Effect of gallopamil on electrophysiologic abnormalities and ventricular arrhythmias associated with left ventricular hypertrophy in the feline heart

Effect of gallopamil on electrophysiologic abnormalities and ventricular arrhythmias associated with left ventricular hypertrophy the feline heart

in

Left ventricular hypertrophy increases vulnerability to ventricular fibrillation. To determine whether calcium channel blockade protects against ventricular arrhythmia in left ventricular hypertrophy, we studied the effects of gallopamil, a potent and specific calcium channel antagonist, in 37 cats undergoing aortic banding (group 1, n = 28) or a sham procedure (group 2, n = 9). Each cat underwent serial echocardiography and was studied after the development of left ventricular hypertrophy, defined as an increase of at least 30% in left ventricular posterior wall thickness. After baseline electrophysiologic testing, animals received gallopamil (70 pglkg loading dose followed by 2.5 pglkglmin infusion) (n = 19) or a control infusion of saline solution (n = 18), and testing was repeated. There was no significant difference between groups 1 and 2 in baseline excitability thresholds intraventricular conduction times, ventricular effective refractory periods, or monophasic action potential durations. Thresholds for induction of ventricular fibrillation were lower in group 1 than in group 2, and only in group 1 was ventricular fibrillation inducible during programmed stimulation. This altered vulnerability was associated with a significantly greater dispersion of excitability thresholds, ventricular effective refractory periods, and monophasic action potential durations. Gallopamil did not change baseline measurements except for prolonging sinus cycle length and atrioventricular conduction time. Ventricular fibrillation thresholds were similar to pretreatment values (12.3 + 2 vs 11.9 ? 3 mA; p = NS) as were dispersion of excitability thresholds (0.45 t 0.17 vs 0.49 ? 0.14 mA; p = NS), ventricular effective refractory periods (30.5 f 9 vs 33.6 + 12 msec; p = NS), and monophasic action potential durations (27.5 t 11 vs 28.2 + 14 msec; p = NS). A similar percentage of animals in group I were inducible by programmed stimulation before and after treatment with gallopamil (11/14 vs 8/12; p = NS). Thus calcium channel blockade, even with a potent agent, does not protect against susceptibility to ventricular arrhythmia caused by left ventricular hypertrophy. (AM HEART J 1992;124:898.)

Peter R. Kowey, MD, Robert O’Brien, PhD, Ying Wu, MD, Joseph Sewter, BS, Alexis Sokil, MD, James Nocella, RCVT, and Seth J. Rials, MD, PhD Wynnewood and Philadelphia,

Pa.

Hypertrophic heart disease is associated with an increased incidence of ventricular arrhythmias, some of which may be lethal. l-3 Treatment of hypertension appears to improve the prognosis, but whether this salutary effect is mediated by an antiarrhythmic efFrom the Cardiovascular Research Laboratories of The Lankenau Hospital and Medical Research Center, and The Medical College of Pennsylvania. Supported in part by a grant-in-aid from the Southeastern Pennsylvania Chapter of the American Heart Association and by a grant from Knoll Pharmaceuticals, Whippany, N.J. Received for publication Feb. 24, 1992; accepted April 10, 1992. Reprint requests: Peter R. Kowey, MD, Division of Cardiovascular Diseases, The Lankenau Hospital, 100 Lancaster Ave., Room 2221 Medical Science Building, Wynnewood, PA 19096. 4/l/39817

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feet of the antihypertensive medication has been the subject of intense controversy. It has recently come to light that calcium channel antagonists not only lower blood pressure but also cause regression of left ventricular hypertrophy. 4, 5 Furthermore, verapamil appears to reduce the frequency of ventricular ectopic beats in association with its effect on left ventricular mass.4 It remains to be determined whether calcium channel antagonists have a direct antiarrhythmic effect on the hypertrophied myocardium or whether the protective effects that have been described are attributable to some other mechanism, such as reduction of left ventricular mass or a chronic decrease in left ventricular afterload. To examine this question we produced left ventricular hypertro-

