Pulsed low-energy stimulation initiates electric turbulence in cardiac tissue.

Interruptions in nonlinear wave propagation, commonly referred to as wave breaks, are typical of many complex excitable systems. In the heart they lead to lethal rhythm disorders, the so-called arrhythmias, which are one of the main causes of sudden death in the industrialized world. Progress in the treatment and therapy of cardiac arrhythmias requires a detailed understanding of the triggers and dynamics of these wave breaks. In particular, two very important questions are: 1) What determines the potential of a wave break to initiate re-entry? and 2) How do these breaks evolve such that the system is able to maintain spatiotemporally chaotic electrical activity? Here we approach these questions numerically using optogenetics in an in silico model of human atrial tissue that has undergone chronic atrial fibrillation (cAF) remodelling. In the lesser studied sub-threshold illumination régime, we discover a new mechanism of wave break initiation in cardiac tissue that occurs for gentle slopes of the restitution characteristics. This mechanism involves the creation of conduction blocks through a combination of wavefront-waveback interaction, reshaping of the wave profile and heterogeneous recovery from the excitation of the spatially extended medium, leading to the creation of re-excitable windows for sustained re-entry. This finding is an important contribution to cardiac arrhythmia research as it identifies scenarios in which low-energy perturbations to cardiac rhythm can be potentially life-threatening.

Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis.

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.

The Rapidly-Developing Area of Radiocardiology: Principles, Complications and Applications of Radiotherapy on the Heart.

Ventricular arrhythmias are the leading cause of sudden cardiac death. Current treatment strategies for ventricular tachycardia, including antiarrhythmic drugs and catheter ablation, have limited efficacy in patients with structural heart disease. Noninvasive ablation with the use of externally applied radiation (cardiac radioablation) has emerged as a promising and novel approach to treating recurrent ventricular tachycardias. However, the heart is generally an "organ at risk" for radiation treatments, such that very little is known on the effects of radiotherapy on cardiac ultrastructure and electrophysiologic properties. Furthermore, there has been limited interaction between the fields of cardiology and radiation oncology and physics. The advent of cardiac radioablation will undoubtedly increase interactions between cardiologists, cardiac electrophysiologists, radiation oncologists and physicists. There is an important knowledge gap separating these specialties, but scientific developments, technical optimisation, and improvements depend on intense multidisciplinary collaboration. This manuscript seeks to review the basic of radiation physics and biology for cardiovascular specialists in an effort to facilitate constructive scientific and clinical collaborations to improve patient outcomes.

Epicardial infrared ablation to create a linear conduction block on a beating right atrium.

BACKGROUND: It is still difficult to create a secure linear conduction block on a beating heart from the epicardial side. To overcome this drawback we developed an infrared coagulator equipped with a cuboid light-guiding quartz rod. This study was designed to electrophysiologically confirm the efficacy of a new ablation probe using infrared energy in a clinical case. METHODS: The infrared light from a lamp is focused into the newly developed cuboid quartz rod, which has a rectangular distal exit-plane that allows 30 mm × 10 mm linear photocoagulation. Two pairs of electrodes were attached to the right atrium of a patient who was undergoing surgery. Each pair of electrodes was placed 10 mm from an ablation line. The change in conduction time between the two pairs of electrodes was measured during ablation. The predicted conduction time delay ratio was 1.54. RESULTS: The actual conduction time after ablation was 1.38-1.43 times longer than the pre-ablation conduction time. CONCLUSIONS: The infrared ablation using a newly developed cuboid probe made it possible to create a linear conduction block on the beating right atrial free wall clinically.

Influence of Low-Intensive Red Light on the Myocardium in Experimental Asphyxia.

We studied the effects of low-intensity broadband red light on electrical activity of the heart and oxidative modification of proteins in the myocardium of rats after asphyxia. It was shown that low-intensity red light reduced the content of oxidatively modified proteins in rat heart after oxidative stress caused by asphyxia. Exposure to low-intensity red light normalized ECG parameters in rats after asphyxia.

Safety and efficacy of stereotactic radioablation targeting pulmonary vein tissues in an experimental model.

