1.The concept of atrial vulnerability and the basis of electrophysiology (EP)
In clinical and basic research on atrial fibrillation (AF), many scholars have used the term “atrial vulnerability” to indicate the ease of triggering AF, however, the exact concept of atrial vulnerability is understood differently. The majority of the literature favors the notion that atrial vulnerability in AF is the ease of inducing AF when additional stimuli are applied to the atria. In a study on conduction velocity and AF vulnerability, DRAGOS COZMA [1] and others expressed the vulnerability of AF by programmed atrial stimulation (PAS) of S1S2 on the basis of sinus rhythm, in terms of whether AF could be induced. The susceptibility to atrial fibrillation was expressed by the programmed atrial stimulation (PAS) based on sinus rhythm.
Domestic scholars have reached similar conclusions on the main factors influencing atrial vulnerability by studying the cardiac electrophysiology in atrial fibrillation, and the main factors affecting atrial vulnerability in atrial fibrillation are: atrial dispersion of refractoriness (dEPR, Disp-A) [2-6] and delayed intra-atrial conduction or decreased atrial conduction velocity [1, 7, 8, 9]. Among them, the atrial vulnerability is most studied by the increased atrial susceptibility due to the atrioventricular dissociation.
1.1 Atrial expiration dispersion (dEPR)
Atrial non-response dispersion: is the presence of significant differences between myocardial ERPs in different parts of the atria. It is measured in cardiac electrophysiology by dERP, the magnitude of which is expressed as the maximum ERP minus the minimum ERP at different sites on cardiac electrophysiological examination. dERP can be caused by cell repolarization inhomogeneity, and increased atrial dERP leads to electrophysiological inhomogeneity of atrial myocytes, allowing atrial myocytes with different ERPs (e.g., between atria or atria and pulmonary veins) to more easily form random foldback or conduction block, which would be more conducive to AF formation [2][10]. In cardiac electrophysiological examinations (EP), the effective nonstop period is usually measured in at least five sites, such as the right auricle (RAA), the posterior lateral wall of the right atrium (LRA), the high atrial septum (IAS), the Hitchcock bundle area (HBE), and the coronary sinus (CS). To calculate the dEPR, simply subtract the longest of these effective nonreturn periods from the shortest effective nonreturn period.
d E R P = E R P MAX – E R P MIN
Although there is a general consensus among domestic and international scholars regarding the significance of dEPR on atrial vulnerability in atrial fibrillation, there is a controversy among domestic and international studies regarding whether the maintenance of atrial fibrillation is related to dEPR. sato S [11] et al, concluded that discrete periods of inactivity have some significance in the maintenance of atrial fibrillation (MAINTENANCE), and Misier A [ 6] et al. reached similar conclusions in their study. In contrast, the study by Mario Oliveira [3] et al. concluded that dEPR is not a determining factor in maintaining AF maintenance, because in AF episodes paroxysmal AF > no AF. The effect of action potential temporal alternation on atrial vulnerability will be an important direction for future electrophysiological studies.
In domestic and international studies, the quantification of atrial vulnerability by the window of vulnerability (WOV) [16, 17] has been reported in the literature. The so-called atrial vulnerability window is the difference between the longest and shortest intervals of programmed S1S2 stimuli that can induce AF.
WOV=S1S2MAX-SIS2MIN
By summing all vulnerability windows, we can obtain . This index provides a simple and clear quantification of atrial vulnerability. However, whether this index accurately reflects atrial vulnerability in atrial fibrillation requires further scientific study.
= WOV1+WOV2+……+WOVn (n=number of cases in the study group)
2. Confusion in the study of arrhythmias that have a significant effect on atrial vulnerability in atrial fibrillation
Currently, studies on arrhythmias with significant effects on atrial vulnerability in atrial fibrillation have focused on WolffCParkinsonCWhite syndrome (WPW) and Brugada syndrome, and most of the studies have focused on the effects of bypass (AP) and bypass ablation on atrial vulnerability in WPW. The majority of studies have focused on the effect of bypass on WPW (AP) and bypass ablation on atrial vulnerability.
