Effects of oral diltiazem on ventricular premature contractions

J. ELECTROCARDIOLOGY 19 (1), 1986, 59-66

E f f e c t s of Oral Diltiazem on Ventricular P r e m a t u r e Contractions BY MoRro ITO, M.D.,* YASUIIIRO MAEDA,M.D.,* MAKOTO ARITA, M.D.,I" SUKENOBU Iwo, M.D.,** TETSVSOal SAIKAWA,M.D.,** ICHXkO OMUnA, M.D.,** TAKEIIIKO FUJINO, M.D.,~ TEnUO FUKUMOTO, M.D.,*** YUTAKA KIKUCUl, M . D . , ~ KENSUKE YAMADA, M.D.,**** ANn TAKASHXYANAGA,M . D . ~

SUMMARY The effects of oral diltiazem (90-180 mg/day for four weeks) on ventricular premature contractions (VPCs) were studied in 16 patients with frequent VPCs using 24-hour ambulatory ECG recordings. VPC frequency was evaluated as a function of underlying heart rate. Plots of VPC frequency vs. heart rate were made at 1-beat/min intervals for all heart rates recorded for at least five minutes during 24 hours. P a t t e r n s of correlation between VPC frequency and heart rate observed before diltiazem therapy included: 1) a relatively linear increase in VPCs with heart rate (positive correlation) in ten patients, 2) a linear decrease (negative correlation) in one patient, and 3) an increase at low heart rates and a decrease at high heart rates (bidirectional correlation) in five patients. Diltiazem significantly reduced the mean VPC frequency per 24 hours for patients with a positive correlation, but induced no significant change for patients with a negative or a bidirectional correlation. A t the 65% level of VPC reduction, diltiazem was effective in eight of ten patients with a positive correlation but was not effective in the six patients with other correlations (p<0.01). These results suggest t h a t an evaluation of VPC frequency as a function of heart rate predicts the response of VPCs to diltiazem.

daily activity in patients with frequent VPCs. s Although most studies on the efficacy of antiarrhythmic agents have been simply concerned with the number of VPCs, an evaluation of VPC frequency as a function of heart rate is expected to provide new and important information concerning the mechanisms of VPCs and to provide a clue as to the choice of antiarrhythmic agents for the treatment of VPCs. Thus, we examined the relationship between the responses of VPCs to diltiazem and the patterns of correlation between VPC frequency ancl underlying heart rate. We found t h a t the effects of diltiazem on VPCs are quite different, depending on whether the VPCs were accelerated or suppressed at high heart rates. Diltiazem suppressed only the VPCs which increased in frequency at high heart rates.

The efficacy of calcium channel blockers in the suppression of AV nodal re-entrant excitation has been well documented. 16 However, there are few clinical reports on the effects of calcium channel blockers on ventricular arrhythmias. 7 Accordingly, we studied the effects of oral diltiazem on ventricular premature contractions (VPCs), using 24-hour a m b u l a t o r y ECG recordings. Winkle reported a distinct relationship between VPC frequency and underlying heart rate during routine From the Department of Laboratory Medicine, Medical College of Oita, Oita;* the Department of Physiology, Medical College of Oita, Oita;t the Department of Internal Medicine, Medical College of Oita, Oita;** the First Department of Internal Medicine, School of Medicine, Kyushu University, Fukuoka;~J" tim School of Nursing and Medical Technology, University of Occupational and Environmental Health, Kitakyushu;*** the Department of Internal Medicine, Kyushu Koseinenkin Hospital, K i t a k y u s h u ; t t t the Department of Internal Medicine, ttamanomachi Hospital, Fukuoka;**** and the Department of Bioclilnatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Beppu, J a p a n . l t l t

MATERIALS AND METHODS Sixteen patients (ten men and six women) aged 12-79 years (mean__SD: 49.4_+21.2 years) were studied. The clinical characteristics are listed in Table I. This study included only patients with VPCs of more than 2,000 per 24 hours, before the initiation of diltiazem therapy. Patients gave informed consent. Patients with acute myocardial infarction, decompensated heart failure, marked bradycardia, AV block or atrial fibrillation were excluded. Of 16 patients, one had mitral valve prolapse

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 solely to indicate this fact. Reprint requests to: Morio Ito, M.D., the Department of Laboratory Medicine, Medical College of Oita. 1-1506, Idaigaoka, ttazama-machi, Oita-gun, 879-56, Oita, Japan.

