The Ithildin library for efficient numerical solution of anisotropic reaction-diffusion problems in excitable media.

Ithildin is an open-source library and framework for efficient parallelized simulations of excitable media, written in the C++ programming language. It uses parallelization on multiple CPU processors via the message passing interface (MPI). We demonstrate the library's versatility through a series of simulations in the context of the monodomain description of cardiac electrophysiology, including the S1S2 protocol, spiral break-up, and spiral waves in ventricular geometry. Our work demonstrates the power of Ithildin as a tool for studying complex wave patterns in cardiac tissue and its potential to inform future experimental and theoretical studies. We publish our full code with this paper in the name of open science.

Efficacy of a surgical cardiac ablation clamp using nanosecond pulsed electric fields: An acute porcine model.

OBJECTIVE: To examine the effectiveness of a recently developed nonthermal technology, nanosecond pulse-field ablation (nsPFA), for surgical ablation of the atria in a beating heart porcine model. METHODS: Six pigs underwent sternotomy and ablation using an nsPFA parallel clamp. The ablation electrodes (53 mm long) were embedded in the jaws of the clamp. Nine lesions per pig were created in locations chosen to be representative of the Cox-maze procedure. Four lesions were intended to electrically isolate parts of the atrium: the right atrial appendage, left atrial appendage, right pulmonary veins, and left pulmonary veins. For these lesions, exit block testing was performed both after ablation and before euthanasia; the time between the 2 tests was 3.3 ± 0.5 hours (range, 2-4 hours). Using purse string sutures, 5 more lesions were created up to the superior vena cava, down to the inferior vena cava, across the right atrial free wall, and at 2 distinct locations on the left atrial free wall. The clamp delivered a train of nanosecond duration pulses, with a total duration of 2.5 seconds, independent of tissue thickness. The heart tissue was stained with 1% triphenyltetrazolium chloride after a dwelling period of 2 hours. Subsequently, each lesion was cross sectioned at 5-mm intervals to assess the ablation depth and transmurality. In some sections, transmurality could not be established on the basis of triphenyltetrazolium chloride staining alone; for these lesions, Gomori-trichrome stains were used, and the histologic sections were evaluated for transmurality. RESULTS: The ablation time was 2.5 seconds per lesion, for a total of only 22.5 seconds ablation time to create 9 lesions. A total of 53 lesions were created, resulting in 388 separate histologic sections. Transmurality was established in 386 sections (99.5%). Mean tissue thickness was 3.1 ± 1.5 mm (range, 0.2-8.6 mm). Exit block was confirmed in 23 of the 24 lesions (96%) postablation and 23 of 24 (96%) before the animals were humanely killed. Over the course of the procedure, neither pulse-induced arrhythmias nor any other complications were noted. CONCLUSIONS: The novel nsPFA clamp device was effective in creating acute conduction block and transmural lesions in both the right and left atria in an acute porcine model. This nonthermal energy source has great potential to both shorten procedural time and enable effective ablation in the beating heart.

Minimally Invasive Mitral Valve Surgery With Concomitant Cox Maze Procedure Is as Effective as a Median Sternotomy With Decreased Morbidity.

OBJECTIVE: A right minithoracotomy (RMT) is a minimally invasive surgical approach that has been increasingly performed for the concomitant Cox maze IV procedure (CMP) and mitral valve surgery (MVS). Little is known regarding whether long-term rhythm and survival outcomes are affected by the RMT as compared with the traditional median sternotomy (MS) approach. METHODS: Between April 2004 and April 2021, 377 patients underwent the concomitant CMP and MVS, of whom 38% had RMT. Propensity score matching yielded 116 pairs. Freedom from atrial tachyarrhythmias (ATA) was assessed with prolonged monitoring annually for 8 years. Survival, rhythm, and perioperative outcomes were compared. RESULTS: The unmatched RMT cohort had a greater freedom from ATA recurrence at 1 year (99% vs 90%, P = 0.001) and 3 years (94% vs 86%, P = 0.045). The matched RMT cohort had longer cardiopulmonary bypass (median: 215 [199 to 253] vs 170 [136 to 198] min, P < 0.001) and aortic cross-clamp (110 [98 to 124] vs 86 [71 to 102] min, P < 0.001) times but shorter intensive care time (48 [24 to 95] vs 71 [26 to 144] h, P = 0.001) and length of stay (8 [6 to 11] vs 10 [7 to 14] h, P < 0.001). More pacemakers (18% vs 4%, P < 0.001) and postoperative transfusions (57% vs 41%, P = 0.014) occurred in the MS cohort. The 30-day mortality (P = 0.651) and 8-year survival (P = 0.072) was not significantly different between the cohorts. CONCLUSIONS: Early 1-year and 3-year freedom from ATA recurrence was better in the RMT cohort compared with the MS cohort. Despite longer operative times, the RMT cohort had shorter lengths of stay, fewer postoperative transfusions, and fewer pacemakers placed.

