Background The incidence and cause of sudden cardiac death (SCD) in athletes is debated with hypertrophic cardiomyopathy often reported as the most common cause. Methods and results A database of all National Collegiate Athletic Association deaths (2003-2013) was developed. Additional information and autopsy reports were obtained when possible. Cause of death was adjudicated by an expert panel. There were 4 242 519 athlete-years (AY) and 514 total student athlete deaths. Accidents were the most common cause of death (257, 50%, 1:16 508 AY) followed by medical causes (147, 29%, 1:28 861 AY). The most common medical cause of death was SCD (79, 15%, 1:53 703 AY). Males were at higher risk than females 1:37 790 AY versus 1:121 593 AY (incidence rate ratio, 3.2; 95% confidence interval, 1.9-5.5; P Conclusions The rate of SCD in National Collegiate Athletic Association athletes is high, with males, black athletes, and basketball players at substantially higher risk. The most common finding at autopsy is autopsy-negative sudden unexplained death. Media reports are more likely to capture high-profile deaths, and insurance claims are not a reliable method for case identification.

Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes a decade in review

There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca 2+ ) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca 2+ -handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca 2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca 2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca 2+ -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca 2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

Calcium Signaling and Cardiac Arrhythmias.

Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.

The sudden death of a young, apparently fit and healthy person is amongst the most challenging scenarios in clinical medicine. Sudden cardiac death (SCD) is a devastating and tragic outcome of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, genetic (inherited) cardiac disorders comprise a substantial proportion of SCD cases aged 40 years and less. This includes the primary arrhythmogenic disorders such as long QT syndromes and inherited cardiomyopathies, namely hypertrophic cardiomyopathy. In up to 30% of young SCD, no cause of death is identified at postmortem, so-called autopsy-negative or sudden arrhythmic death syndrome (SADS). Management of families following SCD begins with a concerted effort to identify the cause of death in the decedent, based on either premorbid clinical details or the pathological findings at postmortem. Where no cause of death is identified, genetic testing of deoxyribonucleic acid extracted from postmortem blood (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Irrespective of the genetic testing considerations, all families in which a sudden unexplained death has occurred require targeted and standardized clinical testing in an attempt to identify relatives who may be at-risk of having the same inherited heart disease and therefore also predisposed to an increased risk of SCD. Optimal care of SCD families therefore requires dedicated and appropriately trained staff in the setting of a specialized multidisciplinary cardiac genetic clinic.

/pdf/sudden-cardiac-death-in-the-young-the-molecular-autopsy-and-2ogahhvmcm.pdf

Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely ...

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome

Background—Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-...

Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G.

Annually, the sudden death of thousands of young people remains inadequately explained despite medicolegal investigation. Postmortem genetic testing for channelopathies/cardiomyopathies may illuminate a potential cardiac mechanism and establish a more accurate cause and manner of death and provide an actionable genetic marker to test surviving family members who may be at risk for a fatal arrhythmia. Whole exome sequencing allows for simultaneous genetic interrogation of an individual's entire estimated library of approximately 30000 genes. Following an inconclusive autopsy, whole exome sequencing and gene-specific surveillance of all known major cardiac channelopathy/cardiomyopathy genes (90 total) were performed on autopsy blood-derived genomic DNA from a previously healthy 16-year-old adolescent female found deceased in her bedroom. Whole exome sequencing analysis revealed a R249Q-MYH7 mutation associated previously with familial hypertrophic cardiomyopathy, sudden death, and impaired β-myosin heavy chain (MHC-β) actin-translocating and actin-activated ATPase (adenosine triphosphatase) activity. Whole exome sequencing may be an efficient and cost-effective approach to incorporate molecular studies into the conventional postmortem examination.

http://www.sads.org/SADS/media/Literature-Review/ConfirmationofCauseandMannerofDeath.pdf

Confirmation of cause and manner of death via a comprehensive cardiac autopsy including whole exome next-generation sequencing.

Introduction: Cardiac channelopathies such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) may lead to potentially lethal ventricular fibrillation and sudden unexplained death in the young (SUDY, 1-35 years of age). Two of the three genes ( CALM1 and CALM2 ) that encode for calmodulin have been implicated recently in LQTS and CPVT and associate with a very malignant phenotype with early onset typically within the first decade of life. Therefore, given its apparent early and malignant expressivity, we set out to determine the spectrum and prevalence of CALM1, CALM2, and CALM3 mutations in LQTS, CPVT, idiopathic ventricular fibrillation (IVF), and SUDY.

Methods: Using PCR, DHPLC, and direct DNA sequencing, a comprehensive coding region mutational analysis of CALM1, CALM2 and CALM3 was performed on genomic DNA isolated from 39 unrelated LQTS, 13 CPVT, 16 IVF, and 107 SUDY cases that remained genotype-negative following KCNQ1 , KCNH2 , SCN5A , and RYR2 analysis. To be considered a potential pathogenic mutation, identified variants had to be non-synonymous and absent among three publicly available exome databases (1000 Genomes Project, NHLBI Exome Sequencing Project, and 12000 Exome Chip).

Results: Six missense CALM1 or CALM2 mutations were found in 6 cases (LQTS, 3/39 [7.7%], 1 male; SUDY, 3/107 [2.8%], 2 males). Two of the mutations (N54I-CALM1 and D96V-CALM2) were reported in the original discoveries and have been functionally characterized as abnormal. All 3 LQTS patients manifested a severe phenotype (QTc > 550 ms, 2 with cardiac arrest). The yield of CALM1/CALM2 mutations was significantly higher among cases ≤ 10 years of age compared to those case > 10 years (LQTS, 3/12 [25%] vs. 0/27 [0%], p = 0.04; SUDY, 3/29 [10%] vs. 0/78 [0%], p = 0.02). A novel CALM3 mutation (A103V) was identified in a 12-year-old female with CPVT.

Conclusion: Calmodulin-mediated channelopathies potentially account for up to 25% of otherwise genetically elusive and severe LQTS and 10% of genotype-negative SUDY cases under the age of 10 years. Here in, we also report for the first time a CALM3 mutation identified in a single case of CPVT. The pedigree expansion and functional characterization of the novel calmodulin mutations are currently underway.

Abstract 14699: Spectrum and Prevalence of CALM1, CALM2, and CALM3 Mutations in Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Idiopathic Ventricular Fibrillation, and Sudden Unexplained Death in the Young

Christina G. Loporcaro

Papers

Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G.

Confirmation of cause and manner of death via a comprehensive cardiac autopsy including whole exome next-generation sequencing.

Abstract 14699: Spectrum and Prevalence of CALM1, CALM2, and CALM3 Mutations in Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Idiopathic Ventricular Fibrillation, and Sudden Unexplained Death in the Young