Enhancing the interpretation of genetic observations in KCNQ1 in unselected populations: relevance to secondary findings.

AIMS: Rare variants in the KCNQ1 gene are found in the healthy population to a much greater extent than the prevalence of Long QT Syndrome type 1 (LQTS1). This observation creates challenges in the interpretation of KCNQ1 rare variants that may be identified as secondary findings in whole exome sequencing.This study sought to identify missense variants within sub-domains of the KCNQ1-encoded Kv7.1 potassium channel that would be highly predictive of disease in the context of secondary findings. METHODS AND RESULTS: We established a set of KCNQ1 variants reported in over 3700 patients with diagnosed or suspected LQTS sent for clinical genetic testing and compared the domain-specific location of identified variants to those observed in an unselected population of 140 000 individuals. We identified three regions that showed a significant enrichment of KCNQ1 variants associated with LQTS at an odds ratio (OR) >2: the pore region, and the adjacent 5th (S5) and 6th (S6) transmembrane (TM) regions. An additional segment within the carboxyl terminus of Kv7.1, conserved region 2 (CR2), also showed an increased OR of disease association. Furthermore, the TM spanning S5-Pore-S6 region correlated with a significant increase in cardiac events. CONCLUSION: Rare missense variants with a clear phenotype of LQTS have a high likelihood to be present within the pore and adjacent TM segments (S5-Pore-S6) and a greater tendency to be present within CR2. This data will enhance interpretation of secondary findings within the KCNQ1 gene. Further, our data support a more severe phenotype in LQTS patients with variants within the S5-Pore-S6 region.

Perioperative Safety and Early Patient and Device Outcomes Among Subcutaneous Versus Transvenous Implantable Cardioverter Defibrillator Implantations : A Randomized, Multicenter Trial.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) improve survival in patients at risk for cardiac arrest, but are associated with intravascular lead-related complications. The subcutaneous ICD (S-ICD), with no intravascular components, was developed to minimize lead-related complications. OBJECTIVE: To assess key ICD performance measures related to delivery of ICD therapy, including inappropriate ICD shocks (delivered in absence of life-threatening arrhythmia) and failed ICD shocks (which did not terminate ventricular arrhythmia). DESIGN: Randomized, multicenter trial. (ClinicalTrials.gov: NCT02881255). SETTING: The ATLAS trial. PATIENTS: 544 eligible patients (141 female) with a primary or secondary prevention indication for an ICD who were younger than age 60 years, had a cardiogenetic phenotype, or had prespecified risk factors for lead complications were electrocardiographically screened and 503 randomly assigned to S-ICD (251 patients) or transvenous ICD (TV-ICD) (252 patients). Mean follow-up was 2.5 years (SD, 1.1). Mean age was 49.0 years (SD, 11.5). MEASUREMENTS: The primary outcome was perioperative major lead-related complications. RESULTS: There was a statistically significant reduction in perioperative, lead-related complications, which occurred in 1 patient (0.4%) with an S-ICD and in 12 patients (4.8%) with TV-ICD (-4.4%; 95% CI, -6.9 to -1.9; P = 0.001). There was a trend for more inappropriate shocks with the S-ICD (hazard ratio [HR], 2.37; 95% CI, 0.98 to 5.77), but no increase in failed appropriate ICD shocks (HR, 0.61 (0.15 to 2.57). Patients in the S-ICD group had more ICD site pain, measured on a 10-point numeric rating scale, on the day of implant (4.2 ± 2.8 vs. 2.9 ± 2.2; P < 0.001) and 1 month later (1.3 ± 1.8 vs. 0.9 ± 1.5; P = 0.035). LIMITATION: At present, the ATLAS trial is underpowered to detect differences in clinical shock outcomes; however, extended follow-up is ongoing. CONCLUSION: The S-ICD reduces perioperative, lead-related complications without significantly compromising the effectiveness of ICD shocks, but with more early postoperative pain and a trend for more inappropriate shocks. PRIMARY FUNDING SOURCE: Boston Scientific.

