Metabolic adaptations to cardiac rehabilitation through physical exercise: Insights from untargeted metabolomics using dried blood spots in post-myocardial infarction patients

Ischemic heart disease remains the leading cause of death from cardiovascular diseases worldwide. The beneficial effects of cardiac rehabilitation (CR) through physical exercise on disease progression in patients after acute myocardial infarction (AMI) are well known, while knowledge of the effects on metabolic processes is still limited. Blood microsampling is a promising tool for blood collection as it is simple, minimally invasive, allows remote and multiple sampling and is optimal for longitudinal studies. For these reasons, it has gained attention and has been applied to metabolomics. This study aims to evaluate the metabolic response to CR using dried blood spots (DBS). 17 male subjects undergoing CR after a first AMI participated in this study. DBS were collected at 6 different time-points during the three CR weeks: before and after the first training, before and after training halfway through the CR protocol, and before and after the last training. Untargeted metabolomics and lipidomics analyses using ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) were performed to assess training-induced changes in these subjects. Comparisons between pre- and post-training samples showed a long-term effect, mostly on energy metabolism, associated with increased exercise performance after three weeks. On the other hand, time-dependent changes in the lipidome, especially of phosphatidylserine lipid species, were compatible with the waning effect of the previous AMI. Moreover, CR monitoring showed that blood levels of N-acetyl-L-tyrosine (NAT) increased during the rehabilitation time. This metabolite has been shown to induce mitohormesis, a mitochondrial salvage response, in mice and insects under stress stimuli. Mitohormesis has also been observed in humans after physical training, but it has not yet been linked to blood NAT levels. Overall, our results indicate that, along with physical performance, CR affects energy metabolism; moreover, they point to NAT as a potential biomarker of CR efficacy over time.