A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network.

BACKGROUND: The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by ZFPM2) is observed in human ventricles during HF and causes HF in mice. METHODS: FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription. RESULTS: FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by TBX5. FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus. Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency. CONCLUSIONS: Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.

A premature truncation of MYBPHL in humans and a loss of Mybphl in mice is associated with dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL). Prior work in mice indirectly identified Mybphl expression in the atria and in small puncta throughout the ventricle. Because of its genetic association with human and mouse cardiac conduction system disease, we evaluated the anatomical localization of MyBP-HL and the consequences of loss of MyBP-HL on conduction system function. Immunofluorescence microscopy of normal adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles had a marked reduction of MyBP-HL-positive cells compared to controls. Lightsheet microscopy of normal perinatal day 5 mouse hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the contactin-2-positive ventricular conduction system, but this association was not apparent in Mybphl heterozygous hearts. Surface telemetry of Mybphl-null mice revealed atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a shorter atrial relative refractory period and atrial tachycardia. Calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrated an increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls. Super-resolution microscopy of Mybphl heterozygous and homozygous null atrial cardiomyocytes showed ryanodine receptor disorganization compared to wild type controls. Abnormal calcium release, shorter atrial refractory period, and atrial dilation seen in Mybphl null, but not wild type control hearts, agree with the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene contributes to ventricular arrhythmias and ventricular dysfunction.

Transcriptional Patterning of the Ventricular Cardiac Conduction System.

RATIONALE: The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood. OBJECTIVE: To study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. METHODS AND RESULTS: Using mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS. CONCLUSIONS: The CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.

ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.

RATIONALE: ZO-1 (Zona occludens 1), encoded by the tight junction protein 1 (TJP1) gene, is a regulator of paracellular permeability in epithelia and endothelia. ZO-1 interacts with the actin cytoskeleton, gap, and adherens junction proteins and localizes to intercalated discs in cardiomyocytes. However, the contribution of ZO-1 to cardiac physiology remains poorly defined. OBJECTIVE: We aim to determine the role of ZO-1 in cardiac function. METHODS AND RESULTS: Inducible cardiomyocyte-specific Tjp1 deletion mice (Tjp1fl/fl; Myh6Cre/Esr1*) were generated by crossing the Tjp1 floxed mice and Myh6Cre/Esr1* transgenic mice. Tamoxifen-induced loss of ZO-1 led to atrioventricular (AV) block without changes in heart rate, as measured by ECG and ex vivo optical mapping. Mice with tamoxifen-induced conduction system-specific deletion of Tjp1 (Tjp1fl/fl; Hcn4CreERt2) developed AV block while tamoxifen-induced conduction system deletion of Tjp1 distal to the AV node (Tjp1fl/fl; Kcne1CreERt2) did not demonstrate conduction defects. Western blot and immunostaining analyses of AV nodes showed that ZO-1 loss decreased Cx (connexin) 40 expression and intercalated disc localization. Consistent with the mouse model study, immunohistochemical staining showed that ZO-1 is abundantly expressed in the human AV node and colocalizes with Cx40. Ventricular conduction was not altered despite decreased localization of ZO-1 and Cx43 at the ventricular intercalated disc and modestly decreased left ventricular ejection fraction, suggesting ZO-1 is differentially required for AV node and ventricular conduction. CONCLUSIONS: ZO-1 is a key protein responsible for maintaining appropriate AV node conduction through maintaining gap junction protein localization.

Inconsistency in Self-Reporting the Use of Substances over Time.

