Increasing age associated with elevated cardio–ankle vascular index scores in patients with type 2 diabetes mellitus

Abstract

Objective

The study investigated the relationship between arterial stiffness calculated using the cardio–ankle vascular index (CAVI), diagnosis of type 2 diabetes mellitus and type 2 diabetes-related cardiovascular complications, in patients with type 2 diabetes mellitus (type 2 diabetes) and nondiabetic patients.

Methods

A retrospective cross-sectional study was conducted in patients with type 2 diabetes and age-matched nondiabetic patients. CAVI was measured using an automatic vascular screening system. Parameters associated with type 2 diabetes and cardiovascular complications were also measured.

Results

A total of 51 patients with type 2 diabetes and 59 nondiabetic patients were enrolled in the study. Significantly higher CAVI scores were observed in patients with type 2 diabetes compared with nondiabetic patients (mean ± SD: 9.55 ± 1.13 versus 8.54 ± 0.94, respectively). Multivariate linear regression analyses demonstrated that age was the only significant factor influencing the CAVI score, in patients with type 2 diabetes.

Conclusion

Patients with type 2 diabetes had an increased risk of arterial stiffness, based on the CAVI score, compared with nondiabetic patients; this, in turn, could increase their risk of developing other cardiovascular complications.

Keywords

Type 2 diabetes mellitus cardio–ankle vascular index hypertension arterial stiffness

Introduction

Type 2 diabetes mellitus (type 2 diabetes) is a metabolic disease characterized by a high blood glucose level and insulin deficiency, accompanied by atherosclerotic macrovascular cardiovascular complications such as arterial endothelial dysfunction, vascular smooth-muscle proliferation, thrombogenesis and proatherogenic cellular processes.^1–3 Chronic hyperglycaemia and hyperinsulinaemia can increase local activity of the renin–angiotensin–aldosterone system, resulting in increased vascular tissue expression of angiotensin II receptor type I,⁴ promoting cardiovascular wall hypertrophy and fibrosis.^5,6 Nonenzymatic protein glycation can further alter the mechanical properties of interstitial tissues,⁷ increasing large elastic artery stiffness associated with cardiovascular disease in patients with type 2 diabetes.^8–10 Increased arterial stiffness has been suggested as a predictive factor for cardiovascular disease that requires further exploration in patients with type 2 diabetes.¹¹

The cardio–ankle vascular index (CAVI) was developed as the successor to Bramwell’s original technically complex pulse wave velocity (PWV) method for the evaluation of aortic stiffness, by combining a stiffness parameter β and the Bramwell-Hill’s formula.^12,13 CAVI has since been demonstrated to be superior to brachial-ankle pulse wave velocity (baPWV),^14,15 and to show a close association with cardiovascular conditions including coronary atherosclerosis, carotid intima–media thickness and homocysteine levels.^16,17 CAVI measurements have also been associated with the presence of microvascular complications in patients with type 2 diabetes.^14,18 While drug therapies (such as glimepiride) can improve CAVI in patients with type 2 diabetes,¹⁹ the mechanism of action requires further study in patients with type 2 diabetes.

The current study investigated the relationship between arterial stiffness calculated using CAVI scoring methods, a diagnosis of type 2 diabetes, and type 2 diabetes-related cardiovascular complications in patients with type 2 diabetes and nondiabetic patients, in order to identify any risk factors associated with an increased CAVI score and evaluate potential pathological mechanisms involved in the development of cardiovascular complications in these patient groups.

Patients and methods

Patient population

This retrospective cross-sectional study enrolled consecutive outpatients with type 2 diabetes attending the Department of 4^th Cadres Ward, General Hospital of the Beijing Military Command, Beijing, China for treatment between June 2008 and July 2010. A diagnosis of type 2 diabetes was made using the American Diabetes Association (2003) standard.²⁰

Patients with type 2 diabetes met the following inclusion criteria: (i) ages 30–70 years; (ii) presence of complete diabetic complication workups using CAVI and ankle–brachial index (ABI); (iii) successful completion of a same-day 24-h urine collection test for albuminuria and proteinuria. This study also recruited age-matched nondiabetic patients who were inpatients in the same department at the same time, who met the criteria above, to serve as the control group.

