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To determine if systemic lupus erythematosus (SLE) is associated with a higher prevalence of coronary artery disease (CAD) in selected patients undergoing coronary angiography, we compared the extent of angiographic abnormalities, CAD risk factors, and all-cause mortality in SLE patients with non-SLE controls.
We identified SLE patients (N=86) and controls matched by sex and year of cardiac catheterization (N=258) undergoing cardiac catheterization for the evaluation of CAD (median follow up of 4.3 years). Multivariable logistic regression was used to determine if SLE was associated with obstructive CAD defined as ≥ 70% stenosis in a major epicardial coronary artery. Risk adjusted survival differences between the two groups were assessed using Cox proportional hazards modeling.
SLE patients (85% female) were younger than non-SLE patients (median age 49 years vs. 70 years, p<0.001) and were less likely to have diabetes and hyperlipidemia, but had similar rates of hypertension (70% vs.71%, p=0.892). In unadjusted analyses, SLE patients and non-SLE patients had similar rates of obstructive CAD by angiography (52% vs. 62% overall p=0.11). After adjustment for known CAD risk factors, SLE was associated with a significantly increased likelihood of CAD (OR 2.24, 95% CI: 1.08, 4.67). SLE was also associated with a non-significant increase in all-cause mortality (HR 1.683, 95% CI: 0.98, 2.89 p=0.060).
In this selected population, SLE was significantly associated with the presence of CAD as defined by coronary angiography, the gold standard for assessing flow-limiting lesions in this disease. The patients with SLE showed a similar severity of CAD as the controls despite having less than half the rate of diabetes and being 20 years younger.
Coronary artery disease (CAD) is a significant cause of morbidity and mortality for patients with systemic lupus erythematosus (SLE) 1. Epidemiologic data suggest that SLE is an independent risk factor for CAD 2-5 and in a prospective study, after controlling for traditional risk factors, the relative risk for development of myocardial infarction (MI) was shown to be 10.16. Women with SLE between the ages of 35 and 44 years old are particularly more likely to have a MI than controls2. It is believed that these adverse cardiovascular outcomes are a result of accelerated atherosclerosis, leading to the development of occlusive CAD.
To date, however, most of our understanding about atherosclerosis in patients with SLE is derived from autopsy studies or investigations of surrogates of atherosclerosis, such as increased carotid intima and media thickening (IMT), reduced brachial artery flow-mediated dilation (BAFMD), and coronary artery calcification as detected by electron-beam computed tomography (EBCT) 7-10. Recent studies have suggested that these modalities may not be as reliable in patients with SLE as in the general population. In a previous study of SLE patients, the results of BAFMD correlated poorly with those of myocardial perfusion scanning 11; other studies in this patient population have shown that carotid IMT measurements do not correlate with the presence of carotid plaque8.
Little is known about the severity and distribution of coronary atherosclerosis in patients with SLE. The gold standard for measuring flow-limiting CAD is coronary angiography -- an invasive procedure with its own inherent risks. Most descriptions of the coronary angiograms of SLE patients are from case reports. There are a few studies evaluating coronary angiograms in SLE 12, 13, but none to our knowledge have explored in a large cohort the severity of CAD defined by coronary angiography in this population.
Therefore, we took advantage of a large cardiovascular databank at our institution to investigate the severity of CAD by coronary angiography in a selected population of patients with SLE. We investigated the role of SLE in predicting coronary angiographic abnormalities and adverse clinical outcomes after accounting for traditional CAD and SLE-related risk factors.
Patients undergoing cardiac catheterization for the evaluation of CAD between January 1986 and October 2008, with ICD-9 diagnoses of SLE (710.0), SLE and rheumatoid arthritis (710.0 and 714.0) and/or undifferentiated connective tissue disease (710.9), up to five years pre-catheterization or 1-year post catheterization were identified. Inclusion criteria were as follows: a) diagnosis of SLE, confirmed by chart review or through communication with primary physician (detailed below) and b) cardiac catheterization performed to evaluate for suspected CAD, including acute coronary syndrome, angina, or findings of cardiac ischemia by noninvasive stress testing, as well as patients with clinical heart failure or valvular heart disease believed to be related to CAD. This selection included patients in whom the cardiologist at the time of intervention had reasonable clinical suspicion for CAD. Patients with ICD-9 codes for scleroderma (ICD-9 710.1), dermatomyositis (ICD-9 710.3) or polymyositis (ICD-9 710.4), as well has history of congenital heart disease or heart transplant were excluded.
