Treatment of cardiac arrhythmias: When, how and … WELLENS AND BRUGADA TREATMENT OF CARDIAC ARRHYTHMIAS JACC Vol. 14, No. 6 November 15. 1989:1417-28 Table 1. …

JACC Vol. 14, No. 6 November 15. 1989 1417-28

1417

Treatment of Cardiac Arrhythmias: When, How and Where?

HEIN J. J. WELLENS, MD, FACC, PEDRO BRUGADA. MD

Maastricht, The Netherlands

Despite major advances in the understanding of mechanisms, better diagnostic methods and a wide array of new modes of therapy, management of cardiac arrhythmias continues to be a challenge. Because of possible deleterious effects of antiarrbythmic therapy, the decision about when and how to treat should be weighed carefully with emphasis

on symptoms and the prognostic significance of the arrbyth- mia. When possible, the high risk patient should be referred to a center where expertise and diagnostic and therapeutic possibilities allow optimal treatment.

(J Am Co11 Cardiol1989;14:1417-28)

Cardiac “arrhythmology” has seen major changes during the last 40 years. The introduction of several new techniques has contributed to better understanding of the mechanism, site of origin, prognosis and treatment of arrhythmias.

the atria. In principle, the same holds for any type of supraventricular or ventricular arrhythmia.

Clinical factors. Figure 1 illustrates the many factors that play a role in the occurrence of an arrhythmia and how they

These developments have improved the care are interrelated. Some of these factors are of patients, but the wide range of possible diag- 1 ,k+( 1 c : ‘c : present over a long period of time-for example, nostic techniques and treatment modes has in- - - - - - . . . ?? .

c

the degree of vessel narrowing in chronic coro- creased the risk of overtreatment or even mal- * * * nary artery disease or an increased or decreased treatment and unnecessary cost. What, then, is 1 ’

. *&

.

‘0

. amount of heart muscle as in ventricular hyper- needed to know when, how and where to treat an

‘m . trophy or after an old myocardial infarction.

arrhythmia successfully, safely and cost effec- Other factors are dynamic-for example, tively? We have listed those requirements in

ANNIVERSARY changes in platelet function, degree of ischemia,

Table 1 and will discuss these in more detail in the neurophysiologic system and so forth. this review.

1 ‘3 4 9

Relation Between Pump Function, Blood Supply, Neurocontrol and Cardiac Rhythm

It is a mistake to prescribe antiarrhythmic medication without realizing that abnormalities of pump function, blood supply or neurocontrol of the heart may be totally or partially responsible for a cardiac arrhythmia. Most physi- cians know that atria1 fibrillation is a rare arrhythmia in the healthy heart and that proper treatment requires a careful evaluation to identify, and when possible correct, causes like cardiac muscle stretch, ischemia, inflammation, fibrosis, infiltration. intoxication or abnormalities in neurocontrol of

From the Department of Cardiology, Academic Hospital Maastricht and the Interuniversity Cardiology Institute, The Netherlands.

Address for reorints: Hein J. J. Wellens, MD, Department of Cardiology. Academic Hospital Maastricht. P.0. Box 1918, 6201 BX Maastricht. The Netherlands.

01989 by the Americ,m College of Cardiology

I Y 8 Y The finding of a cardiac arrhythmia should

always be a stimulus for careful history taking and an appropriate physical examination. These should be followed by suitable noninvasive and invasive studies in search of indications for heart disease. The discovery of ventricular premature beats in a patient after a myocardial infarction should first be a stimulus to rule out (and when present, treat!) ischemia outside the infarcted area and disturbances of pump function rather than a cue to prescribe antiarrhythmic medication.

A good arrhythmologist shouldfirst be a good clinician! He or she should not only identify (and possibly correct)

This article is part of a series of articles celebrating the 40th anniversary of the American College of Cardiology. The series attempts to set the stage for the

future by describing current state of the art management of selected major cardiovascular problems and the basic knowledge that will provide directions for advances in diagnosis and therapy.

0735-1097/89/$3.50

1418 WELLENS AND BRUGADA TREATMENT OF CARDIAC ARRHYTHMIAS

JACC Vol. 14, No. 6 November 15. 1989:1417-28

Table 1. Requirements for the Cardiologist Treating Arrhythmias

1.

2.

3.

4. 5.

Understanding of the relation between pump function, blood supply, neurocontrol and rhythm of the heart. Knowledge of the different types of cardiac arrhythmias, their site of origin, electrocardiographic diagnosis, mechanism and importance of their etiology. Knowledge of when to treat and understanding of the value and limitations of the different diagnostic techniques. Understanding risk stratification of arrhythmias. Knowledge of the value, limitations and costs of the different therapeutic options.

static contributing factors but also control (as far as possible) dynamic changes.

