Coronary artery calcium and sudden cardiac death: current evidence and future directions

Abstract

Purpose of review

To provide a summary of the current evidence and highlight future directions regarding coronary artery calcium (CAC) and risk of sudden cardiac death (SCD).

Recent findings

Although up to 80% of all SCD is attributed to coronary heart disease (CHD), the subclinical atherosclerosis markers that help to improve SCD risk prediction are largely unknown. Recent observational data have demonstrated that, after adjustment for traditional risk factors, there is a stepwise higher risk for SCD across increasing CAC burden such that asymptomatic patients without overt atherosclerotic cardiovascular disease (ASCVD) experience a three-fold to five-fold higher SCD risk beginning at CAC at least 100 when compared with CAC = 0. Although the mechanisms underlying increasing CAC and SCD risk have yet to be fully elucidated, risk for myocardial infarction and scar, and/or exercise-induced ischemia may be potential mediators.

Summary

High CAC burden is an important risk factor for SCD in asymptomatic middle-aged adults, suggesting that SCD risk stratification can begin in the early stages of CHD via measurement of calcific plaque on noncontrast computed tomography. Despite the clinical inertia for downstream functional cardiac testing after detecting high CAC, comprehensive ASCVD prevention strategies should be the primary focus for SCD risk reduction.

INTRODUCTION

Sudden cardiac death (SCD) is defined as a death secondary to cessation of cardiac activity within 1 h of clinical status among persons with or without overt atherosclerotic cardiovascular disease (ASCVD) [1]. As one of the leading causes of mortality, SCD contributes to up to 15% of all mortality in the United States and other major developed countries [2,3]. In 2019, a total of 370 000 deaths were attributable to SCD in the United States [3]. Although there have been major advancements to the treatment of coronary heart disease (CHD), which is implicated in up to four out of every five SCD cases [4], risk assessment and prevention of SCD remains suboptimal.

Beyond inheritable causes of SCD, including but not limited to congenital long QT syndrome, Brugada syndrome, and hypertrophic cardiomyopathy, most efforts regarding SCD risk assessment have largely focused on secondary prevention patients, including those who have already experienced a myocardial infarction or who have a left ventricular ejection fraction less than 35% [5,6]. This current landscape of SCD risk assessment is justifiable, as such patients are at the highest risk for fatal ventricular arrhythmias. However, there remains a large knowledge gap regarding SCD risk prediction in asymptomatic primary prevention patients [7–10].

Recent observational analyses have shown that elevated coronary artery calcium (CAC) burden is a risk factor for SCD among asymptomatic patients without overt clinical ASCVD [11^▪▪]. In the present review, we summarize evidence and highlight future directions regarding CAC and the risk of SCD. Although careful prospective follow-up data is required, the independent association between CAC and SCD is important for several reasons. First, it suggests that SCD risk stratification can begin much earlier in ASCVD through measurement of calcified plaque in the coronary arteries and that comprehensive prevention strategies, including statin and aspirin therapy when CAC at least 100 Agatston Units or at least 75th percentile, can help reduce SCD risk. Further, it suggests that noncontrast computed tomography (CT) has the potential to serve as the initial gatekeeper modality to guide the careful use of downstream testing for select primary prevention patients who become symptomatic and have a future risk for SCD. We believe these findings have implications for routine SCD risk assessment, including within sports cardiology practice.

CORONARY ARTERY CALCIUM AND SUDDEN CARDIAC DEATH

CAC is the most frequently utilized measure of subclinical atherosclerosis and is quantified non-invasively on noncontrast cardiac-gated CT via the Agatston method [12]. Over the past three decades, an abundance of evidence has demonstrated that CAC is closely associated with ASCVD risk and, thus, is now currently a guideline-indicated approach to guide the initiation of statin, nonstatin, and aspirin therapy for the primary prevention of myocardial infarction and stroke [13,14]. However, evolving evidence is demonstrating a potential broader role for CAC in risk assessment [15^▪,16], particularly with respect to SCD risk assessment in patients who do not have clinical ASCVD.

