Jose F Vilela-Martin

Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial

BackgroundBlood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.MethodsThis is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.DiscussionThe early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.Trial RegistrationClinical Trials NCT00970931.

Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER‐Prevention Randomized Clinical Trial

Background Prehypertension is associated with higher cardiovascular risk, target organ damage, and incidence of hypertension. The Prevention of Hypertension in Patients with PreHypertension (PREVER‐Prevention) trial aimed to evaluate the efficacy and safety of a low‐dose diuretic for the prevention of hypertension and end‐organ damage. Methods and Results This randomized, parallel, double‐blind, placebo‐controlled trial was conducted in 21 Brazilian academic medical centers. Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention were randomized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment. The primary outcome was incidence of hypertension. Development or worsening of microalbuminuria, new‐onset diabetes mellitus, and reduction of left ventricular mass were secondary outcomes. Participant characteristics were evenly distributed by trial arms. The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo (hazard ratio 0.56, 95% CI 0.38–0.82), resulting in a cumulative incidence of 11.7% in the diuretic arm versus 19.5% in the placebo arm (P=0.004). Adverse events; levels of blood glucose, glycosylated hemoglobin, creatinine, and microalbuminuria; and incidence of diabetes mellitus were no different between the 2 arms. Left ventricular mass assessed through Sokolow‐Lyon voltage and voltage‐duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo (P=0.02). Conclusions A combination of low‐dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension. Clinical Trial Registration URL: http://www.ClinicalTrials.gov, www.ensaiosclinicos.gov. Unique identifiers: NCT00970931, RBR‐74rr6s.

Is there an association between vitamin D and hypertension

Vitamin D has an important role in bone mineralization and maintenance of calcium homeostasis. Thus, vitamin D deficiency is better characterized in the situations that involve the musculoskeletal system and bone metabolism. Recently, there is an interest in the association of vitamin D deficiency with the presence of metabolic syndrome, diabetes mellitus, cardiovascular disease and arterial hypertension. The mechanism underlying the inverse relationship between vitamin D levels and blood pressure is not completely understood, but it seems to involve several systems. Clinical and experimental studies suggest that vitamin D may influence blood pressure by regulating renin-angiotensin system, improving endothelial function, blunting cardiomyocyte hypertrophy, improving insulin sensitivity, reducing the concentrations of serum free fatty acids and regulating the expression of the natriuretic peptide receptor. In accordance with recent clinical studies and meta-analyses, the association between blood 25-hydroxyvitamin D concentrations and hypertension is controversy. There is no doubt about the role of vitamin D in skeletal health. However, the vitamin D supplementation to prevent or treat hypertension has been the subject of recent debate. Thus, the decision to use supplementation with vitamin D would be important in patients with vitamin D deficiency. This review article discusses the association between vitamin D and hypertension, vitamin D supplementation and some recent patents related to vitamin D and hypertension.

Fatores associados ao aumento no índice de incremento de pressão radial em indivíduos hipertensos

BACKGROUND Arterial stiffness is a variable predictor of morbidity and mortality and a possible marker of vascular injury. Its non-invasive assessment by radial tonometry and analysis of the augmentation index (r-AI) allows identifying patients exposed to higher cardiovascular risk. OBJECTIVE To analyze the influence of r-AI on clinical-biochemical variables and its influence on the prevalence of target-organ damage in hypertensive patients. METHODS 140 consecutive hypertensive patients, followed-up in an outpatient clinic, were analyzed in a cross-sectional study. Blood pressure (BP) levels and r-AI were obtained by applanation tonometry of the radial artery (HEM-9000AI, Onrom). The patients were allocated into r-AI tertiles (r-AI < 85%; 85< r-AI < 97%; r-AI > 97%). RESULTS The sample was predominantly composed of women (56.4%), mean age of 61.7 ± 11.7 years and body mass index 29.6 ± 6.1 Kg/m². The highest tertile showed higher proportion of women (p = 0.001), higher systolic BP (p = 0.001) and pulse pressure (p = 0.014), and lower weight (p = 0.044), height (p < 0.001) and heart rate (p < 0.001). Multivariate analysis demonstrated that weight (β = -0.001, p = 0.017), heart rate (β = -0.001, p = 0.007) and central pressure (β = 0.015, p < 0.001) correlated independently with r-AI. In logistic regression analyses, the 3rd r-AI tertile was associated to lower levels of diabetes (DM) (OR = 0.41; 95% CI 0.17-0.97; p = 0.042). CONCLUSION This study demonstrated that weight, heart rate and central BP were independently related to r-AI.