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phy in a feline model, acutely administered a potent calcium channel antagonist (gallopamil), and studied the effects of this agent on the electrophysiologic abnormalities associated with hypertrophy. METHODS General methods. Forty semiconditioned cats of either sex were used in the study. All experiments were carried out in conformance with guidelines established by the American Heart Association concerning use of research animals and in accordance with a protocol approved by the animal care and use committee at our institution. Animals were anesthetized with ketamine (10 mg/kg intramuscularly followed by 2.5 mg/kg intravenously), a cuffed endotracheal tube was placed, and the lungs were ventilated with nitrous oxide and oxygen via a Harvard respirator (Harvard Apparatus Co., Inc., South Natick, Mass.) with parameters adjusted to maintain POT, PCOZ, and pH within physiologic range. A heating blanket was used to regulate body temperature. Under sterile conditions a small right anterior thoracotomy was performed one interspace superior to the cardiac apical impulse. The pericardium was opened, and the plane between the aorta and pulmonary artery was dissected. In 30 animals a band consisting of polyethylene tubing with 24-gauge copper wire and 00 silk suture through its lumen was preformed into a circle with an internal diameter of 3.2 to 3.5 mm and placed around the ascending aorta, then sutured into place. Banding was not carried out in the other 10 animals. The chest was closed and the animals recovered. Biweekly echocardiographic/Doppler ultrasound studies were performed. After light sedation each animal was studied by means of an Irex Meridian echocardiograph (Johnson & Johnson, Ramsey, N.J.) with a 5 MHz phasedarray transducer. Diastolic measurements of the thickness of the left ventricular posterior wall were made from a derived M-mode image at the level between the mitral valve and papillary muscle by use of the leading-edge method. A 2.0 MHz continuous-wave imaging transducer was used to obtain Doppler flow signals in the aorta. During surgical exposure the transducer was placed 12 mm above the band and angulated into the left ventricular cavity. The audible signal was optimized to obtain the highest velocities, and the subsequent spectral display was frozen. On-line measurements of peak velocity were obtained and converted to peak pressure gradients by means of the modified Bernoulli equation. These flow velocity spectra were then recorded with the use of a strip-chart recorder for later reference. The animals underwent an electrophysiologic study when left ventricular wall thickness had increased by at least 30 “E over the values in the initial postoperative study. Animals were reanesthetized with 50 to 70 mg/kg of oc-chloralose delivered intraperitoneally. The femoral artery and vein were cannulated to measure blood pressure and administer drugs. A thoracotomy was performed and the pericardium opened. Paired transmural plunge electrodes were positioned on the anterior, posterolateral, and apical left ventricle and the anterior right ventricle. The sites were selected by proximity of major coronary artery distribu-

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tions. Endocardial pacing catheters were passedfrom the atria1 appendagesto the right and left ventricular apexes. After electrical testing the animals were killed and the hearts removed. The left ventricular wall thickness was measuredwith calipers and the left ventricle weighed. Electrical testing. A Bloom stimulator (Bloom Ltd., Reading, Pa.) wasusedto deliver constant-current rectangular impulses ranging from 0.1 to 100 mA with pulse widths of 2 to 5 msec.Electrogramswere amplified and recorded on a VR 12 physiologic recorder (Electronics-forMedicine, Kingwood, Texas). Conduction time wasdefined asthe time elapsedbetween the earliest and latest activations seenat any of the recording sites. The onset of ventricular activation wasregarded asthe point at which the initial rapid deflection of the electrogram crossedthe baseline. Excitability threshold was defined as the minimum current that causedconsistent ventricular capture. Ventricular effective refractory periodswere obtained by useof twice threshold extrastimuli delivered in 10 msec decrementsduring ventricular pacing at the longestcycle length that consistently captured the ventricle. Mean paced cycle lengths did not vary among experiments by more than 30 msec.The effective refractory period was recorded as the longest SiSs coupling interval that failed to capture the ventricle. Monophasic action potentials were recorded on the epicardial surface adjacent to the site of plunge electrode placement by means of a hand-held Franz contact electrode (model 501, EP Technologies Inc., Mountainview, Calif.). Monophasic action potential durations were measured where the downward deflection of the signal had reached90% (MAPDSO) and 50% (MAPD50) of complete repolarization. The value reported for each electrophysiologic parameter actually represents a mean for all sites tested in eachchamber.Dispersionof thoseparameterswas defined asthe maximum difference among all sitestested either within or between the right and left ventricles. Endocardial catheters were used to measure ventricular fibrillation thresholds. For this purpose we used the single-stimulustechnique describedpreviously.6 A 5 msec extrastimulus was introduced in midelectrical diastole during ventricular pacing at an initial intensity of 4 mA. The vulnerable period wasscannedin 10msecdecrements until refractorinesswasreached.The current wasincreased in 2 mA increments, and scanningof the vulnerable period continued with incremental currents until ventricular fibrillation was induced. The arrhythmia was terminated within 15 secondsof its initiation by meansof a lo- to 20joule shock applied directly to the heart. Testing was repeated to ensurereproducibility. Inducibility of ventricular arrhythmia wasalsoassessed with the useof endocardial catheters. At twice threshold a 2 msecextrastimulus wasdelivered during ventricular drive. The method of extrastimulation usedwas the sameas that reported previ0us1y.~An initial extrastimulus (Ss)wasset 250 msecafter the pacing artifact and delivered decrementally until refractoriness.If a sustainedarrhythmia wasnot provoked, a second (Ss) and then a third (SQ)extrastimulus was introduced. The end point of testing was the induction of

