© 1996 American Heart Association, Inc.
Articles |
Cellular and Ionic Basis of Arrhythmias in Postinfarction Remodeled Ventricular Myocardium
the Cardiology Division, Department of Medicine, State University of New York Health Science Center, and Veterans Affairs Medical Center, Brooklyn, NY.
Correspondence to Nabil El-Sherif, MD, Cardiology Division, Box 1199, SUNY Health Science Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail el-sherif.nabil@brooklyn.va.gov.
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Abstract |
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After myocardial infarction (MI), the noninfarcted myocardium undergoes significant hypertrophy as part of the post-MI structural remodeling. Electrophysiological changes associated with the hypertrophied remodeled myocardium may play a key role in arrhythmia generation in the post-MI heart. We investigated the cellular and ionic basis of arrhythmias in remodeled left ventricular (LV) myocardium 3 to 4 weeks after MI in the rat. We analyzed (1) the incidence of induced ventricular tachyarrhythmias (VTs) in the in vivo heart, (2) action potential characteristics and arrhythmia mechanisms in multicellular preparations and isolated remodeled LV myocytes, and (3) the density and kinetics of the L-type Ca2+ current (ICa-L) and the fast and slow components of transient outward K+ currents (Ito-f and Ito-s, respectively). The results were compared with those from sham-operated rats. In vivo, programmed stimulation induced sustained VT in 80% of post-MI rats but not in sham-operated rats. The capacitance of post-MI hypertrophied myocytes was significantly increased compared with myocytes from sham-operated rats. Post-MI myocytes had prolonged action potential duration (APD) with marked heterogeneity of the time course of repolarization. The prolongation of APD could be explained by the significant decrease of the density of both Ito-f and Ito-s. There was no change in the kinetics of both currents compared with control. Both the density and kinetics of ICa-L were not significantly different in post-MI remodeled myocytes compared with control. The cellular studies showed that reentrant excitation secondary to dispersion of repolarization and triggered activity from both early and delayed afterdepolarizations are potential mechanisms for VT in the post-MI remodeled heart.
Key Words: myocardial infarction • hypertrophy • patch clamp • single cell • ion channel
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Introduction |
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In recent years, the importance of ventricular remodeling after MI on long-term survival has been better appreciated.1 2 The structural remodeling of the LV after MI involves both the region of necrosis and the noninfarcted myocardium.3 4 The noninfarcted myocardium undergoes significant hypertrophy, which is considered an adaptive universal response of the heart to increased workload from whatever cause.5 The features of myocardial hypertrophy after MI are more consistent with volume-overload than pressure-overload hypertrophy.3 Clinical and experimental data strongly suggest that the risk of ventricular arrhythmias correlates with the degree and characteristics of post-MI remodeling.6 7 8 Although post-MI remodeling is a complex time-dependent process that involves structural, biochemical, neurohumoral, and electrophysiological alterations, there is considerable evidence that electrophysiological changes associated with the hypertrophied noninfarcted myocardium play a key role in the arrhythmogenicity of the post-MI heart. For example, although ß-blockers and angiotensin-converting enzyme inhibitors have very different effects on ventricular dilatation, both agents have been shown to prevent the development of myocardial hypertrophy9 10 and may thus decrease the susceptibility to ventricular arrhythmias.11 On the other hand, there are considerable data from other models of hypertrophy showing that hypertrophied myocardium can generate arrhythmias more readily than normal tissue.12 13 14 15 16 The most consistent electrical abnormality that has been described in association with myocardial hypertrophy is prolongation of APD.17 Several potential electrophysiological mechanisms of arrhythmia generation have been described at the cellular level in different models of hypertrophy, and widely varying, sometimes inconsistent, abnormalities of sarcolemmal ion channel currents, which may contribute to arrhythmogenicity, have been reported.17 However, there are surprisingly little data concerning the cellular and ionic basis of arrhythmias in post-MI hypertrophied myocardium.
The present study was conducted to investigate the cellular and ionic basis of arrhythmias in the post-MI rat heart. The rat has been used more than any other animal for electrophysiological and molecular studies of the hypertrophied heart.17 Although there are some similarities with other models of hypertrophy, it has been suggested that myocardial hypertrophy after MI, which compensates for the lack of substance, may involve different sets of signal transduction pathways compared with hypertrophy secondary to mechanical overload.18 Some of our recent data seem to support this view. For example, we have shown that ICa-T, present in neonatal rat but not in adult ventricular myocytes, is reexpressed in post-MI remodeled myocytes.19 Similarly, the fetal isoforms of the 
1 subunit of the ICa-L are reexpressed in post-MI myocardium.20 None of these changes has been described in other models of hypertrophied rat heart.17 There is also evidence, from other hypertrophy models,16 21 22 that time-varying abnormalities in ion channel characteristics may contribute to arrhythmias at different phases after MI.
We chose to investigate the cellular and ionic basis of arrhythmias 3 to 4 weeks after MI. This period coincides with the phase of established compensatory hypertrophy and precedes the later phase of decompensated heart failure.4 Preliminary data have been reported previously.19 23 24
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Materials and Methods |
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Experimental MI
The experimental protocol was approved by the local institutional review board and conformed to the guiding principles of the Declaration of Helsinki. Female Sprague-Dawley rats weighing 200 to 250 g underwent either left anterior descending coronary artery ligation or sham operation as previously described.25 Briefly, after anesthesia with 35 mg/kg IP methohexital and local anesthesia with 1% xylocaine, the trachea was exposed in the midline, and the rats were intubated under direct vision and ventilated with room air. The chest was opened by anterolateral thoracotomy, and the pericardium was removed. The heart was retracted with an apical suture, and the left anterior descending coronary artery was occluded with a 6-0 suture 1 to 2 mm below the left atrial appendage. Successful occlusion was confirmed by pallor of the anterior wall of the LV and ST-segment elevation. If neither of these changes was observed, the occlusion was reattempted. The incision was closed, and 100 000 U benzathine penicillin was administered intramuscularly as a prophylaxis against infection. The rats were extubated and allowed to recover in individual cages. Sham-operated animals underwent an identical surgical procedure without coronary ligation. All rats received standard care, including ad libitum food, water, and a 12-hour day/night cycle.
