Carotid artery atherosclerosis and ECG changes in patients with systemic lupus erythematosus: relation to disease activity and severity

Aim This study aimed to detect atherosclerotic changes in the carotid arteries of systemic lupus erythematous (SLE) patients as an indicator of cardiovascular risk factors and to correlate the findings with disease severity and activity parameters as well as to study specific ECG changes in these patients to elucidate possible associations between these variables. Patients and methods This study included 30 SLE patients who met the Systemic Lupus International Collaborating Clinics (SLICC) criteria (group I), 30 rheumatoid arthritis (RA) patients diagnosed according to the American College of Rheumatology/European league against rheumatism (EULAR) 2010 criteria (group II), and 30 apparently healthy volunteers age and sex matched to the SLE patients’ group (group III). All patients were subjected to full history taking, thorough clinical examination, assessment of disease activity using the Systemic Lupus Erythematous Disease Activity Index (2 K) score and assessment of damage by the SLICC/American College of Rheumatology Damage Index (SDI). Laboratory investigations included: complete blood count, erythrocyte sedimentation rate, lipid profile, immunological profile (antinuclear antibodies, anti-double-stranded DNA antibody, anticardiolipin antibody, and complements C3 and C4). The right common carotid artery was scanned by ultrasound and the average of carotid intima media thickness (CIMT) was calculated (mean of four readings) for all participants participating in the study. ECG was also done for all participants. Results The mean CIMT was higher in RA patients (0.71±0.194 mm) with a nonsignificant difference compared with SLE patients (0.68±0.197 mm) and a high statistically significant difference (P<0.001) compared with healthy controls (0.34±0.09 mm). There was no statistically significant correlation of the mean CIMT (mm) with SLICC damage index (P=0.09) and disease activity score (P>0.05). Abnormal ECG findings were observed in 3/30 SLE patients (10%), 10/30 RA patients (33.3%), and one/30 healthy control (3.3%), with statistically significant difference (P<0.03) among groups. The presence or absence of abnormal ECG findings showed statistically insignificant differences regarding patients’ disease activity and mean CIMT. Conclusion Although ECG changes were present in 10% of our SLE patients, association of specific ECG changes could not be confirmed. A greater prevalence of increased CIMT was observed in SLE patients, emphasizing the important role of this disease in the development of premature atherosclerosis which did not correlate with disease activity or severity parameters.


Introduction
Systemic lupus erythematous (SLE) is an autoimmune rheumatic disease characterized by autoantibody production and variable organ system manifestations, associated with increased risk of cardiovascular disease (CVD) [1]. SLE can affect any layer of the heart and cause endocarditis, myocarditis, and pericarditis which are generally reflected by symptoms and functional disability [2]. Despite improvements in survival in the past decades, mortality due to CVD in SLE remains unchanged [3]. SLE disease is an independent risk factor for CVD [4]. This makes traditional CV risk stratification scores developed for the general population less accessible in identifying patients with SLE at high risk for CVD. Consequently, there is a growing interest in improving CV risk stratification in SLE [5].
Subclinical atherosclerosis can be detected using several modalities, such as carotid intima media thickness (CIMT), flow-mediated dilation, coronary artery calcification by computed tomography scan, and myocardial perfusion using single-photon emission computed tomography [6]. CIMT assessed by Bmode ultrasound is a simple and noninvasive inexpensive tool that can be used to identify subclinical atherosclerotic disease; it is an independent predictor of future CV risk [7].
ECG is a useful universally available noninvasive inexpensive tool. Screening for resting ECG abnormalities in asymptomatic adults found that resting ECG serves as predictors of CV events and might help better guide use of risk-reduction therapies [8].

Aim
This study aimed to detect atherosclerotic changes in the carotid arteries of SLE patients as an indicator of CV risk factors and to correlate the findings with disease activity and severity parameters as well as to study specific ECG changes in these patients to elucidate possible associations between these variables.

