Bethan Freestone

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

Background—Congestive heart failure (CHF) is associated with endothelial perturbation (as defined by flow-mediated endothelial-dependent vasodilation [FMD, an index of endothelial dysfunction], circulating endothelial cells [CECs, an index of endothelial damage], or plasma indexes of endothelial damage/dysfunction [eg, von Willebrand factor (vWf) and soluble thrombomodulin (sTM)]) and raised plasma levels of brain natriuretic peptide (BNP, a peptide hormone associated with left ventricular systolic dysfunction and prognosis). However, the relations between these parameters are unclear. Methods and Results—To test the hypothesis that there is a relation between endothelial perturbation (defined by FMD, CECs, vWf, and sTM) and BNP in CHF, we studied these indexes in 30 patients with CHF who were compared with 20 age-matched control subjects. FMD, CECs, plasma vWf, and BNP levels (but not sTM) were all abnormal in patients with CHF. There were significant inverse correlations between FMD and vWf (P=0.001), CECs (P=0.002) and BNP (P=0.006) as well as a positive correlation between CECs and vWf (P=0.032). In multivariate analysis, BNP (P<0.001) and FMD (P<0.001) were both independently associated with CHF. Conclusions—Ample evidence of endothelial cell damage/dysfunction in CHF cannot be fully explained by the variance in plasma BNP per se. Therefore, the routes by which these indexes influence the pathophysiology of CHF as well as predict adverse outcomes may be independent.

Increased circulating endothelial cells in acute heart failure: comparison with von Willebrand factor and soluble E-selectin.

Circulating endothelial cells (CECs) in the peripheral blood, probably representing the most direct evidence of endothelial cell damage, are increased in myocardial infarction, unstable angina and critical limb ischaemia. As chronic heart failure is also associated with endothelial abnormalities, we hypothesised that CECs are raised in acute heart failure and that they would correlate with plasma indices of endothelial perturbation, that is, von Willebrand factor (vWf) and soluble E‐selectin.

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

BACKGROUND Endothelial dysfunction is present in patients with heart failure (HF) due to left ventricular systolic dysfunction, as well as in patients with atrial fibrillation (AF) who have normal cardiac function. It is unknown whether AF influences the degree of endothelial dysfunction in patients with systolic HF. METHODS We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. RESULTS One hundred ninety patients (73% men; mean age, 69.0 +/- 10.1 years [+/- SD]) with systolic HF were studied, who were compared to 117 healthy control subjects: 52 subjects (27%) were in AF, while 138 subjects (73%) were in sinus rhythm. AF-HF patients were older than SR-HF patients (p = 0.046), but left ventricular ejection fraction and New York Heart Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoc analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels when compared to SR-HF patients. On multivariate analysis, the presence of AF was related to plasma vWF levels (p = 0.018). Plasma vWF was also significantly correlated with NT-proBNP levels (Spearman r = 0.139; p = 0.017). CONCLUSIONS There is evidence of greater endothelial damage/dysfunction in AF-HF patients when compared to SR-HF patients. The clinical significance of this is unclear but may have prognostic value.

Angiogenic factors in atrial fibrillation : A possible role in thrombogenesis?

Background. The precise pathophysiological processes underlying the prothrombotic or hypercoagulable state in atrial fibrillation (AF) remain uncertain. We hypothesized a relationship between abnormal endothelial damage/dysfunction, coagulation, and angiogenic factors, thereby contributing to increased thrombogenicity. Methods. Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and tissue factor (TF, an index of coagulation), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2), were measured by enzyme‐linked immunosorbant assay (ELISA) in 59 chronic AF patients. Data were compared to 40 age‐ and sex‐matched healthy controls in sinus rhythm. Results. Plasma vWF, VEGF and Ang‐2 were significantly higher in AF patients compared to healthy controls (P = 0.005, P = 0.0055 and P<0.0001 respectively) but there were no significant differences in plasma Ang‐1 or TF levels between the two groups (P = 0.925 and P = 0.121 respectively). Significant correlations were found between VEGF and vWF levels (Spearman, r = 0.262, P = 0.011) and between VEGF and Ang‐2 (r = 0.333, P = 0.001). Conclusions. Raised VEGF in association with Ang‐2 and vWF may reflect a link between abnormal endothelial damage/dysfunction and angiogenic factors. These may act together to alter TF expression and endothelial integrity, thereby contributing to the prothrombotic state in AF.

