Low voltage-guided ablation of posterior wall improves 5-year arrhythmia-free survival in persistent atrial fibrillation.

INTRODUCTION: The posterior wall (PW) has been proposed as a standard target for ablation beyond pulmonary vein antral isolation (PVI) in patients with persistent atrial fibrillation (AF). However, studies have shown inconsistent outcomes with the addition of PW ablation. The presence or absence of low voltage on the PW may explain these inconsistencies. We evaluated whether PW ablation based on the presence or absence of low voltage improves long-term arrhythmia-free outcomes. METHODS: We retrospectively reviewed 5-year follow-up in 152 consecutive patients who received either standard ablation (SA) with PVI alone or PVI + PW ablation (PWA) based on physician discretion (n = 77) or voltage-guided ablation (VGA) with PVI and addition of PWA only if low voltage was present on the PW (n = 75). RESULTS: The two groups were well matched for baseline characteristics. At 5-year follow-up, 64% of patients receiving VGA were atrial tachyarrhythmia (AT)/AF free compared to 34% receiving SA (HR 0.358 p < .005). PWA had similar AF recurrence in SA and VGA groups (0.30 vs. 0.27 p = .96) but higher AT recurrence when comparing SA and VGA groups (0.39 vs. 0.15 p = .03). In multivariate analysis, both VGA and PWA predicted AF arrhythmia-free survival (HR 0.33, p = .001 and HR 0.20, p = .008, respectively). For AT, VGA predicted arrhythmia-free survival (HR 0.22, p = .028), while PWA predicted AT recurrence (HR 4.704, p = .0219). CONCLUSION: VGA of the posterior wall ablation beyond PVI in persistent AF significantly improves long-term arrhythmia-free survival when compared with non-voltage-guided ablation. PW ablation without voltage-guidance reduced AF recurrence but at the cost of a higher incidence of AT.

Use of the cryoballoon to ablate pulmonary vein-dependent left atrial flutter.

New atrial flutter (AFL) that arises after pulmonary vein isolation (PVI) by catheter or surgical ablation can originate from reconnection of a pulmonary vein (PV). Reisolation of PVs with cryoballoon ablation (CBA) for treatment of peri-PV AFL after Maze or PVI has not previously been reported. The present case series describes use of CBA to treat post-PVI and post-Maze PV-dependent AFL. In these cases, CBA was used to reisolate the PVs and terminate AFL without requiring additional lesion sets for treatment of AFL.

Patient characteristics as predictors of recurrence of atrial fibrillation following cryoballoon ablation.

BACKGROUND: While several studies have evaluated predictors for atrial fibrillation (AF) recurrence following catheter ablation, there are limited data specific to cryoballoon ablation (CBA). METHODS: We analyzed a prospective registry of patients at a single institution who underwent CBA. Recurrence of AF (RAF) was defined as recurrence of AF by 12-month follow-up, excluding the 3-month blanking period. Univariate analysis was performed to evaluate predictors of RAF. Receiver operating characteristic analysis was used to compare and evaluate the performance of various risk scores for discriminating risk of RAF. RESULTS: There were 542 patients included in the analysis with mean age 61.3 ± 10.6 years, 67.9% male, and 51.6% paroxysmal AF (PAF). Overall, only left atrial diameter (LAD) > 40 mm and ERAF (early recurrence of AF within 0-3 month blanking period) were significant predictors of RAF. In the PAF specific subgroup, LAD > 40 mm, AF duration > 12 months, prior stroke or transient ischemic attack, ERAF, and having previously failed an antiarrhythmic drug were significant predictors of RAF. In persistent AF (PeAF) subgroup, obstructive sleep apnea (OSA) and ERAF were significant predictors of RAF. Out of clinical risk scores tested, BASEAF2 had the highest performance with area under the curve of 0.646 (95% confidence interval [0.548, 0.708]; P < .01). CONCLUSIONS: In this single-center retrospective study of CBA, we found only LAD > 40 mm and ERAF to be predictors of RAF. We identified OSA as a potential targetable risk factor in PeAF patients undergoing CBA. Out of risk scores tested for discriminating risk of RAF, BASEAF2 had the best performance.

Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway.

