Abstract
Atrial fibrillation (AF) is associated with an increased risk of mortality and morbidity from stroke and thromboembolism. Endothelial damage or dysfunction may contribute to this increased risk of thromboembolism via the mediation of a prothrombotic or hypercoagulable state. However, the precise pathophysiological mechanism(s) relating endothelial (dys)function to AF and thromboembolism are yet to be fully elucidated. This review article aims to provide a comprehensive overview of endothelial (dys)function and AF, as well as the merits and limitations of the different methods used to assess endothelial function in AF.
Introduction
Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia and is associated with a substantial increase in mortality and morbidity, particularly from stroke and thromboembolism Citation[1]. This risk of stroke is not homogeneous and has been related to various clinical and echocardiographic risk factors Citation[2] irrespective of whether AF is paroxysmal or sustained Citation[3], Citation[4]. Furthermore, anticoagulation therapy with warfarin has shown substantial benefit in reducing the risk of stroke and thromboembolism Citation[5]. The increased risk of thromboembolism in AF may be related to the presence of a prothrombotic or hypercoagulable state, by virtue of the fulfilment of Virchow's triad for thrombogenesis Citation[6]. However, the contribution of these individual components of Virchow's triad (abnormal blood stasis, abnormal blood constituents, and blood vessel abnormalities) towards the prothrombotic state in AF appears largely heterogeneous. Indeed, AF patients with a previous history of stroke or transient ischaemic attack(s), increasing age (>75 years), coexistent structural heart disease or left ventricular dysfunction, diabetes, hypertension, and coronary or peripheral artery disease have a higher thromboembolic risk either with one risk factor alone but more so with those in combinations. This cumulative higher stroke risk in these patients may well be related to the additional damage in those components of Virchow's triad with the coexisting cardiovascular risk factors on top of AF per se.
However, increasing attention has been directed towards the ‘blood vessel abnormalities’ component of Virchow's triad as a key component mediating thrombogenesis in AF, which can be recognized as the presence of endothelial damage and/or dysfunction Citation[7]. Indeed, a continuum of endothelial activation, dysfunction, and (ultimately) damage has been proposed Citation[8].
Different techniques of assessing endothelial function have been described and extensively reported, particularly in studies of cardiovascular disease Citation[9]. However, the inherent beat-to-beat variability in AF provides some technical challenges. This review article aims to provide a comprehensive overview of endothelial (dys)function and AF, as well as the merits and limitations of the different methods used to assess endothelial function in AF. Furthermore, the potential clinical significance of endothelial (dys)function in patients with AF will be discussed.
Key messages
Atrial fibrillation (AF) is associated with an increased risk of mortality and morbidity from stroke and thromboembolism.
Endothelial damage or dysfunction may contribute to this increased risk of thromboembolism via the mediation of a prothrombotic or hypercoagulable state.
This review article provides a comprehensive overview of endothelial (dys)function and AF, as well as the merits and limitations of the different methods used to assess endothelial function in AF.
Search strategy
MEDLINE and EMBASE were searched using the terms ‘endothelial function’, ‘endothelial dysfunction’, ‘atrial fibrillation’, ‘non-valvular AF’, ‘von Willebrand factor’, ‘E-selectin’, ‘soluble thrombomodulin’, ‘circulatory endothelial cells’, ‘flow mediated dilatation’, ‘arterial stiffness’, and ‘venous occlusion plethysmography’ to August 2008. Only studies in patients with AF were included. We excluded animal studies, abstracts, and individual case reports. Articles relating specifically to inflammation and thrombosis in AF were excluded. References from the relevant articles were reviewed and related articles were identified.
Abbreviations
Assessment of endothelial function in atrial fibrillation
The endothelium maintains haemostatic balance and vascular tone via the production of nitric oxide (NO). The latter suppresses smooth muscle proliferation Citation[10] and inhibits platelet adhesion Citation[11] (an antithrombotic effect) and leucocyte adhesion (with an inflammatory effect on the vascular wall) Citation[12]. Damaged or dysfunctional endothelium may result in the release of prothrombotic and proinflammatory molecules (e.g. von Willebrand factor, selectins, and adhesion molecules) and increased vascular tone and/or reduced vascular reactivity. However, this continuum of endothelial dysfunction and damage appears to accentuate the highly complex pathophysiological process and perpetuates the disease progression in AF.
Therefore, the assessment of endothelial function has conventionally included the measurement of circulating biochemical markers related to the endothelium (e.g. von Willebrand factor, vascular cell adhesion molecule, and E-selectin levels) and the vasomotor response to endothelium-dependent (e.g. increased blood-flow, acetylcholine, or salbutamol) relative to endothelium-independent mechanisms (e.g. glyceryl trinitrate). More recently, the quantification of circulating endothelial cells has been proposed as an additional measure of endothelial damage.
All these diverse methods have been used to assess endothelial function in patients with AF by various investigators, as summarized in . provides a concise summary of all the available studies of endothelial function and their key findings in patients with AF.
Table I. Techniques used in the assessment of endothelial function in atrial fibrillation.
Table II. Summary of the studies assessing endothelial function in atrial fibrillation.
Circulating markers of endothelial dysfunction in AF
Von Willebrand factor
Von Willebrand factor (vWF) is a glycoprotein secreted by vascular endothelial cells into the circulation in response to endothelial damage Citation[13]. Von Willebrand factor promotes platelet adhesion to the damaged endothelium and may be the first step in the formation of thrombus in the arterial circulation. Of note, vWF is also produced by megakaryocytes but contained within the platelets. Under normal physiological conditions, circulating plasma vWF is derived predominantly from endothelial cells, but platelets may contribute to the circulating pool in pathological states Citation[14].
