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European Journal of Echocardiography 2006 7(6):439-446; doi:10.1016/j.euje.2005.12.002
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Copyright © 2005, The European Society of Cardiology

Abnormal pulmonary vascular responses in patients registered with a systemic autoimmunity database: Pulmonary Hypertension Assessment and Screening Evaluation using stress echocardiography (PHASE-I)

Nicholas Collinsa,*, Bruce Bastiana, Laurent Quiquereea, Carol Jonesb, Renae Morganb and Glenn Reevesb

aCardiovascular Unit, John Hunter Hospital, Lookout Road, New Lambton, Newcastle, NSW 2305, Australia
bHunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia

Received 30 June 2005; received in revised form 20 November 2005; accepted after revision 4 December 2005.

* Corresponding author. C/-11 Orchard Road, Beecroft, NSW 2119, Australia. Tel.: +1 416 726 9452. nandl_collins{at}yahoo.com.au


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Patients with autoimmune disease, and in particular limited systemic sclerosis (CREST syndrome), are at risk of developing pulmonary artery hypertension (PAH) which is associated with a poor prognosis. With improvements in therapy offering improved survival and functional capacity, there has been an emphasis on screening to identify patients at risk. Assessment of patients during exercise may enable early identification of patients with this condition.

Aims and methods We aimed to assess the ability of exercise stress echocardiography to evaluate the change in pulmonary artery pressure in 51 patients with autoimmune disease (systemic lupus erythamatosus (SLE), limited systemic sclerosis (LSS or "CREST") and diffuse systemic sclerosis (DSS)). Systolic pulmonary artery pressure (sPAP) was estimated using interrogation of the tricuspid incompetence jet before and after exercise. PAH was classified as normal, mild, moderate or severe using echocardiographic assessment of sPAP.

Results We were able to estimate pre-exercise and post-exercise sPAP in 92% and 90% of patients, respectively.

Pulmonary pressures rose or remained unchanged in all screened individuals, with a mean rise during stress of 14.1mmHg (±1.1). Pulmonary artery pressure rose significantly in each of three subgroups (p<0.05).

Stress echocardiography demonstrated PAH (using a cut-off of >35mmHg) in 59% of all individuals with systemic autoimmunity.

Conclusion Stress echocardiography is a useful tool in identifying individuals with autoimmune disease who may have underlying pulmonary arterial disease that may be amenable to therapy. We noted a consistent elevation in sPAP across all autoimmune subtypes, suggesting an abnormal pulmonary vascular response to exercise exists in these patients.

Keywords: PAH; Pulmonary artery hypertension; PAP; Pulmonary artery pressure; RHC; Right heart catheterisation; PHASE-I; Pulmonary Hypertension Assessment and Screening Evaluation; SE; Stress echocardiography; SLE; Systemic lupus erythamatous; SLARC; Scleroderma-Lupus Autoimmune Resource Centre; DSS; Diffuse systemic sclerosis; LSS; Limited systemic sclerosis; BDI; Borg dyspnoea index; WHO; World Health Organisation; 6MWT; Six-minute walk test; Ox0; Oximetry at rest; Ox6; Oximetry after 6MWT; PFT; Pulmonary function testing; DLCO; Carbon dioxide diffusing capacity; TLC; Total lung capacity; HRCT; High Resolution Computed Tomography; ECG; Electrocardiogram; TR; Tricuspid regurgitant; sPAP; Systolic pulmonary artery pressure; sPAPPRE; Systolic pulmonary artery pressure before exercise; sPAPPOST; Systolic pulmonary artery pressure after exercise; {Delta}PAP; Change in PAP; CXR; Chest X-ray; VQ; Lung ventilation perfusion


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Pulmonary arterial hypertension (PAH) is a common cause of morbidity in scleroderma and related illnesses, affecting up to 35% of these individuals.1 The condition is often silent,2 with the development of clinical symptoms often signaling the presence of advanced disease, associated with poor survival.3,4 This has prompted the need for methods of detecting PAH, including annual echocardiographic screening of asymptomatic individuals with systemic autoimmunity.2,5 Therapeutic nihilism no longer surrounds this entity, with a range of treatments (phosphodiesterase inhibitors,6 prostacyclin analogues,7–9 and dual-receptor endothelin blockade10–12) improving exercise capacity and survival. With these therapeutic developments, and given the irreversibility of advanced pathology associated with PAH, a new impetus has been provided for earlier detection of PAH in at-risk populations, with exercise proposed as a useful stress tool.13

Abnormal pulmonary vascular reserve in response to stress is an important feature of PAH, with exercise inducing a paradoxical rise in pulmonary arterial pressure (PAP), in contrast to the exercise response in normal individuals, where PAP remains essentially unchanged.14 PAH may be defined by the presence of elevated resting PAP or by elevation in PAP with exercise. The prevalence of this functional, subclinical form of PAH has not been widely studied.