BACKGROUND: The reliability of reporting the use of substances has important implications for researchers, policymakers, treatment providers, and other stakeholders. Recanting, defined as endorsing use of a particular substance initially and later denying it, threatens such reliability. Methods: Data from the National Longitudinal Study of Adolescent to Adult Health are utilized. This is a longitudinal nationally representative study of the U.S. individuals who have participated in five waves of interviews, starting in adolescence in 1994 and 1995 (Wave 1) and ending with the most recent wave (2016-2019) where respondents were aged 33-44 (Wave 5). Results: We found substantial recanting across years. From 2 to 17% of respondents recant over time. Misuse of prescription drugs is the most commonly recanted substance use behavior, at 16.8%. After this, alcohol use, and smoking are the most recanted substances. Race-ethnicity and education have a widespread association with recanting the various substances, and age and gender are also of importance. Conclusion: In the present study, we examined the issue of recanting of substance use over duration of up to 18 years. This extends the previous work on recanting by examining this phenomenon over a considerably longer period of time. We found substantial recanting across years, and that race-ethnicity and education are of significance in association with recanting.

Predictors of Safe Prescription Opioid Storage and Participation in Drug Take-Back Events: Results from a Statewide Survey.

Improper storage and disposal of prescribed opioids can lead to diversion or accidental poisonings. Studies of emergency department and cancer patients suggest prescription opioids are rarely stored securely or disposed of when unneeded. Safe storage and disposal practices reduce risks for others living in or visiting a household. The purpose of this study is thus to examine prescription opioid storage and participation in drug take-back events among Michigan adults. Participants (N = 702) were recruited through social media advertisements to complete an online survey in July and August 2018. Logistic regression was used to examine correlates of safe storage and disposal. 8.4% (n = 59) of participants reported always keeping opioids locked; 29.8% (n = 209) reported attending a drug take-back event. Black participants and those who believed that illegal drug use was a serious problem had greater odds of locking opioids; participants with higher levels of education or who knew someone who used heroin or misused prescription opioids had lesser odds of locking opioids. Age and race were associated with take-back event participation. Findings identify factors associated with safe prescription opioid storage/disposal and indicate safe storage/disposal seldom occurs. Education and provision of safe storage equipment should be designed for diverse ages, races/ethnicities, and levels of education. Drug take-back events not hosted by law enforcement may have broader appeal, as may those led by Black or other people of color. Wider use of drug donation boxes may facilitate increased disposal among those who do not wish to or cannot attend take-back events.

Intracardiac Delineation of Septal Conduction in Left Bundle-Branch Block Patterns.

BACKGROUND: Septal activation in patients with left bundle-branch block (LBBB) patterns has not been described previously. We performed detailed intracardiac mapping of left septal conduction to assess for the presence and level of complete conduction block (CCB) in the His-Purkinje system. Response to His bundle pacing was assessed in patients with and without CCB in the left bundle. METHODS: Left septal mapping was performed with a linear multielectrode catheter in consecutive patients with LBBB pattern referred for device implantation (n=38) or substrate mapping (n=47). QRS width, His duration, His-ventricular (HV) intervals, and septal conduction patterns were analyzed. The site of CCB was localized to the level of the left-sided His fibers (left intrahisian) or left bundle branch. Patients with ventricular activation preceded by Purkinje potentials were categorized as having intact Purkinje activation. RESULTS: A total of 88 left septal conduction recordings were analyzed in 85 patients: 72 LBBB block pattern and 16 controls (narrow QRS, n=11; right bundle-branch block, n=5). Among patients with LBB block pattern, CCB within the proximal left conduction system was observed in 64% (n=46) and intact Purkinje activation in the remaining 36% (n=26). Intact Purkinje activation was observed in all controls. The site of block in patients with CCB was at the level of the left His bundle in 72% and in the proximal left bundle branch in 28%. His bundle pacing corrected wide QRS in 54% of all patients with LBBB pattern and 85% of those with CCB (94% left intrahisian, 62% proximal left bundle-branch). No patients with intact Purkinje activation demonstrated correction of QRS with His bundle pacing. CCB showed better predictive value (positive predictive value 85%, negative predictive value 100%, sensitivity 100%) than surface ECG criteria for correction with His bundle pacing. CONCLUSIONS: Heterogeneous septal conduction was observed in patients with surface LBBB pattern, ranging from no discrete block to CCB. When block was present, we observed pathology localized within the left-sided His fibers (left intrahisian block), which was most amenable to corrective His bundle pacing by recruitment of latent Purkinje fibers. ECG criteria for LBBB incompletely predicted CCB, and intracardiac data might be useful in refining patient selection for resynchronization therapy.

