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Biomedical subjects

Igor R Efimov

Publications and source records attributed to Igor R Efimov.

At least 37 records · Page 2Linked to original sources
PubMed2004

Optical imaging of the heart.

Optical techniques have revolutionized the investigation of cardiac cellular physiology and advanced our understanding of basic mechanisms of electrical activity, calcium homeostasis, and metabolism. Although optical methods are widely accepted and have been at the forefront of scientific discoveries, they have been primarily applied at cellular and subcellular levels and considerably less to whole heart organ physiology. Numerous technical difficulties had to be overcome to dynamically map physiological processes in intact hearts by optical methods. Problems of contraction artifacts, cellular heterogeneities, spatial and temporal resolution, limitations of surface images, depth-of-field, and need for large fields of view (ranging from 2x2 mm2 to 3x3 cm2) have all led to the development of new devices and optical probes to monitor physiological parameters in intact hearts. This review aims to provide a critical overview of current approaches, their contributions to the field of cardiac electrophysiology, and future directions of various optical imaging modalities as applied to cardiac physiology at organ and tissue levels.

Action Potentials↗
PubMed2004

Virtual electrode theory explains pacing threshold increase caused by cardiac tissue damage.

The virtual electrode polarization (VEP) effect is believed to play a key role in electrical stimulation of heart muscle. However, under certain conditions, including clinically, its existence and importance remain unknown. We investigated the influence of acute tissue damage produced by continuous pacing with strong current (40-mA, 4-ms biphasic pulses with 4-Hz frequency for 5 min) on stimulus-generated VEPs and pacing thresholds. A fluorescent optical mapping technique was used to obtain stimulus-induced transmembrane potential distribution around a pacing electrode applied to the ventricular surface of a Langendorff-perfused rabbit heart (n = 5). Maps and pacing thresholds were recorded before and after tissue damage. Spatial extents of electroporation and cell uncoupling were assessed by propidium iodide (n = 2) and connexin43 (n = 3) antibody staining, respectively. On the basis of these data, passive and active three-dimensional bidomain models were built to determine VEP patterns and thresholds for different-sized areas of the damaged region. Electrophysiological results showed that acute tissue damage led to disappearance of the VEP with an associated significant increase in pacing thresholds. Damage was expressed in electroporation and cell uncoupling within an approximately 1.0-mm-diameter area around the tip of the electrode. According to computer simulations, cell uncoupling, rather than electroporation, might be the direct cause of VEP elimination and threshold increase, which was nonlinearly dependent on the size of the damaged region. Fiber rotation with depth did not substantially affect the numerical results. The study explains failure to stimulate damaged tissue within the concepts of the VEP theory.

Acute Disease↗
PubMed2004

Functional imaging of the embryonic pacemaking and cardiac conduction system over the past 150 years: technologies to overcome the challenges.

Early analyses of cardiac pacemaking and conduction system (CPCS) development relied on classic histology and visual inspection of the beating heart. Current techniques that facilitate delineation of the CPCS include the use of specific antibody markers and transgenic mouse lines specifically expressing reporter genes. Assaying the function of tiny embryonic hearts required an increase in the level of spatial and temporal resolution. Current methods for such analyses include the use of intracellular and extracellular microelectrodes, echocardiography, rapid optical imaging using fluorescent dyes, and most recently optical coherence tomography. This review will focus on methods developed to investigate the functional emergence of the embryonic cardiac conduction system. Where appropriate, the methods used to delineate the anatomic pathways will also be discussed. The combination of techniques to capture both morphological and functional data from the CPCS will further improve with continued interdisciplinary collaboration. The Supplementary Material referred to in this article can be found at the Anatomical Record website (http://www.interscience.wiley.com/jpages/0003-276X/suppmat).

Action Potentials↗
PubMed2004

Structure-function relationship in the AV junction.

