Response by Rivarola and Scanavacca to Letter Regarding Article, "Targets and End Points in Cardiac Autonomic Denervation Procedures".

In Response: We would like to thank Drs Pachón-Mateos and Pachón-Mateos for their interesting remarks on the article, Targets and End Points in Cardiac Autonomic Denervation Procedures and Editorial, Selective Modulation of the Cardiac Autonomic Nervous System: A New Strategy for Treatment of Cardioinhibitory Syncope. In his letter, Dr Pachón-Mateos raises important questions about the mapping technique and denervation end points and proposes that 1. cardioneuroablation must be validated by extracardiac vagal stimulation; 2. preablation atropine test must be used to identify responders; 3. specific mapping technique should be performed to guide ablation; 4. extensive ablation, including pulmonary veins antra, is needed. In our opinion, the clinical limitations of the cardiac denervation procedure lies in the complexity of the intrinsic autonomic system—a structure composed by a dense network of sympathetic and parasympathetic fibers that ultimately innervates the myocite. This system cannot be completely lateralized in the sense that almost all epicardial ganglia have dual innervation. Therefore, the purpose of the procedure must be a titrated ablation with the net result of a vagal attenuation. It might be difficult, though, to find absolute end points. Extracardiac vagal stimulation is an insightful technique for denervation confirmation. However, we must keep in mind that the extrinsic autonomic system has dual innervation as well, and parasympathetic efferents unrelated to the vagus nerve also project to the heart through the sympathetic thoracic chain. Parasympathetic fibers are present in almost every thoracic sympathetic nerve, with the exception being the purely sympathetic stellate cardiac nerve. Hence, while simple, extracardiac vagal stimulation might have lower sensitivity and specificity than expected. Again, the complexity of the system imposes itself as an obstacle in the search for a perfect end point. Possibly, a randomized study comparing all available techniques for denervation confirmation might demonstrate which one is the most appropriate strategy. We agree that a preablation atropine test might be helpful in identifying responders. Still, we were able to observe a shortening of R–R and HV intervals immediately after ablation also in nonresponders and that raises the question: is it possible to consistently anticipate a poor respose when we are dealing with such complex patterns of divisions and overlaps of innervation supply? Ganglionated plexi location is another fundamental issue. Indeed, ganglionated plexis are not always in the same anatomic location, and there is significant variation in their distribution. In our article, we discuss the available mapping strategies and their limitations, and as no consensus yet exists on the best strategy, it is our opinion that extensive ablation must be avoided in such a young and otherwise healthy population. While a pure anatomic (restricted to the interatrial septum) ablation may present limited success rates, more aggressive strategies might carry excessive risks, such as proarrhythmia, esophagus thermal injury, or phrenic nerve paralysis. In conclusion, we think that adopting a restricted anatomic (septal) approach and immediate electrophysiologic end points might be enough to treat most patients. Atropine test and extracardiac vagal stimulation could provide significant information, although the complexity of the cardiac autonomic interface prevents us from achieving an ultimate technique.