International Journal of Cardiology - oct 2008
Article in Press, Corrected Proof
'Lone' atrial fibrillation:next term Hunting for the underlying causes and links
Department of Cardiology, University of Ioannina School of Medicine, Ioannina, Greece bDepartment of Cardiology,
Abstract
The presence of lone fibrillation presupposes the absence of structural heart disease, hypertension, or other known predisposing factors. However, several recent clinical and experimental data provide novel insights into the pathogenesis of lone fibrillation. In addition, modern diagnostic techniques often reveal some previously unappreciated abnormalities. Therefore, the increasing recognition of potential causes and links sets the base for a more complete elucidation of its etiology in the near future. This concise review article discusses the contemporary advances in the understanding of this form of fibrillation.
< br/>1. Introduction
2. Causes and links of lone atrial fibrillation
2.1. Epidemiologic associations
2.2. Triggering factors
2.3. Atrial substrate
2.4. Electrophysiological considerations
2.5. Genetic factors
2.6. Structural changes
3. Conclusion
References
1. Introduction
Atrial fibrillation (AF) represents a growing epidemic with significant health consequences and often a difficult management [1], [2] and [3]. It has been proposed that the aging of the population along with the increasing prevalence of associated risk factors accounts for the increase in AF incidence and prevalence during the past few decades [1] and [2]. Although most of the cases are attributable to other cardiovascular disorders such as hypertension, heart failure, and coronary artery disease, a small proportion is considered to be 'lone'; namely without obvious structural heart disease [4]. The diagnosis of lone AF is a diagnosis of exclusion a nd besides the absence of other cardiopulmonary disease presupposes the absence of hypertension, or any other known and easily identifiable cause, in relative young individuals (< 60 years old) [5]. However, the term 'lone AF' has been variously defined [5]. For example a recent international consensus on nomenclature and classification of AF mentions that only AF in the absence of heart disease is termed 'lone' while in the absence of any disease is termed 'idiopathic' [6]. The investigation for structural heart disease includes history, physical examination, electrocardiography, chest X-ray, and echocardiography.
The natural history of lone AF has not been well-studied. However, accumulating data suggest that it is associated with a low risk of progression to permanent AF, mortality, congestive heart failure, and stroke/transient ischemic attack [4] and [7]. The increased thromboembolic risk as well as the tendency to become sustained over time seems to be rela ted to aging and other comorbidities that presumably create a substrate for arrhythmia maintenance leading to a vicious cycle [4] and [7]. In other words, the atrial remodeling that facilitates AF progression and thrombus formation may be more prominent in the case of other coexistent morbidities. Of note, the development of AF in the context of other cardiovascular disorders significantly increases morbidity and mortality [2] and [3]. In addition, AF adversely affects the quality of life and exercise capacity of affected individuals [8]. Therefore, the understanding of the underlying pathophysiological mechanisms may be of special value in order to manage these unfavourable effects.
As mentioned before, lone AF does not necessarily mean 'idiopathic'. As Lorbar and Spodick pointed out in the case of pericarditis: 'nothing is idiopathic'; suggesting that meticulous investigation and consideration of contemporary pathogenetic mechanisms may reveal or clarify, at least in part, the underlying etiology [9]. Nevertheless, this point of view could also be applied in the case of lone AF. Recently, an increasing body of evidence indicates several novel epidemiologic and pathophysiologic associations of AF [1] and [10]. It could therefore be hypothesized that many of the recorded lone or idiopathic AF cases are linked to other not well-known factors [11]. In this context, there seems to be an emerging challenge for the identification of the underlying causes and links in order to perform a timely intervention for the interruption of the vicious cycle that leads to atrial remodeling.
2. Causes and links of lone atrial fibrillation
Undoubtedly, AF is a highly heterogeneous disorder with multiple causes, triggers, and substrates that interact with each other [12]. This interplay may be even more complex in the case of apparently lone AF where an overt cardiovascular disorder is lacking.
As outlined before, recent data support the notion that lone AF is a rhythm disturbance with other accompanied abnormalities. It is therefore reasonable to assume that, as medical knowledge advances, truly lone AF will be very rare [7], [11] and [13]. As Frost recently stated: "Perhaps we should stop using terms such as idiopathic or lone because in the end we will find a cause" [11]. This view is also supported by the high reported variation in the prevalence of lone AF (2–11%) indicating that after applying strict criteria this form of AF is much more rare than previously considered [7] and [13].
