Abstract
Restless legs syndrome (RLS) is a common sensorimotor disorder that, in case of severe symptoms, can be very distressing and negatively interfere with quality of life. Moreover, increasing evidences associate RLS with higher risk of cerebrovascular and cardiovascular disease (CVD). The purpose of this study was to quantify two proteins, previously identified by proteomics and potentially linked with CVD risk, namely kininogen-1 (KNG1) and alpha-1-antitrypsin (A1AT), in primary RLS patients at high severity grade (HS-RLS) in comparison to healthy control subjects. Proteins were quantified through enzyme-linked immunosorbent assay (ELISA) in plasma samples from 14 HS-RLS patients and 15 control individuals. The two groups were closely matched for age and gender. The expression level of KNG1 resulted significantly higher (p < 0.001), while A1AT was significantly decreased (p < 0.05) in HS-RLS patients compared to controls, confirming the relationship between these proteins and the disease severity. Furthermore, in patients group the association between the protein concentrations and the following parameters was further evaluated: age, disease onset and diagnosis, scores obtained from the RLS rating scales (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory) and smoking habit. All the considered variables resulted independent of protein levels, so the disease can be reasonably considered the main cause of protein changes. As emerged from the literature, high levels of KNG1 and low amounts of A1AT seem to be related with a highest probability to develop CVD. Consequently, these proteins may be reliable candidate biomarkers of CVD risk in patients with RLS at high severity grade.
Similar content being viewed by others
References
Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ (2013) The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 88:261–264
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB (2014) Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15:860–873
American Academy of Sleep Medicine (2014) International classification of sleep disorders (ICSD3), 3rd edn. American Academy of Sleep Medicine, Darien
Baskol G, Korkmaz S, Erdem F, Caniklioglu A, Kocyigit M, Aksu M (2012) Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome. Sleep Med 13:414–418
Beck AT, Steer RA, Carbin MG (1988) Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 8(1):77–100
Beiko T, Ma S, Strange C, Turino GM (2018) Biomarker indicators of elastin degradation in asymptomatic alpha-1 antitrypsin deficiency. Pulm Crit Care Med 3(3):1–5
Bellei E, Monari E, Ozben S, Koseoglu Bitnel M, Topaloglu Tuac S, Tomasi A, Bergamini S (2018) Discovery of restless legs syndrome plasmatic biomarkers by proteomic analysis. Brain Behav 8(10):e01062. https://doi.org/10.1002/brb3.1062
Benes H, Walters AS, Allen RP, Hening WA, Kohnen R (2007) Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov Disord 22:S401–S408
Bertisch SM, Muresan C, Schoerning L, Winkelman JW, Taylor JA (2016) Impact of restless legs syndrome on cardiovascular autonomic control. Sleep 39(3):565–571
Bogan RK (2006) Effects of restless legs syndrome (RLS) on sleep. Neuropsychiatr Dis Treat 2(4):513–519
Budhiraja R (2013) Is restless legs syndrome associated with cardiovascular disease? Am J Med 126(3):189–190
Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 28(2):193–213
Cho YW, Song ML, Earley CJ, Allen RP (2015) Prevalence and clinical characteristics of patients with restless legs syndrome with painful symptoms. Sleep Med 16:775–778
Curjuric I, Imboden M, Bettschart R, Caviezel S, Dratva J, Pons M, Rothe T, Schmidt-Trucksass A, Stolz D, Thun GA, von Eckardstein A, Kronenberg F, Ferrarotti I, Probst-Hensch NM (2018) Alpha-1 antitrypsin deficiency: from the lung to the heart? Atherosclerosis 270:166–172
Fang Z, Liu YW, Zhao LY, Xu Y, Zhang FX (2015) Sleep-associated movement disorders and the risk of cardiovascular disease: a systematic review and meta-analysis. World J Meta-Anal 3(3):181–187
Feng Y, Hu L, Xu Q, Yuan H, Ba L, He Y, Che H (2015) Cytoprotective role of alpha-1 antitrypsin in vascular endothelial cell under hypoxia/reoxygenation condition. J Cardiovasc Pharmacol 66:96–107
Ferini-Strambi L, Walters AS, Sica D (2014) The relationship among restless legs syndrome (Willis-Ekbom Disease), hypertension, cardiovascular disease, and cerebrovascular disease. J Neurol 261:1051–1068
Gottlieb DJ, Somers VK, Punjabi NM, Winkelman JW (2017) Restless legs syndrome and cardiovascular disease: a research roadmap. Sleep Med 31:10–17
Guo S, Huang J, Jiang H, Han C, Li J, Xu X, Zhang G, Lin Z, Xiong N, Wang T (2017) Restless legs syndrome: from pathophysiology to clinical diagnosis and management. Front Aging Neurosci 9:171
Hu Z, Liu J, Song Z, Hou Q, Fan X, Hou D (2015) Variants in the atherogenic ALOX5AP, THBD, and KNG1 genes potentiate the risk of ischemic stroke via a genetic main effect and epistatic interactions in a Chinese population. J Stroke Cardiovasc Dis 24(9):2060–2068
