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I R Efimov

Publications and source records attributed to I R Efimov.

At least 19 recordsLinked to original sources
PubMed2006

Connexins in the sinoatrial and atrioventricular nodes.

The sinoatrial node (SAN) and the atrioventricular node (AVN) are specialized tissues in the heart: the SAN is specialized for pacemaking (it is the pacemaker of the heart), whereas the AVN is specialized for slow conduction of the action potential (to introduce a delay between atrial and ventricular activation during the cardiac cycle). These functions have special requirements regarding electrical coupling and, therefore, expression of connexin isoforms. Electrical coupling in the center of the SAN should be weak to protect it from the inhibitory electrotonic influence of the more hyperpolarized non-pacemaking atrial muscle surrounding the SAN. However, for the SAN to be able to drive the atrial muscle, electrical coupling should be strong in the periphery of the SAN. Consistent with this, in the center of the SAN there is no expression of Cx43 (the principal connexin of the working myocardium) and little expression of Cx40, but there is expression of Cx45 and Cx30.2, whereas in the periphery of the SAN Cx43 as well Cx45 is expressed. In the AVN, there is a similar pattern of expression of connexins as in the center of the SAN and this is likely to be in large part responsible for the slow conduction of the action potential.

Action Potentials↗
PubMed2005

Computer three-dimensional reconstruction of the sinoatrial node.

BACKGROUND: There is an effort to build an anatomically and biophysically detailed virtual heart, and, although there are models for the atria and ventricles, there is no model for the sinoatrial node (SAN). For the SAN to show pacemaking and drive atrial muscle, theoretically, there should be a gradient in electrical coupling from the center to the periphery of the SAN and an interdigitation of SAN and atrial cells at the periphery. Any model should include such features. METHODS AND RESULTS: Staining of rabbit SAN preparations for histology, middle neurofilament, atrial natriuretic peptide, and connexin (Cx) 43 revealed multiple cell types within and around the SAN (SAN and atrial cells, fibroblasts, and adipocytes). In contrast to atrial cells, all SAN cells expressed middle neurofilament (but not atrial natriuretic peptide) mRNA and protein. However, 2 distinct SAN cell types were observed: cells in the center (leading pacemaker site) were small, were organized in a mesh, and did not express Cx43. In contrast, cells in the periphery (exit pathway from the SAN) were large, were arranged predominantly in parallel, often expressed Cx43, and were mixed with atrial cells. An approximately 2.5-million-element array model of the SAN and surrounding atrium, incorporating all cell types, was constructed. CONCLUSIONS: For the first time, a 3D anatomically detailed mathematical model of the SAN has been constructed, and this shows the presence of a specialized interface between the SAN and atrial muscle.

Animals↗
PubMed2005

[Pattern of excitation in isolated heart of hibernator ground squirrel Citellus undulatus].

Aim of our study was to measure conduction velocity and pattern of excitation during hypothermia in hearts of ground squirrels Citellus undulatus, known to be most resilient hibernators. We imaged electrical conduction in intact isolated hearts of summer active and winter hibernating ground squirrels at temperatures varying from +37 degrees C to +3 degrees C. Electrical activity was mapped using CCD camera (500 frames/sec) and voltage-sensitive dye di-4-ANEPPS during normal sinus rhythm and ventricular pacing. No spontaneous tachyarrhythmia was observed in all hearts at any temperature. Hearts were able to maintain spontaneous sinus rhythm and normal pattern of epicardial excitation throughout the whole range of studied temperatures. Despite responsiveness to pacing in all hearts ventricular conduction velocity was significantly reduced (about 10-fold) at low temperatures +3 degrees C. Our data provides the first direct demonstration that isolated heart of the summer active and winter hibernating ground squirrel Citellus undulatus is able to maintain normal excitation pattern in a range of temperatures from +37 degrees C to +3 degrees C.

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PubMed2004

Electrophysiology and anatomy of embryonic rabbit hearts before and after septation.

