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Andréa Vasconcellos Batista da Silva,1 Sonia Alves Gouvea,2 Aurélio Paulo Batista da Silva,1 Saulo Bortolon,3 Anabel Nunes Rodrigues,2 Glaucia Rodrigues Abreu,2 Fernando Luiz Herkenhoff,2 1Department of Morphology, 2Department of Physiological Sciences, Health Sciences Center, 3Department of Technology, Informatic Center, Federal University of Espírito Santo, Vitoria, Espirito Santo, Brazil Background and objectives: Diabetic retinopathy is the main microvascular complication in diabetes mellitus and needs to be diagnosed early to prevent severe sight-threatening retinopathy. The purpose of this study was to quantify the retinal microvasculature pattern and analyze the influence of blood glucose level and the duration of diabetes mellitus on the retinal microvasculature. Methods: Two groups were analyzed: patients with diabetes (N=26) and patients without diabetes, ie, controls (N=26). A quantitative semiautomated method analyzed retinal microvasculature. The diameters of arterioles and venules were measured. The total numbers of arterioles and venules were counted. The ratio of arteriole diameter to venule diameter was calculated. The retinal microvasculature pattern was related to clinical and biochemical parameters. Results: Patients with diabetes exhibited larger venule diameters in the upper temporal quadrant of the retina compared to the lower temporal quadrant (124.85±38.03 µm vs 102.92±15.69 µm; P

Estrogen is a steroidal hormone involved in several physiological functions in the female body including regulation of serum lipid metabolism and breast cancer (BC). Estrogen actions on serum lipids mostly occur through its binding to intracellular Estrogen Receptor alpha (ERalpha) isoform, expressed in most of tissues. This gene (ESR1) exhibit many polymorphic sites (SNPs) located either on translated and non-translated regions that regulate ERalpha protein expression and function. This paper aimed to investigate the association of two intronic SNPs of ESR1 gene, namely c454-397T>C (PvuII) and c454-351A>G (XbaI) to alterations in serum levels of total cholesterol (T-chol), total lipid (TL), low density lipoprotein cholesterol (LDL), high density lipoprotein (HDL), and triglycerides (TG) in a cohort of post-menopausal women. In addition, we aimed to associate presence of these SNPs to development of BC along 5 years period. To do so, a group of healthy 499, highly miscigenated, post-menopausal Brazilian women, were carried using PCR-FRLP technique and further confirmed by automatic sequence analysis as well followed through 5 years for BC incidence. Measurements of serum lipid profile by standard commercial methods were carried individually whereas Dual Energy X-ray Absorciometry (DXA) measured Body Mass Indexes (BMI), Fat Mass (FM), Lean Body Mass (LBM), and Body Water Content (BWC). No effects of PvuII SNP on ESR1 gene were observed on patient´s serum T-chol, TL, LDL, HDL, and TG. However, c454-397T>C PvuII SNP is associated to lower body fat and higher levels of lean mass and body water and lower incidence of BC. On the other hand, statistically significant effect of XbaI c454-351A>G SNP on serum TG and TL levels. Patients homozygous for X allele were followed up from 2010-2015. They showed higher incidence of breast cancer (BC) when compared to either heterozygous and any P allele combination. Moreover, the increasing of TG and TL serum concentrations associated to SNP XbaI c454-351A>G on ESR1 gene is enhanced in both obese (higher BMI) and elder women. Taken together, these results suggested that XbaI c454-351A>G SNP is associated to changes in lipid profile, particularly in serum TG and TL, in this cohort of post-menopausal woman. Also, this paper shows another link between obesity and BC corroborating the current thesis that both diseases are interlinked.

Background and Objectives: Diabetic retinopathy is the main microvascular complication in diabetes mellitus and needs to be diagnosed early to prevent severe sight-threatening retinopathy. The purpose of this study was to quantify the retinal microvasculature pattern and analyze the influence of blood glucose level and the duration of diabetes mellitus on the retinal microvasculature., Methods: Two groups were analyzed: patients with diabetes (N=26) and patients without diabetes, ie, controls (N=26). A quantitative semiautomated method analyzed retinal microvasculature. The diameters of arterioles and venules were measured. The total numbers of arterioles and venules were counted. The ratio of arteriole diameter to venule diameter was calculated. The retinal microvasculature pattern was related to clinical and biochemical parameters., Results: Patients with diabetes exhibited larger venule diameters in the upper temporal quadrant of the retina compared to the lower temporal quadrant (124.85±38.03 µm vs 102.92±15.69 µm; P<0.01). Patients with diabetes for 5 or more years had larger venule diameters in the upper temporal quadrant than patients without diabetes (141.62±44.44 vs 112.58±32.11 µm; P<0.05). The degree of venodilation in the upper temporal quadrant was positively correlated with blood glucose level and the estimated duration of diabetes mellitus., Interpretation and Conclusion: The employed quantitative method demonstrated that patients with diabetes exhibited venule dilation in the upper temporal quadrant, and the duration of diabetes mellitus was positively correlated with blood glucose level. Therefore, the early assessment of retinal microvascular changes is possible prior to the onset of diabetic retinopathy.

