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Prevention of ventricular fibrillation through de‐networking of the Purkinje system

Abstract Introduction Sudden cardiac death from ventricular fibrillation (VF) remains a major health problem worldwide. Currently, there are limited treatment options available to patients who suffer from episodes of VF. Because Purkinje fibers have been implicated as a source of initiation of VF, we are presenting the first paper of a series highlighting the promising results of substrate modulation through “De‐Networking” of the Purkinje system preventing VF in patients without an alternative ablation strategy. Methods and Results We studied 10 consecutive patients (two female) all but one implanted with an ICD with documented VF or fast polymorphic Ventricular tachycardia (VT) (five patients without history of structural heart disease, two with ischemic cardiomyopathy, one with hypertrophic obstructive cardiomyopathy, one with dilated cardiomyopathy, and one with aortic valve disease). After 3D electroanatomical mapping, the left bundle branch (LBB) and left ventricular Purkinje potentials were annotated creating a virtual triangle with the apex formed by the distal LBB and the base by the most distal Purkinje potentials. Linear radiofrequency catheter ablation at the base of the triangle was performed, followed by ablation within the virtual triangle sparing the LBB and both fascicles (“de‐networking”). All patients were treated without complications. During 1‐year follow‐up, only 2/10(20%) patients experienced recurrence in form of a single episode of polymorphic VT/VF. Conclusion Catheter ablation of VF through “de‐networking” of the Purkinje system in patients without overt arrhythmia substrate or trigger appears safe and effective and will require further study in a larger patient cohort.


INTRODUCTION
Ventricular fibrillation (VF) is a fatal cardiac arrhythmia in patients with cardiac and noncardiac diseases. 1,2 Currently, there are limited causal treatment options available to patients who suffer an episode of VF. 3,4 Purkinje fibers (PF) have been implicated as a source for VF initiation and a number of studies have shown their potential role in some cases of idiopathic VF. 5 network can effectively prevent recurrent VF. [7][8][9][10][11] The current case series is the first to describe substrate ablation of VF through "denetworking" of the Purkinje system in patients without overt arrhythmia substrate or VF trigger.

METHODS AND RESULTS
The study included 10   In these two patients, catheter ablation of residual scar channels and late potentials was performed before Purkinje network substrate modulation.
It should be noted, that in all cases presented in this study, we were able to map LBB-potentials and at least 3-4 distal Purkinje potentials.
In cases where the Purkinje fiber potentials are not recognized, ventricular pacing with extra stimuli or pacing with high and low output should be considered.
After detailed mapping of the LV, the multipolar high-density map-

Clinical findings
Clinical outcome of Purkinje "de-networking" in the first 10 patients is promising. We used this technique in patients without overt trigger or arrhythmia substrate accounting for fast VT or VF. It seems to be effective in patients with and without structural heart disease.
The development of this method was based on clinical observations in concordance to existing anatomical, experimental, and preliminary clinical data. In the very first patient from the group presented in this article, we found no endocardial scar or spontaneous PVCs during the mapping procedure. The patient had frequent VT/VF runs, which were induced mechanically or during programmed ventricular stimulation. Using the PentaRay mapping catheter (Figure 2), rapid PF activation was observed which was isolated from ventricular activation and demonstrated a "figure-of-eight" (when transferred to an anatomical surface) irregular propagation pattern through the Purkinje network.
The faster the activation, the faster the tachycardia and, once the PF activation disappeared, the tachycardia slowed and terminated. This finding was reproducible several times and inspired us to modulate the PF network. The result was distinctly positive: no PF activation was recorded after ablation and no VT/VF induction was possible.

Anatomy of the left ventricular conduction system
Knowledge of the anatomy and physiology of the conduction system and the myocardium can help to develop potentially useful therapies for some forms of cardiac arrhythmia, particularly VF.

Ventricular fibrillation-experimental data
Ventricular fibrillation occurs as a primary or secondary event and is a terminal cardiac dysrhythmia in patients with cardiac and noncardiac diseases. 1, 2 Purkinje fibers have been implicated as a source for VF initiation. A number of studies have shown that they may play a role in some cases of idiopathic VF. 5,6 Studies using a canine heart model showed that the PF system may play an integral role in the maintenance of long-duration VF (LDVF). 23 Although the refractory period for Purkinje fibers in sinus rhythm is longer than those for myocardial cells. PF accommodate so that their refractory period shortens more than myocardial cells when activated rapidly. 24 The rapid activation during the LDVF is because the PF are more resistant to the global ischemia caused by the lack of perfusion during VF compared to working myocardial cells. [25][26][27][28][29] This may be due to the increased metabolic load required for the contractions of the myocardial cells and to the increased glycogen stored in the PF. 30,31 Compared with other mammals-in dogs, as well as in humans, the PF are near the endocardium so that they are less ischemic than the working myocardium because of the diffusion of oxygen from the nearby LV cavity. 32 All of these findings suggest that the Purkinje system is important for the maintenance of VF. As such, catheter ablation of PF is a promising approach and requires further study for the treatment of VF.
Currently, there is no cure for VF, with only limited treatment options available for patients. Thus, sudden cardiac death from VF remains a major health problem worldwide. 3,4 In select cases, this lethal arrhythmia may be amenable to radiofrequency catheter ablation targeting VF triggers such as PVCs emanating from the Purkinje tissue. [7][8][9][10][11] This current proof-of-concept paper is the first to describe substrate ablation of VF in patients without an overt VF trigger by means of "de-networking" the Purkinje system of the human heart. The Purkinje network that we targeted for substrate modification in this series does not include the moderator band, right ventricular exits, or the so-called "dead-end tracts", which are seen in addition to the right and left bundle branch, fading out on the crest of the muscular ventricular septum. Their potential role as a substrate for an arrhythmogenesis role was recently discussed. 36,37 As such, our method describes a partial Purkinje de-networking, which provides modest but significant results. On the other hand, the LV septal section of the Purkinje network is the largest section of the total network. It is always located in the same place, and is invariably shaped like a triangle. 38 Therefore, the mapping and creation of a virtual triangle is easy-even if we have a minimal number of targets (eg, LBB potential or Purkinje potential).
Moreover, according to some experimental data from the animal during the next stage of our investigation, we feel it would be prudent to clarify whether or not the additional mapping and ablation of the right-sided exits and "dead-end tracts" increase the success rates of the treatment.
In reflection, it is also interesting that the role of the subendocardial Purkinje network in triggering torsade de pointes has been confirmed in vivo in long QT syndrome. 43 The ablation strategy we have presented might also be considered in patients with long QT syndrome and intractable episodes of Torsade-de-Pointes tachycardia (TdP).

CONCLUSION
Substrate modulation in VF and fast polymorphic VT through "denetworking" of the Purkinje system is feasible and appears safe and highly effective in patients without overt trigger or arrhythmia substrate. The presented ablation technique is relatively easy to perform and contains no increased complication risk and might be a "rescue approach" in patients with otherwise untreatable fast VT or VF.

STUDY LIMITATIONS
While the number of patients reported is small, this report can function as a preliminary proof-of-concept that can potentially be further explored via a multi-centered approach, or at least provide fodder for further clinical reports.
In this study, we did not provide a quantitative assessment of the thresholds in the induction of ventricular fibrillation and ventricular defibrillation before and after ablation. This topic should be addressed in the next series.
Strong measures were not taken to evaluate dyssynchrony (between endo-and epicardial sides) before and after ablation in this case series. During the next step of this process, we plan to use the coronary sinus branches to look at the simultaneous differences between the epicardium and endocardium during VT/VF, both before and after ablation.