#229 ‒ 了解心血管疾病风险、胆固醇与载脂蛋白B

现在转到LDL APOB这边，最丰富的APOB100（简称APOB）脂蛋白就是低密度脂蛋白。

Okay, so over on the LDL APO B side, the most abundant APO B100 or APO B for short lipoprotein is the low density lipoprotein.

这就是被称为‘坏胆固醇’的那种。

That's the one that gets called bad cholesterol.

而APOA这边对应的HDL，则被称为‘好胆固醇’。

And again, on the APO A side, have HDL, which gets called good cholesterol.

关于这点我有几个观点要说明。

So a couple of things I want to say on this.

其一，当你说LDL时，指的是低密度脂蛋白。

One, if you're talking LDL, you are referring to the low density lipoprotein.

若提及HDL，则是指高密度脂蛋白。

If you say HDL, you are referring to the high density lipoprotein.

但如果有人问'你的HDL是多少'

But if someone says, what is your HDL?

或'你的LDL是多少'

What is your LDL?

他们实际是在询问实验室指标。

They're asking for a laboratory metric.

这种问法本身是错误的。

They are asking incorrectly.

实验室指标中并不存在名为LDL或HDL的检测项目。

There is no laboratory metric called LDL or HDL.

正确的指标是HDL胆固醇和LDL胆固醇，缩写为LDL-C和HDL-C。

There is HDL cholesterol, LDL cholesterol, abbreviated LDL C and HDLC.

还有LDL-P和HDL-P，即通过电泳或核磁共振测定的LDL颗粒数量。

There's LDL P and HDLP, which is the particle number of LDL, which can be counted via electrophoresis or NMR.

当然，我个人更倾向于通过载脂蛋白B（ApoB）来计量这些颗粒数量。

Of course, my preferred way to count the number of these particles is to look at ApoB.

在我看来，ApoB浓度是最关键的数值——从生物标志物角度评估心脏代谢风险和动脉粥样硬化性心血管疾病风险时，它能涵盖所有致动脉粥样硬化颗粒。

The ApoB concentration to me is the most important number you want to understand to predict from a biomarker standpoint, your cardiometabolic risk, ASCVD risk, because it captures all of the atherogenic particles.

因此ApoB可统计LDL总量（包括LP）、极低密度中间脂蛋白（IDL，虽然几乎不存在因其半衰期极短）以及极低密度脂蛋白（VLDL，对代谢综合征和高甘油三酯人群可能构成风险）。

So APO B counts the total of the LDLs inclusive of the LP, IDLs, although they virtually never exist, they have such a short residence time and the VLDLs, can become problematic in people with metabolic syndrome and high triglycerides.

APO B可以反映这些脂蛋白的总体致动脉粥样硬化负担

So APO B gives you the total atherogenic burden of those lipoproteins.

因此我认为这是评估风险的首选指标

And therefore I think it's the preferred metric by which we want to assess risk.

但如果要分析LDL，你需要看LDL-C即低密度脂蛋白胆固醇

But if you want to look at LDL, you have to look at LDL C, LDL cholesterol.

而高密度脂蛋白则要看HDL胆固醇

And HDL, you have look at HDL cholesterol.

那么，高密度脂蛋白中的胆固醇与低密度脂蛋白中的胆固醇有区别吗？

Now, is the cholesterol in the HDL any different from the cholesterol in the LDL?

当然没有区别

No, of course not.

因此，将HDL称为'好胆固醇'而LDL是'坏胆固醇'的说法是完全错误的

Therefore, it is totally erroneous to say HDL is good cholesterol and LDL is bad cholesterol.

正确的理解应该是：低密度脂蛋白本身作为载脂蛋白是有害的，这是由其行为决定的

No, instead what is true is that LDLs themselves as lipoproteins are bad actors because of what they do.

它们会进入动脉壁被氧化，随后将氧化后的固醇类物质释放到内皮下间隙，从而引发免疫反应等一系列导致动脉粥样硬化的过程（具体机制暂不展开）

What they do is they go into artery walls where they get oxidized and they basically dump their oxidized sterile contents into the sub endothelial space, which elicits an immune response and a whole bunch of other things that lead to atherosclerosis, which I'm not going to get into now.

但本次讨论的重点是希望大家明白：LDL和HDL都是脂蛋白

But the point of this discussion that I want people to understand that LDLs and HDLs are lipoproteins.

如果要讨论胆固醇，应该区分低密度脂蛋白胆固醇和高密度脂蛋白胆固醇，但它们携带的胆固醇分子是完全相同的

If you want to talk about the cholesterol, you talk about LDL cholesterol and HDL cholesterol, but the cholesterol in them is the exact same.

根本不存在所谓'好胆固醇'和'坏胆固醇'的区别

There is no such thing as good cholesterol or bad cholesterol.

所以当你看到那些带着特定视角写的内容时，必须保持警惕，因为这表明作者根本不了解脂质和脂蛋白的基础知识。

And so you just have to be careful when you see things written that are written through that lens, because what it tells you is the person writing this doesn't understand the basics of lipids and lipoproteins.

如果他们连脂质和脂蛋白的基础知识都不懂——毕竟我刚才告诉你们的就是这个领域最基础的入门知识。

If they don't understand the basics of lipids and lipoproteins, because what I just told you guys is literally the 101 on this subject.

我们连高年级课程内容都没涉及，更不用说研究生级别的课程了。

We didn't get to the senior level class, let alone the graduate level class.

一旦深入到那个层次，这些都是非常复杂的内容。

And this is complicated stuff once you get into that level.

所以如果有人在给我写的东西里连基础知识都搞错，那你就可以不用往下读了。

So if someone writing to me is butchering the 101, you can stop reading.

因为无论他们还在说些什么，肯定都是错的。

Because whatever else they're saying, they're undoubtedly screwing it up.

就是这么回事。

So there it is.

这就是关于脂质的太长不看版总结。

There's the TLDR on lipids.

现在医生拿到的报告会显示总胆固醇、甘油三酯、非高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇。

If a doctor gets a report now, he gets total cholesterol, triglycerides, non HDLC, LDL C, HDLC.

五个数值。

Five numbers.

你觉得他真的会仔细看这些数字吗？

Do you think he actually looks at any of those numbers?

他其实是想做好工作的。

He's trying to do a good job.

他是这样的。

He does.

但假设甘油三酯偏高。

But let's say the triglycerides are high.

他能对此采取什么措施吗？

Can he do anything with that?

不能。

Nope.

因为一切都基于低密度脂蛋白胆固醇（LDL-C）。

Because everything is based on LDL C.

所以他实际上有四个毫无意义的数值。

So he's got, in reality, four numbers that are doing nothing.

艾伦，我们需要向听众解释清楚这点——虽然你我深谙其中门道，但现场多数人可能分不清计算法与实测法得出的LDL区别。

Let's explain that to people, Alan, because you and I know the ins and outs of that very well, but I think most people here don't understand the difference between the calculated and measured LDL.

那我们就从这里切入，再讨论极低密度脂蛋白（VLDL）的估算原理。

So let's start with that, and then let's talk about how VLDL has been estimated.

最后可以结合你之前关于甘油三酯在载脂蛋白B（ApoB）中作用的研究来串联这些内容。

And let's bring this all back in terms of some other work you've done, which is understanding the role of triglyceride in ApoB.

让我们从最基础的开始讲起。

So let's start with the basic.

你去医院做化验，报告显示LDL数值是140毫克/分升——

You go to the doctor, you get a set of labs done and the LDL number comes back at 140 per deciliter.

这个数值真的准确吗？

Is that actually what it is

或者那是个估计值？

or is that an estimation?

那是个估计值。

That's an estimation.

几乎总是通过计算得出，至少有八种不同的方法来计算低密度脂蛋白胆固醇。

It's almost always a calculation, and there are at least eight different methods to calculate LDL cholesterol.

所以，既然有八种不同的方法，它们不会都给出相同的答案，否则就不需要八种方法了。

So, if there are eight different methods, they don't all give the same answer or you wouldn't have eight different methods.

低密度脂蛋白胆固醇也可以直接测量。

LDL cholesterol can also be measured directly.

该检测方法从未在疾病患者中得到验证，也无人发表过论文证明其在疾病识别方面比计算得出的低密度脂蛋白胆固醇更准确。

That assay has never been validated in disease patients and no one has ever published a paper showing that it's more accurate in terms of disease identification than calculated LDL cholesterol.

