CHAPTER 7

The Ticker

Confronting—and Preventing—Heart Disease, the Deadliest Killer on the Planet

There is some risk involved in action, there always is. But there is far more risk in failure to act.

—Harry S. Truman

One downside of my profession is that too much knowledge can become its own kind of curse. As I delved back into the practice of medicine, after my hiatus in the business world, it dawned on me that I already know how I am likely to die: I seem destined to die from heart disease.

I wonder what took me so long to get the hint. When I was five, my father’s older brother Francis—his favorite of eight siblings—died of a sudden heart attack at forty-six. When my own brother Paul was born two days later, my grief-stricken father chose Francis as his middle name. Just as certain names run in families, a propensity for early cardiovascular disease seems to run in mine. Another uncle suffered a fatal heart attack at forty-two, while a third made it to age sixty-nine before his heart killed him, which is perhaps more typical but still way too young.

My dad is lucky, because he has lived to the ripe old age of eighty-five (so far). But even he has a stent in one of his coronary arteries, a souvenir of his own minor event in his midsixties. He felt chest pain one day at the limestone quarry where he worked, and ended up in the ER, where it was determined that he had had a recent infarction. The stent, a little sleeve of metal wire, was put in a year or so later. I’m not actually convinced that the stent did anything—he was not experiencing symptoms at the time it was placed—but perhaps it scared him enough to be more diligent with his medications and his diet.

So even though my cholesterol profile is excellent, and I eat sensibly, never smoke, have normal blood pressure, and rarely drink alcohol, I’m still at risk. I feel like I’m trapped in that Charlie Munger anecdote, about the guy who just wants to know where he’s going to die, so he’ll make sure never to go there. Unfortunately, too often heart disease finds you.

When I was in medical school, my first-year pathology professor liked to ask a trick question: What is the most common “presentation” (or symptom) of heart disease? It wasn’t chest pain, left arm pain, or shortness of breath, the most common answers; it was sudden death. You know the patient has heart disease because he or she has just died from it. This is why, he claimed, the only doctors who truly understand cardiovascular disease are pathologists. His point: by the time a pathologist sees your arterial tissue, you are dead.

While mortality rates from those first, surprise heart attacks have dropped significantly, thanks to improvements in basic cardiac life support and time-sensitive interventions such as cardiac catheterization and clot-obliterating drugs that can halt a heart attack almost in its tracks, they are still fatal roughly one-third of the time, according to Ron Krauss, senior scientist and director of atherosclerosis research at Children’s Hospital Oakland Research Institute.

Globally, heart disease and stroke (or cerebrovascular disease), which I lump together under the single heading of atherosclerotic cardiovascular disease, or ASCVD, represent the leading cause of death, killing an estimated 2,300 people every day in the United States, according to the CDC—more than any other cause, including cancer. It’s not just men who are at risk: American women are up to ten times more likely to die from atherosclerotic disease than from breast cancer (not a typo: one in three versus one in thirty). But pink ribbons for breast cancer far outnumber the American Heart Association’s red ribbons for awareness of heart disease among women.

My uncles’ deaths remain a mystery to me. They lived in Egypt, and I have no idea what their blood work looked like or, more importantly, what kind of shape their coronary arteries were in. I’m pretty sure they smoked, but perhaps if they had had access to better medical care they too might have survived their heart attacks, as my father did. Or perhaps their fates were inescapable, tied to their genes. All I know is that forty-two seems really young to keel over from a heart attack.

I’d known about my uncles all my life, but the implication of their stories only really hit me in my midthirties, when I became a father for the first time. All of a sudden, the awareness of my own mortality crashed over my head like a rogue wave, coming out of nowhere on one of my long swims. This book probably wouldn’t have been written if not for that family history.

