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Prevalence of coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis
  1. Gene-Siew Ngian1,
  2. Joanne Sahhar2,
  3. Susanna M Proudman3,
  4. Wendy Stevens4,
  5. Ian P Wicks1,
  6. Sharon Van Doornum1
  1. 1Department of Medicine (RMH/WH), The University of Melbourne, Victoria, Australia
  2. 2Rheumatology Unit, Monash Medical Centre, Melbourne, Australia
  3. 3The University of Adelaide and Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia
  4. 4Rheumatology Unit, St Vincent's Hospital, Melbourne, Australia
  1. Correspondence to Gene-Siew Ngian, Department of Medicine (RMH/WH)The University of Melbourne, Grattan StParkville 3050, Victoria, Australia; gngian{at}student.unimelb.edu.au

Abstract

Objectives To determine the prevalence of coronary heart disease (CHD) and cardiovascular risk factors in a well-characterised cohort of systemic sclerosis (SSc) patients, and to compare this with the general population.

Methods A cross-sectional study of the prevalence of CHD and cardiovascular risk factors in participants in the Australian Scleroderma Cohort Study was performed. Controls were drawn from the 2007–8 National Health Survey (NHS) and the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). OR and 95% CI were calculated to determine the prevalence of CHD and cardiovascular risk factors in SSc patients compared with controls.

Results Data were available for 850 SSc patients (86% female), 15 787 NHS participants (53% female) and 8802 AusDiab participants (56% female). Adjusted for age and gender, the OR of CHD in SSc patients was 1.9 (95% CI 1.4 to 2.4) compared with controls from AusDiab and 2.0 (95% CI 1.5 to 2.5) compared with controls from the NHS. The OR of CHD increased to 3.2 (95% CI 2.3 to 4.5) for SSc patients compared with controls from AusDiab after further adjustment for cardiovascular risk factors. Hypercholesterolaemia, diabetes mellitus and obesity were significantly less prevalent in the SSc cohort than in AusDiab. Within the SSc cohort, the presence of pulmonary arterial hypertension was associated with CHD.

Conclusions This is the first report of an increased prevalence of CHD in SSc patients. Further studies are required to determine the relative contribution of scleroderma-specific factors such as microvascular disease to the development of CHD.

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It is well established that autoimmune rheumatic diseases such as rheumatoid arthritis (RA)1 ,2 and systemic lupus erythematosus3 are associated with increased rates of cardiovascular disease; however, it is unclear whether this is true for systemic sclerosis (SSc).4 Although there are reports on the prevalence of angiographic5 and CT6 coronary artery abnormalities in SSc, there are no large cohort studies on the prevalence of coronary heart disease (CHD). Furthermore, little is known about the prevalence of cardiovascular risk factors in SSc.

The aim of this study was to determine the prevalence of CHD and cardiovascular risk factors in a cohort of SSc patients and compare these results with two separate, population-based control groups.

Patients and methods

SSc cohort

The Australian Scleroderma Cohort Study (ASCS) is a longitudinal cohort study of predictive factors for the development of cardiopulmonary complications and outcomes of therapy in SSc. Patients over 18 years of age with a clinical diagnosis of SSc according to the American College of Rheumatology criteria7 or the LeRoy and Medsger criteria8 are recruited from community and hospital rheumatology practices throughout Australia. They are classified using the LeRoy criteria for limited or diffuse SSc9 and followed prospectively with annual physician review, echocardiography and respiratory function tests to screen for pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). PAH is diagnosed based upon right heart catheterisation findings of a mean pulmonary artery pressure of greater than 25 mm Hg at rest or greater than 30 mm Hg on exercise, in the presence of a pulmonary capillary wedge pressure of less than 18 mm Hg. ILD is defined as the presence of interstitial abnormalities on high-resolution CT or lung biopsy, and scleroderma renal crisis is defined as the presence of at least two of: new-onset hypertension, microangiopathic anaemia or rising creatinine. Patients are defined as having CHD if they report a history of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), angina or myocardial infarction (MI). Cardiovascular risk factors are defined as in table 1, which is presented to facilitate the comparison of definitions used in the three cohorts.

