Factors Associated with Primary Hypertension in Pediatric Patients: An Up-to-Date.

BACKGROUND: Arterial hypertension in children is considered a common alteration nowadays, mainly because obesity is a growing worldwide problem closely related to increased blood pressure. Childhood hypertension can be classified as primary or secondary, depending on the etiology. Primary or essential hypertension still has its pathophysiology not fully elucidated, and there is no consensus in the literature on most underlying mechanisms. In this review, genetic and environmental factors, including sodium and potassium intake, socioeconomic status, ethnicity, family structure, obesity, sedentary lifestyle, prematurity and low birth weight, prenatal and postnatal exposures are highlighted. OBJECTIVE: The present study aimed to perform an update on primary hypertension in childhood, providing clinicians and researchers an overview of the current state of the literature regarding the influence of genetic and environmental factors. METHODS: This integrative review searched for articles on genetic and environmental factors related to primary hypertension in pediatric patients. The databases evaluated were PubMed and Scopus. RESULTS: The studies have provided insights regarding many genetic and environmental factors, in addition to their association with the pathophysiology of primary hypertension in childhood. Findings corroborated the idea that primary hypertension is a multifactorial disease. Further studies in the pediatric population are needed to elucidate the underlying mechanisms. CONCLUSION: The study of primary hypertension in pediatrics has utmost importance for the adoption of preventive measures and the development of more efficient treatments, therefore reducing childhood morbidity and the incidence of cardiovascular diseases and other health consequences later in life.

The APLNR gene polymorphism rs7119375 is associated with an increased risk of development of essential hypertension in the Chinese population: A meta-analysis.

Hypertension (HT) has recently been defined as a systolic blood pressure (BP) of ≥130 mm Hg and/or a diastolic BP of ≥80 mm Hg. It is important to further understand the pathophysiology of essential HT as its proportion is larger among most of the diagnosed HT cases. The apelin and apelin receptor (APLNR) are known to play roles in regulating BP, but the putative associations of single nucleotide polymorphisms in the APLNR gene with the risk of development of essential HT have not yet been fully investigated. Herein, we conducted a meta-analysis to investigate the relationship between single nucleotide polymorphisms in the APLNR gene and the risk of essential HT.We conducted a search in the PubMed and Web of Science databases for eligible studies. The pooled odds ratios (ORs) with their 95% confidence intervals (CI) were calculated using random-effects models when heterogeneity was expected across the studies. Otherwise, fixed-effect models were used.Regarding the SNP rs7119375, 5 studies were analyzed, which included a total of 3567 essential HT patients and 3256 healthy controls. Four of the 5 studies were from China and 1 was from Mexico. The meta-analysis showed the existence of a significant association between the AA genotype of rs7119375 and the risk of developing essential HT in the Chinese population, as determined using additive and recessive models (OR, 2.11; 95% CI, 1.12-3.96; I = 86% for AA vs GG. OR, 1.53; 95% CI, 1.21-1.94; I = 28% for AA vs AG. OR, 1.88; 95% CI, 1.13-3.12; I = 79% for AA vs AG + GG).Our study showed, for the first time, the existence of an association between rs7119375 and the risk of development of essential HT in the Chinese population, although the sample size was small and there was considerable population heterogeneity. The apelin/APLNR system could be a novel therapeutic target for the treatment of essential HT, and more studies are warranted to further investigate the association.

Perinatal taurine exerts a hypotensive effect in male spontaneously hypertensive rats and down-regulates endothelial oxide nitric synthase in the aortic arch.

Essential hypertension is considered to be a result of the interaction between genetic and environmental factors, including perinatal factors. Different advantageous perinatal factors proved to have beneficial long-lasting effects against an abnormal genetic background. Taurine is a ubiquitous sulphur-containing amino acid present in foods such as seafood. The antihypertensive effects of taurine have been reported in experimental studies and in human hypertension. We aimed to investigate the effects of perinatal treatment with taurine in spontaneously hypertensive rats (SHR), a known model of genetic hypertension. Female SHR were administered with taurine (3 g/L) during gestation and lactation (SHR-TAU). Untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. Long-lasting effects in offspring were investigated. Addition of taurine to the mother's drinking water reduced blood pressure in adult offspring. No differences were observed in cardiac hypertrophy. Findings on morphometric evaluations suggest that perinatal treatment with taurine would be partially effective in improving structural alterations of the aorta. Modifications in gene expression of Bcl-2 family members and upregulation of endothelial nitric oxide synthase in the aorta of 22-week-old male offspring were found. No differences were observed on relative telomere length in different cardiovascular tissues between SHR and SHR-TAU. Altogether results suggest that taurine programming, albeit sex specific, is associated with gene expression changes which ultimately may lead to improvement of aortic remodelling and enhanced endothelial function because of augmented nitric oxide (NO) production.

