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Central blood pressure (BP) is recognised as a predictor of cardiovascular disease (CVD). Moderate alcohol consumption has been shown to have a beneficial effect on CVD. However, consumption of a lipid-rich meal may exert the opposite effect. Thus, the aim of the present study was to examine whether the immediate effect of a medical conference dinner was associated with reduced central BP and hence improved vascular age. We examined attendees at a medical conference before and after the conference dinner which included a three course meal and wine menu. Participants had brachial and central BP measured. Central BP was measured in duplicate over the right radial artery using the Sphygmocor device (Atcor Medical, Sydney, Australia). The cohort consisted of 60 attendees (43% women) with a median age of 40 years (IQR 35 – 54) and a mean follow-up period of 4 ± 1 hour. Only one attendee smoked, whereas six took antihypertensive medication. While heart rate increased, all measurements of brachial and central BP were reduced after the dinner (Table 1). Multiple regression showed that central systolic BP and augmentation index (Alx) was reduced after the dinner independently of age, gender, height, and baseline heart rate (p = 0.008 and p = 0.01). Furthermore, calculations of the slope of the regression lines between Alx@HR75 and age before and after the dinner revealed a reduction of 5.5 years in the vascular age. In conclusion, central BP was reduced and vascular age improved by 5.5 years after intake of a medical conference dinner.

Objective. Physical activity (PA) has been associated with reduced cardiovascular disease (CVD). However, improvements in conventional risk factors do not explain the full benefit of PA on CVD risk. Therefore, we examined the association between PA and central haemodynamics to provide new insight into the link between PA and CVD. Methods. We performed cross-sectional analyses of data from a health examination of 1,607 Danish adults at low to high diabetes risk. PA energy expenditure (PAEE) was measured by combined accelerometry and heart rate monitoring (ActiHeart®) expressed as kJ/kg/day. Aortic stiffness was assessed by applanation tonometry (SphygmoCor®), as aortic pulse wave velocity (aPWV), and central blood pressure was estimated from wave forms recorded at the radial artery. Associations between PAEE and central haemodynamics were examined by linear regression successively adjusted for sex, age, waist circumference, and smoking. Additionally, aPWV was adjusted for mean blood pressure. aPWV was logarithmically transformed. Individuals with previously myocardial or cerebral infarction were excluded (n = 183). Results. Median age was 66 years (IQR: 61;71), 52% was men, median PAEE was 28 kJ/kg/day (IQR: 20;39), and median aPWV 8.0 m/s (IQR: 6.9;9.4). A higher PAEE of 10 kJ/kg/day was associated with a 1.0 % lower aPWV (CI: −0.17; −0.03). Associations with systolic blood pressure and pulse pressure were not statistically significant (−0.5 mmHg (CI: −0.11;0.01) and −0.02 mmHg (CI: −0.06;0.03)). Conclusion. A higher level of PAEE is associated with lower levels of aortic stiffness indicating that the beneficial effects of PA on CVD are partially mediated by aortic stiffness.

Introduction: Assessment of pulse wave velocity (PWV) is recognized as a marker of arterial stiffness within human medicine. Non-invasive evaluation of arterial structural changes in relation to atherosclerosis in porcine models of cardiovascular disease, would be valuable in longitudinal assessment of pathophysiological changes, e.g. in relation to drug effect. Objective: To evaluate the feasibility and reproducibility of PWV in anesthetized male Göttingen minipigs. Method: Animals were anesthetized every second day (three days in total) using constant intravenous infusion of ketamine and midazolam. Mean arterial blood pressure (MAP) assessed by oscillometry and heart rate (HR) were registered. PWV was calculated as the distance between the carotid and femoral artery divided by the time delay of pressure pulses, assessed by aplanation tonometry and simultaneously recorded electrocardiography (ECG). Results: MAP was 87.6 mmHg ± 11.9 (mean ± SD), 80.5 mmHg ± 12.7 and 84.3 mmHg ± 19.4 at the three examinations respectively, and HR was 77 beats per minute (BPM) ± 12, 71 BPM ± 8 and 74 BPM ± 9. PWV was 6.3 m/s ± 2.19, 5.7 m/s ± 0.6 and 5.9 m/s ± 1.4, respectively. There was no significant effect of examination day, MAP, or HR on PWV, evaluated by analysis of variance. Mean inter-examination coefficient of variation was 16%. Conclusion: Assessment of PWV is feasible in anesthetized Göttingen minipigs, and therefore could have perspectives in a porcine model of atherosclerosis. Furthermore, reference values from this study corresponded to PWV values obtained from infants or young human individuals.

