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(Circulation. 1998;98:1383-1393.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure

A Decrease in Kv4.3 mRNA Correlates With a Reduction in Current Density

S. Kääb, MD, PhD; J. Dixon, PhD; J. Duc, MD; D. Ashen, PhD; M. Näbauer, MD; D. J. Beuckelmann, MD; G. Steinbeck, MD; D. McKinnon, PhD; ; G. F. Tomaselli, MD

From the Department of Medicine (S.K., J. Duc, D.A., G.F.T.), Division of Molecular and Cellular Cardiology, Johns Hopkins University, Baltimore, Maryland; Department of Neurobiology and Behavior (J. Dixon, D.M.), State University of New York at Stony Brook; Department of Medicine I (S.K., M.N., G.S.), Ludwig Maximilians University of Munich (Germany); and Department of Medicine III (D.J.B.), University of Cologne (Germany).

Correspondence to Gordon Tomaselli, MD, 720 N Rutland Ave, Ross 844, Johns Hopkins University, Baltimore, MD 21205. E-mail gtomasel{at}welchlink.welch.jhu.edu

	Abstract

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Background—Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K⁺ currents—prominently, the Ca²⁺-independent transient outward current (I_to). The mechanism for the reduction of I_to in heart failure is unknown. The K⁺ channel -subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I_to in humans.

Methods and Results—We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I_to in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak I_to density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kv1.4, Kir2.1, Kvß1.3, and the 1C subunit of the Ca²⁺ channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle.

Conclusions—These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac I_to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.

Key Words: currents • sodium • potassium • heart failure • repolarization

	Introduction

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Congestive heart failure is a major cause of death worldwide, with as many as 50% of affected patients dying suddenly.¹ Ventricular tachyarrhythmias are a common cause of sudden death in patients with heart failure² ; however, the underlying mechanism of these tachyarrhythmias is poorly understood.³ Action potential prolongation in the absence of other significant electrophysiological changes is a hallmark of failing ventricular myocardium.^{4 5 6 7 8} Prolongation of the action potential, particularly if it is heterogeneous, can predispose to exaggerated dispersion of repolarization and nonexcitable gap reentry.⁹ However, action potential prolongation itself is arrhythmogenic; longer action potentials can be associated with repolarization abnormalities such as afterdepolarizations, which can predispose to triggered arrhythmias.

Voltage-dependent K⁺ currents mediate repolarization of cardiac myocytes and hence are critical determinants of the action potential duration. Differential expression of a variety of K⁺ currents may be important in defining regional differences in the action potential profile in the heart.^{10 11 12} Recently, the cellular and molecular bases of action potential prolongation in failing human myocardium were described. Terminal human heart failure is associated with a functional downregulation of the Ca²⁺-independent transient outward K⁺ current (I_to) and inward rectifier K⁺ current (I_K1).^{7 13} The mechanism of the functional downregulation is unknown, but it may involve altered transcription, translation, membrane trafficking, subunit assembly, post-translational modification, degradation of channel proteins, or a combination. We sought to determine the mechanism of action potential prolongation in human heart failure by quantifying the level of K⁺ channel gene transcripts in normal and failing myocardium.

There are species-specific differences in voltage-dependent K⁺ channel expression. For example, significant levels of mRNA encoding the rapidly inactivating K⁺ channels Kv1.4, Kv4.2, and Kv4.3 have been observed in rat ventricle,¹⁴ whereas in canine and human ventricle, there is no detectable Kv4.2, but mRNA encoding Kv1.4, Kv1.5, Kv3.4, and Kv4.3 is present.¹⁵ Based on the biophysical properties and pharmacology of expressed Kv4.3 and its abundance in human ventricle, this gene has emerged as the leading candidate for encoding I_to in both dogs and humans.¹⁵ We measured I_to in cells isolated from normal and failing human myocardium and performed ribonuclease protection assays (RPAs) on samples from the same hearts excised from regions immediately adjacent to the sections used for cell isolation. The level of Kv4.3 mRNA in ventricular myocardium was compared with the I_to density in isolated myocytes. To determine whether Kv4.3 encodes all or part of I_to in the human ventricle, we took advantage of the known reduction in current density in myocytes isolated from failing human ventricles compared with cells isolated from nonfailing hearts. We measured a statistically significant reduction in the level of Kv4.3 mRNA in failing ventricle compared with nonfailing controls. The steady-state level of Kv4.3 mRNA correlated with the density of I_to measured in cells isolated from adjacent regions of the myocardium. These data provide further support for the hypothesis that hKv4.3 encodes at least part of the native I_to channel and that the reduction in I_to in heart failure is consistent with transcriptionally mediated regulation.

	Methods

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Preparation of cRNA Probes
The templates for preparing the human cRNA probes were generated by subcloning small fragments of the cDNAs encoding ion channel and control genes into pBluescript-SK, pBluescript II-SK (Stratagene), pGEM7, or pSP73 (Promega). The cDNA fragments were isolated by amplification of regions of the full-length cDNA clones using the polymerase chain reaction (PCR), creating appropriate restriction sites for subsequent subcloning. All constructs were confirmed by DNA sequencing. Probe sequences were selected so that no probe had long uninterrupted regions of identity with any mRNA other than the transcript to be tested. There was no evidence for unwanted cross-reaction between any probe and a nonspecific transcript. Protected fragments of the anticipated size confirm specific interaction of the cRNA probe and its target transcript. The hH1 template was designed to protect a fragment in the I-II linker of the Na⁺ channel, which exists only in the cardiac isoform; thus, this is a myocyte-specific cRNA probe.

The standard nomenclature for K⁺ channel genes is used throughout.¹⁶ For each control or target transcript, probes were generated by PCR amplification of a region of the cDNA as described in Table 1. This table gives the probe, the reference, the numbers of the nucleotide sequence that are protected, and the size of the protected fragment. Each PCR primer pair includes a KpnI site (forward) and a HindIII site (reverse) for cloning. The riboprobe for Kv4.3 is as previously described.¹⁵ A commercially available cDNA probe with a protected size of 103 base pairs (bp) was used for human cyclophilin (Ambion).

