Drugs 41 (Suppl. 2); 16-23, 1991 0012-6667/ 91 /0200-0016/$04.00

© Adis International Limited All rights reserved. DRSUP1973a

Mechanisms of Sudden Cardiac Death

Pedro Brugada, Erik W. Andries, Lluis Mont, Sinan Gursoy, Hilde Willems and Samira Kaissar Cardiovascular Centre, Postgraduate School of Cardiology, OL V Hospital, Aalst, Belgium

SlImmary Although coronary artery disease is the most frequent cause of sudden cardiac death, it may be caused by a heterogeneous group of disorders. Acute ischaemia is responsible for about half the cases of sudden death after acute myocardial infarction, and is man­ifested through ventricular fibrillation or polymorphic ventricular tachycardia. Several factors affect the haemodynamic consequences of a ventricular arrhythmia. Re-entry is the mechanism involved in patients with a history of myocardial· infarction and therapy should be individualised and directed to the arrhythmia. Simple decision trees are avail­able that can help to find the most appropriate therapy; implantable defibrillators are the most effective modality in certain very high risk subsets.

There are many causes of sudden cardiac death. From an epidemiological point of view, most sud­den cardiac deaths occur in patients with coronary artery disease that mayor may not have been pre­viously diagnosed. Thus, sudden death may be the first manifestation of the disease.

The pathophysiological events leading to sud­den cardiac death are relatively simple. It can sometimes occur as a result of the following: acute ischaemia leading to severe electrical instability or irreversible pump failure; acute pump failure re­sulting in severe electrical instability and/or acute ischaemia; or acute, primary electrical instability leading to inadequate pump function and acute is­chaemia. However, combinations of these factors are likely to be the rule rather than the exception.

In recent years, many new methods of investi­gating cardiac physiology and physiopathology have become available. Almost without exception, methods employed in clinical investigation have

been derived from experimental studies. Although extrapolation of experimental data into the clinical situation must be done cautiously, the basic mech­anisms remain the same. Whatever the ultimate cause of sudden cardiac death, I of the following 3 factors is likely to initiate the event: • acute cardiac ischaemia • acute mechanical dysfunction • or inappropriate electrical activity.

Understanding the exact role of each of these factors in a particular patient can be difficult.

1. Acute Ischaemia

It is well known that acute ischaemia may lead to ventricular fibrillation and sudden cardiac death. Acute ligation of a coronary artery causes acute mechanical dysfunction and acute electrical instab­ility. Electrical instability most commonly results in either polymorphic ventricular tachycardia or

Mechanisms of Sudden Cardiac Death

ventricular fibrillation; however, in some cases a bradyarrhythmia (asystole) may develop.

The reported incidence of acute ischaemic ven­tricular fibrillation varies greatly according to the delay before admission of patients into hospital and is necessarily an underestimation of the true inci­dence. Indeed, some statistics suggest that about 30% of patients suffering from acute myocardial infarction never reach hospital because they do not survive the initial ischaemic episode. During acute, severe spasm of a coronary artery, acute poly­morphic ventricular tachycardia or ventricular fi­brillation is frequently observed.

Short lasting ischaemia can be well tolerated by most patients. Ventricular fibrillation is a rare complication of coronary angioplastly, even after inflation of the balloon for several minutes. These observations raise many questions about the role of acute ischaemia in the precipitation of sudden cardiac death. Experimental studies have found answers to many of these. According to their stud­ies, the incidence of acute ischaemic arrhythmias is influenced by the size of the ischaemic area, the presence of pre-existing collaterals to the ischaemic area, the mode of coronary occlusion, heart rate, the activity of the autonomic nervous system, and the presence of a previous myocardial infarction. For an ischaemic area of given size, the mode of coronary occlusion and the presence ofa previous myocardial infarction are the 2 factors most likely to play a role in the development of acute isch­aemic ventricular fibrillation and sudden cardiac death. It is notable that a sustained monomorphic ventricular tachycardia has never been observed to result from acute ischaemia in the absence of a pre­vious myocardial infarction.

Progressive occlusion of a coronary artery may allow sufficient time for compensatory mechan­isms to prevent acute electrical instability. In con­trast, sudden occlusion of a coronary artery may result in acute electrical instability. It would appear that patients reaching hospital after an acute is­chaemic event represent a group with a good prog­nosis in terms of acute electrical instability. Those patients with sudden occlusion of a coronary artery leading to extensive acute ischaemia probably never

17

reach hospital. Survivors of the acute ischaemic episode who do reach hospital may have some form of intermittent coronary occlusion, with episodes of sufficiently preserved coronary flow in between the periods of total occlusion. From unstable an­gina to acute ischaemic death, a spectrum of clinical manifestations of acute coronary occlusion can be envisaged. Unfortunately, no experimental studies have assessed the consequences of these different patterns of coronary occlusion in terms of arrhyth­mogenesis.

