The Heart Healers (38 page)

Confronting his critics across this scientific chasm stood Ancel Keys. His trial was his baby, his progeny to be defended against all detractors. Keys understood his child’s limitations. He countered that his correlations remained true after statistical correction for every one of the Framingham risk factors. Neither the press, nor the public nor most of cardiology, however, cared a whit about such statistical nuances. Ancel Keys’s Seven Countries Study had forever linked diet and heart disease in the public mind. And so the Cholesterol War was joined.

Even Keys had to admit that he could not dismiss one obvious objection to his statistics: genetics. Perhaps the Finns were genetically predisposed to get atherosclerosis, and the Japanese were not. This possibility could hardly be rejected when it was so obvious in a glance that Japanese and Finns were vastly different in other genetically determined features. A counterargument that suggested Keys’s findings were not due to genetics soon emerged from Hawaii. Investigators compared blood cholesterol levels and heart attack rates among ethnic Japanese living in Hawaii, San Francisco, and Honshu, Japan. First-generation Hawaiian Japanese had a higher blood cholesterol level, and with it came a parallel increase in heart attack rate. Both numbers were even higher in San Francisco. The obvious conclusion was that the difference between the Japanese in Honshu, Hawaii, and San Francisco was not genetics. It was diet. We now know that as the winds of Western lifestyle carry our diet east and south to less-developed countries, coronary disease follows like an unwanted lightning storm. The prevalence of atherosclerotic disease clearly increases as societies modernize in the twenty-first century, bringing us full circle back to the long-rejected hypothesis that the Industrial Revolution caused CAD. Machines don’t cause CAD; it is diet. Historians had been right, but for the wrong reasons.

As opinion swung toward the lipid hypothesis, the anticholesterol gang raged against the dying of the light. A 1976
British Heart Journal
editorial concluded, “The view that raised plasma cholesterol is per se a cause of coronary heart disease is untenable.” Edinburgh’s leading cardiologist Michael Oliver maintained that “It is probably of little value to reduce raised serum cholesterol concentrations in patients with CAD.” Michael was one of my favorites—a cardiologic version of contemporary writers Christopher Hitchens and Sam Harris. He was erudite, analytical, and charming, a curmudgeonly critic of unproven theories. Others disagreed. A British newspaper dubbed Oliver the “Abominable No-man,” and the
Journal of the American College of Cardiology
crowned him “The Cholesterol Pessimist.”

Hoping to resolve the debate the NIH organized a randomized trial of cholestyramine, a drug that inhibits cholesterol uptake from the gut. After seven years, the trial announced a very modest difference of 1.6% in coronary death and myocardial infarction (7% vs. 8.6%), favoring the treatment group. When the NIH and the lipidology establishment ballyhooed the result as “statistically significant,” Vanderbilt University’s Dr. George Mann fumed, “They have manipulated the data to reach the wrong conclusion. The managers at NIH have used Madison Avenue hype to sell this failed trial in the way the media people sell an underarm deodorant.”
Atlantic
magazine science writer Thomas J. Moore went further, calling the report an “extravaganza that resembles a medical version of the military-industrial complex,” then named five lipidology leaders, darkly suggesting that “It is likely that one reason these physicians consented to [promote the results] is that their laboratories were heavily involved in research funded by Merck.”

The NIH countered by issuing the groundbreaking declaration that blood cholesterol lowering was now a major national health goal. But there was a problem. Cholestyramine lowered cholesterol and in theory could save some lives, but only the most dedicated believer would willingly swallow the massive pill for any period of time after experiencing the indigestion, burping, and loss of appetite that accompanied its ingestion. The NIH had run afoul of Karl Marx’s century-old critique of Hegel that “In theory, there’s no difference between theory and practice, but in practice, there is.” For management of high-risk asymptomatic patients our arsenal of cholesterol lowering drugs remained empty.

The Cholesterol War ended suddenly, on a single day, not with a whimper but a bang. On November 19, 1994, the first large randomized trial of a cholesterol lowering statin drug versus placebo was published in the prestigious British journal
The Lancet
. Over five years of follow-up, simvastatin had lowered bad LDL (low-density lipoprotein) cholesterol by 35% and the risk of coronary death by 42% compared to placebo-treated patients. The investigators concluded, “This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.” On that day, the Cholesterol War ended. The lipid hypothesis, it seemed, had won.

