(Circulation. 1999;99:1898-1905.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Transient Outward Current, Ito1, Is Altered in Cardiac Memory
From the Departments of Physiology and Biophysics and Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY (H.Y., D.M., J.E.D., J.G., R.W., I.S.C.), and the Departments of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY (P.D., A.S., E.P.A., E.A.S., M.H., M.R.R.).
Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 W 168 St, PH 7West-321, New York, NY 10032. E-mail emf3{at}columbia.edu
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Background—Cardiac memory refers to an altered T-wave morphology induced by ventricular pacing or arrhythmias that persist for variable intervals after resumption of sinus rhythm.
Methods and Results—We induced long-term cardiac memory (LTM) in conscious dogs by pacing the ventricles at 120 bpm for 3 weeks. ECGs were recorded daily for 1 hour, during which time pacing was discontinued. At terminal study, the heart was removed and the electrophysiology of left ventricular epicardial myocytes was investigated. Control (C) and LTM ECG did not differ, except for T-wave amplitude, which decreased from 0.12±0.18 to -0.34±0.21 mV (±SEM, P<0.05), and T-wave vector, which shifted from -37±12° to -143±4° (P<0.05). Epicardial action potentials revealed loss of the notch and lengthening of duration at 20 days (both P<0.05). Calcium-insensitive transient outward current (Ito) was investigated by whole-cell patch clamp. No difference in capacitance was seen in C and LTM myocytes. Ito activated on membrane depolarization to -25±1 mV in C and -7±1 mV (P<0.05) in LTM myocytes, indicating a positive voltage shift of activation. Ito density was reduced in LTM myocytes, and a decreased mRNA level for Kv4.3 was observed. Recovery of Ito from inactivation was significantly prolonged: it was 531±80 ms (n=10) in LTM and 27±6 ms (n=9) in C (P<0.05) at -65 mV.
Conclusions—Ito changes are associated with and can provide at least a partial explanation for action-potential and T-wave changes occurring with LTM.
Key Words: electrocardiography • ventricles • pacing • myocytes
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Introduction |
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Cardiac memory" refers to a change in the T wave induced by and persisting for minutes to months after cessation of a period of altered ventricular activation.1 2 3 4 Canine studies have shown that short-term T-wave memory is prevented by intravenous 4-aminopyridine (4-AP), suggesting that the memory might depend on pacing-induced changes in the transient outward current, Ito.5 Studies of an isolated tissue model of cardiac memory supported this view, demonstrating that an altered epicardial-endocardial voltage gradient contributes to memory and that 4-AP abolishes it.6
The expression of 4-AP–sensitive Ito is heterogeneous through the canine ventricular wall, with current density higher in epicardial than endocardial myocytes.7 8 We hypothesized that the 4-AP–sensitive Ito might be altered during the evolution of cardiac memory and used a chronic canine model to study it. The persistence of memory long after cessation of pacing permitted us to perform our experiments without fear that decay of the memory phenomenon would occur. We focussed on the 4-AP–sensitive Ito1 in normal canine epicardial myocytes and those from animals with "long-term memory." For convenience, we use the term Ito instead of Ito1 throughout.
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Mongrel dogs weighing 20 to 26 kg premedicated with propafol 5 mg/kg IV were anesthetized with 3% isoflurane and subjected to a left thoracotomy under sterile conditions. A Medtronic 5069 screw-in pacemaker (contact diameter, 0.020 inches) was inserted transepicardially into the anteroapical left ventricle (LV) and attached to a Medtronic 8340 programmable pacemaker embedded in a subcutaneous pocket. Animals recovered for 2 to 3 weeks, during which time ECGs were recorded every 2 to 3 days with the animal resting comfortably in a sling. Within 3 weeks, all postsurgical ECG changes had disappeared, and stable, reproducible recording of standard limb leads was demonstrated over a period of 1 week. LV pacing was then initiated at 120 bpm and maintained for 23 hours of each day. Holter monitoring was performed for 2 to 3 days of the pacing period. In no animal was there <75% capture. While pacing was discontinued, the ECG was recorded continuously to permit determination of ST-T waves in sinus rhythm. After 20 to 22 days of pacing, we performed terminal studies, which began within 3 hours of discontinuation of ventricular drive.