An experimental model of chronic severe mitral regurgitation.

Objective: To develop a minimally invasive, reproducible model of chronic severe mitral regurgitation (MR) that replicates the clinical phenotype of left atrial (LA) and left ventricular dilation and susceptibility to atrial fibrillation. Methods: Under transesophageal echocardiographic guidance, chordae tendinae were avulsed using endovascular forceps until the ratio of regurgitant jet area to LA area was ≥70%. Animals survived for an average of 8.6 ± 1.6 months (standard deviation) and imaged with monthly transthoracic echocardiography (TTE). Animals underwent baseline and preterminal magnetic resonance imaging. Terminal studies included TTE, transesophageal echocardiography, and rapid atrial pacing to test inducibility of atrial tachyarrhythmias. Results: Eight dogs underwent creation of severe MR and interval monitoring. Two were excluded-one died from acute heart failure, and the other had resolution of MR. Six dogs underwent the full experimental protocol; only one required medical management of clinical heart failure. MR remained severe over time, with a mean terminal regurgitant jet area to LA area of 71 ± 14% (standard deviation) and regurgitant fraction of 52 ± 11%. Mean LA volume increased over 130% (TTE: 163 ± 147%, P = .039; magnetic resonance imaging: 132 ± 54%, P = .011). Mean left ventricular end-diastolic volume increased by 38 ± 21% (P = .008). Inducible atrial tachyarrhythmias were seen in 4 of 6 animals at terminal surgery, and none at baseline. Conclusions: Within the 6 dogs that successfully completed the full experimental protocol, this model replicated the clinical phenotype of severe MR, which led to marked structural and electrophysiologic cardiac remodeling. This model allowed for precise measurements at repeated time points and will facilitate future studies to elucidate the mechanisms of atrial and ventricular remodeling secondary to MR and the pathophysiology of valvular atrial fibrillation.

Performance of an Irrigated Bipolar Radiofrequency Ablation Clamp on Explanted Human Hearts.

BACKGROUND: Bipolar radiofrequency (RF) clamps are commonly used during surgical ablation for atrial fibrillation (AF). This study examined the efficacy of an irrigated bipolar RF clamp to create transmural lesions in an ex vivo human heart model. METHODS: Ten donor hearts, turned down for transplantation, were explanted and arrested with cold cardioplegia. The ablations of the Cox Maze IV procedure were performed using the Cardioblate LP (Medtronic, Inc) irrigated bipolar RF clamp. In the first 5 hearts, each lesion was created with a single application of RF, whereas in the remaining 5 hearts, each lesion was created with a double application of RF without unclamping. Each lesion was cross-sectioned and stained with 2,3,5-triphenyl-tetrazolium chloride to assess ablation depth and transmurality. RESULTS: A total of 100 lesions were analyzed. In the single-ablation group, 222 of 260 sections (85%) and 37 of 50 lesions (74%) were transmural. The efficacy improved significantly in the double-ablation group, in which 348 of 359 sections (97%, P < .001) and 46 of 50 lesions (92%, P = .017) were transmural. Overall, in nontransmural lesions, the epicardial fat thickness was significantly greater (1.69 ± 0.70 mm vs 0.45 ±0.10 mm, P < .001) than the transmural lesions. CONCLUSIONS: A single ablation on human atrial tissue with an irrigated bipolar RF clamp was insufficient to reliably create transmural lesions, but a double ablation significantly increased the lesion and section transmurality. Nontransmural lesions were associated with significantly thicker layers of epicardial fat, which likely decreased tissue energy delivery due to the higher resistance of fat to current flow.

