- Email: [email protected]
Electrophysiologic testing of antiarrhythmic agents
April,
Horowitz
et al.
American
them are beyond 2 months of infarction; presumably moat of the healing has taken place and the electrophysiologic findings are stable. We have studied patients for 6 months and some for several years, and VT is just as inducible years later as during the initial study. Coupling intervals and refractory periods are different, but if VT was induced with programmed stimulation on the first study, it was also induced in the second study, and if it wasn’t inducible the first time, it usually is not inducible the next time. Dr. Conti: In your laboratory or in other laboratories, what are the complications of the procedure in those who fibrillate? Stroke, myocardial infarction, or death? Dr. Horowitz: I am aware of only two deaths that have occurred during serial studies for the evaluation of therapy for VT in all laboratories worldwide; both patients had VT. That doesnot mean, of course,that there have been no other deaths. In our laboratory, the complications of venous catheterization are about the same as those reported from large catheterization series;i.e., about 5% of the patients have local complications. Arterial catheter-
Heart
1992
Journal
ization used to be done by arteriotomy, but we use arteriotomy now only if we can’t get in percutaneously. We have had two significant complications with percutaneous left ventricular catheterization; both patients required cardioversion, and when they moved, their arteries were torn, but later were repaired. We have had no other serious arterial complications. One patient had a transient neurologic event, presumably due to a plaque that was knocked off, but the deficit cleared within 30 minutes. There have been no myocardial infarctions. We have performed approximately 200 left ventricular catheterizations, and I would say that the complications are comparableto those of angiographic catheterization. I am aware of a few deaths worldwide, and I cannot even guess the number of patients who have been studied. We evaluate about 200 patients a year and probably do 750 studies a year. The complications are low, but there is a risk, and patients are made aware of that. I believe that the risk-to-benefit ratio is still on the side of doing the studies in the population at risk of VT or VF.
of
The purpose of these studies is to ilfustrate that the time of drug admin#Wation in expertmental animals subjected to coronary artery occlusion Is an impor@&t infiuetrca on the myocardfal distribution of the drug as well as its electrophysiologic and arrhythmogenlc effacts. Also, because several drugs have active metabolites, some stud&as qust be done after oral administration. Finally, electrophysiologic testing to determine drug effkacy may give misleading results with some drugs. (AM HEART J 103:610, 1982.)
Douglas P. Zipes, M.D., E. N. Prystowsky, Indianapolis, Ind.
M.D., and J. J. Heger, M.D.
Several factors that may influence the results obtained and conclusions drawn from testing the effects of antiarrhythmic agents clinically and in animals are discussed here.
From the K.rannert Indiana University tion Hospital. Supported HL-07182, Institute, Association, Reprint Medicine,
610
Institute of Cardiology, the Department School of Medicine, and from the Veterans
of Medicine, Administra-
in part by the Herman C. Krannert Fund; by grants HL-06308, and HL-18795 from the National Heart, Lung and Blood National Institutes of Health; and by the American Heart Indiana Affiliate, Inc. requests: Douglas I?. Zipes, M.D., Indiana University 1100 West Michigan St., Indianapolis, IN 46202.
School
of
APRINDINE
An early question of ours concerned the influence of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. Accordingly, we examined the effecta of administrating aprindine to five groups of open-cheat dogs.’ Group 1 (35 dogs) received aprindine immediately before one-stage left ant&or descending coronary artery (LAl% occlusion; group 2 (34 dogs) received wine 5 minutes after LAD occlusion; group 3 (16 dogs) was administered aprindine without LAQ oc&sion; group 4 (10 dog%) underw&nt, LAD occlu&on but received no aprindine; and group 5 (10 dogs) was administered aprindine 24 hours after LAD occlu0002-8703/82/040610
+ 06$00.60/O
‘?’ 1982
The
C. V.
MosbyCo.
Volume
103
Number
4, part 2
Electrophysiologic
EXPERIMENTAL
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of
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1. Ratio of IZ to NZ aprindine concentrations over time. Group 1 dogs (who received aprindine before coronary artery occlusion)had substantially higher ratios after coronary occlusion than did group 3 dogs, who received aprindine without undergoing coronary artery occlusion (p < 0.01). The ratios amonggroup 3 dogsdid not change over time and were significantly greater than the ratios of both group 2 dogs, who received aprindine immediately after coronary artery occlusion (p < 0.00, and group 5 dogs, who received aprindine 24 hours after coronary artery occlusion(p < 0.01). (From Nattel S, PedersenDH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in the dog. Cardiovasc Res 15530, 1981.) Fig.
sion. Groups 3 and 4 served as the control animals. We measured the aprindine concentrations in the serum and in ventricular myocardial samples taken from the ischemic zone (IZ), the border zone (BZ), and the normal zone (NZ) at various times after LAD occlusion. Coronary artery occlusion performed after aprindine administration slowed the rate of disappearance of aprindine from the IZ. As can be seen in Fig. 1, the aprindine concentrations decreased more slowly in the IZ than in the NZ, with the IZ concentrations averaging more than twice the NZ aprindine concentrations 1 hour after LAD occlusion. When LAD occlusion was performed before aprindine administration, the aprindine concentrations in the IZ were initially less than 15% of those in the NZ but increased with time to approach half the NZ aprindine concentration 70 minutes after LAD occlusion. BZ aprindine concentrations were intermediate between NZ and IZ concentrations (Fig. 2). Seventeen dogs in group 1 (49%) experienced sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). This compares with five dogs in group 2 (14% ; p < O.Ol), one dog in
I 40
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2. Ratio of BZ to NZ aprindine concentrations over time. The changes are in the same direction among different groups of dogs as the changes in IZ to NZ aprindine concentration ratios (Fig. 1) but are less in magnitude. (From Nattel S, Pedersen DH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusionin the dog. Cardiovasc Res 15230, 1981.) Fig.
group 4 (10% ; p < 0.05), and no dogs in group 3 (0%; p < 0.01) experiencing VT or VF. When aprindine was administered 24 hours after LAD occlusion, premature ventricular complexes were reduced from a mean of 35/100 beats to 12/100 beats (p < 0.01). These results suggest that the temporal relationship between aprindine administration and LAD occlusion importantly modifies the regional myocardial distribution of aprindine and its effects on ventricular arrhythmias following coronary artery occlusion. The exact mechanism for the arrhythmogenic effect of aprindine administered before coronary artery occlusion is uncertain. Ventricular arrhythmias occurring soon after coronary artery occlusion are thought to be due to a reentrant mechanism in part related to slowed conduction in the ischemic myocardium. Aprindine produces further slowing of conduction in ischemic myocardium and a tendency to increase ventricular arrhythmia in the presence of ischemia in animal models.2 Significant quantities of aprindine in the IZ would thus increase the prevalence of ventricular arrhythmias in animals subjected to coronary occlusion, as it did in group 1 dogs. Group 2 dogs had a much lower prevalence of ventricular arrhythmia than group 1 dogs, despite similar aprindine concentrations in the serum and normal myocardium. The effects of aprindine when administered 24 hours after coronary artery occlusion were markedly different from its effects when given before or just
612
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and Heger
CONTROL
American
ISCHEMIA
April, 1982 Heart Journal
ISCH. and VERAP.
