Suresh Krishnamoorthy

Assessment of endothelial (dys)function in atrial fibrillation.

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.

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.

Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation

Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E‐selectin (sE‐sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF.

Antiarrhythmic drugs for atrial fibrillation: focus on dronedarone

Patients with atrial fibrillation have an increased risk of stroke and heart failure, as well as impairment of their quality of life. Most trials have primarily focused on the prevention of stroke and heart failure, and the improvement of symptoms in these patients. More recently, a rate-control strategy has been reported to be a noninferior strategy compared with a rhythm-control strategy in atrial fibrillation patients. Many different classes of antiarrhythmic drugs have been used for rhythm control, with inconsistent results and adverse effects on mortality and morbidity. Of the available antiarrhythmic drugs, amiodarone is the single most effective drug in the prevention of atrial fibrillation recurrences and maintaining sinus rhythm; however, it is vastly limited by its various systemic side effects, especially those observed with long-term use. However, recent trial data from a new antiarrhythmic agent, dronedarone, suggest that this drug may be a safe alternative to amiodarone; however, its long-term efficacy and safety still require exploration.

Hypertension, stroke and the impact of atrial fibrillation.

It is well-recognized that hypertension is associated with an increased risk for stroke, coronary heart disease and renal failure; importantly, blood pressure (BP) control markedly reduces major adverse cardio vascular events [1]. This result has been seen consistently with different drug regimens, with a reduction in the risk of nonfatal or fatal strokes of up to 30–40% with optimal BP control [2]. The improved clinical outcome relates more to systolic BP reduction than the reduction of diastolic BP per se [3]. Indeed, systolic BP levels are more predictive of cardiovascular mortality and morbidity in patients aged 60 years and over, when compared with diastolic BP levels [3]. The management of hypertension is very relevant to routine clinical practice with

Predictive value of atrial high-rate episodes for arterial stiffness and endothelial dysfunction in dual-chamber pacemaker patients

Various pacing studies have demonstrated an association between right ventricular pacing (RVp) and atrial fibrillation (AF), even after preserving atrioventricular (AV) synchrony. We aimed to assess the interaction between arterial stiffness, endothelial function and atrial high‐rate episodes (AHRE) in patients with dual‐chamber pacemakers.

Novel antiarrhythmic drugs in atrial fibrillation: focus on tedisamil

Background: Even established and effective antiarrhythmic drugs (AADs) in atrial fibrillation (AF) are limited by their pro-arrhythmic and non-target organ side effects. Therefore the search continues for safer and effective new AADs. Objective: This review will examine a novel AAD, tedisamil – a multichannel potassium channel blocker – and its antiarrhythmic properties, focusing on AF. Methods: Review of the literature and studies assessing the effect of tedisamil in humans and animal models with atrial arrhythmia(s). Conclusion: Tedisamil appears to be effective for rhythm restoration in acute-onset AF patients. The proven anti-ischemic effect with tedisamil may be an added benefit. Further studies with tedisamil are needed to confirm its safety and long-term efficacy.

