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Association between resting painless ST-segment depression with sudden cardiac death in middle-aged population: A prospective cohort study
IJCA-28182; No of Pages 6 International Journal of Cardiology xxx (xxxx) xxx
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Association between resting painless ST-segment depression with sudden cardiac death in middle-aged population: A prospective cohort study Xue-Qiong Deng a,d,1, Xiong-Jun Xu b,1, Su-Hua Wu a,d, Hai Li c,⁎, Yun-Jiu Cheng a,d,⁎⁎ a
Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Department of Stomatology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China c Department of Endocrinology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China d Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China b
a r t i c l e
i n f o
Article history: Received 29 March 2019 Received in revised form 18 October 2019 Accepted 26 November 2019 Available online xxxx Keywords: Electrocardiography Sudden cardiac death ST-segment depression Epidemiology
a b s t r a c t Backgound: Silent electrocardiographic ST change predicts future coronary heart disease (CHD) incidence and mortality, but the prognostic significance of painless ST-segment depression (STD) with respect to sudden cardiac death (SCD) in subjects without apparent CHD remain unclear. This study sought to test the association between non-ischemic resting STD and risk of SCD in the general population. Methods: A total of 14,935 middle-aged subjects from the prospective, population-based Atherosclerosis Risk in Communities (ARIC) study were included in this analysis. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. STD was defined as ST-segment depression of ≥0.05 mV in two or more contiguous leads. Results: A total of 626 sudden cardiac death occurred during the mean follow-up of 20.4 years. Compared with those without STD, subjects with resting painless STD of at least 0.05 mV had a significantly increased risk of developing SCD (adjusted HR, 1.45; 95% CI, 1.20 to 1.76), and those with STD ≥ 0.1 mV had even higher risk of SCD (adjusted HR, 1.90; 95% CI, 1.25 to 2.88). Significant interactions were present between gender and STD (P = .03), and between race and STD (P = .01). STD was significantly predictive of SCD in males (adjusted HR, 1.57; 95% CI, 1.22–2.01) and in whites (adjusted HR, 1.65; 95% CI, 1.27–2.14). STD in lateral leads and global leads were strong predictors of SCD. Conclusions: Resting painless STD was an independent predictor of SCD in the middle-aged population without previously diagnosed CHD. © 2019 Published by Elsevier B.V.
1. Introduction Sudden cardiac death (SCD) remains a major public health problem that accounts for a currently estimated incidence of 4–5 million deaths annually and 50% of all cardiovascular mortality around the world [1,2]. In spite of advancements in emergency medical systems, N95% of sudden cardiac arrest victims do not survive to hospital discharge. Most SCD cases, however, occur in the general population, and the majority have no clinically recognized heart disease prior to the event [3]. ⁎ Correspondence to: H. Li, Department of Endocrinology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. ⁎⁎ Correspondence to: Y.J. Cheng, Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510700, China. E-mail addresses: [email protected] (H. Li), [email protected] (Y.-J. Cheng). 1 These authors contributed equally to this work.
Hence, identification of individuals at increased risk of SCD may allow targeted prevention strategies. The presence of ST-segment depression (STD) on the standard 12‑lead electrocardiogram (ECG) has been well recognized to be a powerful predictor of coronary heart disease (CHD) incidence and mortality [4,5]. However, the relation of STD to the risk for SCD is less clear. In men without evident CHD, silent STD during exercise test has been associated with a higher incidence of SCD [6]. More recently, Bundgaard H et al. identified five families with SCDs characterized by widespread non-ischemic STD, raising the possibility that painless STD at rest would have prognostic significance with regard to the risk of SCD in persons without evident CHD [7]. The goal of this study was therefore to examine the association of non-ischemic STD at rest with risk of SCD in participants of the Atherosclerosis Risk in Communities (ARIC) study, a large, multicenter, biracial, community-based cohort, with outcomes surveillance spanning N2 decades.
https://doi.org/10.1016/j.ijcard.2019.11.148 0167-5273/© 2019 Published by Elsevier B.V.
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2. Methods 2.1. Study population The ARIC Study is a prospective epidemiologic study sampled from 4 US communities (Forsyth County, North Carolina; Jackson, Mississippi; suburban Minneapolis, Minnesota; and Washington County, Maryland) [8,9]. Details of the study design have been published elsewhere [10]. During follow up, participants were contacted annually by phone to gather information on hospital admission and verify vital status. Participant follow-up through annual telephone interviews and review of hospitalization records and vital status is ongoing. Institutional review boards at each participating institution approved the ARIC study, and all participants provided informed consent before each examination. We obtained the cohort data sets from the NIH Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) [11,12].For the present analysis, we excluded the following participants: (1) subjects for whom ECGs were missing or incomplete; (2) subjects with ventricular conduction abnormalities (eg, complete left or right bundle branch blocks), pacemakers, Wolff-Parkinson-White syndrome, Brugada syndrome, left ventricular hypertrophy, QRS duration ≥120 ms; Left ventricular hypertrophy was determined by resting ECG (using both Sokolow-Lyon and Cornell criteria) or echocardiography. (3) subjects with symptoms suggestive of prevalent CHD at the baseline. Prevalent CHD was defined as either a history of myocardial infarction or angina pectoris, angina pectoris on effort, or the use of nitroglycerin for chest pain once a week or more frequently; (4) subjects with other diseases that would also cause STD on ECG, such as anaemia, chronic heart failure, pneumonia, stroke, pulmonary embolism and structural heart disease. 2.2. Electrocardiographic measurement Digital 12‑lead ECGs were obtained at baseline as described previously [13]. At the examination, a standard resting supine 12‑lead ECG using MAC PC ECG machines (Marquette Electronics, Milwaukee, Wisconsin) was obtained for each subject a minimum of 1 h after any smoking or caffeine ingestion. Tracings were sent via a phone modem to be computer coded at the ARIC ECG Reading Center. All records with significant Minnesota Code findings as determined by the computer, as well as a random sample of tracings, were independently visually coded by 2 trained coders (cardiologists blinded to outcome status). Final decisions about the discrepancies between the computer code and visual code were made by another senior coder. ST-segment depression was measured on median complexes from the 10 s tracings at the midpoint of the ST segment between the Jpoint and the end of the ST segment using a fully automated method, defined as 1/8 the average R-R interval from the J-point. ST-segment depression of ≥0.05 mV (0.5 mm) in two or more contiguous leads (excluding aVR) was considered abnormal, a value that corresponded to the 95th percentile of ST depression findings in the current population and parallels use of this threshold for detection of ST depression by Minnesota Code [14,15]. 2.3. Ascertainment of outcomes In the present study, SCD was defined as sudden unexpected arrest of presumed cardiac origin without traumatic nature of death. The arrest should have occurred within 24 h after onset of any symptoms that could retrospectively be interpreted as being cardiac origin. The methods for ascertainment of SCD events have been described previously [13]. In order to identify SCD, all fatal cardiovascular events in ARIC were reviewed by an independent panel of physicians. Pairs of physician adjudicators blinded to clinical data and follow-up status, independently assessed the death information using a standard coding form. In case of divergent results, the case was re-coded by paired
