Background
Pulse wave velocity (PWV) is the gold-standard method for the assessment of arterial stiffness and is an independent predictor of cardiovascular morbidity and mortality [
1]. Previous studies have shown that arterial stiffness is increased in people with diabetes [
2,
3] and that PWV independently predicts mortality in this group of patients [
3].
Cardiac autonomic dysfunction is a common although underestimated chronic microvascular complication of diabetes [
4]. Cardiac autonomic dysfunction is a well-established risk factor for cardiovascular morbidity and all-cause and cardiovascular mortality [
5]. Decreased heart rate variability (HRV) and low baroreflex sensitivity (BRS) are considered to be early markers of cardiac autonomic dysfunction [
6,
7].
Several studies have reported that early in the course of type 1 diabetes impaired cardiac autonomic function and arterial stiffness are strongly associated [
8,
9]. Moreover, patients without diabetes but with primary autonomic failure have stiffer aortas when compared with healthy age- and sex-matched control individuals [
10]. These findings imply that there is a pathophysiological link between cardiac autonomic dysfunction and arterial stiffness and that the preservation of the elastic properties of the arteries strongly depends on the integrity of the autonomic nervous system.
Recent guidelines emphasize that use of normal and abnormal PWV values according to age represent a critical step in the implementation of PWV as a clinical tool for identification of people at higher cardiovascular risk [
11]. It is known for several decades that people with type 2 diabetes (T2DM) have a 2–4 higher relative risk for cardiovascular disease [
12]. Previous studies in patients with T2DM have shown that arterial stiffness is associated with age, blood pressure, duration of diabetes and cardiac autonomic dysfunction [
2,
13,
14]. However, no data exist on the potential association between abnormal PWV, defined according to recent guidelines, impaired cardiac autonomic function and classical risk factors for atherosclerosis in people with T2DM.
Based on the above literature data, the research hypothesis we examined in this study is that impaired cardiac autonomic function is associated with abnormal PWV in people with T2DM, when diabetes-related and classical risk factors for atherosclerosis are taken into consideration.
Results
The demographic and clinical characteristics of the study participants classified according to their PWV status are depicted in Table
1. Patients with abnormal PWV were older, had higher arterial blood pressure (
P < 0.001) and higher heart rate (
P < 0.001) than those with normal PWV; additionally, they were treated more often with insulin (
P = 0.033) and less often with diuretics. Participants with normal and abnormal PWV did not differ in terms of gender, BMI, duration of diabetes, waist circumference, HbA
1c, smoking status, lipid profile, treatment for dyslipidemia or hypertension, use of antiplatelets, prevalence of macrovascular complications and prevalence of retinopathy or nephropathy, except for peripheral neuropathy which was more common in participants with abnormal PWV (
P = 0.030).
Table 1
Demographic, clinical characteristics and laboratory parameters of the study participants
PWV (m/s) | 9.1 ± 1.7 | 12.6 ± 2.5 | <0.001* |
PWV (m/s) | 9.0 [8.0, 10.4] | 12.8 [10.4, 14.1] | <0.001** |
Age (years) | 60.5 ± 9.5 | 63.8 ± 7.8 | 0.004* |
Duration of diabetes (years) | 10.0 [5.0, 18.0] | 9.0 [3.0, 16.0] | 0.130** |
Male gender n (%) | 114 (59.1) | 49 (50.5) | 0.166*** |
Height (m) | 1.65 ± 0.10 | 1.66 ± 0.10 | 0.223* |
Weight (kg) | 84.5 ± 16.3 | 85.6 ± 16.3 | 0.577* |
Body mass index (kg/m2) | 31.1 ± 4.8 | 30.9 ± 4.8 | 0.755* |
