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Background: Glucose data from intermittently scanned continuous glucose monitoring (isCGM) is a combination of scanned and imported glucose values. The present knowledge of glycemic metrics originate mostly from glucose data from real-time CGM sampled every five minutes with a lack of information derived from isCGM. Methods: Glucose data obtained with isCGM and hemoglobin A1c (HbA1c) were obtained from 169 patients with type 1 diabetes. Sixty-one patients had two observations with an interval of more than three months. Results: The best regression line of HbA1c against mean glucose was observed from 60 days prior to HbA1c measurement as compared to 14, 30, and 90 days. The difference between HbA1c and estimated HbA1c (=glucose management indicator [GMI]) first observed correlated with the second observation (R2 0.61, P < .001). Time in range (TIR, glucose between 3.9 and 10 mmol/L) was significantly related to GMI (R2 0.87, P < .001). A TIR of 70% corresponded to a GMI of 6.8% (95% confidence interval, 6.3-7.4). The fraction of patients with the optimal combination of TIR >70% and time below range (TBR) 4% was four times higher for those with high glycemic variability (coefficient of variation [CV] >36%) than for those with lower CV. Conclusion: The individual difference between HbA1c and GMI was reproducible. High glycemic variability was related to increased TBR. A combination of TIR and TBR is suggested as a new composite quality indicator.

PURPOSE: Risk of cardiovascular disease (CVD) is increased in Graves' disease (GD). CVD is predicted by increased pulse wave velocity (PWV) and blood pressure (BP). GD and these risk factors are all associated with lower levels of vitamin D. We aimed to assess the effect of supplemental vitamin D on PWV and BP in GD.METHODS: In a double-blinded trial, newly diagnosed GD patients were randomized to vitamin D3 70 µg/day (n = 44) or placebo (n = 42) as add-on to anti-thyroid medication. At baseline, 3 and 9 months PWV, BP and wave analysis were performed in office and 24 h setting. Between-group differences in change at 9 months were analyzed using linear mixed modelling. In subanalysis, effect of intervention in regard to baseline vitamin D insufficiency (25(OH)D RESULTS: PWV was unaffected by intervention in main analysis. However in the subanalysis, comparing the response to intervention in the vitamin D insufficient (n = 28) and the vitamin D replete patients, supplemental vitamin D induced a significant decrease in office PWV of 1.2 (95% CI: -2.3; -0.1) m/s compared to placebo. Of notice, baseline PWV was non-significantly higher among the vitamin D insufficient as compared to the replete participants. In response to vitamin D, office central systolic BP (-3.9 (95% CI: -7.5; -0.3) and brachial mean BP (-3.3 (95% CI: -6.5; -0.3) declined whereas 24 h measurements were unaffected.CONCLUSIONS: High-dose vitamin D supplementation did not affect PWV. We observed significant reduction in office but not 24 h BP. Subanalysis showed a clinically relevant PWV reduction among vitamin D insufficient participants, although regression towards the mean might contribute to findings. Further studies on supplemental vitamin D in GD should focus on patients with vitamin D insufficiency.

Background: Reduced muscle strength is an acknowledged symptom of Graves' disease, but the knowledge on severity is sparse. This study aimed to investigate muscle strength, balance, and muscle function in patients with Graves' disease compared to age-and sex-matched healthy controls. Methods: Using a cross-sectional design, 55 patients newly diagnosed with Graves' disease were compared to 55 euthyroid controls, matched on sex, age, and menopausal status. Isometric muscle strength (N) and maximum force production (N/s) were measured across different muscles groups using a dynamometer chair and postural stability (balance) in different positions using a stadiometer. Muscle function was assessed using the Timed-Up-and-Go test and the Repeated Chair Stand test. Results: Patients and controls were well matched. Handgrip maximum muscle strength as well as strength at elbow and knee flexion and extension were significantly impaired in patients compared to controls. Maximum force production was only significantly reduced at elbow flexion. Patients performed the Timed-Up-and-Go and the Repeated Chair Stand test significantly slower than controls, and postural stability was significantly reduced in patients compared to controls in all positions. Free triiodothyronine correlated with reduced muscle strength and postural stability. Conclusions: At the time of diagnosis, Graves' disease is associated with impaired maximum muscle strength, performance, and balance, whereas maximum force production is overall comparable to euthyroid controls.

OBJECTIVE: Aortic pulse pressure (PP) represents the hemodynamic cardiac and cerebral burden more directly than cuff PP. The objective of this study was to investigate whether invasively measured aortic PP confers additional prognostic value beyond cuff PP for cardiovascular events and death. With increasing age, cuff PP progressively underestimates aortic PP. Whether the prognostic association between cuff PP and outcomes is age-dependent remains to be elucidated.METHODS: Cuff PP and invasively measured aortic PP were recorded in 21 908 patients (mean age 63 years, 58% men, 14% with diabetes) with stable angina pectoris undergoing elective coronary angiography during January 2001--December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination was assessed using Harrell's C-index.RESULTS: During a median follow-up period of 3.7 years (range 0.1-10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both cuff and aortic PP were associated with stroke, myocardial infarction, and death in crude analyses. However, only cuff PP remained associated with stroke (hazard ratio per 10 mmHg, 1.06 (95% confidence interval (CI) 1.01--1.12)] and myocardial infarction [hazard ratio per 10 mmHg 1.05 (95% CI 1.01--1.11)] in multivariate Cox models. Both cuff and aortic PP lost significance as predictors of death in multivariate models. Age did not modify the prognostic association between cuff PP and stroke, myocardial infarction, and death.CONCLUSION: Invasively measured aortic PP did not add prognostic information about cardiovascular outcomes and death beyond cuff PP in patients with stable angina pectoris.

Aims We assessed adherence and long‐term effects on HbA1c of unrestricted access to flash glucose monitoring (FGM) in a single diabetes centre. Methods In this observational study, we reviewed data files for all 411 patients with type 1 diabetes attending our clinic during a 2‐year period. Adherence was reported in those who initiated FGM in our clinic (n = 321). Baseline and final HbA1c were noted for patients who continued FGM for more than 6 months without clinical conditions or interventions at baseline that could interfere with the effect of FGM on glycaemic control (n = 270). Results After 2 years, the fraction of patients using FGM increased from 3% to 72%. Adherence to FGM was 88%. Baseline and final HbA1c was median (interquartile range) 63 mmol/mol (56, 74) (7.9% (7.3, 8.9)) and 59 mmol/mol (53, 68) (7.6% (7.0, 8.4)), respectively. The estimated difference final‐baseline HbA1c was −4 mmol/mol (95% CI −5, −3) (−0.4% (−0.5, −0.3)) (P, This observational study of unlimited access to flash glucose monitoring demonstrates good adherence and a clinically significant long‐term improvement for all patients who are in nonoptimal glycaemic control.

