There is mounting clinical evidence that elevated tHcy is an independent risk factor for the development of cardiovascular disease. Meta-analysis of clinical studies has established that a 5 μmol/L increase in tHcy is equivalent to approximately 20 mg/dL increase in total cholesterol levels. Many studies have shown that the connection between tHcy levels and atherosclerosis is even stronger than the connection between atherosclerosis and cholesterol. A dose-dependent correlation between tHcy and cardiovascular risk has been established as shown in Figures 5 and 6 from the Framingham Study, N. Engl J. Med. (1995), 232, 268-91. The study has shown that the risk of cardiovascular disease is doubled by a 5 μmol/L increase of plasma tHcy.
Perspective studies have demonstrated that tHcy levels are a strong indicator of cardiovascular related mortality (Figure 7). Nygard, et al., (N.Engl. J. 337: 230-6, 1997), found that the mortality ratio doubled when plasma tHcy level was twice as high (Table 2).
Boushey, et al., performed a meta-analysis of 27 clinical studies, and summarized the odds ratio between elevated tHcy and development of vascular disease (Table 3).
(Table 3) Meta-analysis of 27 Clinical Studies
Hcy also predicts late outcome of survival rates from coronary events as described in the findings by Schnyder, et al. (J. Am. Coll. Cardiol. 2002, 20: 40(10), 1769-1776). This study followed 549 patients for 58 weeks after successful coronary angioplasty. As shown in Figure 8, the percentages of event-free survival are reciprocally proportional to the plasma levels of tHcy. That is, the higher the tHcy level, the lower the survival rate.
Hcy is a strong predictor of ischemic stroke recurrence. Boysen, et al., studied the association between Hcy and stroke. They investigated whether elevated total Hcy measured within 24 hours of acute stroke was an independent risk factor for recurrent stroke. They found that serum Hcy was significantly higher in the 105 patients who experienced a recurrent stroke during the follow-up period than in patients without recurrence. The geometric mean was 13.4 versus 11.8 (Figure 9).
Interactions of Hcy with Classical Risk Factors
Graham, et al., (1997) examined the interactions between elevated tHcy and classical (conventional) risk factors in a multi-center European case-control study involving 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years old.
This study found that the increased fasting tHcy level showed supra-additive effects on risk in both smokers and hypertensive subjects, especially in women. The authors concluded that an increased plasma tHcy level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. Synergistic effects on risk were observed between elevated tHcy and smoking and hypertension, respectively (Figure 14).
Hcy and Heart Disease Test Panel
Surprisingly, 30% mortality associated with cardiovascular disease (CVD) occurs in individuals without conventional risk factors such as HDL, LDL, hypertension, smoking, and obesity. As shown in Figure 15, conventional risk factors do not account for all mortality from CVD.
Recently, three new risk factors for heart disease appear promising as independent risk factors in predicting progression to CVD. They are increased levels of Hcy, lipoprotein a (Lp[a]), and C-reactive protein (CRP). These new risk factors, in combination with conventional HDL and LDL analysis, form a new risk profile and a new test panel that offers better diagnostic value for CVD (Clinical Laboratory news, Oct. 2000) (Figure. 16).
Recommendation from the American Heart Association
There are three main indications for determining tHcy:
- to diagnose homocystinuria
- to identify individuals with or at risk of developing B12 and folate deficiency, and
- to assess tHcy as a risk factor for cardiovascular disease and other diseases
Presently, Hcy screening in an unselected population is not recommended. However, there is a growing consensus that Hcy measurement in high-risk patients and their siblings is recommended. Furthermore, Hcy tests are recommended to assess the total risk profile of patients with manifest cardiovascular disease.
In connection with cardiovascular disease, the Nutrition Committee of the American Heart Association issued a statement in 1999 regarding Hcy testing. It states as follows:
"...a reasonable approach is to determine levels of fasting homocysteine in "high-risk patients", i.e., in those with strong family history for premature atherosclerosis or with arterial occlusive diseases, particularly in the absence of other risk factors, as well as in members of their families. Other conditions that may be associated with high homocysteine are advanced age, hypothyroidism, impaired kidney function, systemic lupus erythematosus, and certain medications, e.g., nicotinic acid, nitrous oxide exposure, theophylline, methotrexate, and L-dopa."