Association of Prolong PR and QTC Intervals with Cardiovascular Events and Mortality: The Isfahan Cohort Study

Association of Prolong PR and QTC Intervals with Cardiovascular Events and Mortality: The Isfahan Cohort Study. Biomed Sci 29(5)-2020. ABSTRACT This study aimed to assess PR interval and heart rate-corrected QT (QTC) interval prolongation with cardiovascular events (CVEs) and mortality in Iranian adult population. It is a nested case-control study within the Isfahan Cohort Study (ICS). The ICS is an ongoing longitudinal population based study of 6504 adults aged 35 and older and without history of CVEs. PR and QTC interval was assessed with baseline electrocardiogram. CVEs and mortality defined as fatal and non-fatal acute myocardial infarction and stroke, unstable angina and Sudden Cardiac Death (SCD). The odds ratio was calculated by conditional logistic regression. Totally 432 subjects with CVEs and 394 participants free of CVEs in the control group were included in the analysis. There was not association between prolonged PR interval and CVEs, SCD and cardiovascular mortality in crude and all adjusted models. The same results were seen in prolonged QTC interval and CVEs and SCD; but there was significant relationship between prolonged QTC interval and cardiovascular mortality in crude model, 2.98 (95% CI: 1.16-7.66, P = 0.023). However, in adjusted models there was no significant difference. In conclusion, prolonged PR and QTC intervals were not associated with an increased risk of CVEs and mortality in Iranian adult. coronary artery disease hospitalization, Atrial Fibrillation


Introduction
As has been well established, the resting Electrocardiogram (ECG) findings provide valuable diagnostic and prognostic information for the occurrence of Cardiovascular Events (CVEs), independent of traditional risk factors. Abnormal QRS complex and ST-T segment changes are the most common finding that predictive Cardiovascular Diseases (CVD) and mortality [1][2][3]. However, the predictive role of some finding like heart-rate corrected QT (QTC) and especially PR interval are still not fully understood. Despite the benign nature of prolonged PR interval and contrary to previous studies; prolongation of the PR interval was also associated with mortality [4,5]. As we know, prolonged QTC interval (genetically or acquired) predisposes to malignant Ventricular Arrhythmias (VT) and Sudden Cardiac Death (SCD) [6,7]; although different results have been reported in various studies regarding its association with CVD or mortality [8][9][10]. On the other hand, some studies reported the differences by communities and race/ethnic in the prevalence of numerous ECG findings [11,12]. To our knowledge there has not been any records regarding the association of PR and QTC interval and CVD in Iranian adults. Therefore, the purpose of this study is to explore the association of PR and QTC interval prolongation with CVEs and mortality in adults who participated in the Isfahan Cohort Study (ICS).

The Population and Data Collection
This was a nested case-control study within the ICS. The ICS is an ongoing longitudinal population-based study of 6504 adults aged 35 and older at baseline, living in urban and rural (27.5 %) areas from three counties in central Iran [13]. Participants were selected through multistage random sampling from January 2 to September 28, 2001. Details of the sampling method are described in a previous publication [13,14]. Ethical approval was obtained from the Ethics Committee of Isfahan Cardiovascular Research Institute, a WHO collaborating center. Written informed consents were obtained from each subject. After the baseline assessment, followup of the participants was carried out every 2 years by telephone or in-person interview, physical and biochemical measurements.
The interview and attendance to clinical examination response rate were 98% and 95% respectively [14]. Blood pressure, fasting blood sugar, lipid profile tests and anthropometric parameters were measured following standard protocols [14,15]. Among anti-hypertension drugs used by some subjects, beta adrenergic blocker (metoprolol, atenolol, propranolol, carvedilol and timolol), calcium channel blocker (verapamil and diltiazem), digoxin, and amiodarone were defined as heart rate-lowering drugs. The follow up period for this survey was the first seven years of ICS. Ischemic

Heart Diseases (IHD) including Acute Myocardial Infarction (AMI)
and Unstable Angina (UA), and stroke were defined as CVEs. Thirty minute or more typical chest pain with ST elevation more than 0.1 mV in at least 2 adjacent ECG leads and increase in cardiac troponin or creatine kinase were AMI definition criteria [16]. UA was defined as typical crescendo and severe chest discomfort lasting more than 20 minute preceding hospitalization with or with ECG change [17]. Stroke was explored as a rapid-onset vascular origin focal neurological defects in last 24 hour. Fatal Myocardial infarction and stroke were categorized in cardiovascular mortality. Death within one hour of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by more than one hour of symptoms were SCD criteria.
The reported events were re-checked and reviewed within Isfahan cardiovascular research institute by known cardiologists and neurologists monthly [14]. The control group were selected among subjects without the aforementioned events but were matched with the case group on follow-up time (density sampling) to make time at risk similar between each pair. For each case, the controls were chosen randomly from those members of the study who were at risk at the failure time (event date). In other words, the resulting case-control sample was matched with respect to the time scale used for survival analysis.

