Professor Kerry Anne Rye 澳大利亚悉尼大学教授，悉尼心脏研究所副主任、脂质研究组主任，学术重点是高密度脂蛋白的结构和功能，对动脉粥样硬化、糖尿病和炎症反应的影响
International Circulation: As chair of the organizing committee for ISA2012， what are the aims of and what were some of the highlights of the meeting?
《国际循环》：您是ISA2012大会组织委员会主席，请问本次大会的主要目标是什么？有哪些亮点？
Prof Rye: It was really a very successful meeting and I think everyone really enjoyed it. In terms of highlights， the talks that attracted the most attention were probably the plenary lectures and particularly one talk which is a little bit out of the field for some of those who work in the atherosclerosis field， given by an immunologist， Eicke Latz， who has two labs (one in the US and another at the University of Bonn in Germany). He was talking about inflammasomes. What happens when people develop atherosclerosis is that they get cholesterol crystals deposited in their arteries in the lesions. Everyone knows that this is occurring but no one has taken any notice of it. Eicke has actually identified that these crystals form complexes with other molecules called inflammasomes and these drive inflammatory responses. So you get inflammation in the artery which worsens the situation because atherosclerosis is basically initiated as an inflammatory response. I assumed people would know about this but it attracted a lot of attention. It is applicable to other diseases also such as people who develop mesothelioma from exposure to asbestos. These people have crystalline structures deposited in their lungs and that sets up an inflammatory response. People with gout have uric acid crystals deposited in their joints setting up an inflammatory response. As it turns out， there are a lot of people in the atherosclerosis arena who are not aware of this phenomenon so it was really interesting for many of them and maybe more so than many other topics. There were other talks that were equally good and equally enlightening. There was a simpler presentation but no less interesting talk on biomarkers for determining cardiovascular disease， identifying what biomarkers are and whether they are related to the disease or just a marker of disease (i.e. there is no mechanistic relationship between the two). John Kastelein， from the Amsterdam Medical Center， spoke about agents that increased HDL levels and a great overview of the current understanding of that. It is an exciting time in that respect because these agents are in large scale clinical outcome trials. It will be a few years before we see some results. We do know that they do what they need to do， but we don’t know if they are going to reduce the number of cardiovascular deaths or not. There are some smaller trials ongoing and some have already reported and some will be reporting very soon. It is not a hard endpoint they are looking at as they are looking at the thickness of carotid artery walls and so on. So we won’t have any hard answers until the first of these large outcomes trials reports. There are two ongoing and a third due to begin during the meeting. The other topic which has underlying interest and people are just starting to talk about ， is whether there is any benefit in raising HDL for diseases other than cardiovascular disease such as diabetes. We have some evidence in vitro and in vivo that HDL actually improves beta-cell function and insulin secretion. There was a trial back in 2006 using the CETP inhibitor， torcetrapib， which did not work， but we did an analysis of a subgroup from that trial. These were people who had type 2 diabetes and what we found was that treating them with the CETP inhibitor which raises HDL levels， showed very important improvements in their glycemic control. This is really nice because there is a lot of chatter around at the moment with statins， which are the major lipid-lowering drugs used world-wide， actually causing diabetes. There is no direct evidence at present but there is still a lot of talk. There is another type of drug which raises HDL levels called niacin which is in use and looks very interesting but it too has a question mark over it. What happens in that case is that people tend to get a worsening of their diabetes when initially started on the drug but they do bounce back. So there are issues with niacin; it also has some nasty side effects which make it unpopular. There is also a very large outcomes trial discussed at the meeting using niacin called HPS2-THRIVE which will probably be the crunch-point for niacin. Niacin has been around for thirty years or so and small trials have indicated that it is effective at reducing cardiovascular deaths and disease but the size of these trials has put doubt on whether niacin should continue to be used. So if this large trial proves positive， I think niacin will have its place; but if it’s negative， I doubt niacin will survive especially if the CETP inhibitors are found to be efficacious. That will be the way that everyone will go. In the meantime we have to wait until those results are available.