An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Hypertrophic Cardiomyopathy-Related Sudden Cardiac Death in Young People in Ontario.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is considered a leading cause of sudden cardiac death (SCD) in younger people. The incidence of HCM-related SCD and its relationship to exercise have not been well studied in large comprehensive studies outside of tertiary care settings. This study sought to estimate the incidence of HCM-related SCD and its association with exercise in a large unselected population. METHODS: Using the Office of the Chief Coroner of Ontario database encompassing all deaths attended by the coroner, we identified all HCM-related SCDs in individuals 10 to 45 years of age between 2005 and 2016 (70 million person-years). Confirmation of HCM was based on typical macroscopic and microscopic features (definite HCM-related SCD). Sudden deaths with a prior clinical diagnosis of HCM but no autopsy were considered probable HCM-related SCDs. Cases with typical features but no myofiber disarray were considered possible HCM. The completeness of data was verified in a subset of patients in the Toronto area with the use of a registry of all emergency medical services-attended cardiac arrests, with an autopsy rate of 94%. To estimate the number of HCM-related aborted cardiac arrests and lives potentially saved by implantable cardioverter-defibrillators, all de novo implantations for secondary prevention and all implantations and appropriate shocks for primary prevention in patients with HCM 10 to 45 years of age, respectively, were identified with the use of a registry containing data on implantable cardioverter-defibrillator implantations from all implanting sites throughout Ontario. RESULTS: Forty-four, 3, and 6 cases of definite, probable, and possible HCM-related SCDs, respectively, were identified, corresponding to estimated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24-0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.34-0.62) for definite or probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95% CI, 0.28-0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years of observation). The estimated annual incidence rate for HCM-related SCD plus aborted cardiac arrest and HCM-related life-threatening arrhythmia (SCD, aborted cardiac arrest, and appropriate implantable cardioverter-defibrillator shocks) was 0.84 per 1000 HCM person-years (95% CI, 0.70-1.0). The majority (70%) of SCDs occurred in previously undiagnosed individuals. Most SCDs occurred during rest (64.8%) or light activity (18.5%). CONCLUSIONS: The incidence of HCM-related SCD in the general population 10 to 45 years of age is substantially lower than previously reported, with most cases occurring in previously undiagnosed individuals. SCDs are infrequently related to exercise.

Rationale and design of the randomized prospective ATLAS study: Avoid Transvenous Leads in Appropriate Subjects.

BACKGROUND: The defibrillator lead is the weakest part of the transvenous (TV) implantable cardioverter defibrillation (ICD) system and a frequent cause of morbidity. Lead dislodgement, cardiac perforation, insertion-related trauma including pneumothorax and vascular injury, are common early complications of TV-ICD implantation. Venous occlusion, tricuspid valve dysfunction, lead fracture and lead insulation failure are additional, later complications. The introduction of a totally sub-cutaneous ICD (S-ICD) may reduce these lead-related issues, patient morbidity, hospitalizations and costs. However, such benefits compared to the TV-ICD have not been demonstrated in a randomized trial. DESIGN: ATLAS (Avoid Transvenous Leads in Appropriate Subjects) is a multi-centered, randomized, open-label, parallel group trial. Patients younger than 60 years are eligible. If older than 60 years, patients are eligible if they have an inherited heart rhythm disease, or risk factors for ICD-related complication, such as hemodialysis, a history of ICD or pacemaker infection, heart valve replacement, or severe pulmonary disease. This study will determine if using an S-ICD compared to a TV-ICD reduces a primary composite outcome of perioperative complications including pulmonary or pericardial perforation, lead dislodgement or dysfunction, tricuspid regurgitation and ipsilateral venous thrombosis. Five hundred patients will be enrolled from 14 Canadian hospitals, and data collected to both early- (at 6 months) and mid-term complications (at 24 months) as well as mortality and ICD shock efficacy. SUMMARY: The ATLAS randomized trial is comparing early- and mid-term vascular and lead-related complications among S-ICD versus TV-ICD recipients who are younger or at higher risk of ICD-related complications.