In Vivo Electrophysiological Studies
Three to 4 weeks after occlusion of the left anterior descending coronary artery, the rats were anesthetized with ketamine (60 mg/kg IP) and diazepam (7.5 mg/kg IP), intubated, and artificially ventilated with humidified room air supplemented with oxygen. Body temperature was maintained at 37°C by a thermostatically controlled heated lamp. Leads I, aVF, and V1 of the ECG were recorded on a physiological recorder. Programmed electrical stimulation was performed through platinum electrodes sewn on the epicardial surface of the right ventricular outflow tract. Pacing was performed by means of a programmable stimulator (Bloom DTU-101). To induce ventricular arrhythmias, eight paced beats at a CL of 100 ms (S1) were applied, followed by one to three extrastimuli (S2, S3, and S4) at shorter coupling intervals. The end point of programmed electrical stimulation was the induction of VTs. The VT was considered nonsustained if it lasted 
15 beats and was considered sustained when it lasted >15 beats before terminating spontaneously or by overdrive pacing.11
Cellular Electrophysiological Studies
Two methods for electrophysiological studies were used: (1) conventional microelectrode recordings of transmembrane APs from strips of noninfarcted remodeled LV and (2) APs recorded from isolated LV myocytes using the current-clamp configuration of the patch-clamp technique. For microelectrode recordings, the preparation was superfused with Tyrode's solution equilibrated with 95% O2/5% CO2 and at a constant temperature of 36±1°C. The Tyrode's solution had the following composition (mmol/L): Na+ 150.8, K+ 4.0, Ca2+ 2.7, Mg2+ 0.5, Cl- 146.1, HCO3- 24.0, H2PO4- 1.8, and dextrose 5.5. The pH was 7.4, as measured by a Radiometer ABL 1 acid-base laboratory. Transmembrane potentials were measured using glass microelectrodes filled with 3 mol/L KCl and having a resistance of 10 to 30 M
. Each microelectrode was coupled to a microprobe system (model M-707, World Precision Instruments) using Plexiglas holders with an integral Ag/AgCl electrode.26
The tissue preparations consisted of epicardial, endocardial, or transmural slices from the remodeled hypertrophied LV free wall. The transmural slices were prepared according to the method described by Sicouri and Antzelevitch.27 A Dermatome power handle No. 3293 with cutting head No. 3295 (Davol Simon) was used with the cut made perpendicular to the surface of the LV free wall. For each heart, one to three 1-mm-thick transmural slices were studied. Simultaneous AP recordings could be obtained and stored in an MP100 data acquisition system (Biopac Systems) with AcqKnowledge 4.0 software. Recordings were made from subepicardial, midmyocardial, and subendocardial locations. Recordings from separate endocardial and epicardial preparations were obtained from the same 5x5 full-thickness block of tissue from the LV free wall and were placed side by side in the same tissue chamber. APs were analyzed for resting potential, AP amplitude, dV/dtmax, and APD25, APD50, and APD90. The preparations were stimulated at different CLs for varying durations, and the possible development of EADs at long CLs and DADs after pacing at short CLs was observed.
AP recordings were obtained at 36±1°C from isolated myocytes. Cells were current-clamped using a Dagan 3900 patch-clamp amplifier (Dagan Corp). APs were elicited with 2-ms current pulses applied at different CLs. AP recordings were also analyzed for AP characteristics and the possible development of EADs. Because of partial buffering of Ca2+ by EGTA in patch-clamp recording, analysis of DAD induction in isolated myocytes, which is critically dependent on [Ca2+]i, was not investigated.
Voltage-Clamp Studies
Cell Preparation
Details of the cell isolation procedures have been previously reported.28 29 Briefly, at the end of the collagenase perfusion, the atria were removed, the LV was dissected out, and the infarcted section was carefully separated, leaving only the noninfarcted LV. The minced tissue pieces were gently stirred, and isolated cells were filtered through a nylon gauze (300 µm). Cells were suspended in Petri dishes containing HEPES buffer with 1 mmol/L CaCl2 and 0.5% bovine serum albumin (pH 7.4). Rod-shaped noncontracting myocytes with clear striations were used for whole-cell voltage-clamp studies within 10 hours of isolation. Current recordings were carried out at room temperature (22±1°C).
Solutions
The composition of external and internal solutions for recording AP, Ca2+, and K+ currents is given in Table 1
. To record ICa-L, the fast INa was blocked by a prepulse to -40 mV in the presence of tetrodotoxin (50 µmol/L), and Ito-f and Ito-s were abolished by replacement of internal K+ with equimolar Cs+. For outward K+ current recordings, NaCl was replaced by choline chloride in the external solution to eliminate the fast INa, and the ICa-L was blocked by cobalt (5 mmol/L). In addition, 14 mmol/L EGTA was applied to the internal solution to buffer the Ca2+ transient and minimize the contribution of the Na+-Ca2+ exchange.
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Voltage-Clamp Recording and Current Analysis
The methods used for whole-cell patch-clamp recordings were previously reported.28 29 Capacitive currents were elicited by 10-mV depolarizing pulses from -80 mV and acquired at a sampling rate of 33.3 kHz. The capacitance of the membrane was calculated according to the following equation: Cm=
c·Io/
Em(1-I
/Io), where Cm is membrane capacitance, c is the time constant of the membrane capacitance, Io is maximum capacitance current value, Em is the amplitude of voltage step, and I is the amplitude of steady state current.30 Series resistance was calculated as Em/Io. Membrane capacitance and series resistance were compensated. Membrane currents were generated by appropriate protocols as described in "Results." The currents were digitally recorded and analyzed using pCLAMP software (pCLAMP Version 6.02, Axon Instrument Inc). Clampfit software was used to measure amplitudes and time constants of ionic currents. Sigma Plot (Jandel Scientific) and Origin (Version 3.0, Microcal Software, Inc) were used to fit activation and inactivation of currents with the Boltzmann equation: Y=1/{1+exp[(V-V0.5)/K]}, where V is voltage potential, V0.5 is half-activation potential, and K is the slope factor.
Statistical Analysis
Data are presented as mean±SEM. Current amplitude, current density, and time constants were determined at different test potentials. When the data could be fit to a physiologically appropriate model with R2>.80, the parameters for that model were tested for differences between the sham-operated and post-MI groups. In experiments in which the response pattern could not be fit, repeated measures ANOVA was used to test for differences between groups. Only linear models fit the criteria for acceptance, and for these models, the slope and intercept differences between groups were tested using multiple regression. In all other cases, localization of differences between groups was determined using t tests, with the Bonferonni correction applied to yield an experimental level of P.05.
