Evaluation of a portable retinal imaging device: towards a comparative quantitative analysis for morphological measurements of retinal blood vessels.

This study investigated the possibility of using low-cost, handheld, retinal imaging devices for the automatic extraction of quantifiable measures of retinal blood vessels. Initially, the available handheld devices were compared using a Zeiss model eye incorporating a USAF resolution test chart to assess their optical properties. The only suitable camera of the five evaluated was the Horus DEC 200. This device was then subjected to a detailed evaluation in which images in human eyes taken from the handheld camera were compared in a quantitative analysis with those of the same eye from a Canon CR-DGi retinal desktop camera. We found that the Horus DEC 200 exhibited shortcomings in capturing images of human eyes by comparison with the Canon. More images were rejected as being unevaluable or suffering failures in automatic segmentation than with the Canon, and even after exclusion of affected images, the Horus yielded lower measurements of vessel density than the Canon. A number of issues affecting handheld cameras in general and some features of the Horus in particular have been identified that might contribute to the observed differences in performance. Some potential mitigations are discussed which might yield improvements in performance, thus potentially facilitating use of handheld retinal imaging devices for quantitative retinal microvascular measurements.

Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine.

PURPOSE: This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated. METHODS: The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV. RESULTS: Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots. CONCLUSIONS: Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.

Identification of Distinct Arterial Waveform Clusters and a Longitudinal Evaluation of Their Clinical Usefulness.

Clustering of arterial blood pressure (BP) waveform parameters could summarize complex information into distinct elements, which could be used to investigate cumulative (nonredundant) associations. We investigated this hypothesis in a large, adult population-based study (ViDA trial [Vitamin D Assessment] trial). To interpret the clusters and evaluate their usefulness, we examined their predictors and associations with cardiovascular events. In 4253 adults (mean age 65 years; 55% male) without a prior cardiovascular event, suprasystolic oscillometry was performed, yielding aortic pressure waveforms and several hemodynamic parameters. Participants were followed up for 4.6 years (median), accruing 300 cardiovascular events. Principal component analysis reduced 14 arterial waveform parameters to 3 uncorrelated factors that together explained 90% of the variability of the original data. Factors 1, 2, and 3 appeared to represent BP pulsatility, mean BP, and wave reflection, respectively. Across 6 antihypertensive drug classes, there were no differences in brachial systolic (P=0.23) and diastolic (P=0.13) BP; but there were significant variations in factor 3 (P<0.0001), especially for ß-blocker use. The first and third factors were positively associated with cardiovascular events (multivariable-adjusted standardized hazard ratio [95% CI]=1.33 [1.18-1.50] and 1.15 [1.02-1.30], respectively), whereas the second factor had a J-shaped relationship, with a nadir corresponding to a brachial diastolic BP of ≈75 mm Hg. In conclusion, BP pulsatility, mean BP, and wave reflection are prognostically meaningful, distinct aspects of arterial function that can be used to summarize physiological variations in multiple arterial waveform parameters and identify truly cumulative associations when used as cardiovascular risk outcomes.

Effect of Monthly, High-Dose, Long-Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy.

BACKGROUND: The effects of monthly, high-dose, long-term (≥1-year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. METHODS AND RESULTS: A total of 517 adults (58% male, aged 50-84 years) were recruited into a double-blinded, placebo-controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9-1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000-IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow-up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25-hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow-up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were -5.3 mm Hg (95% confidence interval [CI], -11.8 to 1.3) for brachial systolic BP (P=0.11), -2.8 mm Hg (95% CI, -6.2 to 0.7) for brachial diastolic BP (P=0.12), -7.5 mm Hg (95% CI, -14.4 to -0.6) for aortic systolic BP (P=0.03), -5.7 mm Hg (95% CI, -10.8 to -0.6) for augmentation index (P=0.03), -0.3 m/s (95% CI, -0.6 to -0.1) for pulse wave velocity (P=0.02), -8.6 mm Hg (95% CI, -15.4 to -1.9) for peak reservoir pressure (P=0.01), and -3.6 mm Hg (95% CI, -6.3 to -0.8) for backward pressure amplitude (P=0.01). CONCLUSIONS: Monthly, high-dose, 1-year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943.

