Definition of benign versus malignant ventricular arrhythmias: Targets for treatment

Definitionof Benign Versus Malignant Ventricular Arrhythmias:Targets for Treatment J. THOMAS BIGGER, Jr., MD

The most important characteristics of arrhythmias that determine the need for treatment are the prevalence and clinical significance of the ventricular arrhythmia. Ventricular arrhythmias occur more frequently with advancing age, severity of heart disease and ventricular hypertrophy. Malignant ventricular arrhythmias are of 3 forms: out-of-hospital ventricular fibrillation (VF), recurrent sustained ventricular tachycardia and torsades de pointes ventricular tachycardia in the long QT syndrome. Each condition has a high l-year mortality rate.

Potentially malignant ventricular arrhythmias are ventricular premature complexes (VPCs) of > 10 per hour 10 to 16 days afler acute infarction and repetitive VPCs. The most malignant arrhythmias occur with severely depressed ventricular function, but VPCs alone have independent prognostic significance. Benign ventricular arrhythmias occur in patients without known heart disease and do not require treatment. The exact effect of frequent and complex VPC in these patients needs further definition. (Am J Cardiol 1983;52:47C-54C)

An important and controversial question in antiarrhythmic therapy is: Which ventricular arrhythmias should be treated? Several factors determine decisions about treatment: the mortality force of the ventricular arrhythmias, the presence and perception of symptoms and the efficacy, safety and convenience of treatment. My purpose is to examine the rationale to categorize patients with arrhythmia into groups based on prognosis and to outline which patients should be treated. A ftindamental prerequisite for a rational decision about therapy is knowledge of the prevalence and significance of the ventricular arrhythmias. This knowledge is needed to plan strategies for detection and for treatment. Prevalence of ventricular arrhythmia determines the feasibility of screening programs. The significance of an a.rrhythmia is an important determinant of treatment. The more malignant a ventricular arrhythmia is, the more important it is to treat it. Benign but symptomatic ventricular arrhythmias also may require treatment to alleviate the annoyance or anxiety they produce.

For malignant arrhythmias, the primary concern is for efficacy of treatment. Inconvenience and even significant safety risks are worth taking in order to control the most malignant ventricular arrhythmias, such as frequently recurring ventricular fibrillation (VF). For benign arrhythmias, safety is the paramount consideration. Often, the significance of the arrhythmia in terms of short- and long-term morbidity and mortality rates is unknown; this makes decisions about treatment empiric. Symptoms and patient attitudes often play a critical role in modifying decisions that otherwise would be clear as to the significance of the arrhythmias and the attributes of the best available treatment. Background Knowledge Important general facts about ventricular arrhythmias are listed in Table I. Studies using 24-hour electrocardiographic (ECG) recordings show that ventricular arrhythmias are common. even in young, normal persons who do not have heart disease.l-3 The prevalence of ventricular arrhythmias increases with age in subjects without clinically evident heart disease.4 Also, adjusted for age, the prevalence of ventricular arrhythmias is greater in persons with heart disease.4 The main feature of heart disease that is associated with ventricular arrhythmias seems to be scarring of the ventricular walls. The broader and more confluent the scarring of the ventricles, the more likely that ventric-

From the Division of Cardiology, Department of Medicine, Columbia University, and The Arrhythmia Control Unii, the Columbia-Presbyterian Medical Center, New York, New York. This study was supported in part by Grants HL-22982, HL-12738, and HL-70204 from the National Heart, Lung, and Blood Institute, the National Institutes of Health, Bethesda, Maryland; by Grant RR-00645 from the Research Resources Administration, Bethesda, Maryland; by a &ant-in-Ad from the American Heart Association, Dallas, Te:KaS; and by grants from the Winthrop and Chernow Foundations, Nlew York, New York.