A comparison between diuretics and angiotensin- receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): study protocol for a randomized double-blind controlled trial

BackgroundCardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted.Methods/designThis is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution.DiscussionThe putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil.Clinical trials registration numberClinicalTrials.gov: NCT00971165

Blockade of Renin Angiotensin System in Heart Failure Post-Myocardial Infarction: What is the Best Therapy?

Heart Failure (HF) is a progressive and fatal disorder, which ranks among the major public health problems in Brazil and worldwide. However, survival for patients who developed the syndrome after myocardial infarction (MI) enhanced significantly, as a result of an improvement of pharmacological therapies. A medical breakthrough was the discovery that remodelling of the left ventricle (LV) may be limited by the blockade of the renin-angiotensin system (RAS), at the level of angiotensin converting enzyme (ACE) and binding of angiotensin (Ang) II to its AT1 receptor. This review shows that the therapeutic effects of both ACE inhibitors and the angiotensin receptor blockers (ARB) go beyond the interference in the biochemical pathway ACE-Ang II AT1-receptor. Such effects are also related to the potentiation of bradykinin and increased beneficial effects mediated by the AT2 receptor. Therefore, the results of five randomized trials were presented, which evaluated the use of losartan, valsartan or candesartan, considering their effects on survival and risk of clinical deterioration in patients with symptomatic HF after MI. These studies confirmed the advantage of ARBs over inhibitors in case of cough, rashes and angioneurotic edema, despite similar adverse effects, such as hyperkalemia, renal failure and hypotension. Thus, in this article we have discussed with patents that ACE inhibitors also appear as the first option as RAS inhibitors in search of relevant results for the patient, allowing the alternative use of ARBs to those patients with intolerance.

Effectiveness of low-dose diuretics for blood pressure reduction to optimal values in prehypertension: a randomized clinical trial

Background: To determine the effectiveness of low-dose diuretic therapy to achieve an optimal level of blood pressure (BP) in adults with prehypertension. Methods: The PREVER-prevention trial was a randomized, parallel, double-blinded, placebo-controlled trial, with 18 months of follow-up, conducted at 21 academic medical centers in Brazil. Of 1772 individuals evaluated for eligibility, 730 volunteers with prehypertension who were aged 30–70 years, and who did not reach optimal blood pressure after 3 months of lifestyle intervention, were randomized to a fixed association of chlorthalidone 12.5 mg and amiloride 2.5 mg or placebo once a day. The main outcomes were the percentage of participants who achieved an optimal level of BP. Results: A total of 372 participants were randomly allocated to diuretics and 358 to placebo. After 18 months of treatment, optimal BP was noted in 25.6% of the diuretic group and 19.3% in the placebo group (P < 0.05). The mean net reduction in SBP and DBP for the diuretic group compared with placebo was 2.8 mmHg (95% CI 1.1 to 4.5) and 1.1 mmHg (95% CI −0.09 to 2.4), respectively. Most participants in the active treatment group (74.5%) and in the placebo group (80.7%) continued to have BP in the prehypertension range or progressed to hypertension. Conclusion: Low-dose diuretic therapy increased the probability of individuals with prehypertension to achieve optimal BP but most of those treated continued to have a BP in the prehypertension range or progressed to having overt hypertension.