Effect of Early Normotension with Olmesartan on Rho-kinase Activity in Hypertensive Patients.

BACKGROUND: Angiotensin II is a potent activator of the Rho-kinase (ROCK) pathway, through which it exerts some of its adverse vasoconstrictor effects. Clinical evidence on the effects of blocking the angiotensin II receptor 1 on ROCK activity in hypertensive patients is scarce. OBJECTIVE: To demonstrate that ROCK activity in peripheral blood mononuclear cells (PMBCs) in patients with essential hypertension is reduced earlier than previously observed, along with blood pressure (BP) lowering on treatment with olmesartan. METHODS: Prospective pilot open study; 17 hypertensive patients were treated with progressive olmesartan doses starting with 20 mg qd. BP was measured at 3, 6 and 9 weeks after treatment initiation. If treatment failed to normalize BP after 3 weeks, olmesartan dose was increased to 40 mg qd, and if still hypertensive after 6 weeks, 12.5 mg of hydrochlorothiazide qd was added. ROCK activity was measured at baseline and 9 weeks after treatment as myosin phosphatase target subunit 1 phosphorylation (MYPT1-p/T ratio) in PBMC. RESULTS: Mean baseline BP was 162 ± 4.9/101 ± 2.4 mmHg. After 9 weeks of treatment, both systolic and diastolic BP were reduced by 41 and 22 mmHg, respectively (p<0.05). Mean pretreatment MYPT1- p/T ratio in PMBCs was significantly reduced by 80% after 9 weeks with olmesartan (p<0.01). CONCLUSION: Normotension achieved after 9 weeks in 82% of the patients treated with olmesartan was associated with a significant reduction of ROCK activity in PBMC.

Effects of Transcutaneous Electrical Nerve Stimulation in Autonomic Nervous System of Hypertensive Patients: A Randomized Controlled Trial.

BACKGROUND: Patients with hypertension have altered autonomic nervous system function, which are increased sympathetic activity. Transcutaneous Electrical Nerve Stimulation (TENS) is a useful modality for pain control and has also been shown to be effective in the reduction of sympathetic activity in healthy subjects and individuals with cardiovascular diseases. OBJECTIVE: The aim of this study was to verify the effects of transcutaneous electrical nerve stimulation by the evaluation of heart rate variability (HRV) in patients with essential hypertension. METHOD: Twenty-eight patients received an application of low-frequency TENS(4 Hz) n=8, highfrequency TENS (100 Hz) n=10 or placebo TENS n=10 in paravertebral ganglionar region during thirty minutes. RESULTS: After 4 Hz TENS, there was a decrease in the low-frequency (LFn.u.) component (57.71±9.46 vs 45.58±13.51, p<0.026) and an increase in the high-frequency (HFn.u.) component (33.03±13.83 vs 45.83±20.19, p <0.05) of HRV. After 100 Hz TENS and placebo, there were no changes in the LF and HF components. No significant differences were found in systolic blood pressure with low-frequency TENS (129.37± 15.48 vs 126.69 ± 15.21, p<0.490). There was an increase, although not significant, with high-frequency TENS (131.00 ± 15.97 vs 138.75 ± 25.79, p<0.121) and placebo (133.80 ± 29.85 vs 134.80 ± 29.72, p< 0.800). No differences were found in the diastolic blood pressure with low-frequency TENS and placebo, but there was a significant increase in high-frequency TENS (81.00 ± 11.78 vs 85.65 ± 13.68, p< 0.018). CONCLUSION: Low-frequency TENS decreases sympathetic nervous system activity and increases parasympathetic nervous system activity and high-frequency TENS increases diastolic blood pressure, when applied on the paravertebral ganglionar region in the hypertensive patients.