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BENIGN VERSUS MALIGNANT VENTRICULAR ARRHYTHMIAS

TABLE I

Characteristics of Ventricular Arrhythmias in Man

They are common They increase with age They increase with ventricular scarring Infarction Hypertrophy Infection They do not increase with coronary atherosclerosis per se They can be precipitated/aggravated by exercise lschemia Increased sympathetic activity Increased heart rate Electrocardiographically similar arrhythmias may have different causes and significance

ular arrhythmias will occur. There is evidence to suggest that in chronic coronary heart disease, larger scars judged by electrocardiographic Q-wave scores or by left ventricular (LV) ejection fraction (EF) are associated with a significantly greater chance of ventricular arrhythmias.5-7 The same relation holds early after myocardial infarction. 8 There is strong experimental evidence that infarct size is very strongly related to the inducibility of sustained ventricular tachycardia (VT) with programmed ventricular stimulation and to the VF threshold.g The ventricular scarring associated with myocardial hypertrophy in systemic hypertension or valvular heart disease and the fibrosis that follows a variety of diffuse myocardial injuries, for example, viral myocarditis, also increase the likelihood of developing ventricular arrhythmias. The overwhelming importance of scarring in chronic coronary heart disease was shown by Califf et al;596the extent of coronary atherosclerosis has no significant association with ventricular arrhythmias after adjusting for the association between LVEF and ventricular arrhythmias. Ventricular arrhythmias may be precipitated or aggravated by exercise. lo Triggering of arrhythmias by exercise is an important feature to contend with in arrhythmia detection and management. The primary mechanisms of exercise enhancement of arrhythmias are ischemia, enhanced sympathetic activity and the increase in rate per se. Finally, arrhythmias can appear similar in electrocardiographic recordings but, nevertheless, have different causes and significance. This fact leads to the conclusion that important collateral evidence must be examined before drawing conclusions about how to manage ventricular arrhythmias. I divide the ventricular arrhythmias into malignant, potentially malignant and benign, based on outcome. Malignant Ventricular Arrhythmias There are 3 frequently recognized malignant, that is, lethal, ventricular arrhythmias in man: out-of-hospital VF, recurrent sustained VT, and torsades de pointes VT in the long QT syndrome. Each condition has a high mortality rate. Out-of-hospital cardiac arrest: Much of what we know about the important syndrome of out-of-hospital cardiac arrest comes from work done by community-

based emergency medical programs.11-15 First, coronary heart disease is the most common etiologic form of heart disease in the population that has out-of-hospital cardiac arrest. Cardiomyopathy and valvular heart disease are also well represented. Every series of out-of-hospital cardiac arrest has a small and puzzling group that has no apparent heart disease. Studies by Cobb et a114J5 show that acute myocardial infarction is not a common cause of out-of-hospital cardiac arrest, especially in patients who are resuscitated and admitted to the hospital. However, significant coronary heart disease is common among the survivors of out-of-hospital cardiac arrest and advanced coronary atherosclerosis, previous myocardial infarction and poor LVEF are all common in this group.i“J5 Studies to date suggest that the 2 most common causes of out-of-hospital cardiac arrest are ischemic VF and sustained VT that degenerates into VF. Studies by Goldstein et a116 suggest that as many as half of the out-of-hospital cardiac arrests are caused by ischemic episodes. Many of these episodes result in instantaneous death and the victims are not resuscitated. About 70% of survivors respond to programmed ventricular stimulation with inducible sustained VT that may or may not degenerate into VF. 17-20This suggests that a similar sequence of events may have occurred during the previous spontaneous cardiac arrest. Kehoe et aPgp20have presented evidence to support the proposal that some of the noninducible patients had VF as a result of ischemic episodes. Almost all patients who have VT or VF induced during ventricular stimulation have evidence of a ventricular scar, usually from previous myocardial infarction. It is quite likely that studies of survivors of out-of-hospital cardiac arrests are biased, that is, the samples are enriched with scar-related VT or VF. This is because patients with VT are more likely to remain awake, even if symptomatic, during attacks. An extended period of consciousness during VT gives these patients a chance to summon help and to survive until help arrives. Intense myocardial ischemia is more likely to produce abrupt VF without preceding VT and allow the victim no opportunity to seek aid. The longer time from the initiating event to the loss of consciousness in patients with scar-related VT makes it likely that this group is overrepresented among survivors of out-of-hospital cardiac arrest. Three therapeutic approaches have been proposed for survivors of out-of-hospital cardiac arrest: electrophysiologically guided medical or surgical treatment,‘7-20 medical therapy guided by arrhythmias detected during 24-hour ECG recordings and exercise testslo and blood level control only.21 Treatment of survivors of out-of-hospital cardiac arrests is mandatory because untreated patients have a recurrence rate of about 25 to 30% within the year. Recurrent sustained ventricular tachycardia: Recurrent sustained VT has been the subject of intensive study during the past 5 years. The causes of heart diseases for this arrhythmia are similar to those in survivors of out-of-hospital cardiac arrests. Coronary heart disease and cardiomyopathy account for almost