然而人们还是为这项实验室检测支付了不少钱。

And yet people have paid good money for that lab test.

毫无疑问，低密度脂蛋白颗粒数量比低密度脂蛋白胆固醇更能准确反映风险。

There's no question that the number of LDL particles is a more accurate index of risk than the LDL cholesterol.

极低密度脂蛋白胆固醇存在于极低密度脂蛋白颗粒中，这些颗粒由肝脏产生。

The VLDL cholesterol is a cholesterol that's in the very low density lipoprotein particles, particles that come out of the liver.

这种胆固醇会导致动脉粥样硬化。

That cholesterol is atherogenic.

该颗粒中含有大量甘油三酯。

There's a lot of triglyceride in that particle.

因此，测量甘油三酯的人会说：看，甘油三酯水平很高。

So, the people who measure triglycerides say, well, the triglycerides are high.

那一定是问题所在。

That must be the problem.

毫无疑问，高甘油三酯人群患心脏病的风险更高。

And there's no question that people with high triglycerides are at increased risk of heart disease.

但这些高甘油三酯且心脏病风险增加的人群，其LDL颗粒和VLDL颗粒数量也更多。

But the people with the high triglycerides who are at increased risk of heart disease have a higher number of LDL particles and VLDL particles.

关键在于颗粒本身。

It's the particle.

当你测量甘油三酯时，你只是在测量一堆颗粒中的液体团块，而你需要知道的是它们的数量。

And when you're measuring the triglyceride, you're just measuring a blob of liquid in a bunch of particles and you need to know the number of them.

因此，从脂蛋白研究角度来看这是个重要数值——如果数值极高，会增加胰腺炎风险。

So, it's an important number in the sense of if you're a lipoprotein guy trying to figure things out, if it's extremely high, it increases the risk of pancreatitis.

但我尚未看到任何确凿证据表明甘油三酯本身会导致动脉粥样硬化。

But I haven't seen any solid evidence that triglyceride itself is proatherogenic.

真正致动脉粥样硬化的是VLDL颗粒内的胆固醇。

What's atherogenic is the cholesterol inside the VLDL particles.

关键是进入血管壁的颗粒数量。

It's the number of those particles that get into the wall.

现在有个复杂情况：通常我只需要知道载脂蛋白B（ApoB）即可。

Now, there's a complicating reality because in general, all I need to know is the ApoB.

但有种称为'布伦病'（第三型血脂蛋白异常症）的病症。

But there is a disorder called Bremen, type three dyslipoproteinemia.

这是种非常特殊且极易致动脉粥样硬化的疾病，表现为高甘油三酯、高胆固醇——但 paradoxically（注意：此处保留英文术语）低ApoB。

And that's a very specific highly atherogenic condition that manifests with high triglycerides, high cholesterol, but get this, you know, low ApoB.

所以当我测量我的载脂蛋白B（ApoB）时，我就能识别出这一点。

So when I measure my lipids in ApoB, I can recognize that.

但如果你不测量ApoB——这适用于大多数正在收听这个播客的听众——如果他们去看医生，这种状况就无法被诊断出来。

But if you don't measure the ApoB, and this applies to most of the people who are listening to this podcast, if they go to see their doctors, that condition can't be diagnosed.

我们最后这组片段将重点讨论为什么我认为在预测风险时，ApoB是比低密度脂蛋白胆固醇（LDL）甚至非高密度脂蛋白胆固醇更优越的脂质指标。

Our last set of clips will focus on why I think ApoB is a superior lipid metric to LDL cholesterol or even non HDL cholesterol when trying to predict risk.

你对此持乐观态度吗？

Are you optimistic?

我是说，这只是时间问题吗？

I mean, is this just a question of time?

比如十年后，医学院的学生们会学习ApoB而不是LDL吗？

I mean, in ten years, will kids in med school be learning about ApoB instead of LDL?

我很悲观。

I'm pessimistic.

欧洲2019年的指南非常支持ApoB。

Europe, the 2019 guidelines were very pro ApoB.

像孟德尔随机化这类新技术的证据，简直就是为ApoB提供了铁证。

The evidence from Mendelian randomization like the newer technologies, Mendelian randomization, they've just been slam dunk for ApoB.

让我们向听众解释一下，因为我想谈谈其中的因果关系，这可能是解释ApoB在这种工具背景下因果关系的绝佳方式。

Let's explain that to folks because I wanna talk about the causality of this, and this might be the perfect way to actually explain the causality of ApoB in the context of this tool.

那么你能向大家解释什么是孟德尔随机化吗？

So can you explain to folks what a Mendelian randomization is?

人们经常在研究中看到这个术语，但我认为对普通人来说它的含义并不完全清楚。

Where people see this all the time in studies, but I don't think it's entirely clear for the average person what it means.

我会试试。

I'll try.

好吗？

Okay?

这不是我的专长，但我会试试。

It's not my expertise, but I'll try.

传统方法如弗雷明汉研究这类观察性研究，由于无法处理的混杂因素，你的结论确定性存在局限。

The conventional ways of taking things apart with perspective observational studies like Framingham, there's a limited amount of the certainty of your conclusions because of confounding you can't deal with.

你在20岁时测量数据，然后跟踪某人接下来的三十年。

You take measurements at age 20 and you follow someone for the next thirty years.

未来三十年会发生许多你无法掌控的变化。

Well, a lot of things change in the next thirty years that you don't have a handle on.

你的推论是或然而非因果性的。

Your inferences are probable but not causal.

孟德尔随机化能让你更接近因果关系。

What Mendelian randomization allows you to do is to come a lot closer to causality.

例如，你可以识别出与胆固醇水平略微降低或升高相关的基因群组。

Because for example, you can identify groups of genes that are associated where changes in the gene are associated with a little lower cholesterol or a little higher cholesterol.

当你将那些可能因基因组成容易改变而产生不同影响的基因组合在一起时，就能观察到相当显著的胆固醇差异。

And when you lump together a bunch of those different genes that can have different makeups because you can change the makeup of a gene pretty easily, you can see fairly substantial differences in cholesterol.

所以你得到的是一个人出生时就固定的信息。

So, what you've got is information on somebody that's fixed at birth.

然后你会看到，这是否与结果差异相关？

And you see, is that associated with a difference in outcome?

你已经在中间环节去除了很多内容。

You've gotten rid of a lot of stuff in the middle.

大量孟德尔随机化研究表明，载脂蛋白B（APO B）包含了甘油三酯、低密度脂蛋白胆固醇（LDL-C）乃至高密度脂蛋白胆固醇（HDL-C）的所有信息。

And what a number of Mendelian randomizations have shown is that APO B includes all the information in triglycerides, LDL cholesterol, and even HDL cholesterol.

它将这些指标综合起来——从极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）的角度来看完全合理。

It sums them, which in the sense of VLDL and LDL makes perfect sense.

不过孟德尔随机化研究也存在局限性。

So, there are caveats in Mendelian randomization.

你不能简单地按个按钮就说：给我答案。

You can't just push a button and say, give me the answer.

乔治·戴维·史密斯可以说是孟德尔随机化研究的奠基人之一（确切地说就是），他通过多项孟德尔随机化研究指出，载脂蛋白B（ApoB）整合了各项指标，因此比甘油三酯和低密度脂蛋白胆固醇更具参考价值。

But George Davy Smith, really arguably one of the founders of Mendelian randomization, or not arguably, he was, he's the author of a number of the Mendelian randomization saying ApoB incorporates and therefore beats triglycerides and LDL cholesterol.

如此重要的信息却在几乎所有指南中都没有被提及。

So, that's a huge level of information that isn't even mentioned in almost any of the guidelines.

是的。

Yeah.

我们需要确保大家能理解你刚才说的所有内容，因为你讲了很多重要信息。

So let's make sure people understand everything you just said because you said a lot of things in there.

当你对队列进行前瞻性追踪时——就像弗雷明汉队列研究、弗雷明汉子代研究、MESA队列研究等所做的那样——你可以选取人群样本，测量他们的载脂蛋白B（APOB）或低密度脂蛋白胆固醇（LDL-C）等指标，从而验证这些指标是否与目标疾病存在因果关系。

When you prospectively follow a cohort, the way the Framingham cohort was followed or the Framingham offspring or the Mesa cohort or any of these cohorts have been followed, you can take a bunch of people and you could measure their APOB or their LDL C or whatever metric it is that you're trying to determine if it in fact has a causal relationship to the disease of interest.

