Borderline Mean Pulmonary Artery Pressure in Patients With Systemic Sclerosis: Transpulmonary Gradient Predicts Risk of Developing Pulmonary Hypertension

Authors

  • Christopher J. Valerio,

    1. Royal Free Hospital, London, UK
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    • Dr. Valerio has received speaking fees and honoraria from Actelion (less than $10,000) and educational grants from Pfizer and Actelion.

  • Benjamin E. Schreiber,

    1. Royal Free Hospital, London, UK
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    • Dr. Schreiber has received consulting fees, speaking fees, and/or honoraria from Pfizer, GlaxoSmithKline, Eli Lilly, and Actelion (less than $10,000 each).

  • Clive E. Handler,

    1. Royal Free Hospital, London, UK
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    • Dr. Handler has received consulting fees, speaking fees, and/or honoraria from Actelion, GlaxoSmithKline, and Pfizer (less than $10,000 each).

  • Christopher P. Denton,

    1. Royal Free Hospital, London, UK
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    • Dr. Denton has received consulting fees, speaking fees, and/or honoraria from Actelion, GlaxoSmithKline, Pfizer, Roche, and Novartis (less than $10,000 each).

  • John G. Coghlan

    Corresponding author
    1. Royal Free Hospital, London, UK
    • National Pulmonary Hypertension Unit, Royal Free Hospital, Pond Street, London NW3 2QG, UK

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    • Dr. Coghlan has received consulting and speaking fees from Actelion, GlaxoSmithKline, United Therapeutics, and Pfizer (less than $10,000 each).


Abstract

Objective

To determine whether patients with systemic sclerosis (SSc) and borderline mean pulmonary artery pressure (PAP) at cardiac catheterization are more likely to develop pulmonary hypertension (PH) than those in whom pulmonary pressure is normal.

Methods

Patients with SSc in whom PH and significant interstitial lung disease had been excluded at baseline were enrolled in our prospective cohort. Analysis of followup data identified patients who met prespecified criteria prompting repeat catheterization to reassess for possible PH. Using Kaplan-Meier, receiver operating characteristic, and Cox regression methods, we studied the development of PH and death.

Results

Of 228 patients in this study, 86 had borderline mean PAP (21–24 mm Hg) at baseline. Following prespecified criteria, 76 patients underwent repeat catheterization, and 29 of these developed PH. Two cases were related to disease of the left side of the heart. The average mean PAP increased from baseline (20.2 mm Hg) to followup (24.3 mm Hg) (P < 0.05 by Student's t-test). Patients with borderline mean PAP were more likely to develop PH than patients with mean PAP ≤20 mm Hg (P < 0.001 by log rank test, hazard ratio [HR] 3.7). A transpulmonary gradient (TPG) ≥11 mm Hg at baseline also predicted PH (P < 0.001 by log rank test, HR 7.9). Incident development of pulmonary arterial hypertension (PAH) was not benign, with a mortality of 18% within 3 years.

Conclusion

Our findings indicate that borderline mean PAP and an elevated TPG in patients with SSc predict progression to PH. These patients should be monitored closely for the development of PH. Our findings indicate that catheterization data are useful in patients considered at risk of PAH.

Pulmonary arterial hypertension (PAH) is generally a progressive condition characterized by increasing resistance of the precapillary pulmonary vascular tree. PAH is an important complication of systemic sclerosis (SSc) with high mortality. The prevalence of PAH in SSc, derived from prospective screening studies, is 7–12% (1, 2). In the European League Against Rheumatism Scleroderma Trial and Research database, 14% of deaths in SSc patients were directly attributed to PAH, an additional 5 patients died of right-sided heart failure without pulmonary hypertension (PH) having been diagnosed, and nearly half of the 14 patients who died of arrhythmia had a history of PH (3). PAH is progressive, and even “mild” disease deteriorates if left untreated (4). Survival in SSc-associated PAH remains poor as compared to that in idiopathic PAH (5). Therefore, earlier diagnosis of PAH in SSc is a recognized clinical priority.