September 22, 1983

90% of these patients, with about 75% having coronary heart disease.22-24 Ventricular scar also plays a major role in the pathogenesis of this syndrome; almost all of the coronary heart disease group have had a previous myocardial infarctio:n and many have had a ventricular aneurysm. Viewed from the perspective of acute myocardial infarction, recurrent sustained VT is a rare syndrome, occurring in the postinfarction year in about 1 to 3 of 1,000 patients. However, these patients accumulate in considerable numbers because myocardial infarction is so common and because these patients often survive multiple episodes of VT. Untreated, recurrent sustained VT has a recurrence or mortality rate of about 40% during a year of follow-up study. Therefore, treatment is imperative. Although there is 1 report of successful treatment of recurrent, sustained VT guided by Holter ECG recordings and exercise testing,lO the accepted approach to the therapy for this condition is electrophysiologic because the method is sensitive and specific.25 The recurrence rate is substantially lower for patients who have conversion from inducible to noninducible during electrophysiologic studies done with drug treatment. 26-2*Also, there is substantial success with map-guided arrhythmia surgery in the patients in whom VT remains inducible while receiving the drugs t&ed.2g Amiodarone has significant long-term efficacy, although it apparently fails during electrophysiologic studies.30 There has been no randomized comparison of amiodarone and surgery in patients who have failed with conventional and experimental type 1 antiarrhythmic drugs. Thkerefore, the better choice between these 2 treatments is not yet clear. Torsades de poiintes in the long QT syndrome: Torsades de pointes is a rapid polymorphic VT with unique ECG features: The polarity of the QRS complex repeatedly twists from upright to inverted and back.31 This type of ECG appearatice usually is associated with a prolonged QT interval. There are 2 congenital forms of the long QT syndrome: one has dominant inheritance and is associated with congenital deafness and one has recessive inheritance and has no association with deafness.s2 In addition, there is a so-called acquired form of the long QT syndrome that is usually caused by electrolyte abnormalities, such as hypokalemia or hypomagnesemia or drug toxicity (for example, quinidine or tricyclic antidepressants).33 As suggested by its bizarre ECG appearance, torsades de pointes is an unstable form of VT and is likely to deteriorate into VF. There is no doubt that torsades de pointes is a malignant arrhythmia that requires treatment. The approach to therapy of this condition is as unusual as the ECG appearance. Emergency treatment includes avoidance of type 11antiarrhythmic drugs, use of ventricular pacing and, occasionally, infusion of catecholamines. Evaluation of therapy usually is accomplished by on-line, real-tilme ECG monitoring and later by 24-hour ECG recordings. Long-term drug treatment almost always includes beta-adrenergic blocking agents and occasionally plhenytoin. Drug-resistant cases usually can be successfully treated by left stellate ganglionectomy.33-35

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I-

I-

I

,

0

loo

K33o

VW Per Hour FIGURE 1. Cumulativefrequencydistributionof ventricularpremature complexes(or depolarizations [VPDs])expressedas the hourlyavera9s over 24-hours.The 50th percentileis just below 1 VPD/hour,the 75th percentile is at 10 VPDs/hour and the 90th percentileis at 60 VPDsl hour.