SLE diagnosis was confirmed by chart review and through communication with other physicians involved in the patient’s care using a previously validated physician SLE criteria checklist14 which includes components of the American College of Rheumatology (ACR) classification criteria for SLE. If patients fulfilled ACR criteria for SLE, they were referred to as “definite SLE”. Patients whose medical information was insufficient to fulfill ACR criteria for the diagnosis of SLE were categorized as “clinical SLE” if they had a history of immunomodulatory or immunosuppressive medication use (prednisone, hydroxychloroquine, azathioprine, mycophenolate mofetil, methotrexate, or cyclophosphamide) for treatment of active SLE (confirmed by a physician caring for the patient). For the purposes of this study, both groups were analyzed as one group.
Controls were randomly selected and matched by sex and year of catheterization. According to our study design, three controls were matched to every one SLE patient. Similar to the SLE patients, controls were individuals who had undergone cardiac catheterization for the evaluation of CAD. Possible controls were excluded if they had any of the following ICD-9 codes: 710.x (diffuse diseases of the connective tissues), 714.x (rheumatoid arthritis and other polyarthropathies), 720.x (ankylosing spondylitis and other spondyloarthropathies), 725 (polymyalgia rheumatica), 446.x (polyarteritis nodosa and allied conditions), 447.x (arteritis, unspecified), and 696.x (psoriasis). Patients with congenital heart disease and history of cardiac transplant were also excluded from the control group.
All subjects were identified from the Duke Cardiovascular Disease Database (DDCD) -- a prospective clinical data set containing detailed clinical, angiographic, and therapeutic data on over 180,000 patients that have undergone cardiac catheterization at Duke University Medical Center. Established in 1969, the DDCD is one of the oldest, largest, continuously maintained observational databases in the world. Patients in the DDCD represent a broad population of individuals with coronary artery disease and varied clinical presentation.
The results of the coronary angiograms are collected to generate a clinical report and are entered into the database by the cardiology fellow in a standardized way shortly after the procedure. This data is reviewed by the attending cardiologist and included in the medical chart as well as distributed to referring physicians. Other data collected in a standardized way on these patients at the time of cardiac catheterization consist of baseline characteristics (age, sex, race, and body mass index), and information about traditional CAD risk factors, including hypertension, diabetes, smoking, hyperlipidemia, and family history, as well as history of peripheral arterial disease, cerebrovascular disease and other comorbidities as specified in the Charlson index 15. Determination of hyperlipidemia as a risk factor is based on a previous diagnosis or a history of statin use; serum cholesterol levels, however, are not routinely collected for the database.
Outcome data are collected for all patients with obstructive CAD by angiogram. These patients are routinely followed at 6 months, one year, and annually thereafter using mailed questionnaires and telephone interviews. Patient medications and vital status, including death, cardiovascular events, hospitalizations and revascularizations are determined during follow-up. A search of the National Death Index, and Social Security Death Index databases, is performed for patients whose vital status or cause of death is unknown. Clinical events are verified using source documentation. Further details regarding the organization of the Duke computerized cardiovascular database and follow-up methods have been previously described16, 17.
For those patients without obstructive coronary atherosclerosis by angiogram, (i.e. atherosclerotic lesion <70%) detailed baseline information is collected in the same manner and included in the database. However, outcome data are not routinely collected and therefore vital status was ascertained from medical chart review and a search of the National Death Index and Social Security Death Index databases.
The Duke University Institutional Review Board (IRB) approved the study. Since it was a retrospective review, the IRB granted a waiver for patient consent.
Baseline characteristics were compared using the Wilcoxon rank-sum test for continuous variables and the Pearson Χ2 test for categorical variables. A multivariable logistic regression model was developed to evaluate variables that were associated with CAD, defined as obstructive stenosis (> 70%) in at least one major coronary artery. Variables examined for possible inclusion in the model were selected by one of three criteria: statistical strength of association with the outcome (unadjusted association p<0.1), known risk factors associated with CAD, and clinical judgment of the investigators regarding other factors that may contribute to accelerated atherosclerosis, such as prednisone or other immunosuppressive use. The final model was developed using forward stepwise selection. Additionally, we examined the following interactions: SLE and age, SLE and diabetes, diabetes and hyperlipidemia, diabetes and race, diabetes and hypertension, diabetes and smoking, and diabetes and prior MI. Interactions were tested in the multivariable setting while including all significant main effects.
