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AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.KEY QUESTION: Expand our understanding of the genetic basis for mitral valve prolapse (MVP). Uncover relevant pathways and target genes for MVP pathophysiology. Leverage genetic data for MVP risk prediction.KEY FINDING: Sixteen genetic loci were significantly associated with MVP, including 13 novel loci. Interesting target genes at these loci included LTBP2, TGFB2, ALKP3, BAG3, RBM20, and SPTBN1. A risk score including clinical factors and a polygenic risk score, performed best at predicting MVP, with an area under the receiver operating characteristics curve of 0.677.TAKE-HOME MESSAGE: Mitral valve prolapse has a polygenic basis: many genetic variants cumulatively influence pre-disposition for disease. Disease risk may be modulated via changes to transforming growth factor-β signalling, the cytoskeleton, as well as cardiomyopathy pathways. Polygenic risk scores could enhance the MVP risk prediction.

Objectives This study sought to investigate the factors associated with repeat infection following lead extraction procedures. Background Although lead extraction is an essential therapy for patients with cardiovascular implantable electronic device (CIED) infection, repeat infection still occurs in some patients. Methods The authors reviewed data for consecutive patients who underwent extraction of infected CIEDs from August 2003 to May 2019. Repeat infection was defined as infective endocarditis, sepsis with no alternative focus, or pocket infection after extraction of infected CIEDs. Results Extraction of infected CIEDs was performed in 496 patients. The most commonly implicated pathogen was Staphylococcus aureus (n = 188). In 449 patients (90.5%), all leads were completely extracted using only transvenous techniques. Thirty-three patients (6.7%) underwent surgical lead extraction, and 14 (2.8%) had retained leads or lead components. After a median follow-up of 352 [40 to 1,255] days after CIED extraction, 144 patients (29.0%) died. Repeat infection occurred in 47 patients (9.5%) with the median time from the extraction to repeat infection of 103 [45 to 214] days. In multivariable analysis, presence of a left ventricular assist device, younger age at extraction, and S. aureus infection were independent predictors of repeat infection. Additionally, chronic kidney disease, congestive heart failure, presence of septic emboli, S. aureus infection, and occurrence of major complications were independent predictors of increased mortality. Conclusions Patients with S. aureus infection have a high risk of repeat infection and poor prognosis after CIED extraction. Repeat infection is also predicted by younger age and the presence of a left ventricular assist device, whereas mortality was predicted by congestive heart failure, chronic kidney disease, and septic emboli.

Background: Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however, (R )-propafenone is an ryanodine receptor inhibitor whereas (S )-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with (R )-propafenone prevents induction of AF compared to (S )-propafenone or placebo in patients referred for AF ablation. Methods: Participants were randomized 4:4:1 to a one-time intravenous dose of (R )-propafenone, (S )-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter. Results: A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving (R )-propafenone, 60 (80.0%) receiving (S )-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the (R )-propafenone (N=23, 32.4%) and (S )-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%, P =0.029). There was no significant difference between (R )-propafenone and (S )-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable ( P =0.522) or multivariable analysis ( P =0.199, adjusted for age and serum drug level). Conclusions: There is no difference in AF inducibility between (R )-propafenone and (S )-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade. Registration: https://clinicaltrials.gov ; Unique Identifier: NCT02710669.

