Acta Diabetol (2014) 51:973–980 DOI 10.1007/s00592-014-0651-6
ORIGINAL ARTICLE
Pulse wave reflection is associated with diabetes duration, albuminuria and cardiovascular disease in type 1 diabetes Simone Theilade • Maria Lajer • Tine Willum Hansen Peter Rossing
•
Received: 20 June 2014 / Accepted: 8 September 2014 / Published online: 2 October 2014 Ó Springer-Verlag Italia 2014
Abstract Aims We investigate associations between the pulsewave-derived measures augmentation pressure (AP) and augmentation index, and diabetic complications in type 1 diabetes. Methods This cross-sectional study from 2009–2011 included 676 type 1 diabetes patients. SphygmoCor (Atcor Medical, Australia) measured AP and heart rate-adjusted augmentation index (AI75). Diabetic complications were micro- or macroalbuminuria [urinary albumin excretion rate (UAER) 30–299 or C300 mg/24-h], cardiovascular disease (CVD) (previous revascularization, myocardial infarction, peripheral arterial disease or stroke), autonomic dysfunction (heart rate variability \11 beats/min), or retinopathy (simple, proliferative or blindness). Adjustments included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication, and smoking. Results AP and AI75 measurements were available in 636 (94.1 %) patients and were 9.9 ± 7.6 mmHg and 16.9 ± 12.0, respectively. After adjustment, AP and AI75 were independently associated with diabetes duration and albuminuria (p B 0.001). Furthermore, higher AP and
Managed by Antonio Secchi. S. Theilade (&) M. Lajer T. W. Hansen P. Rossing Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark e-mail: [email protected]
AI75 were associated with previous CVD [adjusted odds ratios (95 % confidence interval) (per 1 SD increase) 1.9 (1.3–2.7) and 1.5 (1.0–2.2) (p B 0.039)], but not with autonomic dysfunction or retinopathy (p C 0.12). Conclusions In type 1 diabetes, augmentation pressure and heart rate-adjusted augmentation index were associated with diabetes duration, albuminuria, and CVD, independently of conventional risk factors. ClinicalTrials.gov:NCT01171248. Keywords Arterial stiffness Augmentation index Augmentation pressure Diabetic complications Type 1 diabetes Wave reflection Abbreviations AI Augmentation index AI75 Heart rate-corrected augmentation index AP Augmentation pressure CI Confidence intervals CVD Cardiovascular disease GFR Glomerular filtration rate HbA1c Glycated haemoglobin OR Odds ratio PP Pulse pressure PWA Pulse wave analysis PWV Pulse wave velocity RAAS Renin-angiotensin-aldosterone system SD Standard deviation UAER Urinary albumin excretion rate
Introduction P. Rossing Aarhus University, Aarhus, Denmark P. Rossing University of Copenhagen, Copenhagen, Denmark
Hypertension, elevated cholesterol and smoking cause inflammation, oxidative stress and endothelial dysfunction, which in turn trigger increased arterial stiffness [1].
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In insulin-resistant non-diabetic subjects and subjects with metabolic syndrome, vascular damage is increased [2, 3], and in diabetes, hyperglycaemia aggravates these processes further and arterial stiffness is exacerbated [4]. Arterial stiffness is a risk marker for cardiovascular disease (CVD) [5–7], which is particularly prevalent and associated with excess mortality in patients with diabetes. Several biomarkers reflect arterial stiffness including pulse wave velocity (PWV), pulse wave analysis (PWA) and pulse pressure (PP). PWV is regarded as the gold standard measure of arterial stiffness [8, 9], PWA is a noninvasive method for recording of pulse waveforms, composed of outgoing and reflected waves, representing continuous fluctuations in blood pressure [10], while PP is an easily available measure of arterial stiffness. With increasing arterial stiffness, PWV is accelerated and wave reflection is precipitated, which cause central systolic and PP to increase relatively more than peripheral pressures. Hence, it is possible that brachial PP is less valuable as a surrogate marker of arterial stiffness in individuals with higher arterial stiffness in comparison with measures of wave reflection and PWV. Moreover, PP is predominantly a strong risk marker for adverse outcome in older individuals [11, 12], while measures of wave reflection may be more useful for risk prediction of CVD in younger individuals [13]. So far, PWV and augmentation index (AI) are the primarily investigated measures of arterial stiffness and wave reflection and have been shown to be increased in type 1 diabetes and associated with diabetes related complications [14–16]. As measures of PWV and AI are not interchangeable [17, 18], and information on the relation between augmentation pressure (AP) and long-term complications in type 1 diabetes is missing, further studies examining these aspects are required. We have performed PWA and PWV in a large cohort of patients with type 1 diabetes. Results on associations between PWV and diabetic complications in this cohort have previously been published [16].Thus, the focus of this paper is the relationship between AP, AI and diabetic complications. Furthermore, we investigate the impact of normalisation of albuminuria on all three measures of arterial stiffness.
Subjects and methods Study design and population The cohort has been previously described [16]. Briefly, from 2009 to 2011, Caucasian patients with type 1 diabetes but without end-stage renal disease (dialysis, renal transplantation or GFR/eGFR \ 15 ml/min/1.73 m2) attending
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the outpatient clinic at Steno Diabetes Center, Denmark, were recruited to enter the present study examining the presence of arterial stiffness and diabetic complications. Of the 1,285 patients invited to participate, 676 (52.6 %) accepted and were included in the cohort. The study conformed to the Declaration of Helsinki, was approved by the local ethics committee, and all patients provided written informed consent. Clinical and laboratory methods Office blood pressure was measured after 15-min supine rest as the average of three left brachial measurements (A&D Medical, UA787, Tokyo, Japan). Brachial PP was calculated as the difference between systolic and diastolic blood pressure. Immediately following blood pressure measurements, ECG R-wave-gated PWA recordings were performed with the SphygmoCor device (AtCor Medical, Sydney, Australia). This device uses an internal general transfer function to calculate measures of wave reflection [19]. These measures were AP which refers to the pressure generated by the reflected wave, and AI as the percentage-wise difference between AP and PP. AI adjusted for heart rate (AI75) is the standardised AI to a heart rate of 75 beats per minute [20]. Three consecutive 10-s sequences of pulse waves were recorded and analysed, but only readings with an operator index C 75 were stored, averaged and used in the analyses [21]. Aortic (carotid–femoral) PWV was also measured by the SphygmoCor device following the PWA recordings. PWV was calculated as the time delay between carotid and femoral pulsation divided by the distance between the carotid and femoral arteries multiplied by 0.8 [9].Three PWV measurements were recorded, and the two measurements closest to each other were averaged and used in the analyses. In the current paper, PWV data were only used to examine associations between all three measures of arterial stiffness and improvement in albuminuria over time. Both PWA and PWV measurements were performed by trained technicians according to manufacturer’s guidelines. Blood samples were collected from all patients, and phenotypic characteristics were recorded. Glycated haemoglobin (HbA1c) was measured by high-performance liquid chromatography (normal range 4.1–6.4 %, (21–46 mmol/mol) and Variant-analyser (Biorad Laboratories, Munich, Germany), and plasma cholesterol and serum creatinine concentration were determined by standardised methods. Estimated GFR (eGFR) was calculated by the four variable modification of diet in renal disease equation (MDRD) [22]. The urinary albumin excretion rate (UAER) was measured in 24-h urine collections by enzyme immunoassay.