Like most thirty-six-year-olds, Not-Thin Peter scarcely gave a thought to heart disease. Why should I have? My heart was strong enough to have propelled me across the twenty-one-mile-wide Catalina Channel, working steadily for more than fourteen hours, like a Mercedes diesel engine purring along smoothly inside my chest. I was in great shape, I thought. But I was nevertheless worried, on account of my family history. So I insisted that my doctor order a CT scan of my heart, and it wound up changing my whole outlook on life.

The scan was calibrated to detect calcification in my coronary arteries, a sign of advanced atherosclerosis. The results showed that I had a calcium “score” of 6. That sounds low, and in absolute terms it was; someone with severe disease could return a score well over 1,000. But for someone age thirty-six, it should have been zero. My score of 6 meant that I had more calcium in my coronary arteries than 75 to 90 percent of people my age. As I dug deeper into the pathology of this disease, I was dismayed to learn that it was already fairly late in the game. A calcium score is treated as a predictor of future risk, which it is, but it is also a measure of historical and existing damage. And I was already off the charts. I was only in my midthirties, but I had the arteries of a fifty-five-year-old.

I was upset by this revelation, although knowing what I know now, it’s not at all surprising. At the time, I was overweight and borderline insulin resistant, two huge risk factors that by themselves help create an environment that fosters and accelerates the development of atherosclerotic lesions. Yet because my calcium score was “only” 6, and my all-important LDL (“bad”) cholesterol was “normal,” the medical advice I received was—wait for it—to do nothing. Sound familiar?

Doing nothing is not my style, as you may have gathered by now. I sensed that I was not on a good trajectory, and I needed to figure out how to change it. My curiosity launched me on a years-long quest to truly understand atherosclerosis. The story I uncovered, with the generous help of my mentors Tom Dayspring, Allan Sniderman, and Ron Krauss (among others), all of whom are world-renowned experts in cardiac pathology and/or the study of lipids, was flabbergasting.

While heart disease is the most prevalent age-related condition, it is also more easily prevented than either cancer or Alzheimer’s disease. We know a lot about how and why it begins and the manner in which it progresses. While it can’t exactly be cured or reversed the way type 2 diabetes (sometimes) can, it is relatively easy to delay if you’re smart and you get on the case early. It’s also the rare example of a chronic disease where Medicine 2.0 already does focus on prevention, to some extent. We have a cabinet full of blood pressure–and cholesterol–lowering medications that really do reduce the risk of death for many patients, and we have blood tests and imaging tests (like my calcium scan) that can at least give us a snapshot, however blurry, of someone’s cardiovascular health. It’s a start.

In spite of how well we understand atherosclerotic disease and its progression, and how many tools we have to prevent it, it still kills more people than cancer in the United States each year, many of them completely out of the blue. We’re losing the war. I don’t claim to have all the answers, but I think this is at least partly due to the fact that we still have some major blind spots in our understanding of what truly drives our risk for the disease, how it develops, and most of all when we need to act to counter its momentum.

The fundamental problem, I believe, is classic Medicine 2.0: guidelines for managing cardiovascular risk are based on an overly short time horizon, compared to the time line of the disease. We need to begin treating it, and preventing it, much earlier. If we could get it right, the potential payoff would be huge: the high prevalence of male centenarians on the island of Sardinia, for example, has largely been attributed to their ability to avoid or delay circulatory disease. Fewer Sardinian men die from heart disease between the ages of eighty and one hundred than anywhere else in Italy.

But we’re nowhere near that. Heart disease remains our deadliest killer, the worst of the Horsemen. In the next few pages, I hope to convince you that it need not be—that with the right strategy, and attention to the correct risk factors at the correct time, it should be possible to eliminate much of the morbidity and mortality that is still associated with atherosclerotic cardiovascular and cerebrovascular disease.

Bluntly put: this should be the tenth leading cause of death, not the first.

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Scientists have been exploring the medical mysteries of the human heart for almost as long as poets have been probing its metaphorical depths. It is a wondrous organ, a tireless muscle that pumps blood around the body every moment of our lives. It pounds hard when we are exercising, slows down when we sleep, and even microadjusts its rate between beats, a hugely important phenomenon called heart rate variability. And when it stops, we stop.

