Jonathan Wagner, Raphael Knaier, Karsten Königstein, Christopher Klenk, Justin Carrard, Eric Lichtenstein,
Hubert Scharnagl, Winfried März, Henner Hanssen, Timo Hinrichs, Arno Schmidt-Trucksäss and Konstantin Arbeev

Frontiers in Physiology | www.frontiersin.org December 2020 | Volume 11 | Article 596240

Background: Aging and changing age demographics represent critical problems of our
time. Physiological functions decline with age, often ending in a systemic process that
contributes to numerous impairments and age-related diseases including heart failure
(HF). We aimed to analyze whether differences in composite measures of physiological
function [health distance (HD)], specifically physical fitness, between healthy individuals
and patients with HF, can be observed.
Methods: The COmPLETE Project is a cross-sectional study of 526 healthy participants
aged 20–91 years and 79 patients with stable HF. Fifty-nine biomarkers characterizing
fitness (cardiovascular endurance, muscle strength, and neuromuscular coordination)
and general health were assessed. We computed HDs as the Mahalanobis distance
for vectors of biomarkers (all and domain-specific subsets) that quantified deviations
of individuals’ biomarker profiles from “optimums” in the “reference population”
(healthy participants aged <40 years). We fitted linear regressions with HD outcomes
and disease status (HF/Healthy) and relevant covariates as predictors and logistic
regressions for the disease outcome and sex, age, and age2 as covariates in the base
model and the same covariates plus combinations of one or two HDs.
Results: Nine out of 10 calculated HDs showed evidence for group differences between
Healthy and HF (p  0.002) and most models presented a negative estimate of the
interaction term age by group (p < 0.05 for eight HDs). The predictive performance of
the base model for HF cases significantly increased by adding HD General health or
HD Fitness [areas under the receiver operating characteristic (ROC) curve (AUCs) 0.63,
0.89, and 0.84, respectively]. HD Cardiovascular endurance alone reached an AUC of
0.88. Further, there is evidence that the combination of HDs Cardiovascular endurance
and General health shows superior predictive power compared to single HDs.
Conclusion: HD composed of physical fitness biomarkers differed between healthy
individuals and patients with HF, and differences between groups diminished with
increasing age. HDs can successfully predict HF cases, and HD Cardiovascular
endurance can significantly increase the predictive power beyond classic clinical
biomarkers. Applications of HD could strengthen a comprehensive assessment of
physical fitness and may present an optimal target for interventions to slow the decline
of physical fitness with aging and, therefore, to increase health span.