Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the present study was to investigate the effect of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in type 2 diabetic patients. METHODS: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Retinal Measurements study, a substudy of ADVANCE, is a randomised (using a central, computer-based procedure) controlled 2 x 2 factorial trial comprising a double-blind comparison of blood pressure lowering with perindopril-indapamide vs placebo, and an open comparison of standard vs intensive glucose control targeting a HbA(1c) of < or = 6.5% in 1,602 diabetic patients from ADVANCE centres with access to retinal cameras conducted from 2001 to 2008. At baseline and the final visit, seven-field stereoscopic retinal photographs were taken and graded by blinded readers (gradeable baseline and final photographs from 1,241 patients). Progression of > or =2 steps in the Early Treatment of Diabetic Retinopathy Study classification (using the eye with worst grading) was the primary outcome. RESULTS: Retinopathy progressed in 59 (4.8%) patients and developed in 128 (10.3%) patients over 4.1 years. Fewer patients on blood pressure-lowering treatment (n = 623) experienced incidence or progression of retinopathy compared with patients on placebo (n = 618), but the difference was not significant (OR 0.78; 95% CI 0.57-1.06; p = 0.12). Blood pressure-lowering treatment reduced the occurrence of macular oedema (OR 0.50; 95% CI 0.29-0.88; p = 0.016) and arteriovenous nicking compared with placebo (OR 0.60; 95% CI 0.38-0.94; p = 0.025). Compared with standard glucose control (n = 611), intensive glucose control (n = 630) did not reduce (p = 0.27) the incidence and progression of retinopathy (OR 0.84; 95% CI 0.61-1.15). Lower, borderline significant risks of microaneurysms, hard exudates and macular oedema were observed with intensive glucose control, adjusted for baseline retinal haemorrhages. These effects of the two treatments were independent and additive. Adverse events in the ADVANCE study are reported elsewhere. CONCLUSIONS/INTERPRETATION: Blood pressure lowering or intensive glucose control did not significantly reduce the incidence and progression of retinopathy, although consistent trends towards a benefit were observed, with significant reductions in some lesions observed with both interventions. TRIAL REGISTRATION: ClinicalTrials.gov ID no. NCT00145925. FUNDING: Grants from Servier and the National Health and Medical Research Council of Australia.

The effect of dynamic vessel motion on haemodynamic parameters in the right coronary artery: a combined MR and CFD study.

Human right coronary artery (RCA) haemodynamics is investigated using computational fluid dynamics (CFD) based on subject-specific information from magnetic resonance (MR) acquisitions. The dynamically varying vascular geometry is reconstructed from MR images, incorporated in CFD in conjunction with pulsatile flow conditions obtained from MR velocity mapping performed on the same subject. The effects of dynamic vessel motion on instantaneous and cycle-averaged haemodynamic parameters, such as wall shear stress (WSS), time-averaged WSS (TAWSS) and oscillatory shear index (OSI), are examined by comparing an RCA model with a time-varying geometry and those with a static geometry, corresponding to nine different time-points in the cardiac cycle. The results show that the TAWSS is similar for the dynamic and static wall models, both qualitatively and quantitatively (correlation coefficient 0.89-0.95). Conversely, the OSI shows much poorer correlations (correlation coefficient 0.38-0.60), with the best correspondence being observed with the static models constructed from images acquired in late diastole (at t = 0 and 800 ms, the cardiac cycle is 900 ms). These findings suggest that neglecting dynamic motion of the RCA is acceptable if TAWSS is the primary focus but may result in underestimation of haemodynamic parameters related to the oscillatory nature of the blood flow.

Analysis of complex flow and the relationship between blood pressure, wall shear stress, and intima-media thickness in the human carotid artery.

BACKGROUND: Previous clinical studies have observed relationships between increased intima-media thickness (IMT) in the carotid artery, elevated blood pressure, and low wall shear stress (WSS) calculated from the Poiseuille equation. This study used numerical methods to more accurately determine WSS in the carotid artery and to investigate possible determinants of increased IMT. METHODS: IMT [common carotid artery (CCA) and bulb], CCA flow velocity, brachial systolic (SBP) and diastolic blood pressure (DBP), and carotid systolic pressure (cSBP) were measured in 14 healthy subjects (aged 44 +/- 16 yr). Flow patterns in the carotid bifurcation were determined by computational fluid dynamics (CFD) based on three-dimensional ultrasound geometry. Instantaneous and time-averaged wall shear stress (WSS(av)), oscillatory shear index (OSI), and wall shear stress angle gradients (WSSAG) were calculated. RESULTS: IMT was positively related to SBP, DBP, cSBP, and WSSAG and inversely related to WSS(av) in the CCA. In the bulb, IMT was positively related to SBP and cSBP but was not significantly related to WSS(av) or WSSAG. IMT was unrelated to OSI in both the CCA and the bulb. CONCLUSION: Increased carotid artery IMT in healthy subjects with no evidence of focal plaques is primarily a response to elevated pressure.

Wave-energy patterns in carotid, brachial, and radial arteries: a noninvasive approach using wave-intensity analysis.

