Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992–2001

R. Hesselstrand, R. Ekman3, J. Eskilsson1, A. Isaksson2, A. Scheja, A.-K. Öhlin2 and A. Åkesson

Department of Rheumatology, 1 Department of Cardiology and 2 Department of Clinical Chemistry, Lund University Hospital, Lund and 3 Department of Neurochemistry and Psychiatry, Göteborg University, Göteborg, Sweden.

Correspondence to: R. Hesselstrand, Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden. E-mail: roger.hesselstrand{at}skane.se


    Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Objective. To evaluate the longitudinal development of the tricuspid gradient (TG) for screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc).

Methods. Doppler echocardiography was performed 506 times in order to estimate TG in 227 consecutive patients with SSc. The value of biochemical markers for predicting TG levels and development was assessed through analyses of pro-brain natriuretic peptide (proBNP), calcitonin-gene related peptide, thrombomodulin and von Willebrand factor in 76 patients with a borderline increase in TG, defined as TG 24–38 mmHg, and for the purpose of comparison also in 10 patients with a normal TG (<23 mmHg) and in 10 patients with increased TG (TG > 38 mmHg).

Results. TG >23 mmHg was found in 102 patients (44.9%) at the first assessment point and in 139 patients (61.2%) respectively, cumulatively at follow-up. TG values >33 mmHg were measured in 24 patients (10.6%) initially and in 38 patients (16.7%) cumulatively in a subsequent assessment. Age and the presence of interstitial lung disease (ILD) were associated with more frequent occurrence of TG >23 and >33 mmHg initially and at follow-up, but were not associated with progression rate. The change in TG (mean ± S.D.) was 1.34 ± 4.55 mmHg/yr. ProBNP correlated to TG.

Conclusion. An increased TG, indicating possible PAH, is common and progressive in SSc. Age and ILD increase the risk of increased TG. Patients with or without ILD have similar progression of TG. ProBNP has potential as an adjunct to TG in selecting patients eligible for invasive treatment.

KEY WORDS: Systemic sclerosis, Tricuspid gradient, Pulmonary arterial systolic pressure, Pulmonary arterial hypertension, ProBNP


    Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc, scleroderma) is characterized by microvascular injury and abnormalities of the immune system, leading to fibrosis of the skin and internal organs [1]. SSc is associated with increased mortality [2–4], but prognosis is extremely variable. Death rates are dependent on the degree of skin involvement [3, 5, 6], the patient's gender [2, 3, 5, 7], age at diagnosis [4, 5] and any possible involvement of the kidneys, heart or lungs [4, 6, 7].

SSc, when complicated with pulmonary arterial hypertension (PAH), has a poor prognosis once established [8–10]. New treatment strategies in PAH have been reported, however, as having beneficial effects. Treatment with prostacyclin analogues has affected survival rates in primary PAH sufferers [11] and has improved exercise capacity in patients with PAH secondary to SSc [12, 13]. Endothelin receptor antagonists have also been shown to have positive effects on exercise capacity [14, 15]. Improved treatment has increased the interest in and the need for earlier recognition of PAH in SSc patients, and screening is recommended.

Doppler echocardiography has become a useful screening tool for PAH. In a study in which both echocardiography and right heart catheterization were performed, there was a close correlation between these two measurements (r = 0.83, P < 0.001) [16].

Retrospective and cross-sectional studies of the prevalence of PAH in SSc have provided conflicting results, as different cut-off levels and different patient selection procedures have been used. Pulmonary arterial systolic pressure (PASP) is calculated as the tricuspid gradient (TG) plus the right atrial pressure (RAP). PAH defined as PASP ≥30 mmHg was seen in 13% of patients by MacGregor et al. [17] and in 35% of patients by Battle et al. [18]. PASP >35 mmHg was recorded in 4.9% of patients in a study by Koh et al. [8], while Yamane et al. found PASP >40 mmHg in 16% of patients [19].