Many data not directly related also suggest an important role for ischaemia as the primary event in sudden cardiac death in patients with previous myocardial infarction. In recent studies, it was found that acute ischaemia was a possible initiat­ing mechanism in about half the patients dying suddenly after a myocardial infarction. The same study addressed the question of whether sudden death occurring after myocardial infarction in patients with established severe ventricular ar­rhythmias was'the consequence of a recurrence of the ventricular arrhythmia or arose from other mechanisms. On pathological examination, it was found that about half these patients had fresh thrombi in the coronary arteries. This suggests an important role for recurrent ischaemia as a trigger of pre-existing potential re-entry circuits. However, acute ischaemia in some patients may lead to new arrhythmias unrelated to those previously docu­mented. Obviously, these patients may also die as the result of ventricular arrhythmias triggered by mechanisms other than ischaemia.

Whatever the exact mechanisms, it is easy to state that the role of acute or recurrent ischaemia in sudden cardiac death may have been underes­timated. Too much emphasis may have been given to arrhythmias as the initiating cause, when these arrhythmias may, in fact, be caused by an acute ischaemic event. Monomorphic sustained ventric­ular tachycardias require a substrate, i.e. a re-entry circuit; this is commonly created by a myocardial infarction. Polymorphic arrhythmias occur during acute ischaemia in the absence of a previous sub­strate. The mechanisms and management of these arrhythmias must necessarily differ.

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2. Mechanical Dysfunction

Mechanical dysfunction occurs in many acute and chronic cardiac diseases. There are, however, only a limited number of situations in which acute mechanical dysfunction may be so severe as to re­sult in sudden cardiac death. Three examples of this are embolisation of a valvular prosthesis with acute and complete obstruction of aortic flow, massive pulmonary embolism, and cardiac rup­ture. Other conditions, such as acute mitral insuf­ficiency, aortic dissection and cardiac tamponade, usually have a sufficiently prolonged time-course to fall outside the strict definition of sudden card­iac death. It is difficult to make any statements re­garding the role of acute haemodynamic dysfunc­tion as a primary cause of sudden cardiac death. Compared with acute ischaemia and primary elec­trical instability, its role must be minor, with the exception of cardiac rupture in the subacute phase of myocardial infarction.

3. Electrical Instability

The terminal event during sudden cardiac death is always a cardiac arrhythmia. Whatever the ini­tiating factor, the heart ultimately develops ven­tricular fibrillation and finally asystole. Documen­tation of any of these arrhythmias at the time of arrival of a resuscitation team, or documentation by means of long term electrocardiographic moni­toring does not prove that the arrhythmia was the initiating factor. Even in those patients dying in hospital with a clearly documented ventricular ar­rhythmia, other mechanisms (e.g. ischaemia) may have initiated the terminal ~vent.

Sudden death will occur when asystole is suf­ficiently prolonged. Similarly, rapid ventricular tachycardia and ventricular fibrillation will ulti­mately result in sufficient haemodynamic impair­ment and ischaemia to cause sudden circulatory arrest and death. However, the factors determining the consequences of these arrhythmias vary.

Asystole results in the absence of any cardiac action. Perfusion of vital organs (including the heart itself) ceases and death results. The consequences

Drugs 41 (Suppl. 2) 1991

Table I. Factors involved in determining the haemodynamic consequences of a ventricular tachyarrhythmia

Rate Pattern of ventricular contraction Atrioventricular synchrony Abruptness of arrhythmia onset Posture of the patient at the time of onset and state of the

autonomic nervous system Severity of underlying heart disease, if present Duration of the arrhythmia

of asystole are independent of the previous state of the myocardium, coronary arteries and other or­gans. Asystole is fatal both for the normal and ab­normal heart. For rapid arrhythmias, the situation is different. Atrial fibrillation may cause cardio­genic shock in the patient whose pump function depends on atrial contribution to ventricular fill­ing. In contrast, a patient with a mechanically nor­mal heart may be able to walk into the emergency room with atrial fibrillation and mean ventricular rates > 250 beats/min caused by anterograde con­duction over an accessory pathway. For ventricular arrhythmias, the situation is more complex.

3.1 Factors Determining the Haemodynamic Consequences of Ventricular Tachyarrhythmias

The haemodynamic consequences of ventricu­lar arrhythmias depend on several factors (table I), which can be studied separately in individual patients. However, when analysing patient popu­lations, the relative contribution of each of these factors cannot be dissected, since they are closely interrelated.

