Coronary atherosclerosis and sudden cardiac death in the young: another face of the culprit, another way of striking?

Coronary artery atherosclerosis is a major cause of sudden cardiac death (SCD) in the young, accoun ting for nearly 25% of fatalitie s in this age group (≤40 years old) [1]. Interestingl y, the composition of the culprit atherosclerotic plaque in young subjects often shows a pecu- liar morphology, consisting predominantly of smooth muscle cells (SMCs) with a variable amount of extracellular matrix, and minimal or absent lipid core [2] leading to the definition of “non-atheromatous atherosclerosis” or “pathological intimal thickening” [3]. Based on both histopathologic features and the absence of occlusive thrombus at autopsy, a predominant role for coronary artery spasm has been ad- vocated and fortuitously supported by electrocardiographic and coro- nary imaging data [4] as the major trigger for myocardial ischemia in this condition. In this elegant study, Rizzo et al. perform a wide-spectrum immu- nohistochemical analysis of culprit coro nary arterie s from an autopsy sample of young coronary SCD. They show convincing evi- dence of a strong contractile phenotype of SMCs within culprit ath- erosclerotic plaq ues (both ather omatous and non-atheromatous) and i n the underlying media of “young coronary arteries”,ascom- pared to a less dif ferenti ated intimal and medial SMC phenoty pe in the coronary tree of older subjects. These findi ngs support the hy- pothesis th at coronary spasm in the presence of “apparently stable” plaque is a significant cause underlying coronary SCD in the young and point to the need of provocative functional tests when assessing non-complicated coronary stenosis i n patients with is che mic symp- toms and/or signs. In light of the results pre sented in this study there are of course questions still open. Which is the source of intimal SMCs? What are the causative factors for the hyper-contractile SMCs phenotype in atherosclerotic plaques of young individuals? Which could be the causes for coronary spasm in this age gr oup? Are there toxic, such as cocaine abuse [ 5] or mechanical t riggers? Based on additional findings in their series of culprit plaques Rizzo et al. speculate that adventitial vasa vasorum and inflammation may play a role in athero- sclerotic plaque inst ability and vasospasm. The relationship between inflammation and atherosclerosis and its complications is well- known,andindeedthe“non-atheromatous atherosclerosis” shares its main histologic features with the immune-mediated cardiac allograft vasculopathy. Although is tempting to s peculate that ad- ventitial inflammation might induce coronary hyper-constriction, perhaps through Rho-kinase activation in the SMCs, further studies are required to support this hypothesis. The unavoidable limitation of this study is related to the retrospec- tive nature of autopsy investigation. In fact, the role played by coronary vasospasm in the pathogenesis of myocardial ischemia and sudden death can only be inferred retrospectively, after performing a careful ex- amination of the heart and coronary tr ee, according to standardized protocols [6]. The results provided are exquisitely descriptive, and can only suggest working hypotheses, which need to be confirmed by func- tional studies. Finally, Rizzo et al. are to be commended for bringing back into the main stream coronary atherosclerosis as a cause of SCD in the young. The wide variability of coronary atherosclerosis prevalence among pub- lished series in the literature, often with very low numbers, underlies the need to carefully evaluate the coronary artery tree to avoid underes- timation of atherosclerotic lesions with a consequent low attention to risk factors prevention in the young and, at the same time, an overesti- mation of cases of sudden unexpected death with no obvious anatomi- cal substrate, leading to the suspicion of chann elopathies, with all inherent implication in terms of unnecessary family screening and ge- netic testing.