Assessment of cardio-ankle vascular index in patients with abdominal aortic aneurysm: An observational study

Abstract

Objectives

Arterial stiffness is associated with major adverse cardiovascular events. The aim of this study is to investigate arterial stiffness by cardio-ankle vascular index (CAVI) in patients with abdominal aortic aneurysm (AAA).

Methods

This observational and cross-sectional study involved 59 subjects with AAA and 32 healthy subjects. All subjects underwent ultrasonography examination. CAVI was measured by VaSera-1000 CAVI instrument.

Results

Mean abdominal aortic diameter of AAA patients and controls were 43.88 ± 9.28 mm and 20.43 ± 3.14 mm, consecutively. Baseline clinical characteristics of the patients and controls were similar for age, presence of hypertension, diabetes, dyslipidemia, coronary artery disease and smoking. Left ventricle ejection fraction and Left ventricle mass index (LVMI) were similar between groups. CAVI was significantly higher in patients with AAA than controls (9.74 ± 1.50 vs. 7.60 ± 1.07, p < 0.001). CAVI was positively correlated with AAA diameter (r = 0.461, p < 0.001) and negatively correlated with left ventricle ejection fraction (r= –0.254, p = 0.015). CAVI >8.3 had a sensitivity 89.8% and a specificity of 78.1% for predicting the presence of AAA in ROC analysis (area under curve = 0.897, 95%CI = 0.816–0.951, p < 0.001).

Conclusion

CAVI is increased in patients with AAA. Increased arterial stiffness may be a mechanical link between AAA, coronary artery disease and peripheral artery disease or a common mechanism effects the arterial stiffness, coronary artery disease, peripheral artery disease and AAA. Therefore, CAVI may be used as a valuable marker for risk stratification for the development of AAA in susceptible patients.

Keywords

CAVI arterial stiffness abdominal aortic aneurysm

Introduction

Arterial stiffness is related to major adverse cardiovascular events (MACE).¹ Increased arterial stiffness causes systolic blood pressure surge and this promotes ventricular hypertrophy and increased myocardial oxygen demand.² Increased arterial stiffness is associated with coronary atherosclerosis and increased MACE.^3,4 Cardio-ankle vascular index (CAVI) is an accurate and valuable measure of arterial stiffness. Unlike augmentation index, aortic stiffness and pulse wave velocity (PWV), CAVI reflects the stiffness of the aorta, femoral artery and tibial artery as a whole.^4–6 CAVI, which is weakly influenced by systolic blood pressure, is a sensitive marker of atherosclerosis and arteriolosclerosis.^4–6 Abdominal aortic aneurysm (AAA) is defined as focal abnormal dilatation of aorta greater than 3 cm between diaphragmatic hiatus and iliac bifurcation. The prevalence of AAA increases with age and 4–9% of population over the age 60 is estimated to have AAA.⁷ Increased arterial stiffness and AAA have common features including hypertension, aging, sex, smoking, atherosclerosis, hypercholesterolemia, genetic predisposition, connective tissue disorders and oxidative stress.^1–7

PWV and augmentation index were studied in patients with AAA. However, these methods are not suitable for patients with AAA. PWV is calculated on the basis of the Moens–Korteweg formula under the assumption that there are no significant changes in the vessel cross-sectional area or wall thickness along the arterial segment.⁸ However, in patients with aortic aneurysm, dilatation of the aortic radius obviously violates this assumption. AAA is common among elder patients and the augmentation index is not suitable for the evaluation of arterial stiffness in elder patients. Therefore, we used CAVI method for the evaluation arterial stiffness in patients with AAA. To our knowledge, there is no study in the literature evaluating the CAVI in patients with AAA.

Methods

Patient population

Fifty-nine consecutive patients with AAA and 32 healthy matched subjects were included in this cross-sectional study. This study was performed at our clinics between November 2015 and December 2016. Ultrasonography examination was performed to all subjects. CAVI was measured by VaSera-1000 CAVI instrument. All subjects gave informed consent. The investigation conforms to the principles of Helsinki Declaration. The study protocol was approved by ethics committee.

Patients with acute coronary syndrome, congestive heart failure, peripheral arterial disease, valvular heart disease, stroke atrial fibrillation, atrioventricular block, connective tissue disease, malignancy, infection, inflammatory disease, previous cardiovascular surgery were excluded from the study. Additionally, patients with peripheral artery disease (ankle-brachial index < 0.9) and non-compressible vessels (ankle-brachial index > 1.4) were excluded from the study.