Exclusion criteria for all study participants were: (i) overt macroalbuminuria, defined as a 24-h urinary albumin excretion ≥ 300 mg/day; (ii) angina; (iii) acute myocardial infarction or pulmonary heart disease; (iv) significant valvular disease, including atrial fibrillation or abnormal left ventricular ejection fraction (<50%); (v) prior cerebrovascular accident(s); (vi) renal insufficiency; (vii) a history of peripheral artery disease; (viii) ABI < 0.9; (ix) current acute infectious disease; (x) nonaffiliation with the hospital. Cardiovascular complications were not excluded.

Hypertension was diagnosed in all participants using the World Health Organization – International Society of Hypertension Guidelines for the Management of Hypertension (1999) standards.²¹ Antihypertensive drug use was recorded. Coronary heart disease was diagnosed according to criteria produced by the Joint International Society and Federation of Cardiology and the World Health Organization (1979).²² Left ventricular ejection fraction was assessed by 2-D echocardiography using the biplane Simpson method. Smoking and alcohol consumption habits were recorded for all study participants.

The study protocol was approved by the Ethics Committee of the General Hospital of the Beijing Military Command, consistent with the Declaration of Helsinki (reference number: 004). All study participants provided written informed consent.

Laboratory measurements

On the second day as inpatients, blood samples were collected after a 12-h fast from the ulnar vein of each patient for the analysis of blood cholesterol, glucose and insulin levels. Before analysis, blood samples were kept at room temperature for 1.5 h, then they were centrifuged at approximately 88 g for 10 min, at room temperature. Serum was collected and stored at –80°C. Fasting serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride, and blood glucose levels were measured using an automated clinical analyser (Hitachi 7600-020; Hitachi High-Technologies, Tokyo, Japan). Low-density lipoprotein cholesterol (LDL-C) levels were calculated according to the Friedewald formula (LDL-C = total cholesterol – HDL-C – 1/5 triglycerides, where serum triglyceride levels are ≤ 400 mg/dl).²³ Serum insulin concentrations were evaluated by radioimmunoassay (CMK-004; Beijing Atom High Tech, Beijing, China). Whole-blood glycosylated haemoglobin (HbA_1c) levels were measured using a latex-enhanced immunoturbidimetric assay with a clinical analyser (Hitachi 7600-020; Hitachi). Insulin resistance was estimated using the homeostasis model assessment of insulin resistance as follows: fasting serum insulin (mU/l) × fasting blood glucose (mmol/l)/22.5.²⁴ Body mass index (BMI) was obtained using the ratio of weight (kg) to height squared (m²).

CAVI score

The CAVI score was measured using an automatic vascular screening system (VaSera VS-1000; Fukuda Denshi, Tokyo, Japan) from measurements of blood pressure and PWV. Patients were resting in a supine position during the CAVI measurements. All measurements were conducted under continuous electrocardiogram and heart sound monitoring.^25,26 PWV was calculated by dividing the distance from the aortic valve to the ankle artery by the sum of the time between the aortic valve closing sound and the notch of the brachial pulse wave, and the time between the rise of the brachial pulse wave and the rise of the ankle pulse wave. CAVI was determined using the following equation: CAVI = a[(2ρ/ΔP) × ln (Ps/Pd) PWV²] + b, where Ps and Pd are systolic and diastolic blood pressure, respectively, PWV is the pulse wave velocity between the heart and ankle, ΔP is Ps – Pd; ρ is blood density; and a and b are scale conversion constants to match aortic PWV. The mean value of the right and left CAVI score for each patient was used for analysis.

Statistical analyses

All statistical analyses were performed using the SPSS® statistical package, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows®. Continuous variables are presented as mean ± SD. An unpaired Student’s t-test was used for comparing continuous variables between patients with type 2 diabetes and the nondiabetic patients. Categorical variables were compared between the two groups using χ²-test. Factors independently associated with CAVI were assessed using univariate and multivariate linear regression analyses. A P-value < 0.05 was considered statistically significant.

Results

A total of 51 patients with type 2 diabetes and 59 nondiabetic patients were enrolled in the study. Their demographic and clinical characteristics are presented in Table 1. There were no significant differences between the two groups in terms of sex, age, smoking prevalence, alcohol consumption, presence of coronary heart disease, total cholesterol, LDL-C or HDL-C levels, or left ventricular ejection fraction. Hypertension was significantly more prevalent in the type 2 diabetes group compared with the nondiabetic group (P = 0.02). The following variables were all significantly higher in patients with type 2 diabetes than in nondiabetic patients: triglycerides, fasting blood glucose, HbA_1c, heart rate and BMI (P < 0.05, all comparisons). The mean CAVI score was significantly higher in patients with type 2 diabetes compared with the nondiabetic patients (P < 0.001). A significantly higher proportion of patients with type 2 diabetes exhibited increased aortic stiffness based on a CAVI score > 9.1 compared with the nondiabetic patients (P = 0.003).

