Despite significant advances in the diagnosis and treatment of malignant cardiac arrhythmias, sudden cardiac death (SCD) occurs in 180,000 to 250,000 people annually, mostly in patients with coronary artery disease. Myocardial infarction (MI) remains a vulnerable cardiac pathology that contributes to SCD, and identifying patients with MI who are at heightened risk for SCD continues to be a challenge. Although professional guidelines suggest that patients at risk for SCD after MI often have an impaired left ventricular function (to below 35%), SCD most commonly occurs in those with preserved ejection fraction. Owing to limited or inconclusive data, current professional guidelines simplify SCD risk stratification. However, day-to-day clinical decision making is complex, requiring significant clinical experience and judgment.
The primary difficulty with risk stratification is that it is not clear why some people have ventricular fibrillation (VF) and SCD as a primary manifestation of ischemic heart disease. In view of the fact that a significant number of patients die from out-of-hospital cardiac arrest with no cardiac monitoring at the time, the relationship between ischemia and presumed arrhythmia is difficult to ascertain. Therefore, the current understanding of cardiac arrhythmias in this setting is largely based on experimental models and animal studies, which are imperfect at mimicking the human condition.
Pathobiology of Arrhythmias in Myocardial Infarction
Preclinical Experimental Models
Experimental models have evolved in an attempt to fill gaps in knowledge regarding arrhythmias and SCD after MI. Models adopted to help understand different aspects of SCD include (1) in vitro models for cell-cell physiology; (2) ex vivo Langendorff perfusion models; and (3) in vivo small and large animal models. In vitro models were developed because of the difficulty in obtaining microelectrode recordings from the beating heart. Various preparations can be used to examine transmembrane potentials or to detect changes in intracellular ion concentrations caused by ischemia. However, it is difficult to mimic the in vivo effects of ischemia, hypoxia, acidosis, and high potassium concentrations. The Langendorff perfusion model involves isolation of the heart and perfusion through the coronary arteries. The main disadvantage of this preparation is that the heart is disconnected from the neural cardiac hierarchy (central nervous system, extrathoracic, and intrathoracic ganglia), which could alter arrhythmogenicity, similarly to the conditions after cardiac transplantation.
Many hurdles must be overcome in creating large animal models of MI. The method of occlusion of the coronary artery in a large animal model varies. The coronary artery can be ligated by means of a modified thoracotomy, embolized, or injected with ethanol ( Figure 28-e1 ). The duration of the ischemic period and the timing of reperfusion—early versus late versus non-reperfusion—both contribute to differing patterns of ischemia and scar. Some investigators opt for a two-stage occlusion, with initial partial occlusion to create ischemic preconditioning and subsequent complete occlusion. In these studies, immediate lethal ventricular arrhythmias occur less frequently, probably as a result of neural adaptation or memory to ischemia. Commonly, investigators will create a left anterior descending (LAD) infarct after the first diagonal ( Figure 28-e2 ) or a left circumflex artery infarct.
Porcine models have limited or no coronary collaterals, so in such preparations, at the time of infarction, VF due to accelerated cell death is common. Canine coronary artery occlusion results in a predominantly subendocardial infarction, versus a transmural infarction in the porcine model. Differences in collateral development and patterns of infarction can significantly affect the experimental model and how it relates to clinical findings in humans.
After 6 weeks, the substrate for subacute ventricular arrhythmias can be evaluated. However, arrhythmia induction in the terminal procedure is not guaranteed. Ventricular stimulation protocols, with up to three extra stimuli, at two different sites, epicardial and endocardial, are performed to assess for inducibility of ventricular tachyarrhythmia. On occasion, acute ischemia in a different territory can be induced in the setting of an already established chronic infarct to induce more electrical instability. Sympathetic stimulation with isoproterenol infusions or stellate ganglia stimulation also are employed to potentiate electrical instability. Despite these interventions, arrhythmia induction appears to occur in only 30% to 60% of canines and slightly more frequently in porcine models. Cardiac three-dimensional electroanatomic substrate mapping and cardiac imaging modalities such as magnetic resonance imaging (MRI) or echocardiography often are combined to provide additional information on the relationship of scar to ventricular arrhythmia inducibility ( Figure 28-1 ).
