Cardio‐ankle vascular index as a predictor of major adverse cardiovascular events in metabolic syndrome patients

Abstract Background Arterial stiffness, as reflected in the cardio‐ankle vascular index (CAVI), is a risk factor for major adverse cardiovascular events (MACEs). Hypothesis Combining CAVI and metabolic syndrome (MetS) may enhance prediction of MACEs in a general adult population. Methods A total of 3807 employees of the Electricity Generating Authority of Thailand were enrolled in a longitudinal health study during 2007‐2008. Baseline characteristics were collected and CAVI determined. Subjects with previous coronary artery disease or stroke were excluded from analysis. MetS was defined using the modified NCEP‐ATP III for Asians. The primary study endpoint was occurrence of a MACE (myocardial infarction, stroke, or cardiovascular death). Results MetS was present in 39.2% at study baseline. The prevalence of CAVI > 9 was higher in subjects with MetS compared to those without (33.7% vs. 28.5%, P = 0.001). During the 12.4 ± 0.6 years follow‐up, 227 participants developed MACEs and 350 died. MetS was more common in patients who developed a MACE (8.2% vs. 5.0%, p < 0.001) than was non‐MetS, but it was not a significant risk after adjusting covariables. Participants with CAVI > 9 had greater risk for MACEs 1.34 (95% CI: 1.01, 1.79) relative to those with CAVI < 9. Participants with both MetS and CAVI > 9 had the worst outcomes, with the highest frequency of MACEs, among the four groups. Conclusion Arterial stiffness assessed by CAVI may enhance prediction of future MACEs, adding to the null predictive power of MetS. This index can be used to motivate MetS patients to modify their life‐styles for prevention.


| INTRODUCTION
Metabolic syndrome (MetS) is associated with an increase in major adverse cardiovascular events (MACEs) and all-cause death (ACD). 1,2 Patients with MetS have a 2-fold increase in cardiovascular events (CVEs) and a 1.5-fold increase in ACD. 3 The pathogenesis of atherosclerosis in MetS is related to uncontrolled risk factors, chronic inflammatory processes, and a prothrombotic state. These mechanisms cause progression of premature atherosclerosis and development of early onset type 2 diabetes mellitus (DM).
The prevalence of MetS in adult populations is increasing worldwide as well as in Asia, from 10%-15% in the last decade to 20%-25% currently. [4][5][6] To prevent CVEs and to reduce death, it is important to encourage these vulnerable populations to reduce their risk factors. There are many non-invasive tests available to detect subclinical atherosclerosis in high-risk patients including cardiac stress test, carotid duplex ultrasound, coronary calcium score, coronary computed tomographic angiography, and so forth. However, all of these tests have limitations as screening tools because of their cost and lack of evidence that their use is associated with a reduction in CVEs and death. [7][8][9][10] Thus, there remains a need to identify non-invasive physiologic tests that can be used to risk-stratify MetS subjects, especially early in their disease process.
Arterial stiffness is one of the earliest properties accompanying the development of atherosclerosis. 11 Cardio-ankle vascular index (CAVI), a newly developed indicator of arterial stiffness, has been widely used as a surrogate marker for cardiovascular disease (CVD). 12,13 This non-invasive tool might provide earlier diagnosis and identification of subjects at high risk for CVEs and death. Unlike brachial-ankle pulse wave velocity (PWV), CAVI has the advantage of being unaffected by blood pressure (BP) and gives reproducible results in the clinic. Previous studies have shown that CAVI is able to diagnose subclinical atherosclerosis and to predict future CVEs. 14,15 In patients with metabolic disorders, CAVI has been reported to be a predictor of CVEs, independent of conventional atherosclerosis risk factors. 16,17 This study investigated whether combining arterial stiffness (as reflected by the CAVI) and status regarding MetS may further enhance prediction of MACEs in a general adult population.

