Ischemic preconditioning seems to occur more readily with sustained hypoxemia than with intermittent hypoxemia. Patients with OHS are exposed to both types of hypoxemia; therefore, it is likely that there is an additive effect. In fact in our study, the prevalence of cardiovascular morbidity was lowest in patients with OHS who also had the most severe form of OSA. This finding supports the notion that sustained and intermittent hypoxemia may result in a more powerful angiogenic stimulation than either one alone. Clearly these findings are hypothesis generating, and further research is necessary. In summary, we do not think sustained hypoxemia is the only reason for the protective cardiovascular effect we observed in our patients with OHS and the most severe form of OSA, but rather it is a combination of cumulative exposure to significant hypoxemia during wakefulness due to hypoventilation plus intermittent hypoxemia during sleep due to very severe OSA. It remains unclear whether hypercapnia modulates the effect of hypoxemia, since experiments involving hypoxic preconditioning did not include exposure to hypercapnia.