2.1 Effect of WPW on atrial vulnerability in atrial fibrillation
More than one third of patients with WPW have AF [18, 19]. There are several possible mechanisms for the high incidence of atrial fibrillation in WPW: 1) the electrophysiological function of the accessory pathway (AP); 2) the vulnerability of the atria themselves [20-23]; 3) the rapid stimulation of the atria during atrial fold tachycardia; 4) the effect of the AP on the atrial structure [24]; 5) the effect of autonomic nerves, among others. The effects of the first two of these on atrial vulnerability have received the most attention from investigators.
Numerous clinical studies have shown that the incidence of AF is indeed significantly reduced after successful ablation in patients with WPW [25, 26, 37], and, literature searches can be found a large number of studies on the effect of AP on atrial vulnerability [38-32]. On the other hand, however, a certain incidence of AF remains even after successful bypass ablation. This “residual” incidence suggests the existence of additional factors affecting atrial vulnerability to AF in patients with WPW, and the inherent atrial vulnerability in patients with WPW syndrome is one of the factors that has received the most attention.
Riccardi R [33] et al, found that the effective atrial expiration period in WPW patients with AF was shorter than that in WPW patients without AF, and that it tended to increase with increasing heart rate. However, this only indicates that WPW patients with atrial vulnerability are prone to AF and does not explain whether this vulnerability is caused by the bypass of the syndrome of WPW or by the vulnerability of the atria themselves.Hamada T [34] et al. compared indicators of atrial vulnerability (using conduction velocity delay as an indicator) in WPW patients who developed AF after AP ablation and in WPW patients who did not develop AF and found that In WPW patients with AF, ablation of the bypass did not alter the conduction velocity of the atria. In contrast, conduction velocities in WPW patients without postoperative AF were normalized by ablation of the AP. However, this does not explain whether the postoperative atrial vulnerability is inherent to the WPW syndrome. It is necessary to compare the post-ablation atrial vulnerability of all WPW patients with that of non-AF controls to conclude whether WPW patients have atrial vulnerability other than that affected by AP. However, no such study has been found in the national and international literature. Therefore, more studies are needed to investigate the origin of atrial vulnerability outside of AP in patients with WPW syndrome with concomitant atrial fibrillation.
2.2 Effect of Bruga syndrome on atrial vulnerability in AF.
Hiroshi Morita [35] et al. found that atrial conduction time was prolonged and the proportion of effective nonresponse in the atrial potential was increased in the presence of Bruga syndrome. Bruga syndrome can induce atrial fibrillation compared to controls. They concluded that Bruga syndrome can increase atrial vulnerability and does so mainly through conduction delay. More recently, a study by Kofune M [36] et al. came to a similar conclusion that patients with Bruga syndrome do have atrial conduction delays as well as an increase in the proportion of atrial potentials in which the nonreturn period is elevated, i.e., an increase in atrial vulnerability. However, studies on the mechanism of this increased atrial vulnerability in atrial fibrillation have not been reported and further studies are needed.
3. Some physiological studies on atrial vulnerability in atrial fibrillation
3.1 Effect of vagus nerve stimulation on atrial vulnerability in atrial fibrillation.
Stimulation of the vagus nerve trunk has been found to induce atrial fibrillation for a long time [37][38][39]. Electrical stimulation of the heart’s own ganglia induced atrial fibrillation, which was also discovered by Scherlag, B. J [40] and others in 2005. However, the study of vagus nerve stimulation on atrial vulnerability has only started to receive attention from researchers in the last few years.
Zhibing Lu [16] et al. compared the atrial vulnerability (length of the nonreturn period and WOV) in three groups of cases (atropine + propranolol) by performing ganglion (GP) ablation after 6 hours of electrical stimulation, 6 hours of electrical stimulation after ganglion ablation, and 6 hours of electrical stimulation followed by vagus nerve block (atropine + propranolol) and found that vagus nerve block was as effective as GP ablation in reducing atrial vulnerability. They further concluded that the autonomic nervous system plays an important role in the electrical remodeling of the atria under rapid stimulation, which effectively supports the “AF begets AF” theory of Wijffels and coworkers [41].
