Pulmonary Hypertension Does Not Limit Translational Approaches of Hypoxia Mediated Myocardial Regeneration

Objective: In mice, prolonged exposure to severe ambient hypoxia promotes myocardial regeneration suggesting a novel treatment target for patients following myocardial infarction. However, hypoxia-induced pulmonary hypertension and myocardial ischemia are potential risks in human studies. Therefore, we conducted a pilot study in carefully selected patients with left ventricular scars to test the cardiovascular safety of prolonged exposure to severe hypoxia. Design and method: At the DLR:envihab facility, we enrolled three male patients with 49-126 months past history of myocardial infarction and one healthy man. Patients had an ejection fraction of 47±7%. We applied incremental ambient hypoxia using nitrogen dilution until alveolar oxygen partial pressure had decreased to 35 mmHg. Then, we maintained atmosphere conditions for 14 days (FiO2=0.095) but added 1% oxygen during the night. We assessed right ventricular function and systolic pulmonary artery pressure at baseline, during hypoxia, and 3 days after recovery in normoxia with transthoracic echocardiography. In venous blood samples, we measured high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and glomerular filtration rate (CystatinC) throughout the study. Results: We observed no clinical signs of heart failure throughout the study. Hypoxia increased systolic pulmonary artery pressure, which rapidly normalized during recovery (baseline: 35±3 mmHg hypoxia: 47±9 recovery: 28±1, p=0.029). Tricuspid annular plane systolic excursion was 28±3 mmHg at baseline, 26±1 mmHg in hypoxia, and 29±2 mmHg during recovery (p=0.069). Right ventricular free wall strain -22.4±3.9 mmHg at baseline, -24±5.4 in hypoxia, and -22.7±1.5 during recovery (p=0.84). Glomerular filtration rate was reduced in hypoxia, but recovered at 30 days follow-up. Troponin remained in the reference range throughout the study and NTproBNP was decreased following hypoxia (p=0.047). Conclusions: In highly selected patients with left ventricular scars, prolonged severe normobaric hypoxia while eliciting pulmonary hypertension did not lead to right heart failure or myocardial damage. Our study provides important information regarding safety of exposing patients to hypoxia in clinical studies or during activities at high altitude.