(Circulation. 1997;96:2149-2154.)
© 1997 American Heart Association, Inc.
Articles |
Normalization of Acquired QT Prolongation in Humans by Intravenous Potassium
From the Divisions of Clinical Pharmacology and Cardiology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Division of Clinical Pharmacology, Vanderbilt University, 532C Medical Research Bldg I, Nashville, TN 37232-6602. E-mail dan.roden{at}mcmail.vanderbilt.edu
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Abstract |
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Background QT interval prolongation and dispersion have been implicated in serious arrhythmias in congestive heart failure (CHF) and the congenital and drug-induced long-QT syndromes (LQTS). In a subset of the congenital LQTS, infusion of potassium can correct QT abnormalities, consistent with in vitro increases in outward currents such as IKr or IK1 when extracellular potassium concentration ([K+]o) is increased. Furthermore, increasing [K+]o decreases the potency of IKr-blocking drugs in vitro. The purpose of this study was to test the hypothesis that increasing [K+]o corrects QT abnormalities in CHF and in subjects treated with quinidine.
Methods and Results KCl (maximum, 40 mEq) was infused into (1) 12 healthy subjects treated with quinidine sulfate (5 doses of 300 mg/5 h) or placebo and (2) 8 CHF patients and age-matched normal control subjects. Mean [K+] increased from 4 to 4.2 mEq/L to 4.7 to 5.2 mEq/L. Potassium infusion significantly reversed QTUc prolongation, especially in the precordial leads (quinidine, 590±79 to 479±35 [±SD] ms1/2, P<.001; CHF, 521±110 to 431±47 ms1/2, P<.05). There was no effect in either control group. Similarly, potassium decreased QTUc dispersion (quinidine, 210±62 to 130±75 ms1/2, P<.01; CHF, 132±68 to 84±35 ms1/2, P=.07) and was without effect in the control subjects. QT morphological abnormalities, including U waves and bifid T waves, were reversed by potassium.
Conclusions Potentially arrhythmogenic QT abnormalities during quinidine treatment and in CHF can be nearly normalized by modest elevation of serum potassium.
Key Words: potassium • quinidine • heart failure
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Introduction |
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The QT interval on the surface ECG is an indirect measure of cardiac repolarization in individual cardiac myocytes. The duration of cardiac repolarization is determined by a balance during the plateau of the action potential between inward depolarizing currents and outward repolarizing currents, in which potassium currents play a major role. Important potassium currents in the human heart include the Ito, IK1, and IKs and IKr.1 Reduction in IK1, IKs, or IKr will result in slower repolarization and hence longer action potentials and prolonged QT interval on the surface ECG. Although the effects of reduced Ito may be less predictable, a reduction in Ito in the human heart has been associated with increased action potential duration in heart failure.2 3 The Nernst equation predicts smaller outward K+ currents with higher [K+]o. However, both IK1 (at potentials positive to the resting potential4 5 ) and IKr6 7 display an anomalous response to changes in [K+]o, with activating current increased by elevation in [K+]o. It can therefore be postulated that in vivo, this effect of [K+]o on IKr and/or IK1 would shorten action potentials, thus leading to QT shortening. Indeed, potassium infusion in patients with one form of the congenital LQTS,8 caused by mutations in HERG, the gene responsible for IKr,7 9 has been shown to reverse the characteristic QT prolongation. Thus, although these patients have reduced functional HERG channel protein, increased IKr current in residual functional channels or an IK1 effect appears to have been sufficient to redress the imbalance in repolarizing currents and to thereby normalize the QT interval.
