Aortic Systolic and Pulse Pressure and Type 1 Diabetes
Between September 2009 and June 2011, Caucasian patients with TIDM, were recruited to enter a cross-sectional study at Steno Diabetes Center, Copenhagen, Denmark. Recruitment was in sequential order according to date of birth from a list of all patients attending the outpatient clinic. For power calculations we used an α-value of 5%, a β-value of 20%, and an estimated variance of 9.5 mmHg. For the comparison between controls and patients we estimated a 24 h-CASP-difference of 4 mmHg between groups, which implied that we needed a minimum of 45 participants in each group. For the comparisons between patient groups (3 albuminuria groups), we estimated a 24 h-CASP-difference of 2 mmHg, indicating a need for 177 patients in each group. Thus, we intended to include at least 45 controls and 576 patients. Of 1285 patients invited, 676 (52.6%) agreed to enter the study. Patients declining participation were younger but with similar gender distribution compared to participating patients (49 ± 16 years and 57% males vs. 54 ± 13 years and 56% males (p < 0.001 and 0.62). In addition, a control group of 51 non-diabetic subjects from Copenhagen, Denmark and 46 non-diabetic subjects from Leichester, UK were included.
In total, 654 (96.7%) patients and 90 (92.9%) controls had adequate ambulatory AMBP available, with 46 ± 7 and 18 ± 3 (63.9% and 75.0% of total possible) recordings during day and night, respectively. Four controls and 25 patients with normoalbuminuria and short diabetes duration received AHT and were excluded in order to create two comparable groups not treated for hypertension. The remaining groups of patients had no restriction regarding AHT (Table 1). Hence, the analysed cohort included 715 subjects, comprising of 86 non-diabetic persons (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) and not receiving AHT (SN), 211 patients with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 patients with microalbuminuria (30–299 mg/24 h) (Mi), and 186 patients with macroalbuminuria (> 300 mg/24 h) (Ma). Figure 1 summarise the inclusion and exclusion of the study participants. The 10 year cut-off for defining patients as having short vs. long duration of diabetes was chosen, as complications to diabetes may develop within 5–10 years. The five groups were stratified in order to create groups for comparison of 1) healthy controls to patients without complications, 2) healthy controls to patients with sustained normal kidney function, and 3) patients with increasing degree of impaired kidney function.
(Enlarge Image)
Figure 1.
Flow chart of the cohort.
Patients with ESRD, defined as receiving dialysis or renal transplantation, or GFR/eGFR < 15 ml/min/1.73 m were not included.
The study conformed to the Declaration of Helsinki, was approved by the Danish National Committee on Biomedical Research Ethics (2009–056), and all participants gave written informed consent.
Participant attended one single study visit, during which all clinical and laboratory measurements were performed. For office BP, 15 minutes supine rest was followed by recording and averaging of three separate left brachial measurements (A&D Medical, UA787).
AMBP were recorded non-invasively, using a validated system consisting of a radial arterial tonometer embedded in an articulating strap of a wrist-watch device (BPro™, HealthStats Singapore). The device was calibrated to brachial BP and variations in pulse waveform height over the subsequent measurement period used to calculate brachial AMBP. Calibrated radial waveforms were then processed at the end of each measurement session by applying an N-point-moving average to derive CASP. The device reported CASP, CPP, SBP, diastolic BP (DBP), MAP and heart rate (HR) every 15 minutes during 24 h. Previous validation studies have shown the BPro device to obtain BP measurements independently of arm positioning, with values comparable to those obtained with cuff-based devices. Furthermore, we have shown that CASP measurements obtained by the BPro are comparable to those obtained by accepted gold standard devices for non-invasive measurements of CASP. AMBP data was considered adequate if ≥ 14 and ≥ 7 recordings were obtained during day- and nighttime.
Following 15 minutes supine rest, office measurements of central BP were obtained with the SphygmoCor device (Atcor Medical, Sydney, Australia) by trained laboratory technicians according to guidelines.
Electrocardiographs (ECG) were recorded with Cardiosoft V6.51 (GE Healthcare, USA) and LVH defined according to Sokolow-Lyon, Cornell and/or Romhilt-Estes score by the investigating M.D. Heart rate variability (HRV) was measured after 15 minutes supine rest, during paced deep breathing to classify autonomic dysfunction. HRV was assessed by expiration/inspiration variation in heart rate. While resting in supine position, the patient was asked to breathe deeply at the rate of 6 breaths per minute for 1 minute, during which an electrocardiogram was recorded. Subsequently the means of the difference in highest and lowest heart rates (HR) during each breathing cycle were calculated. An abnormal value was < 11 beats per minute. Retinopathy status obtained from medical records, and assessed from retinal photographs, taken every 3–24 months, were classified as normal if no retinopathy was present, and abnormal if presence of simple or proliferative retinopathy or blindness.