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American

LV-LV Sham Banded

‘1 I-

*

*

TT

October 1992 Heart Journal

LV-RV Sham Banded *

*

TT

0 Saline &j Gallopamil

Fig. 1. Bar graph showingdispersionof refractoriness measuredin milliseconds(msec) amongsitesin the ventricle (LV-LV) and between right ventricle and left ventricle (LV-RV) of sham-operatedand banded cats, before and after infusion of either salinesolution or gallopamil. Banded animalsshowedsignificantly greater dispersionin LV-LV and between LV-RV than did sham-operatedanimals (*p < 0.005 vs sham group). Increased dispersion was not affected by gallopamil or saline. Table I. Hypertrophy indexes Sham-operated (n = 9)

Banded fn = 28)

LV Posteriorwall thickness(cm)

0.42 + 0.027

0.64 f 0.064*

Heart weight (gm) VO of LV/heart weight Doppler gradient (mm Hg)

13.9 * 3.1 66 I~I 2.6

14.7 f 3.6 76 k 3.3 25.9 i- 12.3

*p < 0.001.

a sustainedarrhythmia (lasting >30 secondsor causinghemodynamic instability). If an arrhythmia wasinduced, the testing was repeated to ensure reproducibility. Experimental design. Of the 40 animalsoriginally prepared, 37 survived to repeat study (28 banded and 9 sham operated), After control measurementswere obtained, 19 (14 banded and 5 shamoperated) received gallopamil in a loading doseof 70pg/kg followed by 2.5 ~g/kg/min, whereas the other 18 (14 banded and 4 sham operated) received a control doseof saline solution. Testing wasthen repeated, after which the animalswerekilled asdescribedpreviously. Resultspresentedin the text, tables, and figures represent mean f standard deviation. Student’s t test was used for simple two-way comparisons.However, multiple comparisons required analysis of variance. Results were considered significant if p was <0.05. RESULTS Indexes of hypertrophy are shown in Table I. Animals that underwent the banding procedure had significantly thicker left ventricles compared with

the sham-operated group when measured after death. Total weight of the heart and left ventricular weight expressed as a percentage of total heart weight were increased in banded animals but did not achieve statistical significance. Banded animals had a Doppler gradient across the aortic band of 25.9 mm Hg. The mean time from banding to restudy was 140 days (100 to 170 days). The composite electrophysiologic testing results are shown in Table II. There were trends toward higher values for excitability thresholds in the left ventricles of the banded compared with the sham-operated animals. Similarly, values for left ventricular monophasic action potential durations tended to be higher in the banded group compared with the sham animals. These differences were all marginally significant, as was the increase in sinus cycle length with gallopamil. Gallopamil did not cause any other significant changes in electrophysiologic parameters in either group. As expected gallopamil did prolong the atrioventricular conduction time in both groups of animals, confirming that the drug had been administered in a physiologic dose (Table III). Figs. 1, 2, and 3 portray the data for dispersion of refractoriness, monophasic action potential durations, and excitability thresholds, respectively. In all of these figures the differences within the left ventricle (LV-LV) are presented in parallel with intraventricular dispersion (LV-RV). As demonstrated in previous studies, there was significantly more dispersion of all three parameters within the left ventricle and between the right and left ventricles in the banded animals compared with the sham-operated

