Protocol modifications reduce risk of delayed pericardial effusions after vein of Marshall ethanol infusion: follow-up from the Maine experience.

BACKGROUND: While ethanol infusion into the vein of Marshall (VOM) as an adjunct to atrial fibrillation ablation has shown promise, adoption has been limited by the technical expertise required, unclear antiarrhythmic mechanism, and complication risk. Delayed pericardial effusions have been associated with ethanol infusion into the VOM in prior studies. Very little is known about how the procedural approach itself can impact the risk of delayed effusions. We sought to understand the incidence and influence of procedural technique on complications including delayed pericardial effusions from VOM ethanol infusion at a large single medical center. METHODS: A total of 275 atrial ablation cases wherein VOM ethanol infusion was attempted were identified from the time of the program's inception in 2019 at Maine Medical Center (Portland, ME) until October of 2023. Cases were classified into phase I cases (early experience) and phase II cases (later experience) based upon temporal programmatic changes in the ethanol dose and infusion rate as well as the use of routine VOM venography. Procedural details and complications were adjudicated from the medical record. RESULTS: The overall VOM ethanol infusion success was 91.4%. Nine complications (3.3%) occurred in eight patients (2.9% of patients). These were more frequent in phase I (5.8%) compared to phase II (1.3%, p = 0.047). This difference was driven by a difference in delayed presentations of tamponade, which occurred in four patients in phase I (3.3%) and in no patients in phase II (0%, p = 0.037). Twelve-month estimated atrial arrhythmia freedom did not differ between groups (73.8% phase I vs 70.4% phase II, p = 0.24). CONCLUSION: In our single-center experience, adjustments to the procedural approach with lower ethanol infusion rate and dosage, combined with utilizing selective VOM venography, associated with a lowering of complication rates and in particular, delayed pericardial tamponade.

Predictors of first pass isolation of the pulmonary veins in real world ablations: An analysis of 2671 patients from the REAL-AF registry.

INTRODUCTION: During atrial fibrillation ablation (AFA), achievement of first pass isolation (FPI) reflects effective lesion formation and predicts long-term freedom from arrhythmia recurrence. We aim to determine the clinical and procedural predictors of pulmonary vein FPI. METHODS: We reviewed AFA procedures in a multicenter prospective registry of AFA (REAL-AF). A multivariate ordinal logistic regression, weighted by inverse proceduralist volume, was used to determine predictors of FPI. RESULTS: A total of 2671 patients were included with 1806 achieving FPI in both vein sides, 702 achieving FPI in one, and 163 having no FPI. Individually, age, left atrial (LA) scar, higher power usage (50 W), greater posterior contact force, ablation index >350 posteriorly, Vizigo™ sheath utilization, nonstandard ventilation, and high operator volume (>6 monthly cases) were all related to improved odds of FPI. Conversely sleep apnea, elevated body mass index (BMI), diabetes mellitus, LA enlargement, antiarrhythmic drug use, and center's higher fluoroscopy use were related to reduced odds of FPI. Multivariate analysis showed that BMI > 30 (OR 0.78 [0.64-0.96]) and LA volume (OR per mL increase = 1.00 [0.99-1.00]) predicted lower odds of achieving FPI, whereas significant left atrial scarring (>20%) was related to higher rates of FPI. Procedurally, the use of high power (50 W) (OR 1.32 [1.05-1.65]), increasing force posteriorly (OR 2.03 [1.19-3.46]), and nonstandard ventilation (OR 1.26 [1.00-1.59]) predicted higher FPI rates. At a site level, high procedural volume (OR 1.89 [1.48-2.41]) and low fluoroscopy centers (OR 0.72 [0.61-0.84]) had higher rates of FPI. CONCLUSION: FPI rates are affected by operator experience, patient comorbidities, and procedural strategies. These factors may be postulated to impact acute lesion formation.

Atrioesophageal Fistula Rates Before and After Adoption of Active Esophageal Cooling During Atrial Fibrillation Ablation.

BACKGROUND: Active esophageal cooling reduces the incidence of endoscopically identified severe esophageal lesions during radiofrequency (RF) catheter ablation of the left atrium for the treatment of atrial fibrillation. A formal analysis of the atrioesophageal fistula (AEF) rate with active esophageal cooling has not previously been performed. OBJECTIVES: The authors aimed to compare AEF rates before and after the adoption of active esophageal cooling. METHODS: This institutional review board (IRB)-approved study was a prospective analysis of retrospective data, designed before collecting and analyzing the real-world data. The number of AEFs occurring in equivalent time frames before and after adoption of cooling using a dedicated esophageal cooling device (ensoETM, Attune Medical) were quantified across 25 prespecified hospital systems. AEF rates were then compared using generalized estimating equations robust to cluster correlation. RESULTS: A total of 14,224 patients received active esophageal cooling during RF ablation across the 25 hospital systems, which included a total of 30 separate hospitals. In the time frames before adoption of active cooling, a total of 10,962 patients received primarily luminal esophageal temperature (LET) monitoring during their RF ablations. In the preadoption cohort, a total of 16 AEFs occurred, for an AEF rate of 0.146%, in line with other published estimates for procedures using LET monitoring. In the postadoption cohort, no AEFs were found in the prespecified sites, yielding an AEF rate of 0% (P < 0.0001). CONCLUSIONS: Adoption of active esophageal cooling during RF ablation of the left atrium for the treatment of atrial fibrillation was associated with a significant reduction in AEF rate.

