Association of silent myocardial infarction on electrocardiogram and coronary artery calcium: The Multi‐Ethnic Study of Atherosclerosis

Abstract Background Silent myocardial infarction (SMI) on electrocardiogram (ECG) is associated with atherosclerotic cardiovascular disease, but the relationship between SMI on ECG and coronary artery calcium (CAC) remains poorly understood. Objective Characterize the relationship between SMI on ECG and CAC. Methods Eligible participants from the Multi‐Ethnic Study of Atherosclerosis study had ECG and CAC scoring at study enrollment (2000–2002). SMI was defined as ECG evidence of myocardial infarction in the absence of a history of clinical cardiovascular disease. CAC was modeled both continuously and categorically. The cross‐sectional relationships between SMI on ECG and CAC were assessed using logistic regression and linear regression. Results Among 6705 eligible participants, 178 (2.7%) had baseline SMI. Compared to participants without SMI, those with SMI had higher CAC (median [IQR]: 61.2 [0–261.7] vs. 0 [0–81.5]; p < .0001). Participants with SMI were more likely to have non‐zero CAC (74% vs. 49%) and were more likely to have CAC ≥ 100 (40% vs. 23%). In a multivariable‐adjusted logistic model, SMI was associated with higher odds of non‐zero CAC (odds ratio 2.17, 95% CI 1.48–3.20, p < .0001) and 51% higher odds of CAC ≥ 100 (odds ratio 1.51, 95% CI 1.06–2.16, p = .02). Conclusion An incidental finding of SMI on ECG may serve to identify patients who have a higher odds of significant CAC and may benefit from additional risk stratification to further refine their cardiovascular risk. Further exploration of the utility of CAC assessment in this patient population is needed.

Conclusion: An incidental finding of SMI on ECG may serve to identify patients who have a higher odds of significant CAC and may benefit from additional risk stratification

| INTRODUC TI ON
Silent myocardial infarction (SMI) is defined as electrocardiographic (ECG) evidence of prior myocardial infarction (MI) in the absence of prevalent clinical cardiovascular disease (Soliman, 2019).
Prior reports have found that SMI accounts for about half of all MI (Pride et al., 2013). Several studies have noted that SMI is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) (Casale et al., 1987;Qureshi et al., 2018;Singleton et al., 2020;Zhang et al., 2016), but the relationship between SMI and coronary artery calcium (CAC) is poorly understood. Therefore, we sought to explore the association of SMI by ECG with CAC in a multiethnic cohort initially free of prevalent clinical cardiovascular disease.

| Study population
The design and conduct of the Multi-Ethnic Study of Atherosclerosis (MESA) study have been previously reported (Bild et al., 2002).
In brief, MESA is a prospective cohort of 6814 participants, 45-84 years of age, initially free of clinical cardiovascular disease (2000)(2001)(2002). Participants were recruited from six United States communities: Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; New York City, NY; and Saint Paul, MN. For the present analysis, we excluded 109 participants whose baseline ECG could not be assessed for SMI due to either incomplete ECG data (n = 104) or competing Minnesota codes that preclude ascertainment of SMI by ECG (n = 5), leaving 6705 eligible participants. Study protocols were approved by the institutional review boards at participating institutions. All participants provided written informed consent.

| Outcome variable
The details of the MESA protocols for the measurement of CAC have been reported previously (Carr et al., 2005). Briefly, CAC was assessed by chest computed tomography and referenced to a phantom of known physical calcium concentration. All scans were centrally read at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California. The Agatson score was averaged over two scans for all analyses.