View this table: [in this window] [in a new window]   Table 1. RPA Probes

Tissue and RNA Preparation
Human ventricular myocardium was obtained from explanted failing hearts (failing; n=17) and donor hearts unsuitable for transplantation (normal; n=7). Details of the characteristics of the patients in the heart failure and control groups are given in Table 2. Segments of ventricular myocardium adjacent to the region from which myocytes were isolated for electrophysiological recording were used for RNA isolation. The tissue was excised from the left ventricular free wall between the left anterior descending coronary artery (LAD) and the left circumflex artery. The isolation procedure selects for cells from the midportion of the ventricular wall. The tissue samples used for RNA isolation were transventricular, including both the epicardium and endocardium, and shared a border with the section of the heart used for cell isolation. In the case of an anterior transmural myocardial infarction, the left circumflex artery was perfused for cell isolation and a segment of the lateral wall was used for RNA isolation.

View this table: [in this window] [in a new window]   Table 2. Patient Demographics and Medications at Transplantation of Failing Hearts

The tissue was quick-frozen in liquid nitrogen within 10 to 15 minutes after tissue harvesting and stored at -80°C until further processing. Total RNA was prepared either with TRIzol Reagent (GIBCO BRL) according to the manufacturer's instructions or with centrifugation through a CsCl cushion.²⁵ The integrity of all RNA samples was confirmed by analysis on a denaturing agarose gel and quantified by absorbance measurements at 260 nm.

Ribonuclease Protection Assay
RPAs were performed as described previously.^{14 15 26} All probes contained regions of plasmid sequence at 1 or both ends of the transcript, permitting easy distinction between any remaining undigested probe and the shorter, specifically protected region of the probe. Ten micrograms of yeast tRNA was used as a negative control to test for the presence of probe self-protection. At least duplicate determinations were performed on each ventricular sample, and intrasample variability was <15% (in most cases, <10%). For each sample point, 10 µg of total RNA was used in the assay.

A probe hybridizing to the I-II linker of the cardiac isoform of the Na⁺ channel (hH1) was used as a myocyte-specific control. The hH1 probe was normalized to the level of probe protecting a segment of the 28S ribosomal RNA to correct for differences in RNA loading. In general, the specific activity of the control probes was 5-fold lower than that for the target channel probes.

Steady-state mRNA levels were quantified through exposure of the gels on a storage phosphor screen and then scanning with a PhosphorImager (Molecular Dynamics); quantification of the transcript levels was performed with ImageQuant software (Molecular Dynamics). In cases in which a doublet was observed, both bands were used in the quantification. The level of target gene expression is given as either the absolute density in arbitrary units or the relative density of the protected fragment normalized to the density of the control protected fragment to normalize for both RNA loading and the fraction of the ventricular sample consisting of cardiac myocytes (hH1 probe). The averaged relative density of the channel transcripts from failing samples was compared with nonfailing controls with the use of ANOVA. The relative density of the Kv4.3 protected fragment is compared to the maximal I_to density measured in 2 cells isolated from adjacent regions of ventricular myocardium. I_to was recorded in 2 or 3 cells in the normal hearts; in the failing hearts, I_to was recorded in a median of 3 cells (range, 2 to 6).

Isolation of Ventricular Myocytes and Electrophysiology
Ventricular myocytes were isolated as previously described with minor modifications.^{7 8} The territory perfused by the LAD from the aortic root to the apex was excised and perfused via the coronary artery with a collagenase- and protease-containing Tyrode buffer. The currents described were measured in cells isolated from the central third of the myocardial wall, excluding endocardial and epicardial layers, from the area of the left ventricular anterior free wall between the LAD and the first diagonal branch. Only Ca²⁺-tolerant cells with clear cross striations and without spontaneous contraction or significant granulation (20% to 40% of those isolated in both control and failing hearts) were selected for the experiments.

The whole-cell configuration of the patch-clamp technique²⁷ was used to measure I_to at room temperature (22°C to 23°C) in cells isolated from 4 control and 6 failing ventricles as previously described.²⁸ Cell isolation was either not performed or was inadequate for electrophysiological recording in the other 3 control and 11 failing hearts. I_to was elicited by 500-ms voltage steps at a frequency of 0.1 Hz as previously described.^{7 8 28} The external solution for recording I_to was (in mmol/L) NaCl 138, KCl 4, CaCl₂ 2.0, MgCl₂ 1, glucose 10, NaH₂PO₄ 0.33, HEPES 10, CdCl₂ 0.3, and tetrodotoxin 0.003, pH 7.3. The patch-clamp electrodes contained (in mmol/L) K-glutamate 120, KCl 10, MgCl₂ 2, HEPES 10, EGTA 5, and Mg-ATP 2, pH 7.2. Cell capacitance was calculated by integrating the area under an uncompensated capacity transient elicited by a 20-mV depolarizing test pulse from a holding potential of –80 mV. Series resistance was then compensated as much as possible without ringing, typically 60% to 70%. Given the average series resistance of our electrodes, the maximal uncompensated voltage error was <5 mV for the largest currents studied. Currents were low-pass filtered at 2 kHz and digitized at 5 to 10 kHz with a Digidata 1200 A/D (Axon Instruments) interface for off-line analysis.

The data were analyzed with the use of custom-written software. Pooled data are presented as mean±SD. Statistical comparisons were made with ANOVA, with P<0.05 considered significant. Correlation of the action potential characteristics and current densities to the normalized transcript levels was performed by linear regression.

	Results

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RPAs were used to determine the levels of ion channel mRNAs in normal and failing human myocardium. The levels of K⁺ channel mRNA were correlated with currents measured in myocytes isolated from adjacent segments of tissue. Samples from 7 normal hearts and 17 failing hearts were examined. The average age of the patients from whom the control hearts were obtained was 42±13 years, and that of the transplant recipients from whom the failing hearts were harvested was 52±10 years. Two of the normal and 3 of the failing hearts were from female patients. The cause of heart failure in the transplant recipients was dilated cardiomyopathy in 10 of the patients (59%), ischemic/postinfarction cardiomyopathy in 6 (35%), and postpartum cardiomyopathy in 1 (6%).

The demographics and drug regimens of the patients in the failing cohort are summarized in Table 2. All of the patients were on standard heart failure medical regimens at the time of transplantation, including diuretics, ACE inhibitors, and digitalis; 4 of the patients were taking amiodarone, and no other antiarrhythmic drugs were used in this cohort. The age, sex, and reasons for not transplanting the normal hearts are given in Table 2.

