Ackerman, Michael J.

Background: Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. Methods: Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. Results: Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P =0.05) SCA survivors and 8 out of 68 (11.8%; P =0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P <0.02) SUD cases without ventricular fibrosis. Conclusions: Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

Significance Approximately 400 United States children 1 y of age and older die suddenly from unexplained causes annually. We studied whole-exome sequence data from 124 “trios” (decedent child and living parents) to identify genetic risk factors. Nonsynonymous mutations, mostly de novo (present in child but absent in both biological parents), were highly enriched in genes associated with cardiac and seizure disorders relative to controls, and contributed to 9% of deaths. We found significant overtransmission of loss-of-function or pathogenic missense variants in cardiac and seizure disorder genes. Most pathogenic variants were de novo in origin, highlighting the importance of trio studies. Many of these pathogenic de novo mutations altered a protein network regulating calcium-related excitability at submembrane junctions in cardiomyocytes and neurons.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]). Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0–90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non‐SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2 . Conclusions This study examined one of the largest single‐center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A ; postmortem whole exome sequencing identified 18 ultrarare variants.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by adrenergically-triggered ventricular arrhythmias, syncope, and sudden cardiac death. Several small studies suggest that atrial arrhythmias (AAs) are common in patients with CPVT. Objective: To determine the incidence and type of AAs observed within a large, single-center cohort of CPVT cases as well as the efficacy and durability of AA-directed management. Methods: In this retrospective study, the electronic medical record of 129 patients (52% female; average age at diagnosis 20.8  15.3 years) with CPVT (95% with a putative CPVT1-causative RYR2 variant) between 01/2000 and 09/2019 were reviewed for electrocardiographic evidence of AAs. Clinical features and efficacy of pharmacologic and ablation therapy were assessed. Results: Overall, 10/129 (7.8%) CPVT patients, all RYR2 variant-positive, had evidence of an AA (atrial fibrillation/flutter in 6, atrial tachycardia in 3, and supraventricular tachycardia in 1). The median age at AA diagnosis was 23 (14.2-35.5) years. 8/10 of patients experienced symptoms attributed to their AA, including inappropriate shocks. All patients were trialed on anti-arrhythmics, including -blockers, and/or flecainide. Owing to drug failure (1/10), drug intolerance (1/10), or patient preference (2/10); 4/10 patients received an ablation. Over a median follow-up of 23.5 (4.5-63) months, no AA recurrences were observed. Conclusion: Compared to prior studies, the incidence of AAs in this large, single-center referral cohort of CPVT patients was substantially lower (7.8% vs. 26%-35%). Although larger multi-center studies are needed to confirm, this study suggests that ablation is efficacious and durable in CPVT-associated AAs.

Abstract Background Interval duration measurements (IDMs) were compared between standard 12‐lead electrocardiograms (ECGs) and 6‐lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand‐held mobile device designed for use by patients at home. Methods Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12‐lead and 6‐lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi‐automated technique. Results Despite differences in patient position (supine for 12‐lead ECGs and sitting for 6‐lead ECGs), mean IDMs were comparable, with mean values for the 12‐lead and 6‐lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, −5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities. Conclusions The 6‐lead hand‐held device is potentially useful for a clinical follow‐up of remote patients, and for a safety follow‐up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12‐lead ECG recordings during the current COVID‐19 pandemic as remote patient monitoring becomes more common in virtual or hybrid‐design clinical studies.

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome–related sudden cardiac death), and was applied with the end point of life‐threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow‐up duration among the 767 enrolled women was 22 243 patient‐years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype‐phenotype data, we identified 3 risk groups with 10‐year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10‐year projected rates of life‐threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65–0.71) and 0.71 (95% CI 0.66–0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60–0.70) and 0.77 (95% CI 0.70–0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life‐threatening events in women with type 1 or type 2 long QT based on personalized genotype‐phenotype data. The projected risk estimates can be used to guide female‐specific management in long QT syndrome.

