Roberto Schreiber

Sodium Intake Is Associated with Carotid Artery Structure Alterations and Plasma Matrix Metalloproteinase-9 Upregulation in Hypertensive Adults

The mechanisms by which dietary sodium modulates cardiovascular risk are not fully understood. This study investigated whether sodium intake is related to carotid structure and hemodynamics and to plasma matrix metalloproteinase (MMP) activity in hypertensive adults. One hundred thirty-four participants were cross-sectionally evaluated by clinical history, anthropometry, carotid ultrasound, and analysis of hemodynamic, inflammatory, and metabolic variables. Daily sodium intake (DSI) was estimated by 24-h recall, discretionary sodium, and a FFQ. In 42 patients, plasma MMP-2 and MMP-9 activities were also analyzed. The mean DSI was 5.52 ± 0.29 g/d. Univariate analysis showed that DSI correlated with common carotid artery systolic and diastolic diameter (r = 0.36 and 0.34; both P < 0.001), peak and mean circumferential tension (r = 0.44 and 0.39; both P < 0.001), Youngs Elastic Modulus (r = 0.40; P < 0.001), intima-media thickness (r = 0.19; P < 0.05), and internal carotid artery resistive index (r = 0.20; P < 0.05). Multivariate analyses revealed that only artery diameter, circumferential wall tension, and Youngs Elastic Modulus were independently associated with DSI. Conversely, plasma MMP-9 activity was associated with DSI (r = 0.53; P < 0.001) as well as with common carotid systolic diameter (r = 0.33; P < 0.05) and Youngs Elastic Modulus (r = 0.38; P < 0.01). In conclusion, sodium intake is associated with carotid alterations in hypertensive adults independently of systemic hemodynamic variables. The present findings also suggest that increased MMP-9 activity might play a role in sodium-induced vascular remodeling.

Toll-like receptor 6 Ser249Pro polymorphism is associated with lower left ventricular wall thickness and inflammatory response in hypertensive women.

BACKGROUND Experimental data demonstrated that inactivation of toll-like receptor (TLR) pathway components attenuated left ventricular (LV) remodeling induced by pressure overload. This study investigated the impact of TLR6 Ser249Pro polymorphism on LV structure in hypertensive subjects. METHODS A sample of 443 patients (266 women and 177 men) was evaluated by clinical history, physical examination, analysis of inflammatory and metabolic parameters, echocardiography, and genotyping of the TLR6 variant. Moreover, the relationship between genotypes and in vitro responsiveness of peripheral blood monocytic cells to TLR agonists was also assessed. RESULTS Homozygous women for the TLR6 249Ser allele had lower LV posterior wall thickness (9.4 + or - 0.4 vs. 10.5 + or - 0.1 mm; P = 0.02), interventricular septum thickness (9.7 + or - 0.3 vs. 10.7 + or - 0.1 mm; P = 0.03), and LV relative wall thickness (0.39 + or - 0.02 vs. 0.44 + or - 0.01; P = 0.02) than women with other genotypes. These results were confirmed by stepwise regression analyses adjusted by potential confounders. Conversely, homozygous men for the 249Ser variant showed no differences in LV structure in comparison to males carrying the 249Pro allele. In addition, monocytes from hypertensive women homozygous for the 249Ser allele showed a lower release of tumor necrosis factor-alpha and interleukin-6 in response to zymosan (TLR6 agonist), but not to lipopolysaccharide (TLR4 agonist). CONCLUSION These data suggest that hypertensive women homozygous for the TLR6 249Ser polymorphism might exhibit lower LV wall thickness and reduced TLR6-mediated inflammatory response than females carrying the major allele.

The C242T polymorphism of the p22-phox gene (CYBA) is associated with higher left ventricular mass in Brazilian hypertensive patients.