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Results |
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In Vivo Electrophysiological Studies
The induction of VT by programmed electrical stimulation was investigated in both sham-operated and post-MI rats, 3 to 4 weeks after surgery. Fig 1
illustrates the results of a typical experiment from a rat 3 weeks after MI. Fig 1A illustrates the induction of a 24-beat run of polymorphic VT by programmed stimulation. In the rat, distinction between VT and VF is often difficult, because both arrhythmias can convert several times into each other without a clear-cut interface, and further, VF can terminate spontaneously.11 30 Fig 1B shows spontaneous termination of a 40-s episode of induced VF. Spontaneous termination of VF is sometimes followed by a short period of complete AV block before converting to sinus rhythm.31 Fig 1C illustrates the spontaneous onset of polymorphic VT during an episode of complete AV block. The CL during complete AV block was 580 ms (rate, 103 bpm), which is a relatively slow rate for the rat. The QT interval was markedly prolonged (375 ms) relative to the cardiac CL. The first beat of the VT occurred before the end of the QT interval, reminiscent of torsade de pointes VT in the long-QT syndrome.32 Inducible VT/VF could be consistently induced in 8 of 10 rats with 3-week-old MI (80%). On the other hand, no sustained VT/VF could be induced by S1-S4 stimulation protocol in 8 sham-operated rats. Our observations on induced VT/VF in rats 3 weeks after MI are similar to those recently reported by Belichard et al.11
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Morphometric Changes
Three to 4 weeks after MI, the infarcted area of the LV showed obvious changes. There was a relatively clear border between infarcted and noninfarcted areas. The free wall of the infarcted area was very thin, and under the microscope, the normal muscle structure disappeared and was replaced by connective tissue. The noninfarcted LV wall was much thicker than normal. The cells isolated from the hypertrophied LV were obviously larger than the cells from the same area of the heart of sham-operated rats. Both the width and length of hypertrophied cells were increased compared with sham cells. Fig 2 shows photomicrographs of single ventricular myocytes from the LV of a sham-operated rat and the LV of a post-MI rat. The width and length of the cells were measured with either a graticule mounted on the lens of a microscope or from the screen of a video monitor. With random scanning, the width of the cells varied from 13 to 23 µm (mean±SEM, 17.7±0.6 µm) in the sham-operated group (n=29) compared with 18 to 31 µm (mean±SEM, 24.6±0.5 µm) in the post-MI group (n=50) (P<.001). The length of cells from the sham-operated group varied from 77 to 154 µm (mean±SEM, 116.1±3.7 µm) compared with 102 to 225 µm (mean±SEM, 152.2±3.2 µm) in the post-MI group (P<.001). The cell membrane capacitance varied from 53 to 224 pF (mean±SEM, 129±3.8 pF) in the sham-operated group (n=82) compared with 81 to 418 pF (mean±SEM, 210±5.1 pF) in the post-MI group (n=151) (P<.001). Results are shown in Fig 3.
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Cellular Electrophysiological Changes
AP characteristics of single isolated post-MI myocytes were analyzed and compared with isolated sham myocytes. APs were analyzed at 1-Hz stimulation. APs from remodeled LV wall were significantly prolonged compared with APs from the LV wall of sham-operated rats. APD25, APD50, and APD90 were all significantly longer in MI myocytes. There was no difference in resting membrane potential, AP amplitude, and dV/dtmax between post-MI and sham cells (Table 2). Fig 4 shows AP recordings from two different isolated MI cells superimposed on AP from isolated sham cells to illustrate the changes in APD in post-MI cells. Note the marked variation of the AP configuration of the two post-MI cells in Fig 4. Fig 4, left, shows that APD25, APD50, and APD90 were all prolonged in the post-MI cell compared with the sham cell, whereas Fig 4, right, shows only significant prolongation of APD90 of the post-MI cell.
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The marked variation in the configuration of APD of single post-MI cells obtained from the remodeled LV wall prompted us to study AP characteristics in multicellular preparations from different regions of the LV free wall in hearts from both the sham-operated and post-MI groups. Transmural slices could be obtained only from thick regions of the hypertrophied free wall (six preparations). In these preparations, recordings from subepicardial, midmyocardial, and subendocardial sites were obtained. However, because it was often difficult to obtain a sufficient number of recordings from cells with "normal" resting potential (
-70 mV) in slice preparations, separate epicardial and endocardial preparations from the same region of the LV free wall were studied. Because the data from epicardial and endocardial cells obtained from slice preparations were consistent with data obtained from separate epicardial and endocardial preparations, these data were pooled together. The number of successful impalements from midmyocardial regions was not large enough for a statistical analysis. Table 3 shows that resting membrane potential, action potential amplitude, and APD90 of epicardial cells from the LV free wall of sham-operated rats were not different from endocardial cells. APD25 and APD50 were longer in endocardial cells than in epicardial cells, but the differences were not statistically significant. The dV/dtmax of epicardial cells was lower than that of endocardial cells (P<.002). Comparing epicardial and endocardial APs from sham-operated rats with those from post-MI rats showed that there were no differences in resting membrane potential, action potential amplitude, and dV/dtmax; however, APD25, APD50, and APD90 were all significantly longer in post-MI cells (P<.01). The time course of repolarization of epicardial versus endocardial cells of post-MI rats showed a significant difference (Fig 5). Both APD25 and APD50 were significantly longer in epicardial post-MI cells than in endocardial post-MI cells (P<.01). APD90 was slightly longer in epicardial post-MI cells than in endocardial post-MI cells, but the difference was not statistically significant.
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Evidence of the abnormal electrophysiological response of post-MI cells is shown in Fig 6. The recording was obtained from an endocardial preparation from the LV of a post-MI rat. The preparation was abruptly stimulated after a 20-s pause at a CL of 400 ms. Note the development of marked alternation of APD (Fig 6A). The alternation persisted for 60 cycles. When stimulation was repeated at an even longer CL of 500 ms, alternation of APD still occurred, but it persisted for only 18 cycles. During alternation, the APD90 was as long as 400 ms.
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EADs were commonly observed to develop spontaneously in recordings from isolated post-MI myocytes but not in multicellular preparations. EADs were more easily induced at 0.2-Hz stimulation (9 of 11 cells) than at 1 Hz (3 of 11 cells). Fig 7 illustrates AP recordings from a single post-MI myocyte and shows the development of single and multiple EADs.
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Very low amplitude DADs were observed in recordings from 5 of 9 epicardial preparations from the LV of post-MI rats, following a train of stimulation at short CLs (400 to 500 ms). In these preparations, superfusion with isoproterenol (5 to 10 nmol/L) resulted in increased slope and amplitude of the DAD. Fig 8 shows that during stimulation at a constant CL of 500 ms, increasing the length of the stimulating train resulted in graded increase in the slope and amplitude of the DAD, which eventually reached threshold and triggered two spontaneous APs followed by a subthreshold DAD. In five epicardial preparations from the sham-operated group, stimulating trains at 300 to 500 ms in the presence of up to 50 nmol/L isoproterenol failed to induce DADs or triggered activity.