Expression of Kv4.3 mRNA in Heart Failure
We previously reported that the Kv4.3 channel is likely to underlie a significant fraction, if not all, of the Ca²⁺-independent I_to.¹⁵ The level of Kv4.3 mRNA in the ventricular myocardium of normal and failing hearts was compared to further test the hypothesis that Kv4.3 is a component of the native I_to and to determine whether I_to downregulation in heart failure is correlated with downregulation of Kv4.3 mRNA levels. Figure 1A shows a representative RPA for Kv4.3 mRNA in which samples from normal and failing ventricular myocardium are compared; lane P shows the size of the unprotected probe, and lane t contains tRNA and no protection is observed (5 normal and 7 failing samples are shown). There is sample-to-sample variability in both normal and failing hearts: the range of transcript densities in arbitrary units is 0.79 to 1.34 and 0.36 to 0.81 for normal and failing samples, respectively. Repeated assays on the same samples reveal little intrasample variability; the maximal difference on repeated determinations was 17%, and in general, the densities of the protected fragment for Kv4.3 varied by <8%. Overall, in these 12 samples, there is a 34% reduction in the unnormalized Kv4.3 mRNA in failing myocardium compared with that in the control hearts (Figure 1B, P<0.01).

View larger version (28K): [in this window] [in a new window]   Figure 1. Changes in Kv4.3 mRNA in heart failure. A, Representative RPA with probes designed to protect a 337-bp fragment of human Kv4.3 and a 103-bp fragment of cyclophilin. The first lane (P) contains the probes alone. The lane marked t contains yeast tRNA. Shown is 10 µg of total RNA from 5 normal and 7 failing hearts. B, Bar plot of the unnormalized density of Kv4.3 mRNA in 5 normal and 7 failing left ventricular samples; the values are the average of duplicate determinations. The steady-state level of mRNA encoding Kv4.3 is reduced by 34% in failing hearts compared with controls (P=0.009) C, Representative currents elicited by a series of depolarizing voltage steps from –30 to +80 mV in 10-mV increments from a holding potential of –60 mV. The normal traces are from the heart in lane 4, and the failing traces are from the heart in lane 6 (A). D, Bar plot of the current density measured at a test potential of +40 mV in 16 cells from the 5 normal ventricles and 25 cells from the 7 failing ventricles in A. E, Correlation between Kv4.3 mRNA and Ito density in ventricular myocytes. In 10 samples, 6 from failing and 4 from normal ventricles, RPAs were performed and currents were measured in at least 2 cells isolated from an adjacent region of the myocardium. The maximal Ito density is plotted against the unnormalized level of Kv4.3 mRNA in arbitrary units determined on the same RPA. F, A similar plot of the Kv1.4 mRNA density versus Ito density reveals no correlation.

Correlation Between mRNA Levels and Current Density
Myocytes were isolated from an adjacent region of the ventricle for the 12 samples shown in Figure 1A; I_to current density was recorded in at least 2 cells from 10 of these hearts (normal sample No. 2 and heart failure No. 4 current records were obtained from only 1 cell). Representative current records elicited by a family of depolarizing voltage steps from –30 to +80 mV in increments of 10 mV from a holding potential of –60 mV are shown in Figure 1C. The mean and SD values of the current densities at +40 mV in 25 cells from 7 failing hearts and 16 cells from 5 control hearts are shown in Figure 1D (4.1±2.8 pA/pF for failing and 7.9±3 pA/pF for control, P=0.0035). The change in Kv4.3 mRNA in failing myocardium is consistent in both direction and magnitude with the change in native I_to measured in ventricular myocytes isolated from the same hearts. We previously demonstrated that the reduction in I_to in heart failure is due to a reduced number of functioning channels and therefore is a reasonable index of the level of channel protein.⁸ If Kv4.3 encodes the native channel, we anticipate a correlation between the level of mRNA and the density of I_to. Figure 1E illustrates that such a correlation exists; this is a plot of the unnormalized mRNA density and maximal I_to density at +40 mV (the circles represent normal hearts, and the squares represent failing ventricles). The plot reveals a significant correlation between Kv4.3 mRNA and the current density (r=0.89, P=0.0005). In contrast, the I_to density did not correlate with the abundance of other mRNAs. Another gene encoding an inactivating K channel, Kv1.4, showed no correlation with the density of I_to (Figure 1E; r=0.38, P=0.28).

Expression of the hH1 Na Channel mRNA
It is possible that the change in Kv4.3 mRNA is due to a generalized depression in mRNA levels in failing hearts or to a more specific decline in the expression of genes encoding ion channels. To test this possibility, we examined the level of mRNA encoding the hH1 Na⁺ channel in normal and failing hearts. We designed a probe to the hH1 Na⁺ channel I-II linker, which is unique to the cardiac isoform of this channel and therefore myocyte specific. The level of hH1 mRNA does not change in failing hearts (Figure 2). The level of hH1 mRNA in failing samples is 96% of that of control hearts (Figure 2B, P>0.7). Similarly, when the steady-state level of hH1 mRNA is normalized to the density of 28S ribosomal RNA to control for sample loading, there is no difference between control and failing ventricles (data not shown). Thus, the reduction in Kv4.3 mRNA is not the result of a generalized decrease in mRNA.

View larger version (28K): [in this window] [in a new window]   Figure 2. hH1 mRNA does not change in heart failure. A, A myocyte-specific probe designed to the I-II linker of the cardiac isoform of the Na+ channel is hybridized to 10 µg of total RNA in 5 samples from normal and 4 samples from failing ventricles. In the lane marked tRNA, the probe is hybridized to yeast tRNA rather than myocardial RNA. B, Bar plot of the averaged density of mRNA encoding hH1 reveals no significant difference in failing and control hearts. C, Representative RPA exhibiting reduction of the Kv4.3 protected fragment in failing samples compared with normal controls. No significant change in hH1 density is observed. D, Scatterplot of the density of Kv4.3 mRNA normalized to hH1 from 7 normal and 17 failing hearts. Each data point represents the average of at least 2 determinations ( and , mean values for normal and failing hearts, respectively; 1.2±0.16 control versus 0.84±0.16 failing, P=0.00005).

