Publications by authors named "Heitor Moreno"

110 Publications

Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Arq Bras Cardiol 2021 03;116(3):443-451

Universidade Estadual de Campinas, Campinas, SP - Brasil.

Background: The cytokine tumor necrosis factor-alpha (TNF-α) is elevated in resistant hypertension (RH), but the effects of a TNF-α inhibitor in this population is unknown.

Objective: The aim of this trial was to evaluate whether a single dose of infliximab controlled by placebo acutely reduces blood pressure (BP) in RH subjects.

Methods: A double-blind, placebo-controlled, crossover trial was conducted, and randomized RH subjects received either infliximab or placebo. The primary endpoint was the change in mean BP levels relative to the baseline immediately after the infusion obtained by continuously beat-to-beat non-invasive hemodynamic assessment. Secondary endpoints included changes in office, ambulatory and central BP measurements; endothelial function; and inflammatory biomarkers after 7 days. The level of significance accepted was alpha=0.05.

Results: Ten RH subjects were enrolled. The primary endpoint analysis showed an acute decrease in mean BP values (mean of differences ± standard deviation = -6.3 ± 7.2 mmHg, p=0.02) from baseline, after the application of infliximab compared with placebo. Diastolic BP levels (-4.9 ± 5.5 mmHg, p=0.02), but not systolic BP levels (-9.4 ± 19.7 mmHg, p=0.16), lowered after infliximab infusion. No further significant differences were identified in either the other hemodynamic parameters or in secondary endpoints, except for TNF-α levels, which increased continuously after infliximab infusion. No adverse events were reported during the protocol.

Conclusions: A single-dose of infliximab decreased the mean and diastolic BP levels immediately after its infusion, when compared to the placebo in RH. The anti-TNF-α therapy was found to be safe and well-tolerated. The results of this proof-of-concept are hypothesis-generating and need to be further investigated. (Arq Bras Cardiol. 2021; 116(3):443-451).
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http://dx.doi.org/10.36660/abc.202190703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159563PMC
March 2021

Transcranial direct current stimulation modulates autonomic nervous system and reduces ambulatory blood pressure in hypertensives.

Clin Exp Hypertens 2021 May 11;43(4):320-327. Epub 2021 Jan 11.

Laboratory of Cardiovascular Pharmacology & Hypertension, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.

: Transcranial direct current stimulation (tDCS) seems to positively modulate the autonomic nervous system in different clinical conditions and healthy subjects; however, its effects on hypertensive (HTN) patients are not completely known. This study aimed to evaluate the effects of a tDCS or SHAM session (20 min) on blood pressure (BP) and autonomic variables of HTN patients.: Subjects (n = 13) were randomly submitted to SHAM and tDCS sessions (1 week of ). Hemodynamic and autonomic variables were measured at baseline, during, and immediately after tDCS or SHAM stimulation (Finometer®, Beatscope). Ambulatory BP measurement (ABPM) was evaluated after the experimental period.: Hemodynamic variables were not changed by tDCS, except for the fall in peripheral vascular resistance (Δ = -1696.51 ± 204.65 dyn.s/cm5). After the tDCS, sympathetic modulation was decreased (-61.47%), and vagal modulation was increased (+38.09%). Such acute autonomic changes may have evoked positive results observed in 24 hs-systolic blood pressure (Δ = -8.4 ± 6.2; = .0022) and 24hs-diastolic blood pressure (Δ = -5.4 ± 4.2; = .0010) in tDCS subjects compared with that in SHAM.: These findings suggest that the tDCS could promote positive acute adjustments on cardiac autonomic control and reduced values on 24-hs BP of HTN patients. More than a proof-of-concept, these results may point out to the future, where brain stimulation (tDCS) can be used to HTN syndromes, such as refractory HTN.
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http://dx.doi.org/10.1080/10641963.2021.1871916DOI Listing
May 2021

Obstructive sleep apnea and ambulatory blood pressure monitoring: current evidence and research gaps.

J Hum Hypertens 2021 04 7;35(4):315-324. Epub 2021 Jan 7.

Hypertension Unit, Renal Division, University of São Paulo Medical School, Sao Paulo, Brazil.