In one of the first studies of its kind to date, Razavi et al. [11^▪▪] assessed the association between CAC and SCD among more than 65 000 primary prevention patients with one or more ASCVD risk factors who were referred to undergo CAC scoring for the further evaluation of ASCVD risk. There were 211 SCDs over a median one-decade follow-up, and more than 90% of SCD occurred among patients with prevalent CAC. Similar to previous epidemiological studies [17,18], SCD outcome ascertainment was performed using death certificates and select international classification of disease codes derived from the National Death Index.

There was an exponential increase in absolute SCD event rates with higher CAC scores (Fig. 1), which remained consistent even after adjusting for traditional risk factors. Compared with individuals with CAC=0, those with CAC 100–399 were approximately three times more likely to experience SCD, which approached four-fold to five-fold for persons with CAC 400–999 and CAC at least 1000 after the adjustment for traditional risk factors (Table 1). Furthermore, CAC significantly improved the C-statistic for the discrimination of SCD events versus non-SCD events, most strongly among those with a 10-year ASCVD risk less than 7.5%. The results of this study completed in the CAC Consortium demonstrated that SCD risk stratification can be considered much earlier in the pathogenesis of CHD than initially thought and may be usefully performed via the quantification of CAC. Limitations of the study include a low absolute event rates across CAC burden categories as well as an overall low proportion of nonwhite participants and, therefore, these analyses need to be reproduced in more diverse cohorts.

FIGURE 1.

Sudden cardiac death event rate (per 1000 person-years) across increasing coronary artery calcium burden. *There is an exponential increase in the absolute sudden cardiac death event rate with higher coronary artery calcium scores.

Table 1.

Multivariable-adjusted subdistribution hazard ratio (95% confidence intervals) for coronary artery calcium burden with sudden cardiac death

		Model 2
CAC score group	Events (n=211)	SHR (95% CI)a	P trend
CAC=0	19	–
CAC 1–99	33	1.3 (0.7–2.4)
CAC 100–399	53	2.8 (1.6–5.0)	<0.001
CAC 400–999	49	4.0 (2.2–7.3)
CAC ≥1000	57	4.9 (2.6–9.2)

CAC, coronary artery calcium; SCD, sudden cardiac death; SHR, subdistribution hazard ratio.

^aAdjusted for age, sex, current cigarette smoking, diabetes, hypertension, hyperlipidemia, and a family history of coronary heart disease.

PROPOSED MECHANISMS UNDERLYING THE ASSOCIATION BETWEEN CORONARY ARTERY CALCIUM AND SUDDEN CARDIAC DEATH

The stepwise higher risk of SCD across higher CAC scores may be because of several underlying tertiary variables and/or mechanisms. An important effect modifying variable on the potential biological pathway between CAC and SCD is age [19]. There is an exponential association between age and SCD, such that individuals between 70 and 79 years and at least 80 years have a three-fold and ten-fold higher incidence of SCD compared with those less than 70 years of age, respectively [11^▪▪]. In the United States, four out of every five adults at least 65 years old have CAC greater than 0 [20]. Altogether, these results suggest that CAC, a surrogate for total atherosclerotic burden, may be one important contribution for the strong association between age and SCD via ischemic events. This rationale would further support the concept that coronary plaque burden and not coronary stenosis, per se, is predominantly responsible for an individual’s ASCVD risk, including SCD [21,22]. A higher total plaque burden increases the probability of myocardial infarction because of acute plaque rupture even in the absence of chronic stenosis causing myocardial ischemia that could generate a fatal arrhythmia.

