Christopher J. Boos

The role of inflammation in atrial fibrillation

Patients can be funny (I don’t mean comical, even though many are), but are not always forthcoming about what really motivates them to visit their doctor. Comedy is an important component of medicine and certainly relaxes the consultation. I have appreciated this most in my male cardiac sexual dysfunction clinic. Practising just south of the river Thames, I have often used Tower Bridge to break the ice in discussing erectile dysfunction (ED) – ‘‘up and down’’. Patients bring their own humour – ‘‘it’s no longer a flagpole, more a banana’’. There are many more examples and laughter can be a key to opening-up an often difficult subject – 44% of men visiting a urologist with ED did not mention it (1) – which brings me to the ‘‘by the way’’ moment or ‘doorknob syndrome’. Often a consultation proceeds along a comfortable route – a few palpitations related to alcohol or caffeine, reassurance and advice – and as the patient leaves he/she mentions ‘‘and by the way doc, I had this chest pain yesterday’’. So we sit down and start again. The ‘‘by the way’’ moment may be quite innocuous – a rash or sore throat (‘‘have I got cancer?’’) which can be easily treated and reassurance given. How do we tease out these ‘‘by the way’’ moments which may be important clinically and, whatever their clinical significance, are always important to the patient? Listening to the story carefully with eye contact is a good beginning. Talking and listening to a patient whilst focussing on a computer screen is a deterrent to the patient opening-up to what the problem really is. It is important to make time for the consultation and to try not to be pressured by the ‘Administration’, which thinks in number seen not people seen. We should all refuse to have our clinics overbooked to facilitate some political target which takes no account of a patient’s needs. It is better to talk ‘to and with’ 10 new patients than talk ‘at and not with’ 20. Patients are often frightened, worried and need time – our decision making process still depends on a good history which many times needs to be obtained by direct questioning based on a vague story. The Internet may have helped or more often alarmed a patient, and the resulting confusion can cloud the story. At times I worry that in our hurried medical lives we have forgotten our doctor–patient skills – perhaps technology is to blame to some extent. I try to begin my consultations with an introduction and opening comment along the lines of ‘‘your doctor tells me you have chest pain – what’s the problem?’’ or ‘‘I’m not sure from your doctor’s letter what bothers you – how can I help?’’. The consultation will unfold and I try not to interrupt, but if there are a mixture of symptoms I will interrupt – ‘‘let’s focus on the chest pain – what brings it on?’’. I usually ask a lot of questions and come to the end of the interview which I finish lightheartedly with ‘‘I’ve asked all the questions – now it’s your turn’’ and I close with ‘‘anything else bothering you?’’. I do not know if this approach reduces the ‘doorknob’ problem, but it does allow an opening for that suppressed but critical complaint or worry – ‘‘my wife says I should mention my breathing . . . ’’. My approach is conditioned by my good fortune in being taught in the 1960s and 1970s when a good history and examination (with a stethoscope – remember those?!) was our main, and often only, means of evaluating the initial presentation. I have been pressurised to give my patients less time in order to see more of them (targets, targets, targets) but I have resisted (they are not numbers, they are people). One of the worst developments in the UK National Health Service is the power of those with no clinical training (be they politicians, administrators or outside management ‘consultants’) to dictate to highly experienced clinicians how to run their service. Unless we as a profession provide our patients with time and attention as well as opportunity to communicate fully there will be no doorknobs to hang onto – just closed doors. And ‘‘by the way’’, have you noticed how all those telling us what to do act differently when they become patients?

Inflammation and atrial fibrillation: cause or effect?