Table 1

Definitions of CHD and cardiovascular risk factors in the ASCS, NHS and AusDiab

Patients with mixed connective tissue disease or other overlap syndromes were excluded from the current study. To obtain a cross-sectional view of the cohort, we extracted data from each patient's last review before June 2010.

Controls

We compared our SSc cohort with two contemporary, community-based control groups drawn from similar geographical areas. In Australia, all residents have access to medical care through the publicly funded Medicare system. The first control group was derived from the 2007–8 National Health Survey (NHS).10 This survey was conducted between July 2007 and June 2008 by trained interviewers from the Australian Bureau of Statistics in 15 787 randomly selected Australian dwellings. Participants were defined as having CHD if they reported ever being told by a doctor or nurse that they had angina or MI. Cardiovascular risk factors were defined as in table 1. Body mass index (BMI) was measured in a subset of 10 990 participants. If BMI was 40 or greater, it was recorded as 40 in the dataset.

Our second control group was drawn from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), which is a longitudinal, population-based cohort study of the epidemiology and natural history of diabetes mellitus, cardiovascular disease and renal disease in Australia.11 Trained interviewers administered a standardised questionnaire to 8802 AusDiab participants between 2004 and 2005. Participants were defined as having CHD if they reported ever being told by a doctor or nurse that they had angina or MI, PCI or CABG. Blood pressure, fasting glucose and lipids were measured in a subset of 6400 patients, with cardiovascular risk factors defined as outlined in table 1.

Approval for this project was obtained from the ethics committees covering each of the ASCS, NHS and AusDiab projects.

Verification of self-reported CHD

To determine the accuracy of self-reported CHD in the SSc cohort, medical record adjudication was performed in a subset of 90 (10.6%) patients. If there was documentation of angina, MI, PCI, CABG or CHD, as diagnosed by a cardiologist, patients were considered to have a confirmed diagnosis of CHD. We confirmed CHD in all six patients who reported CHD; however, we detected one patient who had experienced an ischaemic event but not reported CHD. We therefore calculated a positive predictive value (PPV) of 100% and a negative predictive value of 98.8% for self-report of CHD in this subset. The AusDiab investigators also adjudicated the medical records of a subset of patients and found a PPV of 78.6% for MI, 78.1% for PCI and 100% for CABG.12 Although participants tended to overestimate the incidence of single events, a composite of the various measures was a reliable estimate of the presence of CHD in individual patients.13 Data regarding the accuracy of self-reported CHD in the NHS are not available.

Statistical methods

Descriptive data are presented using mean and SD or percentage, as appropriate. The OR and 95% CI of CHD in SSc patients compared with controls from AusDiab was calculated using multivariate logistic regression to adjust for age, sex and cardiovascular risk factors. We also calculated the OR of cardiovascular risk factors in SSc patients compared with AusDiab controls using multivariate logistic regression to adjust for age and sex. The OR of CHD in SSc patients compared with NHS controls was calculated using adjusted logistic regression. As it was not possible to combine the NHS dataset with other data, we were unable to adjust further for cardiovascular risk factors. Within the SSc cohort, χ2 and two-sample t tests were used to compare characteristics of patients with and without CHD, and logistic regression models were used to determine independent predictors of CHD. p Values less than 0.05 were considered statistically significant. All analyses were performed using Stata, version 10.0 statistical software.

Results

Patient demographics

The demographic details of the 850 SSc patients and the two control cohorts (15 787 NHS participants and 8802 AusDiab participants) are summarised in table 2. The SSc cohort was older than the control groups (the mean±SD age of SSc patients was 59±12 years vs 48±18 and 56±14 years in the NHS and AusDiab, respectively) and comprised a higher percentage of women (86% in the SSc cohort vs 53% and 55% in the NHS and AusDiab, respectively). The SSc patients had longstanding disease (mean±SD disease duration 13±10 years) and were classified as limited SSc in 68% of cases and diffuse SSc in 30% of cases. A clinical diagnosis of PAH was present in 16%, and ILD in 25%, of SSc patients.