Housekeeping genes such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or cyclophilin are typically used as probes to normalize for the total amount of RNA. However, we observed changes in the mRNA encoding both of these proteins in heart failure. For example, there is a 17% decrease in the level of cyclophilin mRNA, which does not reach statistical significance (Figure 1A, P>0.15). This trend in the cyclophilin mRNA level does produce problems with respect to normalization of the channel transcript levels to cyclophilin. The hH1 mRNA does not change with heart failure (Figure 2A and 2B), which is consistent with the lack of changes in I_na in human atrial cells²⁹ and canine ventricular cells from failing hearts⁸ ; thus, hH1 may be a more relevant control probe for K⁺ channel target genes. We repeated the Kv4.3 RPA with hH1 as the normalizing control probe in 7 control and 17 failing samples. The level of Kv4.3 mRNA normalized to hH1 is reduced by 30% in failing cells compared with nonfailing controls (Figure 2C and 2D, P=0.0005). Because hH1 mRNA reflects the amount of RNA from cardiac myocytes, the reduction of Kv4.3 mRNA is not simply the result of myocyte dropout; instead, the level of Kv4.3 mRNA in ventricular myocytes decreases. The intersample variability of Kv4.3 mRNA levels in the heart failure cohort could not be ascribed to patient age, cause of heart failure, or treatment with amiodarone. Three patients with heart failure had Kv4.3 mRNA levels that overlapped with the range of values in normal hearts: 2 of these patients had dilated cardiomyopathy, and 1 had ischemic cardiomyopathy and none were being treated with amiodarone.

HERG mRNA in Heart Failure
The ventricular action potential is prolonged in heart failure; similarly, in the genetically determined cardiac arrhythmia, the long QT syndrome (LQTS), repolarization is prolonged. The chromosome 7–associated LQTS is caused by mutations in the human ether a go-go–related gene (HERG).³⁰ To test the possible involvement of the HERG gene product in the abnormal repolarization associated with heart failure, we measured mRNA levels of this gene in control and failing hearts (Figure 3). HERG RNA is abundantly expressed in the human ventricle.^{30 31} There was no significant change in HERG mRNA; the average value for HERG mRNA expression in failing hearts was 85±18% of the control value (Figure 3B, P=NS).

View larger version (21K): [in this window] [in a new window]   Figure 3. HERG mRNA exhibits significant variability but no change in failing ventricular myocardium. A, Representative RPA with 10 µg of control or failing ventricular myocardium per lane. The 7 normal and 17 failing samples exhibit large variability in the density of HERG mRNA. B, The scatterplot of HERG mRNA density illustrates the large range of values in both control and failing ventricles. The mRNA density in normalized to the hH1 signal in control and failing hearts is 1.05±0.43 and 0.9±0.2, respectively (P=0.28).

There was greater intersample variability of HERG mRNA expression in control samples compared with the variability of Kv4.3 and hH1 mRNA levels. The SD for the level of expression of Kv4.3 and hH1 mRNAs in control hearts was 16% and 15% of the mean, respectively. In contrast, the value for HERG mRNA was 28%. We could not find any link between age or tissue handling that could account for the variability in HERG expression in the control samples. The control samples were all taken from the same region of the left ventricle, excluding regional differences in HERG expression as a cause of the variability.

Expression of Inward Rectifier Channel Genes in Heart Failure
The inward rectifier K⁺ current (I_K1) is active in the terminal phases of repolarization and is functionally downregulated in human⁷ and canine⁸ heart failure. The mRNA encoding I_K1 (Kir2.1) is abundant in human ventricle but does not change in failing hearts compared with controls (Figure 4A and 4B). There is significant sample-to-sample variability in the steady-state mRNA levels encoding I_K1; the SD for the level of expression over all samples was 28%. The level of Kir2.1 mRNA in failing hearts is not different from that in control ventricles (Figure 4B, P=0.56).

View larger version (38K): [in this window] [in a new window]   Figure 4. Kir2.1 mRNA does not change with heart failure. A, Representative RPA of Kir2.1 (probe, 235 bp; protected fragment, 194 bp) and hH1 in 5 control and 5 failing ventricular samples. B, Scatterplot of the density of Kir2.1 mRNA normalized to hH1 reveals no difference in control and failing hearts. The normalized mRNA densities in arbitrary units are 0.88±0.16 and 0.94±0.26 for control and failing hearts, respectively (P=0.56).

Expression of Other Ion Channel Genes in Heart Failure
The reduction in Kv4.3 mRNA in failing hearts is in contrast to other mRNAs examined (Figure 5). We evaluated the transcript level of several other channel genes known to be present in ventricular myocardium. There was no change in the level of the Kv1 family gene Kv1.4, and we observed very little Kv1.2 and Kv1.5 in human ventricle. The only member of the Kv2 family of genes expressed in rat heart is Kv2.1,¹⁴ and we detected no Kv2.1 in human ventricle. This result is consistent with the absence of any appreciable ultrarapid delayed rectifier K⁺ current in human ventricular myocytes. In other mammals, Kv3 gene family members are present in low abundance in the heart^{14 32} and are not likely to be relevant to native ventricular I_to.¹⁵

View larger version (58K): [in this window] [in a new window]   Figure 5. The level of mRNA encoding other voltage-dependent channels is not different in normal and failing human myocardium. A, Bar plots are shown for the level of mRNA normalized to hH1, encoding Kv1.4, Kvß1.3, and the 1 subunit of the cardiac Ca2+ channel. There is no significant difference in the level of any of these transcripts in normal compared with failing ventricles. B, Representative RPAs for each of the transcripts shown in A.

The ß-subunits are known to modulate the function of K⁺ channel -subunits, in some cases changing the phenotype of a channel from noninactivating to inactivating.³³ The Kvß1.3 subunit is known to be present in human heart³⁴ but does not change in heart failure (Figure 5).

The L-type Ca²⁺ channel is active during the plateau of the action potential. Alterations in the magnitude of this current can change the plateau voltage and duration. The mRNA encoding the 1C subunit of Ca²⁺ channel is abundant in human ventricle but does not change with heart failure (Figure 5).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
One of the hallmarks of ventricular myocardial failure is prolongation of the cellular action potential duration. In humans and animal models, the action potential profile is changed; often, a reduction in the phase 1 repolarizing notch is observed.^{7 8} The prolongation and change in phase 1 are the result of decrease in the Ca²⁺-independent I_to density.^{7 8} Experiments in small mammals suggest that the Shal subfamily K channel genes Kv4.2 and Kv4.3 encode the native cardiac I_to.^{14 15 35} The K channel, Kv4.3, is the leading candidate gene for I_to in dogs and humans.¹⁵ In further support of this hypothesis, we observed a reduction in Kv4.3 mRNA in heart failure. Remarkably, the reduction in Kv4.3 mRNA is similar to the observed reduction in I_to density in cells isolated from failing human ventricles.⁷ The level of Kv4.3 mRNA was correlated with the I_to density of ventricular myocytes isolated from segments of the heart adjacent to the samples used for RPA. These data suggest that in the human heart, Kv4.3 encodes all or part of the Ca²⁺-independent I_to and that downregulation of this current in heart failure is consistent with altered transcription. However, changes in the steady-state level of mRNA can occur by mechanisms other than altered rates of transcription, and mRNA levels cannot be equated with the level of protein.³⁶