Association of Retinopathy and Retinal Microvascular Abnormalities With Stroke and Cerebrovascular Disease.

BACKGROUND AND PURPOSE: Abnormalities of the retinal circulation may be associated with cerebrovascular disease. We investigated associations between retinal microvascular abnormalities and (1) strokes and subclinical cerebral infarcts and (2) cerebral white matter lesions in a UK-based triethnic population-based cohort. METHODS: A total of 1185 participants (age, 68.8±6.1 years; 77% men) underwent retinal imaging and cerebral magnetic resonance imaging. Cerebral infarcts and white matter hyperintensities were identified on magnetic resonance imaging, retinopathy was graded, and retinal vessels were measured. RESULTS: Higher retinopathy grade (odds ratio [OR], 1.40 [95% confidence interval (95% CI), 1.16-1.70]), narrower arteriolar diameter (OR, 0.98 [95% CI, 0.97-0.99]), fewer symmetrical arteriolar bifurcations (OR, 0.84 [95% CI, 0.75-0.95]), higher arteriolar optimality deviation (OR, 1.16 [95% CI, 1.00-1.34]), and more tortuous venules (OR, 1.20 [95% CI, 1.09-1.32]) were associated with strokes/infarcts and white matter hyperintensities. Associations with quantitative retinal microvascular measures were independent of retinopathy. CONCLUSIONS: Abnormalities of the retinal microvasculature are independently associated with stroke, cerebral infarcts, and white matter lesions.

Impact of blood pressure on retinal microvasculature architecture across the lifespan: the Young Finns Study.

OBJECTIVE: The present study examined the impact of BP from childhood to mid-adulthood on retinal microvascular architecture. METHODS: The Cardiovascular Risk in Young Finns Study included children aged 3-18 years, from five Finnish University cities, with participants chosen randomly from the national population registrar from those areas. The age of participants included in the current analyses in childhood (1980) ranged from three to nine years and in mid-adulthood (2011) ranged from 34 to 40 years (complete data n = 657). Measures of retinal microvasculature architecture measured in adulthood included diameters, tortuosity, lengths, and LDR. RESULTS: Regression analysis showed a strong negative association between childhood systolic BP and adult arteriolar diameter (standardized regression coefficient [ß] -0.300; p < 0.001) and with change in systolic BP from childhood to adulthood (ß = -0.249; p < 0.001). For arteriolar tortuosity, there was a strong positive association between childhood systolic BP and adult arteriolar tortuosity (ß = 0.154; p < 0.001) and no association with change in systolic BP from childhood to adulthood (ß = 0.072; p = 0.110). CONCLUSIONS: High BP in childhood and increased BP from childhood to adulthood impacts on retinal microvascular architecture in mid-adulthood.

A novel measure to characterise optimality of diameter relationships at retinal vascular bifurcations.

Conventionally, the relationship between parent and daughter vessels at vascular bifurcations has been expressed by the junction exponent (x), and deviations of this parameter from the optimal conditions predicted by Murray's law (x = 3) have been shown to be associated with vascular disease. However, the junction exponent is normally calculated iteratively from diameter measurements, and Monte-Carlo simulation studies show the junction exponent to be biased in the presence of measurement noise.We present an alternative parameter, referred to as optimality ratio, that is simpler to compute and also more robust in the presence of noise.To demonstrate the sensitivity of the optimality ratio to alterations in topography of the retinal vascular network, we analysed the effect of inducing endothelial dysfunction by infusion of NG-monomethyl-l-arginine (l-NMMA), a nitric oxide synthase inhibitor, compared to placebo in a double-blind crossover study. The optimality ratio showed a significant increase (p = 0.03) during infusion of l-NMMA compared to placebo.We propose that a measure of the extent of departure of optimality ratio from its optimal value of 2(-1/3) may be a useful indicator of microvascular endothelial dysfunction in vivo.

