Most previously published cross-sectional studies have reported a positive association between RLS and cardiovascular disease. The association between RLS and heart disease was first reported in 4000 Swedish men. In that study participants with RLS more frequently reported heart problems (odds ratio (OR): 2.5; 95% CI: 1.4–4.3). This study was followed by a large multinational sample of European adults that reported an odds ratio of 1.4 (95% CI: 1.2–7.2) between RLS and self-reported heart disease. In the following 10 years, similar significant associations were also observed in several, but not all, cross-sectional studies. Among 18,980 adults living in Europe, ORs for RLS were 1.4 (95% CI: 1.1, 1.9) for subjects with heart disease and 1.4 (95% CI: 1.1, 1.6) for those with hypertension [14]. In the Wisconsin sleep cohort [28], Winkelman et al. observed a linear association between RLS symptom frequency and an increased likelihood of having cardiovascular disease. The OR for cardiovascular disease comparing restless legs ≥7 times/wk to no RLS was 2.6 (95% CI: 1.4, 4.8). A similar positive trend was seen for hypertension, but this was not significant. It is noteworthy that none of above studies employed the set of questions of RLS diagnosis recommended by IRLSSG, and, therefore, may introduce misclassification of RLS diagnosis. However, a recent cross-sectional study (n = 3831) using IRLSSG diagnostic criteria also found that restless legs ≥5 times/month were associated with 2 times increased risk of having coronary artery disease and cardiovascular disease [29]. The association was stronger in those with greater frequency or severity of RLS symptoms. Moreover, PLMS, which is seen in ~80% of RLS patients, has been shown to be associated with the severity of hypertension [30].

The prevalence of PLMS in the general population is likely between 5 and 11%. In a sample of randomly chosen adults between the ages of 18 and 65 years, 7.6% of 592 individuals had PLMS recorded by PSG. Interestingly, PLMS was significantly more common in Caucasians than African-Americans (9.3% vs. 4.3%). The prevalence of PLMS also seems to increase in the elderly, as 45% of 427 elderly over 65 years were found to have PLMS on PSG; a similar number of persons with PLMS were found in a community-dwelling elderly female population. It is important to review the nonspecificity of PLMS as the majority of PLMS outcomes research has been carried out in populations not assessed for RLS symptomatology. Although PLMS is present in the great majority of persons suffering from RLS, these movements during sleep also occur in many circumstances or conditions outside of RLS and in many elderly persons without any sleep complaints. PLMS can be seen in conjunction with other disorders of sleep including obstructive sleep apnea, narcolepsy, and REM sleep behavior disorder, or in disease states outside of sleep including essential hypertension, congestive heart failure (CHF), and end-stage renal disease.

As noted above, in subjects with RLS, individual movements within PLMS clusters are associated with discrete increases in blood pressure. In adults, these observations were noted in two separate but small studies in which 8 and 10 RLS subjects underwent polysomnography and noninvasive blood pressure measurement. Universally, in all subjects and with all movements, there were increases in blood pressure on the order of 25 mmHg systolic units when there was cortical arousal and 18 mmHg systolic units without arousal. In children PLMS also seems to associate with nocturnal hypertension. A study of 17 children with PLMS and 297 children without PLMS who were not assessed for RLS symptomatology, showed that the children with PLMS had an elevated odds of 6.25 (95% CI: 1.87, 20.88) of having nocturnal hypertension, although there was no difference in mean nocturnal blood pressures in the two groups.

Outside of the immediate sympathetic hyperactivity related to PLMS, there is also evidence that nocturnal PLMS associates with diurnal hypertension. In a sample of 91 patients (mean age 49.1 ± 2.3) with essential hypertension without information on RLS symptomatology, PLMS were found in 18.7% more than in the general population. Perhaps more striking was the higher rate of PLMS in patients with grade III than grades I and II hypertension (36.4% vs. 13%). A smaller study of patients with essential grade I hypertension, 14 hypertensive patients, and 28 age- and obesity-matched controls failed to show an increased rate of PLMS in those with hypertension. In a larger study of 861 patients with self-reported RLS symptoms, the odds of having hypertension was more than 2-fold (OR: 2.26; 95% CI: 1.28, 3.99) for persons with a PLMS frequency of more than 30 per hour of sleep, after controlling for age and body mass index.

It should be noted that the relationship between RLS and hypertension, as stated in previous sections of this chapter, is controversial. Data from both the Wisconsin Sleep and Sleep Heart Health cohorts, showed an unadjusted relationship between RLS and hypertension but these relationships became nonsignificant after controlling for age, sex, body mass index, and blood pressure. In the final section of this chapter concerning PLMS and incident cardiovascular disease, evidence further complicating this relationship between hypertension and PLMS will be considered.

PLMS are very common in the setting of CHF, occurring in up to one-half of CHF patients. Most studies have found that about 20–25% of patients with CHF have PLMS but the significance of this finding is uncertain. In a longitudinal study of patients with CHF, 218 subjects with newly diagnosed systolic heart failure were divided into those having a PLMS frequency of more than 5 per hour of sleep (37%) and less than 5 per hour of sleep (63%). The presence of PLMS was associated with a greater than 2-fold increased hazard ratio of death (hazard ratio 2.42, 95% CI: 1.16, 5.02) after adjusting for age, heart failure severity, and sleep apnea. It should be noted that in this analysis, there was a difference in the two groups with those with PLMS compared to without PLMS being significantly older and having more severe heart failure. It is possible that the statistical adjustments were inadequate to offset the dissimilarity of the groups. Other studies have shown that approximately 20% of heart failure subjects have PLMS with an average PLMS index of about 35 per hour [43, 44]. In these studies, other than being older, those with PLMS did not differ from those without PLMS in terms of heart failure severity or presence of sleep disordered breathing, the caveat being the small number in these studies with 55 and 79 subjects, respectively.

PLMS is very prevalent in persons suffering chronic kidney disease, especially those undergoing hemodialysis. Although studies that have assessed the prevalence of PLMS in this population have been small, they have consistently shown that nearly 50% of those with end-stage renal disease have PLMS [45, 46]. Symptoms of RLS are also quite common among the renal disease population. In fact, the presence of RLS in addition to adversely affecting sleep and dialysis compliance has been shown to predict mortality. Mortality may also be increased for end-stage renal disease patients with frequent PLMS. In a study of 29 end-stage renal patients, those with PLMS > 20 per hour of sleep compared to those with less than 20 had 50% versus 10% mortality in 20 months (p = 0.0007). It is important to note the small sample size of 29 subjects and also that those with frequent PLMS were significantly older than those without PLMS. In a larger study of 150 renal failure patients, PLMS independently predicted 10-year risk of coronary heart disease risk, estimated using the Framingham Cardiovascular disease risk profile [47].