The study of wave propagation at different points in the arterial circulation may provide useful information regarding ventriculoarterial interactions. We describe a number of hemodynamic parameters in the carotid, brachial, and radial arteries of normal subjects by using noninvasive techniques and wave-intensity analysis (WIA). Twenty-one normal adult subjects (14 men and 7 women, mean age 44 +/- 6 yr) underwent applanation tonometry and pulsed-wave Doppler studies of the right common carotid, brachial, and radial arteries. After ensemble averaging of the pressure and flow-velocity data, local hydraulic work was determined and a pressure-flow velocity loop was used to determine local wave speed. WIA was then applied to determine the magnitude, timings, and energies of individual waves. At all sites, forward-traveling (S) and backward-traveling (R) compression waves were observed in early systole. In mid- and late systole, forward-traveling expansion waves (X and D) were also seen. Wave speed was significantly higher in the brachial (6.97 +/- 0.58 m/s) and radial (6.78 +/- 0.62 m/s) arteries compared with the carotid artery (5.40 +/- 0.34 m/s; P < 0.05). S-wave energy was greatest in the brachial artery (993.5 +/- 87.8 mJ/m2), but R-wave energy was greatest in the radial artery (176.9 +/- 19.9 mJ/m2). X-wave energy was significantly higher in the brachial and radial arteries (176.4 +/- 32.7 and 163.2 +/- 30.5 mJ/m2, respectively) compared with the carotid artery (41.0 +/- 9.4 mJ/m2; P < 0.001). WIA illustrates important differences in wave patterns between peripheral arteries and may provide a method for understanding ventriculo-arterial interactions in the time domain.

The integration of medical imaging and computational fluid dynamics for measuring wall shear stress in carotid arteries.

The link between atherosclerosis and wall shear stress (WSS) has lead to considerable interest in the in vivo estimation of WSS. Both magnetic resonance imaging (MRI) and three-dimensional ultrasound (3DUS) are capable of providing the anatomical and flow data required for subject-specific computational fluid dynamics (CFD) simulations. This study compares, for the first time, predicted 3D flow patterns based on black blood MRI and 3DUS. Velocity fields in the carotid arteries of nine subjects have been reconstructed, and the haemodynamic wall parameters WSS, oscillatory shear index (OSI), WSS gradients (WSSG) and angle gradients (WSSAG) were computed and compared. There was a good qualitative agreement between results derived from MRI and 3DUS, embodied by a strong linear correlation between the patched representations of the haemodynamic wall parameters. The root-mean-square error between haemodynamic wall parameters was comparable to the range of the expected variability of each imaging technique (WSS: 0.411 N/m; OSI: 0.048; temporal WSSG: 2.29 N/(s.m/sup 2/); spatial WSSG: 150 N/m/sup 3/; WSSAG: 87.6 rad/m). In conclusion, MRI and 3DUS are comparable techniques for combining with CFD in the carotid artery. The relatively high cost of MRI favour 3DUS to MRI for future haemodynamic studies of superficial arteries.

Image-based carotid flow reconstruction: a comparison between MRI and ultrasound.

Atherosclerosis is a major cause of morbidity and mortality. Its apparent link with wall shear stress (WSS) has led to considerable interest in the in vivo estimation of WSS. Determining WSS by combining medical images with computational fluid dynamics (CFD) simulations can be performed both with magnetic resonance imaging (MRI) and three-dimensional ultrasound (3DUS). This study compares predicted 3D flow patterns based on black blood MRI and 3DUS. Velocity fields in the carotid arteries of nine subjects have been reconstructed, and the haemodynamic wall parameters WSS, oscillatory shear index (OSI), WSS gradients (WSSG) and angle gradients (WSSAG) were compared between the two imaging techniques. There was a good qualitative agreement between results derived from MRI and 3DUS (average correlation strength above 0.60). The root mean square error between haemodynamic wall parameters was comparable to the range of the expected variability of each imaging technique (WSS: 0.411 N m(-2); OSI: 0.048; temporal WSSG: 150 N s(-1) m(-2); spatial WSSG: 2.29 N m(-3); WSSAG: 87.6 rad m(-1)). In conclusion, MRI and 3DUS are capable of providing haemodynamic parameters when combined with CFD, and the predictions are in most cases qualitatively and quantitatively similar. The relatively high cost of MRI and continuing improvement in ultrasound favour US to MRI for future haemodynamic studies of superficial arteries.

Accuracy and reproducibility of CFD predicted wall shear stress using 3D ultrasound images.

