Low Arterial Stiffness by Pulse Wave Analysis and Aortic Diseases

Abstract

Background: The cardio-ankle vascular index (CAVI) is an important marker of arterial stiffness, providing a blood pressure-independent assessment of vascular function. However, the clinical significance of low CAVI values remains unclear. Some connective tissue diseases are associated with aortic diseases due to intrinsic arterial wall abnormalities and may exhibit low CAVI values. This study aimed to investigate whether low CAVI is associated with these connective tissue diseases and succeeding aortic diseases.

Methods and Results: This was a single-center, retrospective observational study conducted at Juntendo University Hospital. A total of 17,364 patients aged 20–80 years who underwent arterial stiffness analysis using CAVI were included. Low CAVI was defined as the lowest 2.5 percentile within each sex- and age-specific distribution. The prevalences of aortic diseases (dissection and/or aneurysm) and Marfan syndrome were similar between the between the low CAVI and normal CAVI groups (aortic disease, 3.99% vs. 3.99%, P>0.99; Marfan syndrome, 0.04% vs. 0.07%, P>0.99, for the low and normal CAVI group, respectively).

Conclusions: This study found no evidence that patients with low CAVI had an increased prevalence of aortic dissection, aortic aneurysm, or Marfan syndrome. Further studies are needed to clarify the clinical implications of low CAVI in vascular diseases.

Aortic aneurysm and aortic dissection are critical cardiovascular diseases that can sometimes take a fatal course.^1–6 Chronic vascular inflammation has been implicated in their pathogenesis, with hypertension,⁷ diabetes mellitus,⁸ and dyslipidemia^9,10 being recognized as contributing factors. Additionally, a genetic predisposition has been reported, with connective tissue diseases such as Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome being associated with an increased risk.³

Arterial stiffness is commonly assessed using indices such as the cardio-ankle vascular index (CAVI), which is an arterial stiffness parameter that is independent of blood pressure and allows for simple, yet accurate assessment associated and clinical outcomes.^11–14 Although CAVI is widely recognized as an important indicator of arterial stiffness, the clinical significance of low CAVI values remains unclear. In particular, patients with connective tissue diseases, including Marfan syndrome, may theoretically exhibit lower CAVI values due to intrinsic changes in arterial wall elasticity, which subsequently result in aortic aneurysms and dissection.¹⁵ However, no large-scale studies have investigated this relationship, and data on the association of low CAVI with these diseases are lacking. A better understanding of the implications of low CAVI values could provide further insights into vascular remodeling in these conditions. Thus, we sought to assess the prevalence of aortic aneurysm, aortic dissection, and Marfan syndrome in patients with normal and low CAVI.

Methods

Study Design

This was a single-center, retrospective observational study conducted at Juntendo University Hospital. It included patients aged 20–80 years who underwent arterial stiffness analysis using CAVI. In this study, CAVI values were defined based on the lower value between the left and right measurements. Patients were stratified into 2 groups based on their CAVI values: a low CAVI group consisting of patients with CAVI values in the lowest 2.5 percentile for their sex- and age-specific distribution, and a normal CAVI group consisting of those with CAVI values above this threshold. The prevalence and number of patients diagnosed with specific cardiovascular conditions were compared between groups. Diagnoses were identified using ICD-10 codes from the electronic chart (I710–I719 for aortic dissection and aortic aneurysm and Q874 for Marfan syndrome).

Assessment of Arterial Stiffness

CAVI is a noninvasive measure that reflects the stiffness of the arterial tree from the ascending aorta to the ankle, independent of blood pressure.¹⁶ Measurements of CAVI were performed with the patient in a supine position after at least 5 min of rest, using an automatic vascular screening device, the VaSera VS-2500 Premium and VS-3000 (Fukuda Denshi Co., Ltd., Tokyo, Japan). Cuffs were placed on both the upper arms and ankles, and electrocardiographic electrodes were attached to both wrists. A phonocardiogram sensor was placed on the sternum to detect heart sounds. The pulse wave velocity (PWV) was recorded, and blood pressure at the 4 extremities was measured using the oscillometric method. CAVI was calculated using the following equation:¹¹

CAVI = a [2ρ / (P_sys − P_dia) ∙ ln (P_sys /P_dia) ∙ (haPWV)²] + b

where a and b are constants used for converting PWV into CAVI values, ρ represents blood density, P_sys is systolic blood pressure, P_dia is diastolic blood pressure, and haPWV is pulse wave velocity from the aortic valve to the ankle. In this study, a lower CAVI value in the left and right measurements was used as the patient’s personal CAVI value.

Statistical Analysis

Data are presented as mean±standard deviation (SD) for continuous variables, as appropriate, and as frequencies (%) for categorical variables. Group differences were evaluated using Welch’s t-test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. For comparisons of proportions between groups, a two-proportion z-test was performed when the sample size was sufficiently large, and Fisher’s exact test was used for smaller sample sizes. All statistical analyses were conducted using R (version 4.4.1; The R Foundation for Statistical Computing, Vienna, Austria). A two-tailed P value <0.05 was considered statistically significant.