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ICa-L in Sham and Post-MI Myocytes
To record ICa-L, the cells were depolarized every 10 s from a holding potential of -80 mV to a prepulse level of -40 mV for 250 ms and, subsequently, to different test potentials at 5-mV increments up to +60 mV. ICa-L was measured as the difference between peak inward current and the current at the end of the 250-ms pulses. Fig 9A shows typical ICa-L tracings from sham and post-MI cells. Fig 9B compares the I-V curves of ICa-L in sham and post-MI cells. The I-V curves have a typical bell-shaped configuration, with a peak at +10 mV in both sham and post-MI cells. The averaged peak of ICa-L was 1.98±0.15 nA in post-MI cells (n=14) compared with 1.27±0.12 nA in sham cells (n=23). The difference in peak currents was significant (P<.001). However, when the current was normalized to membrane capacitance, the average current density in post-MI cells (9.24±0.39 pA/pF) was not significantly different from that of sham cells (9.26±0.90 pA/pF) (P=.982, Fig 9C).
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Fig 10 illustrates the voltage dependence of the time constants of ICa-L inactivation in both sham and post-MI cells. The current decay was best fitted by the sum of two exponentials in both cells. f ranged from 10 to 20 ms in sham cells and 12 to 23 ms in post-MI cells between voltages of -20 to +40 mV. In both sham and post-MI cells, f showed gradual increase with depolarization up to +40 mV. The f in post-MI cells was slightly larger at all voltages compared with sham cells, but the difference did not reach statistical significance. On the other hand, s had a U-shaped dependence on the membrane potential, with a minimum of 61 ms in sham cells and 70 ms in post-MI cells between 0 and +10 mV. Although the s in post-MI cells was larger than s in sham cells at all voltages, the difference was not statistically significant.
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Fig 11 illustrates the kinetics of ICa-L in sham and post-MI cells. Steady state inactivation was obtained with a two-pulse protocol. The holding potential was -80 mV, and prepulse potentials of 250 ms, ranging from -100 to +60 mV, were separated from the test pulse (0 mV, 250 ms) by a 3-ms delay to allow better resolution of ICa-L from the variable capacitive current. Pulse pairs were applied every 10 s. The currents resulting from the test pulse were normalized and plotted as a function of the prepulse potential from 12 sham cells and 14 post-MI cells. V0.5 and slope factor K of sham cells were -30.3±4.1 and 6.0±0.9 mV, respectively. V0.5 and K values of post-MI cells were -30.0±3.9 and 5.2±0.8 mV, respectively. The differences were not statistically significant. For the steady state activation curves, the reversal potential was estimated by the intercept of the slope of the descending part of the I-V curves. The slope conductances were estimated for different membrane potentials, normalized to the maximal slope conductance, and plotted as a function of potential. For activation, the V0.5 and K values were -8.9±0.4 and 5.5±0.2 mV, respectively, for sham cells compared with -8.8±0.5 and 5.1±0.3 mV, respectively, for post-MI cells. The differences were not statistically significant.
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Outward K+ Currents in Sham and Post-MI Myocytes
Outward K+ currents were evoked by a step depolarization to positive potentials from a holding potential of -100 mV. All depolarization-activated outward currents were blocked when internal K+ was replaced by equimolar Cs+, suggesting that K+ was the carrier of the recorded outward currents. To eliminate the fast INa and ICa-L, Na+ was replaced by choline, and cobalt (5 mmol/L) was added to the external solution.33 Recent studies suggest that choline used to replace Na+ and inhibit INa may in some experiments induce a time-dependent noninactivated K+ current.34 This choline-induced current may have existed in some of our recordings. However, the recordings were similar to those reported by Apkon and Nerbonne,35 who, in the absence of choline, used a voltage clamp protocol that included brief depolarizations to -20 mV to inactivate INa. Similar to Apkon and Nerbonne, a negative holding potential of -100 mV and a depolarization pulse of 5 s were used to enhance analysis of the slow component of the outward K+ current.
After reaching maximum amplitude, the outward K+ currents decayed with apparently two phases (Fig 12). The current decay in both sham and post-MI cells was best fitted by the sum of two exponentials. At a test potential of +40 mV, the decay time constant and weight were 62.6±1.6 ms and 2.1±0.09 nA, respectively, for the fast component and 2769±87 ms and 0.72±0.03 nA, respectively, for the slow component in sham cells (n=52). The respective values from post-MI cells (n=63) were 60.3±1.6 ms and 1.81±0.11 nA for the fast component and 2840±94 ms and 0.68±0.03 nA for the slow component. These results indicated the presence of two distinct components of outward K+ current in adult rat myocytes. The characteristic of the fast component is similar to the 4-aminopyridine–sensitive Ito and is termed Ito-f in the present study. The slow component has been termed IK by Apkon and Nerbonne35 and Ito-slow (Ito-s) by Dukes and Morad33 and by our group.36
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To obtain I-V curves for Ito-f and Ito-s, the cell membrane potential was stepped from a holding potential of -100 mV to potentials of -50 to +60 mV for 5 s. The total outward current was measured as the difference between the maximal level of evoked current and the current remaining at the end of the test pulse. The Ito-f and Ito-s were estimated by the weights of the two components of the fitted exponential curves. The average Ito-f and Ito-s were plotted against the test potential. Fig 13 illustrates the I-V curves of Ito-f and Ito-s in sham and post-MI cells. The Ito-f started to activate at 
-20 mV, whereas Ito-s activated at a slightly more negative potential of -30 mV. Both currents gradually increased in amplitude at more positive potentials. There was no significant difference in the amplitude of Ito-f and Ito-s between sham and post-MI cells at any test potential.
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Fig 14 shows that when Ito-f and Ito-s were normalized to cell capacitance, both current densities were significantly reduced in post-MI cells compared with sham cells. At a test voltage of +60 mV, the density of Ito-f was 20.6±1.1 pA/pF in sham cells (n=50) versus 11.4±0.6 pA/pF in post-MI cells (n=60, P<.001). The density of Ito-s at +60 mV was 6.7±0.4 pA/pF in sham cells versus 4.1±0.3 pA/pF in post-MI cells (P<.001).
