Sudden Cardiac Death 1978

BERNARD LOWN, M.D.

SUMMARY With the development of coronary care units in the 1960s, attitudes toward sudden cardiacdeath (SCD) began to change as physicians learned that cardiac arrest was reversible. The problem of SCDhas two aspects an acute, precipitating factor and a chronic predisposition to electrical instability of themyocardium. Resolution of the problem requires identification and protection of the potential victim. Ven-tricular premature complexes (VPCs) have been related to the development of serious arrhythmias and earlydeath, but the mere presence of VPCs does not discriminate risk of subsequent fatality. VPCs should begraded according to frequency, persistence, multiformity, repetitive pattern and degree of prematurity.Provocation of repetitive extrasystoles by R-on-T pacing may indicate the presence of a reduced threshold forventricular fibrillation (VF). Prophylactic antiarrhythmic therapy may help protect patients resuscitated fromVF against recurrent cardiac arrest. Neuropharmacologic factors perhaps affecting central nervous systemsympathetic activity can alter cardiac vulnerability and may protect against VF. Findings in dogs indicate thatpsychologic stress can reduce the cardiac threshold for VF. If psychologic factors predispose to ventriculararrhythmias by increasing the level of sympathetic tone, lessening neural sympathetic activity should reducethe incidence of SCD.

SUDDEN CARDIAC DEATH (SCD) is one of themajor challenges to contemporary cardiology. Itssheer magnitude demands attention, claiming over400 thousand lives annually, or about 60% of all cor-onary heart disease fatalities. The problem of suddendeath has been recognized since the beginning ofrecorded history, yet before the 1960s, SCD receivedscant attention from clinical and research com-munities. In part this related to the prevailing percep-tion that SCD was the ultimate expression of severe,far-advanced and irreversible coronary athero-sclerosis. Since the SCD was unexpected and struckdown the seemingly healthy subject outside the hospi-tal, the physician deemed it an act of fate before whichhe or she was largely helpless.As is often true in science, new methodologies not

only usher in new content, but also mold new at-titudes. In the case of SCD it was the burgeoning cor-onary care units (CCU) of the 1960s that stimulated anew direction. CCU experience largely dispelled thesense of futility, for it became rapidly evident that car-diac arrest was reversible. Patients promptlyresuscitated from primary electrical failure con-sistently recovered and survived for variable andprolonged periods determined by the extent of theirunderlying heart disease. Because ventricular fibrilla-tion (VF) had its highest incidence at the beginning ofa myocardial ischemic episode, it was logical toassume that this same mechanism accounted for out-of-hospital sudden death.The CCU demonstrated that VF can be reversed as

well as prevented. These findings have led to thedevelopment of two distinct strategies:' 1) to reach the

From the Cardiovascular Research Laboratories, Department ofNutrition, Harvard University School of Public Health, Boston,Massachusetts.

Supported in part by grants MH-21384 from the NIMH, HL-07776, HL-05242 and HL-18783 from the NHLBI, NIH, USPHS.

Address for correspondence: Bernard Lown, M.D., Professor ofCardiology, Department of Nutrition, Harvard School of PublicHealth, 665 Huntington Avenue, Boston, Massachusetts 02115.

Circulation 60, No. 7, 1979.

patient promptly and initiate effective cardio-pulmonary resuscitation,2 and 2) to identify thepatient at increased risk for SCD and institute aprophylactic program against potentially fatal ven-tricular arrhythmias.3

Community Response to Cardiac Arrest

The logic of a well-organized community programpermitting immediate response to out-of-hospital car-diac arrest is not debatable. The critical factor is theexpeditious reaching of the victim by personnel fullytutored in basic life support. This necessarily requiresthat large sectors of the population be trained andtheir skill in cardiopulmonary resuscitation be finelyhoned at all times for the unexpected emergency. InSeattle, where such a program has been in operationfor over 6 years, there have been 346 long-term sur-vivors out of 1710 episodes of VF encountered in thecommunity.4 The percentage of immediate resus-citations has improved annually, as has the yield inlong-term survivors. A disquieting aspect of the Seat-tle experience is the high incidence of recurrent car-diac arrest. The mortality rate has been 26% at 1 yearand 36% at two years. The problem of SCD has twoaspects - an acute, precipitating trigger as well as achronic predisposition to electrical instability of themyocardium. The mere reversal of the cardiac arrestdoes not obviate the underlying electrophysiologic ab-normality. For those successfully resuscitated therecan be no assurance that the good fortune of a promptresponse by a trained medical team will be repeated.Resolution of the problem of SCD ultimately requiresidentification and protection of the potential victim.