Obstructive Sleep Apnea (OSA) is a common condition characterized by intermittent collapse of the upper airway during sleep, resulting in partial (hypopnoeas) and total obstructions (apneas). These respiratory events observed in OSA may trigger multiple pathways involved in the blood pressure (BP) instability during the night and potentially influencing daytime BP as well (carry-over effects). This review provides an update about the impact of OSA and its treatments on 24-h BP control. Overall, there is growing evidence suggest that OSA is associated with higher frequency of nondipping BP pattern and nocturnal hypertension in a dose-dependent manner. The presence of nondiping BP (especially the reverse pattern) is independently associated with OSA regardless of sleep-related symptoms suggesting a potential tool for screening OSA in patients with clinical indication for performing ABPM. Beyond dipping BP, preliminary evidence associated OSA with white-coat effect and higher frequency of masked hypertension and BP variability than the control group (no OSA). Unfortunately, most of the evidence on the evidence addressing the impact of OSA treatment on BP was limited to office measurements. In the last years, data from observational and randomized studies pointed that CPAP is able to promote 24-h BP decrease especially in patients with resistant and refractory hypertension. A randomized trial suggests that CPAP is able to decrease the rate of masked hypertension as compared to no treatment in patients with severe OSA. Interestingly, nondipping BP is a good predictor of BP response to CPAP making ABPM an interesting tool for better OSA management.
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http://dx.doi.org/10.1038/s41371-020-00470-8DOI Listing
April 2021

Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation.

Cardiovasc Res 2021 04;117(5):1358-1371

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Room 536 Robinson Research Building, Nashville, TN 37232-6602, USA.

Aims: Prior studies have focused on the role of the kidney and vasculature in salt-induced modulation of blood pressure; however, recent data indicate that sodium accumulates in tissues and can activate immune cells. We sought to examine mechanisms by which salt causes activation of human monocytes both in vivo and in vitro.

Methods And Results: To study the effect of salt in human monocytes, monocytes were isolated from volunteers to perform several in vitro experiments. Exposure of human monocytes to elevated Na+ex vivo caused a co-ordinated response involving isolevuglandin (IsoLG)-adduct formation, acquisition of a dendritic cell (DC)-like morphology, expression of activation markers CD83 and CD16, and increased production of pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-6, and IL-1β. High salt also caused a marked change in monocyte gene expression as detected by RNA sequencing and enhanced monocyte migration to the chemokine CC motif chemokine ligand 5. NADPH-oxidase inhibition attenuated monocyte activation and IsoLG-adduct formation. The increase in IsoLG-adducts correlated with risk factors including body mass index, pulse pressure. Monocytes exposed to high salt stimulated IL-17A production from autologous CD4+ and CD8+ T cells. In addition, to evaluate the effect of salt in vivo, monocytes and T cells isolated from humans were adoptively transferred to immunodeficient NSG mice. Salt feeding of humanized mice caused monocyte-dependent activation of human T cells reflected by proliferation and accumulation of T cells in the bone marrow. Moreover, we performed a cross-sectional study in 70 prehypertensive subjects. Blood was collected for flow cytometric analysis and 23Na magnetic resonance imaging was performed for tissue sodium measurements. Monocytes from humans with high skin Na+ exhibited increased IsoLG-adduct accumulation and CD83 expression.

Conclusion: Human monocytes exhibit co-ordinated increases in parameters of activation, conversion to a DC-like phenotype and ability to activate T cells upon both in vitro and in vivo sodium exposure. The ability of monocytes to be activated by sodium is related to in vivo cardiovascular disease risk factors. We therefore propose that in addition to the kidney and vasculature, immune cells like monocytes convey salt-induced cardiovascular risk in humans.
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http://dx.doi.org/10.1093/cvr/cvaa207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064439PMC
April 2021

A Novel Analysis via Micro-CT Imaging Indicates That Chemically Modified Tetracycline-3 (CMT-3) Inhibits Tooth Relapse after Orthodontic Movement: A Pilot Experimental Study.

Int J Dent 2019 1;2019:3524207. Epub 2019 Apr 1.

Department of Medical Sciences, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Zip Code: 70910-90, Brasilia, DF, Brazil.

Objective: To evaluate the effect of chemically modified tetracycline-3 (CMT-3) and simvastatin on tooth relapse after orthodontic movement in rats using a novel analysis method employing high-resolution micro-CT (Micro-CT) images. In addition, the correlation between bone density and orthodontic relapse was also evaluated for each experimental group.