Our vascular network is equally miraculous, a web of veins, arteries, and capillaries that, if stretched out and laid end to end, would wrap around the earth more than twice (about sixty thousand miles, if you’re keeping score). Each individual blood vessel is a marvel of material science and engineering, capable of expanding and contracting dozens of times per minute, allowing vital substances to pass through its membranes, and accommodating huge swings in fluid pressure, with minimal fatigue. No material created by man can even come close to matching this. If one vessel is injured, others regrow to take its place, ensuring continuous blood flow throughout the body.

Incredible as it is, however, our circulatory system is far from perfect—in fact, it is almost perfectly designed to generate atherosclerotic disease, just in the course of daily living. This is in large part because of another important function of our vasculature. In addition to transporting oxygen and nutrients to our tissues and carrying away waste, our blood traffics cholesterol molecules between cells.

It’s practically a dirty word, cholesterol. Your doctor will probably utter it with a frown, because as everyone knows, cholesterol is evil stuff. Well, some of it is—you know, the LDL or “bad” cholesterol, which is inevitably counterpoised against the HDL, or “good” cholesterol. I practically need to be restrained when I hear these terms, because they’re so meaningless. And your “total cholesterol,” the first number that people offer up when we’re talking about heart disease, is only slightly more relevant to your cardiovascular risk than the color of your eyes. So let’s hit rewind and look at what cholesterol really is, what it does, and how it contributes to heart disease.

Cholesterol is essential to life. It is required to produce some of the most important structures in the body, including cell membranes; hormones such as testosterone, progesterone, estrogen, and cortisol; and bile acids, which are necessary for digesting food. All cells can synthesize their own cholesterol, but some 20 percent of our body’s (large) supply is found in the liver, which acts as a sort of cholesterol repository, shipping it out to cells that need it and receiving it back via the circulation.

Because cholesterol belongs to the lipid family (that is, fats), it is not water soluble and thus cannot dissolve in our plasma like glucose or sodium and travel freely through our circulation. So it must be carted around in tiny spherical particles called lipoproteins—the final “L” in LDL and HDL—which act like little cargo submarines. As their name suggests, these lipoproteins are part lipid (inside) and part protein (outside); the protein is essentially the vessel that allows them to travel in our plasma while carrying their water-insoluble cargo of lipids, including cholesterol, triglycerides, and phospholipids, plus vitamins and other proteins that need to be distributed to our distant tissues.

The reason they’re called high- and low-density lipoproteins (HDL and LDL, respectively) has to do with the amount of fat relative to protein that each one carries. LDLs carry more lipids, while HDLs carry more protein in relation to fat, and are therefore more dense. Also, these particles (and other lipoproteins) frequently exchange cargo with one another, which is part of what drives me crazy about labeling them “good” and “bad.” When an HDL transfers its “good cholesterol” to an LDL particle, does that cholesterol suddenly become “bad”?

The answer is no—because it’s not the cholesterol per se that causes problems but the nature of the particle in which it’s transported. Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provide structure, stability, and, most importantly solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB). This distinction may seem trivial, but it goes to the very root cause of atherosclerotic disease: every single lipoprotein that contributes to atherosclerosis—not only LDL but several others[*1]—carries this apoB protein signature.

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Another major misconception about heart disease is that it is somehow caused by the cholesterol that we eat in our diet. According to this dated and simplistic view, eating cholesterol-rich foods causes the so-called bad cholesterol to accumulate in our blood and then build up on our artery walls, as if you poured bacon grease down the kitchen drain every time you made breakfast. Sooner or later, your sink will back up.