The relationship between the quantitative extent of late gadolinium enhancement and burden of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy: A delayed contrast-enhanced magnetic resonance study.

OBJECTIVES: To examine the relationship between late gadolinium enhancement (LGE) extent and nonsustained ventricular tachycardia (NSVT) characteristics in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: NSVT has been shown to be independently associated with sudden cardiac death (SCD) in HCM. Previous studies have found LGE on cardiac magnetic resonance (CMR) to be independently associated with NSVT. METHODS: Seventy-three patients who had 14-day Holter monitoring for either risk stratification for SCD (n = 62) or evaluation of atrial fibrillation (n = 11) on a CMR study were included. Areas of LGE in left ventricle (LV) were visually identified and analyzed quantitatively for both high (≥6 SD above the mean signal intensity of normal myocardium) and intermediate (≥4 but <6 SD) LGE signal intensity. RESULTS: Patients with more extensive LGE had longer (P = 0.0028) and more frequent (P = 0.02) episodes of NSVT. In univariate analyses, frequency of NSVT was associated with LGE extent (rs = 0.43, P = 0.001), LV ejection fraction (rs = -0.38, P < 0.001), LV mass (rs = 0.32, P = 0.005), LV maximal wall thickness (rs = 0.28, P = 0.016), and left atrium diameter (rs = 0.29, P = 0.001); maximal length of NSVT was associated with LGE extent (rs = 0.52, P < 0.001), LV ejection fraction (rs = -0.44, P < 0.001), LV mass (rs = 0.37, P = 0.001), and left atrium diameter (rs = 0.3, P < 0.001). In multivariable analyses, LGE extent remained the sole variable independently associated with frequency (P = 0.001) and maximal length of episodes of NSVT (P = 0.001). No significant association was found between the rate of NSVT and LGE extent. CONCLUSIONS: LGE extent is independently associated with a greater burden and longer episodes of NSVT in HCM. These findings support the association between myocardial fibrosis as represented by LGE and ventricular tachyarrhythmias in HCM.

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.

Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family members.

Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both ventricles. Among hereditary DCM, the genetic causes are heterogeneous, and include mutations encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. We report three severely affected males, in a four-generation pedigree, with DCM phenotype who underwent cardiac transplant. Cardiomegaly with marked biventricular dilation and fibrosis were noticeable histopathological findings. The affected males had tested negative on a 46-gene pancardiomyopathy panel. Whole Exome Sequencing (WES) was performed to reveal mutation in the gene responsible in generation of DCM phenotypes. The 1-bp (Chr10:121435979delC; c.913delC) novel heterozygous deletion in exon 4 of BAG3, was identified in three affected males, resulted in frame-shift and a premature termination codon (p.Met306-Stop) producing a truncated BAG3 protein lacking functionally important PXXP and BAG domains. WES data were further utilized to map 10 SNP markers around the discovered mutation to generate shared disease haplotype in all affected individuals encompassing 11 Mb on 10q25.3-26.2 harboring BAG3. Finally genotypes were inferred for the unavailable/deceased individuals in the pedigrees. Here we propose that Chr10:121435979delC in BAG3 is a causal mutation in these subjects. Our and earlier studies indicate that BAG3 mutations are associated with DCM phenotypes. BAG3 should be added to cardiomyopathy gene panels for screening of DCM patients, and patients previously considered gene elusive should undergo sequencing of the BAG3 gene. © 2017 Wiley Periodicals, Inc.

Evaluation of Prolonged QT Interval: Structural Heart Disease Mimicking Long QT Syndrome.