Methods: Forty adult male Wistar rats had stainless steel springs installed on their left upper first molars in order to generate tooth movement for 18 days. After this initial period, the animals were divided into three groups: (1) 30 mg/kg of CMT-3; (2) 5 mg/kg of simvastatin; and (3) 0.5% carboxymethylcellulose, and each group was treated for 20 days. Micro-CT images were analyzed (conventional method and 3D reconstruction) on the 7th and 18th days following spring fixation and finally, 20 days after treatment either with CMT-3 or simvastatin (38th day). Bone mineral density (BMD) of the mesial and distal roots of the upper first molar was also analyzed.

Results: The difference was statistically significant between the groups as to recurrence (=0.048), and the post hoc test identified the value of =0.007 between the control group and the CMT-3 group. Simvastatin was not able to inhibit tooth relapse. The bone mineral densities of both the mesial and distal roots were different between the three groups, after the 20th day of drug use (=0001 and < 0001).

Conclusion: Our findings support the initial evidence that CMT-3 is able to prevent relapse after tooth movement. Future trials in humans should evaluate such treatment as a promising approach to preventing this common phenomenon.

Clinical Relevance: Considering the results obtained, CMT-3 can be used to avoid relapse after tooth movement.
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http://dx.doi.org/10.1155/2019/3524207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466921PMC
April 2019

Oral lichen planus and malignant transformation: The role of p16, Ki-67, Bub-3 and SOX4 in assessing precancerous potential.

Exp Ther Med 2018 May 20;15(5):4157-4166. Epub 2018 Mar 20.

Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil.

The association of oral lichen planus (OLP) lesions with malignant transformation risk has remained a controversial topic and is of clinical importance. Therefore, the present study evaluated the expression levels of p16, Ki-67, budding uninhibited by benzimidazoles 3 (Bub-3) and sex-determining region Y-related high mobility group box 4 (SOX4), and their roles as precancerous biomarkers in OLP. A retrospective study was performed, in which tissue blocks of OLP, oral dysplasia (OD), cutaneous lichen planus (CLP) and oral fibrous hyperplasia (OFH) were used (n=120). A positivity index (PI) for p16, BUB3, Ki-67 and SOX4 expression was calculated in each group. The PI for p16 was 20.65% for OLP, 7.85% for OD, 86.59% for CLP and 11.8% for OFH, and the difference between these groups was statistically significant (P<0.001). PIs of Ki-67 were indicated as 11.6% for OLP, 14.4% for OD, 8.24% for CLP and 5.5% for OFH, and a statistically significant difference was observed between the groups (P<0.001). Notably, the expression levels of BUB3 were not statistically different among groups. The highest expression levels of SOX4 were identified in CLP (P<0.001 vs. OLP/CLP; P=0,001 vs. CLP/OD). The determined expression levels of p16 and Ki-67 suggest that specific OLP lesions may have an intermediate malignant potential and should be carefully followed up. The intense SOX4 staining in CLP indicated a different proliferation pattern of epithelium compared with oral mucosa cells. These findings suggest that SOX4 expression may also be associated with the different clinical courses of OLP and CLP.
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http://dx.doi.org/10.3892/etm.2018.5971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920964PMC
May 2018

Glycated hemoglobin correlates with arterial stiffness and endothelial dysfunction in patients with resistant hypertension and uncontrolled diabetes mellitus.

J Clin Hypertens (Greenwich) 2018 05 5;20(5):910-917. Epub 2018 May 5.

Laboratory of Cardiovascular Pharmacology, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

This study aimed to evaluate the effects of glycated hemoglobin (HbA ) on flow-mediated dilation, intima-media thickness, pulse wave velocity, and left ventricular mass index in patients with resistant hypertension (RHTN) comparing RHTN-controlled diabetes mellitus and RHTN-uncontrolled type 2 diabetes mellitus. Two groups were formed: HbA <7.0% (RHTN-controlled diabetes mellitus: n = 98) and HbA ≥7.0% (RHTN-uncontrolled diabetes mellitus: n = 122). Intima-media thickness and flow-mediated dilation were measured by high-resolution ultrasound, left ventricular mass index by echocardiography, and arterial stiffness by carotid-femoral pulse wave velocity. No differences in blood pressure levels were found between the groups but body mass index was higher in patients with RHTN-uncontrolled diabetes mellitus. Endothelial dysfunction and arterial stiffness were worse in patients with RHTN-uncontrolled diabetes mellitus. Intima-media thickness and left ventricular mass index measurements were similar between the groups. After adjustments, multiple linear regression analyses showed that HbA was an independent predictor of flow-mediated dilation and pulse wave velocity in all patients with RHTN. In conclusion, HbA may predict the grade of arterial stiffness and endothelial dysfunction in patients with RHTN, and superimposed uncontrolled diabetes mellitus implicates further impairment of vascular function.
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http://dx.doi.org/10.1111/jch.13293DOI Listing
May 2018

Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial.

