High mean corpuscular volume (MCV), also known as macrocytosis, is associated with vitamin B12 and folic acid deficiency, liver disease, hyperglycemia, alcoholism, smoking habits, and other pathologic conditions [1,2]. Moreover, a high MCV is associated with increased all-cause mortality and cancer mortality in non-anemic cancer-free individuals [3].

Pulse wave velocity (PWV) is one of various markers of early arterial wall changes such as arterial wall thickness and stiffness [4]. It is defined as the velocity of blood streaming from the heart to peripheral arteries through the aorta and is known to increase with blood vessel stiffness [5,6]. Brachial-ankle pulse wave velocity (baPWV) is also strongly correlated with aortic PWV and can be used as a simple, noninvasive, and automatic method to measure arterial stiffness in the primary care setting [7]. Previous studies have shown that increased PWV is independently associated with cardiovascular disease (CVD) incidence and mortality. Moreover, high baPWV was a strong predictor of early carotid atherosclerosis [8]. A baPWV of >1,400 cm/s is an independent risk factor for moderate risk (≥10%) stratification according to the Framingham risk scoring system, and a baPWV of >1,600 cm/s is an independent factor for high risk stratification according to the European systematic coronary risk evaluation (SCORE) system [9].

Although high MCV has been implicated in various health problems, the clinical significance of borderline-high MCV is poorly understood among apparently healthy Korean individuals in the primary care setting. Therefore, this study aimed to examine whether borderline-high MCV is related to arterial stiffness in Korean adults as measured using baPWV.

Table 1 shows the clinical characteristics of the study population (330 men and 252 women). The mean age and BMI were 47.8±11.7 years and 23.8±2.9 kg/cm2, respectively. The mean systolic and diastolic blood pressure were 119.5±15.2 mm Hg and 73.1±11.9 mm Hg, respectively. The proportion of participants with borderline-high MCV was 10.5%. Compared with controls, age, male sex, and γ-glutamyltransferase were higher in the borderline-high MCV group.

Table 2 shows the univariate analysis between high baPWV and some indicators for cardiovascular risk. BaPWV was found to be significantly associated with age (OR, 1.13; P<0.001), BMI (OR, 1.17; P<0.001), systolic blood pressure (OR, 1.08; P<0.001), diastolic blood pressure (OR, 1.11; P<0.001), fasting plasma glucose (OR, 1.02; P<0.001), hsCRP (OR, 1.43; P<0.001), and borderline-high MCV (OR, 3.05; P<0.001).

Figure 1 shows the means and standard errors of baPWV (cm/s) according to borderline-high MCV after adjusting for age, sex, BMI, hsCRP, hypertension medication, and diabetes medication. The mean baPWV in the borderline-high MCV group was significantly higher than that in the control group (1,386.2±22.7 mm Hg versus 1,322.7±8.7 mm Hg, P=0.024).

Table 3 shows the ORs for high PWV according to the borderlinehigh MCV. The OR (95% CI) of the borderline-high MCV group was 3.21 (1.22–8.48) after adjusting for age, sex, BMI, alcohol intake, smoking status, regular exercise, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, HDL-cholesterol, WBC count, C-reactive protein, γ-glutamyltransferase, and uric acid, hypertension medication, and diabetes medication.

In this cross-sectional study, borderline-high MCV was independently associated with high baPWV. This effect remained even after adjusting for potential confounding factors, including the presence of drugs that could influence the vascular function. Although the reference value for baPWV is different according to age and blood pressure categories [12,13], a baPWV of >1,400 cm/s has been shown as a useful predictor of CVD [7], and >1,800 cm/s may be a marker of target organ damage [14]. Previous Korean studies showed that a baPWV of >1,600 cm/s was an independent risk factor for greater atherosclerotic disease complexity based on the virtual histology intravascular ultrasound analysis and high risk stratification based on the SCORE model [9,15].

Although underlying mechanisms of increased baPWV were not investigated, some biological mechanisms may help explain the association between borderline-high MCV and arterial stiffness. First, increased MCV reflects folate and vitamin B12 deficiencies, which can lead to high homocysteine level, a cardiovascular risk factor. Folate and vitamin B12 play an important role in regulating the conversion of homocysteine. Homocysteine concentrations are strongly negatively correlated with folate and vitamin B12 levels [16,17]. Homocysteine induces proliferation of smooth muscle cells in the artery, resulting in impaired vascular endothelial function and blood coagulability. High homocysteine level is thought to contribute to atherosclerosis and increased thickness and blood vessel stiffness [10]. Accordingly, lack of folate and vitamin B12 induces elevated MCV and homocysteine levels, resulting in elevated arterial stiffness. Second, elevated MCV is an indicator of liver function deterioration, which might be closely related to CVD development. Macrocytosis is commonly found in various liver diseases. In individuals with liver disease, the membrane lipid composition changes, affecting the membrane surface area, leading to increased MCV. This mechanism depends on the pathogenesis and severity of liver disease [2]. Moreover, elevated serum γ-glutamyltransferase level is strongly associated with increased oxidative stress [18,19]. Increased oxidative stress induced by decreased liver function is positively correlated with CVD development [20]. Thus, decreased liver function seems to manifest in elevated MCV as well as arterial stiffness. Finally, elevated MCV implies thyroid dysfunction, which could also be associated with arterial stiffness. Thyroid hormone is involved in the regulation of hemoglobin synthesis. MCV values were significantly increased in both overt and subclinical hypothyroidism [21]. Moreover, hypothyroidism led to increased vascular resistance and arterial wall thickness, which could be attributed to lipid abnormalities, homocysteine levels, and abnormal coagulability [22]. Therefore, elevated MCV and arterial stiffness might be caused by thyroid dysfunction. Therefore, our findings indicate borderline-high MCV may be accompanied by several unfavorable metabolic alterations, which can be implicated in increased arterial stiffness.

Several limitations should be acknowledged in this study. First, the causality cannot be concluded due to the cross-sectional design of the study. Moreover, other confounding factors affecting baPWV, such as thyroid disease, homocysteine levels, and dyslipidemia medication, were not considered because these indicators were not fully measured at the beginning of this study. Study participants were volunteers visiting for a health promotion screening at a single hospital. Thus, the study population appeared to be slightly healthier than communitybased cohorts and may not be representative of the general population in Korea, and selection bias may have affected the results.

In conclusion, we found that borderline-high MCV was independently associated with arterial stiffness among apparently healthy Korean individuals. Further larger-scale prospective cohort studies are warranted to validate these associations in the future.