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Urine collections were obtained in connection with the study visit and/or based on historical samples from medical records at Steno Diabetes Center, Denmark. Patients were stratified as normoalbuminuric if they had UAER \ 30 mg/24-h; or as micro- or macroalbuminuric if the UAER was between 30-299 or C300 mg/24-h, respectively, in two out of three consecutive measurements within 6 months, in the absence of other kidney or urinary tract diseases. Patients with a history of persistently elevated UAER, subsequently reduced with treatment, were categorised according to historically elevated levels. Based on standardised questionnaires, current smoking was defined as C 1 cigarettes/cigars/pipes per day. CVD was defined as previous revascularization, myocardial infarction, peripheral arterial disease or stroke. Instead of investigating cardiac autonomic neuropathy, which requires several different tests, we only assessed autonomic function by heart rate variability recorded during paced deep breathing. An abnormal value of \11 beats per minute defined autonomic dysfunction [23]. Retinopathy status was obtained from medical records, based on regular fundus photographs taken every 3–24 months. Nil retinopathy was defined by normal fundus photographs, while simple or proliferative retinopathy or blindness was collectively classified as retinopathy. Information on antihypertensive treatment was obtained from questionnaires and cross-checked against medical records at the Steno Diabetes Center. Statistical analysis Normally distributed variables are given as mean ± standard deviation (SD), whereas the non-normally variables are given as median (interquartile range) and log10 transformed before analysis. Univariate and multivariate linear regression compared AP and AI75 with covariates. Variance of inflation factor was calculated to test for multicollinearity between covariates. Comparisons between groups were performed by unpaired Student’s t test and analysis of variance (ANOVA), while analysis of covariance (ANCOVA) was applied for adjusted analyses. Multiple logistic regression analyses calculated odds ratios (ORs) with 95 % confidence intervals (95 % CI) for complications per 1 SD increase in AP and AI75. All adjusted models included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication and smoking. A two-tailed p value \0.05 was considered significant. Statistical analyses were performed using SPSS for Windows, version 20.0 (SPSS, Chicago, IL, USA).
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Results Characteristics The original cohort included 676 patients, of which 636 (94.1 %) and 639 (94.5 %) had successful PWA and PWV measurements available, respectively. A flow chart of the cohort is depicted in Fig. 1. Patients without PWA or PWV measurements were older (57 vs. 55 years) with longer diabetes duration (39 vs. 34 years), higher body mass index (26.2 vs. 24.7 kg/m2) and lower mean arterial pressure (90 vs. 94 mmHg) (p B 0.043). All other baseline characteristics were similar in patients with and without SphygmoCor measurements (p C 0.057). Baseline clinical characteristics of the included 676 patients are shown in Table 1. Overall, 304 (45 %) were female, mean age was 55 ± 11 years and diabetes duration was 33 ± 16 years. In univariate regression analyses, AI75 and AP correlated with age, diabetes duration, mean arterial pressure, heart rate, eGFR (negatively), UAER, height total daily insulin dose, height, (p \ 0.001) and each other (r = 0.78, p \ 0.001). Results of the multivariate linear regression analyses are shown in Table 2. Increased AP and AI75 were significantly associated with higher age, MAP, UAER, longer diabetes duration, lower height and eGFR, smoking and female gender (p B 0.034). In addition, higher AI75 was associated with HbA1c (p = 0.029), while higher AP was associated with lower heart rate (p \ 0.001). Neither AI75 nor AP was associated with total cholesterol, antihypertensive treatment or total daily insulin dose in adjusted analyses (p C 0.25). When testing for multicollinearity, including all adjusting variables, the variance of inflation was B1.7 for all covariates. Relation to diabetes duration To investigate whether AP and AI75 were associated with diabetes duration, we compared normoalbuminuric patients with short duration of diabetes (\10 years) (n = 93/93) to normoalbuminuric patients with long duration (C10 years) (n = 208/211). Both AP and AI75 were significantly lower in patients with short versus longer diabetes duration: 5.4 ± 6.5 versus 10.6 ± 7.6 mmHg and 7.5 ± 15.7 versus 17.9 ± 10.8 (p \ 0.001 for both). Following adjustment (not including diabetes duration), both measures remained significantly lower in normoalbuminuric patients with short diabetes duration (p B 0.001). Furthermore, both AP and AI75 were associated with diabetes duration in adjusted linear regression models (p \ 0.001; Table 2).
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Fig. 1 Flow chart of the cohort according to albuminuria group. PWA pulse wave analyses, PWV pulse wave velocity, y years, UAER urine albumin excretion rate
Association to albuminuria
Impact of normalisation of albuminuria
In crude analyses, AP was lowest in normoalbuminuric patients (n = 301) (p \ 0.001), but similar in micro(n = 158) and macroalbuminuric (n = 177) patients (p = 0.22), while AI75 showed a stepwise increase from normo-, to micro- and macroalbuminuric patients (p \ 0.001) (Table 1). Following fully adjustment (excluding albuminuria), AP was lowest in normoalbuminuric patients (p = 0.005), but remained similar in micro- and macroalbuminuric patients (p = 0.93), while AI75 increased with albuminuria degree (p = 0.028). Furthermore, in adjusted linear regression models higher UAER was associated with higher AP and AI75 (p \ 0.001; Table 2). Further inclusion of PP and antihypertensive treatment dose in the adjusted model did not alter the results when investigating albuminuria neither as a continuous or categorical variable (p B 0.02). In addition, we examined whether the level of albuminuria in the normoalbuminuric range was associated with AP and AI75 and divided the normoalbuminuric patients according to UAER below or above the median (8 mg/24-h) (n = 143 and 135). In these two groups, levels of AP were: 9.0 ± 8.0 vs. 9.5 ± 7.3 mmHg and AI75: 15.2 ± 13.8 vs. 15.5 ± 12.4 (p C 0.59, adjusted p C 0.50). Results were similar when UAER as a continuous variable was analysed in linear regression models restricted to the normoalbuminuric patients (p C 0.16, adjusted p C 0.50).