Physiological optimization of robotic endoscopic epicardial CRT-D implantation using multielectrode electroanatomic mapping.

Multielectrode epicardial mapping during robotic implantation of cardiac resynchronization-defibrillator system. Robotically assisted endoscopic implantation of cardiac implantable devices is well documented to be both feasible and safe, and this technique provides particular benefit in patients with limited vascular access. In a patient meeting Class I indication for cardiac resynchronization therapy with defibrillator and inaccessible vascular access, we describe in this case an optimization strategy for intraoperative left ventricular lead placement utilizing robotic epicardial electroanatomic mapping as well as the feasibility of implanting a totally epicardial biventricular cardioverter-defibrillator system.

Impact of high-grade atrioventricular block and cumulative frequent pacing on atrial arrhythmias.

BACKGROUND: The relationship between high-grade atrioventricular block (HGAVB) with cumulative frequent pacing and risk of atrial arrhythmias (AAs) has not been well characterized. We hypothesized HGAVB and pacing may have significant impact on incidence and prevalence of AAs by modulating atrial substrate. OBJECTIVE: To determine impact of HGAVB and pacing on AAs including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT). METHODS: All consecutive patients who underwent dual-chamber pacemaker implantation for HGAVB from 2005 to 2011 at the University of Chicago were included. AAs and percent of pacing were detected through device interrogation. Patients' data were collected from electronic medical records and clinic visits. RESULTS: A total of 166 patients (mean age 71 ± 15 years; 54% female, 56% African American) were studied. AF was documented in 27% of patients before pacemaker implantation. During a mean 5.8 ± 2.2 years of follow-up, 47% had device-detected AF, 10% AFL, and 26% AT. New-onset AF was documented in 40 of the 122 patients without prior AF (33%). Continuous (≥ 99%) right ventricular pacing was associated with significantly decreased AF prevalence (34% vs 59%, P = 0.005), and correlated with lower incidence (26% vs 41%, P = 0.22). Pacing suppressed AF in 14% of patients with baseline AF; those patients had lower atrial pacing (3.2% vs 45%, P < 0.0001). Left atrial dilation was the only independent predictor of AF with frequent pacing (P = 0.009). CONCLUSIONS: HGAVB is associated with high incidence and prevalence of AAs with and without pacing. Cumulative frequent (≥99%) ventricular pacing reduces risk of AF in patients with HGAVB.

FOG-2 mediated recruitment of the NuRD complex regulates cardiomyocyte proliferation during heart development.

FOG-2 is a multi-zinc finger protein that binds the transcriptional activator GATA4 and modulates GATA4-mediated regulation of target genes during heart development. Our previous work has demonstrated that the Nucleosome Remodeling and Deacetylase (NuRD) complex physically interacts with FOG-2 and is necessary for FOG-2 mediated repression of GATA4 activity in vitro. However, the relevance of this interaction for FOG-2 function in vivo has remained unclear. In this report, we demonstrate the importance of FOG-2/NuRD interaction through the generation and characterization of mice homozygous for a mutation in FOG-2 that disrupts NuRD binding (FOG-2(R3K5A)). These mice exhibit a perinatal lethality and have multiple cardiac malformations, including ventricular and atrial septal defects and a thin ventricular myocardium. To investigate the etiology of the thin myocardium, we measured the rate of cardiomyocyte proliferation in wild-type and FOG-2(R3K5A) developing hearts. We found cardiomyocyte proliferation was reduced by 31±8% in FOG-2(R3K5A) mice. Gene expression analysis indicated that the cell cycle inhibitor Cdkn1a (p21(cip1)) is up-regulated 2.0±0.2-fold in FOG-2(R3K5A) hearts. In addition, we demonstrate that FOG-2 can directly repress the activity of the Cdkn1a gene promoter, suggesting a model by which FOG-2/NuRD promotes ventricular wall thickening by repression of this cell cycle inhibitor. Consistent with this notion, the genetic ablation of Cdkn1a in FOG-2(R3K5A) mice leads to an improvement in left ventricular function and a partial rescue of left ventricular wall thickness. Taken together, our results define a novel mechanism in which FOG-2/NuRD interaction is required for cardiomyocyte proliferation by directly down-regulating the cell cycle inhibitor Cdkn1a during heart development.

