Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Anmol Shahid, Vaibhav B. Patel, Jude S. Morton, Trevor H. Stenson, Sandra T. Davidge, Gavin Y. Oudit, Michael S. McMurtry, Vincenzo Lionetti.
Humans have a lower risk of death from myocardial infarction (MI) living at low elevations (<2500 m), which are not high enough to induce hypoxia. Both chronic hypoxia pre-MI, achieved by altitude simulation >5000 m, and intermittent hypobaric hypoxia post-MI can reduce MI size in rodents, and it is believed that hypoxia is the key stimulus. To explore mechanisms beyond hypoxia we studied whether altitude simulation <2500 m would also be associated with reduced infarct size. We performed left-anterior descending artery ligation on C57BL6 mice. Control mice (n = 12) recovered at 754 mmHg (atmospheric pressure, control), and treatment group mice (n = 13) were placed in a hypobaric chamber to recover 3-hours daily at 714 mmHg for 1 week. Echocardiographic evaluation of left ventricular function was performed on Day 0, Day 1 and Day 8. Intermittent hypobaric treatment was associated with a 14.2±5.3% improvement in ejection fraction for treatment group mice (p<0.01 vs. Day 1), with no change observed in control mice. Cardiac output, stroke volume, and infarct size were also improved in treated mice, but no changes were observed in HIF-1 activation or neovascularization. Next, we studied the acute hemodynamic effects of low altitude stimulation in intact mice breathing 100% oxygen using left ventricular catheterization and recording of pressure-volume loops. Acute reductions in barometric pressure from 754 mmHg to 714 mmHg and 674 mmHg were associated with reduced systemic vascular resistance, increased stroke volume and cardiac output, and no change in blood pressure or heart rate. Ex-vivo vascular function was studied using murine mesenteric artery segments. Acute reductions in barometric pressure were associated with greater vascular distensibility. We conclude that intermittent hypobaric treatment using simulated altitudes <2500 m reduces infarct size and increases ventricular function post-MI, and that these changes are related to altered arterial function and not hypoxia-associated neovascularization.
Myocardial infarction (MI) is very common and is associated with significant morbidity and mortality . Most risk for MI is related to exposure to modifiable risk factors, including abnormal lipids, smoking, hypertension, diabetes, obesity, psychosocial factors, low consumption of fruits and vegetables, consumption of alcohol, and low levels of physical activity . However, other exposures may modify the risk.
To explore why patients living at low altitudes that are not associated with hypoxia have less mortality from myocardial infarction, we conducted a set of experiments to determine whether normoxic low altitude simulation after the induction of a severe MI in mice could improve myocardial function and reduce infarct size. We found of improvements in fractional shortening, ejection fraction, stroke volume, and cardiac output with 7 days of normoxic low altitude simulation treatment in mice with severe MI, consistent with altitude exposures to higher elevations associated with hypoxia. Unlike prior work, however, we found that cardiac function improvement after MI due to normoxic low altitude simulation treatment was not associated with a HIF1a mediated responses (Fig 3) or neovascularization . Our findings are novel in that previous studies have only evaluated the therapeutic benefit of altitude simulation to elevations high enough to cause hypoxia .