The preventive effects of angiotensin II receptor blocker on lethal ventricular arrhythmias, a leading cause of sudden cardiac death, in experimental failing animal hearts

几项大型前瞻性随机研究表明，血管紧张素转换酶抑制剂（ACE-I）治疗可改善慢性心力衰竭（CHF）患者的预后。虽然ACE-I发挥许多病理生理作用，但通常认为抑制血管紧张素-II（Ang-II）的形成可以解释其有益作用。然而，血管紧张素Ⅱ受体阻滞剂（ARB）对CHF患者的疗效是否与ACE-Ⅰ相似或上级ACE-Ⅰ仍有待确定。本文应用放射性核素显像和电泳方法，比较ACE-Ⅰ和ARB对实验性衰竭心脏的作用，特别是对致死性室性心律失常的预防作用。我们建立了一种在表现出充血性心力衰竭的大鼠中制造心肌梗死的方法。我们的第一个目标是评估心肌脂肪酸代谢（BMIPP）以及交感神经活动（MIBG）在心力衰竭的不同阶段的变化，并阐明这些代谢和自主神经改变与心肌发生之间的关系。然后，我们将研究ACE-I和ARB如何影响这些病理生理过程。本实验采用BMIPP观察心肌梗塞大鼠的缺血性记忆，并探讨其机制。此外，“缺血性记忆”与致死性室性心律失常的发生之间存在有趣的关系。虽然我们的项目仍在进行中，但这些初步结果促使我们进一步阐明CHF患者猝死的机制。从理论观点来看，对Ang-II 1型受体（AT 1-R）具有高选择性的ARB可能比ACE-I更有效。我们希望继续进行研究，以获得明确的答案。

Several large prospeptive randomized studies demonstrated that treatment with angiotensin converting enzyme inhibitors (ACE-I) improved the prognosis of patients suffering from chronic heart failure (CHF). Although ACE-I exerts many pathophysiological actions, it is generally thought that inhibition of angiotensin-II (Ang-II) formation could account for the beneficial effects. However, it is still to be determined whether Ang-II receptor blocker (ARB) has the similar or superior effects on CHF patients compared to those of ACE-I. By using radionucleotide imaging and electrophyiological methods, we tried to compare the effects of ACE-I and ARB on experimental failing animal hearts, especially preventive effects on lethal ventricular arrhythmias, a leading cause of sudden cardiac death. We established a method of making myocardial infarction in rats that manifest congestive heart failure. Our first goal was to evaluate the changes in myocardial fatty acid metabolism (by BMIPP) as well as sympathetic nerve activity (by MIBG) at the different stages of heart failure, and to clarify the relation between these metabolic and autonomic alterations and arrhythmogenesis. Then, we will examine how ACE-I and ARB affect these pathophysiological processes. With the use of BMIPP, we observed, so called, "ischemic memory" in rats with myocardial infarction and investigated its mechanisms. In addition, there was an interesting relationship between "ischemic memory" and genesis of lethal ventricular arrhythmias. Although our project is still under way, these preliminary results have prompted us to further clarify the mechanisms of sudden death in patients with CHF. In the theoretical viewpoints, it is likely that ARB with high selectivity to Ang-II type 1-receptor (AT1-R) is more effective than ACE-I. We would like to continue our study in order to obtain the definitive answers.