Acquired QT prolongation and increased dispersion of the QT interval have been associated with an increase of SCD10 and have been reported in a number of settings such as CHF,11 hypertension,12 13 dilated and hypertrophic cardiomyopathy,14 15 after myocardial infarction,16 17 and during antiarrhythmic drug treatment.18 These cardiac repolarization abnormalities are important because they not only appear to predict SCD but also may be involved in its pathogenesis.2 Thus, reversal of QT prolongation and QT dispersion seen in these patients may be protective against the risk of SCD.19 In CHF, the pathogenesis of QT abnormalities is likely to be multifactorial; however, reduced repolarizing currents, including Ito and IK1, have been implicated.20 Similarly, drugs that cause LQTS can act by multiple mechanisms, including block of multiple potassium channels, including IKr, or even by increased inward current, one possible mechanism of ibutilide action.21 22 Some potassium channel blockers (such as dofetilide) target IKr specifically,23 24 whereas others, such as quinidine25 26 27 28 29 and sotalol,30 31 block multiple currents.
Importantly, irrespective and independent of the underlying mechanism of QT prolongation in these settings, increasing IKr or IK1 by elevation of serum potassium should lead to an overall increase in repolarizing current, thus shortening the action potential and reversing QT prolongation. In addition, our group has shown that elevation of [K+]o markedly inhibits block of IKr by drugs such as quinidine or dofetilide.25 Thus, potassium administration should be especially effective in reversing repolarization changes due to drug block of IKr. The purpose of this study, therefore, was to test the hypothesis that increasing serum potassium will normalize QT prolongation and QT dispersion in two clinical settings in which QT prolongation can be associated with arrhythmias: quinidine treatment and advanced CHF.
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Methods |
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Quinidine in Normal Subjects
Twelve healthy subjects (3 women, 9 men), mean age 39±18 (±SD) years, were studied twice, once on quinidine and once on placebo, at least 5 days apart. The treatments were double blind. Before each study day, subjects were randomized to receive either five doses of 300 mg quinidine sulfate or placebo every 5 hours. Because dietary sodium may affect QT interval,32 all subjects were started on a fixed sodium diet (70 mEq/d with 100 mEq/d potassium) 5 days before the study.
CHF Subjects
Eight patients (7 men, 1 woman) with severe CHF (NYHA functional
class III to IV) were studied. They were recruited consecutively from
the Vanderbilt Heart Failure Clinic. Their mean age was 52±9 years,
and mean ejection fraction was 17±9%. All patients had exertional
breathlessness or fatigue or both, despite therapy with ACE
inhibitors, digoxin, and diuretic drugs, and were
classified in NYHA functional class III to IV. None had
peripheral edema, ascites, or angina pectoris at the time
of study. Before enrollment in the study, all patients were optimally
treated with diuretics and showed no evidence of fluid
retention. Left ventricular dysfunction was attributed to
coronary artery disease in 3 and to idiopathic dilated
cardiomyopathy in 5 patients. Concomitant
medication in the CHF patients were diuretics (8), ACE
inhibitor (6), digoxin (7), potassium chloride supplements
(6), and amiodarone (2). Six age-matched normal volunteers
(mean age, 54±15 years) (2 women, 4 men) were recruited as control
subjects. All normal control subjects were given a low-sodium cardiac
diet equivalent to the CHF patient diet.
All studies were approved by Vanderbilt University Institutional Review Board, and all subjects provided written informed consent.
Protocol
After venous access via a large vein, subjects rested supine for
60 to 90 minutes and then were studied. Mean baseline serum potassium
was 4.11±0.06 mEq/L (range, 3.3 to 4.8 mEq/L) before study. Potassium
chloride was administered at 0.5 mEq/kg (to a maximum of 40 mEq) in a
0.9% saline infusion over a period of 60 to 70 minutes, according to
subject comfort. Venous samples were collected for serum potassium (and
magnesium in the quinidine/placebo study) before and at the end of
potassium infusion. Samples for measurement of plasma quinidine were
collected before infusion. Surface 12-lead ECGs were recorded with
the patient resting supine at baseline before and at the end of
the infusion.
QT Analysis
The ECGs were analyzed with a semiautomated digitizing
program by a single observer blinded to the diagnosis and intervention.
The QT (QTU) interval was measured in each of the 12 leads from the
onset of the QRS to the end of the T wave (ie, return to the T/P
baseline) or the end of the U wave, if present and >25% of the
T-wave amplitude. QTUc was calculated by Bazett's formula:
QTUc=QTU/
(RR).33 QTUc
dispersion was calculated as the difference between the maximal and
minimal QTUc intervals occurring in any of the 12 leads.