Detecting the Patient at Risk

The essential strategy currently followed in iden-tifying the patient at risk and in preventing VF relieson the hypothesis that the ventricular premature com-plex (VPC) constitutes a risk factor.1 3Two questions,therefore, must be answered: 1) What is the evidencethat VPCs indeed indicate predisposition to suddendeath? 2) Is there any basis for concluding that controlof VPCs will protect against VF?

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Experience with patients who have an acutemyocardial infarction in the CCU has shown the im-portant relationship of VPCs to the development ofmore serious cardiac arrhythmias and early death.5-'The significance of VPCs occurring in coronarypatients at times other than during the acute episoderequires separate consideration. Recent reports haveassociated VPCs with an increased risk of out-of-hospital cardiac death.8-16 However, when longerperiods of ambulatory monitoring are done, nearly90% of patients with coronary heart disease exhibit ec-topic activity.'7 18 Thus, the mere presence of VPCscannot be a significant prognostic discriminator ofrisk for subsequent fatality. It has been our view thatVPCs need to be graded according to certain at-tributes of frequency, persistence, multiformity,repetitive pattern and degree of prematurity3' 18 (table1). Only frequent advanced grades or complex formsof VPCs impart enhanced risk for future SCD inpatients with coronary heart disease. This thesis hasnow been corroborated in the Health Insurance Planof New York prospective epidemiologic studies.'9From a male population of 120,000 aged 35-74 years,1739 with prior myocardial infarction were monitoredfor 1 hour at a standard baseline examination andwere followed for mortality for an average period of24.4 months. The presence of complex VPCs (R-on-T,runs of two or more, multiform or bigeminal) in themonitoring hour was associated with a risk of SCDthree times that of the men free of such arrhythmia.The VPCs made an independent contribution to in-creased risk of fatality that persisted throughout theobservation period.

Inadequacies of VPCs as Risk Indicators for SCDWe do not know whether the VPC represents the

trigger for repetitive activity leading to VF or ismerely an innocuous concomitant in the electricallyunstable heart. In the former case, its suppressionmight prove protective; in the latter, the underlyingelectrophysiologic derangement may continue, eventhough ectopic activity is controlled. In animal ex-periments, a dissociation between the presence ofVPCs and predisposition to VF can be shown. Thus,when dogs are pretreated with antiarrhythmic drugsand then subjected to acute coronary artery occlusion,they are protected against VF, though no substantialreduction may be observed in either the frequency orthe grade of ectopic activity (fig. 1). The clinician alsoconfronts the problem that in using the VPC as amarker of enhanced risk for SCD, there is no certaintyas to the extent of ectopic activity suppressionnecessary to provide adequate prophylaxis. This issueis further complicated by the random occurrence andlow reproducibility of advanced grades of VPCs. In 65patients with angiographically proved coronary dis-ease and VPCs on 24-hour monitoring, repetitivearrhythmias were reproducible in only 40% ofpatients'9 (fig. 2). The need is urgent for more directindicators of the electrophysiologic lesions thatpredispose the myocardium to VF.

