Narrower Retinal Arteriolar Caliber Research Articles

Deep-learning retinal vessel calibre measurements and risk of cognitive decline and dementia.

Previous studies have explored the associations of retinal vessel calibre, measured from retinal photographs or fundus images using semi-automated computer programs, with cognitive impairment and dementia, supporting the concept that retinal blood vessels reflect microvascular changes in the brain. Recently, artificial intelligence deep-learning algorithms have been developed for the fully automated assessment of retinal vessel calibres. Therefore, we aimed to determine whether deep-learning-based retinal vessel calibre measurements are predictive of risk of cognitive decline and dementia. We conducted a prospective study recruiting participants from memory clinics at the National University Hospital and St. Luke's Hospital in Singapore; all participants had comprehensive clinical and neuropsychological examinations at baseline and annually for up to 5 years. Fully automated measurements of retinal arteriolar and venular calibres from retinal fundus images were estimated using a deep-learning system. Cox regression models were then used to assess the relationship between baseline retinal vessel calibre and the risk of cognitive decline and developing dementia, adjusting for age, gender, ethnicity, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes, and smoking. A total of 491 participants were included in this study, of whom 254 developed cognitive decline over 5 years. In multivariable models, narrower retinal arteriolar calibre (hazard ratio per standard deviation decrease = 1.258, P = 0.008) and wider retinal venular calibre (hazard ratio per standard deviation increase = 1.204, P = 0.037) were associated with increased risk of cognitive decline. Among participants with cognitive impairment but no dementia at baseline (n = 212), 44 progressed to have incident dementia; narrower retinal arteriolar calibre was also associated with incident dementia (hazard ratio per standard deviation decrease = 1.624, P = 0.021). In summary, deep-learning-based measurement of retinal vessel calibre was associated with risk of cognitive decline and dementia.

Associations of Retinal Vessel Caliber With Hearing Status in Childhood and Midlife

Microvascular phenotypes, which can be assessed using retinal imaging, may be informative about the life course pathogenesis of hearing loss. To investigate whether differences in retinal vessel caliber (specifically wider venules and narrower arterioles) are associated with hearing threshold and hearing loss in mid-childhood and midlife. A population-based cross-sectional study (Child Health CheckPoint) was nested within the Longitudinal Study of Australian Children. A total of 1281 children and 1255 attending parents were assessed using retinal microvasculature and air conduction audiometry data at a main assessment center in 7 large cities in Australia. Air conduction audiometry was used to calculate the high Fletcher index (mean threshold of 1, 2, and 4 kHz), and bilateral hearing loss was defined as a high Fletcher index greater than 15 dB hearing level in the better-hearing ear. Retinal arteriolar and venular caliber were measured from fundus photographs using validated computer-based software. Linear and logistic regression quantified the associations of retinal vessel caliber with hearing threshold and hearing loss, respectively. Of the 1281 included children (mean age, 11.4 years; 49.1% boys), the mean (SD) high Fletcher index was 7.9 (5.8) dB hearing level. Of the 1255 included adults (mean age, 43.8 years; 86.6% women), the mean (SD) high Fletcher index was 13.0 (6.8) dB hearing level; 109 of 1281 children (8.5%) and 328 of 1255 adults (26.1%) had hearing loss. In adults, each 1-SD (18.6-μm) wider retinal venular caliber (worse) was associated with higher (worse) hearing threshold at lower individual frequencies (eg, 2 kHz: β = 0.63; 95% CI, 0.10-1.17) and overall high Fletcher index (eg, 2 kHz: β = 0.52; 95% CI, 0.07-0.96), as well as a 1.20-fold (95% CI, 1.03-1.40) higher odds of hearing loss. In children, patterns of venular associations were similar but smaller and less certain. Narrower retinal arteriolar caliber (worse) was associated with a 1.16-fold (95% CI, 1.00-1.37) higher odds of hearing loss in adults (per 1-SD [14.0-μm] narrower arteriolar caliber) but not in children. Adverse retinal microvascular characteristics are associated with hearing loss by midlife, with venular associations possibly emerging by age 11 to 12 years. Microvascular health may contribute to the pathogenesis of hearing loss across the life course, warranting replication and mechanistic studies to inform causal inference and prevention efforts.

