| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 92 === The epidemic of enterovirus 71 infection causes the death of many children in Taiwan in 1998. The patients have three major complications including rhombencephalitis （brain-stem encephalitis）, pulmonary edema and heart failure. Because most of the patients has a normal heart size in chest radiogram and the heart specimen does not show the finding of myocarditis, most clinicians do not recognize the hear failure. Previous studies reported that the cause of death was pulmonary edema, which was neurogenic. Nevertheless, they did not clarify the role of heart. According to our meticulous observations of the patients, hypersympathetic activities including tachycardia, hypertension, and excessive release of the catecholamines precede the heart failure. We hypothesize that the pathogenesis of enterovirus 71 is as below: Enterovirus 71 infection causes rhombencephalitis, which activates the sympathetic nervous system. The overwhelming release of catecholamines results in the heart failure, causing shock and death. We conduct 5 experiments to prove this hypothesis, including 2 clinical studies, 1 animal model experiment, and 2 in-vitro cell experiments. The results showed that the pulmonary edema of enterovirus 71 rhombencephalitis is associated with heart failure. The heart failure is the critical cause of death and is complicated in 19% patients with enterovirus 71 rhombencephalitis. The mortality rate is 77%. Hypersympathetic activity including tachycardia, hypertension, and excessive release of catecholamines precedes the heart failure. Pathological examination does not show the findings of myocarditis, but reveals coagulative myocytolysis, myofibrillar degeneration and apoptosis of cardiomyocytes, which are the characteristics of catecholamine cardiotoxicity. Animal model of cats with norepinephrine cardiotoxicity shows the similar echocardiographic and pathological findings to those of patients with enterovirus 71 rhombencephalitis. In-vitro cell experiments show that norepinephrine is able to induce apoptosis in neonatal rat cardiomyocytes and endothelial cells through a β-adrenergic receptor-reactive oxygen species-tumor necrosis factor-caspase signaling pathway. The above findings prove that the heart failure in patients with enterovirus 71 rhombencephalitis is not caused by myocarditis but caused by catecholamines, which are released due to infection of vasomotor center. Early recognition and management of the heart failure are crucial to save patients’ lives. β-blockers, anti-oxidants, antibodies of tumor necrosis factor, and caspase inhibitors may be able to prevent the heart failure in patients with enterovirus rhombencephalitis.
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