Michelle Trindade

How Can Diet Influence the Risk of Stroke

Cerebrovascular diseases are the second cause of mortality in the world, and hypertension is considered a main risk factor for occurrence of stroke. The mechanisms responsible for the increased stroke risk remain unclear. However, dietary interventions have been applied in the management and treatment of their risk factors, which include increased blood pressure levels, obesity, diabetes, and dyslipidemia. Further studies should be conducted to assess the effects of carotenoids, flavonoids, n-3 polyunsaturated fats, and lower salt and high glycemic index intake in risk of stroke.

Beneficial Effects of Dietary Nitrate on Endothelial Function and Blood Pressure Levels

Poor eating habits may represent cardiovascular risk factors since high intake of fat and saturated fatty acids contributes to dyslipidemia, obesity, diabetes mellitus, and hypertension. Thus, nutritional interventions are recognized as important strategies for primary prevention of hypertension and as adjuvants to pharmacological therapies to reduce cardiovascular risk. The DASH (Dietary Approach to Stop Hypertension) plan is one of the most effective strategies for the prevention and nonpharmacological management of hypertension. The beneficial effects of DASH diet on blood pressure might be related to the high inorganic nitrate content of some food products included in this meal plan. The beetroot and other food plants considered as nitrate sources account for approximately 60–80% of the daily nitrate exposure in the western population. The increased levels of nitrite by nitrate intake seem to have beneficial effects in many of the physiological and clinical settings. Several clinical trials are being conducted to determine the broad therapeutic potential of increasing the bioavailability of nitrite in human health and disease, including studies related to vascular aging. In conclusion, the dietary inorganic nitrate seems to represent a promising complementary therapy to support hypertension treatment with benefits for cardiovascular health.

Evaluation of Clinical Variables Associated with Increased Carotid Intima-Media Thickness in Middle-Aged Hypertensive Women

It has been previously documented that carotid intima-media thickness (cIMT) is a predictor of cardiovascular disease. The aim of this study was to identify clinical parameters associated with an increased cIMT treated hypertensive women. Female patients (n = 116) with essential hypertension, aged 40–65 years, were included in this study. Vascular ultrasound was performed and the patients were divided into two groups according to the values of cIMT (< or ≥0.9 mm). Patients with greater cIMT presented significantly higher systolic blood pressure and pulse pressure. Serum HDL-cholesterol was significantly lower and CRP was significantly higher in the same group. There was a significant correlation between cIMT and age (r = 0.25, P = 0.007), systolic blood pressure (r = 0.19, P = 0.009), pulse pressure (r = 0.30, P = 0.001), and LDL-cholesterol (r = 0.19, P = 0.043). cIMT was correlated to CRP (r = 0.31, P = 0.007) and negatively correlated to HDL-cholesterol (r = 0.33, P = 0.001). In logistic regression, only HDL-cholesterol, CRP, and pulse pressure were shown to be independent variables associated to increased cIMT. In conclusion, pulse pressure, HDL-cholesterol, and CRP are variables correlated with cIMT in treated hypertensive women.

Beneficial effects of acute trans-resveratrol supplementation in treated hypertensive patients with endothelial dysfunction

ABSTRACT Endothelial dysfunction is a surrogate marker of cardiovascular risk. Resveratrol is known to improve endothelial function in animals, however, clinical trials are limited. We hypothesized that the acute trans-resveratrol supplementation improves endothelial function in treated hypertensive patients with endothelial dysfunction. Twenty-four hypertensive patients between 45 and 65 years-old with baseline endothelial dysfunction were enrolled in a randomized, cross-over, double-blind, placebo-controlled trial. Individuals received either a single dose of trans-resveratrol (300 mg) or placebo and were crossed-over after a one-week washout period. Blood pressure (BP) measurements, aortic systolic blood pressure (SBP) and brachial flow-mediated dilation (FMD) were performed before and 1.5 hours after the intervention. FMD was significantly increased in women (4.2 ± 0.5 vs 7.1 ± 1.3%, p = 0.026) but not in men (4.4 ± 0.9 vs 4.9 ± 0.8%, p = 0.588) in the trans-resveratrol group. There was no statistical difference between baseline and final values of brachial BP and also no changes in aortic SBP. Patients with higher low-density lipoprotein (LDL) cholesterol had better FMD response to trans-resveratrol than patients with lower LDL cholesterol (7.4 ± 1.2 vs 4.3 ± 1.0%, p = 0.004). Our study demonstrated that the acute supplementation of trans-resveratrol promoted an improvement in endothelial function, especially in women and those with higher LDL-cholesterol, despite no changes in BP. List of Abbreviation: Aix: augmentation index; AP: augmentation pressure; BP: blood pressure; BMI: body Mass Index; CVD: cardiovascular disease; FMD: flow-mediated dilation; FRS: Framingham Risk Score; HDL: high-density lipoprotein; LDL: low-density lipoprotein; NO: nitric oxide; SPSS: Statistical Package for Social Sciences; ROS: reactive oxygen species; SBP: systolic blood pressure; TG: triglycerides.