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Fig 15 illustrates the voltage dependence of current decay of Ito-f and Ito-s in both sham and post-MI cells. In both sham and post-MI cells, the time constants of Ito-f had a U-shaped relation to membrane potential, with the shortest value of 45 ms at membrane potential of 0 mV. On the other hand, the time constants of Ito-s showed gradual acceleration of decay at positive potentials. There was no significant difference in the time constant of both Ito-f and Ito-s between sham and post-MI cells.
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The time course of recovery from inactivation of Ito-f and Ito-s was studied with a double-pulse protocol and is shown in Fig 16. For Ito-f, the pulse duration was 600 ms, and the double-pulse depolarizations were applied every 10 s. The interpulse duration was in the range of 10 to 310 ms and increased in steps of 25 ms (Fig 16A). Longer pulse duration (3750 ms) and interpulse intervals (125 to 2350 ms, increased in steps of 250 ms) were used to test the recovery of Ito-s; the double-pulse depolarizations were delivered every 20 s (Fig 16B). The amplitudes of Ito-f and Ito-s were measured as the weights of the fast and slow components of the exponential decay. The amplitude of the current evoked by the second pulse was expressed as a fraction of the current during the first pulse and plotted against the interpulse intervals. Recovery of Ito-f and Ito-s followed a single-exponential time course. The time constant of recovery of Ito-f was 32.1±0.9 ms in sham cells and 31.2±0.7 ms in post-MI cells. The time constant of recovery of Ito-s was 30 times slower at 889±54 ms in sham cells and 883±59 ms in post-MI cells. The differences between sham and post-MI cells were not statistically significant.
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Discussion |
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Hypertrophy is the primary long-term response of the heart to overload, from whatever cause.5 The nature and severity of the lesion giving rise to hypertrophy, the animal chosen, the age at which the lesion is produced, and the duration of the period for hypertrophy should be considered as potentially influencing the final results.17 The most consistent electrical abnormality that has been described in association with myocardial hypertrophy is prolongation of APD.17 Aronson37 was the first to show that APD was prolonged in the Goldblatt model of hypertrophy in the rat. Utilizing floating microelectrode recordings, Thollon et al38 were the first to report prolongation of APD of post-MI remodeled hypertrophied ventricular myocytes in the rat and showed that angiotensin-converting enzyme inhibitors can cause reversal of these changes.
Ionic Basis of Prolonged APD of Post-MI Remodeled Ventricular Myocytes
The results of the present study indicate that the prolonged APD of post-MI remodeled ventricular myocytes could be explained by the marked decrease of the density of the two outward K+ currents, Ito-f and Ito-s. The kinetics of both Ito-f and Ito-s were not different between post-MI and sham cells. On the other hand, the density and kinetics of ICa-L were not significantly different in post-MI myocytes compared with control. Thus, alteration of ICa-L does not seem to contribute to prolongation of APD 3 to 4 weeks after MI. The electrophysiological data are consistent with our recent observations that the expression of the adult isoform of the 1 subunit of the L-type Ca2+ channel is not changed compared with control in the remodeled LV 3 weeks after MI.20
The time course of repolarization in the remodeled post-MI LV showed significant differences between epicardial and endocardial regions. Regional heterogeneity of APD has been described in both normal and hypertrophied hearts and was explained on the basis of differential distribution of key ion channels, most notably Ito.39 40 In the post-MI remodeled LV, differences in the relative densities of Ito-f and Ito-s can explain the difference in the time course of repolarization between epicardial and endocardial myocytes. Recently, the expression of Kv4.2, the most likely candidate for the wild-type Ito-f channel,41 was found to be eight times higher in rat epicardial muscle than in papillary muscle.42 In the rat ventricular myocyte, Ito-f is thought to underlie the initial rapid repolarization phase of the AP; Ito-s, the slower phase of repolarization back to the resting potential.35 The predominance of Ito-f could explain the shorter APD25 and APD50 in sham epicardial myocytes compared with sham endocardial myocytes. On the other hand, the decreased density of Ito-f in the post-MI remodeled LV could be expected to result in longer duration of APD25 and APD50 of epicardial versus endocardial myocytes. The decreased density of Ito-s can explain the increased duration of APD90 in both epicardial and endocardial post-MI myocytes. These conclusions remain speculative in the absence of reconstruction of a simulated rat AP incorporating complete data on the density, time course, and voltage dependence of all currents that contribute to the repolarization phase. Although the data involving decreased density of Ito-f and Ito-s in post-MI myocytes represented pooled results from all myocytes across the LV wall, the primary conclusion, ie, that increased APD of post-MI myocytes could be explained by the changes in the densities of both currents, remains valid. However, it would be necessary to analyze separately the relative densities of Ito-f and Ito-s in isolated myocytes from epicardial and endocardial regions of LV from both the sham-operated and post-MI groups to provide support for conclusions regarding the basis for the different time course of repolarization across the LV wall.