Association between blood pressure and retinal arteriolar and venular diameters in Chinese early adolescent children, and whether the association has gender difference: a cross-sectional study

BackgroundTo establish the independent association between blood pressure (BP) and retinal vascular caliber, especially the retinal venular caliber, in a population of 12-year-old Chinese children.MethodsWe have examined 1501 students in the 7th grade with mean age of 12.7 years. A non-mydriatic fundus camera (Canon CR-2, Tokyo, Japan) was used to capture 450 fundus images of the right eyes. Retinal vascular caliber was measured using a computer-based program (IVAN). BP was measured using an automated sphygmomanometer (HEM-907, Omron, Kyoto, Japan).ResultsThe mean retinal arteriolar caliber was 145.3 μm (95% confidence interval [CI], 110.6–189.6 μm) and the mean venular caliber was 212.7 μm (95% CI, 170.6–271.3 μm). After controlling for age, sex, axial length, BMI, waist, spherical equivalent, birth weight, gestational age and fellow retinal vessel caliber, children in the highest quartile of BP had significantly narrower retinal arteriolar caliber than those with lower quartiles (P for trend< 0.05). Each 10-mmHg increase in BP was associated with narrowing of the retinal arterioles by 3.00 μm (multivariable-adjusted P < 0.001), and the results were consist in three BP measurements. The association between BP measures and retinal venular caliber did not persist after adjusting for fellow arteriolar caliber. And there was no significant interaction between BP and sex, age, BMI, and birth status.ConclusionsIn a large population of adolescent Chinese children, higher BP was found to be associated with narrower retinal arterioles, but not with retinal venules. Sex and other confounding factors had no effect on the relationship of BP and retinal vessel diameter.

Gestational retinal microvasculature and the risk of 5year postpartum abnormal glucose metabolism.

Changes in retinal microvasculature may reflect insulin resistance. We examined the association of changes in retinal microvasculature during pregnancy and risk of subsequent abnormal glucose metabolism in a cohort of mothers at baseline and 5years postpartum. Of the participants from the Singapore birth cohort (Growing Up in Singapore Towards Healthy Outcomes [GUSTO]), 276 mothers attended both baseline (at 26-28weeks of gestation) and follow-up (5year postpartum) visits. At baseline we performed retinal photography and assessed retinal microvascular variables using a validated grading system. At follow-up, we assessed glucose tolerance using a 75g OGTT. We defined abnormal glucose metabolism if participants: (1) had onset of gestational diabetes mellitus (GDM) in subsequent pregnancies within a 5year follow-up period (n=103) or (2) had prediabetes (impaired fasting glucose, impaired glucose tolerance or HbA1c 5.7-6.4% [39-46mmol/mol]) and diabetes diagnosed at the 5year follow-up visit (n=84), according to WHO guidelines. The incidence of GDM in subsequent pregnancy and abnormal glucose metabolism 5years postpartum was 25.2% and 30.4%, respectively. Each 10μm widening in retinal venular calibre was associated with a significant risk of postpartum abnormal glucose metabolism (RR 1.2 [95% CI 1.0, 1.5]), independent of maternal age, college education, ethnicity, pre-pregnancy BMI and GDM at baseline. Narrower retinal arteriolar calibre and venular branching angle at baseline was associated with a higher insulin resistance index (1.4 [95% CI 1.1, 1.7] and 1.3 [95% CI 1.1, 1.6], respectively) at follow-up. Retinal microvasculature in pregnant women was associated with abnormal glucose metabolism 5years postpartum. Alteration of microvascular structure during pregnancy may signal subclinical changes that underlie the development of prediabetes and diabetes.

PP.19.28] DETECTION OF RETINAL MICROVASCULAR ALTERATIONS IN RHEUMATOID ARTHRITIS PATIENTS WITHOUT CARDIOVASCULAR DISEASES