Mechanisms of cardiac pacemaking and conduction system (CPCS) development are difficult to study, in part because of the absence of models that are physiologically similar to humans in which we can label the entire CPCS. Investigations of the adult rabbit heart have provided insight into normal and abnormal cardiac conduction. The adult and the embryonic rabbit have an endogenous marker of the entire cardiac conduction system, neurofilament 160 (NF-160). Previous work suggested that ventricular septation correlates with critical phases in avian CPCS development, in contrast to the mouse CPCS. Combining high-resolution optical mapping with immunohistochemical analysis of the embryonic rabbit heart, we investigated the significance of ventricular septation in patterning the rabbit embryonic conduction system. We hypothesized that 1) completion of ventricular septation does not correlate with changes in the ventricular activation sequence in rabbit embryos and 2) CPCS anatomy determines the activation sequence of the embryonic heart. We found that preseptated (days 11-13, n = 13) and postseptated (day 15, n = 5) hearts had similar "apex-to-base" ventricular excitation. PR intervals were not significantly different in either group. CPCS anatomy revealed continuity of the NF-160-positive tract connecting the presumptive sinoatrial node, atrioventricular (AV) junction, and ventricular conduction system. The presence of collagen in the AV junction coincided with the appearance of an AV interval. We conclude that the apex-to-base ventricular activation sequence in the rabbit embryo is present before completion of ventricular septation. CPCS anatomy reflects global cardiac activation as demonstrated by high-resolution optical mapping.

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PubMed2003

Effects of electroporation on optically recorded transmembrane potential responses to high-intensity electrical shocks.

The outcome of defibrillation shocks is determined by the nonlinear transmembrane potential (DeltaVm) response induced by a strong external electrical field in cardiac cells. We investigated the contribution of electroporation to DeltaVm transients during high-intensity shocks using optical mapping. Rectangular and ramp stimuli (10-20 ms) of different polarities and intensities were applied to the rabbit heart epicardium during the plateau phase of the action potential (AP). DeltaVm were optically recorded under a custom 6-mm-diameter electrode using a voltage-sensitive dye. A gradual increase of cathodal and well as anodal stimulus strength was associated with 1) saturation and subsequent reduction of DeltaVm; 2) postshock diastolic resting potential (RP) elevation; and 3) postshock AP amplitude (APA) reduction. Weak stimuli induced a monotonic DeltaVm response and did not affect the RP level. Strong shocks produced a nonmonotonic DeltaVm response and caused RP elevation and a reduction of postshock APA. The maximum positive and maximum negative DeltaVm were recorded at 170 +/- 20 mA/cm2 for cathodal stimuli and at 240 +/- 30 mA/cm2 for anodal stimuli, respectively (means +/- SE, n = 8, P = 0.003). RP elevation reached 10% of APA at a stimulus strength of 320 +/- 40 mA/cm2 for both polarities. Strong ramp stimuli (20 ms, 600 mA/cm2) induced a nonmonotonic DeltaVm response, reaching the same largest positive and negative values as for rectangular shocks. The transition from monotonic to nonmonotonic morphology correlates with RP elevation and APA reduction, which is consistent with cell membrane electroporation. Strong shocks resulted in propidium iodide uptake, suggesting sarcolemma electroporation. In conclusion, electroporation is a likely explanation of the saturation and nonmonotonic nature of cellular responses reported for strong electric stimuli.

Action Potentials↗
PubMed2001

The mechanisms of the vulnerable window: the role of virtual electrodes and shock polarity.