The humble egg, in particular, was singled out in a 1968 proclamation by the American Heart Association, accused of causing heart disease because of its high cholesterol content. It has remained in nutritional purgatory for decades, even after reams of research papers showing that dietary cholesterol (and particularly egg consumption) may not have much to do with heart disease at all. Eating lots of saturated fat can increase levels of atherosclerosis-causing lipoproteins in blood, but most of the actual cholesterol that we consume in our food ends up being excreted out our backsides. The vast majority of the cholesterol in our circulation is actually produced by our own cells. Nevertheless, US dietary guidelines warned Americans away from consuming foods high in cholesterol for decades, and nutrition labels still inform American consumers about how much cholesterol is contained in each serving of packaged foods.

Even Ancel Keys, the famed nutrition scientist who was one of the founding fathers of the notion that saturated fat causes heart disease, knew this was nonsense. The problem he recognized was that much of the basic research into cholesterol and atherosclerosis had been conducted in rabbits, which have a unique ability to absorb cholesterol into their blood from their food and form atherosclerotic plaques from it; the mistake was to assume that humans also absorb dietary cholesterol as readily. “There’s no connection whatsoever between cholesterol in food and cholesterol in blood,” Keys said in a 1997 interview. “None. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”

It took nearly two more decades before the advisory committee responsible for the US government dietary guidelines finally conceded (in 2015) that “cholesterol is not a nutrient of concern for overconsumption.” Glad we settled that.

The final myth that we need to confront is the notion that cardiovascular disease primarily strikes “old” people and that therefore we don’t need to worry much about prevention in patients who are in their twenties and thirties and forties. Not true. I’ll never forget the one-question pop quiz that Allan Sniderman dropped on me over dinner at Dulles Airport, back in 2014: “What proportion of heart attacks occur in people younger than age sixty-five?” I guessed high, one in four, but I was way low. Fully half of all major adverse cardiovascular events in men (and a third of those in women), such as heart attack, stroke, or any procedure involving a stent or a graft, occur before the age of sixty-five. In men, one-quarter of all events occur before age fifty-four.

But while the events themselves may have seemed sudden, the problem was likely lurking for years. Atherosclerosis is a slow-moving, sneaky disease, which is why I take such a hard line on it. Our risk of these “events” rises steeply in the second half of our lifespan, but some scientists believe the underlying processes are set into motion in late adolescence, even as early as our teens. The risk builds throughout our lives, and the critical factor is time. Therefore it is critical that we understand how it develops, and progresses, so we can develop a strategy to try to slow or stop it.

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Back when I had an office, pre-COVID, I kept a clutter-free desk, but one book in particular was always there: Atlas of Atherosclerosis Progression and Regression, by Herbert C. Stary. It will never be a bestseller, but in the field of cardiovascular pathology it is legendary. It also happens to be a highly effective tool for communicating the seriousness of this disease to my patients, thanks to its lavish and gruesome photographs of arterial lesions as they form, develop, and rupture—all taken of the arteries of dead people, many of them in their twenties and thirties. The story it lays out, in graphic detail, is equal parts fascinating and terrifying. By the time I finished, my patients would often have this kind of harrowed expression on their faces, as if they’d just leafed through a coffee-table book documenting their own death.

This isn’t a perfect analogy, but I think of atherosclerosis as kind of like the scene of a crime—breaking and entering, more or less. Let’s say we have a street, which represents the blood vessel, and the street is lined with houses, representing the arterial wall. The fence in front of each house is analogous to something called the endothelium, a delicate but critical layer of tissue that lines all our arteries and veins, as well as certain other tissues, such as the kidneys. Composed of just a single layer of cells, the endothelium acts as a semipermeable barrier between the vessel lumen (i.e., the street, where the blood flows) and the arterial wall proper, controlling the passage of materials and nutrients and white blood cells into and out of the bloodstream. It also helps maintain our electrolyte and fluid balance; endothelial problems can lead to edema and swelling. Another very important job it does is to dilate and contract to allow increased or decreased blood flow, a process modulated by nitric oxide. Last, the endothelium regulates blood-clotting mechanisms, which can be important if you accidentally cut yourself. It’s a pretty important little structure.