| Covariates
Baseline covariates were obtained at the initial MESA examination (2000)(2001)(2002). Current smoking was defined as smoking at least one cigarette in the preceding 30 days. Diabetes mellitus was defined as a fasting glucose concentration ≥126 mg/dL or the use of hypoglycemic medication. Antihypertensive medication use was determined from a review of prescription medications. Electrocardiographic left ventricular hypertrophy was assessed by Novacode criteria (Rautaharju et al., 1998). Self-reported physical activity was mod-

| Statistical methods
Baseline characteristics of the study population stratified by SMI were compared using mean ± standard deviation for continuous variables and frequency (percentage) for categorical variables.
Between-group differences were assessed using analysis of variance for continuous variables and chi-squared tests for categorical variables. Initially, CAC was modeled as a categorical variable and the odds of elevated CAC using two different thresholds (CAC > 0 and CAC ≥ 100) were compared in participants without and with SMI using logistic regression. Our initial model was unadjusted, with subsequent models adjusted for covariates believed to be of clinical significance or that might confound the relationship between SMI and CAC, including age, sex, and race/ethnicity in Model 2, with Model 3 to further refine their cardiovascular risk. Further exploration of the utility of CAC assessment in this patient population is needed.

K E Y W O R D S
atherosclerotic cardiovascular disease, biomarkers, coronary artery calcium score, risk, silent myocardial infarction also adjusting for current smoking, diabetes, systolic blood pressure, antihypertensive medication use, statin use, high-density lipoprotein cholesterol, total cholesterol, body mass index, left ventricular hypertrophy by electrocardiogram, and self-reported physical activity. Our secondary analysis considered CAC as a continuous variable and used linear regression to determine the relationship between SMI and CAC. A secondary analysis was performed, in which the CAC score was log-transformed. The consistency of the above relationships was explored in prespecified subgroups by sex and race/ ethnicity by including an interaction term in the model. Two-sided p-values below .05 were considered to be statistically significant.
All statistical analyses were conducted at Wake Forest University School of Medicine using SAS version 9.4.

| RE SULTS
Among the 6705 eligible MESA participants (mean age 62.2 ± 10.2 years, 53% women, 38% white, 12% Chinese-American, 28% African-American, 22% Hispanic), 6527 (97.3%) did not have SMI at baseline, while 178 (2.7%) had SMI at baseline. Baseline characteristics of the study population stratified by SMI are presented in Table 1. Participants with SMI at baseline were older, more likely to be male, and more likely to have higher systolic and diastolic blood pressures, diabetes or impaired fasting glucose, hypertension requiring antihypertensive therapy, and left ventricular hypertrophy by ECG.
Compared to participants without SMI, those with SMI were more likely to have non-zero CAC (74% vs. 49%) and were more likely to have CAC ≥ 100 (40% vs. 23%; Table 2). In an unadjusted logistic model, SMI was associated with higher odds of non-zero CAC and higher odds of CAC ≥ 100. After adjusting for demographics and clinical covariates, SMI remained independently associated with higher odds of CAC ≥ 0 and CAC ≥ 100 ( Figure 1). When CAC was modeled as a continuous variable, participants with SMI had higher CAC than those without SMI (Table 3). In a multivariableadjusted linear regression model, SMI remained independently associated with higher CAC. In light of the lack of normal distribution of CAC, we then log-transformed the CAC score (natural logarithm of CAC plus 1)-findings were overall similar ( Table 4). The above relationships were consistent in prespecified subgroups by sex and race/ethnicity, with p-values for sex-SMI interaction and p-values for race/ethnicity-SMI interaction all >.40.

| DISCUSS ION
In this cross-sectional analysis of a contemporary multiethnic United States cohort, we found that SMI on ECG was independently associated with increased odds of elevated CAC.
Since SMI was first described 70 years ago (Hipp et al., 1949), most of the published literature suggests that SMI conveys a worse prognosis and a higher risk of subsequent cardiovascular events (Godsk et al., 2012;Merkler et al., 2019;Qureshi et al., 2018;Stokes & Dawber, 1959). Despite this fact, the way in which an incidental finding of SMI on ECG is incorporated into clinical medicine remains TA B L E 1 Characteristics of MESA study participants (n = 6705) stratified by prevalent SMI.

TA B L E 2
The association between silent myocardial infarction (SMI) and elevated coronary artery calcium (CAC) score using two thresholds (coronary calcium greater than zero or 100 Agatson units) is provided using a multivariable logistic regression model.