通过数十年的追踪研究，正如已有证据表明的那样，载脂蛋白B（B）、低密度脂蛋白胆固醇（LDL-C）、非高密度脂蛋白胆固醇（non-HDL-C）水平较高而高密度脂蛋白胆固醇（HDL-C）水平较低的人群，随时间推移发展动脉粥样硬化的风险更高。

You can follow them over decades and you would demonstrate as has been demonstrated that the people with higher B, higher LDL C, higher non HDL C and lower HDL C all have a higher risk of developing atherosclerosis over time.

但仅凭这些信息很难断言因果关系，因为在后续二十年的追踪期间，研究对象可能做出其他选择，从而影响这些目标变量及其他变量。

But it's hard to say that that's causal just based on that information because over the ensuing twenty years that you follow them, they are free to make other choices that may impact those variables of interest and other variables.

孟德尔随机化试图通过指出——我本想说是出生时，但实际上是在受孕时——我们都被随机分配了一套基因来规避这个问题。

So the Mendelian randomization attempts to get around that by saying at the time of I was gonna say birth, but really at the time of conception, we all get randomized to a set of genes.

我们被分配了一套基因。

We get assigned a set of genes.

我想它们并非完全随机，因为这些基因来自我们的父母。

I guess they're not perfectly random because they come from our parents.

但就保持不变的目的而言，它们确实是一种固定的随机分配。

But for the purpose of not changing, they are indeed a random assignment that is fixed.

如果我们能确定哪些基因对应哪些表型，并找出与我们感兴趣的性状（例如升高或降低ApoB等目标变量）相关的基因，那么我们就不必担心中间可能存在的混杂因素，因为基因不会改变。

If we can identify which genes map to which phenotype and we can figure out the genes that map to the phenotype of our interest, namely driving up or down a variable of interest such as ApoB, then we don't really have to worry about the confounders that occur in between because the genes can't change.

简而言之，现在当你看到结果差异时，它更可能与目标表型存在因果关系，因为作为基础的基因并未改变。

Just to put a bow on that, basically, now when you see a difference in outcome, it's much more likely to be causally related to the phenotype of interest because the gene has not changed that underlies it.

那么，我们在使用孟德尔随机化时可能会遇到哪些陷阱呢？

Now, what are some of the ways that we can get tripped up with Mendelian randomization?

我是说，有些陷阱相当明显。

I mean, there's some pretty big ones.

是的。

Yeah.

在我们讨论之前，HDL胆固醇曾风靡一时。

Before we get there, HDL cholesterol was the rage.

对吧？

Okay?

当时完全风靡，因为流行病学证据再明确不过了。

The total rage because the epidemiological evidence couldn't be clearer.

事实上，它清晰了四倍。

In fact, it was four times more clear.

我记得弗雷明汉研究显示，低高密度脂蛋白胆固醇对心脏事件的预测性是高低密度脂蛋白胆固醇的四倍。

My recollection was that Framingham demonstrated low HDLC was four times more predictive of cardiac events than high LDL C.

我记对了吗？

Am I remembering that correctly?

不确定

Not sure

就是这个倍数。

it's that multiple.

是的，但它是倍数的关系。

Yeah, but it's multiples.

结果发现，至少从CTP抑制剂来看，我们现在知道无法通过调节高密度脂蛋白来改变预后。

And it turns out, as we know now, at least from the CTP inhibitors, that you can't manipulate HDL and change outcomes.

这是证明整体因果关系的关键要素之一。

And that's one of the elements of demonstrating an overall causal relationship.

孟德尔随机化研究表明高密度脂蛋白并非因果因素，而载脂蛋白B才是。

And the Mendelian randomization show HDL is not causal, whereas they show ApoB is.

顺便说一句，胆固醇也是。

And cholesterol is too, by the way.

艾伦，这两项研究非常重要。

Those are two very important studies, Alan.

我是说这两项研究都是过去十年内完成的。

I mean and both of those have been in the last ten years.

是的。

Yeah.

这是一项令人难以置信的技术进步，能够研究传统研究中难以想象的人群规模的问题。

It's a incredible technical advance in being able to examine questions and look at numbers of people that would be unimaginable in conventional studies.

孟德尔随机化研究总是涉及数十万人，因为他们拥有庞大的基因数据库。

The Mendelian Rand, they're always talking hundreds of thousands of people, cause they've got these huge data banks with genes.

这些庞大的数据量能帮你绕过混杂因素的干扰。

And those numbers get you around the confounding of things.

你拥有海量的数据。

You have huge numbers.

但就像任何方法学一样，没有方法是完美的。

But it's like any methodology, no method is perfect.

这种方法也可能误导你，特别是当你面对一系列相关变量时。

This one can mislead you to, particularly when you've got a sequence of associated variables.

例如，有人通过孟德尔随机化研究显示甘油三酯具有因果性或与风险增加相关。

For example, people showed using MR that triglycerides were causal or associated with increased risk.

但当你考虑非高密度脂蛋白胆固醇或载脂蛋白B时，这种关联就消失了。

But when you took into account the non HDL cholesterol or the ApoB, it disappears.

所以当你面对一个相互关联的代谢链时，必须谨慎地追踪到链条末端。

So, when you've got a linked metabolic chain, you've got to be careful that you've gone to the end of it.

你要找到真正的'演员'，而不是第一幕导致后续情节的假象。

You've got the real actor, not act one leading to, that.

你要找到真正的戏剧主角。

You've got the real persona dramatis.

正因如此，令人惊讶的是HDL甚至在一阶分析中未能证明因果关系——因为从表型上看，高甘油三酯低HDL的表型与代谢综合征高度相关，这已是五项诊断标准中的两项。

Which is why it's surprising that HDL didn't at least at the first order demonstrate causality because there's no doubt that phenotypically, the high triglyceride low HDL phenotype is so associated with metabolic syndrome that it makes up two of the five criteria.

这是个不完整的描述。

That's an incomplete description.

就像你自称身高六英尺（我倒是希望），却不提体重让我猜你的BMI指数。

That's like you describing yourself as six feet tall, I wish, and not giving your weight and letting me guess your BMI.

没有载脂蛋白B（ApoB）就无法完整描述任何表型特征。

You cannot characterize any phenotype without the ApoB.

当人们说'我掌握了某人的甘油三酯和HDL数据就了解其状况'时，这真让我抓狂。

It really drives me around the bend when people speak saying, I got somebody because I got their triglycerides and their HDL.

我就会问：好吧，那他们的ApoB是多少？

Well, I say, okay, what's their ApoB?

你连致动脉粥样硬化颗粒的数量都没计算，怎么能假装评估了整个系统？

How can you pretend you've evaluated the system when you haven't counted the number of atherogenic particles?

因为它们可能处于正常水平。

Because they could be normal.

也可能偏高。

They could be high.

或者可能是第三型。

Or you can have a type three.

他们根本不知道。

They don't know.

这根本称不上是表型特征。

And it's not a phenotype.

没有PO B的参与，就不会有表现型。

There is no phenotype without putting any PO B in there.

它们是脂蛋白颗粒。

They're lipoprotein particles.

它们是脂蛋白颗粒代谢紊乱的表现。

They're disorders of lipoprotein particle metabolism.

当然，甘油三酯和胆固醇很重要，但我的类比不太恰当——这个基础概念如此重要，以至于我实在想不通为什么有人会拒绝了解这个核心知识点。

Of course, the triglycerides and cholesterol are important, but my analogy, I didn't do a good analogy there, but it's so fundamental that it drives me to distraction as to why you wouldn't want to know a core element of knowledge.

但我的许多朋友似乎并不在意这点。

But it doesn't seem to bother many of my friends.

你详细阐述了载脂蛋白B颗粒如何在临床事件发生前多年就已在动脉壁内造成破坏的病理生理机制。

You walked through the pathophysiology of how the ApoB bearing particle wreaks havoc in the artery wall many, many years before we see clinical events.

你还提到有其他因素可能加剧这一过程。

And you also mentioned that there are other factors that can amplify or exacerbate that.

我记不清原话了，但大意如此。

I can't remember exactly how you said it, but that was the gist of it.

