summarize this "It’s not as if they were about to have heart attacks. The atherosclerotic
process moves very slowly. This may be partly because of the action of
HDLs. If an HDL particle arrives at our crime scene, with the foam cells and
fatty streaks, it can suck the cholesterol back out of the macrophages in a
process called delipidation. It then slips back across the endothelial layer and
into the bloodstream, to deliver the excess cholesterol back to the liver and
other tissues (including fat cells and hormone-producing glands) for reuse.
Its role in this process of “cholesterol efflux” is one reason why HDL is
considered “good,” but it does more than that. Newer research suggests that
HDL has multiple other atheroprotective functions that include helping
maintain the integrity of the endothelium, lowering inflammation, and
neutralizing or stopping the oxidation of LDL, like a kind of arterial
antioxidant.
The role of HDL is far less well understood than that of LDL. The
cholesterol content in your LDL particles, your “bad” cholesterol number
(technically expressed as LDL-C),
[*3] is actually a decent if imperfect proxy
for its biologic impact; lots of studies have shown a strong correlation
between LDL-C and event risk. But the all-important “good cholesterol”
number on your blood test, your HDL-C, doesn’t actually tell me very much
if anything about your overall risk profile. Risk does seem to decline as HDLC rises to around the 80th percentile. But simply raising HDL cholesterol
concentrations by brute force, with specialized drugs, has not been shown to
reduce cardiovascular risk at all. The key seems to be to increase the
functionality of the particles—but as yet we have no way to do that (or
measure it).
HDL may or may not explain why centenarians develop heart disease two
decades later than average, if at all; remember, three of the most prominent
“longevity genes” discovered to date are involved with cholesterol transport
and processing (APOE and two others, CETP and APOC3). And it’s not just
centenarians: I have patients walking around whose lipoprotein panels read
like a death sentence, with sky-high LDL-C and apoB, but by every single
measure that we have—calcium score, CT angiogram, you name it—they
show no sign of disease. Yet as of now, we cannot give a satisfactory
explanation for why. I feel strongly that if we are to make any further
progress attacking cardiovascular disease with drugs, we must start by better
understanding HDL and hopefully figuring out how to enhance its function.
But I digress. Back at the crime scene, the ever-growing number of foam
cells begin to sort of ooze together into a mass of lipids, like the liquefying
contents of a pile of trash bags that have been dumped on the front lawn. This
is what becomes the core of our atherosclerotic plaque. And this is the point
where breaking and entering tilts over into full-scale looting. In an attempt to
control the damage, the “smooth muscle” cells in the artery wall then migrate
to this toxic waste site and secrete a kind of matrix in an attempt to build a
kind of barrier around it, like a scar. This matrix ends up as the fibrous cap
on your brand-new arterial plaque.
More bad news: None of what’s gone on so far is easily detectable in the
various tests we typically use to assess cardiovascular risk in patients. We
might expect to see evidence of inflammation, such as elevated levels of Creactive protein, a popular (but poor) proxy of arterial inflammation. But it’s
still mostly flying below our medical radar. If you look at the coronary
arteries with a CT scan at this very early stage, you will likely miss this if
you’re looking only for calcium buildup. (You have a better chance of
spotting this level of damage if using a more advanced type of CT scan,
called a CT angiogram, which I much prefer to a garden-variety calcium
scan[*4] because it can also identify the noncalcified or “soft” plaque that
precedes calcification.)
As this maladaptive repair or remodeling process continues, the plaque
will continue to grow. At first, this expansion is directed toward the outer
arterial wall, but as it continues it may encroach on the lumen, the passage
through which blood flows—in our analogy, blocking traffic in the street
itself. This luminal narrowing, known as stenosis, can also be seen in an
angiogram.
At a certain point in this process, the plaque may start to become
calcified. This is what (finally) shows up on a regular calcium scan.
Calcification is merely another way in which the body is trying to repair the
damage, by stabilizing the plaque to protect the all-important arteries. But it’s
like pouring concrete on the Chernobyl reactor: you’re glad it’s there, but you
know there’s been an awful lot of damage in the area to warrant such an
intervention. A positive calcium score is really telling us that there are almost
certainly other plaques around that may or may not be stabilized (calcified).
If the plaque does become unstable, eroding or even rupturing, you’ve
really got problems. The damaged plaque may ultimately cause the formation
of a clot, which can narrow and ultimately block the lumen of the blood
vessel—or worse, break free and cause a heart attack or stroke. This is why
we worry more about the noncalcified plaques than the calcified ones.