In patients previously diagnosed with microalbuminuria (PWA/PWV measurements n = 158/154), only AP was higher in patients with current microalbuminuria (n = 72/ 72) compared to patients with current treatment induced normoalbuminuria (n = 80/77) (p = 0.005). However, after adjustment, all measures of arterial stiffness (AP, AI75 and PWV) were similar in the two groups (p C 0.34). In patients previously diagnosed with macroalbuminuria, measures of arterial stiffness in those with treatment induced normalised (\30 mg/24-h) (n = 35/40) vs. persistent elevated UAER ([30 mg/24-h) (n = 137/136) were AP: 9.8 ± 6.1 vs. 10.5 ± 6.9 mmHg (p = 0.60); AI75: 18.8 ± 8.1 vs. 19.9 ± 9.2 (p = 0.51); and PWV 10.0 ± 2.2 vs. 11.9 ± 3.1 m/s (p = 0.001). Following adjustment, AP and AI75 remained similar in the two groups (p C 0.17), while PWV persisted significantly lower in patients with normalised UAER [adjusted mean (95 % CI) 9.8 (8.8–10.8) vs. 12.1 (11.7–12.5) m/s] (p \ 0.001).
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Relation to CVD, retinopathy and autonomic dysfunction A total of 132 (20.8 %) patients were previously diagnosed with CVD, 358 [of 612 investigated (58.5 %)] had autonomic dysfunction and 481 [of 616 investigated (78.1 %)] had retinopathy.
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Table 1 Baseline characteristics
Female (%)
All patients (n = 676)
Normoalbuminuria (n = 316)
Microalbuminuria (n = 169)
Macroalbuminuria (n = 191)
45
49
39
42
p
0.074
Age (years)
55 ± 13 (49–64)
53 ± 13 (48–64)
57 ± 12 (54–66)
54 ± 10 (47–62)
Diabetes duration (years)
33 ± 16
28 ± 17
35 ± 15
38 ± 11
0.001
eGFR (ml/min/1.73 m2)
83 ± 28
93 ± 21
84 ± 26
63 ± 29
\0.001
UAER (mg/24-h)*
17 (8–65)
8 (6–13)
33 (17–61)
139 (39–507)
\0.001
HbA1c (mmol/mol)
64 ± 13
62 ± 11
65 ± 13
68 ± 14
\0.001
HbA1c (%) Total cholesterol (mmol/l)
8.0 ± 1.2 4.7 ± 0.9
7.8 ± 1.0 4.7 ± 0.8
8.1 ± 1.2 4.7 ± 0.9
8.4 ± 1.3 4.6 ± 1.0
\0.001 0.36
\0.001
Height (cm)
173 ± 10
174 ± 9
174 ± 9
172 ± 12
Antihypertensive medication (%)
72
46
90
98
\0.001
0.057
RAAS inhibition (%)
67
43
82
94
\0.001
Number of antihypertensive agents in documented daily dose
1 (1.0–2.25)
0 (0–1.25)
1.5 (1.5–2.5)
2.0 (1.08–2.75)
0.005
Total daily insulin dose (international units)
42 (31–58)
40 (30–55)
43 (29–62)
46 (34–60)
0.014
Smokers (%)
21
19
20
25
0.23
Cardiovascular disease (%)
21
10
30
31
\0.001
Myocardial infarction or revascularization (%)
10
5
17
12
\0.001
Stroke (%)
8
4
11
13
0.002
Peripheral arterial disease (%)
7
3
8
13
\0.001
Augmentation index (heart rate-corrected)
16.9 ± 12.0 (10.7–25.0)
14.7 ± 13.4 (7.2–24.0)
18.0 ± 11.6 (12.7–25.5)
19.8 ± 8.9 (14.0–26.2)
\0.001
Augmentation pressure (mmHg)
9.9 ± 7.6 (4.7–14.0)
9.0 ± 7.6 (4.0–13.3)
11.2 ± 8.2 (5.3–16.0)
10.4 ± 6.8 (5.3–14.0)
Pulse wave velocity (m/s) Systolic blood pressure (mmHg)
10.4 ± 3.3 132 ± 18
9.5 ± 3.1 130 ± 17
11.0 ± 3.6
11.4 ± 3.0
133 ± 18
135 ± 18
0.007 \0.001 0.005
Mean arterial pressure (mmHg)
94 ± 11
93 ± 10
93 ± 10
94 ± 11
0.35
Diastolic blood pressure (mmHg)
74 ± 9
75 ± 9
73 ± 9
74 ± 10
0.029
Pulse pressure (mmHg)
58 ± 15
55 ± 14
62 ± 16
61 ± 16
\0.001
Heart rate (beats per minute)
67 ± 12
65 ± 10
67 ± 11
72 ± 12
\0.001
Data represent percentage (%), mean ± SD [and (interquartile range)] or median (interquartile range) eGFR estimated glomerular filtration rate, UAER urinary albumin excretion rate, RAAS renin-angiotensin-aldosterone system p values are for unadjusted comparisons (ANOVA or v2) between normo-, micro- and macroalbuminuric patients * Some patients with previously persistent macroalbuminuria had values \300 mg/24-h at the time of investigation
The adjusted standardised ORs with 95 % CI for previous CVD, autonomic dysfunction and retinopathy related to AP and AI75 are shown in Table 3. Higher AP and AI75 were significant associated with presence of CVD (p B 0.039). In addition, inclusion of PP and antihypertensive treatment dose in the adjusted model did not alter the results (p B 0.041). Moreover, neither AP nor AI75 were related to autonomic dysfunction or retinopathy in adjusted analyses (p C 0.12).
