Impact of severe sustained hypoxia on cardiac glucose uptake and DNA-damage response in patients with ischemic heart disease

J.-N. Hönemann (Köln)¹, H. Weis (Köln)², J. Manuel (Köln)³, D. Gerlach (Köln)³, A. Bach (Köln)³, F. Hoffmann (Köln)⁴, L. de Boni (Köln)³, C. Hellweg (Köln)³, B. Konda (Köln)³, V. Zaha (Dallas)⁵, H. Sadek (Tuscon)⁶, L. Kessler (Essen)⁷, H. Reuter (Köln)⁸, M. Halbach (Köln)⁹, S. Baldus (Köln)¹, G. Lewin (Berlin)¹⁰, S. Kempa (Berlin)¹¹, S. Hersel (Bonn)¹², F. Splettstoesser (Bonn)¹², S. Frede (Bonn)¹², B. Levine (Dallas)¹³, J. Jordan (Köln)¹⁴, U. Limper (Köln)¹⁵, J. Tank (Köln)^3
1Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland; ²Universitätsklinik Köln Nuklearmedizin Köln, Deutschland; ³Deutsches Zentrum für Luft- und Raumfahrt Köln, Deutschland; ⁴Universitätsklinikum Köln Klinik und Poliklinik für Herz- und Thoraxchirurgie, Herzzentrum Köln, Deutschland; ⁵UT Southwestern Medical Center Division of Cardiology, Department of Internal Medicine Dallas, USA; ⁶University of Arizona Tucson Division of Cardiology, Department of Medicine Tuscon, USA; ⁷Klinik für Nuklearmedizin Essen, Deutschland; ⁸Evangelisches Klinikum Köln Weyertal Klinik für Innere Medizin Köln, Deutschland; ⁹Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; ¹⁰Max Delbrück Center for Molecular Medicine Department of Neuroscience Berlin, Deutschland; ¹¹Max Delbrück Center for Molecular Medicine Department for integrative proteomics and metabolomics Berlin, Deutschland; ¹²Universitätsklinikum Bonn Klinik für Anästhesiologie Bonn, Deutschland; ¹³Institute for Exercise and Environmental Medicine / Texas Health Presbyterian Hospital Dallas, USA; ¹⁴Deutsches Zentrum für Luft- und Raumfahrt Linder Höhe Köln, Deutschland; ¹⁵Kliniken der Stadt Köln gGmbH, Krankenhaus Merheim Abteilung für Anästhesiologie Köln, Deutschland

A metabolic switch from anerobic glycolysis to fatty acid oxidation meets the need for higher energy demand of the mammalian heart after birth, but leads to cell cycle arrest of cardiomyocytes by increased DNA-damage. In mice with myocardial infarction, prolonged, severe hypoxia increases myocardial glycolysis, reactivates cardiomyocyte regeneration, and improves contractility. In this proof of concept study, aimed to translate these findings to patients, we enrolled three men with myocardial infarction 49-126 months prior to study and one control with no evidence of coronary artery disease (CAD). Corresponding to the murine hypoxic model, participants acclimatized at FiO2=11.6% for 4 days in the Italian Alps at 4554 m, then housed at progressively lower, normobaric ambient oxygen through nitrogen dilution over 28 days to alveolar oxygen partial pressure < 40 mmHg, maintained over 14 consecutive day (FiO2=0.095) - night (FiO2=0.105) cycles. Parameters assessed before, at the end of, and 30 days after hypoxia exposure (follow-up): LV global longitudinal strain (LVGLS) echocardiographically; NTproBNP, high-sensitivity Troponin I (hs-TnI), and glycolytic products levels in blood, myocardial 18F-FDG-uptake by FDG-PET-MRI; DNA-damage response in PBMC (peripheral blood mononuclear cell); by detecting the γH2AX-induction in response to radiation exposure. LVGLS increased in the viable myocardium in patients (LVGLS: baseline: -12.57±2.4%, end of hypoxia: -14.37±2.62%, recovery day 3: -14.33±2.72%, follow-up: -15.2±3.11%, p=0.0182) but not in the control. NTproBNP decreased (p=0.0278) and hs-TNI was unchanged in all participants. Glucose-6-phosphate was 67±30% higher and dihydroxyacetone phosphate was reduced to 30±7% in patients at follow-up compared to baseline; both were unchanged in the control. 18F-FDG-uptake increased in the viable myocardium by 15.9% and in scar by 18.5±14.5% in patients and decreased by 14.5% in control at follow-up compared to baseline. There were less PBMCs with residual DNA-damage in patients after 2h of 1Gy irradiation (p=0.0462) and 24h of 4Gy irradiation (p= 0.0444) compared to control. Our study reveals potential effects of hypoxia mediated pathways on crucial parameters of myocardial repair and underscores the need for studies in larger sample sizes.