Downregulation of connexin43 by microRNA-130a in cardiomyocytes results in cardiac arrhythmias.

MicroRNAs (miRNAs) are now recognized as critical regulators of diverse physiological and pathological processes; however, studies of miRNAs and arrhythmogenesis remain sparse. Connexin43 (Cx43), a major cardiac gap junction protein, has elicited great interest in its role in arrhythmias. Additionally, Cx43 was a potential target for miR-130a as predicted by several computational algorithms. This study investigates the effect of miR-130a overexpression in the adult heart and its effect on cardiac rhythm. Using a cardiac-specific inducible system, transgenic mice demonstrated both atrial and ventricular arrhythmias. We performed ventricular-programmed electrical stimulation and found that the αMHC-miR130a mice developed sustained ventricular tachycardia beginning 6weeks after overexpression. Western blot analysis demonstrated a steady decline in Cx43 after 2weeks of overexpression with over a 90% reduction in Cx43 levels by 10weeks. Immunofluorescent staining confirmed a near complete loss of Cx43 throughout the heart. To validate Cx43 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts and HL-1 cardiomyocytes, both known to endogenously express miR-130a. Using a luciferase reporter fused to the 3'UTR of Cx43, we found a 52.9% reduction in luciferase activity in 3T3 cells (p<0.0001) and a 47.6% reduction in HL-1 cells (p=0.0056) compared to controls. Addition of an antisense miR-130a inhibitor resulted in a loss of inhibitory activity of the Cx43 3'UTR reporter. We have identified an unappreciated role for miR-130a as a direct regulator of Cx43. Overexpression of miR-130a may contribute importantly to gap junction remodeling and to the pathogenesis of atrial and ventricular arrhythmias.

Demographic, substance use, and mental well-being correlates of high-intensity drinking among college students and non-college young adults: implications for intervention.

OBJECTIVE: To assess demographic, substance use, and mental wellbeing factors associated with high-intensity drinking (HID; 10+ drinks on one occasion) among college- and non-college young adults, to inform prevention and intervention efforts. PARTICIPANTS: A total of 1,430 young adults (819 in college and 611 not attending college) in a Midwestern state who reported trying alcohol at least once. METHODS: Participants were recruited via social media between November 2019 and February 2020 to complete a web-based survey assessing demographics, substance use, and mental well-being. Logistic regression was conducted to assess relationships between these measures and HID among (1) college students and (2) non-college young adults. RESULTS: About 14.0% of participants reported past-month HID. Among both college- and non-college young adults, men, those who perceived slight or no risk of harm from binge drinking, and those who used alcohol and marijuana simultaneously in the past year had greater odds of reporting past-month HID. Among students, past-year prescription drug misuse was also associated with HID. CONCLUSIONS: High intensity-drinking is concerning given potential adverse consequences. Campus programming should address norms that may promote such drinking and other high-risk substance use associated with HID.

Experiences of healthcare and substance use treatment provider-based stigma among patients receiving methadone.

