Towards defining endotype-specific mechanisms of sub-clinical atherosclerosis to advance precision medicine for cardiovascular disease.

Sub-clinical atherosclerosis is prevalent in over 60% of middle-aged adults in population-based screening studies,1 and so it is unsurprising that most acute cardiovascular events occur suddenly in individuals without prior symptoms. Indeed, the dynamic and unpredictable nature of atherosclerotic plaque progression, rupture, and healing means that we do not currently know which people with atherosclerotic cardiovascular disease (ASCVD) will suffer clinical events, nor do we know who would most benefit from novel therapies. The traditional view of atherogenesis as an indolent disease that begins in early adulthood and slowly progresses through a series of predictable histopathological stages to advanced atherosclerotic lesions with increased propensity to rupture and thrombose, does not resolve this fundamental clinical conundrum. There is no single blood-based biomarker, polygenic risk score, or cardiovascular imaging test that can accurately predict the timing or location of an acute plaque event. Even in patients with symptoms of angina due to so-called ‘obstructive’ coronary lesions, current prognostic biomarkers provide little incremental gain above clinical cardiovascular risk factors and simple measures of overall plaque burden on an individual patient level. Therefore, shifting focus from late-stage prediction to prioritise early intervention could have a more fruitful impact on clinical outcomes. Highly targeted therapies are emerging from the discovery pipeline to tackle residual lipid and inflammatory risk in ASCVD.2 But before deploying these new therapies that are expensive and not without risk of side-effects in unselected ASCVD cohorts, there is a need to better understand the complex mechanisms underlying individual variability in disease pathology and response to treatments. To facilitate the future clinical implementation of a precision medicine strategy for ASCVD, meaningful insights can be gained from multi-dimensional research studies through the integration of large-scale ‘omics data with detailed clinical observations, laboratory and imaging-based measurements of disease severity.