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Rheumatology Advance Access originally published online on April 10, 2006
Rheumatology 2006 45(11):1395-1398; doi:10.1093/rheumatology/kel120
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Angiographically proven coronary artery disease in scleroderma

M. R. Akram, C. E. Handler, M. Williams, M. T. Carulli1, M. Andron, C. M. Black1, C. P. Denton1 and J. G. Coghlan

Department of Cardiology and 1Centre for Rheumatology, Royal Free Hospital, London, NW3 2QG, UK.

Correspondence to: Dr Christopher P. Denton, Centre for Rheumatology, Royal Free Hospital, London, NW3 2QG, UK. E-mail: c.denton{at}medsch.ucl.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. It has been suggested that macrovascular disease is more common in patients with scleroderma (SSc). We investigated the prevalence of coronary artery disease (CAD) in SSc using coronary angiography.

Methods. Coronary angiography was performed in 172 patients with SSc and suspected CAD to examine the prevalence of significant CAD. The prevalence of CAD was estimated in the whole group and also according to age, gender and type of symptoms (typical angina, atypical angina and non-anginal pain or breathlessness). Standardized prevalence ratios (SPRs) were calculated in each symptomatic group in order to compare CAD rates amongst our observed population with those predicted using the Diamond and Forrester (D & F) probability analysis. This analysis provides an estimate of the probability of CAD based on gender, age and symptoms in subjects aged between 30–69 yrs.

Results. The observed prevalence of CAD in the whole population was 22% (38/172); 17% (6/36) in males and 23% (32/136) in females. A total of 41 patients were excluded because they were outside the age range for D & F analysis. Compared with the reference population, the SPRs for CAD in the three SSc groups were: 47% (95% CI 21.7–89.9) in the typical angina group (22 patients), 50% (95% CI 13.6–128) in the atypical angina group (22 patients) and 93% (95% CI 49.4–158.8) in the non-anginal pain or breathlessness group (87 patients).

Conclusion. The prevalence of CAD in patients with SSc is similar and not greater to that expected in individuals without SSc.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Scleroderma (SSc) is a multisystem disorder of connective tissue characterized by widespread vascular lesions and fibrosis of the skin and internal organs (gut, heart, lungs and kidney) [1, 2]. SSc has the highest case-specific mortality of the autoimmune rheumatic conditions [3]. Cardiac disease is one of the major causes of death in SSc and it is plausible that cardiac disease contributes to mortality from other causes in SSc [4]. Subclinical cardiac involvement, including conduction abnormalities, myocardial and pericardial disease, is thought to be common in SSc [5]. Autopsy studies have suggested a high frequency of abnormalities, particularly replacement fibrosis and contraction band necrosis [6]. However, clinically apparent cardiac disease has been reported in only 10% of the patients and was associated with an adverse prognosis [7]. In addition to fibrotic changes in the myocardium, a ‘cardiac Raynaud's phenomenon’ involving small myocardial vessels and an immune-mediated myocarditis has been suggested, but the exact pathogenesis of myocardial involvement in SSc is unclear.

Microvascular dysfunction in SSc is well-established in scleroderma [8]. Although carotid and peripheral artery disease have been described in patients with SSc [9], it is not known whether the SSc vasculopathy predisposes patients to CAD, because no studies have addressed this clinical issue with coronary angiography in a large group of patients. If peripheral vascular disease is more common in SSc, then it might be expected that CAD would be more common in patients with SSc compared with individuals without SSc. However, the epicardial coronary arteries in patients with SSc have been reported to be free of significant disease even in the setting of myocardial infarction, congestive cardiac failure and sudden cardiac death, but these reports included only small number of patients [10, 11]. Studies of vessel wall mechanics suggest that elastic rather than muscular arteries are abnormal in SSc and the degree of abnormality associates with the extent of skin sclerosis [12].

Non-invasive studies have been carried out to investigate myocardial perfusion in SSc. Nuclear myocardial perfusion studies generally have a low predictive accuracy of around 30% [13]. In SSc, the false positive rate is not known because no large studies have been performed assessing both perfusion defects and coronary anatomy with angiography. Echocardiography and Doppler imaging have reported impaired coronary flow in SSc patients, both with and without cardiac symptoms [14–16]. However, most of these studies did not include coronary angiography.