BackgroundReactive oxygen species have been implicated in the physiopathogenesis of hypertensive end-organ damage. This study investigated the impact of the C242T polymorphism of the p22-phox gene (CYBA) on left ventricular structure in Brazilian hypertensive subjects.MethodsWe cross-sectionally evaluated 561 patients from 2 independent centers [Campinas (n = 441) and Vitória (n = 120)] by clinical history, physical examination, anthropometry, analysis of metabolic and echocardiography parameters as well as p22-phox C242T polymorphism genotyping. In addition, NADPH-oxidase activity was quantified in peripheral mononuclear cells from a subgroup of Campinas sample.ResultsGenotype frequencies in both samples were consistent with the Hardy- Weinberg equilibrium. Subjects with the T allele presented higher left ventricular mass/height2.7 than those carrying the CC genotype in Campinas (76.8 ± 1.6 vs 70.9 ± 1.4 g/m2.7; p = 0.009), and in Vitória (45.6 ± 1.9 vs 39.9 ± 1.4 g/m2.7; p = 0.023) samples. These results were confirmed by stepwise regression analyses adjusted for age, gender, blood pressure, metabolic variables and use of anti-hypertensive medications. In addition, increased NADPH-oxidase activity was detected in peripheral mononuclear cells from T allele carriers compared with CC genotype carriers (p = 0.03).ConclusionsThe T allele of the p22-phox C242T polymorphism is associated with higher left ventricular mass/height2.7 and increased NADPH-oxidase activity in Brazilian hypertensive patients. These data suggest that genetic variation within NADPH-oxidase components may modulate left ventricular remodeling in subjects with systemic hypertension.

Physical Activity and Improved Diastolic Function in Spinal Cord-Injured Subjects.

PURPOSE Subjects with spinal cord injury (SCI) have been reported to present impaired left ventricular (LV) diastolic function in comparison with able-bodied (AB) ones. The present study investigated the effect of regular physical activity on the cardiac structure and function of SCI subjects. METHODS Fifty-eight SCI men (29 sedentary [SCI-S] and 29 athletes [SCI-A]) and 29 AB men were cross-sectionally evaluated by clinical, laboratory, hemodynamic, and echocardiographic analysis. All enrolled subjects were normotensive, nondiabetic, nonsmoker, and normolipemic, and the studied groups presented similar age and body mass index. RESULTS SCI-S presented similar LV structural and systolic parameters but higher E/Em (8.0 ± 0.5) and lower Em/Am (1.18 ± 0.09) ratios than SCI-A and AB (E/Em = 6.4 ± 0.3 and 5.9 ± 0.3, respectively; Em/Am = 1.57 ± 0.12 and 1.63 ± 0.08, respectively; all P < 0.05 compared with SCI-S). Analysis of SCI individuals according to injury level revealed that tetraplegic athletes had similar features compared with sedentary tetraplegic subjects, except for higher Em (10.9 ± 0.6 vs 8.6 ± 0.7 cm s, P < 0.05) and lower E/Em ratio (6.3 ± 0.4 vs 8.8 ± 0.8, P < 0.05), whereas paraplegic athletes had similar features compared with sedentary paraplegic individuals, except for higher LV end-diastolic diameter (49.4 ± 1.4 vs 45.0 ± 1.0 mm, P < 0.05) and Em/Am ratio (1.69 ± 0.20 vs 1.19 ± 0.08, P < 0.05) and lower LV relative wall thickness (0.330 ± 0.012 vs 0.369 ± 0.010, P < 0.05) and heart rate (67.1 ± 4.2 vs 81.9 ± 2.8 bpm, P < 0.05). CONCLUSION Regular physical activity is associated with improved LV diastolic function in SCI subjects and might exert distinct cardiac structural effects in tetraplegic and paraplegic subjects.

Physical activity is associated with improved subclinical atherosclerosis in spinal cord injury subjects independent of variation in traditional risk factors.

injury subjects independent of variation in traditional risk factors☆ Jose R. Matos-Souza , Anselmo A. Silva , Luis F. Campos , Debora Goulart , Roberto Schreiber , Guilherme de Rossi , Jose A. Pio-Magalhaes , Mauricio Etchebehere , Jose I. Gorla , Alberto Cliquet Jr. , Wilson Nadruz Jr. a,⁎ a Department of Internal Medicine, School of Medical Sciences, State University of Campinas, Campinas, SP, Brazil b School of Physical Education, State University of Campinas, Campinas, SP, Brazil c Department of Orthopaedics, School of Medical Sciences, State University of Campinas, Campinas, SP, Brazil d Department of Electrical Engineering, University of Sao Paulo (USP), Sao Carlos, SP, Brazil

Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy.