Screening for PAH will serve to identify not only a number of patients with either high or normal PASP, but also, more importantly, some with mild or borderline PAH; early therapeutic intervention among this group could be beneficial. Many patients display borderline PAH, but it is not possible to identify those who will develop manifest PAH. Identification by biochemical markers or other variables, therefore, could be helpful. Plasma pro-brain natriuretic peptide (proBNP) levels increase in proportion to the degree of right ventricular dysfunction in PAH [20], they can be a predictor of death [21] and they could be applied as a parameter in the assessment of the efficacy of the treatment of PAH [22]. In a pilot study, calcitonin gene-related peptide (CGRP), a potent endogenous vasodilator, unexpectedly correlated with PASP [23], probably as a result of compensatory mechanisms. In primary PAH, plasma levels of thrombomodulin (TM) are decreased in severe cases that have been referred for transplantation [24], but increased in less severe cases in which PAH is secondary to systemic sclerosis, perhaps as a consequence of vascular injury [25]. An increased level of plasma von Willebrand factor (vWf), caused by endothelial perturbation, is an indicator of disease activity and poor prognosis [26].


    Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The study population comprised 227 patients, referred from hospitals throughout Sweden during the 10-yr period 1992–2001. All subjects met the ACR criteria for SSc [27]. The disease was classified as diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) depending on the extent of skin involvement [1]. Disease onset was determined by first indications of skin involvement. The first SSc-related visit to the department determined the patient's point of entry into the study, which was also, in the majority of cases, the time of diagnosis. After the first assessment, 72 patients were treated with oral cyclophosphamide, replaced after 1 yr by azathioprine in 50 cases. Twenty-one patients with digital ulcers were treated with regular doses of iloprost administered intravenously, and three patients with PAH were prescribed iloprost inhalations. No patients were treated with endothelin receptor antagonists.

Echocardiography was performed on all patients at the first visit and after 1 yr. Thereafter, only patients on immunosuppressive medication were investigated annually. In the remaining patients, those with dSSc were examined every 2 yr and those with lSSc every 3 yr. Patients who entered the study late or who died early were only investigated once, but 145 patients were investigated on two or more occasions. The second echocardiography was done at a median of 366 days after baseline. The third echocardiography (77 patients) was done at a median of 911 days after baseline, the fourth (27 patients) at a median of 1.277 days, the fifth (13 patients) at a median of 1.553 days, the sixth (seven patients) at a median of 1.887 days, the seventh (four patients) at a median of 2.267 days, the eighth (four patients) at a median of 2.692 days and the ninth (two patients) at a median of 3.318 days after baseline. TG was determined by Doppler echocardiography [28] and calculated by using the modified Bernoulli equation. PASP was calculated, assuming the RAP to be 7 mmHg. Measurement of left heart disease was not considered in this study. In order to analyse the progression of TG, the slope of the linear regression of each subject's measurements on time was used as an appropriate summary measure of the rate of change. Subjects were also investigated by chest radiography using standard posteroanterior and lateral radiographs. The 123 patients who entered the study after 1995 were also investigated using high-resolution computed tomography (HRCT) of the lungs. Vital lung capacity (VC) was measured with a water-filled spirometer and the transfer factor for carbon monoxide (DLCO) was ascertained by application of the single breath method. Interstitial lung disease (ILD) was defined as pulmonary fibrosis indicated by chest radiography or as VC <70% of predicted value (p%). The results of HRCT of the lungs were not taken into account when defining ILD since only 123 patients were examined by this method.

ProBNP, CGRP, TM and vWf were analysed in 76 patients with a borderline increase in TG, defined as TG 23–38 mmHg. These 76 patients included all patients ever having had TG 23–38 mmHg and also a subsequent measurement. For comparison purposes, 10 patients with normal (<23 mmHg) TG, indicated by three or more measurements, and 10 patients with increased TG (TG >38 mmHg), shown in three or more measurements, were randomly selected and investigated. Patients with TG 23–38 mmHg were selected since they are often asymptomatic and/or false-positive, i.e. the results of examination by right heart catheter may be normal despite the presence of PAH on echocardiography. The hypothesis tested was whether biochemical markers could identify patients at risk of developing increased TG. Blood samples were taken from patients between 09:00 and 10:00 h after 30 min in bed without smoking. Samples were stored at –70°C before analysis. Serum was used for the analysis of proBNP, and ethylene diamine tetraacetate (EDTA) plasma was used to analyse CGRP, vWf and TM.