59

60

ITO ET A L

syndrome and one had hypertension (190/100 mmHg). Other than frequent VPCs the remaining 14 patients had no evidence of cardiac disease by history, physical examination, 12-lead electrocardiograms, echocardiograms and chest X-ray films. All antiarrhythmic drugs including digitalis were discontinued for a period of at least 5 halflives of the drug. Diltiazem hydrochloride was given orally three times daily in a dose of 90 mg (in 2 patients) or 180 mg (in 13 patients). In the remaining patient, the daily dose was 90 mg for the initial two weeks and then was increased to 180 mg for the next two weeks, because her physician noted frequent VPCs on a routine electrocardiogram at the two-week period. Twenty-four-hour ambulatory ECG recordings were made before and four weeks after the administration of diltiazem in all 16 patients. In 12 of these patients, recordings were also made at the 2 week period. An ambulatory ECG was recorded with a two-channel Avionics recorder and was analyzed with the Avionics computer system {DCG 7 Dynamic Electroscanner). With this system, the total number of VPCs during 24 hours and the mean daily heart rate (total number of heart beats during 24 hours divided by all minutes in 24 hours: 60• minutes) were obtained to analyze the diltiazem effects. With the use of another computer system (M-343, Sord Computer Systems, Inc.) in conjunction with the Avionics system, we obtained tabular and graphic information concerning the relationship between VPC frequency and heart rate. The methods were fundamentally the same as those reported by Winkle. 8 In brief, the heart rate and VPC frequency were tabulated for each

minute during 24 hours. The number of minutes at each heart rate (in 1-beat/min increments) and the number of VPCs in these minutes were determined. VPC frequency per minute was calculated for each heart rate by the formula: number of VPCs in all minutes at a given heart rate/number of minutes at the same heart rate. VPC frequency per minute was plotted vs. heart rate for all heart rates recorded for at least five minutes during 24 hours. When VPC frequency showed only an increase or a decrease over the entire range of heart rate, regression line and correlation coefficient were obtained by the leastsquares methods. In addition, we compared the time course of changes in VPC frequency and heart rate. The heart rate was calculated for every consecutive three minutes during 24 hours according to the formula: number of heart beats during three minutes/3. The VPC frequency per minute was also determined for every three minutes. The heart rate and the VPC frequency thus obtained were plotted vs. time (at 3-minute intervals). Accuracy of this system was previously evaluated in ten patients with frequent VPCs by means of randomly selected 120-minute recordings in which the computergenerated counts were compared with the manual counts in paper records. Errors (manual counts minus computergenerated counts) were estimated in all individual minutes during the selected 120-minute period. The errors of the heart beat counts ranged from 5 to - 4 per minute, but remained within -+1 per minute in most minutes, i.e., 117.0_+2.2 minutes (mean_+SD) out of the total period of 120 minutes. The errors of the VPC counts ranged 3 to - 3 per minute and were within _+1 per minute

TABLE I Clinical characteristics of patients studied and findings on 24-hour ambulatory ECG records Case no.

Age/sex

1 2 3 4 5 6 7 8 9

62/M 651M 51/M 76/F 671M 79/M 46/M 53/M 66/M

10

21/M

11 12 13 14 15 16

49/F 53/M 12/F 54/F 22/F 151F

VPCs/24 hours a)

Correlation c)

Cardiac diagnosis

Diltiazem (mglday)

Control

4 weeks b)

(- ) (-) (-) (- ) (- ) (- ) (- ) (- ) (- ) Mitral valve prolapse (- ) (-) (- ) Hypertension (- ) (-)

180 180 180 180 90 180 180 90 180

8,869 18,792 4,077 2,119 34,764 17,952 18,744 25,056 23,544

2,703 6,557 1,327 10 277 6,168 2,304 1,368 12,648

(((((((((-

69.5) 65.1) 67.5) 99.5) 99.2) 65.6) 87.7) 94.5) 46.3)

Positive Positive Positive Positive Positive Positive Positive Positive Positive

180

20,415

21,294

(

4.3)

Positive

180 180 180 90 - 180 ~) 180 180

24,444 7,404 13,489 4,843 9,504 9,905

24,023 8,287 9,008 4,838 8,832 11,374

( - 1.7) ( 11.9) ( - 33.2) ( - 0.1) ( - 7.1) ( 14.8)

(% change)

Negative Bidirectional Bidirectional Bidirectional Bidirectional Bidirectional

a) frequency of ventricular pemature contractions per 24 hours, b) 4 weeks after diltiazem treatment, c) correlation between frequency of ventricular premature contractions and heart rate observed at pre-treatment, d) 90 rag/day for the initial 2 week and 180 mg/day for the next 2 weeks.