Patients and methods
This study included: All patients were selected from the inpatients' and the outpatient's clinic of the Rheumatology, Rehabilitation and Physical Medicine Department, Benha University Hospitals. Controls were recruited from the hospital personnel and relatives of other patients.
The study was conducted according to the Helsinki Declaration and approved by the ethics committee of Benha Faculty of Medicine. An informed written consent was obtained from all the patients and control groups prior to the study.
Patients and controls were excluded from the study if their age is less than 16 years, had diabetes mellitus, hyperlipidemia on statins, hypertension, BMI greater than 25, smoking, previous history of CV events, and other autoimmune or inflammatory diseases.
All SLE patients were subjected to full medical history taking and thorough clinical examination. The SLE Disease Activity Index 2000 (SLEDAI 2 k) [11] and the SLICC/American College of Rheumatology Damage Index (DI) [12] were used to assess disease activity and damage, respectively.
Laboratory investigations included complete blood count, erythrocyte sedimentation rate (ESR), highsensitivity C-reactive protein, antinuclear antibodies, C3, C4, immunoglobulin G (IgG) antibodies to dsDNA, IgG/IgM anticardiolipin antibodies, complete urine analysis, renal function tests, 24 h proteins in urine, and fasting blood glucose. Total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were evaluated in blood samples taken in the morning after 14 h of fasting using standard enzymatic methods with an autoanlyzer. Measurement of the CIMT by carotid ultrasound scan and ECG for patients and healthy controls were done by an experienced cardiologist who is one of the authors of this work.

Ultrasonographic study
Ultrasonography was performed with a GE Vivid 7 system (GE Healthcare, Milwaukee, WI) equipped with a 13 MHz linear array imaging probe. The right common carotid artery was examined with the patient lying supine, the head directed away from the side of examination, and the neck extended slightly. The transducer is manipulated so that the near and far walls of the common carotid artery are parallel to the transducer footprint, and the lumen diameter was maximized in the longitudinal plane. A region 1 cm proximal to the carotid bifurcation was identified, and the intima media thickness of the far wall was evaluated as the distance between the lumen-intima interface and the media-adventitia interface. The CIMT measurement is obtained from four contiguous sites at 1 mm intervals, and the average of the four measurements is used for the analyses. The performing investigator was blinded to all clinical data. Upper normal average intima media thickness is estimated to be up to 0.8 mm with plaque defined as a thickness greater than 1.5 mm as measured from the media-adventia interface to the intima-lumen interface [13].

ECG
A standard digitally recorded 12-lead resting supine ECG was performed in the Cardiology Department, Benha University Hospitals. It was performed by Nihon Kohden's Cardiofax C ECG (Nihon Kohden's, Japan). ECG-CVD were considered if there was one or more of the following four elements (ECG-4): ST-segment and/or T-wave abnormalities, left ventricular hypertrophy (LVH), left axis deviation (LAD), left bundle branch block (LBBB), and right bundle branch block (RBBB). ECG was interpreted by one of the authors who was blinded to the patients' data.

Statistical analysis
Data were tabulated, coded, and then analyzed using the computer program SPSS (Statistical Package for the Social Sciences; SPSS Inc., Chicago, Illinois, USA) version 22. Descriptive statistics were calculated for the data in the form of mean±SD and number and percentage. Analysis of variance test was used to compare between more than two groups of numerical (parametric) data, for continuous nonparametric data. Kruskal-Wallis test was used for intergroup analysis; post-hoc test (LSD, Least significant diference) was used to compare between every two groups; and Student's t-test was used to compare between two groups of numerical (parametric) data. Mann-Whittney test was used for intergroup analysis; χ 2 -test was used for comparison of categorical data. Correlation coefficient (r) was used to detect the association between different variables. A P value less than 0.05 was considered statistically significant and a P value less than 0.0001 was considered highly significant in all analyses.
Clinical features of SLE patients were malar rash in 25 (83.4%) patients, photosensitivity in 18 (60%) patients, oral ulcers in 20 (66.7%) patients, arthritis and/or arthralgia in all of the patients (100%), pulmonary manifestations in the form of pleuritis and/or effusion in 10 (33.3%) patients, neurological manifestations in the form of headache, seizures were found in three (10%) patients, 23 (76.7%) patients had lupus nephritis based on the presence of proteinuria, active urine sedimentation, or biopsyproven renal disease.
CIMT findings in the studied groups SLE patients had a CIMT that ranged from 0.25 to 1.1 mm thickness (mean±SD 0.68±0.197 mm), only 10 out of 30 SLE cases showed an increased CIMT of above 0.8 mm, while RA patients had a CIMT ranged from 0.39 to 1.2 mm thickness (mean±SD 0.71 ±0.194 mm), only 12 out of 30 RA cases showed an increased CIMT of above 0.8 mm (Table 1). SLE patients had a nonsignificant difference compared with RA controls (P>0.05) and a significant difference compared with healthy controls (P<0.05).
There were no statistically significant correlations of mean CIMT values with patients' ages (r=0.18; Comparative studies of ECG findings in the SLE group regarding patients age (years), BMI (kg/m 2 ),    There was no significant difference of mean CIMT between patients with and without ECG changes (Fig. 2).

