Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial.

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 HbA1c 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 HbA1c. 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).

Progression in risk factors during 36 years of follow-up and prediction of carotid intima-media thickness in a large cohort of adults with and without diabetes.

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.

Intensive versus conventional blood pressure monitoring in a general practice population. The Blood Pressure Reduction in Danish General Practice trial: a randomized controlled parallel group trial.

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.

Carotid intima media thickness and ankle brachial index are inversely associated in subjects with and without diabetes.

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/m2). 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.

Additive prognostic value of plasma N-terminal pro-brain natriuretic peptide and coronary artery calcification for cardiovascular events and mortality in asymptomatic patients with type 2 diabetes.

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.

Measuring systolic ankle and toe pressure using the strain gauge technique--a comparison study between mercury and indium-gallium strain gauges.

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.

Prognostic implications of myocardial perfusion imaging by 82-rubidium positron emission tomography in male and female patients with angina and no perfusion defects.

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.

Quality of life, patient satisfaction, and cardiovascular outcomes of the randomised 2 x 3 factorial Copenhagen insulin and Metformin therapy (CIMT) trial - A detailed statistical analysis plan.

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, 8th of April 2008).

Myocardial Flow Reserve, an Independent Prognostic Marker of All-Cause Mortality Assessed by 82Rb PET Myocardial Perfusion Imaging: A Danish Multicenter Study.

BACKGROUND: Rubidium-82 positron emission tomography (82Rb PET) myocardial perfusion imaging is used in clinical practice to quantify regional perfusion defects. Additionally, 82Rb PET provides a measure of absolute myocardial flow reserve (MFR), describing the vasculature state of health. We assessed whether 82Rb 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 82Rb 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.

NT-proBNP, echocardiographic abnormalities and subclinical coronary artery disease in high risk type 2 diabetic patients.

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.

NT-proBNP levels, atherosclerosis and vascular function in asymptomatic type 2 diabetic patients with microalbuminuria: peripheral reactive hyperaemia index but not NT-proBNP is an independent predictor of coronary atherosclerosis.

UNLABELLED: Intensive multifactorial treatment aimed at cardiovascular (CV) risk factor reduction in type 2 diabetic patients with microalbuminuria can diminish fatal and non-fatal CV. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the utility of P-NT-proBNP in screening for atherosclerosis is unclear. We examined the interrelationship between P-NT-proBNP, presence of atherosclerosis and/or vascular dysfunction in the coronary, carotid and peripheral arteries in asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment. METHODS AND RESULTS: P-NT-proBNP was measured in 200 asymptomatic type 2 patients without known cardiac disease that received intensive multifactorial treatment for CV risk reduction. Patients were examined for coronary, carotid and peripheral atherosclerosis, as defined by coronary calcium score≥400, carotid intima-media thickness (CIMT)>0.90 mm, ankle-brachial index<0.90, and/or toe-brachial index<0.64, respectively. Carotid artery compliance was also determined and the reactive hyperaemia index (RHI) measured by peripheral artery tonometry was used as a surrogate for endothelial function.P-NT-proBNP was associated with atherosclerosis in the unadjusted analysis, but not after adjustment for conventional risk factors. P-NT-proBNP was not associated with vascular dysfunction. The prevalence of atherosclerosis in the coronary, carotid and peripheral arteries was 35%, 10% and 21% of all patients, respectively. In total 49% had atherosclerosis in one territory and 15.6% and 1.0% in two and three territories. Low RHI was an independent predictor of coronary atherosclerosis (odds ratio [CI], 2.60 [1.15-5.88] and systolic blood pressure was the only independent determinant of CIMT (0.02 mm increase in CIMT per 10 mmHg increase in systolic blood pressure [p=0.003]). CONCLUSIONS: Half of asymptomatic patients with type 2 diabetes mellitus and microalbuminuria had significant atherosclerosis in at least one vascular territory despite receiving intensive multifactorial treatment for CV risk reduction. Coronary atherosclerosis was most prevalent, whereas carotid disease was more rarely observed. RHI but not plasma NT-proBNP was predictive of coronary atherosclerosis.

Osteoprotegerin and coronary artery disease in type 2 diabetic patients with microalbuminuria.