investigators. If further disagreement occurred, a preliminary decision was achieved by consensus. In general, the adjudication committee made use of death for witnessed and unwitnessed events, respectively. Only cases of definite SCD were included in the present analysis. 2.4. Statistical analysis Characteristics of the participants at each visiting time point were compared across categories of STD status. Baseline characteristics of participants are presented as means and standard deviations (SDs) for continuous variables and percentages for categorical variables. Tests for differences in means were assessed using unpaired t-tests for continuous variables and χ2 tests for independence for categorical variables. We used Cox's proportional hazards models to obtain unadjusted and multivariate adjusted hazard ratios (HRs) for SCD of subjects with versus those without STD, as well as test for modification of the association between STD and SCD for a series of potential effect modifiers. Follow-up was defined as the time between the baseline visit until the death, loss to follow-up, or end of follow-up. Potential covariates included in the initial model were: age, gender, race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, QTc duration and T-wave inversion. We used an overall measure of STD in any ECG lead and also grouped the leads into inferior (II, III, aVF), lateral (I, aVL, V5-6), and precordial (V1-4) leads. As correlation tests of Schoenfeld residuals and the rank order of event time for assessing Cox proportional hazard assumption indicated that application of the Cox proportional hazard model was appropriate. Kaplan-Meier survival curves were plotted for the outcome of SCD according to different amplitudes of STD, and different races and genders. In sensitivity analyses, we explored the possible role of incident CHD or myocardial infarction in the association between STD and SCD by censoring the analyses at time of CHD or acute myocardial infarction. We also evaluated the impact of competing risk adjustment of death due to all other (non-SCD) causes. Furthermore, we compared the HRs of SCD with those of total mortality and total cardiovascular mortality, as well. We used Stata version 13.0 for all analyses. Statistical tests were 2sided and used a significance level of P b .05. 3. Results 3.1. Baseline characteristics After application of exclusion criteria (including 186 participants with missing or incomplete ECGs), a total of 14,935 participants were included in this study. The baseline characteristics stratified by STD status are shown in Appendix Table 1. In the study cohort, 45.36% were males and 74.13% were whites. Individuals with STD were more likely to have history of diabetes mellitus and prevalence of T-wave inversion on ECG. They were more often older, had a higher fasting blood glucose, blood cholesterol, and QTc duration, and had a lower serum potassium and serum magnesium than those without STD. Of note, ECG changes affecting the ST segment seem to be a more common background variation in blacks than whites. However, the prevalence of STD was not significant different between males and females (p = .11).In addition, 47.7% of the total participants underwent stress testing, coronary angiography or computed tomography examination to rule out the possibility of coronary artery disease at the baseline when ECGs were performed. Among all the participants, the ECGs indicated no signs of ventricular hypertrophy, and the diagnosis was further confirmed by echocardiography for 37.2% of the participants. In our study population the overall prevalence of STD was 14.78%. Distribution of STD was as follows: 1162 (7.78%) in inferior leads only, 195 (1.31%) in lateral leads only, 515 (3.45%) in precordial leads only, 262 (1.88%) in two lead
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territories, and 74 (0.53%) in global leads. Representative examples of STD in our study population are shown in Appendix Fig. 1. 3.2. Risk of sudden cardiac death After a maximum follow-up of 23.9 years and a mean of 20.4 ± 5.5 years, a total of 626 SCD events occurred (incidence rate = 1.1 per 1000 person-years). Subjects with painless STD ≥ 0.05 mV at rest experienced a higher risk of developing SCD (unadjusted HR, 2.31; 95% CI, 1.94 to 2.76; adjusted HR, 1.45; 95% CI, 1.20 to 1.76) compared with those without STD after adjusting for multiple conventional risk factors. Painless STD ≥ 0.1 mV was associated with an even higher risk of SCD (unadjusted HR, 4.47; 95% CI, 3.11 to 6.43; adjusted HR, 1.90; 95% CI, 1.25 to 2.88). The cumulative hazard curves for SCD continued to diverge during the follow-up period (Fig. 1). Using the information on person-years in subjects with and without STD, we could calculate absolute annual rates of SCD from the population: 154.2 cases per 100,000
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person-years in subjects without STD and 2221.9 cases in those with STD, corresponding to an absolute risk increase of 2067.7 (95% CI 1735.2 to 2400.2) cases per 100,000 person-years. Censoring the analyses at the time of incident CHD or acute myocardial infarction did not alter risk estimates meaningfully (Appendix Table 2). The subdistribution HRs obtained from the competing risk model remained qualitatively similar to main results (for STD ≥ 0.05 mV: adjusted HR, 1.55; 95% CI, 1.28 to 1.88; for STD ≥ 0.1 mV: adjusted HR, 1.99; 95% CI, 1.22 to 3.22).In comparison with the SCD analyses, the risk estimates were slightly lower for cardiovascular mortality and total mortality (Appendix Table 3). Furthermore, limiting analyses to subjects with imaging evidence showing no coronary artery disease did not change the results materially (for STD ≥ 0.05 mV: adjusted HR, 1.51; 95% CI, 1.31 to 1.74; for STD ≥ 0.1 mV: adjusted HR, 1.93; 95% CI, 1.29 to 2.89). In addition, analyses confining to subjects with no ventricular hypertrophy in echocardiography yielded similar results to main findings (for STD ≥ 0.05 mV: adjusted HR, 1.48; 95% CI, 1.25 to 1.75; for STD ≥ 0.1 mV: adjusted HR, 1.96; 95% CI, 1.31 to 2.93).
3.3. Stratified analyses
Fig. 1. Kaplan-Meier survival curves for sudden cardiac death in subjects with asymptomatic ST-segment depression. Subjects with ST-segment depression of N0.05 mV on standard 12‑lead electrocardiography had an elevated risk of sudden cardiac death, as compared with those without an ST-segment depression, with an unadjusted HR of 2.31 (95% CI, 1.94 to 2.76, P b .001) (Panel A). Subjects with STsegment depression of N0.1 mV had an unadjusted HR of sudden cardiac death of 4.47 (95% CI, 3.11 to 6.43, P b .001) (Panel B).