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Table

II. Electrophysiologic measurements(msec) of banded and sham-operatedanimals

Calcium

Measurements Banded animals XL PCL RIVCT LIVCT R-L IVCT ET LV (mA) ET RV (mA) ERP LV ERP RV MAPDw LV MAPDoo RV MAPDso RV MAPDR(, LV Sham-operated XL PCL

blockade on LVH abnormal

Basal

Saline

Gallopamil

n = 28

n = 14 308 zt 42

n = 14 339 * 48* -

294 264 34.1 32.4 35.1 0.57 0.37 146.5 144.9 177 176 1.57 162

?I 36 ?z 32 ?T 3.6 -t- 2.9 i 3.5 I!I 0.17t z!I 0.04 + 17.4 k 14.7 +- 18 + 24 t 17 t 21t

34.7 32.6 34.5 0.59 0.41 149.3 144.4 183 192 165 178

n=9 291 f 43 254 +- 27

animals

33.3 34.0 36.2 0.48 0.39 139 139 168 169 139 1:39

RIVCT LIVCT R-L IVCT ET LV (mA) ET RV (mA) ERP LV ERP RV MAPDw LV MAPDoe RV MAPDSo RV MAPDSO LV

electrophysiology

f 2.5 t 1.6 I!I 1.6 z!z 0.04 z!z 0.03 + 17 + 15 + 20 +- 19 k 23 k 21

+ 2.8 LII 2.9 i 3.7 + 0.16 zk 0.10 + 17.6 * 13.4 * 19 + 26t i 20 + 24t

34.4 32.7 35.5 0.64 0.45 148.5 142.2 185 192 161 175

+ t k i * + + + i tz t

4.0 1.9 3.8 0.19t 0.11 17.8 9.9 24 2ot 19 21t

n=4 315 k 64

n=5 328 s 36* -

33.8 34.8 38.0 0.51 0.46 149 148 187 183 146 152

34.6 34.0 36.0 0.52 0.42 134 133 174 171 143 147

k it * k k + f zk k k +

3.5 0.5 2.2 0.02 0.04 15 12 18 16 16 18

rf+ + + + * -e i k t f.

901

2.5 1.6 1.6 0.05 0.06 10 8 15 27 15 14

SCL, Sinus cycle length; PCL, pace cycle lenth; RIVCT, right intraventricular conduction time; LZVCT, left intraventricular conduction time; R-L IVCT; conduction time between right and left ventricle; ET, excitability threshold; LV, left ventricle; RV, right ventricle; ERP, effective refractory period; MAPDeo, monophasic action potential duration measured at 90 SE repoiarization; MAPDss, monophasic action potential duration measured at 50% repolarization. *p < 0.05 compared with basal values. tp < 0.05 compared with sham-operated animals.

Table

Ill. Atrioventricular

conduction times (msec) Sham-operated (n = 9) Before

Saline Gallopamil *p < 0.001 compatible

with predrug

drug

55 _t 4.8 52 +- 0.6

Banded (n = 28)

After drug

Before drug

After drug

56 ~fr 4.6 72 zk 4.7*

55 f 2.9 52 k 6.2

55 + 2.8 75 rt 11.1*

value.

group. Neither saline solution nor gallopamil had any effect on these differences. Fig. 4 is a summary of the results of ventricular fibrillation threshold testing in the two groups. Again, as seen in our earlier studies, significantly lessenergy was required to induce ventricular fibrillation in the banded animals compared with the sham-operated control group. Gallopamil had no significant effect on ventricular vulnerability with this method of measurement; neither did it influence the results of programmed stimulation as shown in Table IV. In the

majority of the banded animals, ventricular fibrillation was induced repeatedly with programmed stimulation, before and after treatment with either saline solution or gallopamil, compared with the sham-operated group’s complete noninducibility. DISCUSSION

The last several years decline in cardiovascular are responsible, including therapy for patients with

have witnessed a distinct mortality. Several factors better and more aggressive hypertension. How antihy-

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Sham

LV-LV Banded

October 1992 Heart Journal

LV-RV Sham Banded fl Saline 1 Gallopamil

Fig. 2. Bar graph showingdispersionof monophasicaction potential duration measuredat 90% repolarization in milliseconds(msec) (format and abbreviations asin Fig. 1). Banded animalsshowedsignificantly greater dispersionwithin left ventricle (LV-LV) and between ventricles (LV-RV) than did sham-operated animals (*p < 0.05 vs sham group). Increased dispersionwas not affected by gallopamil or saline. Table

