Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

BACKGROUND: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. METHODS: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. RESULTS: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. CONCLUSIONS: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier; NCT03394859.

Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2.

The ACTN2 gene encodes α-actinin 2, located in the Z-disc of the sarcomeres in striated muscle. In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant. This variant is in the EF 3-4 domain known to interact with titin and α-actinin. At the ultrastructural level, ACTN2 A868T cardiac samples presented small structural changes in cardiomyocytes when compared to healthy donor samples. However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca2+ levels. Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics. Molecular dynamics simulations indicated that while the mutation does not significantly impact the structure of α-actinin on its own, it likely alters the conformation associated with titin binding. Our results can be explained by two Z-disc mediated communication pathways: one pathway that involves α-actinin's interaction with actin, affecting thin filament regulation, and the other pathway that involves α-actinin's interaction with titin, affecting thick filament activation. This work establishes the role of α-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium as well as how it can be involved in the development of cardiac disease.

Durable pulmonary vein isolation with diffuse posterior left atrial ablation using low-flow, median power, short-duration strategy.

INTRODUCTION: To target posterior wall isolation (PWI) in atrial fibrillation (AF) ablation, diffuse ablation theoretically confers a lower risk of conduction recovery compared to box set. We sought to assess the safety and efficacy of diffuse PWI with low-flow, medium-power, and short-duration (LF-MPSD) ablation, and evaluate the durability of pulmonary vein isolation (PVI) and PWI among patients undergoing repeat ablations. METHODS: We retrospectively studied patients undergoing LF-MPSD ablation for AF (PVI + diffuse PWI) between August 2017 and December 2019. Clinical characteristics were collected. Kaplan-Meier survival analysis was performed to study AF/atrial flutter (AFL) recurrence. Ablation data were analyzed in patients who underwent a repeat AF/AFL ablation. RESULTS: Of the 463 patients undergoing LF-MPSD AF ablation (PVI alone, or PVI + diffuse PWI), 137 patients had PVI + diffuse PWI. Acute PWI with complete electrocardiogram elimination was achieved in 134 (97.8%) patients. Among the 126 patients with consistent follow-up, 38 (30.2%) patients had AF/AFL recurrence during a median duration of 14 months. Eighteen patients underwent a repeat AF/AFL ablation after PVI + diffuse PWI, and 16 (88.9%) patients had durable PVI, in contrast to 10 of 45 (23.9%) patients who had redo ablation after LF-MPSD PVI alone. Seven patients (38.9%) had durable PWI, while 11 patients had partial electrical recovery at the posterior wall. The median percentage of area without electrical activity at the posterior wall was 70.7%. Conduction block across the posterior wall was maintained in 16 (88.9%) patients. CONCLUSION: There was a high rate of PVI durability in patients undergoing diffuse PWI and PVI. Partial posterior wall electrical recovery was common but conduction block across the posterior wall was maintained in most patients.

How Will Genetics Inform the Clinical Care of Atrial Fibrillation?

Susceptibility to atrial fibrillation (AF) is determined by well-recognized risk factors such as diabetes mellitus or hypertension, emerging risk factors such as sleep apnea or inflammation, and increasingly well-defined genetic variants. As discussed in detail in a companion article in this series, studies in families and in large populations have identified multiple genetic loci, specific genes, and specific variants increasing susceptibility to AF. Since it is becoming increasingly inexpensive to obtain genotype data and indeed whole genome sequence data, the question then becomes to define whether using emerging new genetics knowledge can improve care for patients both before and after development of AF. Examples of improvements in care could include identifying patients at increased risk for AF (and thus deploying increased surveillance or even low-risk preventive therapies should these be available), identifying patient subsets in whom specific therapies are likely to be effective or ineffective or in whom the driving biology could motivate the development of new mechanism-based therapies or identifying an underlying susceptibility to comorbid cardiovascular disease. While current guidelines for the care of patients with AF do not recommend routine genetic testing, this rapidly increasing knowledge base suggests that testing may now or soon have a place in the management of select patients. The opportunity is to generate, validate, and deploy clinical predictors (including family history) of AF risk, to assess the utility of incorporating genomic variants into those predictors, and to identify and validate interventions such as wearable or implantable device-based monitoring ultimately to intervene in patients with AF before they present with catastrophic complications like heart failure or stroke.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Prevalence and predictors of pacing-induced cardiomyopathy in young adult patients (<60 years) with pacemakers.