Introduction: Although the vast majority of mitral valve prolapse (MVP) is benign, women with bileaflet MVP (biMVP), complex ventricular ectopy (VE), and abnormal T waves may comprise the recently described malignant biMVP syndrome. The mechanism of ventricular arrhythmia is unknown. To further characterize the arrhythmic substrate, we reviewed our center’s ablation experience in 6 biMVP patients with prior cardiac arrest and recurrent ICD shocks for drug refractory ventricular fibrillation (VF). Methods and Results: Six women with biMVP (median age 31.5 [range 24.2 - 58.7] years, EF 65 [45 - 67]%, all ≤moderate mitral regurgitation) experienced 6 (3 - 25) appropriate ICD shocks over 4.8 (2.8 - 10.7) years and underwent index ablation between 2/2007 - 10/2013. All had multiple VE morphologies (median 7 [3 - 24]) with variable coupling intervals but with a predominant VE trigger for the VF. A median 2 (1 - 4) VE foci were ablated. Sites of successful ablation of VF-triggering and other dominant VE were left ventricular papillary muscles [PM] (1 anterior, 1 posterior, 1 both), fascicles (1 anterior, 1 posterior), or both (1 both PM and posterior fascicle). Outflow tract VE was also present and targeted (1 left, 1 right)i. Two underwent repeat ablation (288 and 312 days) for recurrent complex VE without shocks, with different foci to the index ablation (1 posterior fascicle, 1 both fascicles). The VF-triggering VE in all patients was confirmed as originating from within the left fascicular system, which in 3/6 was at a papillary muscle. Acute procedural success was seen in all with no complications to date. A VF storm occurred within 24 hours of ablation in a single patient. At follow-up of a mean 662 (47 - 2099) days, 1 patient received a single shock (p=0.03 vs. preablation). Symptomatic VE was reduced in all; while 3/6 continue Class 1c antiarrhythmics and 5/6 have beta blockade. Conclusion: Malignant biMVP syndrome is characterized by fascicular and papillary muscle PVCs that trigger ventricular fibrillation, yet in all patients, the VE is multifocal. Ablation of at least one focus appears to improve symptoms and reduce shocks.

Introduction: Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant which remains unexplained after comprehensive clinical and pathological assessment. Prior studies have implicated inherited cardiac conditions (ICC). Hypothesis: Whole exome sequencing will identify a significant burden of putative pathogenic (PP) and rare functionally significant (RFS) cardiac genetic variants in SIDS. Methods: 96 SIDS cases with complete phenotypic data were selected from 434 cases. Prone sleeping position was excluded to enrich for genetic risk. Genomic DNA underwent target enrichment using Agilent SureSelect Human All Exon v5 kit and sequencing on Illumina HiSeq. Reads were aligned to GRCh37 reference genome with Novoalign and variants called with SAMtools. Principal component analysis identified 82 cases of North European (NE) ancestry. Variants were annotated with Annovar and compared to control data from a local exome database, 1000 Genomes and ESP. Analysis focused on 83 known ICC susceptibility genes (27 channelopathy-associated [CH]; 56 cardiomyopathy-associated [CM]). PP was defined as ultra rare nonsense or frameshift mutations or other variants previously reported as disease-associated and absent in controls. RFS was defined as variants with abnormal functional characterization and <0.5% prevalence in controls. Results: 20/82 cases (24%) carried at least 1 PP/RFS variant: 12 CH variants in 9 genes (AKAP9, ANK2, CACNB2, CAV3, KCNE2, RYR2, SCN5A, SNTA1, TRDN) in 13 cases; 7 CM variants in 5 genes (ABCC9, ACTN2, CSRP3, TCAP, TTN) in 8 cases. Variants were most commonly identified in the 3-6 months age group (p=0.009). There were no other significant phenotypic differences between variant-positive and negative cases (Table 1). Conclusions: There was an 11% yield of PP variants in non-prone sleeping SIDS cases of NE ancestry, with an additional 13% hosting RFS variants. These may provide a potential substrate in the pathophysiology of SIDS.