Counterpoint: Ablation in long QT syndrome

Long QT syndrome (LQTS) is the most common and most well established genetic arrhythmia syndrome/primary electrical disease, caused by pathogenic disease–causative variants in genes that encode either the critical alpha subunits or channel interacting proteins of the heart’s ion channels that are directly or indirectly involved in the repolarization process.1Schwartz P.J. Ackerman M.J. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.Eur Heart J. 2013; 34: 3109-3116Crossref PubMed Scopus (252) Google Scholar,2Wilde A.A.M. Amin A.S. Postema P.G. Diagnosis, management and therapeutic strategies for congenital long QT syndrome.Heart. 2022; 108: 332-338Crossref PubMed Scopus (58) Google Scholar The diagnosis of LQTS relies on prolongation of the heart rate corrected QT (QTc) interval, which together with a number of other electrocardiographic parameters and elements obtained by history taking (eg, symptoms and family history) form the LQTS probability score (also known as the “Schwartz score”). A score of ≥3.5 points indicates a high probability of LQTS.1Schwartz P.J. Ackerman M.J. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.Eur Heart J. 2013; 34: 3109-3116Crossref PubMed Scopus (252) Google Scholar,2Wilde A.A.M. Amin A.S. Postema P.G. Diagnosis, management and therapeutic strategies for congenital long QT syndrome.Heart. 2022; 108: 332-338Crossref PubMed Scopus (58) Google Scholar Patients with LQTS suffer from cardiac arrhythmias, typically of the torsades de pointes (TdP) type, an arrhythmias with a typical initiation (see below) and rate around 220 beats/min, which give rise to arrhythmic/cardiogenic syncope but can also culminate in either sudden cardiac arrest or even tragically sudden cardiac death. Most LQTS-triggered cardiac events seem to occur in the pediatric population; data from the largest LQTS registry reveal a percentage of 50%–67% of first cardiac events (syncope, sudden cardiac arrest and sudden cardiac death) to occur in the first 20 years of life in female and male patients, respectively.3Goldenberg I. Moss A.J. The long QT syndrome.J Am Coll Cardiol. 2008; 51: 2291-2300Crossref PubMed Scopus (403) Google Scholar These statistics bear a genotype-specific characteristic in the sense that specifically in LQTS type 1 (LQT1), most events occur in early childhood. Finally, genotype-specific triggers for arrhythmias are pertinent,4Schwartz P.J. Priori S.G. Spazzolini C. et al.Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.Circulation. 2001; 103: 89-95Crossref PubMed Scopus (1513) Google Scholar with the most common genetic subtype (LQT1) often presenting during exercise including swimming in the undiagnosed and therefore untreated state while LQT2 is often triggered by auditory stimuli. Therapeutic options rely heavily on nonselective β-blockers (preferentially nadolol or propranolol), in selected cases sodium channel blockers (ie, mexiletine) and less frequent invasive procedures such as surgical interruption of the adrenergic activation of the ventricular myocardium with left cardiac sympathetic denervation or device therapy with an implantable cardioverter-defibrillator (ICD).1Schwartz P.J. Ackerman M.J. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.Eur Heart J. 2013; 34: 3109-3116Crossref PubMed Scopus (252) Google Scholar,2Wilde A.A.M. Amin A.S. Postema P.G. Diagnosis, management and therapeutic strategies for congenital long QT syndrome.Heart. 2022; 108: 332-338Crossref PubMed Scopus (58) Google Scholar Over many years, the advancement of knowledge in the LQTS domain has been enormous with a documented change from general treatment for all patients with LQTS to genotype-guided/patient-tailored therapies.1Schwartz P.J. Ackerman M.J. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.Eur Heart J. 2013; 34: 3109-3116Crossref PubMed Scopus (252) Google Scholar,2Wilde A.A.M. Amin A.S. Postema P.G. Diagnosis, management and therapeutic strategies for congenital long QT syndrome.Heart. 2022; 108: 332-338Crossref PubMed Scopus (58) Google Scholar This development has led to more accurate risk stratification, genotype-specific treatment modalities, and significantly reduced mortality.5Rohatgi R.K. Sugrue A. Bos J.M. et al.Contemporary outcomes in patients with long QT syndrome.J Am Coll Cardiol. 