Coronary Flow Velocity Reserve is Decreased in Patients with Restless Leg Syndrome; Case Control Study

doi:10.21203/rs.3.rs-4722589/v1

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Coronary Flow Velocity Reserve is Decreased in Patients with Restless Leg Syndrome; Case Control Study

https://doi.org/10.21203/rs.3.rs-4722589/v1

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Background

Restless leg syndrome (RLS) has been associated with an increased risk of vascular disorders, which suggests that endothelial dysfunction plays important role in the pathogenesis of RLS. In this study, we aimed to evaluate coronary endothelial dysfunction in RLS patients using coronary flow velocity reserve (CFVR) and compared it with healthy controls.

Methods

In this study, the participants were divided into two groups as group RLS (n=42) and group HC (n=41). The primary outcome was the CFVR compared between groups. The number of participants with a CFVR value below 2.0 was also evaluated. In addition, a correlation between the international restless legs scale (IRLS) and CFVR, white-blood-cell-count (WBC), C-reactive-protein (CRP) were analyzed. Secondary outcomes were the WBC, hemoglobin, CRP, blood glucose, high-density-lipoprotein (HDL), low-density-lipoprotein (LDL), and creatinine compared between the two groups.

Results

In the group RLS, CFVR was measured lower than healthy controls (p<0.001). When the groups were compared in terms of the number of participants with a CFVR less than 2.0, the difference between the groups was significant (p<0.001, 0/41 in group HC and 14/42 in group RLS).

Patients with RLS had higher WBC and CRP values. There was a negative correlation between CFVR and IRLS (p<0.001). The relationship between WBC, CRP, and IRLS was not statistically significant (p=0.691).

Conclusions

We conclude that RLS patients had lower CFVR compared with healthy controls and there was a negative correlation between the severity of RLS and CFVR. Therefore, we think that it may be beneficial to follow up patients with RLS in terms of coronary heart disease.

Coronary flow velocity reserve

coronary heart disease

endothelial dysfunction

restless leg syndrome.

Restless legs syndrome (RLS) is a chronic movement disorder in which patients feel unpleasant leg sensations and the urge to move their legs during rest ^{[1, 2, 3]}. This syndrome has been associated with an increased risk of several vascular disorders ^{[4, 5]}, which suggests that endothelial dysfunction plays important role in the pathogenesis of RLS. Endothelial dysfunction is also thought to be effective in the pathogenesis of coronary heart disease (CHD) ^[6]. Studies on the association between RLS and CHD are controversial ^{[7, 8, 9, 10]}. In this study, we evaluated coronary endothelial dysfunction in RLS patients using coronary flow velocity reserve (CFVR) measurements and compared it with healthy controls.

Between October 2020 and February 2021, 702 patients with normal coronary arteries who underwent coronary angiography in our hospital were included in this prospective observatinonal study, and 58 of these were diagnosed with RLS for the first time (Group RLS). Diagnosis of RLS was established according to the rating scale (International Restless Legs Scale or IRLS) for the severity of RLS designed by the International RLS study group^[11]. A ten-question scale was developed on the basis of repeated expert evaluation of potential items. Each question had a set of five response options graded from no RLS or impact (score = 0) to very severe RLS or impact (score = 4). This produced a total scale whose overall score could range from 0 to 40. Patients were classified into four groups with scores of mild (0–10), moderate (11–20), severe (21–30), and very severe (31–40) RLS according to this scale. Age and sex-matched healthy controls (n = 58) were selected from patients with normal coronary arteries with similar age and gender distribution to the RLS patients (Group HC). The exclusion criteria for participants were as follows; participants who use drugs that affect the CFVR, comorbidities likely to be associated with secondary RLS (such as pregnancy, chronic kidney disease, iron deficiency, or peripheral neuropathy), clinical conditions that could mimic RLS symptoms (such as neuropathic pain syndromes, nocturnal leg cramps, myalgia, venous stasis, leg edema, arthritis, positional discomfort, habitual foot tapping), and uncontrolled hypertension, diabetes mellitus, and dyslipidemia.

The study was approved by the ethics committee of Medicana International Hospital (037-24.06) and was in accordance with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from all of the participants. The participants were divided into two groups as group RLS (n = 42) and group HC (n = 41). The patient's backround characteristics (such as age, gender, body mass index (BMI), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and heart rate (HR)) were recorded and compared between groups. The blood pressure and HR of the participants were measured just before the coronary angiography procedure. White blood cell count (WBC), hemoglobin, C-reactive protein (CRP), blood glucose, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and serum creatinine values of the participants were also recorded.