Different Types of Cardiac Arrhythmias, Their Site of Origin, Electrocardiographic Diagnosis, Mechanism and the Importance

of Their Etiology Observations in the tissue bath, the isolated and intact

animal heart and the human heart have resulted in a better understanding of the possible mechanisms of cardiac arrhythmias (l-6). Programmed electrical stimulation of the heart combined with the recordings of local endocardial and epicardial electrical activity frequently allows us to localize the site of origin or pathway of the arrhythmia in the intact human heart (7-11). Careful evaluation of the 12 lead electrocardiogram (ECG) during the arrhythmia at the time of programmed electrical stimulation and cardiac activation mapping has resulted in the recognition of specific ECG patterns. This has made it possible to distinguish among the different types of supraventricular tachycardia, to locate the site of atrioventricular (AV) block, the site of origin of a ventricular tachycardia and the ventricular and atria1 end of

an accessory AV pathway and to differentiate between a supraventricular and a ventricular origin of a wide QRS tachycardia (12-26). A review of these advances has recently been published elsewhere (27).

Mechanism of reentry. The observation that most clinically occurring regular sustained tachycardias can reproduc- ibly be initiated and terminated by timed extrastimuli during programmed electrical stimulation suggests that reentry is the most common mechanism of these arrhythmias. How- ever, proof that reentry is the tachycardia mechanism can only be provided by delineating the pathway and demon- strating that the arrhythmia can be terminated temporarily by creating refractoriness in a part of the circuit and defini- tively by (surgical, electrical or chemical) ablation of part of the pathway.

Other arrhythmogenic mechanisms: early and late afterdepolarizations. In recent years, increasing attention has been given to other arrhythmogenic mechanisms that may play a role in clinically occurring arrhythmias. In isolated tissue, early and late afterdepolarizations have been shown to lead to arrhythmias (6). Early afterdepolarizations, which can be produced experimentally by barium, hypoxia, high concen- tration of cathecholamines, sotalol, N-acetyl procainamide and cesium (6), have been suggested as a cause of torsade de pointes in patients with the congenital or acquired long QT syndrome (28,29). Late afterdepolarizations can be induced experimentally by digitalis and seem to be responsible for some clinical arrhythmias occurring in digitalis intoxication (30). Arrhythmogenic mechanisms based on afterdepolarizations and their possible clinical implications were recently discussed by Zipes (2). Unfortunately, intracellular recordings are not possible in the intact human heart, making the study of the relevance of these mechanisms to human arrhythmias extremely difficult. A possible solution might be the development of drugs specifically counteracting early or

CHRONIC STENOSIS

/.,.,..\

SPASM 4

/ \

-THROMBOSIS

Figure 1. Model showing the factors that play a role in cardiac arrhythmias. The basic triangle consists of electrical instability, hemodynamic

,~~~~~~~~~A~oRs dysfunction and ischemia. Each of these three cornerstones has static and dynamic compo- nents. Modulating (MOD.) factors include the autonomic nervous system, electrolytes, hor- mones and drugs. COND = conduction.

am 4 _)

COND.VELOCITY REFRACTORINESS


WELLENS AND BRUGADA 1419 TREATMENT OF CARDIAC ARRHYTHMIAS

Table 2. Relation Between Etiology of Ventricular TachycardiaNentricular Fibrillation (VTIVF) and Arrhythmia Recurrence and Death During Follow-Up

Old MI SMVT

RVD Idiopathic

VF SMVT SMVT VF

Total no. of patients 79 31 II 52 6 Total deaths I5 (1%) 13 (35%) I(l9%) I* (2%) 0 Sudden cardiac deaths 5 (6%) 5 (14%) 0 0 0 No. of patients with VTlVF recurrence 24 (30%) 7 (19%) 6 (67%) I5 (28%) 2 (33%) Length of follow-up (mo) 26 22 39 86 39

*Patient died of cancer. MI = myocardial infarction; RVD = right ventricular dysplasia: SMVT = sustained monomorphic ventricular tachycardia

delayed afterdepolarizations (31) or the use of special elec- surgical, electrical or chemical ablative therapy is consid- trode catheters that record a monophasic action potential ered, but also allows the evaluation of the effect of pharma- resembling an intracellular recording (32). cologic or nonpharmacologic therapy (38).