Normally, however, most atherosclerotic plaques are fairly undramatic.
They grow silently and invisibly, gradually occluding the blood vessel until
one day the obstruction, due to the plaque itself or a plaque-induced clot,
becomes a problem. For example, a sedentary person may not notice that she
has a partially blocked coronary artery until she goes outside to shovel snow.
The sudden demands on her circulatory system can trigger ischemia
(decreased blood delivery of oxygen) or infarction (tissue death from no
blood flow)—or, in layman’s terms, a heart attack or a stroke.
It may seem sudden, but the danger was lurking all along.
—
When I finally recognized my own cardiovascular risk, back in my thirties, I
had no idea about how any of this complex disease process worked. Looking
back, it’s clear that I had quite a few of the major and lesser risk factors
already checked off. I didn’t smoke, which is perhaps the most potent
environmental risk driver, and my blood pressure was normal, but I had other
problems. And as my calcium score revealed, I already had a small, calcified
plaque in the upper part of my left anterior descending (LAD) artery, one of
the main arteries supplying my heart. There may have been other bad things
happening there as well, but because I did not have a CT angiogram at this
time, I had no sense of what kind of damage existed elsewhere in my
coronary arteries. Anything shy of calcification is not identified by the
calcium score.
Clearly, Not-Thin Peter was already on the road to heart disease. My
waist size was on track to hit 40 by the time I turned forty, a clear sign of my
metabolic dysfunction. Underneath my belt, I was likely accumulating visceral
fat. I was also insulin resistant, an enormous risk driver for cardiovascular
disease. Though my blood pressure was fine, I suspect it would have
deteriorated fairly rapidly as I aged, as hypertension seems rampant in my
family. I probably also had high levels of uric acid, which as we saw in the
previous chapter is often found in the company of high blood pressure and
other signs of metabolic dysfunction. All of these contribute to another
necessary (but not sufficient) condition that is required for atherosclerosis to
develop, and that is inflammation. The endothelial barrier, in particular, is
uniquely vulnerable to damage from inflammation.
But no physician would likely have treated me for any of this. My blood
panel did not signal any significant risk. My LDL-C tested at 110 to
120 mg/dL, just slightly higher than normal but not a cause for concern,
particularly in a younger person. My triglycerides were on the higher side,
slightly north of 150 mg/dL, but that did not set off any alarm bells either. I
now know that these numbers almost certainly indicated a high concentration
of atherogenic apoB particles—but no one bothered to test my apoB number,
either.
Back then, nearly fifteen years ago, the apoB test (simply, measuring the
concentration of apoB-tagged particles) was not commonly done. Since then,
evidence has piled up pointing to apoB as far more predictive of
cardiovascular disease than simply LDL-C, the standard “bad cholesterol”
measure. According to an analysis published in JAMA Cardiology in 2021,
each standard-deviation increase in apoB raises the risk of myocardial
infarction by 38 percent in patients without a history of cardiac events or a
diagnosis of cardiovascular disease (i.e., primary prevention). That’s a
powerful correlation. Yet even now, the American Heart Association
guidelines still favor LDL-C testing instead of apoB. I have all my patients
tested for apoB regularly, and you should ask for the same test the next time
you see your doctor. (Don’t be waved off by nonsensical arguments about
“cost”: It’s about twenty to thirty dollars.)
I was still in my thirties, yet I likely already had all three of the major
prerequisites for heart disease: significant lipoprotein burden or apoB, LDL
oxidation or modification (leading to the plaques that my calcium scan
revealed), and a high level of background inflammation. None of these is
enough to guarantee that someone will develop heart disease, but all three are
necessary to develop it. We are fortunate that many of these conditions can be
modulated or nearly eliminated—including apoB, by the way—via lifestyle
changes and medications. As we’ll discuss in the final section, I take a very
hard line on lowering apoB, the particle that causes all this trouble. (In short:
get it as low as possible, as early as possible.)
But before we go there, I want to talk about another deadly but relatively
little-known lipoprotein that is likely responsible for graveyards full of sudden
cardiac arrest victims, people whose conventional cholesterol panels and risk
factor profiles otherwise looked fine. I don’t have this particular issue,
thankfully, but a very good friend of mine does, and finding out about it in a
timely manner likely saved his life"