Atrial fibrillation (AF) is associated with significant morbidity and mortality. It is also a progressive disease secondary to continuous structural remodelling of the atria due to AF itself, to changes associated with ageing, and to deterioration of underlying heart disease. Current management aims at preventing the recurrence of AF and its consequences (secondary prevention) and includes risk assessment and prevention of stroke, ventricular rate control, and rhythm control therapies including antiarrhythmic drugs and catheter or surgical ablation. The concept of primary prevention of AF with interventions targeting the development of substrate and modifying risk factors for AF has emerged as a result of recent experiments that suggested novel targets for mechanism-based therapies. Upstream therapy refers to the use of non-antiarrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. Such agents include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins, n-3 (ω-3) polyunsaturated fatty acids, and possibly corticosteroids. Animal experiments have compellingly demonstrated the protective effect of these agents against electrical and structural atrial remodelling in association with AF. The key targets of upstream therapy are structural changes in the atria, such as fibrosis, hypertrophy, inflammation, and oxidative stress, but direct and indirect effects on atrial ion channels, gap junctions, and calcium handling are also applied. Although there have been no formal randomized controlled studies (RCTs) in the primary prevention setting, retrospective analyses and reports from the studies in which AF was a pre-specified secondary endpoint have shown a sustained reduction in new-onset AF with ACEIs and ARBs in patients with significant underlying heart disease (e.g. left ventricular dysfunction and hypertrophy), and in the incidence of AF after cardiac surgery in patients treated with statins. In the secondary prevention setting, the results with upstream therapies are significantly less encouraging. Although the results of hypothesis-generating small clinical studies or retrospective analyses in selected patient categories have been positive, larger prospective RCTs have yielded controversial, mostly negative, results. Notably, the controversy exists on whether upstream therapy may impact mortality and major non-fatal cardiovascular events in patients with AF. This has been addressed in retrospective analyses and large prospective RCTs, but the results remain inconclusive pending further reports. This review provides a contemporary evidence-based insight into the role of upstream therapies in primary (Part I) and secondary (Part II) prevention of AF.

Patients with diabetes mellitus have an increased prevalence of vascular disease. Pathologic thrombosis associated with atherosclerotic plaque rupture is a major cause of morbidity and mortality. Platelets are intimately involved in the initiation and propagation of thrombosis. Evidence suggests that platelets from patients with type 2 diabetes have increased reactivity and baseline activation compared to healthy controls. We review the pathophysiology of platelet hyperreactivity in DM patients and its implications in clinical practice, with particular focus on acute coronary syndromes, percutaneous coronary intervention, and novel antiplatelet agents.

Fundamental research into molecular mechanisms of atrial fibrillation (AF) and improved understanding of processes involved in the initiation and maintenance of AF have transformed the traditional approach to its management by targeting only the electrical aspects, usually with antiarrhythmic drugs and, recently, by ablation. The antiarrhythmic potential of upstream therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), statins, and n-3 (ω-3) polyunsaturated fatty acids, extends beyond the benefit of treating underlying heart disease to modifying the atrial substrate and intervening in specific mechanisms of AF. The key target is structural remodelling of the atria, particularly inflammation and fibrosis, although there is evidence to suggest the direct involvement at the ion channel level. Positive clinical reports supported by robust experimental data have suggested that upstream therapies can be valuable strategies for primary prevention of AF in selected patients and have resulted in several class IIA recommendations in the new European guidelines on AF. However, these results have not been consistently replicated in the secondary prevention setting, and several recent randomized controlled studies failed to demonstrate any effect of upstream therapies on AF burden or on major cardiovascular outcomes. Part II of the review summarizes the evidence base for the use of upstream therapies for secondary prevention of AF.

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Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, occurring in 20% to 60% of patients. Advanced age, history of atrial fibrillation (AF), heart failure, peripheral arterial disease and chronic obstructive pulmonary disease are predictors of POAF. The pathogenesis of AF seems to be multifactorial, and includes electrical and structural remodeling as well as inflammation (a systemic response caused by cardiopulmonary bypass and cardiotomy). Numerous pharmacologic agents can decrease the incidence of POAF. It is also necessary to evaluate an agent's ability to decrease stroke, mortality, length of stay and hospital costs. Currently, the use of beta-blockers with adjunctive amiodarone has been shown to reduce POAF and several of its complications. Two therapeutic choices exist in patients with POAF: rate control and rhythm control. The decision which is more important to target should be based on the symptoms of the individual patient. Unlike in patients with chronic AF, POAF is generally transient, and the risks of anticoagulation may outweigh the benefits. Surgical ablation techniques and ablation devices have progressed considerably. This made the procedures quicker and simpler, and therefore feasible in virtually all clinical contexts. In turn, this has raised the issue of post-ablation arrhythmias. Although relapsing AF is generally addressed conservatively, it may require ablation, frequently transseptal. Further research is needed to identify the predictors of POAF and the most effective pharmacological and invasive methods for the prevention and treatment of POAF.

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Co-existent mitral regurgitation may adversely influence both morbidity and mortality in patients undergoing aortic valve replacement for severe aortic stenosis. Whilst it is accepted that concomitant mitral intervention is required in severe, symptomatic mitral regurgitation, in cases of mild-moderate non-structural mitral regurgitation, improvement may be seen following aortic valve replacement alone, avoiding the increased risk of double-valve surgery. The exact benefit of such a conservative approach is, however, yet to be adequately quantified. We performed a systematic literature review identifying 17 studies incorporating 3053 patients undergoing aortic valve replacement for aortic stenosis with co-existing mitral regurgitation. These were meta-analysed using random effects modelling. Heterogeneity and subgroup analysis were assessed. Primary end points were change in mitral regurgitation severity and 30-day, 3-, 5- and 10-year mortality. Secondary end points were end-organ dysfunction (neurovascular, renal and respiratory), and the extent of ventricular remodelling following aortic valve replacement. Our results revealed improvement in the severity of mitral regurgitation following aortic valve replacement in 55.5% of patients, whereas 37.7% remained unchanged, and 6.8% worsened. No significant difference was seen between overall data and either the functional or moderate subgroups. The overall 30-day mortality following aortic valve replacement was 5%. This was significantly higher in moderate-severe mitral regurgitation than nil-mild mitral regurgitation both overall (p=0.002) and in the functional subgroup (p=0.004). Improved long-term survival was seen at 3, 5 and 10 years in nil-mild mitral regurgitation when compared with moderate-severe mitral regurgitation in all groups (overall p<0.0001, p<0.00001 and p=0.02, respectively). The relative risk of respiratory, renal and neurovascular complications were 7%, 6% and 4%, respectively. Reverse remodelling was demonstrated by a significant reduction in left-ventricular end-diastolic diameter and left-ventricular mass (p=0.0007 and 0.01, respectively), without significant heterogeneity. No significant change was seen in left-ventricular end-systolic diameter (p=0.10), septal thickness (p=0.17) or left atrial area (p=0.23). We conclude that despite reverse remodelling, concomitant moderate-severe mitral regurgitation adversely affects both early and late mortality following aortic valve replacement. Concomitant mitral intervention should therefore be considered in the presence of moderate mitral regurgitation, independent of the aetiology.