Objective: Quantitative evaluation of the retinal vasculature using the non-mydriatic fundus camera is gaining increasing attention as an early, subclinical indicator of cardiovascular risk. Subtle alterations of the retinal vessels have been consistently observed in populations with cardiovascular diseases. However, it has not been investigated whether the retinal microvasculature is affected in patients with autoimmune rheumatic diseases, who are typically perceived as a high-cardiovascular risk population, in the absence of established cardiovascular disease. Design and method: Consecutive patients with rheumatoid arthritis were recruited from the Rheumatology Outpatient Unit of our Department and were matched with healthy, nontreated volunteers for the purposes of the study. Patients were free from cardiovascular comorbidities including high blood pressure, diabetes mellitus, heart diseases and stroke. All participants underwent fundus photography with a non mydriatic NIDEK AFC-230/210 camera. Semi-automated software was developed to calculate central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), as well as the retinal arteriovenus ratio (AVR). Results: A total of 28 patients with rheumatoid arthritis and 32 controls aged 57.1 ± 10.9 years were included in the study. Patients were matched with controls in terms of age, gender, systolic/diastolic blood pressure and cholesterol levels (p > 0.05 for all). Patients exhibited significantly lower CRAE compared to controls (81.1 ± 11.0 vs 92.9 ± 8.3, p < 0.001), and the same was observed with AVR (0.70 ± 0.09 vs 0.83 ± 0.08, p < 0.001). CRVE was comparable between patients and controls (117.2 ± 15.4 vs 112.7 ± 11.2, p = 0.204). Conclusions: Narrower retinal arteriolar calibre and lower AVR were observed in a meticulously selected sample of rheumatoid arthritis patients without established cardiovascular diseases. Rheumatoid arthritis patients may exhibit subtle retinal microvascular abnormalities, even in the absence of clinically evident cardiovascular disease.

Influence of Maternal Gestational Hypertensive Disorders on Microvasculature in School-Age Children: The Generation R Study.

Gestational hypertensive disorders may lead to vascular changes in the offspring. We examined the associations of maternal blood pressure development and hypertensive disorders during pregnancy with microvasculature adaptations in the offspring in childhood. This study was performed as part of the Generation R Study in Rotterdam, the Netherlands (2002-2012), among 3,748 pregnant mothers and their children for whom information was available on maternal blood pressure in different periods of pregnancy and gestational hypertensive disorders. Childhood retinal arteriolar and venular calibers were assessed at the age of 6 years. We found that higher maternal systolic and diastolic blood pressures in early pregnancy were associated with childhood retinal arteriolar narrowing (P < 0.05). Higher maternal systolic blood pressure in late pregnancy, but not in middle pregnancy, was associated with childhood narrower retinal venular caliber (standard deviation score per standardized residual increase in systolic blood pressure: -0.05; 95% confidence interval: -0.08, -0.01). Paternal blood pressure was not associated with childhood retinal vessel calibers. Children of mothers with gestational hypertensive disorders tended to have narrower retinal arteriolar caliber (standard deviation score: -0.13, 95% confidence interval: -0.27, 0.01). Our results suggest that higher maternal blood pressure during pregnancy is associated with persistent microvasculature adaptations in their children. Further studies are needed to replicate these observations.

Inter-Relationships Between Retinal Vascular Caliber, Retinal Nerve Fiber Layer Thickness, and Glaucoma: A Mediation Analysis Approach.

The purpose of this study was to explore the interrelationships among retinal vascular caliber, retinal nerve fiber layer (RNFL), and glaucoma; in particular, whether the relationship between narrower retinal vascular caliber and glaucoma is mediated by thinning of RNFL. A total of 9407 participants, including 253 glaucoma and 195 primary open-angle glaucoma (POAG) cases from the Singapore Epidemiology of Eye Diseases Study were included in this study. All participants underwent standardized examinations. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. Logistic regression analyses were used to determine the total direct effects of retinal vascular calibers on glaucoma. Regression-based mediation analyses were used to evaluate the indirect effects of retinal vascular caliber on glaucoma through RNFL thinning. After we adjusted for relevant covariates, narrower retinal arteriolar caliber (per standard deviation [SD], 15.1-μm decrease) was associated with glaucoma (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.06-1.38) and POAG (OR, 1.23; 95% CI, 1.06-1.43). Similarly, narrower retinal venular caliber (per SD, 21.6μm decrease) was associated with glaucoma (OR, 1.51; 95% CI, 1.32-1.73) and POAG (OR, 1.64; 95% CI, 1.41-1.91). In addition, there were significant indirect effects of retinal vascular narrowing on glaucoma through thinning of RNFL (all P < 0.001), with mediated proportion of 36.9% and 12.9% in retinal arteriole- and venule-related analysis, respectively. Mediation analyses indicated that the effect of retinal vascular narrowing on glaucoma was partially the result of thinning of RNFL. These findings provide additional mechanistic insights linking retinal vascular narrowing and glaucoma.