Serum Uric Acid Elevation is Associated to Arterial Stiffness in Hypertensive Patients with Metabolic Disturbances.

INTRODUCTION: Chronic serum uric acid elevation (SUA) is known to be induced by dyslipidemia, hypertension, inflammation, and insulin resistance. Therefore, it has been associated with higher risk for coronary artery disease and cardiovascular mortality. Also, increased levels of SUA have been associated with regional arterial stiffness, assessed by pulse wave velocity (PWV). AIMS: To evaluate the relationships of PWV, SUA and different metabolic parameters in essential hypertensive patients. MATERIAL AND METHODS: We evaluated 445 essential hypertensive patients, by measuring office blood pressure (BP), weight, height, and waist circumference. In each patient, blood samples were drawn for biochemical evaluations and 24h urine collection. Body Mass Index (BMI) and Glomerular Filtration Rate (GFR) were calculated. Carotid-Femoral PWV and Left Ventricular Mass Index (LVMI) were measured in all patients. RESULTS: All subjects (n=402), 242 males (55±0.9 yrs.; BMI: 28.9±0.3 Kg/m2) and 160 females (58±1 yrs.; BMI: 28.1±0.4 Kg/m2) had normal renal function. PWV values showed a significant association with SUA (p<0.001), Systolic BP (p<0.025) and LVMI (p<0.05). SUA showed a significant association, p<0.025: with BMI, Waist Circumference, and HDL-C; p<0.05: with Glycaemia at 120 min, Insulin at 120 min, TG, and LVMI; and p<0.001: with serum Creatinine. Backward Stepwise Regression showed that PWV could be predicted from SUA (p<0.001) and Systolic BP (p<0.05). BMI, Waist Circumference, DBP and HR did not significantly add to the ability of the equation to predict PWV. CONCLUSIONS: In this population of essential hypertensive patients, SUA was associated to increased arterial stiffness and to components of the Metabolic Syndrome. These results raise the possibility that a new approach to the role of SUA, linked to cardiovascular stratification, and a most appropriate treatment might be considered.

Heat shock proteins and cardiovascular disease.

The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.

Xuezhikang reduced arterial stiffness in patients with essential hypertension: a preliminary study.

This study aimed to test the effects of xuezhikang, a cholestin extract that contains statin-like components, on arterial stiffness in patients with essential hypertension. One hundred hypertensive patients from the Chinese PLA General Hospital were randomly allocated to receive xuezhikang (1200 mg/day, orally) or placebo (same capsules containing only pharmaceutical excipients). Physical examination outcomes, lipid profile, high sensitivity C-reactive protein (hs-CRP) levels, matrix metalloproteinases-9 (MMP-9) levels, and arterial outcomes, including stiffness parameter (ß), pressure-strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and one-point pulse wave velocity (PWVß) were obtained at baseline and after 6 months of the intervention. Xuezhikang significantly reduced ß (8.4±3.1 vs 6.8±2.1, P=0.007), Ep (122.8±43.9 vs 100.7±33.2, P=0.009), PWVß (6.7±1.2 vs 6.1±1.0, P=0.013), low-density lipoprotein cholesterol (3.4±0.6 vs 2.9±0.5, P=0.001), hs-CRP [2.1 (0.4-10.0) vs 1.4 (0.3-4.1), P=0.020], and MMP-9 (17.2±2.4 vs 12.7±3.8, P <0.001) compared to baseline. The placebo had no effect on these parameters. The changes of PWVß in the xuezhikang group was significantly associated with the changes of hs-CRP and MMP-9 (r=0.144, P=0.043; r=0.278, P=0.030, respectively) but not with lipid profile changes. Our research showed xuezhikang can improve the parameters of arterial stiffness in hypertensive patients, and its effect was independent of lipid lowering.

Angiotensin-converting enzyme inhibitors reduce mortality compared to angiotensin receptor blockers: Systematic review and meta-analysis.