J. ELECTROCARDIOLOGY 19(1), 1986

DILTIAZEM ON V E N T R I C U L A R PREMATURE C O N T R A C T I O N S

O

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Fig. 1. Correlation between frequency of ventricular premature contractions (VPCs) and heart rate in a 62-year-old man (case 1) (A) and a 67-year-old man (case 5) (B). Open circles represent the data obtained before, triangles 2 weeks, and closed circles 4 weeks after diltiazem therapy. In A and B, there was a positive correlation between VPC frequency and heart rate. Diltiazem reduced VPC frequency per 24 hours by 70% in A and 99% in B. The regression line in A is Y=0.335X-17.3 (r=0.94, p<0.01) (open circles) and Y=0.129X-6.5 (r=0.91, p<0.01) (closed circles), and in B, Y=0.870X-56.6 (r=0.97, p<0.01) (open circles) and Y=0.202X-7.7 (r=0.77, p<0.01) (triangles), where X and Y represent respectively heart rate and VPC frequency per minute. In bo.th A and B, diltiazem significantly reduced the slope of regression line (p<0.01).

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RESULTS Correlation between VPC Frequency and Heart R a t e o b s e r v e d at the Control P e r i o d In all p a t i e n t s , t h e r e was a d i s t i n c t relationship between VPC frequency and heart rate, and the patt e r n s of relationship could be classified into t h r e e b r o a d categories. I n c l u d e d were: 1) an increase in V P C f r e q u e n c y a t h i g h e r h e a r t rates (positive correlation) in ten p a t i e n t s (Figs. 1A and 1B, open circles), 2) a decrease in V P C f r e q u e n c y at h i g h e r h e a r t rates (negative correlation) in one p a t i e n t (Fig. 2A, open circles), and 3) an increase at relatively low h e a r t rates and a decrease at high h e a r t rates (bidirectional correlation) in five p a t i e n t s (Fig. 2B, o p e n circles). In seven of ten p a t i e n t s w i t h a p o s i t i v e correlation, V P C f r e q u e n c y showed a relatively linear increase over the entire r a n g e of h e a r t rates (Fig. 1B). However, the r e m a i n i n g three p a t i e n t s had r a t h e r a sigmoidal p a t t e r n of relationship (i.e., a l m o s t no V P C s at low h e a r t rates and relatively linear increase a t the i n t e r m e d i a t e h e a r t rates, reaching a plateau at higher heart rates) (Fig. 1A). The relationship between VPC freq u e n c y and h e a r t r a t e was statistically significant for all p a t i e n t s with a positive (r=0.60 to 0.97,

d. ELECTROCARDIOLOGY 19(1), 1986

I

120

Heart rate

in 114.2___4.7 minutes out of the 120 minutes. The error rate (the percentage difference of computer-generated counts vs manual counts) calculated for the total period .of 120 minutes ranged from 0.3 to -0.2% (mean___SD: 0.10+0.14%) in the heart beat counts and 1.6 to -1.0% (mean_SD: 0.40_+0.9%) in the VPC counts. All measured parameters are reported as mean_+SD unless otherwise specified. The data were analyzed by Student's t test for significance of difference. P values of 0.05 or less were considered statistically significant.

61

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0 Control

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70 90 Heart rate

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110

0

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Fig. 2. Correlation between frequency of ventricular premature contractions (VPCs) and heart rate in a 49-year-old woman (case 11) (A) and a 54-year-old woman (case 14) (B). Open and closed circles resp-ctively represent the data obtained before and 4 weeks after diltiazem therapy. In A, there was a negative correlation before diltiazem therapy, and the correlation changed to a bidirectional one after diltiazem therapy. The regression line for open circles in A is Y=-0.329X+34.6 (r=0.97, p<0.01), where X and Y represent respectively heart rate and VPC frequency per minute_ In B, there was a bidimctional correlation before diltiazem therapy, and the same pattern of correlation was seen after diltiazem therapy. In both A and B, diltiazem therapy induced virtually no change in VPC frequency per 24 hours.