Potentially

Malignant Ventricular Arrhythmias

The aforementioned arrhythmias classified as “malignant” were all examples of sustained ventricular activity. Studies performed over the past 10 years have identified several “potentially malignant” ventricular arrhythmias. These include frequent and repetitive but nonsustained ventricular premature complexes (VPCs) in patients with coronary heart disease, particularly those with previous myocardial infarction, and in patients with cardiomyopathy. Because the significance of ventricular arrhythmias in coronary heart disease and cardiomyopathy appears to be similar, these will be discussed together. Frequent ventricular premature complexes: The prevalence and significance of ventricular arrhythmias in coronary heart disease have usually been studied after acute myocardial infarction. Most studies were done at about the time of patient discharge after an index myocardial infarction because this is a convenient time for both physician and patient and because of the high mortality rate 6 to 12 months after infarction.*3s The prevalence of VPCs 10 to 16 days after myocardial infarction is shown in Figure 1. Fifteen to 20% have no VF’Csin a 24-hour recording, about 50% have an average of
sot

BENIGN VERSUS MALIGNANT

VENTRICULAR

ARRHYTHMIAS

TABLE II

Relation Between Repetitive Ventricular Premature Complexes and Mortality, Adjusted for the Effects of Frequency of Ventricular Premature Complexes Status

VPC Frequency Repetitive VPCS (per hour)
Absent Present Absent Present Total

Dead

Alive

Total

31 18 6

349

380

:I

::

5:;

:z 110 616

Odds Mortality Ratio 8% ;;y :$ 00

i:i i:i ...

Chi-squaretotal = 12.11, df = 2; chi-squareinteraction= 0.59, df = 1; chi-squareassociation= 11.52, df = 1; summaryoddsratio = 2.5. VPC = ventricularprematurecomplex.

mortality rates. If one assumes that treatment can reduce mortality, one would reasonably conclude that patients with VPC frequencies >lO per hour should be treated; a cogent argument can be made for using an even lower frequency value as the criterion for treatment. The relation in Figure 2 calls into question the conventional frequency criteria for treatment of ventricular arrhythmias after infarction, usually 60 to 100 per hour or even more. Repetitive ventricular premature complexes: The complex feature of postinfarction VPC with the greatest significance is repetitiveness. Multiform VPCs have very little significance and R-on-T complexes have less prognostic significance.ssJe About 25% of 24-hour predischarge ECG recordings contain repetitive VPCs; about 15% contain paired complexes only, and 10% contain both paired complexes and >l episodes of nonsustained VPC runs (~3 consecutive ventricular complexes at any rate). Recordings with runs but no pairs are extremely rare, only about 5% of the recordings with runs. The significance of repetitive VPCs in a Columbia University study is shown in Table II, adjusted for VPC frequency. Overall, the odds of dying are 2.5 times greater for patients who have repetitive VPCs compared with those who do not. Although there is a significant and moderately strong association between VPC frequency and repetitive VPCs, there is no interaction between these 2 factors with respect to mortality. The mortality rate for patients with VPC runs is sigence on postinfarction

4 ko.l ’

0

I

I

I

IO

I

1 1000

100

VP0 per Hour FIGURE 2. Mortalityrate as a functionof averagehourlyfrequencyof ventricularprematurecomplexes(or depolarizations[VPDS]).Patients with
are made at 3 to 5 days after infarction, any level of VPC frequency is less prevalent. Recordings made 6 to 12 weeks after infarction show a higher prevalence of frequent VPCs. The relation between the first-year postdischarge mortality rate and frequency of VPCs is shown in Figure 2. Interestingly, the relation is Sshaped. About half of the VPC-associated mortality rate increase is achieved at frequencies of 1 per hour and the mortality rate plateaus are at about 10 per hour. This means that the mortality rate is 20 to 25% for patients with L 10 VPCs; patients with 1100 per hour are at no greater risk than those with 10 to 100 per hour. As mentioned by Furberg elsewhere in this symposium, there has been no definitive trial to evaluate whether reducing the frequency of VPCs has a beneficial influ-

TABLE III

Ventricular Tachycardia Recorded Just Before Discharge From Hospital After Yyocardlal Infarction VentricularTachycardia

Study

No. of Patients

Age Limit (yr)

l-Year Mortality

Durationof Recording (hours)

915

<66

4%

6

430

<76

13%

24

289

<71

9%

10

Andersonet a140 Biggeret a14’ Kleiger et al42 VPC = ventricularprematurecomplex. VT = ventriculartachycardia.