Waist circumference (cm) | 104.3 ± 11.6 | 105.6 ± 12.1 | 0.395* |
Current smoking n (%) | 40 (20.7) | 20 (20.6) | 0.983*** |
Pack-years | 37.5 [21.3, 65.3] | 40 [32.0, 50.0] | 0.070** |
SBP (mmHg) | 139.5 ± 18.4 | 148.9 ± 19.8 | <0.001* |
DBP (mmHg) | 75.7 ± 9.4 | 81.4 ± 10.2 | <0.001* |
Peripheral MBP (mmHg) | 97.5 ± 10.6 | 104.8 ± 11.9 | <0.001* |
Central MBP (mmHg) | 94.0 ± 10.6 | 100.9 ± 11.7 | <0.001* |
HR (bpm) | 66.4 ± 9.3 | 70.6 ± 9.6 | <0.001* |
Hypertension n (%) | 145 (75.1) | 76 (78.4) | 0.543*** |
Antihypertensive drugs n (%) |
Use of ACEi or ARBs n (%) | 121 (62.7) | 62 (63.9) | 0.839*** |
Use of CCBs n (%) | 58 (30.1) | 21 (21.6) | 0.129*** |
Use of β-blockers n (%) | 59 (30.6) | 30 (30.9) | 0.950*** |
Use of diuretics n (%) | 70 (36.3) | 24 (24.7) | 0.048*** |
Total cholesterol (mmol/L) | 4.40 ± 0.84 | 4.37 ± 1.18 | 0.491* |
HDL-cholesterol (mmol/L) | 1.19 ± 0.29 | 1.21 ± 0.32 | 0.571* |
LDL-cholesterol (mmol/L) | 2.55 ± 0.91 | 2.53 ± 0.85 | 0.571* |
Triglycerides (mmol/L) | 1.33 [1.02, 1.78] | 1.42 [1.12, 2.11] | 0.069** |
Dyslipidemia n (%) | 155 (80.3) | 84 (86.6) | 0.185*** |
Treatment with statins n (%) | 154 (79.8) | 80 (82.5) | 0.585*** |
Cardiovascular disease n (%) | 45 (23.3) | 24 (24.7) | 0.788*** |
Coronary heart disease | 45 (23.3) | 15 (15.5) | 0.119*** |
Peripheral arterial disease | 22 (11.4) | 11 (11.3) | 0.988*** |
Stroke | 11 (5.7) | 3 (3.1) | 0.329*** |
Treatment with antiplatelets n (%) | 100 (51.8) | 56 (60.2) | 0.340*** |
Glucose (mmol/L) | 8.1 ± 2.6 | 8.4 ± 2.9 | 0.335* |
HbA1c (%) | 7.1 [6.5,7.9] | 7.1 [6.5, 8.0] | 0.725** |
Antidiabetic treatment n (%) |
Oral medications | 122 (63.2) | 56 (57.7) | 0.366*** |
Insulin | 13 (6.7) | 14 (14.4) | 0.033*** |
Both | 58 (30.1) | 27 (27.8) | 0.696*** |
Nephropathy n (%) | 66 (34.2) | 40 (41.2) | 0.240*** |
eGFR (ml/min/1.73 m2) | 75.3 ± 21.2 | 70.9 ± 27.6 | 0.308* |
Microalbuminuria n (%) | 38 (19.7) | 19 (19.6) | 0.984*** |
Peripheral neuropathy n (%) | 31 (16.1) | 26 (26.8) | 0.030*** |
Retinopathy n (%) | 29 (15.0) | 22 (22.6) | 0.106*** |
The values of log TP, log power HF, log r-MSDD and the log NN mean of the HRV were lower in participants with abnormal PWV than in those with normal PWV (
P = 0.010,
P = 0.014,
P = 0.034 and
P = 0.042, respectively). The values of the log power LF, the ratio LF/HF, the log SDNN and the log BRS did not differ between the two groups (Table
2).
Table 2
The values of parameters of heart rate variability and of baroreflex sensitivity stratified according to the pulse wave velocity status
Log total Power (msec2) | 2.44 ± 0.58 | 2.17 ± 0.62 | 0.010** |
Log Power HF (msec2) | 2.03 ± 0.65 | 1.75 ± 0.61 | 0.014** |
Log Power LF (msec2) | 2.01 ± 0.63 | 1.82 ± 0.69 | 0.087** |
LF/HF | 1.1 [0.5, 1.9] | 1.1 [0.6, 2.5] | 0.399* |
Log NN mean (msec) | 2.96 ± 0.06 | 2.93 ± 0.06 | 0.042** |
Log SDNN (msec) | 1.48 ± 0.25 | 1.40 ± 0.29 | 0.073** |
Log r-MSDD (msec) | 2.65 ± 0.65 | 2.41 ± 0.66 | 0.034** |
Log BRS (msec/mmHg) | 0.76 ± 0.24 | 0.72 ± 027 | 0.368** |
Univariate logistic regression analysis demonstrated that there were significant associations between abnormal PWV, SBP, DBP, pMBP and cMBP, heart rate, triglycerides, peripheral neuropathy, and most of the parameters of HRV; no significant association was found between log BRS and PWV (Table
3). Multivariate logistic regression analysis, after adjustment for the effect of age, gender, heart rate and triglycerides, demonstrated that the odds of abnormal PWV were associated significantly and independently only with higher pMBP, cMBP and worse cardiac autonomic nervous system function indices such as lower log TP and lower log HF, while there was a trend for association with lower log r-MSDD (Table
3).