Background: Medications for Opioid Use Disorder (MOUD) are efficacious, however only one-third of individuals with an opioid use disorder (OUD) enter into treatment. Low rates of MOUD utilization are partially due to stigma. This study examines provider-based stigma toward MOUD and identifies factors associated with experiencing stigma related to MOUD from substance use treatment and healthcare providers among people receiving methadone. Methods: Clients receiving MOUD at an opioid treatment program (N = 247) were recruited to complete a cross-sectional computer-based survey assessing socio-demographics, substance use, depression and anxiety symptoms, self-stigma, and recovery supports/barriers. Logistic regression was used to examine factors associated with hearing negative comments about MOUD from substance use treatment and healthcare providers. Results: 27.9% and 56.7% of respondents reported they sometimes/often hear negative comments about MOUD from substance use treatment and healthcare providers, respectively. Logistic regression results indicate that individuals who experience more negative consequences resulting from their OUD (OR=1.09, p=.019) had greater odds of hearing negative comments from substance use treatment providers. Age (OR=0.966, p=.017) and treatment stigma (OR=1.42, p=.030) were associated with greater odds of hearing negative comments from healthcare providers. Conclusions: Stigma can be a deterrent to seeking substance use treatment, healthcare, and recovery support. Understanding factors associated with experiencing stigma from substance use treatment providers and healthcare providers is important as these individuals may act as advocates for those with OUD. This study highlights individual factors associated with hearing negative comments about methadone and other MOUD and point to areas for targeted education.

Cumulative barriers to retention in methadone treatment among adults from rural and small urban communities.

BACKGROUND: Though methadone has been shown to effectively treat opioid use disorder, many barriers prevent individuals from accessing and maintaining treatment. Barriers are prevalent in less populated areas where treatment options are limited. This study examines barriers to retention in methadone treatment in a small Midwest community and identifies factors associated with greater endorsement of barriers. METHODS: Patients at an opioid treatment program (N = 267) were recruited to complete a computer-based survey onsite. Surveys assessed demographics, opioid misuse, depression and anxiety symptoms, trauma history and symptoms, social support, and barriers to retention in treatment (e.g., childcare, work, housing, transportation, legal obligations, cost, health). Descriptive statistics were used to examine individual barriers and multiple regression was calculated to identify demographic and psychosocial factors associated with greater cumulative barriers. RESULTS: Most participants reported at least one barrier to retention in treatment and more than half reported multiple barriers. Travel hardships and work conflicts were the most highly endorsed barriers. Past year return to use (B = 2.31, p = 0.004) and more severe mental health symptomology (B = 0.20, p = 0.038) were associated with greater cumulative barriers. Greater levels of social support were associated with fewer barriers (B = - 0.23, p < 0.001). CONCLUSION: This study adds to the limited research on barriers to retention in methadone treatment among patients in rural and small urban communities. Findings suggest flexible regulations for dispensing methadone, co-location or care coordination, and family or peer support programs may further reduce opioid use and related harms in small communities. Individuals with past year return to use reported a greater number of barriers, highlighting the time following return to use as critical for wraparound services and support. Those with co-occurring mental health issues may be vulnerable to poor treatment outcomes, as evidenced by greater endorsement of barriers. As social support emerged as a protective factor, efforts to strengthen informal support networks should be explored as adjunctive services to methadone treatment.

Long-Term Effects of Sulfadiazine-Trimethoprim Medicated Diet on Cardiac Function, Hematology, and Weight Gain in Hsd:ICR (CD1) and Tac:SW Mice.