BACKGROUND: Stereotactic radioablation (SR), a commonly used therapy to treat malignant tumors, has been used to treat refractory ventricular tachycardia, but the feasibility of treating atrial fibrillation with SR is unknown. OBJECTIVE: We evaluated the safety and efficacy of SR targeting pulmonary vein (PV) antral tissues as a potential therapy for atrial fibrillation. METHODS: Seventeen adult canines and 2 adult swine underwent surgical fiducial marker placement, 3-dimensional anatomic rendering computed tomography angiogram of the left atrium, and creation of a treatment plan targeting the right superior PVs. Four treatment doses (15, 20, 25, and 35 Gy) were administered to 4 cohorts. Subjects were monitored for 3-6 months, followed by electrophysiological testing, gross pathological examination, and histopathology in 2 subjects. RESULTS: All subjects received SR treatment without complication. Electrophysiology study and gross pathological analysis demonstrated treatment effect in all treated PVs at 35 Gy and 25 Gy (n = 11 of 11 [100%]), with a partial effect at 20 Gy (n = 4 of 5 [80%]; 1 did not undergo repeat electrophysiology study) and 15 Gy (n = 1 of 2 [50%]). No evidence of collateral injury was found in tissues directly adjacent to the treated PVs. In 2 subjects, detailed histopathology demonstrated evidence of circumferential, transmural scar at the PV ablation sites, with sparing of the surrounding structures. CONCLUSIONS: SR is safe and effective for creating precise circumferential scar and electrical isolation of the right superior PV in an experimental model, with dose dependence between delivered radioablative energy and observed electrical effects.

Amiodarone and dronedarone: An update.

This article provides a contemporary review of the current role of amiodarone and dronedarone in patients with atrial fibrillation who need to undergo rhythm control therapy for relief of symptoms. Amiodarone is the most widely prescribed antiarrhythmic drug for this indication. Recent findings show that its use is not associated with increased mortality even in patients with advanced structural heart disease. However, its extracardiac side effect profile may limit its widespread use. Dronedarone appears to be a useful drug in patients with paroxysmal or persistent atrial fibrillation. However, the compound cannot be used in patients with heart failure. In permanent atrial fibrillation, dronedarone is likewise contraindicated based on findings from the PALLAS trial.

Predictability of lesion durability for AF ablation using phased radiofrequency: Power, temperature, and duration impact creation of transmural lesions.

BACKGROUND: Long-term clinical outcomes for atrial fibrillation ablation depend on the creation of durable transmural lesions during pulmonary vein isolation and on substrate modification. Focal conventional radiofrequency (RF) ablation studies have demonstrated that tissue temperature and power are important factors for lesion formation. However, the impact and predictability of temperature and power on contiguous, transmural lesion formation with a phased RF system has not been described. OBJECTIVE: The purpose of this study was to determine the sensitivity, specificity, and predictability of power and temperature to create contiguous, transmural lesions with the temperature-controlled, multielectrode phased RF PVAC GOLD catheter. METHODS: Single ablations with the PVAC GOLD catheter were performed in the superior vena cava of 22 pigs. Ablations from 198 PVAC GOLD electrodes were evaluated by gross examination and histopathology for lesion transmurality and contiguity. Lesions were compared to temperature and power data from the phased RF GENius generator. Effective contact was defined as electrodes with a temperature of ≥50°C and a power of ≥3 W. RESULTS: Eighty-five percent (168 of 198) of the lesions were transmural and 79% (106 of 134) were contiguous. Electrode analysis showed that >30 seconds of effective contact identified transmural lesions with 85% sensitivity (95% confidence interval [CI] 78%-89%), 93% specificity (95% CI 76%-99%), and 99% positive predictive value (95% CI 94%-100%). Sensitivity for lesion contiguity was 95% (95% CI 89%-98%), with 62% specificity (95% CI 42%-78%) and 90% positive predictive value (95% CI 83%-95%). No char or coagulum was observed on the catheter or tissue. CONCLUSION: PVAC GOLD safely, effectively, and predictably creates transmural and contiguous lesions.

Anatomical predictors for successful pulmonary vein isolation using balloon-based technologies in atrial fibrillation.