Table 3
Associations between the studied parameters and abnormal pulse wave velocity in participants with type 2 diabetes
Univariate logistic regression analysis |
Age (years) | 0.956 | 0.936–1.033 | 0.504 |
Gender (men vs. women) | 0.707 | 0.433–1.155 | 0.167 |
Diabetes duration (years) | 0.979 | 0.951–1.008 | 0.150 |
Height (m) | 4.513 | 0.400–50.860 | 0.223 |
Body mass index (kg/m2) | 0.992 | 0.942–1.044 | 0.754 |
Waist circumference (cm) | 1.009 | 0.988–1.031 | 0.394 |
Current smoking n (%) | 0.994 | 0.544–1.815 | 0.983 |
SBP (mmHg) | 1.026 | 1.012–1.040 | <0.001 |
DBP (mmHg) | 1.065 | 1.035–1.095 | <0.001 |
Peripheral MBP (mmHg) | 1.062 | 1.037–1.089 | <0.001 |
Central MBP (mmHg) | 1.059 | 1.033–1.086 | <0.001 |
HR (bpm) | 1.049 | 1.021–1.077 | 0.001 |
Total cholesterol (mmol/L) | 0.785 | 0.626–1.285 | 0.136 |
HDL-cholesterol (mmol/L) | 0.784 | 0.339–1.814 | 0.569 |
LDL-cholesterol (mmol/L) | 0.571 | 0.791–1.138 | 0.571 |
Triglycerides (mmol/L) | 0.674 | 0.496–0.916 | 0.012 |
Treatment with statins (yes vs. no) | 0.538 | 0.326–1.386 | 0.115 |
Glucose (mmol/L) | 0.956 | 0.874–1.047 | 0.335 |
HbA1c (%) | 0.996 | 0.809–1.227 | 0.971 |
Nephropathy (yes vs. no) | 1.422 | 0.854–2.367 | 0.176 |
Peripheral neuropathy (yes vs. no) | 2.018 | 1.111–3.667 | 0.021 |
Log Power LF (msec2) | 0.625 | 0.364–1.074 | 0.089 |
Log Power HF (msec2) | 0.499 | 0.284–0.878 | 0.016 |
Log Total Power (msec2) | 0.452 | 0.244–0.838 | 0.012 |
LF/HF | 1.117 | 0.901–1.386 | 0.312 |
Log NN mean (msec) | 0.004 | 0.000–0.866 | 0.044 |
Log SDNN (msec) | 0.295 | 0.077–1.130 | 0.075 |
Log r-MSDD (msec) | 0.556 | 0.321–0.963 | 0.036 |
Log BRS (msec/mmHg) | 0.529 | 0.133–2.105 | 0.366 |
Multivariate logistic regression analysesa
|
Model 1 |
Central MBP (mmHg) | 1.052 | 1.016–1.088 | 0.004 |
Log Total Power (msec2) | 0.490 | 0.258–0.932 | 0.030 |
Model 2 |
Central MBP (mmHg) | 1.050 | 1.015–1.087 | 0.005 |
Log Power HF (msec2) | 0.546 | 0.301–0.991 | 0.047 |
Model 3 |
Central MBP (mmHg) | 1.053 | 1.017–1.091 | 0.004 |
Log r-MSDD (msec) | 0.572 | 0.319–1.024 | 0.060 |
Discussion
In the present study, we showed that beyond blood pressure, impaired cardiac autonomic function assessed by determination of HRV was a significant determinant of abnormal PWV in people with T2DM. Furthermore, lower values of the frequency-dependent domains of the HRV were independently associated with higher odds of abnormal PWV.
The findings of our study are in accordance with those of previous published studies that investigated the association between cardiac autonomic dysfunction and aortic stiffness in patients with T2DM [
13,
14]. Our group described previously that patients with T2DM and cardiac autonomic neuropathy had reduced aortic distensibility, an index of aortic stiffness, when compared with patients with T2DM without cardiac autonomic neuropathy, while duration of diabetes and presence of cardiac autonomic neuropathy were the main determinants of reduced aortic distensibility [
13]. Another study also demonstrated a significant association between autonomic neuropathy, assessed using HRV, and systemic arterial compliance as well as PWV in patients with T2DM [
14]. It should be taken into account that the diabetic population in these two studies was a selected group without macrovascular disease or hypertension, whereas in our study we did not exclude patients with macrovascular complications. Thus, our sample is more representative of the general diabetic population. In addition, the present study is the first to use the age-corrected reference values for PWV.