The secretion of vWF is mediated through multiple cytokines (e.g. interleukin (IL)-1, tumour necrosis factor (TNF)-alpha, and endotoxin), and thus vWF has been described as an acute phase protein Citation[15]. However, other work has suggested that high vWF antigen levels in the absence of other indicators of an acute phase response may be suggestive of damage/injury to the endothelium Citation[16]. Circulating vWF levels are also related to blood group, being higher in non-O blood groups compared to the O group Citation[17]. Despite these pathophysiological determinants, measurement of plasma vWF by enzyme-linked immunosorbent assay (ELISA) is frequently used as a plasma biomarker of endothelial damage/dysfunction.
High plasma vWF levels have been reported in various studies of patients with AF. In an early Swedish study, Gustafsson et al. clearly demonstrated higher levels of vWF in patients with AF with or without strokes, when compared to controls in sinus rhythm Citation[18]. In a cross-sectional study, Lip et al. demonstrated raised vWF levels in patients with chronic AF, independent of underlying structural heart disease Citation[19]. Similarly, Freestone et al. reported significantly higher levels of plasma vWF in patients with systolic heart failure who were in AF compared to patients in sinus rhythm Citation[20]. In the Rotterdam study Citation[21], there was a positive linear relationship between vWF level and the presence of AF among women (odds ratio (OR) 1.17; 95% confidence interval (CI) 1.02–1.34) per 10 IU/dL increase in vWF levels, but not among men. Whilst female gender is independently associated with increased risk of stroke and thromboembolism with AF, even after adjusting for other confounders Citation[22], a noticeably greater endothelial dysfunction in females has been postulated as one of the possible mechanism(s) attributing to their higher stroke risk. Of note, plasma vWF does not appear to be affected by treatment with either aspirin or warfarin Citation[19], Citation[23].
Structural abnormalities within the left atrial endocardium have been related to circulating vWF levels. For example, Goldsmith et al. found that higher systemic levels of vWF were correlated to the degree of left atrial appendage endocardial damage in patients with mitral valve disease, especially those who were in AF Citation[24]. In addition, studies using immunohistochemistry of the left atrial appendage samples in patients with non-valvular AF found over-expression of vWF which correlated well with the degree of platelet adhesion and the presence of structural heart disease Citation[25], Citation[26]. Raised vWF levels have been reported in other studies of patients with mitral stenosis in AF, and levels were not significantly different in samples from the left/right atria when compared to peripheral venous sampling Citation[27], Citation[28]. Abnormal vWF levels also correlate with risk factors for thrombus on transoesophageal echocardiography. Indeed, Heppell et al. reported that raised levels of vWF correlated with spontaneous echo contrast and the presence of left atrial thrombus in patients with non-rheumatic AF Citation[29].
Elevated levels of plasma vWF have prognostic implications. In the Stroke Prevention in Atrial Fibrillation III (SPAF III) study Citation[30] higher vWF levels were independently associated with increased risk of cardiovascular events, with an absolute increase in risk of stroke of 1.2% per 20 IU/dL increase in vWF levels. Advancing age, prior cerebral ischaemia, heart failure, and diabetes were independently associated with higher levels of vWF Citation[31]. This is consistent with other data, suggesting that raised levels of vWF predicted future cardiovascular events (stroke, myocardial infarction, and death) and were associated with poor prognosis in patients with coronary artery disease Citation[32]. Importantly, the addition of plasma vWF levels to clinical stroke risk factors appears to improve the risk stratification of patients with AF Citation[33].
Asymmetric dimethyl arginine
Asymmetric dimethyl arginine (ADMA) is an endogenous substance produced from proteolysis of methylated arginine-related proteins. ADMA exerts a competitive inhibitory effect on nitric oxide synthase (NOS) and reduces the bioavailability of NO Citation[34]. Dimethyl arginine and dimethyl hydrolase (DDAH) metabolizes ADMA to L-citrulline and dimethylamine, and pharmacological inhibition of DDAH causes vasoconstriction of arterial segments in vitro, restored by administration of L-arginine. Thus, DDAH levels are inversely related to the levels of ADMA Citation[35]. Elevated levels of ADMA have been reported in patients with coronary artery disease Citation[36], hypertension Citation[37], diabetes Citation[38], hypercholesterolaemia Citation[39], atherosclerosis Citation[40], and renal failure Citation[41]. ADMA levels can be measured using high-performance liquid chromatography or by an ELISA technique.
Higher levels of ADMA have been shown in patients with acute AF (compared to chronic AF and healthy controls) prior to cardioversion, suggesting that AF may acutely and adversely affect endothelial function Citation[42]. In another study, higher ADMA levels prior to electrical cardioversion may predict the recurrence of AF Citation[43].
Adhesion molecules
Adhesion molecules are expressed on the endothelial cell surfaces that promote leucocyte adhesion. E-selectin is specific for endothelial cells and not expressed under normal physiological states Citation[44], but its expression may be increased under pathological conditions. Indeed, raised plasma levels of E-selectin are believed to reflect endothelial activation Citation[45].
Other adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are also expressed on macrophages and lymphocytes. These molecules play a vital role in chemotaxis and recruitment of leucocytes and macrophages during the process of inflammation by the activation of various cytokines (IL-1, TNF-alpha) Citation[46]. E-selectin levels can be measured using ELISA, and higher E-selectin levels have been reported in hypertension Citation[47], atherosclerosis Citation[48], coronary artery disease Citation[49], and cancer Citation[50]. Raised levels of E-selectin may predict a higher risk of cardiovascular events in patients with coronary artery disease (CAD) Citation[49].