Vulnerability and defibrillation are mechanistically dependent upon shock strength, polarity, and timing. We have recently demonstrated that shock-induced virtual electrode polarization (VEP) may induce reentry. However, it remains unclear how the VEP mechanism may explain the vulnerable window and polarity dependence of vulnerability. We used a potentiometric dye and optical mapping to assess the anterior epicardial electrical activity of Langendorff-perfused rabbit hearts (n = 7) during monophasic shocks (+/-100 V and +/-200 V, duration of 8 ms) applied from a transvenous defibrillation lead at various coupling intervals. Arrhythmias were induced in a coupling interval and shock polarity dependent manner: (i) anodal and cathodal shocks induced arrhythmias in 33.2 +/- 30.1% and 53.1 +/- 39.3% cases (P < 0.01), respectively, and (ii) the vulnerable window was located near the T-wave. Optical maps revealed that VEP was also modulated by the coupling interval and shock polarity. Recovery of excitability produced by negative polarization, known as de-excitation, and the resulting reentry was more readily achieved during the relative refractory period than the absolute refractory period. Furthermore, anodal shocks produced wavefronts propagating in an inward direction with respect to the electrode, whereas cathodal shocks propagated in an outward direction. Wavefronts produced by anodal shocks were more likely to collide and annihilate each other than those caused by cathodal shocks. The probability of degeneration of the VEP-induced phase singularity into a sustained arrhythmia depends upon the gradient of VEP and the direction of the VEP-induced wavefront. The VEP gradient depends upon the coupling interval, while the direction depends upon shock polarity; these factors explain the vulnerable window and polarity-dependence of vulnerability, respectively.

Action Potentials↗
PubMed2000

The role of electroporation in defibrillation.

Electric shock is the only effective therapy against ventricular fibrillation. However, shocks are also known to cause electroporation of cell membranes. We sought to determine the impact of electroporation on ventricular conduction and defibrillation. We optically mapped electrical activity in coronary-perfused rabbit hearts during electric shocks (50 to 500 V). Electroporation was evident from transient depolarization, reduction of action potential amplitude, and upstroke dV/dt. Electroporation was voltage dependent and significantly more pronounced at the endocardium versus the epicardium, with thresholds of 229+/-81 versus 318+/-84 V, respectively (P=0.01, n=10), both being above the defibrillation threshold of 181.3+/-45.8 V. Epicardial electroporation was localized to a small area near the electrode, whereas endocardial electroporation was observed at the bundles and trabeculas throughout the entire endocardium. Higher-resolution imaging revealed that papillary muscles (n=10) were most affected. Electroporation and conduction block thresholds in papillary muscles were 281+/-64 V and 380+/-79 V, respectively. We observed no arrhythmia in association with electroporation. Further, preconditioning with high-energy shocks prevented reinduction of fibrillation by 50-V shocks, which were otherwise proarrhythmic. Endocardial bundles are the most susceptible to electroporation and the resulting conduction impairment. Electroporation is not associated with proarrhythmic effects and is associated with a reduction of vulnerability.

Action Potentials↗
PubMed2000

Direct evidence of the role of virtual electrode-induced phase singularity in success and failure of defibrillation.

INTRODUCTION: We recently demonstrated that virtual electrode-induced phase singularity is responsible for arrhythmogenesis during T wave shocks and explains the upper and lower limits of vulnerability. Furthermore, we suggested that the same mechanism might be responsible for defibrillation failure. The aim of this study was to experimentally support this hypothesis. METHODS AND RESULTS: We used the voltage-sensitive dye di-4-ANEPPS and fast imaging to assess electrical activity in Langendorff-perfused rabbit hearts. Ventricular arrhythmias were induced by monophasic shocks applied during T wave. Three types of defibrillation shocks (n = 79) were delivered from an intravenous right ventricular electrode: monophasic (8 msec), optimal biphasic (8/8 msec, 2/1 leading-edge voltage ratio), and nonoptimal biphasic (8/8 msec, 1/1 leading-edge voltage ratio). We found that a monophasic shock extinguished arrhythmic pattern of electrical activity via a virtual electrode polarization effect. However, the virtual electrode polarization was likely to produce phase singularities, leading to another arrhythmia and defibrillation failure. Nonoptimal biphasic shocks produced similar effects. Optimal biphasic shocks were successful because the first phase of the shock erased the arrhythmia via the virtual electrodes effect, whereas the second phase canceled the virtual electrodes, eliminating the substrate for phase singularities and arrhythmia resulting from them. CONCLUSION: Our data provide the first experimental support of the hypothesis implicating virtual electrode-induced phase singularity in defibrillation failure in the Langendorff-perfused rabbit heart. Optimal biphasic shock has a higher defibrillation efficacy because it does not produce virtual electrode-induced phase singularities.

