Tumor necrosis factor-α: a new mechanism of ischemic ventricular fibrillation?

Ventricular fibrillation (VF) in myocardial ischemia is called “ischemic VF”. As a severe morbid state and a leading cause of sudden cardiac attack, ischemic VF induces approximately 3 million deaths in the United States each year. Ischemic VF is caused by “triggers” such as ventricular premature beat or ventricular tachycardia in the presence of a suitable “substrate”. The triggers frequently occur at the border zone and the substrate is required for the maintenance of ischemic VF. The critical factors for the initiation and maintenance of ischemic VF are obscure. Tumor necrosis factor-α (TNF-α), an inflammatory cytokine expressed in myocardial ischemia, plays an important role in the pathophysiological process of acute myocardial infarction (AMI). TNF-α also causes arrhythmia by action potential prolongation and abnormal Ca2+ handling, which also contribute to ischemic VF. But the relationship between TNF-α and ischemic VF is unknown. In this article, we suggest that TNF-α may be a novel substrate of ischemic VF. This may be a new mechanism for ischemic VF. TNF-α EXPRESSION IN MYOCARDIAL ISCHEMIA TNF-α is an acute phase reactive protein and a basic medium of immunological regulation, and it is also an inflammatory cytokine with pleiotropic biological effects. In the circulatory system, TNF-α is responsible for many myocardial diseases such as acute coronary syndrome,1 AMI,2,3 myocarditis,4 dilated cardiomyopathy5 and congestive heart failure (CHF).6,7 Currently, inflammation is thought to be an important process in myocardial ischemia.8,9 Augmented in the myocardium of AMI, TNF-α plays an important role in this pathophysiological process.10 TNF-α serves as one of cytokine-mediated attractants for neutrophil migration into the ischemic region and enhances the inflammatory reaction that is related to progressive tissue destruction.11 Inflammatory reaction caused by TNF-α stimulates paraplasm, hypertrophia of the myocardium, and contributes to recovery and ventricle remodeling after AMI.12 Matrix metalloproteinases have been implicated in cardiac remodeling and can be regulated by TNF-α. Dysregulation of the myocardial extracellular matrix may lead to the abnormality of cardiac muscle function. Changes in the balance between matrix deposition and matrix degradation by matrix metalloproteinases lead to cardiac fibrosis and dilation. This process is regulated by TNF-α.13 In our previous studies, we got similar results.14,15 TNF-α AND ARRHYTHMIAS Although the relationship between TNF-α and ischemic VF is not clear, TNF-α is thought to be involved in the onset of atrial and ventricular arrhythmias. Atrial fibrillation is found to be closely related to TNF-α. Pulmonary veins are critical in initiating paroxysmal atrial fibrillation. TNF-α increases the PV arrhythmogenicity and induces abnormal calcium homeostasis, thus causing inflammation-related atrial fibrillation.16 TNF-α also participates in the pathogenesis of postoperative atrial fibrillation after on-pump coronary artery bypass grafting.17 In TNF-α mice (transgenic mice, TNF1.6) compared with control mice, atrial muscle and cells from TNF1.6 exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca2+ handling. The abnormalities in action potential propagation and Ca2+ handling help to initiate atrial arrhythmias in this mouse model.18 In transgenic mice overexpressing TNF-α as compared with controls, hearts have prolonged action potential durations and prolonged Ca2+ transients. Both action potential prolongation and abnormal Ca2+ handling may help to initiate reentrant arrhythmias in this model by mechanisms different from enhanced dispersion of refractoriness or triggered activity. 19 In patients with sick sinus syndrome, asynchronous ventricular activation caused by right apical ventricular pacing leads to an undesirable increase in TNF-α.20 In L-thyroxine-induced cardiomyopathy, the mRNA expression of TNF-α is found to be associated with the incidence of VF produced by coronary ligation/reperfusion in rats.21 In patients with CHF, TNF-α/ TNF-α receptor (TNFR1) system impairs HERG/I(Kr) function mainly by stimulating reactive oxygen species, particularly superoxide anion. This effect contributes to the prolongation of action potential duration by TNF-α, suggesting a novel mechanism for electrophysiological abnormalities and lethal arrhythmias in CHF.22 In contrast, Konstantino et al23 found no correlations among plasma levels of IL-6, TNF-α, high-sensitivity C-reactive protein (hsCRP), brain natriuretic peptide (BNP), and ventricular arrhythmic events in patients with stable CHF during a follow-up of 5.1 months. The complicated mechanisms of ventricular arrhythmias in CHF patients include reentry, abnormal automaticity and triggered activity. The physiopathologic factors include myocardial ischemia, inflammation, electrolyte