On the Electrophysiology and Mapping of Intramural Arrhythmic Focus.

BACKGROUND: Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface indices to predict the site and depth of ventricular arrhythmogenic focal sources. METHODS: An experimental beating-heart model used Langendorff-perfused, healthy swine hearts. A custom 56-pole electrode array catheter was positioned on the left ventricle. A plunge needle was placed perpendicular in the center of the grid to simulate arrhythmic foci at variable depths. Unipolar electrograms and local activation times were generated. Simulation models from 2 human hearts were also included with grids positioned simultaneously on the endocardium-epicardium from multiple left ventricular, septal, and outflow tract sites. RESULTS: A unipolar Q or QS complex lacks specificity for superficial arrhythmic foci, as this morphology pattern occupies a large surface area and is the predominant pattern as intramural depth increases without developing a R component. There is progressive displacement from the arrhythmic focus to the surface exit as intramural focus depth increases. A shorter total activation time over the overlying electrode array, larger surface area within initial 20 ms activation, and a dual surface breakout pattern all indicate a deep focus. CONCLUSIONS: Displacement from the focal intramural origin to the exit site on the mapping surface could lead to erroneous lesion delivery strategies. Traditional unipolar electrogram features lack specificity to predict the intramural arrhythmic source; however, novel endocardial-epicardial mapping surface indices can be used to determine the depth of arrhythmic foci.

Role of Purkinje-muscle junction in early ventricular fibrillation in a porcine model: Beyond the trigger concept.

BACKGROUND: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. AIM: We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. METHODS: In a healthy, porcine, beating-heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial-endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re-induction and mapping and finally, histological evaluation. RESULTS: Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p < .0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p < .0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p = .0002), respectively]. In controls, epicardial-endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p < .001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p < .001) and to 2.2 ± 0.3 Hz (early VF, p <.001). Endocardial-epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. CONCLUSIONS: Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF.

Multi-Axes Lead With Tetrahedral Electrode Tip for Cardiac-Implantable Devices: Creative Concept for Pacing and Sensing Technology.

BACKGROUND: We developed a multi-axes lead (MaxLead) incorporating 4 electrodes arranged at the lead-tip, organized in an equidistant tetrahedron. Here, we studied MaxLead performance in sensing, pacing, and activation wavefront-direction analysis. METHODS: Sixteen explanted animal hearts (from 7 pigs, 7 sheep, and 2 rabbits) were used. Pacing threshold was tested from all axes of MaxLead from right-ventricular (RV) apex before and after simulated dislodgement. In addition, conduction-system pacing was performed in sheep heart preparations from all axes of MaxLead. Sensing via MaxLead positioned at RV apex was tested during sinus rhythm (SR), pacing from RV and left-ventricular (LV) free-wall, and ventricular fibrillation (VF). MaxLead-enabled voltage (MaxV), defined as the largest span of the sensed electric field loop, was compared with traditional lead-tip voltage detection. RESULTS: Pacing: MaxLead minimized change in pacing threshold owing to lead dislodgement (average voltage change 0.2 mV; 95% confidence interval [CI], -0.5 to 0.9), using multiple bipoles available for pacing. In animals with high conduction system-pacing thresholds (> 2 mV) in 1 or more bipoles (3 of 7), acceptable thresholds (< 1 mV) were demonstrated in an average of 2.5 remaining bipoles. Sensing: MaxV of SR and VF was consistently higher than the highest bipolar voltage (voltage difference averaged -0.18 mV, 95% CI, -0.28 to -0.07), P = 0.001). Electric field-loop geometry consistently differentiated ventricular activation in SR from that during pacing from RV and LV free walls. CONCLUSIONS: The multi-axes MaxLead electrode showed advantages in pacing, sensing, and mapping and has the potential to allow for improvements in lead-electrode technology for cardiac-implanted electronic devices.

Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy.

AIM: An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. MAIN METHODS: Experiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. KEY FINDINGS: LG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during ß-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. SIGNIFICANCE: LG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than ß-blockade.

Stimulation and propagation of activation in conduction tissue: Implications for left bundle branch area pacing.