Table 2

Patient demographics and clinical characteristics

Cardiovascular risk factors

The unadjusted prevalence of cardiovascular risk factors in each cohort is shown in table 2. Given the significant differences in age and gender between the SSc and control cohorts, limited conclusions can be drawn from these unadjusted comparisons. However, the AusDiab data were provided in a format that allowed for an adjusted comparison. Hypercholesterolaemia (OR 0.2; 95% CI 0.2 to 0.3), diabetes mellitus (OR 0.5; 95% CI 0.3 to 0.7) and obesity (OR 0.6; 95% CI 0.5 to 0.8) were less prevalent in the SSc cohort than in AusDiab after adjustment for age and gender, while smoking was more prevalent (OR 1.5; 95% CI 1.2 to 1.9). There was no significant difference in the prevalence of hypertension between the two groups (OR 1.1; 95% CI 0.9 to 1.3).

Prevalence of CHD

The unadjusted prevalence of CHD in the SSc, NHS and AusDiab cohorts was 10.4%, 4.9% and 7.3%, respectively. The age and gender-adjusted OR of CHD in SSc patients compared with AusDiab controls was 1.9 (95% CI 1.4 to 2.4). Further adjustment for hypertension, hypercholesterolaemia, diabetes mellitus, smoking and BMI resulted in an increase in the OR to 3.2 (95% CI 2.3 to 4.5). The age and gender-adjusted OR of CHD in SSc patients compared with controls from the NHS was 2.0 (95% CI 1.5 to 2.5). Because of the format in which data from the NHS were available, we were unable to adjust further for cardiovascular risk factors.

Predictors of CHD in SSc patients

On univariate analysis, factors significantly associated with CHD in the SSc cohort were male gender, older age, hypertension, hypercholesterolaemia, diabetes mellitus, duration of SSc and the presence of PAH (table 3). On multivariate analysis, male gender, older age, hypercholesterolaemia and PAH remained significant predictors of CHD (table 3).

Table 3

Predictors of CHD within the SSc cohort on univariate and multivariate analysis

Discussion

In this cross-sectional study of 850 SSc patients and two community-based control groups, we found a significantly increased prevalence of CHD in the SSc patients. When compared with the AusDiab cohort, SSc patients had over three times the prevalence of CHD (fully adjusted OR 3.2). To our knowledge, this is the largest cohort study of CHD in SSc and the first report of an increased prevalence of clinical CHD. Most studies to date have examined coronary artery abnormalities in SSc patients undergoing clinically indicated coronary angiography or interrogated surrogate markers of CHD. A systematic review of studies of angiography, autopsy and surrogate markers of atherosclerosis in SSc concluded that SSc patients have an increased risk of atherosclerosis compared with healthy individuals.14 Of the three studies in this review that examined the coronary arteries, a retrospective chart review15 revealed no difference in the prevalence of CHD, while an autopsy study16 and cardiac CT study17 found an increased prevalence of CHD in SSc patients compared with controls. More recently, Mok et al6 reported that the prevalence of coronary atherosclerosis as assessed by coronary artery calcium score was higher in 53 SSc patients than in 106 age and gender-matched controls.

Our findings can be compared with studies in other inflammatory rheumatological conditions, of which RA is the most studied. The risk of incident cardiovascular disease in RA is reported to be in the order of 1.5–2.0 times that of the general population.2 ,18 Furthermore, Lindhardsen et al19 have demonstrated that RA patients have an incidence rate ratio of MI (1.7; 95% CI 1.5 to 1.9) equivalent to that of patients with diabetes (1.7; 95% CI 1.6 to 1.8). As a result of these and other data, cardiovascular screening has become widely accepted as an important aspect of the care of RA patients.20

An adjusted comparison of the prevalence of traditional cardiovascular risk factors between SSc patients and the AusDiab cohort was also performed. We found that smoking was more prevalent, whereas hypercholesterolaemia, diabetes mellitus and obesity were less prevalent in the SSc cohort than in AusDiab. The higher prevalence of diabetes mellitus and hypercholesterolaemia in AusDiab may reflect increased ascertainment in this cohort, in which subjects underwent an oral glucose tolerance test in addition to measurement of fasting plasma glucose and lipid levels. However, the observation that the prevalence of these three metabolic conditions is reduced in SSc is intriguing and could point to a disease-related effect, perhaps mediated by (subclinical) malabsorption, present in up to one-third of SSc patients.21 Previous studies have demonstrated lower levels of high-density6 ,22 and low-density lipoprotein6 cholesterol in SSc patients compared with controls, although this finding has not been consistently reproduced.23 ,24