It is clear that the faster a ventricular arrhyth­mia, the greater its haemodynamic consequences. Given the same severity of underlying heart dis­ease, the same pattern of ventricular contraction and the same degree of atrioventricular synchrony, a faster arrhythmia results in more severe haemo­dynamic impairment than a slower one.

However, 2 identical arrhythmias have very dif­ferent haemodynamic consequences in the normal and abnormal heart.

Mechanisms of Sudden Cardiac Death

The pattern of ventricular activation plays a major role in the haemodynamic consequences of ventricular arrhythmias. The more 'normal' (septal origin) the pattern of ventricular activation, the less the consequences for pump function. For a given rate, a ventricular tachycardia originating very far from the conduction system of the heart results in more abnormal patterns of ventricular contraction and poorer haemodynamic performance during the arrhythmia. The most extreme example of the im­portance of the pattern of ventricular activation is ventricular fibrillation. The totally erratic pattern of activation results in a completely inefficient me­chanical function.

Atrioventricular synchrony may be maintained because of retrograde conduction during a ventric­ular tachycardia. Atrial pacing, triggered by the QRS complex, was previously used to temporarily im­prove mechanical performance in patients with in­cessant, uncontrollable ventricular tachycardia re­sulting in cardiogenic shock. Atrial pacing was triggered in response to the QRS complex after a certain V-A interval so that the best possible con­tribution of atrial contraction to ventricular filling resulted. Although this pacing mode is no longer used, it served to illustrate that atrioventricular dissociation may add to the poor haemodynamic performance during ventricular tachyarrhythmias.

The abruptness of onset of a ventricular tachy­cardia determines its initial haemodynamic con­sequences. Some patients present with ventricular tachycardia that is relatively well tolerated at the time of admission, although the initial symptom may have been a syncopal episode. After an abrupt drop in blood pressure at the onset of the arrhy­thmia, compensatory mechanisms may stabilise the haemodynamic condition. Abruptness of onset is actually a concept including several factors: (a) the posture of the patient at the time of onset of the arrhythmia; (b) the state of the autonomic nervous system; and (c) the heart rate at the time of onset. These factors explain why a ventricular tachycar­dia occurring during exercise (with a high adren­ergic tone and a fast sinus rate) may not be felt at all by the patient. The same arrhythmia may, how-

Table II. Possible mechanisms of ventricular arrhythmias

Re-entry (including reflection)

Enhanced automaticity

Early afterdepolarisations (phase 2)

Late afterdepolarisations

Boundary currents during ischaemia

Prolonged repolarisation-dependent re-excitation

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ever, result in syncope when the patient is stand­ing, not exercising, and the sinus rate is slow.

The degree ofleft ventricular dysfunction is per­haps the major determinant of the haemodynamic consequences of ventricular tachycardias as seen clinically. The patient with idiopathic ventricular tachycardia (normal heart) can tolerate extremely rapid arrhythmias. The patient with severe left ventricular dysfunction may be unable to tolerate a ventricular tachycardia at 110 beats/min.

The duration of the arrhythmia is an important factor in determining whether or not sudden death will ultimately result. Irrespective of symptoms re­lated to the onset of the arrhythmia (syncope), a minimal duration of a cardiac arrhythmia is re­quired to result in sudden death. When untreated, a ventricular arrhythmia must last sufficiently long to cause irreversible damage to the myocardium (through ischaemia) and death. On the other hand, a ventricular tachycardia causing no more than moderate pump dysfunction can be tolerated for hours or even days. Ventricular fibrillation can be present for only a few minutes before irreversible damage occurs. Beyond that point, resuscitative measures are ineffective. The same applies for asystole.

Understanding these factors is essential before discussing the electrophysiological properties of tachyarrhythmias leading to sudden cardiac death.

3.2 Electrophysiological Properties of Ventricular Tachyarrhythmias Leading to Sudden Cardiac Death

Ventricular arrhythmias may be caused by a variety of electrophysiological mechanisms (table II). Of these, re-entry seems to be most common

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in patients with ventricular tachycardia after myo­cardial infarction and in patients with the right ventricular dysplasia syndrome. Early afterdepo­larisations playa role in arrhythmias caused by the long QT syndromes, both congenital and acquired. Late afterdepolarisations are the underlying mech­anism of arrhythmias caused by digitalis intoxi­cation. They may also be operative in some forms of ventricular tachycardias observed in the other­wise structurally normal heart. However, abnormal automaticity may be the mechanism of ventricular tachycardia in some of these patients.