The aim of our study was to assess the prevalence of clinically significant CAD in SSc using the ‘gold standard’ of coronary angiography and to clarify whether there is an excess of CAD in the SSc population. We examined the prevalence of angiographically documented CAD in SSc patients and compared the observed prevalence of CAD in these patients with that predicted for the general population using the D & F probability analysis to provide a reference population [17]. We also analysed the subset of SSc, duration of Raynaud's phenomenon, skin sclerosis score, auto-antibody profile and pattern of organ involvement for the SSc cases to see whether these variables associated with CAD.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
From a large cohort of approximately 1000 SSc patients, under regular follow-up between 1998 and 2004 in the Royal Free Hospital Scleroderma Clinic, we reviewed patients who had had coronary angiography during this time. A total of 174 SSc patients underwent coronary angiography. These patients had been referred for cardiovascular assessment to investigate suspected cardiac or pulmonary arterial disease for different clinical reasons. Two asymptomatic patients were excluded because coronary angiography had been performed as a part of lung transplant assessment. The study population of 172 patients (136 females, age range 26–80 yrs, mean 61 yrs) fulfilled the American College of Rheumatology classification criteria for SSc [18]. Forty-two (24%) patients were in the diffuse cutaneous subset and 130 (76%) had limited disease. Patients with diffuse SSc were designated as early-stage (<2 yrs duration) or late-stage disease, determined by duration of more than 2 yrs from onset of the first non-Raynaud's manifestation of SSc. The study cohort characteristics are shown in Table 1.


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  		TABLE 1. Patient characteristics

 
Hospital case notes and departmental databases (SSc, pulmonary hypertension and laboratory data) were reviewed to obtain details about their disease including: clinical classification of SSc, extent of internal organ involvement, skin score to measure disease activity, serological markers and indications for coronary angiography. The Royal Free Hospital Local Research Ethics Committee approved the study and patient consent was obtained.

Patients were grouped according to their main cardiac symptom. Coronary angiography was performed in 27 patients with typical angina (TA) and 29 patients with atypical angina (AA). Coronary angiography was performed in further 116 patients with breathlessness on exertion (non-anginal chest pain, NAP group), because they did not have sufficiently severe structural or vascular pulmonary disease to account for their symptoms.

The D & F tables provide an estimate of the probability of CAD based on gender, age, symptoms in patients aged between 30–69 yrs. The D & F tables were used for comparison because of their validity and simplicity. Of the 172 patients who had coronary angiography, 131 patients were aged between 30–69 yrs and so could be compared with the D & F probability analysis tables. Significant CAD was defined using the D & F criteria (stenosis of at least 50% in a major coronary artery and/or at least 70% in a branch artery). The prevalence of CAD was estimated in the whole group and also according to age, gender and type of symptoms. For 131 patients aged between 30–69 yrs, the observed prevalence of significant CAD in each symptomatic group was compared with the expected prevalence in the general population having similar characteristics derived from the D & F table.

Statistical analysis
Chi-squared test and Fisher's exact tests were used as appropriate in order to assess whether there was a significant association between all categorical variables listed and the occurrence of CAD. For continuous measures, this association was further evaluated using either Student's t-test or Mann–Whitney U-tests for normally or non-normally distributed variables, respectively. An adjusted logistic regression model was used in order to assess whether variables were independent significant predictors of CAD. A standardized prevalence ratio (SPR) was calculated in order to compare CAD prevalence amongst our observed population and the D & F published population. An SPR of 100% implies that the rates are the same for the population of interest and the standard population. An SPR >100% implies that the rate is greater for the population of interest and SPR <100% implies that the CAD rate is lower for the population of interest compared with the standard population.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
The prevalence of significant CAD in this SSc population was 22% (37/172) with a prevalence of 17% in males and 24% in females. Amongst the 172 patients who were investigated for suspected CAD, the percentage (proportion) of patients with significant CAD in the three symptomatic groups was 48% (13/27) for TA, 17% (5/29) for AA and 16% (19/116) for NAP. A total of 131 (76%) of the SSc subsets were aged between 30 and 69 yrs and therefore could be compared with those described by D & F. Twenty-one (16%) patients (21F, age range 39–68 yrs, mean 60 yrs) had TA, 22 (17%) patients (20F, age range 36–69 yrs, mean 54 yrs) had AA and 87 (67%) patients (61F, age range 30–69 yrs, mean 57 yrs) had NAP.

