Focal atrial tachycardia : Insights concerning the arrhythmogenic substrate based on analysis of intracardiac electrograms and inflammatory markers

Abstract: Background: Focal atrial tachycardias are tachycardias characterized by a radial spread of activation from a discrete area of the atrial myocardium. They account for 10-15% of supraventricular tachycardias and are generally poorly responsive to pharmacological treatment. The pathophysiologic substrate of these arrhythmias remains poorly understood. Computational studies suggest that a certain degree of intercellular uncoupling and anisotropy are important prerequisites for the development of focal arrhythmias. The anisotropy and intercellular uncoupling could promote focal arrhythmias by minimizing the suppressive effect of the surrounding atrial muscle on the pacemaking process in the focus. This hypothesis would be in agreement with the fact that fractionated electrograms, a marker of anisotropy and reduced intercellular coupling, are often recorded at the site of earliest activated site. Reduced intercellular coupling could be induced by factors enhancing the amount of intracardiac connective tissue, such as advancing age or cardiac disease states. Indeed, focal inflammatory processes have been reported in atrial specimens resected from patients with focal tachycardia undergoing arrhythmia surgery.Methods: In a group of patients with paroxysmal and permanent atrial fibrillation we sought to assess whether there is a link between inflammation and the occurrence of atrial arrhythmia. We therefore analyzed different inflammatory markers (C-reactive protein and interleukin-6 and 8) in the systemic and pulmonary circulation as well as in the heart in these patients. In addition, we assessed the extent of intercellular uncoupling in the vicinity of tachycardia origin in patients with focal atrial tachycardia. We also assessed the impact of electrogram fractionation on the method of activation time determination, by comparing different methods for estimating activation time with regard to the appearance of the resultant activation maps and the location of the foci. We also assessed the observer variability in the estimation of activation time during mapping of these tachycardias.Results: There was no evidence of elevated circulatory levels of inflammatory markers in patients with paroxysmal atrial fibrillation. However, patients with permanent atrial fibrillation had increased levels of inflammatory markers (interleukin-8) in the systemic circulation but not in the pulmonary circulation or in the heart. In patients with focal atrial tachycardia, a higher degree of electrogram fractionation existed in the region surrounding the earliest activation site and activated within the first 15 ms as compared with the remaining atrium. Moreover, within this region, from the periphery towards the earliest activated site, there was a gradual increase in electrogram fractionation as well as a gradual decrease in the peak-to-peak voltage. When comparing different methods for estimating local activation time we found that different methods can generate activation maps with different appearances and foci with different locations. However, regardless of the method of activation time determination, the foci tend to cluster within relatively large areas of low-amplitude fractionated electrograms. In addition we found significant observer variability in the estimation of the local activation time.Conclusion: Patients with paroxysmal atrial fibrillation (and probably focal atrial tachycardia) do not have elevated levels of inflammatory markers. The increased levels of interleukin-8 in the systemic circulation suggest a link between long-lasting arrhythmia and inflammation. A relatively wide area of increased electrogram fractionation exists around the site of origin of focal atrial tachycardia. These findings suggest a sizeable atrial region with particular electrophysiological proprieties and raise the possibility of an anatomical substrate of the tachycardia. Increased electrogram fractionation can impact the process of activation determination, as suggested by the fact that different methods compute foci with different locations. In addition, there is significant observer variability in the estimation of local activation time in these patient.