BACKGROUND: Characterizing wavefront generation and impulse conduction in left bundle (LB) has implications for left bundle branch area pacing (LBBAP). OBJECTIVES: The purpose of this study was to describe the pacing characteristics of LB and to study the role of pacing pulse width (PW) in overcoming left bundle branch block. METHODS: Twenty fresh ovine heart slabs containing well-developed and easily identifiable tissues of the conduction system were used for the study. LB stimulation, activation, and propagation were studied under baseline conditions, simulated conduction slowing, conduction block, and fascicular block. RESULTS: The maximum radius of the LB early activation increased up to 13.4 ± 2.4 mm from the pacing stimulus, and the time from stimulus to evoked potential shortened when pacing PW was increased from 0.13 to 2 ms at baseline. Conduction slowing and block induced by cooling could be resolved by increasing pacing PW from 0.25 to 1.5 ms over a distance of 10 ± 1.5 mm from the pacing stimulus. The LB strength-duration (SD) curve was shifted to the left of the myocardial SD curve. CONCLUSION: Increasing PW resolved conduction slowing and block and bypassed the experimental model of fascicular block in LB. Precise positioning of the LB lead in left ventricular subendocardium is not mandatory in LBBAP, as the SD curve of LB was shifted to the left of the myocardium SD curve and could be captured from a distance by optimizing PW.

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model.

INTRODUCTION: Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional following VF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. METHODS: Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. RESULTS: Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. CONCLUSION: Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

The effect of left ventricular pacing on transmural activation delay in myopathic human hearts.

Aims: Left ventricular (LV) epicardial pacing (LVEpiP) in human myopathic hearts does not decrease global epicardial activation delay compared with right ventricular (RV) endocardial pacing (RVEndoP); however, the effect on transmural activation delay has not been evaluated. To characterize the transmural electrical activation delay in human myopathic hearts during RVEndoP and LVEpiP compared with global epicardial activation delay. Methods and results: Explanted hearts from seven patients (5 male, 46 ± 10 years) undergoing cardiac transplantation were Langendorff-perfused and mapped using an epicardial sock electrode array (112 electrodes) and 25 transmural plunge needles (four electrodes, 2 mm spacing), for a total of 100 unipolar transmural electrodes. Electrograms were recorded during LVEpiP and RVEndoP, and epicardial (sock) and transmural (needle) activation times, along with patterns of activation, were compared. There was no difference between the global epicardial activation times (LVEpiP 147 ± 8 ms vs. RVEndoP 156 ± 17 ms, P = 0.46). The mean LV transmural activation time during LVEpiP was significantly shorter than that during RVEndoP (125 ± 44 vs. 172 ± 43 ms, P < 0.001). During LVEpiP, of the transmural layers endo-, mid-myocardium and epicardium, LV endocardial layer was often the earliest compared with other transmural layers. Conclusion: In myopathic human hearts, LVEpiP did not decrease global epicardial activation delays compared with RVEndoP. LV epicardial pacing led to early activation of the LV endocardium, revealing the importance of the LV endocardium even when pacing from the LV epicardium.

Physiological Assessment of Ventricular Myocardial Voltage Using Omnipolar Electrograms.

BACKGROUND: Characterization of myocardial health by bipolar electrograms are critical for ventricular tachycardia therapy. Dependence of bipolar electrograms on electrode orientation may reduce reliability of voltage assessment along the plane of arrhythmic myocardial substrate. Hence, we sought to evaluate voltage assessment from orientation-independent omnipolar electrograms. METHODS AND RESULTS: We mapped the ventricular epicardium of 5 isolated hearts from each species-healthy rabbits, healthy pigs, and diseased humans-under paced conditions. We derived bipolar electrograms and voltage peak-to-peak (Vpps) along 2 bipolar electrode orientations (horizontal and vertical). We derived omnipolar electrograms and Vpps using omnipolar electrogram methodology. Voltage maps were created for both bipoles and omnipole. Electrode orientation affects the bipolar voltage map with an average absolute difference between horizontal and vertical of 0.25±0.18 mV in humans. Vpps provide larger absolute values than horizontal and vertical bipolar Vpps by 1.6 and 1.4 mV, respectively, in humans. Bipolar electrograms with the largest Vpps from either along horizontal or vertical orientation are highly correlated with omnipolar electrograms and with Vpps values (0.97±0.08 and 0.94±0.08, respectively). Vpps values are more consistent than bipoles, in both beat-by-beat (CoV, 0.28±0.19 versus 0.08±0.13 in human hearts) and rhythm changes (0.55±0.21 versus 0.40±0.20 in porcine hearts). CONCLUSIONS: Omnipoles provide physiologically relevant and consistent voltages that are along the maximal bipolar direction on the plane of the myocardium.

Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping.

BACKGROUND: Low-voltage-guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (Vpp) from variations in wavefront direction relative to electrode orientation and from fractionation and collision events. We aim to compare bipole Vpp with novel omnipolar peak-to-peak voltages (Vmax) in sinus rhythm (SR) and AF. METHODS AND RESULTS: A high-density fixed multielectrode plaque was placed on the epicardial surface of the left atrium in dogs. Horizontal and vertical orientation bipolar EGMs, followed by omnipolar EGMs, were obtained and compared in both SR and AF. Bipole orientation has significant impact on bipolar EGM voltages obtained during SR and AF. In SR, vertical values were on average 66±119% larger than horizontal (P=0.004). In AF, vertical values were on average 31±96% larger than horizontal (P=0.07). Omnipole Vmax values were 99.9±125% larger than both horizontal (99.9±125%; P<0.001) and vertical (41±78%; P<0.0001) in SR and larger than both horizontal (76±109%; P<0.001) and vertical (52±70%; P value <0.0001) in AF. Vector field analysis of AF wavefronts demonstrates that omnipolar EGMs can account for collision and fractionation and record EGM voltages unaffected by these events. CONCLUSIONS: Omnipolar EGMs can extract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation, compared with contemporary bipolar techniques.

Resolving Myocardial Activation With Novel Omnipolar Electrograms.

BACKGROUND: With its inherent limitations, determining local activation times has been the basis of cardiac mapping for over a century. Here, we introduce omnipolar electrograms that originate from the natural direction of a travelling wave and from which instantaneous conduction velocity amplitude and direction can be computed at any single location without first determining activation times. We sought to validate omnipole-derived conduction velocities and explore potential application for localization of sources of arrhythmias. METHODS AND RESULTS: Electrograms from omnipolar mapping were derived and validated using 4 separate models and 2 independent signal acquisition methodologies. We used both electric signals and optical signals collected from monolayer cell preparations, 3-dimensional constructs built with cardiomyocytes derived from human embryonic stem cells, simultaneous optical and electric mapping of rabbit hearts, and in vivo pig electrophysiology studies. Conduction velocities calculated from omnipolar electrograms were compared with wavefront propagation from optical and electric-mapping studies with a traditional local activation time-based method. Bland-Altman analysis revealed that omnipolar measurements on optical data were in agreement with local activation time methods for wavefront direction and velocity within 25 cm/s and 30°, respectively. Similar agreement was also found on electric data. Furthermore, mathematical operations, such as curl and divergence, were applied to omnipole-derived velocity vector fields to locate rotational and focal sources, respectively. CONCLUSIONS: Electrode orientation-independent cardiac wavefront trajectory and speed at a single location for each cardiac activation can be determined accurately with omnipolar electrograms. Omnipole-derived vector fields, when combined with mathematical transforms may aid in real-time detection of cardiac activation sources.

Feature-based MRI data fusion for cardiac arrhythmia studies.

