Recent advances in gene therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments for AF are suboptimal as they are not targeting the molecular mechanisms underlying AF. In this regard, gene therapy is emerging as a promising approach for mechanism-based treatment of AF. In this review, we summarize recent advances and challenges in gene therapy for this important cardiovascular disease.

A novel octaray multielectrode catheter for high-resolution atrial mapping: Electrogram characterization and utility for mapping ablation gaps.

INTRODUCTION: Multielectrode mapping catheters improve the ability to map within the heterogeneous scar. A novel Octaray catheter with eight spines and 48 electrodes may further improve the speed and resolution of atrial mapping. The aims of this study were to (1) establish the Octaray's baseline mapping performance and electrogram (EGM) characteristics in healthy atria and to (2) determine its utility for identifying gaps in a swine model of atrial ablation lines. METHODS AND RESULTS: The right atria of eight healthy swine were mapped with Octaray and Pentaray catheters (Biosense Webster, Irvine, CA) before and after the creation of ablation lines with intentional gaps. Baseline mapping characteristics including EGM amplitude, duration, number of EGMs, and mapping time were compared. Postablation maps were created and EGM characteristics of continuous lines and gaps were correlated with pathology. Compared with Pentaray, the Octaray collected more EGMs per map (2178 ± 637 vs 1046 ± 238; P < 0.001) at a shorter mapping duration (3.2 ± 0.79 vs 6.9 ± 2.67 minutes; P < 0.001). In healthy atria, the Octaray recorded lower bipolar voltage amplitude (1.96 ± 1.83 mV vs 2.41 ± 1.92 mV; P < 0.001) while ablation gaps were characterized by higher voltage amplitude (1.24 ± 1.12 mV vs 1.04 ± 1.27 mV; P < 0.001). Ablation gaps were similarly identified by both catheters (P = 1.0). The frequency of "false gaps," defined as intact ablation lines with increased voltage amplitude was more common with Pentaray (6 vs 2) and resulted from erroneous annotation of far-field EGMs. CONCLUSION: The Octaray increases the mapping speed and density compared with the Pentaray catheter. It is as sensitive for identifying ablation gaps and more specific for mapping intact ablation lines.

Use of Atrial Fibrillation Electrograms and T1/T2 Magnetic Resonance Imaging to Define the Progressive Nature of Molecular and Structural Remodeling: A New Paradigm Underlying the Emergence of Persistent Atrial Fibrillation.

BACKGROUND: The temporal progression states of the molecular and structural substrate in atrial fibrillation (AF) are not well understood. We hypothesized that these can be detected by AF electrograms and magnetic resonance imaging parametric mapping. METHODS AND RESULTS: AF was induced in 43 dogs (25-35 kg, ≥1 year) by rapid atrial pacing (RAP) (3-33 weeks, 600 beats/min), and 4 controls were used. We performed high-resolution epicardial mapping (UnEmap, 6 atrial regions, both atria, 130 electrodes, distance 2.5 mm) and analyzed electrogram cycle length, dominant frequency, organization index, and peak-to-peak bipolar voltage. Implantable telemetry recordings were used to quantify parasympathetic nerve activity over RAP time. Magnetic resonance imaging native T1, postcontrast T1, T2 mapping, and extracellular volume fraction were assessed (1.5T, Siemens) at baseline and AF. In explanted atrial tissue, DNA oxidative damage (8-hydroxy-2'-deoxyguanosine staining) and percentage of fibrofatty tissue were quantified. Cycle length and organization index decreased (R=0.5, P<0.05; and R=0.5, P<0.05; respectively), and dominant frequency increased (R=0.3, P n.s.) until 80 days of RAP but not thereafter. In contrast, voltage continued to decrease throughout the duration of RAP (R=0.6, P<0.05). Parasympathetic nerve activity increased following RAP and plateaued at 80 days. Magnetic resonance imaging native T1 and T2 times increased with RAP days (R=0.5, P<0.05; R=0.6, P<0.05) in the posterior left atrium throughout RAP. Increased RAP days correlated with increasing 8-hydroxy-2'-deoxyguanosine levels and with fibrosis percentage (R=0.5, P<0.05 for both). CONCLUSIONS: A combination of AF electrogram characteristics and T1/T2 magnetic resonance imaging can detect early-stage AF remodeling (autonomic remodeling, oxidative stress) and advanced AF remodeling due to oxidative stress and fibrosis.