2.1. Epidemiologic associations
Several novel epidemiological associations of AF have recently emerged. The conditions that have been implicated include obesity, sleep apnea, diabetes, metabolic syndrome, increased alcohol consumption, anger and hostility (in men), pulse pressure, and subclinical atherosclerosis (assessed by carotid intima–media thickness) [1], [14], [15], [16], [17], [18], [19 ], [20] and [21]. The underlying pathophysiological mechanisms include atrial and ventricular structural changes, increased atrial stretch, autonomic imbalance, systemic inflammation, oxidative stress, and others [14], [15], [16], [17], [18], [19], [20] and [21]. It is therefore tempting to speculate that these conditions, when present in individuals without structural heart disease and hypertension, might contribute to the development of apparently lone AF. Nevertheless, it should be acknowledged that a cause–effect relationship has not been clearly established while some inconsistent results have been reported [1]. It is also worth noting that some patients may represent occult cases of arterial hypertension that becomes apparent after the initial diagnosis of the arrhythmia [22].
2.2. Triggering factors
Lone AF appears to be more prevalent among males of relative young age [22] and [23]. The majority of patients are initially presented with paroxysmal A F most commonly triggered by sleep, exercise, alcohol use, and eating [23]. Moreover, there seems to be a predilection for tall, lean, and physically fit individuals [24]. It has also been suggested that in this young, apparently healthy, population the relative significance of triggers may be greater than the atrial substrate [24]. It is known that the progression from paroxysmal to persistent and permanent AF implies the development of atrial remodeling, namely electrophysiological and structural changes that promote AF. Consequently, the reported low risk of progression of lone AF to the permanent form [7] reinforces the view for the pivotal role of triggering factors. The pathogenic role of autonomic nervous system in AF is well-documented [25]. Fluctuations of the autonomic tone could be operative in several forms of lone AF such as exercise-induced (sympathetic), and sleeping-induced (parasympathetic) [23] and [24]. However, in most patients there is an interplay betwe en sympathetic and parasympathetic stimulations. Vagal stimulation results in shortening of the atrial effective refractory period and hyperpolarization of atrial fibers, leading to increased conduction velocity [26]. These changes occur in some but not all of the atrial tissue, and this is the way re-entry is facilitated [26]. Vagal AF is considered idiopathic in most cases and occurs more frequently in men during periods of increased vagal tone, such as at night or early in the morning [26]. Furthermore, most of the available data support the association between sport practice and lone AF implicating the increased vagal tone as the principal underlying mechanism [27] and [28] R. Elosua, A. Arquer and L. Mont et al., Lone atrial fibrillation and sport practice. The no gain without pain history revisited again?, Int J Cardiol 118 (2007), pp. 414–415. Article | PDF (85 K) | View Record in Scopus | Cited By in Scopus (0)[28]. It has also been proposed that the relative h ypoglycemia as well as the associated hypokalemia and hypomagnesemia observed during the nighttimes may increase the susceptibility to the vagally-mediated lone AF [24].
It is also of clinical importance to recognize drugs or other agents that trigger AF [29]. Several classes of drugs may induce AF in patients without apparent heart disease, although the relative evidence is largely based on individual case reports [29]. These include cardiac stimulants, antiarrhythmics, cholinergics, sympathomimetic inhalants, xanthines, cytostatics, central nervous system drugs, and others. Most of these agents possibly affect the autonomic tone promoting AF triggering, even in 'healthy' patients without any cardiopulmonary disease [29].