其中被广泛认可的两个风险加剧因素是吸烟和高血压。

Well, two of those things that are widely accepted to exacerbate risk are smoking and hypertension.

事实上，吸烟和高血压对动脉粥样硬化的风险可能比载脂蛋白B更高？还是并非如此？

In fact, smoking and hypertension probably carry a greater risk for atherosclerosis than ApoB or is that not the case?

这取决于你的思考角度。

It all depends the way you think about it.

因为如果你单纯问'高血压患者面临什么风险？'

Because if you just say, what's the risk somebody with hypertension faces?

他们面临高风险。

They have high risk.

毫无疑问。

No question.

但你会问，什么是高血压？

But then you say, what is hypertension?

过去三四十年间，关于高血压的基础科学研究几乎数不胜数。

The last thirty or forty years, there have been almost an infinite number of basic science studies on hypertension.

当你们在医学院时，甚至更早在我读医学院时，我们讨论的是高血压的病理生理学。

And when you were in medical school, and even before that when I was in medical school, we talked about pathophysiology of hypertension.

令我震惊的是，我们不再讨论高血压的病理生理学了。

And what strikes me is we don't talk about the pathophysiology of hypertension anymore.

但基础科学研究在老鼠身上进行得比以往更健康。

But the basic science goes on in rats that's healthier than ever.

据我所知，过去三十年来这些基础科学成果中没有任何临床实用的发现。

And there isn't anything I know of that's come out of that basic science that's been clinically useful in the last thirty years.

我们使用的药物之所以被使用，是因为它们有效。

The drugs we use, we use them because they work.

那么，什么是高血压？

So, what is hypertension?

就是血压高于我们应有的水平。

It's a higher blood pressure than we should have.

导致这种血压升高的疾病根源在哪里？

And where is the disease that produces that higher blood pressure?

这是阻力吗？

Is it resistance?

我们毫无头绪，明白吗？

We don't have a clue, okay?

我们毫无头绪。

We don't have a clue.

这让我想到，就像脂质领域关于ApoB的争论一样，或者像醉汉只在路灯下找钥匙——因为那里有光，而不是他丢钥匙的地方。

And it strikes me it's the same thing as much of the debate in lipids about ApoB or the drunk looking for the key under the light because this is where the light is, not where he lost it.

所有重要人物都持相同观点。

Everybody who's anybody has the same viewpoint.

我打赌问题出在近端主动脉。

My bet is it's in the proximal aorta.

我打赌事情没那么复杂。

My bet is that it isn't that complicated.

我们在近端主动脉失去了弹性。

We lose elastance in the proximal aorta.

这就是收缩期高血压。

And that's systolic hypertension.

非常感谢。

Thank you very much.

什么会加速这个过程？

What could accelerate that process?

主流观点认为这是肾脏问题吗？

What's the mainstream view that this is renal?

当我读到高血压时，我就晕头转向，因为看到的全是关于外周动脉张力、复杂代谢研究和精密动物模型的一页又一页内容。

When I read hypertension, I get lost because I get page after page after page of peripheral arterial tone and very complex metabolic studies and very sophisticated animal models.

还有些肾脏相关的内容。

There's some renal left.

对我来说这简直是一团乱麻，彻头彻尾的乱麻。

It's a miasma for me, an absolute miasma.

我之前没听说过近端主动脉的事。

I hadn't heard about the proximal aorta.

那请多讲讲这方面吧。

So, say a bit more about that.

嗯，我觉得这就是我的专长。

Well, I'd say this is me.

近端主动脉是有弹性的。

The proximal aorta is elastic.

如果你观察血流曲线和静水压曲线，年轻时曲线是圆润的——因为当左心室快速将血液射入主动脉时，主动脉会扩张。

And if you look at a flow curve, a hydrostatic pressure curve, when we're young, it's rounded because as the left ventricle ejects blood rapidly into the aorta, the aorta expands.

这样就能吸收部分冲击能量。

So, it absorbs some of that energy.

记得学校里提过的弹性储器血管（Windkessel）吗？

You know that wind kessel that they mentioned in school?

虽然这个概念不算太重要，但能量确实会被部分吸收和回收，血管壁就不会受到剧烈冲击。

That's not that big a deal, but the energy is partially captured, partially regained, but the wall isn't battered.

血管壁是具有让步空间的。

The wall can give way.

就我个人而言，就在我脑海中央想象一下，如果那些弹性纤维开始退化，血管壁就会变硬。

Me, personally, just in the middle of my brain, imagine that if those elastic fibers start to go, then the wall is stiff.

所以现在当左心室射血时，压力上升得更快，在舒张期下降得也更快。

So now when the left ventricle ejects blood, the pressure goes up more rapidly and it falls more rapidly in diastole.

这就是为什么会出现收缩期高血压伴随正常舒张压的情况。

And that's why you get systolic hypertension with normal diastolic pressures.

因此我推测，如果我不是现在这个年纪，我会重新关注像心输出量这样的因素——这在过去曾是主要考量。

So my bet would be, if I was not the age I am, I would be looking at factors like cardiac output again, which used to be way back when.

这些因素对近端主动脉行为的影响程度，在我看来比那些病理生理学上更可能相关的因素还要大。

That alter the behavior of the proximal aorta as much as something that's to me, pathophysiologically, much more likely to be involved.

所以一旦患上高血压，就有了推动粒子进入血管壁的驱动力。

So once I got hypertension, okay, then I've got a driving force to push particles into the wall.

所以你认为这是血浆压力的实际增加导致的？

And so you think it's the actual increase in the pressure of the plasma?

以及血管壁的响应。

And the response of the wall.

我认为血管壁会产生一系列反应。

I think there are responses to the wall.

血管壁会增厚。

The wall thickens up.

粒子更难穿透。

It gets harder for particles to go through.

它是否也会损伤内皮细胞？

Does it also damage the endothelium?

你

Do you

认为这起到作用了吗？

think that plays a role?

没错。

That's right.

我不理解内皮功能障碍。

I don't understand endothelial dysfunction.

对我来说这更像是语言表述问题而非现实情况。

It's more a language thing to me than it is a reality.

我知道内皮细胞至关重要。

I know the endothelium is critically important.

它功能异常时就是内皮功能障碍。

It functions abnormally, and that's endothelial dysfunction.

这如何融入整体机制，我不清楚。

How that fits into the overall thing, I don't know.

我推测ApoB颗粒是诱发内皮功能障碍过程的一部分，但实验数据尚不明确。

My bet is ApoB particles are part of the process of inducing endothelial dysfunction, but I don't know that clearly experimentally.

那么回到最初的问题，比较高血压和ApoB是否有意义？

So going back then to the question at the top, does it make sense to even compare hypertension to ApoB?

两者似乎都起到因果作用。

They both seem to play a causal role.

哪个因果性更强？或者这个问题本身就很蠢，因为它们并非二元且静态的？

Is one more causal than the other, or is that a silly question because they're not binary and static?

我认为这不是正确的问题。

I think that's not the right question.

我认为我们的血压会随着年龄增长而升高。

I think our blood pressure goes up as we age.

我的意思是，高血压涉及如此多的人口，以至于我不清楚‘疾病’这个词的确切含义。

I mean, hypertension involves so much of the population that it's not clear to me what the word disease means.

随着年龄增长，患病率如此之高，以至于在我看来，这几乎成为一种衰老过程，因为我们的寿命远超设计预期。

The prevalence as we age is so high that to me, it's becoming almost an aging process because we're lasting a lot longer than we were probably designed to go.

因此，近端主动脉会遭受这种反复性损伤。

So, you have this repetitive injury to the proximal aorta.

它逐渐变得难以应对这种损伤。

It gets a little progressively less able to deal with it.

那么，在五十岁时，比例是多少？

So, with a time where fifty, what percent?

百分之六十的人血压偏高。

Sixty percent have higher blood pressure.

我的意思是，这些数字令人震惊。

I mean, the figures are staggering.

真有那么高吗？

Is it really that high?

我不确定。

I'm not sure.

别引用我的话，但确实非常高，非常高。

Don't quote me on that, but it's high, high, high.

但ApoB不是也会随着年龄增长而升高吗？

But doesn't ApoB also rise with age?

确实会随年龄增长，但幅度不大。

It does rise with age, but not that much.