Background Vitamin D deficiency has been proposed a role in development and course of Graves' disease (GD). Muscle weakness and quality of life (QoL) impairments are shared features of GD and vitamin D deficiency. We aimed to investigate whether vitamin D supplementation would improve restoration of muscle performance and thyroid-related QoL in GD and to describe the effect of anti-thyroid medication (ATD) on these outcomes. Methods. In a double-blinded clinical trial, hyperthyroid patients with a first time diagnosis of GD were randomized to vitamin D 70 mcg (2800 IU)/day or matching placebo as add-on to standard ATD. At baseline and after three and nine months of intervention, we assessed isometric muscle strength, muscle function tests, postural stability, body composition, and QoL-impairment using ThyPRO. Linear mixed modelling was used to analyze between-group differences in change and the effects of ATD. (The DAGMAR study clinicaltrials.gov ID NCT02384668). Results. Nine months of vitamin D supplementation caused an attenuation of muscle strength increment in all muscle groups investigated, significant at knee extension 60° where the increase was 24% smaller (p=0.04) in the vitamin D group compared with placebo. Compared to placebo, vitamin D supplementation tended to reduce gain of lean body mass (-24%, p=0.08). Vitamin D supplementation significantly impeded alleviation of Composite QoL and the same tendency was observed for the Overall QoL-Impact and Impaired Daily Life scales. In response to ATD, all measures improved significantly. The increase in muscle strength ranged from 25-40% (Pall < 0.001) and increment of lean body mass was 10% (p

OBJECTIVE: The aim of this study was to evaluate the usefulness of Microlife WatchBP Office and the effect of increasing the number of measurements in the clinical evaluation of systolic interarm difference (IAD).PATIENTS AND METHODS: Office blood pressure was measured simultaneously on both arms in 339 patients (85% diabetic) using the Microlife WatchBP Office, a fully automatic, oscillometric device. The patients included were all scheduled for ambulatory blood pressure measurement at the outpatient clinic of endocrinology at Silkeborg Regional Hospital, Denmark. Two successive sets of three individual measurements were made. A statistical analysis of variance was carried out on the measurements.RESULTS: In the first set of measurements, the mean IAD was -0.3 mmHg and the prevalence of IAD greater than or equal to 10 mmHg was 9.1%. Only 7.6% of the patients with an IAD less than 10 mmHg in the first set of measurements had an IAD greater than or equal to 10 mmHg in the second set of measurements. The 95% limits of agreement for the mean IAD for a single set of three measurements were ±13.16 mmHg. The probability of detecting an IAD more than 10 mmHg only increased slightly with an increasing number of measurements.CONCLUSION: A single set of triplicate measurements using Microlife WatchBP is an acceptable method for evaluating IAD as more measurements do little to improve the probability of detecting an IAD more than 10 mmHg because of high intraindividual variation.

Introduction and Objective: The excess cardiovascular morbidity and mortality in hyperthyroidism and Graves’ disease (GD) is inadequately understood. We aimed to elucidate whether well-established cardiovascular risk factors such as arterial stiffness in terms of pulse wave velocity (PWV) and blood pressure differ in GD and controls. Methods: This was a cross-sectional study comparing 55 hyperthyroid patients with newly diagnosed GD and 55 euthyroid, population-based controls matched for age, sex and menopausal status. PWV and blood pressure were measured in office (SphygmoCor Xcel) and 24-h ambulatory settings (Arteriograph). Differences between groups were assessed using adjusted linear regression analysis. Results: Compared to controls, GD patients showed higher PWV in the 24-h but not in the office setting with an adjusted 24-h PWV difference of 1.0 (95% CI: 0.6–1.5) m/s. PWV was higher in GD at both day and night, and nightly PWV dipping was lower (–5.5, 95% CI: –10.4 to –0.6%). Furthermore, central and brachial pulse pressure was significantly higher in both the office and 24-h setting, whereas nightly central pulse pressure dipping was significantly lower in GD (–5.4, 95% CI: –10.5 to –0.2%). Mean arterial pressure did not differ between the groups. Conclusions: Despite comparable blood pressure, GD is associated with a higher 24-h PWV that was not detected in the office setting. Pulse pressure was higher in GD, whereas mean arterial pressure did not differ between the groups. Longitudinal studies should pursue whether higher PWV might be a piece to the puzzle of understanding the increased risk of cardiovascular disease in hyperthyroidism and GD.

OBJECTIVES: We studied cardiac autonomic changes in relation to metabolic factors, body composition and 24-hour ambulatory blood pressure measurements in Turner syndrome patients without known hypertension.DESIGN: Cross sectional.PATIENTS: Participants were 48 TS women and 24 healthy female controls aged over 18 years.METHODS: Short-term power spectral analysis was obtained in supine-standing-supine position. Bedside tests included three conventional cardiovascular reflex tests of heart rate response to standing up, heart rate response to deep breathing and blood pressure response to standing up. Mean heart rate during the last 2 minutes of work was used to calculate the maximal aerobic power (VO2max ).RESULTS: We found a significantly higher mean reciprocal of the heart rate per second (RR) in TS. Testing for interaction between position and status (TS or control), there were highly significant differences between TS and controls in high-frequency (HF) power, the coefficient of component variation (square root of HF power/mean RR) and low-frequency (LF): HF ratio, with a dampened decline in vagal activity among TS during standing. Bedside test showed TS had a significantly higher diastolic BP in the supine position compared to controls, and the adaptive rise in BP, when changing to upright position was reduced. VO2max and self-reported level of physical activity were significantly correlated to systolic ambulatory blood pressure both 24-hour and night diastolic ambulatory blood pressure.CONCLUSION: Vagal tone and modulation of the sympathovagal balance during alteration in body position are impaired in TS. These changes can be risk factors for cardiovascular disease.

BACKGROUND The pathophysiological perturbations underlying the unfavorable cardiovascular prognosis in women with type 2 diabetes (T2DM) remain elusive. Low subendocardial viability ratio (SEVR), an index of myocardial oxygen supply and demand, has been associated with intermediate cardiovascular risk markers and cardiovascular mortality in various populations. However, whether SEVR is associated with sex and cardiovascular risk markers in patients with T2DM remains to be clarified. METHODS We examined 86 T2DM patients (mean age 59±10 years, 47% women, median diabetes duration 1.9 (range 0.2-5.0) years) and 86 sex- and age-matched control subjects in a cross-sectional study. SEVR was noninvasively assessed by tonometry and markers of cardiovascular risk by carotid-femoral pulse wave velocity (PWV), homeostasis model assessment of insulin resistance (HOMA2-IR), C-reactive protein, urinary albumin/creatinine ratio, and heart rate variability. RESULTS Women with diabetes had significantly lower SEVR compared to both men with diabetes (161% ± 26% vs. 178% ± 32%, P < 0.01), women without diabetes (185% ± 24%, P < 0.001), and men without diabetes (188% ± 28%, P < 0.001). The differences remained significant after adjustment for age, systolic blood pressure, heart rate, diabetes, and smoking. SEVR was associated with PWV, HOMA2-IR, C-reactive protein, and reduced heart rate variability in patients and control subjects, but the associations became nonsignificant after adjustment for heart rate. CONCLUSIONS SEVR is reduced in women with short duration of T2DM and associated with cardiovascular risk markers. The latter association seems to be at least partly mediated via heart rate. We hypothesize that reduced SEVR may contribute to the unfavorable cardiovascular prognosis in women with diabetes.