Fig. 3. Effect of verapamil on the fractionation of the epicardial electrogram recorded from the IZ 5 minutes after occlusionof the LAD coronary artery during pacing at a cycle length of 500 msec.Left panel: Before coronary occlusion. Center panel: Before administration of verapamil. Right panel: 11 minutes
later. Note that verapamil prevented the fractionation recorded from the IZ. (From EIharrar V, Gaum WE, Zipes DP: Effect of drugs on conduction delay and the incidence of ventricular arrhythmias induced by acute coronary occlusionin dogs.Am J Cardiol 39:544, 1977.)
of aprindine on ventricular arrhythmia when given just after coronary artery occlusion and those 24 hours later are not due to differences in drug distribution, because the relative concentrations of aprindine in different zones are very similar at these two times (Figs. 1 and 2). It is likely that the mechanisms of the early and later phases of ventric-
aprindine administered, and in the fact that the heart rate of the pigs was not controlled. The implication of our study is that if drugs possessing negative dromotropic effects are present in sufficiently high concentrations in the myocardial IZ, the propensity to developing ventricular arrhythmias may increase. Conceivably, this may happen when patients chronically treated with oral antiar-
ular arrhythmia
rhythmic
after occlusion. The difference between the effects
are different3 and that aprindine
suppresses the enhanced ventricular automaticity thought to be responsible for the arrhythmia occurring 24 hours after coronary artery occlusion. The
regional distribution of aprindine in group 5 dogs suggests either that automatic foci within the IZ are sensitive to low concentrations of aprindine or that the ventricular arrhythmia at 24 hours arises within the BZ, where aprindine concentrations are only slightly less than in normal myocardium. Although the total dose of aprindine was comparable to what we have used experimentally2 and clinically,4 a short period of drug infusion was included in order to evaluate the rapid changes in distribution occurring immediately after coronary artery occlusion. Rapid drug infusion could have magnified the temporal and spatial heterogeneity in distribution of aprindine and its effects on arrhythmias. Nevertheless, serum aprindine concentrations at the time of coronary ligation among group 1 dogs averaged within the therapeutic range achieved in humans with long-term aprindine administration orally. Studies evaluating the prevalence of ventricular arrhythmias in animals given long-term therapy orally before coronary artery occlusion are necessary
to assess the clinical relevance of our observations. In contrast to our findings that aprindine was
agents that
have negative dromotropic
effects undergo myocardial infarction. Experimentally, the concept has been confirmed by Gerin and Kulbertus,G who showed that quinidine (8 to 16 mg/kg), mexiletine, and two new experimental antiarrhythmic agents administered before coronary artery occlusion slowed IZ conduction and increased the prevalence of VT and VF in dogs. We have found that ethmozin, a new phenothisxine antiarrhythmic
agent, has a similar effect7 Lidocaine also slows conduction in ischemic myocardium8 and appears to increase the prevalence of VF when administered to a small group of dogs before coronary occlusion.9 An
antiarrhythmic
agent that is not distributed
uni-
formly througbout the myocardium may exert heterogeneous electrophysiologic effects that may be
conducive to the development of ventricular arrhythmias. Clinically, although it has been amply demonstrated that aprindine effectively suppresses recurrent life-threatening ventricular tachyarrhythmias in humans;l these potential ben&Icial effects may be
partially offset by an increased risk of development of ventricular arrhythmias should myocardiil infarction occur. This factor may explain why Hugenholtz et al. lo found that the incidence of sudden death among aprindine-treated patients
arrhythmogenic when given intravenously before coronary artery occlusion in dogs, Vedouw et al5 demonstrated that it prevents ventricular arrhythmias when administered before a 75% reduction in blood flow in the LAD of pigs. However, that study
with coronary disease was similar to that among patients receiving placebos.
differed from ours in the animal
tion also can be demonstrated with other agents. For example, several years ago, we showed that vera-
model used, in the
extent of coronary artery occlusion, in the dose of
VERAPAWL
The impomce
of .the time of drug administra-
Volume Number
103 4, part 2
pamil, administered before coronary artery occlusion in dogs, reduced the extent of ischemia-induced conduction delay and the development of VF (Fig. 3).2 However, when verapamil was given after coronary artery occlusion, Kupersmith et al.” found that it increased the severity of conduction delay. It seems quite clear that the effects of a drug will be influenced by whether it reaches the IZ and in what concentrations. Verapamil has not been as effective in treating recurrent sustained ventricular tachyarrythmias as it has been in treating recurrent sustained supraventricular tachyarrhythmias in patients. However, it may be beneficial in preventing ventricular tachyarrhythmias caused by myocardial ischemia in marP by a mechanism similar to that shown in the dog.” ENCAINIDE
The electrophysiologic effects of a drug that has one or more active metabolites must be determined after several days of administration. In evaluating antiarrhythmic drug efficacy in patients, we feel that it is important also to study the patients while they are receiving the drug orally, because that is how they will be taking it after discharge. Using this approach, we noted that encainide, a new antiarrhythmic agent, prolonged atrioventricular (AV) nodal conduction time and refractoriness in the atrium and ventricle12 in patients who had received it orally for several days (after providing informed consent of the study approved by our institutional review board). These changes were not observed when the drug was studied following a single dose intravenously in humans13 or dogs.‘* It is likely that the electrophysiologic effects of encainide given orally are due to the development of one or more active metabolites.15 The finding that the drug affects the AV nodal conduction time is very important, because it implies that one of the metabolites exhibits slow-channel blocking propertieP and thus could affect arrhythmias due to the slow response,17 as well as myocardial contractility. AMIODARONE
Amiodarone is another drug that is metabolized in a complex fashion. Very little is known about its pharmacokinetics,4 although it is being used investigationally in the United States on a fairly wide scale. Of interest, our preliminary data suggest that, although amiodarone is an extremely effective antiarrhythmic agent for long-term treatment of patients who have supraventricular or ventricular tachyarrhythmias, drug efficacy may not necessarily be predicted by results at electrophysiologic study.18 Thus ventricular tachyarrhythmias can still be