| Study design
The Electricity Generating Authority of Thailand (EGAT) study is a large prospective cohort study conducted in adult employees to better understand the occurrence and influence of risk factors on progression of CVD in Thais. 18

| Measurement of CAVI
CAVI was measured using a Vasera VS-1000 vascular screening system (Fukuda Denshi, Japan). 21 In brief, patients were in the supine position with pressure cuffs applied bilaterally to upper arms and ankles. After resting for 10 min, the electrocardiogram and phonocardiogram were monitored the heart rhythm and heart sound, respectively. Pulse wave velocity (PWV) was obtained by measuring the distance between the aortic valve to the ankle (L) divided by time for the pulse wave to propagate from the aortic valve to the ankle (T).
CAVI is derived from this PWV and BP using the following equation: where Ps and Pd are the SBP and DBP, respectively; PWV is the pulse wave velocity between the heart and ankle; ρ is blood density; ΔP is Ps-Pd; a and b are scale conversion constants ( Figure 1). 21 This index is calculated from the heart-ankle pulse wave velocity (haPWV), and adjusted for BP based on a stiffness parameter. In our study, the mean value of right and left CAVI was used for analyses. According to the manufacturer, values <8 are considered as normal, 8 to <9 as borderline, and ≥ 9 as high and suggestive of the presence of arteriosclerosis. 22 In our study, we used CAVI values ≥9 as a candidate risk factor for subclinical atherosclerosis in MetS patients. 23 This machine also measured the ABI, another physiological test for diagnosis of peripheral arterial disease.

| Enrolled subjects
Subjects were randomly enrolled from the ongoing EGAT study, among EGAT employees in the Bangkok metropolitan area (EGAT 1) and at three different sites in Western and Northern Thailand (EGAT 2). The age range was selected as 35-54 years old, to maximize the probability of CVD events, given that the retirement age in EGAT in 1985 was 55 years. A large variety of people were recruited, from illiterates working as cleaners to truck drivers, security guards, office clerks, administrators, architectures, engineers, field explorers, lecturers, lawyers, health-care practitioners, and those on executive boards.
Inclusion criteria included the presence of atherosclerosis risk factors but absence of related symptoms. Exclusion criteria included a diagnosis CVD at baseline, either coronary artery disease (CAD), myocardial infarction (MI), or stroke. To ensure correct CAVI measurements, participants with any of the following characteristics were also excluded: 1) abnormal ABI <0.9, 2) interference waveform of phonocardiogram and arterial (brachial or ankle) pulse waves, 3) atrial fibrillation, and 4) outlier CAVI values (≤3 or ≥ 18). 22  haPWV, heart ankle pulse wave velocity; Ps, systolic blood pressure; Pd, diastolic blood pressure; DP, Ps-Pd; ρ, blood density; tba, time between rise in brachial pulse wave and rise in ankle pulse wave; tb, time between closing sound of aortic valve and notch in brachial pulse wave; t'b, time between opening sound of aortic valve and rise in brachial pulse wave; a and b, scale conversion constants. Source: Modified from Shirai et al. 21 death (e.g., heart failure, valvular heart disease, or PAD), noncardiovascular death (i.e., malignancy, respiratory and gastrointestinal diseases, accident, sepsis, metabolic (DM, hypertension, dyslipidemia), or unknown).

| Statistical analysis
Characteristics at enrollment were described using mean ± SD for continuous variables and percentages for categorical variables. These corresponding variables for the MetS groups were compared using a   Table 1. Participants with MetS were older, and more frequently smoked, DM, hypertension, dyslipidemia, and had higher BMI, waist circumference, FPG, TG, and lower total cholesterol, LDL-C, and HDL-C. In addition, significant arterial stiffness, defined as CAVI≥9, was found more frequently in individuals with MetS than non-MetS (33.7% vs 28.5%, respectively: p = .001). ABI classified as above or below the median (1.12), was found to be independent of the presence of MetS.

