International Circulation: Could you please discuss some of the new myocardial protection therapies for treatment of acute myocardial infarction.
《国际循环》：能否介绍下急性心梗的新型心肌保护治疗手段？
Heusch: From the experimental side， we have learned over the last 25 years that there are a number of mechanical interventions that can actually protect the myocardium， which are pre-， post-， and remote conditioning. All contain a brief period of ischemia and reperfusion in conjunction with the culprit infarction. Pre-conditioning is a protocol of brief cycles of myocardial ischemia/reperfusion to precede the culprit infarction， post-conditioning is a similar protocol immediately at reperfusion following the culprit infarction， and remote is a protocol of ischemia/reperfusion cycles in a distant organ away from the heart itself. It can be the arm， the liver， the kidney， etc. All of these interventions actually protect the myocardium in the sense that， eventually， the resulting infarction is reduced. Now what can we use for the patient? The problem with pre-conditioning is that you cannot know when a patient undergoes an infarction， so it can only be utilized in elective interventions. For instance， if you plan an intervention such as cardiac surgery， you can utilize pre-conditioning to attenuate the eventual damage.
Heusch教授：在过去的20年中，通过基础研究我们了解到有一些机械干预手段实际上能够保护心肌，即缺血预适应、缺血后处理和远隔预适应，三者都包括罪犯血管短暂的缺血和再灌注。因此预适应是在罪犯血管闭塞之前短暂的心肌缺血再灌注的循环，而缺血后处理则是在罪犯血管闭塞之后，远隔预适应则是在心脏以外远隔器官的缺血再灌注循环。可以是双臂、肝脏和肾脏等。这些干预手段实际上能够保护心肌，最终缩小梗死体积。哪些可以用在患者身上呢？缺血预适应有一个问题，就是你不知道患者何时会发生心梗，因此只能用在择期PCI的情况下。例如计划心脏外科手术等干预时可以利用缺血预适应来减少最终的损害。
International Circulation: How far in advance would the pre-conditioning need to be?
《国际循环》：预适应的时机是什么？
Heusch: There are two time windows. One is one or two hours before the culprit infarction， which is acute pre-conditioning， and the other is later， weaker， but more sustained pre-conditioning， at 24 hours before the culprit infarction. I think， of more practical relevance is post-conditioning， considering you do not know when you will undergo an infarction. The patient who comes in with an infarction can still undergo post-conditioning. Once the artery has been opened， you can use a few cycles of ischemia and reperfusion， called a “stuttering reperfusion.” This will attenuate the resulting infarct which is quite useful. Most proof of concept studies have shown that this is effective. Also， remote conditioning， which is done by inflating a blood pressure cuff around the arms several cycles， will eventually protect the myocardium and reduce infarction.
Heusch教授：有两个时间窗。一个是在干预之前1~2小时，即急性预适应。另一个是在干预之前24小时，虽然作用弱一些，但是作用更为持久。我想更为实用的是缺血后处理，因为我们不知道患者何时会发生心梗。已经发生心梗的患者还可以接受缺血后处理。至少在动脉一旦开通时，可以进行几个缺血再灌注循环，也就是所谓的“stuttering reperfusion”。这有助于缩小梗死体积，很有帮助，众多研究证实了它的有效性。远隔预适应即在手臂用袖带进行充气放气几个循环，最终有助于保护心肌和缩小梗死体积。
International Circulation: Do we know of any other mechanisms?
《国际循环》：还有其他机制吗？
Heusch: That is the major problem. We know hundreds of mechanisms from thousands of studies， literally. But they are all in isolated cells， isolated sub-cellular systems， they are in experimental animals ranging from far away zebra fish to monkeys or pigs or dogs. However， there is very little transfer in all these single signal transduction mechanisms that we have pinpointed in animals in various preparations to human hearts. Very little is actually known for the human heart and this is， in my view， the explanation why mechanical interventions work but the translation into drugs and into chemicals has been largely failing. People have focused on individual signaling molecules that have a certain importance in the reductionist model， but they are not explaining the full picture of the entire complex of the signal transduction cascade. Therefore， when we are translating it to the human being， it fails.
Heusch教授：这是主要的问题。实际上通过大量的研究，我们了解到了成千上万个机制。但是，这些机制来自于单个细胞、分离的亚细胞器，来自于形形色色的试验动物，从斑马鱼到猴子、猪和狗。但是，来自动物制备物的单一信号转导机制转化到人体心脏的还非常少。对于人体心脏，我们的了解还非常有限，我认为这就是缺血预适应、缺血后处理和远隔适应虽然有效，但是转化为药物的努力大部分失败的原因所在。可能是由于人们关注了动物模型中有一定重要性的单个信号分子但是没有解释清楚整个复杂的信号转导级联反应的整体图像，因此当应用于人体时，就会失败。
International Circulation: I have a question about why there are so few drugs out there. Is it because the human model is vastly more complicated?