Discussion In this observational study of 676 patients with type 1 diabetes, we investigated AP and AI75 and their association to diabetes duration and diabetes related complications. The key findings were as follows: (1) Increased AP and AI75 were associated with longer diabetes duration. (2) AP and AI75 were associated with albuminuria. (3) AP and AI75 were associated with presence of CVD, but not with
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Table 2 Adjusted linear regression coefficients Variable (SD)
Heart rate-corrected augmentation index
Augmentation pressure
Regression coefficient (SE)
Regression coefficient (SE)
P
P
Age (13 years)*
5.45 (0.41)
\0.001
3.21 (0.24)
\0.001
Female gender
5.34 (0.85)
\0.001
2.84 (0.48)
\0.001
Smoking
3.87 (0.84)
\0.001
1.79 (0.47)
\0.001
Mean arterial pressure (11 mmHg)*
3.58 (0.35)
\0.001
3.41 (0.19)
\0.001
Height (10 cm)*
-2.22 (0.42)
\0.001
-1.04 (0.24)
\0.001
Urinary albumin excretion rate
1.78 (0.59)
0.003
1.29 (0.33)
\0.001
Diabetes duration (16 years)*
1.38 (0.43)
\0.001
1.63 (0.23)
\0.001
eGFR (28 ml/ min/1.73 m2))*
0.88 (0.39)
0.026
0.47 (0.22)
0.034
HbA1c (13 mmol/ mol)*
0.81 (0.37)
0.029 -3.31 (0.20)
\0.001
Heart rate (12 beats per minute)*
The model included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication and smoking. Only variables with significant association are shown * Regression coefficient given as standardised coefficient Model R2 was 0.55 for heart rate-corrected AI and 0.66 for AP
Table 3 Standardised ORs for diabetic complications Heart rate-adjusted augmentation index (SD = 12)
Augmentation pressure (SD = 7.6 mmHg)
Cardiovascular disease (n = 132)
1.48 (1.02–2.17)
1.90 (1.33–2.72)
p = 0.039
p \ 0.001
Autonomic dysfunction (n = 358) Retinopathy (n = 481)
1.22 (0.86–1.73)
1.36 (0.93–1.99)
p = 0.26
p = 0.12
1.34 (0.90–1.99)
1.21 (0.75–1.97)
p = 0.15
p = 0.43
Values are ORs and 95 % CI adjusted for age, gender, diabetes duration, mean arterial pressure, heart rate, height, eGFR, UAER, HbA1c, total cholesterol, total daily insulin dose, antihypertensive treatment and smoking
autonomic dysfunction or retinopathy, independently of mean arterial pressure and conventional risk factors. (4) Previously macroalbuminuric patients with normalised UAER had lower PWV compared with patients with persistently elevated UAER.
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We and others have previously shown that arterial stiffness (measured with the gold standard—PWV) is increased in presence of diabetes [24], associated with complications to diabetes [14, 16, 25], and connected to increased risk of CVD [26, 27]. In the current manuscript, we present two measures of pulse wave reflection obtained by PWA, which are also related to diabetes duration and associated with complications. Furthermore, both AP and AI75 were independently associated with albuminuria. In explanatory analyses, we compared patients who were previously diagnosed as macroalbuminuric, whom in connection with the study visit had either normalised or sustained elevated UAER. Arterial stiffness (PWV) was reduced in patients with normalised albuminuria, suggesting that arterial stiffness may be reversible with reno-protective treatment (95 % of the patients with previously diagnosed macroalbuminuria were treated with RAAS inhibition), as previously shown by Mitchell et al. [28] in a cohort of patients with coronary heart disease and heart failure. Another explanation could be that responders to reno-protective treatment may have less arterial stiffness; however, this can only be clarified in a longitudinal study design. A recent study contradicts our findings by showing that patients with type 1 diabetes undergoing pancreas and renal transplantation, thereby normalising albuminuria as well as hyperglycaemia, did not decrease their arterial stiffness (measured as PWV) [29]. However, it is possible, that immunosuppressive treatment given to transplant patients would counteract the expected beneficial effect on the vasculature of the achieved improved glycemic control and reduced albuminuria induced by pancreas and renal transplantation. Similarly, the relative short median followup period of 4 years may have been too short to demonstrate a favourable effect on arterial stiffness. Nevertheless, it has recently been shown that increased arterial stiffness is associated with incident albuminuria and decline in kidney function in type 2 diabetes [30] and with increasing albuminuria degree in type 1 diabetes [16]. Whether reversibility of arterial stiffness is possible by reducing albuminuria is the key question. Guerin et al. [31] have previously demonstrated that in patients with endstage renal disease, reduction in arterial stiffness by antihypertensive treatment improves survival beyond the blood pressure lowering effect. Furthermore, large studies have shown that a decline in albuminuria is associated with decreased risk of CVD [32–34]. In the RENAAL trial, treatment with RAAS inhibition reduced progression of nephropathy and subsequently progression to end-stage renal disease in patients with type 2 diabetes and diabetic kidney disease [25]. It has also been shown that RAAS inhibition improves endothelial function in patients with coronary artery disease, microalbuminuric type 1 diabetes
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and hypertensive type 2 diabetes [35–37] and that statin administration reduce arterial stiffness [38]. PWV and AP increase with age, whereas AI75 only rises till the age of approximately 55 years [39]. Thus, AI75 may not be optimal for measuring wave reflection in elderly populations. We previously showed PWV to be associated with retinopathy and autonomic dysfunction in addition to CVD and albuminuria [16]. Thus, overall PWV appears to be superior to AP and AI75 as a risk marker for diabetes related complications. Given the reported association between arterial stiffness and diabetic complications [7, 15, 26, 27], measures of arterial stiffness and pulse wave reflection may constitute novel markers of subclinical organ damage [40, 41]. Pulse wave measurements could easily be implemented as a measure of disease, a target for personalised treatment and a focus for monitoring treatment effect. However, longitudinal studies showing that normalisation of arterial stiffness is associated with better outcome are still lacking.
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Conclusion In patients with type 1 diabetes, increased AP and AI75 were associated with longer diabetes duration, albuminuria and CVD, independently of age, mean arterial pressure, kidney function and other conventional risk factors. PWV was lower in previous macroalbuminuric patients with normalised UAER on treatment. Efforts to prevent and reverse increased arterial stiffness are being made. However, future studies are required to investigate whether reduced arterial stiffness also improves outcome. Conflict of interest Simone Theilade, Maria Lajer, Tine Willum Hansen and Peter Rossing have no conflicts of interest to declare. Human and Animal Rights disclosure All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent disclosure Informed consent was obtained from all patients for being included in the study.
Strengths and limitations References Our study has some limitations. First, it is cross-sectional in design, thus excluding our ability to confer causality. Second, analyses are based on relatively few PWA and PWV recordings at a single visit. However, they were obtained under uniform conditions by four trained laboratory technicians, with coefficients of variation between the three PWA and PWV measurements of B2.6 % for AP, AI75 and PWV. Furthermore, PWV and PWA measurements have acceptable reproducibility for use in larger studies [42]. Third, patients were not fasting, as otherwise recommended for measurement of PWA and PWV [8], as they are sensitive to feeding state [43]. However, as the patients had insulin-dependent diabetes, we did not consider fasting a safe option in this large-scale cohort. Finally, given the cross-sectional design of the study, we used historical data when exploring the associations between diabetic complications and AP and AI75. Furthermore, we dichotomised presence of retinopathy and autonomic dysfunction and only used one test to define autonomic function. Thus, all three measures of complications are crude, as we may have underestimated the prevalence of CVD (silent ischaemia) and weakened the retinopathy and autonomic function variables. However, the majority of patients had been followed at the Steno Diabetes Center for more than a decade, rendering the information on diabetic complications very reliable. Major strengths are the remarkably high sample size, and the study being from a single center, why the cohort was likely rather homogenous and receiving similar treatment.