BACKGROUND: In about 20-25% of patients with congenital long QT syndrome (LQTS) a causative pathogenic mutation is not found. The aim of this study was to explore the prevalence of alternative cardiac diagnoses among patients exhibiting prolongation of QT interval with negative genetic testing for LQTS genes. METHODS: We conducted a retrospective analysis of 239 consecutive patients who were evaluated in the inherited arrhythmia clinic at the Toronto General Hospital between July 2013 and December 2015 for possible LQTS. A detailed review of the patients' charts, electrocardiograms, and imaging was carried out. RESULTS: The analysis included 56 gene-negative patients and 61 gene-positive patients. Of the gene-negative group, 25% had structural heart disease compared to only 1.6% of gene-positive patients (P < 0.001). Structural heart disease was more likely if only one abnormal QTc parameter was found in the course of the evaluation (35.2% vs 9.1%, P = 0.01). The most common structural cardiac pathology was bileaflet mitral valve prolapse (8.9%). No gene-positive patient had episodes of nonsustained ventricular tachycardia, compared to seven of the gene-negative patients (0% vs 12.5%, P = 0.005). CONCLUSIONS: Structural pathology was detected in a quarter of gene-negative patients evaluated for possible LQTS. Hence, cardiac imaging and Holter monitoring should be strongly encouraged to rule out structural heart disease in this population.

Genetic Testing in Inherited Heart Diseases: Practical Considerations for Clinicians.

PURPOSE OF REVIEW: Genetic testing has become an important element in the care of patients with inherited cardiac conditions (ICCs). The purpose of this review is to provide clinicians with insights into the utility of genetic testing as well as challenges associated with interpreting results. RECENT FINDINGS: Genetic testing may be indicated for individuals who are affected with or who have family histories of various ICCs. Various testing options are available and determining the most appropriate test for any given clinical scenario is key when interpreting results. Newly published guidelines as well as various publicly accessible tools are available to clinicians to help with interpretation of genetic findings; however the subjectivity with respect to variant classification can make accurate assessment challenging. Genetic information can provide highly useful and relevant information for patients, their family members, and their healthcare providers. Given the potential ramifications of variant misclassification, expertise in both clinical phenotyping and molecular genetics is imperative in order to provide accurate diagnosis, management recommendations, and family risk assessment for this patient population.

Rapid Device-Detected Nonsustained Ventricular Tachycardia in the Risk Stratification of Hypertrophic Cardiomyopathy.

BACKGROUND: Nonsustained ventricular tachycardia (NSVT) detected by ambulatory Holter (Holter NSVT) is a major risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM). We hypothesized that the prognostic utility of Holter NSVT in HCM would improve with prolonged monitoring and a higher heart rate cut-off for detection. METHODS: We enrolled 60 patients (44 ± 14 years) with HCM, who had a prophylactic implantable cardioverter defibrillator (ICD). Positive Holter NSVT (prior to implant) was defined as ≥3 beats at ≥120 beats per minute (bpm). We assessed the prevalence of rapid NSVT (RNSVT) detected by their ICD within 12 months of its implant, defined as 4-16 beats at ≥150-200 bpm. The primary outcome was appropriate ICD therapy (antitachycardia pacing and shocks) for sustained ventricular arrhythmia (VA). RESULTS: Holter NSVT was detected in 34 patients. RNSVT occurred in 21 (35%) patients of whom five did not have Holter NSVT. Over a median follow-up of 61 (interquartile range 29, 129) months after ICD implant, nine patients had VA. RNSVT, but not Holter NSVT, was significantly associated with VA (hazard ratio 6.2, 95% confidence interval [1.3-30], P = 0.01) by multivariable Cox regression analysis that included conventional risk factors. Receiver operating characteristic analysis for RNSVT (area under curve 0.80, P = 0.005) showed that the occurrence of ≥2 episodes of RNSVT discriminated patients for VA optimally (sensitivity 78%, specificity 84%, positive predictive value 47%, negative predictive value 96%). CONCLUSIONS: In this pilot study, RNSVT detected by continuous monitoring independently predicted VA in HCM and offered superior discrimination of VA risk compared to conventional risk factors, including Holter NSVT. Future studies are needed to validate these findings in a larger, unselected HCM cohort.