Prof Rye: 这是一次非常成功的大会，我想每位参会者都获益匪浅。至于亮点，最引人注目的讲座可能是全体大会，其中特别要提到的是由Eicke Latz教授所作的演讲，他是一位免疫学专家，领导着2个实验室（一个在美国，另一个在德国波恩大学）。他演讲的内容对于动脉粥样硬化领域的医务工作者而言，与工作实践多少有些距离。他谈到了炎症组学。人类动脉粥样硬化的发生是由于胆固醇结晶沉积于病变处的动脉壁，每个人都知道这一点，但无人予以重视。Eicke阐明了这些结晶与其他分子即所谓的炎症组构成了复合物，并启动了炎症反应，在人体动脉内发生炎症，使病情进一步恶化，所以说炎症反应是动脉粥样硬化病理过程始动的基础。我想人们已经了解这一点，但这个讲座吸引了极大的关注。这一理论同样适用于其他疾病，如由于石棉暴露而导致的间皮瘤。这些患者的肺部沉积了大量结晶样结构，从而触发炎症反应。痛风患者由于尿酸结晶沉积于关节部位而引起炎症反应。正如我们看到的，许多动脉粥样硬化领域的临床医生不了解这些现象，因此这一讲座比其他主题吸引了更多的听众。还有许多其他讲座同样精彩。有一个讲座虽然相对简单，但对听众的吸引力却毫不逊色，其主题是心血管疾病的生物标志物，阐述了什么是生物标志物、以及他们与疾病有关还是仅仅只是疾病的一个标志物（即两者之间不存在机制性的关联）。来自阿姆斯特丹医学中心的John Kastelein介绍了升高HDL水平的药物以及当前人类对该领域理解的概况。这是一个令人兴奋的领域，这些药物正在接受大型临床终点试验的评估，还要等待数年我们才能看到结果；我们知道这些药物能够升高HDL水平，但我们不清楚的是他们能否减少心血管死亡。有一些较小规模的试验正在进行中，一些已经报告了结果，一些将在近期公布结果，但这些试验都不是硬终点研究，他们观察的都是颈动脉壁厚度等一些替代终点。因此，在这些大型试验公布结果之前我们还没有任何“硬”答案。会议期间有2项正在进行中和1项即将开始的试验举行报告。另一个人们刚刚开始谈论的有趣话题是，升高HDL对心血管疾病以外的疾病如糖尿病是否有益。有一些体内和体外实验证据表明，升高HDL的确可改善β细胞功能和胰岛素分泌。2006年一项试验使用了CETP抑制剂torcetrapib，结果未能奏效，但我们进行了一项2型糖尿病患者的亚组分析，发现使用能够升高HDL水平的CETP抑制剂治疗这部分患者，显著改善了其血糖控制。这是非常有利的发现，因为当前对他汀的使用存在很多的议论，他汀是全球范围内广泛使用的降脂药物，但他汀可导致糖尿病。尽管目前并无直接证据，但人们对此议论纷纷。升高HDL水平的另一种药物是烟酸，但也存在相关的问题，当开始使用烟酸时，患者存在糖尿病恶化的趋势，但随后病情又有所恢复。因此使用烟酸亦存在问题，一些不良反应限制了其广泛应用。本次大会期间还将对一项规模非常大的烟酸终点试验进行讨论，即HPS2-THRIVE，这项试验可能成为决定烟酸命运的分界点。烟酸已问世30余年，一些小型试验提示其能够有效降低心血管死亡和疾病，但试验规模过小使其是否应该继续使用受到质疑。因此，如果这项大型试验得出阳性结果，我想烟酸将仍然发挥作用；但如果为阴性结果，尤其是CETP抑制剂若被证实有效，那么我怀疑烟酸还能否继续生存下去。就目前而言，我们还必须等待这项结果的公布。
International Circulation: There are a number of mechanisms by which HDL may influence type 2 diabetes. Could you outline those?
《国际循环》：HDL影响2型糖尿病的可能机制有很多，您能否简单列举一下？
Prof Rye: There are two points to consider. Firstly， you are likely to improve beta-cell function so that there is more insulin secreted. We know this happens in cultured cells but the question is whether it happens in people whose HDL levels are raised. The other point is that in people with diabetes， their insulin doesn’t work very well so they end up with insulin resistance. What should happen is that a lot of the glucose in circulation should be taken up by skeletal muscle cells， by the liver， by adipose tissue， and that is not happening. The beta-cells keep pumping out more and more insulin until they are exhausted and disappear. That is the point where someone goes from being insulin resistant to having diabetes. This is still a new area of study and we don’t know too much about it yet. One point of action of HDL is at the level of the pancreas and insulin secretion; and the other is uptake of glucose into skeletal muscle. There was a study that was done probably four years ago by an Australian group where they infused reconstituted HDL into diabetes sufferers and they saw increased insulin levels and also improvement in insulin resistance. The numbers again were small but it looked promising.