Electrophysiologic
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induced in many patients receiving amiodarone who subsequently have no spontaneous episodes during long-term follow-up. The reasons for this are unknown at present. It is important to remember that, in general, a drug that prevents the initiation of VT by cardiac stimulation in the control state also prevents spontaneous recurrence of that tachycardia. The reverse may not be true. A drug that fails to prevent initiation of VT during electrophysiologic testing may still successfully prevent a spontaneous recurrence. CONCLUSIONS
The animal studies are presented to illustrate that the time of drug administration in relation to coronary artery occlusion influences the myocardial concentration of the drug as well as its electrophysiologic effects. Whether these observations have clinical importance remains to be established. The clinical studies illustrate that the presence of active metabolites can be missed if electrophysiologic studies are confined to testing the period immediately following a single dose intravenously of a drug. Finally, electrophysiologic studies of drug efficacy may give misleading results in some patients, probably depending on the type of drug being tested. REFERENCES
1. Nattel S, Pedersen DH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in dog. Cardiovasc Res 15:80, 1981. 2. Elharrar V, Gaum WE, Zipes DP: Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 39:544, 1977. 3. Scherlag BJ, El-Sherif N, Hope R, Lazzara R: Characterization and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res 35:372, 1974. 4. Zipes DP, Troup PJ: New antiarrhythmic agents: Amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am-J Cardiol 41:1005, 1978. 5. Verdouw PD. Remme WJ. Huaenholtz PG: Cardiovascular and antiarrhythmic affects of iprindine (AC-1802) during partial occlusion of a coronary artery in the pig. Cardiovasc Res 11:317, 1977. 6. Gerin MG, Kulbertus HE: Effects of various antiarrhythmic agents on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dog. In Sande E, Julian DG, Bell JW, editors: Management of ventricular tachycardia: Role of mexiletine. Amsterdam, 1978, Excerpta Medica, p 299. 7. Rutfy R, Rozenshtraukh LV, Elharrar V, Zipes DP: Electrophysiologic effects of ethmozin on canine myocardium. Cardiovasc Res 13:354, 1979. 8. Kupersmith J, Antman EM, .Hoffman BF: In vivo electrophysiological effects of lidocaine in canine acute myocardial infarction. Circ Res 36:84, 1975. 9. Stephenson SE Jr, Cole RK, Parrish TF, Bauer FM Jr, Johnson IT Jr, Kochtitzky M, Anderson JS Jr, Hibbitt LL, McCarty JE, Young ER, Wilson JR, Meiers HN, Meador CK, Ball COT, Meneely GR: Ventricular fibrillation during and after coronary artery occlusion. Am J Cardiol 5:77, 1960.
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and Heger
10. HugenholtzPG, HagemeijerF, LubsenJ, GlaserB, VanDurmeJP, BogaertMC: Oneyearfollow-upin patientswith persistentventriculardysrhythmiasafter myocardialinfarction treatedwith aprindineor placebo.In SandeE, Julian JG, Bell JW editors:Managementof ventricular tachycardia:Roleof mexiletine.Amsterdam,1978,ExcerptaMedica, p 572. 11. KupersmithJ, ShiangH, Litwak RS, HermanMV: Electrophysiologiceffectsof verapamilin caninemyocardialischemia.Am J Cardiol37:149,1976.(Abst.) lla. ZipesDP, GilmoreRF Jr: Calciumantagonistsand their potentialrole in the preventionof suddencoronarydeath. Ann NY AcadSci. (In press.) 12. JackmanWM, Zipes DP, RinkenbergerRL, Heger JJ, PrystowskyEN: Electrophysiology of oral encainide.Am J Cardiol.(In press.) 13. Sami M, Mason JW, Peters F, Harrison DC: Clinical electrophysiologic effectsof encainide,a newly developed antiarrhythmicagent.Am J Cardiol44:526,1979. 14. SamiM, MasonJW, Oh G, HarrisonDC: Canineelectrophysiologyof encainide,a newantiarrhythmicdrug. Am J Cardiol&1149, 1979. 15. Elharrar V. ZiaesDP: Electronhvsioloeic effectsof encainide and two metabolites.J. Pharmacil Exp Therap. (In press.) 16. ZipesDP, FischerJC: Effectsof agentswhich inhibit the slowchannelon sinusnodeautomaticityandAV conduction in the dog.Circ Res34:184,1974. 17. ZipesDP, Bailey JC, Elharrar V: The slowinwardcurrent and cardiacarrhythmias.The Hague,1980,Martinus Nijhoff. 18. HegerJJ, PrystowskyEN, JackmanWM, NaccarelliGV, Warfel KA. Rinkenberner RL. ZincsDP: Amiodarone:Clinical andelcctrophysiol~gic eff% duringlong-termtherapy for recurrent ventricular tachycardia. N Engl J Med 305539,1981. DISCUSSION Dr. Epstein: I was interested in your commentson the relative effects of the different calcium-channel blocking agents. The results you showed with verapamil in acute ischemia are fascinating. Have you done any work with nifedipine? Does nifedipine have markedly different effects on this slow-current type of automaticity? Dr. Zipes: We have not performed any electrophysiologic studieswith nifedipine. In dosesthat are tolerable in humans, nifedipine does not exert the electrophysiologic effects that verapamil does.Patients develop such peripheral vasodilation that the clinical dosesare roughly a tenth of the verapamil or diltiazem doses.However, if you usean experimental animal preparation to achieve doseswith nifedipine that are comparableto verapamil or diltiazem, nifedipine mimics many of the electrophysiologic effects of the other agents. The slow-channelblockers really are different drugs, with different chemical structures and different electrophysiologic and slow-channel effects. To lump them all under the classificationcalcium antagonists is incorrect. Dr. J. Mason: I can addressDr. Epstein’s question, at least partially, because we have studied the calcium antagonist diltiazem. First of all, in the catheterization laboratory, human subjects showed electrophysiologic effects that were basically indistinguishable from those with verapamil. However, in an interesting study in dogs by Dr. William Clusin of our division, diltiazem markedly
American
Heart
1982 Journal