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ORIGINAL ARTICLE
Pulse wave reflection is associated with diabetes duration, albuminuria and cardiovascular disease in type 1 diabetes Simone Theilade • Maria Lajer • Tine Willum Hansen Peter Rossing
•
Received: 20 June 2014 / Accepted: 8 September 2014 / Published online: 2 October 2014 Ó Springer-Verlag Italia 2014
Abstract Aims We investigate associations between the pulsewave-derived measures augmentation pressure (AP) and augmentation index, and diabetic complications in type 1 diabetes. Methods This cross-sectional study from 2009–2011 included 676 type 1 diabetes patients. SphygmoCor (Atcor Medical, Australia) measured AP and heart rate-adjusted augmentation index (AI75). Diabetic complications were micro- or macroalbuminuria [urinary albumin excretion rate (UAER) 30–299 or C300 mg/24-h], cardiovascular disease (CVD) (previous revascularization, myocardial infarction, peripheral arterial disease or stroke), autonomic dysfunction (heart rate variability \11 beats/min), or retinopathy (simple, proliferative or blindness). Adjustments included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication, and smoking. Results AP and AI75 measurements were available in 636 (94.1 %) patients and were 9.9 ± 7.6 mmHg and 16.9 ± 12.0, respectively. After adjustment, AP and AI75 were independently associated with diabetes duration and albuminuria (p B 0.001). Furthermore, higher AP and
Managed by Antonio Secchi. S. Theilade (&) M. Lajer T. W. Hansen P. Rossing Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark e-mail: [email protected]
AI75 were associated with previous CVD [adjusted odds ratios (95 % confidence interval) (per 1 SD increase) 1.9 (1.3–2.7) and 1.5 (1.0–2.2) (p B 0.039)], but not with autonomic dysfunction or retinopathy (p C 0.12). Conclusions In type 1 diabetes, augmentation pressure and heart rate-adjusted augmentation index were associated with diabetes duration, albuminuria, and CVD, independently of conventional risk factors. ClinicalTrials.gov:NCT01171248. Keywords Arterial stiffness Augmentation index Augmentation pressure Diabetic complications Type 1 diabetes Wave reflection Abbreviations AI Augmentation index AI75 Heart rate-corrected augmentation index AP Augmentation pressure CI Confidence intervals CVD Cardiovascular disease GFR Glomerular filtration rate HbA1c Glycated haemoglobin OR Odds ratio PP Pulse pressure PWA Pulse wave analysis PWV Pulse wave velocity RAAS Renin-angiotensin-aldosterone system SD Standard deviation UAER Urinary albumin excretion rate
Introduction P. Rossing Aarhus University, Aarhus, Denmark P. Rossing University of Copenhagen, Copenhagen, Denmark
Hypertension, elevated cholesterol and smoking cause inflammation, oxidative stress and endothelial dysfunction, which in turn trigger increased arterial stiffness [1].
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In insulin-resistant non-diabetic subjects and subjects with metabolic syndrome, vascular damage is increased [2, 3], and in diabetes, hyperglycaemia aggravates these processes further and arterial stiffness is exacerbated [4]. Arterial stiffness is a risk marker for cardiovascular disease (CVD) [5–7], which is particularly prevalent and associated with excess mortality in patients with diabetes. Several biomarkers reflect arterial stiffness including pulse wave velocity (PWV), pulse wave analysis (PWA) and pulse pressure (PP). PWV is regarded as the gold standard measure of arterial stiffness [8, 9], PWA is a noninvasive method for recording of pulse waveforms, composed of outgoing and reflected waves, representing continuous fluctuations in blood pressure [10], while PP is an easily available measure of arterial stiffness. With increasing arterial stiffness, PWV is accelerated and wave reflection is precipitated, which cause central systolic and PP to increase relatively more than peripheral pressures. Hence, it is possible that brachial PP is less valuable as a surrogate marker of arterial stiffness in individuals with higher arterial stiffness in comparison with measures of wave reflection and PWV. Moreover, PP is predominantly a strong risk marker for adverse outcome in older individuals [11, 12], while measures of wave reflection may be more useful for risk prediction of CVD in younger individuals [13]. So far, PWV and augmentation index (AI) are the primarily investigated measures of arterial stiffness and wave reflection and have been shown to be increased in type 1 diabetes and associated with diabetes related complications [14–16]. As measures of PWV and AI are not interchangeable [17, 18], and information on the relation between augmentation pressure (AP) and long-term complications in type 1 diabetes is missing, further studies examining these aspects are required. We have performed PWA and PWV in a large cohort of patients with type 1 diabetes. Results on associations between PWV and diabetic complications in this cohort have previously been published [16].Thus, the focus of this paper is the relationship between AP, AI and diabetic complications. Furthermore, we investigate the impact of normalisation of albuminuria on all three measures of arterial stiffness.
Subjects and methods Study design and population The cohort has been previously described [16]. Briefly, from 2009 to 2011, Caucasian patients with type 1 diabetes but without end-stage renal disease (dialysis, renal transplantation or GFR/eGFR \ 15 ml/min/1.73 m2) attending
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the outpatient clinic at Steno Diabetes Center, Denmark, were recruited to enter the present study examining the presence of arterial stiffness and diabetic complications. Of the 1,285 patients invited to participate, 676 (52.6 %) accepted and were included in the cohort. The study conformed to the Declaration of Helsinki, was approved by the local ethics committee, and all patients provided written informed consent. Clinical and laboratory methods Office blood pressure was measured after 15-min supine rest as the average of three left brachial measurements (A&D Medical, UA787, Tokyo, Japan). Brachial PP was calculated as the difference between systolic and diastolic blood pressure. Immediately following blood pressure measurements, ECG R-wave-gated PWA recordings were performed with the SphygmoCor device (AtCor Medical, Sydney, Australia). This device uses an internal general transfer function to calculate measures of wave reflection [19]. These measures were AP which refers to the pressure generated by the reflected wave, and AI as the percentage-wise difference between AP and PP. AI adjusted for heart rate (AI75) is the standardised AI to a heart rate of 75 beats per minute [20]. Three consecutive 10-s sequences of pulse waves were recorded and analysed, but only readings with an operator index C 75 were stored, averaged and used in the analyses [21]. Aortic (carotid–femoral) PWV was also measured by the SphygmoCor device following the PWA recordings. PWV was calculated as the time delay between carotid and femoral pulsation divided by the distance between the carotid and femoral arteries multiplied by 0.8 [9].Three PWV measurements were recorded, and the two measurements closest to each other were averaged and used in the analyses. In the current paper, PWV data were only used to examine associations between all three measures of arterial stiffness and improvement in albuminuria over time. Both PWA and PWV measurements were performed by trained technicians according to manufacturer’s guidelines. Blood samples were collected from all patients, and phenotypic characteristics were recorded. Glycated haemoglobin (HbA1c) was measured by high-performance liquid chromatography (normal range 4.1–6.4 %, (21–46 mmol/mol) and Variant-analyser (Biorad Laboratories, Munich, Germany), and plasma cholesterol and serum creatinine concentration were determined by standardised methods. Estimated GFR (eGFR) was calculated by the four variable modification of diet in renal disease equation (MDRD) [22]. The urinary albumin excretion rate (UAER) was measured in 24-h urine collections by enzyme immunoassay.