Current approaches to noninvasive assessment necessitate identification of patients in whom PAH is suspected, and these patients then undergo definitive assessment by right-sided heart catheterization (RHC). The normal resting mean pulmonary artery pressure (PAP) is 14 mm Hg, with an upper limit (based on 2 SD) of 20.6 mm Hg and varies little with age (6). A mean PAP of ≥25 mm Hg at rest, measured at RHC, is required for a diagnosis of PH (7). However, a significant number of patients have borderline elevation of mean PAP (defined as 21–24 mm Hg) in the absence of known cardiac or respiratory disease. Although this category of patients has been identified as discrete, the outcome of these cases is unclear. They may warrant more intensive followup or, conversely, may represent a relatively stable population in whom progression to significant or established PAH is unlikely.

The European Society of Cardiology/European Respiratory Society guidelines recommend Doppler echocardiography to determine the maximum jet velocity of tricuspid regurgitation (VTR) for SSc patients with cardiorespiratory symptoms and consideration of Doppler echocardiography for asymptomatic patients (8). This approach is known to be unreliable, with high rates of false positives and false negatives (9, 10). Nevertheless, with baseline echocardiography screening, 33 of 578 SSc patients in the ItinérAIR-Sclérodermie study were identified as having possible PAH. Following RHC, 18 patients were confirmed to have PAH, and these screened patients had significantly lower mean PAP and pulmonary vascular resistance (PVR) than the patients with prevalent PAH in their SSc cohort (2).

Efforts to refine screening algorithms continue. Annual pulmonary function testing in patients with SSc is advocated for the detection of interstitial lung disease (ILD) and PH. A low diffusing capacity for carbon monoxide (DLCO) in the absence of changes of fibrosis observed on computed tomography (CT) or emphysema is very suggestive of PAH (11). We have attempted to find ways of using pulmonary function tests (predominantly forced vital capacity [FVC], DLCO, and carbon monoxide transfer coefficient [KCO]) to detect PH in SSc (12). Meune et al have produced a PH risk prediction score using FVC, KCO, and age (13). N-terminal pro–brain natriuretic peptide (proBNP) is a serum marker of cardiac dysfunction found to be elevated in SSc-associated PAH (14). Allanore et al combined NT-terminal proBNP with KCO (% predicted) to risk-stratify SSc patients for PH (15).

Patients with suspected PAH undergo invasive, hemodynamic catheter studies to confirm or exclude the diagnosis. A proportion of SSc patients who undergo RHC have an elevated, borderline mean PAP (21–24 mm Hg) that does not meet current diagnostic criteria for PAH. Guidelines do not address the integration of information obtained at RHC from SSc patients without PH. Understanding the outcomes in patients with modest hemodynamic abnormalities may offer an opportunity to improve screening programs by identifying the individuals who are at highest risk.

In this study, we evaluated the rate of development of PH and survival in patients with SSc in whom PH had been excluded, and we determined whether SSc patients with borderline mean PAP (21–24 mm Hg) were at increased risk of developing PH compared to patients with a normal mean PAP (≤20 mm Hg).

PATIENTS AND METHODS

Patients, screening, and followup.

The Royal Free Hospital Pulmonary Hypertension database includes more than 1,000 patients with connective tissue diseases, principally SSc, who have undergone RHC studies. Patients with SSc according to the American College of Rheumatology criteria (16) are screened with annual echocardiography and lung function tests. Our policy was to perform RHC in patients with maximum jet VTR ≥3.0 meters/second on Doppler echocardiography, maximum jet VTR ≥2.5 meters/second with other features suggestive of PH, DLCO <60% predicted, ≥20% decrease in DLCO without a concomitant drop in FVC, or new or worsening breathlessness or decline in exercise tolerance. The study cohort comprises patients with SSc in whom ILD (FVC <70% predicted and/or confirmed fibrosis affecting >20% of lung volume on high-resolution CT as described by Goh et al [17]) and PH had been excluded at the time of the initial RHC (Figure 1).

Figure 1.

Study flow diagram. PAH = pulmonary arterial hypertension; RHC = right-sided heart catheterization; ILD = interstitial lung disease; mPAP = mean pulmonary artery pressure.

Patients without PAH did not receive treatment and were followed up with annual assessment of symptoms, Doppler echocardiography, and lung function tests as standard of care. Repeat RHC was performed if new or worsening abnormalities of the screening parameters were observed. Thus, an asymptomatic patient with a DLCO >60% and a maximum jet VTR of 3.0 meters/second would undergo repeat catheterization if symptoms developed, the DLCO dropped below 60%, or the maximum jet VTR increased to ≥3.0 meters/second. Patients were followed up routinely in NHS rheumatology clinics. We obtained data from followup screening tests only when patients were re-referred because of deterioration or when followup took place at our tertiary center.