Left ventricular hypertrophy (LVH) is a complication that may result from chronic hypertension. While nitric oxide (NO) deficiency has been associated with LVH, inconsistent results have been reported with regards to the association of endothelial NO synthase (eNOS) polymorphisms and LVH in hypertensive patients. This study aims to assess whether eNOS haplotypes are associated with LVH in hypertensive patients. This study included 101 healthy controls and 173 hypertensive patients submitted to echocardiography examination. Genotypes for three eNOS polymorphisms were determined: a single-nucleotide polymorphism in the promoter region (T-786C) and in exon 7 (Glu298Asp), and variable number of tandem repeats in intron 4. We found no significant association between eNOS genotypes and hypertension or with LVH (all p > 0.05). However, while we found two eNOS haplotypes associated with variable risk of hypertension (all p < 0.05), we found no significant associations between eNOS haplotypes and LVH (all p > 0.05), even after adjustment in multiple linear regression analysis. These findings suggest that eNOS haplotypes that have been associated with variable susceptibility to hypertension were not associated with LVH in hypertensive patients. Further studies are necessary to examine whether other genes downstream may interact with eNOS polymorphisms and predispose to LVH in hypertensive patients.

Oxidized low-density lipoprotein, matrix-metalloproteinase-8 and carotid atherosclerosis in spinal cord injured subjects.

OBJECTIVE Previous reports have indicated that subjects with chronic spinal cord injury (SCI) exhibit increased cardiovascular risk compared to able-bodied individuals. This study investigated the relationship between plasmatic oxidized low-density lipoprotein (OxLDL), matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) levels and vascular remodeling in SCI subjects and the role of physical activity in this regard. METHODS We studied 42 men with chronic (≥2 years) SCI [18 sedentary (S-SCI) and 24 physically active (PA-SCI)] and 16 able-bodied men by clinical, anthropometric, laboratory, and carotid intima-media thickness (IMT) analysis. All enrolled subjects were normotensive, non-diabetics, non-smokers and normolipemic. Plasmatic OxLDL, MMP-2, MMP-8, MMP-9, TIMP-1 and TIMP-2 levels were determined by enzyme-linked immunosorbent assay. RESULTS Carotid IMT, IMT/diameter ratio and OxLDL levels of PA-SCI and able-bodied subjects were statistically similar. Conversely, S-SCI subjects exhibited higher IMT, IMT/diameter ratio and OxLDL levels compared to PA-SCI (p < 0.01, p < 0.001 and p = 0.01, respectively) and able-bodied (p < 0.001 for all) individuals. Results of bivariate correlation analysis including all injured subjects showed that carotid IMT and IMT/diameter ratio only correlated with OxLDL, MMP-8 and MMP-8/TIMP-1 ratio. Further stepwise regression analysis adjusted for the presence or not of physical activity and age showed that OxLDL was associated with carotid IMT and IMT/diameter ratio, while MMP-8 was associated with IMT/diameter ratio in SCI individuals. CONCLUSIONS Plasmatic OxLDL and MMP-8 levels are associated with carotid atherosclerosis and there is an interaction among physical inactivity, atherosclerosis and OxLDL in SCI individuals.