Electrophysiologal Effects of Myocardial Ischemia
Myocardial ischemia affects the resting membrane potential and inward and outward currents, altering conduction, refractoriness, and automaticity. During ischemia, an initial increase in extracellular K + results in a reduction in resting membrane potential. Within the first 15 minutes of ischemia, these changes in resting membrane potential are rapidly reversible and can return to normal. The increase in extracellular K + occurs in two phases: After the first 15 minutes, a plateau or slight decrease is seen in extracellular K + , which then starts to rise again in the second phase, corresponding with irreversible cell death. It is thought that the plateau phase may be related to the release of catecholamines, which pushes K + intracellularly owing to enhanced activation of the Na + -K + pump. This pump, which is responsible for K + influx into the cell, is energy-consuming. A reduction in available energy in the first 10 to 15 minutes may result in depression of the Na + -K + pump. Efflux of K + is due to a complex set of changes that are a result of net inward currents and accumulation of ischemic metabolites. Other elements that contribute to membrane potential alterations, such as Ca 2+ and magnesium, potentially have some effect on depolarization as a consequence of intracellular accumulation. Additionally, accumulation of the metabolites of phospholipids in the ischemic myocardium may affect the membrane potential.
Myocardial Scar Development Secondary to Ischemia
After 15 to 20 minutes of complete coronary occlusion in a canine model, signs of cell death are evident. The exact timing of cell death with occlusion in humans is not clear. MI can result in transmural necrotic myocardial tissue, but more commonly seen are patchy areas of surviving myocytes. During ischemia, the cells die gradually, and the infarct can increase in size, initially being localized to the subendocardial layer and then spreading to the endocardium and mid- and subepicardium. This pattern evolves because under normal conditions, the coronary blood supply is greatest in the mid- and subepicardial layers, and collaterals are more numerous in the subepicardium. After ischemic injury, necrotic myocardium is replaced by fibrotic tissue that surrounds the surviving myocytes. Ischemia results in abnormal refractoriness, abnormal conduction velocities, altered excitability, and automaticity, which can facilitate ventricular arrhythmias. Surrounding the infarcted tissue, a “border zone” separates normal myocytes from scar. A border zone region can function as an essential region of slow conduction for reentry or as a site of focal impulse origin ( Figure 28-2 ).
Timing of Ventricular Arrhythmias
Early Ventricular Arrhythmias
Early ventricular arrhythmias occur in two phases in animal models. The first phase, called Harris phase 1a (made up of so-called immediate ventricular arrhythmias), occurs in the first 2 to 10 minutes after coronary occlusion, with the highest incidence of arrhythmias at approximately 5 to 6 minutes. The second phase, called 1b, usually occurs from 12 to 30 minutes after coronary occlusion, with a peak at 15 to 20 minutes. This description is based on small and large animal models, and it is unclear if humans have the same two-phase response with early arrhythmias. The mechanism appears to be different for each component.
The phase 1a arrhythmias appear to demonstrate conduction slowing and delayed activation of the subepicardial electrograms. The electrograms in these arrhythmias are markedly heterogeneous, with the sharp action potential becoming slurred and biphasic and even spanning diastole (diastolic bridging). Other features include an increase in the refractory period and marked conduction delay. It is thought that phase 1a arrhythmias are caused by reentrant arrhythmias with an appropriately timed trigger, such as a premature ventricular contraction (PVC), along with a heterogeneous electrical activation between the epicardium and the endocardium, and a delay after depolarization, allowing a reentrant circuit to develop.
Phase 1b arrhythmias are thought to be a result of endogenous catecholamine release, which could occur in the 12- to 30-minute period after MI. Information is lacking about whether arrhythmias occur in the same pattern in humans during the first 30 minutes of ischemia. After 3 to 6 hours, arrhythmias are very infrequent and after 8 to 24 hours, PVCs gradually increase in frequency.