Background Microvascular impairment is well documented in hypertension. We investigated the effect of renal sympathetic denervation (RDN) on cardiac and peripheral microvasculature in patients with treatment-resistant essential hypertension (TRH). Methods A randomized, single centre, double-blinded, sham-controlled clinical trial. Fifty-eight patients with TRH (ambulatory systolic BP (ASBP) ≥ 145 mm Hg) despite stable treatment were randomized to RDN or SHAM. RDN was performed with the unipolar Medtronic Flex catheter. Coronary flow reserve (CFR) and coronary- and forearm minimum vascular resistance (C-Rmin and F-Rmin) were determined using transthoracic Doppler echocardiography and F-Rmin with venous occlusion plethysmography at baseline and at six-months follow-up. Results RDN was performed with 5.3 ± 0.2 lesions in the right renal artery and 5.4 ± 0.2 lesions in the left. Baseline ASBP was 152 ± 2 mm Hg (RDN, n = 29) and 154 ± 2 mm Hg (SHAM, n = 29). Similar reductions in MAP were seen at follow up (− 3.5 ± 2.0 vs. − 3.2 ± 1.8, P = 0.92). Baseline CFR was 2.9 ± 0.1 (RDN) and 2.4 ± 0.1 (SHAM), with no significant change at follow-up (0.2 ± 0.2 vs. − 0.1 ± 0.2, P = 0.57). C-Rmin was 1.9 ± 0.3 (RDN) and 2.7 ± 0.6 (SHAM) (mm Hg min/ml pr. 100 g) and did not change significantly (0.3 ± 0.5 vs. − 0.4 ± 0.8, P = 0.48). F-Rmin was 3.6 ± 0.2 (RDN) and 3.6 ± 0.3 (SHAM) (mm Hg min/ml pr. 100 ml tissue) and unchanged at follow-up (4.2 ± 0.4 vs. 3.8 ± 0.2, P = 0.17). Left ventricular mass index was unchanged following RDN (− 4 ± 7 (RDN) vs. 3 ± 5 (SHAM) (g/m2) P = 0.38). Conclusion The current study does not support positive effects of RDN on microvascular impairment in TRH.

AIMS: Insulin treatment in type 1 diabetes encompasses multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). Both population-based studies and comparative studies regarding CSII use are sparse. The aim of the current study was to describe the prevalence and distribution of CSII use among adults with type 1 diabetes in the Central Denmark Region and to compare metabolic control in CSII-treated patients to those treated with MDI.METHODS: A database was constructed using the Danish Adult Diabetes Registry in 2014/2015 in combination with an audit of the patients' medical records.RESULTS: 3909 adults with type 1 diabetes patients were included. The proportion of patients treated with CSII differed significantly between the 8 regional hospitals from 12.0 % to 31.1 %. CSII users had a significantly lower HbA1c compared to MDI treated patients (7.6 % (60 mmol/mol) versus 8.0 % (64 mmol/mol)) in unadjusted analyses. After adjustment for clinically relevant characteristics the difference between CSII and MDI-treated patients was attenuated, but remained statistically significant.CONCLUSION: The distribution of CSII differed markedly between hospitals and CSII users had better glycemic control, even after adjustment for sex, age, BMI, diabetes duration, smoking, use of lipid-lowering and blood pressure-lowering medication.

OBJECTIVES: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension.METHODS: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity Flex(TM) catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor(®)-device.RESULTS: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. -0.6 ± 1.3 (RDN) m/s), systolic C-BP (-2 ± 17 (SHAM) vs. -8 ± 16 (RDN) mmHg), diastolic C-BP (-2 ± 9 (SHAM) vs. -5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN.CONCLUSIONS: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

Several studies in different populations have suggested that nighttime blood pressure (BP) is a stronger predictor of cardiovascular events than daytime BP. Consequently, treatment strategies to target nighttime BP have come into focus. The aim of the present study was to investigate the effect of change of administration time of antihypertensive drugs. We included 41 patients with type 2 diabetes mellitus and nocturnal hypertension (nighttime systolic BP >120 mm Hg) in an open-label, crossover study. Patients were randomized to 8 weeks of either morning or bedtime administration of all of the individual’s once-daily antihypertensive drugs, followed by 8 weeks of switched dosing regimen. Bedtime administration of antihypertensive drugs resulted in a significant reduction in nighttime (7.5 mm Hg; P P =0.014) systolic BP, with a nonsignificant reduction in daytime (1.3 mm Hg; P =0.336) systolic BP. We did not find morning BP surge to be different between dosing regimens. Levels of C-reactive protein were significantly lower with bedtime administration, which may indicate an effect on low-grade inflammation. We found no difference in urinary albumin excretion, regardless of albuminuria status. Urinary sodium/creatinine was significantly increased and urinary osmolality significantly reduced with bedtime administration, which can be interpreted as increased nocturnal natriuresis. In patients with type 2 diabetes mellitus and nocturnal hypertension, administration of once-daily antihypertensive drugs at bedtime may be favorable. The increased nocturnal natriuresis may reflect increased effect of bedtime-administered thiazides and renin–angiotensin system inhibitors, suggesting a potential mechanism of the observed effects on BP with chronotherapeutic intervention.

BACKGROUND Central blood pressure (BP) has attracted increasing interest because of a potential superiority over brachial BP in predicting cardiovascular morbidity and mortality. Several devices estimating central BP noninvasively are now available. The aim of our study was to determine the validity of the Arteriograph, a brachial cuff-based, oscillometric device, in patients with type 2 diabetes. METHODS We measured central BP invasively and compared it with the Arteriograph-estimated values in 22 type 2 diabetic patients referred to elective coronary angiography. RESULTS The difference (invasively measured BP minus Arteriograph-estimated BP) in central systolic BP (SBP) was 4.4±8.7 mm Hg (P = 0.03). The limits of agreement were ±17.1 mm Hg. CONCLUSIONS Compared with invasively measured central SBP, we found a systematic underestimation by the Arteriograph. However, the limits of agreement were similar to the previous Arteriograph validation study and to the invasive validation studies of other brachial cuff-based, oscillometric devices. A limitation in our study was the large number of patients (n = 14 of 36) in which the Arteriograph was unable to analyze the pressure curves. In a research setting, the Arteriograph seems applicable in patients with type 2 diabetes. CLINICAL TRAIL REGISTRATION ClinicalTrials.gov ID NCT01538290.

Aims. Patients with type 2 diabetes have increased arterial stiffness and a high incidence of cardiovascular disease compared with non-diabetics. Arterial stiffness and central waveforms can be assessed by carotid-femoral pulse wave velocity (PWV) and pulse wave analysis (PWA) using the SphygmoCor device. These methods can potentially improve cardiovascular risk stratification in the future. However, a prerequisite is acceptable reproducibility. The objective of this study was to assess the intra- and inter-observer reproducibility of PWV and PWA indices in patients with type 2 diabetes using the SphygmoCor device. Methods. Two trained observers (A and B) each undertook two PWA and two carotid-femoral PWV recordings in random order in 20 patients with type 2 diabetes under standardized conditions on the right side of the patients. Observer A also made double recordings on the left side. The mean of the two recordings was used for inter-observer comparison. Data were analyzed by Bland-Altman plots. Results. The mean intra-observer differences (± 2SD) on the right side for observer A and B, respectively, were 0.0 ± 2.8 mmHg and 0.3 ± 3.2 mmHg (aortic systolic blood pressue (BP)), 0.0 ± 1.2 mmHg and 0.1 ± 1.0 mmHg (aortic diastolic BP), - 1.1 ± 3.2% and 1.1 ± 9.6% (central augmentation index (Aix)), - 1.6 ± 6.6% and 0.1 ± 9.0% (Aix normalized to heart rate 75 beats/min (Aix@HR75)) and 0.1 ± 1.8 m/s and 0.0 ± 1.6 m/s (PWV). The mean inter-observer differences (± 2SD) were - 2.6 ± 13.0 mmHg (aortic systolic BP), - 2.1 ± 7.4 mmHg (aortic diastolic BP), - 0.8 ± 8.4% (Aix), - 1.5 ± 7.4% (Aix@HR75) and - 0.3 ± 1.6 m/s (PWV). Left-vs-right comparison showed comparable results (observer A). Conclusions. PWA and PWV assessed with the SphygmoCor device are characterized by good reproducibility in patients with type 2 diabetes.

