The relationship between restless legs syndrome (RLS) and cardiovascular disease remains enigmatic in the general population, and its prognostic value in patients with coronary artery disease (CAD) is unknown. In this study, the frequency of RLS-like symptoms was assessed using a validated instrument in 3,266 patients undergoing cardiac catheterization (mean age 64 years, 62% male, 23% Black, and 74% with obstructive CAD). Patients were followed for primary end points of cardiovascular death or incident myocardial infarction. Fine and Gray hazard models explored the association between RLS and incident events after adjustment for demographic and clinical risk factors. In the total cohort, 29% of patients reported mild (rare or sometimes) symptoms, and 15% of patients had moderate/severe (often to almost always) symptoms of RLS. Female sex (odds ratio [OR] 2.11, 95% confidence interval (CI), 1.68 to 2.57), body mass index (OR 1.12 per 5 kg/m 2 , 95% CI, 1.04 to 1.22), diabetes (OR 1.43, 95%,1.15 to 1.79), and β-blocker use (OR 1.35, 95% CI, 1.07 to 1.72) were independently associated with moderate/severe symptoms of RLS compared with no symptoms. Over a 5-year follow-up period, 991 patients suffered an adverse event. Compared with those with no symptoms, patients with moderate/severe RLS had significantly higher risk of the primary end point (hazard ratio [HR] = 1.33, 95%),CI 1.01 to 1.76) after adjustment for demographic and clinical risk factors. The association was more significant in men than women, HR 1.98, 95% CI, 1.41 to 2.78 versus HR 0.99 (,95% CI, 0.64 to 1.52, p interaction= 0.013. In conclusion, among men with CAD, moderate-to-severe symptoms of RLS are associated with significantly higher risk of adverse cardiovascular outcomes, independent of traditional risk factors.
Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an irresistible urge to move the legs that improves with movement and exhibits a propensity to manifest at nighttime due to circadian influences. Dopaminergic neural pathways, iron deficiency, and sympathetic nervous system hyperactivation are potential pathogenic mechanisms underlying RLS. RLS is commonly associated with traditional cardiovascular disease (CVD) risk factors such as obesity, dyslipidemia, diabetes mellitus, and obstructive sleep apnea, and emerging evidence suggests that microvascular dysfunction and arterial stiffness may accompany RLS and predict response to treatment. RLS of 3 or more years’ duration is associated with a higher risk of developing CVD in women. It is unclear whether patients with established CVD and comorbid RLS are at greater risk for adverse CVD consequences. In a large cohort of patients with coronary artery disease (CAD), we investigated the association between the presence of RLS-like symptoms and incident cardiovascular (CV) events. We hypothesized that participants with moderate-to-severe RLS are at higher risk for adverse CV events, including CV death and myocardial infarction (MI).
Methods
The study population was derived from the Emory Cardiovascular Biobank (EmCAB), an ongoing prospective cohort established in 2003 of patients aged 20 to 90 years recruited from Emory Healthcare facilities. The research protocol has been approved by the ethics committee at Emory University and Emory Institutional Review Board. Informed consent has been obtained from all participants at enrollment. Patients were enrolled at the time of coronary angiography for the evaluation and management of suspected or known CAD. Participants were interviewed to collect information about demographic characteristics, smoking history, medical history, and medication use as previously described. The prevalence of diabetes, hypertension, hypercholesterolemia, and established CV disease subtypes (CAD, heart failure [HF], and peripheral artery disease) was determined by physician diagnosis and/or treatment. Medical records were reviewed to confirm self-reported medical histories. Weight and height were measured at enrollment, and body mass index was calculated by dividing weight (in kg) by height (in meters-square). Serum creatinine was measured at enrollment, and the estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Approximately 5% of patients were excluded from enrollment in the EmCAB because of congenital heart disease, severe valvular heart disease, severe anemia, a recent blood transfusion, myocarditis, history of active inflammatory disease, cancer, or history of cardiac transplantation.
At the time of cardiac catheterization, subjects were asked to answer the following RLS assessment question: “Do you have unpleasant feelings in your legs – for example, creepy crawling or tingly feelings when you lie down at night that make you feel restless and keep you from getting a good sleep?” The response was categorized into 3 groups (none, mild, moderate to severe) based on the frequency of symptoms; participants who answered “never” were considered negative for RLS, whereas those who answered “rare” or “sometimes” were considered to have mild symptoms.) Participants who answered “often” and “almost always” were considered to have moderate-to-severe RLS. A total of 3,266 participants enrolled in EmCAB completed the RLS questionnaire and long-term follow-up ( Supplementary Figure 1 ).
Follow-up for adverse CV outcomes was conducted by independent personnel blinded to the RLS assessment survey, and clinical data. Adverse CV outcomes were determined through verbal communications with the participant, family, Georgia vital records, or the Social Security Death Index. Medical records were accessed or requested to validate all self-reported events, and death certificates were obtained and reviewed by an adjudication committee of 2 cardiologists with a third arbitrator in case of disagreement. CV death was defined as death attributable to an ischemic cardiovascular cause (fatal MI), cardiac arrhythmia, heart failure, or fatal stroke. Our primary end point was a combined outcome of MI or CV death. Additionally, we considered 2 secondary end points, CV death/MI/HF hospitalization and CV death/MI/revascularization. The time of follow-up was defined as days from coronary angiography performed at enrollment to the occurrence of first incident event, death, or end of follow-up, whichever occurred earlier.