Current practices in studying cardiac arrhythmias primarily use electrical or optical surface recordings of a heart, spatially limited transmural recordings, and mathematical models. However, given that such arrhythmias occur on a 3D myocardial tissue, information obtained from such practices lack in dimension, completeness, and are sometimes prone to oversimplification. The combination of complementary Magnetic-Resonance Imaging (MRI)-based techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) could provide more depth to current practices in assessing the cardiac arrhythmia dynamics in entire cross sections of myocardium. In this work, we present an approach utilizing feature-based data fusion methods to demonstrate that complimentary information obtained from electrical current distribution and structural properties within a heart could be quantified and enhanced. Twelve (12) pairs of CDI and DTI image data sets were gathered from porcine hearts perfused through a Langendorff setup. Images were fused together using feature-based data fusion techniques such as Joint Independent Component Analysis (jICA), Canonical Correlation Analysis (CCA), and their combination (CCA+jICA). The results suggest that the complimentary information of cardiac states from CDI and DTI are enhanced and are better classified with the use of data fusion methods. For each data set, an increase in mean correlations of fused images were observed with 38% increase from CCA+jICA compared to the original images while mean mutual information of the fused images from jICA and CCA+jICA increased by approximately three-fold. We conclude that MRI-based techniques present potential viable tools in furthering studies for cardiac arrhythmias especially Ventricular Fibrillation.

The need for and the challenges of measuring renal sympathetic nerve activity.

Renal denervation (RDN) was primarily developed to treat hypertension and is potentially a new method for treating arrhythmias. Because of the lack of a standardized protocol to measure renal sympathetic nerve activity, RDN is administered in a blind manner. This inability to assess efficacy at the time of treatment delivery may be a large contributor to the ambiguity of RDN outcomes reported in the hypertension literature. The advancement of RDN as a treatment of hypertension or arrhythmias will be hampered by the lack of delivery assessment, a deficiency that the cardiovascular electrophysiology community, with its expertise in recording and mapping, may have a role in addressing and overcoming. The development of endovascular recording of renal nerve action potentials may provide a useful accessory tool for RDN. Innovation in this area will be crucial as we as a community reconsider the therapeutic value of RDN.

Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF.

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrode's buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.

Tracking rotors with minimal electrodes: modulation index-based strategy.

BACKGROUND: High-frequency periodic sources during cardiac fibrillation can be detected by phase mapping techniques. To enable practical therapeutic options for modulating periodic sources (existing techniques require high density multielectrode arrays and real time simultaneous mapping capability), a method to identify electrogram morphologies colocalizing to rotors that can be implemented on few electrograms needs to be devised. METHOD AND RESULTS: Multichannel ventricular fibrillation electrogram data from 7 isolated human hearts using Langendorff setup and intraoperative clinical data from 2 human hearts were included in the analysis. The spatial locations of rotors were identified using phase maps constructed from 112 electrograms. Electrograms were analyzed for repeating patterns and discriminating signal morphologies around the locations of rotors and nonrotors were identified and quantified. Features were extracted from the unipolar electrogram patterns, which corroborated well with the spatial location of rotors. The results suggest that using the proposed modulation index feature, and as low as 1 sample point in the vicinity of the rotors, an accuracy as high as 86% (P<0.001) was obtained in separating rotor locations versus nonrotor locations. The analysis of bipolar electrogram signatures in the vicinity of the rotor locations suggest that 62.5% of the rotors occur at locations where the bipolar electrogram demonstrates continuous activities during ventricular fibrillation. CONCLUSIONS: Unipolar electrogram extracted modulation index-based detection of rotors is feasible with few electrodes and has greater detection rate than bipolar approach. This strategy may be suitable for nonarray-based single mapping catheter enabled detection of rotors.

Mechanisms of Long-Duration Ventricular Fibrillation in Human Hearts and Experimental Validation in Canine Purkinje Fibers.

