Atherosclerosis, or hardening of the arteries, is very complex, and hard to pinpoint in terms of any one mechanism or cause. To date, many factors have been identified which have been shown to increase the risk of developing atherosclerotic plaque. At the same time, traditional risk factors for cardiovascular disease (CVD) may account for only part of the actual risk of atherosclerosis development. In the past, when a patient was considered at risk for heart disease, treating physicians examined the usual suspects, such as smoking, obesity, high cholesterol, family history, physical inactivity, diabetes mellitus, hypertension and other health conditions. Yet these risk factors cannot account for all incidence of CVD. New risk factors whose role is being seriously investigated include estrogen deficiency, different types of cholesterol, plasma and fibrinogen (protein essential for blood clot formation), C-reactive protein and homocysteine.
In the late 1960s, the first association emerged between elevated plasma homocysteine concentrations and atherosclerosis. A Harvard pathologist observed severe atherosclerosis in two young children with rare diseases marked by very high homocysteine levels. Children with this defect typically succumb at an early age to complications of arteriosclerosis. If great excesses of homocysteine can cause this, could moderately elevated levels contribute to heart disease in middle-aged and older people? Although initially not accepted as a valid theory, numerous studies have shown significant evidence to validate this relationship.
Researchers in at least three large, well-known studies have examined the complex association between hyperhomocysteinemia (a medical condition characterized by an abnormally high level of homocysteine in the blood) and CVD.
The Physicians' Health Study followed 14,916 male physicians without known atherosclerosis for an average of five years after baseline homocysteine measurement. In an analysis of data from 271 men who subsequently developed myocardial infarctions or MI (or heart attack) and paired controls, researchers found a relative risk for MI of 3.1 among men with homocysteine levels in the highest 5%; compared with those in the lowest 90%; that risk rose to 3.4 after adjustment for diabetes, hypertension and other potential confounding conditions.
In another study by the Physicians' Health Study, researchers examined plasma levels of folate and vitamin B6 in relation to subsequent MI occurrence. Over 7.5 years, 333 men experienced MI. In a comparison with paired controls, the researchers found that men with the lowest 20% of folate levels had a relative risk for developing MI of 1.4 compared with those in the remaining 80%. During the first half of follow-up, men with homocysteine levels in the top 5% had a nearly threefold increase in risk of MI.
Investigators in the ten-year Framingham Heart Study examined stroke incidence and all-cause and CVD mortality and determined that the relative risk for stroke rose in correlation to the increase in homocysteine levels. A second long-term Framingham sub study confirmed the results of the first study, in that subjects with higher homocysteine levels had an increased relative risk for all-cause mortality and for cardiovascular disease.
A Tufts University study of the elderly adds to the mounting evidence that blood levels of homocysteine can predict odds for having a stroke or heart attack. The study showed that the higher the homocysteine level, the greater the chance of carotid artery obstruction, a warning sign of increased risk for both stroke and coronary heart disease. Another finding was that odds for carotid blockage also rose as levels of folic acid and vitamin B6 dropped.
Based on their results, the authors propose clinical trials of the vitamins to determine whether fatal and nonfatal vascular disease in the elderly can be reduced. Using noninvasive ultrasound imaging to measure the degree of carotid artery narrowing, these researchers examined 418 men and 623 women who participated in the Framingham Heart Study. The subjects, ranging in age from 67 to 96 years, were divided into two groups. The first included people in whom no more than 24 percent of a carotid artery was obstructed. The second group consisted of those with a carotid blockage of at least 25 percent, a cutoff point above which stroke and coronary heart disease rates have been shown to rise.
The more dangerous obstructions were detected in 43 percent of men and 34 percent of women. An examination of the relationship between these blockages and the subjects' blood level of homocysteine strongly implicated homocysteine as an independent risk factor for vascular disease. Among men in the study, the odds for carotid blockage were more than twice as high in the 25 percent of the group with the highest homocysteine levels as in the bottom quartile. Disease risk increased gradually as homocysteine levels rose. Although women's risk did not increase with moderately elevated readings and somewhat fewer women with the highest levels had carotid blockages, the link between homocysteine levels and vascular disease was also statistically significant.
Among 27 studies of homocysteine and vascular disease cited by the University of Washington review was a Harvard project involving 15,000 physicians. The results showed that although relatively few of the doctors had coronaries, those in the five percent of the group with the highest homocysteine readings had a 3.4 fold increase in heart attack risk. Similarly a Tufts University study of over 1,000 elderly men and women showed that high homocysteine levels raised odds for significant carotid artery obstruction. A carotid blockage is considered a warning sign of above-average risk for both stroke and coronary artery disease.
The Washington researchers concluded that a 5 u.mol/L increment in homocysteine level raises coronary artery disease risk as much as a 20 mg/dL rise in cholesterol. No one has yet proven how homocysteine causes atherosclerosis, but scientists suspect it may do its harm during one or more steps in the process that transforms a healthy blood vessel into the site of a heart attack. The arteries of animals injected with homocysteine showed changes that may lay the groundwork for the buildup of atherosclerotic plaques. There is also evidence suggesting that homocysteine stimulates proliferation of blood vessel cells that may contribute to plaque formation, and that it encourages clotting.