Dynamics Of Ventricular Fibrillation Research Articles

Mapping and ablation of ventricular fibrillation substrate.

Ventricular fibrillation (VF) is a life-threatening arrhythmia and a common cause of sudden cardiac death (SCD). A basic understanding of its mechanistic underpinning is crucial for enhancing our knowledge to develop innovative mapping and ablation techniques for this lethal rhythm. Significant advances in our understanding of VF have been made especially in the basic science and pre-clinical experimental realms. However, these studies have not yet translated into a robust clinical approach to identify and successfully ablate both the structural and functional substrate of VF. In this review, we aim to (1) provide a conceptual framework of VF and an overview of the data supporting the spatiotemporal dynamics of VF, (2) review experimental approaches to mapping VF to elucidate drivers and substrate for maintenance with a focus on the His-Purkinje system, (3) discuss current approaches using catheter ablation to treat VF, and (4) highlight current unknowns and gaps in the field where future work is necessary to transform the clinical landscape.

Pro- and anti-arrhythmic effects of TRPM4 inhibition on ventricular fibrillation trigger and substrate mechanisms

Ventricular Fibrillation (VF) is a major cause of sudden cardiac death. Purkinje fibers (PF) are known to play an important role in triggering and maintaining VF. Previous studies have highlighted the role of TRPM4 channels in repolarization properties of PFs, but their potential impact on arrhythmogenesis and VF dynamics remains unknown. To investigate the role of TRPM4 channels in Purkinje-mediated trigger and substrate mechanisms. Endocardial optical mapping experiments were performed in sheep perfused left ventricular wedge preparations using a high-resolution CMOS camera. Purkinje-Muscle Junctions (PMJ) were localized through PF stimulation and identification of the breakthrough sites. Arrhythmias were induced either by isoprenaline perfusion (ISO; 1 μM; n = 7) or by endocardial burst pacing (10 Hz; n = 6) and their spatiotemporal dynamics quantified with or without 9-Phenanthrol (9PHE; 45 μM), a known TRPM4 inhibitor. ISO perfusion provoked focal tachy-arrhythmias originating from the PFs confirmed by the co-localization of the exit sites with previously identified PMJs. 9PHE reduced the rate of spontaneous focal activity and activation patterns were no longer correlated to the PMJs. However, following burst pacing, inhibition of TRPM4 led to a higher propensity of VF than ventricular tachycardia (VT). For the induced VT episodes, we observed a significant increase of DF (3.7 ± 0.7 Hz vs. 4.8 ± 0.8 Hz) and a significant decrease of regularity index (0.94 ± 0.05 vs. 0.84 ± 0.07) at the PMJs after 9PHE perfusion, while a significant increase in long lasting rotors was observed ( P = 0.044; for rotor number and P = 0.005; for rotor duration). A significant increase in focal activity (15 ± 2 μpixel/ms vs. 30 ± 9 μpixel/ms) was found during VF episodes. These results suggest that TRPM4 inhibition has anti-arrhythmic effects by preventing VF triggers from PFs, while at the same time increasing the complexity of induced ventricular arrhythmias.

Regional repolarization shortening is more arrhythmogenic than regional conduction slowing in an ex vivo porcine experimental model

Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In patients without apparent structural heart disease, J-point elevation and J waves are often associated with an increased risk to VF. The mechanisms underlying these ECG patterns and the associated arrhythmogenesis are still debated. To investigate the respective role of conduction and repolarization heterogeneities in the emergence of J-waves and in the vulnerability to VF. Epi- and endocardial optical mapping experiments were performed in porcine right ventricular (RV) wedge preparations ( n = 26). Both right coronary and left anterior descending (LAD) arteries were perfused separately with Tyrode, followed by addition of either pinacidil (PINA; 20 μM, n = 14) or flecainide (FLECA; 2 μM, n = 12) in the LAD only. RV action potentials (AP) properties were assessed at 1 to 4 Hz stimulation frequencies, and a bath ECG was recorded to evaluate ST segment changes. Spontaneous or induced arrhythmias were quantified and analyzed to calculate dominant frequencies (DF) and regularity index (RI). Local perfusion of PINA induced strong AP duration and repolarization time (RT) heterogeneity on epi- and endocardial surfaces while regional FLECA perfusion significantly prolonged total activation time and increased RT heterogeneity. Both models were associated with changes in ST segment, but those of conduction heterogeneity were more subtle. They both decreased RI of arrhythmias compared to the baseline (0.53 vs. 0.84 P = 0.02 for PINA; 0.47 vs. 0.76 P = 0.06 for FLECA), and DF were significantly higher for PINA compared to FLECA (9.41 vs. 7.74 P = 0.03). Spontaneous VFs are more frequent with a local perfusion of PINA compared to FLECA (86 vs. 8% P = 0.0001). Regional repolarization shortening and conduction slowing result in specific ECG phenotypes and distinct VF dynamics. In our porcine model, repolarization heterogeneity is associated with a higher risk to VF.

Insights Into the Spatiotemporal Patterns of Complexity of Ventricular Fibrillation by Multilead Analysis of Body Surface Potential Maps.

BackgroundVentricular fibrillation (VF) is the main cause of sudden cardiac death, but its mechanisms are still unclear. We propose a noninvasive approach to describe the progression of VF complexity from body surface potential maps (BSPMs).MethodsWe mapped 252 VF episodes (16 ± 10 s) with a 252-electrode vest in 110 patients (89 male, 47 ± 18 years): 50 terminated spontaneously, otherwise by electrical cardioversion (DCC). Changes in complexity were assessed between the onset (“VF start”) and the end (“VF end”) of VF by the nondipolar component index (NDIBSPM), measuring the fraction of energy nonpreserved by an equivalent 3D dipole from BSPMs. Higher NDI reflected lower VF organization. We also examined other standard body surface markers of VF dynamics, including fibrillatory wave amplitude (ABSPM), surface cycle length (BsCLBSPM) and Shannon entropy (ShEnBSPM). Differences between patients with and without structural heart diseases (SHD, 32 vs. NSHD, 78) were also tested at those stages. Electrocardiographic features were validated with simultaneous endocardium cycle length (CL) in a subset of 30 patients.ResultsAll BSPM markers measure an increase in electrical complexity during VF (p < 0.0001), and more significantly in NSHD patients. Complexity is significantly higher at the end of sustained VF episodes requiring DCC. Intraepisode intracardiac CL shortening (VF start 197 ± 24 vs. VF end 169 ± 20 ms; p < 0.0001) correlates with an increase in NDI, and decline in surface CL, f-wave amplitude, and entropy (p < 0.0001). In SHD patients VF is initially more complex than in NSHD patients (NDIBSPM, p = 0.0007; ShEnBSPM, p < 0.0001), with moderately slower (BsCLBSPM, p = 0.06), low-amplitude f-waves (ABSPM, p < 0.0001). In this population, lower NDI (p = 0.004) and slower surface CL (p = 0.008) at early stage of VF predict self-termination. In the NSHD group, a more abrupt increase in VF complexity is quantified by all BSPM parameters during sustained VF (p < 0.0001), whereas arrhythmia evolution is stable during self-terminating episodes, hinting at additional mechanisms driving VF dynamics.ConclusionMultilead BSPM analysis underlines distinct degrees of VF complexity based on substrate characteristics.