Isolated Tissue and Single Myocyte Studies
Animals were anesthetized with pentobarbital sodium 30
mg/kg IV, and the heart was rapidly excised and placed in iced
Tyrode's solution, containing (in mmol/L) NaCl 131, KCl 4,
CaCl2 2.7, NaHCO3 18,
MgCl2 0.5,
NaH2PO4 1.8, and dextrose
5.5, gassed with 95% O2/5%
CO2. For microelectrode studies, strips of LV
free wall epicardium obtained 1 cm below the mitral ring and measuring
1 cmx1 cmx0.5 to 1.5 mm were filleted from control dogs and
those studied at 20 to 22 days of pacing and having cardiac memory.
Tissues were placed in a chamber perfused with Tyrode's solution at
37±0.1°C and stimulated by standard techniques6 via
bipolar silver electrodes insulated with Teflon. The tissue bath was
connected to ground with a 3 mol/L KCl-Ag-AgCl bridge. Glass
microelectrodes filled with 3 mol/L KCl were used to impale the
tissues. Standard means for calibration and recording were
used.6
Single cells were isolated from control hearts and those with cardiac
memory. The free-wall epicardial layer (1 to 3 mm) near the LV
base, 
2 cm from the pacemaker, was excised as above and subjected to
trituration as reported previously.9 Details of the
transport solution and disaggregation have been
described.10 Disaggregated cells were kept in KB
medium11 at room temperature for 1 hour before
electrophysiological experiments.
To avoid Ca2+ current contamination,
Ito was recorded by the whole-cell
patch-clamp technique in modified Tyrode's solution containing
(in mmol/L) NaCl 137.7, NaOH 2.3, MgCl2 1,
glucose 10, HEPES 5, KCl 5.4, CaCl2 1.8,
MnCl2 2, and CdCl2 0.2, pH
7.4). Pipettes were filled with solution containing (in mmol/L)
NaCl 6, potassium aspartate 130, MgCl2 2,
CaCl2 5, EGTA 11, HEPES 10,
Na2-ATP 2, and Na-GTP 0.1; pH was adjusted to 7.2
by KOH. Pipette resistance was 2 to 4 M
. The pH of the Tyrode's
solution containing 4-AP was titrated to 7.4 with HCl. Temperature was
maintained at 30°C to 32°C. An Axopatch 1B amplifier (Axon
Instruments, Inc) was used.
We used Tyrode's solution containing NaCl 137.7 mmol/L to facilitate comparison with action potential studies. Because INa was not blocked, we performed control experiments to determine whether the overlap of INa distorted our estimate of Ito threshold. No change in threshold occurred (ie, in 5 control myocytes, Ito threshold was -24±4 mV in both Na 140 and 10 mmol/L. At the same [Na+]o, the threshold in all 3 myocytes from memory animals was -10 mV.)
Data were collected by FM recording (Hewlett-Packard Co; 3964a, speed 7/8 in s-1, 600-Hz bandwidth) and pClamp software (Axon Instruments, Inc).
Preparation of RNA and RNase Protection Assay
Tissue samples were quick-frozen in liquid
N2 and homogenized in guanidinium
thiocyanate. Total RNA was prepared by pelleting the
homogenate over a CsCl step gradient. All RNA samples were
quantified spectrophotometrically.
Canine Kv4.3 and cyclophilin probes were prepared as
previously.12 Significant nonhybridizing sequence
(50 bp) was included in the probes to facilitate distinction between
the probe and the specific protected band. There was no evidence for
unwanted cross-reaction between probes and nonspecific transcripts.