Computational fluid dynamics (CFD) flow simulation techniques have the potential to enhance our understanding of how haemodynamic factors are involved in atherosclerosis. Recently, 3D ultrasound has emerged as an alternative to other 3D imaging techniques, such as magnetic resonance angiography (MRA). The method can be used to generate realistic vascular geometry suitable for CFD simulations. In order to assess accuracy and reproducibility of the procedure from image acquisition to reconstruction to CFD simulation, a human carotid artery bifurcation phantom was scanned three times using 3D ultrasound. The geometry was reconstructed and flow simulations were carried out on the three sets as well as on a model generated using computer aided design (CAD) from the geometric information given by the manufacturer. It was found that the three reconstructed sets showed good reproducibility as well as satisfactory quantitative agreement with the CAD model. Analyzing two selected locations probably representing the 'worst cases,' accuracy comparing ultrasound and CAD reconstructed models was estimated to be between 7.2% and 7.7% of the maximum instantaneous WSS and reproducibility comparing the three scans to be between 8.2% and 10.7% of their average maximum.

Pre-eclampsia, antiretroviral therapy, and immune reconstitution.

Antiretrovirals are standard treatment for HIV-1-positive women during pregnancy in the UK, but little is known about maternal or fetal safety. In our cohort study of 214 pregnant women with HIV-1 infection, those who received no antiretroviral therapy had a rate of pre-eclampsia significantly lower (none of 61) than those on triple antiretroviral therapy (8 of 76; odds ratio 15.3, 95% CI 0.9-270, p=0.0087). However, the rate of pre-eclampsia in HIV-1-positive women on treatment did not differ from that in uninfected controls (12 of 214; p=0.2). The association of HIV-1-related immune deficiency with a low rate of pre-eclampsia, and the restoration of this rate in women treated with triple antiretroviral therapy to the expected rate indicates a pivotal role of the immune system in the pathogenesis of pre-eclampsia. The clinical presentation of pre-eclampsia and toxic effects of antiretroviral therapy could overlap and complicate diagnosis and management in these patients.

Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects.

Endothelin-1 (ET-1) has been proposed to contribute to the regulation of vascular tone in humans. BQ-123, an ET(A) receptor antagonist, has also been reported to increase forearm blood flow (FBF) in vivo; however, the efficacy of BQ-123 as an antagonist of ET-1 has not been evaluated in the forearm. The present study investigated the effects of BQ-123 on changes in FBF in response to ET-1 and noradrenaline (NA; norepinephrine), taking into account the possible influence of vasodilator effects of BQ-123 on responses to vasoconstrictors. Six subjects (age 25-34 years) participated in a double-blind randomized study. FBF was measured by forearm occlusion plethysmography. Drugs were infused intra-arterially into the non-dominant arm (study arm) on four separate occasions; the non-infused arm was used as a control. The effects of BQ-123 (50 nmol/min for 60 min, or 300 nmol/min for 5 min followed by saline for 55 min) were compared with the effects of infusion of sodium nitroprusside (SNP; 12 nmol/min for 60 min) or saline on vasoconstriction induced by ET-1 (10 pmol/min for 7 min) and NA (120 pmol/min for 7 min). Infusion of BQ-123 at either dose did not significantly increase FBF, whereas SNP increased FBF by 134% (P=0.03). ET-1 significantly reduced FBF, and this effect was almost completely inhibited by both doses of BQ-123, but was unaffected by SNP. NA also reduced FBF, and this action was unaffected by BQ-123 or SNP. The data show that BQ-123 is a selective ET-1 antagonist, but do not confirm a major role for ET-1 in influencing resting forearm vascular tone in young normotensive subjects.

Racial differences in cardiac structure and function in essential hypertension.

OBJECTIVE: To assess racial differences in cardiac structure and function in patients presenting with previously untreated hypertension. DESIGN: Untreated black patients with hypertension were compared with untreated white patients matched for age and sex. Both groups had similar body mass indices, blood pressures, and reported duration of hypertension. SETTING: Cardiovascular risk factor clinic for outpatients. SUBJECTS: 36 men and 22 women with untreated essential hypertension. MAIN OUTCOME MEASURES: Variables of heart structure and function on cross sectional and Doppler echocardiography. RESULTS: The black patients had a significantly greater interventricular septal thickness (mean 1.23 (95% confidence interval 1.14 to 1.33) v 1.09 (1.02 to 1.16) cm; P = 0.02) and posterior wall thickness (mean 1.14 (1.07 to 1.22) v 0.96 (0.88 to 1.03) cm; P = 0.001) than the white patients, although left ventricular internal diameter was not significantly different (mean 4.90 (4.68 to 5.12) v 4.82 (4.64 to 5.01) cm; P = 0.59). This resulted in a significantly greater left ventricular mass index (mean 151 (137 to 164) v 120 (107 to 133) g/m2; P = 0.001) and relative wall thickness (mean 0.47 (0.43 to 0.51) v 0.40 (0.37 to 0.42) cm; P = 0.004) in the black patients. Comparison of Doppler measures of left ventricular diastolic function showed a significantly longer isovolumic relaxation time in black patients (mean 107 (98 to 116) v 92 (83 to 101) ms; P = 0.02) compared with white patients, although peak early to atrial filling ratios were similar in both groups (mean 1.14 (0.95 to 1.32) v 1.04 (0.94 to 1.15); P = 0.37). CONCLUSION: Among previously untreated hypertensive patients, black subjects compared with white subjects have significantly higher left ventricular mass index and relative wall thickness, as well as more impairment of left ventricular function during diastole.