PAH is defined as a mean pulmonary artery pressure >25mmHg at rest, and >30mmHg with exercise.15 The gold standard for the diagnosis of pulmonary hypertension remains right heart catheterisation (RHC). This procedure is not without morbidity, particularly in patients with significant pulmonary hypertension. In addition, it may be difficult for patients to exercise adequately during the RHC procedure. These limitations dictate the need for noninvasive methods of investigation which allow for the role of exercise in assessment, with echocardiography considered a possible diagnostic modality.16 Previous studies have used exercise echocardiography in assessment of patients with scleroderma, familial forms of pulmonary hypertension17 and in patients having previously undergone heart transplantation.18

The Pulmonary Hypertension Assessment and Screening Evaluation (PHASE-I) sought to evaluate the usefulness of stress echocardiography (SE) in assessing pulmonary hypertension in an at-risk population. This is based on the hypothesis that an effective screening tool, without the potential complications of invasive testing, would be useful.

Utilising exercise, we were also able to assess the incidence of pulmonary hypertension in a population with autoimmune disease. A secondary aim was to correlate exercise capacity with pulmonary haemodynamics during exercise to determine if assessment of exercise capacity alone is an adequate predictor of the presence of pulmonary hypertension.

Another focus of the study was to address whether the heightened risk of PAH is confined to scleroderma variants, or exists in other autoimmune subtypes, such as systemic lupus erythematous (SLE).

Finally, we sought to determine whether abnormal pulmonary vascular responsiveness with exercise correlated with a history of Raynaud's phenomenon.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
2.1 Patients
The Hunter Scleroderma-Lupus Autoimmune Resource Centre (SLARC) was established in 1990 to provide education and for the follow up of individuals with a range of systemic and organ-specific autoimmune syndromes. Using the SLARC database, 70 individuals with diffuse systemic sclerosis (DSS), limited systemic sclerosis (LSS, also known as CREST), or SLE were selected for further assessment. The aetiology of the underlying autoimmune disease is outlined in Table 1. Diagnoses were made using the American College of Rheumatology criteria. Raynaud's phenomenon was defined clinically, as being present if there was a history of cold-induced colour-change in the fingers and/or toes, involving a transition from white to blue to red. To be included in the screening study, patients needed to be older than 18, able to give informed consent, weigh more than 40kg and were not pregnant or using oral contraceptive agents.


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  		Table 1 Features of study participants (continuous variables)

 
Study design
These 70 patients were asked to complete the Borg dyspnoea index (BDI) and World Health Organisation functional class (WHO) assessments, a standardised "six-minute walk test" (6MWT) and exercise oximetry (oximetry readings recorded at rest (Ox0) and after 6MWT (Ox6)) before proceeding on to formal pulmonary function testing (PFT) including carbon dioxide diffusing capacity (DLCO). Individuals with total lung capacity (TLC)<60% of predicted were not included for further assessment. An intermediate TLC of 60–70% prompted assessment by High Resolution Computed Tomography (HRCT) scanning of the chest, with any significant pulmonary fibrosis precluding further involvement in the study.

Candidates who met the screening criteria on pulmonary function testing and HRCT indices were assessed using stress echocardiography. The study was performed in accordance with the 1983 revision of the 1975 Helsinki Declaration, and in keeping with local guidelines for good clinical practice. The trial protocol was approved by the Hunter Area Research Ethics Committee and written informed consent was obtained from all patients.

Stress echocardiography
Patients identified as candidates for screening underwent exercise stress testing using either a Bruce or modified Naughton protocol with standard 12 lead electrocardiogram (ECG) and noninvasive blood pressure monitoring. Results of 12 lead ECG were obtained from the institutional database.

