Note: Jerome Sullivan, MD was featured in this article in the Sunday Herald-Sun (Melbourne, Austrailia)/1996. The Science/Medical correspondent, Graeme O'Neill, who wrote this article, made the following comments:

The article received an exceptional response in Melbourne...not the least from the Red Cross Blood Bank, which doubled its donation rate in the week after the Sunday-Herald Sun article. - interestingly, only 20 per cent were new donors, the rest were existing donors who had not given blood for years - what should we make of this? The article ran in the Sunday Telegraph in Sydney, and in the Brisbane Sunday Mail, and the Sunday Mail in Adelaide...

Graeme O'Neill
Science/medical correspondent
Sunday Herald-Sun.

IRON-HEART DISEASE LINK

By GRAEME O'NEILL

It could literally be the bargain of your life: donate blood three or four times times a year, reduce your risk of heart disease by more than 50 per cent - and reduce your risk of cancer at the same time.

If Dr Jerome Sullivan is right, medical science blundered three decades decades in identifying cholesterol as a key risk factor in cardiovascular disease. The real culprit, says Dr Sullivan, is iron - specifically, excess iron that accumulates in body tissues with aging.

When Dr Sullivan, Director of Pathology at the Veterans Affairs Hospital in Charleston, South Carolina, first proposed in 1981 that iron is a major risk factor in cardviovascular disease, he ran into a wall of scepticism - mainstream medicine had virtually accepted the cholesterol theory as fact.

But since then, laboratory and population-based studies have reinforced his hypothesis, and highlighted serious flaws in the "killer cholesterol" theory. Several rigorous studies have failed to confirm that cholesterol-reducing drugs significantly reduce mortality in individuals with high serum cholesterol levels - indeed, they may even increase mortality.

In 1981 Dr Sullivan asked the simple question: why don't younger women get heart disease? Even women with hypercholesterolaemia, a hereditary condition that causes extremely high serum cholesterol levels, seem virtually immune to heart attack until after menopause - even though their brothers, with similarly high cholesterol levels, can die in their early 20s or 30s.

But after menopause women rapidly develop the same risk of cardiovascular disease as men of the same age. Women, according to medical dogma, are protected by the main female hormone, estrogen.

Dr Sullivan believes the real explanation is that women do not accumulate excess iron in their tissues until after menopause, at around age 45, because they regularly lose iron-rich haemoglobin in menstrual blood, depleting their bodies of iron.

Men, on the other hand, begin accumulating excess iron from late adolescence onwards, and male heart disease rates rise sharply from age 20 onwards.

For this reason, says Dr Sullivan, age and sex have long been regarded as the major risk factors in heart disease - and since gender is fixed at birth, and aging is inevitable, nothing could be done to change these factors.

But Dr Sullivan says that these differences in heart disease patterns between the sexes, and the increased risk of heart attack with aging in both sexes, are more easily explained by his toxic iron hypothesis.

"Any iron that the body is not using to make haemoglobin for red blood cells, or for other purposes, is put 'on the shelf' in the form of a protein called ferritin," Dr Sullivan said. "Ferritin is found in all tissues of the body, and there a little circulates in the blood, which is useful for estimating the amount of iron stored in the tissues."

Dr Sullivan says his iron hypothesis does not exclude cholesterol as a significant player in cardiovascular disease; rather, it fits it into a more comprehensive theory.

It proposes that that cholesterol and lipoproteins - blood-borne proteins that transport and deposit fatty lipids around the body - are not the real culprits, but victims of biochemical reactions catalysed by iron.

These reactions cause cholesterol and lipids to be deposited in artery walls, and also target heart muscle and the lining of the heart.

Dr Sullivan says it is not clear precisely how iron triggers these reaction, but it may be significant that iron reacts very strongly with oxygen, producing a highly reactive molecule called a hydroxyl radical as a by-product.