T1, the time interval from the onset of the QRS to the peak
of the T wave in lead V3, was measured. If bifid T waves
were present, both the first and second Q-to-Tpeak time
interval (T1 and T2) and the amplitudes of both
waves were measured.
Statistical analysis was performed by ANOVA (for the quinidine/placebo study), Student's t test, and Fisher's exact test (GraphPad Instat). All hypotheses were two-tailed, and a value of P<.05 was considered to be significant. All data are presented as mean±SD.
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Results |
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Quinidine/Placebo Study
ECG changes in lead V3 observed in two normal subjects who participated in this study are shown in Fig 1
. Marked repolarization abnormalities
were evident with quinidine treatment, particularly in the
precordial leads, and resolved with potassium infusion that raised
serum potassium within the physiological range.
These changes were absent with placebo treatment, and no effect of
potassium was evident in this group. As discussed in further detail
below, the ECG changes observed with quinidine treatment included the
development of bifid T waves, most obvious in the midprecordial
leads (as in Fig 1); the peak of the initial T wave actually occurred
earlier than the peak of the control T wave, and the second peak
occurred later. With potassium infusion, the first peak moved later and
the second earlier, resulting in an ECG pattern of a single peak, as
with control.
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Serum potassium values in all 12 subjects were comparable at baseline (quinidine, 4.08±0.14 mEq/L versus placebo, 4.25±0.25 mEq/L) and after potassium infusion (4.78±0.36 and 4.94±0.31 mEq/L, respectively, both P<.001 versus baseline). The changes in serum potassium after potassium infusion were similar during quinidine (0.62±0.26 mEq/L) and during placebo treatment (0.70±0.27 mEq/L). Serum magnesium in all subjects was within the normal range, and there were no differences in serum magnesium on quinidine compared with placebo (baseline and postinfusion, 1.99±0.14 and 1.92±0.16 mEq/L, respectively, on quinidine and 2.06±0.13 and 2.00±0.13 mEq/L on placebo). Plasma quinidine was analyzed in 8 subjects, and all values were within the therapeutic range, with a mean of 2.8±0.6 µg/mL. There was no change in QRS duration before (96±9 ms) and after (94±9 ms) potassium infusion during quinidine treatment. Heart rate was higher during quinidine (75±10 bpm) than placebo (59±7 bpm), but heart rate did not change with potassium.
Congestive Heart Failure
Mean baseline serum potassium in CHF patients tended to be lower
than in control subjects (3.96±0.58 versus 4.35±0.26 mEq/L); however,
this was not statistically significant. In both groups, serum potassium
was significantly raised by potassium infusion, to 4.68±0.71 mEq/L in
CHF patients and to 5.10±0.32 mEq/L in control subjects (both
P<.01 versus baseline). The mean change in serum potassium
was comparable (0.72±0.55 mEq/L in the CHF group and 0.75±0.29 mEq/L
in the control group). Heart rates were higher in the CHF group (81±18
bpm) than in the control group (60±9 bpm), but these did not change
with potassium.
QTc Intervals and T-Wave Morphology
The most striking changes with potassium infusion were observed in
the precordial leads, as shown in Fig 1
. QTUc values in
each of the 12 leads before and after potassium infusion are
presented in Fig 2 and the
changes in each lead in the Table. In
both CHF patients and subjects treated with quinidine, the greatest
QTUc prolongation was recorded in the precordial
leads, where the effect of potassium was also the most pronounced. For
example, in lead V2, potassium infusion significantly
shortened the marked QTUc prolongation seen on quinidine
treatment (590±79 to 479±35 ms1/2, P<.001),
in contrast to the negligible effects on QTUc during
placebo (390±6 to 398±10 ms1/2). Similarly, potassium
reduced QTUc in CHF patients from 521±110 to 431±47
ms1/2 (P<.05), compared with the minimal
effects seen in control subjects (399±14 to 408±25
ms1/2).