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Urine collections were obtained in connection with the study visit and/or based on historical samples from medical records at Steno Diabetes Center, Denmark. Patients were stratified as normoalbuminuric if they had UAER \ 30 mg/24-h; or as micro- or macroalbuminuric if the UAER was between 30-299 or C300 mg/24-h, respectively, in two out of three consecutive measurements within 6 months, in the absence of other kidney or urinary tract diseases. Patients with a history of persistently elevated UAER, subsequently reduced with treatment, were categorised according to historically elevated levels. Based on standardised questionnaires, current smoking was defined as C 1 cigarettes/cigars/pipes per day. CVD was defined as previous revascularization, myocardial infarction, peripheral arterial disease or stroke. Instead of investigating cardiac autonomic neuropathy, which requires several different tests, we only assessed autonomic function by heart rate variability recorded during paced deep breathing. An abnormal value of \11 beats per minute defined autonomic dysfunction [23]. Retinopathy status was obtained from medical records, based on regular fundus photographs taken every 3–24 months. Nil retinopathy was defined by normal fundus photographs, while simple or proliferative retinopathy or blindness was collectively classified as retinopathy. Information on antihypertensive treatment was obtained from questionnaires and cross-checked against medical records at the Steno Diabetes Center. Statistical analysis Normally distributed variables are given as mean ± standard deviation (SD), whereas the non-normally variables are given as median (interquartile range) and log10 transformed before analysis. Univariate and multivariate linear regression compared AP and AI75 with covariates. Variance of inflation factor was calculated to test for multicollinearity between covariates. Comparisons between groups were performed by unpaired Student’s t test and analysis of variance (ANOVA), while analysis of covariance (ANCOVA) was applied for adjusted analyses. Multiple logistic regression analyses calculated odds ratios (ORs) with 95 % confidence intervals (95 % CI) for complications per 1 SD increase in AP and AI75. All adjusted models included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication and smoking. A two-tailed p value \0.05 was considered significant. Statistical analyses were performed using SPSS for Windows, version 20.0 (SPSS, Chicago, IL, USA).
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Results Characteristics The original cohort included 676 patients, of which 636 (94.1 %) and 639 (94.5 %) had successful PWA and PWV measurements available, respectively. A flow chart of the cohort is depicted in Fig. 1. Patients without PWA or PWV measurements were older (57 vs. 55 years) with longer diabetes duration (39 vs. 34 years), higher body mass index (26.2 vs. 24.7 kg/m2) and lower mean arterial pressure (90 vs. 94 mmHg) (p B 0.043). All other baseline characteristics were similar in patients with and without SphygmoCor measurements (p C 0.057). Baseline clinical characteristics of the included 676 patients are shown in Table 1. Overall, 304 (45 %) were female, mean age was 55 ± 11 years and diabetes duration was 33 ± 16 years. In univariate regression analyses, AI75 and AP correlated with age, diabetes duration, mean arterial pressure, heart rate, eGFR (negatively), UAER, height total daily insulin dose, height, (p \ 0.001) and each other (r = 0.78, p \ 0.001). Results of the multivariate linear regression analyses are shown in Table 2. Increased AP and AI75 were significantly associated with higher age, MAP, UAER, longer diabetes duration, lower height and eGFR, smoking and female gender (p B 0.034). In addition, higher AI75 was associated with HbA1c (p = 0.029), while higher AP was associated with lower heart rate (p \ 0.001). Neither AI75 nor AP was associated with total cholesterol, antihypertensive treatment or total daily insulin dose in adjusted analyses (p C 0.25). When testing for multicollinearity, including all adjusting variables, the variance of inflation was B1.7 for all covariates. Relation to diabetes duration To investigate whether AP and AI75 were associated with diabetes duration, we compared normoalbuminuric patients with short duration of diabetes (\10 years) (n = 93/93) to normoalbuminuric patients with long duration (C10 years) (n = 208/211). Both AP and AI75 were significantly lower in patients with short versus longer diabetes duration: 5.4 ± 6.5 versus 10.6 ± 7.6 mmHg and 7.5 ± 15.7 versus 17.9 ± 10.8 (p \ 0.001 for both). Following adjustment (not including diabetes duration), both measures remained significantly lower in normoalbuminuric patients with short diabetes duration (p B 0.001). Furthermore, both AP and AI75 were associated with diabetes duration in adjusted linear regression models (p \ 0.001; Table 2).
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Fig. 1 Flow chart of the cohort according to albuminuria group. PWA pulse wave analyses, PWV pulse wave velocity, y years, UAER urine albumin excretion rate
Association to albuminuria
Impact of normalisation of albuminuria
In crude analyses, AP was lowest in normoalbuminuric patients (n = 301) (p \ 0.001), but similar in micro(n = 158) and macroalbuminuric (n = 177) patients (p = 0.22), while AI75 showed a stepwise increase from normo-, to micro- and macroalbuminuric patients (p \ 0.001) (Table 1). Following fully adjustment (excluding albuminuria), AP was lowest in normoalbuminuric patients (p = 0.005), but remained similar in micro- and macroalbuminuric patients (p = 0.93), while AI75 increased with albuminuria degree (p = 0.028). Furthermore, in adjusted linear regression models higher UAER was associated with higher AP and AI75 (p \ 0.001; Table 2). Further inclusion of PP and antihypertensive treatment dose in the adjusted model did not alter the results when investigating albuminuria neither as a continuous or categorical variable (p B 0.02). In addition, we examined whether the level of albuminuria in the normoalbuminuric range was associated with AP and AI75 and divided the normoalbuminuric patients according to UAER below or above the median (8 mg/24-h) (n = 143 and 135). In these two groups, levels of AP were: 9.0 ± 8.0 vs. 9.5 ± 7.3 mmHg and AI75: 15.2 ± 13.8 vs. 15.5 ± 12.4 (p C 0.59, adjusted p C 0.50). Results were similar when UAER as a continuous variable was analysed in linear regression models restricted to the normoalbuminuric patients (p C 0.16, adjusted p C 0.50).