*   *   *

ATHEROMA FORMATION (DEPOSIT
of fat in blood vessels), we now know, begins with cholesterol. So let’s describe it. Cholesterol is used for the construction of cell membranes, for making hormones like progesterone, estrogen, and testosterone, and for synthesis of the bile that helps digest food in the intestine. So blood has to transport cholesterol to all parts of the body. To transport cholesterol, Mother Nature links it to one of several proteins. The resultant spitballs of fat (called lipid) and protein are called, logically enough, lipoproteins. The two lipoproteins cardiologists focus on are low-density lipoprotein cholesterol (LDL), nicknamed “bad cholesterol” because high blood levels are associated with CAD (coronary artery disease) and high-density lipoprotein cholesterol (HDL), which is associated with low rates of CAD.

Most of the components of blood, even cells, move in and out of the blood vessel wall. Cholesterol enters the blood vessel as part of the LDL (bad cholesterol) molecule. When it exits the vessel wall, it is transported out as part of HDL (good cholesterol). That is why LDL is bad and HDL is good. Cholesterol trapping in the vessel wall reflects the balance between transport in and transport out, between LDL and HDL. When the amount of cholesterol brought into the blood vessel wall exceeds the removal capacity, when all the garbage trucks are full, some of the cholesterol gets left behind. Now that spot in the vessel becomes New York City during a garbage workers’ strike. The cholesterol left sitting in the blood vessel wall is like butter. It turns rancid. In scientific parlance, it is oxidized. Rancid LDL cholesterol is a potent stimulus for the body’s inflammatory response. That’s why pathologists see a mix of cholesterol and inflammatory cells in coronary obstructions.

The inflammatory response is activated when the cells of the blood vessel, finding themselves contaminated with unwanted oxidized cholesterol, send a chemical call into the blood for help. The chemical signal attracts white blood cells, the immune system’s firemen, to the scene. These newly arrived inflammatory cells charge into the vessel to gobble up the offending oxidized LDL. Bloated to Falstaffian proportions with fat, these cells become trapped in the complex matrix of the vessel wall. Unable to leave, the trapped cells ultimately die there. The oily mixture of cholesterol and dead cells becomes the gruel, the
athera
, that pathologists see when they slice open an atheroma. Other cells, trying to wall off the mess, put a scar on top. Over months and years, this collection of fermenting gruel enlarges. The mass of gruel, covered with a fibrous cap, bulges into the flowing bloodstream, creating the tumor-like
oma
of atheroma. The bulging mass is what we see in our X-ray pictures (angiograms) of the coronary arteries.

Sometimes tissue adjacent to the atheroma breaks down and bleeds beneath the blood vessel surface. The vessel surface becomes the knobby mix of yellow, red, and white that reminds pathologists of pizza. As trapped cells die, the gruel becomes calcified. The calcified atheroma is what we look for when we do heart scans for calcium.

That’s how an atheroma forms. To simplify, atheroma are caused by a local excess of oxidized fat (cholesterol) in the vessel. Over many years, it can grow larger until it partially obstructs coronary blood flow, causing angina.

We finally understood how atheromas form. But knowing how an atheroma forms and expands still leaves us with a giant unanswered question. How could Jim Fixx be such a great runner for many years with atheromas in his coronary arteries, then collapse without prior warning? He died when an atheroma in his coronary artery ruptured. We understood how an atheroma forms; now we needed to know why some plaques rupture, causing heart attack and sudden death.

22

PLAQUE RUPTURE, HEART ATTACK, AND SUDDEN DEATH

The greatest discoveries of science have always been those that forced us to rethink our beliefs about the universe and our place in it.

—ROBERT L. PARK, AMERICAN PHYSICIST

CLINICAL RESEARCH HAD
created balloon angioplasty and bypass surgery. But to explain why neither prevents heart attack even while restoring blood flow, we needed basic research. Clinical research leads to reforms, basic research leads to revolutions.