prolonged the time to VF in acute ligation experiments. Granted, this is a different model, but it suggeststhat this calcium antagonist may be active against ischemiainduced fibriilation. Dr. Bigger: In support of Dr. Zipes’s contention that verapamil might prevent suddendeath in the postinfarction group, we have now recorded, from three patients during sleep, the following events that culminate in sudden death: atria1 fibrillation or flutter with a rapid ventricular rate; within 1 minute, the STs rise, and within another 2 minutes, the patients develop VT and VF and die. So, in casessuch as these, perhaps calcium blockers could prevent sudden death by decreasingthe ventricular response to the atria1 fibrillation and preventing the ischemia and lethal arrhythmias. We just don’t know enoughabout the mechanismsof VF to approach prevention with confidence. Dr. Wellens: I would like to support what Dr. Zipes said regarding the chronic recurrence of sustained VT. The results with verapamil are very disappointing. Somedata from Italy suggestthat this might be useful in patients with acute ischemia,but I totally endorsethe necessityof doing a good study in that particular group. Dr. fipes: It is very important to emphasizeagain the potential heterogeneity of electrophysiologic mechanisms producing sudden death, even when the group appearsto be relatively homogeneous.It may be naive to envision one drug affecting all patients. Dr. Sonnenbiick: If you tie off a coronary artery in dogs, about 30% will fibrillate. Pretreating them with propranolo1will significantly decreasethe incidence of fibrillation in this setting. But is this analogousto suddendeath in humans?Are the mechanismssimilar? In fact, propranolol’s effect in dog modelsis more marked than calcium blockers, but would you feel comfortable in extrapolating this to patients at high risk of sudden death? Dr. Zipes: These animal studies are only models of a clinical event, and they have to be interpreted as such. Indeed, if one treats patients who have chronic recurrent premature ventricular complexes with a drug judged efficacious basedsolely on percent of PVC reduction, one has data gathered in just another model and the data may provide information no more clinically relevant than the animal models. We are trying to replicate the model of sudden death and VF with a variety of models,including dogs and swine, and relate to them the importance of ambulatory arrhythmias in patients. How relevant any of them is to VF is questionable.Returning to the question about judging whether a drug is successfulas an antiarrhythmic agent, my responseis, look to seewhether the patient is still breathing. Prevention of death, of syncope, and of disabling symptoms is the important criterion. That is what we’re trying to achieve. Dr. Temple: Just a piece of information. One caicium antagonist, lidoflazine, has been studied in Belgium in a postinfarction population of about 600 patients, There was no apparent beneficial effect on survival or sudden death. Now, that drug prolongs the QT, so it is possible that on the one hand it provides someprotection and at
Volume Number
103 4, part 2
Electrophysiologic
the same time it predisposes to some kinds of arrhythmia. Dr. Zipes: It may be quite different, yes. Dr. Lown: An important point that needsmuch repetition is that when we focus exclusively on the heart, we “decerebrate” in the process both the animal and the patient entrusted to our care. In the animal laboratory, the role of higher nervous activity in affecting cardiac rhythm is readily demonstrable(Lown et al.: Am J Cardiol 39:627, 1977). At the bedside,physicians repeatedly confront the consequencesof psychosocialinfluences on the heart. The fact that this aspect is not dealt with in the present is telling us something, namely, that our profession continues in a mechanistic stance more relevant to the nineteenth than to the late twentieth century.
testing
of
antiarrhythmic
agents
Dr. Sonnenblick raised the issue of the disparity between the efficacy of beta blockers in the animal laboratory and their unremarkable efficacy in a majority of patients with malignant ventricular arrhythmias. The major types of ventricular arrhythmia for which betaadrenergic blocking drugs appear to work are those provoked by exercise. An aspectthat has puzzled me is that patients who exhibit diminution of ventricular arrhythmia during sleep may not show a decreaseof ectopic activity with beta-adrenergic blocking drugs. Yet the lesseningof arrhythmia with sleephas been ascribed to a lesseningof sympathetic drive and vagotonia, which are believed to account for the bradycardia. Perhaps we have focusedtoo narrowly on the beta-adrenergic system for comprehending neural integration of cardiavascular function.
Evolving concepts of management potentially lethal arrhythmias
of stable and
Recent studies indicate that the eradication of premature ventricular complexes (PVCs) by antiarrhythmic agents is an inadequate end point for estimating long-term protection against potentially lethal arrhythmias. In a study of survivors of prehospital ventricular fibrillation (VF), who have a 30% risk for recurrent VF during the first year of follow-up, we observed an apparent protection against recurrent VF by antiarrhythmic agents even if chronic PVCs were not suppressed by stable therapeutic plasma levels. To expand the data base pertinent to the relationships between PVCs and advanced arrhythmias, we studied six patients with chronic recurrent ventricular tachycardia (VT) and frequent PVCs between episodes of VT. Plasma levels of procainamide (PA) required to protect against recurrent VT averaged 9.4 3t 3.4 pg/ml, compared with mean levels of 14.9 + 3.8 Ag/ml for 85% suppression of PVCs (p < 0.01). PVC frequency decreased by a mean of only 36% (range - 11% to -63%) at plasma levels of PA sufficient to prevent spontaneous VT. Concentration-response relationships between [PA] and PVC suppression were also compared in patients with PVCs during acute myocardial infarctfon and in patients with PVCs in stable chronic ischemic heart disease. in the former group of patients the mean plasma level of PA required to suppress 85% of the PVCs was 5.0 + 0.5 pg/ml, and in the latter group was 9.3 & 0.7 pg/ml (p < 0.001). We conclude that the relationship between plasma levels of PA and PVC suppression is different in the two groups of patients, and furthermore, that a high degree of PVC suppression may not be a necessary end point for protecting patients against symptomatic recurrent VT or VF. (AM HEART J 103:615, 1982.)
Robert J. Myerburg,
M.D., Liaquat Zaman, M.D., Kenneth
Agustin
M.D. Miami,
Castellanos,
Flu.
From the Division of Cardiology, Department of Medicine, University of Miami School of Medicine. Supported in part by a grant-in-aid from the National Heart, Lung and Blood Institute (HL 18769-06) and NHLBI training grant HL-07436 (Dr. Zaman). Reprint requests: Robert J. Myerburg, M.D., Professor of Medicine and Physiology, Director, Division of Cardiology, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. OOOZ-8703/82/040615
+ 11$01.10/O
M. Kessler, M.D., and
@ 1982 The
C. V. Mosby
Co.
Although premature ventricular contractions (PVCs) are a risk factor for total cardiac mortality and for sudden cardiac death in patients with organic heart disea,se,*-g no studies to date have determined whether effective suppression of chronic PVCs directly results in a reduction of potentially lethal arrhythmias or sudden death.lO During acute 615
Horowitz
et al.
