Author + information
- Received May 1, 2018
- Revision received July 25, 2018
- Accepted September 13, 2018
- Published online October 31, 2018.
- David J. Tester, BSa,
- Jaeger P. Ackerman, BSa,
- John R. Giudicessi, MD, PhDb,
- Nicholas C. Ackermana,
- Marina Cerrone, MDc,
- Mario Delmar, MD, PhDc and
- Michael J. Ackerman, MD, PhDa,d,e,∗ ()
- aDepartment of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
- bDepartments of Cardiovascular Medicine and Internal Medicine (Clinician-Investigator Training Program), Mayo Clinic, Rochester, Minnesota
- cThe Leon H. Charney Division of Cardiology. New York University School of Medicine, New York, New York
- dDepartment of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota
- eDepartment of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
- ↵∗Address for correspondence:
Dr. Michael J. Ackerman, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street, Southwest, Guggenheim 501, Rochester, MN 55905-0001.
Objectives This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY).
Background Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT.
Methods A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic.
Results Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10−13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death.
Conclusions Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.
- arrhythmogenic right ventricular cardiomyopathy
- catecholaminergic genetic testing
- polymorphic ventricular tachycardia
- sudden unexplained death in the young
Dr. M.J. Ackerman was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Delmar was supported by grants RO1HL134328 and RO1HL136179 from the National Institutes of Health. Dr. Cerrone was supported by grant AHA14SDG18580014 from the American Heart Association. Dr. M.J. Ackerman has been a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical, and he and Mayo Clinic have an equity/royalty relationship (without remuneration so far) with AliveCor, Blue Ox Health Corporation, and StemoniX. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Mr. Tester and Mr. J.P. Ackerman contributed equally to this work and are joint first authors.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Received May 1, 2018.
- Revision received July 25, 2018.
- Accepted September 13, 2018.
- 2018 American College of Cardiology Foundation
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