Potential Role of Endothelin in Early Vascular Aging

Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.

OS 21-01 NOX1 OR NOX4 DELETION PREVENTS TYPE 1 DIABETES-INDUCED ENDOTHELIAL DYSFUNCTION.

Objective : The prognosis of type-1 diabetes remains poor and is primarily related to the increased risk of vascular complications. Overproduction of reactive oxygen species by NADPH oxidase (NOX) is believed to play an important role in diabetes-related vascular injury. NOX1 may play a role in the macrovascular disease, whereas NOX4 may have protective actions. Nevertheless, their role in diabetic microangiopathy is less well understood. We hypothesized that deletion of Nox1 would prevent diabetes-induced endothelial dysfunction and vascular remodeling of small arteries whereas Nox4 would exaggerate vascular injury. Design and Method : Diabetes-related vascular injury were studied in atherosclerosis-prone apolipoprotein knockout (Apoe-/-) mice. Six-week-old male Apoe-/- mice, Apoe-/- mice deficient in Nox1 (Apoe-/-/Nox1y/-) and Nox4 (Apoe-/-/Nox4-/-) were rendered diabetic by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days. Mice were studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Results: Apoe-/- mice presented a maximal endothelium-dependent vasodilatory response to acetylcholine of only 46%, which was further decreased by ∼50% by diabetes. In contrast, endothelium-dependent relaxations to acetylcholine were 1.5-fold higher in diabetic Apoe-/-/Nox1y/- and Apoe-/-/Nox4-/- mice compared to vehicle-treated Apoe-/- mice. Endothelium-independent relaxation responses to the nitric oxide donor, sodium nitroprusside, were similar in all groups. Diabetes decreased MA stiffness in Apoe-/- mice, as indicated by a rightward displacement of the stress-strain curves, which was blunted by Nox1 or Nox4 knockout. MA media/lumen was unaltered by diabetes. Knockout of Nox4 but not Nox1 increased MA media/lumen 1.4-fold in diabetic Apoe-/- mice. Conclusions: These results suggest that NOX1 and NOX4 play a pathophysiological role in diabetes-induced endothelial dysfunction and contribute to potentially maladaptive changes in vascular stiffness. NOX4 also seems to have dual actions on the vasculature, as it is also protective against vascular remodeling of small arteries in type 1 diabetes.

MPS 18-02 ENDOTHELIN-1 OVEREXPRESSION PRESERVES ENDOTHELIAL FUNCTION IN MICE WITH VASCULAR SMOOTH MUSCLE CELL-SPECIFIC DELETION OF PPAR-GAMMA

Objective: Peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;) agonists reduce blood pressure (BP) and vascular injury in hypertensive rodents. Ppar&ggr; inactivation in vascular smooth muscle cells (VSMC) using a tamoxifen inducible Cre-Lox system enhanced angiotensin II-induced vascular damage. Transgenic mice overexpressing endothelin (ET)-1 in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar gene in VSMC (smPpar&ggr;−/−) will exaggerate ET-1-induced vascular damage. Design and Method: Eleven week-old male control, eET-1, smPpar&ggr;−/− and eET-1/smPpar&ggr;−/− mice were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and sacrificed 4 weeks later. BP was measured by telemetry. Endothelial function and vascular remodeling using pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining, monocyte/macrophage infiltration by immunofluorescence and mRNA expression by reverse transcription-quantitative PCR were assessed in mesenteric arteries (MA) or perivascular fat (PVAT). Spleen T cell and monocyte profiles were assessed by flow cytometry. Results: Systolic BP was 20 mmHg higher in eET-1 and unaffected by Ppar&ggr; inactivation. MA vasorelaxation to acetylcholine was impaired 37% only in smPpar&ggr;−/−. Likewise, ET-1-induced contractions were enhanced only in smPpar&ggr;−/−. ROS levels were increased 1.7-fold in smPpar&ggr;−/− and 2.5-fold in eET-1/smPpar&ggr;−/−. Monocyte/macrophage infiltration in PVAT was 2-fold higher in eET-1 and smPpar&ggr;−/−, which was further increased 2-fold in eET-1/smPpar&ggr;−/−. The percentage of CD11b+ cells was increased 2.3-fold in smPpar&ggr;−/− and further increased 1.5-fold in eET-1/smPpar&ggr;−/−. The percentage of Ly-6Chi monocytes was increased ∼1.8-fold in eET-1 and smPpar&ggr;−/− but not eET-1/smPpar&ggr;−/−. The percentage of T regulatory cells was increased 1.5-fold in smPpar&ggr;−/− and decreased by 26% in eET-1, which was further decreased by 38% in eET-1/smPpar&ggr;−/−. Conclusions: These results suggest that increased ET-1 paradoxically preserves endothelial function in mice with inactivated VSMC Ppar&ggr; despite enhanced oxidative stress. Flow cytometry data indicate that infiltrating monocyte/macrophages in these mice might be anti-inflammatory.