It is important to recognize not only the type, site of origin and mechanism of the arrhythmia but also its etiology. As shown in Table 2, the value of ventricular tachycardia/fibrillation as a prognostic indicator for cardiac death in patients with an old myocardial infarction is totally different from the value in patients who have arrhythmogenic right ventricular dysplasia or are without heart disease (so called idiopathic ventricular tachycardia or ventricular fibrillation). Similarly, the prognostic importance of advanced forms of ventricular arrhythmias has been well documented in ventricular hypertrophy (of all causes) and cardiomyopathy (33-35).

Holter versus electropbysiologic study. An important question is which of the two methods (ambulatory ECG recording or an electrophysiologic study) provides the most accurate prediction of antiarrhythmic drug efficacy. The only available randomized comparison of the two methods (39) suggests that electrophysiologic study is better than Holter monitoring in predicting success of therapy. Limitations of this investigation include the small number of patients studied and the use of nonstandardized drug therapy. A multicenter study (the Electrophysiologic Study Versus Electro- cardiographic Monitoring [ESVEM] trial) (40) involving a much larger number of patients is currently addressing this problem. It should be realized, however, that Holter monitoring primarily registers the effect of an intervention on spontaneously occurring arrhythmias whereas the electrophysiologic study gives information on the effect on the substrate of the arrhythmia. Information from both tests is therefore frequently required to obtain optimal information on the response to therapy.

Value and Limitations of Different Diagnostic Techniques

Ambulatory electrocardiographic recordings. Several noninvasive and invasive tests are currently used in patients suffering from arrhythmias. The type, incidence, etiology and significance of an arrhythmia determine which diagnostic test or tests should be performed. That choice is also influenced by the preferred treatment (drugs, surgery, electrical ablation, pacing, and so forth). As pointed out by several investigators, frequently occurring arrhythmias can best be studied by 24 h ECG ambulatory (Holter) recordings. Such recordings can also give information about the role of the autonomic nervous system and the effect of therapeutic interventions (36). Unfortunately, however, 35% to 50% of patients with documented sustained ventricular tachycardia or ventricular fibrillation do not show complex arrhythmias on Holter monitoring (37).

Invasive electropbysiologic study. Such a study is usually selected when the arrhythmia occurs infrequently and the somatic or psychologic consequences, or both, require information as to the site of origin and the best therapeutic approach. An electrophysiologic study not only identifies the site of origin of the arrhythmia, which is essential when

Signal-averaged electrocardiogram. This recording usually shows late potentials in patients having a myocardial area of slow conduction as the basis for their reentrant ventricular tachycardia (41). The finding of late potentials does not establish the presence of a reentrant circuit but may only indicate an area of delayed activation. The prognostic significance of a ventricular late potential on the signal- averaged surface ECG as a marker for an increased incidence of life-threatening ventricular arrhythmias and sudden death is currently being investigated (42). It is less com- monly found in patients with spontaneous ventricular fibrillation than in patients with spontaneous ventricular tachycardia (43). Controversies exist about the signal-processing techniques for detecting ventricular late potentials (44-46). We believe that more follow-up studies are needed to establish the true value (alone or in combination with other techniques, like the left ventricular ejection fraction) of the signal-averaged ECG to identify patients at high risk for the

1420 WELLENS AND BRUGADA JACC Vol. 14, No. 6 TREATMENT OF CARDIAC ARRHYTHMIAS November 15, 1989:1417-28

1. CARDIAC ARREST DUR!NG FIRST

EPISODE SPONTANEOUS VTIVF?

+/80 140 \- J

15% \

2%

J \ 2. NYHA- 37 2. VT< 2 MONTHS AFTER Ml?

3. MULTIPLE MI’S? 3. NYtiA - 37

A + 10 50 -

28% 12% 20% 10% 11% 4%

27% 4%

42% 22%

3. CARDIAC ARREST DURING WORST

BOUS VTIVF?

Figure 2. Estimation of risk of sudden death based on the four clinical variables discussed in the text. As shown in this group of 200 consecutive patients with a previous myocardial infarction (MI) develonine ventricular tachvcardia (VT) or ventricular fibrillation (VF), he; was a 6% incidence of dying suddenly within 2 years. NYHA = New York Heart Association classification for dyspnea.

Figure 3. Estimation of risk of nonsudden cardiac death in the same patients as in Figure 2. The overall incidence of nonsudden cardiac death at 2 years was 9%. Abbreviations as in Figure 2.

spontaneous occurrence of sustained ventricular tachycardia.

Role of exercise testing. Exercise testing should not only be performed in patients with a history of exercise-related arrhythmias or to identify ischemia in a patient with an arrhythmia but also because induction of a sustained ventricular arrhythmia by exercise carries a poor prognosis. Exercise testing should always be performed when a patient is placed on an antiarrhythmic drug regimen because drugs, especially those slowing intraventricular conduction, may promote the occurrence of ventricular tachycardia during exercise (47,48). Exercise testing is therefore an essential investigation to identify a possible proarrhythmic effect of a drug (49).