Trials 2018 Feb 12;19(1):101. Epub 2018 Feb 12.

Hypertension Clinic, Department of Internal Medicine, State Medical School of São José do Rio Preto (FAMERP), Rua Tocantins 2971 Votuporanga, São Paulo, CEP 15505-188, Brazil.

Background: Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney.

Methods/design: This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group.

Discussion: In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney.

Trial Registration: Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.
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http://dx.doi.org/10.1186/s13063-017-2343-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810004PMC
February 2018

The rs243866/243865 polymorphisms in MMP-2 gene and the relationship with BP control in obese resistant hypertensive subjects.

Gene 2018 Mar 27;646:129-135. Epub 2017 Dec 27.

Laboratory of Cardiovascular Pharmacology, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil; Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, SP, Brazil.

We sought to investigate whether the polymorphisms rs243865 (-1306C>T); rs243866 (-1575G>A) and rs2285053 (-735C>T) in metalloproteinases 2 - MMP-2 gene and rs17576 (Q279R), rs17577 (Q668R) and rs3918242 (-1562C>T) in MMP-9 gene are associated with clinical outcomes in obese resistant hypertensive (RH) subjects. One hundred and twenty RH were enrolled in this cross-sectional study and divided into obese (n=63) and non-obese (n=57) according to body mass index. Genotypes were determined by real-time PCR using TaqMan probes. We determined pulse wave velocity (PWV), microalbuminuria and left ventricular mass index (LVMI) to assess TODs. Obese and non-obese RH had similar allele, genotype and haplotype distributions for all polymorphisms assessed but obese RH subjects carrying the low frequency allele for SNPs in MMP-2 gene had higher ambulatory diastolic blood pressure. Also, PWV and LVMI were higher in subjects carrying the low frequency allele for SNPs in MMP-2 gene. Regarding MMP-9 gene, office diastolic BP levels were higher in the AA genotype individuals compared to the G allele group for rs17576 polymorphism, while the opposite was found regarding the microalbuminuria level. Independent multiple linear regression analyses revealed that both A allele for rs243865 and T allele for rs243866 in MMP-2 gene were associated with ambulatory diastolic levels in obese RH subjects, apart from potential confounders. Our study suggests that rs243866/rs243865 in the MMP-2 gene are related to BP levels in obese RH subjects, although TODs present in this population seem to be dependent of a combination of other factors besides the genetic polymorphisms.
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http://dx.doi.org/10.1016/j.gene.2017.12.023DOI Listing
March 2018

Do thiazide diuretics reduce central systolic blood pressure in hypertension?

J Clin Hypertens (Greenwich) 2018 01 6;20(1):133-135. Epub 2017 Nov 6.

Department of Internal Medicine, Hypertension Clinic, State Medical School of São José do Rio Preto (FAMERP), São Paulo, Brazil.

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http://dx.doi.org/10.1111/jch.13134DOI Listing
January 2018

Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists.

Vasc Health Risk Manag 2017 16;13:403-411. Epub 2017 Oct 16.

School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Mineralocorticoid-receptor antagonists (MRAs) have proven to be effective in some types of hypertension, especially in resistant hypertension (RHTN). In this phenotype of hypertension, the renin-angiotensin-aldosterone pathway plays an important role, with MRAs being especially effective in reducing blood pressure. In this review, we show the relevance of aldosterone in RHTN, as well as some clinical characteristics of this condition and the main concepts involving its pathophysiology and cardiovascular damage. We analyzed the mechanisms of action and clinical effects of two current MRAs - spironolactone and eplerenone - both of which are useful in RHTN, with special attention to the former. RHTN represents a significant minority (10%-15%) of hypertension cases. However, primary-care physicians, cardiologists, nephrologists, neurologists, and geriatricians face this health problem on a daily basis. MRAs are likely one of the best pharmacological options in RHTN patients; however, they are still underused.
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http://dx.doi.org/10.2147/VHRM.S138599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652936PMC
November 2017

Matrix metalloproteinase-2 -735C/T polymorphism is associated with resistant hypertension in a specialized outpatient clinic in Brazil.