OBJECTIVE: Plasma osteoprotegerin (P-OPG) is an independent predictor of cardiovascular disease in diabetic and other populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells and increased P-OPG may reflect arterial damage. We investigated the correlation between P-OPG and coronary artery disease (CAD) in asymptomatic type 2 diabetic patients with microalbuminuria. METHODS: P-OPG was measured in 200 asymptomatic diabetic patients without known cardiac disease. Patients with P-NT-proBNP >45.2 ng/l and/or coronary calcium score (CCS) ≥400 were stratified as high risk of 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 CT-angiography (n = 20), and/or coronary angiography (CAG; n = 86). Significant CAD was defined by presence of significant myocardial perfusion defects at MPI and/or >70% coronary artery stenosis at CAG. RESULTS: Significant CAD was demonstrated in 70 of the high risk patients and of these 23 patients had >70% coronary artery stenosis at CAG. Among high risk patients, increased P-OPG was an independent predictor of significant CAD (adjusted odds ratio [CI] 3.11 [1.01-19.54] and 3.03 [1.00-9.18] for second and third tertile vs.first tertile P-OPG, respectively) and remained so after adjustments for NT-proBNP and CCS. High P-OPG was also associated with presence of >70% coronary artery stenosis(adjusted odds ratio 14.20 [1.35-148.92] for third vs. first tertile P-OPG), and 91% of patients with low (first tertile) P-OPG did not have >70% coronary artery stenosis. CONCLUSIONS: Elevated P-OPG is an independent predictor of the presence of CAD in asymptomatic type 2 diabetic patients with microalbuminuria.

Elevated NT-proBNP and coronary calcium score in relation to coronary artery disease in asymptomatic type 2 diabetic patients with elevated urinary albumin excretion rate.

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.

Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study.

BACKGROUND: The use of carotid intima-media thickness (carotid IMT) as a surrogate marker of cardiovascular disease is increasing and the method has now also been applied in several trials investigating patients with type 2 diabetes (T2D). Even though knowledge about methodology is of highest importance in order to make accurate power calculations and analyses of results, no reproducibility studies have been performed in this group of patients. The aim of this study was to quantify the variability of the measurement of carotid IMT in individuals with and without T2D. METHODS: We used B-mode ultrasound and a computerized software programme (MIA vascular tools) for analysis of carotid IMT. Measurement of carotid IMT in the far wall of the common carotid artery (CCA) was done for 30 patients with T2D and 30 persons without T2D. The examinations were done by two different sonographers and two different readers on two separate days in order to quantify sonographer-, reader-, and day-to-day variability. RESULTS: Comparisons of measurement of carotid IMT in CCA between sonographers (sonographer variability) resulted in limits of agreement (LoA) from -0.18 to 0.13 mm for patients with T2D and -0.12 to 0.10 mm for persons without T2D. This means, that a second scanning of the same person with 95% probability would be within this interval of the first scanning. Comparisons between readers assessing the same scanning (reader variability) resulted in LoA from -0.05 to 0.07 mm and -0.04 to 0.05 mm respectively. LoA of the day-to-day variability was -0.13 to 0.18 mm and -0.09 to 0.18 mm respectively. This corresponds to coefficients of variations (CV) of the sonographer- and day-to-day variability of 10% in patients with T2D and 8% in persons without T2D. The CV of the reader variability was 4% and 3% respectively. CONCLUSION: Measurement of carotid IMT in the CCA can be determined with good and comparable reproducibility in both patients with T2D and persons without T2D. These findings support the use of carotid IMT in clinical trials with T2D patients and suggest that the numbers of patients needed to detect a given difference will be the same whether the patients have T2D or not.

High prevalence of peripheral arterial disease in patients with previous cerebrovascular or coronary event.

AIM: The presence of peripheral arterial disease (PAD) in patients with other manifestations of cardiovascular disease identifies a population at increased risk of complications both during acute coronary events and on a long-term basis and possibly a population in whom secondary prevention of cardiovascular events should be addressed aggressively. The present study was aimed at providing a valid estimate on the prevalence of PAD in patients attending their general practitioner and having previously suffered a cardio- or cerebrovascular event. PATIENTS AND METHODS: 1000 patients with a previous cardiovascular event were screened and PAD was considered present when the ankle-brachial index (ABI) of systolic blood pressure was less than 0.90 using the current recommended technique. RESULTS: 965 (659 men) patients met the inclusion criteria and had detectable systolic blood pressures on the arms and ankles. Mean age was 70±8 years, 77% were current or previous smokers, and 188 patients were diabetics. The medical history included stroke in 392, transitory ischemic attacks in 77, acute coronary syndrome in 298, and ST-elevation myocardial infarction in 253. Brachial systolic and diastolic blood pressures were 139±18 mmHg and 79±12 mmHg, respectively. Total and LDL-cholesterols were 4.5±1.0 mmol/l and 2.4±0.8 mmol/l, respectively. 625 patients were without PAD, 322 had mild to moderate PAD and 18 had severe PAD. The overall prevalence of PAD was 35.3%. CONCLUSION: In patients with previous coronary or cerebrovascular events, PAD occurs with a much higher prevalence than previously estimated. It is suggested that screening for PAD is justified and that it should be carried out in these patients in order to regulate the possible lifestyle and medical intervention.

