Chronic coronary syndromes: genetics, shear stress, and biomarkers

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. Atherosclerotic lesions in the coronary system are dynamic: they not only grow over time and eventually cause ischaemia and chest pain, but they may also suddenly obstruct the coronary lumen and/or induce intravascular thrombus formation. The new term chronic coronary syndrome, introduced by the 2019 ESC Guidelines,1 reflects this dynamic course over years and decades. There is no doubt that genetics play an important role in the development of chronic coronary syndrome. Family history is a well-known risk factor, but many single nucleotide polymorphisms have now been described, and recently a genetic risk score was introduced2,3 for coronary artery disease and for sudden cardiac death.4,5 In their article entitled ‘Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin’, Heribert Schunkert and colleagues from the Deutsches Herzzentrum München in Germany remind us that efficacy of aspirin in primary prevention of cardiovascular disease may be influenced by a common allele in guanylate cyclase, GUCY1A3, which modifies platelet function and increases the risk of major cardiovascular events (MACE).6 In two long-term, randomized placebo-controlled trials of aspirin in primary cardiovascular disease prevention, the authors investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin, i.e. the Women’s Genome Health Study with 23 294 patients, and 550 myocardial infarction and 382 stroke patients in a case–control set from the Physician’s Health Study. In the placebo group of the Women’s Genome Health Study, the GUCY1A3 risk (G) allele increased MACE risk with a hazard ratio of 1.38. The random effects meta-analysis of the Women’s Genome Health Study and Physician’s Health Study revealed that aspirin reduced MACE among risk allele homozygotes with an odds ratio of 0.79, but increased MACE among non-risk allele carriers (e.g. G/A) with an odds ratio of 1.39, thus implying an interaction between genotype stratum and aspirin intake. Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes. Thus, in two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of MACE in homozygotes for the GUCY1A3 risk (G) allele, whereas heterozygous individuals had more events when taking aspirin. These findings are truly provocative—particularly in the context of the recent aspirin trials.7–9 They are put into context in an Editorial by Colin Baigent from the Clinical Trial Service Unit in Oxford, UK.10