Kwanghyun Sohn

Experimental and computational studies of strain–conduction velocity relationships in cardiac tissue

Velocity of electrical conduction in cardiac tissue is a function of mechanical strain. Although strain-modulated velocity is a well established finding in experimental cardiology, its underlying mechanisms are not well understood. In this work, we summarized potential factors contributing to strain-velocity relationships and reviewed related experimental and computational studies. We presented results from our experimental studies on rabbit papillary muscle, which supported a biphasic relationship of strain and velocity under uni-axial straining conditions. In the low strain range, the strain-velocity relationship was positive. Conduction velocity peaked with 0.59 m/s at 100% strain corresponding to maximal force development. In the high strain range, the relationship was negative. Conduction was reversibly blocked at 118+/-1.8% strain. Reversible block occurred also in the presence of streptomycin. Furthermore, our studies revealed a moderate hysteresis of conduction velocity, which was reduced by streptomycin. We reconstructed several features of the strain-velocity relationship in a computational study with a myocyte strand. The modeling included strain-modulation of intracellular conductivity and stretch-activated cation non-selective ion channels. The computational study supported our hypotheses, that the positive strain-velocity relationship at low strain is caused by strain-modulation of intracellular conductivity and the negative relationship at high strain results from activity of stretch-activated channels. Conduction block was not reconstructed in our computational studies. We concluded this work by sketching a hypothesis for strain-modulation of conduction and conduction block in papillary muscle. We suggest that this hypothesis can also explain uni-axially measured strain-conduction velocity relationships in other types of cardiac tissue, but apparently necessitates adjustments to reconstruct pressure or volume related changes of velocity in atria and ventricles.

Absence of glucose transporter 4 diminishes electrical activity of mouse hearts during hypoxia

•  What is the central question of this study? The aim of this study was to examine quantitatively whether glucose transporter 4 deficiency leads to more severe alterations in cardiac electrical activity during cardiac stress. •  What is the main finding and what is its importance? When compared with hearts from corresponding control littermates, the measured epicardial potentials from the surface of cardiac‐selective glucose transporter 4‐ablated mouse hearts during hypoxia showed the following differences: (i) significant decreases in the maximal downstroke of the potentials; (ii) increased activation time; and (iii) greater alterations in the activation sequence.

Experimental measures of the minimum time derivative of the extracellular potentials as an index of electrical activity during metabolic and hypoxic stress

The time of the minimum time derivative of the extracellular potentials (Φ∧) is a marker for the instant of activation when the depolarizing sodium current reaches its maximum rate of increase. This study examined the normalized averaged value of Φ∧, Φna∧, as an index of electrical activity under metabolic and hypoxic stresses. Electrical mapping was performed using a 64-electrode cage array on Langendorff perfused isolated mouse hearts at three different glucose and insulin levels during hypoxia. The lower levels of glucose and/or insulin resulted in the largest decrease of Φna∧ during hypoxia. A significant decrease in Φna∧ was a predictor of increased total activation time and propagation pattern change, and irreversible damage was predicted by a 60% decrease of Φna∧. These results supported Φna∧ as an potentially useful index of electrical activity.

The Single Equivalent Moving Dipole Model Does Not Require Spatial Anatomical Information to Determine Cardiac Sources of Activation

Radio-frequency catheter ablation (RCA) is an established treatment for ventricular tachycardia (VT). A key feature of the RCA procedure is the need for a mapping approach that facilitates the identification of the target ablation site. In this study, we investigate the effect of the location of the reference potential and spatial anatomical constraints on the accuracy of an algorithm to identify the target site for ablation therapy of VT. This algorithm involves processing body surface potentials using the single equivalent moving dipole (SEMD) model embedded in an infinite homogeneous volume conductor to model cardiac electrical activity. We employed a swine animal model and an electrode array of nine electrodes that was sutured on the epicardial surface of the right ventricle. We identified two potential reference electrode locations: at an electrode most far away from the heart (R1) and at the average of all 64 body surface electrode potentials (R2). Also, we developed three spatial “constraining” schemes of the algorithm used to obtain the SEMD location: one that does not impose any constraint on the inverse solution (S1), one that constrains the solution into a volume that corresponds to the heart (S2), and one that constrains the solution into a volume that corresponds to the body surface (S3). We have found that R2S1 is the most accurate approach (p <; 0.05 versus R1S1 at earliest activation time-EAT) for localizing epicardial electrical sources of known locations in vivo. Although the homogeneous volume conductor introduces systematic error in the estimated compared to the true dipole location, we have observed that the overall error of the estimated interelectrode distance compared to the true one was 0.4 ± 0.4 cm and 0.4 ± 0.1 cm for the R1S1 and R2S1 combinations, respectively, at the EAT (p = N.S.) and 1.0 ± 0.6 and 0.5 ± 0.4 cm, respectively, at the pacing spike time (PST, ). In conclusion, our algorithm to estimate the SEMD parameters from body surface potentials can potentially be a useful method to rapidly and accurately guide the catheter tip to the target site during a RCA procedure without the need for spatial anatomical information obtained by conventional imaging modalities.