Table 1.

Demographic and clinical characteristics of participants in a study investigating the relationship between arterial stiffness and cardiovascular complications in patients with or without type 2 diabetes mellitus.

Parameter	Patients with type 2 diabetes mellitus n = 51	Nondiabetic patients n = 59	Statistical significance^a
Sex
Male	29 (56.9)	28 (47.5)	NS
Female	22 (43.1)	31 (52.5)	NS
Age, years
< 50	2 (3.9)	5 (8.5)	NS
50–59	13 (25.5)	18 (30.5)
60–69	11 (21.6)	16 (27.1)
≥ 70	25 (49.0)	20 (33.9)
Smoking
No	11 (21.6)	22 (37.3)	NS
Yes	40 (78.4)	37 (62.7)	NS
Alcohol consumption
No	44 (86.3)	43 (72.9)	NS
Yes	7 (13.7)	16 (27.1)	NS
Hypertension
No	7 (13.7)	19 (32.2)	P = 0.02
Yes	44 (86.3)	40 (67.8)	P = 0.02
Coronary heart disease
No	26 (51.0)	33 (55.9)	NS
Yes	25 (49.0)	26 (44.1)	NS
CAVI score
≤ 9.1	21 (41.2)	41 (69.5)	P = 0.003
> 9.1	30 (58.8)	18 (30.5)	P = 0.003
CAVI score	9.55 ± 1.13	8.54 ± 0.94	P < 0.001
TC, mmol/l	4.75 ± 0.94	4.89 ± 1.06	NS
TG, mmol/l	2.29 ± 1.39	1.76 ± 0.99	P = 0.03
LDL-C, mmol/l	3.08 ± 0.62	3.14 ± 0.65	NS
HDL-C, mmol/l	1.38 ± 0.24	1.42 ± 0.31	NS
FBG, mmol/l	8.59 ± 2.84	5.34 ± 0.63	P < 0.0001
HbA_1c, %	8.72 ± 1.84	6.63 ± 0.80	P < 0.0001
LVEF, %	65.84 ± 7.95	66.36 ± 6.14	NS
HR, beats/min	74.80 ± 12.84	69.81 ± 12.35	P = 0.04
BMI, kg/m²	25.95 ± 3.55	24.53 ± 3.50	P = 0.04

Data presented as mean ± SD or n (%) of patients.

P < 0.05; continuous variables between the two groups were compared using an unpaired Student’s t-test; categorical variables were compared between the two groups using χ²-test.

CAVI, cardio–ankle vascular index; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; FBG, fasting blood glucose; HbA_1c, glycosylated haemoglobin; LVEF, left ventricular ejection fraction; HR, heart rate; BMI, body mass index; NS, not statistically significant (P ≥ 0.05).

Subgroup analyses of patients with type 2 diabetes, stratified according to different clinical parameters, demonstrated that an increased CAVI score had a significant association with increasing age, particularly in patients aged ≥ 70 years, smokers, those who consumed alcohol and those with a total cholesterol level ≥ 5.2 mmol/l (all P < 0.05; Table 2). Increasing age was most significantly correlated with an increased CAVI.

Table 2.

Subgroup analyses showing cardio–ankle vascular index (CAVI) scores for patients with type 2 diabetes, stratified according to different clinical parameters (n = 51).