After Russell Ross graduated from the Columbia University School of Dental Medicine in 1955 he migrated west to Seattle for seven years of PhD studies in experimental pathology. He joined the faculty in the department of pathology at the University of Washington and later became its chairman. Tall and willowy, Russell carried himself like the urbane, intellectually curious, elegant symphony buff that he was outside the world of medicine. Ross began by being curious about how a wound heals. The deeper he delved into the body’s healing process, however, the more he became fascinated by a counterintuitive, revolutionary idea. Could Nature have created a yang to healing’s yin? His beguiling thought was that the factors that drove healing could also create disease. His hunch ultimately led him to study the disease he came to believe was the quintessential example of how the healing process creates disease. It was our millennia-old adversary: the atheroma, the cholesterol plaque in the coronary artery.

Peering down through his microscope, Ross was astonished. The very cells that created the scar on healing skin also thronged like members of the congregation around a developing atheroma. But why? Ross made an intuitive leap that enthralls all who love science. He hypothesized that the same cells drove both formation of the atheroma and a scar on the skin. Ross proposed his response-to-injury hypothesis of atheroma formation in the prestigious journal
Science,
suggesting that the atheroma was the product of the body’s normal healing response. He was partly right. Ross and others soon discovered that an even more fundamental biologic process than wound healing was afoot. Atheroma formation and rupture was actually driven by the body’s most basic of all defenses, the inflammatory response. In the case of the atheroma, it was the inflammatory response to cholesterol trapped in the blood vessel wall. Who could have imagined that the long-forgotten inflammation hypothesis would one day marry the lipid hypothesis? The progeny of this marriage is our modern understanding of atheroma formation and plaque rupture.

*   *   *

WHEN WE DISCOVERED
that blood clots cause heart attacks, pathologists made a fascinating discovery. The red worm was clinging to a torn blood vessel surface, and beneath that ruptured surface lay … an atheroma (a plaque). Like a dormant Mauna Kea, the atheroma had suddenly erupted without warning, discharging its molten gruel into the flowing bloodstream. Any tear in the blood vessel surface instantly activates the blood clotting system. With that recognition, a new phrase entered our lexicon. “Plaque rupture” was the cause of heart attack.

The world of cardiac pathologists—England’s Michael Davies, Denmark’s Erling Falk, Renu Virmani in Washington D.C., and our own hospital’s Michael Fishbein all set out to define what made the ruptured plaque different from all the rest of the “stable plaques” in blood vessels. Michael Fishbein walked me through the violent world of plaque rupture under high magnification; he took me to the world of the atheroma, and showed me the enemy up close. What I saw was that each atheroma has its own personality. Most look like dullards, half asleep, doing nothing much. A few atheromas, however, appeared hot-tempered, ready to explode. What’s the difference? Mike showed me: on average, ruptured plaques have four times more cholesterol, four times more inflammatory cells, and the cap over this mess is very, very thin. The cap is ready to rupture, and when it does, the heart attack begins seconds later.

What accounts for these three differences between a quiescent plaque and one that ruptures? It is the magnitude of inflammation in each plaque. Inflammatory cells release enzymes that digest everything around them, including the cap that walls off the atheroma from the flowing bloodstream. The three characteristics of ruptured plaques led pathologists to come up with a new term: the “vulnerable plaque,” the plaque prior to its imminent rupture. The vulnerable plaque is a sinister form of atheroma, among all the cholesterol-filled egg yolks it is the one that splatters. Viewed by coronary angiography, a stable plaque and a vulnerable plaque look the same. The angiographic image does not tell us that one plaque is quiescent and the other is potentially lethal. So like all photos, the coronary angiogram is accurate but it does not tell the whole truth.

Vulnerable plaques, the ones poised to cause a heart attack, come in all sizes. A small vulnerable plaque can cause a heart attack, even though it was too small to have caused chest pain on exertion. That’s what happened to Jim Fixx. He had no symptoms prior to his heart attack because the vulnerable plaque that ruptured was too small to obstruct blood flow. But when a clot that formed on its torn surface, it completely obstructed coronary blood flow, causing a heart attack. Vulnerable plaques are like Usain Bolt, prepared to explode from the starting blocks. Stable large atheromas cause angina, but vulnerable plaques of any size can cause a heart attack.