Role of genetic heart disease in sentinel sudden cardiac arrest survivors 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.
References (35)
- et al.
Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands
Heart Rhythm.
(2010) - et al.
Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes
Heart Rhythm.
(2013) - et al.
Malignant bileaflet mitral valve prolapse syndrome in patients with otherwise idiopathic out-of-hospital cardiac arrest
J. Am. Coll. Cardiol.
(2013) - et al.
HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013
Heart Rhythm.
(2013) - et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Genet Med.
(2015) - et al.
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test
Heart Rhythm.
(2009) - et al.
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing
Heart Rhythm.
(2005) - et al.
Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death
Heart Rhythm.
(2010) - et al.
Etiological diagnoses of out-of-hospital cardiac arrest survivors admitted to the intensive care unit: insights from a French registry
Resuscitation
(2017) - et al.
Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome
J. Am. Coll. Cardiol.
(2017)
Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular fibrillation
Heart Rhythm.
The genetics underlying idiopathic ventricular fibrillation: a special role for catecholaminergic polymorphic ventricular tachycardia?
Int. J. Cardiol.
Heart disease and stroke statistics — 2017 update: a report from the American Heart Association
Circulation
Prospective study of sudden cardiac death among women in the United States
Circulation
Ventricular tachyarrhythmias after cardiac arrest in public versus at home
N. Engl. J. Med.
Public health burden of sudden cardiac death in the United States
Circ Arrhythm Electrophysiol.
Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)
Circulation
Cited by (0)
- ☆
Both authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.