Surgical Ablation of Cardiac Tissue with Nanosecond Pulsed Electric Fields in Swine.

BACKGROUND: Myocardial tissue can be ablated by the application nanosecond pulsed fields (nsPEFs). The applied electric fields irreversibly permeabilize cell membranes and thereby kill myocytes while leaving the extracellular matrix intact. METHODS: In domestic pigs (n = 10), hearts were exposed via sternotomy and either ablated in vivo ([Formula: see text] = 5) or in excised, Langendorff-perfused hearts ([Formula: see text] = 5). The nsPEFs consisted of 6-36 pulses of 300 ns each, delivered at 3-6 Hz; the voltage applied varied from 10 to 12 kV. Atrial lesions were either created after inserting the bottom jaw of the bipolar clamp into the atrium via a purse string incision (2-3 lesions per atrium) or by clamping a double layer of tissue at the appendages (one lesion per atrium). Ventricular lesions were created after an incision at the apex. The transmurality of each lesion was determined at three points along the lesion using a triphenyl tetrazolium chloride (TTC) stain. RESULTS: All 27 atrial lesions were transmural. This includes 13/13 purse string lesions (39/39 sections, tissue thickness 2.5-4.5 mm) and 14/14 appendage lesions (42/42 sections, tissue thickness 8-12 mm). All 3 right ventricular lesions were transmural (9/9 sections, 18 pulses per lesion). Left ventricular lesions were always transmural for 36 pulses (3/3 lesions, 9/9 sections). All lesions have highly consistent width across the wall. There were no pulse-induced arrhythmias or other complications during the procedure. CONCLUSIONS: nsPEF ablation reliably created acute lesions in porcine atrial and ventricular myocardium. It has far better penetration and is faster than both radiofrequency ablation and cryoablation and it is free from thermal side effects.

Delayed-enhancement cardiac magnetic resonance imaging detects disease progression in patients with mitral valve disease and atrial fibrillation.

Objectives: The mechanism by which mitral valve (MV) disease leads to atrial fibrillation (AF) remains poorly understood. Delayed-enhancement cardiac magnetic resonance imaging (DE-MRI) has been used to assess left atrial (LA) fibrosis in patients with lone AF before catheter ablation; however, few studies have used DE-MRI to assess MV-induced LA fibrosis in patients with or without AF undergoing MV surgery. Methods: Between March 2018 and September 2022, 38 subjects were enrolled; 15 age-matched controls, 14 patients with lone mitral regurgitation (MR), and 9 patients with MR and AF (MR + AF). Indexed LA volume, total LA wall, and regional LA posterior wall (LAPW) enhancement were defined by the DE-MRI. One-way analysis of variance was performed. Results: LA volume and LA enhancement were associated (r = 0.451, P = .004). LA volume differed significantly between controls (37.1 ± 10.6 mL) and patients with lone MR (71.0 ± 35.9, P = .020 and controls and patients with MR + AF (99.3 ± 47.4, P < .001). The difference in LA enhancement was significant between MR + AF (16.7 ± 9.6%) versus controls (8.3 ± 3.9%, P = .006) and MR + AF versus lone MR (8.0 ± 4.8%, P = .004). Similarly, the was significantly more LAPW enhancement in the MR + AF (17.5 ± 8.7%) versus control (9.2 ± 5.1%, P = .011) and MR + AF versus lone MR (9.8 ± 6.0%, P = .020). Conclusions: Patients with MR + AF had significantly more total and LAPW fibrosis compared with both controls and lone MR. Volume and delayed enhancement were associated, but there was no difference between MR and MR + AF.

Efficacy of a Novel Bipolar Radiofrequency Clamp: An Acute Porcine Model.