In the normal heart, the atrioventricular node (AVN) is part of the sole pathway between the atria and ventricles. Under normal physiological conditions, the AVN controls appropriate frequency-dependent delay of contractions. The AVN also plays an important role in pathology: it protects ventricles during atrial tachyarrhythmia, and during sinoatrial node failure an AV junctional pacemaker can drive the heart. Finally, the AV junction provides an anatomical substrate for reentry. Using fluorescent imaging with voltage-sensitive dyes and immunohistochemistry, we have investigated the structure-function relationship of the AV junction during normal conduction, reentry, and junctional rhythm. We identified molecular and structural heterogeneity that provides a substrate for the dual-pathway AVN conduction. We observed heterogeneity of expression of three isoforms of connexins: Cx43, Cx45, and Cx40. We identified the site of origin of junctional rhythm at the posterior extension of the AV node in 79% (n = 14) of the studied hearts. This structure was similar to the compact AV node as determined by morphologic and molecular investigations. In particular, both the posterior extension and the compact node express the pacemaking channel HCN4 (responsible for the I(F) current) and neurofilament 160. In the rabbit heart, AV junction conduction, reentrant arrhythmia, and spontaneous rhythm are governed by heterogeneity of expression of several isoforms of gap junctions and ion channels. Uniform neurofilament expression suggests that AV nodal posterior extensions are an integral part of the cardiac pacemaking and conduction system. On the other hand, differential expression of Cx isoforms in this region provides an explanation of longitudinal dissociation, dual-pathway electrophysiology, and AV nodal reentrant arrhythmogenesis.

Animals↗
PubMed2004

Dynamics of virtual electrode-induced scroll-wave reentry in a 3D bidomain model.

Functional reentry in the heart can be caused by a wave front of excitation rotating around its edge. Previous simulations on the basis of monodomain cable equations predicted the existence of self-sustained, vortex-like wave fronts (scroll waves) rotating around a filament in three dimensions. In our simulations, we used the more accurate bidomain model with modified Beeler-Reuter ionic kinetics to study the dynamics of scroll-wave filaments in a 16 x 8 x 1.5-mm slab of ventricular tissue with straight fibers. Wave fronts were identified as the areas with inward current. Their edges represented the filaments. Both transmural and intramural reentries with I- and U-shaped filaments, respectively, were obtained by the S1-S2 point stimulation protocol through the virtual electrode-induced phase singularity mechanism. The filaments meandered along elongated trajectories and tended to attach to the tissue boundaries exposed to air (no current flow) rather than to the bath (zero extracellular potential). They completely detached from electroporated (zero transmembrane potential) boundaries. In our simulations, the presence of the bath led to generation of only U-shaped filaments, which survived for the 1.5-mm-thick slab but not for the slabs of 0.5- or 3-mm thicknesses. Thus boundary conditions may be another determinant of the type and dynamics of reentry.

Action Potentials↗
PubMed2003

Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart.

During failure of the sinoatrial node, the heart can be driven by an atrioventricular (AV) junctional pacemaker. The position of the leading pacemaker site during AV junctional rhythm is debated. In this study, we present evidence from high-resolution fluorescent imaging of electrical activity in rabbit isolated atrioventricular node (AVN) preparations that, in the majority of cases (11 out of 14), the AV junctional rhythm originates in the region extending from the AVN toward the coronary sinus along the tricuspid valve (posterior nodal extension, PNE). Histological and immunohistochemical investigation showed that the PNE has the same morphology and unique pattern of expression of neurofilament160 (NF160) and connexins (Cx40, Cx43, and Cx45) as the AVN itself. Block of the pacemaker current, If, by 2 mmol/L Cs+ increased the AV junctional rhythm cycle length from 611+/-84 to 949+/-120 ms (mean+/-SD, n=6, P<0.001). Immunohistochemical investigation showed that the principal If channel protein, HCN4, is abundant in the PNE. As well as the AV junctional rhythm, the PNE described in this study may also be involved in the slow pathway of conduction into the AVN as well as AVN reentry, and the predominant lack of expression of Cx43 as well as the presence of Cx45 in the PNE shown could help explain its slow conduction.