Risk Stratification of Arrhythmias As already discussed (Table 2) etiology plays an impor-

tant role in the prognostic significance of an arrhythmia. But even within a seemingly homogeneous group such as that of patients developing monomorphic ventricular tachycardia or ventricular fibrillation outside the acute phase of myocardial infarction, marked differences in risk can be (and have to be) recognized.

Risk factors for cardiac death. Figures 2 and 3 present four questions related to the clinical history that can be of great help in assessing risk for nonsudden and sudden cardiac death in these patients (50). These questions are: 1) What is the New York Heart Association functional classification exclusive of the arrhythmia? 2) Did the patient lose consciousness during the arrhythmia? 3) Did the first episode

of ventricular tachycardia or ventricular fibrillation occur between day 3 to day 60 after myocardial infarction, or later? 4) Has the patient had more than one prior myocardial infarction?

We found in 200 consecutive patients with ventricular tachycardia or fibrillation after a myocardial infarction (Fig. 2) that with these questions we could recognize patients with a very low chance of dying suddenly (those not losing consciousness during the first episode of their spontaneous ventricular tachycardia or fibrillation and having the arrhythmia >2 months after their myocardial infarction). In contrast, the question also identified patients who had a 25% chance of sudden cardiac death within 2 years (Fig. 2).

Figure 3 shows that pump function is the most important discriminatorfor risk of nonsudden cardiac death in patients with ventricular tachycardia and ventricular fibrillation after a myocardial infarction. Figure 4 indicates how the total score of the four variables from the clinical history influ- ences the risk for sudden and total cardiac death in the first 2 years in patients whose first episode of ventricular tachyarrhythmia occurs >3 days after a myocardial infarction. Figure 5 shows (using the same variables as in Figures 2 to 4) that, in contrast to survival, recurrences of ventricular tachycardia are not related to the score of the four questions from the clinical history.

Risk of fatal arrhythmia after infarction without spontaneous arrhythmia. All patients shown in Figures 2 to 5 entered the study after they had had a spontaneous episode of ventricular tachycardia and ventricular fibrillation after a myocardial infarction. A much more difficult problem is to estimate risk of dying from an arrhythmia in the survivor of a myocardial infarction without a spontaneously occurring life-threatening ventricular arrhythmia. It has been recog-

JACC Vol. 14, No. 6 November 15, 1989:1417-28


% INCIDENCE %

a) NYHA CLASS 3 3

b) SYMCOPE DURING VT/VF

C) VTlVF C DAY 3-60 AFTER MI

$1 MULTIPLE MI

40_ a SUDDEN DEATH

0 TOTAL CARMAC DEATH

PTS: 55 86 40 13 6

0. 1 2 3 4

NUMBER DF VARIABLES PRESERT

Figure 4. Incidence of total cardiac death (0) and sudden cardiac death (A) in relation to the total score of four clinical variables in 200 patients (pts) with ventricular tachycardia (169 patients) or ventricular fibrillation (VF) (31 patients) after myocardial infarction (MI). The four clinical variables are listed in the upper right corner of the figure. As shown, depending on the number of variables present, marked differences exist in sudden and total cardiac death after 2 years of follow-up.

nized that the finding of complex forms of ventricular arrhythmia, primarily runs of nonsustained ventricular tachycardia on ambulatory ECG monitoring, is associated with an increased risk of sudden cardiac death (51-54). Similar observations have been made in patients with hypertrophic or dilated cardiomyopathy (55-57). Additional im- pairment of left ventricular function leads to an exponential increase in incidence of sudden death (58).

Apart from information about spontaneous ventricular arrhythmias on ambulatory ECG monitoring, pump function (usually obtained by measuring left ventricular ejection fraction) and reversible myocardial ischemia at exercise testing, the use of other techniques has been suggested to improve stratification of risk for a life-threatening arrhythmia after a myocardial infarction. Richards et al. (59) indicated that induction of a “slow” ventricular tachycardia (shortly after myocardial infarction, cycle length ~230 ms) by programmed stimulation of the heart was a strong pre- dictor of sudden death or spontaneous ventricular tachycardia in the first year after a myocardial infarction. This finding was independent of left ventricular ejection fraction and was of more value than the signal-averaged ECG. There is discussion, however, about the value of programmed electrical stimulation in risk stratification after myocardial infarction (60-63). This factor and the risks and costs of the test do

100

1 -I

8o cl TOTAL MORTALITY

-cl SUDDEN DEATH

60- Kll CARDIAC DEATH

RECURRENT VENTRICULAR TACHYCARDIA

40

1

I: i n,,l o-1 2-4

NUMBER OF CLINICAL VARIABLES

N=l41 N-49

Figure 5. Risk of dying suddenly and nonsuddenly and of recurrent episodes of ventricular tachycardia in relation to the presence of the same four variables shown in Figure 4. Recurrences of ventricular tachycardia were at least as common in patients with no or one variable as in patients having two to four variables.

not support its use for routine risk stratification of patients recovering from an acute myocardial infarction.