Prediction of carotid intima-media thickness and its relation to cardiovascular events in persons with type 2 diabetes.

AIMS: To investigate measures of carotid intima-media thickness (IMT) and conventional cardiovascular (CV) risk factors as predictors of future carotid IMT, and the prediction of CV events during follow-up based on measures of carotid IMT. METHODS: Observational longitudinal study including 230 persons with type 2 diabetes (T2D). RESULTS: Mean age at follow-up was 66.7 (SD 8.5) years, 30.5% were women and mean body mass index (BMI) was 31.8 (4.4) kg/m2. Carotid IMT was measured at baseline, after 18 months of intervention in the Copenhagen Insulin and Metformin Therapy (CIMT) trial and after a mean follow-up of 6.4 (1.0) years. Baseline carotid IMT, carotid IMT after 18 months' intervention, and CV risk factors (age, sex and baseline systolic blood pressure) gave the best prediction of carotid IMT (root mean-squared error of prediction of 0.106 and 95% prediction error probability interval of -0.160, 0.204). CONCLUSIONS: Measures of carotid IMT combined with CV risk factors at baseline predicts attained carotid IMT better than measures of carotid IMT or CV risk factors alone. Carotid IMT did not predict CV events, and the present results do not support the use of carotid IMT as a predictor of CV events in persons with T2D.

Coronary and peripheral endothelial function in HIV patients studied with positron emission tomography and flow-mediated dilation: relation to hypercholesterolemia.

BACKGROUND: The mechanisms underlying increased cardiovascular risk in HIV patients in antiretroviral therapy (ART) are not known. Our aim was to study the endothelial function of the coronary arteries by cardiac perfusion positron emission tomography (PET), in HIV patients with normal or high cholesterol levels. Flow mediated dilation (FMD) of the brachial artery and circulating endothelial markers were also assessed. METHODS AND RESULTS: HIV patients in ART with total cholesterol or= 6.5 mmol/L (254 mg/dL; n = 12) and healthy controls (n = 14) were included. (13)NH(3) perfusion PET, FMD, and measurement of plasma levels of E-Selectin, ICAM-1, VCAM-1, tPAI-1, and hs-CRP were performed. Baseline myocardial perfusion and the coronary flow reserve measured by PET (3.2 +/- 0.3, 3.2 +/- 0.3 and 3.0 +/- 0.3; ns) was similar in HIV patients with normal or high total cholesterol and controls. FMD did not differ between the groups and was 4.6 +/- 1.1%, 5.1 +/- 1.2%, and 4.6 +/- 0.8%, respectively. Increased levels of plasma E-Selectin, ICAM-1, tPAI-1, and hs-CRP were found in HIV patients when compared to controls (p < 0.05). E-Selectin and ICAM-1 levels were higher in HIV patients receiving protease inhibitors (PI) compared to those not receiving PI (p < 0.05). None of the measured endothelial biomarkers differed between the normal and high cholesterol HIV groups. CONCLUSIONS: In ART-treated HIV patients with a low overall cardiovascular risk, no sign of endothelial dysfunction was found not even in hypercholesterolemic patients. Also, the increased level of plasma endothelial markers found in HIV patients was not related to hypercholesterolemia.

Oscillometric blood pressure measurement: a simple method in screening for peripheral arterial disease.