American
them are beyond 2 months of infarction; presumably moat of the healing has taken place and the electrophysiologic findings are stable. We have studied patients for 6 months and some for several years, and VT is just as inducible years later as during the initial study. Coupling intervals and refractory periods are different, but if VT was induced with programmed stimulation on the first study, it was also induced in the second study, and if it wasn’t inducible the first time, it usually is not inducible the next time. Dr. Conti: In your laboratory or in other laboratories, what are the complications of the procedure in those who fibrillate? Stroke, myocardial infarction, or death? Dr. Horowitz: I am aware of only two deaths that have occurred during serial studies for the evaluation of therapy for VT in all laboratories worldwide; both patients had VT. That doesnot mean, of course,that there have been no other deaths. In our laboratory, the complications of venous catheterization are about the same as those reported from large catheterization series;i.e., about 5% of the patients have local complications. Arterial catheter-
Heart
1992
Journal
ization used to be done by arteriotomy, but we use arteriotomy now only if we can’t get in percutaneously. We have had two significant complications with percutaneous left ventricular catheterization; both patients required cardioversion, and when they moved, their arteries were torn, but later were repaired. We have had no other serious arterial complications. One patient had a transient neurologic event, presumably due to a plaque that was knocked off, but the deficit cleared within 30 minutes. There have been no myocardial infarctions. We have performed approximately 200 left ventricular catheterizations, and I would say that the complications are comparableto those of angiographic catheterization. I am aware of a few deaths worldwide, and I cannot even guess the number of patients who have been studied. We evaluate about 200 patients a year and probably do 750 studies a year. The complications are low, but there is a risk, and patients are made aware of that. I believe that the risk-to-benefit ratio is still on the side of doing the studies in the population at risk of VT or VF.
of
The purpose of these studies is to ilfustrate that the time of drug admin#Wation in expertmental animals subjected to coronary artery occlusion Is an impor@&t infiuetrca on the myocardfal distribution of the drug as well as its electrophysiologic and arrhythmogenlc effacts. Also, because several drugs have active metabolites, some stud&as qust be done after oral administration. Finally, electrophysiologic testing to determine drug effkacy may give misleading results with some drugs. (AM HEART J 103:610, 1982.)
Douglas P. Zipes, M.D., E. N. Prystowsky, Indianapolis, Ind.
M.D., and J. J. Heger, M.D.
Several factors that may influence the results obtained and conclusions drawn from testing the effects of antiarrhythmic agents clinically and in animals are discussed here.
From the K.rannert Indiana University tion Hospital. Supported HL-07182, Institute, Association, Reprint Medicine,
610
Institute of Cardiology, the Department School of Medicine, and from the Veterans
of Medicine, Administra-
in part by the Herman C. Krannert Fund; by grants HL-06308, and HL-18795 from the National Heart, Lung and Blood National Institutes of Health; and by the American Heart Indiana Affiliate, Inc. requests: Douglas I?. Zipes, M.D., Indiana University 1100 West Michigan St., Indianapolis, IN 46202.
School
of
APRINDINE
An early question of ours concerned the influence of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. Accordingly, we examined the effecta of administrating aprindine to five groups of open-cheat dogs.’ Group 1 (35 dogs) received aprindine immediately before one-stage left ant&or descending coronary artery (LAl% occlusion; group 2 (34 dogs) received wine 5 minutes after LAD occlusion; group 3 (16 dogs) was administered aprindine without LAQ oc&sion; group 4 (10 dog%) underw&nt, LAD occlu&on but received no aprindine; and group 5 (10 dogs) was administered aprindine 24 hours after LAD occlu0002-8703/82/040610
+ 06$00.60/O
‘?’ 1982
The
C. V.
MosbyCo.
Volume
103
Number
4, part 2
Electrophysiologic
EXPERIMENTAL
testing
of
I
I 30
agents
611
GROUPS
I
I IO
20 TIME WINS)
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antiarrhythmic
20 TIME WINS1
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40
50
60
70
AFTER DRUG ADMINISTRATION
1. Ratio of IZ to NZ aprindine concentrations over time. Group 1 dogs (who received aprindine before coronary artery occlusion)had substantially higher ratios after coronary occlusion than did group 3 dogs, who received aprindine without undergoing coronary artery occlusion (p < 0.01). The ratios amonggroup 3 dogsdid not change over time and were significantly greater than the ratios of both group 2 dogs, who received aprindine immediately after coronary artery occlusion (p < 0.00, and group 5 dogs, who received aprindine 24 hours after coronary artery occlusion(p < 0.01). (From Nattel S, PedersenDH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in the dog. Cardiovasc Res 15530, 1981.) Fig.
sion. Groups 3 and 4 served as the control animals. We measured the aprindine concentrations in the serum and in ventricular myocardial samples taken from the ischemic zone (IZ), the border zone (BZ), and the normal zone (NZ) at various times after LAD occlusion. Coronary artery occlusion performed after aprindine administration slowed the rate of disappearance of aprindine from the IZ. As can be seen in Fig. 1, the aprindine concentrations decreased more slowly in the IZ than in the NZ, with the IZ concentrations averaging more than twice the NZ aprindine concentrations 1 hour after LAD occlusion. When LAD occlusion was performed before aprindine administration, the aprindine concentrations in the IZ were initially less than 15% of those in the NZ but increased with time to approach half the NZ aprindine concentration 70 minutes after LAD occlusion. BZ aprindine concentrations were intermediate between NZ and IZ concentrations (Fig. 2). Seventeen dogs in group 1 (49%) experienced sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). This compares with five dogs in group 2 (14% ; p < O.Ol), one dog in
I 40
I
I
I
50
60
70
,
AFTER DRUG ADMINISTRATION
2. Ratio of BZ to NZ aprindine concentrations over time. The changes are in the same direction among different groups of dogs as the changes in IZ to NZ aprindine concentration ratios (Fig. 1) but are less in magnitude. (From Nattel S, Pedersen DH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusionin the dog. Cardiovasc Res 15230, 1981.) Fig.
group 4 (10% ; p < 0.05), and no dogs in group 3 (0%; p < 0.01) experiencing VT or VF. When aprindine was administered 24 hours after LAD occlusion, premature ventricular complexes were reduced from a mean of 35/100 beats to 12/100 beats (p < 0.01). These results suggest that the temporal relationship between aprindine administration and LAD occlusion importantly modifies the regional myocardial distribution of aprindine and its effects on ventricular arrhythmias following coronary artery occlusion. The exact mechanism for the arrhythmogenic effect of aprindine administered before coronary artery occlusion is uncertain. Ventricular arrhythmias occurring soon after coronary artery occlusion are thought to be due to a reentrant mechanism in part related to slowed conduction in the ischemic myocardium. Aprindine produces further slowing of conduction in ischemic myocardium and a tendency to increase ventricular arrhythmia in the presence of ischemia in animal models.2 Significant quantities of aprindine in the IZ would thus increase the prevalence of ventricular arrhythmias in animals subjected to coronary occlusion, as it did in group 1 dogs. Group 2 dogs had a much lower prevalence of ventricular arrhythmia than group 1 dogs, despite similar aprindine concentrations in the serum and normal myocardium. The effects of aprindine when administered 24 hours after coronary artery occlusion were markedly different from its effects when given before or just
612
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ISCHEMIA
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ISCH. and VERAP.