The Maine vein of Marshall ethanol experience: learning curve and safety.

BACKGROUND: The marginal benefit of ethanol infusion into the vein of Marshall (VOM) as an adjunct to atrial fibrillation ablation has shown promise in a single randomized study and case series from very experienced centers. However, adoption has not been widespread and the impact on real-world outcomes outside of leading centers is not established. The objective in this study is to understand the learning curve, and explore procedural outcomes and safety with VOM ethanol infusion from a large single medical center. METHODS: One hundred twenty nine atrial ablation cases wherein VOM ethanol infusion was attempted were identified from the time of the program's inception in 2019 at Maine Medical Center (Portland, ME). Our technical approach, procedural success, and complications were adjudicated from the medical record. RESULTS: The overall VOM ethanol infusion success was 90%. Infusion success rates improved and fluoroscopy utilization decreased with experience. Arrhythmia recurrence was 14% after a mean follow-up of 9.5 months. Complications occurred in 5.4% of patients, including a 3.1% risk of delayed tamponade. CONCLUSION: In our single center experience, VOM ethanol infusion was feasible with a high technical success rate. These positive results are balanced against a concerning rate of delayed tamponade.

Management of patients with interrupted inferior vena cava requiring electrophysiology procedures.

BACKGROUND: Interrupted inferior vena cava (IVC) is a rare venous anomaly that complicates the treatment of patients who require electrophysiology (EP) procedures. METHODS: We describe five consecutive cases of patients with interrupted IVC who presented to the EP laboratory requiring interventional procedures including catheter ablation for atrial fibrillation and supraventricular tachycardia and left atrial appendage closure. All cases were successfully completed utilizing a variety of approaches to vascular access including transseptal puncture via transhepatic and internal jugular approaches. CONCLUSION: Procedures in the EP lab can be performed successfully in patients with interrupted IVC.

Experience With Wearable Cardioverter-Defibrillators at 2 Academic Medical Centers.

OBJECTIVES: This study sought to characterize the experience in a cohort of patients prescribed a wearable cardioverter-defibrillator (WCD) over a 2-year interval at 2 academic medical centers. BACKGROUND: The WCD is available for patients felt to be at high risk of sudden cardiac death. However, there is a lack of randomized data to guide its use and prescribing patterns vary. METHODS: We retrospectively reviewed indications and therapies of all WCD prescriptions over a 2-year period from 2 large academic medical centers. Data on compliance and treatment events of patients wearing the WCD were reviewed. RESULTS: Among the 147 patients prescribed a WCD, 80% were male with an age of 59 ± 14 years. The WCD was prescribed for the following reasons: primary prevention in the setting of a left ventricular ejection fraction ≤35% (53%), secondary prevention when an implantable cardioverter-defibrillator was not implanted (16%), implantable cardioverter-defibrillator explantation (23%), and other high-risk scenarios for arrhythmic sudden death (9%). The median wear duration was 50 days (interquartile range [IQR]: 25 to 85 days) with a median of 21.0 h of wear per day (IQR: 15.0 to 22.8 h). High-voltage treatment was delivered in 3 separate patients, 2 of whom died. The third patient received 3 WCD shocks without restoration of a perfusing rhythm and ultimately was resuscitated by emergency responders. No patients received inappropriate therapies. CONCLUSIONS: Events requiring therapy were rare and no lives were directly saved by the WCD. Future efforts are needed to improve identification of patients most likely to benefit from a WCD.

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

BACKGROUND: Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. METHODS AND RESULTS: We sequenced a ≈158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. CONCLUSIONS: We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.

Novel Pacing Strategies for Heart Failure Management.

OPINION STATEMENT: Cardiac resynchronization therapy has emerged as the gold standard for heart failure patients with left ventricular systolic dysfunction and electrical dyssynchrony from an intrinsic intraventricular conduction delay or right ventricular pacing. However, the limits imposed by the coronary sinus venous anatomy restrict the applicability of the technology for many potential recipients. Furthermore, conventional resynchronization, by virtue of utilizing a single site of epicardial origin for left ventricular activation, is non-physiological. Several technologies on the horizon, including multisite pacing, left ventricular endocardial, and leadless devices, and direct His-bundle pacing are aimed at improving the response rate of cardiac resynchronization and extending candidacy to patients ineligible for conventional therapy. In this review, we discuss the limitations of the present technology and the role for these new therapies.

Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.

Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.

Pluripotent stem cells as a platform for cardiac arrhythmia drug screening.

OPINION STATEMENT: Since the first demonstrations of the differentiation of pluripotent stem cells to produce functional human cellular models such as cardiomyocytes, the scientific community has been captivated [1, 2••, 3]. In the time since that seminal work, the field has been catapulted forward by the demonstration that adult somatic cells can be reprogrammed to an induced state of pluripotency [4••], and more recently by the development of efficient and sophisticated genome editing tools [5••, 6••, 7], which together afford a theoretically unlimited supply of relevant genetic disease models. In particular, many of the early successes with induced pluripotent stem cell technology have been realized with cardiac arrhythmia syndromes [8••, 9-15]. There is interest in applying stem cell models in large-scale screens to discover novel therapeutics or drug toxicities. This manuscript aims to discuss the potential role of hPSC-derived cardiomyocyte models in therapeutic arrhythmia screens and review recent advances in the field that bring us closer to this reality.

Rapid cellular phenotyping of human pluripotent stem cell-derived cardiomyocytes using a genetically encoded fluorescent voltage sensor.

In addition to their promise in regenerative medicine, pluripotent stem cells have proved to be faithful models of many human diseases. In particular, patient-specific stem cell-derived cardiomyocytes recapitulate key features of several life-threatening cardiac arrhythmia syndromes. For both modeling and regenerative approaches, phenotyping of stem cell-derived tissues is critical. Cellular phenotyping has largely relied upon expression of lineage markers rather than physiologic attributes. This is especially true for cardiomyocytes, in part because electrophysiological recordings are labor intensive. Likewise, most optical voltage indicators suffer from phototoxicity, which damages cells and degrades signal quality. Here we present the use of a genetically encoded fluorescent voltage indicator, ArcLight, which we demonstrate can faithfully report transmembrane potentials in human stem cell-derived cardiomyocytes. We demonstrate the application of this fluorescent sensor in high-throughput, serial phenotyping of differentiating cardiomyocyte populations and in screening for drug-induced cardiotoxicity.

Usefulness of hemoglobin A(1c) to predict outcome after cardiac resynchronization therapy in patients with diabetes mellitus and heart failure.

Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control.

Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase.

OBJECTIVES: The aim of this study was to determine whether activation of ß3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload. BACKGROUND: ß3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike ß1- and ß2-ARs, ß3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a "brake" to protect the heart from catecholamine overstimulation. METHODS: C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (ß3 agonist, BRL 0.1 mg/kg/h), or both. RESULTS: Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS(-/-) mice. CONCLUSIONS: These results are the first to show in vivo cardioprotective effects of ß3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart.

Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor.

Stimulation of the beta-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of beta-blockers in heart failure. The beta3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, G(i), with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of beta3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking beta3-AR (beta3(-/-)) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. beta3(-/-) mice had much greater mortality after transverse aortic constriction (TAC) than WT controls. By 3 weeks of TAC, systolic function was worse. After 9 weeks of TAC, beta3(-/-) mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in beta3(-/-)TAC hearts after 9 weeks, and total and NOS-dependent superoxide rose, indicating heightened oxidative stress and NOS uncoupling. The level of eNOS phosphorylation in beta3(-/-)TAC hearts was diminished, and nNOS and iNOS expression levels were increased. GTP cyclohydrolase-1 expression was reduced, although total BH4 levels were not depleted. 3 weeks of BH4 treatment rescued beta3(-/-) mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of beta3-AR signaling exacerbates cardiac pressure-overload induced remodeling and enhances NOS uncoupling and consequent oxidant stress, all of which can be rescued with exogenous BH4. These data suggest a cardioprotective role for the beta3-AR in modulating oxidative stress and adverse remodeling in the failing heart.

Design of a side-view particle imaging velocimetry flow system for cell-substrate adhesion studies.

Experimental models that mimic the flow conditions in microcapillaries have suggested that the local shear stresses and shear rates can mediate tumor cell and leukocyte arrest on the endothelium and subsequent sustained adhesion. However, further investigation has been limited by the lack of experimental models that allow quantitative measurement of the hydrodynamic environment over adherent cells. The purpose of this study was to develop a system capable of acquiring quantitative flow profiles over adherent cells. By combining the techniques of side-view imaging and particle image velocimetry (PIV), an in vitro model was constructed that is capable of obtaining quantitative flow data over cells adhering to the endothelium. The velocity over an adherent leukocyte was measured and the shear rate was calculated under low and high upstream wall shear. The microcapillary channel was modeled using computational fluid dynamics (CFD) and the calculated velocity profiles over cells under the low and high shear rates were compared to experimental results. The drag force applied to each cell by the fluid was then computed. This system provides a means for future study of the forces underlying adhesion by permitting characterization of the local hydrodynamic conditions over adherent cells.