When stratifying for localization of STD ≥ 0.05 mV, we found that global distribution conferred the strongest risk for SCD (adjusted HR, 3.76; 95% CI, 1.93 to 7.33), followed by lateral distribution (adjusted HR, 3.31; 95% CI, 2.13 to 5.14), while inferior or precordial distribution was of no significance in predicting SCD in multiple variables adjusted analysis. In addition, subjects with STD ≥ 0.1 mV in global leads and lateral leads had markedly elevated risk of developing SCD (for global leads: adjusted HR, 4.21; 95% CI, 2.03 to 8.73; for lateral leads: adjusted HR, 5.78; 95% CI, 2.10 to 15.93) (Table 1). Among subjects with STD in any lead, a significant interaction was present between gender and STD for the outcome of SCD. Males with STD had a higher risk of SCD (adjusted HR, 1.57; 95% CI, 1.22 to 2.01) than did males without STD. However, STD did not confer an increased risk of SCD among females (adjusted HR, 1.19; 95% CI, 0.86 to 1.65). The ratio of HRs for males compared with females was 1.34, indicating significant difference between these groups in the risk associated with STD (p = .03) (Fig. 2). A significant interaction between race and STD was also present. STsegment depression was associated with significantly increased risk of SCD in whites (adjusted HR, 1.65; 95% CI, 1.27 to 2.14). However, STD was not a marker of increased risk of SCD in blacks (adjusted HR, 1.20; 95% CI, 0.89 to 1.61). The ratio of HRs for whites compared with blacks for SCD was 1.38, indicating that STD connotes a greater risk of SCD in whites than it does in blacks (p = .01) (Fig. 2). Further analysis of subjects with imaging evidence showing no coronary artery disease still showed that only whites with STD experienced increased risk of SCD (adjusted HR, 1.72; 95% CI, 1.39 to 2.13). Notably, STD was associated with significantly increased risk of developing SCD in subjects without hypertension (adjusted HR 1.53, 95% CI 1.13 to 2.07),but not in those with hypertension (adjusted HR 1.21, 95% CI 0.94 to 1.56; p = .05 for interaction).In addition, the risk estimates of SCD associated with STD seemed to be higher in subjects without diabetes mellitus (adjusted HR 1.67, 95% CI 1.33 to 2.10) compared with those with diabetes mellitus (adjusted HR 1.03, 95% CI 0.72 to 1.48; p = .005 for interaction). No significant interaction effects were identified between subjects aged ≥55 years and b55 years, with and without dyslipidaemia, or between smokers and non-smokers (Fig. 2). Given that the relationship between STD and SCD differed based on gender and race, the four subgroups (white males, white females, black males, and black females) were examined separately. Only white males were found to have a significantly increased risk of SCD when STD was present (adjusted HR, 1.75; 95% CI, 1.28 to 2.38) (Appendix Table 4). Fig. 3 show the Kaplan-Meier curves for SCD in subjects with STD stratified by race and gender simultaneously.
Please cite this article as: X.-Q. Deng, X.-J. Xu, S.-H. Wu, et al., Association between resting painless ST-segment depression with sudden cardiac death in middle-aged ..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.148
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Table 1 Hazard ratios (HRs) of various ST-segment depression patterns for sudden cardiac death. SCD Events
Total Participants
Model 1 HR (95% CI)a
Model 2 HR (95% CI)b
Model 3 HR (95% CI)c
Model 4 HR (95% CI)d
458
12,727
1.00
1.00
1.00
1.00
ST-segment depression ≥0.05 mV Any leads 168 Inferior leads only 72 Lateral leads only 24 Precordial leads only 25 Global Leads 12
2208 1162 195 515 74
2.31 (1.94–2.76) 1.78 (1.39–2.28) 4.72 (3.13–7.12) 1.39 (0.93–2.08) 7.42 (4.18–13.17)
2.17 (1.82–2.59) 1.68 (1.31–2.16) 3.93 (2.60–5.94) 1.38 (0.92–2.07) 6.21 (3.49–11.02)
1.64 (1.37–1.98) 1.20 (0.93–1.55) 3.15 (2.03–4.87) 1.18 (0.78–1.76) 4.08 (2.24–7.45)
1.45 (1.20–1.76) 1.18 (0.92–1.54) 3.31 (2.13–5.14) 1.10 (0.72–1.66) 3.76 (1.93–7.33)
ST-segment depression ≥0.1 mV Any leads 31 Inferior leads only 12 Lateral leads only 4 Precordial leads only 1 Global Leads 6
253 104 16 26 33
4.47 (3.11–6.43) 3.53 (1.99–6.27) 12.48 (4.66–33.41) 1.34 (0.19–9.55) 7.88 (3.52–17.65)
3.83 (2.66–5.52) 3.29 (1.85–5.83) 11.17 (4.17–29.90) 1.03 (0.14–9.55) 6.15 (2.74–13.78)
2.26 (1.54–3.32) 1.81 (1.01–3.24) 5.52 (2.03–15.00) 0.97 (0.14–6.92) 4.94 (2.55–9.57)
1.90 (1.25–2.88) 1.64 (0.91–2.97) 5.78 (2.10–15.93) 0.67 (0.09–4.85) 4.21 (2.03–8.73)
No ST-segment depression
a
Model 1 adjusted for no cardiovascular risk factor. Model 2 adjusted for age and gender. c Model 3 adjusted for variables in model 2 plus race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, and QTc duration. d Model 4 adjusted for variables in model 3 plus T-wave inversion. b
4. Discussion This study is, to the best of our knowledge, the first to investigate the association of resting STD with the risk of SCD in a large middle-aged
population without evident CHD, and several of our findings add to current knowledge. First, resting STD is associated with increased risk of SCD independent of traditional cardiovascular risk factors. In absolute risk, STD would account for an estimated 2067.7 additional SCDs per
Fig. 2. Stratified analysis of hazard ratios (HRs) of sudden cardiac death associated with asymptomatic ST-segment depression. *Cox's proportional hazards model, adjusted for age, gender, race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, QTc duration and T-wave inversion.
Please cite this article as: X.-Q. Deng, X.-J. Xu, S.-H. Wu, et al., Association between resting painless ST-segment depression with sudden cardiac death in middle-aged ..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.148
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Fig. 3. Kaplan-Meier survival curves for sudden cardiac death in white subjects (Panel A) and black subjects (Panel B) with and without ST-segment depression, stratified by gender. WM: white males; WF: white females; BM: black males; BF: black females.
100,000 subjects per year in the general population. Second, the increased risk was present predominantly in whites and males, and those without history of hypertension and diabetes mellitus. Third, STD in lateral leads and global leads, and STD with the amplitude of N0.1 mV appeared to strong predictors of SCD. Painless STD is a not uncommon finding, and 10.3% of middle-aged men free of evidence of CHD, had STD at least once in annual resting ECG examinations during 5 years in the Chicago Western Electric Study [5]. Kannel et al. reported that in Framingham Study examinations 8 to 12, 14.1% of population aged 44 to 74 years had nonspecific STD [16]. In our study, we observed that painless STD at rest was present in 14.7% of the middle-aged biracial population. Therefore, STD in the absence of pain might be more common than with angina in daily life. The predictive value of STD for future coronary events in patients with CHD has been well established, but few studies assessed the association between STD and future risk of SCD. Hagnäs et al. reported a 4.8fold increase of SCD in subjects with both low cardiorespiratory fitness and exercise-induced STD in 2328 middle-aged men [17]. In another
