops, the patient's prognosis deteriorates rapidly. Early detection of PAH ensures timely treatment. We investigated the prevalence of exercise-induced PAH in a cohort of patients with SSc, and examined the relation between exercise-induced PAH and clinical characteristics and biochemical markers. METHODS: Patients with SSc and normal resting systolic pulmonary arterial pressure (sPAP) were studied. Eligible patients were asked to perform cycloergometer exercise until exhaustion, and exercise sPAP was measured. All patients had their pulmonary function tested and underwent echocardiography at rest. Brain natriuretic peptide (BNP) was also determined. RESULTS: Forty-one patients with SSc were studied. Mean sPAP at rest was 29.7 mm Hg, rising to a mean of 41.4 mm Hg on exercise. Eleven of 41 patients (26.8%) had sPAP post-exercise > 50 mm Hg and 8/41 (19.5%) > 55 mm Hg. A significant correlation was found between exercise sPAP and DLCO (p = 0.008) and between sPAP and BNP levels (p = 0.04). Pre-existing severe Raynaud's phenomenon was more prevalent (50% vs 20%), DLCO levels lower (78.9 vs 92.7 % predicted), and BNP levels higher (72.6 vs 42.1 pmol/ml) in patients with exercise sPAP > 55 mm Hg. CONCLUSION: The prevalence of exercise-induced PAH in patients with scleroderma is high. Patients with lower DLCO and higher levels of BNP are at higher risk of developing higher sPAP. Studies with longterm followup are required to evaluate the risk of developing resting PAH in these patients.     

Isolated diffusing capacity reduction in systemic sclerosis.

OBJECTIVE. To determine the long-term outcome of patients with systemic sclerosis (SSc) and an isolated reduction in the diffusing capacity for carbon monoxide (DLCO) at the time of initial evaluation. METHODS. Patients with an isolated reduction in DLCO (i.e., normal forced vital capacity [FVC] and normal ratio of the forced expiratory volume in one second [FEV1] to the FVC) on initial evaluation were identified from among 815 patients with SSc who were carefully followed up throughout their illness. We requested that patients have repeat pulmonary function testing (PFT), and the outcomes of these tests, as well as cardiopulmonary and survival outcomes, were determined. RESULTS. An isolated reduction in DLCO, with a normal FVC was detected in 152 (19%) of the 815 patients. A subset of those with an isolated reduction in DLCO (11%) developed isolated pulmonary hypertension and had severely reduced survival rates. Pulmonary hypertension was strongly associated with an initial DLCO of less than 55% of predicted normal and a FVC (% predicted)/DLCO (% predicted) ratio of greater than 1.4. Among all patients in whom this ratio was greater than 1.4, 22% developed isolated pulmonary hypertension, compared with only 2% of those whose ratio was less than 1.4 (P less than 0.01). Of the 152 patients with isolated DLCO reduction, 73 (48%) underwent PFTs a mean of 5.4 years (range 2.0-13.2) after the initial PFT. Only 6 (8%) of these 73 patients ever had serious pulmonary disease: 5 had isolated pulmonary hypertension, and 1 had severe pulmonary fibrosis. Half of the patients with a low initial DLCO demonstrated a significant improvement (greater than 20%) at followup testing that could not be explained by the demographic, clinical, or laboratory findings at the first visit. CONCLUSION. Isolated reduction in DLCO is a frequent abnormality in SSc. Overall, it is associated with a good prognosis for survival and for pulmonary morbidity. A small subset of patients (11%) who have a very low DLCO (less than 55% of predicted) have developed isolated pulmonary hypertension, all of whom had limited scleroderma.     

Exhaled nitric oxide in systemic sclerosis: relationships with lung involvement and pulmonary hypertension

