Contemporary reviewIschemic ventricular arrhythmias: Experimental models and their clinical relevance
Introduction
Lethal ventricular arrhythmias, including sustained ventricular tachycardia (VT) and, in particular, ventricular fibrillation (VF), are the immediate cause of cardiac arrest in the majority of the estimated 300,000 to 350,000 cases of sudden cardiac death (SCD) that occur annually in the United States.1, 2, 3 SCD comprises 13% of all deaths from natural causes when defined as that occurring within 1 hour from the onset of symptoms.4 A major cause of SCD in the United States is acute myocardial infarction (AMI; ∼250,000 cases per year) during both the reversible phase (ischemic phase) and the infarct evolution phase. Cardiac arrest secondary to AMI-induced VF occurs commonly without warning. Because the spontaneous conversion of VF to nonlethal rhythms is rare, out-of-hospital VF progresses to death within minutes in more than 95% of the victims. AMI-induced VF leads to SCD as the first manifestation of a preexisting coronary artery disease in about 80,000 people per year.1, 2, 3
Experimental studies indicate that ischemia- or infarction-induced heterogeneities in excitability, refractoriness, and/or conduction create the substrate and that ectopic excitation by a variety of mechanisms may provide the extrasystoles that trigger lethal ventricular arrhythmias.5, 6, 7, 8, 9, 10, 11, 12
Section snippets
Mechanisms of ischemic ventricular arrhythmias
Following total occlusion of a coronary artery, ventricular arrhythmias (phase 1 [A and B] and phase 2; see the following text) develop as a consequence of focal as well as nonfocal mechanisms, the former because of automatic and nonautomatic ectopic excitation and the latter involving reentry (Figure 1). Automatic focal excitation in depolarized ventricular myocytes may be the consequence of depolarization-induced automaticity (or abnormal automaticity [AA]). It may also result from early
Temporal distribution of IVAs
Two temporally distinct phases of ventricular arrhythmia develop in response to ischemic injury. Phase 1 is the reversible phase of AMI, whereas phase 2 is the infarct evolution phase (Figure 1). Phase 1, occurring during the first 2 to 30 minutes, is divided into 2 subphases called phase 1A (2–10 minutes) and phase 1B (15–30 minutes). The bimodal nature of phase 1, however, is not universal among species. For instance, 2 peaks of early IVA can be readily observed in canine and pig models, but
Biochemical and electrophysiological characteristics of phase 1 and phase 2 ischemia-related ventricular arrhythmias
Depletion of intracellular adenosine ATP combined with the buildup of ADP and accumulation of products of anaerobic glycolysis, including lactic acid and ATP-derived hydrogen ions, which cause a fall in intracellular pH, underlie the metabolic dysfunction that occurs during the reversible phase of an AMI (phase 1 IVA, first 30 minutes; Figure 3). This phase is also associated with the interstitial accumulation of K+, catecholamines, and amphiphiles such as lysophosphatidylcholine (a
Experimental models of IVA
Various experimental models have been developed to examine the electrophysiologic disturbances associated with AMI. Isolated ventricular myocytes are used to study the electrophysiologic effects of “simulated” ischemia on APs, membrane currents, and exchangers by exposing the cells to metabolic inhibitors as well as hypoxic, acidic, and hyperkalemic solutions. However, in vivo or in vitro studies using experimental models undergoing “regional ischemia” have proved to be ideal for studying
Conclusion
While our understanding of the mechanisms underlying AMI-induced ventricular arrhythmias is coming into better focus, risk stratification of patients with AMI remains a major challenge. A number of well-established experimental models and some recently developed models suggest that prevention of AMI-induced life-threatening ventricular arrhythmias is an achievable goal. Identification of the genetic predisposition to the development of arrhythmogenesis post-MI is another major goal for future
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Cited by (0)
This study was supported by a Grant-in-Aid (10GRNT4210016) from the American Heart Association (Dr Di Diego), by grant HL47678 from the NHLBI (Antzelevitch), and by New York State and Florida Masons. Dr Antzelevitch is a consultant to and has received grant support from Gilead Sciences.