Results

A total of 17,364 patients were included in this study, with data collected between May 2011 and June 2024. Baseline characteristics are summarized in Table 1. The mean age was 63.4±12.2 years, and 36% of the cohort was female. The overall mean CAVI value was 8.13±1.45. When stratified by CAVI categories based on the lowest 2.5% within each age and sex group, 14,736 patients were classified as normal CAVI, and 2,628 as low CAVI. The mean age and body mass index were slightly higher in the low CAVI group (age, 64.0±12.7 vs. 63.3±12.1 years, P<0.001; body mass index, 23.4±3.7 vs. 24.6±4.5, P<0.001). However, there was no significant sex difference between the groups (P>0.99). The mean CAVI values were 8.47±1.22 in the normal CAVI group and 6.22±1.09 in the low CAVI group (P<0.001). Age-stratified analysis (Table 2) revealed a clear increase in CAVI values with advancing age. The mean CAVI was 6.41±0.91 in the 21–40 years group, 7.43±1.11 in the 41–60 years group, and 8.60±1.38 in patients aged ≥61 years (P<0.001). Figure 1A illustrates the distribution of CAVI values for those in the normal and low CAVI groups. There was a small overlap between the groups because the normal range of CAVI values varies depending on age and sex. Figure 1B displays the association between age and CAVI values, showing a clear increase and a wider range of CAVI values in the older population.

Table 1.

Characteristics of Patients in the Normal and Low CAVI Groups

Characteristic	Overall (N=17,364A)	Normal CAVI (N=14,736A)	Low CAVI (N=2,628A)	P valueB
Female, n (%)	6,325 (36)	5,365 (36)	960 (37)	>0.99
Age, years	63.4±12.2	63.3±12.1	64.0±12.7	<0.001
Body mass index, kg/m2	23.5±3.9	23.4±3.7	24.6±4.5	<0.001
Systolic BP, mmHg	131±19	131±19	127±19	<0.001
Diastolic BP, mmHg	82±12	83±11	78±12	<0.001
Pulse pressure, mmHg	49±13	49±13	49±14	0.20
CAVI	8.13±1.45	8.47±1.22	6.22±1.09	<0.001
ABI	1.10±0.09	1.10±0.08	1.10±0.12	<0.001

^AMean±SD; n (%). ^BWilcoxon rank sum test; Pearson’s Chi-squared test. ABI, ankle-branchial index; BP, blood pressure; CAVI, cardio-ankle vascular index.

Table 2.

Patients’ Characteristics Stratified by Age Group

Characteristic	20–40 years		41–60 years		61–80 years
	Normal CAVI (N=777A)	Low CAVI (N=150A)	Normal CAVI (N=4,431A)	Low CAVI (N=742A)	Normal CAVI (N=9,528A)	Low CAVI (N=1,736A)
Female, n (%)	320 (41)	76 (51)	1,577 (36)	232 (31)	3,468 (36)	652 (38)
Body mass index	22.7±4.4	25.8±6.3	23.9±4.1	26.0±5.0	23.2±3.4	23.8±3.9
Systolic BP, mmHg	122±16	125±18	128±18	125±17	133±19	129±19
Diastolic BP, mmHg	78±12	75±13	84±12	79±13	82±11	77±11
Pulse pressure, mmHg	44±9	49±14	44±10	45±11	51±13	51±15
CAVI	6.67±0.70	5.09±0.72	7.71±0.89	5.77±0.79	8.98±1.05	6.51±1.10
ABI	1.08±0.09	1.08±0.14	1.11±0.08	1.12±0.12	1.10±0.08	1.09±0.11

All abbreviations and data formats (e.g., Mean±SD; n (%)) used in Table 2 are defined in the footnote of Table 1.

Figure 1.

Comparison of CAVI distribution between normal and low CAVI groups. (A) Histogram of CAVI values in the normal and low CAVI groups. There was a small overlap because the normal ranges vary based on age and sex. (B) Scatterplot of CAVI values by age. CAVI, cardio-ankle vascular index.

To assess the prevalence of aortic aneurysm and aortic dissection and Marfan syndrome, disease codes were extracted from electronic medical records based on ICD-10 classifications. The prevalence of these conditions was then compared between the normal CAVI and low CAVI groups. For aortic aneurysm and aortic dissection, 588 patients (3.99%) in the normal CAVI group and 105 patients (3.99%) in the low CAVI group were identified (Figure 2). The prevalence did not significantly differ between the 2 groups (P>0.99, 2-sample test for equality of proportions). Regarding Marfan syndrome, 11 patients (0.07%) in the normal CAVI group and 1 patient (0.04%) in the low CAVI group were identified. Similarly, there was no significant difference between the groups (P>0.99, Fisher’s exact test) (Figure 2). These results suggested that CAVI levels were not associated with the prevalence of aortic aneurysm, aortic dissection, or Marfan syndrome in this cohort.