《国际循环》：现在新药很少，这是因为人体模型过于复杂吗？
Heusch: First of all， translating across species is a big problem. That is one issue. The second issue is that the signal transduction， as far as we can schematize， is very complex. The expectation to just hit a single signaling button and assume that this will work was na?ve to begin with. That is why the mechanical intervention that recruits the entire signaling scheme works in humans， but just taking and picking out one single signal and adding that as an exogenous drug has not worked so far. The only drug trial that has worked is the one using cyclosporin A. There is an explanation for its effectiveness， because cyclosporin A hits a target very far downstream， where all the signals converge on the mitochondria. That is also the only signal that is working in humans. It is both the complexity of the signal transduction scheme and the translations from animal preparations to the humans that present difficult complications..
Heusch教授 ：首先，显然药物由一个种属应用到另一个种属是个大问题。其次，我们目前所了解到的信号转导通路非常复杂，因此只针对单一信号分子并认为这样会有效是个天真的想法。因此，机械上干预整个信号通路对人体有作用，但是只针对一个信号分子的药物是无效的，到目前来讲还是如此。目前唯一一个被临床试验证实有效的此类药物是环孢素A。同样地，考虑到信号通路的复杂性，对此也有解释，因为在该信号通路中，环孢素A针对的是一个非常下游的靶点，该靶点是所有信号交汇之处，该靶点位于线粒体上，该信号是唯一一个在人体和动物都发挥作用的信号。因此，是信号转导通路的复杂性以及将动物研究的结果推及到人体这两方面使得新药的研发变得复杂化。
International Circulation: So what is it about the animal models， does it have the same complexity?
《国际循环》：动物模型是否跟人体模型同样复杂？
Heusch: Well first of all， it is just a different species. In the evolutionary process， some proteins are very conserved in their function and structure， and others are not. Sometimes， a different isoform of a protein or a different molecule altogether is performing the same function in different species. The assumption of a straightforward transfer is probably even na?ve to begin with. Then again， most animals are being studied while they are young and healthy whereas human patients are old， sick， have had a multitude of diseases – hypertension， diabetes， hyperlipidemia， hypertriglyceridemia， hypercholestermia. This patient has these diseases over decades before eventually suffering a myocardial infarction. He has also received multiple treatments for all of these diseases， so you are dealing with an aged organism of a different species with comorbidities and co-medications. In retrospect， it was probably quite na?ve to assume to just take a molecule from an animal model and have it work in humans..
Heusch教授：首先，只是种属之间的区别。我的意思是存在进化过程。某些蛋白的功能和结构非常保守，其他蛋白则不是如此，有时候不同亚型的蛋白或化学、构成或结构不同的蛋白发挥同样的作用，在其他动物则由另一种蛋白发挥该作用。因此，假定可以把动物实验的结果直接推及到人体是天真的想法。另外，大多数实验动物是年轻且健康的，而患者年龄大且有疾病，通常有多种疾病，例如高血压、糖尿病、高脂血症、高甘油三酯血症、高胆固醇血症。在发生心梗之前，已经有上述病史几十年，也接受了多种药物治疗，因此我们面对的是老化的器官，有并存疾病，同时因为多种疾病接受了治疗。因此，我还想说的是，认为只是来自动物身上的一个分子会在人体发挥作用是一个天真的想法。
International Circulation: What are some of the predictive values for prognosis using MRI， SPECT and other techniques to evaluate myocardial ischemia and reperfusion?
《国际循环》：MRI、SPECT和其他技术评价心肌缺血和再灌注的预后的预测价值如何？
Heusch：That is a slightly different question. Once a patient comes in with the onset of an acute myocardial infarction， the biggest predictor of further prognosis is simply the size of the territory affected by it. The second most important factor， which is closely related to the first one， is the left ventricular function that results from the infarction. Those two parameters， infarct size and left ventricular dysfunction， largely determine the further fate of the patient and therefore it is good to reduce infarct size and to improve function quickly because that will have a prognostic impact.
Heusch教授：这是另外一个问题。我认为，一旦患者因急性心梗入院，我认为最佳的预后预测指标实际上是梗死区域的大小。第二个重要的预后指标与第一个指标紧密相关，即左室功能或相反的指标——心梗所导致的左室功能下降。梗死灶大小和左室功能障碍这两个指标在很大程度上决定了患者未来的命运，因此尽快缩小梗死体积和改善心室功能是正确的做法，因为这会对预后有影响。
International Circulation: So what is the relationship between ischemia reperfusion injury and the time interval between the infarct and the interventions?