Definition of VT

No. With VT(%)

13 VPC > lOO/min 13 VPC Any rate L3 VPC Any rate

10 (1.1) (ii.6) (3.4)

September 22, 1983

TABLE IV

Nonsustained Ventricular Tachycardia After Infarction and Long-Term Mortality Mortality (%)

Study Bigger Andersonet a14’ et a140 Kleiger et a14’ VT = ventricular

Patients (n)

Age

430 915 289

X66
Follow-up (months) 40 36 12

With VT :: 14

Without

VT

:; 7

tachycardia.

nificantly higher than for patients with pairs but no runs (chi-square association 11.52; p
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relations should they exist. Nearly all episodes of VPC runs recorded predischarge are brief, infrequent, and asymptomatic.40T41 Half of the patients have only 3 VPCs in the longest run and 30% have only a single run in the 24-hour recording. Considering these facts, it is remarkable that patients with runs have such a high mortality rate during follow-up study after infarction. Relation of ventricular arrhythmias to left ventricular dysfunction: There are 2 hypotheses about the relation between ventricular arrhythmias and LV dysfimction: that ventricular arrhythmias contribute independent mortality force after adjusting for LV dysfunction, and that ventricular arrhythmias are strongly associated with LV dysfunction and that ventricular arrhythmias do not contribute independently to mortality after adjusting for LV dysfunction. Ruberman,3g Moss,~~ and their co-workers analyzed for a relation between “complex” ventricular arrhythmias (bigeminy, multiform, pairs, runs or R on T) and postinfarction mortality rates, adjusting for LV dysfunction using the clinical diagnosis of heart failure. Both of these studies were large-l,739 and 940 patients, respectively; both used fairly brief ECG recordings, ! hour and 6 hours, respectively; and both used clinical heart failure to adjust for LV dysfunction. Both analyses yielded a similar result: complex ventricular arrhythmias were significantly associated with follow-up mortality after adjusting for LV dysfunction. In a study of 395 coronary heart disease patients referred for cardiac catheterization, Califf et al6 addressed the same question; only 53% of their patients had a previous myocardial infarction and most of these were in the remote past. Angiographic LVEF was used to adjust for LV dysfunction. A hierarchical scoring system using frequency, multiformity,

I23456769 1020

40

60

80

100200

EPISODES OF VT

60

80

IO0

I20 140

fester

publisher.

345678910111213

I6

IE

LOMGEST RUN OF VT

I60

I80

200

AVERAGE VT RATE

FfGlJRe 3. Characteristics of ventriculer tachycardii (VT) 2 weeks after myocardial infarction in 50 patients. The black porlion of the bars indicatesthe deaths. There is no indication that patients with more frequent, longer or episodes of VT have a higher deeth rate. However, this sample is too smell to settle this question definitively. Reproduced from Bigger et a141with permission of the

SlC

2122

25

749

I.0

1.4

RV/OT

I.8

L 2.2

OFVT

2.6

10

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BENIGN VERSUS MALIGNANT VENTRICULAR ARRHYTHMIAS

TABLE V

Mortality 1 Year After Infarction as a Function of Lefl Ventricular Ejection Fraction and Repetltive Ventricular Premature Complexes43

TABLE VI

One-Year Mortality Rate in Patients With Inducible Ventricular Tachycardla/Ventrtcular Flbrtllation After Myocardlal Infarctlonq6 Death in 1 Year

Ejection Fraction (%I

Repetitive VPCS

Status Dead

Alive

Total

>40

Present Absent

:

196

55 199

140

Absent Present Total

6

:; 3::

t 388

::

S

Mortality ? 00 2$ 00

Odds Ratio 4:9 4:4 ...