Background: Data on atrial fibrillation (AF) ablation and outcomes are limited in patients with congenital heart disease (CHD). We aimed to investigate the characteristics of patients with CHD presenting for AF ablation and their outcomes. Methods: A multicenter, retrospective analysis was performed of patients with CHD undergoing AF ablation between 2004 and 2020 at 13 participating centers. The severity of CHD was classified using 2014 Pediatric and Congenital Electrophysiology Society/Heart Rhythm Society guidelines. Clinical data were collected. One-year complete procedural success was defined as freedom from atrial tachycardia or AF in the absence of antiarrhythmic drugs or including previously failed antiarrhythmic drugs (partial success). Results: Of 240 patients, 127 (53.4%) had persistent AF, 62.5% were male, and mean age was 55.2±13.3 years. CHD complexity categories included 147 (61.3%) simple, 68 (28.3%) intermediate, and 25 (10.4%) severe. The most common CHD type was atrial septal defect (n=78). More complex CHD conditions included transposition of the great arteries (n=14), anomalous pulmonary veins (n=13), tetralogy of Fallot (n=8), cor triatriatum (n=7), single ventricle physiology (n=2), among others. The majority (71.3%) of patients had trialed at least one antiarrhythmic drug. Forty-six patients (22.1%) had reduced systemic ventricular ejection fraction Conclusions: AF ablation in CHD was safe and resulted in AF control in a majority of patients, regardless of complexity. Future work should address the most appropriate ablation targets in this challenging population.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

This study sought to define the association between conduction recovery across the cavotricuspid isthmus (CTI) and typical atrial flutter (AFL) recurrence when CTI ablation is performed with pulmonary vein isolation (PVI) compared with a stand-alone procedure.CTI ablation is commonly performed at the same time as PVI to treat AFL or as an empiric therapy. Conduction recovery is a recognized problem after linear ablation in the left atrium (e.g., mitral isthmus ablation) and is proarrhythmic. Less is known about conduction recovery after CTI ablation and possible differences in outcomes when performed at the time of PVI compared with at the time of a stand-alone procedure.Eligible participants who underwent stand-alone CTI ablation were compared with those who underwent a combined (CTI+PVI) procedure. CTI conduction recovery was assessed at the time of a second ablation. Conduction recovery across the CTI (primary outcome) and recurrence of typical AFL (secondary outcome) were studied using multivariable logistic regression.Among 295 eligible participants (median age: 64 years [interquartile range: 55 to 69 years]; 33% women), recovery was assessed in 232 and was more common after combined versus stand-alone CTI ablation (52% [72 of 139] vs. 13% [12 of 93]; p 0.001). In multivariable analysis, CTI ablation performed as a combined procedure increased odds of CTI conduction recovery 7.8-fold (odds ratio: 7.8; 95% confidence interval: 3.3 to 18.3; p 0.001) and clinical AFL recurrence 4.1-fold (odds ratio: 4.1; 95% confidence interval: 1.0 to 16.9; p = 0.049).CTI ablation performed at the time of atrial fibrillation ablation is associated with higher rates of conduction recovery and typical flutter recurrence.

Importance Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. Objective To examine the results of genetic testing for early-onset AF. Design, Setting, and Participants This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. Exposures Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. Main Outcomes and Measures Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. Results Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes wereTTN(n = 38),MYH7(n = 18),MYH6(n = 10),LMNA(n = 9), andKCNQ1(n = 8). Conclusions and Relevance In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

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.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

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

Background Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules. Methods The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch. Discussion The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF. Trial registration ClinicalTrials.gov NCT04433091. Registered on June 3, 2020.