OBJECTIVE: Expert consensus guidelines recommend surgical ablation (SA) for patients with symptomatic atrial fibrillation (AF), but less than half of patients with AF undergoing cardiac procedures receive concomitant SA. Complete isolation of the left atrial posterior wall (LAPW) has been shown to be the most critical part of the Cox maze procedure. The purpose of this study was to investigate the performance of a novel radiofrequency (RF) bipolar device, EnCompass™ (AtriCure, Inc., Mason, OH, USA), designed to isolate the LAPW in a single application. METHODS: Five adult pigs underwent SA in a beating heart model. After a single ablation, the heart was arrested, explanted, and stained with triphenyl-tetrazolium-chloride for histological assessment. Each lesion was sectioned, and the ablation depth, muscle, and fat thickness were determined. The lesion width, energy delivery, and ablation times were compared with those from a reference RF clamp (Synergy™, AtriCure). RESULTS: Transmurality was documented in 100% of lesions (5 of 5) and cross sections (160 of 160). Electrical isolation was documented in every instance. There was no evidence of clot, charring, or pulmonary vein stenosis. Compared with the reference clamp, the lesions created by the EnCompass™ clamp were 1.5 times wider on average. The average energy delivered was 5 times higher over a duration that was 4.5 times longer due to the increased volume of tissue ablated. CONCLUSIONS: The EnCompass™ clamp reproducibly created transmural isolation of the LAPW with a single application. This may allow for simplification of the SA strategy and increased adoption of AF treatment during concomitant surgery.

Surgical ablation for atrial fibrillation is efficacious in patients with giant left atria.

OBJECTIVE: The Cox-Maze IV procedure (CMP-IV) is the most effective treatment for atrial fibrillation. Increased left atrial (LA) size has been identified as a risk factor for failure to restore sinus rhythm. This has biased many surgeons against ablation in patients with giant left atrium (GLA), defined as LA diameter >6.5 cm. In this study we aimed to define the efficacy of the CMP-IV in patients with GLA. METHODS: From April 2004 through March 2020, 786 patients with a documented LA diameter underwent elective CMP-IV, 72 of whom had GLA. Median follow-up duration was 4 years (interquartile range, 1-7 years). Recurrence was defined as any documented atrial tachyarrhythmia (ATA) lasting 30 seconds. ATA recurrence and survival were analyzed across GLA versus non-GLA groups. RESULTS: Median age at surgery was 65 (interquartile range, 56-73) years. Median LA diameter within the GLA group was 7.0 (range, 6.6-10.0) cm. There were no differences in rates of postoperative complications for the 2 groups, including rate of postoperative stroke and pacemaker placement (GLA 14%; non-GLA 12%; P = .682). A trend toward increased 30-day mortality in the GLA group did not reach statistical significance (GLA 6%; non-GLA 2%; P = .051). Freedom from ATAs at 5 years postoperatively was comparable for the 2 groups (GLA 82%; non-GLA 84%). CONCLUSIONS: The CMP-IV had good efficacy in patients with GLA. Our results suggest that LA diameter >6.5 cm should not preclude a patient from undergoing surgical ablation for atrial fibrillation.

Electroporation safety factor of 300 nanosecond and 10 millisecond defibrillation in Langendorff-perfused rabbit hearts.

AIMS: Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation. METHODS AND RESULTS: The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes was used to apply shocks of varying voltage. Propidium iodide (PI) staining at the surface of the heart showed that nanosecond shocks had a slightly lower safety factor (6.50) than millisecond shocks (8.69), p = 0.02; while PI staining cross-sections in the electrode plane showed no significant difference (5.38 for 300 ns shocks and 6.29 for 10 ms shocks, p = 0.22). CONCLUSIONS: In Langendorff-perfused rabbit hearts, nanosecond defibrillation has a similar safety factor as millisecond defibrillation, between 5 and 9, suggesting that nanosecond defibrillation can be performed safely.

Safety factor for electrostimulation with nanosecond pulses.

While electrical stimulation with pulses of milli- or microsecond duration is possible without electroporation, stimulation with nanosecond pulses typically entails electroporation, and nanosecond pulses can even cause electroporation without stimulation. A recently proposed explanation for this intriguing finding is that stimulation requires not only that a threshold membrane potential is reached, but also that it is sustained for a certain time tmin, while electroporation occurs almost immediately after a higher threshold potential is reached. Here we analytically derive stimulation and electroporation thresholds for membranes that satisfy these assumptions. We analyze the safety factor, i.e. the ratio between electroporation and stimulation threshold and its dependence on pulse duration, membrane charging time constant, and tmin. We find that the safety factor is sharply reduced if both the pulse duration and the membrane charging time constant are below tmin. We discuss different approaches to get models with varying tmin that could be used to experimentally test this theory and cardiac applications.