Atrial natriuretic peptide accelerates onset and dynamics of ventricular fibrillation during hypokalemia in isolated rabbit hearts

BackgroundAtrial natriuretic peptide (ANP), which is released by the heart in response to acute cardiac stretch, possesses cardiac electrophysiological properties that include modulation of ion channel function and repolarization. However, data regarding whether ANP can directly modulate electrical instability or arrhythmias are largely lacking. ObjectiveThis study sought to determine whether ANP modifies onset or electrophysiological characteristics of ventricular fibrillation (VF) induced by severe hypokalemia in an isolated heart model. MethodsLangendorff-perfused rabbit hearts in the absence and presence of 10 nM ANP (n = 9 in each group) were subjected to a low potassium (K+) perfusate (1.2 mM K+). Left ventricular (LV) epicardial monophasic action potential (MAP) and pressure were monitored continuously. Incidence and time to onset of VF and dominant frequency during VF determined by spectral analysis were evaluated. ResultsANP did not alter ventricular repolarization (MAP duration) or LV pressure during perfusion with physiologic, K+-containing solution. Within the first 30 s after low K+ perfusion, ANP accelerated the onset of beat-to-beat repolarization alternans (100% vs. 33% in ANP-treated vs. non-treated hearts, p < 0.01). During low K+ perfusion, the incidence of VF did not differ between ANP-treated and non-treated hearts (8 of 9 [89%] in each group). However, VF occurred sooner (3.75 ± 0.33 vs. 5.78 ± 0.70 min, P < 0.05) and immediately after VF onset, peak dominant frequency was higher (24.1 ± 7.3 vs. 14.2 ± 2.3 Hz, P = 0.01) in ANP-treated than in non-treated hearts. ConclusionsANP accelerates initiation of VF and increases maximum dominant frequency during VF in isolated hearts subjected to severe hypokalemia.

In-silico study of the cardiac arrhythmogenic potential of biomaterial injection therapy

Biomaterial injection is a novel therapy to treat ischemic heart failure (HF) that has shown to reduce remodeling and restore cardiac function in recent preclinical studies. While the effect of biomaterial injection in reducing mechanical wall stress has been recently demonstrated, the influence of biomaterials on the electrical behavior of treated hearts has not been elucidated. In this work, we developed computational models of swine hearts to study the electrophysiological vulnerability associated with biomaterial injection therapy. The propagation of action potentials on realistic biventricular geometries was simulated by numerically solving the monodomain electrophysiology equations on anatomically-detailed models of normal, HF untreated, and HF treated hearts. Heart geometries were constructed from high-resolution magnetic resonance images (MRI) where the healthy, peri-infarcted, infarcted and gel regions were identified, and the orientation of cardiac fibers was informed from diffusion-tensor MRI. Regional restitution properties in each case were evaluated by constructing a probability density function of the action potential duration (APD) at different cycle lengths. A comparative analysis of the ventricular fibrillation (VF) dynamics for every heart was carried out by measuring the number of filaments formed after wave braking. Our results suggest that biomaterial injection therapy does not affect the regional dispersion of repolarization when comparing untreated and treated failing hearts. Further, we found that the treated failing heart is more prone to sustain VF than the normal heart, and is at least as susceptible to sustained VF as the untreated failing heart. Moreover, we show that the main features of VF dynamics in a treated failing heart are not affected by the level of electrical conductivity of the biogel injectates. This work represents a novel proof-of-concept study demonstrating the feasibility of computer simulations of the heart in understanding the arrhythmic behavior in novel therapies for HF.

Ventricular fibrillation mechanism and global fibrillatory organization are determined by gap junction coupling and fibrosis pattern.

AimsConflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganized multiple-wavelet activation to organized rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.Methods and resultsOptical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact fibrosis (CF), diffuse fibrosis (DiF), and patchy fibrosis (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organized fibrillation in a concentration-dependent manner; increasing FDI (0 nM: 0.53 ± 0.04, 80 nM: 0.78 ± 0.03, P < 0.001), increasing RA-sustained VF time (0 nM: 44 ± 6%, 80 nM: 94 ± 2%, P < 0.001), and stabilized RAs (maximum rotations for an RA; 0 nM: 5.4 ± 0.5, 80 nM: 48.2 ± 12.3, P < 0.001). GJ uncoupling with carbenoxolone progressively disorganized VF; the FDI decreased (0 µM: 0.60 ± 0.05, 50 µM: 0.17 ± 0.03, P < 0.001) and RA-sustained VF time decreased (0 µM: 61 ± 9%, 50 µM: 3 ± 2%, P < 0.001). In CF, VF activity was disorganized and the RA-sustained VF time was the lowest (CF: 27 ± 7% vs. PF: 75 ± 5%, P < 0.001). Global fibrillatory organization measured by FDI was highest in PF (PF: 0.67 ± 0.05 vs. CF: 0.33 ± 0.03, P < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411 ± 266 ms vs. compact: 354 ± 38 ms, P < 0.001). DiF (n = 11) exhibited an intermediately organized VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs.ConclusionThe degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organization in VF, ranging between globally organized fibrillation sustained by stable RAs and disorganized, possibly multiple-wavelet driven fibrillation with no RAs.

4969Enhanced gap junction coupling organised and terminated acute ventricular fibrillation in ex-vivo perfused hearts

Abstract Background The underlying mechanism of ventricular fibrillation (VF) remains unclear. There are both experimental and clinical data to support the existence of rotational drivers (RDs), though other opposing studies suggest that VF is the result of disorganized myocardial activation. Abnormal electrical coupling between cardiomyocytes through gap junctions (GJ) has been considered an important factor in the genesis and maintenance of VF and pre-treatment with GJ couplers, rotigaptide (RTG), has been shown to reduce VF inducibility. Purpose We hypothesized that the degree of GJ coupling determines the underlying mechanism of VF, and that changes in GJ coupling can shift or modify the predominant mechanism of fibrillation along the spectrum between disorganised activity and organised drivers. We proposed that increased organisation of VF is critical to its termination. Methods Thirty Sprague-Dawley rat hearts were explanted, perfused ex-vivo and acute VF was induced with burst pacing and 30μM pinacidil. Optical mapping of transmembrane potential was performed at baseline and the effects of GJ coupling on VF dynamics were studied in an acute VF model by perfusing with increasing concentrations of a GJ uncoupler; carbenoxolone (0–50μM, CBX, n=10) or a GJ coupling-enhancer; RTG (0–80nM, n=10). A chronic diffuse fibrosis model (n=10) was generated with 4 weeks of in-vivo angiotensin infusion (500nm/kg/min). Fibrillation dynamics were quantified using phase analysis, phase singularity (PS) tracking and our novel method of global fibrillation organisation quantification, frequency dominance index (FDI), which is a power ratio of highest amplitude dominant frequency in the frequency spectrum. Results RTG increased average rotations per RD (Baseline: 2.86±0.10 vs 80nM: 5.66±0.43, p&lt;0.001) whilst CBX caused a reduction (Baseline: 3.77±0.39 vs 50μM: 0.26±0.26, p&lt;0.001). Maximum rotations for a RD increased with RTG (5.4±0.45 vs 48.20±12.32, p&lt;0.001) and decreased with CBX (8.0±1.3 vs 0.3±0.3, p&lt;0.001). Proportion of time PSs were detected in VF increased with RTG (0.44±0.06 vs 0.93±0.02, p&lt;0.001) and decreased with CBX (0.61±0.9 vs 0.03±0.02, p&lt;0.001). RTG reduced meander of longest duration RD (20.6±1.68 vs 11.51±0.77 pixels, p&lt;0.001) for PS &gt;5 rotations. FDI increased with RTG (0.53±0.04 vs 0.78±0.3, p&lt;0.001) and decreased with CBX (0.60±0.05 vs 0.17±0.03, p&lt;0.001). In the diffuse fibrosis group, in comparison to baseline RTG 80nM increased FDI (0.35 vs 0.65, p&lt;0.001) and terminated VF in 40% of hearts. Conclusion The degree of GJ coupling is a key determinant of the underlying mechanism of VF. RTG organised fibrillation and stabilised RDs in a concentration-dependent manner whilst CBX disorganised VF. Enhancing GJ coupling with RTG in diseased hearts with fibrosis can terminate VF and may be a potential therapeutic target in acute VF. Acknowledgement/Funding BHF Programme Grant PG/16/17/32069

In vivo ratiometric optical mapping enables high-resolution cardiac electrophysiology in pig models.

AimsCardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models.Methods and resultsFirst, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63–138) cm/s vs. 51 (41–64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217–254) ms vs. 192 (182–233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min−1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA.Conclusions In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.

Application of Entropy-Based Features to Predict Defibrillation Outcome in Cardiac Arrest

Prediction of defibrillation success is of vital importance to guide therapy and improve the survival of patients suffering out-of-hospital cardiac arrest (OHCA). Currently, the most efficient methods to predict shock success are based on the analysis of the electrocardiogram (ECG) during ventricular fibrillation (VF), and recent studies suggest the efficacy of waveform indices that characterize the underlying non-linear dynamics of VF. In this study we introduce, adapt and fully characterize six entropy indices for VF shock outcome prediction, based on the classical definitions of entropy to measure the regularity and predictability of a time series. Data from 163 OHCA patients comprising 419 shocks (107 successful) were used, and the performance of the entropy indices was characterized in terms of embedding dimension (m) and matching tolerance (r). Six classical predictors were also assessed as baseline prediction values. The best prediction results were obtained for fuzzy entropy (FuzzEn) with m = 3 and an amplitude-dependent tolerance of r = 80 μ V . This resulted in a balanced sensitivity/specificity of 80.4%/76.9%, which improved by over five points the results obtained for the best classical predictor. These results suggest that a FuzzEn approach for a joint quantification of VF amplitude and its non-linear dynamics may be a promising tool to optimize OHCA treatment.

Optical Mapping of Ventricular Fibrillation Dynamics.

There is very limited information regarding the dynamic patterns of the electrical activity during ventricular fibrillation (VF) in humans. Most of the data used to generate and test hypotheses regarding the mechanisms of VF come from animal models and computer simulations and the quantification of VF patterns is non-trivial. Many of the experimental recordings of the dynamic spatial patterns of VF have been obtained from mammals using "optical mapping" or "video imaging" technology in which "phase maps" are derived from high-resolution transmembrane recordings from the heart surface. The surface manifestation of the unstable reentrant waves sustaining VF can be identified as "phase singularities" and their number and location provide one measure of VF complexity. After providing a brief history of optical mapping of VF, we compare and contrast a quantitative analysis of VF patterns from the heart surface for four different animal models, hence providing physiological insight into the variety of VF dynamics among species. We found that in all four animal models the action potential duration restitution slope was actually negative during VF and that the spatial dispersion of electrophysiological parameters were not different during the first second of VF compared to pacing immediately before VF initiation. Surprisingly, our results suggest that APD restitution and spatial dispersion may not be essential causes of VF dynamics. Analyses of electrophysiological quantities in the four animal models are consistent with the idea that VF is essentially a two-dimensional phenomenon in small rabbit hearts whose size are near the boundary of the "critical mass" required to sustain VF, while VF in large pig hearts is three-dimensional and exhibits the maximal theoretical phase singularity density, and thus will not terminate spontaneously.

Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts.

RationaleStructural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role.ObjectivesTo define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics.Methods and ResultsHigh throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na+/K+ ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships.ConclusionsIon channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.

