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.