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cohort study by Laukkanen et., silent STD during and after maximal symptom-limited exercise test increased the risk of SCD by 2.1 and 3.2 folds, respectively [6]. In subjects with hypertrophic cardiomyopathy, STD in the high lateral leads is a strong predictor of sudden death or appropriate implantable cardioverter-defibrillator therapy (odds ratio: 20.0, 95% CI: 12.7 to 27.5) [18]. No previous study has examined the predictive value of painless resting STD for future SCD among the general population. In the present study, the risk magnitude of SCD associated with resting STD was 1.64, which appears to be less robust than those reported for exerciseinduced STD. However, the ECGs during or after exercise stress test are not easily accessible. In addition, resting STD is a common electrocardiographic finding around the world, and the absolute risk of SCD associated with resting STD is very high, the total number of excess SCD may not be negligible. Furthermore, N85% of all sudden cardiac events occurred out of hospital that makes the registration of painless STD in the prediction of SCD highly valuable [3]. Despite recent advances in technology, survival from out-of-hospital SCD remains low throughout the word at about 5%. More importantly, we identified that white males and those with STD in lateral leads and global leads and STD ≥ 0.1 mV were at greater risk of SCD, which makes it more meaningful in the clinical practice. Therefore, our results could have some implications for the clinicians: a middle-aged white male with painless STD at rest and “normal” coronaries could experience increased risk of SCD, and thus further evaluations including electrophysiological studies should be performed for those at high risk, aiming to prevent the risk of SCD. Despite the fact that the presence and specific phenotypes of resting STD is associated with risk for SCD, the underlying mechanisms remain unclear. A number of situations, including myocardial ischaemia, ventricular hypertrophy, hyperventilation, electrolyte abnormalities, anaemia, and increased sympathetic activity are known to cause STD [19]. In light of these concerns, our present analyses excluded persons with chest discomfort, CHD, ventricular hypertrophy and anaemia, and controlled for serum electrolytes. This ensured that the prognostic evaluation involved only isolated nonspecific STD. Our results indicated the association between STD and SCD could not be solely explained by myocardial ischaemia. First, censoring the analyses at the time of incident CHD or acute myocardial infarction yielded similar results to the main finding. Second, subjects without history of hypertension and diabetes mellitus tend to have higher risk compared with those with these conditions. Therefore, we propose another possible mechanism: the involvement of hereditary susceptibility in the pathogenesis of STD and development of SCD. First, twenty-eight genetic loci in a set of genes involved in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) had been associated with ST-segment amplitudes of the ECG [20]. Second, Bundgaard et al. has recently described five families with a novel cardiac syndrome characterized by nonischemic STD and SCD, which was considered to be inherited as an autosomal dominant trait [7]. Third, we have observed differences in risk of SCD between males and females, whites and blacks, and this could be partly explained by genetic mechanisms. ST-segment depression could be a single phenotypic manifestation of a diverse array of genotypes. These genotypic variations may be differentially distributed between various racial and gender groups. Some genotypes may increase risk of SCD, whereas others might be completely benign while producing similar ECG findings. Major strengths of our study are the relatively large sample size, sensitivity analyses, and multiple confounding factors included in the analyses. All data were collected irrespective of the current hypothesis. The setting of a population-based cohort and the long follow-up allowed for the estimation of long-term absolute risks. Furthermore, the cases of SCD were ascertained by a strict adjudication process, which might provide a more accurate definition of SCD than is often available in other epidemiological studies. In addition, the application of an entirely
Please cite this article as: X.-Q. Deng, X.-J. Xu, S.-H. Wu, et al., Association between resting painless ST-segment depression with sudden cardiac death in middle-aged ..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.148
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automated method to detect STD eliminates bias and enables us to compare the prognostic significance of this pattern. Furthermore, all ECGs indicated no signs of ventricular hypertrophy, which was an established risk factor for both STD and SCD. Given that ECG only might not be reliable for defining ventricular hypertrophy, we also performed sensitivity analyses by limiting to subjects with no ventricular hypertrophy in echocardiography, but the results did not materially change. Several limitations of the present study warrant consideration. First, although we adjusted for multiple conventional risk factors, possible residual confounding might still exist, and the availability of 1 baseline measurement of ECG did not allow for assessment of temporal changes of STD. Second, this study included only individuals between the ages of 45 and 64 years, and thus we cannot comment on the influence of resting STD outside this age range. Third, patients with diagnosed cardiovascular disease may change their lifestyle to decrease the levels of risk factors and use cardiovascular medication regularly to reduce the risk of SCD. In addition, not every subject underwent coronary angiography or computed tomography examination. It is therefore possible that the higher SCD rates in subjects with resting STD were partly due to underlying undiagnosed CHD that increased the risk of SCD. However, the risk of SCD did not materially change even after censoring the analyses at the time of incident CHD or acute myocardial infarction, which might greatly reduce the influence of CHD. Fourth, because very few cases had autopsies in our study, we could not exclude the possibility that a small proportion of SCD might be caused by myocardial ischemia. However, sensitivity analyses of subjects with imaging evidence showing no coronary artery disease changed the overall risk estimate little, indicating the influence of myocardial ischemia on the main outcome, if exists, might be minimal. In conclusion, this study has shown that the presence of painless STD increased the risk of SCD. In particular, much attention should be paid to STD in whites and males, STD in lateral leads and global leads, and STD with the amplitude of N0.1 mV. Future clinical and experimental studies should focus on understanding the exact mechanisms for SCD associated with STD. Declaration of competing interest None. Acknowledgment The authors thank the staff and participants of the ARIC study and BioLINCC for their important contributions. Funding The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts. The study was also financially supported by the grants from National Natural Science Foundation of China (81600260), Guangdong Natural Science Foundation (2016A030313210), the Science and Technology Planning Project of Guangdong Province (2017A020215174), Medical and Health Project of Huangpu District (201607), the Fundamental Research Funds for the Central Universities in Sun Yat-Sen University (18ykpy08), and the project of Kelin new star of the First Affiliated Hospital of Sun Yat-Sen University (Y50186).