It has to be realised that obtaining exact proof of the electrophysiological mechanism of a ven­tricular tachycardia in a particular patient is very difficult. Because sudden death mostly occurs in patients with coronary heart disease, re-entry is likely to be the most common mechanism of ar­rhythmic sudden death. Treatments aimed at pre­venting these arrhythmias must take into account the electrophysiological mechanisms, although a multifactorial approach to the problem of sudden death is necessary.

Recently, doubts have arisen about the value of antiarrhythmic drug treatment in the prevention of sudden death. In 1986, we predicted the results of the Cardiac Arrhythmia Suppression Trial (CAST) by carefully analysing the arrhythmia substrate in patients with and without ventricular arrhythmias after myocardial infarction. In an analysis of 160 patients with previous myocardial infarction, pro­grammed electrical stimulation according to a standardised protocol was used to assess the inci­dence of induction of ventricular arrhythmias. One group of 35 patients had no evidence of spontan­eous ventricular arrhythmias; another of 37 patients had a single episode of spontaneous nonsustained ventricular tachycardia, butno sustained ventric­ular arrhythmias; a third group of 31 patients had spontaneous ventricular fibrillation late after in­farction; and a fourth group included 57 patients with spontaneous sustained ventricular tachycar­dia after infarction. The incidence of induction of a sustained ventricular tachycardia in the 4 groups and the mode of initiation are summarised in table III. As shown, a sustained monomorphic ventric-

Drugs 41 (Suppl. 2) 1991

ular tachycardia was initiated in 93% of patients with clinically documented arrhythmia, a finding which was expected, given the ability of our stimu­lation protocol to reproduce clinically occurring sustained monomorphic ventricular tachycardia after myocardial infarction. This arrhythmia was also initiated in 61 % of patients with clinical docu­mentation of ventricular fibrillation, also an ex­pected finding. However, it was surprising to ob­serve that a sustained monomorphic ventricular tachycardia could be initiated in more than 40% of patients without clinical evidence or documenta­tion of sustained ventricular arrhythmias. The in­duced arrhythmia was faster and more difficult to initiate in these patients than in patients with ventricular fibrillation or spontaneous sustained monomorphic ventricular tachycardia.

From this study, it was concluded that about half the patients without spontaneous sustained ventricular arrhythmias after myocardial infarc­tion have a potential re-entry circuit capable of serving as a substrate for sustained monomorphic ventricular tachycardia. However, the potential re­entry circuit of these patients has short refractory periods, making initiation of the arrhythmia dif­ficult, and faster conduction velocities, also mak­ing perpetuation difficult. We hypothesised that drugs slowing conduction and/or prolonging re­fractoriness may result in the spontaneous occur­rence of sustained ventricular arrhythmias in these otherwise asymptomatic patients. The results of the CAST have confirmed this hypothesis. In patients without spontaneous sustained arrhythmias who were included in the CAST, administration of en­cainide or flecainide increased mortality compared with the corresponding placebo groups. The CAST has proven that criteria for antiarrhythmic efficacy as assessed from long term electrocardiographic monitoring are obsolete. Moreover, the CAST has also forced a major revision of the extrasystolic hy­pothesis of sudden death. Extrasystoles may trigger ventricular arrhythmias, but do not per se cause sudden death. Suppression of extrasystoles does not mean that the properties of the potential re-entry circuit have been favourably changed.

Mechanisms of Sudden Cardiac Death

4. Future Strategies in the Prevention of Sudden Death

There is no doubt that the major contribution to the prevention of sudden death after myocardial infarction has been the implementation of throm­bolysis during the acute phase of myocardial in­farction and the aggressive treatment of unstable angina pectoris to prevent myocardial infarction. This has been shown, not only by the results of large clinical trials, but also by smaller studies into the effects of early reperfusion on spontaneous and induced arrhythmias. Limitation of infarct size re­sults in a less arrhythmogenic substrate. However, we will continue to see patients in whom throm­bolysis is ineffective or unfeasible and who de­velop a large myocardial infarction with mechan­ical and electrical complications. For those patients with ventricular tachycardia or ventricular fibril­lation late after myocardial infarction, very effec­tive therapies exist when used properly. Our pre­sent approach to these patients is shown in figure I. The first question is whether the patient devel­oped cardiac arrest/syncopal ventricular tachycar­dia. For patients in this category, the functional class for dyspnoea (NYHA ~ 3) differentiates a group with a high incidence of sudden death on optimal medical treatment alone (expected inci­dence of sudden death at 2 years 25%). Patients with cardiac arrest or syncopal ventricular tachy­cardia and a good functional class for dyspnoea can be stratified on the basis of a history of a single myocardial infarction or more than one myocard­ial infarction. The expected incidence of sudden