OBJECTIVE Patients with type 2 diabetes have a high incidence of cardiovascular events including stroke. Increased arterial stiffness (AS) predicts cardiovascular events in the general population. Cerebral white matter lesions (WMLs) are associated with an increased risk of stroke. It is unknown whether AS in patients with type 2 diabetes is associated with WMLs. RESEARCH DESIGN AND METHODS We examined 89 patients recently diagnosed with type 2 diabetes ( RESULTS The diabetic population had excellent glycemic control (HbA1c, 6.5% [6.2–6.8]; median [interquartile range {IQR}]) and had, compared with the controls, lower office blood pressure (BP) (127 ± 12/79 ± 8 vs. 132 ± 14/84 ± 10 mmHg) and total cholesterol (4.3[3.9–4.7] vs. 5.6 [5.1–6.4]; mmol/L; median [IQR]), (P < 0.01 for all). Despite this, PWV was higher in the patients with diabetes compared with controls (9.3 ± 2.0 vs. 8.0 ± 1.6 m/s; P < 0.0001). PWV was associated with Breteler score (OR 1.36 [95% CI 1.17–1.58]; P < 0.001) and WML volume (OR 1.32 [95% CI 1.16–1.51]; P < 0.001) per 1 m/s increase in PWV. These associations remained significant when adjusted for age, sex, diabetes, 24-h mean arterial BP, BMI, heart rate, and use of antihypertensives and statins (Breteler score: OR 1.28 [95% CI 1.03–1.60]; P < 0.05 and WML volume: OR 1.30 [95% CI 1.06–1.58]; P < 0.05). CONCLUSIONS PWV was higher among patients with well-controlled type 2 diabetes compared with controls and was independently associated with WMLs. PWV may represent a clinically relevant parameter in the evaluation of cerebrovascular disease risk in type 2 diabetes.

BACKGROUND: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP.METHOD: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA).RESULTS: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [-6.2 ± 18.8 mmHg (RDN) vs. -6.0 ± 13.5 mmHg (SHAM)] and at 6 months [-6.1 ± 18.9 mmHg (RDN) vs. -4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)].RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial.CONCLUSION: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

Aortic systolic blood pressure (BP) represents the hemodynamic cardiac and cerebral burden more directly than office systolic BP. Whether invasively measured aortic systolic BP confers additional prognostic value beyond office BP remains debated. In this study, office systolic BP and invasively measured aortic systolic BP were recorded in 21 908 patients (mean age: 63 years; 58% men; 14% with diabetes mellitus) with stable angina pectoris undergoing elective coronary angiography during January 2001 to December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination and reclassification were assessed using Harrell’s C and the Continuous Net Reclassification Index. Data were analyzed with and without stratification by diabetes mellitus status. During a median follow-up period of 3.7 years (range: 0.1–10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both office and aortic systolic BP were associated with stroke in patients with diabetes mellitus (hazard ratio per 10 mm Hg, 1.18 [95% confidence interval, 1.07–1.30] and 1.14 [95% confidence interval, 1.05–1.24], respectively) and with myocardial infarction in patients without diabetes mellitus (hazard ratio, 1.07 [95% confidence interval, 1.02–1.12] and 1.05 [95% confidence interval, 1.01–1.10], respectively). In models including both BP measurements, aortic BP lost statistical significance and aortic BP did not confer improvement in either C-statistics or net reclassification analysis. In conclusion, invasively measured aortic systolic BP does not add prognostic information about cardiovascular outcomes and all-cause mortality compared with office BP in patients with stable angina pectoris, either with or without diabetes mellitus.

Udgivelsesdato: 2009-Dec-24 OBJECTIVES: The ambulatory arterial stiffness index (AASI) has been proposed as a novel indirect measure of arterial stiffness. We compared the repeatability of AASI and pulse pressure (PP), another marker of arterial stiffness, both computed from repeat 24-h ambulatory blood pressure recordings in patients with type 1 diabetes mellitus. METHODS: Twenty-eight patients with type 1 diabetes mellitus and no previous or present treatment with antihypertensive drugs were recruited from outpatient clinics in Aarhus County and underwent two 24-h ambulatory blood pressure measurements, performed within 2 weeks in all participants except one. The repeatability of AASI and PP was assessed by (i) the Intraclass Correlation Coefficient (ICC) and (ii) the percentage of maximal variation, i.e. two times SD of the difference in the percentage of four times the SD of the mean of the paired measurements. RESULTS: The repeatability of AASI was considerably lower than for PP as estimated by ICC (0.38 vs. 0.90). The difference between ICCPP and ICCAASI was 0.51 confidence interval (0.25-0.82). Similarly, percentage of maximal variation was 68 and 23% respectively. CONCLUSION: AASI has a low repeatability compared with PP in type 1 diabetic patients. This questions the potential implementation of AASI in the daily clinic as a measure of arterial stiffness. Further studies are necessary to clarify this.

BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease.METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE).RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03).CONCLUSION: MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.

This article will discuss classification of early diabetic renal involvement or disease in diabetic patients, with the perspective of effective intervention, considering glycemic as well as nonglycemic treatment modalities

OBJECTIVE—To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes. RESEARCH DESIGN AND METHODS—This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35–74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure. RESULTS—Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups. CONCLUSIONS—There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is an efficacious treatment for patients diagnosed with obstructive sleep apnea (OSA). However, there are only few data on long-term adherence. The aim of this study is to quantify the extent of non-adherence and describe the clinical characteristics.METHODS: A retrospective study including 695 patients with newly diagnosed OSA and prescribed CPAP therapy within an inclusion period of 14 months. All patients were offered free of charge individually adjusted CPAP therapy. Data on comorbidity, medication, BMI and Epworth Sleepiness Score (ESS) were obtained by questionnaires and consultation with an otorhinolaryngeal specialist.RESULTS: The median follow-up time after initiating CPAP therapy was 3.0 (range 2.4-3.6) years. An adherence rate of 89% was found for severe OSA, 71% for moderate OSA and 55% for mild OSA. 18% initiated humidification. Patients adherent to CPAP had a significantly higher Body Mass Index (BMI), Apnea Hypopnea Index (AHI), Oxygen Desaturation Index (ODI) and ESS compared to non-adherent patients. Furthermore, adherence was associated with a higher frequency of observed interrupted breathing, a less frequent use of hypnotic drugs, fewer smokers, and they were more often offered humidification. Age, gender and comorbidity were not significantly associated with adherence. In a Cox model only AHI (Hazard Ratio (HR) 0.963, p < 0.001), ESS (HR 0.939, p = 0.001) and smoking (HR 1.576, p = 0.022) were independently associated with CPAP non-adherence.CONCLUSIONS: The severity of OSA, subjective daytime sleepiness and smoking status are independently related to adherence to CPAP therapy.

Background: Pulse wave analysis from a brachial cuff permits ambulatory measurements of pulse wave velocity (PWV) and central blood pressure parameters. The diurnal variation of PWV in type 2 diabetes is unknown. Methods: We evaluated the Arteriograph24 which is a brachial cuff based equipment for estimating PWV and central blood pressure data without the use of a transfer function, in 22 type 2 diabetic patients, who had two 24 h measurements performed. Results: The mean number of valid day time and nighttime measurements were 29 (range 16–50) and 18 (11–25), respectively. 21 patients had at least one qualifying report. Nighttime PWV was significantly lower than during the day (9.1 vs. 9.7 ± 0.8 mm/s, p < 0.01). Systolic aortic blood pressure was 6 mmHg lower than brachial blood pressure in the day time (p < 0.01) and 4 mmHg lower during the night (p < 0.05). Each single measurement was standardized with the 24 h average as reference thus generating data from 1004 paired observations. The standardized PWV correlated with standardized values of heart rate (r = 0.24, p < 0.001) and systolic aorta blood pressure (r = 0.20, p < 0.001). A stepwise multiple regression model with standardized pulse wave velocity as dependent variable included standardized heart rate, systolic aorta blood pressure and a dummy variable for day/night status (R2 = 0.091, p < 0.001). Conclusion:The Arteriograph24 is applicable for research purpose. PVW in type 2 diabetes is modestly reduced during the night. The intraindividual variation of heart rate contributed independently to the variation of PWV.

