The cardiovascular robustness hypothesis: Unmasking young adults' hidden risk for premature cardiovascular death.

An undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor levels is an acknowledged obstacle to CVD prevention. In this paper, we present the hypothesis that the vasculature's robustness against risk factor load will complement conventional risk factor models as a novel stratifier of risk. Figuratively speaking, mortality risk prediction without robustness scoring is akin to predicting the breaking risk of a lake's ice sheet considering load only while disregarding the sheet's bearing strength. Taking the cue from systems biology, which defines robustness as the ability to maintain function against internal and external challenges, we develop a robustness score from the physical parameters that comprehensively quantitate cardiovascular function. We derive the functional parameters using a recently introduced novel system, VascAssist 2 (iSYMED GmbH, Butzbach, Germany). VascAssist 2 (VA) applies the electronic-hydraulic analogy to a digital model of the arterial tree, replicating non-invasively acquired pule pressure waves by modulating the electronic equivalents of the physical parameters that describe in vivo arterial hemodynamics. As the latter is also subject to aging-associated degeneration which (a) progresses at inter-individually different rates, and which (b) affects the biomarker-mortality association, we express the robustness score as a correction factor to calendar age (CA), the dominant risk factor in all CVD risk factor models. We then propose a method for the validation of the score against known time-to-event data in reference populations. Our conceptualization of robustness implies that risk factor-challenged individuals with low robustness scores will face preferential elimination from the population resulting in a significant robustness-CA correlation in this strata absent in the unchallenged stratum. Hence, we also present an outline of a cross-sectional study design suitable to test this hypothesis. We finally discuss the objections that may validly be raised against our robustness hypothesis, and how available evidence encourages us to refute these objections.