To accomplish MODELAGE objectives, myocardial tissue samples, electrocardiograms and blood samples were collected from individuals of various ages as well as from large mammals, like pig and sheep, for prior optimization of the protocols required to process the collected data. In vitro investigations were additionally undertaken to characterize cellular and subcellular properties as a function of age.
Results from the in vivo, ex vivo and in vitro studies were integrated into mathematical models. A Bayesian methodology was developed in MODELAGE to identify the parameters and state variables of those models based on whole-cell experimental measurements, both at baseline conditions and in response to sympathetic provocations. Simulations were run using the developed mathematical models to investigate cardiac spatio-temporal dynamics. Tissue characterizations were additionally incorporated to build multi-scale computational models, which were used to relate spatio-temporal dynamics with chronological / biological age and ascertain underlying mechanisms. Genes involved in cardiac electro-mechanical activity that were differentially expressed in young vs old individuals, considering both chronological and biological age, were identified and the role of microRNAs in their regulation was ascertained.
At the level of the body-surface electrocardiogram, novel non-invasive markers providing a more comprehensive characterization of cardiac variability were proposed as part of MODELAGE investigations. Robustness against noise and artifacts was first tested in synthetically generated data and, next, electrophysiological modeling and simulation was used to show the markers’ capacity to reflect heterogeneities in temporal and/or spatial cardiac activity. In electrocardiographic recordings of healthy subjects spanning a wide range of ages, MODELAGE quantified changes in the proposed indices in relation to chronological age and other variables related to cardiorespiratory fitness. The association with arrhythmic risk of some of the proposed markers was subsequently demonstrated in followed-up patient populations, individually and in combination with other clinical and electrocardiographic variables.
The achieved results were disseminated in multiple publications, conferences, seminars, workshops as well as in the media.