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2019.11.148. References [1] V. Waldmann, W. Bougouin, N. Karam, F. Dumas, A. Sharifzadehgan, E. Gandjbakhch, et al., Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation, Eur. Heart J. 39 (2018) 1981–1987. [2] S.S. Chugh, K. Reinier, C. Teodorescu, A. Evanado, E. Kehr, S.M. Al, et al., Epidemiology of sudden cardiac death: clinical and research implications, Prog. Cardiovasc. Dis. 51 (2008) 213–228. [3] Survivors of out-of-hospital cardiac arrest with apparently normal heart. Need for definition and standardized clinical evaluation, Consensus statement of the joint steering committees of the unexplained cardiac arrest registry of Europe and of the idiopathic ventricular fibrillation registry of the United States, CIRCULATION. 95 (1997) 265–272. [4] R. Auer, D.C. Bauer, P. Marques-Vidal, J. Butler, L.J. Min, J. Cornuz, et al., Association of major and minor ECG abnormalities with coronary heart disease events, JAMA. 307 (2012) 1497–1505. [5] M.L. Daviglus, Y. Liao, P. Greenland, A.R. Dyer, K. Liu, X. Xie, et al., Association of nonspecific minor ST-T abnormalities with cardiovascular mortality: the Chicago Western Electric Study, JAMA. 281 (1999) 530–536. [6] J.A. Laukkanen, T.H. Makikallio, R. Rauramaa, S. Kurl, Asymptomatic ST-segment depression during exercise testing and the risk of sudden cardiac death in middle-aged men: a population-based follow-up study, Eur. Heart J. 30 (2009) 558–565. [7] H. Bundgaard, C. Jons, E.M. Lodder, J. Izarzugaza, H.J. Romero, S. Pehrson, et al., A novel familial cardiac arrhythmia syndrome with widespread ST-segment depression, N. Engl. J. Med. 379 (2018) 1780–1781. [8] R. Florido, L. Kwak, M. Lazo, V. Nambi, H.M. Ahmed, S.M. Hegde, et al., Six-year changes in physical activity and the risk of incident heart failure: ARIC study, CIRCULATION. 137 (2018) 2142–2151. [9] A.V. Khera, C.A. Emdin, I. Drake, P. Natarajan, A.G. Bick, N.R. Cook, et al., Genetic risk, adherence to a healthy lifestyle, and Coronary Disease. N Engl J Med. 375 (2016) 2349–2358. [10] The ARIC investigators (Ed.), The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives, Am J Epidemiol 129 (1989) 687–702. [11] C.A. Giffen, E.L. Wagner, J.T. Adams, D.M. Hitchcock, L.A. Welniak, S.P. Brennan, et al., Providing researchers with online access to NHLBI biospecimen collections: the results of the first six years of the NHLBI BioLINCC program, PLoS One 12 (2017), e178141. [12] C.A. Giffen, L.E. Carroll, J.T. Adams, S.P. Brennan, S.A. Coady, E.L. Wagner, Providing contemporary access to historical biospecimen collections: development of the NHLBI biologic specimen and data repository information coordinating center (BioLINCC), BIOPRESERV BIOBANK. 13 (2015) 271–279. [13] W.T. O'Neal, M.J. Singleton, J.D. Roberts, L.G. Tereshchenko, N. Sotoodehnia, L.Y. Chen, et al., Association between QT-interval components and sudden cardiac death: the ARIC study (atherosclerosis risk in communities), Circ. Arrhythm. Electrophysiol. 10 (2017). [14] S. Zarafshar, M. Wong, N. Singh, S. Aggarwal, C. Adhikarla, V.F. Froelicher, Resting ST amplitude: prognosis and normal values in an ambulatory clinical population, Ann. Noninvasive Electrocardiol. 18 (2013) 519–529. [15] L.J. OSTRANDER, R.L. BRANDT, M.O. KJELSBERG, F.H. EPSTEIN, Electrocardiographic findings among the adult population of a total natural community, Tecumseh, Michigan, Circulation. 31 (1965) 888–898. [16] W.B. Kannel, K. Anderson, D.L. McGee, L.S. Degatano, M.J. Stampfer, Nonspecific electrocardiographic abnormality as a predictor of coronary heart disease: the Framingham Study, Am. Heart J. 113 (1987) 370–376. [17] M.J. Hagnas, T.A. Lakka, S. Kurl, R. Rauramaa, T.H. Makikallio, K. Savonen, et al., Cardiorespiratory fitness and exercise-induced ST segment depression in assessing the risk of sudden cardiac death in men, HEART. 103 (2017) 383–389. [18] M. Haghjoo, S. Mohammadzadeh, M. Taherpour, B. Faghfurian, A.F. Fazelifar, A. Alizadeh, et al., ST-segment depression as a risk factor in hypertrophic cardiomyopathy, EUROPACE. 11 (2009) 643–649. [19] J.L. Fleg, G. Gerstenblith, A.B. Zonderman, L.C. Becker, M.L. Weisfeldt, P.J. Costa, et al., Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers, Circulation. 81 (1990) 428–436. [20] N. Verweij, L.I. Mateo, A. Isaacs, D.E. Arking, J.C. Bis, T.H. Pers, et al., Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram, Hum. Mol. Genet. 25 (2016) 2093–2103.
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Association between resting painless ST-segment depression with sudden cardiac death in middle-aged population: A prospective cohort study Xue-Qiong Deng a,d,1, Xiong-Jun Xu b,1, Su-Hua Wu a,d, Hai Li c,⁎, Yun-Jiu Cheng a,d,⁎⁎ a
Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Department of Stomatology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China c Department of Endocrinology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China d Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China b
a r t i c l e
i n f o
Article history: Received 29 March 2019 Received in revised form 18 October 2019 Accepted 26 November 2019 Available online xxxx Keywords: Electrocardiography Sudden cardiac death ST-segment depression Epidemiology
a b s t r a c t Backgound: Silent electrocardiographic ST change predicts future coronary heart disease (CHD) incidence and mortality, but the prognostic significance of painless ST-segment depression (STD) with respect to sudden cardiac death (SCD) in subjects without apparent CHD remain unclear. This study sought to test the association between non-ischemic resting STD and risk of SCD in the general population. Methods: A total of 14,935 middle-aged subjects from the prospective, population-based Atherosclerosis Risk in Communities (ARIC) study were included in this analysis. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. STD was defined as ST-segment depression of ≥0.05 mV in two or more contiguous leads. Results: A total of 626 sudden cardiac death occurred during the mean follow-up of 20.4 years. Compared with those without STD, subjects with resting painless STD of at least 0.05 mV had a significantly increased risk of developing SCD (adjusted HR, 1.45; 95% CI, 1.20 to 1.76), and those with STD ≥ 0.1 mV had even higher risk of SCD (adjusted HR, 1.90; 95% CI, 1.25 to 2.88). Significant interactions were present between gender and STD (P = .03), and between race and STD (P = .01). STD was significantly predictive of SCD in males (adjusted HR, 1.57; 95% CI, 1.22–2.01) and in whites (adjusted HR, 1.65; 95% CI, 1.27–2.14). STD in lateral leads and global leads were strong predictors of SCD. Conclusions: Resting painless STD was an independent predictor of SCD in the middle-aged population without previously diagnosed CHD. © 2019 Published by Elsevier B.V.
1. Introduction Sudden cardiac death (SCD) remains a major public health problem that accounts for a currently estimated incidence of 4–5 million deaths annually and 50% of all cardiovascular mortality around the world [1,2]. In spite of advancements in emergency medical systems, N95% of sudden cardiac arrest victims do not survive to hospital discharge. Most SCD cases, however, occur in the general population, and the majority have no clinically recognized heart disease prior to the event [3]. ⁎ Correspondence to: H. Li, Department of Endocrinology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. ⁎⁎ Correspondence to: Y.J. Cheng, Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510700, China. E-mail addresses: [email protected] (H. Li), [email protected] (Y.-J. Cheng). 1 These authors contributed equally to this work.
Hence, identification of individuals at increased risk of SCD may allow targeted prevention strategies. The presence of ST-segment depression (STD) on the standard 12‑lead electrocardiogram (ECG) has been well recognized to be a powerful predictor of coronary heart disease (CHD) incidence and mortality [4,5]. However, the relation of STD to the risk for SCD is less clear. In men without evident CHD, silent STD during exercise test has been associated with a higher incidence of SCD [6]. More recently, Bundgaard H et al. identified five families with SCDs characterized by widespread non-ischemic STD, raising the possibility that painless STD at rest would have prognostic significance with regard to the risk of SCD in persons without evident CHD [7]. The goal of this study was therefore to examine the association of non-ischemic STD at rest with risk of SCD in participants of the Atherosclerosis Risk in Communities (ARIC) study, a large, multicenter, biracial, community-based cohort, with outcomes surveillance spanning N2 decades.
https://doi.org/10.1016/j.ijcard.2019.11.148 0167-5273/© 2019 Published by Elsevier B.V.
