Sympathetic Activity, Hypertension, and The Importance of a Good Night’s Sleep

Obstructive sleep apnea (OSA) is associated with multiple cardiovascular diseases, such as ischemic heart disease, heart failure, stroke, atrial fibrillation and overall cardiovascular mortality, but the strongest association is with hypertension, and in particular with resistant hypertension.¹

The negative health effects of OSA are thought to be due to fragmented sleep, negative intrathoracic pressure surges, hypercapnea, and intermittent hypoxia. Most of the research on the pathophysiology of OSA has focused on the importance of intermittent hypoxia stimulating body chemoreceptors to induce sympathetic activation. There is substantial basic and clinical data supporting this pathway. Clinical studies have shown that acute hypoxic episodes induce sympathetic activation, as measured by muscle sympathetic nerve activity (MSNA). Importantly, this effect is continues after the acute hypoxic episodes, resulting in sustained daytime sympathetic activity, possibly through long-term facilitation of chemosensory drive by the carotid body.^{2, 3} Experimental models of rodents exposed to chronic intermittent hypoxia reproduce several of the cardiovascular pathologic features of OSA including hypertension and sympathetic hyperactivity,² and these derangements are prevented by carotid body denervation.

Even if the evidence for intermittent hypoxia inducing sympathetic activation is solid, it is less clear if this alone mediates the increase in sympathetic activity and cardiovascular risk; for example, nocturnal oxygen supplementation prevents hypoxic episodes, but only CPAP and not oxygen supplementation reduced blood pressure in patients with OSA.⁴ The study of Floras et al in this issue of the Journal⁵ suggests that sleep fragmentation also contributes to sympathetic activation. The investigators studied 48 patients, half with no or mild OSA and half with moderate to severe OSA, and correlated sleep apnea indices with MSNA. They found that the strongest correlation was between MSNA and sleep arousal index, and the association remained significant independent on the frequency of apneic episodes or severity of oxygen desaturation. The implication of this finding is that the increase in sympathetic activation associated with OSA is not only or mainly due to frequency of hypoxic episodes, but is seemingly more strongly related to lack of a good night's sleep. This is not a new concept; poor sleep quality has already been linked to a heightened inflammatory state, higher nighttime blood pressure and other cardiovascular disorders.⁶

One limitation of the study by Floras et al is that the patients they studied were healthier than the typical American patient suffering from OSA; the average BMI was less than 30 kg/m2 and their blood pressure was within normal range. In correlation studies a wider range of patients’ characteristics is usually preferable. The number of subjects studied was probably too small to draw conclusions about the impact of their findings on blood pressure. More importantly, this study has the limitations inherent to an association study, where causality cannot be inferred. Nonetheless, it does open the possibility that sleep fragmentation and arousals, an important contributor to poor sleep quality, not only impacts quality of life, but contributes to sympathetic activation and cardiovascular morbidity. If so, similar positive correlations between MSNA and nocturnal arousals from other causes, such as periodic limb movements or insomnia, would be anticipated.

Ultimately, proof of causality relies on intervention studies, and CPAP is the intervention most widely studied. The data indicating a beneficial effect of CPAP on blood pressure is compelling, but not dramatic. Even in patients with resistant hypertension, where the effect of CPAP is arguably larger,⁷ the effect is relatively modest; results of a meta-analysis found decreases of about 5 mm Hg in systolic and 3 mm Hg in diastolic blood pressures with many studies showing even smaller changes.⁸ The magnitude of this effect is, however, clinically relevant, as it is comparable with the effects of adding an antihypertensive medication. Nonetheless, the range of responses and inconsistencies between studies implies that many patients do not benefit from CPAP in regards to blood pressure control.

It is assumed that the beneficial effects of CPAP derive from reduction in nocturnal hypoxia, but CPAP does also improve sleep quality. Furthermore, the reduction in blood pressure induced by CPAP is greater in those in whom daytime sleepiness is improved. It is likely, therefore, that some of the cardiovascular effects of CPAP derive from improved sleep quality. We are not aware of studies large enough to try to determine if the improvement in sleep quality is independent of the reduction in nocturnal hypoxia. Conversely, it is possible that failure to improve sleep quality contributes to low CPAP compliance, which may explain why in many patients CPAP use is not accompanied by a reduction in blood pressure.

A better approach to define the relative contribution of hypoxic events and poor sleep quality to the deleterious effects of OSA would be to selectively target each therapeutically, but this is not easily done with currently available approaches. Selective targeting of carotid body chemoreceptors is being considered in the treatment of hypertension;⁹ when and if effective therapeutic approaches are developed, they could be used to determine the specific contribution of carotid body chemoreceptors on the increase in MSNA, blood pressure, and cardiovascular morbidity associated with OSA. Equality challenging is choosing treatments that can selectively improve sleep quality. Hypnotics have been used to improve CPAP compliance with mixed results, but to our knowledge they have not been tested to see if they would provide additional cardiovascular benefits in OSA patients.

Finally, if both sleep arousal and nocturnal hypoxia have sympathetic activation as a common final pathway, should we not use centrally-acting sympatholytics for the treatment of OSA-associated hypertension? There is little available data about the use of sympatholytics in OSA patients, but randomized trials testing for the beneficial cardiovascular effects of CPAP do not even mention this category of drugs in the list of antihypertensive medications used in these patients⁸. The data on the effect centrally-acting sympatholytics on sleep and OSA is sparse. Clonidine is known to reduce REM sleep, and a small study showed that clonidine reduced nocturnal hypoxia in OSA patients by suppressing REM-related apneic episodes.¹⁰ An experimental study in normal volunteers showed that clonidine reduced the susceptibility for central apnea during non-REM sleep.¹⁰ Whether either of these effects will translate into cardiovascular benefit is not known.

Translating the significant advances made in our understanding of OSA into improved cardiovascular outcomes remains challenging. CPAP compliance remains a large problem, as is the wide interindividual variability in its ability to lower blood pressure. This also offers opportunities in testing approaches that can maximize the beneficial effects of CPAP. We should continue to emphasize weight loss while being cognizant of the low likelihood of it be achieved and maintained.. The study by Floras et al highlights the need to use sleep quality in addition to hypoxia suppression to assess the efficacy of CPAP.