RNase protection assays were performed as previously.13 For each sample point, 5 or 10 µg total RNA was used. A cyclophilin probe was included as an internal control to confirm that the sample was not lost or degraded during the assay. Yeast RNA 35 µg was a negative control to test for the presence of probe self-protection bands. RNA expression was quantified directly from dried RNase protection gels by use of a PhosphorImager (Molecular Dynamics). There was no significant change in cyclophilin expression between the control and memory samples (average cyclophilin expression in long-term memory samples was 96% of control, P>0.05).
Statistical Analysis
Data are presented as mean±SEM. Comparisons of control
and cardiac memory ECG from the same animals were done by paired
t test. Comparisons of control and cardiac memory action
potentials and ion currents were by t test for grouped data.
A value of P<0.05 was considered significant.
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ECGs and Epicardial Action Potentials
Cardiac memory was seen as an altered T-wave vector angle and amplitude (Table 1
). No other
significant ECG changes occurred. Persistence of memory for 3 days
after cessation of pacing is shown in Figure 1. Action potential
characteristics for tissue slabs from control and memory epicardial
muscle are presented in Table 2.
The maximum diastolic potential and overshoot do not differ
significantly in control and memory. However, the latter shows a
smaller phase 1 notch and a longer action potential duration (APD) at
day 20 (see example in Figure 2).
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Capacitance of Myocytes
To test whether the pacing protocols might alter cell size, we
determined the capacitance of disaggregated myocytes from control and
memory epicardium. The capacitance of control myocytes was 104±8 pF
(n=26) and that of memory myocytes, 107±9 pF (n=19)
(P>0.05).
Properties of Ito in Normal and Memory
Epicardial Myocytes
Activation Threshold
The action potential results suggested that alterations in
Ito could be important to the genesis of
long-term memory. Figure 3 demonstrates
that Ito activates at a more
positive potential in a myocyte from a dog with memory than in a
control. The voltage thresholds for Ito in
Figure 3 are -30 mV for the control and 0 mV for memory. The
changes in Ito threshold are summarized in
Table 3 and include an 18-mV positive
shift in threshold. We could not construct complete activation curves
because even at extremely positive voltages, saturation was not
reached.
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Inactivation
Voltage Dependence.
We next examined steady-state dependence of inactivation on voltage. We
held the cell at a given potential for 400 ms and then stepped to the
same test potential of 0 mV (see protocol, Figure 4, inset). Results and a Boltzmann
2-state model fit to the data are provided in Figure 4, and midpoint values and slope factors are in Table 3
. There is an
8-mV positive shift of the inactivation-versus-voltage curve in
myocytes from hearts with memory, and no change in slope factor. Six
additional experiments were performed with memory myocytes, with
2-second prepulses. No change in midpoint for inactivation voltage
occurred (-35±3 mV, n=6).
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Kinetic Properties of Inactivation.
Figure 5 shows results from a protocol
demonstrating the inactivation kinetics of
Ito from normal and memory myocytes. Each
cell was held at -65 mV and depolarized to the values indicated on the
figure. There were no significant differences in inactivation time
constants, although a positive shift in their voltage dependence was
observed (for average values for time constants of inactivation at +20
mV, see Table 3).
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Despite the lack of significant difference in inactivation
kinetics in memory, recovery from inactivation was dramatically altered
(see Figure 6). From a holding potential
of -65 mV, we depolarized to +5 mV in control and +20 mV in memory (to
maintain approximately equal activation), returned to the holding
potential for a variable time, and again depolarized to the test
potential. The ratio of Ito amplitude in
the second pulse compared with the amplitude in response to the first
was plotted against time along with the best fit to a
monoexponential function in Figure 6C. In Figure 6, the time constant of recovery was 33 ms in control and 531 ms
in memory. As summarized in Table 3, the recovery time constant
is more than an order of magnitude slower in cells from animals with
memory.