N-terminal proBNP was determined by application of an electrochemiluminescence immunoassay (proBNP, Roche Diagnostics). The expected values of proBNP <50 and >50 yr are <153 and <227 ng/l, respectively, in women and <88 and <227 ng/l in men in the same age groups. The procedure has a total, intra-assay and interassay coefficient of variation of 4.2, 2.9 and 3.0%, respectively, at 200 ng/l, and 3.3, 2.3 and 2.3% at 4000 ng/l [29].

Samples of 200 µl were incubated with 200 µl CGRP antiserum (K-8429 T10 850213), final dilution 1/30 000 in assay buffer (0.25% bovine serum albumin, 500 KIE/ml trasylol in 0.05 M sodium phosphate and 6.7 mM EDTA, pH 7.4), at 6°C for 24 h. A second incubation in the same manner was performed after addition of 200 µl 125I-CGRP (diluted to 20 000 ± 10% c.p.m. in assay buffer with 0.004% Triton X-100). Free and bound tracer was separated using 500 µl sheep anti-rabbit serum (Pharmacia Decanting Suspension III), incubation at room temperature for 30 min and centrifugation (1 500 g, 20°C, 10 min). The supernatant was discarded and the precipitate measured in a gamma counter. The intra- and interassay coefficients of variation for controls at 33 and 55 pmol/l were <9% [30].

Plasma concentrations of soluble TM were analysed by applying an enzyme-linked immunosorbent assay (ELISA) method, essentially as described [31]. The reference intervals for men and women were 3.2–8.4 and 2.6–7.0 ng/ml, respectively (A.-K. Öhlin, unpublished).

Analysis of vWf was by ELISA, using a rabbit antihuman vWf antibody (Dako A082), a monoclonal mouse antihuman vWf antibody (Dako M0616) and a rabbit anti-mouse immunoglobulin conjugated to alkaline phosphatase (Dako D0314). The standard error of the mean in healthy controls was 9%. Results are expressed as the percentage of a normal plasma pool (NPP). The NPP comprised eight healthy, non-smoking persons, two male and six female, aged between 36 and 76 yr, with a median age of 54 yr. These results were from in-house tests.

Differences between groups were analysed using the Mann–Whitney U test or the {chi}2 test. Correlations between variables were calculated using Spearman's {rho}.

Ethical approval and informed patient consent were not required.


    Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Values of TG >23 mmHg were measured in 102 patients (44.9%) at the first assessment point and in 139 patients (61.2%) cumulatively at follow-up. TG >33 mmHg was measured in 24 patients (10.6%) at the first assessment point and in 38 patients (16.7%) cumulatively at follow-up. At the first assessment point, TG >23 mmHg was measured in 37 out of 91 patients (40.7%) with disease duration of 2 yr or less. The demographic features of the study population, presented in Table 1, show ILD to be more common in dSSc than lSSc patients.


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TABLE 1. Demographic characteristics of 227 SSc patients

 
In 145 out of 227 patients, the TG was determined on more than one occasion. Mean change in TG (S.D.) was 1.34 ± 4.55 (S.D.) mmHg/yr. Higher TG was associated with longer disease duration, age, the presence of anti-DNA topoisomerase I antibodies, ILD, alveolitis on HRCT of the lungs and treatment with cyclophosphamide (Table 2; Fig. 1A and B). The results derived from patients with TG >33 mmHg compared with those with TG <33 mmHg are shown in Table 2. Investigation of patients with TG > or ≤23 mmHg showed similar results. There appeared to be no relationship between TG and the following variables: follow-up time, gender, the extent of skin involvement (lSSc or dSSc), the presence of anti-centromere antibodies and fibrosis on HRCT of the lungs. At the first assessment point, TG in patients with ILD was 26.8 ± 9.7 mmHg, and it increased 2.0 ± 5.7 mmHg/yr; TG in patients without ILD, by comparison, was 23.5 ± 8.6 mmHg (P = 0.031 compared with patients with ILD) and increased by 1.0 ± 3.5 mmHg/yr (not significant).


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TABLE 2. Comparison between patients with normal and high TG

 



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FIG. 1. Cumulative development of the TG in SSc patients without (A) or with (B) ILD.