The functional Toll-like receptor 4 Asp299Gly polymorphism is associated with lower left ventricular mass in hypertensive women

BACKGROUND This study investigated the impact of a putative functional TLR4 polymorphism (Asp299Gly) on left ventricular (LV) structure in hypertensive subjects. METHODS A sample of 443 patients (266 women and 177 men) was evaluated by clinical history, physical examination, anthropometry, analysis of inflammatory and metabolic parameters, echocardiography and TLR4 Asp299Gly genotyping. In addition, the relationship between the polymorphism and in vitro lipopolysaccharide responsiveness of peripheral blood monocytic cells was also assessed. RESULTS Women carrying the 299Gly allele presented lower posterior wall thickness (p=0.01), interventricular septum thickness (p=0.04), LV mass (p=0.01) and LV mass index (p=0.03), as well as a reduced prevalence of LV hypertrophy (p=0.002), in comparison to women with the wild-type genotype. These results were confirmed by stepwise and logistic regression analyses adjusted for potential confounders. Conversely, the 299Gly allele did not influence LV structure in men. Furthermore, in vitro assays revealed that monocytes of either men or women heterozygous for the 299Gly allele presented a lower lipopolysaccharide-induced production of interleukin-6, compared to non-carriers. CONCLUSIONS The functional TLR4 Asp299Gly polymorphism is associated with lower LV mass in hypertensive women. These findings suggest that interactions among gender, LV remodeling and TLR4 gene variants may occur in hypertensive subjects.

Metabolism of chylomicron-like emulsions in carriers of the S447X lipoprotein lipase polymorphism

BACKGROUND Lipoprotein lipase catalyzes the hydrolysis of the triglycerides contained in both very-low-density lipoproteins and chylomicrons for storage in the adipose tissue and muscle of fats of both hepatic and dietary origin. The S447X-Stop lipoprotein lipase is the most common polymorphism of the enzyme, affecting roughly 20% of the population and is accompanied by normal or diminished fasting triglycerides and perhaps lower incidence of coronary artery disease (CAD). Delay in the removal of chylomicron and remnant is now an established risk factor for CAD. METHODS Currently, the chylomicron metabolism has been evaluated in 12 normolipidemic subjects with the S447X-Stop and in 13 age- and sex-paired control subjects with no mutation. The doubly labeled chylomicron-like emulsion method was used to evaluate chylomicron metabolism. The emulsions labeled with cholesteryl-oleate (14C-CE) and tri[9,10-3H]oleate (3H-Tg) were injected intravenously and the decay curves of the labels were determined by blood sampling over 60 min followed by radioactive counting. RESULTS The fractional clearance rate (FCR, min(-1)) of the labels was not different in the S447X carriers compared with the noncarriers (FCR 3H-Tg 0.035 +/- 0.019 and 0.030 +/- 0.009; FCR 14C-CE 0.008 +/- 0.007 and 0.009 +/- 0.007, respectively). CONCLUSIONS The chylomicron intravascular lipolysis monitored by the 3H-Tg emulsion and the remnant removal monitored by the 14C-CE emulsion were not altered by the presence of this polymorphism of great populational impact.

Response to cold pressor test predicts long-term changes in pulse wave velocity in men.

BACKGROUND Aortic stiffness is associated with increased cardiovascular mortality. However, the determinants of aortic stiffness progression are not fully established. This study evaluated the predictive value of blood pressure (BP) response to cold pressor test (CPT) in the progression of carotid-femoral pulse wave velocity (PWV) in men and women. METHODS A total of 408 individuals (165 men, 243 women) from Vitoria, Brazil, underwent BP evaluation, clinical and laboratorial investigations, and CPT and PWV assessment. Five years later, the studied individuals were re-evaluated, except for the CPT. RESULTS In men, 5-year PWV change correlated inversely with baseline PWV (P < 0.001) and directly with BP response to CPT (P < 0.05) and 5-year BP change (P < 0.05). In women, 5-year PWV change correlated inversely with baseline PWV (P < 0.001) and directly with age (P < 0.01), glycemia (P < 0.05) and 5-year BP change (P < 0.05) but not with BP response to CPT. Further linear regression analysis showed that 5-year PWV change was associated with baseline PWV, systolic BP response to CPT, and 5-year systolic BP change in men and with baseline PWV, age, glycemia, and 5-year systolic BP change in women. CONCLUSIONS BP response to CPT was a predictor of PWV progression in men after 5 years of follow-up. These findings provide further insights into the pathophysiologic mechanisms of arterial stiffness, suggesting that elevated sympathetic reactivity may be a predisposing factor for future increases in aortic stiffness, at least in men.