Animals↗
PubMed2003

Shock-induced arrhythmogenesis is enhanced by 2,3-butanedione monoxime compared with cytochalasin D.

Investigation of the mechanisms of arrhythmia genesis and maintenance has benefited from the use of optical mapping techniques that employ excitation-contraction uncouplers. We investigated the effects of the excitation-contraction uncouplers 2,3-butanedione monoxime (BDM) and cytochalasin D (Cyto D) on the induction and maintenance of arrhythmia by electric shocks. Electrical activity was optically mapped from anterior epicardium of rabbit hearts (n = 9) during shocks (-100 V, 8 ms) applied from a ventricular lead at various phases of action potential duration (APD). Restitution curves were obtained using S1-S2 protocol and measurement of APD values at 70% of repolarization. Compared with Cyto D, BDM significantly shortened APD at 90% of repolarization, although no significant difference in dispersion of repolarization was observed. Wavelength was also shortened with BDM. In general, shock-induced arrhythmias with BDM and Cyto D were ventricular tachycardic in nature. With respect to shock-induced sustained arrhythmias, the vulnerable window was wider and the incidence was higher with BDM than with Cyto D. There was also a difference in the morphology of ventricular tachycardia (VT) between the two agents. The arrhythmias with BDM usually resembled monomorphic VT, especially those that lasted >30 s. In contrast, arrhythmias with Cyto D more resembled polymorphic VT. However, the average number of phase singularities increased under Cyto D vs. BDM, whereas no significant difference in the dominant frequency of shock-induced sustained arrhythmia was observed. BDM reduced the slope of the restitution curve compared with Cyto D, but duration of arrhythmia under BDM was significantly increased compared with Cyto D. In conclusion, BDM increased arrhythmia genesis and maintenance relative to Cyto D.

Action Potentials↗
PubMed2003

Cx43 and dual-pathway electrophysiology of the atrioventricular node and atrioventricular nodal reentry.

Fluorescent imaging has revealed that posterior nodal extensions provide the anatomical substrate for the dual-pathway electrophysiology of the atrioventricular (AV) node during normal conduction and reentry. The reentry can be intranodal, or as well as the posterior nodal extensions, it can involve an endocardial layer of atrial/atrial-nodal (A/AN) cells as part of the AV nodal reentry (AVNR) circuit. Using fluorescent imaging with a voltage-sensitive dye and immunolabeling of Cx43, we mapped the electrical activity and structural substrate in 3 types of AVNR induced by premature atrial stimulation in 8 rabbit hearts. In 6 cases, the AVNR pathway involved (1) a fast pathway (FP), (2) the A/AN layer, and (3) a slow pathway (SP). In 4 cases, reentry took the path (1) SP, (2) A/AN layer, and (3) FP. In 2 cases, reentry was intranodal, propagating between the 2 posterior nodal extensions. Immunolabeling revealed that the FP and SP are formed by Cx43-expressing bundles surrounded by tissue without Cx43. Cx43-expressing posterior nodal extensions are the substrate of AVNR during both intranodal and extranodal reentry.

Animals↗
PubMed2003

Optical mapping technique applied to biventricular pacing: potential mechanisms of ventricular arrhythmias occurrence.