The correlation of the mRNA encoding Kv4.3 and the current density suggests that changes in the message levels parallel reduction in the functionally important, sarcolemmal component of the I_to protein. In both human^{7 13} and animal⁸ models of heart failure, there are no significant changes in I_to kinetics or single-channel current amplitude in cells isolated from the same region of normal and failing ventricles; indeed, nonstationary fluctuation analysis was consistent with a reduction in the number of functioning channels in the cell membrane.⁸ The number of functioning ion channels serves as a surrogate for the level of channel protein. Therefore, it is reasonable to suggest that the reduction in mRNA transcript is associated with a reduction in the level of immunoreactive protein. However, it is possible that the level of protein does not change despite a reduction in the steady-state level of mRNA encoding Kv4.3 and reduction in I_to density, and post-translational modifications occur that reduce channel function without altering its biophysical properties. Alternatively, changes in membrane trafficking may result in a reduction in the amount of channel protein in the sarcolemma without a change in the total cellular protein. It will be necessary to generate specific antibodies to Kv4.3 and measure the protein levels directly to distinguish among these possibilities. If Kv4.3 is a component of a heteromultimeric channel that encodes I_to, based on these data it appears to be rate limiting in terms of production of functional I_to channel.

The inward rectifier, I_K1, is functionally downregulated in human⁷ and canine⁸ heart failure. In contrast to Kv4.3 and similar to other K⁺ channel subunits measured by RPA in this study, there is no change in the level of Kir2.1 mRNA in failing ventricles compared with controls. It is possible that the reduction in I_K1 is mediated by a post-translational change that eliminates channel function without changing the steady-state level of RNA. It is also possible that the current reduction is mediated post-transcriptionally and that protein levels are indeed reduced in heart failure. Other Kir2 family members have been cloned from human brain^{37 38} and murine heart and brain,^{39 40 41} suggesting the changes in the expression of these other genes could underlie the change in I_K1.

The delayed rectifier K channel is important in repolarization in heart in a number of species. In humans, the HERG gene encodes the rapid component of the inward rectifier (I_Kr) and is mutated in the chromosome 7–linked form of the long QT syndrome, a congenital cardiac arrhythmia characterized by disordered ventricular repolarization.⁴² When the HERG gene is expressed in oocytes or mammalian cells, its electrophysiology and pharmacology resemble those of I_Kr.^{42 43 44} I_Kr blockers prolong the human ventricular action potential,^{45 46} and recently both the rapid component, I_Kr, and the slow component, I_Ks, of the delayed rectifier current were measured in human cardiac myocytes.⁴⁶ The mRNA level of HERG is quite variable in human ventricle, but in transmural sections from control and failing left ventricles, it does not change with heart failure. The large variability might be the result of differences in expression of the mRNA⁴⁷ and current regionally, so we cannot exclude the possibility that regional changes in HERG mRNA expression occur with heart failure. Alternatively spliced mRNA species of HERG and other mammalian homologs have been recognized recently; the probe used in this study is common to all of the HERG splice variants.^{48 49}

Further study of the apparent transcriptional regulation of Kv4.3 in human heart failure will require study of the regulatory region of this gene. Is the change in the transcript level an epiphenomenon due to the altered neurohumoral environment in heart failure, or do the changes in Kv4.3 transcript levels contribute to the development of heart failure? Can the change in expression of this or other K channel genes be altered pharmacologically: If so, will the change in expression alter the incidence of sudden death due to ventricular arrhythmias in heart failure?

Study Limitations
A significant limitation of any study in humans is the lack of control of the conditions of the normal and especially the failing ventricles. The anesthetic agents used at the time of cardiac explantation were similar in patients with control and failing hearts, but many other parameters were significantly different. The cause of heart failure was variable, and the duration and severity of myocardial dysfunction and the medical therapy at the time of explantation of the failing hearts obviously were not controlled. Our experiments were designed to correlate the level of functional protein (ie, I_to density) in cells isolated from these hearts with mRNA levels in immediately adjacent tissue from the same hearts. A limitation of this design is the necessarily small amount of tissue from which all of the measurements can be made; thus, in this study the amount of immunoreactive hKv4.3 protein in the region adjacent to the section of the ventricle used for cell isolation was not determined. Despite these limitations, it is notable that we were able to measure a statistically significant reduction in the mRNA level encoding a K⁺ channel gene that is likely to play a significant role in repolarization of the human heart. Furthermore, the transcript level of Kv4.3 correlates well with the current density of I_to in heart cells, consistent with the hypothesis that this gene encodes a component of the native channel in humans.

We did not evaluate changes in the level of the mRNA across the ventricular wall and in different areas of the ventricles. Regional changes in the K⁺ currents expressed are likely to be important in the local control of ventricular repolarization. However, a study of this sort is better suited to an animal model in which the degree of heart failure, treatment regimen, tissue harvesting, and cell isolation can be controlled.

View this table: [in this window] [in a new window]   Table 3. Patient Demographics and Medications at Transplantation of Control Hearts

	Acknowledgments

 
This work was supported by NIH grant HL-P50–52307 (SCOR in Sudden Cardiac Death) and by Deutsche Forschungsgemeinschaft (S.K.). We thank the following for generous gifts of the cDNA clones: Drs Mike Tamkun (hKv1.4 and 1.5), Steve Ikeda and Rolf Joho (hKv2.1), Barbara Wible (hKvß1.3), Barry Ganetsky and Jeff Warmke (HERG), and Roland Kallen (hH1). We thank Colleen McCormack and Qing Xheng for technical support and Dr Eduardo Marban for critical review of the manuscript. We gratefully acknowledge the support of our colleagues, the members of the heart failure and cardiac transplantation services at the University of Munich and Johns Hopkins University.

Received February 10, 1998; revision received May 22, 1998; accepted June 3, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study. N Engl J Med. 1986;314:1547–1552.[Abstract]

2. Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation. 1993;88:2953–2961.[Free Full Text]

3. Packer M. Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure. Circulation. 1992;85(suppl I):I-50–I-56.

4. Aronson RS. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res. 1980;47:443–454.[Free Full Text]

5. Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman MD, Grossman W, Morgan JP. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987;61:70–76.[Abstract/Free Full Text]

6. Scamps F, Mayoux E, Charlemange D, Vassort G. Calcium current in single cells isolated from normal and hypertrophied rat heart: effects of ß-adrenergic stimulation. Circ Res. 1990;67:199–208.[Abstract/Free Full Text]

7. Beuckelmann DJ, Näbauer M, Erdmann E. Alterations of K⁺ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:379–385.[Abstract/Free Full Text]

8. Kääb S, Nuss HB, Chiamvimonvat N, O'Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res. 1996;78:262–273.[Abstract/Free Full Text]

9. Di Diego JM, Antzelevitch C. High [Ca²⁺]_o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Circulation. 1994;89:1839–1850.[Abstract/Free Full Text]

10. Barry DM, Nerbonne JM. Myocardial potassium channels: electrophysiological and molecular diversity. Annu Rev Physiol. 1996;58:363–394.[Medline] [Order article via Infotrieve]

11. Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di Diego JM, Gintant GA, Liu D-W. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res. 1991;69:1427–1429.[Free Full Text]

12. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. 1994;23:259–277.[Abstract]

13. Näbauer M, Beuckelmann DJ, Erdmann E. Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:386–394.[Abstract/Free Full Text]

14. Dixon JE, McKinnon D. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res. 1994;75:252–260.[Abstract/Free Full Text]

15. Dixon JE, Shi W, Wang H-S, McDonald C, Yu H, Wymore RS, Cohen IS, McKinnon D. The role of the Kv4.3 potassium channel in ventricular muscle. Circ Res. 1996;79:659–668.[Abstract/Free Full Text]

16. Chandy KG. Simplified gene nomenclature. Nature. 1991;352:26.[Medline] [Order article via Infotrieve]

17. Gellens ME, George AL Jr, Chen LQ, Chahine M, Horn R, Barchi RL, Kallen RG. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci U S A. 1992;89:554–558.[Abstract/Free Full Text]

18. Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B, Sinke RJ, Weghuis DO, Klockner U, Wakamori M, Schwartz A. Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci U S A. 1993;90:6228–6232.[Abstract/Free Full Text]

19. Ashen MD, O'Rourke B, Kluge KA, Johns DC, Tomaselli GF. Inward rectifier K⁺ channel from human heart and brain: cloning and stable expression in a human cell line. Am J Physiol. 1995;268:H506–H511.[Abstract/Free Full Text]

20. Warmke JW, Ganetsky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A. 1994;91:3438–3442.[Abstract/Free Full Text]

21. Ramashwami M, Gautam M, Kamb AA, Rudy B, Tanouye MA, Mathew MK. Human potassium channel genes: molecular cloning and functional expression. Mol Cell Neurosci. 1990;1:214–223.

22. Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, Glover DM. Molecular cloning and characterization of two voltage-gated K⁺ channel cDNAs from human ventricle. FASEB J. 1991;5:331–337.[Abstract]

23. Ikeda SR, Soler F, Zuhlke RD, Joho RH, Lewis DL. Heterologous expression of the human potassium channel Kv2.1 in clonal mammalian cells by direct cytoplasmic microinjection of cRNA. Pflugers Arch. 1992;422:201–203.[Medline] [Order article via Infotrieve]

24. Majumder K, De Biasi M, Wang Z, Wible BA. Molecular cloning and functional expression of a novel potassium channel beta-subunit from human atrium. FEBS Lett. 1995;361:13–16.[Medline] [Order article via Infotrieve]

25. Sambrook J, Fritsch EF, Maniatis T. Extraction, purification, and analysis of messenger RNA from eukaryotic cells. In: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989:7.6–7.23.

26. Krieg PA, Melton DA. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415.[Medline] [Order article via Infotrieve]

27. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981;391:85–100.[Medline] [Order article via Infotrieve]

28. Näbauer M, Beuckelmann DJ, Überfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of the human left ventricular. Circulation. 1996;93:168–177.[Abstract/Free Full Text]

29. Sakakibara Y, Furukawa T, Singer DH, Jia H, Backer CL, Arentzen CE, Wasserstrom JA. Sodium current in isolated human ventricular myocytes. Am J Physiol. 1993;265:H1301–H1309.[Abstract/Free Full Text]

30. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause the long QT syndrome. Cell. 1995;80:795–803.[Medline] [Order article via Infotrieve]

31. Wymore RS, Gintant GA, Wymore RT, Dixon JE, McKinnon D, Cohen IS. Tissue and species distribution of mRNA for the I_Kr-like K⁺ channel, erg. Circ Res. 1997;80:261–268.[Abstract/Free Full Text]

32. Ghanshani S, Pak M, McPherson JD, Strong M, Dethlefs B, Wasmuth JJ, Salkoff L, Gutman GA, Chandy KG. Genomic organization, nucleotide sequence, and cellular distribution of a Shaw-related potassium channel gene, Kv3.3, and mapping of Kv3.3 and Kv3.4 to human chromosomes 19 and 1. Genomics. 1992;12:190–196.[Medline] [Order article via Infotrieve]

33. Rettig J, Heinemann SH, Wunder F, Lorra C, Parcej DN, Dolly JO, Pongs O. Inactivation properties of voltage-gated K⁺ channels altered by presence of beta-subunit. Nature. 1994;369:289–294.[Medline] [Order article via Infotrieve]

34. Wible BA, De Biasi M, Majumder K, Taglialatela M, Brown AM. Cloning and functional expression of an inwardly rectifying K⁺ channel from human atrium. Circ Res. 1995;76:343–350.[Abstract/Free Full Text]

35. Barry DM, Trimmer JS, Merlie JP, Nerbonne JM. Differential expression of voltage-gated K⁺ channel currents in rat ventricular myocytes. Circ Res. 1995;77:361–369.[Abstract/Free Full Text]

36. Xu H, Dixon JE, Barry DM, Trimmer JS, Merlie JP, McKinnon D, Nerbonne JM. Developmental analysis reveals mismatches in the expression of K⁺ channel -subunits and voltage-gated K⁺ channel currents in rat ventricular myocytes. J Gen Physiol. 1996;108:405–419.[Abstract/Free Full Text]

37. Makhina EN, Kelly AJ, Lopatin AN, Mercer RW, Nichols CG. Cloning and expression of a novel human brain inward rectifier potassium channel. J Biol Chem. 1994;269:20468–20474.[Abstract/Free Full Text]

38. Perier F, Radeke CM, Vandenberg CA. Primary structure and characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc Natl Acad Sci U S A. 1994;91:6240–6244.[Abstract/Free Full Text]