 
In the 145 patients with a follow-up echocardiography, annual TG changes were subdivided into quartiles. The changes in TG for the four quartiles (mean ± S.D.) were –2.94 ± 1.20, –0.26 ± 0.52, 1.32 ± 0.63 and 7.17 ± 5.22 mmHg. No differences between the four quartiles of progression rate of TG were found when account was taken of the following: TG at first measurement, age at the onset of skin involvement, age at inclusion, gender, lSSc or dSSc, anti-centromere antibodies, anti-DNA topoisomerase I antibodies, ILD, alveolitis or fibrosis on HRCT of the lungs at the initial visit. Those patients above the 90th percentile of rate of increase of TG had higher plasma proBNP (P = 0.002). There was a correlation between DLCO and TG at the first assessment point (Spearman's {rho} = – 0.26, P<0.01) (Fig. 2A and B).




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FIG. 2. Correlation between DLCO and PASP at the first assessment point. PASP was calculated as TG + 7 mmHg. (A) Open circles represent patients without ILD (Spearman's {rho} = – 0.177, P = 0.044). (B) Closed circles represents patients with ILD (Spearman's {rho} = – 0.246, P = 0.031).

 
In 96 patients whose levels of proBNP, CGRP, TM and vWf were analysed, there was a correlation between TG and proBNP ({rho} = 0.39, P = 0.001). When the population was subdivided, the correlation remained for patients without ILD ({rho} = 0.33, P = 0.017), but not for patients with ILD. Differences in proBNP were found between the four subsets of patients with different TG progression rates (Table 3). ProBNP could not discriminate, however, between patients with progressive and non-progressive TG 23–38 mmHg. No differences in CGRP, TM or vWf were found between the four subgroups (Table 3).


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TABLE 3. Analyses of proBNP, CGRP, TM and vWf in relation to the development of TG

 

    Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study shows the occurrence of increased TG among patients with early SSc. It was not designed to evaluate the late occurrence of PAH. It appears probable, however, that the relation between time and the development of TG is not linear. It is also important to note that the patients in the sample were not untreated. There was, however, no difference in progression of TG between patients with or without iloprost therapy, given as regular doses for digital ulcers.

In this study, PAH is reported as more common than in other comparable studies [8, 17, 18]. For example, MacGregor et al. [17] found PASP ≥30 mmHg in 13% of patients compared with 61% in this study. Such a difference might be attributable to the fact that, in this study, all referred patients were investigated rather than only those displaying symptoms. In the cross-sectional study by Battle et al. [18], 35% of patients had PASP ≥30 mmHg, a rate of occurrence less than in this study. Yamane et al. [19] reported 16% of patients having PASP >40 mmHg in a cross-sectional study, a frequency comparable to this study's findings of 10.6% at the initial assessment and a cumulative incidence of 16.7% (Table 2). MacGregor et al. [17] reported the annual increase in PASP to be 1.2 mmHg in 83 patients out of 930 who were investigated by echocardiography more than once, a finding similar to the 1.34 mmHg found in this study. It is not possible to determine if some of the differences in the PASP levels recorded might be attributed to different kinds of therapy, since few details of treatment are included in these studies.

Some of the apparent discrepancies found in the studies may be attributable to different definitions of PASP or PAH based on echocardiographic findings. The results of the Bernoulli equation depend upon the level of RAP adopted, which in echocardiography-based studies often is assumed to be between 5 and 15 mmHg. The notion of the normal PASP level is also debatable. In a database study of 102 818 patients referred for Doppler echocardiography at a general hospital, 15 596 were considered to be normal based on normal cardiac structure and function. McQuillan et al. found PASP >30 mmHg, measured by echocardiography, in 28% of these 15 596 patients [32]. When assuming RAP to be 10 mmHg, the McQuillan study estimated that the upper 95% limit for PASP among lower-risk subjects was 37 mmHg. The uncertainty of Doppler echocardiography compared to right heart catheter, the gold standard, may also limit the results of this and above mentioned studies. A recent study [33] recognizes Doppler echocardiography as an accurate screening tool in patients with advanced PAH, but less reliable in others. In the present study, we do not have data on right heart catheter assessed pressures.