Ventricular remodelling in rabbits with sustained high‐fat diet

Excess weight gain and obesity are one of the most serious health problems in the western societies. These conditions enhance risk of cardiac disease and have been linked with increased prevalence for cardiac arrhythmias and sudden death. Our goal was to study the ventricular remodelling occurring in rabbits fed with high-fat diet (HFD) and its potential arrhythmogenic mechanisms. We used 15 NZW rabbits that were randomly assigned to a control (n = 7) or HFD group (n = 8) for 18 weeks. In vivo studies included blood glucose, electrocardiographic, and echocardiographic measurements. Optical mapping was performed in Langendorff-perfused isolated hearts. Body weight (3.69 ± 0.31 vs. 2.94 ± 0.18 kg, P < 0.001) and blood glucose levels (230 ± 61 vs. 141 ± 14 mg dL(-1) , P < 0.05) were higher in the HFD group vs. controls. The rate-corrected QT interval and its dispersion were increased in HFD rabbits vs. controls (169 ± 10 vs. 146 ± 13 ms and 37 ± 11 vs. 9 ± 2 ms, respectively; P < 0.05). Echocardiographic analysis showed morphological and functional alterations in HFD rabbits indicative of left ventricle (LV) hypertrophy. Isolated heart studies revealed no changes in repolarization and propagation properties under conditions of normal extracellular K(+) , suggesting that extrinsic factors could underlie those electrocardiographic modifications. There were no differences in the dynamics of ventricular fibrillation (frequency, wave breaks) in the presence of isoproterenol. However, HFD rabbits showed a small reduction in action potential duration and an increased incidence of arrhythmias during hyperkalaemia. High-fat feeding during 18 weeks in rabbits induced a type II diabetes phenotype, LV hypertrophy, abnormalities in repolarization and susceptibility to arrhythmias during hyperkalaemia.

Different Ventricular Fibrillation (VF) Dynamics in Long QT Syndrome Type 1 vs. 2 in a Transgenic Rabbit Model

Long QT syndrome (LQTS) is a congenital disease characterized by APD prolongation and associated with sudden cardiac death. LQT1 and LQT2, the most common types of LQTS, lack delayed rectifying potassium currents, IKs and IKr, respectively. We hypothesize that the differential kinetic properties of IKs and IKr can influence vulnerability to ventricular fibrillation (VF) through genotype-specific enhancement of VF maintenance. We investigated VF dynamics in transgenic rabbit models of LQT1, LQT2, and littermate controls (LMC) with optical mapping (n=6). VF frequency (VFF) analysis showed wave propagation to be slowest in LQT2 in line with APD gradient in groups (LQT2=7.06Hz, LQT1=11.72Hz, LMC=12.14Hz). Despite low frequency in LQT2, complexity of VFs was comparable to LMC. Further pattern analysis revealed that LQT2 exhibited higher incidence of wave breaks per wave while LQT1 shows even lower than LMC (LQT2=0.374 vs. LQT1=0.234, LMC=0.320). These results highlight role of IKr vs. IKs in VF maintenance, suggesting that VFs in LQT1 and 2 are maintained by different mechanisms such as wave breaks and re-initiation of reentry vs. triggered activity.View Large Image | View Hi-Res Image | Download PowerPoint Slide

Studying semblances of a true killer: experimental model of human ventricular fibrillation

It is unknown whether ventricular fibrillation (VF) studied in experimental models represents in vivo human VF. First, we examined closed chest in vivo VF induced at defibrillation threshold testing (DFT) in four patients with ischemic cardiomyopathy pretransplantation. We examined VF in these same four hearts in an ex vivo human Langendorff posttransplantation. VF from DFT was compared with VF from the electrodes from a similar region in the right ventricular endocardium in the Langendorff using two parameters: the scale distribution width (extracted from continuous wavelet transform) and VF mean cycle length (CL). In a second substudy group where multielectrode phase mapping could be performed, we examined early VF intraoperatively (in vivo open chest condition) in three patients with left ventricular cardiomyopathy. We investigated early VF in the hearts of three patients in an ex vivo Langendorff and compared findings with intraoperative VF using two metrics: dominant frequency (DF) assessed by the Welch periodogram and the number of phase singularities (lasting >480 ms). Wavelet analysis (P = 0.9) and VF CL were similar between the Langendorff and the DFT groups (225 ± 13, 218 ± 24 ms; P = 0.9), indicating that wave characteristics and activation rate of VF was comparable between the two models. Intraoperative DF was slower but comparable with the Langendorff DF over the endocardium (4.6 ± 0.1, 5.0 ± 0.4 Hz; P = 0.9) and the epicardium (4.5 ± 0.2, 5.2 ± 0.4 Hz; P = 0.9). Endocardial phase singularity number (9.6 ± 5, 12.1 ± 1; P = 0.6) was lesser in number but comparable between in vivo and ex vivo VF. VF dynamics in the limited experimental human studies approximates human in vivo VF.