Background: Carotid intima-media thickness (IMT) measured by B-mode ultrasound is a sensitive and non-invasive method for detection of subclinical cardiovascular disease (CVD) and is often used as primary outcome measure in clinical trials as a surrogate marker of CVD. The purpose of the present study was to quantify the repeatability of this method between and within sonographers and readers. Furthermore we studied the day-to-day variation. Methods: We used B-mode ultrasound and a computerized software programme (MIA vascular tools) for analysis of Carotid IMT (far wall of the common carotid artery). Measurement of Carotid IMT was done for 30 healthy persons and 28 T2D patients by two different sonographers and two different readers on two separate days. Results: Comparisons of Carotid IMT between readers assessing the same picture (reader variability) resulted in limits of agreement on the relative scale from 0.92 to 1.07, i.e. there is a 95% probability that the reading of a given picture by a second reader gives a thickness between 0.92 and 1.07 of the first reading. Comparing different sonographers resulted in limits of agreement from 0.83 to 1.22 We found no differences between healthy persons and patients with T2D. Conclusion: Measurement of carotid IMT has the same accuracy in both healthy persons and patients with T2D. The major sources of variation are the differences between sonographers and the day-to-day variation whereas the following reading of the recording using computerized software shows very little variation.

Background: Rubidium-82 positron emission tomography ( 82 Rb PET) myocardial perfusion imaging is used in clinical practice to quantify regional perfusion defects. Additionally, 82 Rb PET provides a measure of absolute myocardial flow reserve (MFR), describing the vasculature state of health. We assessed whether 82 Rb PET-derived MFR is associated with all-cause mortality independently of the extent of perfusion defects., Methods: We conducted a multicenter clinical registry-based study of patients undergoing 82 Rb PET myocardial perfusion imaging on suspicion of chronic coronary syndromes. Patients were followed up in national registries for the primary outcome of all-cause mortality. Global MFR ≤2 was considered reduced., Results: Among 7169 patients studied, 38.1% were women, the median age was 69 (IQR, 61-76) years, and 39.0% had MFR ≤2. A total of 667 (9.3%) patients died during a median follow-up of 3.1 (IQR, 2.6-4.0) years, more in patients with MFR ≤2 versus MFR >2 (15.7% versus 5.2%; P <0.001). MFR ≤2 was associated with all-cause mortality across subgroups defined by the extent of perfusion defects (all P <0.05). In a Cox survival regression model adjusting for sex, age, comorbidities, kidney function, left ventricular ejection fraction, and perfusion defects, MFR ≤2 was a robust predictor of mortality with a hazard ratio of 1.62 (95% CI, 1.31-2.02; P <0.001). Among patients with no reversible perfusion defects (n=3101), MFR ≤2 remained strongly associated with mortality (hazard ratio, 1.86 [95% CI, 1.26-2.73]; P <0.01). The prognostic value of impaired MFR was similar for cardiac and noncardiac death., Conclusions: MFR ≤2 predicts all-cause mortality independently of the extent of perfusion defects. Our results support the inclusion of MFR when assessing the prognosis of patients suspected of chronic coronary syndromes., Competing Interests: Disclosures None.

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear., Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death., Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses., Trial Registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8 th of April 2008)., Competing Interests: Sten Madsbad: Advisory boards: AstraZeneca; Boehringer Ingelheim; Eli Lilly; Intarcia Therapeutics; Merck Sharp & Dohme; Novartis; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Research Grant Recipient: Novo Nordisk; Boehringer Ingelheim. Leif Breum: Advisory boards: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Lundbeck, Otsuka. Louise Lundby-Christensen, Christian Ovesen, Thomas Almdal: own shares in Novo Nordisk A/S. Elisabeth R Mathiesen: Advisory board: Novo Nordisk. Markus Harboe Olsen. Janus C Jakobsen, Christian Gluud, Simone B Sneppen, Christoffer Hedetoft, Michael E. Røder, Henrik Vestergaard, Niels Wiinberg, Thure Krarup: none declared., (© 2023 The Authors.)