OBJECTIVE: To measure nitric oxide (NO) concentration in exhaled air of patients with systemic sclerosis (SSc) and to investigate its relationships with lung involvement, complicated or not by pulmonary hypertension (PH). METHODS: Exhaled NO was measured by chemiluminescence in 47 patients with SSc (16 with PH) and in 30 controls. All the patients underwent Doppler echocardiography to assess pulmonary artery pressure (PAP), lung function tests, and thin section computed tomographic scans of the lung to quantify the extent of fibrosing alveolitis. RESULTS: Exhaled NO levels were higher in patients with SSc (16.6 +/- 9.1 ppb), particularly those with interstitial lung disease (ILD) (18.3 +/- 10.4 ppb), compared to controls (9.9 +/- 2.9 ppb; p < 0.0001). In patients with PH, exhaled NO was less than in patients without PH (10.7 +/- 5.9 vs 19.6 +/- 9 ppb, respectively; p < 0.001), and patients with PH without ILD had even lower exhaled NO than patients with PH and ILD (6.6 +/- 1.1 vs 12.6 +/- 6.3 ppb; p = 0.004). There was an inverse correlation between PAP and exhaled NO (r = 04).53, p = 0.004). Exhaled NO was not correlated to age, disease duration, current therapy, or form of disease (limited or diffuse). CONCLUSION: The increased concentration of exhaled NO in patients with SSc may reflect respiratory tract inflammation. The relatively low value of exhaled NO in patients with PH and the negative correlation between PAP and exhaled NO suggest the important role of NO in regulating pulmonary vascular resistance in patients with SSc.     

Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests

Objective

To construct a readily applicable formula for selecting patients with systemic sclerosis (SSc) for right‐sided heart catheterization (RHC) based on the results of their pulmonary function tests (PFTs).

Methods

The diagnostic value of PFT variables was quantified in 386 patients with SSc against data obtained from RHC.

Results

We derived the following formula using data from 257 patients: predicted mPAP = 136 – SpO ₂ – 0.25 × DLCO % predicted, where mPAP is the mean pulmonary artery pressure, SpO ₂ is the oxygen saturation as measured by pulse oximetry, and DLCO is the diffusing capacity for carbon monoxide. We validated the formula in the remaining 129 SSc patients. The area under the curve was 0.75 (95% confidence interval [95% CI] 0.67, 0.84). Using a predicted threshold of 25 mm Hg, the sensitivity was 90.1% (95% CI 82, 96) and the specificity was 29.2% (95% CI 17, 44). When used as a screening procedure in a typical scleroderma patient population, it is projected that those with an mPAP below 25 mm Hg are unlikely to have pulmonary hypertension (PH; prevalence 4.4%), those with a predicted mPAP of 25–35 mm Hg are at average risk of having PH (prevalence of 11.3%), and those with a formula‐predicted mPAP above 35 mm Hg are likely to have PH (prevalence of 62.9%), thus justifying RHC. In patients with equivocal findings on echocardiography, a high formula‐predicted mPAP is strongly associated with the presence of PH.

Conclusion

We derived and validated an easily applied formula for determining pulmonary function in patients with SSc that identifies subgroups with a low, average, or high prevalence of PH. It provides information that is complementary to echocardiography and that should improve the selection of patients for RHC.

     

Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement

BACKGROUND: Isolated pulmonary hypertension (iPHT) is a near-fatal consequence of systemic sclerosis (SSc); in female patients, the risk of its development is increased during the post-menopausal period, when the protective effects of oestrogens on the endothelium decrease. In many animal and human models, hormone replacement therapy (HRT) and oestrogen administration proved efficacious in counteracting many mechanisms that might be implicated in the pathogenesis of iPHT. Accordingly, it has been hypothesized that HRT might help to prevent the development of iPHT. METHODS: A retrospective cohort study was conducted on 61 SSc patients with the limited cutaneous form of the disease and no sign of pulmonary hypertension on echocardiogram (pulmonary artery pressure, PAP > 35 mmHg) at the time of menopause. All the patients had to be stably treated with calcium-channel blockers and not to have risk factors for secondary PHT throughout the duration of the observational period. RESULTS: Twenty patients (32.8%) received HRT for a mean of 6.7 +/- 3.7 years. None of these patients developed iPHT after a mean of 7.2 +/- 3.5 years from menopause, whereas eight out of 41 patients not receiving HRT (19.5%) developed iPHT after a similar time period (7.5 +/- 3.9 years, p = 0.032). These rates were not explained by differences between the two groups with respect to autoantibodies, age, age at onset of SSc, diffusing capacity of the lung for carbon monoxide (DLCO) at menopause, or duration of therapy with calcium-channel blockers. CONCLUSION: HRT administration may be effective in SSc post-menopausal women, preventing the development of iPHT.     