Hwang IC, Na KS, Lee YJ, Kang SG (2018) Higher prevalence of hypertension among individuals with restless legs syndrome: a meta-analysis. Psychiatry Investig 15(7):701–709
Innes KE, Selfe TK, Agarwal P (2012) Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review. Sleep Med Rev 16:309–339
Izci B, Ardic S, Firat H, Sahin A, Altinors M, Karacan I (2008) Reliability and validity studies of the Turkish version of the Epworth Sleepiness Scale. Sleep Breath 12:161–168
Karroum EG, Golmard JL, Leu-Semenescu S, Arnulf I (2015) Painful restless legs syndrome: a severe, burning form of the disease. Clin J Pain 31:459–466
Katsanos AH, Kosmidou M, Konitsiotis S, Tsivgoulis G, Fiolaki A, Kyritsis AP, Giannopoulos S (2018) Restless legs syndrome and cerebrovascular/cardiovascular events: systematic review and meta-analysis. Acta Neurol Scand 137:142–148
Katsi V, Katsimichas T, Kallistratos MS, Tsekoura D, Makris T, Manolis AJ, Tousoulis D, Stefanadis C, Kallikazaros I (2014) The association of restless legs syndrome with hypertension and cardiovascular disease. Med Sci Monit 20:654–659
Koo DL, Nam H, Thomas RJ, Yun CH (2018) Sleep disturbances as a risk factor for stroke. J Stroke 20(1):12–32
Langhauser F, Göb E, Kraft P, Geis C, Schmitt J, Brede M, Gobel K, Helluy X, Pham M, Bendszus M, Jakob P, Stoll G, Meuth SG, Nieswandt B, McCrae KR, Kleinschnitz C (2012) Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation. Blood 120(19):4082–4092
Li Y, Walters AS, Chiuve SE, Rimm EB, Winkelman JW, Gao X (2012) Prospective study of restless legs syndrome and coronary heart disease among women. Circulation 126:1689–1694
Li Y, Li Y, Winkelman JW, Walters AS, Han J, Hu FB, Gao X (2018) Prospective study of restless legs syndrome and total and cardiovascular mortality among women. Neurology 90:e135–e141
Morange PE, Suchon P, Trégouet DA (2015) Genetic of venous thrombosis: update in 2015. Thromb Haemost 114:910–919
Picchietti DL, Van Den Eeden SK, Inoue Y, Berger K (2017) Achievements, challenges, and future perspectives of epidemiologic research in restless legs syndrome (RLS). Sleep Med 31:3–9
Ribeiro MS, Dellalibera-Joviliano R, Becari C, Roberti Teixeira F, Vasconcelos Araujo P, Piccinato CE, Campos CP, Evora PRB, Joviliano EE (2014) Characterization of the kallikrein-kinin system, metalloproteinases, and their tissue inhibitors in the in-stent restenosis after peripheral percutaneous angioplasty. Ann Vasc Surg 28:1005–1015
Sateia MJ (2014) International classification of sleep disorders-third edition: highlights and modifications. Chest 146(5):1387–1394
Sevim S, Dogu O, Kaleagasi H, Aral M, Metin O, Camdeviren H (2004) Correlation of anxiety and depression symptoms in patients with restless legs syndrome: a population based survey. J Neurol Neurosurg Psychiatry 75:226–230
Stoll M, Cowley AW Jr, Tonellato PJ, Greene AS, Kaldunski ML, Roman RJ, Dumas P, Schork NJ, Wang Z, Jacob HJ (2001) A genomic-systems biology map for cardiovascular function. Science 294:1723–1726
Szentkiralyi A, Volzke H, Hoffmann W, Happe S, Berger K (2013) A time sequence analysis of the relationship between cardiovascular risk factors, vascular diseases and restless legs syndrome in the general population. J Sleep Res 22:434–442
Szentkiralyi A, Volzke H, Hoffmann W, Trenkwalder C, Berger K (2014) Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies. Neurology 82:2026–2033
Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J (2016) Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology 86:1336–1343
Varim P, Varim C, Acar T, Acar BA, Gokosmanoglu F, Yaylaci S, Cengiz H, Karacaer C (2019) Frequency of cardiovascular diseases in the patients with restless legs syndrome. Int J Adv Med 6(1):131–134
Vila N, Millan M, Ferrer X, Riutort N, Escudero D (2003) Levels of α-1-antitrypsin in plasma and risk of spontaneous cervical artery dissection: a case-control study. Stroke 34:e168–e169
Walters AS, Rye DB (2009) Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease, and stroke. Sleep 32(5):589–597
Winkelman JW, Shahar E, Sharief I, Gottlieb DJ (2008) Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology 70:35–42
Winkelman JW, Blackwell T, Stone K, Ancoli-Israel S, Redline S (2017) 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 40
Winter AC, Schurks M, Glynn RJ, Buring JE, Gaziano JM, Berger K, Kurth T (2012) Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open 2:e000866
Wu Y (2015) Contact pathway of coagulation and inflammation. Thrombosis J 13:17
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All Authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bellei, E., Bergamini, S., Monari, E. et al. Evaluation of potential cardiovascular risk protein biomarkers in high severity restless legs syndrome. J Neural Transm 126, 1313–1320 (2019). https://doi.org/10.1007/s00702-019-02051-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-019-02051-7