INTRODUCTION: Clinical trials and observational studies of pacing-induced cardiomyopathy (PICM) have largely included elderly patients with mean age >70 years. The prevalence and predictors of PICM in younger patients (age < 60 years) after pacemaker implantation are not known. METHODS: Adults (18-59 years) who received single-chamber ventricular or dual-chamber pacemakers at Vanderbilt University Medical Center from 1986 to 2015 were included. Patients without documented ventricular pacing burden and patients with baseline left ventricular ejection fraction (LVEF) <35% were excluded. PICM was defined as LVEF decrease of ≥ 10% and LVEF < 50% during follow-up with right ventricular pacing ≥20%, and without alternative explanations for cardiomyopathy. RESULTS: A total of 325 patients were included in the study. During a median follow-up duration of 11.5 (Interquartile range 7-17) years, 38 patients (11.7%) developed PICM (1.3 per 100 patient-year). Older age (HR 2.5 for age ≥50 years, p = .013), reduced baseline LVEF (HR 2.4, p = .022), and preimplant AVB (HR 2.7, p = .007) were associated with an increased risk of PICM in the multivariate analysis. Furthermore, baseline AF conferred an increased risk of PICM only in patients without preimplant AVB but not patients with pre-implant AVB. CONCLUSIONS: The incidence of PICM in young patients was low, but PICM could occur more than a decade after pacemaker implantation. Older age, baseline reduced LVEF, and preimplant AVB were associated with an increased risk of PICM in the young patient cohort.

Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery.

BACKGROUND: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. METHODS: We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201). RESULTS: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5). CONCLUSIONS: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.

Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults.

OBJECTIVES: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU. DESIGN: Retrospective sub-study of a prospective observational cohort study. SETTING: Medical and general surgical ICUs in a tertiary academic medical center. PATIENTS: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30-0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27-2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009). CONCLUSIONS: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.

Atropine-induced sinus tachycardia protects against exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by exercise-induced ventricular arrhythmias, sudden death, and sinus bradycardia. Elevating supraventricular rates with pacing or atropine protects against catecholaminergic ventricular arrhythmias in a CPVT mouse model. We tested the hypothesis that increasing sinus heart rate (HR) with atropine prevents exercise-induced ventricular arrhythmias in CPVT patients. METHODS AND RESULTS: We performed a prospective open-label trial of atropine prior to exercise in CPVT patients (clinicaltrials.gov NCT02927223). Subjects performed a baseline standard Bruce treadmill test on their usual medical regimen. After a 2-h recovery period, subjects performed a second exercise test after parasympathetic block with atropine (0.04 mg/kg intravenous). The primary outcome measure was the total number of ventricular ectopic beats during exercise. All six subjects (5 men, 22-57 years old) completed the study with no adverse events. Atropine increased resting sinus rate from median 52 b.p.m. (range 52-64) to 98 b.p.m. (84-119), P = 0.02. Peak HRs (149 b.p.m., range 136-181 vs. 149 b.p.m., range 127-182, P = 0.46) and exercise duration (612 s, range 544-733 vs. 584 s, range 543-742, P = 0.22) were not statistically different. All subjects had ventricular ectopy during the baseline exercise test. Atropine pre-treatment significantly decreased the median number of ventricular ectopic beats from 46 (6-192) to 0 (0-29), P = 0.026; ventricular ectopy was completely eliminated in 4/6 subjects. CONCLUSION: Elevating sinus rates with atropine reduces or eliminates exercise-induced ventricular ectopy in patients with CPVT. Increasing supraventricular rates may represent a novel therapeutic strategy in CPVT.