2.3. Atrial substrate
Despite the aforementioned considerations with respect to the role of triggers, several recent studies aimed to investigate the underlying substrate and genetic background in patients with lone AF. Firstly, a maj or concern has been arisen with regard to the proper diagnosis of lone AF given that the application of contemporary echocardiographic techniques often reveals some relevant abnormalities. For instance, modern indexes of diastolic function are not routinely employed during the evaluation of lone AF patients. Left ventricular (LV) diastolic dysfunction relates to left atrial dilatation and stretch as well as to the development of AF [30]. Li and Wang demonstrated increased serum B-natriuretic peptide (BNP) levels in paroxysmal lone AF patients compared to age- and sex-matched control subjects without differences in left atrial (LA) diameter and LV ejection fraction [31]. However, LV diastolic function parameters and LA volume had not been assessed [31]. On the contrary, Lee et al. showed independent correlations between BNP levels and LA volume index, pulmonary artery systolic pressure, and E/E′ (an index of LV end-diastolic pressure) in lone AF patients indicating ear ly LV dysfunction and LA enlargement [32]. It has also been shown that LA volume is a predictor of cardiovascular events in patients originally diagnosed with lone AF [33]. In addition, a recent echocardiographic case–control study demonstrated that in patients with lone paroxysmal AF, LA area and volume were larger than in healthy volunteers, despite there being similar LV dimensions, ejection fraction, and diastolic function and regardless of the recurrence of the arrhythmia [34]. Thus, 2-dimensional echocardiography in the anteroposterior dimension underestimates the true LA size in patients with lone paroxysmal AF [35]. Even in the presence of normal LV systolic and diastolic functions, LA diameter, and LA systolic activity, the LA diastolic performance may be compromised in patients with lone AF as evidenced by abnormalities of the systolic phase of pulmonary vein (PV) flow [36]. Collectively, it appears that LV diastolic and LA abnormalities are prevalent in appa rently lone AF but it is still unclear whether they represent a cause and/or consequence of the arrhythmia. Remarkably, Reant et al. demonstrated reverse morphological remodeling of the LA and improvement of LV diastolic and systolic functions after restoration of sinus rhythm by ablation for isolated ('lone') AF [37].
2.4. Electrophysiological considerations
The anatomical site of arrhythmia initiation was recently investigated by mapping techniques in a group of adolescents with symptomatic, drug-refractory lone AF [38]. These patients were found to have firing irregular foci in the PVs, LA, or crista terminalis whereas in 88.9% of them successful catheter ablation was performed [38]. However, most of them demonstrated repetitive nonsustained atrial firing, with rapid irregular cycle lengths that did not precipitate AF during mapping [38]. With regard to adult patients, Todd et al. have indicated that total electrical isolation of the PV region, by surgical me ans, is highly effective in the management of drug-refractory lone AF [39]. The authors did not perform pre-surgical electrophysiologic studies, but spontaneous sustained AF from the isolated PV region was recorded postoperatively in 4/14 patients [39].
Focal discharges from the pulmonary veins and posterior LA are important in the initiation of AF in patients with structurally normal hearts [40] and [41]. Moreover, increasing evidence suggests that sustained AF is the result of a combination of PV vein focal discharge and PV-LA re-entrant activity [42].
2.5. Genetic factors
A growing body of evidence suggests that familial AF is more frequent than previously considered while genetic influences are increasingly recognized as pathogenetic factors [43]. In the Framingham Heart Study, it was demonstrated that the presence of AF in at least 1 parent increases the risk of offspring AF by a factor of 1.85 [44]. Moreover, an analysis of AF cases from an arrhyt hmia clinic indicated that 5% of all AF patients and 15% of lone AF patients had a family history of the arrhythmia [45]. The identification of genetic susceptibility may be of special clinical importance, especially in lone AF patients, providing an etiologic background as well as the basis for therapeutic manipulations and prevention strategies. It has been reported that a substantial proportion (38–39%) of lone AF patients have evidence of familial disease [23] and [46]. It has also been demonstrated that the family members of probands with lone AF have a significantly increased risk of AF compared to that of the general population [46]. Bearing in mind that most episodes of lone AF are short and self-terminated (paroxysmal) or even asymptomatic, it could be concluded that the extent of AF familial aggregation may be underestimated [46].
Familial lone AF appears to be genetically heterogeneous. Genetic linkage analysis and candidate gene association studies have implicated several chromosomal loci and genes [43] and [47]. Recent studies have identified mutations in a series of ion channels; however, these channels appear to be relatively rare causes of AF [48]. Particularly, genes encoding repolarizing potassium channels (KCNQ1, KCNE, KCNJ2, KCNA5, KCNH2), connexins, and components of the renin–angiotensin system have been involved [43], [47], [48], [49], [50], [51] and [52]. Given the demonstrated low prevalence of mutations in the aforementioned potassium channels it can be hypothesized that additional disease genes for familial AF remain to be discovered [48]. For example, genes that encode other types of ion channels or atrial structural proteins can be considered as potential candidates [48].
