Intense light as potential future therapy for myocardial injury in patients after non cardiac surgery: lessons from mice and men.

Abstract

Background: Studies on light-elicited endothelial period circadian regulator 2 (PER2) mediated cardioprotection revealed a critical role of PER2/hypoxia inducible factor 1 alpha (HIF1A) regulated endothelial factor ANGPTL4 for endothelial barrier protection during myocardial ischemia and reperfusion injury (IRI). Based on these observations, we deepened our studies on light-elicited cardioprotective mechanisms.

Methods: All animal and human studies had Institutional Animal Care and Use Committee (IACUC) and Colorado Multiple Institutional Review Board (COMIRB) approval. To study myocardial IRI, an in-situ mouse model for myocardial IRI was used. To study light-elicited mechanisms during myocardial IRI, endothelial-specific Per2-deficient mice were treated with the PER2 enhancer nobiletin (NOB), with the HIF1A activator dimethyloxalylglycine (DMOG), or with recombinant ANGPTL4. To evaluate whether light could increase ANGPTL4 or decrease troponin levels in patients, we exposed patients undergoing elective spine surgery postoperatively for 5 days with intense light for 30 minutes at sunrise. Patient's plasma samples were tested for melatonin, ANGPTL4 and troponin levels using enzyme-linked immunosorbent assay (ELISA).

Results: The PER2 enhancer NOB or the HIF1A activator DMOG protected from myocardial IRI, which was abolished in endothelial-specific Per2-deficient mice. ANGPTL4 was able to overcome an endothelial Per2 deficiency and revealed protection during myocardial IRI in endothelial-specific Per2-deficient or control mice. Intense light therapy in patients undergoing non-cardiac surgery showed increased ANGPTL4 and decreased troponin plasma levels.

Conclusions: Our study demonstrates that only the PER2/HIF1A downstream target ANGPTL4 can overcome an endothelial Per2 deficiency. Moreover, we discovered that intense light therapy in patients following non-cardiac surgery can be used to increase plasma levels of the endothelial protective factor ANGTL4 and decrease troponin levels, an indicator of myocardial injury in non-cardiac surgery (MINS). Further research with larger, more diverse human cohorts and long-term follow-up is needed to validate these findings and develop targeted therapies.