TUMOR NECROSIS FACTOR -ALPHA ANTAGONISM: A POTENTIAL THERAPEUTIC TARGET FOR PREVENTION OF ARRHYTHMOGENESIS IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION ?
Kenan YALTA, MD
Nasir SIVRI, MD
Bilal GEYIK, MD
Ertan YETKIN, MD
Trakya ?niversity, Cardiology Department, Edirne, Turkey
Corresponding Author: Kenan Yalta , e-mail: email@example.com
In their recently published elegant article (1), Padfield GJ et al have reported potential cardiovascular effects of tumor necrosis factor alpha (TNF-alpha) antagonism in patients with non-ST elevation acute myocardial infarction (NSTEMI). In this first in human study, the authors have demonstrated that a single dose of etanercept (a TNF- alpha antagonist) infusion might blunt systemic inflammatory response , but might appear to enhance platelet aggregation along with its neutral effects on fibrinolytic and peripheral vasomotor functions in these patients at 24 hr after infusion suggesting that TNF alpha antagonism should not be regarded as a promising therapeutic strategy in the setting of acute myocardial infarction (AMI) (1). We also agree that currently, this strategy should be regarded with caution in the setting of acute coronary syndromes (ACS) . However, based on the multi -faceted nature of systemic inflammation and its detrimental effects, modulation of cytokine response in conditions with heightened systemic inflammation might be associated with favorable outcomes including suppression of life-threatening arrhythmias,etc. particularly in the setting of ACSs. Therefore; regarding the study by Padfield GJ et al (1), it is still too early to conclude that TNF-alpha antagonism appears to be totally useless in AMI patients solely based on its adverse effects on platelet aggregation.
In the recent years, there has been growing interest towards the potential link between systemic inflammation and arrhythmogenesis particularly in the setting of atrial fibrillation (AF) (2). AMI, an important trigger of inflammatory response, is regarded as an important cause of acute arrhythmogenesis leading to significant morbidity and mortality. Arrhythmias in the setting of AMI are generally attributable to a variety of factors including ongoing ischemia (due to ischemia at a distance or in infarct zone), congestive heart failure, peri-infarct scar tissue, electrolyte imbalance, and sympathetic discharge, etc. (3). Interestingly, it was previously suggested that enhanced inflammatory response might potentially have a role in the genesis of malign ventricular arrhythmias and sudden cardiac death during or after an AMI (3,4). Consistent with this, a previous clinical study comprising patients with ACSs suggested a potential link between TNF-alpha and reduced hear t rate variability (HRV) (5), a well known index of arrhythmogenesis and sudden cardiac death (SCD). Moreover, it was previously suggested in a viewpoint article that TNF-alpha might be regarded as a novel substrate of ischemic ventricular fibrillation (VF), and inhibition of secretion and expression of TNF-alpha in the ischemic myocardium might therefore serve as a therapeutic option for ischemic VF (6). However, in conditions with modest inflammation including ACSs, it seems plausible that TNF-alpha may not be regarded as the sole actor, but may only serve as a contributor to other arrhythmogenic substrates including peri-infarct scar tissue, ongoing ischemia, electrolyte imbalance etc. possibly through reduction in arrhythmia threshold in atrial and ventricular tissues. Mechanistically, defective calcium handling and prolongation in action potential duration (APD) were previously suggested as potential mechanisms regarding TNF- alpha mediated arrhythmogenesis in myocardial tissue (6).
Therefore; based on current literature (2-6), it is of possibility that TNF-antagonism during early AMI (when the inflammatory response is the highest) may be considered as a promising approach for the prevention of a variety of supraventricular and ventricular arrhythmias in the hospital setting , and hence might potentially improve in- hospital prognosis and reduce the need for anti-arrhythmics and/or implantable cardioverter defibrillator (ICD) therapy, etc. in AMI patients. Within this context, even though the study by Padfield GJ et al (1) was not spesifically designed for the investigation of clinical end -points, we wonder whether etanercept use might have an influence on arrhythmic end-points in AMI patients. The authors may want to make clear whether there were any significant differences in terms of arrhythmic events and arrhythmic mortality between etanercept and placebo groups in an effort to uncover any potential anti-arrhythmic benefit of TNF-antagonism, and to suggest a potential therapeutic implication of etanercept, if any, with regards to arrhythmia prevention in AMI patients in the hospital setting. However, future studies are still warranted to further investigate the potential role of anti- inflammatory agents in the management of arrhythmias in the setting of ACSs.
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