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Rec) was
obtained by fitting data with 1 exponential function
{ y=ax[1-exp(-x/t)+b]}. B,
Ito recovery from inactivation in a memory
myocyte. C, Fraction of Ito with respect to
first pulse is plotted against pulse interval. Data were fit by a
single exponential. D, Voltage dependence of time constant for
Ito recovery from inactivation in control
(right ordinate) and memory (left ordinate). Holding current at -65 mV
was +120 pA in A and +212 pA in B.
Studies of hearts from several species have shown that
Ito recovery from inactivation proceeds
more rapidly with
hyperpolarization.14 We
investigated whether a similar voltage dependence exists for control
and memory myocytes (Figure 6D). Although
Ito recovery from inactivation is an order
of magnitude slower in memory than control, there is still the same
speeding of recovery with hyperpolarization.
Ito Conductance
The changes in activation threshold and inactivation recovery
kinetics provide a potential explanation for the reduction in the
action potential notch recorded during cardiac memory. We also
asked whether Ito conductance was reduced.
Ideally, to estimate this conductance, one would saturate activation,
measure tail currents at the same voltage, and normalize the tail
currents to the capacitance of the cells. This was not possible because
we could not fully activate the current at depolarized
potentials. We therefore quantified Ito
amplitude at each test potential and then divided current magnitude by
the driving force to estimate the conductance at each potential. We
corrected the measured conductance by the difference in inactivation
between control and memory myocytes that we measured in Figure 4
at the holding potential of -65 mV. Finally, we divided the measured
values by the capacitance to obtain the normalized conductance against
membrane potential (Figure 7). Because
activation threshold differs in the 2 preparations, we could not
compare conductance at the same voltage. Instead, we compared
conductance by fitting the data by linear regression. The slope of the
line gives the increase in conductance normalized to capacitance per
change in membrane potential. This slope was 2.3 pS/(pF · mV) in
control and 1.5 pS/(pF · mV) in memory. Thus, the slope of
conductance versus potential for Ito in
memory is 65% of control.
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V
(
Ito Block by 4-AP
Figure 8 shows the effects of 4-AP
on Ito in control (A, B, and C) and memory
(D, E, and F). The holding potential was -65 mV for both cells,
although the test potentials differed to allow for the differences in
activation threshold. In both cells, 1 mmol/L 4-AP blocked 50%
of the Ito at potentials 20 mV positive
to voltage threshold. We found little difference in percentage block by
1 mmol/L 4-AP at +15 mV in control and memory (see Table 3).
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Changes in Kv4.3 mRNA |
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TopAbstractIntroductionMethodsResultsChanges in Kv4.3 mRNADiscussionReferences |
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The Kv4.3 gene encodes a potassium channel that underlies the bulk of Ito in canine ventricular myocytes.12 In rat heart, regulation of Ito expression appears to be determined predominantly at the level of transcription.13 15 Therefore, we were interested in ascertaining whether changes in the level of expression of the Kv4.3 gene could contribute to the decline in Ito in memory. The value of Kv4.3 expression in memory was 65±7% (n=6, P<0.05) of control (Figure 9
), a change similar in magnitude to that
in Ito conductance with voltage. This
result suggests that expression of the Kv4.3 gene is
downregulated in ventricular muscle during memory and that
this downregulation may contribute to changes in the
Ito magnitude observed in the isolated cell
recordings.
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Discussion |
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TopAbstractIntroductionMethodsResultsChanges in Kv4.3 mRNADiscussionReferences |
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Explanations accounting for cardiac memory have included an altered repolarization pattern resulting in a changed electrical gradient across the myocardium,1 16 ischemia,2 17 18 changes in mechanoelectrical feedback,19 protein phosphorylation, and gene expression.3 The hypothesis that ion channel alterations induce changes in the voltage-time course of repolarization and myocardial voltage gradients contributing to the evolution of memory is based on the following:
First, the T wave is generated by the voltage gradient during ventricular repolarization. Action potential configurations vary transmyocardially, one significant difference being the phase 1 "notch" seen in epicardium and midmyocardium but not endocardium.14 20 Ito appears to be largely responsible for this notch14 20 ; when Ito is blocked, the plateau is elevated and the time course of repolarization changes.