Gene 2017 Jul 5;620:23-29. Epub 2017 Apr 5.

Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.

Background: Matrix metalloproteinases (MMPs) are enzymes involved in cardiovascular (CV) remodeling and hypertension-mediated target organ damage (TOD). Genetic polymorphisms in matrix metalloproteinase 2 (MMP-2) gene [-1575G/A (rs243866); -1306C/T (rs243865); and -735C/T (rs2285053)] are associated with several CV conditions, however the relationship between MMP-2 polymorphisms and resistant hypertension (RH) is unknown. We evaluated whether these genetic single nucleotide polymorphisms (SNPs) in MMP-2 gene are associated with 1) MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) levels in RH and mild to moderate hypertensive (HT) subjects, 2) left ventricular hypertrophy (LVH) and arterial stiffness and 3) the presence of RH.

Methods: One hundred and nineteen RH and 136 HT subjects were included in this cross-sectional study. Genotypes were determined by real-time PCR using TaqMan probes. Haplotypes were estimated using Bayesian method.

Results: The levels of MMP-2 and TIMP-2 were similar among genotypes and haplotypes for the three studied polymorphisms in HT and RH groups. RH showed higher frequency for GCC haplotype and lower frequency of GCT and ATC haplotypes (-1575G/A, -1306C/T and -735C/T, respectively) compared to HT (0.77 vs. 0.64; 0.09 vs. 0.17; 0.13 vs. 0.19, p=0.003 respectively). GCC haplotype was associated to RH apart from potential confounders (odds ratio (OR)=2.09; 95% confidence interval (CI)=1.20-3.64; p=0.01). In addition, CC genotype (OR=2.93; 95% CI=1.22-7.01; p=0.02) and C allele (OR=2.81; 95% CI=1.26-6.31; p=0.01) for -735C/T polymorphism were independently associated with RH. GCT haplotype was associated with reduced probability of having RH (OR=0.35; 95% CI=0.16-0.79; p=0.01). Finally, no relationship was found between studied MMP-2 SNPs and left ventricular hypertrophy and arterial stiffness in both groups.

Conclusion: GCC haplotype carriers showed higher probability to have RH (odds ratio>1), while the GCT haplotype carriers showed lower probability to have RH, suggesting that the GCT haplotype may represent a protective genetic factor for the development of RH. These finds suggest that GCC and GCT haplotypes, and C allele and CC genotype of the -735C/T MMP-2 gene polymorphism may have a role in RH.
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http://dx.doi.org/10.1016/j.gene.2017.04.004DOI Listing
July 2017

MCP-1 Levels are Associated with Cardiac Remodeling but not with Resistant Hypertension.

Arq Bras Cardiol 2017 04 30;108(4):331-338. Epub 2017 Mar 30.

Universidade Estadual de Campinas (UNICAMP), Campinas, SP - Brazil.

Background: Hypertension is a chronic, low-grade inflammation process associated with the release of cytokines and development of target organ damage. Deregulated monocyte chemoattractant protein-1 (MCP-1) levels have been associated with high blood pressure and cardiovascular complications; however, the mechanisms involved are complex and not fully understood.

Objective: This study aimed to compare the levels of MCP-1 in patients with resistant (RH) versus mild-to-moderate (HTN) hypertension and their association with the presence or absence of left ventricular hypertrophy (LVH) in all hypertensive subjects.

Methods: We enrolled 256 hypertensive subjects: 120 RH and 136 HTN, investigating the relationship between circulating MCP-1 levels and blood pressure, biochemical data, hematologic profile, and cardiac damage within the RH and HTN groups. Plasma MCP-1 levels were measured by ELISA and LVH was assessed by echocardiography.

Results: We found no difference in MCP-1 levels between RH and HTN subjects. On the other hand, we encountered lower MCP-1 levels in patients with LVH (105 pg/mL [100 - 260 pg/mL] versus 136 pg/mL (100 - 200 pg/mL), p = 0.005, respectively] compared with those without LVH. A logistic regression model adjusted for body mass index (BMI), age, race, aldosterone levels, and presence of diabetes and RH demonstrated that median levels of MCP-1 (2.55 pg/mL [1.22 - 5.2 pg/mL], p = 0.01) were independently associated with LVH in the entire hypertensive population.