Aims: Myocardial perfusion imaging with 82-rubidium positron emission tomography (82Rb-PET) is increasingly used to assess stable coronary artery disease (CAD). We aimed to evaluate the prognostic value of 82Rb-PET-derived parameters in patients with symptoms suggestive of CAD but no significant reversible or irreversible perfusion defects., Methods and Results: Among 3726 consecutive patients suspected of stable CAD who underwent 82Rb-PET between January 2018 and August 2020, 2175 had no regional perfusion defects. Among these patients, we studied the association of 82Rb-PET-derived parameters with a composite endpoint of all-cause mortality, hospitalization for unstable angina pectoris, acute myocardial infarction, heart failure, or ischaemic stroke. During a median follow up of 1.7 years (interquartile range 1.1-2.5 years), there were 148 endpoints. Myocardial blood flow (MBF) reserve (MFR), MBF during stress, left ventricular ejection fraction (LVEF), LVEF-reserve, heart rate reserve, and Ca score were associated with adverse outcomes. In multivariable Cox model adjusted for patient and 82Rb-PET characteristics, MFR < 2 (hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.24-2.48), LVEF (HR 1.38 per 10% decrease, 95% CI 1.24-1.54), and LVEF-reserve (HR 1.19 per 5% decrease, 95% CI 1.07-1.31) were significant predictors of endpoints. Results were consistent in subgroups defined by gender, history of ischaemic heart disease, low LVEF, and atrial fibrillation., Conclusion: MFR, LVEF, and LVEF-reserve derived from 82Rb-PET provide prognostic information on cardiovascular outcomes in patients with no perfusion defects. This may aid in identifying patients at risk and might provide an opportunity for preventive interventions., Competing Interests: Conflict of interest: Nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Carotid intima-media thickness (IMT) can assess the cumulative effect of atherosclerotic risk factors and provides an independent predictor of future cardiovascular (CV) risk. The aim of this study was to investigate the progression of conventional risk factors in 933 long-term survivors from a Danish cohort with and without diabetes mellitus (DM) as predictors for attained carotid IMT during 35.6 (0.7) years of follow-up. Persons who participated in the first, the last and one of the intermediate rounds of the Copenhagen City Heart Study, and who had had an ultrasound-derived measure of the carotid IMT performed at the last examination were included in the analyses. The risk factors varied between persons with and without DM during the 36 years, but the difference in blood pressure disappeared in the fifth examination, where, in addition, total cholesterol was found to be lower in persons with DM. In this cohort there were no difference in attained carotid IMT between persons with and without DM at the last examination. The following risk factors were found to best predict carotid IMT: age, maximum systolic BP, average systolic BP, average BMI, minimum BMI, sex and years of smoking. The prediction of carotid IMT was clinically poor with a root mean-squared error of prediction (RMSEP) of 0.134 mm and a 95% prediction error probability interval of (-0.22; 0.30). Furthermore, the distribution of prediction errors was skewed to the right indicating that the prediction errors were larger among persons with high carotid IMT.

Background: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM)., Methods: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed., Results: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA 1c did not confound the associations., Conclusions: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA 1c . Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Carotid intima-media thickness (IMT) and ankle brachial index (ABI) are non-invasive indicators of generalised atherosclerosis. The aim was to determine the association between carotid IMT and ABI in subjects with and without diabetes mellitus (DM), and to analyse specific age change-points. We included 2744 subjects from the Copenhagen City Heart Study (mean age (SD) 56.6 (17.2) years, 56.8% women and body mass index (BMI) 25.4 (4.1) kg/m 2 ). Carotid IMT and ABI measurements were performed during the fifth examination. Of the 2744 subjects, 125 subjects (4.6%) had DM. Average carotid IMT was 0.667 (0.145) mm and ABI was 1.06 (0.14). Subjects with DM were older, had higher BMI and systolic blood pressure (SBP) (all p < .001). Carotid IMT was higher in subjects with DM (0.754 (0.150) mm) compared to subjects without DM (0.662 (0.144) mm) (p < .001), whereas there was no difference in ABI between the two groups. ABI was inversely associated with carotid IMT (slope = -0.17 [-0.207; -0.137] (p < .001). The association remained significant after adjustment for risk factors both in subjects with DM (slope = -0.168 [-0.328; -0.007], p = .040), and in subjects without DM (slope = -0.100 [-0.148; -0.052], p < .001), with a stronger effect of carotid IMT on ABI among subjects with DM. Carotid IMT and ABI were inversely associated in subjects with DM and without DM, but with a stronger effect in subjects with DM. Age and ABI revealed a change-point with a stronger inverse association among subjects aged >60 years.

Objective: To compare the effect of a conventional to an intensive blood pressure monitoring regimen on blood pressure in hypertensive patients in the general practice setting., Design: Randomized controlled parallel group trial with 12-month follow-up., Setting: One hundred and ten general practices in all regions of Denmark., Participants: One thousand forty-eight patients with essential hypertension., Intervention: Conventional blood pressure monitoring ('usual group') continued usual ad hoc blood pressure monitoring by office blood pressure measurements, while intensive blood pressure monitoring ('intensive group') supplemented this with frequent home blood pressure monitoring and 24-hour ambulatory blood pressure monitoring., Primary Outcome Measures: Mean day- and night-time systolic and diastolic 24-hour ambulatory blood pressure., Secondary Outcome Measures: Change in systolic and diastolic office blood pressure and change in cardiovascular risk profile., Results: Of the patients, 515 (49%) were allocated to the usual group, and 533 (51%) to the intensive group. The reductions in day- and night-time 24-hour ambulatory blood pressure were similar (usual group: 4.6 ± 13.5/2.8 ± 82 mmHg; intensive group: 5.6 ± 13.0/3.5 ± 8.2 mmHg; P = 0.27/P = 0.20). Cardiovascular risk scores were reduced in both groups at follow-up, but more so in the intensive than in the usual group (P = 0.02)., Conclusion: An intensive blood pressure monitoring strategy led to a similar blood pressure reduction to conventional monitoring. However, the intensive strategy appeared to improve patients' cardiovascular risk profile through other effects than a reduction of blood pressure., Trial Registration: Clinical Trials NCT00244660.