Effects of longitudinal body mass index variability on microvasculature over 5 years in adult Chinese

To explore the associations of 5-year trend and fluctuation in body mass index (BMI) with retinal vascular caliber in a middle-aged and elderly Chinese population. Participants age ≥40 years were recruited in a prospective study. Baseline BMI data were collected in 2008, and the participants were re-examined annually until 2012. Retinal vascular caliber was measured from fundus photographs collected in 2012. BMI trend was calculated as the slope of BMI against the time of examinations. BMI fluctuation was defined as the root mean square error around the regression line of BMI over time (BMI RMSE) and the coefficient of variation of BMI (BMI CV). Rising BMI trend was associated with narrower retinal arteriolar and wider venular calibers in the overall subjects, especially among persons with overweight and obesity (BMI ≥ 25 kg/m(2) , P = 0.004 and 0.033, respectively). Rising BMI trend was also significantly associated with narrower retinal arteriole even in nonobese individuals with BMI < 25 kg/m(2) (P = 0.017) when eliminating the effects of hypertension and diabetes. Neither BMI RMSE nor BMI CV was statistically associated with retinal vascular caliber (all P > 0.05). Annual rising trending BMI was associated with retinal microvascular alteration. The results suggest that weight gain probably increases the risk of cardiovascular diseases among middle-aged and elderly people.

Prevalence and risk factors for diabetic retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes.

The aim of this study was to investigate the prevalence of, and traditional and emerging risk factors associated with, retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes. This was a cross-sectional study of 483 children and adolescents with type 1 diabetes. Medical files were audited to collect all relevant clinical data. Diabetic retinopathy was assessed from colour retinal images by an ophthalmologist. Diabetic retinopathy was observed in 11 (2.3%) participants. Logistic regression revealed that the principal components analysis derived risk profile of: higher serum creatinine, older age, higher systolic blood pressures, higher body mass index, abnormal estimated glomerular filtration rate (eGFR) (<59 mL/min), lower high density lipoproteins (HDL) cholesterol, higher serum sodium, longer duration of diabetes and narrower retinal arteriolar calibre was associated with diabetic retinopathy (ExpB=2.60, 95% CI 1.36/4.96, p=0.004). These results support the concept that the pathogenesis of diabetic retinopathy is likely due to the combined influence of various risk factors, many already identified.

Ambulatory aortic stiffness, independently of static, associates with narrower retinal arteriolar calibers in hypertensives: The SAFAR study

Ambulatory aortic stiffness, independently of static, associates with narrower retinal arteriolar calibers in hypertensives: The SAFAR study

Metabolic syndrome and retinal microvascular calibre in a high cardiovascular disease risk cohort

AimsTo investigate the independent associations between metabolic syndrome and retinal vessel calibre in a high cardiovascular risk cohort, and to determine whether these associations also exist in patients without diabetes,...

Influence of breastfeeding on retinal vessel calibers in school-age children. The Generation R Study

A shorter breastfeeding duration is associated with an increased risk of cardiovascular disease in adulthood. Early microvasculature structure adaptations may be part of the underlying mechanism. We examined the associations of ever breastfeeding, breastfeeding duration and exclusivity, and the timing of introduction of solid foods with retinal vessel calibers in children. We performed a population-based prospective cohort study from fetal life onwards in the city of Rotterdam, the Netherlands. We obtained information on ever breastfeeding, breastfeeding duration and exclusivity, and age at introduction of solid foods from postal questionnaires at the ages of 2, 6 and 12 months after birth. At the median age of 6.0 years (90% range: 5.7-6.8), we measured retinal arteriolar and venular calibers from digitized retinal photographs among 3220 children. Grader-specific s.d. scores (SDS) for both central retinal and arteriolar equivalents were constructed. We observed that in the models only adjusted for child's age, sex and ethnicity, children who were never breastfed had narrower retinal arteriolar and venular calibers in childhood as compared with children who were breastfed (differences in retinal arteriolar and venular calibers, respectively: -0.16 SDS (95% confidence interval (CI): -0.29, -0.03) and -0.18 SDS (95% CI: -0.32, -0.04)). After additional adjustment for maternal and childhood socio-demographic and lifestyle-related characteristics, never breastfeeding was only associated with narrower retinal venular caliber (difference: -0.15 SDS (95% CI: -0.29, -0.02)). We did not observe associations of breastfeeding duration or exclusivity, or age at introduction of solid foods with retinal vessel calibers. Children who were never breastfed tended to have narrower retinal venular calibers. We did not observe associations of breastfeeding duration with retinal vessel calibers. Family-based socio-demographic factors, maternal lifestyle-related factors and childhood factors only slightly influenced the observed associations. These results should be considered a hypothesis generating for further observational and experimental studies.