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2. Methods 2.1. Study population The ARIC Study is a prospective epidemiologic study sampled from 4 US communities (Forsyth County, North Carolina; Jackson, Mississippi; suburban Minneapolis, Minnesota; and Washington County, Maryland) [8,9]. Details of the study design have been published elsewhere [10]. During follow up, participants were contacted annually by phone to gather information on hospital admission and verify vital status. Participant follow-up through annual telephone interviews and review of hospitalization records and vital status is ongoing. Institutional review boards at each participating institution approved the ARIC study, and all participants provided informed consent before each examination. We obtained the cohort data sets from the NIH Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) [11,12].For the present analysis, we excluded the following participants: (1) subjects for whom ECGs were missing or incomplete; (2) subjects with ventricular conduction abnormalities (eg, complete left or right bundle branch blocks), pacemakers, Wolff-Parkinson-White syndrome, Brugada syndrome, left ventricular hypertrophy, QRS duration ≥120 ms; Left ventricular hypertrophy was determined by resting ECG (using both Sokolow-Lyon and Cornell criteria) or echocardiography. (3) subjects with symptoms suggestive of prevalent CHD at the baseline. Prevalent CHD was defined as either a history of myocardial infarction or angina pectoris, angina pectoris on effort, or the use of nitroglycerin for chest pain once a week or more frequently; (4) subjects with other diseases that would also cause STD on ECG, such as anaemia, chronic heart failure, pneumonia, stroke, pulmonary embolism and structural heart disease. 2.2. Electrocardiographic measurement Digital 12‑lead ECGs were obtained at baseline as described previously [13]. At the examination, a standard resting supine 12‑lead ECG using MAC PC ECG machines (Marquette Electronics, Milwaukee, Wisconsin) was obtained for each subject a minimum of 1 h after any smoking or caffeine ingestion. Tracings were sent via a phone modem to be computer coded at the ARIC ECG Reading Center. All records with significant Minnesota Code findings as determined by the computer, as well as a random sample of tracings, were independently visually coded by 2 trained coders (cardiologists blinded to outcome status). Final decisions about the discrepancies between the computer code and visual code were made by another senior coder. ST-segment depression was measured on median complexes from the 10 s tracings at the midpoint of the ST segment between the Jpoint and the end of the ST segment using a fully automated method, defined as 1/8 the average R-R interval from the J-point. ST-segment depression of ≥0.05 mV (0.5 mm) in two or more contiguous leads (excluding aVR) was considered abnormal, a value that corresponded to the 95th percentile of ST depression findings in the current population and parallels use of this threshold for detection of ST depression by Minnesota Code [14,15]. 2.3. Ascertainment of outcomes In the present study, SCD was defined as sudden unexpected arrest of presumed cardiac origin without traumatic nature of death. The arrest should have occurred within 24 h after onset of any symptoms that could retrospectively be interpreted as being cardiac origin. The methods for ascertainment of SCD events have been described previously [13]. In order to identify SCD, all fatal cardiovascular events in ARIC were reviewed by an independent panel of physicians. Pairs of physician adjudicators blinded to clinical data and follow-up status, independently assessed the death information using a standard coding form. In case of divergent results, the case was re-coded by paired
investigators. If further disagreement occurred, a preliminary decision was achieved by consensus. In general, the adjudication committee made use of death for witnessed and unwitnessed events, respectively. Only cases of definite SCD were included in the present analysis. 2.4. Statistical analysis Characteristics of the participants at each visiting time point were compared across categories of STD status. Baseline characteristics of participants are presented as means and standard deviations (SDs) for continuous variables and percentages for categorical variables. Tests for differences in means were assessed using unpaired t-tests for continuous variables and χ2 tests for independence for categorical variables. We used Cox's proportional hazards models to obtain unadjusted and multivariate adjusted hazard ratios (HRs) for SCD of subjects with versus those without STD, as well as test for modification of the association between STD and SCD for a series of potential effect modifiers. Follow-up was defined as the time between the baseline visit until the death, loss to follow-up, or end of follow-up. Potential covariates included in the initial model were: age, gender, race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, QTc duration and T-wave inversion. We used an overall measure of STD in any ECG lead and also grouped the leads into inferior (II, III, aVF), lateral (I, aVL, V5-6), and precordial (V1-4) leads. As correlation tests of Schoenfeld residuals and the rank order of event time for assessing Cox proportional hazard assumption indicated that application of the Cox proportional hazard model was appropriate. Kaplan-Meier survival curves were plotted for the outcome of SCD according to different amplitudes of STD, and different races and genders. In sensitivity analyses, we explored the possible role of incident CHD or myocardial infarction in the association between STD and SCD by censoring the analyses at time of CHD or acute myocardial infarction. We also evaluated the impact of competing risk adjustment of death due to all other (non-SCD) causes. Furthermore, we compared the HRs of SCD with those of total mortality and total cardiovascular mortality, as well. We used Stata version 13.0 for all analyses. Statistical tests were 2sided and used a significance level of P b .05. 3. Results 3.1. Baseline characteristics After application of exclusion criteria (including 186 participants with missing or incomplete ECGs), a total of 14,935 participants were included in this study. The baseline characteristics stratified by STD status are shown in Appendix Table 1. In the study cohort, 45.36% were males and 74.13% were whites. Individuals with STD were more likely to have history of diabetes mellitus and prevalence of T-wave inversion on ECG. They were more often older, had a higher fasting blood glucose, blood cholesterol, and QTc duration, and had a lower serum potassium and serum magnesium than those without STD. Of note, ECG changes affecting the ST segment seem to be a more common background variation in blacks than whites. However, the prevalence of STD was not significant different between males and females (p = .11).In addition, 47.7% of the total participants underwent stress testing, coronary angiography or computed tomography examination to rule out the possibility of coronary artery disease at the baseline when ECGs were performed. Among all the participants, the ECGs indicated no signs of ventricular hypertrophy, and the diagnosis was further confirmed by echocardiography for 37.2% of the participants. In our study population the overall prevalence of STD was 14.78%. Distribution of STD was as follows: 1162 (7.78%) in inferior leads only, 195 (1.31%) in lateral leads only, 515 (3.45%) in precordial leads only, 262 (1.88%) in two lead
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territories, and 74 (0.53%) in global leads. Representative examples of STD in our study population are shown in Appendix Fig. 1. 3.2. Risk of sudden cardiac death After a maximum follow-up of 23.9 years and a mean of 20.4 ± 5.5 years, a total of 626 SCD events occurred (incidence rate = 1.1 per 1000 person-years). Subjects with painless STD ≥ 0.05 mV at rest experienced a higher risk of developing SCD (unadjusted HR, 2.31; 95% CI, 1.94 to 2.76; adjusted HR, 1.45; 95% CI, 1.20 to 1.76) compared with those without STD after adjusting for multiple conventional risk factors. Painless STD ≥ 0.1 mV was associated with an even higher risk of SCD (unadjusted HR, 4.47; 95% CI, 3.11 to 6.43; adjusted HR, 1.90; 95% CI, 1.25 to 2.88). The cumulative hazard curves for SCD continued to diverge during the follow-up period (Fig. 1). Using the information on person-years in subjects with and without STD, we could calculate absolute annual rates of SCD from the population: 154.2 cases per 100,000
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person-years in subjects without STD and 2221.9 cases in those with STD, corresponding to an absolute risk increase of 2067.7 (95% CI 1735.2 to 2400.2) cases per 100,000 person-years. Censoring the analyses at the time of incident CHD or acute myocardial infarction did not alter risk estimates meaningfully (Appendix Table 2). The subdistribution HRs obtained from the competing risk model remained qualitatively similar to main results (for STD ≥ 0.05 mV: adjusted HR, 1.55; 95% CI, 1.28 to 1.88; for STD ≥ 0.1 mV: adjusted HR, 1.99; 95% CI, 1.22 to 3.22).In comparison with the SCD analyses, the risk estimates were slightly lower for cardiovascular mortality and total mortality (Appendix Table 3). Furthermore, limiting analyses to subjects with imaging evidence showing no coronary artery disease did not change the results materially (for STD ≥ 0.05 mV: adjusted HR, 1.51; 95% CI, 1.31 to 1.74; for STD ≥ 0.1 mV: adjusted HR, 1.93; 95% CI, 1.29 to 2.89). In addition, analyses confining to subjects with no ventricular hypertrophy in echocardiography yielded similar results to main findings (for STD ≥ 0.05 mV: adjusted HR, 1.48; 95% CI, 1.25 to 1.75; for STD ≥ 0.1 mV: adjusted HR, 1.96; 95% CI, 1.31 to 2.93).