Second, epicardial action potentials recorded during memory in isolated tissue models6 and the present experiment lack a notch; they resemble those from endocardium. This observation led to the hypothesis that cardiac memory is largely due to a change in the voltage gradient that normally exists between epicardium and endocardium.6 It was also hypothesized that if this voltage gradient were minimized by pharmacological interventions, memory might be prevented. This hypothesis gained support when 4-AP (an Ito blocker) prevented development of memory in the intact canine heart5 and an isolated tissue model.6
The above-described work was performed in models of short-term cardiac memory, lasting minutes. Such models are of limited value in evaluating ion channel contributions to memory, because the electrophysiological changes do not persist long enough to ensure a stable substrate for myocardial disaggregation and whole-cell study. The use of a long-term memory model that we have demonstrated to be unassociated with cardiac failure21 or hypertrophy (cell capacitance, reflecting cell size, is unchanged) provides long-term T-wave changes that render the study of disaggregated myocytes practicable. Moreover, we have previously shown that the statistically insignificant variations in sinus rate occurring before and after pacing cannot be the cause of these T-wave changes.21
The action potentials we recorded are entirely consistent
with results from earlier isolated tissue studies in that the notch of
the epicardial action potential in T-wave memory is smaller than in
controls.6 In short-term pacing, however, the epicardial
APD did not manifest the prolongation seen with long-term pacing and
cardiac memory in our present or previous study. The fact that the
APD is not significantly prolonged in a memory model of short
duration6 suggests that in the long-term setting,
repolarizing currents other than Ito may be
involved (possibly ICa,L,
IK, Na/K pump current,
IK1). This possibility is also suggested by
the study of Shvilkin et al.21 Here, epicardial,
endocardial, and midmyocardial action potentials were studied with
microelectrodes in animals paced for 20 days. Significant
prolongation of epicardial and endocardial action potentials as well as
reduction of the difference in duration between the 2 types of action
potentials occurred, such that epicardial action potentials prolonged
to a greater extent than endocardial. In contrast, APDs of
midmyocardial cells were unchanged. Hence, with memory, there was a
reorientation of the interrelationships of APDs of each myocardial
tissue. A prolongation of endocardial action potentials, which have a
small notch and little Ito, and no change
in duration of M cell action potentials, which have significant
Ito, provides a further argument that
currents other than Ito are involved in the
memory process.
Kinetics of Ito
Despite the need to expand our studies to include other ion
channels, our observations concerning Ito
provide an understanding of the fundamental alterations in one ion
channel that contribute to the memory phenomenon. Specifically, the
shift in long-term memory Ito activation
toward more positive potentials by almost +20 mV (Table 3) is
consistent with the absence of a notch in
ventricular epicardial action potentials from dogs with
cardiac memory. Ito activation at
relatively positive potentials will contribute reduced outward current
to phase 1 repolarization. In the physiological
voltage range, the memory-induced positive shift of
Ito activation along the voltage axis in
epicardium mimics the activation of Ito in
endocardium and therefore would decrease the voltage gradient from
epicardium to endocardium.
A significantly longer time course of Ito
recovery from inactivation was found in memory myocytes. This
phenomenon is an additional contributor to the loss of the action
potential notch recorded in epicardial myocytes from animals with
cardiac memory; eg, at a ventricular pacing rate 20%
greater than sinus rate, the basic cycle length was 500 ms. Here, a
531-ms time constant of recovery from inactivation will not allow
Ito to recover to a significant degree
(even if it is activated at the end of phase 0).