2017; 70: 453-462Crossref PubMed Scopus (73) Google Scholar Indeed, 5-year mortality has dropped from 0.69% in 2000 to 0.05% in the most recent single-center series from Mayo Clinic,5Rohatgi R.K. Sugrue A. Bos J.M. et al.Contemporary outcomes in patients with long QT syndrome.J Am Coll Cardiol. 2017; 70: 453-462Crossref PubMed Scopus (73) Google Scholar which has used up to 20 distinct treatment configurations.6Neves R, Bains S, Bos JM, MacIntyre C, Giudicessi JR, Ackerman MJ. Precision therapy in congenital long QT syndrome [published online ahead of print June 27, 2022]. Trends Cardiovasc Med. https://doi.org/10.1016/j.tcm.2022.06.006.Google Scholar The initiation of ventricular arrhythmias in LQTS also seems to have a genotype-specific character.7Tan H.L. Bardai A. Shimizu W. et al.Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications.Circulation. 2006; 114: 2096-2103Crossref PubMed Scopus (113) Google Scholar In patients with LQT2, arrhythmias most often occur after a pause, while in patients with LQT1, their ventricular arrhythmias are tachycardia dependent.7Tan H.L. Bardai A. Shimizu W. et al.Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications.Circulation. 2006; 114: 2096-2103Crossref PubMed Scopus (113) Google Scholar In LQT3, arrhythmias typically occur during bradycardia. Based on these initiation sequences, the most likely arrhythmogenic mechanism for the initiation of TdP arrhythmias is early afterdepolarizations originating from prolonged action potentials, explaining the long to very long coupling interval of the initiating beat. Whether the arrhythmias originate from the specialized conduction system is an ongoing debate,8Wilde A.A.M. Garan H. Boyden P. Role of the Purkinje system in heritable arrhythmias.Heart Rhythm. 2019; 16: 1121-1126Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar but it has been at the basis of initial endocardial catheter ablation attempts in patients with therapy-resistant LQTS with variable success.9Haissaguerre M. Extramiana F. Hocini M. et al.Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.Circulation. 2003; 108: 925-928Crossref PubMed Scopus (448) Google Scholar Now fast forward 2 decades, Pappone and his group recently published the result of epicardial catheter ablation in 11 patients reported to have LQTS (mean age 44 ± 7.8 years), all of whom experienced several appropriate ICD interventions before the procedure (range 2–8; interquartile range 3–6),10Pappone C. Ciconte G. Anastasia L. et al.Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.Europace. 2023; 25: 948-955Crossref PubMed Scopus (10) Google Scholar and elaborates on this approach in this issue of Heart Rhythm Journal.11Pappone C. Ciconte G. Vicedomini G. Anastasia L. Santinelli V. Epicardial arrhtyhmogenic substrate in long-QT syndrome.Heart Rhythm. 2023; XX (XX-XX)Google Scholar In these 11 patients, the average QTc interval was 500 ± 30.2 ms and all major genotypes were represented. A common finding in these 11 patients was the presence of abnormal electrical substrate (low-voltage, fragmented and prolonged electrograms) in areas of the right ventricle (right ventricular [RV] anterior and RV inferolateral). Removal of this substrate (average size 15 cm2) by radiofrequency (RF) ablation resulted in an arrhythmia-free follow-up, of just less than 1 year. Interestingly, the QTc interval shortened significantly in half of the patients.11Pappone C. Ciconte G. Vicedomini G. Anastasia L. Santinelli V. Epicardial arrhtyhmogenic substrate in long-QT syndrome.Heart Rhythm. 2023; XX (XX-XX)Google Scholar The authors are aware of several limitations, the most important one probably being the absence of “normal values” of epicardial electrical signals. Are the recorded “abnormal signals” really abnormal or the result of layers with different fiber orientation? Shortening of the QTc interval in itself is not a proof that the LQTS substrate is addressed and is likely the result of exclusion of the myocardium that depolarizes last. Indeed, similar QTc shortening is observed after epicardial ablation in Brugada syndrome.11Pappone C. Ciconte G. Vicedomini G. Anastasia L. Santinelli V. Epicardial arrhtyhmogenic substrate in long-QT syndrome.Heart Rhythm. 2023; XX (XX-XX)Google Scholar As indicated, the vast majority of patients with LQTS experience their LQTS-triggered cardiac events at a much younger age than these 11 patients, and with standard contemporary guideline-directed medical therapies (drugs, denervation, and devices), the current management challenge is seldom treatment-resistant LQTS but instead suboptimal quality of life from our current therapies.12Martinez K. Bains S. Giudicessi J.R. Bos J.M. Neves R. Ackerman M.J. Spectrum and prevalence of side effects and complications with guideline-directed therapies for congenital long QT syndrome.Heart Rhythm. 