当我们观察35岁人群时，可以相当准确地将他们归入35岁时的所属组别。

When we look at people at age 35, we can pretty accurately categorize the group they belong to at age 35.

倒不是说他们完全不会变化。

Not that they won't change somewhat.

所以如果你35岁时指标偏高，那么有约95%的概率会持续偏高。

So, if you're high at age 35, you've got about a ninety five percent chance of staying high.

只有5%的人会脱离高值区间。

Five percent will go out of the high zone.

他们也不会降到很低很低。

They won't go low low.

因此如果你35岁时指标高，我敢打赌没什么能让你降下来。

So, if you're high at age 35, I wouldn't bet anything's going to move you down.

这就是为什么我认为这是决定何时开始治疗的最佳信号。

That's why I think it's such a good signal for when we should start thinking about treating people.

而如果你指标低，虽然部分人会从低值向高值移动，但大多数人不会——我们会持续跟踪他们。

And if you're low, some people go from low towards high, but the majority don't and we keep following them.

但如果你指标高——这方面我们已发表不少研究——

But if you're high, no, we've published a fair amount of this.

虽然不是100%，但约有90%的概率你会持续偏高。

If you're high, it's not a 100%, but it's about 90% that you're going to be high.

是否存在性别差异？

Is there a gender difference?

至少在临床上，我似乎观察到女性在经历更年期时会出现血脂异常，而男性在同一十年甚至五年的过渡期内则不会出现这种情况。

At least clinically, I seem to see women as they go through menopause experience dyslipidemia that men wouldn't experience over that same decade or even five year transition.

我认为确实存在变化，ApoB水平会随着更年期上升。

I think there are changes and ApoB goes up with menopause.

我希望能有更多数据支持。

I'd like there to be more data.

我认为ApoB未被重视的部分原因是人们过去不常测量它。

I think part of the reason that's held ApoB back is that people didn't measure it.

所以他们某种程度上觉得——既然我测了这个指标，那它肯定重要，因为我无法回答你的问题。

So they were sort of, well, what I measured has to be important because I can't answer your question.

希望未来会有更多数据出现。

Hopefully, more data will be coming.

但我同意你的观点。

But I agree with you.

人们在更年期时确实可能发生变化。

People can change at the menopause.

所以，我并不是说我们不需要持续观察人群，但当你遇到35到40岁指标就偏高的人，他们大概率会持续偏高。

So, I'm not saying we don't keep looking at people, but when you have somebody at age 35 to 40 who's high, the odds are high that they're going to stay high.

我们在治疗高血压方面是否比治疗血脂异常做得更好？

Are we doing a better job treating hypertension than dyslipidemia?

我完全不知道。

I have no idea.

过去五年中，冠心病的发病率在上升，尽管有他汀类药物治疗。

The incidence of coronary disease is going up in the last five years, and that's despite statin therapy.

这与肥胖糖尿病有关。

And that's the obesity diabetes.

所以，我认为我们对自己表现良好的祝贺来得太快了。

So, I think we've been too quick to congratulate ourselves at how well we're doing.

治疗未能达到预期效果的原因有很多。

There are many reasons that treatment is not succeeding as well as it should.

而脂质表型的复杂性是部分答案所在。

And I complexity of the lipid phenotype of the lipid model is part of the answer.

对我来说很简单。

It's easy for me.

我能让载脂蛋白B达到目标水平。

I get the ApoB where I want it to go.

是的，我的意思是，对你观察结果的一个解释可能是：过去五到十年间，尽管医疗进步，动脉粥样硬化或主要不良心脏事件的发病率仍在上升——你可以认为，如果我们以LDL-C作为治疗指标，但随着代谢背景下血脂异常的增加（即更多代谢综合征、胰岛素抵抗和二型糖尿病），我们知道这些表型会导致载脂蛋白B与LDL-C的更大程度分离，这意味着越来越多人会被漏诊或低估风险——因为你只治疗他们的LDL-C，而实际上他们的风险更高（因为载脂蛋白B更高）。

Yeah, I mean, an explanation for your observation would be if in the last five to ten years, the incidence of atherosclerosis or major adverse cardiac events is rising despite the advances we have, you would argue or could argue that if we're measuring LDL C and that's our proxy for treatment, But as dyslipidemia is growing in the metabolic context, meaning if you have more MetSin and more insulin resistance and more type two diabetes, we know that those phenotypes are associated with greater discordance between ApoB and LDL suggesting that you'd have a greater and greater portion of the population that is being undiagnosed or being underdiagnosed because you're treating their LDL C and you believe that it's lower than their risk actually is because their APO B is higher.

我知道你听懂了我的话。

I know you know what I just said.

希望听众能理解我刚刚说的内容。

I hope the listener understands what I just said.

是的，你刚才说的很重要。

Yeah, what you just said was important.

这是另一个令人遗憾的悲伤案例。

It's another example, an unfortunate sad example.

仅凭脂质来量化脂蛋白是不够的。

That trying to quantify lipoproteins based just on lipids is not adequate.

你并未获取所有必要的信息。

You're not capturing all the information that you should.

让我们回到关于APO B的宏观观点上，即越来越多人认同APO B浓度的重要性。

Let's go back to kind of the macro point here around APO B, which is a greater coalescing around the idea that that APO B concentration matters.

我认为大家都很清楚，心血管疾病的两大风险因素是吸烟和高血压。

So I think it's very well understood that two of the biggest risk factors for cardiovascular disease are smoking and hypertension.

毫无疑问，吸烟和高血压会增加心血管疾病风险，它们似乎都是通过削弱内皮或造成内皮损伤的机制来实现的。

I don't think there is any ambiguity that cigarette smoking and high blood pressure increase the risk of cardiovascular disease, and they both appear to do so through a mechanism that weakens the endothelium or creates an injury to the endothelium.

现在的问题在于，正如你所说，Tom，关于载有ApoB的颗粒在受损内皮存在时成为特洛伊木马，开启将胆固醇带入内皮下空间、滞留并经历化学氧化过程这一破坏性轨迹的说法，其确定性有多高？这一过程会引发炎症反应，而 paradoxically，这种试图修复损伤的反应反而可能导致致命伤害。

The question now becomes, as you put it, Tom, how ironclad is the story that it's the ApoB bearing particle in the presence of injured endothelium that is the Trojan horse that begins this destructive trajectory of taking that cholesterol into the subendothelial space, becoming retained, undergoing this chemical oxidation process, which then kicks off an inflammatory response that paradoxically, as an attempt to repair the damage, results in what can be a fatal injury.

还存在其他假说。

There are other hypotheses.

例如，有人指出——我是说，Tom，我们诊所就有这样一位患者。

For example, there are people who note, and we have I mean, look, I have a patient in our practice, Tom.

你曾参与她的病例讨论，她的总胆固醇高达300多，LDL胆固醇为220毫克/分升，APO B为170毫克/分升。

You've weighed in on her case, walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams per deciliter, an APO B of a 170 milligrams per deciliter.

她已近七十岁，但冠状动脉钙化积分为零。

She's in her late sixties and her coronary artery calcium score is zero.

我们决定不对她进行任何降脂治疗。

We have elected to not treat her with any lipid lowering therapy.

换句话说，这种情况存在例外。

In other words, there are exceptions to this.

我们该如何调和这一点？

How do we reconcile that?

嗯，这是医学中的人体。

Well, it's the human body in medicine.

如你所知，并非所有吸烟者都会患上肺癌或慢性阻塞性肺病。

As you know, not all smokers are gonna come down with lung cancer or chronic obstructive lung disease.

如果这是如此可怕的风险因素，为什么不会呢？

Why not if that's such a horrible risk factor?

我试图解释这一点，阿科尔，我当然见过像你说的那种病例——天啊，如果我要说，给我你的载脂蛋白B或任何胆固醇指标，你现在就得立刻服用三种药物。

I try to explain this, Akol, and I've certainly seen cases like you say where, oh my god, if I was just gonna say, give me your APOB or whatever cholesterol metric, You're going on three drugs right now.

你别无选择。

You got no choice.

也许在过去我们会这样对待病人，但现在不再这样了。

And maybe in the old days, we, approach people that way, but no more.

我认为你必须根据发现的任何可能导致动脉粥样硬化的风险因素进行个性化处理，然后再找出解决方案。

I think you have to individualize your whatever risk factors you discover that might wind up causing atherogenesis, and then figure it out.