3.3. Stratified analyses
Fig. 1. Kaplan-Meier survival curves for sudden cardiac death in subjects with asymptomatic ST-segment depression. Subjects with ST-segment depression of N0.05 mV on standard 12‑lead electrocardiography had an elevated risk of sudden cardiac death, as compared with those without an ST-segment depression, with an unadjusted HR of 2.31 (95% CI, 1.94 to 2.76, P b .001) (Panel A). Subjects with STsegment depression of N0.1 mV had an unadjusted HR of sudden cardiac death of 4.47 (95% CI, 3.11 to 6.43, P b .001) (Panel B).
When stratifying for localization of STD ≥ 0.05 mV, we found that global distribution conferred the strongest risk for SCD (adjusted HR, 3.76; 95% CI, 1.93 to 7.33), followed by lateral distribution (adjusted HR, 3.31; 95% CI, 2.13 to 5.14), while inferior or precordial distribution was of no significance in predicting SCD in multiple variables adjusted analysis. In addition, subjects with STD ≥ 0.1 mV in global leads and lateral leads had markedly elevated risk of developing SCD (for global leads: adjusted HR, 4.21; 95% CI, 2.03 to 8.73; for lateral leads: adjusted HR, 5.78; 95% CI, 2.10 to 15.93) (Table 1). Among subjects with STD in any lead, a significant interaction was present between gender and STD for the outcome of SCD. Males with STD had a higher risk of SCD (adjusted HR, 1.57; 95% CI, 1.22 to 2.01) than did males without STD. However, STD did not confer an increased risk of SCD among females (adjusted HR, 1.19; 95% CI, 0.86 to 1.65). The ratio of HRs for males compared with females was 1.34, indicating significant difference between these groups in the risk associated with STD (p = .03) (Fig. 2). A significant interaction between race and STD was also present. STsegment depression was associated with significantly increased risk of SCD in whites (adjusted HR, 1.65; 95% CI, 1.27 to 2.14). However, STD was not a marker of increased risk of SCD in blacks (adjusted HR, 1.20; 95% CI, 0.89 to 1.61). The ratio of HRs for whites compared with blacks for SCD was 1.38, indicating that STD connotes a greater risk of SCD in whites than it does in blacks (p = .01) (Fig. 2). Further analysis of subjects with imaging evidence showing no coronary artery disease still showed that only whites with STD experienced increased risk of SCD (adjusted HR, 1.72; 95% CI, 1.39 to 2.13). Notably, STD was associated with significantly increased risk of developing SCD in subjects without hypertension (adjusted HR 1.53, 95% CI 1.13 to 2.07),but not in those with hypertension (adjusted HR 1.21, 95% CI 0.94 to 1.56; p = .05 for interaction).In addition, the risk estimates of SCD associated with STD seemed to be higher in subjects without diabetes mellitus (adjusted HR 1.67, 95% CI 1.33 to 2.10) compared with those with diabetes mellitus (adjusted HR 1.03, 95% CI 0.72 to 1.48; p = .005 for interaction). No significant interaction effects were identified between subjects aged ≥55 years and b55 years, with and without dyslipidaemia, or between smokers and non-smokers (Fig. 2). Given that the relationship between STD and SCD differed based on gender and race, the four subgroups (white males, white females, black males, and black females) were examined separately. Only white males were found to have a significantly increased risk of SCD when STD was present (adjusted HR, 1.75; 95% CI, 1.28 to 2.38) (Appendix Table 4). Fig. 3 show the Kaplan-Meier curves for SCD in subjects with STD stratified by race and gender simultaneously.
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Table 1 Hazard ratios (HRs) of various ST-segment depression patterns for sudden cardiac death. SCD Events
Total Participants
Model 1 HR (95% CI)a
Model 2 HR (95% CI)b
Model 3 HR (95% CI)c
Model 4 HR (95% CI)d
458
12,727
1.00
1.00
1.00
1.00
ST-segment depression ≥0.05 mV Any leads 168 Inferior leads only 72 Lateral leads only 24 Precordial leads only 25 Global Leads 12
2208 1162 195 515 74
2.31 (1.94–2.76) 1.78 (1.39–2.28) 4.72 (3.13–7.12) 1.39 (0.93–2.08) 7.42 (4.18–13.17)
2.17 (1.82–2.59) 1.68 (1.31–2.16) 3.93 (2.60–5.94) 1.38 (0.92–2.07) 6.21 (3.49–11.02)
1.64 (1.37–1.98) 1.20 (0.93–1.55) 3.15 (2.03–4.87) 1.18 (0.78–1.76) 4.08 (2.24–7.45)
1.45 (1.20–1.76) 1.18 (0.92–1.54) 3.31 (2.13–5.14) 1.10 (0.72–1.66) 3.76 (1.93–7.33)
ST-segment depression ≥0.1 mV Any leads 31 Inferior leads only 12 Lateral leads only 4 Precordial leads only 1 Global Leads 6
253 104 16 26 33
4.47 (3.11–6.43) 3.53 (1.99–6.27) 12.48 (4.66–33.41) 1.34 (0.19–9.55) 7.88 (3.52–17.65)
3.83 (2.66–5.52) 3.29 (1.85–5.83) 11.17 (4.17–29.90) 1.03 (0.14–9.55) 6.15 (2.74–13.78)
2.26 (1.54–3.32) 1.81 (1.01–3.24) 5.52 (2.03–15.00) 0.97 (0.14–6.92) 4.94 (2.55–9.57)
1.90 (1.25–2.88) 1.64 (0.91–2.97) 5.78 (2.10–15.93) 0.67 (0.09–4.85) 4.21 (2.03–8.73)
No ST-segment depression
a
Model 1 adjusted for no cardiovascular risk factor. Model 2 adjusted for age and gender. c Model 3 adjusted for variables in model 2 plus race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, and QTc duration. d Model 4 adjusted for variables in model 3 plus T-wave inversion. b
4. Discussion This study is, to the best of our knowledge, the first to investigate the association of resting STD with the risk of SCD in a large middle-aged
population without evident CHD, and several of our findings add to current knowledge. First, resting STD is associated with increased risk of SCD independent of traditional cardiovascular risk factors. In absolute risk, STD would account for an estimated 2067.7 additional SCDs per
Fig. 2. Stratified analysis of hazard ratios (HRs) of sudden cardiac death associated with asymptomatic ST-segment depression. *Cox's proportional hazards model, adjusted for age, gender, race, heart rate, hypertension, body mass index, dyslipidaemia, diabetes, smoking status, physical activity, serum electrolytes, QTc duration and T-wave inversion.
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Fig. 3. Kaplan-Meier survival curves for sudden cardiac death in white subjects (Panel A) and black subjects (Panel B) with and without ST-segment depression, stratified by gender. WM: white males; WF: white females; BM: black males; BF: black females.