Wave reflection predicts cardiovascular events in hypertensive individuals independent of blood pressure and other cardiovascular risk factors: an ASCOT (Anglo-Scandinavian Cardiac Outcome Trial) substudy.

OBJECTIVES: This study investigated whether wave reflection measured by wave intensity analysis predicts future cardiovascular events in individuals with hypertension and sought to establish whether this relationship is independent of other cardiovascular risk factors and is associated with evidence of increased load on the left ventricle. BACKGROUND: Wave reflection may impose an additional load on the left ventricle, and augmentation index, a surrogate of wave reflection, has been reported to predict cardiovascular events in some, but not all studies. METHODS: Measurements of brachial and carotid blood pressure (BP) measurement, carotid ultrasound, echocardiography, and blood chemistry analyses were performed on 259 ASCOT (Anglo Scandinavian Cardiac Outcomes Trial) participants approximately 1 year after randomization, and wave intensity analysis was used to calculate wave reflection index (WRI), the ratio of peak forward to peak backward pressure (P(b)/P(f)), and carotid augmentation index (cAI(x)). All participants were followed up for a median period of 5.9 years, accruing 33 cardiovascular events. RESULTS: WRI, P(b)/P(f), and to a lesser extent, cAI(x), were correlated. WRI predicted cardiovascular events (hazard ratio: 2.10; 95% confidence interval: 1.10 to 3.99; p = 0.02) in an unadjusted model. Multivariate analysis showed that this association was independent of BP. P(b)/P(f) and cAI(x) did not significantly predict cardiovascular events. WRI was also positively associated with increased left ventricular mass index and elevated B-type natriuretic peptide adjusted for age and sex, and these associations were independent of BP or other cardiovascular risk factors. CONCLUSIONS: Higher wave reflection predicts future cardiovascular events independent of conventional risk factors in people with treated hypertension.

Differential effects of antihypertensive treatment on left ventricular diastolic function: an ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) substudy.

OBJECTIVES: We hypothesized that an amlodipine-based regimen would have more favorable effects on left ventricular (LV) diastolic function. BACKGROUND: Different antihypertensive therapies may vary in their effect on LV diastolic function. METHODS: The HACVD (Hypertension Associated Cardiovascular Disease) substudy of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) collected detailed cardiovascular phenotypic data on a subset of 1,006 participants recruited from 2 centers (St. Mary's Hospital, London, and Beaumont Hospital, Dublin). Conventional and tissue Doppler echocardiography and measurement of plasma B-type natriuretic peptide (BNP) were performed approximately 1 year after randomization to atenolol-based or amlodipine-based antihypertensive treatment to assess LV diastolic function. RESULTS: On-treatment blood pressure (BP) (mean +/- SD) was similar in both groups: atenolol-based regimen, systolic BP of 137 +/- 17 mm Hg, diastolic BP of 82 +/- 9 mm Hg; amlodipine-based regimen, systolic BP of 136 +/- 15 mm Hg, diastolic BP of 80 +/- 9 mm Hg. Ejection fraction did not differ between groups, but early diastolic mitral annular velocity (E'), a measure of diastolic relaxation, was lower in patients on the atenolol-based regimen: atenolol-based regimen, 7.9 +/- 1.8; amlodipine-based regimen, 8.8 +/- 2.0. A measure of left ventricular filling pressure, E/E', and BNP were significantly higher in patients on the atenolol-based regimen. Differences in E', E/E', and BNP remained significant after adjustment for age and sex. Further adjustment for systolic BP, LV mass index, and heart rate had no impact on differences in mean E' or BNP. The difference in E/E' was attenuated. CONCLUSIONS: Patients receiving treatment with an amlodipine-based regimen had better diastolic function than patients treated with the atenolol-based regimen. Treatment-related differences in diastolic function were independent of BP reduction and other factors that are known to affect diastolic function.

