Could Sleep Apnea Produce Higher Levels of EPCs that Help Heart Attack Patients?

Lena Lavie, PhD, discusses the findings of her counter-intuitive study that continues to build momentum.

People who suffer from breathing disorders such as sleep apnea, are usually at higher risk for cardiovascular disease. However, a recent study from Technion-Israel Institute of Technology scientists suggests that some heart attack patients with these conditions may actually benefit from mild to moderate sleep-disordered breathing.

The study, entitled Endothelial Progenitor Cells in Acute Myocardial Infarction and Sleep-disordered Breathing appeared in the American Journal of Respiratory and Critical Care Medicine (vol 1. 187, no1). Click Here to Read Abstract.

Lena Lavie, PhD, along with researchers Slava Berger, PhD, Doron Aronson, PhD, and Peretz Lavie, PhD, essentially concluded that apnea and other types of sleep-disordered breathing can boost the numbers and functions of rare cells (endothelial progenitor cells or EPCs) that help to repair and build new blood vessels. They say the findings could help predict which patients are at a greater health risk after a heart attack, and may even suggest ways to rebuild damaged heart tissue.

Reaction to studies in the medical world can be notoriously slow, and co-lead researcher Lena Lavie acknowledges that it is still too early to gauge the study’s impact.

“Usually, the impact of a study is built over time,” muses Lavie, a senior research fellow for The Lloyd Rigler Sleep Apnea Research Laboratory at Israel’s Technion Institute of Technology. “For instance, the seminal paper on ischemic preconditioning by Murry et al. published in 1986 [6] was scarcely cited for the first 4 years after its publication. Reviewers complimented our study and pointed to the possible implications toward sleep apnea patients. We also received several e-mails from colleagues in the field that congratulated us on the study.”

Lena Lavie, who also serves as a professor on The Ruth and Bruce Rappaport Faculty of Medicine, agreed to sit down with Sleep Diagnosis & Therapy to talk about the ground-breaking—and somewhat counterintuitive—results of the study.

When did you get the idea for your study?

Lena Lavie, PhD, senior research fellow at The Lloyd Rigler Sleep Apnea Research Laboratory, and a member of the The Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Israel: Obstructive sleep apnea is strongly associated with increased cardiovascular morbidity and mortality, however not all sleep apnea patients develop cardiovascular consequences. The question is why?

The idea that sleep apnea may also activate protective mechanisms came up for the first time around 2002 when we acquired data on increased levels of stress proteins in sleep apnea patients [1]. These protective proteins are synthesized under various stresses, including intermittent decreases in blood oxygen levels, that are the hallmark of  sleep apnea. However, this notion crystalized in 2005 when we analyzed mortality data of sleep apnea patients and found out that in comparison with standard mortality data of the general population, the risk of mortality in sleep apnea patients declined with age [2].

Thus, in patients older than 50 the risk of mortality did not exceed that of the general population. Since these findings confirmed preliminary data we reported 10 years earlier, in 1995, we hypothesized that the syndrome may also activate protective mechanisms in some individuals (probably depending also on their genetic makeup). At that time we had evidence that sleep apnea is associated with increased levels of Vascular Endothelial Growth factor (VEGF), a protein responsible for angiogenesis [3] and that there are large inter-individual differences in VEGF levels in response to hypoxia [4]. This led us to hypothesize that the protective mechanisms may be related to enhanced cardiac collateralization [5].

Some summaries of your work concluded that sleep disorders could somehow “help” heart health. Is this an oversimplified conclusion? If so, how would you sum up your conclusions?

Yes, we believe that some of the health summaries are an oversimplification. We can conclude from our study that intermittent hypoxia in patients with mild to moderate sleep apnea syndrome, who suffered acute myocardial infarction (AMI), enhance the cardiac collateralization and repair of damaged tissue. This may confer protection and facilitate recovery from heart attack in some individuals. And the emphasis of our study is on “mild to moderate sleep apnea.”

What surprised you most about your study?

The great similarity between the impact of the nocturnal exposure to intermittent hypoxia because of the sleep apnea and the exposure to intermittent hypoxia in vitro, on the function of the EPCs was surprising. Even though the rate of the hypoxic events was widely different in the two conditions, the effects on cells’ activity was almost identical.

What did you expect to find when you started the study?