CAC often precedes the association between cardiac structural abnormalities and SCD within the atherosclerotic cascade. Myocardial scar is an important and well known risk factor for SCD [23]; however, up to 78% of myocardial scars go unrecognized according to observational cohort data among individuals without known clinical ASCVD [24]. Independent of traditional risk factors as well as left ventricular mass, end-diastolic volume, and ejection fraction, prevalent CAC is longitudinally associated with 2.2-fold higher odds of myocardial scar over a 10-year follow-up [24]. Thus, the association between CAC and SCD may mediated by myocardial scar that serves as an arrhythmogenic substrate. Such subclinical myocardial damage may reflect silent and/or remote ischemia, which is reasonably prevalent among individuals with CAC at least 400 based on single-photon emission CT imaging [25].

Exercise-induced ischemia among those with very-high CAC scores may also be an important consideration for the association between CAC and SCD. Individuals with very-high CAC burden may have obstructive coronary artery stenosis, which with high intensity exercise may lead to supply/demand mismatch and subsequent myocardial ischemia and ventricular arrhythmia. Regular physical activity helps protect against the development of CAC; however, extremely vigorous exercise is positively associated with CAC progression. Among middle-aged men, very vigorous exercise [≥9 metabolic equivalent of task (MET) hours/week] conferred 7% higher odds for the development of calcified plaque on coronary CT angiography [26]. Furthermore, individuals with consistent exercise greater than 2000 MET minutes/week have a significantly higher prevalence of CAC greater than 0 compared with those with less than 1000 MET minutes/week (68 versus 43%) [27]. Although one previous study has suggested that there is no observed increased mortality risk from high levels of physical activity among individuals with CAC at least 100 [28], the association between physical activity and CAC is important because vigorous exercise may be associated with a transient increase in risk for SCD among those vulnerable to coronary events [29].

CLINICAL IMPLICATIONS

There are important clinical questions and implications to consider when evaluating the association between CAC and SCD in patients without overt ASCVD. First, the detection of CAC (especially ≥100 Agatston Units or ≥75th percentile) in asymptomatic individuals should warrant the initiation of comprehensive ASCVD prevention strategies, specifically moderate-to-high intensity statin and aspirin therapy for risk reduction [30] (Fig. 2). Furthermore, individuals with absolute Agatston CAC scores at least 1000 are recommended to have low-density lipoprotein cholesterol goals less than 70 mg/dl and can thus also be eligible to receive nonstatin lipid-lowering therapies, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors [14]. Hypertension and/or type 2 diabetes should also be aggressively treated among individuals with CAC via guideline-recommended pharmacotherapies and a plant-based dietary pattern, low in sodium [30]. Additionally, risk-enhancing factors, including lipoprotein(a) [Lp(a)] should be checked because CAC and Lp(a) confer independent risks for ASCVD [31], and individuals with elevated Lp(a) who have high CAC can likely benefit from current [32] and emerging therapies [33] for Lp(a) reduction.

FIGURE 2.

Proposed sequential testing pathway for sudden cardiac death risk stratification after an initial coronary artery calcium score at least 100 Agatston Units on noncontrast cardiac computed tomography. *Sequential structural and/or functional testing may benefit symptomatic individuals with an elevated baseline risk, those in high-risk occupations or initiating a new moderate–vigorous physical activity regimen.

There are currently no diagnostic recommendations for SCD risk stratification among asymptomatic individuals with detectable CAC, as the current diagnostic approach for SCD prevention are discussed in the context of individuals with suspected ventricular arrhythmias [34]. Here, AHA/ACC guidelines provide a level I recommendation for a 12-lead electrocardiogram, exercise treadmill test, and echocardiography, and provide a IIa for cardiac CT and/or cardiac MRI (cMRI) for the diagnosis of potential underlying structural heart disease [34]. Given the possible interaction of CAC with ventricular structure and function, it is unclear whether the addition of CAC to current clinical risk factors, including ejection fraction and myocardial scar, better predicts SCD than either marker alone. Results from such analyses may guide the utility of sequential testing in SCD risk stratification. For example, given that equivalent secondary prevention level risk may begin as low as CAC at least 300 in those without overt ASCVD [35], it is possible that select individuals in this patient population may benefit from assessment of ventricular structure and function on echocardiogram for SCD risk stratification.