Basal demographic, clinical and echocardiography evaluation

Patient’s heights and weights were measured in light clothes without shoes and body mass index (BMI, kg/m²) was calculated. Transthoracic echocardiography assessment was performed according to the standards of the American Society of Echocardiography. Left ventricular mass was calculated according to Devereux formula and left ventricular mass index was calculated.

Patients smoked during the previous six months were classified as smokers. Venous blood samples were drawn after a 12-h overnight fast. Serum glucose, total cholesterol and triglycerides were determined using standard automatic enzymatic methods.

Blood pressure and cardio-ankle vascular index measurements

Blood pressure was measured, in compliance with World Health Organization guidelines, by using a mercury sphygmomanometer (ERKA, Germany) with a cuff appropriate to the arm circumference, in patients at rest for 20 min (Korotkoff phase I for systolic blood pressure and V for diastolic blood pressure).

CAVI was measured using a VaSera VS-1000 CAVI instrument (Fukuda Denshi Co. Ltd., Tokyo, Japan) as previously described.^4–6 Simply, cuffs of instrument were applied to the bilateral upper arms and ankles, with the patient supine and the head held in the midline position. Electrocardiography, phonocardiography, and pressures and waveforms of brachial and ankle arteries were measured and pulse wave velocity and subsequently CAVI were calculated automatically. CAVI measurements were performed by experienced cardiologist who blinded to ultrasonography.

CAVI is determined by the following equation:

CAVI : a [(2r / Δ P) \times ln (Ps / Pd) PWV2] + b

where Ps and Pd are systolic blood pressure and diastolic blood pressure, consecutively. PWV is velocity of the pulse wave from the origin of the aorta to the junction of the tibial artery with the femoral artery, ΔP is Ps–Pd (systolic blood pressure–diastolic blood pressure), r is blood density and a and b are constants. The equation is derived from Bramwell-Hill’s equation and the stiffness parameter β and CAVI was adjusted for blood pressure based on the stiffness parameter β. Therefore, CAVI reflects the stiffness of the aorta, femoral artery and tibial artery as a whole; theoretically, it is not affected by blood pressure. After automatic measurements, the obtained data were analyzed using VSS-10 software (Fukuda Densi), and the values of right and left CAVI were calculated. The average of the right and left CAVIs was used for analysis.

Ultrasonography evaluation

The maximum abdominal aortic diameter was measured by ultrasound. The diameter of the abdominal aorta was defined as the maximum cross-sectional diameter (including the vessel wall), measured orthogonally to the estimated vessel center line. AAA was defined as a diameter of 3 cm or greater in the abdominal section of the infra-diaphragmatic aorta.

Statistical analysis

SPSS 17.0 for Windows was used for statistical analysis. Kolmogorov-Smirnov test was used to evaluate the distribution of variables. Continuous variables are expressed as mean ± standard deviation (SD) and categorical variables are expressed as percentage. Unpaired Student t test or Mann–Whitney U test were used for the analysis of continuous variables. Categorical variables were compared with the chi-square test. Receiver operating characteristic curve (ROC) analysis was carried out to find the cut-off value to predict AAA. A p value of ≤0.05 was considered statistically significant.

Results

Mean age of the patients and control groups were (68.73 ± 7.96 years vs. 68.56 ± 5.98 years, p = 0.918). Diabetes was present in 13.6% of AAA patients and 9.4% of control group (p = 0.559). Hypertension was present in 81.4% of the AAA patients and 78.1% of control group (p = 0.712). Coronary artery disease was present in 13.6% of AAA group and 18.8% of control group (p = 0.512). Mean abdominal aortic diameter of AAA patients and controls were 43.88 ± 9.28 mm vs. 20.43 ± 3.14 mm, consecutively (Table 1). Left ventricle ejection fraction and LVMI were similar between groups. CAVI was significantly higher in patients with AAA than controls (9.74 ± 1.50 vs. 7.60 ± 1.07, p < 0.001).

Table 1.

Characteristics of the patients.