In the present study, age was associated with higher TG. It is unclear if this association results from an underestimation of the true duration of the disease in older patients or if these patients really are more susceptible to the development of PAH. Studies of healthy subjects report an association between PASP and age and body mass index [32, 34]. The physiological increase of PASP is, however, small (0.8 mmHg per decade), and has been attributed to an increase in pulmonary vascular resistance and decreased left ventricle compliance with ageing. This diastolic dysfunction is known to occur often in SSc [35].

In SSc, isolated PAH and PAH associated with ILD are often described as two separate entities. In this study of the early and longitudinal development of TG, the similarities between patients with increased TG levels, with or without ILD, were considerable, suggesting similar disease mechanisms of the arteriopathy. Patients with ILD developed increased TG more often, possibly because the effects of ILD were superimposed upon the existing arteriopathy. The effects of ILD could be a result of hypoxic pulmonary vasoconstriction at sites of fibrosis or compression and obliteration of small arterioles and subsequent shunting of blood to other areas of the lung. A caveat in this study is the more thorough examination of patients with alveolitis who had annual examinations due to the immunosuppressive treatment. This could lead to underestimation of PAH in patients without alveolitis. Another explanation of the higher PASP in patients with ILD could be more frequent occurrence of both systolic and diastolic dysfunction in these patients, caused by fibrosis in the heart ventricles as well as in the lungs. This could be assessed by right heart catheterization. The association between increased TG and anti-DNA topoisomerase I antibodies, alveolitis and treatment by cyclophosphamide is probably explained by their association with ILD.

SSc patients who develop PAH have the worst prognosis, irrespective of the presence of pulmonary fibrosis [10]. Not all SSc patients who develop PAH, however, will die from this complication. PAH may also be a prognostic marker of a more widespread, severe vascular disease.

This study shows that increased TG not only occurs in a subset of lSSc patients and patients with ILD, but also in patients with different degrees of skin involvement and a different autoantibody pattern. The difficulty of predicting PAH due to the late display of symptoms emphasizes the importance of repeated screening by Doppler echocardiography.

In the four subsets of patients with normal, borderline but stable, borderline but increasing and high TG, plasma proBNP was associated with TG, but could not be used to predict increasing TG. All 10 patients with normal TG also had normal proBNP, whereas 8 of the 10 patients with TG >38 mmHg had high proBNP. Those patients above the 90th percentile of the rate of increase of TG had higher plasma proBNP, but there was no correlation between proBNP and the rate of increase of TG when the total population was taken into account. This lack of correlation could be caused by the small number of patients or the insensitivity of echocardiography in measuring the exact TG and thus right heart catheter studies would be of interest. Analysis of proBNP seems to be worthwhile, therefore, in patients with either high or rapidly increasing TG.

In a pilot study, an unexpected relationship between CGRP and TG was reported in patients without ILD [28]. This finding was not confirmed by this more extensive study, possibly because different selection criteria were applied. Neither the pilot nor this larger study, however, found a reduction of CGRP, which might have been expected, since Bunker et al. [36] reported a reduction of CGRP immunoreactive neurons in SSc skin and Tjen et al. [37] a reduction of PASP resulting from exogenous CGRP therapy.

Sakamaki et al. found TM levels to be decreased in primary PAH [24], although in Sakamaki's study patients suffered from more severe PAH than patients reported in the present study, and were referred for transplantation. In SSc, TM levels may be affected both positively and negatively by separate mechanisms. SSc by itself or through an inflammatory response down-regulates TM, whereas PAH increases TM and the net result may be unaltered levels.

Increased levels of vWf have been reported in SSc. vWf is released from activated endothelial cells, but it seems to be of no practical value in the assessment of patients with PAH because of other interfering factors.

In conclusion, this study shows that an increased TG is both common and progressive in SSc, indicating possible PAH. Age and ILD increase the risk of increased TG, although patients with or without ILD have similar progression of TG. ProBNP is useful in the assessment of patients with increasing TG.


    Acknowledgments
 
This study was supported by grants from Reumatikerförbundet, the Österlund Foundation, the Koch Foundation and the Gustav V Foundation.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Submitted 6 June 2004; revised version accepted 19 October 2004.



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