Coronary flow velocity reserve assessment

The intake of stimulants such as alcohol and caffeine was stopped 24 hours before the CFVR measurement. In this non-invasive diagnostic technique, CFVR measurements were performed with the Vivid 7 echocardiography device (General Electric, USA) using a middle-range-frequency (3–8 MHz) broadband transducer in the left anterior descending (LAD) coronary artery by transthoracic colour Doppler echocardiography. The coronary blood in the mid-to-distal LAD coronary artery was examined by colour Doppler flow mapping guidance with the optimal velocity range (+ 12 to + 15 cm/s) (Fig. 1). Then, the sample volume (1.5 or 2.0 mm wide) was positioned on the colour signal in the LAD coronary artery. Variables of the LAD coronary artery velocity were measured using the fast Fourier transformation analysis. After baseline recordings of flows, dipyridamole (0.56 mg/kg; Persantine, Boehringer Ingelheim) was administered over a 4-min period. An additional infusion of dipyridamole (0.28 mg/kg over a 2-min period) was used unless the heart rate was a 10% increase from the baseline. Two minutes after the end of the infusion, hyperaemic spectral profiles in the LAD coronary artery were recorded. All images were recorded for playback analysis and were later measured off-line. Average diastolic peak flow velocity (ADPV) was measured at baseline (ADPV_B) and under hyperaemic conditions (ADPV_H). The coronary flow velocity reserve was defined as the ratio of ADPV_H to ADPV_B. A CFVR value < 2.0 was considered abnormal ^{[12,13 ]}.

Primary and secondary outcomes

The primary outcome was the CFVR compared between group RLS and group HC. In addition, a correlation between IRLS and CFVR, WBC, CRP values were analyzed. The number of participants with a CFVR value below 2.0 was also compared between groups. Secondary outcomes were the WBC, hemoglobin, CRP, blood glucose, HDL, LDL, and serum creatinine values compared between the two groups.

Statistical analyses

Quantitative data were summarized as mean ± standard deviation along with median (minimum-maximum), whereas frequency and percentage were used for qualitative data. The Shapiro-Wilk test was used to check if a quantitative variable follows a normal distribution. Demographical and clinical characteristics between healthy controls and patients with RLS were compared using Student's t-test, Mann-Whitney U test, and Chi-Square test, accordingly. Correlation between IRLS and CRF, WBC, CRP is assessed with Kendall's tau-b (τb) correlation coefficient. The IRLS was used to evaluate the severity of RLS. Patients were classified into four groups with scores of mild (0–10), moderate (11–20), severe (21–30), and very severe (31–40) RLS. The area under the receiver operating characteristic (ROC) curve (AUC) along with its 95% confidence interval (CI) was given to assess the diagnostic value of CRVF, WBC, and CRP to discriminate between mild, moderate, severe, and very severe RLS. Optimal cut-off values of laboratory measurements were determined by Youden’s Index, i.e. the value corresponding to maximum (Sensitivity + 1 Specificity-1). Evaluation of diagnostic validities for the cut-off values was reported with sensitivity and specificity with their 95% CIs. Analyses were performed with R v.3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) statistical programming language. "coin" and "report ROC” libraries were used for nonparametric and diagnostic validity analyses, respectively. p < 0.05 was considered statistically significant.

A total of 116 participants were initially recruited for the study, with 58 individuals in the RLS group and 58 in the HC group. Ultimately, 83 participants (42 in the RLS group and 41 in the HC group) were included for analysis (Fig. 2). In the RLS group, individuals who declined to participate (n = 5), those with iron deficiency (n = 4), chronic kidney disease (n = 1), arthritis (n = 2), uncontrolled hypertension (n = 3), and diabetes mellitus (n = 1) were excluded. Similarly, in the HC group, participants who declined to participate (n = 4), those with iron deficiency (n = 3), arthritis (n = 1), neuropathic pain syndrome (n = 1), dyslipidemia (n = 1), uncontrolled hypertension (n = 4), and diabetes mellitus (n = 3) were excluded. The demographic and clinical characteristics of the participants are summarized in Table 1. Gender distribution, age, BMI, SAP, and HR were comparable between the groups (p > 0.05). Diastolic arterial pressure values were higher in RLS patients compared to HC (76.34 ± 7.91 vs. 79.4 ± 8.35, p = 0.047). The average disease severity score based on IRLSSG criteria was 16.54 ± 7.14 (range: 5–29).

