Original Article

Volume 17, Number 9, October 2025, pages 518-528

Clinical Significance of the Cardio-Ankle Vascular Index as a Cardiovascular Disease Risk Factor in Japanese Elderly Patients With Obesity

Recent epidemiological studies have reported that there are many people with obesity, and that a certain proportion of elderly individuals also have obesity [1]. In daily clinical practice, clinicians encounter many elderly patients with obesity. Several studies have also investigated the relationship between elderly patients with obesity and classical cardiovascular disease (CVD) risk factors, such as hypertension, dyslipidemia, and diabetes mellitus [2, 3]. In fact, even in daily practice, elderly patients complicated by obesity with a classical CVD risk factor are common. However, despite the standard medical treatments for these classical CVD risk factors, such as blood pressure-lowering therapy, blood glucose-lowering therapy, and serum lipid-lowering therapy, a certain number of patients would still develop CVD events. Thus, if a novel CVD risk factor in addition to the classical CVD risk factor can be identified and efficiently intervened in elderly patients with obesity, it can facilitate the prevention of further CVD development, making it clinically meaningful.

The cardio-ankle vascular index (CAVI) was developed as a physiological marker of systemic arterial stiffness that is independent of blood pressure at the time of measurement [4]. In recent years, basic and clinical studies have confirmed the significance of the CAVI as a CVD risk [5-9]. Furthermore, several prospective studies have demonstrated that CAVI is an important indicator for developing CVD [10-14]. Satoh-Asahara et al reported that CAVI can predict CVD events in Japanese patients with obesity with a mean age of 51.5 years [12]. Therefore, the existing study is considered as mainly targeting the middle-aged population. However, to our knowledge, there have been no studies examining the analysis of CAVI limited to elderly patients with obesity, and furthermore, the usefulness of CAVI as a predictor of primary CVD events in such patients has not been validated. Therefore, this prospective study tried to determine the clinical significance of CAVI as a CVD risk factor in Japanese elderly patients with obesity using various analysis.

Inclusion criteria were defined as 452 consecutive Japanese elderly patients with obesity (age ≥ 65 years and body mass index (BMI) ≥ 25.0 kg/m²) without a history of CVD events, who visited Hitsumoto Medical Clinic in Yamaguchi Prefecture between April 2009 and March 2011. Exclusion criteria included cases in which informed consent could not be obtained (14 cases), cases with insufficient data necessary for this study (14 cases), cases with ankle- brachial index < 0.9 (10 cases), and cases in which atrial fibrillation was present during CAVI measurement (12 cases). Finally, 402 patients (male/female ratio: 147/255; mean age ± standard deviation: 72 ± 5 years; mean BMI ± standard deviation: 27.6 ± 2.2 kg/m²) were enrolled in this study. The BMI of 25.0 kg/m² or higher, which was used to define Japanese obesity in this study, was determined with reference to existing reports [15].

This study was performed in accordance with the Declaration of Helsinki and the ethical principles of medical research involving human beings. Informed consent was obtained from all patients, and the study protocol was approved by the Institutional Review Board of Hitsumoto Medical Clinic (date of approval: March 18, 2009; approval number: HMC-2009- 3).

CAVI was measured using a VaSera CAVI instrument (Fukuda Denshi, Tokyo, Japan) based on the previously described methods [4, 16]. In brief, the pulse waves of the upper arm and ankle were determined using an inflatable cuff in which the pressure was maintained at 30 - 50 mm Hg. The systemic blood pressure and pulse pressure were measured simultaneously after the patient had rested in the supine position for 10 min. The formula for measuring the CAVI is as follows: CAVI = a((2ρ/ΔP) × ln (Ps/Pd) × (pulse wave velocity)²) + b, where a and b are constants, ρ is blood density, ΔP is Ps - Pd, Ps is systolic blood pressure, and Pd is diastolic blood pressure. Furthermore, the average coefficient of variation is < 5%, which indicates that the CAVI has good reproducibility [4].