Blood pressure at the ankle level is a reliable indicator of peripheral arterial disease (PAD) and the ankle brachial index (ABI) is a useful non-invasive screening tool for the early detection of atherosclerosis. In the first part of the study, systolic blood pressures obtained by oscillometry and plethysmography were compared in 80 subjects referred for possible vascular disease. In the second part of the study, 31 general practitioners enrolled 1258 consecutive patients aged more than 60 years. ABI was estimated by oscillometry. Patients with an ABI lower than 0.9 were referred to the local hospital for standardized measurements. In the first part, oscillometry showed a sensitivity of 97% and a specificity of 62% with a positive and negative predictive value of 71% and 96%, respectively. In the second part, significant PAD was found in 111 cases corresponding to a prevalence of 12.2%. In this population, the oscillometry showed a positive predictive value of 47%. The presence of PAD was significantly correlated to exercise related leg pain, a diagnosis of hypertension and smoking, whereas no correlation could be found with a diagnosis of heart disease, stroke, or with the presence of diabetes. The prevalence of PAD was sufficiently high in subjects over the age of 60 years to warrant screening. The ankle brachial index based on measurements with an oscillometric device was shown reliable in the exclusion of PAD, thereby fulfilling an important criterion for the use in screening.

Carotid intima-media thickness in HIV patients treated with antiretroviral therapy.

INTRODUCTION: Increased cardiovascular risk in HIV patients in antiretroviral therapy (ART) may be due to HIV infection, direct effect of ART or dyslipidaemia induced by ART. Our aim was to study the relative importance of HIV, ART and dyslipidaemia on atherosclerosis, assessed by the comparison of carotid artery intima-media thickness (IMT) in non-smoking HIV patients with high or low serum cholesterol levels as well as in healthy volunteers. METHODS: HIV patients in ART with normal cholesterol (or=6 x 5 mmol l(-1); n=12) as well as healthy controls (n=14) were included. All were non-smokers and had never received medication for dyslipidaemia or hypertension. IMT was measured by ultrasonography. RESULTS: In HIV patients with normal cholesterol (or=6 x 5 mmol l(-1)) and in controls (5 x 1 +/- 0 x 9 mmol l(-1)) IMT were 683 +/- 119, 656 +/- 99 and 657 +/- 99 microm, respectively. Thus no difference in IMT was found between the three groups. IMT values did not differ between patients receiving and not receiving protease inhibitors (658 +/- 117 microm versus 687 +/- 97 microm, P>0 x 05). In HIV patients IMT correlated inversely with HDL cholesterol levels (r=-0 x 50; P=0 x 01), whereas no correlation was found with total cholesterol or LDL cholesterol. CONCLUSIONS: In non-smoking HIV patients receiving ART no sign of accelerated atherosclerosis was found as assessed by IMT even not in hypercholesterolaemic HIV patients. IMT correlated with HDL cholesterol but not with LDL cholesterol. Based on these observations, one could speculate whether selective lowering of LDL cholesterol will be successful in reducing cardiovascular risk in non-smoking HIV patients.

Autonomic dysfunction in HIV patients on antiretroviral therapy: studies of heart rate variability.

BACKGROUND: The presence of autonomic dysfunction in HIV patients is largely unknown. Early studies found autonomic dysfunction in patients with AIDS. Introduction of highly active antiretroviral combination therapy (ART) has dramatically changed the course of the disease and improved prognosis and decreased morbidity. At present it is not known whether introduction of ART also has decreased autonomic dysfunction. AIM: To evaluate whether autonomic dysfunction is present in an ART-treated HIV population. METHODS: HIV patients receiving ART for at least 3 years (n = 16) and an age-matched control group of healthy volunteers (n = 12) were included. All were non-smokers, non-diabetic and had never received medication for dyslipidaemia or hypertension. Following a 10 min resting period a 5 min ECG recording was performed. Heart rate variability (HRV) analysis was performed in accordance with current guidelines and data reported as median (interquartile range). RESULTS: The resting heart rate was higher in HIV patients compared with controls [69 (62-74) versus 57 (52-60); P<0.001]. Total HRV measured as standard deviation of normal-to-normal (SONN) was lower in the HIV group compared with the controls [36 (25-55) versus 74 (57-84) ms; P<0.01] as was parasympathetic activity measured as square root of the mean squared difference of successive normal-to-normal intervals (RMSSD) [22 (9-30) versus 35 (24-62) ms; P<0.05]. Low frequency power was lower in the HIV group compared with the control group [294 (161-602) versus 946 (711-1668) ms(2); P<0.01]. High frequency power as well as systolic and diastolic blood pressure did not differ between the groups. CONCLUSIONS: The HIV patients in ART have increased resting heart rate and decreased short-term heart rate variability indicating parasympathetic dysfunction.