It has been suggested that a specific polymorphism of matrix metalloproteinase-2 gene is a risk factor for chronic 'lone' AF, while C allele of the interleukin-10 (IL-10) polymorphism represents a protective factor [47 ]. In addition, a recent case–control study demonstrated that a common polymorphism of the cardiac sodium channel (SCN5A) is present in one-third of lone AF patients representing a significant risk factor for the arrhythmia [53]. The association between Brugada syndrome and AF [54] supports the pathogenetic role of SCN5A. It has been reported that the prevalence of AF in these patients is in the order of 20% [55]. In a very recent study, the prevalence of saddleback ST-segment elevation in right precordial leads (types 2,3 of Brugada pattern) was significantly higher in lone AF compared to the control group (10% vs 0.4%, respectively) [56]. Since SCN5A mutations had been excluded, polymorphism or mutation(s) in genes controlling other ion channels could be present [56]. However, the possibility that electrical remodeling may cause the electrocardiographic saddleback pattern cannot be excluded [56]. Of note, it was recently demonstrated that AF patients without structur al heart disease have significantly shorter QT intervals than their age- and gender-matched healthy counterparts [57]. This finding might be explained by alterations in the slow component of the delayed rectifier potassium channel (IKs) [57].
2.6. Structural changes
Besides the electrophysiological changes that may contribute to the development and perpetuation of AF, there is also increasing interest with respect to the microscopic structural abnormalities. The gap-junction proteins have currently attracted much interest. Remarkably, Gollob et al. demonstrated 4 novel mutations of the atrial-specific connexin 40 protein in 4 of the 15 patients with idiopathic AF [50]. Also, the aforementioned studies showing implication of renin–angiotensin related genes in lone AF [51] and [52] reinforce the role of this system in atrial remodeling [58]. Further support to this view was provided by recent findings of reduced apelin levels in lone AF, given that this endo genous peptide hormone has a physiological role in the counter-regulation of the angiotensin and vasopressin systems [59]. Currently, there is an intense research interest on the role of inflammation in the pathophysiology of AF [59] and [60]. Inflammatory indexes, mainly C-reactive protein (CRP) have been related to future AF development, AF recurrences after cardioversion, and to the persistence of the arrhythmia [60] and [61]. The role of inflammation in the pathogenesis of lone AF remains equivocal and limited. Only the study by Frustaci et al. demonstrated abnormal atrial histology in most of the patients with paroxysmal lone AF refractory to conventional antiarrhythmic therapy (inflammatory infiltrates in 66% of patients) [62]. Conversely, other investigators failed to show inflammatory changes in LA histological specimens from lone AF patients [39]. Furthermore, Ellinor et al. failed to demonstrate increased CRP levels in patients with lone AF compared to controls whi le the opposite was observed in patients with AF and hypertension [63]. It has therefore been postulated that markers of inflammation are associated with the presence of other concomitant diseases [63]. Another case–control study showed elevated CRP levels in lone AF patients; however, subjects with hypertension had not been excluded [64]. In a recent observational study, CRP and interleukin-6 tended to be higher in lone AF patients compared to controls, although this difference did not reach statistical significance [65]. On the other hand, the protective role of polymorphism in IL-10 gene against lone AF could imply an anti-inflammatory mechanism since IL-10 is a major anti-inflammatory cytokine [47].
Another possibility of unexplained 'lone' AF is myocarditis and/or pericarditis. These affections may go unrecognized and when we see for the first time the patient it may be virtually impossible to diagnose the disease responsible for the arrhythmia but struct ural changes caused by the inflammatory infection may ensue. Moreover, the autoimmune reactions that follow a myocarditis may cause long-term atrial inflammatory abnormalities. Maixent et al., in a case–control study, demonstrated the presence of circulating autoantibodies against myosin heavy chain in a significant proportion of patients with lone paroxysmal AF raising the possibility of an autoimmune inflammatory process [66].
3. Conclusion
In conclusion, several recent clinical and experimental data provide novel insights into the pathogenesis of lone AF (Fig. 1). Undoubtedly, several issues regarding this form of AF remain elusive and controversial. However, the increasing recognition of potential causes and links will possibly shed more light on its etiology in the near future. The clinicians should be aware of these potential associations and manage effectively all the associated conditions. Finally, the detection of these causes and links using clin ical and laboratory diagnostic methods could potentially lead to the development of specific and individualized therapeutic approaches aiming at the reduction of AF burden.
Xeno Muller, Olympic gold and silver medalist, indoor rowing, rowing technique.
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