Objectives: In the context of screening for diabetes, we examined levels of central haemodynamics among individuals with different levels of diabetes risk and analysed the impact of glycated haemoglobin A (HbA1c) and HbA1c changes on central haemodynamics., Methods: A Danish population-based stepwise screening programme for diabetes including a diabetes risk score (DRS) questionnaire and glucose measurements identified seven groups of individuals at increasing levels of diabetes risk. After 7.8 years of follow-up, 2048 individuals underwent aortic stiffness assessment by carotid-femoral pulse wave velocity (aPWV) and assessment of central blood pressure (BP). We compared differences in central haemodynamics at follow-up between the diabetes risk groups and analysed the impact of HbA1c at screening and HbA1c change on central haemodynamics at follow-up adjusting for relevant confounders., Results: At screening, median age was 59.0 years, and median HbA1c was 5.7%. At follow-up, median aPWV was 8.0 m/s, and median central SBP was 123.5 mmHg. Among individuals with high DRS, aPWV, central SBP and DBP, and pulse pressure were higher in individuals with impaired glucose tolerance than normal glucose tolerance. Per 1%-point higher HbA1c at screening, aPWV was 0.23 m/s (95% confidence interval: 0.00; 0.46) higher, and central DBP was 1.35 mmHg (95% confidence interval: 0.19; 2.51) lower, whereas HbA1c change was not associated with any of the central haemodynamics., Conclusion: Dysglycaemia is associated with future aortic stiffness. However, glycaemic deterioration over 7.8 years does not affect aortic stiffness or central BP independently of other cardiometabolic risk factors.

Objective: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes., Design and Setting: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark., Participants and Interventions: Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol)., Outcomes: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes., Results: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ., Conclusions: Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results., Trial Registration Number: NCT00657943., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes., Design and Setting: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark., Participants and Interventions: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol)., Outcomes: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes., Results: Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001)., Conclusions: Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results., Trial Registration Number: NCT00657943; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Despite aggressive treatment of cardiovascular disease (CVD) risk factors individuals with type 2 diabetes (T2D) still have increased risk of cardiovascular morbidity and mortality. The primary aim of this study was to examine the cross-sectional association between total (25-hydroxy vitamin D (25(OH)D)) and risk of CVD in patients with T2D. Secondary objective was to examine the association between 25(OH)D and bone health. A Danish cohort of patients with T2D participating in a randomised clinical trial were analysed. In total 415 patients (68% men, age 60±9 years (mean±s.d.), duration of diabetes 12±6 years), including 294 patients (71%) treated with insulin. Carotid intima-media thickness (IMT) and arterial stiffness (carotid artery distensibility coefficient (DC) and Young's elastic modulus (YEM)) were measured by ultrasound scan as indicators of CVD. Bone health was assessed by bone mineral density and trabecular bone score measured by dual energy X-ray absorptiometry. In this cohort, 214 patients (52%) were vitamin D deficient (25(OH)D <50 nmol/l). Carotid IMT was 0.793±0.137 mm, DC was 0.0030±0.001 mmHg, YEM was 2354±1038 mmHg and 13 (3%) of the patients were diagnosed with osteoporosis. A 25(OH)D level was not associated with carotid IMT or arterial stiffness (P>0.3) or bone health (P>0.6) after adjustment for CVD risk factors. In conclusion, 25(OH)D status was not associated with carotid IMT, arterial stiffness or bone health in this cohort of patients with T2D. To explore these associations and the association with other biomarkers further, multicentre studies with large numbers of patients are required., (© 2015 The authors.)