The SPRs for CAD in the three groups were: 47% (95% CI 21.7–89.9) in TA group, 50% (95% CI 13.6–128) in AA group and 93% (95% CI 49.4–158.8) in NAP group. Table 2 shows adjusted odds ratios for all the variables in a logistic regression analysis. A value >1 indicates an increased risk for CAD, conversely a value <1 demonstrates a protective effect. Only age, oesophageal involvement, pulmonary hypertension and typical chest pain, were significantly associated with CAD. Oesophageal involvement and/or pulmonary hypertension appear to have a protective effect and reduce the risk of CAD by 80 and 77%, respectively. On the other hand for a 1 yr increase in age, the risk of CAD increases by 12% (P = 0.0009) and typical chest pain increases the risk by nearly 6-fold (P = 0.044).


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  		TABLE 2. Results from a multivariate logistic regression model

 
Out of 38 patients who were found to have significant CAD, 15 were treated with balloon angioplasty and stenting, and two patients successfully underwent coronary artery bypass surgery.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
The frequency of angiographically documented CAD in SSc patients was similar to that expected in a population without SSc. The prevalence of CAD in our largest patient group with NAP (unexplained breathlessness) was similar to the NAP group in the D & F table, suggesting that the prevalence of CAD in SSc patients is similar to that in the general population.

However, some subgroups appear to have a lower prevalence than expected. The lower prevalence of CAD in SSc patients with TA and AA may reflect the small number of patients with these symptoms or the female predominance (41/44) in these groups in our population, where typical chest pain is often associated with normal findings on angiography [19]. Moreover, nearly half (48%) of these patients had oesophageal involvement, which might have influenced the clinical assessment as oesophageal spasm can mimic cardiac symptoms. There was no apparent association between SSc subsets, duration of the disease and duration of Raynaud's phenomenon, skin sclerosis score, auto-antibody profile and CAD. Patients with oesophageal involvement or pulmonary vascular complications of SSc can experience angina-like pain or breathlessness. This may account for an apparently lower prevalence of CAD associated with these complications. The excess of female SSc cases with CAD reflects the demographics of the SSc population.

Ho et al. [9] have reported a higher prevalence of carotid artery disease and peripheral vascular disease in SSc patients. Stafford et al. [20] identified excess ulnar artery disease in SSc. However, these studies used non-invasive methods of blood flow and wall thickness, including Doppler ultrasound and ankle-brachial blood pressure index rather than the ‘gold standard’ of angiography which images the arterial lumen. Ultrasound is also affected by vessel wall thickness secondary to fibrosis, which is a common finding in SSc. Our study showed that the prevalence of CAD in patients with breathlessness rather than TA was 16%.

Our SSc cohort is unusual in several respects. Chest pain in SSc may be due to several causes, for example oesophageal spasm, oesophageal reflux, chest wall arthritis or pericarditis. Breathlessness in SSc can also be multifactorial due to anaemia, pulmonary fibrosis, pulmonary hypertension and muscular weakness. All of these factors might have influenced the clinical judgement for coronary angiography and probably explain the low prevalence of CAD in this SSc cohort. Our patients were mainly female (76%) and most of them had NAP. However, our results strongly suggest that CAD is no more common in SSc than in patients without SSc. Like D & F, we did not analyse our patients for cardiovascular risk factors and our study group was too small for these to be evaluated. There were too few SSc patients aged <40 yrs to allow reliable analysis of this subgroup.

These results suggest that the prevalence of CAD in SSc is probably similar to that of individuals without SSc. Therefore, SSc patients with suspected CAD should be managed in the same way as patients without SSc. Our findings provide a background for any future prospective study examining risk factors, prevalence and clinical features of CAD in SSc. This could be compared with contemporary data from a non-SSc or general population.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We are extremely grateful to Collette Smith (Department of Epidemiology and Populations Sciences, University College London) for invaluable help with statistical aspects of our work.