Background: Pacing-induced cardiomyopathy (PICM) has been increasingly recognized as a cause of heart failure in patients with pacemakers. Thus far, clinical trials and observational studies of PICM have largely included elderly patients with mean age > 70 years. The prevalence and predictors of PICM in younger patients (age ≤ 59 years) after pacemaker implantation are not known. Methods: We retrospectively studied the prevalence and predictors of PICM in younger adults (18-59 years) who received single ventricular chamber or dual chamber pacemakers at Vanderbilt University Medical Center from 1986-2015. Patients without documented ventricular pacing burden, and patients with baseline left ventricular ejection fraction (LVEF) < 30% were excluded. PICM was defined as LVEF drop of ≥ 10% and LVEF < 50% during follow up in the setting of significant right ventricular pacing (≥ 20%), without alternative explanations for cardiomyopathy. Univariate and multivariable Cox proportional hazards regression models were utilized to study the factors associated with hazard of developing PICM. Results: A total of 325 patients were included in the study. 182 patients had high ventricular pacing (≥ 20%), which was associated with pre-existing atrial fibrillation (AF) and reduced baseline LVEF in addition to atrioventricular block (AVB) in the multivariate analysis. During the median follow up duration of 11.5 (Interquartile range 7 - 17) years, 38 patients (11.7%) developed PICM (1.3 per 100 patient-year). The median time to the development of PICM was 5 (Interquartile range 2 - 10) years. Older age (HR 2.5 for age ≥ 50 years, P = 0.013), reduced baseline LVEF (HR 2.4, P = 0.022), and AVB (HR 2.7, P = 0.007) were associated with an increased risk of PICM in the multivariate analysis. Furthermore, pre-existing AF was associated with an increased risk of PICM in patients without pre-implant AVB (HR 8.8 compared to the absence of both AF and AVB, P = 0.039). Conclusion: The incidence of PICM in young patients was low in this cohort of younger patients. Older age, baseline reduced LVEF, and AVB were associated with an increased risk of PICM in the young patient cohort. AF was associated with an increased risk of PICM in a subset of patients without pre-existing AVB at implant.

Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.

Type 2 diabetes is increasing in all ancestry groups1. Part of its genetic basis may reside among the rare (minor allele frequency 2. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program2 to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h2=53% (P=4.2×10−5) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures3 to annotate and group rare variants with respect to gene expression4, chromatin state5 and three-dimensional chromatin architecture6, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h2=8%, P=2.4×10−3). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22–1.58]; P P P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99–1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98–1.15]; P =0.13). Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Background Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes (“endophenotypes”) of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. Methods Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as “non-PV mediated AF”. A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for “PV-mediated AF”. Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. Results Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P

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 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.

Background: This study will evaluate whether or not texting frequency while driving and/or texting frequency in general are associated with an increased risk of incurring a motor vehicle collision (MVC) resulting in orthopaedic trauma injuries. Methods: All patients who presented to the Vanderbilt University Medical Center Orthopaedic Trauma Clinic were administered a questionnaire to determine background information, mean phone use, texting frequency, texting frequency while driving, and whether or not the injury was the result of an MVC in which the patient was driving. Results: 237 questionnaires were collected. 60 were excluded due to incomplete date, leaving 57 questionnaires in the MVC group and 120 from patients with non-MVC injuries. Patients who sent more than 30 texts per week (“heavy texters”) were 2.22 times more likely to be involved in an MVC than those who texted less frequently. 84% of respondents claimed to never text while driving. Dividing the sample into subsets on the basis of age (25 years of age or below considered “young adult,” and above 25 years of age considered “adult”),young, heavy texters were 6.76 times more likely to be involved in an MVC than adult non-heavy texters (p = 0.000). Similarly, young adult, non-heavy texters were 6.65 (p = 0.005) times more likely to be involved in an MVC, and adult, heavy texters were 1.72 (p = 0.186) times more likely to be involved in an MVC. Conclusions: Patients injured in an MVC sent more text messages per week than non-MVC patients. Additionally, controlling for age demonstrated that young age and heavy general texting frequency combined had the highest increase in MVC risk, with the former being the variable of greatest effect.

Background Disturbing trends regarding the sex, age, and race of gunshot victims have been reported in previous national studies; however, gunshot trends have not been well documented in individual cities in the southeastern United States. Objectives 1) Analyze trends in gunshot wounds, particularly the association between gunshot wounds and race, among victims presenting to a Level I Trauma Center in Middle Tennessee; 2) Compare specific characteristics of gunshot victims to the general Emergency Department (ED) population. Methods This is a retrospective cohort study of 343,866 ED visits from 2004 to 2009. Results Compared to the general ED population, gunshot victims were more predominantly male (87.5% vs. 43.4%), black (57.6% vs. 29.5%), younger (47.8% under age 25 years vs. 31.6%), and demonstrated higher Medicaid enrollment (78.6% vs. 44.7%). The majority of black gunshot victims were aged 18–25 years (47.1%) and victims of assault (65.9%). Non-black gunshot victims suffered more unintentional (40.2% vs. 28.2%) and self-inflicted (9.1% vs. 0.4%) injuries and were more evenly distributed among ages 18–55 years. Black patients were 3.03 (95% confidence interval 2.93–3.14) times more likely to present to this ED for gunshot wounds than non-black patients, after controlling for age, sex, and insurance status ( p Conclusions Our study demonstrates that black patients between 18 and 25 years of age presenting to this trauma center are more likely to be victims of gun violence than their non-black counterparts. Our study evaluates trends in gun violence in the Southeast, particularly in relation to race, age, and insurance status.