Background: In patients with type 2 diabetes, cardiovascular disease (CVD) is the major cause of morbidity and mortality. We evaluated the combination of NT-proBNP and coronary artery calcium score (CAC) for prediction of combined fatal and non-fatal CVD and mortality in patients with type 2 diabetes and microalbuminuria (>30 mg/24-h), but without known coronary artery disease. Moreover, we assessed the predictive value of a predefined categorisation of patients into a high- and low-risk group at baseline., Methods: Prospective study including 200 patients. All received intensive multifactorial treatment. Patients with baseline NT-proBNP > 45.2 ng/L and/or CAC ≥ 400 were stratified as high-risk patients (n = 133). Occurrence of fatal- and nonfatal CVD (n = 40) and mortality (n = 26), was traced after 6.1 years (median)., Results: High-risk patients had a higher risk of the composite CVD endpoint (adjusted hazard ratio [HR] 10.6 (95 % confidence interval [CI] 2.4-46.3); p = 0.002) and mortality (adjusted HR 5.3 (95 % CI 1.2-24.0); p = 0.032) compared to low-risk patients. In adjusted continuous analysis, both higher NT-proBNP and CAC were strong predictors of the composite CVD endpoint and mortality (p ≤ 0.0001). In fully adjusted models mutually including NT-proBNP and CAC, both risk factors remained associated with risk of CVD and mortality (p ≤ 0.022). There was no interaction between NT-proBNP and CAC for the examined endpoints (p ≥ 0.31)., Conclusions: In patients with type 2 diabetes and microalbuminuria but without known coronary artery disease, NT-proBNP and CAC were strongly associated with fatal and nonfatal CVD, as well as with mortality. Their additive prognostic capability holds promise for identification of patients at high risk.

Physical activity is associated with reduced cardiovascular disease risk. However, improvements in conventional risk factors due to physical activity do not explain its full benefit. Therefore, we examined associations of objectively measured physical activity energy expenditure and intensity with central hemodynamics to provide new insight into the link between physical activity and cardiovascular disease. We analyzed data from 1816 Danes (median age: 66 years) without cardiovascular disease. Physical activity was estimated using combined accelerometry and heart rate monitoring. Aortic stiffness was assessed by applanation tonometry, as aortic pulse wave velocity, and central blood pressure was estimated from radial waveforms. Associations between physical activity energy expenditure and central hemodynamics were examined by linear regression. Furthermore, the consequence of substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity on central hemodynamics was examined. Median physical activity energy expenditure was 28.0 kJ/kg/d (IQR: 19.8; 38.7). A 10 kJ/kg/d higher energy expenditure was associated with 0.75% lower aortic pulse wave velocity (CI: -1.47; -0.03). Associations with central systolic blood pressure and central pulse pressure were not statistically significant. We observed no difference in central hemodynamics when substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity. In this relatively inactive population, higher physical activity energy expenditure was associated with lower aortic stiffness, while there was no statistically significant association between substitution of activity intensity and central hemodynamics. This suggests that lower aortic stiffness is one of a number of health benefits attributed to higher habitual physical activity.

Few methods for noninvasive assessment of arterial stiffness and endothelial dysfunction in porcine models are available. The aim of this study was to evaluate methods for assessment of arterial stiffness and endothelial dysfunction in anesthetized Göttingen minipigs. Pulse-wave velocity (PWV) was assessed in male Göttingen minipigs (n = 8; age approximately 60 wk) by using applanation tonometry of the carotid and femoral arteries. In addition, flow-mediated vasodilation (FMD) was assessed by using vascular ultrasonography of the brachial artery to evaluate endothelial dysfunction. To evaluate the reproducibility of the methods, minipigs were anesthetized by intravenous infusion of ketamine and midazolam and examined every other day for a total of 3 trials. Neither examination day nor systolic, diastolic, or mean arterial blood pressure statistically influenced PWV or FMD. The median interexamination coefficient of variation was 17% for PWV and 59% for FMD. Measured values of PWV corresponded largely to those in clinically healthy humans, but FMD values were lower than expected for lean, young animals. Although the ketamine-midazolam anesthesia we used has been associated with minor hemodynamic effects in vivo, in vitro studies suggest that both drugs are vasodilatory. Therefore anesthesia might have influenced the endothelial response, contributing to the modest FMD response and the concurrent high coefficients of variation that we noted. We conclude that PWV—but not FMD—showed acceptable interexamination variation for its potential application in porcine models.

Background: Measurement of the ankle and toe pressures are often performed using a plethysmograph, compression cuffs and a strain gauge. Usually, the strain gauge contains mercury but other alternatives exist. From 2014, the mercury-containing strain gauge will no longer be available in the European Union. The aim of this study was to compare an indium-gallium strain gauge to the established mercury-containing strain gauge., Methods: Consecutive patients referred to the Department of Clinical Physiology and Nuclear Medicine at Bispebjerg and Frederiksberg Hospitals for measurements of systolic ankle and toe pressures volunteered for the study. Ankle and toe pressures were measured twice with the mercury and the indium-gallium strain gauge in random order. Comparison of the correlation between the mean pressure using the mercury and the indium-gallium device and the difference between the two devices was performed for both toe and ankle level., Results: A total of 53 patients were included (36 male). Mean age was 69 (range, 45-92 years). Mean pressures at toe and ankle level with the mercury and the indium-gallium strain gauges were 77 (range, 0-180) mm Hg and 113 (range, 15-190) mm Hg, respectively. Comparison between the mercury and the indium-gallium strain gauge showed a difference in toe blood pressure values of - 0.7 mm Hg (SD: 7.0). At the ankle level, a difference of 2.0 mm Hg (SD: 8.6) was found., Conclusion: The two different devices agree sufficiently in the measurements of systolic ankle and toe pressure for the indium-gallium strain gauge to replace the mercury strain gauge.