A major question relates to the identity of the signaling mechanism responsible for the change in Ito. Our work in progress22 23 and the published literature3 19 24 suggest that altered stress-strain relationships induced by ventricular pacing activate the endogenous cardiac renin–angiotensin II system; this protein kinase C–linked signaling cascade both alters channel phosphorylation (perhaps explaining the changes in Ito in short-term memory) and induces the immediate early gene program, which alters new protein (channel) synthesis. Although we hypothesize that new gene expression and protein synthesis are involved in long-term memory, we do not know which genes are expressed and which new proteins are synthesized. Even though the sensitivity to 4-AP is not significantly changed in long-term memory myocytes, this result does not completely rule out the possibility of an altered isoform, which remains to be investigated.
Clinical Importance
The clinical importance of cardiac memory initially was said to
lie in its ECG patterns, mimicking those of
ischemia.1 4 17 However, the potential importance
of the memory phenomenon appears to be greater, as follows: first, any
event that alters repolarization might alter refractoriness as well,
and changes in the effective refractory period can be permissive of or
suppress arrhythmias. Second, in the setting of
tachycardia-induced CHF when heart rate is also rapid,
abnormalities in Ito and in the T wave
occur.25 The possibility exists that the rate- and
activation-induced changes in Ito induced
by the memory phenomenon are important contributors to the T-wave
anomalies in such pathological conditions. Third, recent studies by
Allessie et al26 27 have demonstrated pacing-induced
atrial fibrillation in the goat. This, too, is associated with
accelerated repolarization and loss of the action potential notch.
Here, an atrial analog to the memory phenomenon might be considered.
The statement by Wijffels et al that "fibrillation begets
fibrillation"27 leads us to suggest that any change in
rhythm that alters activation pathway and rate might alter the action
potential and render persistence/recurrence of the
arrhythmia more likely. Similarly, maintenance of sinus
rhythm and normal activation and/or interventions that maximize
Ito might turn out to be antiarrhythmic.
Finally, these initial results demonstrate that this stable canine
model for cardiac memory can provide a "window" through which the
alterations of ion channel characteristics that underlie altered
repolarization and their relationship to signal transduction pathways
can be investigated intensively.
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Acknowledgments |
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These studies were supported by US Public Health Service–NHLBI grants HL-28958, HL-53956, and HL-20558 and a grant from the Wild Wings Foundation. We express our great appreciation to Joan Zuckerman for her excellent cell dissociation; to Judy Samarel, Eileen Franey, Rachel Rosen, and Ester Chin for their patience in data entry and in preparing the manuscript; and to Dr Natalia Egorova for her assistance with the intact animal and microelectrode studies.
Received August 4, 1998; revision received November 23, 1998; accepted November 30, 1998.
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References |
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 L. Xiao, P. Coutu, L. R. Villeneuve, A. Tadevosyan, A. Maguy, S. Le Bouter, B. G. Allen, and S. Nattel Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes Circ. Res., September 26, 2008; 103(7): 733 - 742. [Abstract] [Full Text] [PDF]
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D. Jeyaraj, L. D. Wilson, J. Zhong, C. Flask, J. E. Saffitz, I. Deschenes, X. Yu, and D. S. Rosenbaum Mechanoelectrical Feedback as Novel Mechanism of Cardiac Electrical Remodeling Circulation, June 26, 2007; 115(25): 3145 - 3155. [Abstract] [Full Text] [PDF]