Right-sided heart catheter studies.

Measurements were made according to the Royal Free Hospital cardiac catheter laboratory operational protocol using a 7 French Swan-Ganz catheter via the right femoral vein. Zero pressure calibration was performed at the mid-thoracic level with the patient in the supine position. Pressure measurements were performed at end-expiration from an average of at least 3 ventilatory cycles. Thermodilution cardiac output was measured as the average of 3 consecutive measurements within 10% of each other. PH was defined as a mean PAP of ≥25 mm Hg at rest. SSc patients without significant ILD and with an end-expiratory pulmonary capillary wedge pressure (PCWP) and/or a left ventricular end-diastolic pressure (LVEP) ≤15 mm Hg were classified as having SSc-associated PAH. Patients with SSc-associated PAH were treated according to local protocol (see Supplementary Figure 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/doi/10.1002/art.37838/abstract). Patients with PH and an elevated PCWP or LVEP (>15 mm Hg) were considered to have PH secondary to disease of the left side of the heart. Transpulmonary gradient (TPG) values (mm Hg) were derived according to the equation TPG = mean PAP – PCWP, and PVR values (dynes × seconds/cm5) were derived according to the equation PVR = 80 × (mean PAP − PCWP)/cardiac output.

Statistical analysis.

The date of baseline RHC study was used as the starting time for analysis. Baseline characteristics of the study group were assessed using the mean ± SD for normally distributed data and with ratios expressed as percentages for categorical data. Box and whisker plots and Student's t-test were applied to data from patients undergoing repeat RHC to assess whether mean PAP increased in this selected group. From the followup data, we described the changes in mean PAP and determined the rate of progression to PH. For the study cohort we assumed that if PH was not detected at baseline RHC and repeat screening assessments demonstrated stability then patients did not develop PH. We estimated the incidence of PH using Kaplan-Meier methods. By excluding patients with PH and ILD related to disease of the left side of the heart, we were able to derive a minimum rate of development of PAH in patients with SSc.

We tested the hypothesis that patients with borderline mean PAP of 21–24 mm Hg are more likely to develop PH than patients with mean PAP ≤20 mm Hg. Using Kaplan-Meier methods we plotted time to PH, where the date of followup RHC was used as the end time (where PH was found) or censor (where mean PAP remained <25 mm Hg). For survival analysis in all patients, the last clinical followup was used. A national UK database check was conducted in April 2010 for missing followup data. We compared the data for patients with borderline and normal pressure at baseline using log rank test. Student's t-test was used to test for the significance of the increase in mean PAP in each group. Single-factor regression analysis was undertaken using the mean PAP as a continuous variable and a binary variable (where a mean PAP of 21–24 mm Hg = 1 and a mean PAP ≤20 mm Hg = 0).

Cox regression analysis of the data from patients who underwent repeat RHC was used to identify baseline demographic and hemodynamic variables (Table 1) that might predict the development of PH. Variables with a P value of less than 0.1 on single-factor analysis were included in further multiple-variable regression analysis to determine the independent predictors. Comparison of calculated variables with the composite factors was made using multiple-variable regression to assess possible independent predictors. Following the regression analysis, a further set of analyses were performed using the best predictive parameter, TPG, utilizing the mean value as a cutoff for comparison.

Table 1. Selected variables from Cox regression analysis to predict pulmonary hypertension*
VariableMean ± SDLinear P value per unit increase (hazard ratio)Multivariate P valueHR (95% CI)
  • *

    HR = hazard ratio; 95% CI = 95% confidence interval; PCWP = pulmonary capillary wedge pressure; NS = not significant; mPAP = mean pulmonary artery pressure; TPG = transpulmonary gradient; R-C = resistance–compliance characteristic; PVR = pulmonary vascular resistance. Additional data for progression to pulmonary arterial hypertension are available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/doi/10.1002/art.37838/abstract.

PCWP, mm Hg9.6 ± 2.90.015 (0.88)NS
mPAP, mm Hg20.5 ± 2.80.004 (1.31)NS
TPG, mm Hg10.8 ± 3.3<0.001 (1.22)<0.0011.2 (1.1–1.4)
R-C, seconds0.41 ± 0.11<0.001 (19.8)NS
PVR, dynes × seconds/cm5186 ± 690.002 (1.01)NS

To determine whether certain factors predicted a rapid rate of progression, patients in whom the annual rate of increase in mean PAP exceeded 5 mm Hg/year were compared to those in whom the increase may have been slower. To assess the course and response to therapy, patients were defined as having a benign course if they survived at least 5 years or were still alive at censor, and met 2 of the following 3 criteria: World Health Organization functional class II, increase in 6-minute walk distance by at least 50 meters to >300 meters, and no significant increase in the mean PAP while receiving therapy.