How safe is the antiarrhythmic drug therapy in atrial fibrillation

While the predominant symptom(s) related to atrial fibrillation (AF) are due to either a poorly controlled—or irregular— ventricular rate, still there is some debate with regard to the optimal strategy (that is, rate or rhythm control) to treat individual patients. Indeed, recent large, randomized, controlled trials have shown that neither rate nor rhythm control was superior in reducing mortality in AF patients, although achieving rhythm control appears to improve functional class, 1 at least in the short term. Interestingly, a post hoc analysis from the AFFIRM trial found that sinus rhythm (and warfarin use) was related to improved survival but this was offset by a greater mortality from antiarrhythmic drugs (AADs). 2 Anderson et al., 3 from a large retrospective (n ¼ 40 823) Swedish nationwide study (conducted between 1995 and 2004), reported that AAD therapy was not associated with an increased mortality in AF patients. As expected, various AADs (mainly flecainide, propafenone, sotalol, and amiodarone) were used in the treatment of AF, but in this unselected, non-randomized cohort, considerably more patients were on sotalol (16%) when compared with the rest of the AADs (flecainide 2.4%, propafenone 2.6%, or amiodarone 7.3%). However, in patients with previous myocardial infarction (MI) or ischaemic heart disease, the preferred choice of AAD was amiodarone (24.3%) compared with sotalol (15%) or class-Ic drugs (8.6%). Similarly, more patients with heart failure were on amiodarone (21.5%) when compared with other AADs (sotalol 9.5%, class-Ic drugs 6.1%). The authors quoted annual mortality rates (per year/100 patient-years) of 7.4 vs. 5.3% vs. 4.3% vs. 2.5% with amiodarone, sotalol, propafenone and flecainide, respectively. Approximately a third of these unselected patients were noted to be on digoxin, whilst a fifth were on betablockers or calcium blockers—on top of prescribed AAD therapy for AF. In a Cox-regression analysis, treatment with AAD was generally associated with a lower mortality (flecainide HR 0.38, 95% CI 0.32‐0.44; propafenone HR 0.65, 95% CI 0.58‐0.71; sotalol HR 0.65, 95% CI 0.63‐0.67) but the effect of amiodarone was borderline (HR 0.94, 95% CI 0.89‐1.00). Perhaps AADs may be safe in AF after all? The quoted mortality in the paper by Anderson et l. 3 with individual AADs may well be related to disease progression rather than effect of antiarrhythmic therapy per se, and cause(s) of death in these patients is not that clear. But also, the choice of AADs were carefully selected in individual patients which also might account for the observed low mortality. These observations are contrary to the post hoc analysis of AFFIRM trial data 2,4 that there was a non-significant trend towards a higher mortality in patients assigned to rhythm when compared with rate control, predominantly due to noncardiovascular causes. The significant predictors of higher noncardiovascular mortality on multivariate analysis were rhythm control, male gender, heart failure, age, and coronary artery disease. Nevertheless, this increased mortality seen in rhythm control group may well be related to adverse effects of the various AADs used (amiodarone, sotalol, disopyramide, flecainide, moricizine, procainamide, propafenone, and quinidine) in these AF patients without heart failure, although the precise mechanism(s) was not well elucidated. In a subsequent analysis using time-dependent variables towards in these patients, there was a 1.5-fold increased risk of death noted with AAD therapy after adjusting to co-variables in the presence of sinus rhythm (HR 1.49, 99% CI 1.11‐2.01). 4 The use of digoxin for rate control also appears to increase the risk of death (HR 1.42, 99% CI 1.18‐1.89) in these patients with persistent AF. 2,4 Notably, neither beta-blockers nor calcium-channel blockers had any effect on improving survival of these AF patients. Broadly similar results were noted in the Stroke Prevention in Atrial Fibrillation (SPAF) 5 trial, where there was a 2.5-fold increase in cardiac mortality (HR 2.5, 95%CI 1.3‐4.9) and a 2.6-fold increase in arrhythmic deaths (HR 2.6, 95% CI 1.2‐5.6) in AF patients on AAD therapy, even after adjusting for cardiovascular risk factors. However, AF patients with history of congestive heart failure

Common clinical indications for anticoagulation

As discussed in Chapter 1, an anticoagulant is a substance that possesses the properties to limit clot formation and therefore can be used therapeutically to prevent or treat thrombotic disorders. In this chapter we discuss the common clinical conditions in which anticoagulation should be considered and the evidence available to justify the use of an appropriate antithrombotic therapy in these clinical settings.

Response to Dr Kula: Asymptomatic hypoxia in a young pregnant lady--unusual presentation of atrial septal defect.

We thank Dr Kula and colleagues for their comments [1] on our recent case report ‘Asymptomatic hypoxia in a young pregnant lady—an unusual presentation of atrial septal defect [2]’. The patient described was noted to have an ejection systolic murmur in the pulmonary area with fixed wide splitting of the first heart sound without a loud pulmonary component on clinical examination. A bubble contrast echocardiography which was done as a diagnostic procedure did demonstrated passage of a few bubbles (b5) from the right to left atrium even at rest before a Valsalva manoeuvre but bubbles were more pronounced with the Valsalva manoeuvre (N20) consistent with the diagnosis of an atrial septal defect (ASD) without any evidence of pulmonary hypertension. We agree that the passage of bubbles from right to left side at rest is very common in patients with pulmonary hypertension but still could be seen in patients with large atrial septal defects, as seen in our case. At 3 months after pregnancy, a transoesophageal echocardiography examination demonstrated a Qp/Qs ratio of 1.7:1 without any features suggestive of pulmonary hypertension. She did not undergo any right or left heart catheterisation due to the lack of pulmonary hypertension, well delineated os secundum ASD on echocardiography and a low risk for coronary artery disease. Following referral to a tertiary centre, she had an uncomplicated percutaneous closure of her ASD. We believe that the hypoxia noted during her pregnancy and just immediately post-partum might well be related to transient right to left sided shunting, but after the device closure of the ASD, a subsequent TOE did not demonstrated any residual shunting. There was no further hypoxia after procedure which was confirmed in her arterial blood gas analysis. We agree with Dr Kula colleagues that a differential diagnosis to consider in this kind of scenario is a pulmonary atrio-venous malformations or fistula, as a fifth of patients do remain asymptomatic. This diagnosis was considered in our patient but the subsequent investigations clearly revealed the presence of large os secundum ASD. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [3].