Aim: To investigate whether Roux-en-Y gastric bypass surgery (RYGB) - an in vivo model for normalisation of hyperglycaemia - improves carotid intima-media thickness (IMT) in patients with type 2 diabetes (T2D)/impaired glucose tolerance (IGT) and normal glucose tolerance (NGT)., Methods: Observational prospective study, 34 obese patients (T2D (n = 14)/IGT (n = 4), and NGT (n = 16)) were investigated before and six and 12months after RYGB., Results: Mean carotid IMT was significantly reduced 12months after RYGB in patients with T2D/IGT (-0.041 mm (95% CI -0.069; -0.012, p = 0.005)) but not in patients with NGT (-0.010 mm (-0.039; 0.020, p = 0.52)). The between-group difference was not significant (p=0.13). Twelve months after RYGB, patients with respectively T2D/IGT and NGT demonstrated changes in weight: -29.9 kg, p<0.001/-30.6 kg, p < 0.001, HbA1c: -0.7%, p < 0.001/-0.1%, p = 0.33, systolic blood pressure: -2 mmHg, p = 0.68/-10 mmHg, p = 0.01 and diastolic blood pressure: -8 mmHg, p = 0.003/-11 mmHg, p < 0.001. 80% of T2D patients terminated antihyperglycaemic medication., Conclusion: Mean carotid IMT was significantly reduced 12months after RYGB in patients with T2D/IGT which provides evidence to support that the earliest atherosclerotic changes in the arterial wall are reversible. Although numerically different from the changes observed in patients with NGT, the between-group difference was not statistically significant., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Chronic hepatitis C is a global health problem and has been associated with coronary artery disease. Our aim was to examine the prevalence of coronary artery disease risk markers including endothelial biomarkers in patients with chronic hepatitis C and matched comparisons without manifest cardiovascular disease or diabetes in a cross-sectional design., Methods: Sixty patients with chronic hepatitis C (mean age 51 years) were recruited from the Department of Infectious Diseases at Copenhagen University Hospital, and compared with 60 age-matched non-hepatitis C virus-infected individuals from a general population survey. We examined traditional coronary artery disease risk factors, metabolic syndrome, carotid intima media thickness, and a range of endothelial biomarkers., Results: Patients with chronic hepatitis C had more hypertension (40% versus 25%, prevalence ratio [PR] 1.6; 95% confidence interval [CI] 0.9-2.7) and smoked more (53% versus 38%, PR 1.4; 95% CI 0.9-2.1). The two groups had similar body mass index (mean 25.0 versus 25.7 kg/m(2)), whereas those with chronic hepatitis C had less dyslipidemia (including significantly lower low-density lipoprotein and cholesterol/high-density lipoprotein ratio), higher glycosylated hemoglobin level (mean 6.2 versus 5.7, difference of means 0.5; 95% CI 0.3-0.8), and a higher prevalence of metabolic syndrome (28% versus 18%, PR 1.6; 95% CI 0.8-3.0). Increased carotid intima media thickness above the standard 75th percentile was seen more frequently in chronic hepatitis C (9% versus 3%, PR 1.7; 95% CI 0.4-6.7), though difference of means was only 0.04 mm (95% CI 0.00-0.10). Patients with chronic hepatitis C had increased hsCRP (high-sensitivity C-reactive protein), sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), and soluble E-selectin, but lower levels of tPAI-1 (tissue-type plasminogen activator inhibitor-1), MMP9 (matrix metallopeptidase 9), and MPO (myeloperoxidase) than their comparisons., Conclusion: Our findings indicate that patients with chronic hepatitis C have increased prevalence of several coronary artery disease risk markers. These results may be important when evaluating the appropriateness of screening for coronary artery disease and its risk factors in chronic hepatitis C.