Regions of Highly Recurrent Electrogram Morphology With Low Cycle Length Reflect Substrate for Atrial Fibrillation.

Traditional anatomically guided ablation and attempts to perform electrogram-guided atrial fibrillation (AF) ablation (CFAE, DF, and FIRM) have not been shown to be sufficient treatment for persistent AF. Using biatrial high-density electrophysiologic mapping in a canine rapid atrial pacing model of AF, we systematically investigated the relationship of electrogram morphology recurrence (EMR) (Rec% and CLR) with established AF electrogram parameters and tissue characteristics. Rec% correlates with stability of rotational activity and with the spatial distribution of parasympathetic nerve fibers. These results have indicated that EMR may therefore be a viable therapeutic target in persistent AF.

Expandable Lattice Electrode Ablation Catheter: A Novel Radiofrequency Platform Allowing High Current at Low Density for Rapid, Titratable, and Durable Lesions.

BACKGROUND: High-current short-duration radiofrequency energy delivery has potential advantages for cardiac ablation. However, this strategy is limited by high current density and narrow safety-to-efficacy window. The objective of this study was to examine a novel strategy for radiofrequency energy delivery using a new electrode design capable of delivering high power at a low current density to increase the therapeutic range of radiofrequency ablation. METHODS: The Sphere9 is an expandable spheroid-shaped lattice electrode design with an effective surface area 10-fold larger than standard irrigated electrodes (lattice catheter). It incorporates 9 surface temperature sensors with ablation performed in a temperature-controlled mode. Phase I: in 6 thigh muscle preparations, 2 energy settings for atrial ablation were compared between the lattice and irrigated-tip catheters (low-energy: Tmax75°C/5 s versus 25 W/20 s; high-energy: Tmax75°C/7 s versus 30 W/20 s). Phase II: in 8 swine, right atrial lines were created in the posterior and lateral walls using low- and high-energy settings, respectively. Phase III: the safety, efficacy, and durability at 30 days were evaluated by electroanatomical mapping and histopathologic analysis. RESULTS: In the thigh model, the lattice catheter resulted in wider lesions at both low- and high-energy settings (18.7±3.3 versus 12.2±1.7 mm, P<0.0001; 19.4±2.4 versus 12.3±1.7 mm, P<0.0001). Atrial lines created with the lattice were wider (posterior: 14.7±3.4 versus 9.2±4.0 mm, P<0.0001; lateral: 15.8±4.2 versus 5.7±4.2 mm, P<0.0001) and required 85% shorter ablation time (12.4 versus 79.8 s/cm-line). While current squared (I2) was higher with Sphere9 (7.0±0.04 versus 0.2±0.002 A2; P<0.0001), the current density was lower (9.6±0.9 versus 16.9±0.09 mA/mm2; P<0.0001). At 30 days, 100% of ablation lines created with the lattice catheter remained contiguous compared with only 14.3% lines created with a standard irrigated catheter. This was achieved without steam pops or collateral tissue damage. CONCLUSIONS: In this preclinical model, a novel, high-current low-density radiofrequency ablation strategy created contiguous and durable ablation lines in significantly less ablation time and a comparable safety profile.

Activation During Sinus Rhythm in Ventricles With Healed Infarction: Differentiation Between Arrhythmogenic and Nonarrhythmogenic Scar.