C.M.B. has received honoraria or research funds and has acted as an advisor to Actelion, Encysive, Genzyme Inc. C.P.D. has received research grants, honoraria or acted as a consultant to Actelion Pharmaceuticals, Encysive, Genzyme Corp and Aspreva Pharmaceuticals.

The other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Black CM and Stephens SC. (1993) Systemic sclerosis (Scleroderma) & related disorders. In Maddison PJ, Isenberg DA, Woo P (Eds.). Oxford Textbook of Rheumatology(Medical Publications, Oxford) pp. 771–89.
  2. Le Roy EC. (1996) Systemic Sclerosis (Scleroderma). In Bennet JC, Plumm F, Glass DN (Eds.). Cecil's Textbook of Medicine(WB Saunders, Philadelphia) pp. 1483–8.
  3. Silman AJ. (1997) Scleroderma-demographics and survival. J Rheumatol 48:suppl, 58–61.
  4. Coghlan JG and Denton CP. (2004) The heart in scleroderma. The heart in systemic autoimmune diseases(Elsevier, Amsterdam) pp. 189–95.
  5. Coghlan JG and Mukerjee D. (2001) The heart and pulmonary vasculature in scleroderma: clinical features and pathobiology. Current Opinion in Rheumatol 13:495–99.
  6. Follansbee WP, Miller TR, Curtis EL, et al. (1990) A controlled clinical pathological study of myocardial fibrosis in systemic sclerosis (scleroderma). J Rheumatol 17:656–62.[Web of Science][Medline]
  7. Shand LM, Lunt M, Silman AJ, Black CM, Denton CP. (2004) Relationship between change in skin sclerosis and outcome in diffuse cutaneous systemic sclerosis: application of a linear latent trajectory model. Arthritis Rheum 51:S1048 (abstract).
  8. Flavahan NA, Flavahan S, Mitra S, Chotani MA. (2003) The vasculopathy of Raynaud's phenomenon and scleroderma. Rheum Dis Clin North Am 29:275–91.[CrossRef][Web of Science][Medline]
  9. Ho M, Veale D, Eastmond C, Nuki G, Belch J. (2000) Macrovascular disease and systemic sclerosis. Ann Rheum Dis 59:39–43.[Abstract/Free Full Text]
  10. Bulkley BH, Klaosmann PG, Hutchins GM. (1978) Angina pectoris, myocardial infarction and sudden cardiac death with normal coronary arteries: a clinical pathological study of nine patients with progressive systemic sclerosis. Am Heart J 95:563–9.[CrossRef][Web of Science][Medline]
  11. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. (1976) Myocardial lesions of progressive systemic sclerosis; a cause of cardiac dysfunction. Circulation 53:483–90.[Abstract/Free Full Text]
  12. Cheng KS, Tiwari A, Boutin A, et al. (2003) Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology 42:1299–305.[Abstract/Free Full Text]
  13. Chung G and Lahiri A. (2000) Myocardial perfusion imaging in modern cardiology. Br J Cardiol 7:619–23.
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  15. Sulli A, Ghio M, Bezante GP, et al. (2004) Blunted coronary flow reserve in systemic sclerosis: a sign of cardiac involvement in asymptomatic patients. Ann Rheum Dis 63:210–1.[Free Full Text]
  16. Montisci R, Vacca A, Garau P. (2003) Detection of early impairment of coronary flow reserve in patients with systemic sclerosis. Ann Rheum Dis 62:890–3.[Abstract/Free Full Text]
  17. Diamond GA and Forrester JS. (1979) Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Eng J Med 300:1350–8.[Abstract]
  18. Masi AT, Rodnan GP, Medsger TA Jr, et al. (1980) Preliminary criteria for the classification of systemic sclerosis (Scleroderma). Arthritis Rheum 23:581–90.[Web of Science][Medline]
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Submitted 5 September 2005; revised version accepted 15 March 2006.
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