Relationship between Maximal Upstroke Velocity of Transmembrane Voltage and Minimum Time Derivative of Extracellular Potential

The purpose of this computational study was to test the pertinence of the magnitude of the minimum time derivative of the extracellular potential, |dVes /dtmin |, measured in a thin, conducting solution layer adjacent to the tissue, as an index of cardiac excitability. For this purpose, we performed computational studies characterizing the relationship between |dVes /dtmin | and the maximum upstroke velocity of transmembrane voltage, dVm /dtmax , which has been used in previous studies as an index of excitability. A three-dimensional bidomain model of electrical conduction in cardiac tissue was used based on the Noble-Varghese-Kohl-Noble model of ventricular myocytes. The spatial domain included a slab of cardiac tissue with intra- and extracellular anisotropic conductivities surrounded by a layer of solution. The simulations showed linear relationships between |dVes /dtmin | and dVm /dtmax for reduction of maximum sodium current conductance (G Na ) from 100% to 20%. The relationship was dependent on location and propagation direction. However, when both parameters were normalized, those dependencies disappeared. In summary, our study demonstrated that normalized |dVes /dtmin | is linearly related to normalized dVm /dtmax . The results support our hypothesis that normalized |dVes /dtmin | can be used as an index of cardiac excitability.

Propagation and Electrical Impedance Changes due to Ischemia, Hypoxia and Reperfusion in Mouse Hearts

The purpose of this study is to quantitatively characterize major electrical markers of cardiac ischemia in normal mouse hearts to establish a set of baseline parameters for evaluation of genetically altered mouse hearts. Optical and electrical imaging techniques were coupled with impedance measurements to quantify changes induced by global ischemia. Optical and electrical mapping studies revealed the time course of conduction slowing and local inactivation during 30 minutes of ischemia or hypoxia. Measures of myocardial electrical impedance (MEI) were made during 30 and 120 minutes of global ischemia and proved to be qualitatively similar yet quantitatively distinct when compared to results reported from other mammals. The results of this study can now be applied in the analysis of genetically altered mouse hearts that are currently becoming available to help us understand cardiac death in disease

A Method to Noninvasively Identify Cardiac Bioelectrical Sources

We have introduced a method to guide radiofrequency catheter ablation (RCA) procedures that estimates the location of a catheter tip used to pace the ventricles and the target site for ablation using the single equivalent moving dipole (SEMD).

The Maximal Downstroke of Epicardial Potentials as an Index of Electrical Activity in Mouse Hearts

The maximal upstroke of transmembrane voltage (dV<i>m</i>/dt_max) has been used as an indirect measure of sodium current I_Na upon activation in cardiac myocytes. However, sodium influx generates not only the upstroke of V<i>m</i>, but also the downstroke of the extracellular potentials V including epicardial surface potentials V_es. The purpose of this study was to evaluate the magnitude of the maximal downstroke of V_es (|dV_es/dt_min|) as a global index of electrical activation, based on the relationship of dV<i>m</i>/dt_max to I_Na. To fulfill this purpose, we examined |dV_es/dt_min| experimentally using isolated perfused mouse hearts and computationally using a 3-D cardiac tissue bidomain model. In experimental studies, a custom-made cylindrical “cage” array with 64 electrodes was slipped over mouse hearts to measure V_es during hyperkalemia, ischemia, and hypoxia, which are conditions that decrease I_Na. Values of |dV_es/dt_min| from each electrode were normalized (|dV_es/dt_min|<i>n</i>) and averaged (|dV_es/dt_min|_na). Results showed that |dV_es/dt_min|_na decreased during hyperkalemia by 28, 59, and 79% at 8, 10, and 12 mM [K⁺]<i>o</i>, respectively. |dV_es/dt_min| also decreased by 54 and 84% 20 min after the onset of ischemia and hypoxia, respectively. In computational studies, |dV_es/dt_min| was compared to dV<i>m</i>/dt_max at different levels of the maximum sodium conductance G_Na, extracellular potassium ion concentration [K⁺]<i>o</i>, and intracellular sodium ion concentration [Na⁺]<i>i</i>, which all influence levels of I_Na. Changes in |dV_es/dt_min|<i>n</i> were similar to dV<i>m</i>/dt_max during alterations of G_Na , [K⁺]<i>o</i>, and [Na⁺]<i>i</i>. Our results demonstrate that |dV_es/dt_min|_na is a robust global index of electrical activation for use in mouse hearts and, similar to dV<i>m</i>/dt_max, can be used to probe electrophysiological alterations reliably. The index can be readily measured and evaluated, which makes it attractive for characterization of, for instance, genetically modified mouse hearts and drug effects on cardiac tissue.

Experimental epicardial potential mapping in mouse ventricles: effects of fiber architecture

The purpose of this study is to introduce unique experimental measurements of extracellular potentials mapped from the epicardial surface of mouse hearts that reflect the same structural features seen in larger mammalian hearts. The measurements obtained in this study provide an important tool for studying the impacts of structural changes on propagation in genetically modified mouse models of cardiac disease. Unipolar electrograms were recorded using a high-resolution electrode array to map the epicardial surface of mouse hearts during atrial drive and at increasing transmural pacing depths. The extracellular potential maps revealed the underlying fiber structure of the mouse heart that is shown to be similar to those previously published from other species. This imaging technique, when integrated with computer models and diffusion tensor imaging can substantially contribute to our understanding of innovative genetic mouse models being used in the study of human cardiac disease.