2022; 19: 1666-1672Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar This begs the question as to who are these 11 patients and what is the current and correct diagnosis. Is it still isolated LQTS presenting in the 40s that is surprisingly refractory to contemporary therapy or could these patients be LQTS positive? In other words, are their arrhythmias stemming from their LQTS substrate or has a “second hit” emerged that has caused the proposed microstructural abnormalities (eg, local inflammation)? The onset of the arrhythmia and the arrhythmia rate may provide clues, but the authors are not very generous with providing details about the documented arrhythmias. In the original article, only 1 recording is presented, and in the additional article, 4 are presented in the supplement (all 4 cases were also presented during the live case demonstration in a meeting in Milan). Unfortunately, for 3 of 5, the initiation of the arrhythmia, which is critical for the discrimination whether the arrhythmia is LQTS-related or not, lacks. In the first additional case, the coupling interval of the first extra systole is 343 ms, which is not compatible with a pronounced prolongation of the QT interval and the arrhythmia occurred during a resting heart rate of 65–70 beats/min, which is very unusual for a patient with LQT1. In the third additional case, it is 468 (which could be related). The arrhythmias are all (but potentially 1) not of the TdP type, because the rate is much higher than expected for a true TdP arrhythmia. Instead, these arrhythmias should be qualified as polymorphic ventricular tachycardia and that is the type of arrhythmia typically associated with a structural substrate. Having said that, the possibility that (primary) ion channel disease leads to structural abnormalities, although this remains to be proven for LQTS, is a realistic thought. Brugada syndrome, where a minority of cases (20%) are associated with loss-of-sodium channel function, is a clear example.13Behr E.R. Ben-Haim Y. Ackerman M.J. Krahn A.D. Wilde A.A.M. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?.Eur Heart J. 2021; 42: 1073-1081Crossref PubMed Scopus (48) Google Scholar It is therefore well conceivable that aberrant ion channel function, also when it leads to action potential prolongation, can lead to aberrant calcium homeostasis with, over many years, subclinical/microscopic structural changes as a consequence. Why that would particularly affect the RV wall is not explained yet. Another possibility that cannot be excluded is that any structural substrate with associated benign ventricular ectopy may more easily deteriorate in malignant ventricular arrhythmias in patients with an electrical unstable condition such as LQTS. In both cases, RF ablation of the substrate is an option with potential. However, as we have parroted repeatedly that “most patients with LQTS do not need and should not receive an ICD,” it is worth declaring that even more patients with LQTS do not need and should not receive RF ablation until and unless more substantial and convincing evidence emerges. Finally, a word on semantics. The epicardium is promoted as the “virtual fifth chamber of the heart” because of its distinct electrophysiological characteristics.10Pappone C. Ciconte G. Anastasia L. et al.Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.Europace. 2023; 25: 948-955Crossref PubMed Scopus (10) Google Scholar,11Pappone C. Ciconte G. Vicedomini G. Anastasia L. Santinelli V. Epicardial arrhtyhmogenic substrate in long-QT syndrome.Heart Rhythm. 2023; XX (XX-XX)Google Scholar In echocardiography, the 5-chamber view includes, next to the 4 cardiac chambers, the aorta ascendens as the “fifth chamber.” We will only confuse the field by introducing an electrophysiologically distinct fifth cardiac chamber. The fact that the epicardium has distinct electrophysiological characteristics is a poor argument for renaming, as other cardiac structures (ie, the sinus and atrioventricular nodes and the specialized conduction system) also have distinct electrophysiological characteristics and fortunately have not gone down this path. The authors have no funding sources to disclose.