OBJECTIVES: This study sought to determine the characteristics of human LDVF, particularly as it contrasts with short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance. BACKGROUND: The electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been studied in the human heart. METHODS: VF was induced in 12 human Langendorff hearts, and the hearts were examined from initiation to LDVF (10 min). Endocardial, epicardial, and transmural plunge needle mapping were performed on the hearts. Simulated LDVF was studied in canine hearts to determine the potential role of Purkinje fiber automaticity. RESULTS: The mean age at transplant was 48 ± 20 years, and the mean ejection fraction was <20%. The mean cycle length of local activation times on the endocardium was 252 ± 66 ms in SDVF and 441 ± 80 ms in LDVF (p = 0.0002). On the endocardium and the epicardium in LDVF, cycle length was 441 ± 80 ms and 590 ± 88 ms, respectively (p = 0.0002). No endocardial to epicardial activation frequency gradient was seen in SDVF. Simultaneous transmural needle activation was most common in SDVF, whereas endocardial to epicardial activation was most common in LDVF (47.7% and 38.8% of activations, respectively [p = 0.031]). Re-entry was less common in LDVF, and over time, wave break (i.e., nontransmural propagation of wave fronts) developed. Isochronal maps of the left ventricular endocardium in LDVF identified Purkinje potentials as preceding and predominating endocardial activations. In explanted canine heart preparations, rapid pacing led to spontaneous Purkinje fiber activity that was dependent on pacing rate and duration. CONCLUSIONS: LDVF in human hearts is characterized by focal endocardial activity with mid-myocardial wave break and not by re-entry. This arrhythmia is modulated by rapid activations in early VF that lead to spontaneous Purkinje fiber activity.

Mesenchymal stem cell transplantation mitigates electrophysiological remodeling in a rat model of myocardial infarction.

INTRODUCTION: Transplantation of mesenchymal stem cells (MSCs) has shown therapeutic potential for cardiovascular diseases, but the electrophysiological implications are not understood. The purpose of this study was to evaluate the impact of MSC transplantation on adverse electrophysiological remodeling in the heart following myocardial infarction (MI). METHODS AND RESULTS: Three weeks after coronary ligation to induce MI in rats, MSCs or culture medium were directly injected into each infarct. One to two weeks later, hearts were excised, Langendorff-perfused, and optically mapped using the potentiometric fluorescent dye Di-4-ANEPPS. Quantitative real-time PCR was also performed to assess gene expression. Optical mapping showed that post-MI reduction in conduction velocity (from 0.70 ± 0.04 m/s in 12 normal controls to 0.47 ± 0.02 m/s in 11 infarcted hearts, P < 0.05) was attenuated with MSC transplantation (0.65 ± 0.04 m/s, n = 18, P < 0.05). Electrophysiological changes correlated with higher vascular density and better-preserved ventricular geometry in MSC-transplanted hearts. A number of ion channel genes showed changes in RNA expression following infarction. In particular, the expression of Kir2.1, which mediates the inward rectifier potassium current, I(K1), was reduced in infarcted tissues (n = 7) to 13.8 ± 3.7% of normal controls, and this post-MI reduction was attenuated with MSC transplantation (44.4 ± 11.2%, n = 7, P < 0.05). CONCLUSION: In addition to promoting angiogenesis and limiting adverse structural remodeling in infarcted hearts, MSC transplantation also alters ion channel expression and mitigates electrophysiological remodeling. Further understanding of the electrophysiological impact of MSC transplantation to the heart may lead to the development of cell-based therapies for post-MI arrhythmias.

Effect of global ischemia and reperfusion during ventricular fibrillation in myopathic human hearts.

The effect of lack of global coronary perfusion on myocardial activation rate, wavebreak, and its temporal progression during human ventricular fibrillation (VF) is not known. We tested the hypothesis that global myocardial ischemia decreases activation rate and spatiotemporal organization during VF in myopathic human hearts, while increasing wavebreak, and that a short duration of reperfusion can restore these spatiotemporal changes to baseline levels. The electrograms were acquired during VF in a human Langendorff model using global mapping consisting of two 112-electrode arrays placed on the epicardium and endocardium simultaneously. We found that global myocardial ischemia results in slowing of the global activation rate (combined endo and epi), from 4.89+/-0.04 Hz. to 3.60+/-0.04 Hz. during the 200 s of global ischemia (no coronary flow) (P<0.01) in eight myopathic hearts. Two minutes of reperfusion contributed to reversal of the slowing with activation rate value increasing close to VF onset (4.72+/-0.04 Hz). In addition, during the period of ischemia, an activation rate gradient between the endocardium (3.76+/-0.06 Hz) and epicardium (3.45+/-0.06 Hz) was observed (P<0.01). There was a concomitant difference in wavebreak index (that provides a normalized parameterization of phase singularities) between the epicardium (11.29+/-2.7) and endocardium (3.25+/-2.7) during the 200 s of ischemia (P=0.02). The activation rate, gradient, and wavebreak changes were reversed by short duration (2 min) of reperfusion. Global myocardial ischemia of 3 min leads to complex spatiotemporal changes during VF in myopathic human hearts; these changes can be reversed by a short duration of reperfusion.