Higher E-selectin levels are found in patients with AF (paroxysmal, persistent, permanent, and lone) compared to subjects in sinus rhythm Citation[51]. Interestingly, low base-line E-selectin levels predict the successful maintenance of sinus rhythm at 6 months in AF patients Citation[52]. Circulating E-selectin levels in patients with AF correlate well with endothelial-dependent vasodilatation in the brachial artery using flow-mediated dilatation Citation[53]. In a study of patients with systolic heart failure, plasma E-selectin levels were not significantly different in AF patients compared to those in sinus rhythm, despite increases in vWF and N-terminal pro brain natriuretic peptide (NT-proBNP) Citation[20].
Circulating endothelial cells
Circulating endothelial cells (CECs) are believed to reflect endothelial damage and consequent shedding of endothelial cells from the intima. These cells circulate at very low levels as they are normally scavenged by the reticuloendothelial system Citation[54]. CECs may be measured by an immunomagnetic bead separation technique or by flow cytometry.
Higher CEC levels have been reported in patients with myocardial infarction Citation[55], stroke Citation[56], pulmonary hypertension Citation[57], sickle cell crisis Citation[58], and inflammatory vasculitis Citation[59]. Chong et al. Citation[60] demonstrated a strong correlation between CEC counts and brachial artery reactivity on flow-mediated dilatation, which supports CEC quantification as a measure of endothelial damage/dysfunction. High levels of CEC are associated with adverse cardiovascular events in patients with acute coronary syndrome (ACS) Citation[61].
Nonetheless, abnormal CECs in AF may simply reflect significant target organ damage. Using the magnetic immunobead technique, Freestone et al. Citation[62] reported higher CEC numbers in patients with AF with stroke or cardiac events, when compared to numbers in ‘chronic, stable’ AF and healthy controls. It is, however, possible that quantification of CEC by the immunobead technique may not be sufficiently sensitive to detect Lower levels of endothelial damage/dysfunction, which is seen in chronic, stable subjects. The mechanism of the increased CEC numbers and the prognostic significance of CEC counts in AF also remain unclear.
Another circulating cell phenotype related to the endothelium are endothelial progenitor cells, and Goette et al. Citation[63] have demonstrated higher levels of haematopoietic progenitor cells (CD34 + ) in patients with persistent AF, compared to paroxysmal AF and healthy controls. A further decline in levels of CD34+ cells was seen at 48 hours post direct current cardioversion, compared to base-line levels.
Circulating microparticles (MPs)
Microparticles (MPs) are small membrane-bound vesicles, which are derived from platelets, endothelial cells, leucocytes, and erythrocytes Citation[64]. These microparticles spill into the circulation from the shedding of cells during activation, injury, or apoptosis and may have procoagulant properties Citation[65]. Increased levels of procoagulant microparticles have been found in diverse conditions such as atherosclerosis Citation[66], myocardial infarction Citation[67], diabetes Citation[68], and stroke Citation[69]. However, studies involving microparticles in AF are limited. Ederhy et al. Citation[70] reported higher endothelial-derived microparticles in patients with either permanent or persistent AF compared to controls without any cardiovascular risk factors, but the clinical significance of MPs in AF is not clear.
Soluble thrombomodulin
Soluble thrombomodulin (sTM) is a transmembrane glycoprotein expressed on the surface of vascular endothelial cells Citation[71]. The thrombin-thrombomodulin complex activates protein C and degrades factors V and VIII to mediate a potent anticoagulant property Citation[72]. Soluble thrombomodulin is normally cleared through the kidneys and can be detected in urine even in normal subjects (albeit in small quantities) Citation[73].
Measurement of the plasma sTM using ELISA has been proposed as a marker of endothelial injury in patients with atherosclerosis, but conflicting results are apparent. In cross-sectional studies, raised levels of sTM have been reported in hypertension Citation[74], diabetes Citation[75], ischaemic heart disease Citation[76], dyslipidaemia Citation[77], and renal failure Citation[78]. However, prospective studies suggest that higher levels of sTM might predict a low risk of coronary artery disease and a lower prevalence of asymptomatic carotid atherosclerosis Citation[79]. The precise reasons are unclear, but this may be related to the down-regulation of sTM expression in endothelial dysfunction.
Data on sTM in patients with AF are similarly conflicting. In a study of patients with mitral stenosis prior to valvuloplasty, lower levels of sTM were found in patients with AF (in both cardiac and peripheral blood samples) compared to patients in sinus rhythm Citation[27]. This could be related to the discontinuation of warfarin prior to the surgery or may directly reflect endothelial cell dysfunction through down-regulation of sTM expression. In contrast, Mondillo et al. found increased levels of sTM in patients with lone chronic non-rheumatic AF in peripheral venous samples when compared to controls in sinus rhythm Citation[80].
Non-invasive functional assessment of endothelial function in AF
Flow-mediated dilatation
Flow-mediated dilatation (FMD) is a well established non-invasive method of assessing endothelial function. With the use of high-resolution ultrasound (7–10 Hz), the response of the brachial artery to NO release during both physiological and pharmacological stress can be quantified. The brachial artery, in response to transient occlusion of blood-flow (typically with a pressure cuff) and subsequent increase in blood-flow (on release of occlusion), should vasodilate as increased flow creates an increase in shear stress and release of endogenous NO by the endothelium. Indeed, FMD is used as a measure of endothelium-dependent vascular function and is simultaneously compared to endothelium-independent vasodilatation, typically assessed by the vascular response to exogenous administration of pharmacological agents, such as glyceryl trinitrate (GTN). Hence, the relative change in brachial artery diameter to transient occlusion (endothelium-dependent) relative to exogenous nitrates (endothelium-independent) can be used as an index of endothelial function.
