Pathogenic role of cardiac mast cell activation/degranulation, TNF-α, and cell death in acute drug-related fatalities

Abstract

Nasrin Perskvist1, Carl Söderberg1, Marianne van Hage2, Erik Edston11National Board of Forensic Medicine, Department of Forensic Medicine, Linköping, Sweden; 2Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institute Stockholm, SwedenBackground: Intravenous injection of narcotic stimulants affects many cellular functions relevant for the pathophysiological mechanisms of heart failure. There is considerable evidence that mast cells (MCs), TNF-α, and cell death play crucial roles in the pathogenesis and progression of cardiac arrest. In this study, we examined and compared the participation of MCs, TNF-α, apoptosis and necrosis in the heart of drug-related fatalities and the victims of sudden death due to the cardiac failure or aortic dissection.Methods and results: Serum level of postmortem tryptase was determined in all study subjects that consisted of 50 autopsy cases: 30 drug overdose fatalities which were further divided into two groups with high and low level of tryptase, and 20 cases of sudden natural death (SND). The distribution profile of cardiac infiltrated-MCs and production patterns of TNF and C9 (necrotic marker) were investigated immunohistochemically. In situ-detection of apoptosis with TUNEL was applied to the heart sections. The level of tryptase was elevated (>45 μg/L) in the drug fatalities but remained below the cut-off value in SND. In the myocardium of overdose victims, MC-infiltration and degranulation were significantly increased as well as production of myocytic TNF-α compared with the SND cases. The expressions profile of myocytic TNF varied between the groups. Apoptotic myocytes were seen more frequently in the SND group while necrosis was more evident in the heart of drug-related fatalities.Conclusion: Mast cells are recruited and activated in the heart of drug-associated deaths and the myocytes are the main source of TNF-α with the ability of different production patterns. The high degree of MC degranulation and the elevated levels of tryptase together with the pathological changes in heart of drug-related victims resemble that of the anaphylactic deaths as demonstrated in our previous study.Keywords: mast cells, TNF-α, apoptosis, sudden death, narcotic stimulant