Smokers were defined as patients who had smoking habits at baseline. In this study, the classical risk factors for CVD - hypertension, dyslipidemia, and diabetes mellitus - were defined according to a previous report [11]. The abdominal computed tomography examination measured the visceral fat area (VFA) and subcutaneous fat area at the umbilical level. The blood and urine data were measured in the fasting state. The contents of the data are as follows: serum lipid concentration, blood glucose concentration, blood insulin concentration, preheparin serum lipoprotein lipase mass (pre-LPL mass) concentration, and urinary 8-iso- prostaglandin F2α (U-8-iso-PGF2α) concentration, an in vivo indicator of oxidative stress. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as a marker of insulin resistance by an existing report (HOMA-R = blood glucose concentration × blood insulin concentration/405) [17]. Furthermore, oral medications, such as renin-angiotensin system (RAS) inhibitors, calcium blocker, statin, fibrate, and sulfonylurea were also investigated. None of insulin users were observed in this study

This study evaluated whether the enrolled patients developed primary CVD events during the observation period, which lasted until March 2025. Moreover, primary CVD events were defined as a composite of cardiovascular death, the development of coronary artery disease requiring invasive and/or medical treatment, and nonfatal ischemic stroke. The patients were divided into two groups based on the optimal cut-off value of the CAVI (cut-off value: 9.0), determined by receiver operating characteristic curve analysis for primary CVD events (Fig. 1): high CAVI group (group H: n = 193) and a low CAVI group (group L: n = 209).

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Figure 1. Optimal cut-off value of CAVI to detect primary CVD events using receiver operating characteristic curve analysis. The patients were divided into two groups based on the optimal cut-off value of the CAVI (cut-off value: 9.0): high CAVI group (group H) and a low CAVI group (group L). CAVI: cardio-ankle vascular index; CVD: cardiovascular disease; AUC: area under the curve.

Statistical analysis was performed using the commercialized software Stat View-J 5.0 (HULINKS Inc., Tokyo, Japan) and MedCalc (MedCalc Software, Ostend, Belgium). The optimal cut-off value of the CAVI for primary CVD events was decided via the receiver operating characteristic curve analysis using the Youden index [18]. Continuous variables were expressed as means and standard deviations. Group comparisons were conducted using the unpaired t-test or Mann-Whitney U test, depending in the data distribution. Kaplan-Meier analysis was performed to produce event-free survival curves; with differences between these curves assessed using the log-rank test. Multivariate analysis was performed using multiple Cox proportional hazards regression. Moreover, in this study, the selection of the explanatory variables for the occurrence of primary CVD events in the multiple Cox proportional hazards regression analysis was based on the number of primary CVD events (90 cases), clinical indices that showed the significant differences between the two groups for primary CVD events, based on clinical rationale, and multicollinearity. Finally, nine explanatory variables (i.e., CAVI, age, VFA, diabetes mellitus, HOMA-IR, pre-LPL mass, U-8-iso-PGF2α, RAS inhibitor use, and statin use) were determined. Cut-off values of age, VFA, HOMA-IR, pre-LpL mass, and U-8-iso-PGF2α were decided by receiver operating characteristic curve analysis. In this study, it was determined that the results drawn are statistically significant when the P value is less than 0.05.

Table 1 presents the baseline clinical characteristics of the study population. The mean CAVI for groups H and L were 10.6 and 8.1, respectively. The BMI was significantly lower in group H than in group L. However, the VFA was significantly higher in group H than in group L. Regarding CVD risk factors, the frequency of diabetes mellitus, blood glucose concentration, HOMA-IR, and U-8-iso-PGF2α were significantly higher in group H than in group L. However, the high-density lipoprotein cholesterol concentration and pre-LPL mass were significantly lower in group H than in group L. With regard to the medications, group H had a significantly lower frequency of using RAS inhibitors and statin than group L.

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Table 1. Baseline Clinical Characteristics

Figure 2 shows the results of the Kaplan-Meier curve analysis of all patients who participated in this study regarding the occurrence of primary CVD events. The median observation period was 100 months (range: 2 - 192 months). During the observation period, 90 patients experienced primary CVD events (group L, n = 20 (9.6%), vs. group H, n = 70 (36.3%)). Thus, group H had a significantly higher incidence of primary CVD events than group L (P < 0.001, log-rank test).

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Figure 2. Kaplan-Meier curve analysis for the incidence of primary CVD events in all patients. During the observation period, group H had a significantly higher incidence of primary CVD events than group L (P < 0.001, log-rank test). CVD: cardiovascular disease.