The street is very busy, with a constant flow of blood cells and lipoproteins and plasma and everything else that our circulation carries, all brushing past the endothelium. Inevitably, some of these cholesterol-bearing lipoprotein particles will penetrate the barrier, into an area called the subendothelial space—or in our analogy, the front porch. Normally, this is fine, like guests stopping by for a visit. They enter, and then they leave. This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.

This is what actually makes HDL particles potentially “good” and LDL particles potentially “bad”—not the cholesterol, but the particles that carry it. The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with a highly reactive molecule known as a reactive oxygen species, or ROS, the cause of oxidative stress. It’s the oxidation of the lipids on the LDL that kicks off the entire atherosclerotic cascade.

Now that it is lodged in the subendothelial space and oxidized, rendering it somewhat toxic, the LDL/apoB particle stops behaving like a polite guest, refusing to leave—and inviting its friends, other LDLs, to join the party. Many of these also are retained and oxidized. It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that, in turn, leads to greater retention of LDL. As oxidized LDL accumulates, it causes still more damage to the endothelium.

I’ve been saying LDL, but the key factor here is actually exposure to apoB-tagged particles, over time. The more of these particles that you have in your circulation, not only LDL but VLDL and some others, the greater the risk that some of them will penetrate the endothelium and get stuck. Going back to our street analogy, imagine that we have, say, one ton of cholesterol moving down the street, divided among four pickup trucks. The chance of an accident is fairly small. But if that same total amount of cholesterol is being carried on five hundred of those little rental scooters that swarm around cities like Austin, where I live, we are going to have absolute mayhem[*2] on our hands. So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.

If you take a healthy coronary artery and expose it to high enough concentrations of apoB particles, over a long enough time, a certain amount of LDL (and VLDL) will get stuck in that subendothelial space and become oxidized, which then leads to it sticking together in clumps or aggregates. In response to this incursion, the endothelium dials up the biochemical equivalent of 911, summoning specialized immune cells called monocytes to the scene to confront the intruders. Monocytes are large white blood cells that enter the subendothelial space and transform into macrophages, larger and hungrier immune cells that are sometimes compared to Pac-Man. The macrophage, whose name means “big eater,” swallows up the aggregated or oxidized LDL, trying to remove it from the artery wall. But if it consumes too much cholesterol, then it blows up into a foam cell, a term that you may have heard—so named because under a microscope it looks foamy or soapy. When enough foam cells gather together, they form a “fatty streak”—literally a streak of fat that you can see with your naked eye during an autopsy of a splayed-open coronary artery.

The fatty streak is a precursor of an atherosclerotic plaque, and if you are reading this and are older than fifteen or so, there is a good chance you already have some of these lurking in your arteries. Yes, I said “fifteen” and not “fifty”—this is a lifelong process and it starts very early. Autopsy data from young people who died from accidents, homicides, or other noncardiovascular causes have revealed that as many as a third of sixteen- to twenty-year-olds already had actual atherosclerotic lesions or plaques in their coronary arteries when they died. As teenagers.

Source: Stary, (2003).

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 HDL-C 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 C-reactive 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.

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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.

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I met Anahad O’Connor in 2012 on a junket to France, courtesy of the French-American Foundation and an award we had both won, and we immediately bonded. I think it was because we were the only two guys on the trip who skipped the pain au chocolat and spent our spare time in the gym. Also, he wrote about health and science for The New York Times, so we had plenty to talk about.

Because I am a cholesterol nerd, I badgered Anahad into doing a comprehensive lipoprotein panel when we got back to the United States. He looked at me funny—Why should he do that? He was only in his early thirties, an extremely fit vegetarian with maybe 6 or 7 percent body fat. He should have been fine in the lipid department. But you never know; his father had died of an aneurysm, which may have been a sign of circulatory problems.

As expected, his standard lipid numbers looked great. There was only one thing that seemed off, so I suggested that he should probably also get a calcium scan, as I had done, so we could get a better sense of the state of his arteries. That’s where things got interesting. Recall, my calcium score had come back at 6, placing me at higher risk than 75 to 90 percent of people my age. Anahad’s calcium score was 125—off the charts for someone so young and otherwise healthy. “Can this be real?” he said.