RESULTS

Pulmonary artery pressure in SSc.

RHC studies were performed on a total of 823 patients with suspected SSc-related PAH, and 318 of these patients had a mean PAP of ≤24 mm Hg. Of these 318 patients, 90 had ILD and were considered separately (Figure 1). Eighty-six of the 228 patients in the study cohort had borderline mean PAP (21–24 mm Hg) compared with 41 of the 90 patients with ILD (P not significant). The patients had a mean ± SD age of 59 ± 11 years and were predominantly female (87%). A majority had limited cutaneous SSc (78.1%). Data on antibody status were available for 132 patients, and 59 patients were positive for anticentromere antibodies, 10 were positive for anti–nuclear RNP antibodies, 21 were positive for anti–Scl-70 antibodies, and 7 were positive for anti–U3 RNP antibodies. The median time from SSc diagnosis to baseline RHC was 7 years. The mean ± SD mean PAP in the study cohort was 19.1 ± 3.2 mm Hg, with arterial oxygen saturation 97 ± 3%, heart rate 76 ± 13 bpm, mean systemic arterial pressure 101.6 ± 14.9 mm Hg, and PVR 166 ± 71 dynes × seconds/cm5. Patients with borderline mean PAP at baseline had a higher mean heart rate (78 bpm versus 75 bpm; P < 0.05 by Student's t-test), PCWP (11 mm Hg versus 9 mm Hg; P < 0.0005), TPG (12 mm Hg versus 9 mm Hg; P < 0.0005), and PVR (196 dynes × seconds/cm5 versus 147 dynes × seconds/cm5; P < 0.0005) than those with normal mean PAP. The mean ± SD followup time was 48 ± 35 months.

In total, 76 patients (33%) underwent repeat RHC. The principal reasons for repeat study were a decrease in the DLCO (n = 27), increasing maximum jet velocity of VTR (n = 19), and deterioration in symptoms (n = 30). Twenty-nine patients met diagnostic criteria for PH during followup, and 2 of them had elevated PCWP consistent with postcapillary PH. In those patients selected for repeat RHC, the average mean PAP increased from 20.2 mm Hg (95% confidence interval [95% CI] 14.7–25.8) to 24.3 mm Hg (95% CI 8.4–40.2) (P < 0.05 by Student's t-test). The mean increase in mean PAP was small (1.1 mm Hg/year, derived from the gradient of line of best fit), with considerable variability and several outliers. The overall rate of progression to PAH (excluding the 2 patients with disease of the left side of the heart and 4 patients with lung disease) was 8.3% (95% CI 3.9–12.7) at 3 years and 14.0% (95% CI 8.4–20.6) at 5 years in the study population. (Additional rates of progression are available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/doi/10.1002/art.37838/abstract.) Of the 33 patients with ILD who underwent repeat RHC, 12 developed PH, 2 of whom had elevated PCWP measurements.

Borderline mean PAP.

Patients with a mean PAP of 21–24 mm Hg and those with a normal mean PAP of ≤20 mm Hg made up 10.4% and 17.3%, respectively, of all SSc patients undergoing baseline RHC based on our screening criteria. The calculated hazard ratio (HR) for the diagnosis of PH on subsequent RHC in the group with borderline mean PAP compared with the normal group (mean PAP ≤20 mm Hg) was 3.7 (95% CI 1.7–8.0) (P < 0.001 by log rank test) (Figure 2A). Of the patients with borderline mean PAP, 18.5% (95% CI 8.3–28.7) developed PAH by 3 years of followup, and 27.1% (95% CI 13.9–40.3) had PAH after 5 years. Linear regression analysis showed an association with the development of PH with an HR of 1.4 (95% CI 1.2–1.6) for each mm Hg increase (P < 0.001). Multiple-variable Cox regression analysis demonstrated that the mean PAP is predictive, independently of other directly measured variables at catheterization. Significance was lost when derived variables were included, due to the stronger performance of TPG (Table 1).

