Plasma Homocysteine and Arterial Stiffness: Risk Factors or Risk Markers for Cardiovascular Diseases?

Wang and colleagues1 investigated plasma total homocysteine as a predictor of arterial stiffness in a community‐based cohort of 1447 patients with cardiovascular diseases (CVDs) during 4.8 years of follow‐up. Carotid‐femoral pulse wave velocity (cf‐PWV) and carotid‐radial pulse wave velocity (cr‐PWV) were noninvasively measured for assessment of central and peripheral arterial stiffness, respectively. Their analyses revealed a positive, weak association of baseline homocysteine levels with follow‐up cf‐PWV (Pearson's r=0.274, P<.001) but negligible association with cr‐PWV (r=0.079, P=.006) after controlling for personal (age and sex) and anthropometric variables (body mass index), lifestyle (smoking), systemic (hypertension) and metabolic (diabetes mellitus) diseases, antihypertensive medications, and renal function (estimated glomerular filtration rate, uric acid, and creatinine). Likewise, homocysteine was an independent predictor of increased cf‐PWV (β=0.817, P=.015) but not increased cr‐PWV (β=0.385, P=.152). Finally, no significant association was observed between changes from baseline to follow‐up in homocysteine and cf‐PWV or cr‐PWV. Predictors are used either for diagnostic or prognostic purposes, and although they are not substitutes for clinical reasoning, their role in augmenting clinical judgment is well recognized.2 Therefore, the findings of Wang and colleagues support that homocysteine can be used to predict the presence of central arterial stiffness or its development in patients with CVD.

Homocysteine imbalance appears to be a consistent characteristic of several diseases.3 Currently, there is no doubt that a large proportion of patients with CVD have hyperhomocysteinemia.4 The general mechanisms of cellular metabolism of homocysteine and its excess are currently well described. Hyperhomocysteinemia is associated with reduced methylation potential, whereas folate and vitamin B12 increase that potential. Changes in the concentration of methionine in the body, particularly as a result of dietary intake of methionine, ultimately affect the metabolism of homocysteine.3, 4, 5 Homocysteine is a potent excitatory neurotransmitter that at high levels ultimately leads to endothelial dysfunction and vascular inflammation,6 the former being considered as the earliest manifestation of vascular disease.

McCully7 first proposed that homocysteine plays a role in the pathogenesis of arteriosclerosis, which has been verified by many subsequent studies. Three decades later, the “homocysteine‐CVD” hypothesis began with the report by Clarke and colleagues,8 showing an odds ratio of 3.2 for CVD. However, it remains to be determined how hyperhomocysteinemia is etiologically related to CVD risk.9 Plasma homocysteine levels are increased by a wide range of factors5 and, because of the multifactorial aspect of vascular inflammation, arterial remodeling, and arteriosclerosis, it is of major importance to adjust for important well‐established risk factors, as in Wang and colleagues' study. However, whether lowering homocysteine levels (eg, by administration of folate and vitamins B6 and B12) is associated with any significant decrease in vascular events in populations at risk for CVD remains unclear.5 Current data do not provide support for routine screening for and treatment of elevated homocysteine to prevent CVD.4, 5 In light of these facts, it has been argued whether homocysteine is a risk marker rather than a risk factor for CVD3, 10 or a surrogate marker of another risk factor for CVD.9

Arterial stiffness is also acknowledged to play a predictive role in CVD, and pulse wave velocity (PWV) is a diagnostic method recommended for investigating arterial stiffness in large‐sample studies.11 The Moens‐Korteweg's equation for calculations and Bramwell‐Hills' method for measurements of PWV in patients with CVD comprise two seminal works on this subject.11 Although cf‐PWV is acknowledged as a gold‐standard measurement for arterial stiffness,12 it is not the gold‐standard method for assessing arterial stiffness because ultrasound is the only method to directly quantify in vivo the elastic properties of the arterial wall.5, 12 On the one hand, Moens‐Korteweg's equation established a directly proportional relationship of PWV with arterial wall thickness and its Young's modulus, and an inversely proportional relationship with internal radius and blood density. On the other hand, Bramwell and Hill used the linear relationship between traveled distance between arteries and the time interval spent in such traveling. While both equations relate the PWV to arterial stiffness, they also include other variables that help explain why PWV is also a surrogate measure of arterial stiffness. It is worth noticing that PWV can only indicate the presence or not of arterial stiffness, not revealing whether this effect is caused by an atherosclerotic process and/or an increased peripheral resistance.12 In addition, several clinical conditions are associated with increased arterial stiffness,13 which must also be adjusted for. Finally, the methods for measuring cf‐PWV and cr‐PWV also deserve attention. The linear distance between arteries as measured over the body's surface is plugged in the equation: minor measurement errors might occur because of the nonrectilinear path of the arterial system between carotid and femoral arteries––indeed, in the opposite direction of blood and pressure flow––that might become major errors between the carotid and radial arteries.13 Such measurement errors, among other possible factors, might explain the lack of association between homocysteine and cr‐PWV.

The study by Wang and colleagues1 provided interesting clinical evidence on the association between homocysteine and arterial stiffness using longitudinal data adjusted for many confounders for CVD not simultaneously considered in previous cross‐sectional studies. Nonetheless, a more precise understanding of the relationship between homocysteine balance and CVD remains an important area of investigation, particularly for populations that may be at the greatest risk for developing hyperhomocysteinemia and arterial stiffness.3