Atrial fibrillation (AF) is an emerging epidemic of cardiovascular disease (CVD), being responsible for approximately 1% of the National Health Service budget of the United Kingdom.1 AF is linked to both increased morbidity (eg from ischaemic stroke, heart failure and dementia) and mortality.2 Consequently, the quest to elucidate the complexities of AF pathogenesis and perpetuation continues at a great pace, in the hope of developing future novel and effective therapeutic strategies.nnIncreasing attention has focused on the potential factors that might be involved in both the triggering and the perpetuation of AF. Inflammation has been postulated as a predisposing factor for AF, as well as its complications, including thromboembolism.2 In the first study to identify a potential link between inflammation and AF, Frustaci et al 3 demonstrated evidence of focal myocarditis on left ventricular endocardial biopsies of three out of 14 patients with lone AF. The authors expanded on this initial work 6 years later by performing right atrial biopsies on 12 patients with lone AF, reporting that 67% of these showed evidence of right atrial myocarditis.4nnIn …

Plasma haemoxygenase-1 in coronary artery disease. A comparison with angiogenin, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor.

It was the aim of this study to determine plasma haemoxygenase-1 (HO-1) across the spectrum of health, angina but normal coronary arteries (NCA), stable coronary artery disease (CAD), and acute coronary syndromes (ACS), and relationships with angiogenin, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1, and vascular endothelial growth factor. Plasma markers were measured (ELISA) in peripheral venous citrated plasma from 50 healthy subjects, 30 with NCA, 70 with stable CAD and 24 with an ACS, and from patients aortic root, coronary ostium, coronary sinus and femoral artery. Human umbilical vein endothelial cells (HUVECs) were cultured with or without tumour necrosis factor (TNF), and platelets were probed. HO-1 was raised in stable CAD (p<0.05) and increased further in ACS (p<0.01) compared to healthy controls and NCA. HO-1 correlated only with MMP-9, and then only in the healthy controls. There were no major differences from cardiac or peripheral sites. HO-1 was present in HUVECs and 24-hour HUVEC supernatants but release was abolished by TNF. Platelets had no HO-1. In conclusion, HO-1 is raised in stable CAD and ACS and may arise from the endothelium but not the platelet. This may have implications for our understanding of the pathophysiology of CAD and its acute presentation as ACS.

Antithrombotic therapy for atrial fibrillation

Atrial fibrillation (AF) can significantly increase morbidity and mortality. It is gaining in clinical and economic importance, being the most commonly encountered tachyarrhythmia in clinical practice. Stroke is the most serious complication. Evidence from AF antithrombotic treatment trials is reviewed, risk stratification of patients with AF is discussed, and recommendations for anticoagulation are presented.

Circulating endothelial cells in malignant disease

Cancer is a disease largely dependent on neoangiogenesis. Cancer neoangiogenesis is often disordered and abnormal, with evidence of coexisting vascular endothelial dysfunction. A novel method of assessing vascular endothelial function in cancer is via the quantification of circulating endothelial cells (CEC). Unusual in healthy individuals, their presence in elevated numbers often indicates substantial vascular endothelial perturbation. Another interesting cell type is the endothelial progenitor cell (EPC), whose numbers increase in the presence of vascular damage. Recent research suggests that EPCs have an important role in tumor vasculogenesis. Another marker being investigated in the context of vascular dysfunction and coagulopathy is the endothelial microparticle (EMP). Thus, CECs, EPCs and EMPs may represent potentially novel methods for evaluating the vascular status of cancer patients. This review will summarize the current position of CECs, EPCs and EMPs in cell biology terms, with particular emphasis on their relationship to malignant disease.

Ximelagatran for stroke prevention in atrial fibrillation.

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta®, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.

Antithrombotic treatment in atrial fibrillation

Atrial fibrillation (AF) can significantly increase morbidity and mortality. It is gaining in clinical and economic importance, being the most commonly encountered tachyarrhythmia in clinical practice. Stroke is the most serious complication. Evidence from AF antithrombotic treatment trials is reviewed, risk stratification of patients with AF is discussed, and recommendations for anticoagulation are presented.