The pathophysiological link between aortic stiffness and autonomic dysfunction and whether impaired cardiac autonomic function induces arterial stiffening or whether increased arterial stiffness leads to the impairment of the autonomic function remains obscure. Both arterial stiffness and cardiac autonomic dysfunction share common pathogenetic pathways including chronic hyperglycemia and hyperinsulinemia, formation of advanced glycation end-products (AGEs) and protein kinace C activation, low grade inflammation and endothelial dysfunction [
2]
. One hypothesis is that impaired cardiac autonomic function results in increased arterial stiffness. An explanation could be that patients with cardiac autonomic neuropathy present more often with calcification of the tunica media of the arterial wall [
25]. It is noteworthy that the main determinant of the extent of arterial calcification is the severity of autonomic neuropathy [
25]. On the other hand, arterial calcification has been suggested as an important determinant of arterial stiffness according to findings in humans and experimental models [
26]. These data reveal that calcification of the arterial wall may be an additional common pathophysiological pathway that could explain the relationship between impaired cardiac autonomic function and arterial stiffness.
Another explanation could be that cardiac autonomic dysfunction may affect the elasticity of the arterial wall by changing the smooth muscle tone of large arteries [
8,
27]. Interestingly, people without diabetes but with primary autonomic failure have been found to have stiffer aortas when compared with healthy control individuals [
10]. Although this explanation is rather difficult to be proven in humans, experimental studies have shown that sympathectomized rats exhibit a significant reduction in the elastic properties of the aorta when compared with animals with intact sympathetic ganglia [
28]. In humans on the other hand, high sympathetic activity has been associated with arterial stiffness in hypertensive patients with and without T2DM, as well as in healthy individuals. Increases in heart rate per se may lead to arterial stiffening independently of changes in activity of the autonomic nervous system [
8]. Nevertheless, in the present study the association between autonomic dysfunction and arterial stiffness was not mediated by an increase in heart rate.
The other hypothesis is that arterial stiffness may lead to cardiac autonomic dysfunction via impairment of baroreceptor function induced by stiffening of the arterial wall [
29]. To our knowledge, no literature data exists so far on the relationship between BRS and PWV in people with T2DM. Several studies have found a significant association between low BRS and increased arterial stiffness in patients with congestive heart failure [
30], in older subjects [
29] and in chronic hemodialysis patients [
31]. However, in our study, no difference in central BRS was observed between participants with abnormal and normal PWV. This finding may imply that diabetes per se is a strong factor affecting BRS and outweighs the potential effect of other factors on BRS.
We did not find significant associations between PWV and conventional risk factors like age, smoking habits, microalbuminuria and lipid profile. Moreover, no associations between PWV and macrovascular complications, glycemic control or gender were observed. Our findings are in line with those of a systematic review reporting that, with the exception of age and hypertension, PWV was largely independent of classic risk factors for atherosclerosis, including gender, smoking and lipids [
32]. It was suggested that in the early phases of atherosclerosis increased arterial stiffness is caused not by the atherosclerotic process itself and the formation of the atherosclerotic plaque, for which gender, smoking and lipids are powerful risk factors, but by an alternative pathophysiological mechanism, in which increased blood pressure is one of the most important factors. Although age is a strong determinant of PWV in the general population [
11], we did not find any association between age and abnormal PWV. It could be hypothesized that the presence of diabetes per se has a cardinal impact on arterial stiffness, overcoming the potential effect of other factors [
11]. However, it should be noted that almost 80% of the participants in our study were on statin treatment, while more than 60% received antihypertensive medications and these factors may have influenced our results.
Increasing evidence suggests that central blood pressure may be a more accurate indicator of end organ damage and cardiovascular risk than brachial blood pressure in specific groups of patients, including individuals with T2DM [
33]. A recent meta-analysis reported that central compared with brachial SBP was more closely associated with PWV [
33]. We also found that although both pMBP and cMBP were independently associated with abnormal PWV, the odds for abnormal PWV were slightly higher for cMBP in comparison with pMBP [odds ratio (OR) 1.052, 95% confidence interval (CI) 1.016–1.088,
P = 0.004 vs. OR 1.049, 95% CI 1.015–1.085,
P = 0.005].
The strength of our study is that it is the first to investigate the association between impaired cardiac autonomic function and abnormal PWV using age-corrected values. A limitation is, however, the cross-sectional design that does not allow determination of a causal relationship between PWV and cardiac autonomic function. Although a non-causal association cannot be ruled out, causality could only be determined if the question of which of the two events (impaired cardiac autonomic function or arterial stiffening) appears first could be answered [
27]. Another limitation is that we did not recruit participants without diabetes as a control group to investigate potential differences in the associations of PVW with cardiac autonomic dysfunction between persons with and without T2DM. However, cardiac autonomic dysfunction is not common in persons without diabetes.
Acknowledgement
Not applicable.