Figure 2.

Kaplan-Meier plots of time to the development of pulmonary hypertension (PH) confirmed at repeat right-sided heart catheterization. A, Significantly increased risk in patients with borderline mean pulmonary artery pressure (PAP) versus those without borderline mean PAP (normal) (P = 0.001 by log rank test). B, Significantly increased risk in patients with high transpulmonary gradient (TPG) versus those with low TPG (P < 0.001 by log rank test). Values are the mean ± SEM percent of patients.

Predictors of PH and clinical course, determined by Cox regression.

Cox regression analysis results are summarized in Table 1. TPG was the best predictor of the development of PH. Therefore, we assessed TPG as a predictor of mean PAP progression using the mean value (10.9 mm Hg) as a cutoff. The minimum rate of progression appeared greater when high TPG was used than when criteria for borderline mean PAP were used. The average increase in mean PAP at repeat RHC was significant in patients with high TPG (27.7 versus 21.8; P < 0.0005 by Student's t-test). The rate of development of PH was found to be greater in the high TPG group than in the low TPG group (Figure 2B) (P < 0.001 by log rank test). In regression analysis, the HR for future diagnosis of PH was 7.9 (95% CI 2.7–23.5) for a high TPG. The effect of a 1 mm Hg increase in TPG in the recatheterization cohort was a 1.2-fold increase in PH risk (95% CI 1.1–1.4). Receiver operating characteristic (ROC) analysis for TPG is shown in Figure 3.

Figure 3.

Receiver operating characteristic (ROC) curve predicting pulmonary arterial hypertension (n = 23 events) using transpulmonary gradient (TPG) in patients with systemic sclerosis who underwent repeat catheterization (area under the curve 0.79 [95% confidence interval 0.68–0.89]; n = 76). A cutoff value of 10.5 mm Hg yields a sensitivity of 87% and a specificity of 70%. A TPG threshold of >8.5 mm Hg yields a sensitivity of 96%, and a threshold of 14.5 mm Hg yields a specificity of 90%.

Of the patients who developed PAH, 14 were positive for anticentromere antibodies, 3 showed a nucleolar pattern, 2 were positive for anti–Scl-70, 3 were positive for anti–U3 RNP, and no results were available for 2. Ten of the 23 patients who developed PAH met the criteria for rapid progression (>5 mm Hg/year increase in mean PAP). There were no differences between the patients with rapid progression and those with slow progression in baseline DLCO (48.5 ± 11.6% versus 55.0 ± 7.5%), mean PAP achieved on bench fly exercise (30.5 ± 2.9 versus 30.6 ± 7.7 mm Hg), or TPG (12.7 ± 1.8 versus 13.2 ± 3.3 mm Hg). Of the patients with rapid progression, 7 were anticentromere antibody positive.

Survival from RHC in SSc without PAH.

The observed survival in SSc patients without ILD in this study was 88.9% at 3 years (95% CI 84.1–93.7). Three-year survival in the patients with ILD was 82.5% (95% CI 78.0–87.0). Survival at 5 years was similar in patients with a mean PAP of ≤20 mm Hg and those with a mean PAP of 21–24 mm Hg (89.7% [95% CI 83.7–95.7] and 87.7% [95% CI 69.9–95.5]). The difference in 3-year survival between the group with low TPG (93.6% [95% CI 88.8–98.4]) and the group with high TPG (81.1% [95% CI 71.5–90.7]) was significant (P = 0.01 by log rank test) (Figure 4). Survival at 3 years was 90% (95% CI 72–100) in the group of patients with rapid progression.

Figure 4.

Kaplan-Meier plots of cumulative (cum) survival showing the difference between patients with systemic sclerosis with high transpulmonary gradient (TPG) at baseline and those with low TPG at baseline (P = 0.001 by log rank test).

Outcomes in patients diagnosed as having PAH.

The prognosis of PAH in SSc patients previously identified as having borderline or normal mean PAP is poor (Table 2). Three-year survival from diagnosis of PAH was 82% (95% CI 64–100). Nine of the 23 patients died, mainly of progressive PH with right ventricular failure. Intravenous or combination therapy was required for PAH in 12 patients. It is clear that in SSc comorbidity is common. Patient 22 (Table 2) presented with ischemic heart disease and mild aortic stenosis (valve area 1.5 cm2) but had a good initial response to bosentan. After 3 years, she developed postcapillary PH associated with an aortic valve area of 0.8 cm2. Aortic valve replacement and coronary revascularization improved her well-being and hemodynamics, but she died suddenly some months later. In patients 13–16 (Table 2), PAH was documented; in 3 cases it was associated with comorbidities that provide alternative possible causes of elevated mean PAP. In 2 of these patients, the excellent long-term clinical response to therapy suggests that pulmonary vasculopathy was the dominant factor.