PURPOSE: We evaluated the correlation between pulmonary venous (PV) anatomy and acute and long-term success of PV isolation (PVI) with two balloon-based ablation catheter techniques. METHODS: One hundred consecutive patients were analyzed in two equal groups treated with either the second-generation cryoballoon (CRYO) catheter or the visually guided laser ablation (VGLA) catheter. All patients underwent multi-detector computed tomography (CT) imaging. The primary and secondary efficacy endpoints were the procedural achievement of proven electrical isolation of all veins and freedom from atrial fibrillation (AF) within a 1-year follow-up period, respectively. RESULTS: Variant PV anatomy was observed in 32% of patients in the CRYO group and in 40% of patients in the VGLA group. All PVs were targeted with either the CRYO catheter (n = 199) or the VGLA catheter (n = 206). One hundred ninety-three of 199 PVs (97%) were successfully isolated in the CRYO group and 194 of 206 PVs (94%) in the VGLA group (p = 0.83). Over a 12-month follow-up, AF recurrence was documented in 11/45 (24%) and 7/43 (16%) patients in the CRYO and the VGLA groups, respectively (p = 0.21). In the CRYO group, a larger left inferior PV size was associated with worse long-term outcome (p = 0.001). In the VGLA group, a larger left superior PV size (p = 0.003) and more oval right inferior PV were associated with worse acute success (p = 0.038). There was no absolute cutoff between PV anatomy and clinical success. CONCLUSIONS: The variability of PV anatomy did not significantly compromise acute success of PVI or patient outcomes.

Extracorporeal acute cardiac pacing by high intensity focused ultrasound.

Ultrasound has been shown to produce Premature Ventricular Contractions (PVC's). Two clinical applications in which acute cardiac pacing by ultrasound may be valuable are: (1) preoperative patient screening in cardiac resynchronization therapy surgery; (2) Emergency life support, following an event of sudden death, caused by cardiac arrest. Yet, previously the demonstrated mean success rate of extra-systole induction by High Intensity Focused Ultrasound (HIFU) in rats is below 4.5% (Miller et al., 2011). This stands in contrast to previous work in rats using ultrasound (US) and ultrasound contrast agents (UCAs), where success rates of close to 100% were reported (Rota et al., 2006). Herein, bi-stage temporal sequences of accentuated negative pressure (rarefaction) and positive pressure HIFU transmission (insonation) patterns were applied to anaesthetized rats under real-time vital-signs monitoring and US imaging. This pattern of insonation first produces a gradual growth of dissolved gas cavities in tissue (cavitation) and then an ultrasonic impact. Results demonstrate sequences of successive successful HIFU pacing. Triggering insonation at different delays from the preceding ECG R-wave demonstrated successful HIFU pacing induction from mid ECG T-wave till the next ECG complex's PR interval. Spatially focusing the beam at different locations allows cumulative coverage of the whole left ventricle. Analysis of the acoustic wave patterns and temporal characteristics of paced PVCs is suggested to provide new insight into the mechanisms of HIFU cardiac pacing. Specifically, the observed HIFU pacing temporal success rate distribution suggests against sarcomere length modulation current being the dominant cellular level mechanism of HIFU cardiac pacing and may allow postulating that membrane deformation currents are dominant at the applied insonation conditions.

Conduction block in novel cardiomyocyte electrical conduction line by photosensitization reaction.

We developed a novel cardiomyocyte electrical conduction line. We studied electrical conduction block by extra-cellular photosensitization reaction with this conduction line to study electrical blockade by the photosensitization reaction in vitro.

Controlling activation site density by low-energy far-field stimulation in cardiac tissue.

Tachycardia and fibrillation are potentially fatal arrhythmias associated with the formation of rotating spiral waves in the heart. Presently, the termination of these types of arrhythmia is achieved by use of antitachycardia pacing or cardioversion. However, these techniques have serious drawbacks, in that they either have limited application or produce undesirable side effects. Low-energy far-field stimulation has recently been proposed as a superior therapy. This proposed therapeutic method would exploit the phenomenon in which the application of low-energy far-field shocks induces a large number of activation sites ("virtual electrodes") in tissue. It has been found that the formation of such sites can lead to the termination of undesired states in the heart and the restoration of normal beating. In this study we investigate a particular aspect of this method. Here we seek to determine how the activation site density depends on the applied electric field through in vitro experiments carried out on neonatal rat cardiac tissue cultures. The results indicate that the activation site density increases exponentially as a function of the intracellular conductivity and the level of cell isotropy. Additionally, we report numerical results obtained from bidomain simulations of the Beeler-Reuter model that are quantitatively consistent with our experimental results. Also, we derive an intuitive analytical framework that describes the activation site density and provides useful information for determining the ratio of longitudinal to transverse conductivity in a cardiac tissue culture. The results obtained here should be useful in the development of an actual therapeutic method based on low-energy far-field pacing. In addition, they provide a deeper understanding of the intrinsic properties of cardiac cells.

Do mobile phones pose a potential risk to autonomic modulation of the heart?