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 R. Coronel, T. Opthof, A. N. Plotnikov, F. J.G. Wilms-Schopman, I. N. Shlapakova, P. Danilo Jr., E. A. Sosunov, E. P. Anyukhovsky, M. J. Janse, and M. R. Rosen Long-term cardiac memory in canine heart is associated with the evolution of a transmural repolarization gradient Cardiovasc Res, June 1, 2007; 74(3): 416 - 425. [Abstract] [Full Text] [PDF]
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 Spontaneous T wave inversion after ventricular pacing: What is the probable mechanism? Postgrad. Med. J., August 1, 2006; 82(970): e21 - e21. [Full Text] [PDF]
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M. N. Obreztchikova, K. W. Patberg, A. N. Plotnikov, N. Ozgen, I. N. Shlapakova, A. V. Rybin, E. A. Sosunov, P. Danilo Jr., E. P. Anyukhovsky, R. B. Robinson, et al. IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory Cardiovasc Res, July 1, 2006; 71(1): 88 - 96. [Abstract] [Full Text] [PDF]
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 M. R. Rosen and I. S. Cohen Cardiac memory ... new insights into molecular mechanisms J. Physiol., January 15, 2006; 570(2): 209 - 218. [Abstract] [Full Text] [PDF]
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 P. Dilaveris, A. Pantazis, G. Giannopoulos, A. Synetos, J. Gialafos, and C. Stefanadis Upgrade to biventricular pacing in patients with pacing-induced heart failure: can resynchronization do the trick? Europace, January 1, 2006; 8(5): 352 - 357. [Abstract] [Full Text] [PDF]
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K. W. Patberg, M. N. Obreztchikova, S. F. Giardina, A. J. Symes, A. N. Plotnikov, J. Qu, P. Chandra, D. McKinnon, S. R. Liou, A. V. Rybin, et al. The cAMP response element binding protein modulates expression of the transient outward current: Implications for cardiac memory Cardiovasc Res, November 1, 2005; 68(2): 259 - 267. [Abstract] [Full Text] [PDF]
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M. J. Janse, E. A. Sosunov, R. Coronel, T. Opthof, E. P. Anyukhovsky, J. M.T. de Bakker, A. N. Plotnikov, I. N. Shlapakova, P. Danilo Jr, J. G.P. Tijssen, et al. Repolarization Gradients in the Canine Left Ventricle Before and After Induction of Short-Term Cardiac Memory Circulation, September 20, 2005; 112(12): 1711 - 1718. [Abstract] [Full Text] [PDF]
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A. Shvilkin, K. K.L. Ho, M. R. Rosen, and M. E. Josephson T-Vector Direction Differentiates Postpacing From Ischemic T-Wave Inversion in Precordial Leads Circulation, March 1, 2005; 111(8): 969 - 974. [Abstract] [Full Text] [PDF]
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 M. Nahlawi, M. Waligora, S. M. Spies, R. O. Bonow, A. H. Kadish, and J. J. Goldberger Left ventricular function during and after right ventricular pacing J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1883 - 1888. [Abstract] [Full Text] [PDF]
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T.-J. Cha, J. R. Ehrlich, L. Zhang, and S. Nattel Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure Circulation, September 21, 2004; 110(12): 1520 - 1526. [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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A. N. Plotnikov, E. A. Sosunov, K. W. Patberg, E. P. Anyukhovsky, R. Z. Gainullin, I. N. Shlapakova, G. Krishnamurthy, P. Danilo Jr, and M. R. Rosen Cardiac Memory Evolves With Age in Association With Development of the Transient Outward Current Circulation, August 3, 2004; 110(5): 489 - 495. [Abstract] [Full Text] [PDF]
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I. Libbus, X. Wan, and D. S. Rosenbaum Electrotonic load triggers remodeling of repolarizing current Ito in ventricle Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1901 - H1909. [Abstract] [Full Text] [PDF]
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M. Zoghi and S. Nalbantgil Electrical stunning and hibernation: suggestion of new terms for short- and long-term cardiac memory Europace, January 1, 2004; 6(5): 418 - 424. [Abstract] [Full Text] [PDF]
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P. Chandra, T. S Rosen, B. Herweg, P. Danilo Jr., and M. R Rosen Left atrial pacing induces memory and is associated with atrial tachyarrhythmias Cardiovasc Res, November 1, 2003; 60(2): 307 - 314. [Abstract] [Full Text] [PDF]