In patients previously diagnosed with microalbuminuria (PWA/PWV measurements n = 158/154), only AP was higher in patients with current microalbuminuria (n = 72/ 72) compared to patients with current treatment induced normoalbuminuria (n = 80/77) (p = 0.005). However, after adjustment, all measures of arterial stiffness (AP, AI75 and PWV) were similar in the two groups (p C 0.34). In patients previously diagnosed with macroalbuminuria, measures of arterial stiffness in those with treatment induced normalised (\30 mg/24-h) (n = 35/40) vs. persistent elevated UAER ([30 mg/24-h) (n = 137/136) were AP: 9.8 ± 6.1 vs. 10.5 ± 6.9 mmHg (p = 0.60); AI75: 18.8 ± 8.1 vs. 19.9 ± 9.2 (p = 0.51); and PWV 10.0 ± 2.2 vs. 11.9 ± 3.1 m/s (p = 0.001). Following adjustment, AP and AI75 remained similar in the two groups (p C 0.17), while PWV persisted significantly lower in patients with normalised UAER [adjusted mean (95 % CI) 9.8 (8.8–10.8) vs. 12.1 (11.7–12.5) m/s] (p \ 0.001).
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Relation to CVD, retinopathy and autonomic dysfunction A total of 132 (20.8 %) patients were previously diagnosed with CVD, 358 [of 612 investigated (58.5 %)] had autonomic dysfunction and 481 [of 616 investigated (78.1 %)] had retinopathy.
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Table 1 Baseline characteristics
Female (%)
All patients (n = 676)
Normoalbuminuria (n = 316)
Microalbuminuria (n = 169)
Macroalbuminuria (n = 191)
45
49
39
42
p
0.074
Age (years)
55 ± 13 (49–64)
53 ± 13 (48–64)
57 ± 12 (54–66)
54 ± 10 (47–62)
Diabetes duration (years)
33 ± 16
28 ± 17
35 ± 15
38 ± 11
0.001
eGFR (ml/min/1.73 m2)
83 ± 28
93 ± 21
84 ± 26
63 ± 29
\0.001
UAER (mg/24-h)*
17 (8–65)
8 (6–13)
33 (17–61)
139 (39–507)
\0.001
HbA1c (mmol/mol)
64 ± 13
62 ± 11
65 ± 13
68 ± 14
\0.001
HbA1c (%) Total cholesterol (mmol/l)
8.0 ± 1.2 4.7 ± 0.9
7.8 ± 1.0 4.7 ± 0.8
8.1 ± 1.2 4.7 ± 0.9
8.4 ± 1.3 4.6 ± 1.0
\0.001 0.36
\0.001
Height (cm)
173 ± 10
174 ± 9
174 ± 9
172 ± 12
Antihypertensive medication (%)
72
46
90
98
\0.001
0.057
RAAS inhibition (%)
67
43
82
94
\0.001
Number of antihypertensive agents in documented daily dose
1 (1.0–2.25)
0 (0–1.25)
1.5 (1.5–2.5)
2.0 (1.08–2.75)
0.005
Total daily insulin dose (international units)
42 (31–58)
40 (30–55)
43 (29–62)
46 (34–60)
0.014
Smokers (%)
21
19
20
25
0.23
Cardiovascular disease (%)
21
10
30
31
\0.001
Myocardial infarction or revascularization (%)
10
5
17
12
\0.001
Stroke (%)
8
4
11
13
0.002
Peripheral arterial disease (%)
7
3
8
13
\0.001
Augmentation index (heart rate-corrected)
16.9 ± 12.0 (10.7–25.0)
14.7 ± 13.4 (7.2–24.0)
18.0 ± 11.6 (12.7–25.5)
19.8 ± 8.9 (14.0–26.2)
\0.001
Augmentation pressure (mmHg)
9.9 ± 7.6 (4.7–14.0)
9.0 ± 7.6 (4.0–13.3)
11.2 ± 8.2 (5.3–16.0)
10.4 ± 6.8 (5.3–14.0)
Pulse wave velocity (m/s) Systolic blood pressure (mmHg)
10.4 ± 3.3 132 ± 18
9.5 ± 3.1 130 ± 17
11.0 ± 3.6
11.4 ± 3.0
133 ± 18
135 ± 18
0.007 \0.001 0.005
Mean arterial pressure (mmHg)
94 ± 11
93 ± 10
93 ± 10
94 ± 11
0.35
Diastolic blood pressure (mmHg)
74 ± 9
75 ± 9
73 ± 9
74 ± 10
0.029
Pulse pressure (mmHg)
58 ± 15
55 ± 14
62 ± 16
61 ± 16
\0.001
Heart rate (beats per minute)
67 ± 12
65 ± 10
67 ± 11
72 ± 12
\0.001
Data represent percentage (%), mean ± SD [and (interquartile range)] or median (interquartile range) eGFR estimated glomerular filtration rate, UAER urinary albumin excretion rate, RAAS renin-angiotensin-aldosterone system p values are for unadjusted comparisons (ANOVA or v2) between normo-, micro- and macroalbuminuric patients * Some patients with previously persistent macroalbuminuria had values \300 mg/24-h at the time of investigation
The adjusted standardised ORs with 95 % CI for previous CVD, autonomic dysfunction and retinopathy related to AP and AI75 are shown in Table 3. Higher AP and AI75 were significant associated with presence of CVD (p B 0.039). In addition, inclusion of PP and antihypertensive treatment dose in the adjusted model did not alter the results (p B 0.041). Moreover, neither AP nor AI75 were related to autonomic dysfunction or retinopathy in adjusted analyses (p C 0.12).
