In the present retrospective cohort study, we aimed to report the prevalence and associated factors of abnormal ventricular repolarisation, which consisted of non-specific ST-T change, prolonged QTc interval, QRS-T angle, etc. The prevalence of newly diagnosed non-specific ST-T changes at baseline and follow-up was higher than reported studies (27% and 20% vs. 17% to 18%). Several factors can explain this difference. Our study population had more moderate and active patients than the previous study cohorts (89.9% vs. 62%, evaluated with DAS28-CRP). When it comes to new-onset prolonged QTc interval at baseline and follow-up, the incidence in our cohort was marked lower than the previous literature (6.2% and 7.4% vs. 30% and cumulative 47.5%), probably because, compared with ours, Chauhan K. et al. had a cohort with a nearly double incidence of hypertension (43% vs. 22.5%) which plays a role in the mechanism of QT interval prolongation. Not yet had published study revealed the occurrence of increased QRS-T angle in RA patients. Our cohort discovered that 5.3% of patients were with increased QRS-T angle.
Non-specific ST-T changes are common findings even in the general population. Previous studies have indicated that these changes significantly correlate with cardiovascular morbidity and mortality[11, 12, 31, 32]. Although the clinical significance of non-specific ST-T changes in patients with RA without CVD is still not certain, it is enticing to speculate that they represent subclinical CVD. QT/QTc interval prolongation is also an independent cardiovascular risk factor [15, 33–35] and is mainly related to cardiac arrest, especially in the RA population. Emerging data have demonstrated the strong relationship between QTc and pro- and anti-inflammatory cytokines[36, 37]. Also, the presence of parasympathetic dysfunction, one of the autonomic dysfunctions in RA patients, could influence the QTc interval.
RF models could help primarily discover associated factors. Inflammatory markers, including ESR and CRP, were important for three kinds of ECG abnormalities. When validated in follow-up patients with multivariate CoxPH regression, increased concentration of rheumatoid factor was found a risk factor for three abnormalities, except the concentration was lower than 900 IU/ml for ST-T changes. The impact of CRP and ESR were significantly associated with QRS-T angel increase and QTc prolongation, respectively; however, due to the limited sample size, we did not discover a significant concentration-effect relationship. ESR and CRP are part of extended DAS-28, but their importance varies from different ECG abnormalities.
Age and disease duration is not critical for the higher risk of non-specific ST-T changes, consistent with the previous study. However, another factor, GC usage period, which could partly reflect age, disease duration, and disease activity, influences differently in ST-T changes and QTc prolongation. A regular, adequate GC therapy might be more vital.
A population-based study has shown that LDL levels are independently associated with subclinical atherosclerosis, one of the magnifications of non-specific ST-T abnormalities, also statistically influencing non-specific ST-T changes in our study, even a near-optimal controlled level of LDL is protective. Nevertheless, when it comes to QRS-T angle increase, LDL should be strictly controlled at or under the optimal level.
Hypertension is a well-documented risk factor for ST-T change; in our cohort, those in graded class-2 or low-risk groups have a higher risk; but hypertensive patients from the high-risk group had a protective effect on ST-T changes. Such difference could be probably because these patients were more cautious and active in controlling blood pressure.
Female has been reported positively related to QTc prolongation in RA. These gender differences appear to correlate with age-dependent changes in serum levels of sex hormones. Androgens would accelerate cardiac repolarisation processes and shorten potential action durations by the effect of testosterone on calcium currents. Moreover, low BMI is an independent predictor of QTc interval prolongation in our cohort, similar to a cross-sectional study in women with eating disorders has demonstrated. Therefore, appropriate nutrition enhancement for underweighted RA patients is recommended for lowering the risk of cardiac conduction abnormalities.
sUA level has a positive correlation with prolonged QTc interval, especially in men. Our result also identified that even in those with sUA slightly increased, the risk of QTc prolongation would be twice. QTc intervals were found shortening in female subjects with sickle cell anemia. Those with QTc prolongation in our cohort were mostly women (6 of 7); therefore, mild anemia might have a protective effect on QTc interval.
The impact of immunoglobulin G on QTc prolongation in RA patients is a novel finding in our study. Abnormal levels of serum IgG are one of the early markers of autoimmune diseases, especially the increased ones. Aberrant glycosylated and autoimmunity-triggered IgG could be responsible for inflammation-associated atherosclerosis cardiovascular symptoms.
In conclusion, machine-learning analysis can be used when multicollinearity occurs or in a high dimension data warehouse. For instance, the disease duration may depend on age; and preselected the essential variables for the following Cox regression. Another strength of the present study is the comparison between several machine learning approaches since each has its unique pros and cons. As a relatively affordable cardiovascular examination, ECG may be recommended for all the RA patients in their first visit and follow-up visits because such a systemic-involved and chronic disease needs interdisciplinary cooperation to assess the condition holistically and longitudinally. Assisted by the machine-learning method and validated by traditional CoxPH regression, some objective information might be acquired before inviting cardiologist consultations and further expensive or intrusive examinations.
There are several limitations of our study that can impact its generalizability to other populations and the interpretation of its clinical significance. First, the sample size was insufficient, especially the follow-up subjects. Second, we only used resting-12-lead ECGs rather than 24-hour ECG monitoring (Holter), which can measure diurnal variations of ECG intervals. It may cause a higher 'false-negative rate' when we diagnosed ECGs. Third, we cannot exclude the possibility of patient selection bias because only a single tertiary referral center participated in this study. Therefore, the prevalence of ECG abnormalities in this study cannot represent the real rate in China. Moreover, although ECG is an affordable, stable, and quick test along with no harm, the information that ECG could offer is limited. Other cardiac imaging examinations, for example, echocardiogram, cardiac magnetic resonance imaging, or radionuclide perfusion, could provide more details about the cardiac lesion. Further longitudinal, prospective studies assessing the role of potential risk factors will help clarify the mechanism of ECG abnormalities among RA patients.