Table 2 shows the association between the presence or absence of primary CVD events and clinical characteristics in this study. BMI was similar in patients with and without primary CVD events. Age, VFA, frequency of diabetes mellitus, fasting blood glucose concentration, HOMA-IR, and U-8-iso-F2α were significantly higher in patients who experienced primary CVD events than in patients who did not. However, the patients who experienced primary CVD events had significantly lower pre-LPL mass, RAS inhibitor use, and statin use than those who did not.

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Table 2. Clinical Characteristics at Registration of Patients With and Without Cardiovascular Disease Events

Figure 3 shows the results of the Kaplan-Meier curve analysis in patients not using RAS inhibitor and statin regarding the occurrence of primary CVD events. During the observation period, 47 patients experienced primary CVD events (group L, n = 9 (17.6%), vs. group H, n = 38 (49.4%)). Thus, group H had a significantly higher incidence of primary CVD events than group L (P =0.013, log-rank test).

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Figure 3. Kaplan-Meier curve analysis in patients not using RAS inhibitor and statin. During the observation period, group H had a significantly higher incidence of primary CVD events than group L (P = 0.013, log-rank test). CVD: cardiovascular disease.

Table 3 shows the results of the multivariable Cox regression analysis for the onset of primary CVD events. Even after being adjusted for covariates, group H had a significantly higher risk of developing primary CVD events than those in group L (hazard ratio: 2.40; 95% confidence interval: 1.37 - 4.24; P = 0.002). With regard to the other factors, six variables (i.e., RAS inhibitor use, low pre-LPL mass, high HOMA-IR, aging, statin use, and high U-8-iso-PGF2α) also showed significant hazard ratios for the onset of primary CVD events. In contrast, the presence of diabetes mellitus and high VFA were not considered as significant variables for the occurrence of primary CVD events.

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Table 3. Multivariate Cox Regression Analysis for Cardiovascular Disease Events

This study aimed to investigate the clinical significance of CAVI as a CVD risk factor in Japanese elderly patients with obesity. When comparing baseline clinical backgrounds, patients with a high CAVI exhibited significantly higher VFA, as measured by abdominal computed tomography, compared to those with a low CAVI. Moreover, high CAVI was significantly associated with several independent risk factors for primary CVD events identified in the multivariable Cox regression analysis, including insulin resistance, low pre-LPL mass, and elevated oxidative stress. Importantly, high CAVI itself was also considered an independent predictor of primary CVD events. Several clinical studies have shown that CAVI is an important predictor of primary CVD events such as patients with cardiovascular risk factors, chronic kidney disease, metabolic syndrome cases, participants of the Malaysian Cohort, and middle-aged patients with obesity [10-14]. However, the findings obtained in this study represent the first report demonstrating that CAVI is an independent predictor of primary CVD events in elderly patients with obesity. In addition, it has been revealed that a single time-point measurement of CAVI, together with several biomarkers at baseline, was found to predict subsequent primary CVD events. However, patients with a high CAVI had a significantly lower frequency of using medications selected as significant inhibitory factors for primary CVD events in this study, such as statins and RAS inhibitors, compared with those with a low CAVI.

Several studies have shown a negative correlation between CAVI and BMI [19, 20]. In the study limited to elderly patients with obesity, those with a high CAVI had a significantly lower BMI compared to those with a low CAVI, confirming the negative association between CAVI and BMI. However, in the studies investigating the relationship between VFA and CAVI, the patients with a high CAVI had a significantly higher VFA than those with a low CAVI. A significant association between CAVI and visceral fat accumulation has been reported in existing research [21, 22]. In this study, similar results in elderly patients with obesity were also observed. Several studies have found that visceral fat accumulation is an important risk factor for CVD [23-25]. In the present study, the VFA of the patients who developed primary CVD events was significantly higher than that of those who did not. However, in the multivariable Cox regression analysis, the VFA was not selected as a significant predictor of primary CVD events. While the importance of visceral fat accumulation in CVD onset is an undeniable fact, the novel insights gained from this study suggest that the increase in the CAVI underlying visceral fat accumulation plays an important role in the onset of primary CVD events in elderly patients with obesity.

