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Volume 14 No. 03
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Scientific Investigations

Evaluation of Cardiovascular Risk Factors and Restless Legs Syndrome in Women and Men: A Preliminary Population-Based Study in China

Yuqiong Liu, MS1,2; Gangqiong Liu, MD3; Ling Li, MD3; Jing Yang, MD3,4; Shengli Ma, MD5
1Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China; 2Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, People's Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China; 4Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China; 5Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China

ABSTRACT

Study Objectives:

Many studies have investigated the association between restless legs syndrome (RLS) and cardiovascular risk factors, leading to conflicting results. Therefore, the aim of the current study was to determine whether RLS is associated with cardiovascular risk factors and disease.

Methods:

This cross-sectional study included 5,324 consecutive subjects who visited the Physical Examination Center of The First Affiliated Hospital of Zhengzhou University for their yearly routine physical examination. Participants underwent a face-to-face interview with a neurologist for the assessment of RLS, based on the International Restless Legs Study Group criteria. They also completed a questionnaire related to cardiovascular risk factors and other health-related and demographic information. Logistic regression was used to assess which of the demographic and cardiovascular risk factors increased the odds of RLS. Then, unadjusted and adjusted models were designed to determine whether RLS was associated with increased odds of cardiovascular disease, coronary artery disease, or hypertension.

Results:

RLS was observed in 9.2% of the participants. Multivariable logistic regression models, which included the covariates age, sex, body mass index, smoking status, hypercholesterolemia, and Pittsburgh Sleep Quality Index score (dichotomized at 5), demonstrated that female sex (odds ratio [OR]: 2.42, 95% confidence interval [CI]: 1.99–2.95), smoking (OR: 1.96, 95% CI: 1.31–2.92), high cholesterol (OR: 1.30, 95% CI: 1.03–1.64), and PSQI score > 5 (OR: 5.61, 95% CI: 2.14–14.69) are significantly associated with RLS. Additionally, RLS was associated with hypertension, after adjusting for age, sex, body mass index, smoking, hypercholesterolemia, Pittsburgh Sleep Quality Index score > 5, diabetes, anemia, and decreased renal function.

Conclusions:

RLS is associated with the prevalence of hypertension but not with that of cardiovascular disease or coronary artery disease.

Citation:

Liu Y, Liu G, Li L, Yang J, Ma S. Evaluation of cardiovascular risk factors and restless legs syndrome in women and men: a preliminary population-based study in China. J Clin Sleep Med. 2018;14(3):445–450.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Epidemiological studies have associated restless legs syndrome (RLS) with the cardiovascular system, but the data are not consistent. This study examined the association between cardiovascular risk factors and RLS in Chinese individuals.

Study Impact: Results from this large cohort of women and men suggest that RLS is associated with the prevalence of hypertension but not with that of cardiovascular disease or coronary artery disease. Screening and diagnosis of RLS in patients with hypertension may alleviate the burden of symptoms in most cases.

INTRODUCTION

Restless legs syndrome (RLS) is a movement disorder characterized by intense, unpleasant leg sensations, and an irresistible urge to move the legs.1 This unpleasant sensation occurs mostly when individuals are at rest, and because it is partially or totally relieved by movement, it often results in sleep disruptions. RLS occurs in approximately 4% to 29% of the population in Europe and North America, and 2% to 12% of the population in Asia.24 The prevalence of RLS also increases with age, and it is higher in women.5 Although dopaminergic dysfunction and iron deficiency are considered the likely pathophysiological culprits of RLS,5 its etiology remains poorly understood.

