Retinal arteriolar narrowing is associated with a 4-year risk of incident metabolic syndrome

We aimed to determine whether retinal microvascular changes in vessel calibers at baseline are associated with the future risk of developing the metabolic syndrome over 4 years in an adult cohort of Japanese individuals (n=90) who attended a health-screening program. Retinal vessel caliber was calculated as the central retinal artery equivalent and vein equivalent (CRAE) from non-mydriatic digital fundus images using semiautomated standardized software. There were 18 cases (20%) that developed metabolic syndrome over 4 years. Narrower arteriolar caliber at baseline was associated with an increased risk of incident metabolic syndrome over 4 years after adjusting for potential confounding risk factors including individual cardiovascular risk factors related to the metabolic syndrome (adjusted odds ratio per 1 s.d. change in CRAE: 2.92, 95% confidence interval 1.03, 8.24; P=0.043). Persons with wider venular caliber at baseline were more likely to have incident metabolic syndrome, but this was not statistically significant. Retinal vascular caliber might provide independent and useful information to predict incident metabolic syndrome in a health screening program.     

Retinal arteriolar narrowing is associated with 5-year incident severe hypertension: the Blue Mountains Eye Study

We assessed whether retinal arteriolar narrowing and structural abnormalities independently predicted 5-year incident severe (grade 2 or 3) hypertension in an older population-based cohort. The Blue Mountains Eye Study baseline (1992 to 1994) examined 3654 residents aged 49 and older in 2 postal code areas, west of Sydney. Of the 2335 participants (75.1% of survivors) who returned at the 5-year examinations, 1319 were normotensive or had mild (grade 1) hypertension at baseline. Baseline retinal photographs were graded for focal retinal vessel wall signs and vessel diameters were measured. Participants were classified as having normal, high-normal blood pressure [BP] (systolic BP 121 to 139 mm Hg and/or diastolic BP 81 to 89 mm Hg), mild hypertension (systolic BP 140 to 159 mm Hg and/or diastolic BP 90 to 99 mm Hg), or severe hypertension if they had a previous diagnosis of hypertension and were receiving antihypertensive medications or had systolic BP > or =160 mm Hg and/or diastolic BP > or =100 mm Hg at examination. Incident severe hypertension was defined in persons who were free of severe hypertension at baseline but classified as having severe hypertension at the 5-year examinations. Of the 1319 baseline subjects at risk, 390 (29.6%) developed severe hypertension. After adjusting for age, sex, body mass index, smoking, glucose, and total cholesterol, generalized retinal arteriolar narrowing at baseline was associated with increased risk of incident severe hypertension (odds ratio 2.6; 95% confidence interval, 1.7 to 3.9) when comparing the narrowest versus widest quintile. This association remained significant after further adjustment for baseline mean arterial BP or BP status. Our findings support the hypothesis that small vessel structural changes may precede the development of severe hypertension.     

Retinal arteriolar narrowing and left ventricular remodeling: the multi-ethnic study of atherosclerosis.

OBJECTIVES: This study sought to examine the relationships of retinal vascular signs with left ventricular (LV) mass, volume, and concentric remodeling. BACKGROUND: Microvascular disease, reflected as retinopathy lesions, has been shown to predict clinical congestive heart failure. Whether these retinal vascular changes are related to early structural alterations and remodeling of the heart in asymptomatic individuals is unknown. METHODS: A cross-sectional, population-based study of 4,593 participants ages 45 to 85 years, free of clinical cardiovascular disease. Retinal vascular calibers and retinopathy were graded from retinal photographs according to standardized protocols. The LV mass and volume were measured from cardiac magnetic resonance imaging. Extent of LV concentric remodeling was determined by the ratio of LV mass to end-diastolic volume (M/V ratio). RESULTS: After controlling for age, gender, race, center, past and current systolic blood pressure, body mass index, smoking, antihypertensive medications, diabetes, diabetes duration, glycosylated hemoglobin, lipid profile, and C-reactive protein, narrower retinal arteriolar caliber was associated with concentric (highest quintile of M/V ratio) remodeling (odds ratio [OR] 2.06, 95% confidence interval 1.57 to 2.70). This association was seen in men and women, and was present even in those without diabetes, without hypertension, and without significant coronary calcification. In multivariate analysis, the presence of retinopathy (OR 1.31, 95% confidence interval 1.08 to 1.61) was also associated with concentric remodeling. CONCLUSIONS: Narrower retinal arteriolar caliber is associated with LV concentric remodeling independent of traditional risk factors and coronary atherosclerotic burden, supporting the hypothesis that microvascular disease may contribute to cardiac remodeling.     

