Homocysteine and Heart Disease

dr_duane_graveline_m.d._134By Duane Graveline, MD, MPH

Ancel Keys started the cholesterol bandwagon in the mid-1950s and soon doctors across the United States and around the world were promoting the low fat, low cholesterol diet. For the next three decades millions of Americans gave up butter for margarine, drank skim or low fat milk and all but stopped egg intake.

Doctor Paul Dudley White, then cardiologist to ailing President Eisenhower, argued against this dietary outrage but was overrun by the pressure of the growing anti-cholesterol lobby. The pharmaceutical industry now had a target and began to churn out cholesterol busters, one after the other.

Fortunately, not everyone accepted the cholesterol theory. Kilmer McCully, MD, working at Harvard during the late 60s, had been involved in research that suggested a role for factors other than cholesterol and LDL in the etiology of arteriosclerosis, an almost inconceivable thought in those days.

His interest was aroused when, as a member of the Harvard human genetics group, he was present when pediatricians presented the story of the death of an eight-year old boy. Suffering from a disease called homocystinuria, the child had died of a stroke at that tender age.

This rare condition had been discovered only six years earlier by medical investigators in Belfast. In the ensuing years several more cases were identified.

In this condition, a genetic error occurs in a liver enzyme known as cystathionine synthase. When this happens, the amino acid, homocysteine, derived from the normal breakdown of protein in the diet, cannot be metabolized by the liver as usual and builds up to toxic levels. The arteries in these cases are abnormal, with hardening and loss of elasticity that greatly increase the tendency for heart attacks and strokes.

Not only did McCully focus on this observation, but he also knew of the work of George Spaeth, an ophthalmologist friend, who informed him of the dramatically beneficial effect of vitamin B6 supplementation on some of the
homocystinuria patients he had treated.

Spaeth's homocystinuria patients often suffered from a dislocated lens. He reported his observation that the excretion of homocysteine in the urine of such patients frequently could be increased dramatically by vitamin B6 to McCully.

Two seeds were planted in Kilmer McCully's mind: the amino acid homocysteine, if elevated, causes a condition remarkably like arteriosclerosis; and a simple vitamin, B6, could lower homocysteine levels.

He was elated with this hint that a nutritional factor other than cholesterol might be involved, but his thinking was nothing more than a tiny candle lighting the darkness of research on the disease. He was alone with his concept and his original ideas fell on ears deafened by the roar of the cholesterol juggernaut.

At his laboratory, McCully began to apply his skills as a pathologist to some of the original material from the homocystinuria case discussed at the genetics meeting. He found some paraffin blocks containing tissue from the young boy and a few of the original slides.

Soon he was able to confirm that the walls of the carotid arteries leading to the brain were severely thickened and damaged by arteriosclerosis, a form of hardening of the arteries.

He now knew this disastrous blood vessel disease had caused the stroke that had killed the young boy. He found scattered, widespread changes in virtually all the small arteries of the body.

Soon he had identified ten more cases of homocystinuria in children, many of whom had died of blood clots to the brain, heart and kidneys. All showed the hardening of the arteries and loss of elasticity associated with fibrous plaques.

An abnormal reactivity of the blood platelets was evident in these patients, which accounted for the tendency toward formation of blood clots. Somehow, the presence of elevated homocysteine in the blood had caused the blood platelets to cluster more readily.

Some time later at a genetics conference, McCully learned of another homocystinuria-like case: a two-month-old baby that had died despite aggressive attempts at therapy. This time, the urine contained both homocysteine and another substance called cystathionine, also related to homocysteine.

In the case of this unfortunate baby, its metabolic passageway was deficient in a different enzyme and the conversion would have required vitamin B12. When McCully examined the slides of the baby's arteries he found the same arteriosclerosis changes noted in all the previous cases.

By now one should call McCully a medical detective, for that is what he had become and his identification of the role of folic acid as the third vitamin involved in homocysteine metabolism soon emerged. He admits he had difficulty sleeping for several weeks after this discovery because he knew he was on to something of extreme importance.

Like many scientists before him McCully had doubted the cholesterol hypothesis because cholesterol makes up so much of the human body and is so intimately involved in metabolism and physiology — and cholesterol is a major component of the human brain.

How could such a substance be sufficiently toxic to cause arterial damage? It did not make any sense to him and thus emerged the seed of the inflammatory concept of cardiovascular disease, now widely accepted.

Driven by the frenzied pharmaceutical industry seeking whatever profitable means possible to control cholesterol, doctors continued to write prescriptions by the thousands. These included many diverse drugs such as niacin, bile acid sequestrants like Questran and the so-called fibric acid derivatives such as Lopid, with mechanisms of action that could only be surmised.

The side effects and limited effectiveness of these early cholesterol control drugs were a constant source of frustration to both the doctor and patient alike, but in those pre-statin days, the scourges of amnesia, forgetfulness, disorientation and confusion were absent. Not so after the statins.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

Updated March 2016


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