Response by Ingles and Semsarian to Letter Regarding Article, "Concealed Arrhythmogenic Right Ventricular Cardiomyopathy in Sudden Unexplained Cardiac Death Events".

Abstract

HomeCirculation: Genomic and Precision MedicineVol. 12, No. 3Response by Ingles and Semsarian to Letter Regarding Article, “Concealed Arrhythmogenic Right Ventricular Cardiomyopathy in Sudden Unexplained Cardiac Death Events” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Ingles and Semsarian to Letter Regarding Article, “Concealed Arrhythmogenic Right Ventricular Cardiomyopathy in Sudden Unexplained Cardiac Death Events” Jodie Ingles, GradDipGenCouns, PhD, MPH and Christopher Semsarian, MBBS, PhD, MPH Jodie InglesJodie Ingles Agnes Ginges Centre for Molecular Cardiology at Centenary Institute and Faculty of Health and Medical Sciences, The University of Sydney, Australia. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Search for more papers by this author and Christopher SemsarianChristopher Semsarian Christopher Semsarian, MBBS, PhD, MPH, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia. Email E-mail Address: [email protected] Agnes Ginges Centre for Molecular Cardiology at Centenary Institute and Faculty of Health and Medical Sciences, The University of Sydney, Australia. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Search for more papers by this author Originally published28 Mar 2019https://doi.org/10.1161/CIRCGEN.119.002475Circulation: Genomic and Precision Medicine. 2019;12:e002475In Response:We thank Krahn et al1 for their insightful letter and providing data from the internationally recognized Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, which support the findings of our small series of patients with concealed arrhythmogenic right ventricular cardiomyopathy (ARVC) who experienced sudden cardiac death events.2 We agree that cascade screening and systematic evaluation are critical if we are to be in a position to prevent serious adverse events, including sudden death. We also support the notion of concealed ARVC, whereby arrhythmic events precede structural changes, highlighting current limitations in the Task Force Criteria used to diagnose ARVC.The overwhelming clinical issue is how do we investigate and manage asymptomatic patients who carry genetic variants, such as truncating variants in PKP2, but have no overt signs of structural abnormalities. Most cardiologists will primarily rely on echocardiographic and cardiac magnetic resonance imaging to assess any structural evidence of ARVC. In a gene carrier where there is no evidence of structural disease on comprehensive imaging, how would such a patient be assessed for arrhythmic risk? Is a normal ECG, exercise test, and 24-hour ambulatory ECG monitoring sufficient level of investigation to reassure the patient that their risk of a life-threatening arrhythmia is low? Should further arrhythmic risk be assessed by additional investigations, such as electrophysiological testing? If all these investigations are normal, how often should the patient be reviewed? Potentially, the most important unanswered question is: Does this risk of an arrhythmic event before structural disease hold true for at-risk relatives shown to be gene positive for the family mutation? Among ARVC families, probands are in many cases the most severely affected, suggesting a complex underlying disease pathogenesis, with emerging evidence pointing to a role for nongenetic factors, such as high-level exercise.3A further area of interest relates to whether the risk of sudden cardiac events is linked to specific genes or variants. We showed in our 4 cases that 2 of the probands carried variants previously described in ARVC cases. Indeed, 1 variant NM_004572.3: c.2489+1G>A in PKP2 has been reported in >25 ARVC probands in the literature.2 Further, since our case series was published, we have identified an additional patient who died suddenly at the age of 21 years with no premorbid diagnosis and postmortem examination essentially unexplained and a pathogenic truncating variant in DSP identified. Collectively, these data from Australia and Canada demonstrate that as yet there is no clear mechanistic reason why these patients would suffer significant ventricular arrhythmias in the absence of overt structural disease, compared with other patients with ARVC. This element of unpredictability creates a clinical dilemma in sudden death risk stratification and overwhelmingly highlights a limitation of the 2010 Task Force Criteria and an area requiring further research. Registries such as Cardiac Arrest Survivors With Preserved Ejection Fraction Registry will no doubt play a critical role in answering these questions.AcknowledgmentsDr Ingles is the recipient of a National Health and Medical Research Council of Australia Career Development Award (No. 1162929). Dr Semsarian is the recipient of an National Health and Medical Research Council Practitioner Fellowship (No. 1154992).DisclosuresNone.FootnotesChristopher Semsarian, MBBS, PhD, MPH, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia. Email c.[email protected]org.au