SUMMARY Aims To establish reference data for ambulatory blood pressure (AMBP) in normotensive, normoalbuminuric Type 1 diabetic patients and characterize the relation to clinic blood pressure (BP). To evaluate the statement of the third working party of the British Hypertension Society (BHS) that a target clinic BP in diabetes 75 mmHg. Conclusions Clinic BP and day-time AMBP measured by the same method were indistinguishable. The target for day-time diastolic AMBP (

Smoking is an important risk factor for the development and progression of diabetic nephropathy. The mechanisms by which smoking increases albuminuria and promotes nephropathy are unknown. Considering the acute pressor effect of smoking and the close association between blood pressure elevation and development of diabetic nephropathy, blood pressure increase might be implicated in the association between smoking and diabetic nephropathy. However, among nondiabetics, smokers have repeatedly been found to have lower blood pressure than nonsmokers. This is possibly mediated by an autonomic adjustment to sustained sympathetic stimulation by nicotine. Impaired modulation of the sympathovagal activity has been described in diabetes. In diabetic patients, the effect of smoking on blood pressure and autonomic function remains unclarified. We examined 24-h ambulatory blood pressure (oscillometric technique) and autonomic function (short-term power spectral analysis as well as conventional tests) in 24 smokers and 24 nonsmokers matched for sex, age, and diabetes duration. All patients were normoalbuminuric insulin-dependent diabetes mellitus patients. Smoking status was assessed by questionnaire with confirmatory determinations of urinary cotinine. Diabetic smokers had significantly higher 24-h mean arterial blood pressure (94 ± 6.7 mm Hg compared to diabetic nonsmokers 90 ± 5.8 mm Hg, P = .04) including higher diastolic nighttime blood pressure (68 ± 7.3 mm Hg v 64 ± 5.2 mm Hg, P = .03). Smokers also had significantly higher 24-h heart rate (80 ± 7.2 compared to 72 ± 9.2 beats/min, P 2 in smokers compared to 6.31 ± 1.11 ln ms 2 in nonsmokers, P v 42.1 ± 16.0 in nonsmokers, P

The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded. The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 microg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1c was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3-6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 +/- 8 mmHg [grade 3-6] and 65 +/- 6 mmHg [grade 2], compared to 61 +/- 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6% +/- 4 [grade 3-6], and 81.2% +/- 6 [grade 2] compared to 79.1% +/- 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3-6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA1c increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 x /divided by 1.7 [grade 1], 3.9 x /divided by 1.8 [grade 2], and 5.1 x /divided by 1.6 microg/min [grade 3-6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients.

BACKGROUND The SphygmoCor is used for noninvasive assessment of ascending aortic blood pressure (BP). However, the validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with substantial imprecision of central BP estimates. We hypothesized that different noninvasive calibration strategies might improve the accuracy of the estimated ascending aortic BPs. METHODS In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor device and compared these data with invasively recorded data. The validity of the transfer function was assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of noninvasive calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs. DBP+MBP using a form factor (ff) of 0.33 and 0.40, respectively. RESULTS When calibrating with invasive BP, the difference between estimated and invasively measured ascending aortic SBP and DBP was -2.3±5.6/1.0±0.9 mm Hg. When calibrating with oscillometric brachial BPs, the differences were -9.6±8.1/14.1±6.2 mm Hg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1 mm Hg (DBP and MBP; ff = 0.33), and 1.9±12.2/14.1±6.2 mm Hg (DBP and MBP; ff = 0.40), respectively. Calibration with the average of 3 brachial BPs did not improve accuracy. CONCLUSIONS The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Noninvasive calibration with DBP and MBP (ff = 0.40) enables accurate estimation of mean ascending aortic SBP at the group level. However, the wide limits of agreement indicate limited accuracy in the individual patient. CLINICAL TRIALS REGISTRATION Clinical Trials No. NCT01538290.

OBJECTIVE To assess the long-term relationships between 24-h ambulatory blood pressure (AMBP), urinary albumin excretion (UAE) rate, and metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with normo- and microalbuminuria. RESEARCH DESIGN AND METHODS We conducted a prospective study of 23 NIDDM patients (11 with normoalbuminuria and 12 with microalbuminuria) receiving standard clinical care, including antihypertensive treatment, attending the outpatient clinic and 8 healthy control subjects. Twenty-four-hour AMBP and UAE were measured synchronously in addition to fasting plasma glucose, HbA1c, and serum creatinine at baseline and after 4.6 (4.2−5.1) years [mean (range)]. RESULTS Baseline systolic, but not diastolic, 24-h AMBP was significantly higher in diabetic patients compared with control subjects (146/80 [16/11] vs. 133/78 [9/9] mmHg, P < 0.05), but was similar in normoalbuminuric (143/81 [11/11] mmHg) and microalbuminuric (148/80 [20/10] mmHg) patients during strict blood pressure control. The annual increase in 24-h AMBP was equivalent in diabetic patients (0.6/−0.2 [2.6/1.5] mmHg/year) and control subjects (0.7/0.2 [1.2/1.4] mmHg/year, NS) and not significantly different from zero. Overall UAE did not change in control subjects (5.6 [1.6] vs. 4.4 [1.9]) (geometric mean [antilog SD]) or in the normoalbuminuric (8.7 [1.7] vs. 11.3 [3.0] ¼g/min) and microalbuminuric (35.7 [2.1] vs. 34.5 [3.2] μg/min) patients. In diabetic patients, the annual change in UAE correlated significantly with the annual change in the systolic (r = 0.61, P < 0.002) and diastolic (r = 0.54, P < 0.008) 24-h AMBP. In microalbuminuric patients, only the annual increase in systolic 24-h AMBP correlated significantly with the annual change in UAE (r = 0.71, P = 0.010), whereas in the normoalbuminuric patients, only the annual increase in diastolic 24-h AMBP and the annual change in UAE were significantly correlated (r = 0.66, P = 0.026). In a stepwise multiple linear regression analysis, the annual progression in albuminuria in NIDDM patients was significantly determined by increases in systolic (parameter estimate 0.018, SE 0.006, P < 0.008) as well as in diastolic 24-h AMBP (parameter estimate 0.026, SE 0.011, P < 0.033). CONCLUSIONS In an outpatient clinical setting, 24-h AMBP is similar in NIDDM patients with normo- and microalbuminuria. Alterations in both 24-h AMBP and UAE are on average moderate and equivalent compared with those in healthy control subjects. Although the average change in albuminuria is small, a progression in albuminuria relates to increments in both systolic and diastolic 24-h AMBP.

