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The detection of high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is a major challenge. Systems biology suggests that the vasculature's functional robustness against risk factor challenges may serve as a novel discriminator of mortality risk under similar risk factor loads. However, principled methods to measure vascular robustness are not available. To develop a score for the vasculature's functional robustness we used a recently presented method that applies computational physiological modeling to the quantitation of vascular function. We hypothesized that the expected inverse robustness-mortality association is verifiable as a significant robustness-calendar age trend in a cross-sectional investigation of a population cohort of risk factor-challenged individuals. Using only functional parameters of the cardiovascular system we applied multivariate linear regression to derive from our study population of 372 adults gender-specific multivariate robustness scoring algorithms. For any individual, the deviation of his/her robustness score from the value of the regression function characterizes the deviation of the individual’s fatal CVD event probability from its age-appropriate fatal CVD event probability. Robustness correlated linearly with calendar age in our risk factor-challenged but not in our unchallenged cohorts. This observation supports the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. We conclude that physiologically principled scoring for vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality.    NEW &amp; NOTEWORTHY We developed a principled method for the derivation of a vascular robustness score that we translated into a correction factor for calendar age. We demonstrated the score’s potential to uncover risk for premature cardiovascular death in apparently healthy young adults whose risk elevation remains hidden in conventional risk factor models.

A novel principled method for the measurement of vascular robustness uncovers hidden risk for premature CVD death