The only other study that systematically compared AP configuration of epicardial versus endocardial cells in a hypertrophy model is by Keung and Aronson43 in the Goldblatt rat model. In this model, APD75, but not APD25 and APD50, was significantly longer in epicardial cells from hypertrophied hearts than from normal hearts. By contrast, APD25, APD50, and APD75 were all prolonged in endocardial cells from hypertrophied hearts compared with control hearts. It is interesting to note that the same group later reported that Ito is increased in this model.44 This would explain, in part, the absence of prolongation of early repolarization of epicardial cells in their model. On the other hand, the authors have explained the increased APD of hypertrophied myocytes in their model on the basis of increased density and slowed kinetics of ICa-L.45
Ionic Current Changes in Different Models of Hypertrophy
Of >20 ion-carrying systems in cardiac myocytes, at least 7 could be implicated in the prolongation of APD of hypertrophied myocytes in general. These are ICa-L, Ito-f and Ito-s, IK, IK1, the Na+-Ca2+ exchanger, and slow INa. Because of its fundamental role in excitation-contraction coupling, ICa-L has been investigated more thoroughly than any other current. An increase in ICa-L density and/or slowing of current inactivation could potentially contribute to prolongation of APD in hypertrophied myocytes. The widely varying reports on ICa-L density in various models of hypertrophy are somewhat disconcerting. In a review of 16 studies,17 ICa-L density was reported as increased, decreased, or unchanged. The kinetics of ICa-L in hypertrophy including steady state inactivation, time course of current inactivation, and current repriming have also been reported to vary in different models of hypertrophy.17 There are several potential explanations for the different results that can also apply, to a varying extent, to published reports on other ionic currents. First, different hypertrophy models may give rise to different changes in ICa-L density, presumably because of differences in the stimulus leading to hypertrophy and the signal transduction pathways involved.5 18 Second, the density of ICa-L may differ at different stages and degrees of hypertrophy.21 22 For example, the density of ICa-L of hypertrophied ventricular myocytes in a pulmonary hypertension model was increased compared with control on day 14, with no significant difference found on day 21. On the other hand, the density of Ito was increased at 14 days and was significantly decreased at 21 days.21 Nuss and Houser22 suggested that the direction of changes in ICa-L may be related to the severity of hypertrophy and the absence or presence of heart failure. Third, the changes in ICa-L may be caused by changes in channel regulation by intermediary metabolism, involving channel protein phosphorylation rather than a change in the sarcolemmal density of the channel protein.46 Fourth, some of the different results may be due to methodological limitations.17 For example, a major problem in recording ICa-L under patch-clamp conditions is the time-dependent rundown of the current.47 Few reports seem to address this problem. Further, most studies reported ICa-L density in relation to cell capacity; the latter is significantly increased in hypertrophied myocytes. Differences between group means, ie, control and hypertrophied myocytes, may not necessarily mean that the populations from which the samples are derived are different unless appropriate statistical techniques are used.17
Ito is a major repolarizing current in cardiac cells of several mammalian species, including humans,48 and regional differences in the distribution of Ito are important in determining regional variations in AP configuration.39 48 With the exception of the study by Li and Keung44 mentioned earlier, Ito-f was reduced in rat ventricular myocytes from most hypertrophy models, and this was thought to play a major role in prolongation of APD.49 50 51 However, the kinetics of Ito-f is usually unchanged in hypertrophied myocytes.49 50 51 The loss of "spike-and-dome" configuration of AP of cells surviving on the epicardial surface of 5-day infarcted dog hearts was also attributed to a reduced or absent Ito.52 No previous studies have investigated the changes in Ito-s in hypertrophied rat myocytes. We have shown that Ito-s is pharmacologically and kinetically different from the reported IK in guinea pig ventricular cells.36 The few reports on IK in hypertrophied myocytes in guinea pig and feline hearts are inconclusive.53 54
IK1 plays an important role in the last phase of repolarization of the AP and may therefore be important in contributing to changes in APD in hypertrophy. IK1 was reported to be increased,54 decreased,55 or unchanged50 53 in different studies.
The Na+-Ca2+ exchanger generates an inward current during repolarization, and changes in this current may play an important part in changes in APD56 as well as in arrhythmia generation in hypertrophied hearts. The time course of decay of Na+-Ca2+ exchange current is determined principally by the rate of Ca2+ uptake by the sarcoplasmic reticulum,57 which is diminished in hypertrophied myocytes.58 Using Ca2+ indicators, several groups have reported prolongation of the Ca2+ transient in hypertrophied and failing heart muscle.50 59 To date, only one study directly examined changes in the exchanger current in hypertrophied cardiac myocytes, and it found that the current is increased compared with control. This was thought to contribute to prolongation of APD in this model of hypertrophy.53
Finally, a potential contribution of an enhanced slow INa to prolongation of APD of hypertrophied myocytes should be considered. A recent preliminary report of whole-cell current recordings suggests the presence of noninactivating inward current (possibly carried by Na+) in cardiac myocytes of dogs with chronic heart failure that may contribute to ventricular arrhythmias in this model.60
Cellular Mechanisms of Arrhythmias in the Post-MI Remodeled Ventricular Myocardium
Hypertrophied myocardium has been shown to generate arrhythmias more readily than normal tissue.12 13 14 15 16 Several electrophysiological mechanisms of arrhythmias have been described in different models of hypertrophy. In the present study, three potential electrophysiological mechanisms for tachyarrhythmia generation in the post-MI remodeled ventricular myocardium have been demonstrated. The increased heterogeneity of APD in the remodeled hypertrophied LV can result in dispersion of refractoriness, a critical substrate for the development of circus movement reentrant tachyarrhythmias.61 Hypertrophy-induced increase in interstitial tissue with possible impairment of cellular coupling can also contribute to the occurrence of reentry.14 15
Another potential mechanism for ventricular tachyarrhythmias in the hypertrophied myocardium is triggered activity from EADs. Prolongation of APD is considered the priming step for the development of EADs.32 Several changes in ionic currents that have been described in different models of hypertrophy favor both the prolongation of APD and the generation of EADs. These include a decrease of Ito and IK, shift of inactivation of ICa-L to more positive potentials, and prolongation of the current inactivation.17 Although spontaneous generation of EADs in hypertrophied myocardium has not been reported, Aronson62 showed that EADs were more easily induced in the hypertrophied rat myocyte if outward K+ currents were suppressed by tetraethylammonium. In the present study, we demonstrated the development of single and repetitive EADs in isolated myocytes. The EADs were more frequent at relatively long CLs. We have not been able to illustrate, however, the spontaneous EAD generation in multicellular preparations from remodeled LV, even though some APDs were markedly prolonged. It is possible that EADs could have been more easily induced in these preparations if outward K+ currents were further suppressed, as previously shown by Aronson. The in vivo representation of EAD-induced triggered activity is a prolonged QT interval associated with polymorphic VT, known as torsade de pointes.32 The characteristics of spontaneous VT in the post-MI rat have not been investigated outside the first 48 hours after MI.31 Fig 1C
illustrated the spontaneous onset of a polymorphic VT in the presence of a prolonged QT interval during a relatively slow cardiac rhythm. It is possible that the arrhythmia was at least initiated by an EAD. However, since the arrhythmia occurred shortly after spontaneous termination of a programmed stimulation-induced VF, it could not be considered representative of VT that may occur spontaneously in rats in the late post-MI phase.