39. Takahashi N, Morishige K, Jahangir A, Yamada M, Findlay I, Koyama H, Kurachi Y. Molecular cloning and functional expression of cDNA encoding a second class of inward rectifier potassium channels in the mouse brain. J Biol Chem. 1994;269:23274–23279.[Abstract/Free Full Text]

40. Morishige K, Takahashi N, Jahangir A, Yamada M, Koyama H, Zanelli JS, Kurachi Y. Molecular cloning and functional expression of a novel brain-specific inward rectifier potassium channel. FEBS Lett. 1994;346:251–256.[Medline] [Order article via Infotrieve]

41. Koyama H, Morishige K, Takahashi N, Zanelli JS, Fass DN, Kurachi Y. Molecular cloning, functional expression and localization of a novel inward rectifier potassium channel in the rat brain. FEBS Lett. 1994;341:303–307.[Medline] [Order article via Infotrieve]

42. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.[Medline] [Order article via Infotrieve]

43. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92–95.[Abstract/Free Full Text]

44. Jurkiewicz NK, Sanguinetti MC. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: specific block of rapidly activating delayed rectifier K⁺ current by dofetilide. Circ Res. 1993;72:75–83.[Abstract/Free Full Text]

45. Ohler A, Ravens U. Effect of E-4031, almokalant and tedisamil on postrest action potential duration in human papillary muscle. J Pharmacol Exp Ther. 1994;270:460–465.[Abstract/Free Full Text]

46. Li G-R, Feng J, Yue L, Carrier M, Nattel S. Evidence for two components of delayed rectifier K⁺ current in human ventricular myocytes. Circ Res. 1996;78:689–696.[Abstract/Free Full Text]

47. Brahmajothi MV, Morales MJ, Campbell DC, Rasmusson RL, Reimer KA, Wang S, Liu S, Strauss HC. Immunolocalization of erg and neurons in the ventricle and SA nodal region of the ferret heart. Circulation. 1997;96(suppl I):I-498. Abstract.

48. Lees-Miller JP, Kondo C, Wang L, Duff HJ. Electrophysiological characterization of an alternatively processed ERG K⁺ channel in mouse and human hearts. Circ Res. 1997;81:719–726.[Abstract/Free Full Text]

49. London B, Trudeau MC, Newton KP, Beyer AK, Copeland NG, Gilbert DJ, Jenkins NA, Satler CA, Robertson GA. Cloning a specific isoform of HERG from the mouse. Circ Res. 1997;81:870–878.[Abstract/Free Full Text]

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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]

				A. G. KLEBER and Y. RUDY Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias Physiol Rev, April 1, 2004; 84(2): 431 - 488. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]

				L. A. Kim, J. Furst, M. H. Butler, S. Xu, N. Grigorieff, and S. A. N. Goldstein Ito Channels Are Octomeric Complexes with Four Subunits of Each Kv4.2 and K+ Channel-interacting Protein 2 J. Biol. Chem., February 13, 2004; 279(7): 5549 - 5554. [Abstract] [Full Text] [PDF]

				F. G. Akar, R. C. Wu, I. Deschenes, A. A. Armoundas, V. Piacentino III, S. R. Houser, and G. F. Tomaselli Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H602 - H609. [Abstract] [Full Text] [PDF]

				H. Diedrichs, M. Chi, B. Boelck, U. Mehlhorm, and R. H.G. Schwinger Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure Eur J Heart Fail, January 1, 2004; 6(1): 3 - 9. [Abstract] [Full Text] [PDF]

				S. A. Cahill and G. J. Gross Propafenone and Its Metabolites Preferentially Inhibit IKrin Rabbit Ventricular Myocytes J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 59 - 65. [Abstract] [Full Text] [PDF]

				D. Fedida, J. Eldstrom, J. C. Hesketh, M. Lamorgese, L. Castel, D. F. Steele, and D. R. Van Wagoner Kv1.5 Is an Important Component of Repolarizing K+ Current in Canine Atrial Myocytes Circ. Res., October 17, 2003; 93(8): 744 - 751. [Abstract] [Full Text] [PDF]

				D. M. Roden A Surprising New Arrhythmia Mechanism in Heart Failure Circ. Res., October 3, 2003; 93(7): 589 - 591. [Full Text] [PDF]

				F. G. Akar and D. S. Rosenbaum Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure Circ. Res., October 3, 2003; 93(7): 638 - 645. [Abstract] [Full Text] [PDF]

				J. BORLAK and T. THUM Hallmarks of ion channel gene expression in end-stage heart failure FASEB J, September 1, 2003; 17(12): 1592 - 1608. [Abstract] [Full Text] [PDF]

				R. L. Winslow and M. S. Boguski Genome Informatics: Current Status and Future Prospects Circ. Res., May 16, 2003; 92(9): 953 - 961. [Abstract] [Full Text] [PDF]

				I. Bodi, J. N. Muth, H. S. Hahn, N. N. Petrashevskaya, M. Rubio, S. E. Koch, G. Varadi, and A. Schwartz Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure: Complex nature of k+ current changes and action potential duration J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1611 - 1622. [Abstract] [Full Text] [PDF]

				S. Kaab, M. Hinterseer, M. Nabauer, and G. Steinbeck Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome--a case-control pilot study using i.v. sotalol Eur. Heart J., April 1, 2003; 24(7): 649 - 657. [Abstract] [Full Text] [PDF]

				R. Sah, R. J Ramirez, G. Y Oudit, D. Gidrewicz, M. G Trivieri, C. Zobel, and P. H Backx Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito) J. Physiol., January 1, 2003; 546(1): 5 - 18. [Abstract] [Full Text] [PDF]

				G.-R. Li, C.-P. Lau, A. Ducharme, J.-C. Tardif, and S. Nattel Transmural action potential and ionic current remodeling in ventricles of failing canine hearts Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1031 - H1041. [Abstract] [Full Text] [PDF]

				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]

				A. A. Fossa, M. J. DePasquale, D. L. Raunig, M. J. Avery, and D. J. Leishman The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 828 - 833. [Abstract] [Full Text] [PDF]

				Y. Matsumoto, H. Aihara, R. Yamauchi-Kohno, Y. Reien, T. Ogura, H. Yabana, Y. Masuda, T. Sato, I. Komuro, and H. Nakaya Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters Circulation, July 30, 2002; 106(5): 613 - 619. [Abstract] [Full Text] [PDF]

				I. Deschenes, D. DiSilvestre, G. J. Juang, R. C. Wu, W. F. An, and G. F. Tomaselli Regulation of Kv4.3 Current by KChIP2 Splice Variants: A Component of Native Cardiac Ito? Circulation, July 23, 2002; 106(4): 423 - 429. [Abstract] [Full Text] [PDF]