264 Is ventricular fibrillation different in ischemic compared to non-ischemic dilated cardiomyopathic human hearts?

It is unknown if VF dynamics are dependent on the etiology of the cardiomyopthay. In this study we compared transmural dominant frequency gradient, during ventricular fibrillation (VF), in ischemic and non-ischemic dilated cardiomyopathic human hearts. The study was conducted in human langendorff model. These were ischemic (ICM, n = 5) and dilated (DCM, n = 5) cardiomyopathic human hearts explanted from patients undergoing cardiac transplant. Data was collected using an epicardial sock and an endocardial balloon each having 112 unipolar electrodes, arranged in 14 columns and 8 rows. Ischemia was induced by halting the perfusion to the heart and VF was initiated by brief application of 9V batter to epicardium. VF was recorded at onset, 90 seconds and 180 seconds for 20 seconds each. Dominant frequency (DF) was computed using Welch periodogram method as described in our previous studies. Repeated measure ANOVA was employed using mixed model in SAS. The mean DF in LV-endocardium and LV-epicardium is reported in table 1. At the onset of VF, no difference was observed between LV epicardium and endocardium in dilated cardiomyopathic hearts (P = 0.6) while the difference was statistically significant in ischemic cardiomyopathic hearts (P < 0.05). After 180 seconds of VF, there was a significant transmural DF gradient in both ischemic and dilated cardiomyopathic hearts (P < 0.05).Tabled 1 There is a LV transmural DF gradient during VF in both DCM and ICM after 3 minutes of ischemia. This gradient is established early in ischemia in ICM but not in DCM. These finding may relate to differential transmural ion channel remodelling that is dependent of the etiology of cardiomyopathic process.

Stochastic dynamics of phase singularities under ventricular fibrillation in 2D Beeler-Reuter model

The dynamics of ventricular fibrillation (VF) has been studied extensively, and the initiation mechanism of VF has been elucidated to some extent. However, the stochastic dynamical nature of sustained VF remains unclear so far due to the complexity of high dimensional chaos in a heterogeneous system. In this paper, various statistical mechanical properties of sustained VF are studied numerically in 2D Beeler-Reuter-Drouhard-Roberge (BRDR) model with normal and modified ionic current conductance. The nature of sustained VF is analyzed by measuring various fluctuations of spatial phase singularity (PS) such as velocity, lifetime, the rates of birth and death. It is found that the probability density function (pdf) for lifetime of PSs is independent of system size. It is also found that the hyper-Gamma distribution serves as a universal pdf for the counting number of PSs for various system sizes and various parameters of our model tissue under VF. Further, it is demonstrated that the nonlinear Langevin equation associated with a hyper-Gamma process can mimic the pdf and temporal variation of the number of PSs in the 2D BRDR model.