Value, Limitations and Costs of the Different Therapeutic Options

Table 3 shows the different therapeutic modes currently available in relation to their effect on the arrhythmia substrate, costs, required expertise, long-term efficacy and side effects,

Antiarrhythmic Drugs

Currently available antiarrhythmic drugs do not destroy the substrate of the arrhythmia. They may change the electrophysiologic properties like conduction velocity or refractory period duration within the substrate or may prevent the trigger of arrhythmia-like ventricular premature beats or sudden changes in heart rate. In Europe, approxi- mately 50 different antiarrhythmic drugs are available. All of these drugs differ in their effects-their half-life (Fig. 6), resorption, breakdown, excretion, active metabolites, side effects, and so forth. To make the situation even more complicated, their electrophysiologic effects may be related to heart rate and may be different in healthy and diseased cardiac tissue.

1422 WELLENS AND BRUGADA JACC Vol. 14, No. 6 TREATMENT OF CARDIAC ARRHYTHMIAS November 15. 1989:1417-2&l

Table 3. Current Modes of Therapy of Arrhythmias in Relation to Effect on Arrhythmia Substrate, Costs, Required Expertise, Long-Term Efficacy and Side Effects

Drugs Surgery Electrical Ablation

Chemical Ablation

Pacing Dev/ Defib

Arrhythmia substrate removed costs Specialized center Long-term efficacy Side effects

No Low

? Yes Yes

Yes High

Required Yes

10 to 15% operative mortality in VT

Yes Moderate Required

7

Myocardial damage

Yes Moderate Required

? Myocardial

damage

No Moderately high

Required Yes

Psychological

Abl = ablation; Defib = implantable defibrillator; Pacing Dev = implantable pacing device; VT = ventricular tachycardia.

The CAST study: role of class Ic drugs. The interim results of the Cardiac Arrhythmia Suppression Trial (CAST) study (64) highlight some of the problems with antiarrhythmic drug therapy. The intention of the CAST study was to answer the question: Does suppression of ventricular ectopic activity after a myocardial infarction result in better outcome? The CAST study was based on the evidence (51-54) that ventricular ectopic activity after myocardial infarction worsens prognosis. Previous studies (65-67) have failed to show benefit of treatment by antiarrhythmic drugs, with the exception of beta-adrenergic blocking agents, but in those studies patients were not selected after it had been shown that the antiarrhythmic drug was able to markedly reduce ventricular ectopic activity.

Although complete data are not available, preliminary results indicate that administration of flecainide and encainide (after having been shown to suppress ventricular ectopic activity) resulted in a higher arrhythmic death rate than that of patients receiving placebo. What caused this unfavorable effect? A few possible mechanisms have to be considered. First, some patients, after administration of a class Ic drug, show widening of the QRS complex on exercise, indicating

PROCAINAYIDE

PROPAFENONE

MEXILETINE

ACTING)

slowing in intraventricular conduction with increasing heart rate. This event may have favored the induction of ventricular tachycardia (48,49). Second, Nattel et al. (68) observed some years ago in dogs, that pretreatment with an antiarrhythmic drug slowing conduction (aprindine) followed by coronary artery occlusion resulted in a much higher incidence of life-threatening ventricular arrhythmias than that of dogs having coronary obstruction without previous antiarrhythmic drug treatment. The investigators found marked slowing in conduction in the ischemic area in the dogs pretreated with aprindine. These observations suggest the possibility that, during an ischemic episode the occurrence of ventricular arrhythmias is facilitated in patients with coronary artery disease treated with an antiarrhythmic drug that slows conduction.

Third, class Ic drugs (like Jiecainide and encainide) slow conduction velocity without affecting the duration of the refractory period of myocardial tissue. Figure 7, which is based on observations by Brugada et al. (69) in an animal model of ventricular tachycardia, shows that, depending on the length of the reentrant circuit, slowing in conduction velocity without lengthening of the refractory period may

Figure 6. The mean half-life of several currently available antiarrhythmic drugs; marked differences exist among these drugs. Half-life is only one property of the drug. There are also differences in pharmacokinetics, breakdown, excretion, active metabolites, side effects, and so forth.