Discussion
SLE is associated with an increased risk of CVD. Measurement of the CIMT is such a marker that can be used to diagnose subclinical atherosclerotic disease. The ECG is a noninvasive screening tool for the evaluation and identification of patients at increased risk for CV events with a relatively minimal cost burden. Dyslipidemia is defined as any alteration in the basic lipid profile that affects about one-third of SLE patients at the time of diagnosis and almost 60% after 3 years [14].
Esdaile et al. [15] reported that the excess of CV events in SLE cannot be explained only by the traditional risk factors but also arises from the underlying disease and/ or its treatment.
Regarding our results, there was a statistically significant difference (P<0.05) between the mean CIMT of SLE patients and the healthy control group (0.68±0.197 vs. 0.34±0.09) respectively, while there was a nonstatistically significant difference (P>0.05) between the mean CIMT of the SLE patients' group and the RA control group (0.68±0.197 vs. 0.71±0.194), respectively. These results are in agreement with those of de Leeuw et al. [16], El Saadany et al. [17], and Uslu et al. [18]. Inflammation plays a role in the development of the atherosclerotic lesion, interaction between traditional risk factors, antibody-mediated vascular injury, and immune dysregulation from the underlying disease, all play vital roles in endothelial dysfunction which accelerates the atherosclerotic development in SLE [19].
We also found that, there was a statistically significant correlation of mean CIMT values with the level of triglycerides (r=0.52; P=0.004), nonstatistically significant correlations (P>0.05) with TC (r=0.08; P=0.68), HDL (r=−0.33; P=0.08) and LDL (r=0.07; P=0.73). This is in agreement with the results of Sozeri et al. [20] and Kiani et al. [21].  Nikpour et al. [14] demonstrated that lipid values may change over time, reflecting changes in disease activity and therapy with antimalarials which exhibit a favorable effect on the lipid profile.
In this study, there were insignificant correlations (P>0.05) of mean CIMT values with patients' ages (r=0.18), sex (P=0.9), lupus disease duration (r=0.23), and patients family history of premature coronary artery disease (P=0.5) in first-degree relatives before the age of 65 years for women and 55 years for men.
Khairy et al. [22] found that SLE cases with a history of CVD had a significantly increased CIMT compared with both those without CVD history or healthy controls (P<0.001). They explained in their study that there was a significant difference regarding CRP and ESR between the two SLE groups. In our study, a higher prevalence of nonspecific ST-T abnormalities occurred in 6/10 (23.3%) of RA patients compared with 2/3 (6.7%) of SLE patients. This was not in agreement with Geraldino-Pardilla et al. [6] who observed that SLE disease has a higher prevalence of nonspecific ST-T abnormalities (56 vs. 17%; P<0.0001) compared with RA, despite the older age, in a higher percentage of men in the RA group. This may be explained by the difference in sample size and races, as our study included only Egyptian patients.
Comparative studies of ECG findings among SLE patients regarding patients' data, disease activity scores, and average CIMT measurements revealed statistically insignificant differences (P=0.05) which are in accordance with Geraldino-Pardilla et al. [6] results. However, Al Rayes et al. [26] reported a higher prevalence of ECG-CVD in patients with a longer SLE disease duration, increased patients' ages, active SLE disease, and damage while treatment of hyperlipidemia was protective against such events.

Conclusion
Ten out of 30 SLE (33.3%) cases showed an increased CIMT of above 0.8 mm of CIMT, emphasizing the important role of this disease in the development of premature atherosclerosis. ECG changes were present in 10% of our SLE patients; meanwhile, the association of specific ECG changes could not be confirmed.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.