A chronological framework for atherosclerosis: from environmental pressure to clinical disease, with vascular aging as a cross-cutting 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 they do not organize the chronological sequence of atherogenesis, assign measurable biomarkers to each stage, or integrate vascular aging. We propose CASCADE (Chronological Atherosclerosis Staging: Connecting Aging, Disease, and Environment), a conceptual framework that applies disease staging to atherosclerosis, organizing it into seven pathophysiological phases (F1-F7) preceded by an upstream environmental and behavioral pressure layer (F0), and spanning the trajectory from adaptive metabolic response to clinical cardiovascular disease. Each phase is mapped to a proposed dominant biomarker - from insulin resistance indices through apolipoprotein B, lipoprotein(a), and coronary artery calcium - and to a reversibility zone (largely reversible, transition, or stabilization only). Vascular aging - characterized by arterial stiffness, cellular senescence(definition), epigenetic drift, and clonal hematopoiesis - traverses all phases as a modifiable cross-cutting dimension, with specific biological clocks applicable at each stage. The framework is developed through narrative synthesis of mechanistic, epidemiological, and clinical trial evidence, integrating current international guidelines and emerging evidence on biological aging and environmental determinants of cardiovascular risk. CASCADE 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. It is proposed as a hypothesis-generating framework, not a validated scoring system, and 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.