BACKGROUND: The paracrine action of non-cardiac progenitor cells is robust, but not well understood. Mesenchymal stem cells (MSC) have been shown to enhance calcium (Ca(++)) cycling in myocytes. Therefore, we hypothesized that MSCs can suppress cardiac alternans, an important arrhythmia substrate, by paracrine action on Ca(++) cycling. METHODS AND RESULTS: Human cardiac myocyte monolayers derived from iPS cells (hCM) were cultured without or with human MSCs (hMSC) directly or plated on a transwell insert. Ca(++) transient alternans (Ca(++) ALT) and Ca(++) transient duration (CaD) were measured from hCM monolayers following application of 200µM H2O2. Ca(++) ALT in hCM was significantly decreased when cultured with hMSCs directly (97%, p<0.0001) and when cultured with hMSC in the transwell insert (80%, p<0.0001). When hCM with hMSCs were pretreated with PI3K or eNOS inhibitors, Ca(++) ALT was larger than baseline by 20% (p<0.0001) and 36% (p<0.0001), respectively. In contrast, Ca(++) ALT was reduced by 89% compared to baseline (p<0.0001) when hCM monolayers without hMSCs were pretreated with 20µM GSNO. In all experiments, changes in Ca(++) ALT were mirrored by changes in CaD. Finally, real time quantitative PCR revealed no significant differences in mRNA expression of RyR2, SERCA2a, and phospholamban between hCM cultured with or without hMSCs. CONCLUSION: Ca(++) ALT is suppressed by hMSCs in a paracrine fashion due to activation of a PI3K-mediated nitroso-redox pathway. These findings demonstrate, for the first time, how stem cell therapy might be antiarrhythmic by suppressing cardiac alternans through paracrine action on Ca(++) cycling.

Determination of sources of error and improvement in accuracy of left ventricular mass measurement by echocardiography.

Abnormal Left ventricular mass (LVM) prognosticates adverse cardiovascular events. Conventionally, LVM measured by echo assumes a prolate ellipsoid (PE) shape; however, it poorly correlates with reference standard of cardiac magnetic resonance imaging (CMR) derived LVM. PE model assumes LVL = 2 × LVID. We developed a new echo LVM formula based on LV length and tested for accuracy against CMR. A retrospective study of consecutive patients with an echocardiogram and CMR within 3 months. Derivation (n = 170) and validation cohorts (n = 54) were used to test the new formula. Following analysis of correlation of interventricular septum (IVS), LV internal dimension (LVID), posterior wall (PW) and LVL between echo and CMR, a novel paraboloid-shape linear regression (PLR) model was derived. LVM by both models were compared to CMR. Poor correlation observed between actual and assumed LVL (0.52 with CMR; 0.44 with echo). Strong correlation was noted between echo and CMR measured LVL, LVID, IVS (r > 0.80) and a moderate correlation with PW (r = 0.62). Strong correlation of LVL was harnessed to develop PLR model, which significantly decreased paired error in derivation cohort (from 64 ± 42 to 22 ± 21 gm) and validation cohort (from 63 ± 46 to 25 ± 18 gm). Furthermore, it demonstrates significant reduction in absolute, relative errors and variability along with superior correlation in both cohorts. Between echo and CMR, LVL demonstrates one of the best correlation among LV dimensions. The assumption, LVL = 2 × LVID appears inaccurate. PLR model incorporates LVL and significantly improves accuracy, reduces variability of LVM.

Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with ß-catenin-dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2-4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2-4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations.

Improvement in renal function following cryoballoon ablation for atrial fibrillation.