因此颗粒数量肯定是推动其发生的主要因素，但并非总是如此。

So particle number is certainly a major factor that might force it in, but not always.

内皮功能方面——虽然你可以回顾这段历史并思考如何真正评估内皮功能——但并非所有最终患上动脉粥样硬化的人都有严重的内皮功能障碍。

Endothelial function, although you can certainly, if you review the history of this and how do you really determine endothelial function, not everybody has serious endothelial dysfunction who winds up with Atherosclerosis.

因此对某些人而言，仅颗粒数量本身就能促使颗粒进入血管壁。

So particle number itself in some people can just make the particles go in.

我认为如果我们以大多数成年人为例，他们多少都会有些内皮功能障碍——所以我同意你的观点。

I think if if we take most adults who's not gonna have a little bit of endothelial dysfunction so I agree with you.

这是关于致动脉粥样硬化颗粒某些特性的综合考量，无论是它们的数量还是内皮功能障碍。

It's a combination of something about atherogenic particles, be it their number, endothelial dysfunction.

但现在我越来越多地在讨论任何类型的脂蛋白时提及这点。

But I'm talking more and more now when I discuss any type of lipoprotein.

我不在乎你们想讨论哪个亚类。

I don't care which subgroup you wanna talk about.

我认为我们必须了解其颗粒浓度，但我更想谈谈颗粒质量。

I think we certainly have to know its particle concentration, but I like to talk about particle quality.

那么，还有哪些脂蛋白的其他特性可能促使其致动脉粥样硬化，或者在某些尚未明确的机制下使其相对不易引发动脉粥样硬化？

So what are the other attributes of any lipoprotein that might contribute to its atherogenicity or in in some perhaps not understood, make it relatively it's not gonna generate ather osclerosis.

这类机制肯定存在。

And there certainly have to be things like that going on.

随着认知深入，我们开始关注脂蛋白的其他组成成分。

So as we're getting smarter, we're looking at other components of the lipoproteins.

可能是其携带的其他蛋白质。

That could be other proteins that are on them.

也可能是它们复杂的脂质组——我们正试图观察，嗯哼。

That could be their complex lipidome And trying to see, uh-huh.

这能否帮助我们判断：在相同颗粒浓度下，某个体的风险是否比另一人更值得担忧？

Can that help us discern whether in you a given particle concentration is more worrisome than it is in the next in the next person?

所以这里涉及很多机制。

So there's a lot going on.

另外通过本次对话的要旨，听众会明白动脉粥样硬化的形成是一种多重复杂、多因素的疾病。

And, also from the gist of this conversation, listeners will know atherosclerosis, atherogenesis is a multi complex, multifactorial disease.

这就是为什么即使当彼得和我会诊一个病例时，发现必须降低该患者的ApoB水平并使其颗粒数达到更生理的范围后，我们也不会就此止步。

And that's why even when Peter and I, if we consult on a case and we realize in this person we have to beat up ApoB and get their particle numbers to a more physiologic range, we don't stop once we do that.

我们会详细检查其他可能损伤内皮或动脉壁的因素，并评估其中是否有可治疗的部分。

We examine in great detail for other things that might be injuring the endothelium or the arterial wall and see are any of those treatable or so.

因此我们对脂蛋白的认识正在逐步深入，但显然这不仅仅关乎颗粒数量。

So we're getting a little bit smarter on lipoproteins, but there certainly is more to it than just particle number.

我们是否认为降低ApoB的益处存在某个极限，超过后收益就会递减甚至出现反向J型曲线？

Do we think that there's a limit to where the benefit of reduction becomes diminishing or even j curves in the other direction.

我们在第一期节目中已经深入讨论过这个问题。

So we discussed it in the first episode significantly.

后来与Ron Krause的对话中又再次探讨过。

We did so again with Ron Krause.

几年后坐下来重新审视数据或许不是最坏的主意。

It wouldn't be the worst idea in the world a couple of years from now to sit down and do it again and reexamine the data.

但我要重申，ApoB与动脉粥样硬化之间的因果关系强度，在医学领域中几乎无出其右——尽管我们无法进行完美实验，只能依赖自然实验数据。

But again, I think the causal relationship between ApoB and atherosclerosis is as strong as virtually anything we see in medicine for which you can't do the perfect experiment where you have to rely on natural experiments.

不过，剂量反应曲线可能尚未完全明确。

Nevertheless, maybe it's not entirely clear what the dose response looks like.

举例来说，当患者ApoB为160毫克/分升时，从160降到100，100降到80，80降到60，每个阶段都能获得风险降低收益。

So if you have somebody whose ApoB is one hundred and sixty milligrams per deciliter, there's a risk reduction that comes to lowering it from one hundred and sixty to 100 and lowering it from 100 to 80 and lowering it from 80 to 60.

那么从60降到40再到20时，我们对这种风险降低了解多少？

What do we know about the risk reduction in lowering it, say, from 60 to 40 to 20?

这个问题我想从药理学和非药理学两个角度来探讨。

And I ask both what we could infer pharmacologically and nonpharmacologically.

换句话说，就是孟德尔随机化与药理学之间的对比。

In other words, from the Mendelian randomization versus the pharmacologic.

嗯，即便使用药理学试验和孟德尔随机化，你将会遇到的概念是'越低越好'。

Well, even using pharmacologic trials and Mendelian randomization, you're the the concept you're gonna come across with is lower is better.

而在药理学方面，我们调节的是那些已有临床试验证明降低它们有益的物质，或是通过孟德尔随机化观察那些药物可能起作用的基因，确实有效。

And with the pharmacologic thing, we're modulating things that either have clinical trial proof that if you lower them, it's good, or the Mendelian randomization, looking at genes where that drug might be doing something, it works.

现在你确实需要一些含有ApoB的脂蛋白。

Now you do need a few ApoB containing lipoproteins.

它们确实负责运输其他脂质。

They do traffic other lipids.

它们运输脂溶性脂蛋白。

They traffic fat soluble lipoproteins.

但我们绝不能混淆无β脂蛋白血症（患者完全无法生成）和低β脂蛋白血症（患者能生成足够运输其他物质所需的少量脂蛋白）。

But we must never confuse abeta lipoproteinemia where nobody or that person can't make them or hypobeta lipoproteinemia where they make a few enough to traffic those other things that a lipoprotein might have to traffic.

但即使在指南中，当医生基于患者基线ApoB或LDL胆固醇水平进行检查时，他们首先建议高风险人群尝试干预——这才是最具性价比的举措。

But even the guidelines where they examine people base looking at their baseline APOB or LDL cholesterol, the first thing they suggest, at least in the higher risk people, is try And that's where most of the bang for the buck is gonna be.

如果你仍有进一步降低指标的选择，试验表明确实能逐步减少事件发生率，但绝对风险降低幅度会小很多，大约在50%左右趋于平缓。

Now if you still have options that you can lower it further, yeah, the trials show, yeah, there is incremental reduction events, but it's a much smaller absolute risk reduction and dropping at the fifty percent or or so.

所以我不确定这是否回答了你的问题。

So I don't know if that answers your question.

因此大多数人的指标水平通过现代治疗和生活方式干预，往往都能达到生理浓度范围。

So most people don't have the type of levels where with modern therapeutics, with modern lifestyle, we can more often than not attain physiologic concentrations.

如果要讨论ApoB的理想值，如果我们能做到的话，可能应该控制在每分升50毫克以下。

And if I wanna talk about ApoB, that's probably under fifty milligrams per deciliter if we can get there.

这就是新生儿所拥有的。

That's what the newborns have.

这就是进入临床试验的时候。

That's when you go in clinical trials.

如果你将其降到那么低，就能看到最大的风险降低。

If you take it down that low, you see your most risk reduction.

到目前为止，至少通过药物降低载脂蛋白B（ApoB），使用目前FDA批准的药物，尚未发现有害信号。

And so far, at least with pharmacologic lowering of ApoB, with the currently FDA approved drugs, there is no signal of harm.

是啊。

Yeah.

说起来有趣，因为我正想说，在当前这批药物中，特别是PCSK9抑制剂，我们经常看到患者能轻松将ApoB降至20-40毫克/分升的范围。

Again, it's funny because I was just about to say with the current crop of drugs, specifically the PCSK nine inhibitors, we are routinely seeing patients who easily can get an ApoB into the twenty to forty milligram per deciliter range.