Impaired arteriolar mechanotransduction in experimental diabetes mellitus

Decreased arteriolar distensibility in diabetes may impair signal transduction mechanisms that are required for converting a pressure stimulus into smooth muscle contraction. These studies aimed to determine if pressure-induced increases in arteriolar intracellular Ca(2+) are altered in diabetes and whether diabetes is associated with alterations in composition of the extracellular matrix. Studies of mechanical properties used single, isolated, and cannulated cremaster arterioles from streptozotocin (60 mg/kg) diabetic rats and age-matched controls. To measure Ca(2+)(i), arterioles were loaded with Fura 2 (5 microM) after which preparations were examined by fluorescence microscopy and image analysis. Matrix protein (type IV collagen, laminin, fibronectin) deposition was studied by immunohistochemistry. Over a range of 30-120 mm Hg control vessels showed a linear relationship (r = 0.98, p < 0.01) between intraluminal pressure and Ca(2+)(i). Vessels from diabetic animals also showed a linear relationship (r = 0.99, p < 0.01), however, the mean slope was significantly (p < 0.02) less in the diabetic (0.17 +/- 0.05, n = 5) compared to controls (0.51 +/- 0.09, n = 7). Similarly, the slope of the wall tension-Ca(2+)(i) relationship was significantly decreased in vessels from diabetic animals. These differences were ameliorated by treatment of diabetic animals (n = 5) with aminoguanidine. Increased content of type IV collagen, laminin and fibronectin in vessel media was evident after 2 weeks of diabetes and showed a further increase with duration of diabetes. The data suggest that for a given increase in luminal pressure arterioles from diabetic animals response with an attenuated rise in smooth muscle Ca(2+)(i). This mechanotransduction defect may relate to alterations in the composition of the extracellular matrix within the arteriolar wall.     

Salt intake, hypertension and diabetes mellitus

Diabetes mellitus affects approximately 135 million people in the world. Diabetes and hypertension are both relatively common diseases in westernised countries. Both entities increase with age. Essential hypertension accounts for the majority of hypertension in people with type 2 diabetes, who constitute more than 90% of those with a dual diagnosis of diabetes and hypertension. The benefit conferred per mm Hg blood pressure reduction appears to be greater in persons with type 2 diabetes than in those with hypertension and non-coexistent diabetes mellitus. Similar to a subset of patients with essential hypertension, type 2 diabetic patients manifest dietary NaCl-induced exacerbation of hypertension. Recent guidelines have emphasised that the target blood pressure levels for patients with diabetes should be lower than in other hypertensive groups. An increased total body sodium and enhanced vascular reactivity are found in people with diabetes and most type 2 diabetic patients are salt sensitive. Type 2 diabetes with hypertension is associated with reduced renal plasma flow when dietary salt intake is high. Experimental, observational and interventional evidence support the benefits of sodium restriction in hypertensives. However, the full effects of sodium restriction are usually not obvious for at least 5 weeks. Other favourable effects of moderate reduction in sodium intake are a regress left ventricular hypertrophy, decrease in diuretic-induced potassium wastage, reduction in proteinuria, protection against stroke and from osteoporosis and renal stones, and enhancement of the antihypertensive effect of the antihypertensive agents.     

