As shown in Table 2, we have established the baseline CAVI scores based on 5,969 CVD risk-free persons selected out of 32,627 persons 20-74 years of age. It is shown that there exists a linear association between CAVI scores and age in both genders confirming that aging is an independent risk factor of atherosclerosis and cardiovascular disease as described in western [22, 23] and Japanese studies . Table 2 and Figure 3 show a biological aging of major arteries among CVD risk-free persons. We found that age-specific average CAVI scores among men were significantly greater than among women. Such a finding is consistent with the fact that men have a higher risk for coronary heart disease (of which one major risk factor is arteriosclerosis) than women [1, 2]. Based on these findings, we need to evaluate an individual's CAVI scores according to his/her age and gender when we conduct screening.
As established by Framingham studies and others [25–27], hypertension is a risk factor of cardiovascular disease. Hypertension is also significantly associated with PWV [9, 10, 28]. High PWV values are found to be an independent predictive factor of cardiovascular disease . Since our results indicate that age-specific average CAVI scores in the hypertension group were significantly higher than those from the CVD risk-free group (Tables 3, 4), it is implied that hypertension is a risk factor of arteriosclerosis.
The association between serum lipid levels and atherosclerotic disease, namely coronary heart disease, has been established through the findings from several epidemiological studies such as the Seven Countries Study , the Multiple Risk Factor Intervention Trial Study , and Klag et al's follow-up study . Namekata et al. reported that abnormally high PWV was significantly associated with 4.5 or greater value of the ratio of total cholesterol to high density lipoprotein (HDL) cholesterol implying that abnormal lipid imbalance is a risk factor of arterial stiffness and arteriosclerosis . Our results support such an association by showing that age-specific average CAVI scores among persons with hypercholesterolemia and hypertriglyceridemia of ages 40 and over were significantly greater than those among CVD risk-free persons for the same age-specific groups (Tables 3, 4).
Diabetes mellitus is proven to be a risk factor for cardiovascular disease [33, 34]. It is reported that CVD risk among diabetics was 2-6 times higher than among non-diabetics and PWV values were associated with fasting glucose levels among diabetics [35, 36]. An odds ratio for having abnormally high PWV among diabetics is also reported to be 3.66 (p < 0.001) as compared to non-diabetics . Our results are consistent with these findings by showing significantly higher average age-specific CAVI scores among persons with hyperglycemia after 40 years of age than those among CVD risk-free persons (Tables 3, 4).
Ischemic changes in ECG and arteriolar changes in retina are considered as surrogate markers of arterial stiffness and arteriosclerosis in the coronary arteries and retinal arteries, respectively. It is also shown that atherosclerotic lesions in the aorta proceeds onset of CVD [37–39], as an increase in PWV values proceeds ischemic changes in ECG and arterial changes in retina appear . We have shown that the age-specific average CAVI scores of the ischemic changes group and of the retinal artery changes group were significantly greater than those of the CVD risk-free group (Tables 3, 4). This implies that CAVI scores reflect the extent of arteriosclerotic changes not only in medium-size and large-size arteries but also in small-size arteries.
We have shown that age-specific average CAVI scores of all CVD high-risk persons combined were significantly higher than those of the CVD risk-free group after 40 years of age (Tables 3, 4), indicating that the overall arteriosclerosis status of the CVD high-risk group was significantly worse than that of the CVD risk-free group. Because no difference in average CAVI scores between the two groups was detected before 40 years of age, effective CAVI screening might be recommended for people age 40 and over.
With regard to the validity to use CAVI scores as an indicator of arteriosclerosis, Otsuka examined 72 deceased patients' ante-mortem PWV (which is a basis for deriving CAVI scores) and pathological changes measured by the diffuse fibrotic thickening, formation of atheroma and calcification in the wall of their aorta. He reported multiple regression coefficient R = 0.810 between PWV and scores of those pathological changes . In addition, other researchers reported that CAVI scores were significantly associated with coronary atherosclerosis , with carotid intima-media thickness and with homocysteine . Thus, the use of CAVI scores derived from PWV values is valid to estimate the extent of arteriosclerosis.
VaSera VS-1000, which was used in our study, was designed to measure CAVI scores independent of blood pressure and CAVI scores represent the extent of arteriosclerosis between the aortic valve and the ankle. We have shown biological aging of the major artery by measuring CAVI scores in the CVD risk-free group and disease-related pathological aging of the major artery in the CVD high-risk group. CAVI scores allow us to evaluate the extent of arteriosclerosis in the major arteries between the aortic valve and the ankle, to screen persons with subclinical stage of CVD, and provide an opportunity to modify diet and lifestyle to improve CAVI scores as reported by Satoh et al . Thus, the use of CAVI scores potentially leads to savings on high treatment costs and to prolonging many productive lives.
There are some limitations in our study. First, the study design was cross-sectional and results were based on our observations at the time of screening. Secondly, our data did not include behavioral and lifestyle factors, although we consider that effects of such factors were reflected on clinical measurements related to CVD which we included. Currently we are examining the association between CAVI scores and lifestyle factors such as smoking, alcohol consumption, and body mass index, and will report results in the near future.