Parameter	n	CAVI	Statistical significance^a
Sex
Male	22	9.64 ± 1.18	NS
Female	29	9.42 ± 1.09	NS
Age, years
< 50	2	7.83 ± 0.81	P = 0.002
50–59	13	8.90 ± 0.35
60–69	11	9.55 ± 1.23
≥ 70	25	10.01 ± 1.12
Smoking
No	11	9.10 ± 0.60	P = = 0.04
Yes	40	9.67 ± 1.22	P = = 0.04
Alcohol consumption
No	44	9.62 ± 1.19	P = 0.02
Yes	7	9.05 ± 0.38	P = 0.02
Hypertension
No	7	9.09 ± 0.94	NS
Yes	44	9.62 ± 1.15	NS
Coronary heart disease
No	26	9.60 ± 1.16	NS
Yes	25	9.43 ± 1.13	NS
TC, mmol/l^b
< 5.2	34	9.28 ± 0.91	P = 0.007
≥ 5.2	16	10.18 ± 1.34	P = 0.007
BMI, kg/m²
< 24	15	9.94 ± 1.15	NS
≥ 24	36	9.38 ± 1.10	NS
FBG, mmol/l^c
≤ 7.0	15	9.76 ± 1.15	NS
> 7.0	35	9.48 ± 1.13	NS
HbA_1c, %^d
< 6.5	3	9.75 ± 0.84	NS
6.5–7.0	4	9.95 ± 1.51
> 7.0	32	9.53 ± 1.13

Data presented as mean ± SD.

P < 0.05; continuous variables between the subgroups were compared using an unpaired Student’s t-test; categorical variables were compared between the subgroups using χ²-test.

Only 50 patients had total cholesterol data.

Only 50 patients had FBG data.

Only 39 patients had HbA_1c data.

TC, total cholesterol; BMI, body mass index; FBG, fasting blood glucose; HbA_1c, glycosylated haemoglobin; NS, not statistically significant (P ≥ 0.05).

Univariate linear regression analyses showed a significant correlation between age and increased CAVI (P < 0.001; Table 3). Multivariate linear regression analyses demonstrated that age was the only significant factor influencing the CAVI score in patients with type 2 diabetes (odds ratio = 2.145; 95% Wald confidence limit = 11.971; P = 0.0002).

Table 3.

Univariate linear regression analyses of the association between clinical parameters and cardio–ankle vascular index (CAVI) scores for patients with type 2 diabetes mellitus (n = 51).

Parameter	CAVI score		Statistical significance
Parameter	≤ 9.1	> 9.1	Statistical significance
Sex
Male	11 (52.4)	18 (60.0)	NS
Female	10 (47.6)	12 (40.0)	NS
Age, years
< 50	2 (9.5)	0 (0.0)	P < 0.001
50–59	10 (47.6)	3 (10.0)
60–69	5 (23.8)	6 (20.0)
≥ 70	4 (19.0)	21 (70.0)
Smoking history
No	7 (33.3)	4 (13.3)	NS
Yes	14 (66.7)	26 (86.7)	NS
Alcohol history
No	17 (81.0)	27 (90.0)	NS
Yes	4 (19.0)	3 (10.0)	NS
Hypertension
No	3 (14.3)	4 (13.3)	NS
Yes	18 (85.7)	26 (86.7)	NS
Coronary heart disease
No	12 (57.1)	14 (46.7)	NS
Yes	9 (42.9)	16 (53.3)	NS
TC, mmol/l^a
< 5.2	15 (75.0)	19 (63.3)	NS
≥ 5.2	5 (25.0)	11 (36.7)	NS
BMI, kg/m²
< 24	4 (19.0)	11 (36.7)	NS
≥ 24	17 (81.0)	19 (63.3)	NS
FBG, mmol/l^b
≤ 7.0	5 (25.0)	10 (33.3)	NS
> 7.0	15 (75.0)	20 (66.7)	NS
HbA_1c, %^c
< 6.5%	1 (6.3)	2 (8.7)	NS
6.5–7.0%	2 (12.5)	2 (8.7)
> 7.0%	13 (81.3)	19 (82.6)

Data presented as n (%) of patients.

Only 50 patients had TC data.

Only 50 patients had FBG data.

Only 39 patients had HbA_1c data.

TC, total cholesterol; BMI, body mass index; FBG, fasting blood glucose; HbA_1c, glycosylated haemoglobin; NS, not statistically significant (P ≥ 0.05).

Discussion

The present study demonstrated that arterial stiffness, as indicated by an elevated CAVI score, was more common in patients with type 2 diabetes than in age-matched nondiabetic patients; and increasing age was significantly correlated with an increased CAVI score. These findings suggest that arterial stiffening may increase with age in patients with type 2 diabetes, potentially increasing the risk of cardiovascular complications. Therefore, clinicians should carefully evaluate older patients with type 2 diabetes for cardiovascular complications, particularly those aged ≥ 70 years.