The present study aimed at examining the interarm difference in blood pressure and its use as an indicator of peripheral arterial disease (PAD). Data were included from consecutive patients referred from their general practitioner to our vascular laboratory for possible PAD aged 50 years or older without known cardiac disease, renal disease, or diabetes mellitus. 824 patients (453 women) with mean age of 72 years (range: 50-101) were included. 491 patients had a diagnosis of hypertension and peripheral arterial disease (PAD) was present in 386 patients. Systolic blood pressure was 143 ± 24 mmHg and 142 ± 24 mmHg on the right and left arm, respectively (P = 0.015). The interarm difference was greater in patients with hypertension (P = 0.002) and PAD (P < 0.0005). 443 patients were measured on two separate occasions and the interarm difference for systolic blood pressure was reproducible for differences >20 mmHg. This study confirmed the presence of a systematic but clinically insignificant difference in systolic blood pressure between arms. The interarm difference was larger in hypertension and PAD. Consistent lateralisation is present for differences ≥20 mmHg and an interarm difference >25 mmHg is a reliable indicator of PAD in the legs.

A total of 60 attendees at a medical conference had their peripheral and central blood pressure measured before and after the conference dinner. While heart rate increased, all measurements of peripheral and central blood pressure showed lower values after dinner. Furthermore, attendees' central vascular age was reduced by 13 years after dinner when augmentation index was evaluated in relation to age. Although 13% experienced postprandial hypotension, the present study motivates attendance at medical conference dinners due to the health implications of lowered blood pressure.

Objectives: to determine the prevalence of asymptomatic ischemic heart disease (IHD) in HIV patients by myocardial perfusion scintigraphy (MPS) and to determine the value of coronary artery calcium score (CACS), carotid intima-media thickness (cIMT) and pericardial fat volume as screening tools for detection of IHD in subjects with HIV., Background: Patients with HIV seem prone to early development of IHD., Methods: 105 consecutive HIV patients (mean age 47.4 years; mean duration of HIV 12.3 years; mean CD4+ cell count 636×10⁶/L; all receiving antiretroviral therapy) and 105 controls matched for age, gender and smoking status, without history of IHD were recruited. MPS, CACS, cIMT, pericardial fat volume, and cardiovascular risk scores were measured., Results: HIV patients demonstrated higher prevalence of perfusion defects than controls (18% vs. 0%; p<0.001) despite similar risk scores. Of HIV patients with perfusion defects, 42% had a CACS = 0. CACS and cIMT were similar in HIV patients and controls. HIV patients on average had 35% increased pericardial fat volume and increased concentration of biomarkers of atherosclerosis in the blood. HIV patients with myocardial perfusion defects had increased pericardial fat volume compared with HIV patients without perfusion defects (314±43 vs. 189±12 mL; p<0.001)., Conclusions: HIV patients had an increased prevalence of silent IHD compared to controls as demonstrated by MPS. The finding was strongly associated with pericardial fat volume, whereas cardiovascular risk scores, cIMT and CACS seem less useful as screening tools for detection of myocardial perfusion defects in HIV patients.

Objective: Diabetes is associated with increased brachial and central blood pressure and aortic stiffness. We examined the effect of intensive multifactorial treatment in general practice on indices of peripheral and central hemodynamics among patients with screen-detected diabetes., Research Design and Methods: As part of a population-based screening and intervention study in general practice, 1,533 Danes aged 40-69 years were clinically diagnosed with screen-detected diabetes. General practitioners were randomized to provide intensive multifactorial treatment or routine care. After a mean follow-up of 6.2 years, an unselected subsample of 456 patients underwent central hemodynamic assessments by applanation tonometry. Central pressure was derived from the radial pulse wave. Aortic stiffness was assessed as carotid-femoral pulse wave velocity (aPWV). The intervention effect on each index of central hemodynamics was analyzed by mixed-effects models adjusted for heart rate, cluster randomization, age, and sex., Results: At screening, median age was 59.2 years (interquartile range 55.2-64.6); 289 patients (63%) were in the intensive treatment group, and 278 patients (61%) were men. Patients in the intensive treatment group had a 0.51 m/s (95% CI -0.96 to -0.05, P = 0.03) lower aPWV compared with routine care. Respective differences for central augmentation index (-0.84% [-2.54 to 0.86]), pulse pressure (0.28 mmHg [-1.75 to 2.32]), and systolic (-1.42 mmHg [-4.47 to 1.64]) and diastolic (-1.79 mmHg [-3.72 to 0.14]) blood pressure were not statistically significant., Conclusions: Intensive multifactorial treatment of screen-detected diabetes during 6 years in general practice has a significant impact on aortic stiffness, whereas the effects on other hemodynamic measures are smaller and not statistically significant.

