Reply to – “Cardiopulmonary Exercise Testing-Guided Beta-Blocker Dosing in Long QT syndrome: Genotype, Methodology, and Adherence Concerns”Iqbal El Assaad, MD;Cleveland Clinic Children’s Hospital - Pediatric Cardiology9500 Euclid Avenue , Cleveland, Ohio 44195United Stateseli5@ccf.orgPeter F. Aziz, MDCleveland Clinic Children’s Hospital - Pediatric CardiologyCleveland, OhioUnited Statesazizp@ccf.orgDear Editor,We appreciate the thoughtful commentary and concerns raised by Kemar et al. and thank the authors for highlighting important limitations – many of which we discussed in our manuscript. That said, perhaps a few key points deserve further emphasis to ensure our central message remains clear.Our manuscript portrays the real-world experience of managing patients with long QT syndrome (LQTS) as it specifically pertains to beta-blocker therapy tolerance. While we always strive to follow guidelines recommending maximal dosing, the reality in clinical practice is that not all patients can tolerate this approach. As demonstrated in our study, at least one-third of patients experienced significant side effects that precluded the use of maximal therapy. We believe that some beta-blocker therapy is better than none, particularly when the alternative is non-adherence due to intolerable side effects.This practical dilemma is one clinicians often face: how to provide arrhythmic protection while preserving quality of life? For patients who are intolerant of maximal therapy, we advocate for anindividualized approach – utilizing the exercise stress test (EST) to objectively assess chronotropic suppression and determine whether the patient is deriving measurable benefit from beta-blocker therapy. Currently, EST is the only tool we have to quantify therapeutic effect in this context. We could not agree more with the authors’ conclusion: “Guideline-directed maximal beta-blocker therapy remains the standard for LQTS patients, with individualized approaches for those intolerant to standard therapy, supervised by specialized experts .” In fact, our manuscript states:“It is important to note that submaximal dosing should not be used as a universal approach, as there are still patients who experience breakthrough events despite being on submaximal therapy. Therefore, it is crucial that this approach is implemented intentionally and under the guidance of an experienced inherited arrhythmia specialist after careful risk stratification of the patient.”In our clinical practice, we aim to find the optimal balance – a beta blocker dose that provides adequate chronotropic suppression while minimizing side effects that could compromise adherence. It is also worth mentioning that we also routinely discuss the role of left cardiac sympathetic denervation (LCSD) therapy in patients who are intolerant of beta-blocker therapy, especially those who are considered high risk (i.e. males with LQTS1 with QTc> 550 ms, post pubertal females with LQTS2 with QTc>500 ms). However, it should be noted that LCSD comes with its own set of complications.1 Again, when options are limited, we believe that objective assessment – though imperfect – is preferable to nothing. The proposed approach is not intended to replace maximal therapy, but to optimize care for those who cannot tolerate it.Regarding the definition of adequate beta blockade, we acknowledge the concern that our 15-20% heart rate blunting threshold during maximal exercise may appear arbitrary. However, we found evidence to guide this decision in the literature. We followed Dr. Krahn’s practical approach, as outlined in his review article on congenital LQTS, where he describes using this threshold to demonstrate adequate effect.2This is also consistent with our clinical practice.Finally, we concur with the authors’ comments on medication adherence. Adherence is difficult to measure reliably. Although we address adherence at every clinic visit, this remains a common limitation across all therapeutic areas. We also agree we should not assume that beta blockers have a protective effect due to heart rate suppression only and that the full mechanism underlying protection is multifaceted and not completely understood. This underscores yet another reason to aim for maximal therapy in all patients and utilize the individualized EST guided plan in those who are intolerant of beta-blockers to help them maximize compliance and medication adherence. Importantly, this strategy should be implemented only under the guidance of an experienced inherited arrhythmia specialist and must be tailored to each patient’s specific risk for life-threatening arrhythmias.References:Niaz T, Bos JM, Sorensen KB, Moir C, Ackerman MJ. Left Cardiac Sympathetic Denervation Monotherapy in Patients With Congenital Long QT Syndrome. Circ Arrhythm Electrophysiol. 2020 Dec;13(12):e008830. doi: 10.1161/CIRCEP.120.008830. Epub 2020 Nov 16. PMID: 33198487.Krahn AD, Laksman Z, Sy RW, et al. Congenital Long QT Syndrome.J Am Coll Cardiol EP . 2022;8:687–706