Efficacy of the stand-alone Cox-Maze IV procedure in patients with longstanding persistent atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and results in significant morbidity and mortality. The Cox-Maze IV procedure (CMP-IV) has been shown to have excellent efficacy in returning patients to sinus rhythm, but there have been few reports of late follow-up in sizable cohorts of patients with longstanding persistent AF, the most difficult type of AF to treat. METHODS AND RESULTS: Between May 2003 and March 2020, 174 consecutive patients underwent a stand-alone CMP-IV for longstanding persistent AF. Rhythm outcome was assessed postoperatively for up to 10 years, primarily via prolonged monitoring (Holter monitor, pacemaker interrogation, or implantable loop recorder). Fine-Gray regression was used to investigate factors associated with atrial tachyarrhythmia (ATA) recurrence, with death as a competing risk. Median duration of preoperative AF was 7.8 years (interquartile range: 4.0-12.0 years), with 71% (124/174) having failed at least one prior catheter-based ablation. There were no 30-day mortalities. Freedom from ATAs was 94% (120/128), 83% (53/64), and 88% (35/40) at 1, 5, and 7 years, respectively. On regression analysis, preoperative AF duration and early postoperative ATAs were associated with late ATAs recurrence. CONCLUSION: Despite the majority of patients having a long-duration of preoperative AF and having failed at least one catheter-based ablation, the stand-alone CMP-IV had excellent late efficacy in patients with longstanding persistent AF, with low morbidity and no mortality. We recommend consideration of stand-alone CMP-IV for patients with longstanding persistent AF who have failed or are poor candidates for catheter ablation.

Analysis of electrostimulation and electroporation by high repetition rate bursts of nanosecond stimuli.

Exposures to short-duration, strong electric field pulses have been utilized for stimulation, ablation, and the delivery of molecules into cells. Ultrashort, nanosecond duration pulses have shown unique benefits, but they require higher field strengths. One way to overcome this requirement is to use trains of nanosecond pulses with high repetition rates, up to the MHz range. Here we present a theoretical model to describe the effects of pulse trains on the plasma membrane and intracellular membranes modeled as resistively charged capacitors. We derive the induced membrane potential and the stimulation threshold as functions of pulse number, pulse duration, and repetition rate. This derivation provides a straightforward method to calculate the membrane charging time constant from experimental data. The derived excitation threshold agrees with nerve stimulation experiments, indicating that nanosecond pulses are not more effective than longer pulses in charging nerve fibers. The derived excitation threshold does not, however, correctly predict the nanosecond stimulation of cardiomyocytes. We show that a better agreement is possible if multiple charging time constants are considered. Finally, we expand the model to intracellular membranes and show that pulse trains do not lead to charge buildup, but can create significant oscillations of the intracellular membrane potential.

Excitation and electroporation by MHz bursts of nanosecond stimuli.

Intense nanosecond pulsed electric field (nsPEF) is a novel modality for cell activation and nanoelectroporation. Applications of nsPEF in research and therapy are hindered by a high electric field requirement, typically from 1 to over 50 kV/cm to elicit any bioeffects. We show how this requirement can be overcome by engaging temporal summation when pulses are compressed into high-rate bursts (up to several MHz). This approach was tested for excitation of ventricular cardiomyocytes and peripheral nerve fibers; for membrane electroporation of cardiomyocytes, CHO, and HEK cells; and for killing EL-4 cells. MHz compression of nsPEF bursts (100-1000 pulses) enables excitation at only 0.01-0.15 kV/cm and electroporation already at 0.4-0.6 kV/cm. Clear separation of excitation and electroporation thresholds allows for multiple excitation cycles without membrane disruption. The efficiency of nsPEF bursts increases with the duty cycle (by increasing either pulse duration or repetition rate) and with increasing the total time "on" (by increasing either pulse duration or number). For some endpoints, the efficiency of nsPEF bursts matches a single "long" pulse whose amplitude and duration equal the time-average amplitude and duration of the bursts. For other endpoints this rule is not valid, presumably because of nsPEF-specific bioeffects and/or possible modification of targets already during the burst. MHz compression of nsPEF bursts is a universal and efficient way to lower excitation thresholds and facilitate electroporation.