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Bifid T waves, as shown in Fig 1, were observed in 11 of 12 subjects
during quinidine treatment, particularly in the precordial leads
(11 of 12 versus 0 of 12 during placebo). Potassium infusion reversed
this effect in 9 of the 11 subjects (P<.01) by
significantly shortening T2 time (365±33 to 311±41 ms,
P<.001) and prolonging T1 time (269±28 to
303±45 ms, P<.01) in contrast to placebo (299±26 to
298±20 ms). Quinidine also induced U waves in 5 of 12 subjects (versus
none during placebo treatment) in lead V3. In all but 2
subjects, potassium infusion eliminated the U waves. Although potassium
infusion had a striking effect on U waves, it also shortened QT in the
absence of U waves.
Apart from QTUc prolongation, no abnormality in T-wave morphology was observed in 7 of the 8 CHF patients. In 1 patient, a significant U wave was observed in lead V3, the amplitude of which was reduced by 30% after potassium infusion. Potassium also appeared to shift the peak of the T wave leftward in CHF patients, as seen by the shortened T1 time (305±59 to 268±33 ms in V3) compared with control subjects (305±17 to 304±19 ms); however, this difference was not statistically significant. T-wave morphology was normal in all control subjects.
QTUc Dispersion
QTUc dispersion (Fig 3)
was significantly increased during quinidine treatment (210±18
ms1/2) compared with placebo (91±10 ms1/2,
P<.001). After infusion of potassium, QTUc
dispersion was significantly reduced (to 130±22 ms1/2,
P<.01) during quinidine treatment but was not changed
(71±8 ms1/2) during placebo.
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Similar but smaller changes were found in CHF. CHF patients tended to have increased QTUc dispersion compared with control subjects (132±24 versus 89±11 ms1/2, P=.08). After potassium infusion, QTUc dispersion in CHF patients was reduced (132±24 to 84±12 ms1/2, P=.08) compared with control subjects (89±11 to 68±14 ms1/2).
In both quinidine-treated subjects and CHF patients, reduction in QTUc dispersion was accomplished largely by reducing QTUc in those leads in which it had been the longest. Thus, maximal QTUc in quinidine-treated subjects fell from 628±89 to 550±52 ms and in CHF patients, from 545±112 to 470±55 ms (both P<.05 by ANOVA). In contrast, minimal QTUc with quinidine fell from 440±49 to 420±61 ms and in CHF patients, from 419±63 to 387±27 ms; neither change was statistically significant.
Adverse Effects
No adverse events were observed after potassium infusion in any of
the groups. During quinidine treatment, no side effects were reported
apart from nasal congestion in 4 subjects.
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Discussion |
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There are two main findings in this study: first, elevation of serum potassium within the physiological range can reduce QTUc prolongation and QTUc dispersion in normokalemic subjects treated with quinidine and in normokalemic patients with congestive heart failure compared with their respective control subjects. Second, in the absence of significant QT abnormalities, elevation of serum potassium had negligible effects on the ECG, in striking contrast to its action when QT abnormalities are present.
Pathophysiology of QT Prolongation in CHF
The pathophysiology underlying QT prolongation and increased QT
dispersion in CHF is unknown but is likely to be multifactorial. Likely
contributors include modulation of ion currents by an activated
autonomic nervous system and by other neurohormones, the presence of
underlying structural heart disease or ischemia (which may
alter ion channel expression34 or
function35 ), and electrolyte disturbances
secondary to diuretic therapy. In animal models of heart
failure36 37 38 and in studies of human cardiac
myocytes20 obtained from patients with heart failure,
action potential prolongation has been reported to be accompanied by
reductions in Ito and
IK1. More recently, we have reported that mRNA
transcripts for both HERG (the gene encoding
IKr) and Kv4.3 (the gene that
probably encodes Ito39 ) are reduced
in the left ventricles of patients with advanced heart
failure.40 The changes were greater with HERG;
however, because there is not a consistent relationship between
mRNA transcript abundance and encoded protein,41 further
study is necessary to delineate the molecular mechanisms underlying
repolarization abnormalities in heart failure.