62

ITO ET AL cy per 24 hours during diltiazem therapy. In most patients with a positive correlation (Fig. 3A), the VPC reduction tended to progress when the duration of diltiazem therapy was prolonged from two to four weeks. In contrast, six patients with a negative or a bidirectional correlation (Fig. 3B) showed little or only a slight change in VPC frequency at the four week period. In some of these patients, VPC frequency increased at two weeks. At the 4-week period of diltiazem treatment, eight of ten patients with a positive correlation achieved a 65% or more reduction in VPC frequency, b u t none of the six patients with a negative or a bidirectional correlation achieved this level of VPC reduction (p<0.01, Chi-square test) (Table 1, Fig. 3). Diltiazem therapy produced several changes in the patterns of correlation between VPC frequency and heart rate. In patients with a positive correlation, the slope of relationship between VPC frequency and heart rate decreased with the reduction of VPC frequency (Figs. 1A and 1B). In one patient with a negative correlation, the relationship changed to a bidirectional one after diltiazem therapy (Fig. 2A). However, in all five patients with a bidirectional correlation, the pattern remained unchanged after diltiazem therapy (Fig. 2B). Time Lag Between the Changes in VPC Frequency and Heart Rate Fig. 4 demonstrates the time course of changes (at 3-minute intervals) in VPC frequency when the heart rate changed rather promptly in a patient

p<0.01) or a negative correlation (r=0.97, p<0.01). Effects of Diltiazem For the entire group of 16 patients, diltiazem significantly reduced the VPC frequency (15,245+_9,171 VPCs/24 hr at the pretreatment, 7,564+7,086 VPCs/24 hr at the 4-week period of treatment; <0.01). However, this drug induced no significant change in the mean daily heart rate (74.7--+7.1 beats/min at pre-treatment, 70.7-+9.4 b e a t s / m i n d u r i n g t r e a t m e n t ) . The e f f e c t s of diltiazem differed depending on whether VPCs were increased or suppressed at high heart rates. Diltiazem Significantly reduced VPC frequency for patients with a positive correlation (17,433-+9,971 VPCs/24 hr at pre-treatment, 5,466-+6,766 VPCs/24 hr during treatment; p<0.01), b u t produced no significant change in patients with a negative or a bidirectional correlation (11,598-+6,915 VPCs/24 hr at pre-treatment, 11,060-+6,689 VPCs/24 hr during treatment). Diltiazem induced no significant change in the mean daily heart rate in patients with a positive correlation (75.6-+8.7 beats/min at pretreatment, 69.4-+ 11.3 beats/min during treatment) and in patients with a negative or a bidirectional correlation (73.2-+3.3 beats/min at pre-treatment, 72.9-+5.0 beats/min during treatment). In the pretreatment period, there was no significant difference between two patient groups in either the mean daily heart rate or the VPC frequency per 24 hours. Fig. 3 shows the percent changes in VPC frequen-

100

(A)

(B)

0 (--

a) o-

Q

50

q-

Fig. 3. Percent changes in the frequency of ventricular premature contractions (VPCs) on diltiazem therapy. A, 10 patients with a positive correlation between VPC frequency and heart rate, and B, 6 patients with a negative or a bidirectional correlation.

0 ~>

0

"6 _~ - 5 0

-100 I 84

0

2

I

I

I

I

4

0

2

4

Duration of diltiazem therapy (weeks) J. ELECTROCARDIOLOGY 19(1), 1986

DILTIAZEM ON VENTRICULAR PREMATURE CONTRACTIONS

Fig. 4. Time lag between the changes in frequency of ventricular premature contractions (VPCs) (open circles) and heart rate (closed circles). The data were obtained from a patient with a positive correlation between VPC frequency and heart rate (case 1) and were equivalent to the 24 data of open circles in Fig. 1A. Panels A and B show the heart rate-related changes 9 20 in VPCs. The basal heart rate before the rapid increase of heart rate was rather low ~16 (about 55 beats/min) in A and relatively .~12 high (about 70 beats/rain) in B. Panel C shows the pooled results of the changes in the heart rate and VPC frequency > ~ (mean_SD) for 13 episodes of heart rate increase. In this analysis, only the episodes in which the basal heart rates were more than 60 beats/min were used. The 3-minute period just prior to the event of heart rate increase was taken as 0 minute in each episode *p<0.05, **p<0.01 vs the values at 0 minute. See text for details.

