Papers by Vladislav Nesterenko
Proceedings Computers in Cardiology
The electrocardiogram (ECG) was reconstructed from extracellular fields generated by action poten... more The electrocardiogram (ECG) was reconstructed from extracellular fields generated by action potentials propagating along a 2-cm linear cable comprising 200 myocardial cells coupled through gap junctions (GJs). Intrinsic APD was varied by altering the maximal conductance of the delayed rectifier (Gx). A longer APD was simulated in the M region by a uniform decrease of Gx. APD prolongation in the
We welcome Dr. Franz’s comments relative to our recent publication dealing with the monophasic ac... more We welcome Dr. Franz’s comments relative to our recent publication dealing with the monophasic action potential (MAP) [1]. We agree and fully appreciate the fact that the Franz contact electrode technique has been successfully used for over 20 years by Dr. Franz and other investigators. This success stems from the fact that the two electrodes of the contact catheter are relatively close to each other so that their combined field of view is fairly localized. However, we do not agree that this success can be used as an argument against our conclusion that it is not the tip electrode that records the MAP. Our study investigated the physical principles behind the MAP recording. We started with a simple definition of voltage as the difference of potential between two points or two electrodes. To determine which of these two potentials carries time-dependent information, we placed the two electrodes at sites with different cellular activity and observed which activity is reflected in the ...
PLOS ONE, 2013
<p>Range of days post-differentiation (Age) at which E-4031 (5 µM) induced EADs <i>wi... more <p>Range of days post-differentiation (Age) at which E-4031 (5 µM) induced EADs <i>with little to no change in MDP</i> vs. those at which it led to depolarization of BC <i>without exhibiting EADs</i>. <b>B:</b> Range of age of BC that depolarized in response to 100 µM BaCl<sub>2</sub> (Depolarization) vs. those that did not (No depolarization). Each point represents an individual BC; horizontal lines are the mean values for each group.</p
American Journal of Physiology-Heart and Circulatory Physiology, 2020
The gene encoding SAP97 ( DLG1) joins a growing list of genes encoding ion channel interacting pr... more The gene encoding SAP97 ( DLG1) joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97’s candidacy as a minor Brugada syndrome susceptibility gene.
American Journal of Physiology-Heart and Circulatory Physiology, 1989
The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolat... more The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potent...
American Journal of Physiology-Heart and Circulatory Physiology, 1990
Models of ion channel blockade are frequently validated with observations of ionic currents resul... more Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding t...
Journal of Clinical Psychopharmacology, 2019
Purpose/Background: Prolonged ventricular repolarization, measured by heart rate-corrected QT int... more Purpose/Background: Prolonged ventricular repolarization, measured by heart rate-corrected QT interval (QTc) prolongation, might be a biomarker for risk of torsade de pointes (TdP) and sudden cardiac death. However, the predictive value of QTc has been challenged, and a component of QTc, peak-to-end of the T-wave (Tpe), and a high Tpe/QT ratio might be superior biomarkers because they better reflect increased transmural dispersion of ventricular myocyte repolarization, which can lead to TDP. The purpose of this pilot study was to provide the first measurements of heart rate, QTc, Tpe, Tpe/QTc, and their variability over 24 hours in medication-free patients with schizophrenia, during treatment with ziprasidone or other antipsychotic drugs, and healthy controls. Methods: Subjects included 12 patients treated with ziprasidone, 30 treated with other antipsychotic drugs, 3 unmedicated patients, and 15 normal controls. Subjects underwent 24-hour analog Holter recording, and the recordings were digitized. A cardiologist blind to treatment selected multiple 10-cycle segments throughout each recording and measured the electrocardiogram metrics. Results: Variability in QTc, Tpe, and Tpe/QTc over the 24 hours was present in all groups; 91.1% of patients and 100% of controls had 1 or more QTc values of 450 milliseconds or greater. Mean QTc length was significantly greater in the ziprasidone-treated than the nonziprasidone-treated patients (P = 0.02). Mean Tpe was not elevated in the ziprasidone patients, whereas mean Tpe/QTc was lower (P < 0.01). Conclusions: The large variability in QTc, Tpe, and Tpe/QTc observed supports the need for 24-hour electrocardiogram recordings to provide an accurate assessment of risk of TdP. Heart rate-corrected QT interval alone does not capture the risk of TdP.
American Journal of Physiology-Heart and Circulatory Physiology, 2001
Action potentials and whole cell sodium current were recorded in canine epicardial, midmyocardial... more Action potentials and whole cell sodium current were recorded in canine epicardial, midmyocardial, and endocardial myocytes in normal sodium at 37°C. Tetrodotoxin (TTX) reduced the action potential duration of midmyocardial cells to a greater degree than either epicardial or endocardial cells. Whole cell recordings in potassium-free and very-low-chloride solutions revealed a slowly decaying current that was completely inhibited by 5 μM TTX or replacement of external and internal sodium with the impermeant cation N-methyl-d-glucamine. Late sodium current density at 0 mV was 47% greater in midmyocardial cells and averaged −0.532 ± 0.058 pA/pF in endocardial, −0.463 ± 0.068 pA/pF in epicardial, and −0.785 ± 0.070 pA/pF in midmyocardial cells. Neither the frequency dependence of late sodium current nor its recovery from inactivation exhibited transmural differences. After a 4.5-s pulse to −30 mV, late sodium current recovered with a single time constant of 140 ms. We conclude that a lar...