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

AIMS: Current conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts. METHODS AND RESULTS: Ablation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs. CONCLUSION: By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.

Exercise-Induced QRS Prolongation in Brugada Syndrome: Implications for Improving Disease Phenotyping and Diagnosis.

BACKGROUND: Abnormal ventricular activation at rest is reported in Brugada syndrome (BrS). OBJECTIVES: The aim of this study was to evaluate the usefulness of dynamic changes in ventricular activation during exercise to improve disease phenotyping and diagnosis of BrS. METHODS: Digital 12-lead electrocardiograms during stress testing were analyzed retrospectively at baseline, peak exercise, and recovery in 53 patients with BrS and 52 controls. Biventricular activation was assessed from QRS duration (QRSd), whereas right ventricular activation was assessed from S wave duration in the lateral leads (I and V6) and terminal R wave duration in aVR. Exercise-induced changes in QRS parameters to predict a positive procainamide response were assessed in separate test and validation cohorts with suspected BrS. RESULTS: Baseline electrocardiogram parameters were similar between BrS and controls. QRSd shortened with exercise in all controls but prolonged in all BrS (-6.1 ± 6.0 ms vs 7.1 ± 6.5 ms [P < 0.001] in V6). QRSd in recovery was longer in BrS compared with controls (90 ± 12 ms vs 82 ± 11 ms in V6; P = 0.002). Both groups demonstrated exercise-induced S duration prolongation in V6, with greater prolongation in BrS (8.2 ± 14.3 ms vs 1.2 ± 12.4 ms; P < 0.001). Any exercise-induced QRSd prolongation in V6 differentiated those with a positive vs negative procainamide response with 100% sensitivity and 95% specificity in the test cohort, and 87% sensitivity and 93% specificity in the validation cohort. CONCLUSIONS: Exercise-induced QRSd prolongation is ubiquitous in BrS primarily owing to delayed right ventricular activation. This electrocardiogram phenotype predicts a positive procainamide response and may provide a noninvasive screening tool to aid in the diagnosis of BrS before drug challenge.

High-resolution 3D scar imaging using a novel late iodine enhancement multidetector CT protocol to guide ventricular tachycardia catheter ablation.

Scar delineation with late gadolinium-enhanced MRI can direct VT substrate mapping and ablation, but imaging is poor and relatively contraindicated in the majority of patients with ICDs. We present a case of scar definition using late iodine-enhanced multidetector CT in a patient with ischemic cardiomyopathy and multiple ICD shocks for VT. CT images were acquired using a novel intracoronary contrast delivery protocol which provided high-resolution subendocardial scar visualization. The segmented scar images were subsequently imported into an electroanatomic mapping platform to guide successful VT ablation.

Assessment of Severity of Long QT Syndrome Phenotype and Risk of Fetal Death.

BACKGROUND: It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes. METHODS AND RESULTS: The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of ß-blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482-519 ms] versus 479 ms [IQR, 454-496 ms], P<0.001). Mothers treated with ß-blockers had babies born at term with lower birth weight compared with untreated women (2973±298 g versus 3470±338 g, P=0.002). In addition, the birth weight of babies born at term to treated women with QTc >500 ms was significantly lower compared with women with QTc <500 ms (2783±283 g versus 3084±256 g, P=0.029). CONCLUSIONS: Women with long QT syndrome with more severe phenotypes have a higher incidence of fetal death. Maternal QTc is longer in pregnancies that result in fetal loss, and the birth weight of babies born to patients taking ß-blockers with a QTc >500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.