Animals↗
PubMed2000

Reversal of repolarization gradient does not reverse the chirality of shock-induced reentry in the rabbit heart.

INTRODUCTION: Two hypotheses have been proposed to explain the mechanisms of vulnerability and related failure of defibrillation therapy: the cross-field-induced critical point hypothesis and the virtual electrode-induced phase singularity hypothesis. These two hypotheses predict the opposite effect of preshock repolarization on the chirality (direction of rotation) of shock-induced reentry. The former suggests its reversal upon reversal of repolarization, whereas the latter suggests its preservation. The aim of this study was to determine, by reversing the repolarization sequence, which of the mechanisms is responsible for internal shock-induced arrhythmia in the Langendorff-perfused rabbit heart. METHODS AND RESULTS: We used high-resolution optical mapping to assess the chirality of postshock reentry in 11 hearts. Hearts were paced at a coupling interval of 300 msec at various sites around the field of view (13.5 x 13.5 to 16.5 x 16.5 mm). Cathodal monophasic implantable cardioverter defibrillator shocks (-100 V, 8 msec) were applied during the T wave from a 10-mm coil electrode placed into the right ventricular cavity. We used 3.5 +/- 0.8 different pacing sites per heart. Change in direction of repolarization did not result in change of chirality. Chirality was constant in all 11 hearts despite the complete reversal of activation and repolarization patterns. However, the position of resulting vortices depended on transmembrane polarization gradient inverted delta Vm and amplitude of negative polarization Vm (deexcitation). Stronger gradients and deexcitation produced earlier epicardial break excitation (P = 0.04 and P < 0.0001, respectively). CONCLUSION: Virtual electrode-induced phase singularity mechanism underlies internal shock-induced arrhythmia in this model.

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PubMed2000

Virtual electrodes and deexcitation: new insights into fibrillation induction and defibrillation.

Previous models of fibrillation induction and defibrillation stressed the contribution of depolarization during the response of the heart to a shock. This article reviews recent evidence suggesting that comprehending the role of negative polarization (hyperpolarization) also is crucial for understanding the response to a shock. Negative polarization can "deexcite" cardiac cells, creating regions of excitable tissue through which wavefronts can propagate. These wavefronts can result in new reentrant circuits, inducing fibrillation or causing defibrillation to fail. In addition, deexcitation can lead to rapid propagation through newly excitable regions, resulting in the elimination of excitable gaps soon after the shock and causing defibrillation to succeed.

Computer Simulation↗
PubMed2000

Virtual electrode polarization in the far field: implications for external defibrillation.

We recently suggested that failure of implantable defibrillation therapy may be explained by the virtual electrode-induced phase singularity mechanism. The goal of this study was to identify possible mechanisms of vulnerability and defibrillation by externally applied shocks in vitro. We used bidomain simulations of realistic rabbit heart fibrous geometry to predict the passive polarization throughout the heart induced by external shocks. We also used optical mapping to assess anterior epicardium electrical activity during shocks in Langendorff-perfused rabbit hearts (n = 7). Monophasic shocks of either polarity (10-260 V, 8 ms, 150 microF) were applied during the T wave from a pair of mesh electrodes. Postshock epicardial virtual electrode polarization was observed after all 162 applied shocks, with positive polarization facing the cathode and negative polarization facing the anode, as predicted by the bidomain simulations. During arrhythmogenesis, a new wave front was induced at the boundary between the two regions near the apex but not at the base. It spread across the negatively polarized area toward the base of the heart and reentered on the other side while simultaneously spreading into the depth of the wall. Thus a scroll wave with a ribbon-shaped filament was formed during external shock-induced arrhythmia. Fluorescent imaging and passive bidomain simulations demonstrated that virtual electrode polarization-induced scroll waves underlie mechanisms of shock-induced vulnerability and failure of external defibrillation.