Fig. 3. Effect of verapamil on the fractionation of the epicardial electrogram recorded from the IZ 5 minutes after occlusionof the LAD coronary artery during pacing at a cycle length of 500 msec.Left panel: Before coronary occlusion. Center panel: Before administration of verapamil. Right panel: 11 minutes
later. Note that verapamil prevented the fractionation recorded from the IZ. (From EIharrar V, Gaum WE, Zipes DP: Effect of drugs on conduction delay and the incidence of ventricular arrhythmias induced by acute coronary occlusionin dogs.Am J Cardiol 39:544, 1977.)
of aprindine on ventricular arrhythmia when given just after coronary artery occlusion and those 24 hours later are not due to differences in drug distribution, because the relative concentrations of aprindine in different zones are very similar at these two times (Figs. 1 and 2). It is likely that the mechanisms of the early and later phases of ventric-
aprindine administered, and in the fact that the heart rate of the pigs was not controlled. The implication of our study is that if drugs possessing negative dromotropic effects are present in sufficiently high concentrations in the myocardial IZ, the propensity to developing ventricular arrhythmias may increase. Conceivably, this may happen when patients chronically treated with oral antiar-
ular arrhythmia
rhythmic
after occlusion. The difference between the effects
are different3 and that aprindine
suppresses the enhanced ventricular automaticity thought to be responsible for the arrhythmia occurring 24 hours after coronary artery occlusion. The
regional distribution of aprindine in group 5 dogs suggests either that automatic foci within the IZ are sensitive to low concentrations of aprindine or that the ventricular arrhythmia at 24 hours arises within the BZ, where aprindine concentrations are only slightly less than in normal myocardium. Although the total dose of aprindine was comparable to what we have used experimentally2 and clinically,4 a short period of drug infusion was included in order to evaluate the rapid changes in distribution occurring immediately after coronary artery occlusion. Rapid drug infusion could have magnified the temporal and spatial heterogeneity in distribution of aprindine and its effects on arrhythmias. Nevertheless, serum aprindine concentrations at the time of coronary ligation among group 1 dogs averaged within the therapeutic range achieved in humans with long-term aprindine administration orally. Studies evaluating the prevalence of ventricular arrhythmias in animals given long-term therapy orally before coronary artery occlusion are necessary
to assess the clinical relevance of our observations. In contrast to our findings that aprindine was
agents that
have negative dromotropic
effects undergo myocardial infarction. Experimentally, the concept has been confirmed by Gerin and Kulbertus,G who showed that quinidine (8 to 16 mg/kg), mexiletine, and two new experimental antiarrhythmic agents administered before coronary artery occlusion slowed IZ conduction and increased the prevalence of VT and VF in dogs. We have found that ethmozin, a new phenothisxine antiarrhythmic
agent, has a similar effect7 Lidocaine also slows conduction in ischemic myocardium8 and appears to increase the prevalence of VF when administered to a small group of dogs before coronary occlusion.9 An
antiarrhythmic
agent that is not distributed
uni-
formly througbout the myocardium may exert heterogeneous electrophysiologic effects that may be
conducive to the development of ventricular arrhythmias. Clinically, although it has been amply demonstrated that aprindine effectively suppresses recurrent life-threatening ventricular tachyarrhythmias in humans;l these potential ben&Icial effects may be
partially offset by an increased risk of development of ventricular arrhythmias should myocardiil infarction occur. This factor may explain why Hugenholtz et al. lo found that the incidence of sudden death among aprindine-treated patients
arrhythmogenic when given intravenously before coronary artery occlusion in dogs, Vedouw et al5 demonstrated that it prevents ventricular arrhythmias when administered before a 75% reduction in blood flow in the LAD of pigs. However, that study
with coronary disease was similar to that among patients receiving placebos.
differed from ours in the animal
tion also can be demonstrated with other agents. For example, several years ago, we showed that vera-
model used, in the
extent of coronary artery occlusion, in the dose of
VERAPAWL
The impomce
of .the time of drug administra-
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103 4, part 2
pamil, administered before coronary artery occlusion in dogs, reduced the extent of ischemia-induced conduction delay and the development of VF (Fig. 3).2 However, when verapamil was given after coronary artery occlusion, Kupersmith et al.” found that it increased the severity of conduction delay. It seems quite clear that the effects of a drug will be influenced by whether it reaches the IZ and in what concentrations. Verapamil has not been as effective in treating recurrent sustained ventricular tachyarrythmias as it has been in treating recurrent sustained supraventricular tachyarrhythmias in patients. However, it may be beneficial in preventing ventricular tachyarrhythmias caused by myocardial ischemia in marP by a mechanism similar to that shown in the dog.” ENCAINIDE
The electrophysiologic effects of a drug that has one or more active metabolites must be determined after several days of administration. In evaluating antiarrhythmic drug efficacy in patients, we feel that it is important also to study the patients while they are receiving the drug orally, because that is how they will be taking it after discharge. Using this approach, we noted that encainide, a new antiarrhythmic agent, prolonged atrioventricular (AV) nodal conduction time and refractoriness in the atrium and ventricle12 in patients who had received it orally for several days (after providing informed consent of the study approved by our institutional review board). These changes were not observed when the drug was studied following a single dose intravenously in humans13 or dogs.‘* It is likely that the electrophysiologic effects of encainide given orally are due to the development of one or more active metabolites.15 The finding that the drug affects the AV nodal conduction time is very important, because it implies that one of the metabolites exhibits slow-channel blocking propertieP and thus could affect arrhythmias due to the slow response,17 as well as myocardial contractility. AMIODARONE