Several studies have confirmed that diabetes mellitus is closely related to obesity and is an important risk factor for the onset of CVD [2, 3, 26, 27]. Moreover, it has been reported that patients with diabetes mellitus tend to have a significantly higher CAVI compared to those with normoglycemia [28]. However, among the elderly patients with obesity in the present study, the proportion of patients with diabetes mellitus among those who developed primary CVD events was significantly higher than that of those who did not develop primary CVD events. In addition, the proportion of patients with diabetes mellitus among those with a high CAVI was also significantly higher than that of those with a low CAVI. Thus, these results are consistent with existing reports. However, the multivariable Cox regression analysis did not consider diabetes mellitus as a significant predictor of primary CVD events. Thus, the results of this study suggest that in elderly patients with obesity, the increase in the CAVI underlying the presence of diabetes mellitus is closely related to the onset of primary CVD events, and it is important to actively intervene with the treatment aimed at reducing the CAVI for the prevention of primary CVD events in elderly patients with obesity and diabetes mellitus.

Basic and clinical studies have indicated that insulin resistance plays a key role in the progression of atherosclerosis [29, 30]. In the present study, HOMA-IR, an indicator of insulin resistance, was selected as an independent predictor of primary CVD events in elderly patients with obesity, suggesting the importance of insulin resistance in the development of primary CVD events in this population. Moreover, several studies have reported a significant association between insulin resistance and CAVI [16, 31, 32]. The present study also found that patients with a high CAVI had a significantly higher HOMA-IR compared with those with a low CAVI, which is consistent with the findings of existing reports. These results suggest that improving insulin resistance, primarily through lifestyle modifications such as diet and exercise, can help prevent primary CVD events in elderly patients with obesity by reducing CAVI. However, recent prospective studies have shown that pioglitazone, a drug used for improving insulin resistance, significantly reduced the occurrence of CVD events [33, 34]. In addition, Ohira et al reported that pioglitazone improves CAVI in patients with type 2 diabetes [35]. Unfortunately, no cases of pioglitazone administration in the study population were observed, making it impossible to determine whether pioglitazone could be involved in the prevention of primary CVD events in elderly patients with obesity. However, based on previous findings, it is expected that pioglitazone could contribute to the prevention of primary CVD events in elderly patients with obesity and high CAVI. Further research is needed to confirm whether this can be achieved by preventing primary CVD events through a reduction in the CAVI.

Several studies have suggested that the pre-LPL mass present in the blood prior to heparin intravenous injection shows lower values in the state of visceral fat accumulation [36], and it has been considered as an important risk factor for CVD, particularly coronary artery disease [37-39]. Moreover, in the present study which specifically targets elderly individuals with obesity, the pre-LPL mass was selected as an independent predictor of the onset of primary CVD events, highlighting its importance as a risk factor for CVD in elderly patients with obesity. However, the pre-LPL mass of the patients with a high CAVI was significantly lower than those with a low CAVI. Moteki et al similarly reported a negative correlation between the CAVI and pre-LPL mass, which confirms the findings of this study [40]. Saiki et al reported that the lipoprotein lipase derived from subcutaneous fat is involved in the reduction of CAVI in patients with visceral fat accumulation [41]. This fact suggests that the lipoprotein lipase in subcutaneous fat exhibits an atheroprotective effect. Thus, the low pre-LPL mass in this study reflects the pathogenesis of visceral fat accumulation, highlighting the importance of targeting visceral fat reduction in the treatment of elderly patients with obesity to prevent primary CVD events from the perspective of in vivo lipoprotein lipase activity.

Several studies have reported that oxidative stress plays an important role in the onset of CVD [42, 43]. In the present study, U-8-iso-PGF2α, a representative oxidative stress marker, was selected as an independent factor predicting primary CVD events in elderly patients with obesity. However, the levels of U-8-iso-PGF2α in patients with a high CAVI were significantly higher than those in patients with a low CAVI. Several researchers have shown a significant association between an elevated CAVI and oxidative stress [44, 45], which is consistent with the results of the present study. Thus, the treatments that reduce oxidative stress may facilitate the prevention of primary CVD events through a reduction in the CAVI.