disturbances, neurohormonal changes, etc. But no exact theory is available for ventricular arrhythmias in CHF patients. MECHANISMS OF ISCHEMIC VF Ischemic heart disease is one of leading killers in the world. The major cause of ischemic heart disease is ventricular arrhythmia event, especially VF. Ischemic VF is usually caused by “triggers” such as ventricular premature beat or ventricular tachycardia in the presence of a suitable “substrate”.24 The ischemic border zone (BZ) represents a tissue with physiological characteristics determined by biochemical processes involving the production or use, diffusion, and accumulation or disappearance of gases and metabolites.25 Most of triggers for ischemic VF occur in the BZ.26 The penultimate substrate that helps precipitate and perpetuate fibrillation presents with the restitution properties of the myocardium.27 Some substrates show the temporal and spatial patterns of arrhythmogenesis during acute regional ischemia,28 hypokalemia, 29 thrombin,30 cellular electrical uncoupling,31 catecholamine,32 stretching,33 genetic predisposition,34 etc. But there are some unknown problems of substrates in ischemic VF.35 TNF-α, which plays an important role in ischemic heart diseases,10 is described as a novel substrate of ischemic VF in this article. SPACE PATTERN OF TNF-α AND WAVE BREAK IN ISCHEMIC MYOCARDIUM Wave break is recognized as the hallmark of VF. In the myocardium of ischemic VF, breaking of waves is characterized by space patterns. When myocardial infarction happens, the myocardium is divided into ischemic zone (IZ), BZ and non-ischemic zone (NIZ). In 15 minutes of regional ischemia, the BZ is marked by wave fragmentation during VF as shown by high (<1 mm) resolution video imaging. The increase of wave break incidence is associated with a steep gradient of refractoriness across the BZ marked by a distribution of excitation frequency during VF.36 It is noteworthy that the central part of the ischemic zone of wave break is decreased. Thus, ischemia increases the wave break incidence in the BZ, while decreasing in the IZ.35 Previously, we observed the space pattern of TNF-α in the ischemic myocardium of AMI rat models. And we also found this difference of spatial distribution. TNF-α was expressed in the myocardium after AMI, especially in the myocardium of the BZ. The expression of TNF-α in the IZ and NIZ was less than that in the BZ. TNF-α AND ISCHEMIC VF TNF-α was expressed in the myocardium of subjects with ischemic heart disease and TNF-α could cause arrhythmia by action potential prolongation and abnormal Ca2+ handling, which also contributed to ischemic VF. Furthermore, TNF-α has the same spatial distribution in the ischemic myocardium as the wave break of ischemic VF. We propose that TNF-α may be a novel substrate of ischemic VF. TNF-α predominating in the BZ may cause wave break by action potential prolongation and abnormal Ca2+ handling and result in ischemic VF. This hypothesis must be subjected to epidemiological and experimental tests. Although some studies have confirmed this hypothesis from different perspectives, there is much more work to do. Shimoda et al37 studied the relationship between activated TNF-α shedding process and in-hospital complication in patients with AMI. They found that spontaneous and stimulated levels of TNF-α-converting enzyme and TNF-α were higher in AMI patients with in-hospital complications (n=15; pump failure in 10, recurrent myocardial infarction in 1, malignant ventricular arrhythmia in 3, and cardiac death in 1) than in those without complications. In other words, 3 AMI patients with malignant ventricular arrhythmia had higher TNF-α levels than those without. The number of cases in this study was too small to find a result of statistical significance. We could only find a tendency from this study. Further experimentation is needed to confirm our viewpoint. The relationship between TNF-α and ischemic VF should be explored in animal models with ischemic VF. In a simulative ischemia environment, effect of TNF-α on ion channels should be studied to elucidate the in-depth mechanism. Moreover, optical mapping is used to determine the role of TNF-α in electric activity of the ischemic myocardium. SUMMARY Ventricular tachyarrhythmia arising from myocardial ischemia and infarction is a major cause of sudden cardiac death.38,39 VF endangers seriously the life of patients with ischemic heart diseases, but its mechanism is still not clear. We suggest TNF-α be a novel substrate of ischemic VF, a new mechanism for ischemic VF. If it is confirmed, how is ischemic VF initiated and what’s a substrate for the maintenance of this disease can be clarified. Besides, TNF-α will be a new target for the therapy of ischemic VF. If the secretion and expression of TNF-α in the ischemic myocardium are inhibited, ischemic VF may be relieved. It would be a significant contribution to the protection of human health if it comes true.