Variable	Control group (32)	AAA group (59)	p
Diabetes, n (%)	3 (9.4%)	8 (13.6%)	0.559
Hypertension, n (%)	25 (78.1%)	48 (81.4%)	0.712
Hyperlipidemia, n (%)	6 (18.8%)	8 (13.6%)	0.512
Coronary artery disease, n (%)	6 (18.8%)	8 (13.6%)	0.512
Chronic renal failure, n (%)	3 (9.4%)	8 (13.6%)	0.559
Beta blockers, n (%)	6 (18.8%)	8 (13.6%)	0.512
ACE inhibitor/ARB, n (%)	7 (21.9%)	14(23.7%)	0.841
Ca Chanel blockers, n (%)	6 (18.8%)	10 (16.9%)	0.839
Statins, n (%)	6 (18.8%)	8 (13.6%)	0.512
Smoking, n (%)	18 (56.3%)	36(61%)	0.658
Age, year	68.56 ± 5.98	68.73 ± 7.96	0.918
Cigarette pack/year	37.55 ± 10.07	41.95 ± 15.23	0.267
Body mass index, kg/m²	27.43 ± 4.90	26.28 ± 4.74	0.277
Abdominal aortic aneurysm diameter, mm	20.43 ± 3.14	43.88 ± 9.28	<0.001
Cardio-ankle vascular index	7.60 ± 1.07	9.74 ± 1.50	<0.001
Systolic blood pressure, mmHg	143.38 ± 18.06	140.75 ± 21.76	0.561
Diastolic blood pressure, mmHg	89.38 ± 14.38	87.05 ± 12.90	0.433
Pulse Pressure, mmHg	54.03 ± 11.26	53.83 ± 15.90	0.950
Heart rate, beat/min	73.13 ± 7.63	74.15 ± 8.83	0.580
Left ventricular ejection fraction, %	63.16 ± 5.34	61.08 ± 5.37	0.082
Triglyceride, mg/dl	118.03 ± 54.06	121.86 ± 47.72	0.554
High density lipoprotein, mg/dl	42.28 ± 6.04	43.34 ± 8.19	0.521
Glucose, mg/dl	95.21 ± 11.06	96.27 ± 9.95	0.645
Low-density lipoprotein cholesterol, mg/dl	135.80 ± 32.35	136.21 ± 37.80	0.958
Creatinine, mg/dl	0.83 ± 0.19	0.85 ± 0.21	0.745
Left ventricle mass index, g/m²	113.99 ± 38.79	111.79 ± 44.18	0.814

ACE, Angiotensin converting enzym inhibitor; ARB, Angiotensin receptor blocker.

CAVI was positively correlated with AAA diameter (r = 0.461, p < 0.001) (Figure 1) and negatively correlated with left ventricle ejection fraction (r= –0.254, p = 0.015).

Figure 1.

Scatter plot of the association between CAVI and abdominal aorta diameter.

CAVI >8.3 had a sensitivity 89.8% and a specificity of 78.1% for predicting the presence of AAA in ROC analysis (area under curve = 0.897, 95%CI = 0.816–0.951, p < 0.001) (Figure 2).

Figure 2.

ROC curve analysis demonstrating the sensitivity and specificity of CAVI to predict AAA.

Discussion

We found that CAVI was increased in patients with AAA compared to controls.

Aorta, a systolic buffer, stores half of the stroke volume during systole. The elasticity of aorta drives this volume to the periphery during diastole.⁹ The Windkessel effect is described as interaction between the compliance of large elastic arteries and the stroke volume. This function of the aorta effects both heart and peripheral circulation. The expansion of the aorta reduces afterload and augments coronary perfusion.⁹ Aging has an important role in aortic degenerative disease process. Fragmentation and loss of elastic fibers of the aortic wall lead to dilatation of the vessel inducing replacement of normal tissue by fibrosis with stiffer collagen and augments the stiffness of vessel wall. Accompanying atherosclerosis and hypertension contribute to emerging of aortic aneurysm and diminished aortic compliance.¹⁰ Reduced aortic compliance induces LV hypertrophy.¹¹