BACKGROUND: In infarct-related ventricular tachycardia (VT), the circuit often corresponds to a location characterized by activation slowing during sinus rhythm (SR). However, the relationship between activation slowing during SR and vulnerability for reentry and correlation to components of the VT circuit are unknown. This study examined the relationship between activation slowing during SR and vulnerability for reentry and correlated these areas with components of the circuit. METHODS: In a porcine model of healed infarction, the spatial distribution of endocardial activation velocity was compared between SR and VT. Isthmus sites were defined using activation and entrainment mapping as areas exhibiting diastolic activity within the circuit while bystanders were defined as areas displaying diastolic activity outside the circuit. RESULTS: Of 15 swine, 9 had inducible VT (5.2±3.0 per animal) while in 6 swine VT could not be induced despite stimulation from 4 RV and LV sites at 2 drive trains with 6 extra-stimuli down to refractoriness. Infarcts with VT had a greater magnitude of activation slowing during SR. A minimal endocardial activation velocity cutoff ≤0.1 m/s differentiated inducible from noninducible infarctions (P=0.015). Regions of maximal endocardial slowing during SR corresponded to the VT isthmus (area under curve=0.84 95% CI, 0.78-0.90) while bystander sites exhibited near-normal activation during SR. VT circuits were complex with 41.7% exhibiting discontinuous propagation with intramural bridges of slow conduction and delayed quasi-simultaneous endocardial activation. Regions forming the VT isthmus borders had faster activation during SR while regions forming the inner isthmus were activated faster during VT. CONCLUSIONS: Endocardial activation slowing during SR may differentiate infarctions vulnerable for VT from those less vulnerable for VT. Sites of slow activation during SR correspond to sites forming the VT isthmus but not to bystander sites.

Modulating the Baseline Impedance: An Adjunctive Technique for Maximizing Radiofrequency Lesion Dimensions in Deep and Intramural Ventricular Substrate: An Adjunctive Technique for Maximizing Radiofrequency Lesion Dimensions in Deep and Intramural Ventricular Substrate.

Background Radiofrequency ablation of intramural ventricular substrate is often limited by insufficient tissue penetration despite high energy settings. As lesion dimensions have a direct and negative relationship to impedance, reducing the baseline impedance may increase the ablation effect on deep ventricular tissue. Methods This study included 16 patients with ventricular tachycardia or frequent ventricular premature complexes refractory to ablation with irrigated catheters. After a failed response to radiofrequency ablation, impedance was modulated by adding or repositioning return patches in an attempt to decrease the circuit impedance. Ablation was repeated at a similar location and power settings, and the effect on arrhythmia suppression and adverse effects were evaluated. Results Six patients with idiopathic ventricular premature complexes originating from the left ventricular summit (n=4) or papillary muscles (n=2), 6 patients with noninfarct related ventricular tachycardia and 4 patients with infarct-related ventricular tachycardia had unsuccessful response to radiofrequency ablation at critical sites (number of applications: 10.4±3.1, power: 42.3±2.9 W, duration: 55.3±25.5 seconds, impedance reduction: 14.6±3.5 Ω, low-ionic solution was used in 81.25%). Modulating the return patches resulted in reduced baseline impedance (111.7±8.2 versus 134.7±6.6 Ω, P<0.0001), increased current output (0.6±0.02 versus 0.56±0.02 Amp; P<0.0001) and greater impedance drop (16.8±3.0 Ω, P<0.001). Repeat ablation at similar locations had a successful effect in 12 out of 16 (75.0%) patients. During a follow-up duration of 13±5 months, 10 out of 12 (83.3%) patients remained free of arrhythmia recurrence. The frequency of steam pops was similar between the higher and lower baseline impedance settings (7.1 versus 8.2%; P=0.74). Conclusions In patients with deep ventricular substrate, reducing the baseline impedance is a simple, safe, and effective technique for increasing the effect of radiofrequency ablation. However, its combination with low-ionic solutions may increase the risk for steam pops and neurological events.

Effect of Baseline Impedance on Ablation Lesion Dimensions: A Multimodality Concept Validation From Physics to Clinical Experience.