				Y. Xu, P. H. Dong, Z. Zhang, G. U. Ahmmed, and N. Chiamvimonvat Presence of a calcium-activated chloride current in mouse ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H302 - H314. [Abstract] [Full Text] [PDF]

				G. Schram, M. Pourrier, P. Melnyk, and S. Nattel Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function Circ. Res., May 17, 2002; 90(9): 939 - 950. [Abstract] [Full Text] [PDF]

				B. J Wilkins and J. D Molkentin Calcineurin and cardiac hypertrophy: Where have we been? Where are we going? J. Physiol., May 15, 2002; 541(1): 1 - 8. [Abstract] [Full Text] [PDF]

				D. Lacroix, P. Gluais, C. Marquie, C. D'Hoinne, M. Adamantidis, and M. Bastide Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy Cardiovasc Res, April 1, 2002; 54(1): 42 - 50. [Abstract] [Full Text] [PDF]

				Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]

				S. S. Po, R. C. Wu, G. J. Juang, W. Kong, and G. F. Tomaselli Mechanism of alpha -adrenergic regulation of expressed hKv4.3 currents Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2518 - H2527. [Abstract] [Full Text] [PDF]

				N. Decher, O. Uyguner, C. R Scherer, B. Karaman, M. Yuksel-Apak, A. E Busch, K. Steinmeyer, and B. Wollnik hKChIP2 is a functional modifier of hKv4.3 potassium channels: Cloning and expression of a short hKChIP2 splice variant Cardiovasc Res, November 1, 2001; 52(2): 255 - 264. [Abstract] [Full Text] [PDF]

				Z. Wang, W. Kutschke, K. E. Richardson, M. Karimi, and J. A. Hill Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy: Role of Calcineurin Circulation, October 2, 2001; 104(14): 1657 - 1663. [Abstract] [Full Text] [PDF]

				S. Kaab and M. Nabauer Diversity of ion channel expression in health and disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K31 - K40. [Abstract] [PDF]

				C. A. Ufret-Vincenty, D. J. Baro, and L. F. Santana Differential contribution of sialic acid to the function of repolarizing K+ currents in ventricular myocytes Am J Physiol Cell Physiol, August 1, 2001; 281(2): C464 - C474. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Molecular basis for the transmural distribution of the transient outward current J. Physiol., May 15, 2001; 533(1): 1 - 1. [Full Text] [PDF]

				B. Rosati, Z. Pan, S. Lypen, H.-S. Wang, I. Cohen, J. E Dixon, and D. McKinnon Regulation of KChIP2 potassium channel {beta} subunit gene expression underlies the gradient of transient outward current in canine and human ventricle J. Physiol., May 15, 2001; 533(1): 119 - 125. [Abstract] [Full Text] [PDF]

				P. B. Adamson and E. Vanoli Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: Characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1741 - 1748. [Abstract] [Full Text] [PDF]

				T. González, M. Longobardo, R. Caballero, E. Delpón, J. Tamargo, and C. Valenzuela Effects of Bupivacaine and a Novel Local Anesthetic, IQB-9302, on Human Cardiac K+ Channels J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 573 - 583. [Abstract] [Full Text]

				M. Nabauer Tuning Repolarization in the Heart : A Multitude of Potassium Channels and Regulatory Pathways Circ. Res., March 16, 2001; 88(5): 453 - 455. [Full Text] [PDF]

				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]

				C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]

				J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]

				P. G.A. Volders, M. A. Vos, B. Szabo, K. R. Sipido, S.H.M. de Groot, A. P.M. Gorgels, H. J.J. Wellens, and R. Lazzara Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts Cardiovasc Res, June 1, 2000; 46(3): 376 - 392. [Full Text] [PDF]

				Y. A. Kuryshev, T. I. Gudz, A. M. Brown, and B. A. Wible KChAP as a chaperone for specific K+ channels Am J Physiol Cell Physiol, May 1, 2000; 278(5): C931 - C941. [Abstract] [Full Text] [PDF]

				L. C. Baker, B. London, B.-R. Choi, G. Koren, and G. Salama Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular Tachycardia Circ. Res., March 3, 2000; 86(4): 396 - 407. [Abstract] [Full Text] [PDF]

				E. Cerbai, A. Crucitti, L. Sartiani, P. De Paoli, R. Pino, M. L. Rodriguez, G. Gensini, and A. Mugelli Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes Cardiovasc Res, January 14, 2000; 45(2): 388 - 396. [Abstract] [Full Text] [PDF]

				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]

				Y. A. Kuryshev, G. M. Brittenham, H. Fujioka, P. Kannan, C.-C. Shieh, S. A. Cohen, and A. M. Brown Decreased Sodium and Increased Transient Outward Potassium Currents in Iron-Loaded Cardiac Myocytes : Implications for the Arrhythmogenesis of Human Siderotic Heart Disease Circulation, August 10, 1999; 100(6): 675 - 683. [Abstract] [Full Text] [PDF]

				P. Schaffer, B. Pelzmann, E. Bernhart, P. Lang, H. Machler, B. Rigler, and B. Koidl Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot Cardiovasc Res, August 1, 1999; 43(2): 332 - 343. [Abstract] [Full Text] [PDF]

				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]

				D. M. Roden and S. Kupershmidt From genes to channels: normal mechanisms Cardiovasc Res, May 1, 1999; 42(2): 318 - 326. [Abstract] [Full Text] [PDF]

				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]

				U. C. Hoppe, D. C. Johns, E. Marban, and B. O'Rourke Manipulation of Cellular Excitability by Cell Fusion : Effects of Rapid Introduction of Transient Outward K+ Current on the Guinea Pig Action Potential Circ. Res., April 30, 1999; 84(8): 964 - 972. [Abstract] [Full Text] [PDF]

				M. Song, G. Helguera, M. Eghbali, N. Zhu, M. M. Zarei, R. Olcese, L. Toro, and E. Stefani Remodeling of Kv4.3 Potassium Channel Gene Expression under the Control of Sex Hormones J. Biol. Chem., August 17, 2001; 276(34): 31883 - 31890. [Abstract] [Full Text] [PDF]

				C. A. Ufret-Vincenty, D. J. Baro, W. J. Lederer, H. A. Rockman, L. E. Quinones, and L. F. Santana Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure J. Biol. Chem., July 20, 2001; 276(30): 28197 - 28203. [Abstract] [Full Text] [PDF]

				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]

				Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]

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