Unadjusted survival results were examined using Kaplan-Meier methods, and comparisons between groups were made using the log-rank test. Variables were examined using Cox proportional hazards regression modeling in both the unadjusted and adjusted setting. Candidate variables were selected using the same criteria as described above, and variables were entered into the model in a stepwise approach. Continuous and ordinal categorical variables were tested for linearity over the log hazard or logit (depending on the model type) and were transformed as necessary to meet this modeling assumption. All tests were two-sided and were carried out using SAS 8.2 (SAS Institute, Cary NC, USA). Results were declared significant at a p-value of <0.05.
Eighty-six patients were confirmed to have SLE (73 with “definite SLE” and 13 with “clinical SLE”) (Figure 1). Two hundred and fifty-eight controls were identified that were matched for gender and year of catheterization. Median follow-up duration for all subjects in this study was 4.3 years (IQR 1.9-8.0). The majority of subjects were women, with significantly more African Americans in the SLE group compared with the non-SLE controls. Both groups had similar rates of cardiovascular risk factors, except for diabetes and hyperlipidemia, which occurred less commonly in patients with SLE. There were also significantly more patients with SLE on dialysis (Table 1).
Seventy-three of the 86 patients fulfilled ACR criteria for the diagnosis of SLE (Table 2). The SLE patients had a mean of 5 (+/- 1) of the 11 ACR criteria for SLE. Although we were unable to assess SLE severity or calculate disease activity scores (i.e. SLICC score) at the time of catheterization, medication use prior to catheterization was collected by chart review. Among patients with SLE, medication use was as follows: prednisone, 64/73 (88%) patients; hydroxychloroquine, 33/73 (45%) patients; cyclophosphamide, 18/73 (25%) patients; azathioprine, 7/73 (10%) patients; methotrexate, 7/73 (10%) patients; and mycophenolate mofetil, 4/73 (5%) patients. Twenty-five percent of the SLE patients had history of kidney disease as defined by ACR classification criteria for SLE, and 10% were receiving hemodialysis. Twenty-six of the SLE patients tested positive for serum antiphospholipid antibodies. Nine of these patients were confirmed by chart review to have a diagnosis of antiphospholipid syndrome. Of the 13 patients categorized as “clinical SLE”, 6 had history of nephritis; the others were confirmed by their referring physician to have SLE or were taking immunosuppressive therapy for non-renal indications related to their SLE.
Overall, at the time of cardiac catheterization, the patients with SLE were significantly younger compared to controls (median age 49 years vs. 70 years, p<0.001). This difference held true when examining the age distribution of only the patients with significant CAD (Table 3). The mean age for the subgroup of SLE patients with CAD was 50 years old (41,59) as compared with 73 years old (66,79) for the subgroup of controls with CAD. Age was a risk factor for CAD in both the SLE and control groups.
The primary indication for catheterization was specified as evaluation for possible CAD in 88% of the patients with SLE and 92% of the non-SLE controls. For the remaining few subjects, the primary indication was listed as shortness of breath, congestive heart failure, or valvular disease, while their secondary indication was given as evaluation for possible CAD. Approximately one-third of both the SLE patients and controls had a history of congestive heart failure or MI. One of the patients with SLE and 4 of the controls had a previous history of percutaneous coronary artery intervention, and 2 patients with SLE and 18 controls had a history of coronary bypass grafting (CABG). At the time of catheterization, equivalent numbers in the SLE group and the control group were taking cardiovascular medications, including aspirin, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors or an angiotensin II receptor blockers (ARBs).
Forty-five (52%) of the SLE patients and 160 (62%) of the controls had obstructive CAD on angiogram (p-value 0.11). The distribution of diseased vessels was similar between the two groups. The most common site of coronary stenosis for both patients with SLE and controls was the left anterior descending artery; and the least common site was the left main artery. There were a higher proportion of patients with SLE without significant CAD than controls; however, a higher proportion of controls had three diseased vessels than SLE patients, although these differences were not statistically significant (Table 4).