《国际循环》：缺血再灌注损伤和梗死发病和干预时间间隔之间的关系是什么？
Heusch: Textbooks will explain that once a coronary artery is occluded， necrosis will start within twenty to forty minutes. We have now learned that this is not necessarily true. It can be true， but in some instances viable myocardium， even with a coronary artery occlusion， can be maintained for hours， up to twelve， or even longer， if there is a slight amount of residual blood flow. As such， a slight amount of residual blood flow in a patient is often present， because a patient who develops coronary artery diseases over a prolonged period of time develops a collateral blood flow， by-passing the actual site of the lesion， such that a little blood flow is maintained distal to the occlusion. That small amount of blood flow can go a long way to sustain residual viability in the myocardium. It is therefore that， even after ten hours or more ， it maybe worth it to reopen the artery to rescue some of the myocardium， maybe not all of it， but at least a significant portion of it.
Heusch教授：通常来讲，即使是一些经典的教科书也指出，冠脉闭塞后20~40分钟心肌开始发生坏死。但是现在我们知道这不一定是正确的。可能是正确的。但是在某些情况下，即使冠脉闭塞了，如果有少量残存血流的话，心肌在几个小时内仍然是存活的，最长可达12小时。实际上，患者通常是有少量残存心肌，因为经过很长时间发生冠心病的患者有侧枝血流供应梗死灶的实际部位，使得闭塞部位远端有少量血流供应，这些血流可以维持残留心肌存活。因此，即使是梗死后10个小时，也值得再通动脉以挽救心肌，也许不会全部挽救，但是至少是一大部分心肌。
International Circulation: Is this happening through angiogenesis?
《国际循环》：侧枝是通过血管生成产生的吗？
Heusch: Yes. Basically collateral growth around a stenotic lesion is a process of angiogenesis. Some people are more specific about it， they call it arteriogenesis because it not capillary growth but it is arterial vessel growth.
Heusch教授：是的，侧枝的生长就像狭窄的病灶一样是血管生成的过程。某些学者对此有特定的叫法，称之为动脉生成，因为并不是毛细血管生长而是血管生长。
International Circulation: Are people targeting this and are there ways to stimulate this arterial genesis?
《国际循环》：人们是否针对血管生长进行治疗？有什么方法能够促进血管增长？
Heusch: Yes. VEGF has been used. Actually there have been clinical trials， unfortunately they failed and for two reasons. One is that VEGF is mostly promoting capillaries and they are of no use.
Heusch教授：是的。人们应用了血管内皮生长因子（VEGF）。实际上有相关临床试验，不幸的是临床试验失败了，原因有两个。一个原因是VEGF主要是促进毛细血管生长，对患者没有用处。
International Circulation: So it is a totally different kinds of muscle tissue?
《国际循环》：因此是完全不同的肌肉组织？
Heusch: Exactly， and this is why the terminology has something to do with it， as we need arteriogenesis. We want the growth of larger conduit vessels， rather than small microvessels. That was one failure， and the other thing of serious concern is that VEGF will not only have vascular growth in that myocardium but， if there is a spill over， also may cause vascular growth in cancers. Attenuating vascular growth is the main treatment target for all anticancer therapies， so you are just in a yin and yang situation here. Therefore angiogenesis， is a very dangerous target: potentially very effective but also very dangerous.
Heusch教授：没错，这就是需要术语的原因，我们需要的是动脉生成。我们需要大血管的生长而不是微血管生长。这是VEGF的问题之一。另一个问题同样是个严重的问题，就是应用VEGF时不仅心肌的血管会生长，同时如果有前列腺癌的话对其也有影响，你可能不希望前列腺癌发生血运重建，因此血管生长的不良反应是区别很大的。基本上来讲，抑制血管生长是所有抗肿瘤治疗的主要治疗目标，因此你现在面临的问题就像硬币的两面。因此，血管生成是一个非常危险的靶点，可能非常有效但是同样非常危险。
International Circulation: Do a lot of your patients with cardiovascular problems also have cancer?
《国际循环》：很多心血管疾病患者有癌症的问题吗？
Heusch: It is the population， it is just because they are old and the longer they survive the treatments for cardiovascular disease the more they develop cancer. They all eventually die， you have to die from something.
Heusch教授：是人群的问题，只是因为该人群年龄更大，他们接受心血管疾病治疗后存活的时间越长，他们发生癌症的风险越大。最后患者都面临死亡，会有一定的死因。
[下一页] [1] [2] [3] [4]