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PubMed1999

Virtual electrode-induced reexcitation: A mechanism of defibrillation.

Mechanisms of defibrillation remain poorly understood. Defibrillation success depends on the elimination of fibrillation without shock-induced arrhythmogenesis. We optically mapped selected epicardial regions of rabbit hearts (n=20) during shocks applied with the use of implantable defibrillator electrodes during the refractory period. Monophasic shocks resulted in virtual electrode polarization (VEP). Positive values of VEP resulted in a prolongation of the action potential duration, whereas negative polarization shortened the action potential duration, resulting in partial or complete recovery of the excitability. After a shock, new propagated wavefronts emerged at the boundary between the 2 regions and reexcited negatively polarized regions. Conduction velocity and maximum action potential upstroke rate of rise dV/dt (max) of shock-induced activation depended on the transmembrane potential at the end of the shock. Linear regression analysis showed that dV/dt(max) of postshock activation reached 50% of that of normal action potential at a V(m) value of -56.7+/-0.6 mV postshock voltage (n=9257). Less negative potentials resulted in slow conduction and blocks, whereas more negative potentials resulted in faster conduction. Although wavebreaks were produced in either condition, they degenerated into arrhythmias only when conduction was slow. Shock-induced VEP is essential in extinguishing fibrillation but can reinduce arrhythmias by producing excitable gaps. Reexcitation of these gaps through progressive increase in shock strength may provide the basis for the lower and upper limits of vulnerability. The former may correspond to the origination of slow wavefronts of reexcitation and phase singularities. The latter corresponds to fast conduction during which wavebreaks no longer produce sustained arrhythmias.

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PubMed1999

Evidence of three-dimensional scroll waves with ribbon-shaped filament as a mechanism of ventricular tachycardia in the isolated rabbit heart.

INTRODUCTION: Rotating vortices have been observed in excitable media of different nature. Vortices may sustain life or kill in different species, by underlining morphogenesis in Dictiostelium discoideum during starvation, or arrhythmias during sudden cardiac death in mammals. Investigation of vortices in the heart has been limited by two-dimensional experimental techniques. In contrast, three-dimensional (3D) Belousov-Zhabotinsky excitable medium and mathematical models have been shown to sustain scroll-shaped waves. The heart is a 3D structure; therefore, scroll waves may underlie cardiac arrhythmias. METHODS AND RESULTS: We used potentiometric dye and optical mapping techniques to study vortices during ventricular arrhythmias. The core of all observed vortices were linearly shaped and > or = 9 mm (48 episodes, six hearts). As shown by Allessie et al. in the rabbit atrium, ventricular signals recorded within 1 to 2 mm from the line of block were dual humped, suggesting there is electrotonic interaction across the line of block. We hypothesized that the line of block represents epicardial intersection of ribbon-shaped filaments, which in some cases may be oriented under an angle or parallel to the epicardium. In 14 episodes we observed dual-humped optical recordings at one side of the line of block at a distance up to 12 mm. The two humps may represent the signatures of two activation wavefronts propagating above and below the filament, which in this area is close to the epicardial surface. The activation sequence of the two waves is consistent with the idea of a scroll wave with ribbon-like filament. CONCLUSION: Our data provide new insights into the shape and dynamics of the filament of the 3D scroll wave, which underlies the mechanism of ventricular tachycardia in the rabbit heart. The filament of the scroll wave may be ribbon shaped, with a significant width > or = 9 mm and a thickness of 1 to 2 mm. No evidence of fully excitable cells in the core of vortex was observed.

Action Potentials↗
PubMed1999

Biventricular shocking leads improve defibrillation efficacy.

