In the past 20 years the Netherlands-based RACE trials have investigated important concepts in clinical atrial fibrillation (AF). Their scope ranged from rhythm versus rate control to early or delayed cardioversion and also included early comprehensive management of AF in two trials, one focusing on early 'upstream therapy' and risk factor management and the other on integrated chronic nurse-led care. Studies were mostly triggered by simple clinical observations including futility of electrical cardioversion in persistent AF; many patients with permanent AF tolerating day-after-day 'uncontrolled' resting heart rates of up till 110 beats/min; patients being threatened more by vascular risks than AF itself; and insufficient guideline-based treatments for AF. Also the observation that recent-onset atrial fibrillation generally converts spontaneously, obviating cardioversion, triggered one of the studies. The RACE trials shifted a number of paradigms and by that could change the AF guidelines. The initial 'shock-and-forget' attitude made place for increased attention for anticoagulation, and in turn, broader vascular risks were recognised. In a nutshell, the adage eventually became: 'look beyond the ECG, treat the patient'.

Atrial fibrillation (AF) is the most challenging rhythm disturbance worldwide. Arrhythmia and its behavior represent complex pathogenesis highly opposing to contemporary curative modalities. Increasing age of patients carries a certain level of risk for AF. Some underlying diseases in concordance with aging actually accelerate the occurrence of AF. Underestimated superimposed risk factors - aging plus any known risk factor or condition (hypertension, diabetes etc.) - elicit great interest and concern. In light of these concerns we offer an elaborated universal hypothesis in attempt to elucidate the genuine origin of AF substrate. Putative chronic toxicity - toxins and/or involution related pseudo-toxins potentially generate micro- and macro-structural changes in atrial myocardium thus inciting both intracellular damage (degeneration of myocites, apoptosis) and extracellular fibrotic proliferation (interstitial fibrosis, formation of matrices, degeneration of cells with fibrotic replacement). The co-products of related underlying diseases in cooperation with cellular senescence, endogenous overproduction of specific lipids/lipoproteins and other pro-atherosclerotic and/or inflammatory components generate a total atrial response - vascular/microvascular damage, intracellular and extracellular injuries. These organizational arrangements covering the entire atrial myocardium and perhaps ganglionated plexi/autonomic branches of the nervous system eventually cause clinical havoc - atrial overstretch, atrial adaptation/maladaptation, electromechanical dysfunction, arrhythmias, heart failure, etc. In essence, valvular heart disease potentially evokes similar changes "violating" thin atrial walls to obey the same scenario. Depicted atriomyodegenerative processes most likely represent the true nature of AF substrate development. Available clinical and morphological evidence potentially designates the atriomyodegenerative or plausible neuro-atriomyodegenerative origin of AF. Deductively fusion of reasons rather than purely heterogeneity is responsible for AF induction. Thus, the uniform approach and synoptic vision of clinical and pathohistological entity may offer an alternative or refreshed viewpoint in AF substrate formation.

Atrial fibrillation (AF) and heart failure often co-exist. It is unknown whether the sequence in which AF and heart failure develop is of significance regarding prognosis. We assessed the prognosis of AF patients hospitalized for heart failure based on the timing of AF and heart failure development.

Consecutive AF patients hospitalized for heart failure were included. Patients who had developed AF before or consecutively with heart failure ('AF first') were compared with patients who had developed heart failure before AF ('heart failure first'). The primary endpoint was a composite of cardiovascular hospitalization or all-cause mortality. The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first (137 of 182 patients, 75%, vs. 45 of 182 patients, 25%). The two groups were similar regarding age and gender, but patients with AF first less often had coronary artery disease and had higher ejection fractions than patients with heart failure first (39 ± 14% vs. 32 ± 13%, P = 0.004). During 16 ± 11 months follow-up, the primary composite endpoint occurred less often in patients with AF first than in patients with heart failure first (49.6% vs. 77.7% of patients, P = 0.001). Development of AF first remained beneficial regarding the primary endpoint on multivariable analysis (adjusted hazard ratio 0.50, 95% confidence interval 0.29-0.86, P = 0.01).

The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first. Prognosis in these patients was relatively benign as compared with those who had developed heart failure first.

Atrial fibrillation (AF) is the most common, sustained clinical tachyarrhythmia associated with significant morbidity and mortality. AF is a persistent condition with progressive structural remodeling of the atrial cardiomyocytes due to the AF itself, resulting in cellular changes commonly observed in aging and in other heart diseases. While rhythm control by electrocardioversion or drug treatment is the treatment of choice in symptomatic AF patients, its efficacy is still limited. Current research is directed at preventing first-onset AF by limiting the development of substrates underlying AF progression and resembles mechanism-based therapy. Upstream therapy refers to the use of non-ion channel anti-arrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) or recurrence of the arrhythmia following (spontaneous) conversion (secondary prevention). Heat shock proteins (HSPs) are molecular chaperones and comprise a large family of proteins involved in the protection against various forms of cellular stress. Their classical function is the conservation of proteostasis via prevention of toxic protein aggregation by binding to (partially) unfolded proteins. Our recent data reveal that HSPs prevent electrical, contractile, and structural remodeling of cardiomyocytes, thus attenuating the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Furthermore, studies in humans suggest a protective role for HSPs against the progression from paroxysmal AF to persistent AF and in recurrence of AF. In this review, we discuss upregulation of the heat shock response system as a novel target for upstream therapy to prevent derailment of proteostasis and consequently progression and recurrence of AF.

Atrial fibrillation (AF) is the most common sustained arrhythmia and an important source for mortality and morbidity on a population level. Despite the clear association between AF and death, stroke, and other cardiovascular events, there is no evidence that rhythm control treatment improves outcome in AF patients. The poor outcome of rhythm control relates to the severity of the atrial substrate for AF not only due to the underlying atrial remodelling process but also due to the poor efficacy and adverse events of the currently available ion-channel antiarrhythmic drugs and ablation techniques. Data suggest, however, an association between sinus rhythm maintenance and improved survival. Hypothetically, sinus rhythm may also lead to a lower risk of stroke and heart failure. The presence of AF, thus, seems one of the modifiable factors associated with death and cardiovascular morbidity in AF patients. Patients with a short history of AF and the underlying heart disease have not been studied before. It is fair to assume that abolishment of AF in these patients is more successful and possibly also safer, which could translate into a prognostic benefit of early rhythm control therapy. Several trials are now investigating whether aggressive early rhythm control therapy can reduce cardiovascular morbidity and mortality and increase maintenance of sinus rhythm. In the present paper we describe the background of these studies and provide some information on their design.