Elsevier

International Journal of Cardiology

Volume 270, 1 November 2018, Pages 214-220
International Journal of Cardiology

Role of genetic heart disease in sentinel sudden cardiac arrest survivors across the age spectrum

https://doi.org/10.1016/j.ijcard.2018.05.100Get rights and content

Highlights

  • The diagnostic yield in non-ischemic cardiac arrest survivors is age-dependent.

  • The yield of genetic testing in unexplained sudden cardiac arrest is low.

  • Arrhythmic mitral valve prolapse is a frequent cause of non-ischemic SCA in adults.

Abstract

Background

Sudden cardiac arrest (SCA) may be the sentinel expression of a sudden cardiac death-predisposing genetic heart disease (GHD). Although shown to underlie many unexplained SCAs in the young, the contribution of GHDs to sentinel SCA has never been quantified across the age spectrum. Thus, we sought to determine the contribution of GHDs in single-center referral cohort of non-ischemic SCA survivors.

Methods and results

Retrospective analysis of 3037 patients was used to identify all individuals who experienced a sentinel event of SCA. Following exclusion of patients with ischemic or complex congenital heart disease, cases were classified by clinical diagnoses. Overall, 180 (5.9%) referral patients experienced a sentinel SCA (average age at SCA 28 ± 15 years, 99 females). An etiology was identified in 113/180 patients (62.8%) including channelopathies in 26.7%, arrhythmogenic bileaflet mitral valve prolapse in 10.6%, cardiomyopathies in 9.4%, other etiologies in 6.7%, acquired long QT syndrome in 6.7%, and multiple disorders in 2.8%. The remaining 67/180 (37.2%) cases were classified as idiopathic ventricular fibrillation (IVF). Interestingly, the contribution of GHDs declined precipitously after the first decade of life [90.0% (age 0–9; n = 20), 58.7% (age 10–19; n = 46), 28.1% (age 20–29; n = 32), 23.8% (age 30–39; n = 42), 16.7% (age 40–49; n = 24), and 12.5% (age 50+; n = 16)].

Conclusions

Within a referral population enriched for GHDs, the ability of a comprehensive cardiac evaluation, including genetic testing, to elucidate a root cause in non-ischemic SCA survivors declined with age. Although rare, GHDs can underlie SCA into adulthood and merit consideration across the age spectrum.

Introduction

Sudden cardiac death (SCD), defined as death due to a cardiovascular etiology ≤1 h after symptom onset, affects all age groups and accounts for ~350,000 deaths in the United States annually [1]. Although the vast of majority of SCD occurs in older individuals and is attributable to arrhythmic sequelae of coronary artery disease [2,3], the incidence of SCD in infants, children, and young adults <40 years of age has been estimated at 1–8/100,000 individuals annually. Although much smaller in sheer numbers, the loss of life-years associated with sudden unexplained death in the young (SUDY) rivals that of most individual cancers and ischemic heart disease [4].

In SUDY victims and to larger extent, young (<40 years of age) non-ischemic sudden cardiac arrest (SCA) survivors, genetic heart diseases (GHDs), specifically hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT), have a predominant role [[5], [6], [7]]. However, the precise contribution of specific GHDs, as well as more recently described clinical entities such as arrhythmogenic bileaflet mitral valve prolapse syndrome (ABiMVPS) [8] and triadin knock-out syndrome (TKOS) [9], to sentinel non-ischemic SCA across the entire age-spectrum remains poorly defined.

As such, this study sought to determine and compare the contribution of GHDs to sentinel SCA across the age spectrum as well as the yield of genetic testing in a unique GHD-enriched single center referral cohort composed of both pediatric and adult non-ischemic SCA survivors.

Section snippets

Study population and definitions

In this Institutional Review Board-approved single-center study, the electronic medical records of 3037 consecutive patients referred to Mayo Clinic's Genetic Heart Rhythm Clinic between January 1999 and April 2017 were reviewed retrospectively to identify all individuals who experienced a sentinel event of SCA. For the purposes of this study, SCA was defined as a witnessed or unwitnessed collapse that required external defibrillation from a shockable rhythm (either ventricular fibrillation or

Baseline demographics and clinical diagnoses in non-ischemic sudden cardiac arrest survivors

Overall, 180/3037 patients (5.9%; 99 females; average age at SCA 28.0 ± 15.4 years) without evidence of ischemic or complex congenital heart disease were referred to Mayo Clinic's Genetic Heart Rhythm Clinic for evaluation after experiencing a sentinel SCA (Table 1). Following comprehensive cardiovascular evaluation, a certain or probable clinical diagnosis was rendered in 113/180 SCA survivors (62.8%; Table 1). This included a cardiac channelopathy in 26.7%, ABiMVPS in 10.6%, cardiomyopathy in

GHDs: a frequent contributor to sentinel SCA across the age-spectrum

In this single center GHD-enriched referral cohort of sentinel SCA survivors without complex congenital or ischemic heart disease, 39.4% of all patients and 62.8% of patients who received a certain or probable clinical diagnosis had an underlying GHD. Consistent with prior studies [6], the yield of GHDs in pediatric SCA survivors was high accounting for 90% of SCAs that occurred during the first decade of life. Notably, although the contribution of GHDs declined precipitously with each

Limitations

Although the number SCA survivors that remained unexplained following a comprehensive cardiovascular evaluation, including specialized studies and genetic testing, is similar to previous studies, the clear over-representation (i.e. LQTS, CPVT, etc.) and under-representation (i.e. HCM) of certain SCD-predisposing disorders underscores the strong referral bias present in this study. As mentioned previously, this inherent bias prevents generalization of this study's results beyond the current

Conclusion

Within a single-center referral population likely enriched for the presence of GHDs, the ability of a comprehensive cardiac evaluation, including genetic testing, to elucidate the root cause for the individual's sentinel event of SCA was highly age-dependent. Nevertheless, GHDs can present as sentinel SCA well into adulthood and merit consideration in all SCA survivors, regardless of age, with otherwise structurally normal hearts. Lastly, in the absence of a discernible GHD phenotype, the yield

Funding sources

This work was supported by the Mayo Clinic Windland Smith Rice Sudden Comprehensive Sudden Cardiac Death Program (to Dr. Ackerman). Dr. Giudicessi thanks the Mayo Clinic Cardiovascular Diseases Fellowship and Clinician Investigator Training Programs for fostering an outstanding environment for physician-scientist training.

Conflict of interest disclosures

Dr. Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. From 2004 to 2016, M.J.A. and Mayo Clinic received sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. M.J.A. and Mayo Clinic have an equity/royalty relationship (without remuneration so far) with AliveCor, Blue Ox Health, and StemoniX. However, none of these entities participated in this study. Dr.

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    Both authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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