BACKGROUND: It has long been speculated that mobile phones may interact with the cardiac devices and thereby cardiovascular system may be a potential target for the electromagnetic fields emitted by the mobile phones. Therefore, the present study was designed to test possible effects of radiofrequency waves emitted by digital mobile phones on cardiac autonomic modulation by short-time heart rate variability (HRV) analysis. METHODS AND RESULTS: A total of 20 healthy young subjects were included to the study. All participants were rested in supine position at least for 15 minutes on a comfortable bed, and then time and frequency domain HRV parameters were recorded at baseline in supine position for 5 minutes. After completion of baseline records, by using a mobile GSM (Global System for Mobile Communication) phone, HRV parameters were recorded at turned off mode, at turned on mode, and at calling mode over 5 minutes periods for each stage. CONCLUSION: Neither time nor frequency domain HRV parameters altered significantly during off mode compare to their baseline values. Also, neither time nor frequency domain HRV parameters altered significantly during turned on and calling mode compared to their baseline values. Short-time exposure to electromagnetic fields emitted by mobile phone does not affect cardiac autonomic modulation in healthy subjects.

Current results of minimally invasive surgical ablation for isolated atrial fibrillation.

The Cox maze surgical ablation operation is a highly effective treatment for patients with atrial fibrillation, but adoption has been limited by procedure complexity and invasiveness. Minimally invasive approaches using nonsternotomy limited access and eliminating cardiopulmonary bypass have been developed. All published series of minimally invasive surgical ablation for isolated, atrial fibrillation were reviewed. Series were analyzed for method of access, energy source, procedure success, and complications. Outcomes were compiled based on type of atrial fibrillation, method and length of follow-up, and freedom from atrial fibrillation with and without antiarrhythmic drugs. There are 14 published series with outcomes reported in 604 unique patients. Most procedures are performed through bilateral minithoracotomies with video assistance, although in later series a totally thoracoscopic approach is more commonly used. Bipolar radiofrequency is the predominant energy source used, and bilateral pulmonary vein isolation the most common lesion set, with some reports adding ganglionic plexi ablation and more extensive ablation lines. Approximately 53% of the procedures were performed for paroxysmal and 47% for persistent/long-standing persistent atrial fibrillation. Overall freedom from atrial fibrillation at 6-12 months is 84% (59%-91%), with 89% (79%-100%) in paroxysmal and 62% (25%-87%) in persistent/long-standing persistent patients. Overall freedom from atrial fibrillation off of antiarrhythmic drugs is 65% (57%-87%). Results approximating those of the Cox maze procedure are achieved with minimally invasive surgical ablation of atrial fibrillation in patients with paroxysmal atrial fibrillation. Further developments are necessary to further simplify and standardize the procedure, to replicate the results in larger series from more centers, to standardize the reporting of results, and to define a more effective procedure for persistent and long-standing persistent atrial fibrillation.

Linear left atrial lesions in minimally invasive surgical ablation of persistent atrial fibrillation: techniques for assessing conduction block across surgical lesions.

Minimally invasive surgical (MIS) ablation, with pulmonary vein (PV) isolation and ganglionated plexi (GP) ablation, has proven highly successful for paroxysmal atrial fibrillation but has limited success in patients with persistent and long-standing persistent (P-LSP) AF. A set of linear left atrial (LA) lesions has been added to interrupt some macroreentrant components of P-LSP AF. This includes a Transverse Roof Line and Left Fibrous Trigone Line (from Roof Line to mitral annulus at the left fibrous trigone). With complete conduction block (CCB), these lesions should prevent single- or double-loop macroreentrant LA tachycardias from propagating around the PVs or mitral annulus. It is critical to identify whether CCB has been achieved and, if not, to locate the gap for further ablation, since residual gaps will support macroreentrant atrial tachycardias. Confirming CCB involves pacing close to one side of the ablation line and determining the direction of activation on the opposite side, by recording close bipolar electrograms at multiple paired sites (perpendicular and close to the ablation line) along the entire length of the line. Simpler approaches have been used, but all have limitations, especially when the conduction time across a gap is long. The extended lesion set was created after PV isolation and GP ablation in 14 patients with P-LSP AF. Mapping after the first set of radiofrequency applications for the Transverse Roof and Left Trigone Lines confirmed CCB in only 3/14 (21%) patients for each line, showing the importance of checking for CCB. During follow-up (median 8 months), 10/14 (71%) patients had no symptoms of atrial arrhythmia (7/10 off antiarrhythmic drugs). Of the remaining four patients, three have only infrequent episodes (self-terminating in 2/3). These preliminary results suggest that adding Roof and Trigone Lines may increase MIS success in patients with P-LSP AF. Accurate mapping techniques verify CCB and effectively locate gaps in ablation lines for further ablation.