Ambulatory blood pressure (AMBP) is of particular interest in diabetes because of the close association between elevated BP and diabetic nephropathy and the attenuated night drop in some diabetic subgroups: (1) Normoalbuminuric patients: If standardized for type of day (work or day off), coefficient of variation (CV) for 24 h AMBP is 2%–3% and 5%–6% for night/day ratio. The male-female difference in AMBP seen in healthy subjects is reduced in diabetes. Smoking did not significantly affect AMBP. AMBP is increased in patents with high normal urinary albumin excretion (UAE). Night/day ratio of AMBP and night heart rate is higher in long than short term diabetic patients. This difference in night/day ratio is not significant if the slightly higher UAE in long-term patients is accounted for. (2) Microalbuminuric patients: Diastolic night/day ratio is increased compared with healthy controls, with the value for normoalbuminuric patients in between. A large overlap between groups is evident. Thus the prognostic value of a single abnormal night/day ratio is doubtful. If divided into dippers and nondippers, no difference in extracellular- or plasma volume is found, but nondippers have a lower plasma aldosterone and arginine vasopressin level, possibly to counteract volume expansion. (3) Patients with overt nephropathy: A marked increased in AMBP and a clear reduction of the nocturnal blood pressure fall is seen. In conclusion, AMBP (but not night/day ratio) is highly reproducible. The association between elevated AMBP, elevated night/day ratio, and pathological UAE is detectable even in normoalbuminuric patients. The prognostic importance of abnormal circadian variation of BP is unsettled.

The influence on blood pressure, glucose metabolism, and lipid levels of an exchange of polyunsaturated fatty acids with monounsaturated fatty acids in the diet was compared in 16 Type 2 diabetic outpatients. In a cross-over study design the patients were randomly assigned to 3 weeks treatments with a diet containing 30% energy as monounsaturated fatty acids, or an isoenergetic diet with 30% energy as polyunsaturated fatty acids. The contents of total fat, saturated fatty acids, cholesterol, and fibre were similar in the two diets. On the last days of the two diet periods, 24-h ambulatory blood pressure was measured and the responses of glucose, hormones, and lipids to a carbohydrate rich test meal were measured. As compared with the polyunsaturated fatty acids diet, the monounsaturated fatty acids diet reduced 24-h systolic (129 +/- 11 vs 124 +/- 8 mmHg (mean +/- SD), p = 0.02) and diastolic blood pressure (76 +/- 11 vs 73 +/- 8 mmHg, p = 0.02). The two diets had similar, beneficial effects on glycaemic control, and cholesterol and lipoprotein concentrations. A diet rich in monounsaturated fatty acids has beneficial effects on the blood pressure, while similar effects on glucose and lipid levels are observed in normotensive Type 2 diabetic subjects.

OBJECTIVE Ambulatory blood pressure monitors are subject to extensive validation protocols, but no international guidelines on the software processing the collected raw data exist. Hence, there seems to be little or no control of ambulatory blood pressure monitoring (ABPM) software with respect to errors. In this paper, we wish to point out an important error in Spacelabs Report Management System 92506 software. METHODS By chance, we noticed discrepancies in the Spacelabs Report Management System 92506 hourly average tabular as shown on-screen and on printout. To exclude the possibility of a random error, 97 ABPM reports were evaluated. In a random patient, we calculated the hourly averages by the arithmetic mean from all measurements. Similarly, the summary average of 24 h, daytime and night-time blood pressure was calculated both by the arithmetic mean of all measurements and by the mean of hourly averages in the respective periods. RESULTS Evaluation of ABPM reports showed errors in 89 out of 97 (92%). In a random patient, the numerical difference between printout and on-screen hourly averages was considerable, ranging from -37 to 18 mmHg systolic and from -16 to 10 mmHg diastolic. Calculation on the basis of raw data established that on-screen hourly average tabular was correct, whereas printout values were erroneous. The erroneous values were also found in the exported hourly average tabular. CONCLUSION If researchers base calculations on the use of erroneous data from printout or exported hourly average tabular, the results and hence the conclusions may be wrong. Focus on ABPM software is warranted.

To describe the development in blood pressure (BP) in relation to urinary albumin excretion (UAE) more exactly, 44 initially normoalbuminuric type I diabetic patients and 21 healthy individuals were included in a 3.1-year follow-up study by using ambulatory BP (AMBP) monitoring. Six patients developed microalbuminuria according to accepted criteria (progressors; UAE at follow-up was >20 μg/min). Initial UAE was higher in this group (9.0 ×/÷ by 1.4 μg/min) compared with both the nonprogressors (5.2 ×/÷ by 1.6 μg/min) and the control subjects (3.9 ×/÷ by 1.6 μg/min), P < 0.01. The values were almost identical for initial 24-h AMBP between the progressors and the two other groups. The transition to microalbuminuria (31.7 ×/÷ by 1.8 μg/min) was associated with an increase in 24-h systolic AMBP of 11.5 ± 8.3 mmHg, which was significantly higher than the increase in the nonprogressors (3.1 ± 7.7 mmHg) and the control subjects (2.2 ± 6.1 mmHg, P = 0.02). Significant correlations were detected between development in UAE and development in systolic and diastolic 24-h AMBP (r = 0.39, r = 0.41, P < 0.01). In addition, an increase in UAE, even including increases within the normoalbuminuric range, was always associated with an increase in 24-h AMBP (P < 0.01). Ordinary clinical measurements did not reveal any of these differences or correlations. In conclusion, a close association between increases in UAE and 24-h AMBP emerges in this study. Initial BP was not increased in the progressors. microalbuminuria is associated with significant BP increases but only when AMBP monitoring is analyzed.

Cigarette smoking and diabetes are well known risk factors for cardiovascular disease. The relation of nocturnal blood pressure (BP) to cigarette smoking is unclarified. We examined ambulatory BP in 18 healthy smokers matched for sex and age to 18 non-smokers. Sixteen smoking type 1 diabetic patients matching 16 non-smoking patients with normal urinary albumin excretion were also investigated. None of the healthy subjects or diabetic patients had a clinic BP160/95 mmHg. Night BP (systolic/diastolic mmHg) in healthy smokers (mean +/- SD) 102 +/- 9/57 +/- 5 was lower than in healthy non-smokers 108 +/- 10/61 +/- 6 (p = 0.06/p0.05). The difference between smokers and non-smokers was most prominent in the 3 h period just before rising (99 +/- 9/57 +/- 6 versus 108 +/- 8/62 +/- 7, p0.01/p0.05). Daytime BP was similar between groups. The night/day ratio (%) of systolic (84 +/- 7) and diastolic (74 +/- 7) BP in healthy smokers was lower than in non-smokers (88 +/- 5 versus 80 +/- 5, p0.05 and p0.01) indicating an altered diurnal rhythm of blood pressure. No statistical significant difference was found for night or day BP in diabetic smokers versus non-smokers. The finding of a significantly lower BP in healthy (supine) smokers at night speaks against dysautonomia explaining the lower clinic BP found in epidemiological studies, as recently proposed. Alternatively a rebound effect or the existence of a substance with vasodilating properties in non-diabetic smokers is suggested.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease (CVD). We examined the predictive ability of 24-hour ambulatory pulse pressure (24-h PP), ambulatory arterial stiffness index (AASI) and diurnal blood pressure (BP) parameters for fatal and non-fatal CVD in patients with type 2 diabetes mellitus. A total of 108 patients with type 2 diabetes mellitus (mean duration 6.6 years) were followed for 9.5 (0.5–14.5) years. At baseline, all patients underwent ambulatory BP monitoring. During follow-up, 45 patients had cardiovascular (CV) events (35 non-fatal and 10 fatal). In bivariate analysis, events during follow-up were predicted by 24-h PP (P

Hermida et al. (1) have recently shown an impressive reduction of asleep blood pressure and associated reduction of cardiovascular disease (CVD) events in type 2 diabetic patients treated with at least one antihypertensive drug at bedtime compared with patients who ingested all drugs in the morning. This is a subgroup analysis of the diabetic patients (20%) enrolled in the MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares [Ambulatory Blood Pressure Monitoring for …