Yuan Zhang [42] et al. applied vagus nerve stem stimulation, representing external stimulation, and ganglion stimulation, representing intrinsic nerve stimulation, to both the right superior pulmonary vein and the right auricle, and compared the atrial vulnerability measured at the two sites. They found that vagal sensory stimulation had a more pronounced effect on the atrial vulnerability window than ganglion stimulation at the right ear (wider WOV), whereas at the right superior pulmonary vein, it was ganglion stimulation that produced a wider WOV. they then proposed that the heart is innervated by both intrinsic and extrinsic nerves, and that the two nerves have different distributions in different parts of the heart.
In a recent study, Xia Sheng [43], from the same laboratory as Zhibing Lu, investigated low-intensity vagal stimulation in the midst of rapid atrial pacing before it was performed. It was found that low-intensity vagus nerve stimulation improved both the vulnerability indexes and atrial nonresponse, and the mechanism of this improvement was probably through the inhibition of the cardiac intrinsic autonomic nervous system, thus finding a new breakthrough point for the prevention and treatment of atrial fibrillation.
Currently, RF ablation modalities with reported effects on atrial vulnerability include fracture potential ablation [44], pulmonary vein isolation ablation [45], Marshall’s ligament ablation [46], epicardial fat pad ablation [47], and circumferential pulmonary vein line ablation and left atrial line ablation [48]. And scientific studies have concluded that ablation is effective in reducing indicators of atrial vulnerability.
Kunihiro Nishida [49] compared circumferential pulmonary vein line ablation with left-sided line ablation and found that pulmonary vein line ablation inhibits the onset of AF (reduces vulnerability) by increasing the effective atrial expiration period, but does not eliminate the underlying mechanism that maintains the onset of AF; left atrial line ablation inhibits the onset of AF, but has no effect on atrial vulnerability. Nishida K [50] et al. compared circumferential pulmonary vein ablation with peripulmonary vein ganglion ablation and found that circumferential pulmonary vein ablation reduced atrial vulnerability in tachycardia-induced atrial fibrillation, but had no effect on the duration of atrial fibrillation episodes or the dominant frequency of atrial fibrillation episodes; peripulmonary vein ganglion ablation reduced the duration of episodes and the dominant frequency.
According to the observations of Yuan Zhang et al, different parts of the atria have different nerve distribution. Different surgical approaches must have different effects on atrial vulnerability. However, there is a lack of research on the comparison of different surgical approaches on atrial vulnerability. Currently, the main circumpulmonary vein ablation and ganglion ablation are focused on eliminating the intrinsic nerves of the heart and have little effect on the extrinsic nerves. Therefore, to further clarify the effect of RF ablation on atrial vulnerability and to reduce the incidence of AF after ablation, more large-scale studies on the innervation of extrinsic cardiac nerves are needed.
3.2 Effect of physiological indices such as pressure, dilation and volume on atrial fibrillation susceptibility.
Numerous studies have shown [51-54] that physiological indicators such as atrial pressure, atrial dilation and atrial volume play an important role in the development of atrial fibrillation and in the remodeling of the atria. The mechanisms may be related to ion channel’s as well as intracellular calcium overload [55, 56].
In a study by Michael Efremidis [57] et al. on intra-atrial pressure and atrial vulnerability (effective nonresponse dispersion as an indicator) in patients with atrial fibrillation, it was found that changes in intra-atrial pressure did not have a significant effect on atrial vulnerability. daniel M [58] et al. distinguished intra-atrial pressure from atrial dilatation in the effect of atrial vulnerability by clever physiological experiments. Their experimental design was based on the premise that intra-atrial pressure is not accompanied by structural changes in atrial dilatation when the pericardium is intact. Based on this premise, they studied atrial vulnerability in rabbit hearts with intact and dissected pericardium. It was shown that there was no tendency to shorten the effective atrial expiration at intra-atrial pressures of >20 mmH2O when the pericardium was intact; however, when the pericardium was excised, a significant shortening of the effective expiration, i.e., an increase in atrial vulnerability, could occur when intra-atrial pressures of >15 mmH2O were required only. From this they concluded that atrial electrophysiological remodeling due to atrial volume overload is caused by atrial dilation rather than by an increase in intra-atrial pressure.The effect of chronic atrial dilation on atrial vulnerability in atrial fibrillation was further investigated by Sander Verheule [59] et al. who created a dog model of mitral stenosis by means of an artificial catheter procedure, thereby producing the effect of chronic atrial dilation and measured the atrial vulnerability (conduction time and effective induction period) in this condition. They found that chronic atrial dilatation increased atrial vulnerability and prolonged the duration of atrial fibrillation episodes. Thus, we can see that both acute and chronic changes in atrial size have a significant impact on atrial vulnerability in AF.
