Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF
Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF
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DOI：
10.1152/ajpheart.00404.2015
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发表时间：
2015-11-01
影响因子：
4.8
通讯作者：
Nanthakumar, Kumaraswamy
中科院分区：
文献类型：
--
作者：
Azam, Mohammed Ali;Wagg, Cory S.;Nanthakumar, Kumaraswamy
心室颤动（VF）是心肌梗死后心脏骤停的重要原因。室颤复苏后，心脏收缩功能下降是一个常见问题。在心肌缺血期间和之后，葡萄糖氧化减少、心脏能量产生的无氧糖酵解增加是有害的并且能量昂贵。本研究的目的是确定二氯乙酸（DCA）（一种葡萄糖氧化刺激剂）对缺血引起的心室颤动后心脏收缩功能障碍的影响。将雄性 Sprague-Dawley 大鼠心脏在 Tyrode 缓冲液中进行 Langendorff 灌注。一旦稳定，在存在或不存在 DCA 的情况下，使心脏经历 15 分钟的整体缺血和 5 分钟的有氧再灌注。再灌注第 6 分钟，电诱导 VF，并终止。使用气球测量左心室（LV）压力。 DCA 预处理显着改善 VF 后左心室发展压 (LVDP) 和 dp/dtmax。在 DCA 预处理的心脏中，VF 后乳酸产生和丙酮酸脱氢酶 (PDH) 磷酸化显着减少，表明刺激了葡萄糖氧化，并通过激活 PDH 抑制无氧糖酵解。心外膜 NADH 荧光在整体缺血期间增加至缺血前水平以上，但在 VF 后降低至缺血前水平以下，未治疗对照和 DCA 预处理心脏之间没有差异，而 DCA 预处理增加非缺血心脏中 NADH 的产生。在灌注溶液中添加外源性脂肪酸 (FA) 后，DCA 预处理还导致 VF 后 LVDP 和 dp/dtmax 的改善，表明外源性 FA 的存在不会影响 DCA 的有益作用。总之，DCA 增强 PDH 激活可减轻缺血引起的 VF 后的心脏收缩功能障碍。
Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemiainduced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrode's buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.