In general, an increase of >10% to stress is accepted as a normal response from base-line Citation[81]. Notably, radial and femoral arteries have been used to assess the vasodilatory response. The vasoresponse from conduit arteries correlates well with invasive techniques in the assessment of endothelial function Citation[82–84]. However, the technique of FMD is technically challenging and heavily operator-dependent Citation[81]. To standardize techniques, guide-lines for the use of FMD in the assessment of endothelial function have been published in 2002 by the International Brachial Artery Reactivity Task Force Citation[81]. Abnormal FMD responses, indicative of endothelial dysfunction, have been described in hypertension Citation[85], diabetes mellitus Citation[86], coronary artery disease Citation[87], dyslipidaemia Citation[88], ageing Citation[89], Citation[90], male sex, and smoking Citation[91]. Subsequent treatment of various cardiovascular risk factors appears to improve FMD Citation[92], Citation[93].
The use of FMD to assess endothelial function in AF is complicated by the beat-to-beat variability in blood-flow and beat-to-beat variations in the pulse pressure. Nonetheless, FMD has been used to study endothelial function in AF in chronic, stable AF patients, who have good heart rate control. For example, Freestone et al. Citation[53] demonstrated abnormal endothelium-dependent FMD, but not endothelium-independent vasodilatation using GTN, in patients with AF compared to controls in sinus rhythm, which was correlated with higher levels of vWF and E-selectin levels. Restoring sinus rhythm following cardioversion in patients with lone AF or those with hypertension can show an improvement in FMD Citation[94], Citation[95]. Although these investigators have used a greater number of cardiac cycles for the assessment of FMD in AF, the intrinsic beat-to-beat variability could limit the reproducibility of this technique in AF patients. The relationship between thromboembolic or cardiovascular complications of AF to endothelial dysfunction as quantified by FMD still remains to be established.
Invasive functional assessments of endothelial function in AF
A direct assessment of endothelial vasomotor function in coronary arteries is considered to be the ‘gold standard’ in assessing coronary vascular endothelial function. Indeed, the coronary flow reserve (CFR) Citation[96] is a measure of endothelial function, calculated from the coronary blood-flow during hyperaemia divided by the blood-flow during base-line. Measurement of CFR correlates well with other modalities of endothelial function, such as flow-mediated dilatation Citation[97], Citation[98]. CFR can be measured non-invasively using echocardiography, positron emission tomography (PET), and magnetic resonance imaging; and invasively by using intracoronary Doppler studies. Maximum hyperaemia is achieved physiologically by transient occlusion of coronary arteries Citation[99], exercise Citation[100], and by pharmacological methods through either intracoronary instillation of adenosine/papaverine Citation[101] or intravenous administration of adenosine/dipyridamole Citation[102]. A normal response refers to a 2–3-fold increase in the myocardial blood-flow during hyperaemia at a given perfusion pressure Citation[103]. An abnormal CFR is a measure of endothelial dysfunction and has been described in conditions like hypertension Citation[104], diabetes Citation[105], atherosclerosis Citation[106], coronary artery disease Citation[107], hypercholesterolaemia Citation[108], renal failure Citation[109], smoking Citation[110], and inflammatory diseases Citation[111], Citation[112]. Coronary artery endothelial dysfunction is strongly associated with poor cardiovascular outcomes Citation[113], Citation[114].
Skalidis et al. Citation[115] have shown impaired myocardial perfusion in patients with lone AF invasively by measuring time-averaged peak coronary blood-flow velocity (APV), using an intracoronary Doppler wire study. Adenosine was used to produce maximal hyperaemia, and this was compared with base-line APV to calculate the CFR. The CFR in the left atrial circumflex branch (LACB) was significantly reduced in lone AF patients compared to healthy subjects, indicating the presence of possible localized microvascular endothelial dysfunction. Using positron emission tomography (PET) scan, Range et al. Citation[116] demonstrated impaired myocardial blood-flow (MBF) at rest and hyperaemia (using adenosine) in AF patients compared to healthy controls. After achieving sinus rhythm by cardioversion (at 4.1±2.3 months) there was partial improvement noted in the MBF at rest, suggestive of improved endothelial function following sinus rhythm restoration.
Takahashi et al. Citation[117] demonstrated impaired endothelial-dependent vasodilatation in AF patients with subsequent improvement after restoring sinus rhythm with cardioversion. The technique used to assess endothelial function was venous occlusion plethysmography and the measurement of forearm blood-flow (FBF) after intra-arterial administration of acetylcholine and nitroglycerine. After restoring sinus rhythm, there was a 45% increase in endothelial-dependent vasodilatation in lone AF patients, compared to a 90% increase in AF patients with heart disease, relative to base-line levels. Using a similar technique, the same group demonstrated improvement in the endothelium-dependent vasodilatation with exercise in patients with AF after restoring sinus rhythm with cardioversion, suggesting an improvement in endothelial function with restoration of sinus rhythm Citation[118]. However, these techniques are invasive, time-consuming, and may not be suitable for large epidemiological studies.
Conclusion
Endothelial damage and dysfunction has been described in patients with AF using a range of different techniques. gives an overall view of the techniques used in the assessment of endothelial function in AF and their advantages and disadvantages in clinical practice. As mentioned above, the inherent beat-to-beat variability in AF may limit or even preclude the use of some methods of assessing endothelial function.
Table III. Techniques used in the assessment of endothelial function in atrial fibrillation; their advantages and disadvantages.