Impact of birth parameters and early life growth patterns on retinal microvascular structure in children: The Generation R Study.

The aim of the study was to examine the associations of birth outcomes and longitudinally measured fetal and infant growth patterns with retinal vessel calibers in childhood. In a population-based prospective cohort study among 4122 children, we measured growth characteristics in second and third trimester of pregnancy, at birth, and at 6, 12, 24, 36, 48, and 72 months. At the age of 6 years, we measured retinal arteriolar and venular calibers from digitized retinal photographs. We observed that compared with term-born children, those born preterm had narrower retinal arteriolar caliber [differences -0.46 standard deviation score (95% confidence interval -0.77 to -0.15) and -0.24 standard deviation score (95% confidence interval -0.42 to -0.05) for children born <34 and 34-37 weeks of gestation, respectively]. Children born with a low birth weight (<2500 g) had narrower retinal arteriolar caliber than children with a normal birth weight, but this association was fully explained by gestational age at birth. Accelerated infant growth until 24 months was associated with narrow retinal arteriolar caliber, especially among preterm-born children (P < 0.05). Early growth measures were not associated with retinal venular caliber. Preterm birth and accelerated infant growth are associated with narrower retinal arteriolar caliber in childhood. Whether these microvascular adaptations explain the well known associations of fetal and infant characteristics with cardiovascular disease in later life should be further studied.

Body fat distribution, metabolic and inflammatory markers and retinal microvasculature in school-age children. The Generation R Study.

To examine the associations of body fatness, metabolic and inflammatory markers with retinal vessel calibers among children. We performed a population-based cohort study among 4145 school-age children. At the median age of 6.0 years (95% range 5.8, 8.0 years), we measured body mass index, total and abdominal fat mass, metabolic and inflammatory markers (blood levels of lipids, insulin and C-peptide and C-reactive protein) and retinal vascular calibers from retinal photographs. We observed that compared with normal weight children, obese children had narrower retinal arteriolar caliber (difference -0.21 s.d. score (SDS; 95% confidence interval (CI) -0.35, -0.06)), but not venular caliber. Continuous analyses showed that higher body mass index and total body fat mass, but not android/gynoid fat mass ratio and pre-peritoneal fat mass, were associated with narrower retinal arteriolar caliber (P<0.05 for body mass index and total body fat mass), but not with retinal venular caliber. Lipid and insulin levels were not associated with retinal vessel calibers. Higher C-reactive protein was associated with only wider retinal venular caliber (difference 0.10 SDS (95% CI 0.06, 0.14) per SDS increase in C-reactive protein). This latter association was not influenced by body mass index. Higher body fatness is associated with narrower retinal arteriolar caliber, whereas increased C-reactive protein levels are associated with wider retinal venular caliber. Increased fat mass and inflammation correlate with microvascular development from school-age onwards.

Microvasculature and incident atrioventricular conduction abnormalities in the Multi-Ethnic Study of Atherosclerosis (MESA)