Assessment of endothelial dysfunction.

The pathophysiology underlying the initiation and progression of cardiovascular disorders is highly complex and multifactorial. The endothelium also plays a crucial role in the pathogenesis of thrombogenesis and atherogenesis, and a continuum of endothelial activation, dysfunction or damage is evident in many cardiovascular disorders both at the macro and microscopic level(s). This review article aims to provide an overview of the assessment of endothelial (dys)function and discuss the implications and limitations of such assessments.

The effect of multi-factorial intervention on plasma von Willebrand factor, soluble E-selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease

Background  Endothelial abnormalities and a hypercoagulable state may contribute to increased cardiovascular risk in diabetes mellitus, particularly in patients with overt cardiovascular disease (CVD). We sought to determine the effect of intensified multi‐factorial cardiovascular risk intervention on indices of endothelial abnormality and hypercoagulability in diabetes, and if patients with overt CVD would derive similar benefit as those without.

Tedisamil: a new novel antiarrhythmic

Solvay Pharmaceuticals is currently developing tedisamil (KC-8857), a novel antiarrhythmic with additional anti-ischaemic properties, which acts via potassium channel blockade. This drug can be categorised as a class III antiarrhythmic agent due to its effects of action potential and QT interval prolongation in these patients. This agent was initially developed for its anti-ischaemic properties and Phase I trials have shown tedisamil to be an effective bradycardic agent, as well as causing a reverse rate-dependent QT interval prolongation. Subsequent Phase II results have confirmed that in patients with ischaemic heart disease, tedisamil had beneficial haemodynamic and anti-ischaemic effects. Phase III studies in patients with ischaemic heart disease indicated that tedisamil is an effective agent for the treatment of angina, resulting in a dose-dependent increase in anginal threshold (with a decrease in anginal attacks, increased exercise capacity during treadmill exercise and decreased electrocardiographic signs of exercise induced ischaemia) in comparison to placebo. Although tedisamil has been shown to be an effective anti-ischaemic agent, with Phase III trials for angina pectoris now completed, the company are now pursuing the use of tedisamil for the treatment of atrial fibrillation, for which tedisamil is still in Phase II/III clinical trials. Launch data are not yet known.

Ethnicity and arrhythmias.

Cardiac arrhythmias are difficult to define epidemiologically. It therefore follows that data available on their actual incidence and prevalence is limited. Although many of the available studies can be criticised due to methodological flaws, overall there do appear to be some differences in the incidence and prevalence of arrhythmias in different ethnic groups. These differences are likely the result of aetiological influences, as the prevalence of ischemic heart disease, hypertension and other contributory causes are known to vary between ethnic groups. Clearly, more epidemiologic information is required in non-white populations in order to further advance understanding of possible aetiology, assess implications on associated morbidity, mortality and therapeutic options, as well as plan efficient health care provision and costing implications.

Prevalence and Risk Factors of Silent Brain Infarcts in the Population

To the Editor: We read with interest the study reported by Vermeer et al on the prevalence and risk factors for silent brain infarcts in the Rotterdam scan study.1 We were, however, very surprised that the authors neither commented on nor investigated the presence of associated atrial fibrillation (AF) as a risk factor in this study population. As we already know, AF is an independent risk factor for stroke,2 and many other investigators have firmly established the presence of silent cerebral infarction (SCI) in patients with atrial fibrillation.3,4⇓ For example, the Veteran Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators reported that 14.7% of neurologically normal male patients with nonvalvular AF had evidence of cerebral infarction on CT scanning.3 As with Vermeer et al,1 they too reported that an increasing age and a history of hypertension was associated with silent cerebral …

Anticoagulation Uptake in Emergency Department Patients With Atrial Fibrillation

To the Editor: Scott et al1 report that atrial fibrillation (AF) is commonly seen in emergency department patients and antithrombotic prophylaxis was suboptimal, despite the well-established benefits of thromboprophylaxis in AF.2 The data reported by Scott et al1 are not altogether unexpected, and we are pleased that they have confirmed our previous observations.3–5 In 1994, we reported that AF was present in 6% of acute medical admissions to a Scottish district general hospital, and there was a suboptimal application of standard investigations for AF and a poor provision of thromboprophylaxis.3 Indeed, of the 102 patients presenting with known AF in a 6-month period, only 20% were taking warfarin and 17% were on aspirin, and of those not on warfarin only 34% had contraindications.3 …