On the basis of these studies, DRAGOS COZMA [60] et al. further investigated the effect of dilatation of the atria on atrial vulnerability. They found that the application of the traditional measurement of atrial diameter to represent atrial size has limitations on the measurement of actual atrial size. They proposed the idea of measuring the left atrial surface area (surface-LA, LAS) as well as the measurement of atrial shape. They also derived the LAS as a cut-off value for the inducibility of AF, i.e., LAS >25 cm2. 72% of the study participants with LAS >25 cm2 had irregularities in atrial shape (atrial septum to left lateral wall diameter greater than left lateral diameter).3 Only 28% of the patients in the CD70 age group had a higher frequency of susceptibility genes to induce AF (<40 age group: 40%, 39% in the 40-50 year old group, 37% in the 50-60 year old group, and 38% in the 60-70 year old group), and the effective atrial expiration period was also significantly longer in the older age group compared with the younger age group. Thus, they concluded that although advanced age is a risk factor for AF, patients in the advanced age group had a tendency to improve AF susceptibility indicators (e.g., prolonged effective atrial expiration period), which may account for the decreased induction of AF in the advanced age group by preperiodic stimulation, and thus implies that the mechanisms of AF occurrence are fundamentally different in the advanced age group and the younger age group. The high incidence of atrial fibrillation in the senior group may be caused by non-electrophysiological factors. Due to, the large number of cases enrolled in the current study and the coincidence with previous findings, the study has high credibility.
Yu Hui Yang [96] et al, studied the distribution of M-like receptors in the heart at different ages and the effect of parasympathetic nerves on AF vulnerability using rabbits aged 36-48 months (senescent group) to represent advanced age, and they used effective nonresponse dispersion and action potential time lengthening as indicators to evaluate vulnerability. They found that M-like receptors were differentially distributed in different locations in the heart, with the highest in the left atrial free wall. The senescent group had significantly higher M receptor expression than the mature group, and the inducibility of atrial fibrillation was higher in the senescent group than in the other groups. After application of M-like receptor blockers, effective nonresponse dispersion as well as action potential time lengthening were attenuated. Thus, they concluded that the age-related changes in the distribution of M-like receptors may explain the high incidence of atrial fibrillation in the older age group, which can be called “age-related vulnerability”.
Whether or not the neural remodeling can be explored in terms of differences in the mechanisms of atrial fibrillation in older and younger age groups requires further investigation, but this study provides an important clue. The different sensitivity to preterm stimulation-induced AF in advanced and advanced age can be investigated in terms of neurohumoral mechanisms, which in turn can provide newer targets for the treatment of advanced AF.
4. Some clinical diseases that have an impact on atrial vulnerability to atrial fibrillation
4.1 Diabetes mellitus
Numerous epidemiological studies have shown [97-99] that the prevalence of atrial fibrillation is increased in patients with diabetes mellitus, and therefore, diabetes mellitus must have an impact on the electrophysiological characteristics of the atria. The combination of diabetes mellitus and atrial vulnerability in atrial fibrillation has been studied only in recent years, and there is no unified conclusion on the mechanism by which diabetes mellitus increases atrial fibrillation vulnerability.