Triggered activity from DADs is yet another potential mechanism of arrhythmias in the post-MI heart. DADs have been shown to be more easily induced in hypertrophied myocytes under the influence of increased extracellular Ca2+62 or in the presence of ß-adrenergic agonists.63 Higher intracellular Ca2+ through the Na+-Ca2+ exchange mechanism associated with the prolonged APD and impaired Ca2+ uptake by the sarcoplasmic reticulum in hypertrophied cells can favor the occurrence of DADs.64 65 There is also evidence that the hyperpolarization-activated current is increased in hypertrophied myocytes and may favor the occurrence of spontaneous APs.66 Further, ICa-T was shown to be reexpressed in some models of hypertrophy,67 including the post-MI model.19 The steady state voltage relations for activation and inactivation of ICa-T are shifted by 35 mV toward negative potentials compared with ICa-L, making ICa-T well suited for participating in pacemaker activity. A current flowing through ICa-T channels might be involved in several types of arrhythmias, including both DADs and EADs.68
In summary, we have shown that remodeled hypertrophied LV myocytes from rats 3 to 4 weeks after MI have prolonged APD with marked heterogeneity of the time course of repolarization across the LV wall. The prolongation of APD could be explained by the decreased density of the two outward K+ currents, Ito-f and Ito-s, rather than by changes in the density or kinetics of ICa-L. Both reentrant excitation secondary to dispersion of repolarization and triggered activity from EADs and DADs are potential mechanisms for ventricular tachyarrhythmias in these hearts.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Veterans Affairs Medical Research Funds. The authors would like to thank Dr Matthew J. Avitable of the SUNY Health Science Center Scientific and Academic Computing Center for his assistance with the statistical analysis, Dr Mark Restivo for his critical review of the manuscript, Dr Venkat Battula for his assistance in performing rat surgery, Antoinette Wells and Joyce Ince for their care of the animals, and Mary Lucas for her excellent secretarial assistance.
Received January 16, 1996; accepted May 23, 1996.
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S. Poelzing and D. S. Rosenbaum Altered connexin43 expression produces arrhythmia substrate in heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1762 - H1770. [Abstract] [Full Text] [PDF]
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Y. Wakisaka, S. Niwano, H. Niwano, J. Saito, T. Yoshida, S. Hirasawa, H. Kawada, and T. Izumi Structural and electrical ventricular remodeling in rat acute myocarditis and subsequent heart failure Cardiovasc Res, September 1, 2004; 63(4): 689 - 699. [Abstract] [Full Text] [PDF]
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S. G. Birnbaum, A. W. Varga, L.-L. Yuan, A. E. Anderson, J. D. Sweatt, and L. A. Schrader Structure and Function of Kv4-Family Transient Potassium Channels Physiol Rev, July 1, 2004; 84(3): 803 - 833. [Abstract] [Full Text] [PDF]
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N. Niwa, K. Yasui, T. Opthof, H. Takemura, A. Shimizu, M. Horiba, J.-K. Lee, H. Honjo, K. Kamiya, and I. Kodama Cav3.2 subunit underlies the functional T-type Ca2+ channel in murine hearts during the embryonic period Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2257 - H2263. [Abstract] [Full Text] [PDF]
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C. F. Rossow, E. Minami, E. G. Chase, C. E. Murry, and L.F. Santana NFATc3-Induced Reductions in Voltage-Gated K+ Currents After Myocardial Infarction Circ. Res., May 28, 2004; 94(10): 1340 - 1350. [Abstract] [Full Text] [PDF]
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G. Heusch and K. R. Sipido Myocardial Hibernation: A Double-Edged Sword Circ. Res., April 30, 2004; 94(8): 1005 - 1007. [Full Text] [PDF]
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 S. Wasson, H. K. Reddy, and M. L. Dohrmann Current Perspectives of Electrical Remodeling and Its Therapeutic Implications Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 129 - 144. [Abstract] [PDF]
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 F R Quinn, S Currie, A M Duncan, S Miller, R Sayeed, S M Cobbe, and G L Smith Myocardial infarction causes increased expression but decreased activity of the myocardial Na+--Ca2+ exchanger in the rabbit J. Physiol., November 15, 2003; 553(1): 229 - 242. [Abstract] [Full Text] [PDF]
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H. El-Adawi, L. Deng, A. Tramontano, S. Smith, E. Mascareno, K. Ganguly, R. Castillo, and N. El-Sherif The functional role of the JAK-STAT pathway in post-infarction remodeling Cardiovasc Res, January 1, 2003; 57(1): 129 - 138. [Abstract] [Full Text] [PDF]
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R. Kaprielian, R. Sah, T. Nguyen, A. D. Wickenden, and P. H. Backx Myocardial infarction in rat eliminates regional heterogeneity of AP profiles, Ito K+ currents, and [Ca2+]i transients Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1157 - H1168. [Abstract] [Full Text] [PDF]
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G. J. Rozanski and Z. Xu Glutathione and K+ channel remodeling in postinfarction rat heart Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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B Huang, D Qin, and N El-Sherif Spatial alterations of Kv channels expression and K+ currents in post-MI remodeled rat heart Cardiovasc Res, November 1, 2001; 52(2): 246 - 254. [Abstract] [Full Text] [PDF]
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J. Meszaros, D. Khananshvili, and G. Hart Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H903 - H914. [Abstract] [Full Text] [PDF]
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P.-S. Chen, L. S Chen, J.-M. Cao, B. Sharifi, H. S Karagueuzian, and M. C Fishbein Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 409 - 416. [Abstract] [Full Text] [PDF]
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F. L Burton and S. M Cobbe Dispersion of ventricular repolarization and refractory period Cardiovasc Res, April 1, 2001; 50(1): 10 - 23. [Full Text] [PDF]
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T.-T. Zhang, K. Takimoto, A. F. R. Stewart, C. Zhu, and E. S. Levitan Independent Regulation of Cardiac Kv4.3 Potassium Channel Expression by Angiotensin II and Phenylephrine Circ. Res., March 16, 2001; 88(5): 476 - 482. [Abstract] [Full Text] [PDF]
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B. Huang, D. Qin, L. Deng, M. Boutjdir, and N. El-Sherif Reexpression of T-type Ca2+ channel gene and current in post-infarction remodeled rat left ventricle Cardiovasc Res, June 1, 2000; 46(3): 442 - 449. [Abstract] [Full Text] [PDF]
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A. D. Wickenden, R. Kaprielian, X.-M. You, and P. H. Backx The thyroid hormone analog DITPA restores Ito in rats after myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1105 - H1116. [Abstract] [Full Text] [PDF]
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I. Kiseleva, A. Kamkin, K.-D. Wagner, H. Theres, A. Ladhoff, H. Scholz, J. Gunther, and M. J. Lab Mechanoelectric feedback after left ventricular infarction in rats Cardiovasc Res, January 14, 2000; 45(2): 370 - 378. [Abstract] [Full Text] [PDF]