其实几个月前我们坐下来计算过，估算循环脂蛋白与细胞膜中实际含有的胆固醇量。

You and I actually sat down a couple of months ago and did a calculation to estimate how much cholesterol is actually contained in the circulating lipoproteins versus that which is in cell membranes.

你还记得和我一起做过这个吗？

Do you remember doing this with me?

不完全是，但我们正在开发相关公式。

Not per se, but and we're we're developing equations.

这方面你是专家。

You're the master of that.

嗯，就是这类事情。

Well, it was one of these things.

对吧？

Right?

这有点像，你看

It was it was sort of like, look.

要知道，当你观察一个人的血浆葡萄糖水平时，很快就能意识到它只占全身葡萄糖总量的极小部分。

You know, when you look at a person's plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body glucose.

同样地，人们对血浆胆固醇水平如此关注，但考虑到胆固醇的重要性，人们担心低胆固醇可能带来问题也是可以理解的。

And similarly, there's such a concern about plasma cholesterol level, but, you know, given how essential cholesterol is, it's understandable why people would be concerned that low cholesterol could be problematic.

但一旦你进行计算，就会发现体内几乎所有胆固醇都存在于细胞膜或类固醇生成组织中，循环中的胆固醇量只是总量的一个非常狭窄的窗口。因此，比如ApoB从60毫克/分升降至50毫克/分升，甚至更极端的如总胆固醇降低50%——

But once you do the calculation and realize virtually all of the cholesterol in the body is contained within the cell membrane or within the steroidal producing tissue, the circulating amount is a very narrow window into the total amount of cholesterol, and therefore a reduction of say 60 milligrams per deciliter to 50 milligrams per deciliter of ApoB or even something more extreme, like a full 50% reduction of total cholesterol.

从200毫克/分升降至100毫克/分升，并不代表全身胆固醇的显著减少。

200 milligrams per deciliter to a 100 milligrams per deciliter does not represent a significant reduction in total body cholesterol.

这是非常重要的一点。

This is a very important point.

明白吗？

Alright?

让我再重复一遍。

Let me repeat it.

你测量血浆中的总胆固醇水平，显示是200毫克/分升。

You have a total body cholesterol that you measure in the plasma that says, oh, it's two hundred milligrams per deciliter.

这个数值降到了100毫克/分升。

That goes down to a 100 milligrams per deciliter.

假设LDL部分从150降到75左右。

Let's say the LDL fraction reduced from, you know, a 150 to 75 or something.

有人可能会说，天啊。

Someone might say, god.

你刚刚把胆固醇减半了。

You just cut cholesterol in half.

考虑到胆固醇的重要性，这对你来说不可能是好事。

That can't be good for you given the importance of cholesterol.

但我的观点是，不行。

But my point is, no.

你只是把血浆中脂蛋白携带的胆固醇量减半了。

You simply cut the amount of cholesterol being carried by the lipoproteins in the plasma in half.

这并没有捕获大部分胆固醇。

That doesn't capture the majority of the cholesterol.

是的。

Yes.

谢谢你帮我回忆你所说的内容。

Thanks for refreshing my memory, what you're talking about.

现在真正重要的是全身各处的胆固醇池。

Now it's really pools of cholesterol throughout the body.

我很高兴你提到这点，因为这甚至在脂质学界都未被充分理解。

And I think I'm so glad you brought this up because this is just not even understood, even in the lipidology community.

我们拥有全身总胆固醇量。

We have a total body cholesterol.

基本上有三个池子。

There are basically three pools.

首先是大脑胆固醇，我们今天讨论的内容与之无关。

There's your brain, and nothing we're talking about today has anything to do with brain cholesterol.

这是一个独立的系统。

It's a separate system.

它不会与你体内的其他细胞相互作用，当然也不会与你血浆中的胆固醇相互作用。

It doesn't interact with the other cells in your body or certainly with the cholesterol in your plasma.

既然它不在大脑中，那么胆固醇在你体内的哪里？

So if it's not in your brain, where is cholesterol in your body?

它要么存在于所有外周细胞中（可能某些细胞含量更高），要么就在血浆中循环。

Well, it's either in all your peripheral cells, perhaps some more than others, or it's circulating in your plasma.

如果在血浆中，它具体在哪里？

And if it's in the plasma, where is it?

有微量胆固醇与白蛋白结合。

There's an itsy weensy amount bound to albumin.

更多胆固醇存在于体内运输的所有脂蛋白中，即你的载脂蛋白B和载脂蛋白A1颗粒。

There's more bound within all of the lip lipoproteins that are trafficking in your body, meaning your ApoB and your ApoA1 particles.

但信不信由你，如果我要为你检测血液胆固醇，我会吸出你的红细胞并从中提取胆固醇。

But believe it or not, if I wanted to search down blood cholesterol for you, I would suck out your red blood cells and extract cholesterol from them.

红细胞携带的胆固醇量远超你所有脂蛋白的总和。

Red blood cells carry far, far more cholesterol than do all of your lipoproteins put together.

你巧妙地提出了另一个关键点——脂蛋白内的胆固醇含量与细胞胆固醇甚至红细胞胆固醇毫无关联，希望大家都听明白了。

And the other crucial point you made subtly, and I hope everybody understood you, the amount of cholesterol within your lipoproteins has no correlation with your cellular cholesterol or even your red blood cell cholesterol.

因此无论你如何调节LDL总胆固醇或HDL胆固醇指标，这些数据都无法反映你对细胞胆固醇含量可能产生的影响。

So whatever however you're modulating some LDL total cholesterol, HDL cholesterol metric, that tells you nothing about what might you be doing to the cholesterol content of your cells.

所以如果你的LDL胆固醇值达到30也不必恐慌，因为我可以保证，即使血浆LDL胆固醇值如此，你体内几乎所有细胞都有充足胆固醇——它们能自主合成。

So don't have a panic attack if you're making LDL cholesterol 30, because I can assure you virtually every cell in your body, even if that's your plasma LDL cholesterol, has more than enough cholesterol because it can de novo synthesize it.

它能将其置于需要胆固醇的细胞膜或其他细胞器中。

It can put it in its cell membranes or other organelles that require cholesterol.

如果是类固醇生成组织，这类组织可以多产生一些或部分去脂化，这样当你通过生活方式或药物调节脂质时，外周细胞就不会缺乏胆固醇。

If it's a steurogenic, steurogenic tissue can produce a little more or perhaps delipidate some so there's no cell that's being deprived of cholesterol in the periphery when you are modulating lipids through lifestyle or drugs.

关于ASCVD（动脉粥样硬化性心血管疾病），我对降低ApoB的时机和幅度也变得更加积极。

So on ASCVD, I've also become far more aggressive on the timing and magnitude of ApoB reduction.

退一步问，ASCVD的主要或可调控病因是什么？

So take a step back and ask what are the leading causes or modifiable causes of ASCVD?

三大病因非常明确：吸烟、高血压和高β脂蛋白血症——后者其实就是指带有ApoB的脂蛋白过多。

The big three are pretty unambiguously smoking, hypertension and hyper beta lipoproteinemia, which is just a really fancy word for saying too many lipoproteins that have ApoB on them.

包括LDL、IDL、VLDL和LP(a)。通过测量ApoB——我之所以推崇测量ApoB而非仅测LP、LDL颗粒数或LDL胆固醇数值——是因为一个数字就能反映ApoB的总浓度。

So that's LDL, IDL, VLDL, LP By measuring ApoB, why I'm such a fan of measuring ApoB as opposed to just measuring LP, LDL particle number or LDL cholesterol number is we have one single number that captures the total concentration of ApoB.

尽管这与非HDL胆固醇高度相关（它比LDL胆固醇更能代表风险），但ApoB仍更优，这点已被证实。

And while that's pretty well associated with non HDL cholesterol, which is a far better surrogate than LDL cholesterol, it's still better and that's been demonstrated.

我想我们在之前的播客中讨论过非HDL胆固醇与ApoB之间的不一致性。

I think we even covered that in a previous podcast where we went over the discordance between non HDL cholesterol and ApoB.

现在问题是：何时开始降低ApoB？该降低多少？

So now the question becomes, well, when should you start ApoB reduction and how much should you lower it?