MR image-based geometric and hemodynamic investigation of the right coronary artery with dynamic vessel motion.

The aim of this study was to develop a fully subject-specific model of the right coronary artery (RCA), including dynamic vessel motion, for computational analysis to assess the effects of cardiac-induced motion on hemodynamics and resulting wall shear stress (WSS). Vascular geometries were acquired in the right coronary artery (RCA) of a healthy volunteer using a navigator-gated interleaved spiral sequence at 14 time points during the cardiac cycle. A high temporal resolution velocity waveform was also acquired in the proximal region. Cardiac-induced dynamic vessel motion was calculated by interpolating the geometries with an active contour model and a computational fluid dynamic (CFD) simulation with fully subject-specific information was carried out using this model. The results showed the expected variation of vessel radius and curvature throughout the cardiac cycle, and also revealed that dynamic motion of the right coronary artery consequent to cardiac motion had significant effects on instantaneous WSS and oscillatory shear index. Subject-specific MRI-based CFD is feasible and, if scan duration could be shortened, this method may have potential as a non-invasive tool to investigate the physiological and pathological role of hemodynamics in human coronary arteries.

Tissue Doppler E/E' ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT substudy.

AIMS: Patients with controlled hypertension are at risk of future cardiac events, but predicting first events remains difficult. We hypothesized that modern echocardiographic measures of left ventricular diastolic function may be more sensitive than traditional echocardiographic methods of risk prediction and set out to test this in a cohort of patients with well-controlled hypertension. METHODS AND RESULTS: Conventional and tissue Doppler echocardiography was performed on 980 participants in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). All subjects had hypertension, but no known cardiac disease. Cardiac events were defined as fatal and non-fatal myocardial infarction (including silent myocardial infarction), coronary revascularization procedures, new-onset angina (stable or unstable), fatal and non-fatal heart failure, and life-threatening arrhythmias. Analysis was performed by a single, blinded observer. There were 56 primary cardiac events during 4.2 +/- 0.7 years follow-up. The ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/E') was the strongest predictor of first cardiac events in Cox-proportional hazards models. Following adjustment for covariates, a unit rise in the E/E' ratio was associated with a 17% increment in risk of a cardiac event (HR 1.17, CI 1.05-1.29; P = 0.003). CONCLUSION: Tissue Doppler E/E', a non-invasive estimate of left atrial filling pressure, independently predicts primary cardiac events in a hypertensive population and out-performed traditional echocardiographic measures in this moderately sized, well-treated hypertensive population. E/E' represents a simple, effective tool for assessing cardiac risk in a hypertensive population.

Determinants of retinal microvascular architecture in normal subjects.

BACKGROUND: Recent studies have shown that changes in the retinal microvasculature predict cardiovascular disease (CVD); however, little is known regarding influences on the retinal microvasculature in healthy people without overt cardiovascular or metabolic disease. METHODS: We used a semiautomated computerized technique to analyze digitized retinal photographs from a total of 167 healthy people (age range, 45-75 years; 83 female), without clinical CVD, diabetes, or hypertension, randomly sampled from the population-based Beaver Dam Eye Study. We assessed arteriolar and venular narrowing, arteriolar optimality deviation, and other quantitative aspects of the retinal microvasculature. RESULTS: Arterioles were significantly narrower and longer, had wider branching angles, and were more tortuous than venules. Increased arteriolar length to diameter ratio (an index of ratio arteriolar narrowing) was positively and independently associated with older age and elevated systolic blood pressure. Arteriolar optimality deviation (an index of microvascular endothelial dysfunction) increased with greater body mass index. Current smoking and increased white blood cell (WBC) count was associated with wider venules. After controlling for smoking, WBC was no longer a significant predictor of venular diameter. CONCLUSIONS: CVD risk factors are associated with retinal microvascular changes in healthy individuals without evidence of CVD, diabetes, or hypertension. CVD risk factors have different influences on the arteriolar and venular bed.