Spatiotemporal frequency analysis of ventricular fibrillation in explanted human hearts.

Ventricular fibrillation (VF) is a medical condition that occurs due to rapid and irregular electrical activity of heart. If undiagnosed or untreated, VF leads to sudden cardiac death. VF has been studied by researchers for over 100 years to elucidate the mechanism that maintains VF, and thus to arrive at therapeutic options. VF is a nonstationary process, and it manifests into variations in the waveform morphology, phase, and frequency dynamics of the surface electrograms. Dominant frequency analysis (DF maps) and phase maps are two widely used complementary approaches in assessing the evolution of VF process. These techniques are applied to electrograms or fluorescence signals obtained with voltage-sensitive dyes. In spite of VF being a nonstationary process, most of the existing literature limits frequency analysis to a segmented, time-averaged spectral analysis, where valuable information on the instantaneous temporal evolution of the spectral characteristics is lost. In order to resolve this issue, in this paper, we present a joint time-frequency approach that is suited for VF analysis and demonstrate the application of instantaneous mean frequency (IMF) in interpreting VF episodes. Human VF sources are rarely anatomically stable and are migratory. Traditional DF techniques fail in tracking this migratory behavior. IMF, on the other hand, can deal with these migratory sources and conduction blocks better than DF approaches. Results of the analysis using the electrograms of 204 VF segments obtained from 13 isolated human hearts (explanted during cardiac transplantation) indicate that in 81% of the VF segments, there were significant changes in the spatiotemporal evolution of the frequency, suggesting that IMF provides better mechanistic insight of these signals. The IMF tool presented in this paper demonstrates potential for applications in tracking frequency patterns, conduction blocks, and arriving at newer therapies to modulate VF.

Optical mapping of Langendorff-perfused human hearts: establishing a model for the study of ventricular fibrillation in humans.

Our objective was to establish a novel model for the study of ventricular fibrillation (VF) in humans. We adopted the established techniques of optical mapping to human ventricles for the first time to determine whether human VF is the result of wave breaks and singularity point formation and is maintained by high-frequency rotors and fibrillatory conduction. We describe the technique of acquiring optical signals in human hearts during VF, their characteristics, and the feasibility of possible analyses that could be performed to elucidate mechanisms of human VF. We used explanted hearts from five cardiomyopathic patients who underwent transplantation. The hearts were Langendorff perfused with Tyrode solution (95% O(2)-5% CO(2)), and the potentiometric dye di-4-ANEPPS was injected as a bolus into the coronary circulation. Fluorescence was excited at 531 +/- 20 nm with a 150-W halogen light source; the emission signal was long-pass filtered at 610 nm and recorded with a mapping camera. Fractional change of fluorescence varied between 2% and 12%. Average signal-to-noise ratio was 40 dB. The mean velocity of VF wave fronts was 0.25 +/- 0.04 m/s. Submillimetric spatial resolution (0.65-0.85 mm), activation mapping, and transformation of the data to phase-based analysis revealed reentrant, colliding, and fractionating wave fronts in human VF. On many occasions the VF wave fronts were as large as the entire vertical length (8 cm) of the mapping field, suggesting that there are a limited number of wave fronts on the human heart during VF. Phase transformation of the optical signals allowed the first demonstration ever of phase singularity point, wave breaks, and rotor formation in human VF. This method provides opportunities for potential analyses toward elucidation of the mechanisms of VF and defibrillation in humans.