坦白说，我曾持这样的观点：如果40岁的人ApoB升高——我们量化来说——

And I'll tell you, I used to take a point of view that if a 40 year old had an elevated ApoB, let's just put some numbers to this, right?

ApoB的第20百分位大约是80毫克/分升。

So the twentieth percentile of ApoB is about eighty milligrams per deciliter.

过去我会说：假设某人处于第50百分位，40岁，冠状动脉钙化积分为零，对降脂治疗犹豫不决，且假设他们没有胰岛素抵抗，你已通过营养干预做了所有合理措施——我就不会太强求治疗。

I used to say that let's say somebody was at the fiftieth percentile, they're 40 years old, their calcium score is zero and they were ambivalent about lipid lowering therapy, and let's assume that they're not insulin resistant and you've done all of the things that you can do reasonably with nutrition, I wouldn't push that hard.

我现在持有一个截然不同的立场，即我对他人的立场与对自己的立场一致：有压倒性证据表明，婴儿水平的ApoB在任何方面都没有危害。

I've now taken a very different stand, which is I've basically taken the stand with others that I've taken with myself, which is the evidence is overwhelming that infantile levels of ApoB are not deleterious in any way.

这意味着30至40毫克/分升的ApoB水平（儿童普遍具有的水平）不仅对儿童毫无风险——这一点无需解释，而且从成人药物干预降低ApoB水平的文献数据来看，我们确实需要更低的数值。

Meaning an ApoB of thirty to forty milligrams per deciliter, which is the level that children would have, poses not only no risk to children as evidenced by the fact that, I mean, that doesn't require an explanation, but as evidenced by what we see in the literature on adults with levels that have been pharmacologically reduced, tells me that we need to be lower.

而显现疗效所需的时间长度告诉我们：不能等到问题出现才行动。

And the amount of time it takes to see a benefit tells me we don't want to wait until there's an issue.

换句话说，如果我们开始治疗仅仅因为某人冠状动脉钙化评分阳性——这个话题我们之前已经详细讨论过。

In other words, if the reason we begin therapy is because somebody has a positive calcium score, which again, we covered this in great detail.

对于听众朋友们，我们有一个专门的ASCVD问答环节，用九十分钟深入探讨相关内容，感兴趣可以关注。

So for people listening, we have a dedicated ASCVD AMA, which goes into heavy detail for about ninety minutes on all this stuff where if this is of interest.

那个问答环节非常精彩，基本涵盖了我主张'早干预、强干预'的所有理论依据。

That's a great AMA that goes super deep on basically all of the reasons why I think my point of view now is treat early and treat aggressively.

现在我要发表一个非常大胆的观点。

And I will now also make a very bold statement.

让我们再次从思想实验开始：

Again, let's start with the thought experiment, right?

如果针对结肠癌的思想实验是：从30岁开始每天做肠镜，能否消除结肠癌死亡病例？

If the thought experiment for colon cancer was do a colonoscopy every day on a person's life starting at the age of 30, would you eliminate colon cancer deaths?

我认为答案是肯定的。

I think the answer is yes.

同理，我会主张让全民在20多岁时就将ApoB药物控制在20-30mg/dL范围内。

And similarly, I would say pharmacologically lower ApoB to somewhere in the twenty to thirty mgdL range for everybody in the population while someone is in their 20s.

这样能否消除动脉粥样硬化性心血管疾病？

Can you eliminate ASCVD?

我认为答案很可能是肯定的。

And I think the answer is probably yes.

换句话说，我认为你基本上要做的是消除由动脉粥样硬化引起的死亡。

In other words, I think what you're basically going to do is eliminate death from atherosclerotic causes.

那需要在二十多岁时就开始吗？

And that would need to be started in twenties?

我想是的。

I think so.

对。

Yeah.

非常早期。

Very early on.

没错。

Yeah.

那么再次强调，如何将这个思想实验转化为实际应用？

So again, how do you take that thought experiment and turn it into a practical implication?

因为我不认为让每个20岁的人都消除他们的ApoB是可行的。

Because I don't think it's practical to take every 20 year old and obliterate their ApoB.

尽管我们确实会对部分有明显基因异常的患者这样做，比如那些患有家族性高胆固醇血症相关基因异常的患者群体。

Although it's clearly something we do in the subset of patients who have significant genetic abnormalities such as the cluster of genetic abnormalities that coalesce around a condition called familial hypercholesterolemia.

我们确实通常会在这些患者十几岁时就开始用药治疗。

We certainly do medicate those patients usually as teenagers.

所以这并不是什么完全疯狂的想法。

So this is not some completely crazy idea.

但从实际意义来说，基本上当你三十多岁或四十出头时，如果你的ApoB指标哪怕只是高于第二十百分位数，都应该完全降低它。

But I think practically what it means is basically by the time you're in your late thirties or early forties, if you have any measure of ApoB that's even north of the twentieth percentile, that should be completely lowered.

所以在某种程度上，我会将ApoB上限值60视为临界线。

So in some ways I would view an APO B ceiling of 60 as the limit.

这大约处于第五百分位水平。

And that's probably at about the fifth percentile.

你大概会希望所有人都低于第五百分位。

You'd sort of want everybody to be below the fifth percentile.

希望您喜欢本期《驱动》特别节目。

We hope you enjoyed this special episode of The Drive.

这是最受热议的话题之一，不仅在我们往期播客中，也是我们通讯简报里经常探讨的内容。

This is one of the most talked about topics, not only on previous podcasts, but also one that we write about frequently in our newsletter.

若想深入了解，相关素材非常丰富，我们会在节目注释中附上所有链接。

If you want to dive deeper, there's no shortage of content and we'll link to it all in the show notes.

不过，我们希望本期内容能让您对ASCVD、胆固醇和ApoB有更深入的认识。

However, we hope this provided you with a little more understanding of ASCVD, cholesterol, and ApoB.

感谢收听本周《驱动》节目。

Thank you for listening to this week's episode of The Drive.

如果您对我们讨论的任何话题想进一步探索，我们创建了会员计划，无需依赖付费广告就能为您带来更多独家深度内容。

If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads.

我们的目标是确保会员获得的回报远超订阅价格。

It's our goal to ensure members get back much more than the price of the subscription.

为此，会员福利包含多项权益。

Now to that end, membership benefits include a bunch of things.

第一，我们每期节目都有超全面的播客笔记，详细记录讨论的每个主题、论文、人物和事物。

One, totally kick ass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode.

坊间传闻，没有哪家的节目笔记能比得上我们的。

The word on the street is nobody's show notes rival these.

每月都有AMA（问我任何问题）特辑，完整收听这些节目。

Monthly AMA episodes or ask me anything episodes, hearing these episodes completely.

加入我们的私密播客订阅，无需听这类宣传就能收听所有内容。

Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this.

QALYs是我们每周二至五发布的超短播客，精选《The Drive》往期节目中最好的问题、话题和策略。

The QALYs, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive.

这是回顾往期内容的绝佳方式，无需逐一听完每期节目。

This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone.

我深信不疑的产品优惠折扣（并非付费推广），以及随时间逐步增加的其他众多福利。

Steep discounts on products that I believe in, but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on.

若想了解更多会员专属福利，请访问peterateamd.com/subscribe。

If you wanna learn more and access these member only benefits, you can head over to peterateamd.com forward slash subscribe.

你可以在Twitter、Instagram和Facebook上找到我，账号均为PeterAttiaMD。

You can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD.

也欢迎在Apple Podcasts或其他播客平台为我们留下评价。

You can also leave us a review on Apple Podcasts or whatever podcast player you listen on.

本播客仅提供一般性信息，不构成医疗、护理或其他专业医疗服务实践，包括医疗建议的提供。

This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

不构成医患关系。

No doctor patient relationship is formed.

本播客信息及链接材料的使用风险由用户自行承担。

The use of this information and the materials linked to this podcast is at the user's own risk.

本播客内容不可替代专业医疗建议、诊断或治疗。

The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment.

用户不应因自身任何健康状况而忽视或延迟获取医疗建议，并应就此类情况寻求医疗专业人员的帮助。

Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions.

最后，我极其重视利益冲突问题。

Finally, I take conflicts of interest very seriously.

关于我的所有披露信息及我投资或顾问的公司，请访问peterattiamd.com/about，我在该页面维护着这些公司的最新动态列表。

For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com slash about where I keep an up to date and active list of such companies.