This is Part 5 of The Cause That Isn’t Destiny, an eight-part series on cholesterol, causality, and the limits of any single measurement to predict an individual’s future.
There’s something genuinely rewarding about looking at a coronary CT scan the way it’s done today. Imaging technology has advanced enormously in recent years, and for an aging cardiologist like me, it’s as if a whole new world has opened up.
In medicine, and in clinical practice, we spend a great deal of time dealing with probabilities. Cholesterol, blood pressure, smoking, diabetes; all of it tells us something about what might happen if nothing is done. But these are just scattered puzzle pieces lying around. We have to put them together, because the outcome is often different from what we expected. That’s exactly what happened with the woman we met at the start of this series.
Her coronary calcium score was zero. No calcification at all in this 78-year-old woman. That’s certainly reassuring, but far from enough. An important piece of the puzzle is still missing. A calcium score, after all, says nothing about plaque that hasn’t calcified.
To get an even better picture of her coronary arteries, she also underwent a contrast-enhanced coronary CT angiogram (CCTA). Contrast shows us the vessel lumen, which lets us identify narrowing, as well as bulges from the vessel wall that reflect soft plaque. None were seen in her.
Let’s recap briefly. The woman is seventy-eight, and her LDL cholesterol is above 200 mg/dL (5.2 mmol/L). We certainly have no idea what it was when she was thirty or forty. There’s every reason to think, though, that she has carried a substantial amount of LDL particles in her blood for a very long time. And yet we find no sign of atherosclerosis, which is quite something for coronary arteries that have been around for seventy-eight years. We haven’t, admittedly, examined her arteries under a microscope, but we still have a good idea of what her coronary arteries look like, and we also know it’s very unlikely she’ll go on to develop serious coronary disease.
So far we’ve spent a good deal of time discussing particles that travel in the blood and can make their way into the artery wall, become lodged there, and set off the so-called atherosclerotic process. Now it’s time to look closer at the artery wall itself, since that’s where it all happens. There’s something in the artery wall that receives the particles, and something else that either sends them back out again, or doesn’t. We need to know what that is.
We tend to talk about LDL exposure as though every LDL particle encounters the same artery wall. It doesn’t. Even within the same person, atherosclerosis has its favorite places. It’s usually most prominent at bends and at points where arteries branch, where blood flow tends to be more turbulent. What’s remarkable about this is that just above or below, where the blood flow is steadier, the artery can stay strikingly clean despite being in contact with exactly the same blood, containing exactly the same LDL particles, for exactly the same number of years.
The artery wall isn’t like a shield that absorbs arrows as they arrive. The innermost surface, the endothelium, is a living layer of cells in direct contact with the blood, constantly responding to what’s happening around it. It senses blood flow and pressure. It controls whether the vessel contracts or dilates. It’s in constant communication with blood cells, inflammatory cells, and various substances in the blood. Some people’s endothelium is clearly better at this job than other people’s, and that difference in permeability shows up from moment to moment and from person to person.
Genetics is thought to play a major role in how the endothelium operates. So do environmental factors. Smoking can damage endothelial function. So can high blood pressure, diabetes, and insulin resistance. Age affects it too.
Many biological variables end up being used largely because they can be measured. We measure blood pressure in millimeters of mercury. We can measure glucose, triglycerides, ApoB, and inflammatory markers in the blood. What we can’t measure is one person’s overall capacity to live with all of this for eighty years. Cholesterol and blood pressure have come to dominate the conversation about cardiovascular risk partly for this reason. They give us a number, and we can measure the effect of various interventions on that number. There’s no equivalent number for the endothelium or the artery wall itself.
I hope I’ve made a convincing case here that endothelial function matters fundamentally to the development of atherosclerosis, and that these properties are decisive for whether ApoB particles get into the artery wall at all.
If such particles have crossed the endothelium, other factors then determine whether they stay behind or leave again. Genetics also plays a role here, along with particle size and density and, to some extent, the composition of the proteoglycans in the artery wall itself. Where and when binding actually occurs within the same artery depends largely on local and acquired factors: branching points, disturbed flow, smoking, high blood pressure, aging. It’s quite clear that genetics lay the foundation. The environment, however, also seems to determine much of how and where atherosclerosis actually develops.