Of note, left ventricular area adjusted to body surface area measured on noncontrast CT is strongly associated with incident heart failure events, independent from traditional risk factors and the CAC score itself [36]. Nevertheless, sequential testing after an initial CAC scan should be considered cautiously to avoid unnecessary downstream testing among asymptomatic individuals who may not benefit from such an approach. The select patient group most likely to benefit from such an approach may be those with an elevated baseline risk, which may be measured via traditional risk factor burden, premature CAC [37], positive family history of myocardial infarction, high polygenic risk [38] and/or family history of SCD [39] as well as individuals who develop any symptoms during the initial risk assessment period (Fig. 2).

Among individuals who could derive maximal benefit from sequential testing for SCD risk stratification involving measurement of CAC may also be those entering high-risk occupations and/or initiating a new exercise program (particularly aerobic/endurance) who have an elevated baseline risk, particularly those who develop symptoms. High-risk occupations of interest with respect to SCD may be commercial motor vehicle drivers and airline pilots, among who require regular medical examinations (every 2 years for all motor vehicle drivers and for airline pilots >40 years old) [40]. Noncontrast cardiac CT is currently recommended as the initial test by the Federal Aviation Administration (FAA) for asymptomatic pilots with an estimated 10-year CHD risk greater than 10% [40].

In the general population, it is unknown whether identification of high-risk CAC (e.g. high total CAC ≥1000 [41] and/or left main CAC [42]) in asymptomatic individuals warrants additional functional evaluation via electrocardiogram or echocardiogram stress testing to guide the safe initiation and/or continuation of moderate-vigorous physical activity regimens. A physical examination and electrocardiogram are the most commonly used modalities for preparticipation screening, although there is no universal sports cardiology standard, and some have recommended exercise tolerance testing to be integrated within risk assessment [43,44]. Future studies in the sports cardiology research space may help to optimize precision in the selection of individuals who may derive maximal benefit from sequential CAC and/or echocardiogram testing for SCD risk stratification. For individuals found to have very high CAC burden and signs suggestive of a previous silent myocardial infarction (e.g. abnormal Q waves on electrocardiogram), cMRI would be required to identify ventricular scar via late gadolinium enhancement.

CONCLUSION

Carefully conducted observational analyses have demonstrated a stepwise higher risk of SCD across increasing CAC burden among asymptomatic middle-aged adults who do not have clinical ASCVD. Although the classical approach for the primary prevention of SCD focuses on those who already have experienced a myocardial infarction and/or have reduced left ventricular ejection fraction, the association between CAC and SCD demonstrates that SCD risk stratification can begin much earlier. The mechanisms underlying the association between CAC and SCD have yet to be elucidated; however, myocardial infarction and scar and/or exercise-induced ischemia are key potential mediators on the proposed causal pathway.

Despite the clinical inertia for downstream functional cardiac testing after detection of high CAC, comprehensive ASCVD prevention strategies should be the primary focus for SCD risk reduction. Future studies may help to determine whether patients with elevated baseline risk, including symptomatic persons with high global CAC scores, left main CAC, and those in high-risk occupational environments who are seeking to initiate moderate–vigorous intensity exercise regimens may benefit from select and precise functional cardiac testing for SCD risk stratification.

KEY POINTS.

• Independent of traditional risk factors, prevalent CAC confers a three-fold to five-fold higher risk for sudden cardiac death beginning at CAC ≥ 100 among asymptomatic patients without overt ASCVD.

• SCD risk stratification can begin in the early stages of coronary heart disease via measurement of calcific atherosclerotic plaque on noncontrast cardiac CT.

• Despite the clinical inertia for downstream functional cardiac testing after detecting high CAC, comprehensive ASCVD prevention strategies should be the primary focus for SCD risk reduction.

• Although the mechanisms underlying CAC and SCD have yet to be elucidated, myocardial infarction and scar, and/or exercise-induced ischemia are potential mediators on the proposed pathophysiological pathway.