Atherosclerosis as an evolutionary mismatch disease: from ancestral biology to cardiometabolic vulnerability

A middle-aged patient with no cardiovascular history, modest cholesterol levels, and a normal stress test may already have extensive subclinical atherosclerosis across multiple vascular territories. Large imaging cohorts have shown that this scenario is far more common than conventional risk stratification would predict. Understanding why requires looking further back than conventional risk scores allow. Atherosclerosis is routinely framed as a disease acquired in adulthood through modifiable risk factors. That framing is clinically useful but biologically incomplete. Arterial lesions are detectable in children; vascular calcifications consistent with atherosclerosis appear in mummified remains from populations thousands of years old; and subsistence communities living closer to ancestral ecologies show extraordinarily low coronary burden despite high infectious loads. The conclusion is consistent: susceptibility to atherosclerosis is intrinsic to human biology. Modern environments activate and sustain it. This narrative review argues that atherosclerosis is best understood as the long-term vascular consequence of a mismatch between biological systems shaped under intermittent metabolic stress and environments that now impose chronic, unrelenting activation of those same pathways. That mismatch deepened across two major historical transitions (agricultural and industrial) and was amplified further by developmental programming established before birth. Insulin resistance, dyslipidaemia, endothelial dysfunction, sustained sympathetic activation, circadian disruption, and exposure to tobacco and air pollutants are not isolated modern risk factors; they are converging expressions of biology operating outside the context in which it evolved. Framed this way, prevention should shift from late event prediction toward earlier trajectory modification, addressing the conditions that accelerate atherogenesis long before conventional risk thresholds are crossed.