PR and QTC Interval
PR and QTC interval was measured using baseline standard 12lead ECG (on average, 6 beats). PR interval were identified as the interval from the onset of the P-wave to the end of the PR segment, and measured from the bipolar limb leads (like lead D2) in which the interval was longest and more accurate. PR interval > 200 msec is considered as prolonged. The QTC interval is defined from the start of the QRS complex to the end of the T-wave with adjustment for heart rate by Bazett formula (QTC= QT / √RR). The American Heart Association (AHA), the American College of Cardiology (ACC) and other professional organization has suggested that the upper limit for QTC be set at 460mesc for women 450msec for men [18].
Intervals were calculated by two cardiologists in two or three leads (D2, V3 and/or V5) and their mean value was calculated for each subject.

Statistical Analysis
All numerical data were presented as mean ± standard deviation.
Categorical factors were reported as number (percentage). A Chisquare test was designed to analyze categorical data and analysis of variance (ANOVA) tests was used for differences between the means. The logistic regression was used to estimate odds ratios, which are unbiased estimates of incidence rate ratios in incidence density sampling independent of any assumption [19]. Conditional logistic regression was employed using incident cardiovascular events and mortality as dependent variables and PR and QTC intervals as independent variable. Analysis was adjusted for age, age and sex, heart rate-lowering drugs and traditional CVD risk factors (multiple) for each of the dependent variables. Statistical procedure was done by Statistical Program for Social Sciences Software (SPSS) version 23. All differences were considered as statistically significant at P value less than 0.050.

Results
We followed the 6054 subjects, aged ≥ 35 years and without history of CVEs from the ICS during median 6.8 years. Totally    Table 2). The same results were seen in prolonged QTC interval and CVEs and SCD; but there was significant relationship between QTC and cardiovascular mortality in crude model, 2.98 (95% CI: 1.16-7.66, P = 0.023). However, in adjusted models there was no significant difference ( Table 2).  such as ischemic cardiomyopathies [24]. A greater incidence of total death or all-cause mortality in subjects with prolonged PR can be attributed to older age and their comorbidity [4]. Like previous studies, our study also showed that mean PR interval was significantly longer in men than in women [20]. Overall, based on previous studies and our study, PR prolongation has no independent and strong association with CVEs and mortality and more prone to induce supraventricular arrhythmias especially AF [4,25].
The second part of this paper is related to QTC interval and its predictive status on CVEs and mortality. Straus et al. in a prospective population based cohort study indicated that prolonged QTC interval was associated with a more than two-fold increased risk of sudden cardiac death as an independent risk factor [26]. In another population-based cohort study by Dekker et al. reported that healthy black and white men and women with QTC prolongation are at increased risk of coronary heart disease and mortality independently [10]. Meta-analysis by Zhang et al. also revealed the associations between prolonged QTC interval and increased risk of total cardiovascular mortality and SCD [9]. On the whole, most studies announced prolonged QTC interval is predictive to coronary artery disease and CVD mortality [7][8][9][10]26].
The mechanism linking prolongation of QTC interval and higher risk of CVD and mortality has been proposed to be the effect of inflammation, ventricular electrical instability, dispersion of repolarization and higher prevalence of traditional metabolic risk factors [26,27]. In contrast to these findings, in our paper and some other studies prolonged QTC was not associated with coronary artery disease, cardiovascular mortality and SCD [11].
The reason for this difference is difficult to explain; but perhaps the variety in races and populations can be explaining the differences in the incidence of CVD risk factors and CVEs [11][12]. On the other hands, low number of CVEs during the follow up period in keeping with little ECG changes especially QTC interval prolongation can describe these differences between our results and other studies.
These mentioned as major limitations of this study.

Conclusion
In conclusion, our findings indicate that prolonged PR and QTC intervals are not associated with an increased risk of CVEs and cardiovascular mortality in Iranian adult population.