Mechanisms of Normalization of QT Abnormalities
Quinidine is a potent blocker of IKr, and
our group has previously reported that even modest elevation of
extracellular potassium markedly inhibits drug block.25
For example, the concentration of quinidine required to half block
IKr was 0.4 µmol/L at
[K+]o of 1 mmol/L and 3.8
µmol/L at [K+]o of 8
mmol/L. Importantly, quinidine also blocks other currents but
generally at concentrations >3 to 10
µmol/L.26 27 28 29 Thus, it is likely that quinidine
block of IKr is a major mechanism underlying the
QT prolongation that the drug produces, and block of other channels, or
autonomic effects,42 may also contribute.
Taken together, the data suggest that the normalization by potassium infusion of quinidine-induced repolarization abnormalities is most likely mediated by increased IKr because of the inhibitory effect of potassium on drug block as well as the recognized effect of potassium to increase this current and IK1. In patients with CHF, on the other hand, the latter mechanism probably contributes. Importantly, this effect of potassium makes no assumptions about the mechanisms underlying QT prolongation. In other words, elevated serum potassium may increase IKr and/or IK1 independently and irrespective of the underlying cause of QT prolongation and hence shorten the QT interval if of sufficient magnitude to shift the balance of inward and outward currents. This scenario would also explain reversal of QT prolongation observed in patients with the congenital LQTS due to mutations in HERG7 and, importantly, would predict a similar effect in patients with other mutations. Increases in other repolarizing potassium currents, such as Ito or IKs, can also shorten the QT interval. However, it is unlikely that these currents are involved in mediating the effect of potassium on the QT interval, because they are not increased by increasing [K+]o. It is even possible that decreased Ito could indirectly cause action potential shortening by altering the phase 1 plateau potential and thereby the balance between inward and other outward currents in phases 2 and 3.
Potassium did not alter QTUc intervals when baseline QTUc interval was normal, either in control subjects for the CHF study or in the placebo arm of the quinidine study. This indicates either that the increases in IKr or IK1 elicited by the changes in potassium are not equivalent to those when QT is prolonged or that under normal conditions, modest increases in these currents elicited by increased potassium are insufficient to significantly alter the balance between inward and outward current during repolarization. It may be that the balance of inward and outward currents late during the action potential is more "delicate" than that earlier in the action potential (ie, that inward and outward currents are smaller later than earlier). In this case, the QT interval would not be expected to shorten beyond normal with a small increase in IKr or IK1 in subjects with normal repolarization. Moreover, IKr activates only after a delay during depolarization, and IK1 passes outward current only at potentials just positive to the resting potential; thus, an increase in these currents would be expected to exert a greater effect late during repolarization than early. The relative roles of IKr and IK1 in mediating [K+]o-induced QT normalization are unknown. IKr probably contributes outward current throughout repolarization, whereas outward IK1 would be most prominent at more negative potentials, corresponding to late phase 3 of the action potential. Indeed, the extent to which IK1 channels conduct outward current is unknown, and some studies have suggested that inward rectification due to [Mg2+]i43 44 may be so prominent as to entirely prevent outward IK1. In this case, our data would suggest a predominant IKr-mediated effect.
