Restless legs syndrome and cardiovascular disease: a research roadmap

In this paper, we first critically appraise the epidemiologic literature examining the association of restless legs syndrome (RLS) with cardiovascular disease (CVD) and then consider whether lessons learned from the study of cardiovascular consequences of other sleep disorders might inform a research agenda to examine the potential mechanisms of cardiovascular morbidity of RLS. Cross-sectional and longitudinal studies are both mixed as to whether there is a meaningful association of RLS and CVD. On the other hand, numerous cross-sectional and longitudinal observational studies have shown a strong association of obstructive sleep apnea (OSA) with CVD risk. Each of the potential mediating mechanisms in OSA may also be assessed in RLS, including 1) neural mechanisms such as increased central sympathetic outflow, impaired baroreflex function, diminished heart rate and blood pressure variability, and increased chemoreflex sensitivity, 2) metabolic mechanisms such as glucose intolerance and reduced insulin sensitivity/diabetes as a result of sleep disturbance in RLS, 3) oxidative stress, 4) systemic or vascular inflammatory mechanisms, and 5) vascular mechanisms including impaired endothelial functioning, increased aortic stiffness, hypothalamic-pituitary axis activation or renin-angiotensin-aldosterone activation. Three known characteristics of RLS may contribute to these specific mechanisms of increased cardiovascular risk: 1) periodic limb movements of sleep, which are associated with large increases in heart rate and blood pressure, 2) sleep fragmentation and sleep deprivation, which are known to produce adverse consequences for neural, metabolic, oxidative, inflammatory, and vascular systems, and 3) iron deficiency, which is an emerging risk for cardiovascular disease. Future research priorities include additional epidemiologic studies which characterize multiple CVD risk factors, case-control studies which examine known markers of cardiovascular risk, and small clinical trials which assess the effects of RLS treatment on intermediate physiological markers such as sympathetic activity or baroreflex control, measures of vascular stiffness and reactivity, or measures of insulin sensitivity and glucose tolerance.