All participants had blood samples and phenotypic characteristics collected. HbA1c was measured by high-performance liquid chromatography (Variant; Biorad Laboratories, Germany), urinary albumin excretion rate (UAER) was measured in 24 h sterile urine collections by enzyme immunoassay, and plasma creatinine concentration by an enzymatic method (Hitachi 912, Roche Diagnostics, Germany).
Patients were stratified as normoalbuminuric if two out of three consecutive measurements contained normoalbuminuria with UAER < 30 mg/24 h, and micro- or macroalbuminuric if UAER was or previously recorded between 30–299 mg/24 h or above 300 mg/24 h, in two out of three consecutive measurements, respectively. Estimated GFR (eGFR) was calculated by the four variable Modification of Diet in Renal Disease (MDRD) formula. Based on standardized questionnaires, current daily use of ≥ 1 cigarettes/cigars/pipes classified smokers. Previous of CVD was myocardial infarction, stroke, or peripheral arterial disease based on standardized WHO questionnaires and patient records from Steno Diabetes Center.
Normally distributed variables are given as mean ± SD. The non-normally distributed variable (UAER) is given as median (range) and log10 transformed before analysis. Comparisons between groups were performed by unpaired Student's t-test or analysis of variance (ANOVA).
Univariate and mulitivariate linear regression compared hemodynamic variables with covariates. Analysis of covariance (ANCOVA) was applied for multivariable adjustment when comparing hemodynamic variables in different groups and in patients with or without complications. Adjustments were made for gender, age, 24 h-MAP, 24 h-HR, eGFR, HbA1c, smoking and antihypertensive treatment. In comparisons including controls HbA1c and antihypertensive treatment was left out.
The multivariate logistic regression between hemodynamic variables and diabetic complications also included UAER and office CASP, CPP or SBP. Although for LVH the analyses were only adjusted for gender, age and 24 h-MAP.
A two-tailed p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows, version 20.0 (SPSS, Chicago, IL).
Methods
Study Population
Between September 2009 and June 2011, Caucasian patients with TIDM, were recruited to enter a cross-sectional study at Steno Diabetes Center, Copenhagen, Denmark. Recruitment was in sequential order according to date of birth from a list of all patients attending the outpatient clinic. For power calculations we used an α-value of 5%, a β-value of 20%, and an estimated variance of 9.5 mmHg. For the comparison between controls and patients we estimated a 24 h-CASP-difference of 4 mmHg between groups, which implied that we needed a minimum of 45 participants in each group. For the comparisons between patient groups (3 albuminuria groups), we estimated a 24 h-CASP-difference of 2 mmHg, indicating a need for 177 patients in each group. Thus, we intended to include at least 45 controls and 576 patients. Of 1285 patients invited, 676 (52.6%) agreed to enter the study. Patients declining participation were younger but with similar gender distribution compared to participating patients (49 ± 16 years and 57% males vs. 54 ± 13 years and 56% males (p < 0.001 and 0.62). In addition, a control group of 51 non-diabetic subjects from Copenhagen, Denmark and 46 non-diabetic subjects from Leichester, UK were included.
In total, 654 (96.7%) patients and 90 (92.9%) controls had adequate ambulatory AMBP available, with 46 ± 7 and 18 ± 3 (63.9% and 75.0% of total possible) recordings during day and night, respectively. Four controls and 25 patients with normoalbuminuria and short diabetes duration received AHT and were excluded in order to create two comparable groups not treated for hypertension. The remaining groups of patients had no restriction regarding AHT (Table 1). Hence, the analysed cohort included 715 subjects, comprising of 86 non-diabetic persons (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) and not receiving AHT (SN), 211 patients with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 patients with microalbuminuria (30–299 mg/24 h) (Mi), and 186 patients with macroalbuminuria (> 300 mg/24 h) (Ma). Figure 1 summarise the inclusion and exclusion of the study participants. The 10 year cut-off for defining patients as having short vs. long duration of diabetes was chosen, as complications to diabetes may develop within 5–10 years. The five groups were stratified in order to create groups for comparison of 1) healthy controls to patients without complications, 2) healthy controls to patients with sustained normal kidney function, and 3) patients with increasing degree of impaired kidney function.