Novel therapies for the prevention of stroke

The health and economic burden of stroke to society is enormous. Pharmacological therapies remain the primary stroke prevention strategy for the vast majority. Several existing and newer pharmacological agents aimed at the treatment of hypertension and lowering cholesterol are proving to be effective. For example, the antiplatelet agent clopidogrel has reduced end points in the secondary prevention of stroke, as have combinations of aspirin with traditional therapies, including dipyramidole. The direct oral thrombin inhibitor ximelagatran is a novel oral anticoagulant that has shown significant potential as a possible replacement to warfarin therapy, for the prevention of stroke for patients with non-valvular atrial fibrillation. Additional novel agents with hypothetical, although not yet proven, benefits in stroke prevention include fish oils, homocysteine-lowering therapy and anti-inflammatory agents. Finally, a controversial novel polypill, which would include fixed combinations of several pharmacological agents, may yet become a realistic and promising stroke prevention option.

Biomarkers in atrial fibrillation: further observations on biologic plausibility, cause and effect.

We read with interest the recent overview by Professor Richard Becker on biomarkers in atrial fibrillation (AF), in relation to biologic plausibility, cause and effect’ [1]. We would like to add to his viewpoint by discussing additional aspects to the prothrombotic or hypercoagulable state in AF. We agree with him that the pathophysiology of thromboembolism is multifactorial. However, there is increasing evidence pointing to the fulfilment of Virchow’s triad (that is, abnormalities of blood flow, blood constituents and vessel wall abnormalities) as a critical platform for thrombogenesis in AF, resulting in this arrhythmia conferring a prothrombotic or hypercoagulable state [2]. Certainly, patients with AF appear to demonstrate abnormalities of haemostasis, platelets and endothelial function, which are independent of associated structural heart disease or underlying aetiology of AF [2]. Biomarkers associated with the prothrombotic state can be altered by cardioversion and antithrombotic therapy. Importantly, these biomarkers can also be related to prognosis (stroke and vascular events) in AF [3–5]. As Professor Becker suggests, many questions on the prothrombotic state in AF remained unanswered with scanty information on its relation to stroke risk and prognosis, or the underlying mechanisms leading to the prothrombotic state—at least until recently. Professor Becker raises several fundamental questions, and answers should be forthcoming, in relation to biomarkers in AF. Firstly, in relation to who is most likely to develop AF, this common cardiac arrhythmia is associated with common cardiovascular conditions—such as hypertension, heart failure, etc—which themselves are associated with abnormal biomarkers of a prothrombotic state [6,7]. Nonetheless, biomarkers are abnormal even in patients with lone AF, where associated vascular risk factors have been excluded [8]. Secondly, “are there identifiable pre-thrombotic and pre-inflammatory phases of the disorder?” Indeed, inflammation and thrombosis are intimately related, and an association between AF and the pro-inflammatory cytokine tumour necrosis factor (TNF)-α has been demonstrated in one albeit small study [9]. We have also shown that patients with AF have higher levels of interleukin (IL)-6, C-reactive protein (CRP), plasma viscosity and tissue factor (TF), with the later relationship being maintained even after adjustment for confounding factors [10]. Importantly, we demonstrated an important relationship between inflammation (by quantification of CRP and IL-6) and the prothrombotic state (TF, plasma viscosity and fibrinogen). High inflammatory indices (eg. CRP) also predict the subsequent development of AF [11]. However, whilst inflammatory markers in AF may suggest a pro-inflammatory state that would enhance hypercoagulability, this may be more related to associated clinical variables of the patients, rather than to the presence of AF per se [12]. Thirdly, “is the thromboembolic risk quantifiable?” Follow-up data from the Stroke Prevention in AF (SPAF) study found that raised plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) levels, but not soluble P-selectin (a marker of platelet activation) were predictive of subsequent cardiovascular events in 994 patients with AF, independently of known clinical risk factors [4]. Also, plasma vWF level can be associated with the presence of four stroke risk factors independently of each other (heart failure, previous stroke, increasing age and diabetes) [13]. This is consistent with other data demonstrating a relation between biomarkers with the CHADS2 and Framingham scores [14] of stroke risk in AF. We would accept that further data on how biomarkers would complement clinical risk stratification criteria in AF are needed.