Past epidemiological studies have investigated the relationship between RLS and the cardiovascular system, but the results of the cross-sectional and prospective studies are inconsistent. Several studies have reported that RLS is associated with cardiovascular disease (CVD) or coronary artery disease (CAD).69 In contrast, other studies have failed to find associations between RLS and CVD.10,11 Subjects with RLS have also been reported to have a higher prevalence of diabetes and stroke than those without RLS.12,13 However, in other population-based studies, RLS was not associated with these conditions.14,15

Some studies have provided evidence for an association between RLS and hypertension, stroke, CAD, and other comorbidities. Erden et al. reported that RLS is strongly linked to nondipping hypertension,16 which is an irregular blood pressure (BP) pattern leading to autonomic imbalance and therefore to an increased cardiovascular risk.17,18 The micro-vascular lesion load of RLS and migraineur patients were measured using brain magnetic resonance imaging, and the results showed that RLS and stroke risk factors combined posed a greater risk for silent stroke.19 Echocardiographic data indicated that left ventricular internal diameter in diastole was significantly increased in hemodialysis patients with RLS, leading to a significant increase in left ventricular mass and other structural abnormalities.20 In addition, RLS has also been associated with an increased risk for several vascular disorders, such as impaired endothelial functioning, increased aortic stiffness, capillary tortuosity, heart rate variability, and peripheral hypoxia.2124

Although RLS has been increasingly studied in recent years, data on the association between RLS and cardiovascular risk factors in China are still lacking. Therefore, we aimed to determine whether RLS is associated with cardiovascular risk factors and disease in the general population of China.

METHODS

Study Subjects

Our study was performed at the Physical Examination Center of The First Affiliated Hospital of Zhengzhou University between May 2013 and December 2015. We asked 5,398 subjects aged 18 to 87 years, who attended their yearly routine physical examination, to participate in this study. At baseline, 5,324 of the 5,398 subjects consented to participate in this study (response rate, 98.6%). Participants' mean age was 47.3 ± 17.9 years, and 51.9% were women. All participants provided written informed consent, and this study was approved by the local ethics committee. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Procedure

All participants underwent a face-to-face interview with a trained and experienced neurologist to assess the presence of RLS, based on the criteria of the International Restless Legs Syndrome Study Group (IRLSSG), published in 2003 (Chinese version).25 In this study, subjects who fulfilled the IRLSSG criteria, and had RLS symptoms at least four times per month, received a diagnosis of RLS. After the interview, the participants were also asked to complete a questionnaire regarding the following: demographic information (age and sex), behavioral factors (smoking status and alcohol consumption status), medical history (eg, a history of hypertension, diabetes, myocardial infarction, hypercholesterolemia, decreased renal function, and anemia), and the presence of snoring; the Pittsburgh Sleep Quality Index (PSQI) score was also determined. The validated Chinese version of the PSQI was used. A global score higher than 5 was considered as an indicator of poor sleep quality.26 The body mass index (BMI) was calculated according to the participants' weight and height. The Chinese version of the International Physical Activity Questionnaire was used to measure the level of physical activity.27 The results were assessed by the metabolic equivalent (MET) value of the participants, according to their latest weekly activities before the interview.28 In the current study, MET values were defined as the ratio of the work metabolic rate to a standard resting metabolic rate of 1.0 kcal/kg/h.

Medical histories were obtained from participants. The presence of diabetes mellitus, hypercholesterolemia, hypertension, myocardial infarction, or anemia was determined by either of the following: (1) patients' medical report on the diagnosis and treatment of the disorder or (2) patients' report of using medication meant for the disorder. A physician blinded to the presence or absence of RLS assessed the patients' diagnoses. The medical records of participants who reported the aforementioned diseases were also reviewed to reconfirm the presence of the disease. In this study, a fasting glucose level of 126 mg/dL or higher, cholesterol level of 240 mg/dL or higher, BP higher than 140/90 mmHg, and hemoglobin levels lower than 13.5 g/dL in men and lower than 11.5 g/dL in women were used to diagnose diabetes, hypercholesterolemia, hypertension, and anemia, respectively. Decreased renal function was defined as a serum creatinine level of 1.3 mg/dL or higher, in addition to medication for related diseases. We defined CAD according to the International Classification of Diseases (Chinese version), Ninth Revision (ICD-9, 410 and 413), or a coronary revascularization procedure; CVD was defined as CAD accompanied by ischemic stroke (ICD-9, 434), transient ischemic attack (ICD-9, 435), or hypertension.