3 6 9 12 15 18 21 24 HOURS

HALF LIFE OF ANTIARRHYTHMIC DRlKiS

JACC Vol. 14, No. h WELLENS AND BRUGADA 1423 November 15, 1989:1417-28 TREATMENT OF CARDIAC ARRHYTHMIAS

wL=cvxNP: 10 CM/S X 250 MS = 2.5 CM 7.5 CM/S X 250 MS = 1.66 CM

ClFlcUlT LENGTH: 4CM 4CM

EXIT ACTIVATED: 150/m 2 X 113/MH = 226iMIN

Figure 7. Possible mechanism of acceleration in rate of tachycardia by a drug that slows conduction velocity but does not prolong the refractory period. Panel A shows a reentrant circuit with a length of 4 cm and a single exit point. The wave length (WL) of the circulating impulse (the product of conduction velocity [CV] and the refractory period [RV]) measures 10 cm/s x 250 ms = 2.5 cm. Each minute, 150 impulses will leave the exit point. Panel B shows the situation after the administration of a drug (like a class Ic drug) that slows conduction without lengthening the refractory period (RP) within the circuit. The wave length (WL) now measures 7.5 cm/s x 200 ms = 1.88 cm. This means that two consecutive impulses can fit within the circuit of 4 cm. Each minute 2 x 133 = 226 impulses will reach the exit point of the circuit.

result in the situation that two (instead of one) circulating impulses can fit within one reentrant circuit. A possible clinical example is given in Figure 8. Theoretically, therefore, after administration of a class Ic drug, acceleration of a ventricular ectopic rhythm (possibly leading to sudden death) may occur if a ventricular reentrant circuit is present after myocardial infarction.

Our group (62) has demonstrated that ventricular reentrant circuits are present in about 40% of patients studied by programmed stimulation of the heart shortly after myocardial infarction. The incidence of such a circuit did not differ in patients with or without documented episodes of nonsustained ventricular tachycardia. A reentrant circuit (as demonstrated by the reproducible initiation of sustained ventricular tachycardia during programmed stimulation) was present in 93% of patients with documented spontaneous episodes of sustained ventricular tachycardia. These observations suggest that in a large number of patients a possible ventricular reentrant circuit is present after myocardial infarction independent of the spontaneous occurrence of ventricular tachycardia. Administration of an agent slowing conduction velocity without lengthening the refractory period may under those circumstances facilitate (as shown in Fig. 7 and 8) the occurrence of a more rapid ventricular tachycardia possibly leading to sudden cardiac death.

Implications. The marked differences in properties among antiarrhythmic drugs can make the selection of such drugs very difficult. This is reason for us to stress that 1) a physician treating arrhythmias should be really knowledge- able about a few antiarrhythmic drugs (and restrict himself

I

Figure 8. Possible clinical example of the situation in Figure 7. During intravenous administration of a class Ic drug a sudden acceleration in rate of ventricular tachycardia is observed without change in QRS configuration. The change in RR interval 500 ms to 380 ms can be explained by assuming a change from one to two circulating impulses within one reentrant circuit. Other possible mechanisms are a sudden change from a larger to a smaller reentrant circuit using the same exit point.

or herself to those drugs); and 2) high risk patients should be referred to a center with expertise and equipment for treating arrhythmias.

Surgery

Identification of the site of origin of an arrhythmia (as in atria1 or ventricular tachycardia) or the essential component in a tachycardia pathway (like the accessory AV pathway in the Wolff-Parkinson-White syndrome) was the basis for the development of new surgical methods for treating arrhythmias. At present, many different types of tachycardias can be approached surgically. In some types, surgical treatment is still in an experimental phase (as in atria1 flutter or atria1 fibrillation), in others (like the Wolff-Parkinson-White syndrome, AV node tachycardia and ventricular tachycardia) their value is well established (7C78). As pointed out in Table 3, by removing, isolating or interrupting the arrhythmia substrate, surgery offers curative treatment. It can only be done, however, in specialized centers having expertise in localizing the arrhythmia. Operative risk depends on the type of arrhythmia. Perioperative mortality varies from 10% to 15% for ventricular tachycardia to almost zero for the Wolff-Parkinson-White syndrome (77,78).

In ventricular tachycardia, operative mortality and long-

1424 WELLENS AND BRUGADA JACC Vol. 14, No. 6 TREATMENT OF CARDIAC ARRHYTHMIAS November 15, 1989:1417-28

term outcome can be improved by careful selection of patients. Van Hemel et al. (79) recently reported on the use of a left ventricular segmental wall motion score for that purpose. They suggested nonsurgical therapy if less than three of nine segments of the left ventricle showed normal motion or slight hypokinesia.