100,000 subjects per year in the general population. Second, the increased risk was present predominantly in whites and males, and those without history of hypertension and diabetes mellitus. Third, STD in lateral leads and global leads, and STD with the amplitude of N0.1 mV appeared to strong predictors of SCD. Painless STD is a not uncommon finding, and 10.3% of middle-aged men free of evidence of CHD, had STD at least once in annual resting ECG examinations during 5 years in the Chicago Western Electric Study [5]. Kannel et al. reported that in Framingham Study examinations 8 to 12, 14.1% of population aged 44 to 74 years had nonspecific STD [16]. In our study, we observed that painless STD at rest was present in 14.7% of the middle-aged biracial population. Therefore, STD in the absence of pain might be more common than with angina in daily life. The predictive value of STD for future coronary events in patients with CHD has been well established, but few studies assessed the association between STD and future risk of SCD. Hagnäs et al. reported a 4.8fold increase of SCD in subjects with both low cardiorespiratory fitness and exercise-induced STD in 2328 middle-aged men [17]. In another
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cohort study by Laukkanen et., silent STD during and after maximal symptom-limited exercise test increased the risk of SCD by 2.1 and 3.2 folds, respectively [6]. In subjects with hypertrophic cardiomyopathy, STD in the high lateral leads is a strong predictor of sudden death or appropriate implantable cardioverter-defibrillator therapy (odds ratio: 20.0, 95% CI: 12.7 to 27.5) [18]. No previous study has examined the predictive value of painless resting STD for future SCD among the general population. In the present study, the risk magnitude of SCD associated with resting STD was 1.64, which appears to be less robust than those reported for exerciseinduced STD. However, the ECGs during or after exercise stress test are not easily accessible. In addition, resting STD is a common electrocardiographic finding around the world, and the absolute risk of SCD associated with resting STD is very high, the total number of excess SCD may not be negligible. Furthermore, N85% of all sudden cardiac events occurred out of hospital that makes the registration of painless STD in the prediction of SCD highly valuable [3]. Despite recent advances in technology, survival from out-of-hospital SCD remains low throughout the word at about 5%. More importantly, we identified that white males and those with STD in lateral leads and global leads and STD ≥ 0.1 mV were at greater risk of SCD, which makes it more meaningful in the clinical practice. Therefore, our results could have some implications for the clinicians: a middle-aged white male with painless STD at rest and “normal” coronaries could experience increased risk of SCD, and thus further evaluations including electrophysiological studies should be performed for those at high risk, aiming to prevent the risk of SCD. Despite the fact that the presence and specific phenotypes of resting STD is associated with risk for SCD, the underlying mechanisms remain unclear. A number of situations, including myocardial ischaemia, ventricular hypertrophy, hyperventilation, electrolyte abnormalities, anaemia, and increased sympathetic activity are known to cause STD [19]. In light of these concerns, our present analyses excluded persons with chest discomfort, CHD, ventricular hypertrophy and anaemia, and controlled for serum electrolytes. This ensured that the prognostic evaluation involved only isolated nonspecific STD. Our results indicated the association between STD and SCD could not be solely explained by myocardial ischaemia. First, censoring the analyses at the time of incident CHD or acute myocardial infarction yielded similar results to the main finding. Second, subjects without history of hypertension and diabetes mellitus tend to have higher risk compared with those with these conditions. Therefore, we propose another possible mechanism: the involvement of hereditary susceptibility in the pathogenesis of STD and development of SCD. First, twenty-eight genetic loci in a set of genes involved in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) had been associated with ST-segment amplitudes of the ECG [20]. Second, Bundgaard et al. has recently described five families with a novel cardiac syndrome characterized by nonischemic STD and SCD, which was considered to be inherited as an autosomal dominant trait [7]. Third, we have observed differences in risk of SCD between males and females, whites and blacks, and this could be partly explained by genetic mechanisms. ST-segment depression could be a single phenotypic manifestation of a diverse array of genotypes. These genotypic variations may be differentially distributed between various racial and gender groups. Some genotypes may increase risk of SCD, whereas others might be completely benign while producing similar ECG findings. Major strengths of our study are the relatively large sample size, sensitivity analyses, and multiple confounding factors included in the analyses. All data were collected irrespective of the current hypothesis. The setting of a population-based cohort and the long follow-up allowed for the estimation of long-term absolute risks. Furthermore, the cases of SCD were ascertained by a strict adjudication process, which might provide a more accurate definition of SCD than is often available in other epidemiological studies. In addition, the application of an entirely
Please cite this article as: X.-Q. Deng, X.-J. Xu, S.-H. Wu, et al., Association between resting painless ST-segment depression with sudden cardiac death in middle-aged ..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.148
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X.-Q. Deng et al. / International Journal of Cardiology xxx (xxxx) xxx
automated method to detect STD eliminates bias and enables us to compare the prognostic significance of this pattern. Furthermore, all ECGs indicated no signs of ventricular hypertrophy, which was an established risk factor for both STD and SCD. Given that ECG only might not be reliable for defining ventricular hypertrophy, we also performed sensitivity analyses by limiting to subjects with no ventricular hypertrophy in echocardiography, but the results did not materially change. Several limitations of the present study warrant consideration. First, although we adjusted for multiple conventional risk factors, possible residual confounding might still exist, and the availability of 1 baseline measurement of ECG did not allow for assessment of temporal changes of STD. Second, this study included only individuals between the ages of 45 and 64 years, and thus we cannot comment on the influence of resting STD outside this age range. Third, patients with diagnosed cardiovascular disease may change their lifestyle to decrease the levels of risk factors and use cardiovascular medication regularly to reduce the risk of SCD. In addition, not every subject underwent coronary angiography or computed tomography examination. It is therefore possible that the higher SCD rates in subjects with resting STD were partly due to underlying undiagnosed CHD that increased the risk of SCD. However, the risk of SCD did not materially change even after censoring the analyses at the time of incident CHD or acute myocardial infarction, which might greatly reduce the influence of CHD. Fourth, because very few cases had autopsies in our study, we could not exclude the possibility that a small proportion of SCD might be caused by myocardial ischemia. However, sensitivity analyses of subjects with imaging evidence showing no coronary artery disease changed the overall risk estimate little, indicating the influence of myocardial ischemia on the main outcome, if exists, might be minimal. In conclusion, this study has shown that the presence of painless STD increased the risk of SCD. In particular, much attention should be paid to STD in whites and males, STD in lateral leads and global leads, and STD with the amplitude of N0.1 mV. Future clinical and experimental studies should focus on understanding the exact mechanisms for SCD associated with STD. Declaration of competing interest None. Acknowledgment The authors thank the staff and participants of the ARIC study and BioLINCC for their important contributions. Funding The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts. The study was also financially supported by the grants from National Natural Science Foundation of China (81600260), Guangdong Natural Science Foundation (2016A030313210), the Science and Technology Planning Project of Guangdong Province (2017A020215174), Medical and Health Project of Huangpu District (201607), the Fundamental Research Funds for the Central Universities in Sun Yat-Sen University (18ykpy08), and the project of Kelin new star of the First Affiliated Hospital of Sun Yat-Sen University (Y50186).
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Please cite this article as: X.-Q. Deng, X.-J. Xu, S.-H. Wu, et al., Association between resting painless ST-segment depression with sudden cardiac death in middle-aged ..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.148