Background There are few reviews comparing the long-term outcomes of the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in a hypertensive population because both are effective in reducing blood pressure. None of them compared angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with a placebo group in patients with essential hypertension, because few studies exist with this design. Methods A systematic search of PUBMED, LILACS, SCIELO, ICTRP, Cochrane, EMBASE and ClinicalTrials.gov from 1 January 2000 until 31 December 2015 selected prospective studies that reported an association between the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in the following cardiovascular outcomes: heart failure/hospitalisation, stroke, acute myocardial infarction, total cardiovascular deaths, total deaths and total outcomes. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were combined by using a fixed-effects model. Results Seventeen studies ( n = 73,761) were included of which 12 studies were randomly assigned to angiotensin II receptor blocker therapy ( n = 24,697) and five to angiotensin-converting enzyme inhibitors ( n = 12,170). Angiotensin-converting enzyme inhibitors proved to be significant in reducing total deaths (OR 0.85, 95% CI 0.78-0.93) and cardiovascular deaths (OR 0.77, 95% CI 0.69-0.87). Angiotensin II receptor blocker therapy did not show a reduction in total deaths (OR 1.02, 95% CI 0.96-1.09) or cardiovascular deaths (OR 0.95, 95% CI 0.86-1.06). For acute myocardial infarction, stroke and heart failure/hospitalisation, the reductions were significant for both classes. Conclusion Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use is similar in preventing major cardiovascular outcomes regarding acute myocardial infarction, stroke and heart failure/hospitalisation. However, the use of angiotensin-converting enzyme inhibitors is more effective in reducing total deaths and cardiovascular deaths than angiotensin II receptor blockers.

Baroreflex gain and vasomotor sympathetic modulation in resistant hypertension.

PURPOSE: The aim of this study was to determine the gain and latency of arterial baroreflex control of heart rate in patients with resistant hypertension compared to patients with essential hypertension and normotensive subjects. METHODS: Eighteen patients with resistant hypertension (56 ± 10 years, mean of four antihypertensive drugs), 17 patients with essential hypertension (56 ± 11 years, mean of two antihypertensive drugs), and 17 untreated normotensive controls (50 ± 15 years) were evaluated by spectral analysis of the spontaneous fluctuations of arterial pressure (beat-to-beat) and heart rate (ECG). This analysis estimated vasomotor and cardiac autonomic modulations, respectively. The transfer function analysis quantified the gain and latency of the response of output signal (RR interval) per unit of spontaneous change of input signal (systolic arterial pressure). RESULTS: The gain was similarly lower in patients with resistant hypertension and patients with essential hypertension in relation to normotensive subjects (4.67 ± 2.96 vs. 6.60 ± 3.30 vs. 12.56 ± 8.81 ms/mmHg; P < 0.01, respectively). However, the latency of arterial baroreflex control of heart rate was significantly higher only in patients with resistant hypertension when compared to patients with essential hypertension and normotensive subjects (-4.01 ± 3.19 vs. -2.91 ± 2.10 vs. -1.82 ± 1.09 s; P = 0.04, respectively). In addition, the index of vasomotor sympathetic modulation was significantly increased only in patients with resistant hypertension when compared to patients with essential hypertension and normotensive subjects (4.04 ± 2.86 vs. 2.65 ± 1.88 vs. 2.06 ± 1.70 mmHg2; P < 0.01, respectively). CONCLUSIONS: Patients with resistant hypertension have reduced gain and increased latency of arterial baroreflex control of heart rate. These patients also have increased vasomotor sympathetic modulation.

Xuezhikang reduced arterial stiffness in patients with essential hypertension: a preliminary study