Chi-square total = 14.37, df = 2; chi-square interaction = 0.27, df = 1; chi-square association = 14.10, df = 1; summary odds ratio = 4.8. VPCs = ventricular premature complexes.

pairs and runs was used to grade the arrhythmias detected using a conventional Holter scanner to analyze 24-hour ECG recordings. However, after adjusting for LVEF, there was no significant independent relation between ventricular arrhythmias and mortality. However, when Califf et al used only clinical and noninvasive measures to adjust for LV dysfunction, they obtained a result similar to that of Ruberman and Moss. This analysis failed to eradicate the relation between ventricular arrhythmias and mortality. Thus, they concluded that the adjustment procedure of Ruberman and Moss failed because they used inadequate variables to represent LV dysfunction. Although the findings of Califf et als were not obtained in patients with recent myocardial infarction, they nevertheless seriously challenge the conclusions of Rubermanss and Moss.~~ More recently, 2 studies have used radionuclide EF to adjust for LV dysfunction in postinfarction patients. The Multicenter Investigation of the Limitation of Infarct Size (MILIS)43 reported findings in 388 patients (Table V) and the Multicenter Post Infarction Program (MPIP)44 in 766 patients. Both of these studies used sensitive and specific computerized methods to analyze the 24-hour electrocardiograms and radionuclide methods to measure LVEF. In these preliminary analyses, MILIS used repetitive VPCs and MPIP used VPC frequency dichotomized at 10 per hour as arrhythmia endpoints. Both studies show that ventricular arrhythmias do contribute independently to the mortality risk in the year after myocardial infarction. This was an important point to settle because it forms a critical basis for treatment strategies aimed at reducing postinfarction death. Our own working hypothesis is that ventricular arrhythmias are significantly and independently related to subsequent cardiac death in patients with coronary heart disease or cardiomyopathy. Also, we believe that certain patients with coronary heart disease and large scars have ventricles capable of supporting reentrant activity and VF even though these patients may not have significant ventricular arrhythmias in 24-hour ECG recordings. The subgroup with arrhythmogenic scars may be detected by programmed ventricular stimulation. Already there is some preliminary evidence for this hypothesis. Hamer,45 Richards,46 and their co-

Inducible VT/VF

Present

Absent

Total

Present Absent Total

10 1;

28 120 148

1;; 165

Mortality with VT/VF: 26%, mortality without VT/VF: 6 %. p
workers found that patients with recent myocardial infarction who have VT or VF in response to programmed ventricular stimulation have a 5 to 6-fold increased likelihood of having death or symptomatic arrhythmias in follow-up (Table VI). Hamer et al did a preliminary and superficial comparison of electrophysiologic studies and Holter recordings before the patients were discharged after myocardial infarction and found a rather poor correlation. So far, preliminary studies show very encouraging results, indicating that from among the group with large, confluent myocardial scars caused by infarction, programmed ventricular stimulation can be used to identify those who have the greatest potential for arrhythmic death. The relation between positive response to programmed ventricular stimulation early after myocardial infarction and spontaneous ventricular arrhythmias is not yet defined. Benign Ventricular Arrhythmias A number of studies have been done in apparently normal patients to determine the prevalence of ventricular arrhythmias and their significance. In a small study of 50 male medical students, Brodsky et al1 found that 25 (50%) had some ventricular arrhythmia, but only 2% had >50 VPCs per 24 hours and only 4% had repetitive VPCs. Frequent and repetitive VPCs were found more often in Hinkle et al’s47 study of 301 apparently normal middle-aged men (median age 55 years) in a random population sample. To eliminate persons with asymptomatic coronary heart disease in their sample, Kostis et a148selected for study a group of 101 persons from 1,500 patients who were referred for coronary angiography. These 101 patients were normal as judged by physical examination, electrocardiography, chest roentgenography, echocardiography, exercise test, coronary angiography, and left ventriculography.48 The group had a mean age of 49 years (range 16 to 68). The prevalence of VPC frequency was as follows: >l per hour, 39%; >lO per hour, 20%; and >lOO per hour, 4%. No repetitive forms were detected in any of the 101 patients and other complex forms were rare as well; multiform VPCs were found in only 4% and R and T in 2%. These findings are strikingly different from those of previous studies. The prevalence of VPC frequency in the Kostis sample is very similar to that found in patients with recent myocardial infarction. However,