Statistical Analysis

SPSS (version 17.0, SPSS, Inc., Chicago, Illinois, United States) was used to perform statistical analysis. Continuous variables were expressed as mean ± standard deviations, and the Student t test was used to compare mean values between the two groups. For categorical variables, the χ2 test was used to determine differences between the two groups. Multivariable logistic regression was used, with RLS as the dependent variable, to determine the demographic and cardiovascular risk factor covariates associated with RLS and whether RLS was independently associated with CAD, CVD, or hypertension, with adjustments for relevant covariates. Unless otherwise stated, a value of P < .05 was set as the level of significance.

RESULTS

Descriptive Data

The characteristics of participants with and without RLS status are presented in Table 1. The overall prevalence of RLS in this study was 9.2%. The prevalence rates of RLS in women and men were 10.8% and 7.4%, respectively. The prevalence of RLS was significantly higher in women than in men (P < .05), and it increased with age (P < .05).

Characteristics of participants with and without RLS.

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Table 1

Characteristics of participants with and without RLS.

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There were also significant differences for several risk factors of CVD and covariates between participants with and without RLS. Compared to participants without RLS, those with RLS were more likely to report a history of hypertension, history of hypercholesterolemia, history of myocardial infarction, fatigue, and PSQI score higher than 5. Participants with RLS weighed more and had a significantly higher BMI than those without RLS. Smoking was also associated with the prevalence of RLS.

Demographics and Cardiovascular Risk Factors Associated With RLS

Table 2 lists the odds ratios (OR) for the prevalence of RLS in the multivariable regression models adjusted for age, sex, smoking, BMI, cholesterol level, and PSQI score. The results demonstrate that female sex (OR: 2.42, 95% confidence interval [CI]: 1.99–2.95), smoking (OR: 1.96, 95% CI: 1.31–2.92), high cholesterol (OR: 1.30, 95% CI: 1.03–1.64), and PSQI score higher than 5 (OR: 5.61, 95% CI: 2.14–14.69) are factors that are significantly associated with RLS.

Independent factors associated with restless legs syndrome.

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Table 2

Independent factors associated with restless legs syndrome.

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Association of RLS With CVD, CAD, and Hypertension

Age-adjusted, sex-adjusted, and multivariable-adjusted ORs (95% CI) for the association between RLS and CVD, CAD, and hypertension are presented in Table 3. RLS was associated with a significantly higher risk of hypertension (OR: 1.87, 95% CI: 1.14–3.05). Participants with RLS had an increased age-adjusted and sex-adjusted OR of 1.49 (95% CI: 1.01–2.21) for CAD. After multivariable adjustment was performed for cardiovascular risk factors, this association became insignificant. RLS was not associated with the prevalence of CVD in the age-adjusted and sex-adjusted or multivariable-adjusted models.

Multivariable-adjusted logistic regression model for the prevalence of cardiovascular disease, coronary artery disease, and hypertension, according to the participants' RLS status.

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Table 3

Multivariable-adjusted logistic regression model for the prevalence of cardiovascular disease, coronary artery disease, and hypertension, according to the participants' RLS status.

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DISCUSSION

To our knowledge, this study is the first population-based survey of cardiovascular risk factors in individuals with RLS, recruited from the general population of mainland China. We found that participants with RLS reported a higher prevalence of cardiovascular risk factors than those without RLS. Participants with RLS had a higher BMI and were more likely to report a history of smoking, hypertension, hypercholesterolemia, and myocardial infarction. Fatigue and PSQI score > 5 were also more prevalent in participants with RLS. However, results of the multivariable-adjusted analysis showed that RLS was not associated with the prevalence of CVD or CAD, but was significantly associated with the prevalence of hypertension.

Previous studies have proven that female sex is associated with the prevalence of RLS,5 and our results reconfirmed this conclusion. Some studies have reported that RLS is significantly associated with hypercholesterolemia.15,29 However, other studies have reported that RLS is not related to this factor.30 In the current study, participants with RLS were more likely to have hypercholesterolemia and a significantly higher cholesterol level than those without RLS.

We also observed a significant relationship between smoking and RLS, which is similar to the results from previous studies.14,15,31,32 Some studies have evaluated the number of cigarettes smoked per day, and its association with RLS.15 However, in our study, data regarding the number of cigarettes smoked were not collected.