Amiodarone is another drug that is metabolized in a complex fashion. Very little is known about its pharmacokinetics,4 although it is being used investigationally in the United States on a fairly wide scale. Of interest, our preliminary data suggest that, although amiodarone is an extremely effective antiarrhythmic agent for long-term treatment of patients who have supraventricular or ventricular tachyarrhythmias, drug efficacy may not necessarily be predicted by results at electrophysiologic study.18 Thus ventricular tachyarrhythmias can still be
Electrophysiologic
testing
of antiarrhythmic
agents 613
induced in many patients receiving amiodarone who subsequently have no spontaneous episodes during long-term follow-up. The reasons for this are unknown at present. It is important to remember that, in general, a drug that prevents the initiation of VT by cardiac stimulation in the control state also prevents spontaneous recurrence of that tachycardia. The reverse may not be true. A drug that fails to prevent initiation of VT during electrophysiologic testing may still successfully prevent a spontaneous recurrence. CONCLUSIONS
The animal studies are presented to illustrate that the time of drug administration in relation to coronary artery occlusion influences the myocardial concentration of the drug as well as its electrophysiologic effects. Whether these observations have clinical importance remains to be established. The clinical studies illustrate that the presence of active metabolites can be missed if electrophysiologic studies are confined to testing the period immediately following a single dose intravenously of a drug. Finally, electrophysiologic studies of drug efficacy may give misleading results in some patients, probably depending on the type of drug being tested. REFERENCES
1. Nattel S, Pedersen DH, Zipes DP: Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in dog. Cardiovasc Res 15:80, 1981. 2. Elharrar V, Gaum WE, Zipes DP: Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 39:544, 1977. 3. Scherlag BJ, El-Sherif N, Hope R, Lazzara R: Characterization and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res 35:372, 1974. 4. Zipes DP, Troup PJ: New antiarrhythmic agents: Amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am-J Cardiol 41:1005, 1978. 5. Verdouw PD. Remme WJ. Huaenholtz PG: Cardiovascular and antiarrhythmic affects of iprindine (AC-1802) during partial occlusion of a coronary artery in the pig. Cardiovasc Res 11:317, 1977. 6. Gerin MG, Kulbertus HE: Effects of various antiarrhythmic agents on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dog. In Sande E, Julian DG, Bell JW, editors: Management of ventricular tachycardia: Role of mexiletine. Amsterdam, 1978, Excerpta Medica, p 299. 7. Rutfy R, Rozenshtraukh LV, Elharrar V, Zipes DP: Electrophysiologic effects of ethmozin on canine myocardium. Cardiovasc Res 13:354, 1979. 8. Kupersmith J, Antman EM, .Hoffman BF: In vivo electrophysiological effects of lidocaine in canine acute myocardial infarction. Circ Res 36:84, 1975. 9. Stephenson SE Jr, Cole RK, Parrish TF, Bauer FM Jr, Johnson IT Jr, Kochtitzky M, Anderson JS Jr, Hibbitt LL, McCarty JE, Young ER, Wilson JR, Meiers HN, Meador CK, Ball COT, Meneely GR: Ventricular fibrillation during and after coronary artery occlusion. Am J Cardiol 5:77, 1960.
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10. HugenholtzPG, HagemeijerF, LubsenJ, GlaserB, VanDurmeJP, BogaertMC: Oneyearfollow-upin patientswith persistentventriculardysrhythmiasafter myocardialinfarction treatedwith aprindineor placebo.In SandeE, Julian JG, Bell JW editors:Managementof ventricular tachycardia:Roleof mexiletine.Amsterdam,1978,ExcerptaMedica, p 572. 11. KupersmithJ, ShiangH, Litwak RS, HermanMV: Electrophysiologiceffectsof verapamilin caninemyocardialischemia.Am J Cardiol37:149,1976.(Abst.) lla. ZipesDP, GilmoreRF Jr: Calciumantagonistsand their potentialrole in the preventionof suddencoronarydeath. Ann NY AcadSci. (In press.) 12. JackmanWM, Zipes DP, RinkenbergerRL, Heger JJ, PrystowskyEN: Electrophysiology of oral encainide.Am J Cardiol.(In press.) 13. Sami M, Mason JW, Peters F, Harrison DC: Clinical electrophysiologic effectsof encainide,a newly developed antiarrhythmicagent.Am J Cardiol44:526,1979. 14. SamiM, MasonJW, Oh G, HarrisonDC: Canineelectrophysiologyof encainide,a newantiarrhythmicdrug. Am J Cardiol&1149, 1979. 15. Elharrar V. ZiaesDP: Electronhvsioloeic effectsof encainide and two metabolites.J. Pharmacil Exp Therap. (In press.) 16. ZipesDP, FischerJC: Effectsof agentswhich inhibit the slowchannelon sinusnodeautomaticityandAV conduction in the dog.Circ Res34:184,1974. 17. ZipesDP, Bailey JC, Elharrar V: The slowinwardcurrent and cardiacarrhythmias.The Hague,1980,Martinus Nijhoff. 18. HegerJJ, PrystowskyEN, JackmanWM, NaccarelliGV, Warfel KA. Rinkenberner RL. ZincsDP: Amiodarone:Clinical andelcctrophysiol~gic eff% duringlong-termtherapy for recurrent ventricular tachycardia. N Engl J Med 305539,1981. DISCUSSION Dr. Epstein: I was interested in your commentson the relative effects of the different calcium-channel blocking agents. The results you showed with verapamil in acute ischemia are fascinating. Have you done any work with nifedipine? Does nifedipine have markedly different effects on this slow-current type of automaticity? Dr. Zipes: We have not performed any electrophysiologic studieswith nifedipine. In dosesthat are tolerable in humans, nifedipine does not exert the electrophysiologic effects that verapamil does.Patients develop such peripheral vasodilation that the clinical dosesare roughly a tenth of the verapamil or diltiazem doses.However, if you usean experimental animal preparation to achieve doseswith nifedipine that are comparableto verapamil or diltiazem, nifedipine mimics many of the electrophysiologic effects of the other agents. The slow-channelblockers really are different drugs, with different chemical structures and different electrophysiologic and slow-channel effects. To lump them all under the classificationcalcium antagonists is incorrect. Dr. J. Mason: I can addressDr. Epstein’s question, at least partially, because we have studied the calcium antagonist diltiazem. First of all, in the catheterization laboratory, human subjects showed electrophysiologic effects that were basically indistinguishable from those with verapamil. However, in an interesting study in dogs by Dr. William Clusin of our division, diltiazem markedly
American
Heart
1982 Journal