BACKGROUND: Radiofrequency ablation using irrigated catheters is performed using a power-controlled mode. However, lesion size is dependent on current delivery at a particular impedance, such that a power value alone may not reflect actual energy delivery, resulting in lesion size variability at similar power settings. We hypothesized that modulating baseline impedance at fixed power settings affects ablation lesion dimensions. METHODS: In 20 ex vivo swine hearts, radiofrequency ablation was performed using an irrigated catheter at a fixed power setting of 30 W per 20 seconds and a multistepped impedance load (100-210Ω). In 4 in vivo thigh muscle preparations and right atria, ablation was performed using similar power settings at 3 baseline impedances: low (90-130Ω), intermediate (131-180Ω), and high (181-224Ω). The relationship between baseline impedance, current, and lesion dimensions was examined. RESULTS: Baseline impedance had a strong negative correlation with current squared ( I2) for all experimental models: ex vivo (R=-0.94; P<0.0001), thigh muscle (R=-0.93; P<0.0001), and right atria (R=-0.94; P<0.0001). Lesion dimensions at similar power settings were highly variable and directly related to I2 (width [R=0.853], depth [R=0.814]). In the thigh muscle, lesion depth was 8.2±0.7, 6.5±0.8, and 4.2±0.5 mm for low, intermediate, and high impedance, respectively ( P<0.0001). In right atria lines, low baseline impedance resulted in wider lines (7.2±1.4 mm) relative to intermediate (5.8±1.8 mm) and high impedance (4.7±1.7 mm; P<0.0001). CONCLUSIONS: Radiofrequency ablation in a power control mode results in variable lesion dimensions that are partially related to differences in baseline impedance and current output. Ablation at a lower baseline impedance results in increased current output and lesion dimensions.

Infarct-Related Ventricular Tachycardia: Redefining the Electrophysiological Substrate of the Isthmus During Sinus Rhythm.

OBJECTIVES: In this study, the scientific objective was to characterize the electrophysiological substrate of the ventricular tachycardia (VT) isthmus during sinus rhythm. BACKGROUND: The authors have recently described the electrophysiological characteristics of the VT isthmus using a novel in vivo high-resolution mapping technology. METHODS: Sixteen swine with healed infarction were studied using high-resolution mapping technology (Rhythmia, Boston Scientific, Cambridge, Massachusetts) in a closed-chest model. The left ventricle was mapped during sinus rhythm and analyzed for activation, conduction velocity, electrogram shape, and amplitude. Twenty-four VTs allowed detailed mapping of the common-channel "isthmus," including the "critical zone." This was defined as the zone of maximal conduction velocity slowing in the circuit, often occurring at entrance and exit from the isthmus caused by rapid angular change in activation vectors. RESULTS: The VT isthmus corresponded to sites displaying steep activation gradient (SAG) during sinus rhythm with conduction velocity slowing of 58.5 ± 22.4% (positive predictive value [PPV] 60%). The VT critical zone displayed SAG with greater conduction velocity slowing of 68.6 ± 18.2% (PPV 70%). Critical-zone sites were consistently localized in areas with bipolar voltage ≤0.55 mV, whereas isthmus sites were localized in areas with variable voltage amplitude (1.05 ± 0.80 mV [0.03 to 2.88 mV]). Importantly, critical zones served as common-site "anchors" for multiple VT configurations and cycle lengths. Isthmus and critical-zone sites occupied only 18.0 ± 7.0% of the low-voltage area (≤1.50 mV). Isolated late potentials were present in both isthmus and nonisthmus sites, including dead-end pathways (PPV 36%; 95% confidence interval: 34.2% to 39.6%). CONCLUSIONS: The VT critical zone corresponds to a location characterized by SAG and very low voltage amplitude during sinus rhythm. Thus, it allows identification of a re-entry anchor with high sensitivity and specificity. By contrast, voltage and electrogram characteristics during sinus rhythm have limited specificity for identifying the VT isthmus.

Nearly asymptomatic left ventricular apical ballooning after a hit-and-run accident.

Tako-tsubo cardiomyopathy is a syndrome that mimics acute myocardial infarction consisting of typical chest pain with acute onset and transient left ventricular wall-motion abnormalities. We present a case of a 53-year-old woman with nearly asymptomatic apical ballooning after a hit-and-run car accident. No blunt force impact occurred over the precordial area. Typical chest pain or dyspnea was not present at any time. Electrocardiogram showed ST-segment elevation and T-wave inversion. Cardiac catheterization revealed the absence of coronary stenosis. Whereas left ventriculography and cardiac magnetic resonance imaging showed apical akinesia and hypercontractility of the basal segments (apical ballooning). Left ventricular systolic function recovered from ejection fraction 34% to 55% in ten days and echocardiographic wall abnormalities returned to normal.