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19C 11C

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5:50AM

9 with a positive correlation between VPC frequency and heart rate (case 1). It appeared that the rapid increase in heart rate preceded, by three or more minutes, the corresponding increase in VPC frequency and the greater the heart rate increase the greater the increase in VPC frequency (Figs. 4A and 4B). Moreover, the increase in VPC frequency seemed to be influenced by the duration of heart rate increase and the level of heart rate held prior to the event of heart rate increase (basal heart rate). As shown in Fig. 4A, when the basal heart rate was about 60 beats/min or less, the heart rate increase of short duration was associated with almost no VPCs (arrow a) but the sustained increase of heart rate (arrow b) was associated with an initiation and then a gradual increase of VPCs. In Fig. 4B, the basal heart rate was relatively high (about 70 beats/min) and thus even a short duration of heart rate increase (arrow d), as well as a sustained increase (arrow c), was followed by a distinct increase of VPCs with a time lag of three minutes. We analyzed all events in which the heart rate increased by 10 beats/min or more as compared to a n y of the p r e c e d i n g four 3-minute p e r i o d s (therefore the total duration of measurement was equivalent to 12 minutes), and identified 20 such episodes during 24 hours in this patient. Out of the 20 episodes of heart increase, 13 episodes had a basal heart rate of more than 60 beats/min. The s u m m a r i z e d analysis of these 13 eposides is presented in Fig. 4C, which shows that a significant increase of heart rate (arrow e) preceded a signifiJ. ELECTROCARDIOLOGY 19(1), 1986

63

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6:50 4:30PM

5:00

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9

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,

,

,

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5:30 -9-6-3 0 3 6 9 12 Time(rain)

cant increase in VPCs (arrow f), by 3 minutes. The same time lag phenomenon was noted in five of ten patients with a positive correlation between VPC frequency and heart rate, but was observed in none of six patients with a negative or a bidirectional correlation. Other Findings In two patients (cases 3 and 4), there was an int e r m i t t e n t Mobitz I AV block on the 24-hour ambulatory ECG records made at the 4-week period of diltiazem therapy. No other arrhythmias or adverse effects were noted.

DISCUSSION Effects of Diltiazem and Correlation Between VPC Frequency and Heart Rate The number of studies on the effects of calcium channel blockers on ventricular arrhythmias is small? Calcium channel blockers are particularly effective in treating AV nodal re-entrant tachycardias. '6 Previous s t u d i e s u s i n g verapamil 4'7"9 showed t h a t this drug is less effective in cases of ventricular tachycardias than in cases of supraventricular tachycardias. A few uncontrolled studies showed the suppressive effects of verapamil on VPCs following acute myocardial infarction and on digitalis-induced VPCs2 We reported the suppressive effects of oral diltiazem on VPCs refractory to procainamide. '~ In the present study, we examined the relationship between the effects of oral d i l t i a z e m on VPCs and the h e a r t ratedependency of VPC frequency. In all 16 patients

64

ITO ET AL

studied, there was a distinct correlation between VPC frequency and underlying heart rate during routine daily activity. The most frequent pattern of correlation was an increase in VPCs with increasing heart rate (10 out of 16 patients). These results are c o n s i s t e n t with the findings reported by Winkle. s Evaluation of the effectiveness of antiarrhythmic therapy for VPCs can be a difficult problem b e c a u s e of the well-documented s p o n t a n e o u s variability of VPC frequency in individual patients. H-~3However, it has been reported that VPC frequency averaged for a group of patients was similar when two control periods were compared, n.'3.~4 Thus, evalution of drug efficacy by examining group response rather than individual response minimizes the effects of spontaneous variability. Concerning the assessment of effectiveness of antiarrhythmic agents in individual patients, Sami et al. TM reported that, if two 24-hour ambulatory monitoring periods are compared, a 65% or greater reduction in VPC frequency is required to establish VPC reduction attributable to drug efficacy rather than spontaneous variation. M o r g a n r o t h et al. ~2 have concluded t h a t t h e minimal VPC reduction required to establish drug efficacy is greater (i.e., 83%) than that reported by Sami et al. In the present study, diltiazem reduced the mean VPC frequency for ten patients with a positive correlation, b u t induced no significant change in six patients with a negative or a bidirectional correlation. When a criterion proposed by Sami et al. TM (i.e., 65% reduction) is used for the evaluation of individual response in the present study, diltiazem was effective in eight of ten patients with a positive correlation compared with an effectiveness in none of six patients with other correlations (p<0.01). These results s u g g e s t t h a t diltiazem is more effective on VPCs which are increased at high heart rates (tachycardia-accelerated VPCs) than on VPCs which are suppressed at high heart rates. M o s t patients examined in this s t u d y had no underlying heart disease. Further studies should be made to determine whether similar response can be obtained in patients with underlying heart disease. Mechanisms of Tachycardia-Accelerated VPCs and the Effects of Diltiazem A n t i a r r h y t h m i c e f f e c t s of calcium channel blockers can be direct, indirect or both. The indirect effects of calcium channel blockers can suppress ischemia-induced arrhythmias by improving coronary perfusion or decreasing myocardial oxygen consumption. '5 Thus, one possible explanation for

