Prevention of sudden death: the role of coronary artery calcification imaging in preventive cardiology

This editorial refers to ‘Screening for cardiovascular disease risk using traditional risk factor assessment or coronary artery calcium scoring: the ROBINSCA trial’, by CM van der Aalst et al., pp. 1216–1224. The number of sudden death in the general population exceeds 10 times the number of patients dying from sudden death with known clinical risk factors.1 Despite a continuous drop of deaths due to myocardial infarction, pre-hospital death rate of 60–80% has not changed between 1991 and 2006.2 The pathogenesis of sudden death is very strongly related to the pathogenesis of coronary atherosclerosis.3 In the beginning, the coronary lumen remains stable due to the remodelling process, which is exhausted as a compensatory mechanism, when the eccentric plaque size exceeds the vessel size by 40–50%.3 Therefore, lumen imaging is unable to detect early signs of atherosclerosis. Calcification, first found intracellularly then extracellularly, is even present in young people with sudden death.4 In autopsy studies, a ratio of about 1:5 between coronary artery calcification (CAC) and plaque size (20–25%) was found.5 The accumulation of lipids, calcium, apoptosis and cell necrosis causes the formation of necrotic cores and vulnerable plaques with thin fibrous cap prone to rupture with a thickness of 60–80 µm.3 The rupture may lead to occlusive or non-occlusive mural thrombi or ulceration, when the necrotic core is washed out leading to coronary embolization, which was found in sudden deaths with and without unstable angina >1 thrombotic episodes (87% vs. 71%).6 Preventive medicine wants to detect those at risk for sudden death in order to reduce cardiovascular risk factors and start treatment. The European Systemic Coronary Risk Evaluation (SCORE), which predicts 10-year risk for fatal and non-fatal cardiovascular events is recommended, adjusted to regional differences in Europe.7 For screening computed tomography (CT) is the best non-invasive method, which allows detection, localization and quantification of CAC8 and was used in the ROBINSCA trial.9 Cardiac CT has reached a high-imaging standard, no contrast, shows a very low X-ray exposure (0.1 to <1.0 mSv). The CAC quantification, introduced by Agatston et al., was accepted worldwide, including measurement of plaque size and estimate of plaque density for all lesions which are summed up to give the total CAC score.10 In large registries, a high predictive value of CT for risk prediction could be demonstrated. In order to overcome criticism of registries, the Multi-Ethnic Study of Atherosclerosis (MESA) was initiated by the National Institute of Health and the Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study supported the Heinz Nixdorf foundation. These studies reported that the age- and gender-related distribution of CAC followed an exponential curvature starting in men in the early 40th and in women 10 years later and an ethnic difference.11 The estimated percentiles of both studies showed a great concordance, despite cohorts of two continents with large differences in risk factor distribution.12 MESA, HNR, and the Rotterdam study were able to demonstrate that CAC, used for risk prediction, was superior to traditional risk factors and showed similar reclassification rates of 26.2%, 22.4% and 21.9%, respectively, with a net reclassification improvement for down-classification to CAC <100 of 21.7% and up-classification to CAC ≥400 of 30.6% for HNR.8 Zero CAC represents an extremely low risk, CAC >0 already an enhanced risk, reaching an intermediate risk at CAC ≥100, and high risk at CAC ≥300, or CAC ≥400. MESA presented a 10-year coronary heart disease risk prediction using CAC and traditional risk factors; available online.13 In a great effort, the ROBINSCA trial was initiated for risk prediction and treatment in a population-based randomized controlled trial in asymptomatic subjects in the Netherlands.14 The study could reach 43.561 (49%) eligible respondents, who were randomized 1:1:1 to the SCORE arm or the CAC arm, as well as a control arm, the latter without any intervention for comparison. For risk stratification, the SCORE arm was stratified to three risk classes <10%, 10–20%, and ≥20%. The CAC scores were stratified into <100, 100–399, and ≥400 Agatston score.15 For those with intermediate risk with ≥1 risk factor and all high-risk cases lifestyle measures were recommended and preventive drug treatment with antihypertensive medication for all with systolic blood pressure >140 mmHg and lipid lowering for all with low-density lipoprotein cholesterol >2.5 mmol/L (96.7 mg/dL). In high-risk CAC subjects, the treatment was discussed with the general practitioner and in cases with CAC ≥100, prescription of ACE—inhibitors and statins were recommended independent on cholesterol and blood pressure levels, except for hypotensive participants.9 Very important was the distribution of individuals in each risk group. Much more cases were classified as low risk according to the CAC results (76%) compared with the SCORE (45.1%), Intermediate and high-risk CAC groups compromised a smaller number of participants than the SCORE groups (15.1% vs. 26.5% and 8.9% vs. 28.4%, respectively). Subsequently, the percentage of women and men, allocated to preventive treatment, was 17% and 31% in the CAC and 27% and 43% in the SCORE group, respectively. Thus, the authors of ROBINSCA can be congratulated to their most important study. The results will have important clinical implications, once the outcome data are ready. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.