With the alarming increase in heart disease and heart failure, the need for appropriate and ethical animal models of cardiac dysfunction continues to grow. Currently, many animal models of cardiomyopathy require either invasive procedures or genetic manipulation, both of which require extensive expertise, time, and cost. Serendipitous findings at our institution revealed a possible correlation between sulfadiazine-trimethoprim (SDZ-TMP) medicated diet and the development of cardiomyopathy in IcrTac:ICR mice. We hypothesized that mice fed SDZ-TMP medicated diet continuously for 3 to 6 mo would develop cardiomyocyte degeneration and fibrosis, eventually leading to dilated cardiomyopathy. A total of 44 mice (22 Hsd:ICR (CD1) and 22 Tac:SW) were enrolled in the study. Half of these 44 mice were fed standard rodent diet and the other half were fed SDZ-TMP medicated diet. Baseline samples, including weights, CBCs, select biochemistry parameters, and echocardiography were performed prior to the start of either diet. Weights were obtained monthly and all other parameters were measured at least once during the study, and again at its conclusion. After 42 wk, mice were euthanized, and heart, lung and bone marrow tissue were submitted for histopathologic evaluation. Histologically, hearts were scored for the degree of degeneration, fibrosis, inflammation, and vacuolation. The data showed that SDZ-TMP did not have a significant effect on cardiac function, RBC parameters, biochemistry parameters (ALT, AST, calcium, magnesium, creatine kinase, and creatinine), hematopoiesis, or histologic heart scores. In addition, mice fed the SDZ-TMP medicated diet gained less weight over time. In summary, we were unable to reproduce the previous findings and thus could not use this approach to develop a novel model of cardiomyopathy. However, these results indicate that SDZ-TMP medicated diet containing 1,365 ppm of SDZ and 275 ppm of TMP does not appear to have long-term detrimental effects in mice.

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

BACKGROUND: Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava-right atrium during transvenous lead extraction is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with transvenous lead extraction difficulty. METHODS: Serial imaging of leads occurred before transvenous lead extraction using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty was calculated for each patient and compared with IVUS findings. RESULTS: One hundred fifty-eight vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, P<0.001) and median laser pulsations delivered (low=0 versus high grade=5852, P<0.001) were significantly higher in high-grade segments. Most patients with low lead extraction difficulty score had low ILA grades. Eighty-six percentage of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores. CONCLUSIONS: IVUS is a feasible imaging modality that may be useful in characterizing ILA in the superior vena cava-right atrium region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging. Graphic Abstract: A graphic abstract is available for this article.

Impact of Atrial Fibrillation Ablation on Recurrent Hospitalization: A Nationwide Cohort Study.

OBJECTIVES: This study assessed the impact of atrial fibrillation (AF) ablation on hospitalization and antiarrhythmic drug use in the community setting. BACKGROUND: Despite the widespread increase in the use of catheter ablation to treat AF in the United States, the impact of ablation on arrhythmic, cardiovascular, and noncardiovascular hospitalizations remains unclear. METHODS: The national prospectively acquired Truven Health MarketScan data set (January 1, 2008 to December 31, 2014) was used to identify patients who underwent first time AF ablation with uninterrupted enrollment for 24 months (12 months pre-ablation and 12 months post-ablation). Multivariate logistic regression was used to determine predictors of hospitalization. RESULTS: Of 5,238 patients who underwent AF ablation for the first time, 2,720 patients with uninterrupted enrollment were analyzed (age 60 ± 10 years; 29% were women, 79% had hypertension, and 23% had heart failure [HF]). AF ablation was associated with significantly reduced all-cause hospitalization from 1,669 hospitalizations in the year before ablation to 1,034 hospitalizations in the year after ablation, which was driven primarily by a 56% reduction in arrhythmic hospitalization. Nonarrhythmic cardiovascular hospitalizations also declined through a 43% drop off in HF hospitalizations. Noncardiovascular hospitalization rates did not significantly change. Age younger than 55 years (odds ratio [OR]: 1.43; p < 0.001), obstructive sleep apnea (OR: 1.38; p < 0.001), and HF (OR: 1.29; p = 0.024) were multivariate predictors for decreased arrhythmic hospitalization. Rates of antiarrhythmic drug use also significantly declined post-procedure by 37.5% (p < 0.001). CONCLUSIONS: In this nationwide cohort, AF ablation was associated with significant decreases in arrhythmic and nonarrhythmic cardiovascular hospitalizations, which was driven by reductions in hospitalization for AF and HF.

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis.

Atrial fibrillation (AF), defined by disorganized atrial cardiac rhythm, is the most prevalent cardiac arrhythmia worldwide. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with AF risk, including the cardiogenic transcription factor genes TBX5, GATA4, and NKX2-5. We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data.

A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice.

Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.