Spatial distribution and extent of electroporation by strong internal shock in intact structurally normal and chronically infarcted rabbit hearts.

INTRODUCTION: Although life-saving, a strong internal defibrillation shock may temporarily or permanently damage the heart via disruption of cell membranes (electroporation). Spatial extent of electroporation in intact, normal, or infarcted hearts has not been investigated. In this study, shock-induced electroporation in intact rabbit hearts with and without chronic (>4 weeks) left ventricular myocardial infarction (MI) was characterized. METHODS AND RESULTS: A coil shock electrode was inserted in the right ventricle of Langendorff-perfused hearts. One truncated exponential monophasic shock (+300 V, 8 ms) was delivered by a 150 microF capacitor clinical defibrillator while the heart was perfused with membrane-impermeant dye propidium iodide (PI). The heart was sectioned transversely, and uptake of PI into ventricular myocardium through electropores was quantified. Histological evaluation was performed via Masson's trichrome staining. PI accumulation was minimal in the control (n = 3) and MI (n = 3) hearts without shock. Following shock delivery, (1) in control (n = 5) and MI (n = 5) hearts, electroporation mostly occurred near the shock electrode and was longitudinally distributed along the active region of the shock electrode; (2) in MI group, electroporation was significantly increased (P < 0.05) in the surviving anterior epicardial layers of the infarcted region; and (3) between the control and MI groups, the overall extent of electroporation was similar. CONCLUSION: Shock-induced electroporation was spatially dependent on the location and dimension of the active region of the shock electrode. The overall extent of electroporation in the MI heart was comparable with the control heart, but the surviving anterior epicardial layers in the infarcted region were more susceptible to electroporation.

Electric field perturbations of spiral waves attached to millimeter-size obstacles.

Reentrant spiral waves can become pinned to small anatomical obstacles in the heart and lead to monomorphic ventricular tachycardia that can degenerate into polymorphic tachycardia and ventricular fibrillation. Electric field-induced secondary source stimulation can excite directly at the obstacle, and may provide a means to terminate the pinned wave or inhibit the transition to more complex arrhythmia. We used confluent monolayers of neonatal rat ventricular myocytes to investigate the use of low intensity electric field stimulation to perturb the spiral wave. A hole 2-4 mm in diameter was created in the center to pin the spiral wave. Monolayers were stained with voltage-sensitive dye di-4-ANEPPS and mapped at 253 sites. Spiral waves were initiated that attached to the hole (n = 10 monolayers). Electric field pulses 1-s in duration were delivered with increasing strength (0.5-5 V/cm) until the wave terminated after detaching from the hole. At subdetachment intensities, cycle length increased with field strength, was sustained for the duration of the pulse, and returned to its original value after termination of the pulse. Mechanistically, conduction velocity near the wave tip decreased with field strength in the region of depolarization at the obstacle. In summary, electric fields cause strength-dependent slowing or detachment of pinned spiral waves. Our results suggest a means to decelerate tachycardia that may help to prevent wave degeneration.

Theoretical possibility of ventricular fibrillation during use of TASER neuromuscular incapacitation devices.

INTRODUCTION: TASER devices deliver electrical pulses that temporarily incapacitate suspects. This study analyzes the theoretical possibility of ventricular fibrillation (VF) induction by TASER currents. METHODS AND RESULTS: Using finite element models (FEM), the results found that the skin, fat and anisotropic skeletal muscle layers attenuated a large portion of TASER currents, allowing just a fractional amount to penetrate transversally into deeper layers of tissue. The TASER current density reached 91 mA/cm(2), the threshold required to induce VF, at less than 14.7 mm away from the skin surface. This distance is significantly lower than the average skin-heart distance of 35 mm, as measured in subjects with a body-mass index (BMI) matched to that of typical in-custody suspects. The theoretical probability of inducing VF is significantly lower than 0.0000008, or 1:1,270,000. By comparison, the standard for basic safety and essential performance of medical electrical equipment, EN 60601-1, accepts as satisfactory a VF induction probability of 0.002, or 1:500. CONCLUSION: The results indicated that TASER devices, while not risk free, have a very low cardiac risk profile when used for suspect temporary incapacitation.