Once particles lodge in the artery wall, other factors come into play. An inflammatory response kicks in. Macrophages arrive at the site. Cholesterol accumulates here and often becomes highly visible. Blood pressure then adds mechanical stress on top of all this, and the higher it is, the worse. All of this leads the artery wall to undergo a process called remodeling. Diabetes and insulin resistance can also have a major effect on what’s happening here.
When we picture this complicated situation, it can be hard to understand why we keep talking about LDL all the time. I’m not saying it doesn’t matter, because the fact is that most ApoB particles lodged in the artery wall are LDL particles. But if we focus only on LDL, we’re looking at the rain itself, not the ground it falls on. Some ground dries well. Some doesn’t.
I don’t know which factors protected the woman we’ve been discussing here. Maybe there were many of them. It could be something related to her genetics, her endothelium, her inflammatory response, or how her arteries handle ApoB particles when they arrive. Maybe there are important protective factors we don’t yet know about. The only thing I know for certain is what I see: after seventy-eight years, there’s remarkably little to find in her coronary arteries, given an LDL cholesterol level most doctors would find uncomfortable.
Her brother is a different matter.
We never saw his coronary arteries before he died. We know he had a sudden heart attack at fifty-two, following an acute occlusion of the left anterior descending artery. He may have had extensive atherosclerosis. We don’t know whether his calcium score would have been 500, 50, or zero, because it was never measured. If he’d had a coronary CT scan a week before his death, there’s a good chance it would still have shown very little. Coronary disease is, after all, often unpredictable, and takes many different forms.
Now we need to talk about something called plaque rupture. Without understanding it, we’ll probably never understand how her brother died.
Size doesn’t tell you which plaque will rupture. A plaque can sit quietly in an artery for years without causing any trouble. The plaques prone to rupture pose the greatest danger, and in that case, plaque size matters less.
When a plaque ruptures, its contents come into contact with the blood. This isn’t unlike what happens when a wound forms in the skin and causes bleeding. Our clotting system then does exactly what it’s meant to do: it tries to seal the wound by forming a clot. At the same time, clot-dissolving systems try to break the clot back down. The outcome depends on which system wins out. Unfortunately, a clot that forms in a coronary artery under these circumstances can block the vessel completely and cause blood flow to stop entirely. This is a coronary occlusion.
It’s not unlikely that this is what happened to the brother. It doesn’t take extensive coronary atherosclerosis or particularly high LDL cholesterol for this to happen. Of course I can’t know this for certain. These are guesses. And there’s something else I don’t know. I don’t know his Lp(a) level.
Lipoprotein(a), usually shortened to Lp(a), is a peculiar particle, and in many ways different from other particles classified as atherogenic. Its structure resembles LDL in many respects. Lp(a) carries ApoB, like LDL, and carries cholesterol too. But it comes with something extra: a second protein stuck onto the particle, called apolipoprotein(a). That addition matters more than it sounds like. Lp(a) gets into the artery wall the same way other ApoB particles do. It might nudge clotting too. Nobody’s really sure how much of Lp(a)’s danger comes from that versus everything else it’s doing. High levels track with atherosclerotic disease, and with calcification of the aortic valve too.
Unlike LDL cholesterol, there’s little we can do to influence the amount of Lp(a) in the blood, since it’s determined almost entirely by genetics. It makes little difference to our Lp(a) level whether we eat a lot of vegetables or take a lot of walks. Lp(a) has to be measured specifically. There’s no other way to estimate it or calculate it.
Lp(a) is especially interesting in people who develop coronary disease unusually early in life, particularly when the usual risk factors don’t seem to explain what happened. Which brings us back, again, to the brother.
Maybe his Lp(a) level was high, maybe it wasn’t. It’s tempting to just assert it and feel like we’ve finally solved the puzzle. I still think we shouldn’t. We’d simply be swapping one number for another, doing exactly what this series is meant to teach us to avoid. But I’ll fully admit I wish someone had measured it. Not because I think it would necessarily have explained his death, but because it could have shed light on one important link in the causal chain, one that his LDL cholesterol clearly did not.
All of this leaves the siblings’ story in a rather interesting place. She has a frightening blood value but reassuring arteries; he had a relatively reassuring blood value but an outcome that was anything but reassuring. We eventually examined her coronary arteries. We only investigated his once it was too late to help him.
Blood tests tell us how much of something is circulating in our bloodstream. Genetics can sometimes tell us why those values are what they are. Imaging can shed light on what that has meant for our coronary arteries. None of this, on its own, tells us what a coronary artery will ultimately do. That’s one of the questions we still have to answer.
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