Within the SSc cohort, the traditional cardiovascular risk factors of age, male gender and hypercholesterolaemia were independently associated with CHD. The other independently associated factor was the presence of PAH. Some authors have attributed cardiac ischaemia and myocardial dysfunction in SSc to microvascular disease.25 The relationship between CHD and PAH is therefore interesting, given the possible contribution of microvascular involvement to both. Alternatively, it may be that patients with PAH are more heavily monitored and investigated, and co-existing CHD are therefore more likely to be detected. Our finding of positive antiphospholipid antibodies in 26% of the SSc cohort is similar to what has been reported in other cohorts.26 ,27 The clinical importance of these antibodies is uncertain; however, the vast majority of our patients did not have antiphospholipid syndrome as currently defined, and antiphospholipid antibodies were not significantly associated with CHD on univariate analysis.

The strengths of our study include the large size and national basis of the SSc cohort, along with the comprehensive nature of our physician-collected prospective clinical data. Comparison of these data with two separate, population-based control groups with similar methods of ascertainment of CHD and cardiovascular risk factors further strengthens our conclusions.

Our study has a number of potential limitations. Relying upon patient self-report of CHD may allow under or over-reporting; however, the same method was used in all three groups, reducing the chance of bias in between-group comparisons. Verification of self-reported CHD in subsamples of the SSc and AusDiab cohorts revealed similar PPV for CHD. The NHS defined CHD using angina and MI, whereas the ASCS and AusDiab definition also included PCI and CABG (table 1). Although the lower prevalence of CHD in the NHS may reflect this difference in ascertainment, the NHS cohort was also substantially younger than the other two cohorts. Given these potential limitations, our finding of similar age and gender-adjusted OR for CHD in the SSc cohort when compared with both the NHS and AusDiab (OR 1.9 and 2.0, respectively) suggests that our findings are robust. While both control groups were population based, the SSc cohort consisted of patients referred to the ASCS, potentially selecting for patients with greater disease severity. The distribution of limited and diffuse patients, however, reflects that reported in other predominantly Caucasian SSc cohorts,28 suggesting that the ASCS cohort is not biased towards patients with the diffuse subtype, who generally have more severe disease. The prevalence of SSc-related complications such as PAH within our cohort also reflects that reported in other community-based cohorts.29 Finally, the aetiology of CHD in these patients, whether atherosclerotic, thrombotic or microvascular, was not addressed by this study.

In conclusion, in this large cohort study of SSc patients we demonstrated a greater than threefold increased prevalence of CHD compared with the general population. This increase is unlikely to be explained by traditional cardiovascular risk factors, most of which seem less prevalent in this group. Further studies, including prospective studies of CHD incidence in SSc, are required to confirm this observation and to investigate the relative contribution of SSc-specific factors such as microvascular disease, systemic inflammation and tissue remodelling. In the meantime, a systematic approach to cardiovascular risk assessment and aggressive treatment of identified risk factors, as is advocated in RA, should also be considered for SSc patients.

Acknowledgments

Members of the Australian Scleroderma Interest Group contributed patient data: Jill Byron, Catherine Hill, Janet Roddy, Peter Youssef, Kathleen Tymms, Leslie Schrieber, Jane Zochling, Peter Nash, Allan Sturgess, Gabor Major. Baker IDI Heart and Diabetes Institute and the Australian Bureau of Statistics contributed control data. The authors also thank Alexandra Gorelik for statistical advice.

References

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Footnotes

  • Funding This study was supported by Scleroderma Australia. The Australian Scleroderma Cohort Study is funded by unrestricted educational grants from Actelion, Bayer, CSL, GSK and Pfizer. IPW is supported by an NHMRC clinical practitioner fellowship 1023407.

  • Ethics approval Approval for this project was obtained from the ethics committees covering each of the ASCS, NHS and AusDiab projects.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.