Continuous variables were presented as mean (SD) or as median (interquartile range), and categorical variables were reported as frequency counts and proportions (%). Chi-square test was used to compare proportions, whereas analysis of variance was conducted to determine whether differences in continuous variables existed between groups stratified by RLS severity. Multivariate logistic regression was performed to identify determinants of more severe symptoms of RLS compared with no symptoms.
In survival analysis, we estimated the cumulative incidence function for the study end point, while treating non-CV death as a competing risk according to the RLS assessment survey using the cumulative incidence function homogeneity test by Gray. Models were adjusted using the aforementioned covariates. Sensitivity analyses were performed to evaluate if results were different by age, race, sex, and the presence of obstructive CAD. Proportional hazards assumption was examined by plotting Schoenfeld residuals for each covariate against RLS severity as well as including an interaction term of each covariate by severity in the Cox models, and no significant violations were observed. Two-tailed p values <0.05 were considered statistically significant, and all analyses were performed with SPSS 24 (IBM Corp, Armonk, New York).
Results
A total of 3,266 patients, 62% male, 23% Black, were followed for a mean duration of 3.1 years (interquartile range 1.3 to 4.9 years). Overall, 38% had diabetes (>90% Type 2), 85% hypertension, 73% had obstructive CAD, and 23% had a prior MI ( Table 1 ).
| Variable | All | Restless legs syndrome symptoms | p Value | |||
|---|---|---|---|---|---|---|
| None | Mild | Moderate-Severe | ||||
| (n = 3,266) | (n = 1,818) | (n = 954) | (n = 494) | |||
| Demographics | ||||||
| Age, y | 64 ± 12 | 64 ± 12 | 64 ± 12 | 64 ± 12 | 0.78 | |
| Women | 1,234(38%) | 593(33%) | 401(42%) | 240(48%) | <0.001 | |
| Black | 749 (23%) | 385 (21%) | 255 (27%) | 109 (22%) | 0.004 | |
| Comorbidities | ||||||
| Body mass index (kg/m 2 ) | 29.9 ± 6 | 29.4 ± 6.1 | 30.2 ± 6.7 | 30.8 ± 6.9 | <0.001 | |
| Smoking history | 2,316 (71%) | 1,279 (70%) | 6,565 (69%) | 382 (77%) | 0.002 | |
| Hypertension | 2,781 (85%) | 1,503 (83%) | 843 (88%) | 435 (88%) | <0.001 | |
| Diabetes mellitus | 1,233 (38%) | 603 (33%) | 408 (43%) | 222 (45%) | <0.001 | |
| Hyperlipidemia | 2,454 (75%) | 1,347 (74%) | 721 (76%) | 386 (78%) | 0.16 | |
| eGFR (ml/min/1.73 m 2 ) | 71 ± 25 | 73 ± 24 | 69 ± 25 | 70 ± 25 | <0.001 | |
| Cardiac risk factors | ||||||
| Prior MI | 741 (23%) | 394 (22%) | 225 (24%) | 122 (25%) | 0.24 | |
| Heart failure | 1,114 (34%) | 586 (32%) | 349 (37%) | 179 (36%) | 0.04 | |
| EF (%) | 53 ± 13 | 53 ± 13 | 52 ± 14 | 53 ± 12 | 0.14 | |
| MI at enrollment | 285 (9%) | 151 (8%) | 92 (10%) | 42 (9%) | 0.49 | |
| Obstructive CAD* | 0.95 | |||||
| Single vessel | 647 (20%) | 382 (21%) | 171 (18%) | 94 (19%) | ||
| Multivessels | 1,083 (33%) | 600 (33%) | 315 (33%) | 168 (34%) | ||
| Prior PCI | 1,360 (42%) | 727 (40%) | 401 (42%) | 232 (47%) | 0.0142 | |
| Prior CABG | 715 (22%) | 382 (21%) | 200 (21%) | 133 (27%) | 0.0048 | |
| Events | ||||||
| Myocardial infarction | 136 (4%) | 73 (4%) | 38 (4%) | 25 (5%) | 0.62 | |
| Heart failure | 285 (9%) | 145 (8%) | 86 (9%) | 54 (11%) | 0.07 | |
| Coronary revascularization | 261 (8%) | 145 (8%) | 67 (7%) | 49 (10%) | 0.43 | |
| Cardiovascular mortality | 290 (9%) | 145 (8%) | 86 (9%) | 59 (12%) | 0.034 | |
| Overall mortality | 505 (15%) | 273 (15%) | 143 (15%) | 89 (18%) | 0.11 | |
| Medication use | ||||||
| Aspirin | 2,492 (76%) | 1,385 (76%) | 732 (77%) | 375 (76%) | 0.93 | |
| Beta blocker | 2,242 (69%) | 1,192 (66%) | 686 (72%) | 364 (74%) | <0.001 | |
| Statin | 2,314 (71%) | 1,283 (71%) | 686 (72%) | 345 (70%) | 0.66 | |
| ACE/ARB | 1,748 (54%) | 945 (52%) | 529 (56%) | 274 (56%) | 0.14 | |
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