It was. It turned out that the culprit was a little-known but very deadly type of particle called Lp(a) (pronounced “el-pee-little-A”). This hot mess of a lipoprotein is formed when a garden-variety LDL particle is fused with another, rarer type of protein called apolipoprotein(a), or apo(a) for short (not to be confused with apolipoprotein A or apoA, the protein that marks HDL particles). The apo(a) wraps loosely around the LDL particle, with multiple looping amino acid segments called “kringles,” so named because their structure resembles the ring-shaped Danish pastry by that name. The kringles are what make Lp(a) so dangerous: as the LDL particle passes through the bloodstream, they scoop up bits of oxidized lipid molecules and carry them along.

As my lipid guru Tom Dayspring points out, this isn’t entirely bad. There is some evidence that Lp(a) may act as a sort of cleansing agent, like a street-sweeping truck that gathers up unpleasant and potentially harmful lipid junk and delivers it to the liver. But because Lp(a) is a member of the apoB particle family, it also has the potential to penetrate the endothelium and get lodged in an artery wall; because of its structure, Lp(a) may be even more likely than a normal LDL particle to get stuck, with its extra cargo of lipids gone bad. Even worse, once in there, it acts partly as a thrombotic or proclotting factor, which helps to speed the formation of arterial plaques.

Often, the way Lp(a) announces itself is via a sudden, seemingly premature heart attack. This is what happened to Biggest Loser host Bob Harper, who suffered cardiac arrest at a gym in New York in 2017, at age fifty-two. Harper’s life was saved by a bystander who performed CPR until the paramedics arrived. He woke up in the hospital two days later, wondering what had hit him. Turns out, his very high level of Lp(a) was what had hit him. He had no idea that he was at risk.

This is not an atypical scenario: when a patient comes to me and says their father or grandfather or aunt, or all three, died of “premature” heart disease, elevated Lp(a) is the first thing I look for. It is the most prevalent hereditary risk factor for heart disease, and its danger is amplified by the fact that it is still largely flying under the radar of Medicine 2.0, although that is beginning to change.

Most people have relatively small concentrations of this particle, but some individuals can have as much as one hundred times more than others. The variation is largely genetic, and an estimated 20 to 30 percent of the US population has levels high enough that they are at increased risk; also, people of African descent tend to have higher levels of Lp(a), on average, than Caucasians. This is why, if you have a history of premature heart attacks in your family, you should definitely ask for an Lp(a) test. We test every single patient for Lp(a) during their first blood draw. Because elevated Lp(a) is largely genetic, the test need only be done once (and cardiovascular disease guidelines are beginning to advise a once-a-lifetime test for it anyway).

Anahad was fortunate that he found out about his situation when he did. His calcium score meant that he had already suffered significant atherosclerotic damage due to his Lp(a). Beyond the harm it causes to coronary arteries, Lp(a) is particularly destructive to the aortic valve, one of the more important structures in the heart, by promoting the formation of tiny, bony particles in the valve leaflets, which leads to stenosis or narrowing of the aortic outlet.

There was no quick fix for Anahad, or anyone else with elevated Lp(a). It does not seem to respond to behavioral interventions such as exercise and dietary changes the way that, say, LDL-C does. A class of drug called PCSK9 inhibitors, aimed at lowering apoB concentrations, does seem to be able to reduce Lp(a) levels by approximately 30 percent, but as yet there are no data suggesting that they reduce the excess events (heart attacks) attributable to that particle. Thus, the only real treatment for elevated Lp(a) right now is aggressive management of apoB overall. Though we can’t reduce Lp(a) directly, beyond what a PCSK9 inhibitor can do, we can lower the remaining apoB concentration sufficiently that we can reduce a patient’s overall risk.[*5] Because Anahad is relatively young, he also has more time to address his other risk factors.

Luckily, we found the trouble before the trouble found him.