Continuous wave Doppler interrogation of the tricuspid regurgitant (TR) jet was used to estimate peak systolic pulmonary artery pressure (sPAP), which is considered to be the most accurate echocardiographic method.15 Interrogation of the TR jet allows an estimation of the peak right ventricle to right atrium gradient using the modified Bernoulli equation (4V2). This was assessed before (sPAPPRE) and after (sPAPPOST) exercise. Change in PAP ({Delta}PAP) was calculated by subtracting sPAPPRE from sPAPPOST. Measurement of the TR jet can estimate systolic pulmonary artery pressure in 39–86% of patients, with significant correlation to the results of right heart catheterisation,19–21 including patients with scleroderma.22

Previous study in assessment of pulmonary artery pressure in patients with scleroderma defined systolic pulmonary artery pressure <35mmHg as normal. Pulmonary hypertension was defined as mild (36–45mmHg), moderate (46–55mmHg) or severe (>55mmHg),23 with right atrial pressure considered to be 10mmHg in all subjects. These parameters formed the basis of our quantitative assessment. An assumed right atrial pressure eliminated the possibility of error in the clinical examination of the jugular venous pressure or Doppler assessment of inferior vena cava flow. Analysis of biochemical markers, such as B type naturietic peptide and troponin I, was not included in the study design.

Those who did not display normal sPAPPRE underwent chest X-Ray (CXR) and Technetium Lung Ventilation–Perfusion (VQ) scanning to exclude pulmonary parenchymal and microvascular thrombotic problems, respectively.

Trans-thoracic echocardiography was performed before and after graduated treadmill exercise, with real-time and videotape analysis of the echocardiographic images and Doppler signal. All echocardiographic studies were performed by a single sonographer and interpreted by a single experienced cardiologist, blinded to full clinical case details. Echocardiographic measures of cardiac output and left ventricular function were performed before and after exercise.

Study logistics
The data were retained and analysed by the study co-ordinators in a confidential password-protected database. Financial support for the study was provided by Actelion (Sydney, Australia), but the trial was designed and constructed independently by the authors, and there was no influence by the company upon study process, analysis or publication.

Statistical analysis
Statistical analyses were performed using Stata version 7 (Stata Corporation, College Station, Texas) and JMP Version 5.1 (SAS, Cary, NC,). Clinical and measured variables were summarized as means±SD (with range) for continuous data, and as proportions (with percentages) for categorical information. Differences between these summary statistics were analysed using the Student t and Mann–Whitney–Wilcoxon tests for continuous variables and the N2 test for categorical variables. The Fisher exact test was employed when the minimum expected value with N2 testing was <5. Linear regression analysis was used to correlate measured parameters. A probability value of p<0.05 (two-sided) was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Seventy individuals were screened with Borg dyspnoea index, WHO functional class, six-minute-walk testing, exercise oximetry, PFT (including DLCO), exercise capacity, and SE. Subsequently, 51 of these people attended for stress echocardiographic assessment (19 individuals were excluded: 2 due to inability to complete stress procedure, 12 due to inability to attend for SE, and 5 failed initial screening criteria due to significant pulmonary disease). The mean age was 53.9 years, with all but two participants being female. All patients were in sinus rhythm at the time of stress echocardiography. None of the resting electrocardiograms were reported as having electrocardiographic evidence of right sided chamber dilatation.

Table 1 summarizes the features of the study population. SLE was the commonest diagnosis, affecting 63% of participants, followed by LSS ("CREST") (20%) and DSS (17%). Echocardiographic measures of cardiac output and left ventricular function were performed before and after exercise in 84% of individual studied. There were no significant differences between disease subgroups in terms of age, BDI, 6MWT, oximetry desaturation, sPAPPRE, and DLCO.

We were able to estimate the baseline and post-exercise peak pulmonary artery pressure in 47/51 (92%) and 45/50 (90%) individuals, respectively. One patient did not undergo exercise due to the presence of severe pulmonary hypertension at rest.

Fig. 1 demonstrates the presence of aberrant elevation in systolic pulmonary artery pressure with exercise in our study population. Pulmonary pressures rose or remained unchanged in all screened individuals, with a mean rise during stress of 14.1mmHg (±1.1). There was a proportion of patients with sPAP>35mmHg after exercise, revealing the presence of SE-defined exercise induced PAH. Each disease subtype demonstrated an increase in systolic pulmonary artery pressure, with PAP rises in all subgroups reaching significance (p<0.05). There was no significant difference in the prevalence of stress-induced aberrant PAP rises between the three disease subgroups.


Figure 1
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  		Figure 1 Change in systolic pulmonary artery pressures before and after exercise.