Abnormalities of the microvasculature are linked to major cardiac events, but their role in the development of atrioventricular conduction abnormalities (AVCA) is unknown. We examined the association between central retinal arteriolar equivalent (CRAE), a measure of the microvasculature, and incident AVCA. This analysis included 3975 participants free of AVCA at baseline from the Multi-Ethnic Study of Atherosclerosis (MESA). Incident AVCA was defined as a composite of new heart rate-adjusted PR interval ⩾ 200 ms (first-degree AV block) and advanced block (second-degree or complete AV block) detected from the MESA exam 5 electrocardiogram (ECG). CRAE was measured from retinal photographs at exam 2. Both ECGs and retinal photographs were collected using standardized methods and read and graded at central core labs. Incident AVCA were present in 7.4% (n=290) of the participants, of which 94% were first-degree AV block. Incident AVCA were increasingly more common in participants with narrower CRAE (4.6% in Q4, 6.4% in Q3, 7.0% in Q2 and 10.8% in Q1, p-value for trend < 0.0001). The socio-demographic and cardiovascular disease risk-adjusted odds of incident AVCA in the Q1 group (the group with the narrowest retinal arteriolar diameter) was nearly twice the odds in the Q4 group (OR: 1.68, 95% CI: 1.15-2.51). This association remained significant after adjustment for major ECG abnormalities and incident cardiovascular disease (Q1 vs Q4, OR: 1.65, 95% CI: 1.01-2.71). In conclusion, narrower retinal arteriolar caliber is associated with development of new AV conduction abnormalities.

Hypertension Editors’ Picks

<i>Hypertension</i> Editors’ Picks

Retinal microvasculature and cardiovascular health in childhood.

Alterations in retinal microvasculature are associated with increased risk of cardiovascular disease. We examined the associations of retinal vessel caliber with cardiovascular markers in school-age children. Among 4007 school-age children (median age of 6.0 years), we measured cardiovascular markers and retinal vessel calibers from digitized retinal photographs. Narrower retinal arteriolar caliber was associated with higher systolic and diastolic blood pressure (-0.20 SD score [SDS] [95% confidence interval (CI) -0.24 to -0.18] and -0.14 SDS [-0.17 to -0.11], respectively, per SDS increase in retinal arteriolar caliber), mean arterial pressure, and pulse pressure, but not with carotid-femoral pulse wave velocity, heart rate, cardiac output, or left ventricular mass. A wider retinal venular caliber was associated with lower systolic blood pressure, mean arterial pressure, and pulse pressure and higher carotid-femoral pulse wave velocity (carotid-femoral pulse wave velocity difference = 0.04 SDS [95% CI 0.01 to 0.07] per SDS increase in retinal venular caliber). Both narrower retinal arteriolar and venular calibers were associated with higher risk of hypertension at the age of 6 years, with the strongest association for retinal arteriolar caliber (odds ratio 1.35 [95% CI 1.21 to 1.45] per SDS decrease in arteriolar caliber). Adjustment for parental and infant sociodemographic factors did not influence the observed associations. Both retinal arteriolar and venular calibers are associated with blood pressure in school-age children, whereas retinal venular caliber is associated with carotid-femoral pulse wave velocity. Microvascular adaptations in childhood might influence cardiovascular health and disease from childhood onward.

Early risk stratification in pediatric type 1 diabetes.

In the late 1980s all Danish children with type 1 diabetes were invited for a nationwide evaluation of glycemic control. Approximately 75% (n = 720) participated and have later been referred to as The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). The results were surprisingly poor glycemic control among these young patients which lead to a great emphasis on glycemic control in the Danish Pediatric Departments. In 1995 the participants were invited for yet another evaluation but this time with main focus on early signs of microvascular complications - 339 participated. The mean HbA1c had remained at high levels (9.6%) and 60% of the participants had some level of Diabetic Retinopathy (DR). However, as the patients with DR mostly had the very milder forms it was believed that stricter glycemic control would reverse or at least stop progression of the disease in accordance with results from the large intervention study DCCT. This was investigated further at follow-up in 2011. The first study in the present thesis aimed to describe the 16-year incidence, progression and regression of DR in 185 participants from the DCPD1987 cohort. The 16-year incidence of proliferative retinopathy (PDR), 2-step progression and regression of DR was 31.0, 64.4, and 0.0%, respectively. As expected, the participants with PDR at follow-up had significantly higher HbA1c-values at both baseline and follow-up than those without PDR. However; a significantly larger decrease in HbA1c was also observed in the group with PDR over the study period, which in accordance with DCCT should have prevented the development of PDR to some extent. A surprisingly high incidence of proliferative retinopathy amongst young patients with type 1 diabetes in Denmark was found despite improvements in HbA1c over time. The improvement in HbA1c was either too small or happened too late. This study highlights that sight-threatening diabetic retinopathy remain a major concern in type 1 diabetes and the importance of early glycemic control. Identifying high-risk patients at a very early stage is not only desired for prevention of diabetic retinopathy - neuropathy and nephropathy similarly remain frequent in type 1 diabetes. Early risk stratification will allow for timely implementation of effective interventions and for individualized screening and diabetes care. The second and third studies of this thesis provide the longest prospective studies to date on both retinal vessel calibers and retinal fractal dimensions and their predictive value on diabetic microvascular complications. Semi-automated computer software has been developed to measure smaller changes in the retinal vessels on retinal photographs. Two of the first parameters to be reliably estimated by these programs were retinal vessel calibers and retinal vascular fractal dimensions (a quantitative measure on vascular complexity). There is very limited knowledge on their predictive value on diabetic complications thus far. In the second and third study, a consistent relation between narrower retinal arteriolar calibers, wider retinal venular calibers, lower fractal dimensions and the 16-year incidences of diabetic neuropathy, nephropathy and proliferative retinopathy was found. This has never been shown before. The results on vessel analyzes provides indications of a common pathogenic pathway for diabetic microvascular complications and therefore a possibility of universal risk estimation for development of neuropathy, nephropathy and retinopathy in type 1 diabetes.