Unadjusted relationships between baseline variables and obstructive CAD are provided (Table 1). Without covariate adjustment in the logistic regression model, SLE was not associated with increased risk. However, after adjustment for traditional risk factors, SLE was significantly associated with presence of CAD on coronary angiogram (Table 5). In the multivariable logistic regression model, other risk factors that were associated with presence of CAD included history of previous MI, age, hyperlipidemia, and male sex. This association with CAD was observed in both the full model with all candidate variables as well as the reduced model of significant covariates (p=.03 in both settings). The only significant interaction was between diabetes and SLE (p=0.04), such that diabetes was associated with the presence of CAD in the controls (OR 1.97 IQR 1.04-13.71), but not in patients with SLE (OR 0.40 IQR 0.10-1.59).
There were a total of 137 deaths over the entire follow-up period. Unadjusted survival was not significantly different in the two groups with a 1-year survival rate in the SLE group of 83% compared with 92% in the control group; and 5-year survival rates were 72% in the SLE group compared with 69% in the control group (Figure 2a). After adjusting for age, ejection fraction, diabetes, hyperlipidemia, glomerular filtration rate (GFR), non-cardiac Charlson comorbidity index, and extent of coronary artery disease, SLE was not found to be significantly associated with all-cause mortality (HR 1.68, 95% CI: 0.98, 2.89, p=0.060) (Figure 2b). However, when the adjusted survival rate was examined at 1-year, it was significantly lower in the SLE group than the control group (p=0.0004). When adding medications to the adjustment, prednisone use prior to catheterization was significantly associated with increased all-cause mortality (HR 2.08, 95% CI: 1.26, 3.45 p=0.005), while azathioprine use appeared to be protective (HR 0.17, 95% CI: 0.04, 0.73 p=0.017). Following cardiac catheterization, the two groups with obstructive CAD did not differ in the use of either medical management or interventional therapy such as percutaneous angioplasty or CABG (overall p= 0.327)
In SLE, occlusive CAD is presumed to be a major cause of increased cardiovascular morbidity and mortality. To date, however, the evidence for this association has been confined to epidemiological observations and surrogate measures of CAD. In this study, SLE was shown in a select group of patients from a cardiovascular disease database to be associated with the presence of CAD based on findings from coronary angiography, the gold standard for assessing flow-limiting lesions.
The results herein also suggest a relationship between SLE and early development of CAD. However, this association does not necessarily prove causality. It has been hypothesized that the systemic inflammation occurring in SLE triggers atherosclerosis in the coronary vessels 18. Alternatively, the cause may not be SLE itself, but the use of corticosteroids and other immunosuppressive agents that influence CAD risk factors such as diabetes or hypertension 19. The extent to which either traditional cardiovascular risk factors, (e.g. diabetes mellitus, smoking, hyperlipidemia, family history, and hypertension) or disease-related risk factors (medication use, systemic inflammation) contribute to the development of CAD in patients with SLE remains unclear. Consistent with previous studies 8, we found in our cohort herein that age and hyperlipidemia were associated with increasing risk of CAD. Results from the Systemic Lupus International Collaborating Clinics (SLICC) registry for atherosclerosis have shown a high prevalence of several risk factors for CAD in patients with SLE at the time of initial diagnosis 20. In our study, the rates of traditional risk factors were equivalent in the patients with SLE and controls at the time of catheterization, except for the rates of hypercholesterolemia and diabetes mellitus (DM), which were less in the SLE group. Previous studies, albeit limited, suggest DM and SLE do not commonly occur in the same individual 20, 21. In our study, DM was diagnosed in only 14% of the selected patients with SLE.
Despite being 20 years younger in age and having about half the rate of diabetes compared with the control group, the selected patients with SLE in our study were similar in their severity of CAD and showed comparable mortality rates. As expected, an increased risk of CAD was found to be associated with age. The interaction of age with SLE was not significant, suggesting that the effect of age was the same for patients with SLE as controls. Our matching strategy had two advantages. First, we were able to study the extent of CAD in a selected group of patients with SLE that could be compared with that of a control group with typical CAD. This approach avoided the possibility of comparing our SLE group with a younger, atypical control group that had unusual susceptibility to CAD. Secondly, it also enabled us to confirm that patients with SLE do in fact develop CAD at a much younger age than is usually the case. Our findings therefore support the hypothesis that patients with SLE prematurely develop coronary atherosclerosis 8.