This study aimed to test the effects of xuezhikang, a cholestin extract that contains statin-like components, on arterial stiffness in patients with essential hypertension. One hundred hypertensive patients from the Chinese PLA General Hospital were randomly allocated to receive xuezhikang (1200 mg/day, orally) or placebo (same capsules containing only pharmaceutical excipients). Physical examination outcomes, lipid profile, high sensitivity C-reactive protein (hs-CRP) levels, matrix metalloproteinases-9 (MMP-9) levels, and arterial outcomes, including stiffness parameter (β), pressure-strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and one-point pulse wave velocity (PWVβ) were obtained at baseline and after 6 months of the intervention. Xuezhikang significantly reduced β (8.4±3.1 vs 6.8±2.1, P=0.007), Ep (122.8±43.9 vs 100.7±33.2, P=0.009), PWVβ (6.7±1.2 vs 6.1±1.0, P=0.013), low-density lipoprotein cholesterol (3.4±0.6 vs 2.9±0.5, P=0.001), hs-CRP [2.1 (0.4-10.0) vs 1.4 (0.3-4.1), P=0.020], and MMP-9 (17.2±2.4 vs 12.7±3.8, P <0.001) compared to baseline. The placebo had no effect on these parameters. The changes of PWVβ in the xuezhikang group was significantly associated with the changes of hs-CRP and MMP-9 (r=0.144, P=0.043; r=0.278, P=0.030, respectively) but not with lipid profile changes. Our research showed xuezhikang can improve the parameters of arterial stiffness in hypertensive patients, and its effect was independent of lipid lowering.

Effect of inspiratory muscle training with load compared with sham training on blood pressure in individuals with hypertension: study protocol of a double-blind randomized clinical trial.

BACKGROUND: Hypertension is a complex chronic condition characterized by elevated arterial blood pressure. Management of hypertension includes non-pharmacologic strategies, which may include techniques that effectively reduce autonomic sympathetic activity. Respiratory exercises improve autonomic control over cardiovascular system and attenuate muscle metaboreflex. Because of these effects, respiratory exercises may be useful to lower blood pressure in subjects with hypertension. METHODS/DESIGN: This randomized, double-blind clinical trial will test the efficacy of inspiratory muscle training in reducing blood pressure in adults with essential hypertension. Subjects are randomly allocated to intervention or control groups. Intervention consists of inspiratory muscle training loaded with 40 % of maximum inspiratory pressure, readjusted weekly. Control sham intervention consists of unloaded exercises. Systolic and diastolic blood pressures are co-primary endpoint measures assessed with 24 h ambulatory blood pressure monitoring. Secondary outcome measures include cardiovascular autonomic control, inspiratory muscle metaboreflex, cardiopulmonary capacity, and inspiratory muscle strength and endurance. DISCUSSION: Previously published work suggests that inspiratory muscle training reduces blood pressure in persons with hypertension, but the effectiveness of this intervention is yet to be established. We propose an adequately sized randomized clinical trial to test this hypothesis rigorously. If an effect is found, this study will allow for the investigation of putative mechanisms to mediate this effect, including autonomic cardiovascular control and metaboreflex. TRIAL REGISTRATION: ClinicalTrials.gov NCT02275377 . Registered on 30 September 2014.

Endothelial nitric oxide synthase tagSNPs influence the effects of enalapril in essential hypertension.

The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are associated with up-regulation of endothelial nitric oxide synthase (NOS3) activity. This mechanism may explain how polymorphisms in NOS3 gene affect the antihypertensive responses to ACEi. While clinically relevant NOS3 polymorphisms were previously shown to affect the antihypertensive responses to enalapril, no study has tested the hypothesis that NOS3 tagSNPs influence the antihypertensive effects of this drug. We examined whether the NOS3 tagSNPs rs3918226, rs3918188, and rs743506, and their haplotypes, affect the antihypertensive responses to enalapril in 101 patients with essential hypertension. Subjects were prospectively treated only with enalapril for 8 weeks. Genotypes were determined by Taqman(®) allele discrimination assay and real-time polymerase chain reaction (PCR) and haplotype frequencies were estimated. We compared the effects of NOS3 tagSNPs on changes in blood pressure after enalapril treatment. To confirm our findings, multiple linear regression analysis was performed adjusting for age, gender, ethnicity, and alcohol consumption. We found that hypertensive patients carrying the AA genotype for the tagSNP rs3918188 showed lower decreases in blood pressure in response to enalapril. Moreover, the TCA haplotype was associated with improved decreases in blood pressure in response to enalapril compared with the CAG haplotype. Adjustment for covariates in multiple linear regression analysis did not change these effects. In addition, when patients were stratified according to the dose of enalapril used, we found that the carries of the T allele for the functional tagSNP rs3918226 showed more intense decreases in blood pressure in response to enalapril 20 mg/day. Our findings suggest that NOS3 tagSNPs influence the effects of enalapril in essential hypertension.