Of the various methods described, measurement of plasma vWF levels has been extensively studied and shown to be independently associated with cardiovascular events in patients with AF; it may also potentially refine thromboembolic risk stratification when combined with clinical risk stratification schemes. Such plasma biomarker studies are suitable for large-scale population studies, in contrast to more specialized imaging or invasive methods of assessing endothelial (dys)function in AF.
Given the associations of endothelial (dys)function with cardiovascular events, further its clinical significance in patients with AF is required. A plausible pathophysiological mechanism underlying endothelial (dys)function and the consequences with respect to recurrence of AF or risk of thrombembolism is uncertain. Therefore further studies need to address the impact of associated comorbidities (such as hypertension, diabetes mellitus, and heart failure—which themselves are associated with endothelial dysfunction) and the difficulty of distinguishing what relates to AF per se, rather than to its comorbidities. Also, many patients with AF are taking drugs, such as angiotensin-converting enzyme inhibitors and statins, which can have significant effects on endothelial function. For our understanding of endothelial dys(function) in AF to advance, further studies in lone AF subjects, with no significant confounders or drug therapies, may be needed.
Acknowledgements
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998; 98: 946–52
- Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007; 69: 546–54.
- Lip GY. Paroxysmal atrial fibrillation, stroke risk and thromboprophylaxis. Thromb Haemost. 2008; 100: 11–3
- Hughes, M, Lip, GY; Guideline Development Group, National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost 2008;99:295–304
- Hart RG, Pearce LA, Aguilar MI. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med. 2007; 147: 590–2
- Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet. 2009; 373: 155–66
- Freestone B, Lip GY. The endothelium and atrial fibrillation. The prothrombotic state revisited. Hamostaseologie. 2008; 28: 207–12
- Blann AD, Choudhury A, Freestone B, Patel J, Lip GY. Soluble CD40 ligand and atrial fibrillation: relationship to platelet activation, and endothelial damage/dysfunction. Int J Cardiol. 2008; 127: 135–7
- Nadar S, Blann AD, Lip GY. Endothelial dysfunction: methods of assessment and application to hypertension. Curr Pharm Des. 2004; 10: 3591–605
- Castellot JJ, Addonizo ML, Rosenberg RD, Karnowsky MJ. Cultured endothelial cells produce a heparin-like inhibitor of smooth muscle growth. J Cell Biol. 1980; 90: 373–9
- Rodomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987; 2: 1057–8
- Kubes P, Suzukii M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991; 81: 4651–5
- Bowie EJW, Solberg LA, Fass DN, Johnson CM, Knutson GJ, Stewart ML, et al. Transplantation of normal bone marrow into a pig with severe von Willebrand disease. J Clin Invest. 1986; 78: 26–30
- Blann AD, Taberner DA. A reliable marker of endothelial cell dysfunction: does it exist?. Br J Haematol. 1995; 90: 244–8
- Pottinger BE, Read RC, Paleolog EG, Higgins PG, Pearson JD. von Willebrand factor is an acute phase reactant in man. Thromb Res. 1989; 53: 387–94
- Blann AD. von Willebrand factor antigen as an acute phase reactant and marker of endothelial cell injury in connective tissue diseases: a comparison with CRP, rheumatoid factor, and erythrocyte sedimentation rate. Z Rheumatol. 1991; 50: 320–2
- Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995; 345: 152–5
- Gustafsson C, Blombäck M, Britton M, Hamsten A, Svensson J. Coagulation factors and the increased risk of stroke in non-valvular atrial fibrillation. Stroke. 1990; 21: 47–51
- Lip GY, Lowe GD, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J. 1995; 73: 527–33
- Freestone B, Gustafsson F, Chong AY, Corell P, Kistorp C, Hildebrandt P, et al. Influence of atrial fibrillation on plasma von willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure. Chest. 2008; 133: 1203–8
- Conway DS, Heeringa J, Van Der Kuip DA, Chin BS, Hofman A, Witteman JC, et al. Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study. Stroke. 2003; 34: 413–7
- Lane DA, Lip GY. Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients. Thromb Haemost. 2009; 101: 802–5
- Li-Saw-Hee FL, Blann AD, Lip GY. Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation. Stroke. 2000; 31: 828–33
- Goldsmith I, Kumar P, Carter P, Blann AD, Patel RL, Lip GY. Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study. Am Heart J. 2000; 140: 777–84
- Fukuchi M, Watanabe J, Kumagai K, Katori Y, Baba S, Fukuda K, et al. Increased von Willebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage. J Am Coll Cardiol. 2001; 37: 1436–42
- Nakamura Y, Nakamura K, Fukushima-Kusano K, Ohta K, Matsubara H, Hamuro T, et al. Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis. Thromb Res. 2003; 111: 137–42
- Yamamoto K, Ikeda U, Seino Y, Mito H, Fujikawa H, Sekiguchi H, et al. Coagulation activity is increased in the left atrium of patients with mitral stenosis. J Am Coll Cardiol. 1995; 25: 107–12
- Li-Saw-Hee FL, Blann AD, Goldsmith I, Lip GY. Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis. Am J Cardiol. 1999; 83: 1206–9
- Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart. 1997; 77: 407–11