PURPOSE: Patients with chronic kidney disease are predisposed to heart rhythm disorders including atrial fibrillation (AF). Several studies have suggested that radiofrequency catheter ablation of AF improves renal function. However, little data exists for pulmonary vein isolation with cryoballoon ablation (CBA). The purpose of this study is to assess change in renal function following CBA for AF. METHOD: This is a single-center retrospective study that included patients who underwent CBA for AF between 2011 and 2016. Patients were grouped by baseline-estimated glomerular filtration rate (eGFR): ≥ 90 (Stage G1), 60-89.9 (Stage G2), and 30-59.9 mL/min/1.73 m2 (Stage G3). Change in eGFR was assessed > 3 months post-ablation. RESULTS: A total of 306 patients with both pre- and post-ablation serum creatinine measurements available were included. Baseline eGFRs for Stages G1, G2, and G3 patients were 103.5 ± 12.9 (n = 82), 74.7 ± 8.2 (n = 184), and 52.6 ± 6.6 mL/min/1.73 m2 (n = 40), respectively. Renal function was assessed 310.8 ± 104.2 days post-ablation. Average intra-procedural contrast use was 58.4 ± 23.8 mL. There was no significant change in eGFR following CBA in Stage G1 patients (p = 0.10). For those with Stages G2 and G3 renal function, eGFR improved by 6.1% (4.2 mL/min/1.73 m2, p < 0.01) and 13.8% (7.2 mL/min/1.73 m2, p < 0.01), respectively. This improvement was seen regardless of the presence or absence of recurrent atrial arrhythmias. CONCLUSIONS: CBA for AF may be associated with an improvement in renal function, particularly among those with a reduced baseline eGFR despite recurrence of atrial arrhythmias and intra-procedural contrast use.

Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

BACKGROUND: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates. METHODS: hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. RESULTS: Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% (P<0.001, n=15), increased Ca2+ alternans by 300% (P<0.001, n=18), and promoted spontaneous calcium release activity (n=14, P<0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1ß (98%, P<0.0001) and IL-6 (460%, P<0.02) compared with nonfailing hMSCs. IL-1ß or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. CONCLUSIONS: We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.

A novel risk model for very late return of atrial fibrillation beyond 1 year after cryoballoon ablation: the SCALE-CryoAF score.

PURPOSE: Cryoballoon ablation (CBA) is an effective technique for pulmonary vein isolation (PVI). To date, there are no risk models to predict very late recurrence of atrial fibrillation (VLRAF) after CBA. METHODS: Retrospective analysis of a single-center database was performed. Inclusion criteria included PVI using CBA for atrial fibrillation (AF) without additional ablation targets, follow-up > 365 days, and no recurrent AF between 90 and 365 days after procedure. The primary endpoint was recurrent AF > 30 s > 12 months post-CBA. A risk model was created using clinical variables. RESULTS: Of 674 CBA performed from 2011 to 2016, 300 patients (200 male, 62.0 ± 9.9 years) met inclusion criteria. Of these, 159 (53.0%) patients had paroxysmal AF. Patients had an average of 9.5 ± 2.7 cryoballoon freezes, and no patients required additional radiofrequency ablation lesion sets. Over a follow-up of 995 ± 490 days, 77/300 (25.7%) patients exhibited VLRAF. Univariate and multivariate analyses demonstrated that Structural heart disease (1 point), Coronary artery disease (3 points), left Atrial diameter > 43 mm (1 point), Left bundle branch block (3 points), Early return of AF (4 points), and non-paroxysmal AF (3 points) were risk factors for VLRAF. Combining these variables into a risk model, SCALE-CryoAF, (min 0; max 15) predicted VLRAF with an area under the curve of 0.73. CONCLUSION: SCALE-CryoAF is the first risk model to specifically predict first recurrence of AF beyond 1 year, VLRAF, after CBA. Model discrimination demonstrates that SCALE-CryoAF predicts VLRAF after CBA significantly better than other risk models for AF recurrence.

Outcomes With Novel Oral Anticoagulants in Obese Patients who Underwent Electrical Cardioversion for Atrial Tachyarrhythmias.

The efficacy of novel oral anticoagulants (NOACs) in severely obese patients is uncertain as volume of distribution is related to weight, and few such patients were enrolled in the pivotal trials. As the month after direct-current cardioversion (DCCV) for atrial fibrillation and atrial flutter is a high-risk period for stroke, we sought to evaluate the safety of performing DCCV in obese patients on NOAC. All patients who underwent DCCV after ≥3 weeks of NOAC or therapeutic warfarin treatment without a previous transesophageal echocardiogram over a 3-year period at a single center were included. Obesity groups were defined as normal (body mass index [BMI] < 25), overweight (BMI 25 to <30), class 1 obesity (BMI 30 to <35), class 2 obesity (BMI 35 to <40), and class 3 or severe obesity (BMI ≥ 40). The primary end point was stroke at 30days. Of 761 patients, 73 were severely obese, 78 class 2 obese, 197 class 1 obese, 254 overweight, and 159 in the normal weight group. Average age 66.4 ± 10.3years and 32.5% women. Mean CHA2DS2-VASc score was 2.6 ± 1.6, and 78.9% were on NOACs with no differences in groups. There were no strokes in the severely obese group, and 1 each in class 2 obesity and normal weight (p = 0.3). In conclusion, there was a low rate of stroke in all weight classes after DCCV in patients taking NOACs and warfarin. NOAC use in severely obese patients who underwent DCCV appears safe even in the absence of transesophageal echocardiogram.