(Enlarge Image)
Figure 1.
Flow chart of the cohort.
Patients with ESRD, defined as receiving dialysis or renal transplantation, or GFR/eGFR < 15 ml/min/1.73 m were not included.
The study conformed to the Declaration of Helsinki, was approved by the Danish National Committee on Biomedical Research Ethics (2009–056), and all participants gave written informed consent.
Clinical and Laboratory Methods
Participant attended one single study visit, during which all clinical and laboratory measurements were performed. For office BP, 15 minutes supine rest was followed by recording and averaging of three separate left brachial measurements (A&D Medical, UA787).
AMBP were recorded non-invasively, using a validated system consisting of a radial arterial tonometer embedded in an articulating strap of a wrist-watch device (BPro™, HealthStats Singapore). The device was calibrated to brachial BP and variations in pulse waveform height over the subsequent measurement period used to calculate brachial AMBP. Calibrated radial waveforms were then processed at the end of each measurement session by applying an N-point-moving average to derive CASP. The device reported CASP, CPP, SBP, diastolic BP (DBP), MAP and heart rate (HR) every 15 minutes during 24 h. Previous validation studies have shown the BPro device to obtain BP measurements independently of arm positioning, with values comparable to those obtained with cuff-based devices. Furthermore, we have shown that CASP measurements obtained by the BPro are comparable to those obtained by accepted gold standard devices for non-invasive measurements of CASP. AMBP data was considered adequate if ≥ 14 and ≥ 7 recordings were obtained during day- and nighttime.
Following 15 minutes supine rest, office measurements of central BP were obtained with the SphygmoCor device (Atcor Medical, Sydney, Australia) by trained laboratory technicians according to guidelines.
Electrocardiographs (ECG) were recorded with Cardiosoft V6.51 (GE Healthcare, USA) and LVH defined according to Sokolow-Lyon, Cornell and/or Romhilt-Estes score by the investigating M.D. Heart rate variability (HRV) was measured after 15 minutes supine rest, during paced deep breathing to classify autonomic dysfunction. HRV was assessed by expiration/inspiration variation in heart rate. While resting in supine position, the patient was asked to breathe deeply at the rate of 6 breaths per minute for 1 minute, during which an electrocardiogram was recorded. Subsequently the means of the difference in highest and lowest heart rates (HR) during each breathing cycle were calculated. An abnormal value was < 11 beats per minute. Retinopathy status obtained from medical records, and assessed from retinal photographs, taken every 3–24 months, were classified as normal if no retinopathy was present, and abnormal if presence of simple or proliferative retinopathy or blindness.
All participants had blood samples and phenotypic characteristics collected. HbA1c was measured by high-performance liquid chromatography (Variant; Biorad Laboratories, Germany), urinary albumin excretion rate (UAER) was measured in 24 h sterile urine collections by enzyme immunoassay, and plasma creatinine concentration by an enzymatic method (Hitachi 912, Roche Diagnostics, Germany).
Patients were stratified as normoalbuminuric if two out of three consecutive measurements contained normoalbuminuria with UAER < 30 mg/24 h, and micro- or macroalbuminuric if UAER was or previously recorded between 30–299 mg/24 h or above 300 mg/24 h, in two out of three consecutive measurements, respectively. Estimated GFR (eGFR) was calculated by the four variable Modification of Diet in Renal Disease (MDRD) formula. Based on standardized questionnaires, current daily use of ≥ 1 cigarettes/cigars/pipes classified smokers. Previous of CVD was myocardial infarction, stroke, or peripheral arterial disease based on standardized WHO questionnaires and patient records from Steno Diabetes Center.
Statistical Analysis
Normally distributed variables are given as mean ± SD. The non-normally distributed variable (UAER) is given as median (range) and log10 transformed before analysis. Comparisons between groups were performed by unpaired Student's t-test or analysis of variance (ANOVA).
Univariate and mulitivariate linear regression compared hemodynamic variables with covariates. Analysis of covariance (ANCOVA) was applied for multivariable adjustment when comparing hemodynamic variables in different groups and in patients with or without complications. Adjustments were made for gender, age, 24 h-MAP, 24 h-HR, eGFR, HbA1c, smoking and antihypertensive treatment. In comparisons including controls HbA1c and antihypertensive treatment was left out.
The multivariate logistic regression between hemodynamic variables and diabetic complications also included UAER and office CASP, CPP or SBP. Although for LVH the analyses were only adjusted for gender, age and 24 h-MAP.
A two-tailed p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows, version 20.0 (SPSS, Chicago, IL).
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