Delayed Ventricular Arrhythmias
Delayed ventricular arrhythmias occur 24 to 72 hours after MI, with PVCs, accelerated idioventricular rhythms, and ventricular tachycardia (VT)/VF seen on the electrocardiogram (ECG). The autonomic component of the peripheral nervous system appears to play a critical role in the emergence of delayed ventricular arrhythmias. In fact, autonomic modulation with therapies such as thoracic epidural anesthesia or sympathetic decentralization is recognized to reduce the incidence of ventricular arrhythmias related to MI; however, the timing of these arrhythmias is not well described.
Several mechanisms may underlie delayed ventricular arrhythmias. Long cycle lengths with a long coupling interval PVC, late in diastole, may result in abnormal impulse initiation. Normally, sinus rhythm prevents activation of ectopic pacemakers by overdrive suppression, but once the sinus rate slows or has pauses, ectopic pacemaker tissue can become active, generating ectopic ventricular rhythms, through an automatic mechanism. Triggered activity due to early afterdepolarizations can result in reentrant arrhythmias.
As a consequence of the lack of clinical studies, the relevance of comparisons of acute phase arrhythmias between animal models and humans is uncertain. In relation to the delayed ventricular arrhythmias, more data are available to help correlate findings in experimental models and in clinical practice.
Experimental models suggest that at least 3 minutes of ischemia is required for the development of reperfusion arrhythmias. In the era of primary percutaneous intervention for MI, reperfusion arrhythmias are commonly seen, ranging from isolated PVCs, accelerated idioventricular rhythms, and VT and VF. In experimental models, phases of arrhythmias related to reperfusion are evident, with none occurring after less than 3 minutes of ischemia. Arrhythmias are more frequent when the ischemic period is increased from 5 minutes to 20 to 30 minutes. Reperfusion arrhythmias are less frequent after 30 to 60 minutes. These arrhythmias are a result of washout of ions such as lactate and potassium and of toxic metabolites from the ischemic zone and also oxidative stress, all of which alter autonomic function.
In humans, the most common rhythm with reperfusion is accelerated idioventricular rhythm, with rates ranging from 70 to 100 beats/min. The absence of reperfusion arrhythmias is thought to be a negative prognostic indicator in that it is suggestive of a longer ischemic period than had been potentially realized. In experimental models, when reperfusion is performed early, a sudden and almost immediate restoration of action potentials to the ischemic area occurs. In the early stages of reperfusion, the action potentials are abnormal, with alternating low to high amplitude. Within the myocardium, marked heterogeneity of action potentials, along with the addition of a trigger, can act as a substrate for arrhythmias. This heterogeneity tends to decrease after the first 30 seconds of reperfusion.
Late or Chronic Ventricular Arrhythmias
Late ventricular arrhythmias occur approximately 1 to 3 weeks after MI, as the infarct evolves and starts to heal. After the early-phase arrhythmias, fewer ventricular arrhythmias typically are seen from 72 hours to 5 days, and then frequent PVCs predominate. The burden of early arrhythmias unfortunately does not predict the frequency of late arrhythmias. The absence of in-hospital or early arrhythmias does not predict the absence of late arrhythmias.
Risk factors predictive of late arrhythmias are the size of the scar, presence of aneurysms, multivessel disease, and anterior location of the MI ( Figure 28-3 ). Before discharge, in the setting of these risk factors, treadmill exercise testing may be helpful in risk stratification (see Chapter 30 ). The development of arrhythmias during exercise testing is predictive of an increased risk for SCD. Electrophysiology testing for induction of ventricular arrhythmias by programmed stimulation is predominantly helpful for late or chronic ventricular arrhythmias. Chronic ventricular arrhythmias, beyond 3 weeks, tend to be reentrant in nature and result from scarring, with zones of either slow conduction or electrical block facilitating initiation and perpetuation of reentry.