Cardiac MRI and Clinical Outcomes in TMEM43 Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy is an inherited cardiomyopathy that can involve both ventricles. Several genes have been identified as pathogenic in arrhythmogenic cardiomyopathy, including TMEM43. However, there are limited data on cardiac MRI findings in patients with TMEM43 variants to date. In this case series, cardiac MRI findings and clinical outcomes are described in 14 patients with TMEM43 variants, including eight (57%) with the pathogenic p.Ser358Leu variant (six female patients; mean age, 33 years ± 15 [SD]) and six (43%) with a TMEM43 variant of unknown significance (three female patients; mean age, 38 years ± 11). MRI findings demonstrated left ventricular systolic dysfunction in eight (57%) patients and right ventricular dysfunction in four (29%) patients. Among the nine patients with late gadolinium enhancement imaging, left ventricular late gadolinium enhancement was present in seven (78%; all subepicardial) patients. In summary, TMEM43 variants are associated with high prevalence of subepicardial late gadolinium enhancement and left ventricular dysfunction. Keywords: Arrhythmogenic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, TMEM43, Cardiac MRI, Genetic Variants Supplemental material is available for this article.

2023 HRS expert consensus statement on the management of arrhythmias during pregnancy.

This international multidisciplinary expert consensus statement is intended to provide comprehensive guidance that can be referenced at the point of care to cardiac electrophysiologists, cardiologists, and other health care professionals, on the management of cardiac arrhythmias in pregnant patients and in fetuses. This document covers general concepts related to arrhythmias, including both brady- and tachyarrhythmias, in both the patient and the fetus during pregnancy. Recommendations are provided for optimal approaches to diagnosis and evaluation of arrhythmias; selection of invasive and noninvasive options for treatment of arrhythmias; and disease- and patient-specific considerations when risk stratifying, diagnosing, and treating arrhythmias in pregnant patients and fetuses. Gaps in knowledge and new directions for future research are also identified.

Use of Wearable Technology and Deep Learning to Improve the Diagnosis of Brugada Syndrome.

BACKGROUND: The diagnosis of Brugada syndrome by 12-lead electrocardiography (ECG) is challenging because the diagnostic type 1 pattern is often transient. OBJECTIVES: This study sought to improve Brugada syndrome diagnosis by using deep learning (DL) to continuously monitor for Brugada type 1 in 24-hour ambulatory 12-lead ECGs (Holters). METHODS: A convolutional neural network was trained to classify Brugada type 1. The training cohort consisted of 10-second standard/high precordial leads from 12-lead ECGs (n = 1,190) and 12-lead Holters (n = 380) of patients with definite and suspected Brugada syndrome. The performance of the trained model was evaluated in 2 testing cohorts of 10-second standard/high precordial leads from 12-lead ECGs (n = 474) and 12-lead Holters (n = 716). RESULTS: DL achieved a receiver-operating characteristic area under the curve of 0.976 (95% CI: 0.973-0.979) in classifying Brugada type 1 from 12-lead ECGs and 0.975 (95% CI: 0.966-0.983) from 12-lead Holters. Compared with cardiologist reclassification of Brugada type 1, DL had similar performance and produced robust results in experiments evaluating scalability and explainability. When DL was applied to consecutive 10-second, clean ECGs from 24-hour 12-lead Holters, spontaneous Brugada type 1 was detected in 48% of patients with procainamide-induced Brugada syndrome and in 33% with suspected Brugada syndrome. DL detected no Brugada type 1 in healthy control patients. CONCLUSIONS: This novel DL model achieved cardiologist-level accuracy in classifying Brugada type 1. Applying DL to 24-hour 12-lead Holters significantly improved the detection of Brugada type 1 in patients with procainamide-induced and suspected Brugada syndrome. DL analysis of 12-lead Holters may provide a robust, automated screening tool before procainamide challenge to aid in the diagnosis of Brugada syndrome.

Automated Quantification of Abnormal QRS Peaks From High-Resolution ECGs Predicts Late Ventricular Arrhythmias in Hypertrophic Cardiomyopathy: A 5-Year Prospective Multicenter Study.