Objective. To test the hypothesis that normoal-buminuric type 1 diabetic patients segregate into groups with normal and elevated ambulatory blood pressure. To evaluate diurnal variation of blood pressure assessed by individual or fixed night-time periods. Design. Cross-sectional study. Setting. Tertiary referral centre. Subjects. Inclusion criteria for type 1 diabetic patients (n = 33): normal urinary albumin excretion (UAE age < 45 < 20 μg min−1), diabetes duration ≤ 20 years, age 45 years. Healthy controls (n = 33) were matched for sex and age. Main outcome measure. Twenty-four hour, day-time, night-time and night/day ratio of ambulatory blood pressure. Results. Twenty-four-hour blood pressure in diabetic patients did not differ significantly from a normal distribution. The 24-h systolic blood pressure was higher in diabetic patients than in healthy controls (difference: 6 mmHg, 95% confidence interval (CI) from 1 to 10 mmHg, P < 0.05), while no significant differences were found for diastolic values. The 24-h systolic blood pressure in diabetic patients with UAE above the median value (5.8 μg min−1) was higher than for those with lower UAE (difference: 7 mmHg, 95% CI from 0.5 to 13 mmHg, P < 0.05). The night/day ratio of diastolic blood pressure based on individual informations of the night period was (mean ± SD) 80 ± 6% in diabetic patients and 78 ± 8% in controls (difference: 2%, 95% CI from −1 to 5%, not significant [NS]). This ratio increase significantly (P < 0.00001) to 90 ± 5% in diabetes and to 84 ± 7% in controls if a fixed night period from 22.30 hours to 06.30 hours was assumed. Conclusions. It was not possible to identify a well-separated group of normoalbuminuric type 1 diabetic patients with elevated ambulatory blood pressure. Values of UAE above the median in diabetic patients are associated with higher ambulatory blood pressure. Assessment of the night/day variation from fixed time-points should be abandoned because this leads to a serious underestimation of the nocturnal reduction in blood pressure.

The renal effects of intravenous injection of 10 mg enalapril were investigated in 16 normotensive microalbuminuric type 1 (insulin-dependent) diabetic patients. After enalapril the following changes were observed: fractional albumin clearance (theta Alb) decreased from 9.9 (3.0-23.8) to 8.2 (2.0-18.3) x 10(-6) (2 P0.01); filtration fraction (FF) decreased from 0.260 (0.225-0.312) to 0.253 (0.190-0.297) (2 P0.01); renal plasma flow (RPF) increased from 565 (411-690) to 623 (449-785) (2 P0.01); and glomerular filtration rate (GFR) remained stable at 149 (128-181) versus 150 (124-185) ml.min-1 (NS). These values were unchanged after placebo (n = 8), except for RFP which decreased from 606 (401-701) to 559 (381-677) ml.min-1 (2 P0.05) and GFR which was reduced from 148 (111-173) to 138 (111-167) (2 P0.05). A reduction in mean blood pressure from 94 (87-103) to 89 (79-101) mmHg (2 P0.05) was found in the enalapril group and a minor reduction in the placebo group from 97 (83-106) to 96 (81-104) mmHg (2 P0.05) was also noted. The relative changes in systolic blood pressure in the enalapril group correlated with changes in theta Alb (Spearman's r = 0.66, 2 P0.02) and FF (r = 0.53, 2 P0.05). Acute inhibition of angiotensin converting enzyme does not reduce the pathological hyperfiltration in these patients and a reduction in theta Alb and FF can not be dissociated from the reduction in blood pressure.

Recent reports have suggested that impaired renal function in type 1 diabetic patients may be present despite normal urinary albumin excretion (UAE). We have studied kidney function by means of a constant‐infusion technique in normoalbuminuric type 1 diabetic patients without antihypertensive medication (UAE < 20 μg min−1, n = 134), in microalbuminuric patients (20 ≥ UAE < 200 μg min−1, n = 50) and in 27 non‐diabetic control subjects. Mean UAE was 4.5 μg min−1 (range 1.0–19.3 μg min−1) in normoalbuminuric patients, 53.1 μg min−1 (range 20.8–147.5 μg min−1) in microalbuminuric patients, and 4.0 μg min−1 (range 2.1–17.9 μg min−1) in controls. Glycosylated haemoglobin A1c was significantly higher in microalbuminuric patients (8.9%, range 5.9–12.6%) than in normoalbuminuric patients (7.9%, range 5.5–11.5%) (P < 0.0001). Glomerular filtration rate in normoalbuminuric patients (135 ml min−1, range 97–198 ml min−1) was significantly higher than in controls (118 ml min−1, range 94–139 ml min−1) (P < 1 times 10−6), and significantly lower than in microalbuminuric patients (142 ml min−1, range 100–186 ml min−1) (P < 0.05). Mean arterial blood pressure was lower in normoalbuminuric patients (91 mmHg, range 78–108 mmHg) than in microalbuminuric patients (98 mmHg, range 82–131 mmHg) (P < 1 times 10−6), but not significantly different from that of controls (89 mmHg, range 73–103 mmHg). We conclude that normal UAE is a reliable indicator of well‐preserved renal function. Glomerular hyperfiltration, elevated blood pressure and poor metabolic control are characteristic features of microalbuminuric patients. 1992 Blackwell Publishing Ltd

Ambulatory blood pressure in microalbuminuric type 1 diabetic patients. Twenty-four-hour ambulatory blood pressure (AMBP) was performed in microalbuminuric (micro.) type 1 diabetic patients, with the aim of comparison with a matched group of normoalbuminuric patients (normo.) and healthy controls. Thirty-four patients without antihypertensive medication were investigated in each group. Urinary albumin excretion (UAE) for micro, was (geometric mean, tolerance factor µg/min) 51.7 x/÷ 1.94, 5.1 x/÷ 1.88 for normo. and 5.2 x/÷ 1.75 for controls. Twenty-four-hour AMBP (mean systolic/diastolic mm Hg ± SD) was significantly higher in micro. (131 ± 10/78 ± 7) than in normo. (122 ± 8/73 ± 6; P < 0.001/P < 0.01). No 24-hour AMBP difference between normo. and controls (120 ± 9/71 ± 7) was found. No difference in the night/day ratio of blood pressure was found between the diabetic groups. Coefficient of variation for day time systolic measurements did not show any intergroup difference. Systolic day time blood pressure for the pooled diabetic group correlated significantly with UAE (r = 0.45, P < 0.001), whereas no significant correlation with auscultatory systolic values in the clinic was found (r = 0.21; 1 = 0.09). In conclusion, blood pressure in micro, as compared to normo. is not more labile but is elevated day and night without significant alteration of the diurnal rhythm. AMBP reflects the association between UAE and blood pressure more precisely than clinical measurements and may be preferable for identifying candidates for antihypertensive treatment.