To investigate what factors contribute to increased length of stay (LOS) and increased costs in treatment of elderly patients with hip fractures.Retrospective chart review.All patients who presented to a large tertiary care center between January 2000 and December 31, 2009.Charts for all patients older than 60 years who presented with isolated low-energy hip fractures were reviewed. Of the 719 patients identified, 660 were included.Patients who underwent operative fixation or hemiarthroplasty secondary to hip fracture were identified using a search of Current Procedural Terminology (CPT) codes search.Gender, height, weight, body mass index, length of procedure, American Society of Anesthesiologists (ASA) classification, and medical comorbidities were gathered and compared with LOS and direct daily inpatient hospital cost.No correlation existed between body mass index or specific comorbidities and LOS, but ASA classification was a predictor. For each ASA increase of 1, average LOS increased 2.053 days (P0.001). Given total daily cost to the hospital for these patients was $4530, each increase in ASA classification translated to an increase of $9300.ASA classification proved useful in estimating LOS and cost for patients undergoing operative fixation of hip fractures. Because ASA classification and cost are universally collected, this method can be employed in almost any hospital. This highlights a role for ASA classification in preoperative estimation of the elderly patient's cost and a potential advantage for incorporating patient factors in the development of tiered reimbursement models.Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

The evolution of high throughput sequencing technologies has facilitated the rapid expansion of genetic testing in individuals with suspected heritable forms of cardiomyopathy. It is challenging to determine the pathogenicity of rare DNA variants in the absence of large kindreds that allow

Background— Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2 ), 1q21 (rs13376333 in KCNN3 ), and 16q22 (rs7193343 in ZFHX3 ) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation. Methods and Results— Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1–1.6]; P =0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence. Conclusions— Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF.

To identify the impact of the American Society of Anesthesiologists (ASA) physical status on postoperative length of stay (LOS) and to document the cost due to LOS after surgical management of the 8 most common lower extremity and 2 most common upper extremity isolated orthopaedic fractures.Retrospective chart review.All patients who presented and underwent one of the 10 selected isolated orthopaedic surgical procedures at a large tertiary care center between January 1, 2000, and December 31, 2010.Charts for patients undergoing the 10 selected isolated orthopaedic surgical fracture procedures more than 10 years were reviewed. Thirteen thousand seven hundred seventy-six distinct operations were identified. One thousand three hundred ninety-eight distinct operations were included in analysis after selection.This was an observational study. Patients who received operative management for isolated orthopaedic fractures were identified utilizing a CPT code search for analysis in a retrospective chart review.LOS and cost secondary to LOS.ASA physical status proved the strongest predictor of postoperative LOS for the 8 most common lower extremity and 2 most common upper extremity isolated orthopaedic procedures. ASA was also a significant predictor of inpatient cost for all isolated orthopaedic procedures included in the study with the exception of CPT code 27536.ASA classification is an indicator for variance in LOS and total inpatient cost for hospitalized patients. Given that ASA classification is a universally collected data point, this method can be used in almost any hospital system and for any operative service. In addition, this study provides a foundation for many other studies to be conducted which will include multiple institutions and fracture types, such that ASA can be used as a more generalizable predictor of LOS and inpatient cost in orthopaedic trauma patients. This model may be used to accurately predict a patient's postoperative course and the expected cost to the health care system of a given procedure.Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI. Methods: Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. Results: One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55–67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381–428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate