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Effects of hyperkalemia on local changes of repolarization duration in canine left ventricle
J. ELECTROCARDIOLOGY 16 (1), 1983, 1-6
Original Communications Effects of Hyperkalemia on Local Changes of Repolarization Duration in Canine Left Ventricle BY TAKESHI TSUTSUMI, M.D.*, ROLAND F.
WYATT,M.PH.I"
AND J . A . ABILDSKOV, M . D . * *
SUMMARY The effect of hyperkalemia on the distribution of ventricular repolarization properties was investigated using the interval between minimum QRS and m a x i m u m T derivatives of multiple electrograms as a measure of local repolarization duration. Local repolariza. tion duration decreased, with more marked reduction at the epicardium than endocardium near the base, and greater decrease at the endocardium than epicardium near the apex. The nonhomogeneous reduction of repolarization duration helps account for T waveform changes'due to hyperkalemia and may be a factor in the occurrence of reentrant ventricular arrhythmias.
Present knowledge of the distribution of ventricular repolarization properties is largely based on extrastimulus techniques of measuring time of recovery of excitability, and on limited sampling of suction electrode and transmembrane action potential recordings. 1"5 Extensive sampling of cardiac potential distributions has also provided information concerning normal repolarization sequence and that following ectopic stimulation. 6 In this study repolarization duration was measured from the interval between the minimum derivative of the QRS and maximum derivative of the T wave in multiple simultaneously recorded unipolar electrograms.7,s The method was ap-
plied to the evaluation of repolarization changes induced by hyperkalemia. Results showed nonhomogeneous reduction of local repolarization duration, with more marked reduction at the epicardium than the endocardium in basilar pottions of the left ventricle, and more marked reduction at the endocardium than the epicardium near the apex. The spatial pattern of local changes of repolarization duration demonstrated in the study has implications regarding the cardiac basis of T waveform with hyperkalemia, and the nonhomogeneous nature of the changes is likely to be a factor favoring the occurrence of reentrant arrhythmias.
From the Nora Eccles Harrison Cardiovascular Research and Training Institute and the Division of Cardiology, Department of Internal Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. * Research Associate, University of Utah College of Medicine, Salt Lake City, Utah. Present address: Showa University Fujigaoka Hospital, Showa University School of Medicine, 1-30 Fujigaoka, Midori-ku, Yokohama 227, Japan. 1" Research Associate, University of Utah College of Medicine, Salt Lake City, Utah. ** Professor of Medicine, University of Utah College of Medicine, Salt Lake City, Utah. This work was supported by Program Project Grant HL 13480 from the National Institutes of Health and grants from the Nora Eccles Treadwell Foundation and the Richard A: and Nora Eccles Harrision Fund for Cardiovascular Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. w 1734 solely to indicate this fact. Reprint requests to: J.A. Abildskov, M.D., Cardiology Division, Building 100, University of Utah, Salt Lake City, Utah 84112.
Experiments were performed on 11 dogs anesthetized with sodium pentobarbital 30 mgndkg IV. A d d i tional bolus injections of pentobarbital were given as needed to mantain deep anesthesia. Under artificial respiration the chest was opened in the mid line and the pericardium incised, to form a cradle supporting the heart. The sinus node was crushed and bipolar stimulating electrodes were attached to the right atrium. The atrium was paced at a cycle length of 400 msec with square wave stimuli of 2 msec duration and twice threshold voltage. Prior to each experiment an electrode array was prepared by attaching 16 silver wires to a nylon stocking stretched over a plaster cast of a dog heart. The wires were insulated except at the point of attachment to the stocking and were sewn through the fabric and secured with a knot. The electrode-stocking assembly was pulled over the exposed heart and sutured to pericardial reflections. Epicardial electrograms were recorded from the wires attached to the stocking. Endocardial electrograms were obtained from stainless steel hook electrodes. The electrodes were inserted in a
MATERIALS
AND METHODS
2
TSUTSUMI ET AL
~
NYLON STOCKING
EPICARDIAL~
- -LEOI:RODE"X,' ' ENDOOARD'AL ~'L~-Ui t~uur_~XECTRODEX~L
/ POSTERIOR 19 (3) 24 (8) 2 7 2 8 29 ANTERIOR (I I) Cl2) (13) 31 32 (15)(16) (2) 23 (7)
APEX
EPICARDIAL SITES
20 (4) 2_5 (9) 30 (14)
21 (5) 26 (10) POSTERIOR
ENDOCARDIAL SITES
Fig. 1. Location of epicardial and endocardial unipolar leads. Left panel: Location of unipolar electrode sites (I ;hrough 16) on the left ventricular epicardium. The diagram represents a lateral view of the left ventricle. Right panel: Schematic grid indicating endocardial electrode sites (17 through 32}. These electrodes were located op?osite the epicardial electrode sites indicated by the numbers in parentheses. kO = aorta, LA ----left anterior descending coronary, LCX = left circumflex coronary, RtC = right coronary. needle passed through the left ventricular wall. The needle was then withdrawn and the electrode wire pulled gently to approximate the uninsulated tip to the endocardium. Sixteen endocardial electrodes were placed approximately opposite the stocking mounted epicardial electrodes. All electrograms were recorded with the cardiac electrodes referenced to a Wilson Central Terminal. The cardiac location of electrodes is illustrated in Fig. 1. The stocking was moistened with saline and a thermometer placed close to the anterior cardiac surface. The thoracic incision was covered with a clear polyethelene sheet which was attached to the edges of the wound, and heated with a surgical lamp. The distance between lamp and cardiac surface was adjusted to maintain the cardiac surface temperature near 36~ A period of 90 minutes was allowed to elapse for temperature stabilization. Electrograms from all endocardial and epicardial sites were simultaneously sampled at a 1 kHz rate with a 32 channel multiplexer. The sampled analog'ctata were converted to 10 bit digital data and stored on magnetic tape via a Digital Equipment Corporation P D P 11/35 computer. The stored electrograms were
visually reviewed and those with isoelectric T waves or ST segment displacement were discarded. Twenty to 30 electrograms in each experiment were satisfactory for analysis. Electrograms were processed on a P D P 11/60 computer programmed to select the minimum derivative during the QRS as a measure of local activation time and m a x i m u m derivative of the T as an index of recovery time. The selected times were reviewed by the operator and edited when necessary. The interval between the minimum and maximum derivatives was taken as a measure of local repolarization duration. This method of evaluating local repolarization durations has been validated by comparison with in vivo transmembrane action potential durations, close bipolar electrode determinations of activation and recovery times and measurements of refractory periods], s High correlation between measurements obtained from minimum and maximum derivatives of unipolar electrograms and the independent measurements of transmembrane action potentials, bipolar electrograms and refractory periods was demonstrated. Records were obtained in the control state and dur-
J. ELECTROCARDIOLOGY 16 (1), 1983
HYPERKALEMIA AND REPOLARIZATION
3
A
Fig. 2. Distribution of repola~ization durations on the epicardial surface of the heart. Is.c~iuration lines for two experiments are plotted at 5 millisecond increments on a schematic lateral view of the left ventricle. Units are in milliseconds. Panel A" shows a distribution of repolarization durations with the shortest occurring uniformly over the base in the control state. In the control shown in panel B, the shortest repolarization durations occurred at the anteror base. In both experiments IV infusion of 2.0 meq/kg potassium chloride resulted in a general shortening of repolarization durations with the shortest present at the posterior base.
ing IV infusion of 200 cc lactated Ringers solution containing 80 meq potassium chloride at a rate of 0.4 meq KCI per minute. Recordings were made at dose levels of 1.5 and 2 meq KClIkg. Plasma potassium was determined at these dose levels in three experiments. Maps of the distribution of repolarization durations were constructed manually and those in the control state were compared to those during KCI infusion.
RESULTS In the control state the duration of local repolarization was longest at the apex and shortest at the base at the epicardial level in all experiments. A t endocardial sites, repolarization duration was usually longer than t h a t of Corresponding epicardial sites. These data confirm previous evidence of the normal distribution of ventricular recovery properties based on measurements of refractory periods, suction potential recordings and isopotential distributionsJ ~ I t was also noted that two patterns of normal repolarization duration occurred at both epicar-
J. ELECTROCARDIOLOGY 16 (1), 1983
CONTROL
KCL INFUSION 2,0 meq/kg
200
CONTROL
KCL INFUSION 2.0 moq/k!
dial and endocardial levels. Although shorter repolarization durations at the epicardial base compared to the apex were present in all experiments, the shortest repolarization duration was located on the posterior wall in six of the 11 experiments and on the anterior wall or diffusely on the base in the other five experiments. A t the endocardial level, the shortest repolarization durations were present at the base in seven of the 11 experiments. In four experiments however, slightly shorter repolarization durations were present at the apex than at the base in the control state. In these four experiments the difference between the longest and shortest repolarization durations was small, with a maximum of only 10 msec. During potassium infusion, repolarization durations shortened but the degree of shortening was nonhomogeneous. A t the epicardium the distribution of repolarization remained t h a t of shorter durations at the base and longer durations at the apex. The detailed p a t t e r n of epicardial repolar-
4
TSUTSUMI ET AL
A
Fig. 3. Distribution of repolarization durations on the endocardial surface of the heart. Isoduration lines for two experiments are plotted at 5 millisecond increments on a schematic grid of endocardial unipolar electrode sites in the left ventricle. Units are in milliseconds. Panel A shows the usual gradient of longer repbtarization durations at the apex in the control state. The control in panel B shows slightly shorter repolarization durations at the apex. Hyperkalemia induced by IV injections of 2.0 and 1.5 meq/kg potassium chloride shown in panels A and B respectively, resulted in spatial distributions having shorter repolarization durations at the apex in both experiments.
ization durations changed in some experiments however. Thus, in two of the five experiments in which the shortest repolarization durations were present anteriorly or uniformly at the base in the control state, hyperkalemia resulted in the shortest repolarization durations on the posterior base. In the other three experiments the shortest repolarization durations remained on the anterior basal portion of the ventricle during hyperkalemia. In all six experiments in which epicardial repolarization durations were shortest at the posterior base during the control state, the shortest durations remained in this location during hyperkalemia. Fig. 2 illustrates changes of repolarization duration on the epicardial surface in two experiments. In both, repolarization durations at the apex exceeded those at the base in the control state. In the experiment illustrated in panel A, the shortest recovery durations were present uniformly over the base, and in that illustrated in B, shortest recovery was present at the anterior base. During hyperkalemia, repolarization durations decreased and in both experiments the shortest repolarization durations were present at the posterior base. At the endocardial level, repolarization durations were shortest at the apex and longest at the
CONTROL
KCL INFUSION 2.0 meglkg
v~
CONTROL
.
KCL INFUSION 1.5 ~q/kg
base during hyperkalemia in all experiments. This distribution occurred in experiments with both patterns of control endocardial repolarization durations. Fig. 3 shows endocardial distributions of repolarization durations in two experiments. In panel A, the usual gradient of longer repolarization durations at the apex in the control state is shown. Panel B shows an example of slightly shorter repolarization durations at the apex in the control state. Hyperkalemia resulted in a spatial distribution of shorter apical than basal repolarization durations in both experiments. The magnitude of changes of repolarization duration in response to the administered dose of potassium were variable, but the most marked changes were usually associated with the largest total dose. Exceptions to this were probably related to potassium excretion rates in comparison to those of infusion. In those experiments in which they were determined, plasma potassium levels varied from 4.9 to 6.4 meq/l at the dose level of 1.5 meq KCl/kg and 6.2 to 6.9 meq/1 at the dose level of 2 meq KCL/kg. Since the purpose of the study was to determine the spatial pattern of changes of repolarization duration rather than the quantitative relation between potassium levels and magnitude of repolarization J. ELECTROCARDIOLOGY 16 (1), 1983
HYPERKALEMIA AND REPOLARIZATION
A Fig. 4. Distribution of average reductions of repolarization durations during hyperkalemia for all 11 experiments. Units are in milliseconds. Panel A shows a slightly nonuniform average reduction of repolarization durations on the epicardium during hyperkalemia, ttyperkalemia also produced nonuniform average reductions in repolarization durations on the endocardium and, as shown in panel B, the reduction was much greater at the apical than at the basal endocardium. Panel C is a difference plot in which the average reductions in"~ndocardial repolarization durations at each site were subtracted from those on the adjacent epicardium. This plot shows that hyperkalemia produced greater shortening on the epicardium at the base while at the apex shortening was greatest on the endocardium. The zero line defines the locus of points having equal shortening on the epicardium and endocardium.
/
///~ //
changes, the states with maximal shortening of repolarization duration were pooled. Fig. 4 shows the distribution of average reductions of repolarization durations from these data. As shown, the average reductions in repolarization duration at the epicardium were more marked than those at the endocardium at the basilar portion of the sampled area. In contrast, the average reduction of repolarization durations near the apex was more marked at endocardial than at epicardial sites. These findings indicate that the normal gradient of repolarization durations on the endocardial-epicardial axis with longer durations at the endocardial level was increased near the base and reduced near the apex. A t both endocardial and epicardial levels the absolute reduction of repolarization durations was more marked at the apex than at the base. The normal apex to base gradient of repolarization durations with longer durations at the apex was therefore reduced by hyperkalemia.
DISCUSSION This s t u d y demonstrated that effect of hyperkalemia on the duration of local ventricular repolarization are nonhomogeneous and have a J. ELECTROCARDIOLOGY 16 (1), 1983
5
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distinctive spatial pattern. The s t u d y also added new detail to the definition of normal ventricular repolarization durations. Major features of the normal distribution, namely endocardial-epicardial and apical-base gradients with longer repolarization durations at the endocardium and apex as indicated b y refractory period measurements, were confirmed. In addition, it was shown that the shortest repolarization duration could be located either anteriorly, posteriorly or diffusely at the basal epicardium. It was also shown that, although the usual apex-base gradient at the endocardium consisted of longer repolarization durations at the apex, there were exceptions, and in four of the 11 experiments, durations were slightly shorter at the apex than the base. Hyperkalemia resulted in reduced duration of local repolarization durations at most locations b u t the degree of reduction was nonuniform and resulted in a distinctive spatial pattern of durations. The pattern was characterized by longer durations at the apex than at the base at the epicardial level and shorter apical than basal durations at the endocardium. Near the base, reductions of repolarization duration were more marked at the epicardium than endocardium, while reductions at the apex were more marked at
6
TSUTSUMI ET AL
endocardial than at epicardial sites. The normal endocardial-epicardial gradient of repolarization durations was therefore increased near the base and reduced near the apex. Absolute reductions of repolarization durations were more marked at the apex than base at both endocardial and epicardial levels, tending to reduce the normal apex-base gradient or repolarization durations. The mechanism of the nonhomogeneous effect of hyperkalemia on local duration of repolarization is not evident from this study. Differences in the degree of local potassium levels related to differences of regional blood flow or differences in the sensitivity of various regions to particular potassium levels are among the possible mechanisms. More-marked reduction of action potential duration in Purkinje fibers than in myocardial cells by increased potassium levels has been demonstrated9 and m a y be a factor in findings of this study. Findings included more marked reduction of repolarization duration at endocardial than at epicardial levels near the apex. It is possible that reduction of repolarization duration in Purkinje fibers m a y electrotonically reduce durations in myocardial cells and that this effect is most marked near the apex where Purkinje fiber density is highJ 0 Further studies will be required to elucidate the mechanism of the nonuniform effects of hyperkalemia on local repolarization durations shown in this study. Whatever the responsible mechanism, the nonuniform effects of hyperkalemia on local repolarization duration have significance with respect to electrocardiographic T waveform and have probable significance regarding cardiac arrhythmias. One of the usual electrocardiographic manifestat i o n s of hyperkalemia is high peaked T waves in ibody surface leads compatible with an increased !gradient of repolarization durations on the ~endocardial-epicardial axis. This s t u d y showed such an increase in the basal portion of the left ventricle and suggests that high T waves are at least in part the result of more marked reduction of repolarization duration in the basal epicardium than at corresponding endocardial sites. The slightly reduced apex-base gradient of repolarization duration on the epicardium and reversed gra.dient on the endocardium are also compatible with high T waves in superior-inferior leads such as II, III, AVF and lead Y of orthogonal lead systems. The normal apex-base gradient with longer repolarization durations at the apex operates in the direction of reducing T wave amplitude in such vertical leads, and reduction of
the gradient can be expected to increase T wave amplitude. The relation between disparate repolarization durations and vulnerability to r e e n t r a n t arrhythmias is well established as is that between hyperkalemia and ventricular tachycardias. The finding in this study of nonhomogeneous effects on local repolarization d u r a t i o n s including evidence of an increased gradient of these durations in some regions suggest that disparate repolarization is one of the factors in ventricular arrhythmias due to hyperkalemia.
REFERENCES 1. VANDAM, R T ANDDURRER,D: Experimental study
on the intramural distribution of the excitability cycle and on the form of the epicardial T wave in the dog heart in situ. Am Heart J 61:537, 1961 2. BURGESS,M J, GREEN,L S, MILLAR'K, WYATT,R ANDAmLDSKOV,J A: The sequence of normal ventricular recovery.Am Heart J 84:660, 1972 3. AUTENRIETII, G, SURAWICZ,B AND KUO, C S: Sequence of repolarizationon the ventricularsurfacein the dog. Am Heart J 89:463, 1975 4. TOYOSIIIMA,H, Lux, R L, WYATT,R F, BURGESS, M
J ANn ABILDSKOV, J A: Sequence of early and late phases of repolarization on dog ventricular epicardium. J Electrocardiol 14:143, 1981 5. ABILDSKOV,J A: The sequence of normal recovery of excitability in the dog heart. Circulation 52:442, 1975 6. SPACH,M S AND BARR, R C: Ventricular intramural and epicardial potential distributions during ventricular activation and repolarization in the intact dog. Circ Res 37:243, 1975 7. WYATT,R F, BURGESS,M J, EVANS,A K, Lux, R L, TSUTSUMI, T ANDABILDSKOV, J A: Estimation of ventricular transmembrane action potential durations and repolarizationtimes from unipo]ar electrograms. Am J Cardio] 47:488, 1981 (abstract) 8. WYATT,R F: Comparison of estimates of activation and recovery times from bipolar and unipolar electrograms to in vivo transmembrane action potential durations. Proc. I E.E.E.IEngineering in Medicine and BiologySociety,2nd Annual Conference,Washington, D C, 1980, pp 22-25 9. CARMELIET,E ANn VEREECKE,J: Electrogenesis of
the action potential and automaticity. In: Handbook of Physiology, Section 2: The Cardiovascular System. R M BERNE, N SPERELAKIS AND S R GEIGER, Eds. American Physiological Society, Bethesda, 1979, pp 269-334 I0. MENDEZ,C, MULLER,W J, MERIDETll, J ANDMOE, G K: Interaction of transmembrane potentials in canine Purkinje fibers and at Purkinje fiber muscle junctions. Circ Res 24:361, 1969
J. ELECTROCARDIOLOGY 16 (1), 1983
Original Communications Effects of Hyperkalemia on Local Changes of Repolarization Duration in Canine Left Ventricle BY TAKESHI TSUTSUMI, M.D.*, ROLAND F.
WYATT,M.PH.I"
AND J . A . ABILDSKOV, M . D . * *
SUMMARY The effect of hyperkalemia on the distribution of ventricular repolarization properties was investigated using the interval between minimum QRS and m a x i m u m T derivatives of multiple electrograms as a measure of local repolarization duration. Local repolariza. tion duration decreased, with more marked reduction at the epicardium than endocardium near the base, and greater decrease at the endocardium than epicardium near the apex. The nonhomogeneous reduction of repolarization duration helps account for T waveform changes'due to hyperkalemia and may be a factor in the occurrence of reentrant ventricular arrhythmias.
Present knowledge of the distribution of ventricular repolarization properties is largely based on extrastimulus techniques of measuring time of recovery of excitability, and on limited sampling of suction electrode and transmembrane action potential recordings. 1"5 Extensive sampling of cardiac potential distributions has also provided information concerning normal repolarization sequence and that following ectopic stimulation. 6 In this study repolarization duration was measured from the interval between the minimum derivative of the QRS and maximum derivative of the T wave in multiple simultaneously recorded unipolar electrograms.7,s The method was ap-
plied to the evaluation of repolarization changes induced by hyperkalemia. Results showed nonhomogeneous reduction of local repolarization duration, with more marked reduction at the epicardium than the endocardium in basilar pottions of the left ventricle, and more marked reduction at the endocardium than the epicardium near the apex. The spatial pattern of local changes of repolarization duration demonstrated in the study has implications regarding the cardiac basis of T waveform with hyperkalemia, and the nonhomogeneous nature of the changes is likely to be a factor favoring the occurrence of reentrant arrhythmias.
From the Nora Eccles Harrison Cardiovascular Research and Training Institute and the Division of Cardiology, Department of Internal Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. * Research Associate, University of Utah College of Medicine, Salt Lake City, Utah. Present address: Showa University Fujigaoka Hospital, Showa University School of Medicine, 1-30 Fujigaoka, Midori-ku, Yokohama 227, Japan. 1" Research Associate, University of Utah College of Medicine, Salt Lake City, Utah. ** Professor of Medicine, University of Utah College of Medicine, Salt Lake City, Utah. This work was supported by Program Project Grant HL 13480 from the National Institutes of Health and grants from the Nora Eccles Treadwell Foundation and the Richard A: and Nora Eccles Harrision Fund for Cardiovascular Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. w 1734 solely to indicate this fact. Reprint requests to: J.A. Abildskov, M.D., Cardiology Division, Building 100, University of Utah, Salt Lake City, Utah 84112.
Experiments were performed on 11 dogs anesthetized with sodium pentobarbital 30 mgndkg IV. A d d i tional bolus injections of pentobarbital were given as needed to mantain deep anesthesia. Under artificial respiration the chest was opened in the mid line and the pericardium incised, to form a cradle supporting the heart. The sinus node was crushed and bipolar stimulating electrodes were attached to the right atrium. The atrium was paced at a cycle length of 400 msec with square wave stimuli of 2 msec duration and twice threshold voltage. Prior to each experiment an electrode array was prepared by attaching 16 silver wires to a nylon stocking stretched over a plaster cast of a dog heart. The wires were insulated except at the point of attachment to the stocking and were sewn through the fabric and secured with a knot. The electrode-stocking assembly was pulled over the exposed heart and sutured to pericardial reflections. Epicardial electrograms were recorded from the wires attached to the stocking. Endocardial electrograms were obtained from stainless steel hook electrodes. The electrodes were inserted in a
MATERIALS
AND METHODS
2
TSUTSUMI ET AL
~
NYLON STOCKING
EPICARDIAL~
- -LEOI:RODE"X,' ' ENDOOARD'AL ~'L~-Ui t~uur_~XECTRODEX~L
/ POSTERIOR 19 (3) 24 (8) 2 7 2 8 29 ANTERIOR (I I) Cl2) (13) 31 32 (15)(16) (2) 23 (7)
APEX
EPICARDIAL SITES
20 (4) 2_5 (9) 30 (14)
21 (5) 26 (10) POSTERIOR
ENDOCARDIAL SITES
Fig. 1. Location of epicardial and endocardial unipolar leads. Left panel: Location of unipolar electrode sites (I ;hrough 16) on the left ventricular epicardium. The diagram represents a lateral view of the left ventricle. Right panel: Schematic grid indicating endocardial electrode sites (17 through 32}. These electrodes were located op?osite the epicardial electrode sites indicated by the numbers in parentheses. kO = aorta, LA ----left anterior descending coronary, LCX = left circumflex coronary, RtC = right coronary. needle passed through the left ventricular wall. The needle was then withdrawn and the electrode wire pulled gently to approximate the uninsulated tip to the endocardium. Sixteen endocardial electrodes were placed approximately opposite the stocking mounted epicardial electrodes. All electrograms were recorded with the cardiac electrodes referenced to a Wilson Central Terminal. The cardiac location of electrodes is illustrated in Fig. 1. The stocking was moistened with saline and a thermometer placed close to the anterior cardiac surface. The thoracic incision was covered with a clear polyethelene sheet which was attached to the edges of the wound, and heated with a surgical lamp. The distance between lamp and cardiac surface was adjusted to maintain the cardiac surface temperature near 36~ A period of 90 minutes was allowed to elapse for temperature stabilization. Electrograms from all endocardial and epicardial sites were simultaneously sampled at a 1 kHz rate with a 32 channel multiplexer. The sampled analog'ctata were converted to 10 bit digital data and stored on magnetic tape via a Digital Equipment Corporation P D P 11/35 computer. The stored electrograms were
visually reviewed and those with isoelectric T waves or ST segment displacement were discarded. Twenty to 30 electrograms in each experiment were satisfactory for analysis. Electrograms were processed on a P D P 11/60 computer programmed to select the minimum derivative during the QRS as a measure of local activation time and m a x i m u m derivative of the T as an index of recovery time. The selected times were reviewed by the operator and edited when necessary. The interval between the minimum and maximum derivatives was taken as a measure of local repolarization duration. This method of evaluating local repolarization durations has been validated by comparison with in vivo transmembrane action potential durations, close bipolar electrode determinations of activation and recovery times and measurements of refractory periods], s High correlation between measurements obtained from minimum and maximum derivatives of unipolar electrograms and the independent measurements of transmembrane action potentials, bipolar electrograms and refractory periods was demonstrated. Records were obtained in the control state and dur-
J. ELECTROCARDIOLOGY 16 (1), 1983
HYPERKALEMIA AND REPOLARIZATION
3
A
Fig. 2. Distribution of repola~ization durations on the epicardial surface of the heart. Is.c~iuration lines for two experiments are plotted at 5 millisecond increments on a schematic lateral view of the left ventricle. Units are in milliseconds. Panel A" shows a distribution of repolarization durations with the shortest occurring uniformly over the base in the control state. In the control shown in panel B, the shortest repolarization durations occurred at the anteror base. In both experiments IV infusion of 2.0 meq/kg potassium chloride resulted in a general shortening of repolarization durations with the shortest present at the posterior base.
ing IV infusion of 200 cc lactated Ringers solution containing 80 meq potassium chloride at a rate of 0.4 meq KCI per minute. Recordings were made at dose levels of 1.5 and 2 meq KClIkg. Plasma potassium was determined at these dose levels in three experiments. Maps of the distribution of repolarization durations were constructed manually and those in the control state were compared to those during KCI infusion.
RESULTS In the control state the duration of local repolarization was longest at the apex and shortest at the base at the epicardial level in all experiments. A t endocardial sites, repolarization duration was usually longer than t h a t of Corresponding epicardial sites. These data confirm previous evidence of the normal distribution of ventricular recovery properties based on measurements of refractory periods, suction potential recordings and isopotential distributionsJ ~ I t was also noted that two patterns of normal repolarization duration occurred at both epicar-
J. ELECTROCARDIOLOGY 16 (1), 1983
CONTROL
KCL INFUSION 2,0 meq/kg
200
CONTROL
KCL INFUSION 2.0 moq/k!
dial and endocardial levels. Although shorter repolarization durations at the epicardial base compared to the apex were present in all experiments, the shortest repolarization duration was located on the posterior wall in six of the 11 experiments and on the anterior wall or diffusely on the base in the other five experiments. A t the endocardial level, the shortest repolarization durations were present at the base in seven of the 11 experiments. In four experiments however, slightly shorter repolarization durations were present at the apex than at the base in the control state. In these four experiments the difference between the longest and shortest repolarization durations was small, with a maximum of only 10 msec. During potassium infusion, repolarization durations shortened but the degree of shortening was nonhomogeneous. A t the epicardium the distribution of repolarization remained t h a t of shorter durations at the base and longer durations at the apex. The detailed p a t t e r n of epicardial repolar-
4
TSUTSUMI ET AL
A
Fig. 3. Distribution of repolarization durations on the endocardial surface of the heart. Isoduration lines for two experiments are plotted at 5 millisecond increments on a schematic grid of endocardial unipolar electrode sites in the left ventricle. Units are in milliseconds. Panel A shows the usual gradient of longer repbtarization durations at the apex in the control state. The control in panel B shows slightly shorter repolarization durations at the apex. Hyperkalemia induced by IV injections of 2.0 and 1.5 meq/kg potassium chloride shown in panels A and B respectively, resulted in spatial distributions having shorter repolarization durations at the apex in both experiments.
ization durations changed in some experiments however. Thus, in two of the five experiments in which the shortest repolarization durations were present anteriorly or uniformly at the base in the control state, hyperkalemia resulted in the shortest repolarization durations on the posterior base. In the other three experiments the shortest repolarization durations remained on the anterior basal portion of the ventricle during hyperkalemia. In all six experiments in which epicardial repolarization durations were shortest at the posterior base during the control state, the shortest durations remained in this location during hyperkalemia. Fig. 2 illustrates changes of repolarization duration on the epicardial surface in two experiments. In both, repolarization durations at the apex exceeded those at the base in the control state. In the experiment illustrated in panel A, the shortest recovery durations were present uniformly over the base, and in that illustrated in B, shortest recovery was present at the anterior base. During hyperkalemia, repolarization durations decreased and in both experiments the shortest repolarization durations were present at the posterior base. At the endocardial level, repolarization durations were shortest at the apex and longest at the
CONTROL
KCL INFUSION 2.0 meglkg
v~
CONTROL
.
KCL INFUSION 1.5 ~q/kg
base during hyperkalemia in all experiments. This distribution occurred in experiments with both patterns of control endocardial repolarization durations. Fig. 3 shows endocardial distributions of repolarization durations in two experiments. In panel A, the usual gradient of longer repolarization durations at the apex in the control state is shown. Panel B shows an example of slightly shorter repolarization durations at the apex in the control state. Hyperkalemia resulted in a spatial distribution of shorter apical than basal repolarization durations in both experiments. The magnitude of changes of repolarization duration in response to the administered dose of potassium were variable, but the most marked changes were usually associated with the largest total dose. Exceptions to this were probably related to potassium excretion rates in comparison to those of infusion. In those experiments in which they were determined, plasma potassium levels varied from 4.9 to 6.4 meq/l at the dose level of 1.5 meq KCl/kg and 6.2 to 6.9 meq/1 at the dose level of 2 meq KCL/kg. Since the purpose of the study was to determine the spatial pattern of changes of repolarization duration rather than the quantitative relation between potassium levels and magnitude of repolarization J. ELECTROCARDIOLOGY 16 (1), 1983
HYPERKALEMIA AND REPOLARIZATION
A Fig. 4. Distribution of average reductions of repolarization durations during hyperkalemia for all 11 experiments. Units are in milliseconds. Panel A shows a slightly nonuniform average reduction of repolarization durations on the epicardium during hyperkalemia, ttyperkalemia also produced nonuniform average reductions in repolarization durations on the endocardium and, as shown in panel B, the reduction was much greater at the apical than at the basal endocardium. Panel C is a difference plot in which the average reductions in"~ndocardial repolarization durations at each site were subtracted from those on the adjacent epicardium. This plot shows that hyperkalemia produced greater shortening on the epicardium at the base while at the apex shortening was greatest on the endocardium. The zero line defines the locus of points having equal shortening on the epicardium and endocardium.
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changes, the states with maximal shortening of repolarization duration were pooled. Fig. 4 shows the distribution of average reductions of repolarization durations from these data. As shown, the average reductions in repolarization duration at the epicardium were more marked than those at the endocardium at the basilar portion of the sampled area. In contrast, the average reduction of repolarization durations near the apex was more marked at endocardial than at epicardial sites. These findings indicate that the normal gradient of repolarization durations on the endocardial-epicardial axis with longer durations at the endocardial level was increased near the base and reduced near the apex. A t both endocardial and epicardial levels the absolute reduction of repolarization durations was more marked at the apex than at the base. The normal apex to base gradient of repolarization durations with longer durations at the apex was therefore reduced by hyperkalemia.
DISCUSSION This s t u d y demonstrated that effect of hyperkalemia on the duration of local ventricular repolarization are nonhomogeneous and have a J. ELECTROCARDIOLOGY 16 (1), 1983
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distinctive spatial pattern. The s t u d y also added new detail to the definition of normal ventricular repolarization durations. Major features of the normal distribution, namely endocardial-epicardial and apical-base gradients with longer repolarization durations at the endocardium and apex as indicated b y refractory period measurements, were confirmed. In addition, it was shown that the shortest repolarization duration could be located either anteriorly, posteriorly or diffusely at the basal epicardium. It was also shown that, although the usual apex-base gradient at the endocardium consisted of longer repolarization durations at the apex, there were exceptions, and in four of the 11 experiments, durations were slightly shorter at the apex than the base. Hyperkalemia resulted in reduced duration of local repolarization durations at most locations b u t the degree of reduction was nonuniform and resulted in a distinctive spatial pattern of durations. The pattern was characterized by longer durations at the apex than at the base at the epicardial level and shorter apical than basal durations at the endocardium. Near the base, reductions of repolarization duration were more marked at the epicardium than endocardium, while reductions at the apex were more marked at
6
TSUTSUMI ET AL
endocardial than at epicardial sites. The normal endocardial-epicardial gradient of repolarization durations was therefore increased near the base and reduced near the apex. Absolute reductions of repolarization durations were more marked at the apex than base at both endocardial and epicardial levels, tending to reduce the normal apex-base gradient or repolarization durations. The mechanism of the nonhomogeneous effect of hyperkalemia on local duration of repolarization is not evident from this study. Differences in the degree of local potassium levels related to differences of regional blood flow or differences in the sensitivity of various regions to particular potassium levels are among the possible mechanisms. More-marked reduction of action potential duration in Purkinje fibers than in myocardial cells by increased potassium levels has been demonstrated9 and m a y be a factor in findings of this study. Findings included more marked reduction of repolarization duration at endocardial than at epicardial levels near the apex. It is possible that reduction of repolarization duration in Purkinje fibers m a y electrotonically reduce durations in myocardial cells and that this effect is most marked near the apex where Purkinje fiber density is highJ 0 Further studies will be required to elucidate the mechanism of the nonuniform effects of hyperkalemia on local repolarization durations shown in this study. Whatever the responsible mechanism, the nonuniform effects of hyperkalemia on local repolarization duration have significance with respect to electrocardiographic T waveform and have probable significance regarding cardiac arrhythmias. One of the usual electrocardiographic manifestat i o n s of hyperkalemia is high peaked T waves in ibody surface leads compatible with an increased !gradient of repolarization durations on the ~endocardial-epicardial axis. This s t u d y showed such an increase in the basal portion of the left ventricle and suggests that high T waves are at least in part the result of more marked reduction of repolarization duration in the basal epicardium than at corresponding endocardial sites. The slightly reduced apex-base gradient of repolarization duration on the epicardium and reversed gra.dient on the endocardium are also compatible with high T waves in superior-inferior leads such as II, III, AVF and lead Y of orthogonal lead systems. The normal apex-base gradient with longer repolarization durations at the apex operates in the direction of reducing T wave amplitude in such vertical leads, and reduction of
the gradient can be expected to increase T wave amplitude. The relation between disparate repolarization durations and vulnerability to r e e n t r a n t arrhythmias is well established as is that between hyperkalemia and ventricular tachycardias. The finding in this study of nonhomogeneous effects on local repolarization d u r a t i o n s including evidence of an increased gradient of these durations in some regions suggest that disparate repolarization is one of the factors in ventricular arrhythmias due to hyperkalemia.
REFERENCES 1. VANDAM, R T ANDDURRER,D: Experimental study
on the intramural distribution of the excitability cycle and on the form of the epicardial T wave in the dog heart in situ. Am Heart J 61:537, 1961 2. BURGESS,M J, GREEN,L S, MILLAR'K, WYATT,R ANDAmLDSKOV,J A: The sequence of normal ventricular recovery.Am Heart J 84:660, 1972 3. AUTENRIETII, G, SURAWICZ,B AND KUO, C S: Sequence of repolarizationon the ventricularsurfacein the dog. Am Heart J 89:463, 1975 4. TOYOSIIIMA,H, Lux, R L, WYATT,R F, BURGESS, M
J ANn ABILDSKOV, J A: Sequence of early and late phases of repolarization on dog ventricular epicardium. J Electrocardiol 14:143, 1981 5. ABILDSKOV,J A: The sequence of normal recovery of excitability in the dog heart. Circulation 52:442, 1975 6. SPACH,M S AND BARR, R C: Ventricular intramural and epicardial potential distributions during ventricular activation and repolarization in the intact dog. Circ Res 37:243, 1975 7. WYATT,R F, BURGESS,M J, EVANS,A K, Lux, R L, TSUTSUMI, T ANDABILDSKOV, J A: Estimation of ventricular transmembrane action potential durations and repolarizationtimes from unipo]ar electrograms. Am J Cardio] 47:488, 1981 (abstract) 8. WYATT,R F: Comparison of estimates of activation and recovery times from bipolar and unipolar electrograms to in vivo transmembrane action potential durations. Proc. I E.E.E.IEngineering in Medicine and BiologySociety,2nd Annual Conference,Washington, D C, 1980, pp 22-25 9. CARMELIET,E ANn VEREECKE,J: Electrogenesis of
the action potential and automaticity. In: Handbook of Physiology, Section 2: The Cardiovascular System. R M BERNE, N SPERELAKIS AND S R GEIGER, Eds. American Physiological Society, Bethesda, 1979, pp 269-334 I0. MENDEZ,C, MULLER,W J, MERIDETll, J ANDMOE, G K: Interaction of transmembrane potentials in canine Purkinje fibers and at Purkinje fiber muscle junctions. Circ Res 24:361, 1969
J. ELECTROCARDIOLOGY 16 (1), 1983