Costs ofsurgery are high because of the detailed electrophysiologic studies required before, during and after opera- tion, but as shown for the Wolff-Parkinson-White syndrome, surgical treatment can be cost effective (80).

Electrical Ablation or Fulguration

An electrical shock can destroy tissue in which an arrhythmia originates or a pathway that plays a role in conduction of the cardiac impulse. At present, it has been used successfully to interrupt conduction in the His bundle and accessory AV pathways and to treat patients with atrial, AV node and ventricular tachycardia (81-86). Its use for treating patients with atria1 flutter is under investigation (87). Again, as with surgery, this treatment requires a specialized center. Good long-term results have been obtained in His bundle ablation. Because of a smaller series of patients long-term outcome is not yet clear for the different types of tachycardia treated with electrical ablation. Use of other techniques like radiofrequency and laser ablation is being studied (88,89).

Chemical Ablation

After experiments by Inoue et al. (90) that showed the possibility of destroying arrhythmogenic myocardial tissue by injecting chemicals into the coronary artery supplying that area, arrhythmias have been successfully treated in humans by transcoronary chemical ablation of the arrhythmia substrate (91). In patients with ventricular tachycardia not responding to or not suitable for pharmacologic or nonpharmacologic intervention, selective injection of alcohol into the coronary artery branch supplying the arrhythmogenic area resulted in cure of the arrhythmia. The technique, which requires expertise in both “angiographic and electrophysiologic mapping” of the site of origin of the arrhythmia, results in a small amount of myocardial damage. We have also applied chemical ablation of AV node conduction by selective injection of alcohol in the AV node coronary artery in patients in whom electrical ablation of AV conduction was unsuccessful. At present, the technique should be considered experimental and long-term results are awaited.

Pacing and Defibrillation Indications. The value of antitachycardia pacemakers in

the management of supraventricular and ventricular reentrant tachycardia has been well demonstrated (92-95). Anti-

tachycardia pacing may be the therapy of choice in patients who do not respond to or cannot tolerate drugs, patients who do not take the prescribed medication, are not suited for or refuse surgery or are not able to tolerate prolonged episodes of tachycardia because of the development of cardiac failure, angina pectoris or dizziness. Patients may prefer treatment with a small reliable pacemaker instead of the long-term intake of antiarrhythmic drugs with possible side effects and accumulating expense. Fully automatic pacemakers may terminate tachycardia so rapidly that the arrhythmia is not noticed or is experienced only as a premature beat.

Role of pacing. In recent years, research has been di- rected to identifying a single and simple mode of pacing that terminates tachycardia rapidly and safely, irrespective of rate, site of origin and body position. We believe that such a “universal” pacing mode can best be achieved by giving premature stimuli during the tachycardia with adaptive coup- ling intervals and an automatically increasing number of stimuli (96). Termination of tachycardia by pacing, especially at the ventricular level, carries the risk of tachycardia acceleration and ventricular fibrillation. In devices implanted for pacing termination of ventricular tachycardia, a back-up defibrillation mode should therefore be imple- mented.

The implantable automatic defibrillator. The value of the implantable automatic defibrillator in properly selected cases has been well documented (97-99). Candidates for implan- tation include patients with cardiac arrest, those with recurrent symptomatic episodes of ventricular tachycardia despite drug therapy and those with syncope. Most patients have underlying coronary artery disease or cardiomopathy. A point of discussion is what should be considered an adequate antiarrhythmic trial before insertion of a defibrillator is advised. Our own approach to this problem will be discussed later.

The Practical Approach to Treatment The decision to treat or not to treat an arrhythmia should

be based on answers to two questions. Is the patient symptomatic during the arrhythmia? Has the arrhythmia prognostic significance (either because of structural cardiac disease or because the arrhythmia will lead to cardiac damage as in incessant tachycardia)? Four answers are possible.

1. The patient is symptomatic and the arrhythmia has prognostic significance. In these patients treatment of the arrhythmia is indicated. An example is the patient with sustained ventricular tachycardia and ventricular fibrillation after a previous myocardial infarction. Depending on the risk profile (Fig. 2 to 4) and after correction (as best as possible) of ischemia and pump failure, the patient with a small chance of dying suddenly is treated with an antiarrhythmic drug, preferably guided by results from programmed electrical stimulation of the heart. Inability to initiate a previously

JACC Vol. 14, No. 6 WELLENS AND BRUGADA 1425 November 15. 1989:1417X28 TREATMENT OF CARDIAC ARRHYTHMIAS

inducible arrhythmia after drug therapy definitely predicts a reduced chance of spontaneous recurrences of ventricular tachycardia (100-102).