Discussion In this observational study of 676 patients with type 1 diabetes, we investigated AP and AI75 and their association to diabetes duration and diabetes related complications. The key findings were as follows: (1) Increased AP and AI75 were associated with longer diabetes duration. (2) AP and AI75 were associated with albuminuria. (3) AP and AI75 were associated with presence of CVD, but not with
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Table 2 Adjusted linear regression coefficients Variable (SD)
Heart rate-corrected augmentation index
Augmentation pressure
Regression coefficient (SE)
Regression coefficient (SE)
P
P
Age (13 years)*
5.45 (0.41)
\0.001
3.21 (0.24)
\0.001
Female gender
5.34 (0.85)
\0.001
2.84 (0.48)
\0.001
Smoking
3.87 (0.84)
\0.001
1.79 (0.47)
\0.001
Mean arterial pressure (11 mmHg)*
3.58 (0.35)
\0.001
3.41 (0.19)
\0.001
Height (10 cm)*
-2.22 (0.42)
\0.001
-1.04 (0.24)
\0.001
Urinary albumin excretion rate
1.78 (0.59)
0.003
1.29 (0.33)
\0.001
Diabetes duration (16 years)*
1.38 (0.43)
\0.001
1.63 (0.23)
\0.001
eGFR (28 ml/ min/1.73 m2))*
0.88 (0.39)
0.026
0.47 (0.22)
0.034
HbA1c (13 mmol/ mol)*
0.81 (0.37)
0.029 -3.31 (0.20)
\0.001
Heart rate (12 beats per minute)*
The model included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication and smoking. Only variables with significant association are shown * Regression coefficient given as standardised coefficient Model R2 was 0.55 for heart rate-corrected AI and 0.66 for AP
Table 3 Standardised ORs for diabetic complications Heart rate-adjusted augmentation index (SD = 12)
Augmentation pressure (SD = 7.6 mmHg)
Cardiovascular disease (n = 132)
1.48 (1.02–2.17)
1.90 (1.33–2.72)
p = 0.039
p \ 0.001
Autonomic dysfunction (n = 358) Retinopathy (n = 481)
1.22 (0.86–1.73)
1.36 (0.93–1.99)
p = 0.26
p = 0.12
1.34 (0.90–1.99)
1.21 (0.75–1.97)
p = 0.15
p = 0.43
Values are ORs and 95 % CI adjusted for age, gender, diabetes duration, mean arterial pressure, heart rate, height, eGFR, UAER, HbA1c, total cholesterol, total daily insulin dose, antihypertensive treatment and smoking
autonomic dysfunction or retinopathy, independently of mean arterial pressure and conventional risk factors. (4) Previously macroalbuminuric patients with normalised UAER had lower PWV compared with patients with persistently elevated UAER.
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We and others have previously shown that arterial stiffness (measured with the gold standard—PWV) is increased in presence of diabetes [24], associated with complications to diabetes [14, 16, 25], and connected to increased risk of CVD [26, 27]. In the current manuscript, we present two measures of pulse wave reflection obtained by PWA, which are also related to diabetes duration and associated with complications. Furthermore, both AP and AI75 were independently associated with albuminuria. In explanatory analyses, we compared patients who were previously diagnosed as macroalbuminuric, whom in connection with the study visit had either normalised or sustained elevated UAER. Arterial stiffness (PWV) was reduced in patients with normalised albuminuria, suggesting that arterial stiffness may be reversible with reno-protective treatment (95 % of the patients with previously diagnosed macroalbuminuria were treated with RAAS inhibition), as previously shown by Mitchell et al. [28] in a cohort of patients with coronary heart disease and heart failure. Another explanation could be that responders to reno-protective treatment may have less arterial stiffness; however, this can only be clarified in a longitudinal study design. A recent study contradicts our findings by showing that patients with type 1 diabetes undergoing pancreas and renal transplantation, thereby normalising albuminuria as well as hyperglycaemia, did not decrease their arterial stiffness (measured as PWV) [29]. However, it is possible, that immunosuppressive treatment given to transplant patients would counteract the expected beneficial effect on the vasculature of the achieved improved glycemic control and reduced albuminuria induced by pancreas and renal transplantation. Similarly, the relative short median followup period of 4 years may have been too short to demonstrate a favourable effect on arterial stiffness. Nevertheless, it has recently been shown that increased arterial stiffness is associated with incident albuminuria and decline in kidney function in type 2 diabetes [30] and with increasing albuminuria degree in type 1 diabetes [16]. Whether reversibility of arterial stiffness is possible by reducing albuminuria is the key question. Guerin et al. [31] have previously demonstrated that in patients with endstage renal disease, reduction in arterial stiffness by antihypertensive treatment improves survival beyond the blood pressure lowering effect. Furthermore, large studies have shown that a decline in albuminuria is associated with decreased risk of CVD [32–34]. In the RENAAL trial, treatment with RAAS inhibition reduced progression of nephropathy and subsequently progression to end-stage renal disease in patients with type 2 diabetes and diabetic kidney disease [25]. It has also been shown that RAAS inhibition improves endothelial function in patients with coronary artery disease, microalbuminuric type 1 diabetes
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and hypertensive type 2 diabetes [35–37] and that statin administration reduce arterial stiffness [38]. PWV and AP increase with age, whereas AI75 only rises till the age of approximately 55 years [39]. Thus, AI75 may not be optimal for measuring wave reflection in elderly populations. We previously showed PWV to be associated with retinopathy and autonomic dysfunction in addition to CVD and albuminuria [16]. Thus, overall PWV appears to be superior to AP and AI75 as a risk marker for diabetes related complications. Given the reported association between arterial stiffness and diabetic complications [7, 15, 26, 27], measures of arterial stiffness and pulse wave reflection may constitute novel markers of subclinical organ damage [40, 41]. Pulse wave measurements could easily be implemented as a measure of disease, a target for personalised treatment and a focus for monitoring treatment effect. However, longitudinal studies showing that normalisation of arterial stiffness is associated with better outcome are still lacking.
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Conclusion In patients with type 1 diabetes, increased AP and AI75 were associated with longer diabetes duration, albuminuria and CVD, independently of age, mean arterial pressure, kidney function and other conventional risk factors. PWV was lower in previous macroalbuminuric patients with normalised UAER on treatment. Efforts to prevent and reverse increased arterial stiffness are being made. However, future studies are required to investigate whether reduced arterial stiffness also improves outcome. Conflict of interest Simone Theilade, Maria Lajer, Tine Willum Hansen and Peter Rossing have no conflicts of interest to declare. Human and Animal Rights disclosure All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent disclosure Informed consent was obtained from all patients for being included in the study.
Strengths and limitations References Our study has some limitations. First, it is cross-sectional in design, thus excluding our ability to confer causality. Second, analyses are based on relatively few PWA and PWV recordings at a single visit. However, they were obtained under uniform conditions by four trained laboratory technicians, with coefficients of variation between the three PWA and PWV measurements of B2.6 % for AP, AI75 and PWV. Furthermore, PWV and PWA measurements have acceptable reproducibility for use in larger studies [42]. Third, patients were not fasting, as otherwise recommended for measurement of PWA and PWV [8], as they are sensitive to feeding state [43]. However, as the patients had insulin-dependent diabetes, we did not consider fasting a safe option in this large-scale cohort. Finally, given the cross-sectional design of the study, we used historical data when exploring the associations between diabetic complications and AP and AI75. Furthermore, we dichotomised presence of retinopathy and autonomic dysfunction and only used one test to define autonomic function. Thus, all three measures of complications are crude, as we may have underestimated the prevalence of CVD (silent ischaemia) and weakened the retinopathy and autonomic function variables. However, the majority of patients had been followed at the Steno Diabetes Center for more than a decade, rendering the information on diabetic complications very reliable. Major strengths are the remarkably high sample size, and the study being from a single center, why the cohort was likely rather homogenous and receiving similar treatment.
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