- Conway DS, Pearce LA, Chin BS, Hart RG, Lip GY. Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation. 2003; 107: 3141–5
- Conway DS, Pearce LA, Chin BS, Hart RG, Lip GY. Plasma von Willbrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 1321 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors. Circulation. 2002; 106: 1962–7
- Jansson J, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991; 66: 351–5
- Lip GY, Lane D, Van Walraven C, Hart RG. Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation. Stroke. 2006; 37: 2294–300
- McDermott JR. Studies on the catabolism of Ng-methyl arginine, Ng, Ng-dimethylarginine and Ng, Ng-dimethylarginine in the rabbit. Biochem J. 1976; 154: 179–84
- Cooke JP. Does ADMA cause endothelial dysfunction?. Arterioscler Thromb Vasc Biol. 2000; 20: 2032–7
- Cooke JP. Asymmetrical dimethyl arginine: the uber marker?. Circulation. 2004; 109: 1813–8
- Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y, et al. Asymmetrical dimethyl arginine, an endogenous nitric oxide synthase inhibitor in experimental hypertension. Hypertension. 1997; 29: 242–7
- Abbasi F, Asagmi T, Cooke JP, Lamendola C, McLaughlin T, Reaven GM, et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with Type 2 diabetes mellitus. Am J Cardiol. 2001; 88: 1201–3
- Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, et al. Asymmetrical dimethyl arginine (ADMA): a novel risk factor for endothelial function: its role in hypercholesterolemia. Circulation. 1998; 98: 1842–7
- Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999; 99: 1141–6
- Vallance P, Leone A, Claver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339: 572–5
- Cengel A, Sahinarslan A, Biberoğlu G, Hasanoğlu A, Tavil Y, Tulmaç M, et al. Asymmetrical dimethylarginine level in atrial fibrillation. Acta Cardiol. 2008; 63: 33–7
- Xia W, Qu X, Yu Y, Zhang X, Feng W, Song Y. Asymmetric dimethylarginine concentration and early recurrence of atrial fibrillation after electrical cardioversion. Pacing Clin Electrophysiol. 2008; 31: 1036–40
- Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993; 14: 506–12
- Blann AS, Lip GYH. The endothelium in atherothrombotic disease: assessment of function, mechanism and clinical implications. Blood Coagul Fibrinolysis. 1998; 9: 297–306
- Cybulsky MI, Gimbrone MA, Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991; 251: 788–91
- Blann AD, Tse W, Maxwell SJ, Waite MA. Increased levels of soluble adhesion molecule E-selectin in essential hypertension. 1994; 12: 925–8
- Blann AS, Waite MA. von Willebrand factor and solute E-selectin in hypertension. Influence of treatment value in predicting the progression of atherosclerosis. Coron Artery Dis. 1996; 7: 143–7
- Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001; 104: 1336–42
- Alexiou D, Karayiannakis AJ, Syrigos KN, Zbar A, Kremmyda A, Bramis I, et al. Serum levels of E-selectin, ICAM-1 and VCAM-1 in colorectal cancer patients: correlations with clinicopathological features, patient survival and tumour surgery. Eur J Cancer. 2001; 37: 2392–7
- Freestone B, Chong AY, Nuttall S, Blann AD, Lip GY. Soluble E-selectin, von Willebrand factor, soluble thrombomodulin, and total body nitrate/nitrite product as indices of endothelial damage/dysfunction in paroxysmal, persistent, and permanent atrial fibrillation. Chest. 2007; 132: 1253–8
- Tveit A, Seljeflot I, Grundvold I, Abdelnoor M, Smith P, Arnesen H. Effect of candesartan and various inflammatory markers on maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation. Am J Cardiol. 2007; 99: 1544–8
- Freestone B, Chong AY, Nuttall S, Lip GY. Impaired flow mediated dilatation as evidence of endothelial dysfunction in chronic atrial fibrillation: relationship to plasma von Willebrand factor and soluble E-selectin levels. Thromb Res. 2008; 122: 85–90
- Blann AD, Woywodt A, Bertolini F, Bull TM, Buyon JP, Clancy RM, et al. Circulating endothelial cells: Biomarker of vascular disease. Thromb Haemostat. 2005; 93: 228–35
- Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood. 1999; 93: 2951–8
- Nadar SK, Lip GYH, Lee KW, Blann AD. Circulating endothelial cells in acute ischaemic strokes. Thromb Haemost. 2005; 94: 707–12
- Bull TM, Golpon H, Hebbel RP, Solovey A, Cool CD, Tuder RM, et al. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost. 2003; 90: 698–703
- Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anaemia. N Engl J Med. 1997; 337: 1584–90
- Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz M. Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis. Lancet. 2003; 361: 206–10
- Chong AY, Blann AD, Patel J, Freestone B, Hughes E, Lip GY. Endothelial dysfunction and damage in congestive heart failure: relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide. Circulation. 2004; 110: 1794–8
- Lee KW, Lip GY, Tayebjee M, Foster W, Blann AD. Circulating endothelial cells, von Willebrand factor, interleukin-6 and prognosis in patients with acute coronary syndromes. Blood. 2005; 105: 526–32
- Freestone B, Lip GY, Chong AY, Nadar S, Lee KW, Blann AD. Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease. Thromb Haemost. 2005; 94: 702–6
- Goette A, Jentsch-Ullrich K, Lendeckel U, Roken C, Agbaria M, Auricchio A, et al. Effect of atrial fibrillation on hematopoietic progenitor cells: a novel pathophysiological role of the atrial natriuretic peptide. Circulation. 2003; 108: 2446–9
- Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F, et al. Procoagulant microparticles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol. 2006; 26: 2594–604
- Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles: new players in the field of vascular disease?. Eur J Clin Invest. 2004; 34: 392–401
- Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999; 99: 348–53
- Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation. 2001; 104: 2649–52
- Morel O, Hugel B, Jesel L, Lanza F, Douchet MP, Zupan M, Chauvin M, Cazenave JP, Freyssinet JM, Toti F. Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb Haemost. 2004; 91: 345–53
- Lee YJ, Jy W, Horstman LL, Janania J, Reyes Y, Kelley RE, et al. Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multi infarct dementias. Thromb Res. 1993; 72: 295–304
- Ederhy S, Di Angelantonio E, Mallat Z, Hugel B, Janower S, Meuleman C, et al. Levels of circulating procoagulant microparticles in nonvalvular atrial fibrillation. Am J Cardiol. 2007; 100: 989–94
- Sadler JE. Thrombomodulin structure and function. Thromb Haemost. 1997; 78: 392–5
- Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J. 1995; 9: 946–55
- Ishii H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest. 1985; 76: 2178–81
- Erdem Y, Usalan C, Haznedaroğlu IC, Altun B, Arici M, Yasavul U, et al. Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension. Am J Hypertens. 1999; 12: 1071–6
- Inukai T, Fujiwara Y, Tayama K, Aso Y, Takemura Y. Clinical significance of measurements of urinary and serum thrombomodulin in patients with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract. 1996; 33: 99–104
- Blann AD, Admiral J, McCollum CN. Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease. Eur J Haematol. 1997; 59: 115–20
- Constans J, Blann AD, Renard M, Guérin V, Conri C. Soluble thrombomodulin in hypercholesterolaemic patients. Lancet. 2000; 355: 145
- Gris JC, Branger B, Vécina F, al Sabadani B, Fourcade J, Schved JF. Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int. 1994; 46: 807–13
- Salomaa V, Matei C, Aleksic N, Sansores-Garcia L, Folsom AR, Juneja H, et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet. 1999; 353: 1729–34
- Mondillo S, Sabatini L, Agricola E, Ammaturo T, Guerrini F, Barbati R, et al. Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic non-rheumatic atrial fibrillation. Int J Cardiol. 2000; 75: 227–32
- Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39: 257–65
- 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
- Matsuo S, Matsumoto T, Takashima H, Ohira N, Yamane T, Yasuda Y, et al. The relationship between flow-mediated brachial artery vasodilation and coronary vasomotor responses to bradykinin: comparison with those to acetylcholine. J Cardiovasc Pharmacol. 2004; 44: 164–70
- Teragawa H, Ueda K, Matsuda K, Kimura M, Higashi Y, Oshima T, et al. Relationship between endothelial function in the coronary and brachial arteries. Clin Cardiol. 2005; 8: 460–6
- Deng YB, Wang XF, Le GR, Zhang QP, Li CL, Zhang YG. Evaluation of endothelial function in hypertensive elderly patients with high-resolution ultrasonography. Clin Cardiol. 1999; 22: 705–10
- Watts GF, O'Brien SF, Silvester W, Millar JA. Impaired endothelium dependent and independent dilatation of forearm resistance arteries in men with diet treated non-insulin-dependent diabetes: role of dyslipidaemia. Clin Sci (Colch) 1996; 91: 567–73
- Takase B, Uehata A, Akima T. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol. 1998; 82: 1535–9
- Stroes ES, Koomans HA, De Bruin TW, Rabelink TJ. Vascular function in the forearm of hypercholesterolemia patients off and on lipid-lowering medication. Lancet. 1995; 346: 467–71
- Celermajer DS, Sorensen KE, Spiegelhalter DJ, Geroggakapoulos D, Robinson J, Deanfield JE. Ageing is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994; 24: 471–6
- van der Heijden-Spek JJ, Staessen JA, Fagard RH, Hoeks AP, Boudier HA, van Bortel LM. Effect of age on brachial artery wall properties differs from the aorta and is gender dependent: a population study. Hypertension. 2000; 35: 637–42
- Raitakari OT, Adams MR, McCredie RJ, Griffiths KA, Celermajer DS. Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults. Ann Intern Med. 1999; 130: 578–81
- O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997; 95: 1126–31
- Muiesan ML, Salvetti M, Monteduro C, Rizzoni D, Zulli R, Corbellini C, et al. Effect of treatment on flow-dependent vasodilatation of the brachial artery in essential hypertension. Hypertension. 1999; 33: 575–80
- Skalidis EI, Zacharis EA, Tsetis DK, Pagonidis K, Chlouverakis G, Yarmenitis S, et al. Endothelial cell function during atrial fibrillation and after restoration of sinus rhythm. Am J Cardiol. 2007; 99: 1258–62
- Guazzi M, Belletti S, Lenatti L, Bianco E, Guazzi MD. Effects of cardioversion of atrial fibrillation on endothelial function in hypertension or diabetes. Eur J Clin Invest. 2007; 37: 26–34
- Collins P. Coronary flow reserve. Br Heart J. 1993; 69: 279–81
- Gullu H, Erdogan D, Caliskan M, Tok D, Yildirim E, Ulus T, et al. Interrelationship between noninvasive predictors of atherosclerosis: transthoracic coronary flow reserve, flow-mediated dilation, carotid intima-media thickness, aortic stiffness, aortic distensibility, elastic modulus, and brachial artery diameter. Echocardiography. 2006; 3: 35–42