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K. W. Patberg and M. R. Rosen On the Role of the cAMP Response Element Binding Protein in Long-Term Cardiac Memory Circ. Res., October 31, 2003; 93 (9): e87 - e87. [Full Text] [PDF]
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M. R. Rosen, O. Binah, and S. Marom Cardiac Memory and Cortical Memory: Do Learning Patterns in Neural Networks Impact on Cardiac Arrhythmias? Circulation, October 14, 2003; 108(15): 1784 - 1789. [Abstract] [Full Text] [PDF]
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K. W. Patberg, A. N. Plotnikov, A. Quamina, R. Z. Gainullin, A. Rybin, P. Danilo Jr, L. S. Sun, and M. R. Rosen Cardiac Memory Is Associated With Decreased Levels of the Transcriptional Factor CREB Modulated by Angiotensin II and Calcium Circ. Res., September 5, 2003; 93(5): 472 - 478. [Abstract] [Full Text] [PDF]
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A. N. Plotnikov, H. Yu, J. C. Geller, R. Z. Gainullin, P. Chandra, K. W. Patberg, S. Friezema, P. Danilo Jr, I. S. Cohen, S. J. Feinmark, et al. Role of L-Type Calcium Channels in Pacing-Induced Short-Term and Long-Term Cardiac Memory in Canine Heart Circulation, June 10, 2003; 107(22): 2844 - 2849. [Abstract] [Full Text] [PDF]
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M. R. Rosen The Electrocardiogram 100 Years Later: Electrical Insights Into Molecular Messages Circulation, October 22, 2002; 106(17): 2173 - 2179. [Full Text] [PDF]
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Members of the Sicilian Gambit New Approaches to Antiarrhythmic Therapy, Part I: Emerging Therapeutic Applications of the Cell Biology of Cardiac Arrhythmias Circulation, December 4, 2001; 104(23): 2865 - 2873. [Abstract] [Full Text] [PDF]
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 Members of the Sicilian Gambit New approaches to antiarrhythmic therapy; emerging therapeutic applications of the cell biology of cardiac arrhythmias Eur. Heart J., December 1, 2001; 22(23): 2148 - 2163. [Abstract] [PDF]
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Members of the Sicilian Gambit New approaches to antiarrhythmic therapy: emerging therapeutic applications of the cell biology of cardiac arrhythmias Cardiovasc Res, December 1, 2001; 52(3): 345 - 360. [Abstract] [Full Text] [PDF]
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S. M Ashamalla, D. Navarro, and C. A Ward Gradient of sodium current across the left ventricular wall of adult rat hearts J. Physiol., October 15, 2001; 536(2): 439 - 443. [Abstract] [Full Text] [PDF]
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A. N Plotnikov, A. Shvilkin, W. Xiong, J. R de Groot, L. Rosenshtraukh, S. Feinmark, R. Gainullin, P. Danilo Jr., and M. R Rosen Interactions between antiarrhythmic drugs and cardiac memory Cardiovasc Res, May 1, 2001; 50(2): 335 - 344. [Abstract] [Full Text] [PDF]
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B. Herweg, F. Chang, P. Chandra, P. Danilo Jr, and M. R. Rosen Cardiac Memory in Canine Atrium : Identification and Implications Circulation, January 23, 2001; 103(3): 455 - 461. [Abstract] [Full Text] [PDF]
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H. Wang, H. Shi, L. Zhang, M. Pourrier, B. Yang, S. Nattel, and Z. Wang Nicotine Is a Potent Blocker of the Cardiac A-Type K+ Channels : Effects on Cloned Kv4.3 Channels and Native Transient Outward Current Circulation, September 5, 2000; 102(10): 1165 - 1171. [Abstract] [Full Text] [PDF]
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A.J. Camm, M.J. Janse, D.M. Roden, M.R. Rosen, J. Cinca, and S.M. Cobbe Congenital and acquired long QT syndrome Eur. Heart J., August 1, 2000; 21(15): 1232 - 1237. [PDF]
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S. Nattel, C. Matthews, E. De Blasio, W. Han, D. Li, and L. Yue Dose-Dependence of 4-Aminopyridine Plasma Concentrations and Electrophysiological Effects in Dogs : Potential Relevance to Ionic Mechanisms In Vivo Circulation, March 14, 2000; 101(10): 1179 - 1184. [Abstract] [Full Text] [PDF]
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