Although it has been suggested that multisite ventricular pacing alleviates heart failure by restoring ventricular electrical synchronization, the respective roles of voltage output, interventricular delay, and pacing sites in the development of ventricular arrhythmias occurrence have not been studied during biventricular pacing or LV pacing. Voltage-sensitive dye was used in eight ischemic Langerdorff-perfused guinea pig hearts to measure ventricular activation times and examine conduction patterns during multisite pacing from three RV and four LV sites. The hearts were stained with di-4-ANEPPS and mapped with a 16 x 16 photodiode array at a resolution of 625 microns per diode. Isochronal maps of RV and LV activation were plotted. Ischemia was produced by gradually halving the perfusion output over 5 minutes. Pacing the RV apex and the base of the LV anterior wall was associated with the most homogeneous and rapid activation pattern (28 +/- 9 vs 41 +/- 12 ms with the other configurations, P < 0.01), and no inducible arrhythmia. In six hearts, ventricular tachycardia could be induced when pacing from the right and left free walls with 20 ms of interventricular delay, at six times the pacing threshold output. In four hearts, simultaneous RV and LV pacing at high voltage output induced ventricular fibrillation with complex three-dimensional propagation patterns, independently of the pacing sites. During biventricular pacing with ischemia, pacing at high voltage output with a long interventricular delay is likely to induce ventricular arrhythmias, particularly when left and right pacing results in a conduction pattern orthogonal to the ventricular myocardial fibers orientation.

Animals↗
PubMed2003

Effects of lidocaine on shock-induced vulnerability.

INTRODUCTION: Lidocaine is known to increase the defibrillation threshold (DFT) of monophasic shocks (MS) and have no effect on DFT of biphasic shocks (BS). The aim of this study was to enhance our understanding of the mechanisms of vulnerability and defibrillation through the investigation of this difference. METHODS AND RESULTS: We studied the effect of 15 microM lidocaine on shock-induced vulnerability using fluorescent imaging of Langendorff-perfused rabbit hearts. Vulnerability was assessed as vulnerable window with shock strengths of 15 to 150 V and vulnerable period (VP) with shock delivery phase of 0% to 100% of action potential duration (% APD). With MS, lidocaine caused a significant increase in both the upper limit of vulnerability (ULV, 71 +/- 17 V vs 120 +/- 1.5 V, P < 0.01) and upper limit of VP (91 +/- 8.0% APD vs 110 +/- 4.2% APD, P < 0.01). With BS, lidocaine had no effect on ULV (40 +/- 3.4 V vs 45 +/- 4.5 V) and did not increase the upper limit of VP (78 +/- 8.9% APD vs 96 +/- 12% APD, P < 0.01). Lidocaine caused reduction of the conduction velocity during pacing (0.58 +/- 0.08 m/s vs 0.44 +/- 0.05 m/s, P < 0.01), shock-induced break excitation (0.82 +/- 0.17 m/s vs 0.30 +/- 0.07 m/s, P < 0.01), and postshock reentry (0.34 +/- 0.07 m/s vs 0.19 +/- 0.08 m/s, P < 0.01). Lidocaine had no effect on shock-induced virtual electrode polarization. CONCLUSION: Lidocaine increased MS ULV due to slowing of shock-induced break-excitation wavefronts, which resulted in enhanced probability of survival of virtual electrode induced phase singularity. Lidocaine had no effect on BS ULV because no break excitation was induced by BS. Reduction of conduction velocity by lidocaine resulted in increased dispersion of repolarization and led to upper limit of VP increase for both MS and BS.

Action Potentials↗
PubMed2003

Nonlinear effects in subthreshold virtual electrode polarization.

Introduction of the virtual electrode polarization (VEP) theory suggested solutions to several century-old puzzles of heart electrophysiology including explanation of the mechanisms of stimulation and defibrillation. Bidomain theory predicts that VEPs should exist at any stimulus strength. Although the presence of VEPs for strong suprathreshold pulses has been well documented, their existence at subthreshold strengths during diastole remains controversial. We studied cardiac membrane polarization produced by subthreshold stimuli in 1) rabbit ventricular muscle using high-resolution fluorescent imaging with the voltage-sensitive dye pyridinium 4-[2-[6-(dibutylamino)-2-naphthalenyl]-ethenyl]-1-(3-sulfopropyl)hydroxide (di-4-ANEPPS) and 2) an active bidomain model with Luo-Rudy ion channel kinetics. Both in vitro and in numero models show that the common dog-bone-shaped VEP is present at any stimulus strength during both systole and diastole. Diastolic subthreshold VEPs exhibited nonlinear properties that were expressed in time-dependent asymmetric reversal of membrane polarization with respect to stimulus polarity. The bidomain model reveals that this asymmetry is due to nonlinear properties of the inward rectifier potassium current. Our results suggest that active ion channel kinetics modulate the transmembrane polarization pattern that is predicted by the linear bidomain model of cardiac syncytium.