Table 2. Selected data from SSc patients who had developed PAH at the time of the followup RHC*
Patient/age/sexBaseline RHCDiagnostic RHCChange in TPG, mm HgFollowup mPAPComorbiditiesTreatment/statusMonths of followup
mPAP, mm HgPCWP, mm HgPVR, dynes × seconds/cm5mPAP, mm HgPCWP, mm HgPVR, dynes × seconds/cm5Y1Y2Y3–7
  • *

    The average age of the patients was 59 years, and the median length of followup was 45 months. The average change in transpulmonary gradient (TPG) from baseline to diagnosis was 9 mm Hg. There was a significant difference between average mean pulmonary artery pressure (mPAP) at diagnosis and mPAP at baseline (32 mm Hg versus 21 mm Hg), between pulmonary capillary wedge pressure (PCWP) at diagnosis and PCWP at baseline (10 mg Hg versus 8 mm Hg), and between pulmonary vascular resistance (PVR) at diagnosis and PVR at baseline (389 dynes × seconds/cm5 versus 216 dynes × seconds/cm5) (all P < 0.05 by Student's t-test). SSc = systemic sclerosis; PAH = pulmonary arterial hypertension; RHC = right-sided heart catheterization; Y1 = year 1; NA = not available; IV = intravenous; RVF = right ventricular failure; ILD = interstitial lung disease; FVC = forced vital capacity; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second.

  • “Mild” indicates presence of lung disease not sufficiently advanced to preclude diagnosis of PAH.

  • Functional class refers to World Health Organization functional classes I–IV.

1/57/F2362393110300440NA53NoneCombination with IV prostanoid/died RVF71
2/70/F23720835854418NANA42Ischemic heart disease, mild ILD, FVC 97%Sildenafil/functional class II66
3/70/M2272262915384933NA44Bronchiectasis, FVC 104%, Parkinson's diseaseCombination oral therapies/died RVF55
4/52/F19101244210711234344NANoneCombination with IV prostanoid/died RVF45
5/45/M1952333614279849NANAEpilepsyCombination oral therapies/died RVF30
6/53/F2182043493331249NANANoneIV prostanoid/died RVF8
7/64/F23620929102142NANA39NoneNo treatment/functional class II121
8/71/F241022032143164NANA39SSc gutCombination oral therapies/died RVF75
9/65/F224277276300331NANANoneCombination oral therapies/functional class III45
10/34/F241217838866718NANANANoneCombination oral therapies/died RVF3
11/47/F216218371237710NANANAIschemic heart disease, ILDBosentan/functional class II15
12/61/F20912427122354NANANARenal diseaseSildenafil/died8
13/63/F211025926113534NANA21BronchiectasisBosentan/functional class III85
14/65/F15711925131884NA2224Peripheral vascular diseaseBosentan/functional class III72
15/57/F21102322510245423NANANoneNo treatment/functional class I142
16/68/F22103312578006NANA26Ischemic heart diseaseBosentan/functional class III23
17/58/M20918730132576NA20NANoneCombination oral therapies/functional class III44
18/63/F17522930935092730NAMild ILD, FVC 97%, ischemic heart diseaseBosentan/functional class III35
19/50/F2213176331423810NA26NAMild COPD, FEV1 87%Bosentan/functional class II34
20/56/M216182316465103528NANoneCombination oral therapies/functional class II61
21/58/F20622447663127NA3342Mild ILD, FVC 100%Combination oral therapies/functional class II62
22/68/F2292263615267844NA39Ischemic heart disease, mild aortic stenosisBosentan/progressive aortic stenosis, died 6 months after aortic valve replacement42
23/54/F23112593394921226NANANoneCombination oral therapies/functional class III39

Thirteen of the 23 patients exhibited a benign course (survived >5 years or, in 6 cases, survived with less than 5 years possible followup, maintained or achieved functional class of I–II, increased 6-minute walk distance >50 meters to >300 meters, and had no significant increase in mean PAP from diagnosis of PAH). Five patients in each group (normal and borderline mean PAP) exhibited rapid progression of the mean PAP up to the time of diagnosis of PAH. Of the 13 patients with a benign course, 8 were anticentromere positive. Seven patients exhibited worsening oxygen saturation and/or worsening DLCO during followup. Repeat high-resolution CT scanning and review by the Royal Brompton Hospital (London, UK) did not lead to a diagnosis of pulmonary venoocclusive disease in these cases.