Prof Rye: 应考虑2点。首先，我们希望改善β细胞功能以分泌更多的胰岛素。在培养细胞中我们证实这是可行的，但问题是在HDL水平升高的人体内是否如此。另一点是，在糖尿病患者中胰岛素作用减弱，存在胰岛素抵抗。正常情况下循环中大量的葡萄糖应被骨骼肌细胞、肝脏和脂肪组织所摄取，但在胰岛素抵抗情况下这一切没有发生。β细胞持续泵出更多的胰岛素，直至其功能衰竭和消失。这就是一些患者从胰岛素抵抗进展为糖尿病的关键点。这仍是一个有待研究的崭新领域，我们还有许多未解之谜。总之，HDL一方面在胰腺和胰岛素分泌的水平发挥作用；另一方面在骨骼肌对葡萄糖的摄取水平发挥作用。大概4年前一个澳大利亚研究组进行了一项试验，他们对糖尿病患者注入重组HDL，观察到胰岛素水平上升以及胰岛素抵抗的改善。然而这项研究规模仍然很小，但似乎显示了光明的前景。
International Circulation: Exactly how does HDL help the beta-cells?
《国际循环》：那么HDL到底是如何对β细胞产生有利影响的？
Prof Rye: This is what we are looking at at the moment. We haven’t got a clear answer yet and we are conducting a range of studies. One of my colleague’s interests is intracellular signaling and we are trying to figure out the pathways by which you get increased insulin secretion from beta-cells by HDL but we have not got there yet. The mechanism， at present， is not known. There is one study showing that beta-cell apoptosis is reduced by HDL. HDL has profound anti-inflammatory effects. Whether that is a mechanism by which they improve beta-cell function， we don’t know as no one has looked directly at that. From an in vitro study from a few years back， we have seen that if you remove cholesterol from beta-cells using HDL， you increase insulin secretion. So there are lots of small bits and pieces but no big picture yet. There is a classical inflammatory pathway in cells and we know that HDL inhibits that pathway. We also know there are many other pathways， equally important but quite different， which are inhibited by HDL in a range of cells like endothelial cells and macrophages. I believe there are multiple mechanisms by which HDL inhibits inflammation. Coming back to inflammasomes; no one has actually done too much in terms of looking at inflammasomes and HDL. It is something I would really like to do and I have talked with Eicke Latz about this. One of the issues is that when doing animal studies， when you look at inflammasomes， any samples you collect by any current techniques such as microscopy or sectioning， melts the cholesterol crystals， which creates somewhat of a problem. We haven’t found a way around this yet.
Prof Rye: 这正是我们当前正在研究的。目前还不能明确回答，我们正在实施多项研究。我们的同仁感兴趣的一点是细胞内信号传导，我们正在努力阐明HDL使β细胞分泌胰岛素增加的旁路机制，但尚未达到目标。目前尚不清楚其作用机制。有一项研究显示HDL使β细胞凋亡减少。HDL有很强的抗炎作用。我们还不清楚这是否HDL改善β细胞功能的机制，因为还没有人直接观察这一点。多年前一项体外研究显示，使用HDL移除β细胞内的胆固醇，可增加胰岛素分泌。因此，可以说，我们得到了大量的片段，但尚未构成完整的拼图。我们知道HDL可抑制细胞内的经典炎症旁路；我们还知道存在许多其他同样重要但完全不同的旁路，HDL同样可抑制内皮细胞和单核细胞等多种细胞内的这些旁路。我相信HDL通过多重机制抑制炎症反应。回到炎症组学，还没有人对炎症组和HDL进行充分的研究，我非常希望进行这方面的研究，并同Eicke Latz进行了交谈。这当中存在的一个问题是，实施动物实验观察炎症组，在利用当前任何技术如显微镜或切片收集样本时，会导致胆固醇结晶的溶解。我们还没有找到解决这一问题的理想方法。
International Circulation: Do you think the HDL-raising drugs such as CETP inhibitors are going to be used in the future for the prevention or treatment of type 2 diabetes?
《国际循环》：您认为升HDL药物如CETP抑制剂未来会用于2型糖尿病的预防或治疗吗？
Prof Rye: That’s a crystal ball gazing question. First of all， CETP inhibitors have to be shown to improve hard endpoints. Without that they are going to fall by the wayside. Everything is pointing to that happening. If and when that happens that we have large scale outcomes trials where there is a reduction in deaths and cardiovascular disease， people are then going to start scrambling to look at the subgroups in these cohorts –those with inflammatory disorders， those with diabetes and so on – and there will be absolute goldmines of information come out of such studies. At the moment， we have a little bit of evidence that is really tantalizing and it looks really good but I think we have to wait and see.
Prof Rye: 这是一个如水晶球预测未来的问题。首先，必须有证据证实CETP抑制剂能够改善硬终点，否则他们只能走向终结。任何事物均是如此。一旦我们从大型终点试验中得出死亡和心血管疾病发生率降低的证据，我们就可以观察其研究队列中的亚组——炎症紊乱的患者、糖尿病患者，等等——由此可从这些研究中得到如金矿般的宝贵信息。就目前而言，我们只有很少的证据，这是一些看起来非常好、非常诱人的数据，但我们还必须等待，继续观察。
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