The phenomenon of preconditioning reflects complex adaptive responses by living organisms to stimuli such as ischemia, hypoxia, hypothermia, or starvation. Acute ischemic preconditioning, initially described by Murry in 1986 (Circulation. 1986;74[5]:1124), occurs when multiple brief episodes of ischemia followed by reperfusion elicit a protective effect on the heart from a subsequent prolonged period of ischemia, such as a heart attack. This protective effect from ischemic preconditioning can be in the form of a smaller heart attack, lower chance of cardiac arrhythmias, less myocardial cell death, and lower risk of heart muscle failure. The cardioprotective effect of ischemic preconditioning is dependent on the duration and strength of the preconditioning stimulus. If the preconditioning stimulus is too strong or prolonged, detrimental effects on the heart may be observed.

Like ischemic preconditioning, hypoxic preconditioning represents a complex adaptive response that organisms have developed to offset damage inflicted by oxygen deprivation. The concept of hypoxic preconditioning is familiar to humans; for years, athletes have been using hypoxic training (high altitude and other newer technologies) to boost their performance in sporting events. Additionally, there is evidence dating back to before the breakthrough findings of Murry and colleagues who confirm the cardioprotective effects of hypoxia. In 1973, Meerson and colleagues (Am J Cardiol. 1973;31[1]:30) reported that mice exposed to high-altitude hypoxia have reduced mortality and smaller areas of necrotic myocardium after coronary artery occlusion.

Both of the ischemic and hypoxic preconditioning animal experiments mentioned above involve acute exposure to the preconditioning stimuli, resulting in a cardioprotective response for a limited time period. In order to afford a sustained period of cardioprotection, recurrent hypoxic exposure may be necessary. Indeed, recent studies have concentrated on just that; repeated exposure to intermittent hypoxia over a few weeks (Manukhina et al. Exp Biol Med. 2013;238[12]:1413) results in robust cardioprotection after coronary artery occlusion and reperfusion.

Despite the convincing cardioprotective discoveries from ischemic and hypoxic preconditioning, translation into clinical practice as a therapeutic modality is absent. This is partly because human beings are more complex than animals. They have comorbidities and are affected by aging, both of which may alter the milieu for preconditioning stimuli. Furthermore, the therapeutic range for any given preconditioning stimulus is unknown.

Sleep apnea (SA) is exceedingly prevalent in the United States. In SA, an individual stops breathing either completely (apnea) or partially (hypopnea) during sleep resulting in intermittent hypoxia, with arousal from sleep and resumption of breathing leading to reoxygenation. Hence, SA is characterized by intermittent hypoxia followed by reoxygenation. So, one can speculate that SA could exert cardioprotective effects as seen in hypoxic preconditioning and ischemic preconditioning. It is important to note, however, that SA is associated with hypercapnic intermittent hypoxia, whereas most of the investigations on ischemic preconditioning and intermittent hypoxia are with eucapnia or hypocapnia.

The potentially cardioprotective role of SA is supported by a growing body of complementary research that indicates that coronary collateral flow is higher in patients with SA vs. control subjects (Steiner. Chest. 2010;137[3]:516) and that there is an increased mobilization, proliferation, and angiogenic capacity of endothelial progenitor cells from patients with myocardial infarction and SA as compared with cells from controls subjects without SA (Berger. Am J Respir Crit Care Med. 2013;187[1]:90). Some epidemiologic data support a weaker relationship between SA and coronary ischemic events compared with other cardiovascular events (Gottlieb. Circulation. 2010;122[4]:352). Hypoxic preconditioning may explain the relatively decreased pro-thrombotic influence of SA in the coronary vascular bed. Nevertheless, more research is needed to determine if SA is cardioprotective. If, however, cardioprotection from SA is confirmed, it may contribute to a paradigm shift in how SA is considered in relationship to coronary heart disease. Furthermore, future investigations would need to focus on what dose and duration of SA is needed for cardioprotection to occur. Prospective studies may also provide an opportunity for investigating interindividual variability in the susceptibility of the myocardium to the hypoxic preconditioning stimulus from SA.

This article highlights how complex the relationship between hypoxia and myocardial response is. This is further supported by results from a recent clinical trial, AVOID (Air Versus Oxygen In ST-elevation MyocarDial Infarction) (Stub. Circulation. 2015;131[24]:2143). Results from the AVOID trial report that routine oxygen use in normoxic patients hospitalized with a heart attack was not beneficial and, in fact, was harmful. Patients who received oxygen had more myocardial injury than those who did not. Therefore, even though for decades we thought that oxygen therapy helps hospitalized heart attack patients, results from the AVOID trial have initiated a paradigm shift. It remains to be determined whether such a paradigm shift will follow for sleep apnea.

Dr. Shah is with the department of epidemiology and population health, Albert Einstein College of Medicine, N.Y.

Sleep apnea and myocardial preconditioning: A paradigm shift?