Increased arterial stiffness is common in patients with type 2 diabetes,²⁷ with microvascular complications commonly revealed by PWV.²⁸ Contemporary CAVI methodology provides a less technically challenging¹² and more accurate measurement tool for identifying arterial stiffening, compared with PWV.^29–33 Furthermore, variations in blood pressure and clinical abnormalities may result in inaccuracies in PWV, but not in CAVI.³⁴ CAVI scoring, developed in 2004, was originally limited by the absence of sex- and age-appropriate baselines for healthy patients.³⁵ As these baselines are now available,¹² CAVI scoring can be employed as an easy, effective, and accurate measure of arterial stiffness in patients with, or without, type 2 diabetes.

The CAVI scores were significantly higher in patients with type 2 diabetes compared with the age-matched nondiabetic patients in the current study. Patients with type 2 diabetes have also demonstrated higher CAVI scores when they also present with diabetic peripheral neuropathy,³⁶ microvascular conditions,¹⁴ intima–media thickening,³² carotid beta stiffness,³² and carotid plaques.^6,32 Thus, CAVI may be particularly useful in the early identification cardiovascular complications, in high-risk patients with type 2 diabetes.

Elevated CAVI scores in patients with type 2 diabetes were most closely associated with increasing age (CAVI scores > 9.1 in 58.8% of patients), which is consistent with previous findings.^26,32 While increasing age was the most significant clinical variable to be associated with an elevated CAVI score (P = 0.002; Table 2), these preliminary findings also identified smoking and elevated total cholesterol levels (≥ 5.2 mmol/l) as other risk factors for an elevated CAVI, and an inverse relationship was observed between alcohol consumption and the CAVI score, although further study of such factors will be required. Relationships between arterial stiffness and age, sex and type 1 diabetes mellitus have also been reported.³⁷ In the current study, no significant relationship between sex and CAVI score was observed, which may reflect the sample size or individual patient pathophysiology. Further investigations of these risk factors, in larger cohorts of more varied ethnic and geographical populations, are required.

Patients with type 2 diabetes often exhibit hyperlipidaemia, resulting in diabetic dyslipidaemia being a well-recognized and modifiable risk factor for cardiovascular conditions.³⁸ In a study of 2383 individuals, cardiovascular symptoms appeared at a mean age of 62 years in patients with type 2 diabetes, resulting in a recommendation that patients aged > 40 years undergo regular cardiovascular evaluation.³⁸ These findings support the implementation of screening during midlife to improve the early detection of cardiovascular complications. The association with hyperlipidaemia suggests a mechanistic relationship, in which a sustained plasma lipid abnormality impacts on cardiovascular function and increases CAVI, requiring further investigation of the processes and pathways involved. Based on univariate linear regression analyses in the current study, however, the CAVI score was not significantly associated with the total cholesterol concentration.

The prevalence and impact of hypertension increases with age, affecting > 40% of older men and women.³⁹ The current study considered hypertension and age as separate risk factors for an elevated CAVI score, but hypertension is known to increase with age. Serum resistin, an adipocyte- and monocyte-derived cytokine, has been shown to have a positive correlation with cardiovascular abnormalities in patients with type 2 diabetes, including hypertension,⁴⁰ suggesting that older patients at greater hypertension risk are also at higher cardiovascular risk. In the current study, blood-pressure analysis suggested no direct correlation with increased CAVI; however, further studies may identify relationships between age and hypertension, in certain groups. Similarly, a recent report from EURODIAB showed that the increased formation of advanced glycation endproducts in patients with type 1 diabetes was associated with postprandial blood sugar magnitude, a parameter implicated in arterial stiffening.³⁸ Thus, sustained abnormal blood parameters (postprandial blood sugar magnitude or hypertension) may promote progressive arterial stiffening by altering the composition of the vascular walls, resulting in heightened risks in patients with longer exposure (i.e. greater age).

In conclusion, the current study demonstrated that patients with type 2 diabetes had an increased risk of arterial stiffness based on the CAVI score, compared with age-matched nondiabetic patients, which could in turn increase their risk of developing other cardiovascular complications. Furthermore, advanced age was associated with an elevated CAVI score. Consistent with previous studies, these findings suggest that clinicians should carefully evaluate older patients with type 2 diabetes for arterial stiffening indicative of progressive cardiovascular disease.

Footnotes

Acknowledgements

The Authors thank Dr Minghai Li from the Department of Medical Engineering, General Hospital of Beijing Military Command, Beijing, China for providing valuable suggestions on the development of CAVI evaluations.

Declaration of conflicting interest

The Authors declares that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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