The etiology of coronary heart disease (CHD) has been debated over the last 60 years. There exists an alternative explanation to the rise in CHD mortality, consonant with knowledge about the role of inflammation. It is proposed that a cohort association existed between rates of vulnerability to influenza deaths in 1918 and CHD mortality among survivors from those vulnerable birth cohorts. According to this hypothesis, hypercholesterolemia may have been a marker of the 1918 immune-priming, with CHD deaths resulting from bursts of endothelial inflammation and thrombosis associated with influenza re-infections during the following decades. We propose a reconsideration of the way we model atherogenesis, from ‘‘initiation’’ and ‘‘promotion’’ to ‘‘vulnerable substrate(s)’’ and ‘‘trigger(s)’’. Also suggested, based on this hypothesis, is a possible shared condition between vulnerable substrates, which upon triggering, is associated with evolution to acute events, through an imbalance between COX and LOX products. This paradigm has implications for global prevention policies.