Free radicals are powerful oxidizing agents, and have variously been been implicated in oxidizing cholesterol and other lipids, disrupting chemical reactions in cells and damaging DNA.

Heart muscle cells may be particularly vulnerable because they are packed with mitochondria, tiny "powerhouses" that use energetic oxidation reactions to produce the chemical energy that powers cells. The unusual vulnerability of heart muscle to damage by excess iron could be explained if hydroxyl radicals are disrupting these vital reactions.

Given that DNA damage leads to cancer, the iron hypothesis may also explain a very recent finding that blood donors are not only at lower risk of heart disease, but are less likely to develop cancer.

While the precise mechanism remains unclear, Dr Sullivan has marshaled solid evidence from laboratory, clinical and epidemiological studies to support his idea that unused iron is toxic to the body, especially to heart muscle.

He notes that iron deficiency is widespread in impoverished populations, especially among the poor in Third World countries, which also have some of the lowest rates of premature death from heart disease in the world. These populations typically have high fiber diets that impede iron absorption, and that many individuals carry a heavy load of gastrointestinal parasites that cause chronic blood loss, often resulting in anemia.

In contrast, industrialized nations have experienced an epidemic of cardiovascular disease this century, coinciding with the transition from difficult to easy acquisition of stored iron - the typical Western diet is high in iron-rich red meat, and low in dietary fiber.

"Recent clinical research has showed clearly that very small amounts of iron can dramatically promote hearte muscle injury," he said. Desferroxamine - a drug that captures and removes excess iron from the body - has been shown to provide significant protection against heart-muscle damage in patients who have already suffered a heart attack.

The first solid evidence that regular blood donors - especially males - have a longer life expectancy than non-donors, emerged in 1984, only three years after Dr Sullivan published his ideas in the British medical journal "The Lancet" in 1981.

A major epidemiological study of 1931 men by Dr Jukka Salonen, of the University of Kuopio in Finland, found that men who regularly donate blood reduced their risk of cardiovascular disease.

Dr Salonen has now tracked the same group of men for 15 years, and in 1992 published another study suggesting that smokers who regularly donate blood significantly reduce their risk of heart attack - the link between smoking and cardiovascular disease has been recognised for 30 years.

The Finnish study found that male smokers, by depleting their stores of iron through regular blood donation, greatly reduced their levels of oxidized serum lipoproteins, the form in which lipids are deposited in artery walls, causing arteriosclerosis.

A more recent study in Germany found that people who had suffered heart attacks had slightly elevated levels of the iron-storage protein ferritin than smoking males in a control group who did not give blood, but the link was not statistically significant.

But Dr Sullivan says this result probably seriously underestimates the role of excess iron in heart disease, because male smokers in the control group would also have had high levels of ferritin in their tissues - for any valid conclusion, the study group needed to be compared compared with a control group who had no surplus iron in their bodies.

A marginal increase in an already high level of stored iron the body may not significantly increase a person's risk of heart attack; the risk threshold may lie at low, "normal" levels of stored iron - so even normal levels of iron in the body may represent a more serious risk for cardiovascular disease than cholesterol.

By Dr Sullivan's argument, cholesterol (and low-density lipoproteins) constitute the loaded gun - but nothing happens until iron pulls the trigger.

Despite serious flaws in the case against cholesterol, medical researchers and doctors continue to make cholesterol the focus of their efforts to control cardiovascular disease.

Dr Sullivan says scientists cling to familiar theories long after losing faith their ability to explain what they observe in their experiments - they will only declare a theory invalid when an alternative candidate becomes available to take its place.

He says the theory that heart disease is a simple function of serum cholesterol has outlived its usefulness, and should be abandoned. But the cholesterol-heart disease link is so deeply entrenched in modern medical thinking that few researchers are able to look beyond it.

Its dominance means that research into alternative hypotheses are being suppressed, so patients with high cholesterol may be receiving inappropriate drug therapies, or pursuing rigorous diets that provide little benefit in terms of reduced risk of cardiovascular disease.