Multiple step-variable pathway hypothesis: a reason why predictions fail in atherosclerosis.

Cardiovascular risk factors are individually only modest predictors of events, and whilst more sophisticated algorithms appear to improve their prediction, a significant proportion of the population is miscategorised and therefore managed inappropriately. It is proposed that atherogenesis is a multi-step process, and that the critical transitions between steps requires 'bundles' of risk factors that may differ for each step. These bundles may not always contain a classical risk factor and may differ between individuals. This hypothesis would predict that the impact of specific risk factors is non-uniform during atherogenesis and therefore the efficacy of interventions will vary with stage. New therapeutic opportunities exist if the factors that promote progression between particular stages could be identified and targeted. The staging of disease using modalities such as imaging and functional assessment may be necessary to deliver the most effective treatment. Finally, risk assessment will invariably be inaccurate, even using complex algorithms.