DISCUSSION

In this observational study of patients with SSc, we show that patients meeting prespecified criteria for repeat RHC were more likely to progress to PH if borderline mean PAP was present at baseline. To our knowledge, this is the first study to demonstrate this association. Autoantibody profile, DLCO, bench fly exercise testing, and TPG were not predictive of those most likely to progress rapidly to PAH nor of subsequent clinical course.

As our understanding of SSc and its complications has developed, it has increasingly been recognized that PAH is a leading cause of mortality in this population. Thirty years ago, PAH was infrequently recognized before progression to overt right-sided heart failure had occurred, and no effective treatments were available. Now, with screening programs, detection of PAH has improved, and the availability of effective treatments has led to better survival (2, 18, 19). However, mortality remains significant. In the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL), 1-year survival is only 82% in SSc-related PAH and is significantly worse than for idiopathic PAH despite more favorable hemodynamics at diagnosis (20). Hachulla et al reported 3-year survival for patients with functional class II SSc-associated PAH to be 80% (21). It is against this background that we strive to further enhance our ability to screen and diagnose PAH in SSc.

Several authors suggest that using a combination of parameters may better identify those at high risk, perhaps due to the limitations of available tools (11–13). RHC is an invasive test that is required for the diagnosis of PH. We estimate that currently proposed screening programs would require up to 4 RHCs per diagnosis of PAH. Therefore, data obtained from patients without PH should be available, but it has not been integrated into screening algorithms yet. The concept of “borderline PH” was defined in 2008, as the notion of exercise-induced PH has been abandoned (7).

In this study, we provide the first robust evidence that borderline mean PAP has real clinical significance in the SSc population as a harbinger of increased risk of subsequent PAH. Using Cox regression analysis to examine the findings in those undergoing repeat RHC, we identified elevated TPG at baseline as the most powerful predictor of this progression. If further studies confirm this observation, TPG may be a better predictor of future PAH than the presence of borderline mean PAP.

We and others have demonstrated the value of regular monitoring with a view to hemodynamic assessment in at-risk populations (18). The cumulative rate of PAH development in our whole cohort, in whom PH had been excluded at baseline by RHC, was 8.3% at 3 years. This is higher than the rate in the ItinérAIR-Sclérodermie cohort, in which PAH was identified in 1.83% of the studied SSc population at 3 years, even though most patients in that study were not catheterized at baseline (18). Our cohort is, however, distinctly different, since it comprises only patients in whom clinical and noninvasive measures had previously suggested a high likelihood of PH. Our cohort has a similar percentage of limited cutaneous SSc and anticentromere- positive patients when compared to the ItinérAIR-Sclérodermie cohort.

The findings of our study help to identify the subgroup at greatest risk of progression, with 18% of patients with borderline mean PAP progressing to PAH in just 3 years. In the recent Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) study, 6 of 28 patients with borderline mean PAP developed overt PH after a median of 18 months. Considering only those in the PHAROS trial without ILD, 3 (14%) of 21 patients with normal mean PAP developed PAH, while 3 (38%) of 8 patients with borderline mean PAP did so, with an average followup of 26 months (22). While smaller in size and lacking prespecified criteria for restudy, the PHAROS data support our findings.

In this study, only 2 of 29 patients were found to have postcapillary PH, less than the 10% reported in previous studies (1, 18). Although we did not perform them routinely, studies of the left side of the heart were conducted in both of the patients with postcapillary PH and 10 of the 27 remaining patients. All but 2 of the patients with PAH had 1 or more followup studies, with only 1 (the patient with progressive aortic stenosis) showing evidence of elevation of PCWP while receiving therapy. We did not administer fluid challenges, but this may give rise to false positives and false negatives (23, 24).