Table 1

Demographic and clinical characteristics of the participants
	All (n = 83)	Group HC (n = 41)	Group RLS (n = 42)	P
Gender F/M (n/%)	44(53)/39(47)	21(51.2)/23(54.8)	20(48.8)/19(45.2)	0.746^*
Age	47.08 ± 6.84 47(34–69)	47.83 ± 7.49 48(36–69)	46.36 ± 6.14 46.5(34–63)	0.330^†
BMI	29.54 ± 3.14 29.3(24.4–35.5)	29.29 ± 3 28.8(24.7–34.7)	29.79 ± 3.28 29.45(24.4–35.5)	0.509^‡
SAP	125.06 ± 10.4 125(95–150)	123.17 ± 8.93 125(100–145)	126.9 ± 11.47 130(95–150)	0.102^†
DAP	77.89 ± 8.23 80(60–100)	76.34 ± 7.91 80(60–90)	79.4 ± 8.35 80(60–100)	0.047^‡
HR	78.18 ± 11.33 78(56–104)	79 ± 10.27 76(63–103)	77.38 ± 12.35 78(56–104)	0.518^†
Numerical data were summarized as mean ± standard deviation along with median (minimum - maximum), whereas frequency and percentage, n (%), were used for categorical data. P values were obtained by Student’s t-test (†), Mann Whitney U test (‡) and Chi-square test (). p < 0.05* was accepted as statistically significant.

Average diastolic peak flow values measured at baseline and under hyperaemic condition of one patient from each of the two groups are shown in Fig. 3. In the RLS group, CFVR and ADPVH values were lower than those in the HC group (p < 0.001 for all). However, baseline ADPV values were similar between the groups (Table 2). All HC group participants had CFVR values above the normal range (CFVR ≥ 2.0), whereas 14 RLS patients had CFVR values below 2.0. The difference in the number of patients with CFVR values less than 2.0 between the groups was statistically significant (p < 0.001, 0/41 in HC group and 14/42 in RLS group).

Table 2

Comparison of groups in terms of CFVR, ADPV_B, and ADPV_H values
	All (n = 83)	Group HC (n = 41)	Group RLS (n = 42)	P
CFVR	2.21 ± 0.19 2.23(1.81–2.53)	2.37 ± 0.08 2.39(2.16–2.53)	2.06 ± 0.12 2.05(1.81–2.31)	< 0.001
ADPV_B	34.8 ± 2.78 34.8(28.3–40.8)	35.36 ± 3.15 35.6(28.3–40.8)	34.25 ± 2.29 33.9(29.8–39.2)	0.071
ADPV_H	76.99 ± 9.53 76.4(61.3–97.1)	83.77 ± 7.84 85.3(66.3–97.1)	70.37 ± 5.56 68.91(61.3–81.2)	< 0.001
Numerical data were summarized as mean ± standard deviation along with median (minimum-maximum).
p values were obtained by Student’s t-test. p < 0.05 was accepted as statistically significant.

Patients with RLS exhibited higher WBC and CRP values compared to healthy controls, while other laboratory parameters showed no significant differences between the groups (Table 3). A statistically significant negative correlation was observed between CFVR and IRLS (p < 0.001, tau_b= -0.48). However, the relationship between WBC, CRP, and IRLS was not statistically significant (p = 0.691, tau_b= -0.05; p = 0.279, tau_b = 137, respectively).