TABLE 1. A Grading System for Ventricular Premature Com-plexes (VPCs)

Grade

0

1A

lB2

34A4B

5

08

Grade0

lAlB

VPC Characteristics

No ventricular beats

Occasional, isolated VPCs (< 30/hr) < 1/minOccasional, isolated VPCs (< 30/hr) > 1/minFrequent VPCs (> 30/hr)Multiform VPCs

Repetitive VPCs; coupletsRepetitive VPCs; salvos

Early VPCs (i.e., abutting or interrupting theT wave)

Sample equation

lA° lB4 2760 32 4A3 4B4-7 33

ExplanationOccurred during 3 hoursNo infrequent VPCsInfrequent VPCs but greater than 1/min ob-

served during 4 hours2 Occurred during 6 hours (with a total of 760

VPCs)3

4AOccurred during 6 hours and exhibited two formsOccurred during 2 hours and their greatest fre-

quency in any 1 hour was three4B Occurred during 2 hours; there were four parox-

ysms; the longest duration was seven cycles5 An early VPC was observed three times during

a single hour in the 24-hour monitoring session

This grading system is applied to a 24-hour monitoringperiod and indicates the number of hours within that periodthat a patient has VPCs of a particular grade, which is ex-pressed in the resulting "equation" as a superscript. Sub-scripts are used to indicate particular aspects of the VPCs ofa given grade. In the sample equation, for example, the sub-script for grade 2 indicates the approximate total number ofgrade 2 VPCs over the 24-hour period; for grade 3 it denotesthe number of different forms observed in any single hour;for grade 4B the two subscripts indicate first the largest num-ber of paroxysms of tachyeardia in a single hour and thesecond denotes the maximum number of successive cycles;for grade 5 the subscript represents the largest number ofearly ectopic beats in any single hour.

Other Markers of Cardiac VulnerabilityHow can the presence of electrical instability be

directly demonstrated? In the normal and the diseasedheart, a single electrical stimulus causes but a singleresponse. However, markedly suprathreshold stimulidischarged during the vulnerable period of the car-diac cycle induce repetitive responses and VF. Evenin the presence of acute myocardial ischemia,suprathreshold discharges are required to evoke VF.A critically important question is whether near-threshold currents, just sufficient for eliciting apropagated response in diastole, can induce repetitiveelectrical activity. We have found in the animal withacute coronary artery occlusion that when threesuccessive early stimuli are used (the so-called R-on-T

-

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FIGURE 1. Within 3 minutes of acute occlusion of the leftanterior descending coronary artery in the awake dog, thereare paroxysms of rapid ventricular tachycardia. While theprevalence of arrhythmia in the procainamide-pretreated isundiminished compared to the control ligation, the oc-

currence of ventricular fibrillation is markedly reduced.

80

60

40

20

1A 1B-2 3 4

GRADE OF V. P C.

FIGURE 2. The reproducibility of a single 24-hourmonitoring session was assessed in a repeat study of 65patients. While low grades of ventricular premature com-

plexes (VPCs) were highly reproducible, this was not thecase with advanced grades.'9

pulsing technique), small physiologic currents aresufficient to provoke VF.20 21 Within approximately 2minutes after the left anterior descending coronaryartery is abruptly occluded in the closed-chest dog,sequential R-on-T pulsing shows a striking drop inthreshold for VF and a lengthened duration of thevulnerable period (table 2).21 These changes are tran-sient; within 4.5 minutes, the threshold returns topreocclusion levels. Similar changes follow reperfu-sion, upon abrupt deflation of the occluding balloon;however, these alterations in cardiac vulnerability aresmaller and briefer. The time course of these changesand the altered susceptibility to VF parallel theemergence and recession of arrhythmias after cor-onary artery occlusion and release (fig. 3).An end point of VF is impermissible as an index of

electrical instability in man: A more innocuousmarker is required. We have found that the evocationof two responses to a single stimulus discharged dur-ing the ventricular vulnerable period is a sensitive in-dicator of susceptibility to VF. The awake animal ex-hibits no overt evidence of awareness of such testing.Repetitive ventricular responses occur reproduciblywhen 66% of the fibrillatory current has been ad-ministered. The nadir of the repetitive extrasystolethreshold in the cardiac cycle coincides with thevulnerable period for VF during various maneuversthat alter cardiac susceptibility to this arrhythmia22(fig. 4).The population that has myocardial electrical in-

stability from which SCD victims are drawn probablyincludes several million people. To screen such mul-titudes for repetitive ventricular responses requiressimple, noninvasive methods. In animals, therefore,we have tested mechanical precordial thumping as apossible method for exposing electrical instability.23Indeed, we have found that a mechanical thump mayinduce ventricular arrhythmia (fig. 5). The basis foreffectiveness of such stimulation is depolarization ofmyocardial fibers by transduction of the mechanicalpulse into an electrical pulse.24 The heart responds as amechano-electrical transducer. By the use of sequen-tial R-on-T pulsing, the provocation of repetitive ex-trasystoles may serve as an indicator of the presenceof a reduced threshold for VF. While these studies arepreliminary, they do suggest a possible direct ap-

