Conduction Slowing

Several mechanisms of atrial fibrillation (AF) have been described in experimental models. For a long time, it was assumed, primarily based on the work of Moe and Abildskov (1) and Allessie et al. (2), that AF in patients was due to random propagation of multiple wandering wavelets over the atria. A breakthrough in AF occurred when Haissaguerre et al. (3) observed that in patients with paroxysmal AF, the sources triggering or sustaining AF originated in the pulmonary veins and were successfully eliminated by ablation. However, in patients with persistent AF, isolating the pulmonary veins alone yielded suboptimal outcomes, suggesting that the sources sustaining AF were mostly present outside these veins. Subsequently, endocardial mapping studies using a proprietary AF algorithm identified 1 or more rotors sustaining AF, which were successfully ablated (4). Although these early studies showed a lot of promise, the results could not be consistently reproduced (5). In patients with persistent AF during open heart surgery, our group reported (using high-resolution epicardial mapping studies) that the wave fronts emanating from focal sources and breakthrough sites maintained AF, but transient rotational wave fronts were rarely seen (6). Other high-resolution epicardial mapping studies by de Groot et al. (7) proposed that AF was sustained by multiple wavelets propagating through the dissociated endocardial and epicardial layers (double-layer hypothesis) of the atrial wall with no evidence for stable rotors or foci.

Although the mechanism(s) sustaining AF remains controversial, the general consensus is that the mechanism maintaining AF likely involves 1 or more foci and/or various types of re-entry. Re-entry was first defined by Mines (8) as an electrical impulse that reactivates an area of previously activated myocardial tissue that is no longer refractory, resulting in a circus movement of activation. For re-entry to occur and sustain, the prerequisites are anatomical and/or functional barriers, unidirectional block, and an area of slow conduction within the re-entrant path. Therefore, a reduction in conduction velocity of myocardial tissue is critical for the creation of a substrate for re-entry (9). Conduction velocity is determined by ion channels, physical properties of cardiac myocytes, and their interconnections. These determinants are altered by a wide range of pathophysiological conditions, such as heart failure, hypertrophy, ischemia, fibrotic changes, and specific antiarrhythmic medications. In contrast to re-entrant arrhythmias, abnormalities in conduction are unlikely to directly play a role in the genesis of focal arrhythmias due to triggered rhythms (early and delayed after depolarization) and abnormal automaticity.

In an elegant work published in this issue of JACC: Clinical Electrophysiology, the study by Heida et al. (10) evaluated conduction times during sinus rhythm for identifying the arrhythmogenic substrate underlying AF and the causal relation between underlying heart disease and AF. The authors hypothesized that structural and electrical remodeled atria contain severe conduction disorders during sinus rhythm. The study aimed to distinguish conduction abnormalities in patients with ischemic, valvular, and congenital heart disease and to determine the influence of AF on conduction abnormalities across the epicardial atrial surface in these patients. Conduction times were measured from the electrodes by subtracting each electrode’s local activation time from the adjacent electrodes. Conduction times <4 ms were considered normal. The frequency of conduction times was defined as median conduction times ≥4 ms, and the magnitude of conduction times was defined as the size of inter-electrode differences in milliseconds. In all 3 underlying heart disease types, the conduction was abnormal, but there was no difference in the frequency and severity of conduction between the 3 groups. However, conduction abnormality in the Bachmann’s bundle (BB) was more severe in patients with a history of AF. The authors concluded that underlying heart disease has no impact on the frequency and severity of conduction abnormalities, and AF episodes were associated with severe conduction abnormality in the BB.

It is an enormous undertaking to perform high-density mapping in 447 patients undergoing various open heart surgeries. Very few groups have the expertise and technology to perform such a study. Local conduction times were used in this study (10) as a surrogate for conduction velocity because this factor can be determined only if the direction of the wave front is known. Conduction times were measured in all patients only during sinus rhythm and not during pacing at different rates or from different sites (change in wave front direction) or during premature atrial beats, all of which could have enhanced abnormalities in conduction. Therefore, conduction times could be an underestimate, which could affect the “normal” cutoff value used and possibly could have affected the findings of the study. A most important limitation of the study is that the conduction abnormalities could be due to AF alone. It has been shown in experimental models of AF that rapid atrial rates during AF by itself can cause electrical and structural remodeling in the form of fibrosis, cell-to-cell uncoupling, and atrial enlargement, all of which can lead to conduction abnormalities. These changes can be present for months after maintaining sinus rhythm (11). Therefore, conduction abnormalities could all be due to atrial remodeling secondary to AF, and thereby likely a consequence rather than a cause of AF.

Another significant limitation of the study (9) is the use of antiarrhythmic medications, especially the ones with sodium channel–blocking effects, such as flecainide, propafenone, and amiodarone, which can all slow conduction. Approximately one-quarter of the patients with prior AF were on these medications. An interesting finding of the study is that the conduction abnormalities in the BB were more severe in patients with a history of AF. If conduction abnormality is causal in AF, it would suggest re-entrant arrhythmias to be located mostly in the BB, for which there has been no evidence thus far. This study was not designed to determine the mechanism(s) behind the abnormalities in conduction. However, correlating the areas of abnormal conduction of the atria with voltage maps and/or with cardiac magnetic resonance information may provide insights regarding the mechanism underlying conduction abnormalities.

The study by Heida et al. (10) described an association between abnormalities in conduction and AF. The relevance of the study is significant and an important first step in understanding the arrhythmogenic substrate for AF. The next step is to design a study that addresses these limitations, 1 that can convincingly show that conduction abnormality is an important causative factor in the mechanism of AF, and that could be a challenge.