Stress phase angle depicts differences in coronary artery hemodynamics due to changes in flow and geometry after percutaneous coronary intervention.

The effects of changes in flow velocity waveform and arterial geometry before and after percutaneous coronary intervention (PCI) in the right coronary artery (RCA) were investigated using computational fluid dynamics. An RCA from a patient with a stenosis was reconstructed based on multislice computerized tomography images. A nonstenosed model, simulating the same RCA after PCI, was also constructed. The blood flows in the RCA models were simulated using pulsatile flow waveforms acquired with an intravascular ultrasound-Doppler probe in the RCA of a patient undergoing PCI. It was found that differences in the waveforms before and after PCI did not affect the time-averaged wall shear stress and oscillatory shear index, but the phase angle between pressure and wall shear stress on the endothelium, stress phase angle (SPA), differed markedly. The median SPA was -63.9 degrees (range, -204 degrees to -10.0 degrees ) for the pre-PCI state, whereas it was 10.4 degrees (range, -71.1 degrees to 25.4 degrees ) in the post-PCI state, i.e., more asynchronous in the pre-PCI state. SPA has been reported to influence the secretion of vasoactive molecules (e.g., nitric oxide, PGI(2), and endothelin-1), and asynchronous SPA ( approximately -180 degrees ) is proposed to be proatherogenic. Our results suggest that differences in the pulsatile flow waveform may have an important influence on atherogenesis, although associated with only minor changes in the time-averaged wall shear stress and oscillatory shear index. SPA may be a useful indicator in predicting sites prone to atherosclerosis.

Comparison of the retinal microvasculature in European and African-Caribbean people with diabetes.

Diabetes aggravates the impact of elevated BP (blood pressure) on the microcirculation, and people of African ancestry with diabetes are more susceptible to microvascular damage than Europeans. In the present study, we investigated possible differences in the retinal microcirculation in people of European and African-Caribbean ethnicity with diabetes that might account for this. A total of 51 subjects with Type 2 diabetes (age 40-65 years; 25 male; 29 African-Caribbean) were studied. Clinic and 24 h ambulatory BP, and fasting glucose, insulin and lipids were measured. Digital retinal images were analysed using custom-written semi-automatic software to determine: LDR (length/diameter ratio) and AVR (arteriolar/venular diameter ratio), branching angles, vessel tortuosity and NT (number of terminal vessel branches). Arterioles were narrower in European people with diabetes than in African-Caribbean people with diabetes [mean (S.D.) arteriolar diameter, 76 (7) compared with 82 (11) microm respectively (P=0.03); arteriolar LDR, 28.1 (8.5) compared with 23.7 (7.0) respectively (P=0.046); and AVR, 0.66 (0.21) compared with 0.90 (0.36) respectively (P=0.028)]. Ethnic differences in arteriolar LDR, arteriolar diameter and AVR were not explained by differences in BP, but were attenuated by adjustment for the duration of diabetes. There was no significant relationship between BP and arteriolar narrowing in the group as a whole, although the relationship between arteriolar LDR and systolic BP was stronger in Europeans than African-Caribbeans [beta=0.08 (0.07) compared with beta=0.03 (0.06); P=0.03]. In conclusion, in the presence of diabetes, a relationship between BP and retinal arteriolar diameter was not evident and implies impaired small artery remodelling in the presence of diabetes. African-Caribbean people with diabetes have wider retinal arterioles and this could contribute to enhanced microvascular damage in this ethnic group.

Evidence of improved regional myocardial function in patients with chronic stable angina and apparent normal ventricular function--a tissue Doppler study before and after percutaneous coronary intervention.