Using Nanosecond Shocks for Cardiac Defibrillation.

The purpose of this review article is to summarize our current understanding of the efficacy and safety of cardiac defibrillation with nanosecond shocks. Experiments in isolated hearts, using optical mapping of the electrical activity, have demonstrated that nanosecond shocks can defibrillate with lower energies than conventional millisecond shocks. Single defibrillation strength nanosecond shocks do not cause obvious damage, but repeated stimulation leads to deterioration of the hearts. In isolated myocytes, nanosecond pulses can also stimulate at lower energies than at longer pulses and cause less electroporation (propidium uptake). The mechanism is likely electroporation of the plasma membrane. Repeated stimulation leads to distorted calcium gradients.

Excitation and injury of adult ventricular cardiomyocytes by nano- to millisecond electric shocks.

Intense electric shocks of nanosecond (ns) duration can become a new modality for more efficient but safer defibrillation. We extended strength-duration curves for excitation of cardiomyocytes down to 200 ns, and compared electroporative damage by proportionally more intense shocks of different duration. Enzymatically isolated murine, rabbit, and swine adult ventricular cardiomyocytes (VCM) were loaded with a Ca2+ indicator Fluo-4 or Fluo-5N and subjected to shocks of increasing amplitude until a Ca2+ transient was optically detected. Then, the voltage was increased 5-fold, and the electric cell injury was quantified by the uptake of a membrane permeability marker dye, propidium iodide. We established that: (1) Stimuli down to 200-ns duration can elicit Ca2+ transients, although repeated ns shocks often evoke abnormal responses, (2) Stimulation thresholds expectedly increase as the shock duration decreases, similarly for VCMs from different species, (3) Stimulation threshold energy is minimal for the shortest shocks, (4) VCM orientation with respect to the electric field does not affect the threshold for ns shocks, and (5) The shortest shocks cause the least electroporation injury. These findings support further exploration of ns defibrillation, although abnormal response patterns to repetitive ns stimuli are of a concern and require mechanistic analysis.

Low-energy defibrillation with nanosecond electric shocks.

AIMS: Reliable defibrillation with reduced energy deposition has long been the focus of defibrillation research. We studied the efficacy of single shocks of 300 ns duration in defibrillating rabbit hearts as well as the tissue damage they may cause. METHODS AND RESULTS: New Zealand white rabbit hearts were Langendorff-perfused and two planar electrodes were placed on either side of the heart. Shocks of 300 ns duration and 0.3-3 kV amplitude were generated with a transmission line generator. Single nanosecond shocks consistently induced waves of electrical activation, with a stimulation threshold of 0.9 kV (over 3 cm) and consistent activation for shock amplitudes of 1.2 kV or higher (9/9 successful attempts). We induced fibrillation (35 episodes in 12 hearts) and found that single shock nanosecond-defibrillation could consistently be achieved, with a defibrillation threshold of 2.3-2.4 kV (over 3 cm), and consistent success at 3 kV (11/11 successful attempts). Shocks uniformly depolarized the tissue, and the threshold energy needed for nanosecond defibrillation was almost an order of magnitude lower than the energy needed for defibrillation with a monophasic 10 ms shock delivered with the same electrode configuration. For the parameters studied here, nanosecond defibrillation caused no baseline shift of the transmembrane potential (that could be indicative of electroporative damage), no changes in action potential duration, and only a brief change of diastolic interval, for one beat after the shock was delivered. Histological staining with tetrazolium chloride and propidium iodide showed that effective defibrillation was not associated with tissue death or with detectable electroporation anywhere in the heart (six hearts). CONCLUSION: Nanosecond-defibrillation is a promising technology that may allow clinical defibrillation with profoundly reduced energies.