The effect of cardiac sympathetic denervation through bilateral stellate ganglionectomy on electrical properties of the heart

The role of the cardiac sympathetic nerve activity in various cardiac diseases is typically evaluated using β-adrenergic receptor antagonists. However, these antagonists induce global denervation effects not only in the cardiovascular system, but also in the brain and kidney. The objective of this study was to detect the electrophysiological property changes due to 8 days of cardiac sympathetic denervation and investigate the possible mechanisms underlying these changes using a more cardiac-specific bilateral stellate ganglionectomy (SGX) rat model. High-resolution optical mapping using a voltage-sensitive dye was performed in isolated Langendorff-perfused sham and SGX hearts, which were paced at progressively reduced basic cycle lengths under several different conditions: control, pretreatment with isoproterenol, and administration of atenolol and esmolol. Several electrophysiological parameters were recorded during periodic pacing and ventricular fibrillation (VF). Our results demonstrate that cardiac sympathetic denervation by bilateral SGX shortens action potential duration (APD) and flattens the APD restitution curve, but does not significantly affect spatial dispersion of APD. We found that, although the vulnerability of sham and SGX hearts to VF is similar, the dynamics of VF are different. The maximum dominant frequency is higher, and the spatial distribution of VF is more complex in the SGX heart, resulting in different mechanisms of VF. We demonstrated that β(1)-adrenergic receptors are downregulated in the SGX compared with sham hearts. In addition, our data suggest that the mechanism of cardiac sympathetic denervation by SGX surgery is more similar to the administration of β-blocker esmolol than atenolol.

A computational study of mother rotor VF in the human ventricles.

Sudden cardiac death is one of the major causes of death in the industrialized world. It is most often caused by a cardiac arrhythmia called ventricular fibrillation (VF). Despite its large social and economical impact, the mechanisms for VF in the human heart yet remain to be identified. Two of the most frequently discussed mechanisms observed in experiments with animal hearts are the multiple wavelet and mother rotor hypotheses. Most recordings of VF in animal hearts are consistent with the multiple wavelet mechanism. However, in animal hearts, mother rotor fibrillation has also been observed. For both multiple wavelet and mother rotor VF, cardiac heterogeneity plays an important role. Clinical data of action potential restitution measured from the surface of human hearts have been recently published. These in vivo data show a substantial degree of spatial heterogeneity. Using these clinical restitution data, we studied the dynamics of VF in the human heart using a heterogeneous computational model of human ventricles. We hypothesized that this observed heterogeneity can serve as a substrate for mother rotor fibrillation. We found that, based on these data, mother rotor VF can occur in the human heart and that ablation of the mother rotor terminates VF. Furthermore, we found that both mother rotor and multiple wavelet VF can occur in the same heart depending on the initial conditions at the onset of VF. We studied the organization of these two types of VF in terms of filament numbers, excitation periods, and frequency domains. We conclude that mother rotor fibrillation is a possible mechanism in the human heart.

Effects of Wall Stress on the Dynamics of Ventricular Fibrillation: A Simulation Study Using a Dynamic Mechanoelectric Model of Ventricular Tissue

To investigate the mechanisms underlying the increased prevalence of ventricular fibrillation (VF) in the mechanically compromised heart, we developed a fully coupled electromechanical model of the human ventricular myocardium. The model formulated the biophysics of specific ionic currents, excitation-contraction coupling, anisotropic nonlinear deformation of the myocardium, and mechanoelectric feedback (MEF) through stretch-activated channels. Our model suggests that sustained stretches shorten the action potential duration (APD) and flatten the electrical restitution curve, whereas stretches applied at the wavefront prolong the APD. Using this model, we examined the effects of mechanical stresses on the dynamics of spiral reentry. The strain distribution during spiral reentry was complex, and a high strain-gradient region was located in the core of the spiral wave. The wavefront around the core was highly stretched, even at lower pressures, resulting in prolongation of the APD and extension of the refractory area in the wavetail. As the left ventricular pressure increased, the stretched area became wider and the refractory area was further extended. The extended refractory area in the wavetail facilitated the wave breakup and meandering of tips through interactions between the wavefront and wavetail. This simulation study indicates that mechanical loading promotes meandering and wave breaks of spiral reentry through MEF. Mechanical loading under pathological conditions may contribute to the maintenance of VF through these mechanisms.