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W. Guo, H. Xu, B. London, and J. M Nerbonne Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes J. Physiol., December 15, 1999; 521(3): 587 - 599. [Abstract] [Full Text] [PDF]
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A. D. Wickenden, P. Lee, R. Sah, Q. Huang, G. I. Fishman, and P. H. Backx Targeted Expression of a Dominant-Negative Kv4.2 K+ Channel Subunit in the Mouse Heart Circ. Res., November 26, 1999; 85(11): 1067 - 1076. [Abstract] [Full Text] [PDF]
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B. Huang, S. Wang, D. Qin, M. Boutjdir, and N. El-Sherif Diminished Basal Phosphorylation Level of Phospholamban in the Postinfarction Remodeled Rat Ventricle : Role of {beta}-Adrenergic Pathway, Gi Protein, Phosphodiesterase, and Phosphatases Circ. Res., October 29, 1999; 85(9): 848 - 855. [Abstract] [Full Text] [PDF]
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T. Kiyosue and M. Arita Altered expression of cardiac K+ channel genes during sub-acute and healing phases of myocardial infarction Cardiovasc Res, October 1, 1999; 44(1): 13 - 16. [Full Text] [PDF]
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J.-A. Yao, M. Jiang, J.-S. Fan, Y.-Y. Zhou, and G.-N. Tseng Heterogeneous changes in K currents in rat ventricles three days after myocardial infarction Cardiovasc Res, October 1, 1999; 44(1): 132 - 145. [Abstract] [Full Text] [PDF]
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X.-J. Du, H. S. Cox, A. M. Dart, and M. D. Esler Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure Cardiovasc Res, September 1, 1999; 43(4): 919 - 929. [Abstract] [Full Text] [PDF]
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E. Bou-Abboud and J. M Nerbonne Molecular correlates of the calcium-independent, depolarization-activated K+ currents in rat atrial myocytes J. Physiol., June 1, 1999; 517(2): 407 - 420. [Abstract] [Full Text] [PDF]
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R Kaprielian, A D Wickenden, Z Kassiri, T G Parker, P P Liu, and P H Backx Relationship between K+ channel down-regulation and [Ca2+ ]i in rat ventricular myocytes following myocardial infarction J. Physiol., May 15, 1999; 517(1): 229 - 245. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli and E. Marban Electrophysiological remodeling in hypertrophy and heart failure Cardiovasc Res, May 1, 1999; 42(2): 270 - 283. [Full Text] [PDF]
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J. M.B Pinto and P. A Boyden Electrical remodeling in ischemia and infarction Cardiovasc Res, May 1, 1999; 42(2): 284 - 297. [Abstract] [Full Text] [PDF]
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S. M Bryant, S.J. Shipsey, and G. Hart Normal regional distribution of membrane current density in rat left ventricle is altered in catecholamine-induced hypertrophy Cardiovasc Res, May 1, 1999; 42(2): 391 - 401. [Abstract] [Full Text] [PDF]
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F. Aimond, J. L Alvarez, J.-M. Rauzier, P. Lorente, and G. Vassort Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction Cardiovasc Res, May 1, 1999; 42(2): 402 - 415. [Abstract] [Full Text] [PDF]
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P. C Viswanathan and Y. Rudy Pause induced early afterdepolarizations in the long QT syndrome: a simulation study Cardiovasc Res, May 1, 1999; 42(2): 530 - 542. [Abstract] [Full Text] [PDF]
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K. M. Hershman and E. S. Levitan Cell-cell contact between adult rat cardiac myocytes regulates Kv1.5 and Kv4.2 K+ channel mRNA expression Am J Physiol Cell Physiol, December 1, 1998; 275(6): C1473 - C1480. [Abstract] [Full Text] [PDF]
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Z. Xu and G. J. Rozanski K+ current inhibition by amphiphilic fatty acid metabolites in rat ventricular myocytes Am J Physiol Cell Physiol, December 1, 1998; 275(6): C1660 - C1667. [Abstract] [Full Text] [PDF]
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W. Kong, S. Po, T. Yamagishi, M. D. Ashen, G. Stetten, and G. F. Tomaselli Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H1963 - H1970. [Abstract] [Full Text] [PDF]
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S. J. Rials, X. Xu, Y. Wu, R. A. Marinchak, and P. R. Kowey Regression of LV hypertrophy with captopril normalizes membrane currents in rabbits Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1216 - H1224. [Abstract] [Full Text] [PDF]
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S. Richard, F. Leclercq, S. Lemaire, C. Piot, and J. Nargeot Ca2+ currents in compensated hypertrophy and heart failure Cardiovasc Res, February 1, 1998; 37(2): 300 - 311. [Abstract] [Full Text] [PDF]
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A. D Wickenden, R. Kaprielian, Z. Kassiri, J. N Tsoporis, R. Tsushima, G. I Fishman, and P. H Backx The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure Cardiovasc Res, February 1, 1998; 37(2): 312 - 323. [Abstract] [Full Text] [PDF]
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M. Nabauer and S. Kaab Potassium channel down-regulation in heart failure Cardiovasc Res, February 1, 1998; 37(2): 324 - 334. [Abstract] [Full Text] [PDF]
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G. J. Rozanski, Z. Xu, K. Zhang, and K. P. Patel Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 1998; 274(1): H259 - H265. [Abstract] [Full Text] [PDF]
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S. E. Litwin and J. H. B. Bridge Enhanced Na+-Ca2+ Exchange in the Infarcted Heart : Implications for Excitation-Contraction Coupling Circ. Res., December 19, 1997; 81(6): 1083 - 1093. [Abstract] [Full Text]
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K. Takimoto, D. Li, K. M. Hershman, P. Li, E. K. Jackson, and E. S. Levitan Decreased Expression of Kv4.2 and Novel Kv4.3 K+ Channel Subunit mRNAs in Ventricles of Renovascular Hypertensive Rats Circ. Res., October 19, 1997; 81(4): 533 - 539. [Abstract] [Full Text]
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S. J. Rials, Y. Wu, X. Xu, R. A. Filart, R. A. Marinchak, and P. R. Kowey Regression of Left Ventricular Hypertrophy With Captopril Restores Normal Ventricular Action Potential Duration, Dispersion of Refractoriness, and Vulnerability to Inducible Ventricular Fibrillation Circulation, August 19, 1997; 96(4): 1330 - 1336. [Abstract] [Full Text]
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M. Gidh-Jain, B. Huang, P. Jain, and N. El-Sherif Differential Expression of Voltage-Gated K+ Channel Genes in Left Ventricular Remodeled Myocardium After Experimental Myocardial Infarction Circ. Res., October 1, 1996; 79(4): 669 - 675. [Abstract] [Full Text]
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G. Bru-Mercier, E. Deroubaix, D. Rousseau, A. Coulombe, and J.-F. Renaud Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1237 - H1247. [Abstract] [Full Text] [PDF]
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G. J. Rozanski and Z. Xu Glutathione and K+ channel remodeling in postinfarction rat heart Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355. [Abstract] [Full Text] [PDF]
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