TABLE 2. Threshold for Ventricular Fibrillation in 10 DogsDuring 10-minute Occlusion and Release of the Left AnteriorDescending Coronary Artery Measured by Sequential R/TPulsing

Vulnerable Duration ofperiod reduced

Period Threshold duration thresholdof study (mA) (msec) (min)

Control 56 7.1 14 7Occlusion 1.6 -4- 0.3* 76 d= 37 4.6 -4= 0.3Release 3.6 i 1.8* 26 = 7 2.1 ='= 0.4

Values are mean -4- SEM.*p < 0.001 from control (t test).

Within 3 min.

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VfT(mO)

0 2 4 6 8 10 12TIME FROM OCCLUSION (m11ni

FIGURE 3. Effect of acute coronary artery occlusion andrelease on the susceptibility to ventricularfibrillation (VF)as related to the spontaneous occurrence of diverse ven-tricular arrhythmias. The predisposition to VF, measuringthe ventricular fibrillation threshold (VFT) in man, is ac-complished by triple R/Tpulsing. Note the correspondencebetween changes in VFT and the occurrence ofarrhythmias.21 VPC = ventricular premature complex,VT= ventricular tachycardia.

o REMO Mult iple RE

(-I1v.120 130 140 150 160

TIME IN CARDIAC CYCLE (msec)FIGURE 4. Relation of repetitive extrasystole (RE) andventricular fibrillation (VF) thresholds determined by scan-

ning the vulnerable period with a 2-mA, constant-currentcathodal stimulus. Electrical diastole was scanned in 1-msec

decrements beginning 10 msec after the T wave and endingat the border of the strength-interval curve (SIC) (left line).The provocation ofRE (B) required 66% of the current forVF while multiple RE (C) occurred with 82%. Vulnerable-period curves for RE and multiple RE have a characteristic"V" shape, the nadir of which coincides temporally withthat for provoking VF.22

4,

FIGURE 5. An external mechanical stimulus induces arepetitive extrasystole (I) analogous to that evoked by elec-trical stimulation with an intracardiac catheter in a dog afteracute myocardial infarction.

proach for determining the existence of myocardialelectrical instability in man.

Protection Against SCDIt is already becoming possible to protect the

patient who has been resuscitated from VF againstrecurrence of cardiac arrest.25' 26 Essential elements ofa prophylactic program involve the use of anti-arrhythmic drugs. Therapy, however, needs to be in-dividualized. The objective of treatment is reduction infrequency or complete abolition of advanced grades ofVPCs rather than suppression of all ectopic activity.Ambulatory monitoring as well as exercise stress test-ing are used to detect VPCs and to gauge thetherapeutic efficacy of selected antiarrhythmicmeasures. In a recent experience with 70 patients withrecurring malignant ventricular arrhythmias, in-dividualized treatment has prevented, in a majority,the recurrence of these life-threatening disorders. Theannual mortality has not exceeded 5% among patientswhose advanced grades of VPCs were controlled.

Institution of appropriate therapy is time consum-ing and costly and is not yet guided by sound elec-trophysiologic principles. However, there is no currentsubstitute for intelligent pragmatism. The physician iscommitted to protect patients entrusted to his or hercare. Developments in both pharmacology and elec-trophysiology have been rapid and promise to improvethe scientific basis for prophylaxis against SCD.