Clinical and laboratory features of scleroderma patients with pulmonary hypertension

OBJECTIVE: Pulmonary hypertension (PH) is a frequent cause of death in patients with systemic sclerosis (SSc). In this study, we examined the occurrence of PH and investigated the clinical and laboratory features of SSc patients with PH. METHODS: A cross-sectional study of 125 Japanese patients with SSc was conducted using Doppler echocardiography, other multiple cardiopulmonary tests, and laboratory examination. RESULTS: PH (systolic pressure >40 mmHg) was diagnosed in 20 patients (16%) by Doppler echocardiography. In the six patients who had secondary pulmonary hypertension (SPH), PH was due to severe pulmonary fibrosis; 14 patients had isolated pulmonary hypertension (IPH). An elevated erythrocyte sedimentation rate (ESR) and increased immunoglobulin G (IgG) were found in a significantly greater proportion of the patients with PH than in those without PH. The incidence of pitting scars/ulcers was significantly greater in the patients with SPH than in those without PH. CONCLUSION: Elevated ESR and increased IgG were common features of scleroderma patients with PH, and scleroderma patients with SPH were inclined to have pitting scars/ulcers.     

Ethnic disparities among patients with pulmonary hypertension associated with systemic sclerosis

OBJECTIVE: To examine a cohort of patients with systemic sclerosis (SSc) and pulmonary hypertension (PH) for ethnic disparities in clinical presentation, disease detection, or management. METHODS: Encounters of patients with SSc seen at the Medical University of South Carolina were recorded in a computerized database from November 1997 through January 2004. Patients were evaluated for discrepancy in disease manifestation and treatment. Evaluation criteria included patient ethnicity (by self report), age, disease duration from onset of first non-Raynaud's symptom, presence or absence of PH, incidence of diastolic dysfunction and left ventricular hypertrophy among patients with PH, severity of interstitial lung disease, and treatment course. RESULTS: African Americans were more likely than Caucasians to have diffuse cutaneous SSc (dcSSc) (69.9% vs 42.9%, p < 0.001) and they presented with PH (defined as right ventricular systolic pressure > 40 mm Hg by echocardiogram or mean pulmonary artery pressure > 25 mm Hg by right heart catheterization (RHC) at a younger age (60.9 yrs vs 49.0 yrs, p < 0.001). There were no ethnic disparities in time from onset of the first non-Raynaud's symptom to detection of PH, method of PH detection, or treatment modalities. Patients with PH were more likely to have diastolic dysfunction than those without PH (52.3% vs 35.9%, p = 0.011). CONCLUSION: In this cohort of patients, African Americans were more likely to have dcSSc. Among patients with PH, African Americans presented at a younger age than their Caucasian counterparts. Incidence of diastolic dysfunction was higher in the PH population. There were no significant ethnic disparities in time of progression to PH or in treatment modalities employed in our cohort.     

Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment

Pulmonary arterial hypertension (PAH) is an important cause of mortality in systemic sclerosis (SSc). The symptoms are non-specific and can be ascribed to other features of the disease, so it is often underrecognized until the late stages. Earlier treatment with new agents is associated with better treatment outcomes. The aim of this article is to develop evidence-based guidelines for screening for PAH and interstitial lung disease (ILD) in SSc. PAH occurs in up to 27% of patients with SSc. Abnormal pulmonary function, particularly a disproportionate fall in carbon monoxide diffusing capacity (DLCO), can identify patients in the early stages of PAH, prompting further investigation in high-risk patients (limited SSc of >10 years' duration, symptoms and/or signs of PAH, DLCO <50% predicted, a rapid or large fall in DLCO without evidence of ILD and/or estimated systolic pulmonary artery pressure >45 mmHg on echocardiography). Right heart catheter remains the diagnostic gold standard. An algorithm for screening with regular pulmonary function tests for the early detection of PAH and ILD in SSc is proposed.     

Pulmonary hypertension is associated with impaired exercise performance in patients with systemic sclerosis