BACKGROUND: The aim of this study was to determine the impact of percutaneous coronary intervention (PCI) on myocardial function assessed by tissue Doppler echocardiography. METHODS: Myocardial tissue peak velocities were recorded at the lateral, septal, posterior, and inferior angles of the mitral annulus as well as at the lateral tricuspid annulus by pulsed-wave tissue Doppler echocardiography before PCI, as well as 1 day and 6 weeks after intervention. RESULTS: Twenty-four consecutive patients with chronic stable angina and preserved systolic left ventricular function (20 men; mean age, 64 +/- 9 years) undergoing PCI were studied. Compared with preinterventional values, early diastolic velocities improved at all sites (P < .05 for each). The most pronounced improvement occurred in the septal area. Similarly, systolic peak velocity improved in the septal, lateral, inferior, and right ventricular areas (P < .04 for each). CONCLUSIONS: Tissue Doppler parameters of diastolic and systolic function improve early after successful PCI, and this effect persists to 6 weeks after intervention.

Retinal vascular lesions in patients of Caucasian and Asian origin with type 2 diabetes: baseline results from the ADVANCE Retinal Measurements (AdRem) study.

OBJECTIVE: The objective of this study was to describe prevalent vascular retinal lesions among patients with type 2 diabetes enrolled in the ADVANCE Retinal Measurements (AdRem) study, a substudy of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Seven-field stereoscopic photographs of both eyes were obtained at the baseline assessment of the ADVANCE trial. All photographs were graded in a central reading center. Gradable retinal images were received from 1,605 patients. RESULTS: The number of patients with any retinopathy (Early Treatment of Diabetic Retinopathy Study [ETDRS] score > or = 20) was 645 (40.2% [95% CI 37.8-42.6]); of these, 35 (2.2% [1.6-3.0]) had severe diabetic retinopathy (ETDRS score > or = 50). Focal arterial narrowing, venous beading, and arteriovenous nicking were present in 3.8, 5.1, and 9.8% of participants, respectively. Among participants included in this study, Chinese and South-Asian patients had more retinopathy than Caucasians, as defined both by ETDRS score (49.4, 46.0, and 31.3%, respectively; P < 0.001, adjusted for age, sex, A1C, systolic blood pressure, and duration of diabetes) and specific vascular lesions (e.g., arteriovenous nicking 12.3, 8.5, and 7.5%, respectively; adjusted P < 0.005). A1C, duration of diabetes, and systolic blood pressure were similarly associated with increased retinal lesions in Chinese, South-Asian, and Caucasian patients. CONCLUSIONS: Using a sensitive diagnostic procedure, more than one-third of patients with type 2 diabetes enrolled in the AdRem study had retinal lesions at baseline. Despite differences in prevalence and severity of retinopathy among Chinese, South-Asian, and Caucasian patients included in this study, the cross-sectional associations among established risk factors for retinopathy and retinal lesions were similar across ethnic groups.

Impact of size at birth on the microvasculature: the Avon Longitudinal Study of Parents and Children.

BACKGROUND: The impact of early life factors on the microvasculature is relatively unknown. OBJECTIVES: We hypothesized that small birth size may be associated with structural variations in the retinal vasculature in children. METHODS: The Avon Longitudinal Study of Parents and Children followed a cohort of children born in 1991-1992 from birth. The current study included the first 263 children who were systematically screened in the year-12 follow-up. Complete data were available for 166 children with a gestation of > or = 37 weeks. Retinal circulatory measures were evaluated, including retinal microvascular tortuosity and bifurcation optimality deviance, an indicator of abnormal endothelial function. RESULTS: Optimality deviance and retinal tortuosity were higher among those with lower birth weight. Linear regression modeling was used to assess the association of retinal microvascular measures with birth weight. The standardized beta coefficient between optimality deviance and birth weight was -.182 adjusted for gender and age in weeks; additional adjustment for systolic blood pressure and heart rate had little impact on the beta coefficient. A similar association was observed for retinal tortuosity. CONCLUSION: The findings of this study suggest that early life factors may have an important impact on retinal vascular structure, possibly through an adverse effect on endothelial function.

Rationale and design of the AdRem study: evaluating the effects of blood pressure lowering and intensive glucose control on vascular retinal disorders in patients with type 2 diabetes mellitus.