Many studies have found that subjects with a history of diabetes, anemia, and decreased renal function have a high prevalence of RLS.12,13 Our study could not confirm these findings, possibly because of the ethnic bias and the small number of subjects with these diseases. Thus, further studies are needed to clarify the association.

Research has suggested the possibility of an association between RLS and hypertension, but conflicting data exist. Some studies have shown a greater likelihood of hypertension in subjects with RLS, compared to controls.14,33,34 Conversely, other studies have failed to find an association between RLS and hypertension.15,35 Some studies have reported that participants with a frequency of RLS higher than 15 d/mo had an OR of 1.41 for having hypertension, whereas those with a lower frequency of RLS did not.36 In our study, RLS was associated with an approximately 1.87-fold higher odds of hypertension, and poor sleep quality was associated with the prevalence of RLS. Sleep disorders are associated with hypertension35,37; therefore, it may be reasoned that the detrimental effect of RLS on sleep quality is one of the causes of high BP. However, as this is a cross-sectional study, the data do not enable us to clearly determine the causal link between RLS and hypertension. Other potential mechanisms should be discussed in the future.

To date, most cross-sectional epidemiological studies have suggested an association between RLS and the prevalence of CVD,2934 which conflicts with our results. Only a few studies have reported no associated or a decreased risk of hypertension and CVD in patients with RLS, compared to those without RLS.3537 A Sleep Heart Health Study conducted by Winkelman et al.6 showed that RLS was associated with an increased prevalence of CAD (OR: 2.05, 95% CI: 1.38–3.04) and CVD (OR: 2.07, 95% CI: 1.43–3.00). They also reported that the association between RLS and CVD is stronger in patients with greater RLS symptom frequency or severity. In our study, data on RLS frequency and severity were not collected; thus, it was impossible to test this association.

Consistent with our results, most prospective studies have reported that although subjects with RLS had a higher prevalence of cardiovascular risk factors than those without RLS, no relationship between RLS and CVD was observed.10,11 However, there are exceptions. Li et al. found that there was a significant association between RLS and coronary heart disease only among women with a longer RLS duration (≥ 3 years) (hazard ratio [HR]: 1.72, 95% CI: 1.09–2.73).38 Van Den Eeden and colleagues identified subjects with primary RLS and secondary RLS, and they reported that only secondary RLS was significantly associated with CVD (HR: 1.33, 95% CI: 1.21–1.46) and CAD (HR: 1.40, 95% CI: 1.25– 1.56).39 However, it should be noted that secondary RLS included RLS secondary to another diagnosis such as anemia, pregnancy, and chronic renal failure. These studies indicated complex associations between RLS and CVD. The severity, duration, and different categories of RLS may affect the association between RLS and CVD. The variability across study populations and diagnostic criteria for RLS may also explain the controversial findings.

CONCLUSIONS

Our study has several limitations. First, this study included only 5,324 participants, from Zhengzhou City, China. Therefore, the data are not representative of the entire Chinese population. Second, this is a cross-sectional study, offering fewer insights than those offered by a prospective study. Third, we did not test whether the severity of the diseases could lead to a bias in the prevalence of RLS.

Importantly, although there have been several studies examining the relationship between CVD and RLS, very few were conducted in the Asian population. The meager research conducted on RLS in Asia has led to the belief that the prevalence of RLS is lower in the Asian population. Is it important to study RLS in the Asian population, as this may reveal patho-physiological variations. Thus, further prospective studies are needed in the Asian population.

Our study results indicate that female sex, smoking, a high cholesterol level, and PSQI score higher than 5 are associated with RLS, which, in turn, is independently associated with an increased odds of hypertension. In contrast, we found that RLS is not associated with CVD and CAD.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. The authors report no conflicts of interest.

ABBREVIATIONS

BMI

body mass index

BP

blood pressure

CAD

coronary artery disease

CI

confidence interval

CVD

cardiovascular disease

HR

hazard ratio

IRLSSG

International Restless Legs Syndrome Study Group

MET

metabolic equivalent

OR

odds ratio

PSQI

Pittsburgh Sleep Quality Index

RLS

restless legs syndrome

ACKNOWLEDGMENTS

The authors thank all the participants and staff who took part in the questionnaire survey.

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