In patients diagnosed as having PAH on followup, the average mean PAP was 32 mm Hg, and PVR was 389 dynes × seconds/cm5. This is relatively “early” disease compared to that in most published cohorts; thus, some may question whether such patients have an adverse prognosis and will benefit from treatment. Although data on populations with early disease are limited, Humbert et al recently published the findings of their long-term followup of “detected” patients (25). In patients with SSc-associated PAH with a mean PAP of 34 mm Hg and a PVR of 361 dynes × seconds/cm5, the 5-year survival was 75%, with 4 of the 5 recorded deaths being due to right-sided heart failure. Prior to the availability of oral therapies, Mukerjee et al found a 3-year survival of only 75% in 47 patients with SSc-associated PAH with a mean PAP ≤32 mm Hg, with most deaths resulting from right ventricular failure (1). The UK registry reported 3-year survival of only 47% in SSc-associated PAH (26). A small study of SSc patients with exercise-induced PAH showed an increase in resting mean PAP by as much as 2.5 mm Hg after 1 year, and this increase responded to PAH therapy (27). In our study, patients who were eventually diagnosed as having PAH had a 3-year survival of 82%. Most deaths were due to progressive right-sided heart failure, despite aggressive therapy. Thus, the available data suggest that progression to hemodynamically “early” PAH is not benign.

Although the mean PAP would seem to be the obvious candidate parameter for predicting increasing PAP, in multiple-variable regression analysis, the TPG was the only independent predictor of future PH. Our understanding of the anatomic location of the pathology in PAH, the pulmonary vascular bed, between the large pulmonary arteries and the left atrium, makes TPG a rational parameter to study. Utilization of TPG also helps to remove the influence of filling pressures, e.g., in dehydration. TPG was higher in patients with borderline mean PAP compared with normal pressure in the PHAROS registry (22) and in the present study. Another study has shown that the TPG was elevated at rest and during exercise in SSc patients with exercise-induced PH compared with a normal exercise response or one suggestive of disease of the left side of the heart (28).

Borderline mean PAP does not seem to confer a poor prognosis overall. Three-year survival was similar to that observed in SSc patients with normal mean PAP in our study and others (22). In contrast, high TPG did predict survival, suggesting that this parameter identifies a subgroup with pulmonary vasculopathy. A recent analysis of UK patients with SSc reported survival of 88% 5 years from disease onset (29). The lower survival in our cohort may be due in part to the start date, which in our study was the date of RHC, not the onset of the first non-Raynaud's symptom. Furthermore, most of our patients had cardiorespiratory symptoms and are thus not directly comparable to other published cohorts.

This was a retrospective analysis using cases from our prospectively collected data registry, subject to entry selection. We repeated studies on patients in whom there was clinical justification, i.e., patients at risk of PAH based on followup screening tests. Invasive assessment of right-sided heart pressure only excluded PH at that point in time. We may have underestimated the rate of progression to PAH, since only a modest proportion of patients underwent followup RHC at irregular intervals. The high degree of variability in the hemodynamic values obtained on repeat assessment may reflect factors other than progressive vasculopathy, including variation in the time to followup catheterization. The high prevalence of comorbidity in these patients means that careful assessment of their cardiorespiratory status is crucial.

While keeping these potential confounders in mind, we have made every effort to minimize bias. The criteria for repeat RHC were prespecified, and baseline mean PAP was not a factor leading to early restudy. The magnitude of change in mean PAP and PVR in those diagnosed as having developed PAH was significant, and thus the findings cannot be dismissed as errors in measurement. Finally, a prospective study where all patients undergo prespecified restudy at a fixed time point would be the ideal way of confirming our findings. However, the financial, practical, and ethical issues concerned mean that cohort studies such as this, with clinically driven justification for catheterization, offer the best available approach to address this topic.

This is the first study to convincingly demonstrate that borderline mean PAP in SSc confers an increased risk of developing PAH. Patients with borderline mean PAP in this study developed PAH at minimum rates of 18.5% and 27.1% at 3 and 5 years, respectively. TPG outperforms mean PAP in identifying those most at risk of progressing to PH and is associated with an adverse prognosis. Patients in whom PH has been excluded are subsequently developing PAH that is not benign, even when caught early. Our data provide support for a recommendation of increased monitoring in SSc patients identified as having borderline mean PAP or elevated TPG at RHC.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Coghlan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Valerio, Schreiber, Handler, Denton, Coghlan.

Acquisition of data. Valerio, Schreiber, Handler, Denton, Coghlan.

Analysis and interpretation of data. Valerio, Schreiber, Denton, Coghlan.

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