SLE was not significantly associated with increased risk of all-cause mortality, although a trend towards this result was detected in our selected group. Since the Cox model proportional hazards assumption was violated for SLE, the power to detect a significant difference in all-cause mortality may be diminished in this case; however, the adjusted survival curves were generated using a stratified model. One -year survival after cardiac catheterization was significantly lower in the SLE group. This finding could be explained by more severe illness in the SLE patients than the controls at the time of catheterization. However, if the patients with SLE survived past this point, they had lower mortality rates than the controls owing to their younger age. The older control group may have had a higher, competing non-CAD mortality risk than the SLE group, resulting in a higher mortality rate than would be expected in a comparable group of patients that was similar in age to the SLE patients.
In our study, the management of cardiovascular disease after cardiac catheterization appeared to be comparable in the SLE and control groups, including use of aspirin, statins, and beta-blockers. Another study also found cardiovascular medication use to be similar in SLE patients and controls following cardiac catheterization and percutaneous coronary intervention20. The SLE patients in this study were more likely during follow-up to develop a MI and undergo repeat percutaneous intervention when compared with controls.
The study herein relied on a select group of SLE patients that underwent cardiac catheterization for suspicion of CAD at a single academic center. The results from this study are not meant to be a generalization of all patients with SLE or imply a prevalence of CAD across the entire spectrum of disease. Our study was also not designed to capture asymptomatic patients with SLE, although there is evidence that these patients may also have cardiac abnormalities 12. This filtering strategy was chosen to enrich the SLE population for CAD. It is therefore notable that almost 50% of the patients with SLE who were being evaluated for CAD had no significant CAD (Table 4), suggesting other causes for cardiac and cardiac-like symptoms are frequent in this disease group (i.e. vasospasm, microvascular disease, etc); however, 40% of the control group also had no significantly diseased vessels and the difference in the proportion of patients with no diseased vessels between the groups was not statistically significant.
Our study does have limitations. Since patients with SLE have a chronic disease and are more closely monitored by physicians than most other patients, our results are subject to surveillance bias leading to earlier referral for cardiac catheterization than the controls. This possibility along with their younger age may allow less time for patients with SLE to develop more advanced CAD, and may explain why SLE patients have less multi-vessel CAD than controls. We emphasize again the selection bias in our study, given that only SLE patients who were referred for cardiac catheterization due to suspicion of CAD were used in this analysis. Additionally, since outcomes in our database are only obtained systematically for patients with obstructive coronary artery disease, there may be some shortcomings in the documentation of survival among those patients in the database with non-obstructive disease. We attempted to overcome this limitation by ascertaining vital statistics from the National Death Index and Social Security Death Index databases. We were unable to determine if non-traditional risk factors such as hemodialysis were potential confounders that may have been associated with increased risk of obstructive CAD. It is unclear, therefore, if renal failure contributes to the development of CAD in the patients with SLE. However, we did select a large control group from the same cohort of patients, using the same filtering strategy to minimize confounders. Although some data were obtained regarding the use of immunosuppressive therapies, we were unable to analyze this issue further by examining the possible effects of dose or duration of use. Similarly, we did not take into account the presence of antiphospholipid antibodies and their possible contribution to the development of atherosclerotic plaques, as these results were not available for all patients. Finally, the definition of hypercholesterolemia is based on history of this diagnosis or statin use. Since cholesterol values were not routinely obtained for these patients, we could not calculate a Framingham risk score.
In this study, we demonstrate that SLE is associated with the presence of CAD on coronary angiogram, the gold standard for measuring obstructive atherosclerosis, in a select group of patients referred for cardiac catheterization. We also show that coronary atherosclerosis develops prematurely in SLE as demonstrated by the significantly younger age of SLE patients with angiographically-defined CAD when compared with controls. Further studies will be required to explore the contribution of genetic risk factors to the premature development of CAD in SLE, as well as improve our understanding about the outcomes in this population of predominately young women with a chronic inflammatory disease.
Supported by the NIH (National Institute of Allergy and Infectious Diseases) grant T32- AI007217 and the Department of Medicine at Duke University Medical Center.