Influence of maternal angiogenic factors during pregnancy on microvascular structure in school-age children.

Reduced placental growth factor (PlGF) levels and higher soluble fms-like tyrosine kinase (sFlt-1) levels in mothers during pregnancy may have persistent effects on vascular structures in their offspring. We examined whether angiogenic factors during pregnancy also affect childhood retinal microvasculature in a population-based prospective cohort study among 3505 mothers and their children. We measured maternal PlGF and sFlt-1 in the first and second trimester of pregnancy. At the age of 6, we measured childhood retinal arteriolar and venular calibers from digitized retinal photographs. We performed multiple linear regression models, taking maternal and childhood sociodemographic and lifestyle-related characteristics, birth characteristics, and childhood current body mass index and blood pressure into account. We observed that first trimester maternal PlGF and sFlt-1 levels were not associated with childhood retinal arteriolar caliber. Lower second trimester maternal PlGF levels, but not sFlt-1 levels, were associated with narrower childhood retinal arteriolar caliber (difference: -0.09 SD score [95% confidence interval, -0.16 to 0.01], per SD score decrease in PlGF). This association was not explained by maternal and childhood sociodemographic and lifestyle-related characteristics, birth characteristics, or childhood current body mass index and blood pressure. Maternal PlGF and sFlt-1 levels in the first or second trimester were not associated with childhood retinal venular caliber. Our results suggest that lower maternal second trimester PlGF levels affect the microvascular development in the offspring, leading to narrower retinal arteriolar caliber in childhood. Further studies are needed to confirm these findings and to explore the underlying mechanisms and long-term cardiovascular consequences.

Retinal arteriolar narrowing and incidence of knee replacement for osteoarthritis: a prospective cohort study

The role of the microcirculation in the pathogenesis of osteoarthritis (OA) remains unclear. This prospective cohort study examined the association between retinal vascular calibre and incidence of knee replacement for OA. 1838 participants of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study had retinal vascular calibre measured using a nonmydriatic digital fundus camera in 1999-2000 and were aged ≥ 40 years at joint replacement data collection commencement. The incidence of knee replacement for OA during 2002-2011 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). 77 participants underwent knee replacement for OA. They had narrower retinal arteriolar calibre compared with those without knee replacement (166.1 ± 24.8 μm vs 174.3 ± 24.5 μm, P = 0.004). For every one standard deviation reduction in retinal arteriolar calibre, the incidence of knee replacement increased by 25% (HR 1.25, 95% confidence interval (CI) 1.00-1.56). Participants in the narrower two-thirds of arteriolar calibre had twice the risk of knee replacement compared with those in the widest one-third (HR 2.00, 95% CI 1.07-3.74, P = 0.03) after adjustment for sex, body mass index (BMI), physical activity and HbA1c. There was no association for retinal venular calibre. Retinal arteriolar narrowing is associated with increased risk of knee replacement for OA suggesting that further work is warranted to determine the role of the microcirculation in the pathogenesis of knee OA.