Atrial fibrillation symptom profiles associated with healthcare utilization: A latent class regression analysis.

BACKGROUND: Symptoms drive healthcare use among adults with atrial fibrillation, but limited data are available regarding which symptoms are most problematic and which patients are most at-risk. The purpose of this study was to: (1) identify clusters of patients with similar symptom profiles, (2) characterize the individuals within each cluster, and (3) determine whether specific symptom profiles are associated with healthcare utilization. METHODS: We conducted a cross-sectional secondary data analysis of 1,501 adults from the Vanderbilt Atrial Fibrillation Registry. Participants were recruited from Vanderbilt cardiology clinics, emergency department, and in-patient services. Subjects included in our analysis had clinically verified atrial fibrillation and a completed symptom survey. Symptom and healthcare utilization data were collected with the University of Toronto Atrial Fibrillation Severity Scale. Latent class regression analysis was used to identify symptom clusters, with clinical and demographic variables included as covariates. We used Poisson regression to examine the association between latent class membership and healthcare utilization. RESULTS: Participants were predominantly male (67%) with a mean age of 58.4 years (±11.9). Four latent classes were evident, including an Asymptomatic cluster (N = 487, 38%), Highly Symptomatic cluster (N = 142, 11%), With Activity cluster (N = 326, 25%), and Mild Diffuse cluster (N = 336, 26%). Highly Symptomatic membership was associated with the greatest rate of emergency department visits and hospitalizations (incident rate ratio 2.4, P < 0.001). CONCLUSIONS: Clinically meaningful atrial fibrillation symptom profiles were identified that were associated with increased rates of emergency department visits and hospitalizations.

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3. Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

Staged versus Simultaneous Thoracoscopic Hybrid Ablation for Persistent Atrial Fibrillation Does Not Affect Time to Recurrence of Atrial Arrhythmia.

INTRODUCTION: Totally thoracoscopic (TT) epicardial ablation combined with endocardial catheter ablation is an emerging treatment for persistent AF. The effects of timing of the TT and endocardial portion on AT/AF recurrence are not known. METHODS: We retrospectively analyzed patients undergoing TT staged versus simultaneous hybrid AF ablation at our institution. Arrhythmia-free outcome was compared using time to recurrence (AF or AT greater than 30 seconds after a 3-month blanking period from endocardial ablation) at 12 months. All subjects had continuous ILR or PM monitoring. RESULTS: Eighty-three patients (52 same-day, 31 staged) underwent TT hybrid AF ablation. Recurrence was observed in 23 (29%) patients at a median time of 147 days (IQR 91,238). In univariate analysis, a staged approach significantly increased the likelihood of detecting incomplete PVI (OR 6 [95% CI 2-17] P = 0.001). However, only longstanding persistent AF (LSP-AF) status predicted recurrence (HR 4 [95% CI 1.4-12] P = 0.01). Neither a staged approach (HR 1.0 [95% CI 0.4-2.4] P = 0.9), nor detection of incomplete PVI (HR 0.9 [95% CI 0.4-2.3] P = 0.8) predicted time to first AF/AT recurrence. CONCLUSIONS: Staged hybrid ablation of AF significantly increases the likelihood of discovering incomplete PVI at the time of endocardial mapping versus a same-day procedure. However, the staged approach did not improve time to first AT/AF recurrence.

Association of atrial fibrillation risk alleles and response to acute rate control therapy.