Platelet-activating factor enhancement of calcium influx and interleukin-6 expression, but not production, in human microglia.

Calcium-sensitive fluorescence microscopy and molecular biology analysis have been used to study the effects of platelet-activating factor (PAF) on intracellular calcium [Ca2+]i and IL-6 expression in human microglia. PAF (applied acutely at 100 nM) elicited a biphasic response in [Ca2+]i consisting of an initial rapid increase of [Ca2+]i due to release from internal stores, followed by a sustained influx. The latter phase of the [Ca2+]i increase was blocked by SKF96365, a non-selective store-operated channel (SOC) inhibitor. RT-PCR analysis showed PAF treatment of microglia induced expression of the pro-inflammatory cytokine IL-6 in a time-dependent manner which was blocked in the presence of SKF96365. However, ELISA assay showed no production of IL-6 was elicited at any time point (1-24 h) for microglial exposures to PAF. These findings suggest that PAF stimulation of human microglia induces expression, but not production, of IL-6 and that SOC-mediated [Ca2+]i influx contributes to the enhanced expression of the cytokine.

Clinical and economic studies of eptifibatide in coronary stenting.

Platelet adhesion and aggregation at the site of coronary stenting can have catastrophic clinical and economic consequences. Therefore, effective platelet inhibition is vital during and after percutaneous coronary intervention. Eptifibatide is an intravenous antiplatelet agent that blocks the final common pathway of platelet aggregation and thrombus formation by binding to glycoprotein IIb/IIIa receptors on the surface of platelets. In clinical studies, eptifibatide was associated with a significant reduction of mortality, myocardial infarction, or target vessel revascularization in patients with acute coronary syndrome undergoing percutaneous coronary intervention. However, recent trials conducted in the era of dual antiplatelet therapy and newer anticoagulants failed to demonstrate similar results. The previously seen favorable benefit of eptifibatide was mainly offset by the increased risk of bleeding. Current American College of Cardiology/American Heart Association guidelines recommend its use as an adjunct in high-risk patients who are undergoing percutaneous coronary intervention with traditional anticoagulants (heparin or enoxaparin), who are not otherwise at high risk of bleeding. In patients receiving bivalirudin (a newer safer anticoagulant), routine use of eptifibatide is discouraged except in select situations (eg, angiographic complications). Although older pharmacoeconomic studies favor eptifibatide, in the current era of P2Y12 inhibitors and newer safer anticoagulants, the increased costs associated with bleeding make the routine use of eptifibatide an economically nonviable option. The cost-effectiveness of eptifibatide with the use of strategies that decrease the bleeding risk (eg, transradial access) is unknown. This review provides an overview of key clinical and economic studies of eptifibatide well into the current era of potent antiplatelet agents, novel safer anticoagulants, and contemporary percutaneous coronary intervention.

Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus.

Minocycline, a second-generation tetracycline compound, has been examined as a neuroprotectant in beta-amyloid (A beta)-injected rat hippocampus. At 7 days post-injection, A beta(1-42) caused a significant loss of granule cell layer neurons (28% reduction) compared to control uninjected hippocampus. Hippocampal injection of A beta peptide also led to marked gliosis with numbers of microglia (increased by 26-fold) and immunoreactivity of astrocytes (increased by 11-fold) relative to control, as determined from immunohistochemical analysis. Intraperitoneal administration of minocycline significantly reduced neuronal loss induced by A beta(1-42) (by 80%) and also diminished numbers of microglia (by 69%) and astrocytes (by 36%) relative to peptide alone. Peptide injection increased expression of cyclooxygenase-2 (COX-2) in most (about 70%) of granule cells, a subset (about 20%) of microglia, but not in astrocytes; in the presence of minocycline, COX-2 immunostaining was abolished in microglia. The results from this study suggest that minocycline may have efficacy in the treatment of AD.