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.

Background— The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) enrolls patients with apparently unexplained cardiac arrest and no evident cardiac disease to identify the pathogenesis of cardiac arrest through systematic clinical testing. Exercise testing, drug provocation, advanced cardiac imaging, and genetic testing may be useful when a cause is not apparent. Methods and Results— The first 200 survivors of unexplained cardiac arrest from 14 centers across Canada were evaluated to determine the results of investigation and follow-up (age, 48.6±14.7 years, 41% female). Patients were free of evidence of coronary artery disease, left ventricular dysfunction, or evident repolarization syndromes. Advanced testing determined a diagnosis in 34% of patients at baseline, with a diagnosis emerging during follow-up in 7% of patients. Of those who were diagnosed, 28 (35%) had an underlying structural condition and 53 (65%) had a primary electric disease. During a mean follow-up of 3.15±2.34 years, 23% of patients had either a shock or an appropriate antitachycardia pacing from their implantable cardioverter defibrillator, or both. The implantable cardioverter defibrillator appropriate intervention rate was 8.4% at 1 year and 18.1% at 3 years, with no clear difference between diagnosed and undiagnosed subjects, or between those diagnosed with a primary electric versus structural pathogenesis. Conclusions— Obtaining a diagnosis in previously unexplained cardiac arrest patients requires systematic clinical testing and regular follow-up to unmask the cause. Nearly half of apparently unexplained cardiac arrest patients ultimately received a diagnosis, allowing for improved treatment and family screening. A substantial proportion of patients received appropriate implantable cardioverter defibrillator therapy during medium-term follow-up. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00292032.

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Background: The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) enrolls patients with apparently unexplained cardiac arrest and no evident cardiac disease, and aims to identify the underlying conditions responsible for the cardiac arrest through systematic clinical testing. A combination of exercise testing, drug provocation, electrophysiological testing, advanced cardiac imaging, and targeted genetic testing may unmask the cause of cardiac arrest when a cause is not apparent. Methods and Results: The first 200 survivors (48.6 ± 14.7 years, 41% female) of unexplained cardiac arrest from CASPER, from 14 centers across Canada were evaluated to determine the results of investigation and follow-up risk of recurrence. Patients were free of evidence of coronary artery disease, left ventricular dysfunction or evident repolarization syndromes. Advanced testing determined a probable or definite diagnosis in 41% of patients. During a median follow-up of 3.15±2.34 years, 23% of patients had either a shock from their ICD or appropriate anti-tachycardia pacing or both. The annual ICD appropriate intervention rate was 0.16 per year (SEM=0.14), with no clear difference in intervention rate between diagnosed and undiagnosed subjects, or between those diagnosed with a primary electrical versus structural etiology. Conclusions: Obtaining a diagnosis in previously unexplained cardiac arrest patients requires systematic clinical testing and regular follow-up to unmask the cause of cardiac arrest. Nearly half of apparent unexplained cardiac arrest patients ultimately received a diagnosis, allowing for improved treatment and family screening. A substantial proportion of patients received appropriate ICD therapy during follow-up.

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