OBJECTIVE: The aim of this study was to evaluate the exercise tolerance by expired gas analysis during stress test in patients with Systemic Sclerosis (SSc). METHODS: Eighteen women (mean age 48.56+/-12.48 years) affected by SSc were studied. A complete echocardiographic examination including pulmonary artery systolic pressure estimation, pulmonary function tests, diffusion lung capacity for carbon monoxide (DLCO), and exercise test were performed. During exercise, breath-by-breath expired gas analysis was performed. RESULTS: Seven patients (39%) had baseline pulmonary systolic hypertension (group A) and 11 patients (61%) did not (group B). Six patients had reduced DLCO values. Both maximal oxygen consumption (VO2max) and anaerobic threshold (VO2AT) values were markedly decreased compared to the predicted values. Seven of 18 patients were unable to complete a maximal exercise (5 of whom affected by pulmonary systolic hypertension). Group A patients showed reduced VO2max, VO2AT, and O2 pulse compared with patients with group B patients (p=0.004, 0.017, and 0.013, respectively); VO2max, VO2AT and O2 pulse were significantly correlated to baseline pulmonary artery systolic pressure. CONCLUSIONS: An exercise intolerance in patients affected by SSc is present. Impairment of exercise performance is associated with pulmonary hypertension.     

Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension

STUDY OBJECTIVES: To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. DESIGN AND SETTING: Consecutive case series in a university hospital. PATIENTS: Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS: Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS: Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSION: SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.     

Severe restrictive lung disease in systemic sclerosis

Objective. We sought to identify risk factors for developing severe restrictive lung disease and to determine the time of onset and rate of progression in patients with systemic sclerosis (SSc). Methods. Using the University of Pittsburgh Scleroderma Databank, we grouped patients according to their lowest forced vital capacity (FVC) value: <75% predicted, 50—75% predicted, and > 50% predicted. In patients with severe restrictive disease, we examined serial pulmonary function test (PFT) results to determine the rate of loss of lung volume over time. Results. Of 890 SSc patients, 60% (n = 531) never had an FVC ⩽75% predicted; 27% (n = 243) had moderate restrictive disease, with an FVC value of 50—75% predicted; and only 13% (n = 116) of the patients had severe restrictive disease, with FVC ⩽50% predicted. Black race, male sex, early disease, and primary cardiac involvement due to SSc were the features most frequently associated with severe restrictive lung disease (by multiple logistic regression). Fifty–five patients with severe restrictive lung disease had their first of at least 2 PFTs during the first 5 years after onset of any SSc (not pulmonary) symptoms. In 30 patients, the FVC declined by 32% per year in the first 2 years of illness, in 16 patients the annual loss was 12% in years 2—4 after disease onset, and in 9 patients annual loss was 3% during years 4—6 of disease (P < 0.005 by 1–way analysis of variance). Conclusion. In SSc patients, black men with early disease who have cardiac involvement are the most likely to have factors associated with the development of severe restrictive lung disease (which is increasingly becoming a major cause of death). Disease subtype (diffuse versus limited cutaneous) and serum antitopoisomerase I antibody do not differentiate between moderate and severe restrictive disease. Careful monitoring of pulmonary function early in the disease, when the greatest loss of lung function occurs, may help identify patients likely to respond to new therapy.     

Determinants of pulmonary arterial hypertension in scleroderma

OBJECTIVE: To define risk factors associated with pulmonary arterial hypertension (PAH) in a large cohort of patients with systemic sclerosis (SSc). METHODS: SSc patients undergoing screening for PAH by means of Doppler echocardiography were identified and their charts were retrospectively reviewed. In all patients, we recorded systolic pulmonary artery pressure along with pulmonary function testing, clinical, and laboratory data. PAH was defined as right ventricular systolic pressure equal or greater than 40 mm Hg. RESULTS: Of 114 SSc patients with echocardiographic measurements, PAH was found in 33 (29%) patients. In a multiple logistic regression analysis, the presence of pulmonary fibrosis on thoracic computed tomography (OR 6.78, CI 1.54 to 29.9), forced vital capacity less than 80% predicted (OR 3.03, CI 1.1 to 8.35), and duration of Raynaud's phenomenon preceding the onset of skin changes for at least 3 years (OR 5.75, CI 1.9 to 17.41) were found to be independent predictors of PAH. Age, disease duration, disease subtype, or autoantibodies were not associated with PAH in our patients. CONCLUSIONS: The present analysis identified pulmonary fibrosis and Raynaud's phenomenon preceding SSc skin manifestations by at least 3 years as risk factors for PAH in our scleroderma cohort. Screening for PAH in these high-risk patients may detect PAH at an earlier stage and guide decisions on therapeutic interventions.     

Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension

RATIONALE: Although pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) associated with high mortality, there exist few data characterizing hemodynamics and cardiopulmonary function in this population. OBJECTIVES: To characterize hemodynamics and cardiopulmonary function in patients with SCD with and without PH. METHODS: Patients with SCD with PH (n = 26) were compared with control subjects with SCD but without PH (n = 17), matched for age, hemoglobin levels, and fetal hemoglobin levels. MEASUREMENTS AND MAIN RESULTS: Upon catheterization, 54% of the patients with PH had pulmonary arterial hypertension, and 46% had pulmonary venous hypertension. When compared with control subjects, patients with PH exhibited lower six-minute-walk distance (435 +/- 31 vs. 320 +/- 20 m, p = 0.002) and oxygen consumption (50 +/- 3% vs. 41 +/- 2% of predicted, p = 0.02), and also had mild restrictive lung disease and more perfusion abnormalities on radionuclide lung scans. The six-minute-walk distance in this population inversely correlated with tricuspid regurgitant jet velocity (r = -0.55, p < 0.001), and mean pulmonary artery pressure (r = -0.57, p < 0.001), and directly correlated with maximal oxygen consumption (r = 0.49, p = 0.004), even after adjustment for hemoglobin, supporting an independent contribution of increasing pulmonary artery pressures to loss of exercise capacity. CONCLUSIONS: Patients with SCD-associated PH have both pulmonary arterial and venous PH associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia. These data support the use of the six-minute-walk distance as an index of PH and cardiopulmonary function in patients with SCD.     

Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis

OBJECTIVE: To determine the serum levels and clinical correlation of connective tissue growth factors (CTGF) in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (lSSc, n = 32), diffuse cutaneous SSc (dSSc, n = 28), systemic lupus erythematosus (SLE, n = 30), polymyositis/dermatomyositis (PM/DM, n = 20), and healthy control subjects (n = 30) were examined by ELISA for detection of CTGF. RESULTS: Serum CTGF levels in patients with SSc were significantly higher than those in patients with SLE or PM/DM, and in controls. CTGF levels in patients with dSSc were significantly higher than those in patients with lSSc. As for clinical correlation of CTGF, SSc patients with elevated CTGF had pulmonary fibrosis, decreased DLCO, and decreased vital capacity more frequently than those with normal CTGF levels. Further, DLCO and vital capacity were inversely and directly correlated with serum CTGF levels in patients with SSc. The dSSc patients with disease duration of 1-3 years had significantly elevated levels of CTGF compared with dSSc patients with duration < 1 year or more than 3 years. CONCLUSION: Serum CTGF levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. In addition, it appears that production of CTGF is involved in the development or maintenance of fibrosis rather than in initiation of fibrosis in SSc. These data suggest that CTGF plays a critical role in the development of fibrosis in SSc.     

Correlation between plasma concentrations of calcitonin gene related peptide and pulmonary pressure in patients with systemic sclerosis

OBJECTIVE: To examine plasma levels of calcitonin gene related peptide (p-CGRP) in patients with systemic sclerosis (SSc) and pulmonary hypertension (PH). MATERIAL AND METHODS: Twenty nine patients with SSc, 10 with diffuse form, 18 with limited form and one with overlapping systemic lupus erythematosus were examined. Twelve patients displayed normal systolic pulmonary artery pressure (PAPsyst) < or =30 mm Hg and 17 increased PAPsyst >30 mm Hg. Eight patients had isolated PH without interstitial lung disease (ILD) and nine had PH and ILD (secondary PH). PAPsyst was measured non-invasively by Doppler cardiography. CGRP was determined by radioimmunoassay. RESULTS: Patients with PH had higher p-CGRP than patients with normal pressure. A positive relation was found between p-CGRP and PAPsyst and between p-CGRP and erythrocyte sedimentation rate (ESR), particularly in patients with isolated PH. CONCLUSION: In patients with SSc p-CGRP correlates with pulmonary pressure and with ESR. Whether CGRP reflects disease activity or is released secondary to pulmonary vasoconstriction needs to be investigated further.     

High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis

OBJECTIVE: To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc). METHODS: Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36-month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea. RESULTS: Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan-Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P<0.01 for each comparison), elevated plasma NT-proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P=0.08), and erythrocyte sedimentation rate >28 mm/hour (P=0.015). In multivariate analyses, an elevated baseline NT-proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69-62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45-387.6]) were predictors of the occurrence of PAH during followup. An increased NT-proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90-450.33]). CONCLUSION: This prospective study identified a decreased DLCO/VA ratio and an increased NT-proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.