Udgivelsesdato: 2009-May BackgroundAmbulatory arterial stiffness index (AASI) has been proposed as an indirect measure of arterial stiffness. The aims of this study were (i) to analyze AASI and pulse pressure (PP) in micro- and normoalbuminuric type 1 diabetes mellitus (T1DM) patients and healthy controls and (ii) to explore the relation between nocturnal blood pressure (BP) reduction, BP variability, and AASI.MethodsAmbulatory BP monitoring was performed in 34 micro- and 34 normoalbuminuric T1DM patients matched for gender, age, and diabetes duration and in 34 nondiabetic controls matched for gender and age. AASI and PP were calculated based on 24-h, day, and night BP recordings.ResultsAASI increased from the control group (0.30 +/- 0.14) to the normo- (0.35 +/- 0.15) and microalbuminuric group (0.41 +/- 0.19; P < 0.05). After adjustment for nightly systolic BP reduction and systolic daytime BP variability (s.d.) in multivariate analysis, the association weakened and became nonsignificant (P = 0.078). No significant intergroup differences were found when AASI was calculated separately from day and night BP data. There was no significant difference between day and night AASI. The 24-h PP increased from the control group (48 +/- 7 mm Hg) to the normo- (50 +/- 6 mm Hg) and microalbuminuric group (54 +/- 9 mm Hg; P < 0.01). The association remained in the multivariate analysis. Day and night PPs were higher in microalbuminuric patients compared to healthy controls.ConclusionsAASI and PP are higher in microalbuminuric T1DM patients compared to healthy controls. The nocturnal BP reduction and systolic daytime BP variability are determinants of AASI. We propose these associations to reflect biological characteristics of arterial stiffness.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.27American Journal of Hypertension 2009; doi:10.1038/ajh.2009.27.

BACKGROUND: Elevated pulse pressure (PP) is strongly associated with micro- and macrovascular complications in type 2 diabetic patients. We examined the effect of 12 months of dual blockade with candesartan and lisinopril vs. high-dose lisinopril monotherapy on ambulatory PP in hypertensive type 2 diabetic patients from the CALM (Candesartan and Lisinopril Microalbuminuria Trial) II study.METHODS: The CALM II study was a 12-month prospective, randomized, parallel-group, double-masked study that included 75 type 1 and type 2 diabetic subjects with hypertension. Participants were randomized for treatment with either high-dose lisinopril (40 mg once daily (o.d.)) or for dual blockade treatment with candesartan (16 mg o.d.) and lisinopril (20 mg o.d.). In this article, we present data from the post-hoc subgroup of 51 type 2 diabetic subjects who completed the full 12-month study period with successful ambulatory blood pressure (BP) measurements at both baseline and follow-up visits.RESULTS: Baseline 24-h BP values were similar in the two groups (24-h systolic BP (SBP) 130 +/- 12 vs. 127 +/- 9, 24-h diastolic BP (DBP) 77 +/- 8 vs. 74 +/- 7, and 24-h PP 53 +/- 8 vs. 53 +/- 7 mm Hg, for the lisinopril and dual blockade groups, respectively, P > 0.2 for all). Compared with lisinopril monotherapy, dual blockade treatment caused a highly significant reduction in 24-h PP levels (-5 +/- 5 mm Hg, P = 0.003), albeit the difference in the BP lowering effect between the treatment groups did not differ significantly for 24-h systolic (P = 0.21) or diastolic (P = 0.49) BP. Dual blockade treatment significantly lowered 24-h SBP (-5 +/- 11 mm Hg, P = 0.03), but not 24-h DBP (-2 +/- 7 mm Hg, P = 0.29), whereas in the lisinopril group, the opposite effect was observed (24-h SBP -1 +/- 9 mm Hg, P = 0.45, 24-h SBP -3 +/- 7 mm Hg, P = 0.03).CONCLUSIONS: Twelve months of dual blockade with candesartan and lisinopril significantly reduced PP when compared with high-dose monotherapy with lisinopril. Larger studies are needed to confirm this observation, and to evaluate whether this effect translates into a greater degree of end-organ protection from dual blockade treatment than from conventional angiotensin-converting enzyme (ACE) inhibition.

Decreased left ventricular long-axis function may be the earliest stage in subclinical heart failure in Type II diabetes. To assess whether a decrease in SBP (systolic blood pressure) or a change in metabolic control would improve the long-axis function, 48 Type II diabetic patients participating in the CALM II (Candesartan and Lisinopril Microalbuminuria II) study were included in the present study. Patients were examined with tissue Doppler echocardiography at baseline and after 3 and 12 months of follow-up. Corresponding blood pressure, fructosamine and HbA1c (glycated haemoglobin) values were obtained. During the follow-up period, a decrease in SBP of 8 mmHg was seen (from 141±11 mmHg at baseline to 133±12 mmHg; P

AIMS: To characterize left ventricular function in hypertensive patients with Type 2 diabetes and normal ejection fraction, and to relate these findings to pathogenic factors and clinical risk markers.METHODS: We examined 70 hypertensive patients with Type 2 diabetes mellitus with ejection fraction > 0.55 and fractional shortening > 0.25, all without any cardiac symptoms. Thirty-five non-diabetic subjects served as control subjects. Left ventricular longitudinal function was examined by tissue Doppler derived myocardial strain rate and peak systolic velocities.RESULTS: Hypertensive patients with diabetes had a significantly higher systolic strain rate (-1.1 +/- 0.3 s(-1) vs. -1.6 +/- 0.3 s(-1), P < 0.001) and lower systolic peak velocities (3.3 +/- 1.0 vs. 5.6 +/- 1.0 cm/s, P < 0.001) compared with control subjects. Myocardial systolic strain rate correlated significantly to left ventricular mass (r = 0.40, P < 0.01) and to both HbA1c (r = 0.43, P < 0.01), and fructosamine (r = 0.40, P < 0.01), but was not related to serum levels of carboxymethyllysine, albuminuria, blood pressure (dipping/non-dipping), or oral hypoglycaemic therapy. Patients with diastolic dysfunction had significantly higher levels of urine albumin [21.0 (5-2500) mg/l, vs. 9.5 (1-360), P < 0.01], heart rate (78 +/- 13 vs. 67 +/- 10 b.p.m., P < 0.005), and seated diastolic blood pressure (85 +/- 6 vs. 81 +/- 7 mmHg, P < 0.05) and non-dipping diastolic blood pressure was more frequent.CONCLUSIONS: Long axis left ventricular systolic function was significantly decreased in hypertensive patients with Type 2 diabetes mellitus, and is associated with hyperglycaemia and left ventricular hypertrophy. Diastolic dysfunction was closely related to increased diastolic blood pressure, non-dipping and increased urinary albumin excretion.

AIMS/HYPOTHESIS: The excess mortality in diabetes is mainly due to cardiovascular causes and almost confined to patients with abnormal albuminuria. Compared to healthy subjects, diabetic patients have a prolonged QT interval and increased QT dispersion. In non-diabetic subjects, as well as in Type 1 diabetic patients with overt nephropathy, a prolonged QT interval and increased QT dispersion are associated with cardiac morbidity and mortality. There is an increasing number of studies on effects of beta blocker treatment on QT interval and QT dispersion in non-diabetic subjects. In contrast, there are no studies on the effects of beta blocker treatment on QT interval and QT dispersion in patients with diabetes. The aim of our study was to describe the effects of metoprolol treatment on QT interval and QT dispersion in a group of well-characterised Type 1 diabetic patients with elevated urine albumin excretion.METHODS: We studied the effects of 6 weeks of treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in a randomised, placebo-controlled, double blind, crossover trial including 20 Type 1 diabetic patients. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording and 24-h fractionated urine collections. On days of investigation 12-lead electrocardiograms were recorded and autonomic tests performed.RESULTS: We found strong associations between both daytime and night-time blood pressure and heart-rate-corrected QT interval dispersion (QTc dispersion). Heart rate variability parameters indicating sympathetic and parasympathetic modulation showed strong correlations with heart-rate-corrected QT interval (QTc interval) and with QTc dispersion. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion.CONCLUSIONS/INTERPRETATION: This study is the first to address the QTc interval and QTc dispersion in Type 1 diabetic patients treated with metoprolol. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. These results may in part explain the pronounced cardioprotective effect of beta blocker treatment in diabetic patients with cardiovascular disease.