A Chronological Framework for Atherosclerosis: From Environmental Pressure to Clinical Disease, with Vascular Aging as a Transversal Dimension

Atherosclerosis is a multiphase disease, yet contemporary cardiovascular risk stratification relies predominantly on calculators that estimate event probability within a limited pathophysiological window. Framingham, SCORE2, GLOBORISK and PREVENT capture lipid burden, metabolic parameters, and renal function but do not organize the full chronological sequence of atherogenesis, do not assign measurable biomarkers to each stage, and do not integrate vascular aging — a biological process that modulates every phase of the cascade. We propose CASCADE (Chronological Atherosclerosis Staging: Connecting Aging, Disease, and Environment), a conceptual framework that applies disease staging to atherosclerosis by organizing it into seven pathophysiological phases with assigned biomarkers and incorporating vascular aging as a transversal dimension. The framework is developed through narrative synthesis of mechanistic, epidemiological, and clinical trial evidence across cardiovascular, metabolic, and aging research, integrating current international guidelines, landmark intervention trials, and emerging evidence on biological aging, endothelial biology, and environmental determinants of cardiovascular risk. CASCADE proposes seven phases preceded by an upstream environmental and behavioral layer (F0) that constitutes the substrate of cumulative exposure rather than a biological phase of the individual: adaptive metabolic response driven by insulin resistance (F1), vascular response and arterial stiffening (F2), endothelial injury and barrier dysfunction (F3), atherogenic lipoprotein retention indexed by apolipoprotein B (F4), plaque vulnerability and biological heterogeneity in which lipoprotein(a) becomes informative (F5), subclinical atherosclerosis (F6), and clinical cardiovascular disease (F7). Each phase is mapped to a proposed dominant biomarker and a reversibility zone (reversible, transition, or irreversible). Vascular aging — characterized by arterial stiffness, cellular senescence, epigenetic drift, and clonal hematopoiesis — traverses all phases as a modifiable dimension, with specific biological clocks applicable at each stage. The framework complements existing risk calculators by providing chronological context for the upstream phases (F0–F3), where conventional tools offer limited guidance and the potential for disease modification is greatest. CASCADE is proposed as a hypothesis-generating organizational framework, not a validated scoring system. It invites prospective evaluation of whether individuals traverse identifiable, modifiable phases of atherosclerotic disease — and whether integrating vascular aging measurement at each stage improves risk assessment and therapeutic decision-making.