- Pellegrino T, Storto G, Filardi PP, Sorrentino AR, Silvestro A, Petretta M, et al. Relationship between brachial artery flow-mediated dilation and coronary flow reserve in patients with peripheral artery disease. J Nucl Med. 2005; 46: 1997–2002
- Marcus M, Wright C, Doty D, Eastham C, Laughlin D, Krumm P, et al. Measurements of coronary velocity and reactive hyperemia in the coronary circulation of humans. Circ Res. 1981; 49: 877–91
- Felder L, Vassalli G, Vassalli F, Jiang Z, Grimm J, Krayenbuehl HP, et al. Clinical significance of coronary flow reserve: effect of papaverine and exercise. Coron Artery Dis. 1994; 5: 347–58
- Christensen CW, Rosen LB, Gal RA, Hasseb M, Lassar TA, Port SC. Coronary vasodilator reserve. Comparison of the effects of papaverine and adenosine on coronary flow, ventricular function and myocardial metabolism. Circulation. 1991; 83: 294–303
- Rossen JD, Quillen JE, Lopez AG, Stenberg RG, Talman CL, Winniford MD. Comparison of coronary vasodilation with intravenous dipyridamole and adenosine. J Am Coll Cardiol. 1991; 18: 485–91
- Marcus ML, Chilian WM, Kanatsuka H, Dellsperger KC, Eastham CL, Lamping KG. Understanding the coronary circulation through studies at the microvascular level. Circulation. 1990; 82: 1–7
- Olsen MH, Wachtell K, Meyer C, Hove JD, Palmieri V, Dige-Petersen H, et al. Association between vascular dysfunction and reduced myocardial flow reserve in patients with hypertension: a LIFE substudy. J Hum Hypertens. 2004; 18: 445–52
- Nahser PJ, Jr, Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation. 1995; 91: 635–40
- Selke FW, Armstrong ML, Harrison DG. Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic patients. Circulation. 1990; 81: 1586–93
- Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stage of coronary atherosclerosis. Circulation. 1991; 83: 391–401
- Yokoyama I, Ohtake T, Momomura S, Nishikawa J, Sasaki Y, Omata M. Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circulation. 1996; 94: 3232–8
- Tok D, Gullu H, Erdogan D, Topcu S, Ciftci O, Yildirim I, et al. Impaired coronary flow reserve in hemodialysis patients: a transthoracic Doppler echocardiographic study. Nephron Clin Pract. 2005; 101: c200–6
- Ashikaga T, Nishizaki M, Fujii H, Niki S, Maeda S, Yamawake N, et al. Examination of the microcirculation damage in smokers versus nonsmokers with vasospastic angina pectoris. Am J Cardiol. 2007; 100: 962–4
- Sulli A, Ghio M, Bezante GP, Deferrari L, Craviotto C, Sebastiani V, et al. Blunted coronary flow reserve in systemic sclerosis. Rheumatology (Oxford) 2004; 43: 505–9
- Hirata K, Kadirvelu A, Kinjo M, Sciacca R, Sugioka K, Otsuka R, et al. Altered coronary vasomotor function in young patients with systemic lupus erythematosus. Arthritis Rheum. 2007; 56: 1904–9
- Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101: 1899–906
- Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101: 948–54
- Skalidis EI, Hamilos MI, Karalis IK, Chlouverakis G, Kochiadakis GE, Vardas PE. Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation. J Am Coll Cardiol. 2008; 51: 2053–7
- Range FT, Schäfers M, Acil T, Schäfers KP, Kies P, Paul M, et al. Impaired myocardial perfusion and perfusion reserve associated with increased coronary resistance in persistent idiopathic atrial fibrillation. Eur Heart J. 2007; 28: 2223–30
- Takahashi N, Ishibashi Y, Shimada T, Sakane T, Ohata S, Sugamori T, et al. Atrial fibrillation impairs endothelial function of forearm vessels in humans. J Card Fail. 2001; 7: 45–54
- Takahashi N, Ishibashi Y, Shimada T, Sakane T, Ohata S, Sugamori T, et al. Impaired exercise-induced vasodilatation in chronic atrial fibrillation—role of endothelium-derived nitric oxide. Circ J. 2002; 66: 583–8
- Freestone B, Chong AY, Blann AD, Lip GY. The effects of direct current cardioversion for persistent atrial fibrillation on indices of endothelial damage/dysfunction. Thromb Res. 2006; 118: 479–85
- Freestone B, Chong AY, Lim HS, Blann A, Lip GY. Angiogenic factors in atrial fibrillation: a possible role in thrombogenesis?. Ann Med. 2005; 37: 365–72
- Lip GY, Pearce LA, Chin BS, Conway DS, Hart RG. Effects of congestive heart failure on plasma von Willebrand factor and soluble P-selectin concentrations in patients with non-valvular atrial fibrillation. Heart. 2005; 91: 759–63
- Marin F, Roldan V, Climent VE, Ibanez A, Garcia A, Marco P, et al. Plasma von Willebrand factor, soluble thrombomodulin and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation. Heart. 2004; 90: 1162–6
- Goette A, Weber M, Lendenckel U, Welte T, Lutze G, Klein HU. Effect of physical exercise on platelet activity and the von Willebrand factor in patients with persistent atrial fibrillation. J Interv Card Electrophysiol. 2004; 10: 139–46
- Roldan V, Marin F, Blann AD, Garcia A, Marco P, Sogrob F, Lip GY. Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J. 2003; 24: 1373–80
- Nikitovic D, Zacharis EA, Manios EG, Malliaraki NE, Kanoupakis EM, Sfiridaki KI, et al. Plasma levels of nitrites/nitrates in patients with chronic atrial fibrillation are increased after electrical restoration of sinus rhythm. J Interv Card Electrophysiol. 2002; 7: 171–6
- Feng D, D'Agostino RB, Silbershatz H, Lipinska I, Massaro J, Levy D, et al. Hemostatic state ad atrial fibrillation (the Framingham Offspring Study). Am J Cardiol. 2001; 87: 168–71
- Li Saw Hee FL, Blann AD, Gurney D, Lip GY. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J. 2001; 22: 1741–7