Action Potentials↗
PubMed2002

The pinwheel experiment re-revisited.

Virtual electrode induced phase singularity hypothesis explains the origin of cardiac arrhythmias caused by artificial electrical induction of rotors, i.e. vortex-like self-sustained sources of activity. This mechanism is thought to underlie both stimulus-induced arrhythmias and shock defibrillation therapy. In this paper, we extend this hypothesis to three dimensions using the bidomain model of cardiac tissue. We predict that virtual electrode polarization can produce three topologically distinct types of rotors anchored to: (1) transmural I-shaped scroll wave filaments; (2) near-surface U-shaped scroll wave filaments; and (3) intramural O-shaped scroll wave filaments.

Arrhythmias, Cardiac↗
PubMed2002

Anode-break excitation during end-diastolic stimulation is explained by half-cell double layer discharge.

The phenomenon of anodal-break excitation during end-diastolic stimulation of the heart was discovered many years ago by B. Hoffman. Yet, the existence and mechanistic explanation of this effect remain controversial. We sought to confirm its existence and to determine a possible role of half-cell potential. We used isolated Langendorff-perfused rabbit hearts (n = 6) which were stained with di-4-ANEPPS and perfused with 15-mM butanedione monoxime (BDM). Transmembrane potentials were optically recorded at the left ventricular epicardium with a high spatial and temporal resolution (200 microm/343 micros) near the tip of a 120-microm platinum-iridium Teflon-coated unipolar pacing electrode to detect virtual electrode polarization and to reconstruct an activation pattern. Hearts were paced at a cycle length of 300 ms by anodal square pulses with an amplitude of 0.1-10 mA and a duration of 5-60 ms. Data revealed that the anodal-break excitation does exists and is accompanied by an overshoot in the recordings of the pacing current. Addition of a diode in the stimulation circuit eliminated both the overshoot and the break excitation. The findings suggest that a half-cell surface potential at the pacing electrode metal-saline interface may influence the pacing currents during unipolar anodal cardiac stimulation providing "break"-like activation. We also confirmed that the threshold of "break"-like excitation is lower than make-excitation. We suggest that further exploration of this effect is needed in order to design improved multiphasic pacing waveforms.

Animals↗
PubMed2002

Phase I and phase II of short-term mechanical restitution in perfused rat left ventricles.

We examined the contributions of the Ca(2+) channels of the sarcolemma and of the sarcoplasmic reticulum to electromechanical restitution. Extrasystoles (F(1)) were interpolated 40-600 ms following a steady-state beat (F(0)) in perfused rat ventricles paced at 2 or 3 Hz. Plots of F(1)/F(0) versus the extrasystolic interval consisted of phase I, which occurred before relaxation of the steady-state beat, and phase II, which occurred later. Phase I exhibited a period of enhanced left ventricular pressure development that coincided with action potential prolongation. Phase I was eliminated by -BAY K 8644 (100 nM) and FPL 64176 (150 nM), augmented by 3 microM thapsigargin plus 200 nM ryanodine and unaffected by KN-93 and KB-R7943. Phase II was accelerated by the Ca(2+) channel agonists and by isoproterenol but was eliminated by thapsigargin plus ryanodine. The results suggest that phase I of electromechanical restitution is caused by a transient L-type Ca(2+) current facilitation, whereas phase II represents the recovery of the ability of the sarcoplasmic reticulum to release Ca(2+).

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