the tachycardia-accelerated VPCs is increased ischemia at higher heart rates, and such VPCs s h o u l d be s u p p r e s s e d by indirect e f f e c t s of diltiazem. However, none of our patients had clinical signs suggestive of ischemic heart disease. Winkle ~ also found that a positive correlation between VPC frequency and heart rate was not confined to patients with coronary artery disease. The direct antiarrhythmic effects of calcium channel blockers would be expected if slow channeldependent activity underlies the genesis of VPCs. Slow channel dependent activity may play a role in mechanisms that have been either suspected or proved to relate to ventricular arrhythmias (e.g., automaticity, re-entry and triggered activity). ~5 However, since intracellular potentials cannot be recorded in the intact human heart at the present, discussion on the possible role of slow channeldependent activity in the genesis of clinically occuring VPCs is purely speculative. An increase in heart rate may be associated with initiation or acceleration of VPCs, regardless of mechanism. For example, increased sympathetic activity increases heart rate and m a y enhance the discharge of an ectopic a u t o m a t i c focus in the Purkinje fibers. However, the automaticity of Purkinje fibers is usually suppressed by stimulation at high rates (overdrive suppression). '6.'7 The automaticity occuring in partially depolarized Purkinje fibers may be slow channel dependent TM and the overdrive of such fibers for a relatively short period either fails to suppress the automaticity, or may slightly enhance it. ~9 Howevel, a sufficiently long period (i.e., several minutes) of overdrive stimulation has been reported to suppress such automaticity29 In addition, true automaticity is not initiated by rapid pacing3 ~ Thus, the tachycardia-accelerated VPCs demonstrated in the present s t u d y may not be due to enhanced automaticity. Re-entrant ventricular tachycardias can be initiated by pacing the ventricle at high rates in animals ~'3 and in humans3 s,25 However, we found t h a t a considerable a m o u n t of catecholamine release is a prerequisite for the maintenance of reentry circuit associated with slow channel dependent conduction. ~6 Such an excess in catecholamines is unlikely in our patients. In addition, it was reported that the initiation of reentrant ventricular tachycardia by ventricular premature stimulation in humans was facilitited by pacing the ventricle at relatively low rather than at high rates. 25 These findings argue against a reentry mechanism for the tachycardia-accelerated VPCs reported in the present study.