Background: A causal relationship between plasma cholesterol and blood pressure remains poorly understood. It has been postulated that the decrease in nitric oxide (NO) availability is a potential mechanism by which hypercholesterolemia may stimulate blood pressure elevation. However, evidence supporting the role of the L-arginine-NO pathway on the relationship between hypertension and hypercholesterolemia is still lacking., Methods and Results: We tested for an association of the expressed NO synthase (eNOS) Glu298Asp gene variant and plasma levels of lipids and lipoproteins in the determination of systolic blood pressure levels in a 1577 individuals randomly selected from the general population. Significant interactions could be disclosed either between the Glu298Asp gene variant and total-cholesterol (p = 0.02), log-transformed triglycerides (p = 0.004) or non-HDL-cholesterol (p = 0.003) in the determination of systolic blood pressure. In addition, although the presence of the AspAsp genotype did not significantly increase the risk of hypertension in individuals in the 50% lowest percentile of total-cholesterol, presence of this genotype significantly increased the risk of hypertension in individuals in the 50% highest percentile. Finally, in a multiple logistic regression model adjusting for age, sex, diabetes, ethnicity, smoking status and BMI, the AspAsp genotype significantly increased the risk of hypertension only in individuals with total-cholesterol above 209 mg/dL (p = 0.05, odds ratios (OR) = 2.0)., Conclusion: Taken together, these results provide evidence supporting the role of the eNOS Glu298Asp gene variant in modulating blood pressure through a relationship with lipid levels.

Background: Microalbuminuria is a risk factor for developing end-stage renal disease and cardiovascular events. Mutations in NPHS2 have been shown to cause autosomal-recessive nephrotic syndrome. Recently, a functional polymorphism of this gene (R229Q) was described and associated with a maturity-onset form of nephrotic syndrome. We have investigated whether the carrier status of this novel genetic variant is associated with microalbuminuria in individuals from the general population., Methods: Demographic, cardiovascular risk factors, and renal phenotypes in 1577 individuals from a cross-sectional-based study were collected following the general guidelines of the WHO-MONICA project (monitoring trends and determinants in cardiovascular diseases). Blood and urine samples were obtained. Microalbuminuria was determined using a semiquantitative protocol, and DNA was extracted from peripheral lymphocytes., Results: A strong association was found between the 229Q allele and microalbuminuria (P= 0.008). The presence of the 229Q allele was still associated with a 2.77-fold increased risk of presenting microalbuminuria even after adjustment for age, ethnicity, hypertension, obesity, and diabetes in a multiple logistic regression model. In addition, a statistically significant interaction was identified between the presence of the 229Q allele and body mass index (BMI) (P= 0.01), suggesting an additive effect between the 229Q allele and other risk factors for microalbuminuria., Conclusion: These data have important implications for the understanding of microalbuminuria in the general population and may contribute to better ways of disease prediction and prevention.

We investigated the association of beta2 adrenoceptor functional gene variants (Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms), obesity phenotypes, and blood pressure levels in a large, ethnically mixed urban population. The individuals (n=1576) were randomly selected for a cross-sectional study of cardiovascular risk factors in Vitória, Brazil. Statistically significant associations among systolic blood pressure and the Arg16Gly and Thr164Ile variants were identified in univariate analysis. The Gly16/Gly16 genotype was still associated with systolic blood pressure (SBP) in multivariate analysis adjusting for age, gender, ethnicity, total cholesterol, diabetes, and body mass index (BMI) (P=0.01). The Arg16 allele was the only genotypic variable associated with BMI, and, in a dominant model, it remained associated with an increased BMI even after adjustment for age, gender, ethnicity, triglycerides, HDL cholesterol, LDL cholesterol, diabetes, and hypertension status (P=0.02). Although the different polymorphisms did not interact in the determination of SBP, a significant interaction with BMI (P=0.02), not through linkage disequilibrium, was identified between the Gln27Glu and the Thr164Ile variants. Furthermore, a significant interaction among the Arg16Gly polymorphism and BMI (P=0.036) and waist-hip ratio (P=0.003) in determining SBP was disclosed by ANOVA factorial modeling, with SBP used as the dependent variable. An interaction between the Thr164Ile polymorphism and waist-hip ratio was also identified (P=0.018). Finally, multiple logistic regression models showed a 1.48-fold increase in the risk of hypertension in individuals harboring the Gly16/Gly16 genotype and a 1.31-fold (P=0.01) and a 1.49-fold (P=0.003) increased risk of obesity in individuals harboring the Gln27/Gln27 genotype or the presence of the Arg16 allele, respectively. Taken together, these data provide evidence for a strong but complex relation between beta-adrenoceptor gene variants, hypertension, and obesity.