 
Thirty-eight (75%) of the study participants belonged to WHO Classes I and II (Table 2), indicating a relative paucity of pre-existing functional limitation by exertional dyspnoea. Peripheral vascular hyper-reactivity (as reflected by Raynaud's phenomenon) affected 89%, 100%, and 72% of those with DSS, LSS and SLE, respectively, with 80% of all individuals affected. The presence of Raynaud's was not correlated with stress-induced rises in PAP. Using an arbitrary normal PAPPOST cut-off of <30mmHg to define the presence of PAH, the prevalence of PAH was found to be 78% in DSS patients, 70% in LSS, and 78% in SLE, with these percentages falling to 67%, 40%, and 63%, respectively, when a more strict PAPPOST cut-off of <35mmHg was used (Table 3). Exercise resulted in a proportion of individuals with normal resting PAP reaching diagnostic threshold (PAPPOST>35mmHg) for the diagnosis of PAH. This occurred in 44% of DSS patients, 40% of those with LSS, and 56% of SLE patients.


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  		Table 2 Patient classification by WHO class

 


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  		Table 3 Features of study participants (categorical variables)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Patient screening using the SLARC database revealed a high prevalence of exercise induced pulmonary vascular hypertension in this group of patients with systemic autoimmune conditions, with pulmonary pressures rising in all screened individuals. These results contrast with the expected maintenance or fall in PAP. SE-demonstrated PAH was seen in 59% of all individuals with systemic autoimmunity (using a cut-off of >35mmHg), affecting 67% of DSS, 40% of LSS, and 63% of patients with SLE. Using established criteria for severe PAH (PAP>55mmHg),23 this represents a prevalence of 11%, 10% and 9%, respectively.

There was no correlation between PAH and dyspnoea-symptom scores. Such a finding is not unexpected, as it is well-recognised that PAH usually manifests symptoms only after significant pulmonary arterial pathology (often with irreversible, fibrotic and plexiform components) has developed.2 Despite 75% of the study population falling into low WHO classes (I, II), PAH was seen in 59%. This implies that targeted investigation of individuals for PAH based upon patient-reported symptoms may result in delayed diagnosis of this condition, compared with a strategy of using a noninvasive screening tool such as SE applied to populations at risk of PAH.

An enhanced ability to detect subclinical PAH has potential public health and therapeutic implications. Prospective studies which are currently under way24 may demonstrate objective benefits from detecting and treating PAH earlier in these populations. However, until definitive data accrue, treatment of PAH outside of symptomatic disease is not currently recommended.

Strong evidence exists for the survival and life-quality benefit of new treatment agents such as the endothelin dual-receptor antagonists in managing PAH complicating autoimmune disease, yet many health systems only support subsidisation of such therapies in the narrow context of symptomatic, scleroderma-associated PAH. This study found that the prevalence of PAH is elevated not only in patients with scleroderma, but also in SLE. This is important, given the current literature emphasis on PAH being largely a condition manifested in the context of scleroderma and related conditions. However, screening of asymptomatic patients with SLE has demonstrated elevation in pulmonary artery pressure.14 Indeed, some authors argue that distinctions between systemic autoimmune disease subsets are often arbitrary and artificial.25 Given their many closely shared pathogenic mechanisms, it would be expected that such therapies would offer similar benefits in SLE patients to those demonstrated in scleroderma, and this has already been shown in some studies.10

While previous studies indicated no clear correlation between PAP and Raynaud's,26 none of these studies used stress to unmask aberrant pulmonary vascular haemodynamics. Raynaud's phenomenon occurs peripherally as a sign of abnormal vascular responsiveness (classically following the stressor of cold exposure). The presence of PAH in patients with autoimmune disease reflects another manifestation of an abnormal vascular response. However, despite both PAH and Raynaud's phenomenon being associated with scleroderma, this study did not find any correlation of Raynaud's phenomenon with either exercise induced PAP elevation or PAH.

Previous studies have suggested that DLCO measurement should be added to echocardiography when screening for suspected PAH.27–29 In contrast, Mukerjee et al. found that just two features (clinical symptoms and echocardiography) in combination provided a high positive predictive value for PAH.30 We were unable to find any correlation between DLCO and PAH in our study. While DLCO measurement is important in excluding interstitial lung disease complicating systemic autoimmunity, our results add to the growing collection of data indicating only a limited role for DLCO assessment in defining possible PAH.

We were able to confidently exclude alternative underlying causes of PAH using our study algorithm. Spirometry, chest radiography and (for equivocal cases) HRCT imaging of the chest addressed possible pulmonary parenchymal disorders, and ventilation–perfusion scanning excluded thromboembolic disease as a cause of PAH.