| Predictors associated with MACEs
Using bivariate analysis, MetS, CAVI, age, sex, ABI, BMI, waist circumference, smoking, FPG, DM, and hypertension were each found to be significantly associated with MACEs, see

| Interaction effects between MetS and CAVI on MACEs
The CAVI ≥ 9, followed by MetS and CAVI < 9, non-MetS and CAVI ≥ 9, and non-MetS and CAVI < 9 (p < .001, Figure 3). Participants with MetS and CAVI ≥ 9 had a MACE about 67% higher than the MetS and CAVI < 9 groups and 93% higher than the non-MetS and CAV-I ≥ 9. The differences between groups were visible as early as year 1, and persisted through the follow-up period.

| DISCUSSION
This is the first study to assess the effects of MetS and CAVI on the occurrence of MACEs in a large longitudinally followed cohort. The prevalence of MetS in our population was nearly 40%, compared to 20%-30% in populations previously reported from Asia and worldwide. 4,24 This emphasizes the scale of this healthcare problem in Arterial stiffness assessed by CAVI has been reported to be a surrogate marker of atherosclerosis and a predictor of future CVEs, independent of conventional risk factors. 16 In our study, the prevalence of CAVI ≥ 9 was higher in participants with, than without, MetS. Having MetS itself carried a 5% higher risk of a MACE, but having CAVI ≥ 9 further increased this risk to 34%. The cut-off of CAVI = 9 captured about 30% of the study group and added to the predictive value the diagnosis of MetS for MACEs.
In this study, we used the CAVI as a categorical rather than a continuous variables. A cut-off of CAVI ≥ 9 is generally considered high and to represent the presence of atherosclerosis and as a predictor of CV risk. 22,26 This is consistent with previous studies that have shown CAVI ≥ 9 to be significantly increased in populations with metabolic CV risk factors, and to predict future CV risk in asymptomatic patients with type 2 DM. 27,28 However, there is still some discrepancy regarding the appropriate cut-off value to use for discriminating CV risk. Sato et al. 16 and Kubota et al. 29 used a cut-off of CAVI ≥ 10. Therefore, to determine the most appropriate CAVI values for prediction of MACEs, especially in MetS populations, further prospective studies are required.
Other risk factors, such as older age, male sex, are also reported to be associated with higher CAVI. 30,31 This might explain why participants in our study who had higher CAVIs were found to have an increased incidence of MACEs and ACD. Almost half of our participants had a history of cigarette use, and smoking is known to influence arterial stiffness. 32 However, in the current study smoking was not significantly associated with MACEs. Furthermore, hypertension, DM, and dyslipidemia were also significantly associated with MACEs, particularly for DM and hypertension in which their effects were much higher than effect of MetS, including them into the same model could dilute effect and resulted in non-significant effect of MetS.
Most participants (especially in the MetS group) were under treatment with lipid lowering agents which resulted in their having lower total cholesterol and LDL-C, and no association with MACEs.
In summary, in patients with MetS, CAVI was an additional risk predictor of future MACEs, independent of traditional coronary risk factors. CAVI was a potentially valuable non-invasive test which identified high-risk MetS patients who were likely to benefit from intensive therapeutic approaches.
Several limitations of the study need to be mentioned. The study population was enrolled only from among EGAT employees and were mostly middle or older age. Thus, the results may not be generalizable to younger populations. The definition of MetS was defined based on the baseline characteristics on the day of enrollment, and there is a possibility that some participants may have switched over during the follow-up period. Such switches may have influenced the long-term clinical outcomes. But since developing MetS was more likely than resolving the syndrome, this influence would tend to underestimate the true differences. Finally, even though this was a cross-sectional, prospective cohort study, it could not prove causality between arterial stiffness and MACEs.

| CONCLUSION
MetS is an important problem that is associated with MACEs and premature death. Arterial stiffness of a person can be assessed noninvasively and semi-quantitatively represented by CAVI, and this index F I G U R E 3 Probability of major adverse cardiovascular events (MACEs) among 3630 subjects grouped by MetS and CAVI status can be used as a screening tool. CAVI may improve prediction of future MACEs, and also used to motivate MetS patients to modify their life-style for CV disease prevention.