Borderline hypertension (BH) has been associated with an exaggerated blood pressure (BP) response during laboratory stressors. However, the incidence of target organ damage in this condition and its relation to BP hyperreactivity is an unsettled issue. Thus, we assessed the Doppler echocardiographic profile of a group of BH men (N = 36) according to office BP measurements with exaggerated BP in the cycloergometric test. A group of normotensive men (NT, N = 36) with a normal BP response during the cycloergometric test was used as control. To assess vascular function and reactivity, all subjects were submitted to the cold pressor test. Before Doppler echocardiography, the BP profile of all subjects was evaluated by 24-h ambulatory BP monitoring. All subjects from the NT group presented normal monitored levels of BP. In contrast, 19 subjects from the original BH group presented normal monitored BP levels and 17 presented elevated monitored BP levels. In the NT group all Doppler echocardiographic indexes were normal. All subjects from the original BH group presented normal left ventricular mass and geometrical pattern. However, in the subjects with elevated monitored BP levels, fractional shortening was greater, isovolumetric relaxation time longer, and early to late flow velocity ratio was reduced in relation to subjects from the original BH group with normal monitored BP levels (P<0.05). These subjects also presented an exaggerated BP response during the cold pressor test. These results support the notion of an integrated pattern of cardiac and vascular adaptation during the development of hypertension.

Previous studies have pointed out that exaggerated blood pressure (BP) response during physical exercise could be an early marker of essential hypertension. Apparently some of the exaggerated BP responders present changes in the heart geometry and function that are usually found in the early course of the hypertensive disease. To evaluate the association between exaggerated BP response and these changes, we submitted 20 normotensive men presenting elevated BP response during bicycle exercise (hyperreactive group, systolic BP > or = 220 mmHg at maximal workload) to 24-h ambulatory blood pressure monitoring (ABPM) and to two-dimensionally guided M-mode echocardiography and pulsed Doppler. The results from this group were contrasted with those of a comparable group, which otherwise, presented normal BP response during the same procedure (control group, systolic BP < or = 210 mmHg at maximal workload). The ABPM measurements were normal and analogous between the two groups: the mean 24-h systolic blood pressure (SBP) was respectively 126 +/- 6 mmHg and 129 +/- 5 mmHg, diastolic blood pressure (DBP) 82 +/- 4 mmHg in both groups, and heart rate (HR), respectively 76 +/- 9 and 74 +/- 7 bpm. The univariate correlation (R) between the maximal BP response during bicycle exercise and BP measurements in the ABPM were in general weak, and as a whole, the hyperreactive group presented the weakest correlation coefficients. M-mode echocardiographic data such as the left ventricular mass index (LVMI, 80 +/- 10 vs. 81 +/- 11 g/m2), posterior wall and interventricular septal thickness (PWT, 8.8 +/- 0.6 vs. 8.6 +/- 0.7 mm; IVST, 9.0 +/- 0.4 vs. 8.8 +/- 0.6) were also normal and comparable between the groups. LV systolic functional indexes such as fractional shortening (LVFS, 39 +/- 2.8 vs. 40 +/- 3.5%) and ejection fraction (LVEF, 70 +/- 3.5 vs. 71 +/- 3.7%) were also normal and similar. Doppler-derived LV diastolic functional indexes such as the peak velocity of early flow divided by the peak velocity of late flow (RE/A) and isovolumetric relaxation time (IVRT) were also equivalent (RE/A, both 1.3 +/- 0.2, IVRT 79 +/- 7 vs. 81 +/- 6 msec). These results support the concept that an exaggerated BP elevation during physical activity, when not accompanied of higher levels of BP during daily activities are not associated with changes in the heart geometry or in the ventricular function, and might represent an hemodynamical behavior of limited pathological and clinical importance. These conclusions must be taken cautiously since personal characteristics such as life style, family history of hypertension, gender, race and also the levels of BP chosen to delimit a normal and an exaggerated BP response might be important factors determining the consequences of the hyperreactive behavior.

Few studies have investigated the significance of abnormal increases in systolic pressure during exercise in patients with high normal blood pressure and its correlation with 24-hour ambulatory blood pressure monitoring and left ventricular structure. This study was performed in 30 sedentary subjects (42 +/- 4 years old) with high normal blood pressure. Fifteen subjects presenting < 220 mm Hg systolic pressure during ergometric exercise were compared with 15 others with systolic pressure > or = 220 mm Hg. Average 24-hour (systolic, 127 +/- 5 versus 142 +/- 4 mm Hg, P < .01; diastolic, 82 +/- 4 versus 92 +/- 3 mm Hg, P < .01), daytime (systolic, 130 +/- 6 versus 144 +/- 4 mm Hg, P < .01; diastolic, 84 +/- 4 versus 92 +/- 4 mm Hg, P < .01), and nighttime (systolic, 116 +/- 7 versus 132 +/- 6 mm Hg, P < .01; diastolic, 72 +/- 6 versus 85 +/- 6 mm Hg, P < .01) ambulatory blood pressure monitoring values were significantly higher in subjects with an exaggerated blood pressure response to exercise. No significant differences were observed in left ventricular morphology. These findings indicate that subjects presenting high normal blood pressure and exaggerated systolic pressure during exercise show significantly high ambulatory blood pressure monitoring values that are not associated with left ventricular hypertrophy.