There is a diflerence in opinion, however, on the effect of suppression of arrhythmia inducibility by drug therapy on the chance of dying suddenly (103-105). Therefore, in the patient with a high chance of an arrhythmic death (Fig. 2, left) in view of the poor outcome with antiarrhythmic drug treatment, nonpharmacologic treatment should be considered in an early stage. If destruction or isolation of the arrhythmia substrate is not possible or too risky, an electrical device able to pace and defibrillate should be implanted.

Another example of an arrhythmia that is symptomatic and of prognostic significance is found in the patient suf- feringfrom cardiomyopathy induced by a tachycardia. Typ- ically, the arrhythmia is incessant (it can be atria1 fibrillation, atria1 flutter, atria1 tachycardia, circus movement tachycardia using an accessory AV pathway with long conduction times or ventricular tachycardia) and cure of the arrhythmia is essential to interrupt a downhill course.

2. The patient is symptomatic hut the arrhythmia has no prognostic significance. In this group we find patients who have a normal heart but arrhythmias leading to symptoms such as dizziness, syncope and dyspnea. Examples are the patients with circus movement tachycardia in the Wolff- Parkinson-White syndrome and the patient with idiopathic ventricular tachycardia. Treatment is selected depending on the incidence and severity of the arrhythmia and the age of the patient. A young patient with frequent episodes of circus movement tachycardia is preferably treated with surgical or electrical ablation of the accessory pathway, whereas a patient with idiopathic ventricular tachycardia should first receive antiarrhythmic drug therapy. In the symptomatic patient having no additional heart disease care should be taken not to prescribe an antiarrhythmic drug that, because of proarrhythmic or other side effects, worsens the situation.

3. The patient is asymptomatic hut the arrhythmia has prognostic significance. In this category we find patients with a complex ventricular arrhythmia after myocardial infarction or in the presence of cardiomyopathy, hypertensive heart disease or congestive heart failure. In these patients the emphasis should primarily be on correction (if possible) of the contributing factors shown in Figure 1. Apart from treatment with beta-blocking agents and the possible exception of the use of amiodarone in hypertrophic cardiomyopathy (106), no convincing evidence has been presented that suppression of the spontaneously occurring arrhythmias by antiarrhythmic drug therapy leads to a decrease in arrhythmic death. The value of nonpharmcologic antiarrhythmic therapy in these patients is not clear.

4. The patient is asymptomatic and the arrhythmia has no prognostic significance. An example is the patient with a (complex) ventricular arrhythmia in the absence of structural

heart disease. No antiarrhythmic treatment should be prescribed.

It is clear that the approach described requires ability to perform reliable risk classification of the patient. As pointed out, this is possible in some patients (for example the patient with ventricular tachycardia/fibrillation after myocardial infarction or the patient with hypertrophic cardiomyopathy) (106) but much more difficult or even impossible in others.

The Future Better risk classification is one of the most important

challenges of the “arrhythmology” of tomorrow. More precise and less costly methods are urgently needed. In risk classification, also, the role of the autonomic nervous system should be known better and methods to evaluate and correct abnormalities should be developed (107,108). It seems un- likely, in view of the different mechanisms of arrhythmias, that a universal antiarrhythmic drug will be developed. Because most clinically occurring arrhythmias seem to be based on a reentrant mechanism, the profile of an ideal antireentrant drug should include the ability to suppress triggering mechanisms, like premature beats, and to lengthen the refractory period of myocardial tissue without affecting conduction velocity. The drug should also prevent rate- related shortening of the refractory period of myocardial tissue, have anti-ischemic properties and reduce sudden oscillations in the balance of the autonomic nervous system. In addition, it should have a long half-life, no side effects and be inexpensive.

Theoretically, by using molecular biologic techniques, agents could be developed that are site specific, selectively inactivating cells in the arrhythmogenic area. These fasci- nating new possibilities have recently been discussed by Zipes (2). In the absence of antiarrhythmic “miracle” drugs, increasing use will be made of electrical devices in the high risk patient. Smaller, less expensive units not requiring thoracotomy will become available. Last but not least, an important aspect in arrhythmia management will be its prevention. In acute myocardial infarction, thrombolytic therapy by reducing infarct size has resulted in a decrease of both spontaneous and inducible ventricular arrhythmias (109,110). Primary prevention of coronary heart disease should lead to a further decrease in serious arrhythmias in the future (Ill).

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Treatment of cardiac arrhythmias: When, how and … WELLENS AND BRUGADA TREATMENT OF CARDIAC ARRHYTHMIAS JACC Vol. 14, No. 6 November 15. 1989:1417-28 Table 1. …