Conclusion: Since MCP-1 levels were similar in both RH and HTN subjects and decreased in hypertensive patients with existing LVH, our study suggests a possible downregulation in MCP-1 levels in hypertensive individuals with LVH, regardless of hypertension strata.
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http://dx.doi.org/10.5935/abc.20170033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421472PMC
April 2017

Crosstalk between obesity and MMP-9 in cardiac remodelling -a cross-sectional study in apparent treatment-resistant hypertension.

Blood Press 2017 Apr 8;26(2):122-129. Epub 2016 Nov 8.

c Laboratory of Pharmacology Cardiovascular, Faculty of Medical Sciences, Department of Internal Medicine , University of Campinas , SP , Brazil.

The balance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) plays a key role in the development of hypertension and obesity. We aimed to evaluate the levels of MMP-2 and 9 and TIMP-2 and -1 in obese and non-obese apparent treatment-resistant hypertensive subjects (aTRH) and its association with cardiac hypertrophy. This cross-sectional study enrolled 122 subjects and divided into obese aTRH (n = 67) and non-obese (n = 55) group. Clinical and biochemical data were compared between both groups, including office BP, ambulatory BP, plasma MMP-2 and 9, TIMP-2 and 1 and left ventricular mass index (LVMI). We found higher MMP-9 levels and MMP-9/TIMP-1 ratio in obese aTRH subjects but no difference in MMP-2 and TIMP-1 levels. Obesity influenced MMP-9 levels [β = 20.8 SE =8.6, p = 0.02) independently of potential confounders. In addition, we found a positive correlation between MMP-9 and anthropomorphic parameters. Finally, obese aTRH subjects with left ventricular hypertrophy (LVH) had greater MMP-9 levels compared with non-obese with LVH. Our study suggests that MMP-9 levels are influenced by obesity and may directly participate in the progressive LV remodelling process, suggesting a possible role for a higher cardiovascular risk in apparent resistant hypertensive subjects.
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http://dx.doi.org/10.1080/08037051.2016.1249336DOI Listing
April 2017

Impact of exercise training associated to pyridostigmine treatment on autonomic function and inflammatory profile after myocardial infarction in rats.

Int J Cardiol 2017 Jan 26;227:757-765. Epub 2016 Oct 26.

Faculty of Physical Education, University of Campinas - UNICAMP, Campinas, SP, Brazil. Electronic address:

Background: The effects of exercise training (ET) associated with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on inflammatory profile after myocardial infarction (MI), are unclear.

Methods: Male Wistar rats were randomly assigned to: control (C); sedentary+infarcted (I); sedentary+infarcted treated with PYR (IP); infarcted submitted to aerobic exercise training (IT); and infarcted submitted to treatment with PYR and aerobic exercise training (ITP). After 12weeks of ET (50-70% maximal running speed; 1h a day, 5days a week) and/or PYR treatment (0.14mg/mL on drink water), hemodynamic, autonomic and cytokines expression were performed.

Results: We observed that both aerobic ET, associated or not with PYR treatment in MI animals, were able to: reduced MI area, improved systolic and diastolic function, baroreflex sensitivity, cardiovascular autonomic modulation, and tonic activity of the sympathetic and parasympathetic nervous system. Also, they led to a reduction of inflammatory profile measured at plasma, left ventricle and soleus skeletal muscle. However, additional effects were observed when ET and PYR were associated, such as an increase in vagal tonus and modulation, reduction of MI area, interferon-γ and tumor necrosis factor-α (TNF-α), as well as an increase of interleukin-10/TNF-α ratio on left ventricle.

Conclusion: These data suggest that associating ET and PYR promotes some additional benefits on cardiovascular autonomic modulation and inflammatory profile in infarcted rats.
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http://dx.doi.org/10.1016/j.ijcard.2016.10.061DOI Listing
January 2017

Acute Sildenafil Use Reduces 24-Hour Blood Pressure Levels in Patients With Resistant Hypertension: A Placebo-Controlled, Crossover Trial.

J Clin Hypertens (Greenwich) 2016 11 1;18(11):1168-1172. Epub 2016 Jun 1.