prolonged the time to VF in acute ligation experiments. Granted, this is a different model, but it suggeststhat this calcium antagonist may be active against ischemiainduced fibriilation. Dr. Bigger: In support of Dr. Zipes’s contention that verapamil might prevent suddendeath in the postinfarction group, we have now recorded, from three patients during sleep, the following events that culminate in sudden death: atria1 fibrillation or flutter with a rapid ventricular rate; within 1 minute, the STs rise, and within another 2 minutes, the patients develop VT and VF and die. So, in casessuch as these, perhaps calcium blockers could prevent sudden death by decreasingthe ventricular response to the atria1 fibrillation and preventing the ischemia and lethal arrhythmias. We just don’t know enoughabout the mechanismsof VF to approach prevention with confidence. Dr. Wellens: I would like to support what Dr. Zipes said regarding the chronic recurrence of sustained VT. The results with verapamil are very disappointing. Somedata from Italy suggestthat this might be useful in patients with acute ischemia,but I totally endorsethe necessityof doing a good study in that particular group. Dr. fipes: It is very important to emphasizeagain the potential heterogeneity of electrophysiologic mechanisms producing sudden death, even when the group appearsto be relatively homogeneous.It may be naive to envision one drug affecting all patients. Dr. Sonnenbiick: If you tie off a coronary artery in dogs, about 30% will fibrillate. Pretreating them with propranolo1will significantly decreasethe incidence of fibrillation in this setting. But is this analogousto suddendeath in humans?Are the mechanismssimilar? In fact, propranolol’s effect in dog modelsis more marked than calcium blockers, but would you feel comfortable in extrapolating this to patients at high risk of sudden death? Dr. Zipes: These animal studies are only models of a clinical event, and they have to be interpreted as such. Indeed, if one treats patients who have chronic recurrent premature ventricular complexes with a drug judged efficacious basedsolely on percent of PVC reduction, one has data gathered in just another model and the data may provide information no more clinically relevant than the animal models. We are trying to replicate the model of sudden death and VF with a variety of models,including dogs and swine, and relate to them the importance of ambulatory arrhythmias in patients. How relevant any of them is to VF is questionable.Returning to the question about judging whether a drug is successfulas an antiarrhythmic agent, my responseis, look to seewhether the patient is still breathing. Prevention of death, of syncope, and of disabling symptoms is the important criterion. That is what we’re trying to achieve. Dr. Temple: Just a piece of information. One caicium antagonist, lidoflazine, has been studied in Belgium in a postinfarction population of about 600 patients, There was no apparent beneficial effect on survival or sudden death. Now, that drug prolongs the QT, so it is possible that on the one hand it provides someprotection and at
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Electrophysiologic
the same time it predisposes to some kinds of arrhythmia. Dr. Zipes: It may be quite different, yes. Dr. Lown: An important point that needsmuch repetition is that when we focus exclusively on the heart, we “decerebrate” in the process both the animal and the patient entrusted to our care. In the animal laboratory, the role of higher nervous activity in affecting cardiac rhythm is readily demonstrable(Lown et al.: Am J Cardiol 39:627, 1977). At the bedside,physicians repeatedly confront the consequencesof psychosocialinfluences on the heart. The fact that this aspect is not dealt with in the present is telling us something, namely, that our profession continues in a mechanistic stance more relevant to the nineteenth than to the late twentieth century.
testing
of
antiarrhythmic
agents
Dr. Sonnenblick raised the issue of the disparity between the efficacy of beta blockers in the animal laboratory and their unremarkable efficacy in a majority of patients with malignant ventricular arrhythmias. The major types of ventricular arrhythmia for which betaadrenergic blocking drugs appear to work are those provoked by exercise. An aspectthat has puzzled me is that patients who exhibit diminution of ventricular arrhythmia during sleep may not show a decreaseof ectopic activity with beta-adrenergic blocking drugs. Yet the lesseningof arrhythmia with sleephas been ascribed to a lesseningof sympathetic drive and vagotonia, which are believed to account for the bradycardia. Perhaps we have focusedtoo narrowly on the beta-adrenergic system for comprehending neural integration of cardiavascular function.
Evolving concepts of management potentially lethal arrhythmias
of stable and
Recent studies indicate that the eradication of premature ventricular complexes (PVCs) by antiarrhythmic agents is an inadequate end point for estimating long-term protection against potentially lethal arrhythmias. In a study of survivors of prehospital ventricular fibrillation (VF), who have a 30% risk for recurrent VF during the first year of follow-up, we observed an apparent protection against recurrent VF by antiarrhythmic agents even if chronic PVCs were not suppressed by stable therapeutic plasma levels. To expand the data base pertinent to the relationships between PVCs and advanced arrhythmias, we studied six patients with chronic recurrent ventricular tachycardia (VT) and frequent PVCs between episodes of VT. Plasma levels of procainamide (PA) required to protect against recurrent VT averaged 9.4 3t 3.4 pg/ml, compared with mean levels of 14.9 + 3.8 Ag/ml for 85% suppression of PVCs (p < 0.01). PVC frequency decreased by a mean of only 36% (range - 11% to -63%) at plasma levels of PA sufficient to prevent spontaneous VT. Concentration-response relationships between [PA] and PVC suppression were also compared in patients with PVCs during acute myocardial infarctfon and in patients with PVCs in stable chronic ischemic heart disease. in the former group of patients the mean plasma level of PA required to suppress 85% of the PVCs was 5.0 + 0.5 pg/ml, and in the latter group was 9.3 & 0.7 pg/ml (p < 0.001). We conclude that the relationship between plasma levels of PA and PVC suppression is different in the two groups of patients, and furthermore, that a high degree of PVC suppression may not be a necessary end point for protecting patients against symptomatic recurrent VT or VF. (AM HEART J 103:615, 1982.)
Robert J. Myerburg,
M.D., Liaquat Zaman, M.D., Kenneth
Agustin
M.D. Miami,
Castellanos,
Flu.
From the Division of Cardiology, Department of Medicine, University of Miami School of Medicine. Supported in part by a grant-in-aid from the National Heart, Lung and Blood Institute (HL 18769-06) and NHLBI training grant HL-07436 (Dr. Zaman). Reprint requests: Robert J. Myerburg, M.D., Professor of Medicine and Physiology, Director, Division of Cardiology, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. OOOZ-8703/82/040615
+ 11$01.10/O
M. Kessler, M.D., and
@ 1982 The
C. V. Mosby
Co.
Although premature ventricular contractions (PVCs) are a risk factor for total cardiac mortality and for sudden cardiac death in patients with organic heart disea,se,*-g no studies to date have determined whether effective suppression of chronic PVCs directly results in a reduction of potentially lethal arrhythmias or sudden death.lO During acute 615