Precipitating Factors of VFIf electrical instability of the myocardium long

antedates the occurrence of SCD, there must be fac-tors that precipitate VF. Current cardiovascularresearch has focused almost exclusively on the elec-trophysiologic abnormalities in the heart that are con-

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ducive to sustained repetitive ventricular activity.Scant attention has been devoted to the operation oftransient risk factors that favor the emergence ofcatastrophic arrhythmia. Among many factors thatmay induce VF, nervous impulses to the heart areprobably of critical importance.27' 28 If these relationsare corroborated in man, new therapeutic possibilitieswill soon emerge.

Evidence Relating Neural Factors to Arrhythmia

The most important subcortical regions involved inregulating cardiac rhythm are located in thehypothalamus and quadrigeminal bodies. In normalhearts, brain stimulation at specific sites does notprovoke VF. However, in dogs with acute myocardialischemia, VF is consistently induced when theposterior hypothalamus is stimulated.29 The fibrilla-tion threshold is lowered after such stimulation, evenwhen concomitant changes in arterial pressure andheart rate are prevented.30 When the stellate ganglia,way stations in sympathetic neural connections frombrain to heart, are stimulated, R-on-T pulsing of theright ventricle with twice threshold currents provokedVF in 60% of animals.30 In the absence of stimulationof these ganglia, R-on-T pulsing never induced VF.Protection against VF has also been shown by reflexlessening of sympathetic tone achieved by raisingblood pressure by injection of the a-adrenergic-stimulating drug phenylephrine. This has been notedin the normal animal as well as in dogs during acutecoronary artery ligation.31

There is evidence that sympathetic neural traffic tothe heart can be diminished by administeringserotonin precursors that localize in the central ner-vous system.32' 33 We examined the question whethermanipulation of central nervous system serotonin canaffect cardiac vulnerability. Dogs were given theserotonin precursors L-tryptophan or 5-hydroxy-L-tryptophane in conjunction with the monoamine ox-idase inhibitor phenelzine and the selective L-aminoacid decarboxylase inhibitor carbidopa.34 Tryptophan,an essential dietary amino acid, is the physiologic,biochemical precursor of serotonin. When tryptophanalone is administered, it is hydroxylated and thendecarboxylated to form serotonin at sites throughoutthe body. Monoamine oxidase then catalyzes a rapiddegradation of the serotonin. The objective of theseexperiments was to concentrate serotonin in the brainbut not in the periphery. This was accomplished by thesimultaneous administration of phenelzine and car-bidopa. Phenelzine inhibits monoamine oxidase sothat serotonin tends to accumulate whenever it isformed. Carbidopa is an L-aromatic amino aciddecarboxylase inhibitor that circulates in theperiphery, but does not cross the blood-brain barrier.In the presence of carbidopa, the decarboxylation oftryptophan is selectively diminished peripherally andtherefore the accumulation of serotonin is largelyrestricted to within the central nervous system. Ven-tricular vulnerability was evaluated in these animalsby measuring the repetitive extrasystole threshold. A

of 50% resulted only when we used biochemicalmeasures that presumably increase central nervoussystem serotonin. These findings suggest thatneuropharmacologic measures perhaps affecting cen-tral sympathetic activity can alter cardiac vulner-ability and may protect against VF.

Psychologic Variables and VF

A major goal of our studies has been to determinewhether behavioral and psychologic factors canchange cardiac vulnerability and thereby predispose toVF. Dogs were exposed to two environments: a cage inwhich the dog was left largely undisturbed and aPavlovian sling in which the dog received a single 5-Jtransthoracic shock at the end of each experimentalperiod for three successive days.35 These two en-vironments were compared on days 4 and 5. At thesetimes, the dogs placed in the sling became restless,they frequently salivated excessively, exhibitedsomatic tremor, and had a mean heart rate of 136beats/min. In the cage, the mean current that elicitedrepetitive extrasystoles was 43 mA (+ SEM). In the sl-ing, the mean threshold was reduced to 14 ± 6 mA(p < 0.001). During these studies, heart rates wereheld constant by cardiac pacing. These findings in-dicate that psychologic stress can profoundly reducethe cardiac threshold for VF.