Dispersion of the QT interval, a measure of interlead QT variability on the 12-lead ECG, is thought to represent heterogeneous repolarization across the myocardium.45 Shortening of repolarization in areas of the myocardium in which it is abnormally prolonged but not where is it normal would produce more uniform repolarization and thus account for the significant reduction in QT dispersion in response to potassium. In support of this hypothesis was the finding that maximal QTUc was reduced by a greater extent than the minimal QTUc both in quinidine-treated subjects and in CHF patients. Bifid T waves, presumably another marker of heterogeneity in repolarization times in individual cells, were also frequently seen in normal subjects treated with quinidine. This effect was also significantly reversed by potassium, by shortening of the T2 peak time, and to a lesser degree, by increasing T1 time. The mechanism underlying such notching is not well established, although an obvious hypothesis is differences in regional expression of ion channels, such as HERG or others. It is interesting that in patients with LQTS caused by HERG mutations, notched T waves were observed in 6 of 7 patients and were abolished by intravenous potassium.8
The QTUc dispersion values in this study are somewhat
greater than previously reported in other studies.10 18 We
believe this reflects methodological differences in measuring the QT
interval. Others have advocated using the nadir between T and U waves
or a tangent drawn to the baseline from the point of greatest negative
slope of the T wave.46 This approach is difficult to adapt
to abnormal QTU intervals, such as those shown in Fig 1. We have
included a U wave, where present and >25% of the amplitude of the
T wave, in the QTU measurement. When the onset of torsades de pointes
is recorded in all 12 leads
simultaneously,47 a prominent U wave is seen
in some leads but not in others. This in turn raises the possibility
that dispersion measurements may be influenced (to a variable
extent) by U waves present only in some leads. Our approach of
including U waves most likely accounts for the greater QTU dispersion
we see compared with others. However, the results of the study stand,
regardless of the specific method used.
Limitations of the Study
One limitation of this study was that the effects of elevated
potassium on QT interval were studied after an acute
intravenous potassium infusion. Our study does not address
the effects of elevated potassium with chronic oral supplementation.
Another limitation was that baseline and postinfusion serum potassium
tended to be lower in CHF patients than in their control group,
although this was not statistically significant and the mean increase
in serum potassium was similar in both groups. All the CHF patients
were on long-term oral diuretic therapy, and this is likely to
account for their reduced serum potassium compared with control
subjects. Importantly, the use of diuretics has been linked to
increased cardiovascular mortality,48 an
effect that may well be attributable to hypokalemia. It should also be
noted that numbers in the CHF group are small and that two CHF patients
had been on chronic amiodarone treatment. Therefore, the
effects of potassium on the QTU interval in these patients cannot be
separated between effects on amiodarone-induced QT changes or
those related to underlying CHF. Normalization of QT interval and QT
dispersion was seen even with elevations to within the
physiological range (3.5 to 5.0 mEq). Although it
might be argued that more profound and statistically significant
reduction in QT prolongation and QT dispersion could have been achieved
at higher serum potassium levels in these patients, this would be at a
risk of hyperkalemia.
Clinical Implications
Treatment of drug-induced acquired LQTS complicated by torsades de
pointes is aimed at increasing heart rate and prevention of
pause-dependent initiation of polymorphic ventricular
tachycardia. Therapies include isoproterenol, pacing, and
magnesium infusion. On the basis of the data we present here,
intravenous potassium infusion to maintain serum potassium
at the upper limit of the physiological range is
another strategy for the treatment of drug-induced torsades de pointes.
It is unknown whether there is any change in the antiarrhythmic
efficacy of quinidine with reversal of QT prolongation. Elevation of
serum potassium did not appear to alter QRS duration, suggesting that
the sodium channel block remains unaffected. Nonetheless, the impact of
changes in serum potassium on antiarrhythmic efficacy warrants further
clinical investigation with quinidine and other
IKr-blocking drugs because of the obvious
clinical implications. QT prolongation and increased QT dispersion are
predictors of SCD in cardiovascular
dis-ease10 11 12 14 15 16 17 and in otherwise
asymptomatic individuals.48 Normalization of
these abnormalities may be expected to result in reduction of this
risk; however, further studies are required to investigate the impact
of chronically elevated serum potassium on morbidity and mortality in
patients with these QT abnormalities.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants GM-31304 and RR-00095 from the NIH. Dr Choy is a recipient of an American Heart Association Fellowship-in Training Award and the Derrick Dunlop Fellowship. Dr Lang is a recipient of a Merck International Fellowship Award in Clinical Pharmacology. Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corporation.
Received February 11, 1997; revision received May 12, 1997; accepted May 22, 1997.
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