IV. Inducibility by programmed stimulation Sham-operated Before drug

Saline Gallopamil Total *p < 0.001 compared

Banded After drug

Before drug

After drug

o/4 O/5 o/9

10/14 10/14 20/28*

9114 8112 17/26*

a/4 o/5 o/9 with sham-operated

values.

pertensive therapy protects persons against cardiac death, especially sudden death, remains an enigma, although there are some clues. Patients with left ventricular hypertrophy have a high incidence of complex ventricular arrhythmia, higher than that seen in patients with hypertension but no left ventricular hypertrophy. l, 2,7 We also know that many of the drugs used to treat hypertension, such as,&blockers and calcium antagonists, have an antiarrhythmic effect; that is, they reduce the number of premature depolarizations seen on monitoring4 or raise the ventricular fibrillation thresho1d.s In addition, in at least one study the reduction in ectopy caused by a calcium antagonist on ambulatory ECG monitoring appeared to correlate with a reduction in left ventricular mass.4 Two important questions remain largely unanswered. First, does the reduction in ectopy seen during therapy with drugs such as verapamil mean that patients so treated are protected from sudden death? Second, is the protection afforded the result of a primary electrophysiologic effect of the antihypertensive drug

or is it a byproduct of some other salutary effect such as regression of left ventricular hypertrophy? These questions would be difficult to answer in a clinical setting because of an inability to control all of the factors thought to play a role in determining a patient’s susceptibility to ventricular arrhythmia. Furthermore, it is difficult to measure vulnerability to lethal arrhythmia without an invasive electrophysiologic study. A clinical study would therefore require a very large population with a long follow-up period to look for differences in treatment groups. The development of an animal model has distinct advantages. It allows us to intensively study the electrophysiologic effects of left ventricular hypertrophy in vivo and to discern the effects of a variety of acute and/or chronic interventions. Our previously published results argue strongly that the dispersion of refractoriness and repolarization seen in this model is the cause of the arrhythmias induced by programmed stimulation.63 g Pivotal to this argument is the evidence that a voltage-dependent potassium channel antagonist, risotilide, narrowed the dispersion in refractoriness and repolarization seen in the hypertrophied heart coincident with a resolution of ventricular vulnerability.6 Similar dispersion has been noted by Cameron et a1.r” with the use of the aortic band model of hypertrophy and in a rat model of hypertrophy.rl Furthermore, preliminary data suggest that dispersion of repolarization is also present in humans with ventricular hypertrophy. Present study. The present study was designed to determine whether a potent inhibitor of the calcium

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LV-LV

0.8 0.7

Sham

Banded

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LV-RV Sham Banded

1

l T

3

Saline Gallopamil

0.6 0.5 2

0.4 0.3

TT

0.2 0.1 0.0

Fig. 3. Bar graph showing dispersionof excitation threshold in milliamperes (mA) (format and abbreviations as in Fig. 1). Banded animalsshowedsignificantly greater dispersionwithin left ventricle (LV-LV) and between ventricles (LV-RV) than did sham-operatedanimals (*p < 0.01 vs shamoperated). Increased dispersion was not affected by gallopamil or saline.

3al-

LV Sham Banded

RV

Sham

Banded g Saline m Gallopamil

20 ii 10

C Fig. 4. Bar graph showingventricular fibrillation threshold measuredin milliamperes (mA) from sitesin left ventricle (LV) and right ventricle (RV), in both banded and sham-operatedcats. Ventricular fibrillation threshold was lower in both the left and right ventricles of banded cats (*p < 0.001vs shamgroup). Ventricular fibrillation threshold was not affected by gallopamil or saline.

channel would offer protection from ventricular arrhythmias in this model to the same extent as is seen with potassium channel blockade. Inasmuch as the studies were very brief, we conclude that any protec-

tion afforded by gallopamil was caused directly by the drug and not by an indirect mechanism such as regression of hypertrophy.13 Before assessing the effects of gallopamil, we performed baseline studies in each animal to confirm both the electrophysiologic abnormalities and the enhanced ventricular vulnerability. As in previous work,6pg we observed disper-

sion of refractoriness, excitability thresholds, and action potential durations in animals with left ventricular hypertrophy, all of which were strikingly different from what we had observed in the shamoperated control animals. This undoubtedly reflects the inhomogeneity of tissue in hypertrophy, which serves as the substrate for the development of ventricular tachyarrhythmias. In fact, as described in the past, the enhanced vulnerability was both measurable and quantifiable in this model. It was logical to hypothesize that calcium channel