Renin Angiotensin System Blockage Associates with Insertion/Deletion Polymorphism of Angiotensin-Converting Enzyme in Patients with Hypertensive Emergency

Hypertensive crisis (HC) stands out as a form of acute elevation of blood pressure (BP). It can manifest itself as hypertensive emergency (HE) or hypertensive urgency (HU), which is usually accompanied with levels of diastolic BP ≥120 mmHg. Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism may influence manifestations of HC. Thus, this study evaluated the influence of ACE I/D polymorphism in individuals with HC. A total of 187 patients admitted with HC (HU [n=69] and HE [n=118]) and 75 normotensive individuals were included in the study. Peripheral blood was drawn for a biochemical and genetic analysis of the ACE I/D polymorphism by Polymerase Chain Reaction. HC group showed higher systolic BP, body mass index (BMI), glycemia, creatinine, and lower high-density lipoprotein (HDL) cholesterol compared with normotensive individuals. The use of renin-angiotensin system (RAS) blockers was more frequent in the HU group than in the HE group (p=0.020). The II genotype was more predominant in normotensive and HU individuals than among HE individuals (18.7%, 11.6%, and 2.5%, respectively; p=0.004). Higher BMI and glycemia were associated with HC in the logistic regression model. ACE II genotype (odds ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.51) and HDL cholesterol were protective for the development of HE. ACE II genotype was present in the HU group, compared with the HE group (OR 0.18; 95% CI 0.04-0.88). This study shows an association between the low prevalence of ACE I/D polymorphism II genotype and a greater occurrence of HE in Brazilian individuals. The lower blockage of RAS, which was detected in the HE group, may interact with the low frequency of II genotype, conferring an increased risk for HE.

[PP.21.02] INDIVIDUALS WITH HYPERTENSIVE EMERGENCY PRESENT ASSOCIATION BETWEEN RENAL DYSFUNCTION AND INFLAMMATORY CYTOKINES

Objective: Chronic hypertension and renal dysfunction are associated. However, scarce studies have evaluated the participation of the inflammatory process in the pathogenesis of acute elevation of blood pressure (BP) (characterized by hypertensive crisis - HC) and kidney dysfunction. Thus, this study had objectives: 1- to identify clinical profile and renal function of the individuals with HC, subdivided in urgency (HU) and hypertensive emergency (HE) and 2- to evaluate relationship between kidney function and inflammatory cytokines: interleukins (IL-1&bgr;,IL-6, IL-8, IL-18), tumoral necrosis factor (TNF-&agr;) and anti-inflammatory cytokine 10 (IL-10) in subjects with HC (HU and HE). Design and method: We studied 274 individuals: 74 normotensive (NT), 74 controlled hypertensive (CHT), 50 with HU and 78 individuals with HE. The glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease equation (MDRD). The serum levels of cytokines were made by MULTIPLEX and ELISA technique. The Kruskall Wallis and Mann Whitney tests, and Spearman correlation were used for comparison between groups, with a significance level for p-value <0.05. Results: The diastolic BP and heart rate were significantly higher in the HC group (120mmHg and 85bpm, respectively) compared to the CHT group (75mmHg and 68 bpm, respectively). Individuals with HE were older. Potassium was significantly lower in HE group (4,2mEq/l) compared to NT, CH and HU groups (4.5, 4.4 and 4.4mEq/L, respectively; p < 0.05). The GFR was significantly lower in HE group (65 ml/min/m2) in comparison to HU (73), CHT (82) and NT (88 mL/min/m2) (p < 0,001). All measured cytokines were significantly higher in patients with HE compared to NT and CHT groups. It was observed negative correlation among GFR, diastolic BP, and creatinine for all the groups (p < 0,0001). There was also negative correlation between GFR and cytokines in HE individuals (p < 0,05). Conclusions: Individuals with HE present GFR reduction in comparison to others studied groups. It is also observed higher cytokines levels in HE group and negative correlation between GFR and inflammatory cytokines. This suggests the involvement of inflammatory cytokines in the pathogenesis of acute hypertensive event and kidney dysfunction.