INTRODUCTION: A single lead active can configuration has been widely used in patients with life-threatening ventricular arrhythmias. Occasionally, however, such a defibrillation lead configuration may not achieve adequate defibrillation threshold (DFT). The purpose of this study was to determine whether addition of a left ventricular (LV) lead can improve defibrillation efficacy. METHODS AND RESULTS: Three transvenous defibrillation leads (8.3-French with a 5-cm long unipolar coil) were placed in the right ventricle (RV), LV, and superior vena cava (SVC), along with an active can (92 cm2) in the left subpectoral area. The DFT stored energy of seven combinations of these defibrillation leads were compared in a pig ventricular fibrillation model using a biphasic defibrillation waveform (125 microF, 6.5/3.5 msec). A biventricular leads active can configuration in which the RV and LV leads were of the same polarity reduced the DFT stored energy by approximately 35% when compared to a single RV lead active can configuration (9.6 +/- 3.0 J vs 15.0 +/- 7.2 J, respectively, P = 0.02). Moreover, adding a SVC lead further reduced the DFT energy (8.4 +/- 3.3 J). CONCLUSION: A biventricular leads active can configuration can significantly improve defibrillation efficacy as compared to a single lead active can configuration. In such a defibrillation lead configuration, the polarity of RV and LV leads should be the same.

Animals↗
PubMed1998

High-resolution, three-dimensional fluorescent imaging reveals multilayer conduction pattern in the atrioventricular node.

BACKGROUND: The atrioventricular node (AVN) is the only normal electrical link between the upper and lower chambers of the heart. The AVN modulates transmission of impulses, thus coordinating the contraction of the atria and ventricles. METHODS AND RESULTS: Structural and functional complexity, combined with the absence of adequate experimental techniques, has complicated attempts to directly evaluate the three-dimensional electrical activity of the AVN. Thus, despite a century of research by conventional electrophysiologic and histologic methods, even the existence of conduction through AVN is still debated. CONCLUSIONS: Using a novel combination of microelectrode recordings and high resolution fluorescent imaging with voltage-sensitive dyes, we have for the first time clearly demonstrated three-dimensional conduction through the AVN.

Animals↗
PubMed1998

Virtual electrode-induced phase singularity: a basic mechanism of defibrillation failure.

Delivery of a strong electric shock to the heart remains the only effective therapy against ventricular fibrillation. Despite significant improvements in implantable cardioverter defibrillator (ICD) therapy, the fundamental mechanisms of defibrillation remain poorly understood. We have recently demonstrated that a monophasic defibrillation shock produces a highly nonuniform epicardial polarization pattern, referred to as a virtual electrode pattern (VEP). The VEP consists of large adjacent areas of strong positive and negative polarization. We sought to determine whether the VEP may be responsible for defibrillation failure by creating dispersion of postshock repolarization and reentry. Truncated exponential biphasic and monophasic shocks were delivered from a bipolar ICD lead in Langendorff-perfused rabbit hearts. Epicardial electrical activity was mapped during and after defibrillation shocks and shocks applied at the plateau phase of a normal action potential produced by ventricular pacing. A high-resolution fluorescence mapping system with 256 recording sites and a voltage-sensitive dye were used. Biphasic shocks with a weak second phase (<20% leading-edge voltage of the second phase with respect to the leading-edge voltage of the first phase) produced VEPs similar to monophasic shocks. Biphasic shocks with a strong second phase (>70%) produced VEPs of reversed polarity. Both of these waveforms resulted in extra beats and arrhythmias. However, biphasic waveforms with intermediate second-phase voltages (20% to 70% of first-phase voltage) produced no VEP, because of an asymmetric reversal of the first-phase polarization. Therefore, there was no substrate for postshock dispersion of repolarization. Shocks producing strong VEPs resulted in postshock reentrant arrhythmias via a mechanism of phase singularity. Points of phase singularity were created by the shock in the intersection of areas of positive, negative, and no polarization, which were set by the shock to excited, excitable, and refractory states, respectively. Shock-induced VEPs may reinduce arrhythmias via a phase-singularity mechanism. Strong shocks may overcome the preshock electrical activity and create phase singularities, regardless of the preshock phase distribution. Optimal defibrillation waveforms did not produce VEPs because of an asymmetric effect of phase reversal on membrane polarization.

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