21

death is 20% on medical treatment alone in the latter group. In patients with a single myocardial infarction, the question of whether or not ventric­ular tachycardia was related to exercise differen­tiates another group with an expected incidence of sudden death of 35%, and a group with an inci­dence of 9%. Stratification of patients who did not suffer syncope or cardiac arrest during ventricular tachycardia is shown on the right of figure I. When ventricular tachycardia was well tolerated and oc­curred more than 2 months after myocardial in­farction, the expected incidence of sudden death at 2 years on medical treatment is practically 0%. For those with ventricular tachycardia occurring from 2 days to 3 months after myocardial infarction, the functional class for dyspnoea allows for identifi­cation of a subgroup with an expected incidence of sudden death of II %. As shown, we believe that patients with expected incidences of sudden death above 10% on medical treatment alone should re­ceive an implantable defibrillator. Patients with ex­pected incidences of sudden death below 10% can be managed medically. The management of fail­ures of medical treatment depends upon operabil­ity and clinical presentation of ventricular tachy­cardia (incessant or paroxysmal). The above approach is based on previously reported clinical data, and a prospective study using it is currently being undertaken.

There is a very clear philosophy behind this ap­proach. The implantable defibrillator terminates ventricular fibrillation whatever the initiating or maintaining mechanism. Thus, the implantable defibrillator may reduce the incidence of sudden

Table III. Incidence, mode of initiation and cycle length of sustained ventricular tachycardia in 4 groups of patients with previous myocardial infarction

No VA NSVT VF SMVT

Number of patients 35 37 31 57 % induced 48 40 61 93 Mean no. of premature beats 2.5 ± 0.6 2.3 ± 0.5 2 ± 0.6 1.8 ± 0.7 Mean cycle length (msec) 214 ± ?5 232 ± 45 274 ± 58 315 ± 79

Abbreviations: VA = ventricular arrhythmias; NSVT = nonsustained ventricular tachycardia; SMVT = sustained monomorphic ventricular tachycardia; VF = ventricular fibrillation.

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death during follow-up by terminating ventricular fibrillation arising as a primary electrical event, or from a recurrent ischaemic episode. There is no other therapy which can cope with these 2 prob­lems simultaneously.

5. Conclusions

Sudden cardiac death has a large variety of in­itiating mechanisms. Although an arrhythmia may be documented at the time of sudden death, that

Drugs 41 (Suppl. 2) 1991

is no proof that a primary electrical event was the initiating mechanism. A sustained monomorphic ventricular tachycardia may be triggered by a large variety of factors. When occurring in patients with a previous myocardial infarction, the arrhythmia points to the presence of a re-entry circuit, the properties of which will not be changed by meas­ures aimed at preventing ischaemia or improv­ing haemodynamic performance. Polymorphic ar­rhythmias and asystole at the time of sudden death may be caused solely by ischaemia. Treatment must

CAROIAC ARREST OR SVNCOPAL VT?

~ NO

NVHA~3? VT < 2 months after MI?

ve/ 25%

.----A-IC-O-'I MULTIPLE MI?

Ves / "'-. No

200/0 ,1 ~ .----A-,C- o--,I EX·R VT?

ves/ "'-. No

~ 0%

NVHA~3? 8 11:.

es I ,\0 4%

AICO I 8 3:':S

/ ~ 9% AICO I 8------------ -:

:--------~

OPERABLE?

Ves No

SURGICAL Rx INCESSANT VT?

Ves ............ .. : No ~ .---

TCAVT ATP + AICO

Fig. 1. Decision tree for patients presenting with spontaneous sustained ventricular tachycardia (VT) or ventricular fibrillation late after myocardial infarction (MI). EX-R VT = exercise related VT; AICD = implantable defibrillator; M = managed medically; A TP = anti tachycardia pacing; Rx = treatment; TCA VT = transcoronary chemical ablation of ventricular tachy­cardia; NYHA = New York Heart Association. Percentages give the expected incidence of sudden cardiac death while on optimal medical treatment and for the first 2 years.

Mechanisms of Sudden Cardiac Death

be carefully individualised in survivors of ventric­ular arrhythmias. On the basis of extensive inves­tigations performed in recent years, decision trees have become available for that purpose. The im­plantable defibrillator is the only therapy able to improve survival in patients with a high expected

23

incidence of sudden death in spite of optimal anti­arrhythmic drug treatment.

Correspondence and reprints: Prof. Pedro Brl/gada, Professor of Cardiology, Cardiovascular Centre, Postgraduate School of Car­diology, OL V Hospital, Moorselbaan 164, 9300 Aalst, Belgium.