Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined SourceFunding None.
04 December 2018
26 June 2019
17 August 2019 (online)
Background and Purpose Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals.
Methods In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5–25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers.
Results Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 μm of microvessel ranging from 5 to 9 μm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01).
Conclusion Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis.
Clinical Trial Registration URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.
- 1 Hart RG, Diener HC, Coutts SB. , et al; Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13 (04) 429-438
- 2 Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 2017; 48 (04) 867-872
- 3 Sanna T, Diener HC, Passman RS. , et al; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370 (26) 2478-2486
- 4 Ryoo S, Chung JW, Lee MJ. , et al. An approach to working up cases of embolic stroke of undetermined source. J Am Heart Assoc 2016; 5 (03) e002975
- 5 Ntaios G, Papavasileiou V, Milionis H. , et al. Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis. Stroke 2015; 46 (01) 176-181
- 6 Leong DP, Joyce E, Debonnaire P. , et al. Left atrial dysfunction in the pathogenesis of cryptogenic stroke: novel insights from speckle-tracking echocardiography. J Am Soc Echocardiogr 2017; 30 (01) 71-79
- 7 Mattace-Raso FU, van der Cammen TJ, Hofman A. , et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006; 113 (05) 657-663
- 8 Martens RJ, Vink H, van Oostenbrugge RJ, Staals J. Sublingual microvascular glycocalyx dimensions in lacunar stroke patients. Cerebrovasc Dis 2013; 35 (05) 451-454
- 9 Mundi S, Massaro M, Scoditti E. , et al. Endothelial permeability, LDL deposition, and cardiovascular risk factors-a review. Cardiovasc Res 2018; 114 (01) 35-52
- 10 Adams Jr HP, Bendixen BH, Kappelle LJ. , et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24 (01) 35-41
- 11 Katsanos AH, Bhole R, Frogoudaki A. , et al. The value of transesophageal echocardiography for embolic strokes of undetermined source. Neurology 2016; 87 (10) 988-995
- 12 Perera KS, Vanassche T, Bosch J. , et al; ESUS Global Registry Investigators. Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. Int J Stroke 2016; 11 (05) 526-533
- 13 Tsivgoulis G, Katsanos AH, Sharma VK. , et al. Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke. Neurology 2016; 86 (12) 1103-1111
- 14 Laurent S, Cockcroft J, Van Bortel L. , et al; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27 (21) 2588-2605
- 15 Ikonomidis I, Marinou M, Vlastos D. , et al. Effects of varenicline and nicotine replacement therapy on arterial elasticity, endothelial glycocalyx and oxidative stress during a 3-month smoking cessation program. Atherosclerosis 2017; 262: 123-130
- 16 Lekakis J, Abraham P, Balbarini A. , et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 2011; 18 (06) 775-789
- 17 Paraskevaidis IA, Panou F, Papadopoulos C. , et al. Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study. Heart 2009; 95 (06) 483-489
- 18 Ikonomidis I, Tzortzis S, Andreadou I. , et al. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ Cardiovasc Imaging 2014; 7 (04) 619-628
- 19 Parissis JT, Kourea K, Andreadou I. , et al. Effects of Darbepoetin Alfa on plasma mediators of oxidative and nitrosative stress in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2009; 103 (08) 1134-1138
- 20 Warner DS, Sheng H, Batinić-Haberle I. Oxidants, antioxidants and the ischemic brain. J Exp Biol 2004; 207 (Pt 18): 3221-3231
- 21 Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 1990; 186: 421-431
- 22 Weber D, Davies MJ, Grune T. Determination of protein carbonyls in plasma, cell extracts, tissue homogenates, isolated proteins: Focus on sample preparation and derivatization conditions. Redox Biol 2015; 5: 367-380
- 23 Santos MT, Valles J, Aznar J, Vilches J. Determination of plasma malondialdehyde-like material and its clinical application in stroke patients. J Clin Pathol 1980; 33 (10) 973-976
- 24 Francesco V, Cesare A, Luigi I, Stefano F, Andrea G, Francesco B. Malondialdehyde-like material and beta-thromboglobulin plasma levels in patients suffering from transient ischemic attacks. Stroke 1985; 16 (01) 14-16
- 25 Lorente L, Martín MM, Abreu-González P. , et al. Serum malondialdehyde levels in patients with malignant middle cerebral artery infarction are associated with mortality. PLoS One 2015; 10 (05) e0125893
- 26 Lee DH, Dane MJC, van den Berg BM. , et al; NEO study group. Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion. PLoS One 2014; 9 (05) e96477
- 27 Grosse GM, Biber S, Sieweke JT. , et al. Plasma dimethylarginine levels and carotid intima-media thickness are related to atrial fibrillation in patients with embolic stroke. Int J Mol Sci 2019; 20 (03) 730
- 28 Tuttolomondo A, Casuccio A, Della Corte V. , et al. Endothelial function and arterial stiffness indexes in subjects with acute ischemic stroke: relationship with TOAST subtype. Atherosclerosis 2017; 256: 94-99
- 29 Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994; 24 (02) 471-476
- 30 Chen Y, Shen F, Liu J, Yang GY. Arterial stiffness and stroke: de-stiffening strategy, a therapeutic target for stroke. Stroke Vasc Neurol 2017; 2 (02) 65-72
- 31 O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 2005; 46 (01) 200-204
- 32 Van Bortel LM, Laurent S, Boutouyrie P. , et al. Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens 2012; 30: 4458
- 33 Triantafyllidi H, Arvaniti C, Lekakis J. , et al. Cognitive impairment is related to increased arterial stiffness and microvascular damage in patients with never-treated essential hypertension. Am J Hypertens 2009; 22 (05) 525-530
- 34 De Silva DA, Woon FP, Gan HY. , et al. Arterial stiffness is associated with intracranial large artery disease among ethnic Chinese and South Asian ischemic stroke patients. J Hypertens 2009; 27 (07) 1453-1458
- 35 Wohlfahrt P, Krajcoviechova A, Jozifova M. , et al. Large artery stiffness and carotid flow pulsatility in stroke survivors. J Hypertens 2014; 32 (05) 1097-1103
- 36 Ikonomidis I, Voumvourakis A, Makavos G. , et al. Association of impaired endothelial glycocalyx with aortic and coronary dysfunction: a pathway leading to impaired myocardial deformation in untreated hypertensives. J Clin Hypertens (Greenwich) 2018; 20 (04) 672-679
- 37 Ikonomidis I, Tzortzis S, Triantafyllidi H. , et al. Association of impaired left ventricular twisting-untwisting with vascular dysfunction, neurohumoral activation and impaired exercise capacity in hypertensive heart disease. Eur J Heart Fail 2015; 17 (12) 1240-1251
- 38 Jalini S, Rajalingam R, Nisenbaum R, Javier AD, Woo A, Pikula A. Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies. Neurology 2019; 92 (04) e288-e294
- 39 Haeren RHL, Rijkers K, Schijns OEMG. , et al. In vivo assessment of the human cerebral microcirculation and its glycocalyx: A technical report. J Neurosci Methods 2018; 303: 114-125