[PP.29.13] LEFT VENTRICLE HYPERTROPHY AND DIASTOLIC DYSFUNCTION ARE ASSOCIATED WITH ABDOMINAL OBESITY IN HYPERTENSIVE WOMEN

Objective: Observational studies have demonstrated that increased abdominal circumference is an important marker of high cardiovascular risk. The purpose of this study was to identify structural and functional cardiac changes in non-diabetic hypertensive women with abdominal obesity (AO). Design and method: Cross-sectional study with 120 hypertensive women, aged 40–65 years, were divided into two groups: without (AO-, n = 42) and with (AO+, n = 78) abdominal obesity according to abdominal circumference < or > = 88 cm, respectively. After clinical evaluation, all the patients carried out biochemical tests, echocardiography, and carotid ultrasound. Results: The mean age was 53 years in both groups. The diastolic blood pressure was significantly higher in the group AO+ (90 ± 1 vs 85 ± 1 mmHg, p < 0.05). On the other hand, the systolic blood pressure, although higher among women AO+, did not reach statistical significance (145 ± 2 vs 140 ± 2 mmHg, p = 0.098). The group AO+ presented greater number of criteria (3.1 ± 0.1 vs 1.4 ± 0.1, p < 0.001) and greater prevalence (62.8 vs 11.9%, p < 0.001) of metabolic syndrome. Despite normal and similar serum glucose levels in both groups, patients AO+ presented HOMA-IR (2.62 ± 0.22 vs 1.61 ± 0.17, p < 0.01) and HOMA-beta (358 ± 57 vs 200 ± 22, p < 0.05) significantly higher than in patients AO-. In echocardiography, the systolic function was comparable between the two groups, but the patients AO+ presented evidences of diastolic dysfunction by tissue Doppler and a higher prevalence of left ventricle hypertrophy (29.2 vs 2.4%). There was no difference in carotid intima-media thickness between the two groups. Conclusions: In this sample of middle-age non-diabetic hypertensive women, abdominal obesity was associated with left ventricle hypertrophy and diastolic dysfunction with no evidence of atherosclerotic process.

PS 16-31 ENDOTHELIN-1 EXAGGERATES TYPE-1 DIABETES-ACCELERATED ATHEROSCLEROSIS THROUGH NADPH OXIDASES 1 AND 4

Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe−/−) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Design and method: Six-week-old male Apoe−/− mice, eET-1/Apoe−/− and eET-1/Apoe−/− mice deficient in Nox1 (eET-1/Apoe−/−/Nox1y/−) or Nox4 (eET-1/Apoe−/−/Nox4−/−) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Results: Diabetic Apoe−/− mice presented an impaired maximal endothelium-dependent vasodilatory response to acetylcholine (21%), which was not observed in diabetic eET-1/Apoe−/−, eET-1/Apoe−/−/Nox1y/− or eET-1/Apoe−/−/Nox4−/− mice (99%). Endothelium-independent relaxation to the nitric oxide (NO) donor sodium nitroprusside was similar between groups. Blockade of NO synthase with L-NAME completely blunted endothelium-dependent relaxation to acetylcholine in diabetic eET-1/Apoe−/− mice, which was prevented by Nox1 but not by Nox4 knockout. ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe−/− mice, which was further exaggerated 1.2-fold by Nox4 but not Nox1 knockout. ET-1 overexpression exaggerated > 2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe−/− mice, which was reduced ∼40% by Nox1 and Nox4 knockout. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.

Cardiometabolic disorders in hypertensive women with abdominal obesity

Weight gain and increased waist circumference are important prognostic indicators of systemic arterial hypertension (SAH) and abdominal obesity (AO) is a relevant indicator of increased cardiovascular risk (CVR).1,2 Recent studies suggest that AO is more strongly associated with blood pressure (BP) than general adiposity3 and its association with SAH is recognized.4 In fact, there seems to be a direct influence of body mass index (BMI) and waist circumference on BP levels since adolescence.5 Additionally, it is well documented that weight loss causes reduced BP.6,7 Besides this direct influence on BP, AO is recognized as one of the main characteristics of metabolic syndrome (MS) and probably one of the most important CVR factors of the syndrome.8