Oliveira M [100] et al. attempted to study the effect of diabetes on atrial vulnerability by using the effect of diabetes on the function of the autonomic nervous system as an entry point. They performed sympathetic and parasympathetic stimulation in diabetic mice and observed atrial electrophysiological alterations, respectively. They found that sympathetic nerve stimulation increased the induction of atrial fibrillation, shortened the effective atrial expiration period and increased the discrete atrial expiration period in diabetic mice, and no such changes were observed in the control group; stimulation of the parasympathetic nervous system also showed the same results. They thus concluded that neural remodeling may have an important effect on atrial vulnerability to atrial fibrillation in diabetic patients.
4.2 Heart valve disease
In developing countries, 40% of patients with mitral stenosis in rheumatic heart disease are associated with the development of atrial fibrillation [101].Bobby John [102] et al. studied atrial vulnerability to atrial fibrillation in patients with mitral stenosis, selecting P-wave duration, conduction velocity, and the length of the effective induction period as indicators of vulnerability. It was found that there was a prolongation of P-wave duration in both left and right atria and a reduction of conduction velocity in the right atrium, with no effect in terms of effective expiration period. In addition, Nitta T [103] et al. made similar findings in their study of the effect of heart valve disease on the vulnerability to atrial fibrillation. Their study, in terms of electrophysiological susceptibility, confirmed the high prevalence of atrial fibrillation in patients with mitral stenosis. However, neither has a further explanation for this phenomenon. As previously belonged, the altered size and shape of the atria caused by the mitral stenosis model may be the mechanism by which mitral valve disease increases the susceptibility to atrial fibrillation. There are no relevant reports on the function of neurohumoral explanation for this phenomenon, so exploring the mechanism of mitral stenosis for increased vulnerability to atrial fibrillation could be a new direction for future scientific work.
.3 Heart Failure
The view that “atrial fibrillation can induce heart failure and heart failure can also induce atrial fibrillation” has been recognized by most scholars. Studies on the mechanism of heart failure on the induction of AF have focused on the promotion of AF by myocardial fibrosis [104-106]. A large number of literature reports on the role of RAAS-blocked antifibrosis, transforming growth factor β (TGF-β) in myocardial fibrosis and the effect of C-reactive protein on myocardial fibrosis can be seen, but few reports have been published nationally and internationally that actually investigate specific indicators of vulnerability to AF in heart failure.
Power JM [107] et al. (full text not seen) studied the effective atrial expiration period in the context of heart failure as well as the atrial conduction time, confirming from an electrophysiological point of view the increased vulnerability to atrial fibrillation present in heart failure.
Since matrix metalloproteinases are involved in the degradation of the extracellular matrix, they have an important role in the fibrotic process of the myocardium GORDON W. MOE, MD [108] et al. investigated the effect of matrix metalloproteinase (MMP) inhibitors on the vulnerability to atrial fibrillation in heart failure. It was concluded that matrix metalloproteinases could reduce atrial fibrillation vulnerability and decrease the maintainability of atrial fibrillation through antifibrotic mechanisms.
In addition to the above literature reports, no literature reports have been seen in China or abroad that investigated the relationship between specific indicators of atrial vulnerability to heart failure and atrial fibrillation. The mechanism of heart failure promoting atrial fibrillation is currently a hot topic of research, and scholars have studied it from various perspectives. Whether there is a need for in-depth research in this area needs to be evaluated.
CONCLUSION: Most investigators currently tend to define atrial vulnerability in atrial fibrillation as the ease of inducing atrial fibrillation when additional stimuli are applied to the atria. The dispersion of atrial expiration (dEPR) and the decreased atrial conduction velocity are widely used indicators to evaluate the magnitude of atrial vulnerability in atrial fibrillation. The dispersion of the effective in-phase and the reduced conduction velocity are electrophysiological markers of increased atrial vulnerability in atrial fibrillation, and atrial fibrillation is easily induced under these two electrophysiological conditions. Factors that can influence atrial vulnerability in AF include common arrhythmias, vagal stimulation, physiological indicators such as atrial size and tone, ion channel gene polymorphisms, function of the gap junctions, clinical disease, and age. A great deal of work is needed to widely apply “atrial vulnerability” to cardiac electrophysiological examinations and to guide the treatment and prognosis of atrial fibrillation.