OBJECTIVES: Given the sparse evidence for selection of first-line therapy for acute atrial fibrillation (AF) based on clinical factors alone, incorporation of genotype data may improve the effectiveness of treatment algorithms and advance the understanding of interpatient heterogeneity. We tested whether candidate nucleotide polymorphisms (SNPs) related to AF physiologic responses are associated with ventricular rate control after intravenous diltiazem in the emergency department (ED). METHODS: We conducted an analysis within a prospective observational cohort of ED patients with acute symptomatic AF, ventricular rate >110 beats per minute within the first 2 hours, initially treated with intravenous diltiazem, and who had DNA available for analysis. We evaluated 24 candidate SNPs that were grouped into 3 categories based on their phenotype response (atrioventricular nodal [AVN] conduction, resting heart rate, disease susceptibility) and calculated 3 genetic scores for each patient. Our primary outcome was maximum heart rate reduction within 4 hours of diltiazem administration. Multivariable regression was used to identify associations with the outcome while adjusting for age, sex, baseline heart rate, and diltiazem dose. RESULTS: Of the 142 patients, 127 had complete data for the primary outcome. None of the genetic scores for AVN conduction, resting heart rate, or AF susceptibility showed a significant association with maximal heart rate response. CONCLUSION: Using a candidate SNP approach, screening for genetic variants associated with AVN conduction, resting heart rate, or AF susceptibility failed to provide significant data for predicting successful rate control response to intravenous diltiazem for treating acute AF in the ED.

Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.

IMPORTANCE: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. OBJECTIVE: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. EXPOSURES: One or more variants designated as pathogenic in SCN5A or KCNH2. MAIN OUTCOMES AND MEASURES: Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. RESULTS: Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. CONCLUSIONS AND RELEVANCE: Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

Comparative outcomes of transvenous extraction of sprint fidelis and riata defibrillator leads: a single center experience.

INTRODUCTION: The FDA has issued class I advisories for Medtronic Sprint Fidelis(®) and St. Jude Medical Riata(TM) ICD lead families. Transvenous Riata(TM) ICD lead extraction is typically considered higher risk than Fidelis(®) extraction, based on longer duration from implant, presence of externalized conductors and lack of silicone backfill in the SVC and RV coils. However, published data comparing procedural outcomes between these leads are limited. METHODS: Records were reviewed for all patients undergoing transvenous extraction of Sprint Fidelis(®) or Riata(TM) ICD leads at the Vanderbilt Heart and Vascular Institute from July 2006 to April 2013 to ascertain indication for extraction, procedural details, complications, and 30-day mortality. RESULTS: There were significant differences between those undergoing extraction of a Sprint Fidelis(®) (n = 145) or Riata(TM) lead (n = 47). In the Riata(TM) group, device-related endocarditis was a more common indication for extraction, the mean duration of implant was longer, and larger excimer laser sheaths were required. Lead malfunction was a more common indication in the Fidelis(®) group. There were no statistically significant differences in median procedure duration, procedural success (97.9% vs 95.7%, P = 0.41), median length of hospital stay (1 day vs 1 day, P = 0.23), procedural complication rate (5.5% vs 10.6%, P = 0.23) or 30-day mortality (2.1% vs 2.1%, P = 0.98). Analyses excluding patients with device infection revealed similar results. CONCLUSION: Despite differences in baseline characteristics, this study indicates that Medtronic Sprint Fidelis(®) and St. Jude Riata(TM) ICD leads have similar procedural outcomes with transvenous lead extraction.

Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes.

Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear. Methods: We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping. The phenotypic architecture in the AF cohort was defined using principal component analysis of 35 expertly curated and uncorrelated clinical features. We applied an unsupervised co-clustering machine learning algorithm to the 35 features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention in the EHR. Polygenic risk scores (PRS) for AF and cytokine levels were used to assess genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from EHR up to the last medical contact. Results: The analysis included 23,271 subjects with AF, of which 6,023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal dysfunction, and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbid cluster, while there was no difference between groups in genetically predicted levels of inflammatory biomarkers. Subgroup assignment was associated with multiple clinical outcomes including mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis. Conclusion: Patient subgroups identified by unsupervised clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes. Polygenic liability to AF across clusters was greatest in the low comorbidity subgroup. Clinical inflammation, as reflected by measured biomarkers, was lowest in the subgroup with lowest comorbidities. However, there were no differences in genetically predicted levels of inflammatory biomarkers, suggesting associations between AF and inflammation is driven by acquired comorbidities rather than genetic predisposition.