F I G U R E 1
Silent myocardial infarction and coronary artery calcium. Multi-Ethnic Study of Atherosclerosis participants with silent myocardial infarction had higher odds of non-zero coronary calcium and coronary calcium greater than 100. Adjusted model includes age, sex, race/ethnicity, smoking, diabetes, systolic blood pressure, antihypertensive medication use, left ventricular hypertrophy by electrocardiogram, and self-reported physical activity.
improves discrimination in select patient populations (Singleton et al., 2020) but not in other patient populations (Singleton et al., 2021), the correlation of SMI on ECG with the presence and burden of scar on advanced imaging is poor to fair (Dastidar et al., 2016;Kaandorp et al., 2005). It is likely that cardiac magnetic resonance imaging (CMRI) is more sensitive for myocardial scar than ECG, as the quantity of myocardium that must be infarcted before there is ECG evidence of infarction is likely greater than the amount that must be infarcted for detection on CMRI. Prior work from MESA is consistent with this hypothesis, as only 9.3% of participants with myocardial scars detected by CMRI had ECG evidence of MI (Turkbey et al., 2015). However, though CMRI has the benefit of higher sensitivity, ECG is much more affordable and is widely available, so there is value in optimizing the use of ECG for refining risk and choosing the optimal patient population to undergo advanced imaging. Our findings of an association between SMI on ECG and elevated CAC suggest that patients with SMI on ECG may benefit from formal CAC screening to further refine risk.
When stratified by sex and race/ethnicity, the reported relationships between SMI and CAC were conserved, with no evidence of interaction between either sex or race/ethnicity and SMI with regard to CAC. This consistency in the SMI-CAC association is interesting since prior analyses have found that the prognostic significance of SMI differs by sex and race/ethnicity (Zhang et al., 2016).
This consistency of association between SMI and CAC, despite the differential effects on outcomes by sex and race/ethnicity, suggests that some of the risk associated with SMI may not be related to CAC, which is consistent with the literature demonstrating that SMI by ECG and myocardial scar by CMRI are only loosely correlated (Turkbey et al., 2015).
Our study should be interpreted in the context of its limitations.
Although we adjusted for covariates with either known or suspected relationships with SMI and CAC, residual confounding always remains a possibility. Our study population was free of known clinical cardiovascular disease at baseline, so our findings may not apply to a higher-risk patient population with prevalent cardiovascular dis- Strengths of our study include the multiethnic cohort, centralized ECG reading center, and consistent CT imaging protocols used for all participants.

TA B L E 3
The association between silent myocardial infarction and elevated coronary artery calcium score (continuous) is provided using a multivariable linear regression model.

SMI Participants (n) CAC (mean ± SD)
Model Note: Silent myocardial infarction is associated with a higher coronary artery calcium score in both unadjusted and adjusted models. Model 1 is unadjusted. Model 2 adjusts for age, sex, and race/ethnicity. Model 3 adjusts for the covariates in Model 2, plus smoking, diabetes, systolic blood pressure, antihypertensive medication use, statin use, high-density lipoprotein cholesterol, total cholesterol, body mass index, left ventricular hypertrophy by electrocardiogram, and self-reported physical activity.

TA B L E 4
The association between silent myocardial infarction and elevated coronary artery calcium score (log-transformed) is provided using a multivariable linear regression model.

| CON CLUS ION
In this analysis of the MESA study, we found that SMI on ECG is associated with higher CAC scores and higher odds of a non-zero CAC score. An incidental finding of SMI on ECG may serve to identify patients who have a higher likelihood of significant CAC and may benefit from additional risk stratification to further refine their cardiovascular risk-further exploration of the utility of CAC assessment in this patient population is needed.

AUTH O R CO NTR I B UTI O N S
Matthew Singleton is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the study's conception and design. Matthew

Dr Elsayed Z. Soliman is an Editorial Board member of both Annals of Noninvasive Electrocardiology and CNS Neuroscience and
Therapeutics and, a co-author of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication.

E TH I C S S TATEM ENT
Study protocols were approved by the institutional review boards at participating institutions. All participants provided written informed consent (Bild et al., 2002).

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available at National Heart, Lung and Blood Institute Biologic Specimen and