Our hypothesis was that intermittent hypoxia activates angiogenesis. This hypothesis was based on our earlier findings that vascular endothelial growth factor (VEGF), which is a growth factor promoting angiogenesis, was higher in OSA. Then, we reasoned that because EPCs are mobilized by hypoxia, we should find more EPCs in patients with sleep apnea than in patients without sleep apnea, and that potentially their EPCs should be more active.

What is the next logical follow-up study (if any) that should be done?

Our study raises many questions both with respect to treatment of patients suffering acute myocardial infraction and treatment of sleep apnea. First our study should be repeated in patients with severe sleep apnea, since as mentioned above the patients in our study had only mild and moderate syndrome.

Second, the same study should be repeated with women, because we studied only men. Third, the question if controlled exposure to intermittent hypoxia (by controlling intermittent hypoxia through breathing) of patients suffering from acute myocardial infarction (AMI) who do not have sleep apnea, can result in the same effects. This should be examined.

Fourth, the cellular measures obtained should be investigated with regard to endothelial function, left ventricular recovery etc., to determine if mild to moderate sleep apnea has measureable beneficial effects on cardiac functioning, as compared to patients without sleep apnea. Also, there should be a long-term follow-up of these patients to determine if these changes improve their prognosis. Fifth, since treatment with nasal continuous positive airway pressure (nCPAP) abolishes intermittent hypoxia in in sleep apnea, its effects on these measures should be studied as well.

Do your findings point to a reconsideration of sleep therapy in some cases? If so, what cases might those be?

Our findings are particularly relevant to the treatment of asymptomatic elderly patients with mild to moderate sleep apnea. Given the fact that approximately 60% of the people older than 65 have at least 15 respiratory events per hour of sleep, which is considered to be moderate sleep apnea, and that most of them are asymptomatic, our findings may suggest that a decision if to treat an elderly with mild-moderate sleep apnea should be based on the existence of symptoms.

What has been the reaction to your study? 

It is too early to say what the reactions to the study are. Usually the impact of a study is built overtime. For instance, the seminal paper on ischemic preconditioning by Murry et al. published in 1986 [6] was scarcely cited for the first 4 years after its publication. The immediate reaction was an editorial that accompanied our paper. The reviewers complemented our study and pointed to the possible implications toward sleep apnea patients. We also received many e-mails from colleagues in the field that congratulated us on the study.

What are your current research efforts?

Generally, our research interests are focused on the functions of various blood cells and how these functions are affected by hypoxia and intermittent hypoxia. Thus far, besides EPCs we have studied endothelial cells that are lining the blood vessels, monocytes, and their development into foam cells which induce atherosclerosis, platelets and their pro-thrombotic effects—neutrophils and lymphocytes—all of which were shown to be activated and to promote inflammatory sequelae in sleep apnea patients as well as in response to intermittent hypoxia in vitro.

How do you think sleep medicine will evolve over the next few years?

Sleep medicine is presently undergoing a major change. In the area of sleep apnea, emphasis is shifting from diagnosis to treatment, and there is a major effort to find an alternative treatment to nCPAP. I believe that this process will continue and that in the next 10 to 15 years sleep apnea will be handled by general practitioners. As sleep apnea is the flagship of sleep medicine, this may have major negative effects on the future of sleep medicine.

About Lena Lavie, PhD

Lena Lavie obtained her PhD from the Department of Biology in the Technion Israel Institute of Technology, and did her post-doctoral training in the department of Biological Chemistry at Harvard Medical School, Boston. She is currently a senior research fellow, an associate professor, and the head of the Lloyd Rigler Sleep Apnea Research Laboratory in the Ruth and Bruce Rappaport Faculty of Medicine at Israel’s Technion Institute of Technology.

References

1.         Lavie, L., Obstructive sleep apnoea syndrome–an oxidative stress disorder. Sleep Med Rev, 2003. 7(1): p. 35-51.

2.         Lavie, P., L. Lavie, and P. Herer, All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age. Eur Respir J, 2005. 25(3): p. 514-20.

3.         Lavie, L., et al., Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med, 2002. 165(12): p. 1624-8.

4.         Schultz, A., et al., Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation. Circulation, 1999. 100(5): p. 547-52.

5.         Lavie, L. and P. Lavie, Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses, 2006. 66(6): p. 1069-73.

6.         Murry, C.E., R.B. Jennings, and K.A. Reimer, Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 1986. 74(5): p. 1124-36.

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