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Jim Mann and Timothy Green
Death rates from cardiovascular disease have fallen in recent years in New Zealand and most other Western countries.1,2 However, coronary heart disease and stroke continue to be the leading causes of death in this country and in most relatively affluent societies throughout the world.1,2 Thus, the identification of new, readily modifiable, risk factors invariably arouse considerable interest. When prospective epidemiological and animal studies as well as small randomised trials suggested that high intakes of antioxidant nutrients might be protective, there were high hopes that supplements containing such compounds might radically reduce cardiovascular risk.3-6 However, such hopes have been dashed by a series of randomised controlled trials (RCTs) that have convincingly shown that the most widely studied such nutrients - β-carotene, vitamin C, and vitamin E - at least in the amounts usually recommended, were ineffective.7-10 It is against this background that the role of homocysteine (Hcy), a sulphur-containing amino acid formed during the metabolism of methionine, must be considered (Figure 1). (Homocysteine as measured in most clinical studies refers to total homocysteine, which is the sum of free homocysteine, protein-bound homocysteine, homocysteine thiolactone, and mixed disulfides involving homocysteine measured in plasma (or serum).)
[Image omitted. See PDF]
[Figure omitted, see PDF]
Figure 1. Simplified schematic of homocysteine metabolism showing vitamin involvement (large block arrows indicate area of vitamin involvement)
CβS = cystathionine β-synthase
Evidence-based medicine demands an impressive array of consistent data before a recommendation is made regarding the measurement and treatment of a putative risk factor.
More than 30 years ago, McCully reported extensive arterial atherosclerosis and thrombosis at post mortem examination in two children with homocystinuria.11 He raised then the possibility that lesser degrees of homocystinaemia than those seen in homocystinuria might be more widely involved in the pathogenesis of atherosclerosis. These observations appear not to have been followed up until Wilcken and Wilcken published their less than convincing, at least by modern standards, case control series in 1976, which suggested that coronary heart disease patients frequently have abnormal Hcy metabolism.12 Indeed, it has only been in the past 10 years or so that more convincing data have started to appear.
The first impressive case control study, undertaken by the European Concerted Action Group and published in 1997,...