The limitations of this technique are similar to those of standard stress echocardiography, in that interpretation depends upon adequate image quality. Additional difficulties relate to the need to accurately interrogate the tricuspid incompetence jet, which may be affected by transducer angulation, cardiac movement within the chest cavity (particularly following exercise) and subjective nature of the interpretation of the Doppler signal. We were able to estimate the baseline and post-exercise peak pulmonary artery pressure in 92% and 90% of subjects, respectively. Our yield of detection of Doppler signals from tricuspid incompetence was in excess of that in previous studies of normal subjects.31 However, similar results have been achieved in echocardiographic assessments of patients with pulmonary hypertension.32 This reflects that this is a selected population, more likely to have a degree of pulmonary hypertension and therefore detectable tricuspid regurgitation. The majority of studies was performed by a single sonographer, and we noted the ability to adequately interrogate the TR Doppler signal did improve with experience. This suggests a learning curve exists and as such it is difficult to comment on the broader reproducibility of this modality.

This study is subject to a number of acknowledged limitations. Right heart catheterisation, generally regarded as the "gold-standard" for diagnosing PAH, was not performed. Echocardiography provides estimation of systolic PAP, while right heart catheterisation measures mean PAP and at present treatment algorithms are based on mean PAP. Recent data suggest systolic PAP measured at cardiac catheterisation can be accurately correlated with mean PAP33 with further study required to confirm echocardiographic derived systolic PAP allows accurate estimation of mean PAP. Given that echocardiographic parameters have already been demonstrated to be useful in monitoring the effect of treatment with endothelin receptor antagonists,34 our data further demonstrate the important role of echocardiography in diagnosis and management of this condition. This reinforces the promising role of echocardiography in noninvasive assessment of pulmonary haemodynamics. The possibility that "false positive" echocardiographic results may represent "latent" PAH which only becomes evident with exercise has not been addressed by functional studies.20 While SE has a number of problems, including assumptions in calculating systolic PAP, RHC is far from a benign procedure and the ability to incorporate more realistic stressors into PAP assessment by SE is attractive. As such, the two tests should be used in a complementary fashion, given the possibility of false positive results in the assessment of pulmonary hypertension by echocardiography.35 Drop-out bias may reduce sensitivity, but this would tend to involve cases of milder disease, hence potentially leading to under detection rather than overestimating the prevalence of PAH.

Investigation of normal subjects may have been useful in terms of confirming the expected level of change in pulmonary artery pressure. However, the aim of our study was to evaluate the usefulness of this modality in a specific patient group to further target investigations and therapy. In addition, difficulties of demonstrating TR suitable for Doppler interrogation in normal individuals make this assessment problematic.

Further study is required to determine if patients detected with early pulmonary hypertension will benefit from therapy in terms of morbidity and mortality. While this modality can allow early identification of patients at risk of developing pulmonary hypertension, we need additional data to confirm that early treatment with endothelial antagonists and other agents will ultimately lead to increased survival. Similarly, prospective analysis is also required to determine the effect of the natural history of these conditions on echocardiographic pulmonary artery parameters, as well as the effect of therapy during follow up assessment.

Given the prevalence of systemic autoimmunity in the community, it is probable that traditional estimates of PAH prevalence (around 1 per million36,37) have significantly underestimated disease burden: assuming prevalence of 1:1000, 1:10,000 and 1:10,000 for SLE, DSS and LSS, respectively, and extrapolating from published data indicating a PAH prevalence of at least 10% in such conditions, then one could expect to detect a PAH prevalence of 1.2 per million in patients with systemic autoimmunity alone, even before addressing idiopathic, familial and sporadic cases.

In conclusion, SE-defined PAH is common in systemic autoimmune conditions, including, but not confined to, scleroderma. We believe stress echocardiography has the potential to significantly add to current standard screening tools in early identification of this dread complication. This is particularly important given a lack of functional limitation by dyspnoea does not exclude the presence of exercise induced pulmonary hypertension. Correlation with invasive exercise testing is essential to confirm the role of stress echocardiography in the future assessment of pulmonary hypertension.

Case-finding through SE-based screening of individuals with systemic autoimmunity may represent an important tool for identification of early PAH, with patient databases representing a powerful diagnostic and research resource. The potential costs and benefits of such approaches, particularly with regard to potentially offering PAH therapies at lower symptomatic and PAP thresholds, will require further analysis. SE screening should be considered in all groups at risk for PAH, including both scleroderma and non-scleroderma-related systemic autoimmune conditions.


   Acknowledgements
 
This study was financially supported by Actelion, Sydney, Australia. All of the authors support Actelion's work as investigators. We are indebted to our local Hunter colleagues for their collaboration and commitment, in particular: Michael Boyle, Robert Clancy, Gabor Major, David Mathers, Siva Ratnarajah, John Glass, John van der Kallen, Hanish Bagga, Theo De Malmanche, Laurent Quiqueree and Elizabeth Hicks.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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