Masked hypertension in diabetes mellitus: a potential risk

The prevalence and clinical significance of masked hypertension (MHT) in diabetics have infrequently been described. The authors assessed the association of MHT (defined using a clinic blood pressure [BP] <140/90 mm Hg and daytime ambulatory BP > or = 135/85 mm Hg) with microvascular and macrovascular end organ damage in 81 clinically normotensive Japanese diabetic persons. The prevalence of silent cerebral infarcts (SCIs), increased left ventricular mass, and albuminuria were evaluated. Of 81 patients, 38 (46.9%) were classified as having MHT and showed significantly more SCIs (mean +/- SE: 2.5+/-0.5 vs 1.1+/-0.2; P=.017), and more albuminuria (39% vs 16%; P=.025), but no increase in left ventricular mass index, than the normotensive persons in office and on ambulatory BP monitoring group. The prevalence of MHT in this diabetic population was high (47%). Diabetic patients with MHT showed evidence of brain and kidney damage. Hence, out-of-office monitoring of BP may be indicated in diabetics whose BP is normal in the clinic.     

Plasma adiponectin concentrations in early pregnancy and subsequent risk of gestational diabetes mellitus

Low plasma adiponectin has been identified as a risk factor for type 2 diabetes. Our objective was to determine the extent to which low maternal plasma adiponectin is predictive of gestational diabetes mellitus (GDM), a condition that is biochemically and epidemiologically similar to type 2 diabetes. We used a prospective, nested case-control study design to compare maternal plasma adiponectin concentrations in 41 cases with 70 controls. Subjects were selected from a population of 968 women who provided blood samples in early pregnancy. Plasma adiponectin was determined using an ELISA. Adiponectin concentrations were statistically significantly lower in women with GDM than controls (4.4 vs. 8.1 micro g/ml, P < 0.001). Approximately 73% of women with GDM, compared with 33% of controls, had adiponectin concentrations less than 6.4 micro g/ml. After adjusting for confounding, women with adiponectin concentrations less than 6.4 micro g/ml experienced a 4.6-fold increased risk of GDM, as compared with those with higher concentrations (95% confidence interval, 1.8-11.6). Our findings are consistent with other reports suggesting an association between hypoadiponectemia and risk of type 2 diabetes. Our findings extend the literature to include GDM. Studies designed to examine the effect of dietary and pharmacological mediators of adiponectin concentrations in pregnant and nonpregnant subjects are warranted.     

Dietary patterns and risk of hypertension,type 2 diabetes mellitus,and coronary heart disease

Dietary pattern analysis, which reflects the complexity of dietary intake, has recently received considerable attention by nutritional epidemiologists. Two general approaches have been used to define these summary variables in observational studies. The so-called a posteriori approach builds on statistical exploratory methods, whereas the so-called a priori approach focuses on the construction of pattern variables that reflect hypothesis-oriented patterns based on available scientific evidence for specific diseases. Several studies, both observational and clinical, suggest that these measures of overall diet predict disease risk, and that its application might be especially valuable in the development of food-based dietary guidelines. In this review, we describe different patterning approaches and the available evidence regarding the relationships between dietary patterns and risk of hypertension, type 2 diabetes mellitus, and coronary heart disease.     

Stress-induced hypertension and diabetes mellitus

Hypertension and diabetes are the basic risk factors of atherosclerosis and its complications. At present new associations are sought which will enable us to describe more satisfactorily the mutual relationship of hypertension, metabolic disorders and cardiovascular disease. One of the systems involved in all substantial physiological processes is the autonomic nervous system. Stimulation of the sympathetic nervous system by chronic stress causes in addition to an elevated pulse rate and cardiac minute output also activation of another important pressor mechanism--the renin-angiotensin-aldosterone system. Increased activity of the sympathetic nervous system plays a part also in the development of impaired glucose and lipid metabolism, which are very frequent in hypertonic subjects. Hyperinsulinaemia, hypertriglyceridaemia and reduced HDL-cholesterol concentration are associated with a decline of the insulin capacity to take up glucose and deposit glycogen and together with a raised blood pressure create the so-called metabolic syndrome of insulin resistance (syndrome X, Reaven's syndrome).     