Various modalities were used for the assessment of arterial stiffness. The simple method of arterial stiffness evaluation is ultrasonography based vascular elasticity evaluation. Dijk et al. reported that carotid artery stiffness was increased in AAA patients.¹² They evaluated carotid artery distensibility. This method provides the measurement of local arterial stiffness and is influenced by blood pressure. Raaz et al. reported that segmental aortic stiffness precedes AAA.¹³ Additionally, they showed that mechanically induced oxidative stress triggered vascular smooth muscle apoptosis, secretion of matrix metalloproteinase and inflammation. Augmentation index is another method of arterial stiffness measurement, and Beckmann et al. studied augmentation index in AAA and reported that augmentation index was increased in patients with AAA.¹⁴ PWV is frequent method of arterial stiffness measurement.¹⁵ Durmus et al. reported that aortic PWV was increased in patients with AAA.¹⁶ However, that study is small-scale study including 20 patients with AAA. There are certain limitations of vascular elasticity, augmentation index and PWV measurements for the evaluation of arterial stiffness. Carotid artery stiffness and segmental abdominal aortic stiffness and elastance are the local and indirect measures of arterial stiffness. PWV is calculated according to the Moens–Korteweg formula which assumes that there are no significant alterations of the cross-sectional area of or wall thickness along the arterial segment.⁸ Calculation of PWV depends on Young’s modulus of the arterial wall, wall thickness, arterial radius at end diastole and blood density. However, in patients with aortic aneurysm, dilatation of the aortic radius obviously violates Moens–Korteweg formula. Therefore, PWV may not represent the true degree of arterial stiffness in aneurysm patients. AAA effects the infra renal aorta and PWV evaluates the stiffness of arterial segments between carotid and femoral arteries. In other words PWV is a segmental stiffness of vasculature. This segmental estimation prone to over or under estimation of true arterial stiffness as in the evaluation of arterial stiffness in AAA. Additionally, escalation of blood pressure is common in patients with AAA. PWV is seriously affected by blood pressure. Therefore, there may be significant variations between PWV measurements in patients with AAA. However, CAVI evaluates the stiffness of whole vascular tree from ascending aorta to the tibial arteries. Additionally, CAVI is not effected from blood pressure and differs from other arterial stiffness measurement methods. Furthermore, CAVI appropriately shows arterial stiffness in elder patients but augmentation index is suboptimal method for the evaluation of arterial stiffness in elder patients as it shows a plateau with age.^15,17 However, AAA is common among elder hypertensive males.

AAA is chronic inflammatory disease and various mechanistic links were present between the pathogenesis of AAA and atherosclerosis. Kadaklou et al. reported that PWV, osteoprotogerin, osteopontin and IL6 values were increased in patients with AAA.¹⁸ AAA, CAD and arterial stiffness shares the common features of oxidative stress and inflammatory pathway.^18–24 ARIC study, a prospective population-based study, showed that carotid atherosclerosis burden and decreased carotid distensibility are markers of increased AAA risk.²⁵

There is a familial trend of AAA formation. De Basso et al. reported that arterial stiffness was increased in first-degree relatives of AAA patients who did not have AAA and they suggested that arterial stiffness may also be associated with genetic susceptibility.²

Hypertension, aging, sex, smoking, atherosclerosis, hypercholesterolemia, genetic predisposition, connective tissue disorders and oxidative stress are the common features of patients with AAA and increased arterial stiffness.² CAVI is related to, atherosclerosis, coronary syndrome-x, epicardial fat thickness, dipping status, chronic obstructive lung disease, silent neuronal injury, chronic venous insufficiency and deep vein thrombosis.^17,26–30 Vascular tree is a whole structure and segmental evaluations may cause misinterpretations. Coronary artery disease is prevalent in patients with peripheral artery disease and vice versa.^31,32 Cardiovascular mortality is the leading cause of death among patients with PAD and AAA. CAVI is a valuable marker of MACE in cardiovascular diseases. Therefore, CAVI may also be valuable tool in patients with AAA for risk stratification. We found that CAVI was increased in patients with AAA and it suggested that AAA screening by ultrasonography in patients with increased CAVI values may be valuable for the detection of AAA.

This study has some limitations. Firstly, our study population is small. Secondly, we made instant measurement of arterial stiffness. A cohort study evaluating the CAVI and development of AAA may provide additional information. Aneurysm size, sex, expansion rate, smoking, sex, uncontrolled hypertension, increased wall stress, arterial wall stiffness and intraluminal thrombus are known factors of aneurysmal rupture.³³ Of these risk factors, AAA size is the most important predictor of rupture and aneurysmal repair is decided according to AAA size. However, small AAA may also rupture. AAA ruptures when the mechanical stress exceeds the local strength of the abdominal aorta wall. Decreased wall stress and arterial stiffness was related to slowing of AAA progression.¹³ Therefore, combination of the mechanical properties of the vessel wall and stresses in the wall besides AAA size could be a better predictor for rupture risk than lone AAA diameter.^33,34 A surveillance study of CAVI and AAA rupture may also provide additional information. Additionally, this study was not a cohort study therefore we could not evaluated future risk of AAA development according to CAVI tertiles.

Conclusion

CAVI is increased in patients with AAA. Increased arterial stiffness may be a mechanical link between AAA, CAD and PAD or a common mechanism effects the arterial stiffness, CAD, PAD and AAA. Therefore, CAVI may be used as a valuable marker for risk stratification for the development of AAA in susceptible patients.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ahmet Çağrı Aykan

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