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blockade might be a useful direct intervention in this model to prevent ventricular arrhythmias. Results of previous studies have suggested that calcium flux is an important principle in the development of the arrhythmias that accompany left ventricular hypertrophy and that blockade of the calcium channel might protect against these arrhythmias.14, I5 Calcium channel blockade appears to shorten action potential duration in vitro,16 but we observed no decrease in refractory period or monophasic action potential duration in the intact animal. In addition, gallopamil had no significant effect on site-to-site differences in these electrophysiologic properties that were observed in the banded animals. Its lack of benefit was also evident, as shown by results of programmed stimulation and direct measurement of ventricular fibrillation thresholds. There are several possible explanations for these apparently discordant observations. One is that the drugs are not protective and the reduction in the number of ectopic beats in clinical studies with calcium antagonists is an artifact resulting from use of Holter techniques to quantitate ectopy. Alternatively calcium antagonists might protect against sudden death by decreasing the number of “triggers” (in this case ventricular premature depolarizations) that may provoke sustained arrhythmia, without a significant effect on the electrophysiologic substrate evaluated in this study (dispersion of refractoriness). Finally, the drugs may be protective by some indirect mechanism such as lessening myocardial compromise by lowering blood pressure, improving myocardial perfusion to zones with marginal reserve, or producing regression of hypertrophy. Limitations. Our study has a number of very important limitations that should be emphasized. The results cannot be extrapolated to other drugs in the same class and, as in all animal experiments, certainly not to the clinical setting. We have previously shown that another calcium channel antagonist, verapamil, is not protective in this model, but even so calcium channel blockers with diverse mechanisms of action might be. The model used for our experiments was an aortic band that does not replicate clinical events. It does not account for changes that may occur in coronary blood flow in hypertension. Furthermore, it causes a sudden increase in left ventricular afterload that is clearly different from the gradual increase that occurs in the setting of aortic stenosis or chronic systemic hypertension. We used a contact electrode to measure action potential durations in vivo. Changes in monophasic action potential durations by use of this technique correlate with what occurs at the cellular level, but no direct cellular

American

October 1992 Heart Journal

recordings were made. We would also emphasize that we made no attempt to quantitate spontaneous arrhythmias, and thus any firm conclusions regarding relevance to the clinical situation in which ectopy is routinely observed is unwarranted. Finally, we used only one dose of gallopamil, which was administered acutely. The number of animals available for restudy did not permit the use of multiple doses. Consequently we cannot state with assurance that the use of a higher dose administered over a longer period of time would have produced similar findings. Conclusions. In a feline model of hypertrophy in which aortic banding was performed, we defined an altered electrophysiologic substrate that may be responsible for the genesis of malignant ventricular arrhythmia. The use of a potent calcium channel antagonist in this model did not alter the abnormal substrate, defined by site-to-site differences in refractoriness and repolarization, and it did not protect against the induction of ventricular arrhythmia. Calcium channel antagonists may protect against arrhythmia and death in left ventricular hypertrophy, but that protection may not be mediated by a direct myocardial electrophysiologic mechanism. We thank the staff of the animal care facility caring for the animals and Ms. Rose Marie Wells the preparation of the manuscript.

for their help in for assistance in

REFERENCES

1. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984;77:18-22. 2. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hvnertronhv. N Enel J Med 1987:317:787-92. 3. Ghali JK,“Kadakia S, Coop& RS, Liao Y. Impact of left ventricular hypertrophy on ventricular arrhythmias in the absence of coronary artery disease. J Am Co11 Cardiol 1991; 17:1217-82. 4. Messerli FH, Nunez BD, Nunez MM, Garavaglia GE, Schmieder RE, Ventura HO. Hypertension and sudden death: disparate effects of calcium entry blocker and diuretic therapy on cardiac dvsrhvthmias. Arch Intern Med 1989:149:1263-7. 5. Schulman SP, Weiss JL, Becker LC, Gottlieb Sb, Woodruff KM, Weisfeldt ML, Gerstenblith G. The effects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 1990;322:1350-6. 6. Kowey PR, Freihling TD, Sewter J, Wu Y, Sokil A, Paul J, Nocella J. Electrophysiologic effects of left ventricular hypertrophy: effect of calcium and potassium channel blockade. Circulation 1991;83:2067-75. 7. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WB. Risk of ventricular arrhvthmias in left ventricular hypertrophy: The Framingham Heart Study. Am J Cardiol 1987;60:560-5. 8. Anderson JL, Rodier HE, Green LS. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol 1983;51:1196-1202. 9. Sheeter JA, O’Connor KM, Friehling TD, Uboh C, Kowey PR. Electrophysiologic effects of left ventricular hypertrophy in the intact cat. Am J Hypertens 1989;2:81-5.