J. ELECTROCARDIOLOGY 19(1), 1986

DILTIAZEM ON VENTRICULAR PREMATURE CONTRACTIONS

A distint time lag between the increases in heart rate and VPC frequency (Fig. 4) is also evidence against the mechanism of either automaticity or re-entry. If the increases in heart rate and VPC frequency are directly inter-related and are mediated by an increased sympathetic activity, both events might be expected to occur without the relatively long time lag evidenced in Fig. 4. Ventricular t a c h y a r r h y m i a s due to a re-entry mechanism reportedly evolve immediately after introduction of only one or, at most, several premature stimuli w i t h appropriate coupling intervals. 2'-25 The findings of an increase in VPCs with increasing heart rate and suppression of such VPCs by diltiazem seem most consistent with the cellular electrophysiologic events characteristic of triggered activity. Single or repetitive triggered activity arising from afterdepolarizations follows rapid stimulation and such activity is readily suppressed by calcium channel blockers. 2729 The amplitude of afterdepolarization increases when the rate of pacing is increased. 27-29 In addition to stimulus frequency, the length of stimulus train also influences " t h e a m p l i t u d e of afterdepolarization, i.e., the amplitude of afterdepolarization increases with the number of driving stimuli (cumulative effects). 27 We observed an apparently cumulative effect of the foregoing heart rate on VPC frequency (Fig. 4). All available evidence indicates t h a t the amplitude of both the afterdepolarization and underlying transient inward current increases under conditions where the intracellular Ca ++ concentration are elevated; e.g., in the presence of cardiac glycosides, catecholamines or elevated external Ca ++ concent r a t i o n s , or when the rate of s t i m u l a t i o n is increased. 2729 With high pacing rates (increased heart rates), a larger Ca ++ influx per unit time would lead to greater loading of intercellular Ca ++ stores and hence induce more triggered activity. 29 Thus, if the tachycardia-accelerated VPCs reported in the present study are due to the triggered activity and this activity is a secondary result of heart rate increase, one m i g h t expect t h a t the initiation or acceleration of such VPCs should lag behind the heart rate increase. These considerations suggest t h a t the characteristics of tachycardia-accelerated VPCs reported here are more consistent with triggered activity rather than enhanced automaticity or re-entry. Triggered activity reportedly occurs in most cardiac tissues, 29 including human atrial 3o and ventricular muscles. 3l Circumstantial evidence also supports the possibility t h a t ventricular tachycardias are due to the triggered activity in some patients.7.32.33

J. ELECTROCARDIOLOGY 19(1), 1986

65

The analysis of VPC frequency as a function of heart rate as described in the present s t u d y may be a useful approach toward elucidation of the mechanisms of ventricular arrhythmias and in predicting the response of the ventricular arrhythmias to diltiazem and possibly other calcium channel blockers. Acknowledgements: We thank Drs. Y. Ishihara and K. Saeki for kind co-operation and hi. Ohara of Kyushu University for comments on the manuscript. REFERENCES 1. BETRIU, A, CIIAITMAN, B R, BOURASSA, M G, BRI~VERS, G, SCIIOLL,J, BRUNEAU, P, GAGN~3,P AND CiIABOT,M: Beneficial effect of intravenous diltiazem in the acute management of paroxysmal supraventricular tachyarrhythmias. Circulation 67:88, 1983 2. ROZANSKI,J J, ZAMAN,L, ANDCASTELLANOS,A: Electrophysiologic effects of diltiazem hydrochloride on supraventricular tachycardia. Am J Cardio149:621, 1982 3. ROWLAND, E, McKENNA, W J, Gi)LKER, H AND KRIKLER,D M: The comparative effects of diltiazem and verapamil on atrioventricular conduction and atrioventricular reentry tachycardia. Circ Res 52(suppl I): 1-163, 1983 4. SCIIAMROTll, L: The clinical use of intravenous verapamil. Am Heart J 100:1070, 1980 5. YEll, S, Kuo, H, LIN, F, HUNG, J AND Wu, D: Effects of oral diltiazem in paroxysmal supraventricular tachycardia. Am J Cardiol 52:271, 1983 6. Zn,ES, D P, RINKENBERGER,R L, HEGER, J J AND PRYSTOWSKY,E N: The role of the slow inward current in the genesis and maintenance of supraventricular tachyarrhythmias in man: In D P Zipes, J C Bailey and V Elharrar, Eds. The slmv inward current and cardiac arrhythmias. Martinus Nijhoff Publishers, The Hague, 1980, p 481 7. WELLENS, H J J, FAaR~, J ANDBiia, F W: The role of the slow inward current in the genesis of ventricular tachyarrhythmias in man. In D P Zipes, J C Bailey and V Elharrar, Ed.: The slow inward current and cardiac arrhythmias. Martinus Nijhoff Publishers, The Hague, 1980, p 507 8. WINKLE,R A: The relationship between ventricular ectopic beat frequency and heart rate. Circulation 66:439, 1982 9. MASON,J W, SWERDLOW,C D, MITCHELL,L B: Efficacy of verapamil in chronic, recurrent ventricular tachycardia. Am J Cardiol 51:1614, 1983 10. ARITA, M, OTAKE, N, KAWASAKI,U ANDTAKASIIIBA, T. The effects of diltiazem on ventricular premature contractions refractory to procainamide. Jap J Clin Exper Med 52:2430, 1975 (in Japanese) 11. WXNKLE,R A: Antiarrhythmic drug effect mimicked by spontaneous variability of ventricular ectopy. Circulation 57:1116, 1978

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J. ELECTROCARDIOLOGY 19(1), 1986