Prevalence and associated factors of resting electrocardiogram abnormalities among systemic lupus erythematosus patients without cardiovascular disease

A standard digitally recorded 12-lead resting supine ECG was performed on consecutive adult SLE patients ≥18 years, with 4 or more of the American College of Rheumatology (ACR) criteria or 3 ACR criteria plus a typical histological lesion of SLE on renal or skin biopsy [9] attending the University of Toronto SLE Clinic from October 2011 to November 2015. All patients were evaluated according to the standard clinic protocol which includes demographics, assessment of disease activity (SLE Disease Activity Index 2000 (SLEDAI-2 K)) [10] and damage (SLICC/American College of Rheumatology Damage Index (SDI)) [11], current and past glucocorticoid, antimalarial, antihypertensive, and immunosuppressant medication use, and laboratory tests at each visit. Patients were followed prospectively every 2 to 6 months. The following data were collected on all patients as part of the regular databank protocol and were made available for this study. Patients were considered to have a positive smoking status if they were documented as a current smoker at any point in the 5 years preceding the date of ECG. History of cardiovascular events (MI, angina, angioplasty, congestive heart failure and pacemaker), diabetes mellitus (DM) 3 years before ECG, hyperlipidemia on statins ever prior to ECG, and hypertension within 5 years from ECG (>140 mmHg systolic or >90 diastolic mmHg, or using medication for hypertension) were extracted. Patients were considered positive for antiphospholipid antibodies (aPLA) if they had ever been positive for aPLA, including total anticardiolipin antibodies and individual anticardiolipin antibodies (aCL IgG/aCL IgM) (Phadia Varelisa kits, Somagen for anticardiolipin antibodies screen and IgG and IgM assays) measured yearly by enzyme-linked immunosorbent assay (ELISA) [12]. The clotting assays for SLE anticoagulant included the dilute Russell viper venom time and the platelet neutralization procedure. SLE anticoagulant (LA) was considered present if patients tested positive on two or more occasions since joining the SLE cohort. Other laboratory variables were evaluated: ANA, anti-ds DNA, anti-Ro, anti-La, anti-Smith, anti-RNP, anti-Jo1 antibodies, ANCA, and Coombs tests (ever-positive 5 years prior to ECG).

The ECGs had all identifying data removed and so were read “blind”. The coded 12-lead ECGs were evaluated and interpreted by one senior cardiologist (PH) using the Minnesota code classification system, which is a widely used method of categorizing ECG abnormalities [13].

All patients provided informed consent for the collection, storage, and use of clinical and laboratory data following procedures in accordance with the Declaration of Helsinki and approved by the University Health Network Research Ethics Board, Toronto, Ontario, Canada.

Consecutive SLE patients seen at the SLE clinic from October 2011 to November 2015 were recruited to this study. Patients were excluded if they had had a CVD event (MI, angina, congestive heart failure (CHF), angioplasty and pacemaker) prior to ECG.

SLE patients were grouped into those with normal ECG and those with ECG-CVD. ECG-CVD patients were further grouped into two: ECG-4 (with one or more of the following abnormalities—LBBB/RBBB, LAD/left anterior fascicular block (LAFB), LVH, and ST-segment and/or T-wave abnormalities); and ECG-5 (any of the above or pathological Q wave) (Fig. 1). Our study focuses on patients with ECG-4 and ECG-5 compared to patients with a normal ECG. Descriptive analyses of patient demographics, disease activity, damage, and antibody abnormalities were studied in the following groups: patients with normal ECG, patients with ECG-4, and patients with ECG-5. The clinical/laboratory data available at the time of ECG were used to study the association with ECG-CVD. The adjusted mean SLEDAI-2 K (AMS) was calculated using SLEDAI-2 K 2 years prior to the ECG visit [14].

A counting process data structure was created for the outcome of both ECG-4 and ECG-5. Patient sex, ethnicity, time from first visit to the clinic to the time of ECG, hypertension, hyperlipidemia on statin therapy, laboratory test (antibodies), smoking ever before ECG, disease activity, and diabetes 3 years before ECG test were extracted as time-fixed variables. Other variables such as organ damage and treatment were extracted as time-variant variables.

Among the 558 adult SLE patients who had an ECG, 44% were inception (patients who joined the SLE clinic within 1 year from the diagnosis of SLE). Seventy-one patients were excluded as they had CAD before the ECG test. A total of 487 ECGs were evaluated of which 314 patients (64.4%) had a normal ECG. The prevalence of ECG-4 was 21.4% (104/487 patients) and the prevalence of ECG-5 was 24.2% (118/487 patients). The most common element of ECG-4 was ST-segment abnormalities and/or T-wave abnormalities (73/104; 70%), followed by LVH in 32%, LAD or LAFB in 20%, and LBBB or RBBB in 11%. In ECG-5, Q-wave was found in 18% (21/118) of the patients. The ECG-CVD elements were found as one ECG-CVD element in 67% (70/104) in the ECG-4, two ECG-CVD elements in 25% (26/104), and 7% (7/104) had three ECG-CVD elements. ECG-CVD was seen more often with longer disease duration (Fig. 2). Other ECG abnormalities documented in 55 patients were: right axis deviation in 9 patients, incomplete RBBB in 3 patients, atrial enlargement in 7 patients, and arrhythmia in 36 patients (sinus tachycardia in 9 patients, sinus bradycardia in 11, short PR in 8, first A-V block in 3, ectopic atrial rhythm in 3, premature atrial contraction in 3, and ventricular bigeminy in 1 (few patients had overlaping types of arrhythmia).

The baseline (at first visit to the clinic) characteristics of the patients were similar in SLE patients with a normal ECG and those with ECG-CVD (Table 1). A higher prevalence of ECG-4 and ECG-5 was identified among older SLE patients. Patients with longer SLE disease duration had more prevalence of ECG-4 and ECG-5 compared to patients with a normal ECG (19.48 ± 11.03 vs. 15.23 ± 10.16, p < 0.001). Patient with longer lupus follow-up duration (13.69 ± 11.29 years) at the time of ECG had a higher prevalence of ECG-4 (p = 0.006) versus a normal ECG with a follow-up duration at the time of the ECG of 10.57 ± 9.40 years. Also, patients with longer lupus follow-up duration at the time of ECG have a higher prevalence of ECG-5. Hypertension within 5 years prior to the ECG was associated with a high prevalence of ECG-4 and ECG-5 (p = 0.015 and p = 0.006, respectively). There were no significant differences between a normal ECG and ECG-4 or ECG-5 among the other variables (SDI, SLEDAI-2 K, smoking, DM, and treatment with antimalarials or immunosuppressives) (Table 1). There was no difference in the antibodies profile between normal ECG and ECG-4 and ECG-5 (data not shown).

Both ECG-4 and ECG-5 were significantly associated with non-Caucasian ethnicity, longer lupus disease duration, and with increasing age of the SLE patients at each visit. Patients with ECG-4 and ECG-5 had more active SLE disease activity (AMS 2 years prior to ECG visit) and more damage (SDI) compared to patients with normal ECG. Treatment, including glucocorticoids, antimalarials, and immunosuppressives, was associated with ECG-4 and ECG-5. Other classic CVD risk factors such as smoking and hypertension were not associated with ECG-4 or ECG-5 in the univariate analysis (Table 2).