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10. Cameron JS, Myerburg RJ, Wong SS, Gaide MS, Epstein K, Alvarez R, Gelband H, Guse PA, Bassett AL. Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload. J Am Co11 Cardiol1983;2:481-7. 11. Keung E, Aronson RS. Non-uniform electrophysiological properties and electrotonic interaction in hypertrophied rat myocardium. Circ Res 1981;49:150-8. 12. Franz MR, Bargheer K, Swerdlow CD, Rafflenbeul W. Increased dispersion of action potential duration and local repolarization time in human left ventricular hypertrophy. [Abstract]. Circulation 1986;74:11-483. 13. Franz IW, Behr U, Ketelhut R, Agrawal B. Regression of left

blockade on LVH abnormal

electrophysiology

ventricular hypertrophy from systemic hypertension by gallopamil. J Cardiovasc Pharmacol 1987;1O:S178-81. 14. Kenyon JL, Sutko JL. Calciumand voltage-activated plateau currents of cardiac Purkinje fibers. J Gen Physiol1987;89:92158. 15. Keung EC. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium. Circ Res 1989; 64:753-63. 16. Kimura S, Bassett AL, Kohya T, Kozlovskis PL, Myerburg RJ. Regional effects of verapamil on recovery of excitability and conduction time in experimental &hernia. Circulation 1987;76:1146-54.

The importance of derived 124ead electrocardiography in the interpretation of arrhythmias detected by Holter recording Holter monitoring has been used extensively for the detection, diagnosis, and evaluation of therapy for cardiac arrhythmias. The availability of three-channel monitors allows for the recording of vectorcardiographic leads X, Y, and 2. One method, which was recently described by Dower et al., (J Electrocardiol 1988;21:5182-7), uses modified vectorcardiographic leads and allows for the acquisition of a derived 12-lead ECG of selected rhythm strips during the recording. In the present study, we evaluated the usefulness of the derived 124ead ECG in the detection of P-wave and ST-segment shifts, assessment of QRST changes, and distinction between ventricular ectopic and aberrant supraventricular complexes. Our preliminary findings indicate that careful analysis of the derived 124ead ECG provides additional information for a more accurate diagnosis of arrhythmias that are detected by the Holter monitor. The clinical importance and cost-effectiveness of the derived 12-lead ECG needs further evaluation. (AM HEART J 1992;124:905.)

Pablo Denes, MD St. Paul,

Minn.

Holter monitoring has been extensively used for the detection, diagnosis, and evaluation of therapy for cardiac arrhythmias.l Recent technologic advances have expanded the use of Holter recording to the detection of silent ischemia, evaluation of heart rate variability, and recording of arrhythmogenic late potentials.2-4 Holter monitoring in its application for arrhythmia detection and evaluation has been limited by the number of ECG leads that are available for recording. In a recent recommendation for standards of instrumentation in the use of ambulatory

From St. Paul-Ramsey ical School. St. Paul. Received

for publication

Medical Feb.

Center, and University 28, 1992;

accepted

Apr.

of Minnesota 16, 1992.

Reprint requests: Pablo Denes, MD, Section of Cardiology, sey Medical Center, 640 Jackson St., St. Paul, MN 55101.

411139822

Med-

St. Paul-Ram-

ECG, it was suggested that a 2-lead ECG system be used.5 The 2-lead system allows for an improved detection of P-wave and ST-segment shifts, QRST changes that result from shifts in body position or appearance of transient conduction blocks, and finally, differentiation between ventricular ectopic and supraventricular aberrant complexes.5 A 2-lead system also provides redundancy, which can prevent loss of data as a result of single-channel dysfunction.5 Dower et a1.6recently described a new 3-lead ECG recording system that can be applied to Holter monitoring and that allows for acquisition of a derived 12-lead ECG recording. In the present study we report our findings on the interpretation of Holter-detected arrhythmias with a 3-lead recording system. We provide examples in which the derived 12-lead ECG provides additional important information for detection of P-wave and ST-segment shifts, QRST 905