Systemic hypertension, diabetes mellitus and the kidney

Diabetic nephropathy is manifested by albuminuria, hypertension and progressive loss of renal function. Only one-third of patients with insulin-dependent diabetes mellitus of juvenile onset develop nephropathy and the risk of nephropathy does not increase with increasing duration of diabetes. Hypertension occurs almost exclusively in patients with nephropathy. Therefore, there is a subset of patients at risk for both nephropathy and hypertension. It is important to identify the patients destined to develop nephropathy, to define the pathophysiology responsible for the nephropathy in this subset of patients and to develop programs to interrupt the pathophysiology early in its course and hopefully prevent the progression to end-stage renal failure. Potential markers to identify patients who will develop nephropathy include a family history of hypertension, increased glomerular filtration rate and renal mass and presence of significant microalbuminuria. Studies are needed to evaluate various classes of drugs for their efficacy in altering the pathophysiologic hemodynamic changes leading to nephropathy.     

Blood pressure and retinal arteriolar narrowing in children

Retinal arteriolar narrowing is a known response of hypertension and independently predicts cardiovascular mortality in adults. Whether elevated blood pressure leads to retinal arteriolar narrowing in young children is unknown. We examined the relationship of retinal vascular caliber and blood pressure levels in 2 population-based cohorts among children aged 6 to 8 years in Sydney, Australia (1572 children) and Singapore (380 children). Participants had digital retinal photographs and measurement of retinal arteriolar (or small artery) and venular (or small vein) caliber. Children with higher quartiles of blood pressure had significantly narrower retinal arterioles than those with lower blood pressure (retinal arteriolar caliber 162.8, 161.0, 157.8, and 157.1 microm (P for trend<0.001), comparing increasing quartiles of systolic blood pressure in Sydney, and 164.9.5, 164.0, 159.1, and 159.4 microm (P for trend=0.0024 in Singapore). After controlling for age, sex, race, body mass index, refraction, and birth parameters, each 10-mm Hg increase in systolic blood pressure was associated with narrowing of the retinal arterioles by 2.08 microm (95% confidence interval: 1.38 to 2.79; P<0.0001) in Sydney children and 1.43 microm (95% confidence interval: 0.27 to 2.59; P=0.016) in Singapore children. These associations were consistent across age, sex, body mass index, and birth parameters. Retinal venules were not affected by blood pressure. We conclude that higher childhood blood pressure is associated with retinal arteriolar narrowing. Our data provide evidence that the effects of elevated blood pressure may manifest early in life.     

Early arteriolar disturbances following streptozotocin-induced diabetes mellitus in adult mice

The early microvascular consequences of streptozotocin-induced diabetes in adult mice were evaluated. Streptozotocin (200 mg/kg) was used to induce diabetes at age 22–24 weeks and the animals were studied at age 32–36 weeks when microvascular disturbances are consistently present. The arterioles within the cremasteric muscle of AOD mice have a significantly (P < 0.05) reduced inner diameter and vessel wall cross-sectional area. In normal animals, inner vessel diameter and vessel wall characteristics remained essentially constant from week 22–36 of life. The average intercapillary distance in passive preparations is 20.6 ± 0.4 μm in normal mice compared to 25.9 ± 0.3 μm in diabetic mice; a loss of capillaries appeared to occur in diabetics but no substantial change in number of arterioles occurred. The ability of vessels to dilate from the innervated to passive state is proportionately equal to or greater than normal in the AOD mice but the actual diameters of innervated and passive arterioles are smaller than normal. The data are interpreted to indicate that an early microvascular manifestation of AOD in mice is an impairment of the vessel wall and a loss of capillaries. However, resting blood flow is only marginally decreased in the early phase of the onset of diabetes in adult mice.