We would like to thank Professors Jáimez and Sánchez for their letter of response commenting on our recent summary of evaluation and outcome of our first 200 unexplained cardiac arrest probands. 1 We would first like to point out that we excluded patients with a manifest diagnosis, so none of these patients had overt evidence of an ion channelopathy or cardiomyopathy that are typically both readily diagnosed and treated. This is reflected in our empirical strength of diagnosis framework, which is necessary when a classic diagnosis is not forthcoming.2 In addition, registries do not mandate care but rather capture it, and reflect the reality of practice with the vagaries of contextual clinical decision making.In response to the concerns about the incidence of shocks and the inefficacy of medical therapy, it is important to point out the difference between efficacy and effectiveness. Without a doubt, a patient who is adherent to β-blockers for long QT syndrome has an extremely low risk of receiving a shock from their implantable cardioverter defibrillator (efficacy). In contrast, many patients do not adhere to recommended medical therapy, particularly when the patient is young and the diagnosis is not compelling (not effective). In our study, 3 of 18 patients diagnosed with long QT and 1 of 10 patients diagnosed with catecholaminergic polymorphic ventricular tachycardia received an appropriate shock. Several patients were on metoprolol before the recent evidence of inefficacy of metoprolol. All 4 patients had adjustment or initiation of medical management and have not received further shocks during follow-up. The β-blocker use in the undiagnosed patients reflects inclusion of weak evidence of disease patients, who may have had a single-prolonged QT interval or QTc prolongation in response to epinephrine, but no other evidence from exercise or genetic testing. These patients are often placed on empirical β-blockade.A valid point is raised with regard to implantable cardioverter defibrillator programming, which again reflects an era of early intervention programming that has evolved in our study as it has in all practices. 3 We did not capture these details and are embarking on data collection to compare the 2 programming eras once sufficient outcomes have been accumulated. Finally, we began a focus on enrolling more family members 3 years ago, and currently have an analysis under consideration that involves 200 unexplained cardiac arrest first-degree relatives. This is a clear priority to understand family implications and enrich gene discovery opportunities. DisclosuresNone.

Lake City, UT (S.P.E.); on behalf of the SAMIS investigators The online-only Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.112.972620/-/DC1. Correspondence to Shubhayan Sanatani, MD, Children's Heart Centre, British Columbia Children's Hospital, 1F9, 4480 Oak St, Vancouver, Canada V6H 3V4. E-mail ssanatani@cw.bc.ca Background-Supraventricular tachycardia (SVT) is one of the most common conditions requiring emergent cardiac care in children, yet its management has never been subjected to a randomized controlled clinical trial. The purpose of this study was to compare the efficacy and safety of the 2 most commonly used medications for antiarrhythmic prophylaxis of SVT in infants: digoxin and propranolol. Methods and Results-This was a randomized, double-blind, multicenter study of infants <4 months with SVT (atrioventricular reciprocating tachycardia or atrioventricular nodal reentrant tachycardia), excluding Wolff-Parkinson-White, comparing digoxin with propranolol. The primary end point was recurrence of SVT requiring medical intervention. Time to recurrence and adverse events were secondary outcomes. Sixty-one patients completed the study, 27 randomized to digoxin and 34 to propranolol. SVT recurred in 19% of patients on digoxin and 31% of patients on propranolol (P=0.25).No first recurrence occurred after 110 days of treatment. The 6-month recurrence-free status was 79% for patients on digoxin and 67% for patients on propranolol (P=0.34), and there were no first recurrences in either group between 6 and 12 months. There were no deaths and no serious adverse events related to study medication. Conclusions-There was no difference in SVT recurrence in infants treated with digoxin versus propranolol. The current standard practice may be treating infants longer than required and indicates the need for a placebo-controlled trial. Clinical Trial Registration Information-http://clinicaltrials.gov; NCT- Sanatani et al Treating Supraventricular Tachycardia in Infants 985during infancy. [8][9][10] As many as 50% of infants presenting with SVT have severe cardiomyopathy and heart failure because of unrecognized tachycardia. [2][3][4]11 Heart failure may progress to cardiovascular collapse and is the genesis of the associated 1% to 4% mortality. 2,5,[12][13][14] Due to concerns for morbidity and mortality and the challenges in detecting SVT in infants, 4,15 the general consensus among pediatric cardiologists who manage these patients has been to use medication to prevent recurrent SVT. In the context of this study, the term prophylaxis refers to the prevention of recurrent episodes of SVT. In a recent survey of pediatric cardiologists and electrophysiologists, Wong et al 16 reported that 98% of respondents recommend prophylactic medication when presented with a hypothetical case of an infant with SVT. Editorial see p 882 Clinical Perspective on p 991There are no randomized controlled trials addressing the most effective medicine for preventing recurrent SVT. The 2 most commo...

Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage-gated sodium channel, Na 1.5. Mutants in Na 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome Na 1.5 mutants. We used whole-cell patch clamp to assess the biophysical properties of Na 1.5 wild-type (WT), ∆KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the Na 1.5 α subunit (WT or mutants), β1 subunit and enhanced green fluorescent protein. Voltage-dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500 and 2500 nm. In silico, action potential (AP) model simulations were performed using a modified O'Hara Rudy model. Elevated cytosolic calcium attenuates the late sodium current in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Elevated cytosolic calcium restores steady-state slow inactivation (SSSI) to the WT-form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency-dependent reduction of AP duration in ∆KPQ, 1795insD and Q1909R carriers. In E1784K, AP duration is relatively prolonged at both low and high heart rates, resulting in a sodium overload. Cellular perturbations during exercise may affect BrS1/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients.

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