Low altitude simulation without hypoxia improves left ventricular function after myocardial infarction by reducing ventricular afterload

Abstract

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.

Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies

“…The main function of the heart in the circulatory system is to pump blood to meet the needs of metabolism. Thus, SV is also a basic indicator used to evaluate cardiac function [ 22 ]. Our present results demonstrated that treatment with SA preserved cardiac function and improved cardiac tissue damage and fibrosis in mice subjected to AMI injury.…”

Normoxic low‐altitude simulation (at 714 mmHg) improves limb blood perfusion in mice with hindlimb ischemia

“…A decreased expression of HIF1α in the calf tissue of treatment mice after exposure to low altitude shows that the benefit of the treatment is not due to a downstream effect of hypoxia. We have previously shown a similar therapeutic benefit in a mouse model of MI (Shahid et al, 2019) and believe a mechanical mechanism where reductions in barometric pressure reduce the external compressive forces on arteries, thereby improving vessel dilation and blood flow to ischemic areas is likely ( Figure 6).…”

“…Immediately after the surgery was completed, animals in the experimental group were placed in an altitude simulation chamber with a barometric pressure of 714 mmHg for a period of 3 hours to simulate low altitude before continuing recovery at room barometric pressure. We have previously shown small reductions in barometric pressure to have an acute and immediate effect on vascular function ex vivo and cardiovascular hemodynamics in vivo and we chose treatment with 714 mmHg at 3 h daily in light of our previous work (Shahid et al, 2016, 2019; Shahid, Patel, et al, 2016). As the animals did not have access to food and water inside the altitude simulation chamber due to space limitations, three hours was deemed to be the maximum amount of time the animals could ethically be kept in the chamber by the Animal Care and Use Committee at the University of Alberta.…”

“…As the animals did not have access to food and water inside the altitude simulation chamber due to space limitations, three hours was deemed to be the maximum amount of time the animals could ethically be kept in the chamber by the Animal Care and Use Committee at the University of Alberta. Furthermore, we predicted three hours to be enough to exert a lasting therapeutic effect as we previously showed immediate increases in tissue perfusion with application of low-altitude simulation (Shahid et al, 2019). Control group animals recovered at room barometric pressure (754 mmHg) following the surgery.…”

“…Despite the limitations of prior reports, there appears to be a strong correlation between low and moderate altitude of residence and protection from atherosclerotic cardiovascular disease. In our previous work with mouse models of MI, we showed that low-altitude simulation treatment could be used to improve left ventricular function after MI (Shahid et al, 2019) by increasing blood perfusion to the ischemic area, leading us to believe altitude simulation may also be beneficial in therapeutic use for PAD.…”