September 22. 1983

the almost total lack of repetitive VPCs is the striking aspect of the study. This finding is in marked contrast to the findings in patients with heart disease4 or in middle-aged men. 47 If validated, those findings indicate that the striking difference between normal and abnormal middle-aged persons is the prevalence of repetitive VPCs. Kenlnedy et a14g asked the opposite question: whether or not frequent and complex ventricular ectopic activity indicates underlying coronary heart disease. From ,a group of 62 patients with ZlOO VPCs per hour and repetitive VPCs but normal 12-lead electrocardiogram, M-mode echocardiogram, and exercise test results, 25 were selected for coronary angiography. The primary indication for angiography was the presence of ventricular arrhythmias in association with coronary risk factors. The average age in the group was 47 years and the ventricular arrhythmias had been present for an average of 3 years. Coronary angiography showed significant coronary lesions in 25% (6 of 25) of the group. This study is very small and should be extended, but tends to support the view that most patients who have striking ventricular arrhythmias but normal noninvasive workup results do not have significant coronary heart disease. Follow-up studies show that normal subjects who have frequent ventricular arrhythmias have an excellent life expectancy without antiarrhythmic drug treatment for follow-up periods of about 2 years. With the studies done so far, it is not possible to say that ventricular arrhythmias do not increase the risk of dying in normal persons compared with appropriate control groups. Given the mortality expectations for normal persons and assuming the same increment in risk attributable to VPCs as occurs in postinfarction populations (that is, relative risks of 2.0 to 3.0), a very large study would be required to detect such a difference. The sample size required would have to be well above 1,000 subjects. Nevertheless, one can say that the mortality rate in persons with apparently normal hearts and frequent ventricular arrhythmias is reasonably good. Given our current antiarrhythmic drugs, it is well not to treat these patients unless they are symptomatic or the arrhythmia demonstrates clear-cut malignant potential.

1. Brodsky M, Wu D, Denes P, Kanakfs C, Rosen KM. Arrhythmias

documented by 24 hour continuous electrocardiogaphic monitoring in 50 male ~g~M$;5students without apparent heart disease. Am J Cardiol 1977;39:

2. Clarke Jk, Hamer J, Shefton JR, Tayfor S, Venning GR. The rhythm of the normal human heart. Lancet 1976;2:508-512. 3. Scott 0, Wiiiiams GJ, Fiddler 01. Results of 24 hour ambulatory monitoring of electrocardiogram in 131 healthy boys aged 10 to 13 years. Br Heart J 1960;44:304-308. 4. Hinkfe LE. Carver ST, Argyros DC. The prognostic significance of ventricular pmmahre contractlcns in healthy people and in people with coronary heart disease. Acta Cardiot 1974;43:5-32. 5. CaMf Y, Surks JM. Behar VS, Margoffs JR, Wagner OS. Relationships among ventricular arrhythmias, coronary artery disease and angiographic and electrocardiographic indicators of myocardial fibrosis. Circulation 1978;57:725-732. 8. Caffff RY, McKfm#s RA, Burks J, Lee KL, Harreii FE, Behar VS, Pryor DB, Wa~rer GS, Rosati RA. Prognostic implications of ventricular arrhythmias during 24-hour ambulatory monitoring in patients undergoin cardiac ~thetenzabon for coronary artery disease. Am J Cardtol 19 8 2;50:237. Ca’Nert A, Lown B, Goriiln R. Ventricular premature beats and anatomically

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