The question of whether a psychologically aversiveenvironment may provoke arrhythmia without elec-trical stimulation of the heart was examined after cor-onary occlusion in dogs. The animals were con-ditioned as described above. After 5 consecutive daysin which they spent an hour in the cage and an hour inthe sling, a balloon occluder, previously implantedaround the left anterior descending coronary artery,was inflated. Once the animals had recovered fromocclusion and were entirely free of arrhythmia, theywere again exposed to the two environments. The slingcondition consistently provoked diverse ventricular ar-rhythmias, including ventricular tachycardia and earlyextrasystoles with T-wave interruption. These effectsdisappeared when the dogs were returned to the non-aversive cage.36

In current experiments, we have shown that whenocclusion of the left anterior descending coronaryartery is accomplished while the dogs are in the non-aversive environment of the cage, there is a low in-cidence of arrhythmia - only one of 12 dogsdeveloped VF. However, six of the dogs developed VFwhen the coronary artery was occluded while the dogwas standing quietly in the sling (figs. 6A and B)(Lown B, Verrier R: unpublished observations).To test whether changes in vulnerability induced by

psychologic stress could be prevented by phar-macologic blockade of adrenergic activity, dogs wereexposed to programmed signal shock avoidance.37Behaviorally induced changes in cardiac excitabilitywere completely abolished by the selective B- 1-adrenergic blocking agent tolamolol hydrochloride.Thus, increase in ventricular vulnerability associatedwith aversive psychologic conditioning appears to be

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mediated primarily by the sympathetic limb of theautonomic nervous system.

Clinical ConsiderationsPhysicians have long been aware that psychologic

stress can provoke arrhythmias. In widely differingcultures, folklore associates sudden death with psy-chologic stress, 7excitement or intense emotion. Tag-gart et al.38 conducted a systematic exploration of therelation between diverse stresses and the cardio-vascular apparatus in patients with ischemic heart dis-ease. A stress such as public speaking inducedprofound ST-segment depression and multiform

VPCs. These changes could be prevented by pretreat-ment with the 3-adrenergic blocking drug oxy-prenolol. Emotional stress has now been shown totrigger VF in the absence of demonstrable heart dis-ease.39 If psychologic factors predispose to ventriculararrhythmia by increasing the level of sympathetic toneaffecting the heart, diminishing of neural sympatheticactivity should reduce the incidence of SCD. Severalrecent studies40-42 indicate that in patients who hadrecovered from acute myocardial infarction, the in-cidence of sudden death was significantly reduced withthe use of d-adrenergic blocking drugs.40-42

Rapidly cumulating scientific and clinical insightsindicate that containment of the problem of SCD is

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within reach. Like the resolution of any medicalproblem, there must be commitment of sufficientresources. The underlying electrophysiologic lesionscontributing to electrical instability need to be defined.Noninvasive screening methods need to be developedfor identifying the subject at increased risk for SCD.The key transient risk factors that can trigger VFmust be catalogued. The role of higher nervous ac-

tivity affecting cardiac rhythm in man needs to be ex-

plored. The development of safe, effective and long-acting antiarrhythmic drugs presents an immediatechallenge.

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23. Lown B, Verrier RL, Blatt CM: Precordial mechanical stimula-tion for exposing electrical instability of the heart. Am J Car-diol 42: 425, 1978

24. Lown B, Taylor J: Thump-version (letter to the editor). N EnglJ Med 283: 1223, 1970

25. Lown B, Graboys T: Management of patients with malignantventricular arrhythmias. Am J Cardiol 39: 910, 1977

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27. Lown B, Verrier RL: Neural activity and ventricular fibrilla-tion. N Engl J Med 294: 1165, 1976

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diovascular effects of 5-hydroxytryptophan in MAO-inhibiteddogs: modification by autonomic antagonists. Arch Int Phar-macodyn Ther 231: 200, 1975

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34. Rabinowitz SH, Lown B: Central neurochemical factors relatedto serotonin metabolism and cardiac ventricular vulnerabilityfor repetitive electrical activity. Am J Cardiol. In press

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scious dog. Am J Cardiol 34: 692, 197437. Matta RJ, Lawler J, Lown B: Ventricular electrical instability

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