Background: Intensive multifactorial treatment aimed at prevention of cardiovascular (CV) disease may reduce left ventricular (LV) echocardiographic abnormalities in diabetic subjects. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the association between P-NT-proBNP and the putative residual abnormalities in such patients are not well described. This study examined echocardiographic measurements of LV hypertrophy, atrial dilatation and LV dysfunction and their relation to P-NT-proBNP levels or subclinical coronary artery disease (CAD) in type 2 diabetic patients with microalbuminuria receiving intensive multifactorial treatment., Methods: Echocardiography including tissue Doppler imaging and P-NT-proBNP measurements were performed in 200 patients without prior CAD. Patients with P-NT-proBNP > 45.2 ng/L and/or coronary calcium score ≥ 400 were stratified as high risk patients for CAD(n = 133) and examined for significant CAD by myocardial perfusion imaging and/or CT-angiography and/or coronary angiography., Results: LV mass index was 41.2 ± 10.9 g/m2.7 and 48 (24%) patients had LV hypertrophy. LA and RA dilatation were found in 54(27%) and 45(23%) patients, respectively, and LV diastolic dysfunction was found in 109(55%) patients. Patients with increased P-NT-proBNP levels did not have more major echocardiographic abnormalities. In 70(53%) of 133 high risk patients significant CAD was demonstrated and patients with LV hypertrophy had increased risk of significant CAD(adjusted odd ratio[CI] was 4.53[1.14-18.06])., Conclusion: Among asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment, P-NT-proBNP levels is not associated with echocardiographic abnormalities. LV diastolic dysfunction was frequently observed, whereas LV hypertrophy was less frequent but associated with significant CAD.

Objective: Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients., Research Design and Methods: We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry., Results: The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02-7.66, P = 0.047)., Conclusions: In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.

Objective: Intensive medical treatment of heart failure (HF) patients with diabetes may reduce the endothelial dysfunction and the accelerated atherosclerotic process seen in these patients. To study this, we investigated the endothelial function and the presence of atherosclerosis as measured by flow-mediated vasodilatation (FMD) and intima-media thickness (IMT) in intensively treated patients with coexisting HF and diabetes., Research Design and Method: FMD of the brachial artery and IMT of the common carotid arteries were determined in 26 patients with systolic HF and diabetes who were in intensive medical therapy, as well as in 19 healthy controls. The two groups were matched according to age and sex. In all subjects left ventricular ejection fraction was measured by two-dimensional echocardiography. Biochemical parameters including serum cholesterol, HDL and LDL, triglyceride, glucose, hemoglobin/hemoglobin-A1C (HbA1C), brain natriuretic peptide (BNP) and N-terminal pro-BNP were also assessed., Results: Mean FMD and IMT did not differ significantly between patients and controls. Left ventricular ejection fraction was lower in patients compared to controls (P < 0.001). The patients had a higher mean BNP, NT pro-BNP, triglyceride, HbA1C and glucose in comparison to controls. Cholesterol, HDL-cholesterol and LDL-cholesterol were lower in patients compared to controls., Conclusions: Intensively treated patients with coexisting systolic HF and diabetes seem to have normal endothelial function as measured by FMD and they have no sign of accelerated atherosclerosis as measured by IMT. This suggests a positive effect of medication on the cardiovascular alterations in this group of patients.

Background: Elevated plasma N-terminal (NT)-proBNP levels and coronary calcium score (CCS) not only predicts myocardial ischaemia and coronary artery stenosis but also adverse cardiovascular events and mortality in type 2 diabetic patients with an increased urinary albumin excretion rate (UAER), whereas low levels are associated with low frequency of coronary artery disease (CAD) and good prognosis. The underlying causes of poor prognosis in patients with elevated NT-proBNP are not known; thus, we investigated the role of putative asymptomatic CAD in type 2 diabetic patients with UAER >30 mg/24 h and elevated P-NT-proBNP and/or CCS., Methods: We identified 200 type 2 diabetic patients without known CAD and with normal creatinine levels. Patients with P-NT-proBNP >45.2 ng/L (the median P-NT-proBNP value in this cohort and in accordance with our previous findings) and/or CCS ≥ 400 were stratified as high-risk patients for CAD (n = 133) and all other patients as low-risk patients (n = 67). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109) and/or computer tomography angiography (n = 20) and/or coronary angiography (CAG; n = 86)., Results: All patients received intensive mulitifactorial intervention. In 70 of 133 (53%) high-risk patients, significant CAD was demonstrated by MPI and/or CAG, corresponding to 35% (70/200) of the total cohort. Among high-risk patients, CCS but not P-NT-proBNP was paralleled by increased prevalence of significant CAD and in the 86 patients where CAG was performed, a CCS <100 had a negative predictive value for coronary artery stenosis of 94% (P = 0.04)., Conclusions: Our study revealed that >50% of asymptomatic type 2 diabetic patients with UAER >30 mg/24 h had significant CAD based on risk stratification with P-NT-proBNP and CCS. This provides some explanation to the previously reported poor prognosis in these asymptomatic patients. Optimized cardio protective treatment in these patients is warranted.