Mechanism of Ventricular Arrhythmias
Reentrant tachycardias require a zone of slow conduction and unidirectional block. The longer it takes for the impulse to traverse the area of slow conduction, the more time is required for the impulse to emerge from the zone of reentry, and the longer the coupling interval before onset of tachycardia. Either a single loop or multiple loops may be present within a reentrant circuit ( Figure 28-4 ). Reentrant tachycardias can be terminated by a critically timed premature stimulus that collides with the reentrant circuit, rendering it refractory. Capture of the ventricular electrical activity with pacing that does not affect the tachycardia also is indicative of a reentrant arrhythmia. Resetting of the reentrant arrhythmia to abort the tachycardia also may occur if pacing delivers a premature stimulus within the circuit. In other words, when resetting occurs, the QRS of the tachycardia occurs earlier than expected as a result of the paced stimulus, which advances the QRS. Termination of the tachycardia by overdrive pacing as well as the ability to entrain the arrhythmia is a feature of reentrant tachycardias. Concealed entrainment involves pacing at a faster rate than the tachycardia, whereby the rate of the tachycardia increases to the pacing rate, maintaining the same QRS morphology as for the baseline tachycardia, and fusion no longer occurs, with return of the tachycardia to the previous cycle length on discontinuation of pacing.
Triggered activity is dependent on afterdepolarizations, either early or late, with at least one action potential preceding it. Triggered activity displays features of both automaticity and reentry. If afterdepolarizations are of sufficient magnitude, they can generate another action potential. The action potential can result from either spontaneous leakage of positive ions intracellularly or a premature ventricular beat ( Figure 28-5 ). Two distinct types of triggered activity exist: pause-dependent arrhythmias and catecholamine-dependent arrhythmias. During a pause, if the afterdepolarization reaches the cellular threshold, another action potential can be generated. This circumstance can allow for impulse initiation from the trigger and subsequent sinus node suppression. With catecholamine-dependent triggers, delayed afterdepolarizations lead to the generation of another action potential secondary to an increase in sympathetic activity.
Automaticity can be described as normal or abnormal impulse initiation. Normal automaticity, as seen in the sinoatrial node or latent subsidiary pacemaker cells, is responsible for the intrinsic rate at which impulses are initiated. Normal automaticity involves a spontaneous decline in transmembrane potential in diastole called diastolic depolarization, followed by a threshold potential, which generates a spontaneous action potential. A subsequent fall in membrane potential alters the membrane currents to a net inward depolarizing current. Abnormal automaticity occurs when the resting membrane potential of cells ordinarily responsible for impulse initiation is reduced sufficiently to allow spontaneous diastolic depolarization in other atrial or ventricular cells, causing overdrive suppression of subsidiary latent pacemakers. An example of abnormal automaticity is that of an idioventricular rhythm after MI. Accelerated idioventricular tachycardias demonstrate characteristics suggestive of abnormal automaticity, in how they fail to respond to pharmacologic agents and lack of overdrive suppression with pacing.
The Autonomic Nervous System and Ventricular Arrhythmias
It is clear that the autonomic nervous system (ANS) plays a critical role in SCD. This nervous system component modulates all physiologic functions of the heart including chronotropy, dromotropy, lusitropy, and inotropy. The ANS is a finely tuned system regulating sympathetic and parasympathetic response, through a complex neural network between the heart and central cortical structures, and maintaining cardiac stability. The progression of heart disease can result in functional denervation and in cardiac and extracardiac neural remodeling. After MI, an imbalance in the autonomic nervous system, with a relative increase in sympathetic activity and a decrease in parasympathetic activity, is seen ( Figure 28-6 ). This response is vital in the short term to maintain cardiac output but in the long term constitutes a maladaptive process resulting in reorganization of the neural network and precipitation of fatal arrhythmias as a consequence of persistent sympathoexcitation. An increase in sympathetic activity not only affects the Na + -K + pump but also increases Ca 2+ influx, which is thought to be a mechanism for enhanced automaticity and triggered activity. MI affects the cardiac myocytes but also has a cascade effect on the cardiac neural hierarchy, including the intrinsic cardiac nervous system, intrathoracic extracardiac ganglia (stellate ganglia), extracardiac ganglia (middle cervical ganglia, nodose ganglia, dorsal root ganglia), and the higher centers. Ischemia is the likely mechanism for disruption of the afferent information being transmitted to the central nervous system, with consequent effects on the central drive or reflex efferent parasympathetic input. It is this neural dysregulation that contributes to the pathophysiologic processes responsible for malignant ventricular arrhythmias and heart failure.