Figure 2.

Prevalence of aortic aneurysm/aortic dissection and Marfan syndrome in normal and low CAVI groups. Bar graphs show that the prevalence of these diseases was comparable between groups. CAVI, cardio-ankle vascular index.

Discussion

In this study, we analyzed data from 17,364 patients and investigated the association between low CAVI (defined as the lowest 2.5% within each age group) and the prevalence of aortic aneurysm, aortic dissection, and Marfan syndrome. The results showed that the prevalence of aortic aneurysm and aortic dissection was 3.99% in both the normal CAVI and low CAVI groups, with no significant difference between them (P>0.99). Similarly, Marfan syndrome was identified in 0.07% of the normal CAVI group and 0.04% of the low CAVI group, with no statistically significant difference (P>0.99). These findings suggested that a lower CAVI is not associated with an increased prevalence of aortic aneurysm, aortic dissection, or Marfan syndrome. In contrast, CAVI showed a clear, increasing trend with age, consistent with previous reports.

CAVI is a widely used index for assessing arterial stiffness, with the advantage of being less influenced by blood pressure than PWV.¹⁷ It also captures important prognostic factors in patients with atherosclerosis.^18,19 In healthy individuals, CAVI increases by approximately 0.5 per decade, and it is generally higher in males than in females by approximately 0.2, corresponding to a vascular age difference of 4–5 years. High CAVI values are observed in various disease states associated with atherosclerosis, such as hypertension, diabetes mellitus, dyslipidemia, metabolic syndrome, and obesity, reflecting its association with lifestyle-related diseases.^13,20–22 However, the clinical implication of low CAVI values has remained unknown.

Our findings demonstrated that a low CAVI value may not be directly associated with the risk of abnormal aortic stiffness, such as that observed in patients with connective tissue diseases, including Marfan syndrome. Connective tissue diseases, including Marfan syndrome, contribute to vascular wall fragility, leading to an increased risk of aortic aneurysm and aortic dissection.^23,24 For example, Marfan syndrome is characterized by mutations in the FBN1 gene, which result in increased elastin degradation, leading to reduced aortic wall elasticity. Additionally, excessive TGF-β signaling causes abnormal vascular remodeling and progressive aortic dilation, while cystic medial necrosis weakens the aortic wall, further predisposing it to dissection and aneurysm formation. PWV, the gold standard for assessing arterial stiffness, measures the rigidity of central arteries, including the aorta, but it is strongly influenced by blood pressure, whereas CAVI incorporates a correction formula to minimize blood pressure dependency. While PWV reflects the instantaneous stiffness of the arteries, CAVI is thought to represent structural arterial stiffness.²⁴ However, in the present study, there was no significant difference in the prevalence of Marfan syndrome, aortic aneurysm, or aortic dissection between patients with normal and low CAVI, which suggests that a low CAVI value cannot be used as a screening tool to detect patients with abnormal aortic stiffness, and an alternative screening strategy is warranted.

Study Limitations

First, it was a single-center, retrospective observational study, which may introduce selection bias. Second, we did not perform long-term follow-up, making it impossible to assess the causal relationship between CAVI and the development of aortic aneurysm or dissection. Third, disease diagnoses were extracted using ICD-10 codes, and therefore, the temporal relationship between CAVI measurement and disease onset could not be evaluated.

Conclusions

A lower CAVI was not associated with the prevalence of aortic aneurysm, aortic dissection, or Marfan syndrome in this study. Although CAVI is widely recognized as an indicator of arterial stiffness and is influenced by atherosclerotic changes, including those related to lifestyle-related diseases, its direct association with aortic pathology remains unclear. Given the complexity of vascular remodeling and disease progression, further studies are needed to better understand the clinical significance of CAVI in relation to aortic diseases.

Funding

This study was partially supported by Japan Society for the Promotion of Science KAKENHI (grant number 21K18086).

Disclosures

N.K. received research grants from AstraZeneca, EchoNous Inc. and AMI Inc. and speaker honoraria from Eli Lilly, Novartis, Otsuka pharmaceutical, Bristol Myers Squibb, and Boehringer-Ingelheim outside this work, and was affiliated with a department funded by Paramount Bed Ltd. Other authors have nothing to disclose regarding the submitted manuscript.

IRB Information

The study protocol was approved by the Ethics Committee of Juntendo University Hospital (E22-0373-H01).

Data Availability

The data underlying this article cannot be shared publicly for the reason of maintaining the privacy of individuals who participated in the study. The data will be shared on reasonable request to the corresponding author.

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