The ADVANCE Retinal Measurements (AdRem) Study is a large intervention study evaluating the effects of target driven intensive glucose control and placebo controlled blood pressure lowering on retinal vascular changes. AdRem is a sub-study of the ADVANCE Study (Action in Diabetes and Vascular disease), a 2x2 factorial randomized controlled trial with an ACE inhibitor-diuretic combination (perindopril-indapamide) and a gliclazide MR-based regimen in patients with type 2 diabetes mellitus. The AdRem study is based on seven-field stereoscopic retinal photographs of both eyes. These are taken within 3 months after randomization in ADVANCE (baseline), at the biennial and at the final visit. The primary outcome is progression of two or more steps in ETDRS classification. Secondary outcomes include progression of retinal vascular lesions and distortion of retinal vascular geometry. Retinal photographs are made on film and digitized at a central laboratory. The AdRem study uses fully digitized quality control and grading. Between August 2002 and January 2004 1978 patients were included in the AdRem study, from 39 centers in 14 countries. Approximately 85% comply with the strict AdRem quality requirements. Publication of the results is expected in early 2008. The AdRem study is designed to provide reliable evidence on the effects of intensive glucose control and blood pressure lowering on both diabetic retinopathy and abnormalities of retinal vasculature in patients with type 2 diabetes mellitus.

Quantification of topological changes in retinal vascular architecture in essential and malignant hypertension.

OBJECTIVE: Grading of hypertension severity by fundoscopic appearance is difficult and inaccurate. We investigated whether essential hypertension (EHT) and malignant phase hypertension (MHT) were associated with quantifiable abnormalities of the topology and architecture of the retinal circulation. METHODS: The topology and architecture of the retinal microvasculature were compared in images from 20 normotensive subjects, 20 patients with EHT and 20 patients with MHT. Digitized retinal photographs were analysed by a novel multiscale image analysis method using a semi-automated program to quantify geometrical and topological properties of arteriolar and venular trees. RESULTS: EHT was associated with an increase in the arteriolar length-to-diameter ratio (P < 0.01). There were also alterations in arteriolar topology indicative of rarefaction, including a marked reduction in the number of terminal branches in EHT (P < 0.01). These changes in the arteriolar network were exaggerated in MHT and there was also increased venular tortuosity and venular rarefaction in MHT compared with normotensive subjects. CONCLUSIONS: Hypertension is associated with marked topological alterations in the retinal vasculature, and quantification of these changes may be a useful novel approach to the assessment of target organ damage in hypertension.

Abnormalities of retinal microvascular structure and risk of mortality from ischemic heart disease and stroke.

Abnormalities of the retinal microcirculation are found in hypertension and diabetes and predict cardiovascular mortality. This study examined the relationship between abnormalities of the retinal microvasculature and death from ischemic heart disease (IHD) and stroke. A population-based, nested case-control study was undertaken within the Beaver Dam Eye Study. Subjects (43 to 74 years) who died of IHD (n=126) or stroke (n=28) over a 10-year period were age and gender matched with controls subjects (n=528; case:control matching, approximately 1:4). Retinal photographs of cases and controls were digitized and analyzed using a computer-based technique. Increased risk of IHD death was associated with a suboptimal relationship of arteriolar diameters at bifurcation (P=0.02 unadjusted) and decreased retinal arteriolar tortuosity (P=0.011 unadjusted). These associations remained significant after adjustment for age, sex, past history of cardiovascular disease, and other known cardiovascular risk factors. Increased arteriolar length:diameter ratio, a measure of generalized arteriolar narrowing, was associated with increased stroke mortality (P=0.02 unadjusted). This association was independent of age and gender but was attenuated by adjustment for systolic blood pressure (P=0.15). Other quantitative measures of the retinal microvascular network (eg, venular tortuosity and arteriolar and venular bifurcation angle) were not associated with death from IHD or stroke. Retinal microvascular abnormalities are predictive of death from IHD and stroke. A detailed assessment of the retinal microvascular network from digitized photographs may be useful in the noninvasive assessment of target organ damage and cardiovascular risk.