Journal of pharmacological and toxicological methods, Jan 8, 2017
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for safety pharma... more Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for safety pharmacology and to investigate genetic diseases affecting cardiac ion channels. It is unclear whether adult myocytes or hiPSC-CMs are the better platform for cardiac safety pharmacology. We examined the biophysical and molecular properties of INa in adult myocytes and hiPSC-CMs. hiPSC-CMs were plated at low density. Atrial and ventricular cells were obtained from dog hearts. Whole cell patch clamp was used to record INa. Voltage clamp recordings showed a large INa in all three cell types but different densities. Small differences in steady-state inactivation and recovery from inactivation were noted in the three cell types. Application of lidocaine to the three cell types showed a similar pattern of block of INa under voltage cl& however, lidocaine produced different effects on AP waveform under current clamp. AP clamp experiments showed that application of ventricular or atrial cell waveform...
Biochemical Medicine, 1979
Computers in Cardiology 1994
Short current pulses with twice threshold intensity applied during the vulnerable window at the e... more Short current pulses with twice threshold intensity applied during the vulnerable window at the end of the basic propagating wave have been shown to produce unidirectional block in a linear cable model. Similar premature point stimuli failed to initiate asymmetric electrical responses in a 2-D homogeneous myocardial surface (3×3 cm, 100 μ steps, Luo-Rudy AP model). However when an additional planar stimulus was introduced after the basic wave, the point extrastimulus initiated an abnormal double electrical activation, leading to “figure-of-eight” reentry. Time course of restitution of the refractory period after a premature stimulus was found to be the most important electrophysiological parameter to determine duration of the vulnerable window
Journal of Cardiovascular Electrophysiology
Cardiac Repolarization
... 10. Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of ... more ... 10. Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. ... 39. Gussak I, Bjerregaard P, Egan TM, Chaitman BR. ECG phenomenon called the J wave. ...
Monophasic Action Potentials, 1997
The discovery and characterization of cells in the midmyocardial layers of ventricular myocardium... more The discovery and characterization of cells in the midmyocardial layers of ventricular myocardium with unique repolarization properties have yielded some interesting observations relative to our understanding of the electrophysiology, pharmacology and pathophysiology of the ventricles of the heart and the electrocardiographic signals that they generate. Our principal aim in this chapter is to review recent experimental data that have advanced our knowledge of the electrical heterogeneity that exists in ventricular myocardium with a focus on the role of the M cell.
Journal of molecular and cellular cardiology, Jan 15, 2015
The inward rectifier potassium current, IK1, contributes to the terminal phase of repolarization ... more The inward rectifier potassium current, IK1, contributes to the terminal phase of repolarization of the action potential (AP), as well as the value and stability of the resting membrane potential. Regional variation in IK1 has been noted in the canine heart, but the biophysical properties have not been directly compared. We examined the properties and functional contribution of IK1 in isolated myocytes from ventricular, atrial and Purkinje tissue. APs were recorded from canine left ventricular midmyocardium, left atrial and Purkinje tissue. The terminal rate of repolarization of the AP in ventricle, but not in Purkinje, depended on changes in external K(+) ([K(+)]o). Isolated ventricular myocytes had the greatest density of IK1 while atrial myocytes had the lowest. Furthermore, the outward component of IK1 in ventricular cells exhibited a prominent outward component and steep negative slope conductance, which was also enhanced in 10mM [K(+)]o. In contrast, both Purkinje and atrial c...
Circulation. Arrhythmia and electrophysiology, 2014
Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patie... more Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome and examines the effectiveness of quinidine, cilostazol, and milrinone to prevent hypothermia-induced arrhythmias. Transmembrane action potentials were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3-10 μmol/L) and verapamil (1 μmol/L) was used to pharmacologically model the genetic mutations responsible for ER syndrome. Acetylcholine (3 μmol/L) was used to simulate increased parasympathetic tone, which is known to promote ER. In controls, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C-34°C) resulted in increased J-wave area on the ECG and accentu...
Biulleten' eksperimental'noĭ biologii i meditsiny, 1981
Calcium ionophore A23187 (2.10(-6) M) increases contractility of the isolated guinea-pig papillar... more Calcium ionophore A23187 (2.10(-6) M) increases contractility of the isolated guinea-pig papillary muscle 3.13 +/- +/- 0.47-fold at 25 degrees C and 1.88 +/- 0.28-fold at 37 degrees C. Prolonged exposure (30 min) to 2 mM of caffeine failed to eliminate positive inotropic effect of ionophore. A23187 (2.10(-6) M) also increased slow response action potential overshoot (18 mM K+ in Tyrode solution, resting potential 46 +/- 1 mV); at 37 degrees C the peak overshoot value was reached by the 2nd min, being equal to 5.2 +/- 0.4 mV; at 25 degrees C the peak value was attained by the 15th min, being equal to 15.5 +/- 0.9 mV with an abrupt increase in the repolarization rate. Overshoot enhancement within the first minutes of A23187 action is concluded to be due to the increased slow inward Ca-current rather than to the decreased outward currents. It is assumed that A23187 facilitates Ca2+ transport to the lipid phase thereby increasing the amount of sarcolemma bound Ca2+ that participates in ...
Biulleten' Vsesoiuznogo kardiologicheskogo nauchnogo tsentra AMN SSSR, 1984
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Papers by Vladislav Nesterenko