Numerous clinical studies have confirmed that statin and RAS inhibitors significantly reduce the CVD risk [46, 47]. In the present study, these medications were also associated with a significant reduction in the onset of primary CVD events among elderly patients with obesity. However, the frequency of using both medications in the high CAVI group was significantly lower than that in the low CAVI group. Several clinical studies have reported that both medications significantly reduce CAVI. Miyashita et al reported that pitavastatin, a type of statin, significantly decreased oxidative stress markers, such as urinary 8-hydroxy-2'-deoxyguanosine, serum malondialdehyde-low density lipoprotein, and CAVI [48]. They also reported that olmesartan, which is one of the RAS inhibitors, showed a significant relationship between the decrease in CAVI and the decrease in urinary 8-hydroxy-2'-deoxyguanosine due to the medication [49]. Moreover, it has been suggested that both medications exhibit an effect of increasing the pre-LPL mass [50-52]. In addition, in the Kaplan-Meier curve analysis of this study, not only was there a significant occurrence of primary CVD events in the high CAVI group compared to the low CAVI group among all subjects, but also in cases that were not taking statin or RAS inhibitor. This suggests that, actively using both drugs in high CAVI cases not taking statins or RAS inhibitors may help suppress primary CVD events in elderly patients with obesity through the pathway of oxidative stress suppression and increase of pre-LpL mass.

In this study, in determining the cut-off value of CAVI for elderly patients with obesity, a receiver operating characteristic curve analysis for primary CVD events was used, resulting in a value of 9.0. The cut-off value of 9.0 for CAVI has also been indicated in existing reports [14, 53]. However, in this study, the cut-off value of 9.0 for CAVI also shows statistically significant results in the multivariate Cox regression analysis for primary CVD events. Therefore, targeting a CAVI value of 9.0 or lower for intervention treatment in elderly patients with obesity suggests the possibility of suppressing primary CVD events in elderly patients with obesity. It is necessary to perform external validation in the future to assess the validity of the cut-off value obtained from this study.

This study has several limitations. First, the study is single-center and limited to elderly Japanese patients with obesity. Therefore, the findings may not be extrapolated to populations with different obesity phenotypes or risk factor profiles. Second, this study showed that a high CAVI is an independent predictor in elderly patients with obesity; however, it did not quantify its additional value against existing risk scores (e.g., Framingham or assessment of 10-year atherosclerotic CVD). In the future, it is desired to strengthen the claim of the clinical utility of this study’s results by reporting C statistics, net reclassification improvement, or integrated discrimination improvement. Third, previous studies in Japanese patients have shown that eicosapentaenoic acid (EPA) improves the arterial stiffness, associated with an increased EPA/arachidonic acid (AA) ratio and decreased inflammation in patients with obesity with dyslipidemia [54]. The clinical relevance of decreased ratios of serum EPA/AA and docosahexaenoic acid (DHA)/AA to impaired arterial stiffness has also been reported [55]. However, in the present study, EPA- and DHA-related data were not found. Therefore, further study is required to clarify the clinical significance of CAVI as a CVD risk factor in elderly patients with obesity, particularly from perspective of omega-3 fatty acids. Finally, this study’s results showed that a high baseline CAVI could be a predictive indicator for primary CVD events in elderly patients with obesity. However, it is necessary to investigate the extent to which primary CVD prevention is possible through interventions such as active lifestyle improvements and medications such as pioglitazone, statins, RAS inhibitors, and omega-3 fatty acids in elderly obese patients with a high CAVI.

This study demonstrated that CAVI increased in the situation of visceral fat accumulation and was significantly associated with important CVD risk factors, such as insulin resistance, low pre-LPL mass, and elevated oxidative stress in Japanese elderly patients with obesity. Furthermore, a high baseline CAVI was found to be a useful predictor of primary CVD events in these patients. Considering the limitations of this study, further research is needed to determine the extent to which primary CVD prevention is possible through interventions such as active lifestyle improvements and medications in elderly patients with obesity and high CAVI.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Informed consent was obtained from all patients who participated in this study.

Author Contributions

Takashi Hitsumoto contributed to research planning, data acquisition and analysis, and manuscript writing and editing.

Data Availability

The author declares that data supporting the findings of this study are available within the article.

Abbreviations

AA: arachidonic acid; BMI: body mass index; CAVI: cardio-ankle vascular index; CVD: cardiovascular disease; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; HOMA-IR: homeostasis model assessment of insulin resistance; pre-LpL mass: preheparin serum lipoprotein lipase mass; RAS: renin-angiotensin system; U-8-iso-F2α: urinary 8-iso-prostaglandinF2α; VFA: visceral fat area

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