Background Patients with hypertrophic cardiomyopathy (HCM) are at risk of ventricular arrhythmia (VA) attributed to abnormal electrical activation arising from myocardial fibrosis and myocyte disarray. We sought to quantify intra-QRS peaks (QRSp) in high-resolution ECGs as a measure of abnormal activation to predict late VA in patients with HCM. Methods and Results Prospectively enrolled patients with HCM (n=143, age 53±14 years) with prophylactic implantable cardioverter-defibrillators had 3-minute, high-resolution (1024 Hz), digital 12-lead ECGs recorded during intrinsic rhythm. For each precordial lead, QRSp was defined as the total number of peaks detected in the QRS complex that deviated from a smoothing filtered version of the QRS. The VA end point was appropriate implantable cardioverter-defibrillator therapy during 5-year prospective follow-up. After 5 years, 21 (16%) patients had VA. Patients who were VA positive had greater QRSp (6.0 [4.0-7.0] versus 4.0 [2.0-5.0]; P<0.01) and lower left ventricular ejection fraction (57±11 versus 62±9; P=0.038) compared with patients who were VA negative, but had similar established HCM risk metrics. Receiver operating characteristic analysis revealed that QRSp discriminated VA (area under the curve=0.76; P<0.001), with a QRSp ≥4 achieving 91% sensitivity and 39% specificity. The annual VA rate was greater in patients with QRSp ≥4 versus QRSp <4 (4.4% versus 0.98%; P=0.012). In multivariable Cox regression, age <50 years (hazard ratio [HR], 2.53; P=0.009) and QRSp (HR per QRS peak, 1.41; P=0.009) predicted VA after adjusting for established HCM risk metrics. In patients aged <50 years, the annual VA rate was 0.0% for QRSp <4 compared with 6.9% for QRSp ≥4 (P=0.012). Conclusions QRSp predicted VA in patients with HCM who were eligible for an implantable cardioverter-defibrillator after adjusting for established HCM risk metrics, such that each additional QRS peak increases VA risk by 40%. QRSp <4 was associated with a <1% annual VA risk in all patients, and no VA risk among those aged <50 years. This novel ECG metric may improve patient selection for prophylactic implantable cardioverter-defibrillator therapy by identifying those with low VA risk. These findings require further validation in a lower risk HCM cohort. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02560844.

Importance of newer cardiac magnetic resonance-based risk markers for sudden death prevention in hypertrophic cardiomyopathy: An international multicenter study.

BACKGROUND: The sudden death (SD) risk stratification algorithm in hypertrophic cardiomyopathy (HCM) has evolved, underscored recently by novel cardiac magnetic resonance (CMR)-based risk markers (left ventricular apical aneurysm, extensive late gadolinium enhancement, and end-stage disease with systolic dysfunction) incorporated into the 2020 American Heart Association (AHA)/American College of Cardiology (ACC) HCM guidelines. OBJECTIVE: The purpose of this study was to assess the specific impact of newer, predominantly CMR-based risk markers in a large multicenter HCM population that underwent primary prevention implantable cardioverter-defibrillator (ICD) implants. METHODS: Longitudinal study of 1149 consecutive HCM patients from 6 North American and European HCM centers prospectively judged to be at high SD risk based on ≥1 AHA/ACC individual risk markers and prophylactically implanted with an ICD was performed. European Society of Cardiology (ESC) risk score was retrospectively analyzed with respect to the known clinical outcome. RESULTS: Of 1149 patients with an ICD, 162 (14%) experienced device therapy terminating ventricular tachycardia/ventricular fibrillation 4.6 ± 4.2 years after implant. CMR-based markers solely or in combination led to ICD implantation in 49 of the 162 patients (30%) experiencing device therapy. Particularly low ESC scores (<4%/5 years) would have excluded an ESC ICD recommendation for 67 patients who nevertheless experienced appropriate ICD therapy, including 26 with the CMR-based risk markers not part of the ESC formula. CONCLUSION: Identification and incorporation of novel guideline-supported CMR-based risk markers enhance selection of HCM patients for SD prevention with ICDs. Absence of CMR-based markers from the ESC risk score accounts, in part, for it not identifying many HCM patients with SD events. These data support inclusion of CMR as a routine part of HCM patient evaluation and risk stratification.