Table 3

Comparison of groups in terms of laboratory parameters
	All (n = 83)	Group HC (n = 41)	Group RLS (n = 42)	P
WBC	6.79 ± 2.34 6(3.6–14.5)	5.91 ± 1.55 5.5(3.6–10.4)	7.64 ± 2.66 6.8(3.9–14.5)	0.001^*
CRP	0.84 ± 0.43 0.8(0.1–2.2)	0.73 ± 0.38 0.6(0.1–1.9)	0.94 ± 0.44 0.95(0.3–2.2)	0.02^*
Glucose	96.25 ± 9.69 96(76–122)	95.41 ± 10.51 95(76–121)	97.07 ± 8.86 97(79–122)	0.439^†
HDL	53.89 ± 14.58 54(26–88)	56.34 ± 14.89 58(29–88)	51.5 ± 14.04 50.5(26–79)	0.131^†
LDL	143.28 ± 43.67 144(67–278)	146.68 ± 42.31 145(67–256)	139.95 ± 45.22 138(69–278)	0.486^†
Creatinine	1.03 ± 0.23 1.1(0.6–1.4)	1.04 ± 0.23 1.1(0.6–1.4)	1.02 ± 0.22 1.1(0.6–1.4)	0.726^*
Hbg	13.79 ± 1.63 13.6(10.5–18.3)	13.86 ± 1.64 13.6(10.5–18.3)	13.72 ± 1.65 13.65(11.1–18.3)	0.538^*
Numerical data were summarized as mean ± standard deviation along with median (minimum-maximum).
P values were obtained by Student’s t-test (†) and Mann Whitney U test (). p < 0.05* was accepted as statistically significant.

This study represents the first investigation into the relationship between RLS and CFVR, building upon recent research linking RLS with CHD ^{[14, 8]}. While previous studies have hinted at a connection between RLS and cardiovascular health, the direct correlation between CFVR and RLS severity had not been explored until now. Our findings reveal that individuals with RLS exhibit lower CFVR values compared to healthy controls, with a higher prevalence of abnormal CFVR values in the RLS group. Notably, as the severity of RLS increased, CFVR values decreased. Additionally, RLS patients displayed elevated WBC and CRP levels.

Coronary endothelial dysfunction serves as an independent predictor of acute cardiovascular events, regardless of angiographically detectable lesions ^{[15,16 ]}. Atherosclerosis begins early in life, and endothelial dysfunction contributes to this process at every phase of atherosclerosis ^[17]. Recently, several non-invasive methods for the assessment of endothelial function were introduced. The forearm flow-mediated vasodilatation (FMD) is one of these, and its measures correlate well with coronary endothelial function ^[18]. However, CFVR reflects directly global coronary endothelial function and atherosclerotic burden ^[19]. Therefore, we preferred CFVR measurement to evaluate the relationship between RLS and coronary endothelial dysfunction in the current study. Recently, it was reported that the FMD was significantly lower in the patients with RLS when compared with healthy controls ^[20]. This has been interpreted as RLS being associated with endothelial dysfunction and therefore cardiovascular diseases. Similarly, Kim MS et al. reported that peripheral vascular endothelial functions are significantly impaired in RLS ^[21]. On the other hand, in a clinical study, RLS patients were found to have lower serum endocan levels, which is the marker of endothelial dysfunction. Authors suggest that patients with RLS may have better endothelial functions and that these patients may be better protected against atherosclerosis ^[22]. Moreover, the protective effects of RLS against atherosclerosis have been demonstrated in another study ^[23]. In the current study, we found that patients with RLS had lower CFVR indicating coronary endothelial dysfunction. The reason for these different results in the literature may be related to the fact that the patients included in these studies were different in terms of gender and age distribution.

Restless leg syndrome may induce transient increases in heart rate and mean arterial pressure, and this sympathetic hyperactivity could lead to endothelial dysfunction and increase the risk for cardiovascular disease. Concerning the cardiovascular risk, while some studies have demonstrated an increased cardiovascular risk in RLS patients ^{[24, 25]}, others have found no such association ^{[26, 27]}. Aksoy D et al. reported that patients with obstructive CHD have higher RLS prevalence. They have found that RLS was 3.05 times higher in patients with obstructive CHD than the patients with coronary arterial stenosis of less than 50%. A study including 3433 patients enrolled determined RLS prevalence in 3.3% of men and 6.8% of women and detected the relationship between RLS and CHD even in a multivariable logistic regression analysis in which RLS patients had 2.2-fold greater odds for CHD⁵. However, in an article by Szentkirályi et al., it was determined that the presence of RLS was not a risk factor for cardiovascular morbidity ^[28]. We found that endothelial dysfunction, which is an early indicator of CHD, is more common in RLS patients and there is a positive correlation between the severity of the disease and the severity of the endothelial dysfunction.

