Arrhythmias and Sudden Cardiac Death After 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

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.

Reentrant 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.