In the literature, it was reported that CFVR < 2.0 is considered abnormal, and lower CFVR indicates coronary endothelial dysfunction ^{[12, 13]}. According to our results, the mean CFVR values of the patients in the group RLS were 2.06. Although the mean CFVR value in patients with RLS was statistically lower than in healthy controls, the mean value of CFVR in this group was above the normal range. This may be related to the fact that none of the patients included in the current study had very severe RLS. On the other hand, the number of participants with a CFVR value below 2 was significantly higher in the RLS group. While there were no patients in the control group with a CFVR value below 2.0, 14 patients in the RLS group had a CFVR lower than 2.0. Moreover, there was a negative correlation between IRLS and CFVR. These findings suggest that there is a non-negligible relationship between RLS and coronary endothelial dysfunction.

A higher prevalence of RLS in patients with systemic inflammatory diseases might demonstrate the role of inflammation in RLS pathophysiology ^[29–32]. Higuchi T et al. reported that serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), ferritin, and N-terminal pro-B type natriuretic peptide were found to be higher in patients with RLS compared to the healthy controls ^[33]. It was also demonstrated that higher serum levels of IL-1β, IL6, and TNF-α in RLS patients as compared to healthy controls ^[34]. In line with the literature, we found higher WBC and CRP values in patients with RLS. All these results show that there may be a close relationship between the systemic inflammatory response and RLS. At the same time, systemic inflammatory response plays a role in the pathogenesis of endothelial dysfunction ^[35]; suggesting that the association between systemic inflammation, endothelial dysfunction, and RLS is not coincidental.

The present study has the following limitations. First, our modest sample size obtained from a single center may make the generalizability of the observed results difficult. Second, an assessment of additional markers of endothelial dysfunction besides CFVR, which could have supported the study results, was not performed. Third, none of the patients included in our study had very severe RLS. The inclusion of very severe RLS patients in the current study could have changed our results. Fourth, is the absence of a long-term follow-up of the participants for CHD.

We conclude that the patients with RLS had lower CFVR values compared with healthy controls and there was a negative correlation between the severity of RLS and CFVR which indicates coronary endothelial function. Therefore, we think that it may be beneficial to follow up patients with RLS, particularly severe RLS patients, in terms of CHD.

ADPV: Average Diastolic Peak Flow Velocity

BMI: Body Mass Index

CHD: Coronary Heart Disease

CFVR: Coronary Flow Velocity Reserve

CRP: C-Reactive Protein

DAP: Diastolic Arterial Pressure

HDL: High-Density Lipoprotein Cholesterol

HC: Healthy Control

HR: Heart Rate

IRLS: International Restless Legs Scale

LAD: Left Anterior Descending

LDL: Low-Density Lipoprotein Cholesterol

RLS: Restless Legs Syndrome

SAP: Systolic Arterial Pressure

WBC: White Blood Cell Count

Ethics approval and consent to participate

Consent for publication

All authors have approved the manuscript and agree with submission to " BMC Neurology”.

Availability of data and materials

All the data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Competing interests

The authors declare no competing interests.

Funding

Not applicable.

Author contributions

G.G. and S.D. were responsible for the study design. G.G. analyzed the data and wrote the initial draft. S.D. conducted literature searches and data extraction. All authors reviewed and approved the final manuscript.

Acknowledgements

The authors would like to thank the chief of the cardiology department of Medicana International Hospital Prof. Dr. Sebahattin Ateşal for their support.

Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-19.
Allen RP. Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome. Am J Med. 2007;120:13-21.
Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev. 2006;10:153-67.
Li Y, Walters AS, Chiuve SE, Rimm EB, Winkelman JW, Gao X. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation. 2012;126:1689-94.
Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology. 2008;70:35-42.
Matsuzawa Y, Guddeti RR, Kwon TG, Lerman LO, Lerman A. Treating coronary disease and the impact of endothelial dysfunction. Prog Cardiovasc Dis. 2015; 57:431-42.
Elwood P, Hack M, Pickering J, Hughes J, Gallacher J. Sleep disturbance, stroke, and heart disease events: evidence from the Caerphilly cohort. J Epidemiol Community Health. 2006; 60:69-73.
Winkelman JW, Blackwell T, Stone K, Ancoli-Israel S, Redline S. Associations of Incident Cardiovascular Events With Restless Legs Syndrome and Periodic Leg Movements of Sleep in Older Men, for the Outcomes of Sleep Disorders in Older Men Study (MrOS Sleep Study). Sleep. 2017;40:zsx023.
Liu J, Weinhandl ED, Gilbertson DT, Collins AJ, St Peter WL. Issues regarding 'immortal time' in the analysis of the treatment effects in observational studies. Kidney Int. 2012;81:341-50.
Winter AC, Schürks M, Glynn RJ, Buring JE, Gaziano JM, Berger K, et al. Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open. 2012;2:e000866.
Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121-32.
Rigo F, Sicari R, Gherardi S, Djordjevic-Dikic A, Cortigiani L, Picano E. The additive prognostic value of wall motion abnormalities and coronary flow reserve during dipyridamole stress echo. Eur Heart J. 2008;29:79-88.
Cortigiani L, Rigo F, Gherardi S, Bovenzi F, Picano E, Sicari R. Implication of the continuous prognostic spectrum of Doppler echocardiographic derived coronary flow reserve on left anterior descending artery. Am J Cardiol. 2010;105:158-62.
Aksoy D, Çelik A, Solmaz V, Çevik B, Sümbül O, Kurt S. The prevalence of restless legs syndrome in patients undergoing coronary angiography and its relationship with the severity of coronary artery stenosis. Sleep Breath. 2021;25:257-62.
Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106: 653-8.
Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Lerman A. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation. 2003;107:2805-9.
Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, Rönnemaa T, et al. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults: the cardiovascular risk in young Finns study. Circulation. 2004;110:2918-23.
Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235-41.
Simova I. Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography. Eur Cardiol. 2015;10:12-8.
Koh SY, Kim MS, Lee SM, Hong JM, Yoon JH. Impaired vascular endothelial function in patients with restless legs syndrome: a new aspect of the vascular pathophysiology. J Neurol Sci. 2015;359:207-10.
Kim MS, Park DG, Yoon JH. Impaired endothelial function may predict treatment response in restless legs syndrome. J Neural Transm (Vienna). 2019;126:1051-9.
Celik K, Cikrikcioglu MA, Halac G, Kilic E, Ayhan S, Ozaras N, et al. Serum endocan levels in women with restless legs syndrome. Neuropsychiatr Dis Treat. 2015;11:2919-25.
Park JH, Han SW, Baik JS. Carotid intima-media thickness in patients with idiopathic restless legs syndrome. Eur Neurol. 2012;67:321-5.
Innes KE, Selfe TK, Agarwal P. Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review. Sleep Med Rev. 2012;16:309-39.
Walters AS, Rye DB. Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease, and stroke. Sleep. 2009;32:589-97.
Elwood P, Hack M, Pickering J, Hughes J, Gallacher J. Sleep disturbance, stroke, and heart disease events: evidence from the Caerphilly cohort. J Epidemiol Community Health. 2006;60:69-73.
Winter AC, Schürks M, Glynn RJ, Buring JE, Gaziano JM, Berger K, et al. Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open. 2012;2:e000866.
Szentkirályi A, Völzke H, Hoffmann W, Trenkwalder C, Berger K. Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies. Neurology. 2014;82:2026-33.
Hassan N, Pineau CA, Clarke AE, Vinet E, Ng R, Bernatsky S. Systemic lupus and risk of restless legs syndrome. J Rheumatol. 2011;38:874-6.
Weinstock LB, Bosworth BP, Scherl EJ, Li E, Iroku U, Munsell MA, et al. Crohn's disease is associated with restless legs syndrome. Inflamm Bowel Dis. 2010;16:275-9.
Weinstock LB, Walters AS, Mullin GE, Duntley SP. Celiac disease is associated with restless legs syndrome. Dig Dis Sci. 2010;55:1667-73.
Becker J, Berger F, Schindlbeck KA, Poddubnyy D, Koch PM, Preiß JC, et al. Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease. Int J Colorectal Dis. 2018;33:955-62.
Trotti LM, Rye DB, De Staercke C, Hooper WC, Quyyumi A, Bliwise DL. Elevated C-reactive protein is associated with severe periodic leg movements of sleep in patients with restless legs syndrome. Brain Behav Immun. 2012;26:1239-43.
Uslu FI, Demir E, Güler EM, Koçyiğit A. Circulating levels of cytokines are increased in restless legs syndrome. Sleep Breath. 2021;25:1581-5.
Beard RS Jr, Yang X, Meegan JE, Overstreet JW, Yang CG, Elliott JA, et al. Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome. Nat Commun. 2016;7:12823.

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Coronary Flow Velocity Reserve is Decreased in Patients with Restless Leg Syndrome; Case Control Study

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Coronary flow velocity reserve assessment

Primary and secondary outcomes

Statistical analyses

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