Laboratory of Cardiovascular Pharmacology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

The authors previously demonstrated that acute administration of sildenafil-a phosphodiesterase 5 (PDE5) inhibitor-improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single-blinded, placebo-controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24-hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (-8.8±1.4 vs 1.3±1.2 mm Hg, P=.02), diastolic (-5.3±3.3 vs 1.8±1.1 mm Hg, P=.03), and mean (-7.9±3.6 vs 0.8±0.9 mm Hg, P=.01) 24-hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic -6.0±4.7 vs 4.4±1.5 mm Hg [P=.02] and mean -4.8±3.9 vs 3.5±1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment.
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http://dx.doi.org/10.1111/jch.12850DOI Listing
November 2016

Increased Circulating Tissue Inhibitor of Metalloproteinase-2 Is Associated With Resistant Hypertension.

J Clin Hypertens (Greenwich) 2016 10 14;18(10):969-975. Epub 2016 Jul 14.

Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil.

Resistant hypertension (RH) is associated with organ damage and cardiovascular risk. Evidence suggests the involvement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in hypertension and in cardiovascular remodeling. The aim of this study was to assess the levels of MMP-2 and TIMP-2 in RH and its relation with organ damage, including arterial stiffness and cardiac hypertrophy. MMP-2 and TIMP-2 levels were compared among 19 patients with normotension (NT), 116 with nonresistant hypertension (HTN) and 116 patients with resistant HTN (RH). MMP-2 levels showed no differences among NT, HTN, and RH groups, while TIMP-2 levels were higher in RH compared with HTN and NT groups (90.0 [76.1-107.3] vs 70.1 [57.7-88.3] vs 54.7 [40.9-58.1] ng/mL, P<.01), respectively. MMP-2/TIMP-2 ratio was reduced in the RH group compared with the HTN and NT groups (2.7 [1.9-3.4] vs 3.3 [2.6-4.2] vs 4.9 [4.5-5.3], P<.01), respectively. No associations were found between MMP-2 levels, TIMP-2, and MMP-2/TIMP-2 ratio with cardiac hypertrophy and arterial stiffness in the RH and HTN groups. Finally, in a regression analysis, reduced MMP-2/TIMP-2 ratio and increased TIMP-2 levels were independently associated with RH. The present findings provide evidence that TIMP-2 is associated with RH and might be a possible biomarker for screening RH patients.
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http://dx.doi.org/10.1111/jch.12865DOI Listing
October 2016

Effects of leptin and leptin receptor SNPs on clinical- and metabolic-related traits in apparent treatment-resistant hypertension.

Blood Press 2017 Apr 16;26(2):74-80. Epub 2016 Jun 16.

a Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences, University of Campinas , Campinas , SP , Brazil.

Leptin is associated to the lack of blood pressure control as well as target organ damage in resistant hypertensive (RH) subjects. Single-nucleotide polymorphisms (SNPs) rs7799039 and rs1137101 in leptin (LEP) and leptin receptor (LEPR) genes, respectively, are associated with cardiovascular disease and metabolic syndrome. We evaluated the association of these two SNPs with clinical and biochemical features in 109 apparent treatment-RH subjects (aTRH) and 125 controlled hypertensives. Homozygous genotypes GG (n = 43) vs. AA (n = 14) for rs7799039 and AA (n = 34) vs. GG (n = 26) genotypes for rs1137101 were compared in aTRH subjects. There was no difference in leptin levels among both SNPs. On the other hand, LEP SNP (GG vs. AA) associated with the levels of glycated haemoglobin (6.4 ± 1.4 vs. 7.8 ± 2.3%, p = 0.03), insulin (8.6 ± 4.6 vs. 30.6 ± 27.7 uUI/mL, p = 0.01), HDL-cholesterol (51 ± 16 vs. 39 ± 11 mg/dL, p = 0.001) and PWV (9.5 ± 2.1 vs. 11.2 ± 2.8 m/s, p = 0.03). LEPR SNP (AA vs. GG), associated with heart rate (69 ± 12 vs. 67 ± 12 bpm, p = 0.03), fat mass (31 ± 11 vs. 24 ± 8 kg, p = 0.03) and triglycerides levels (175 ± 69 vs. 135 ± 75 mg/dL, p = 0.03). These findings may be clinically useful for identifying a group of aTRH who may have a LEP and/or LEPR gene variants, which may predispose this specific group to worse or better outcomes.
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http://dx.doi.org/10.1080/08037051.2016.1192945DOI Listing
April 2017

A practical approach for measurement of antihypertensive medication adherence in patients with resistant hypertension.

J Am Soc Hypertens 2016 06 5;10(6):510-516.e1. Epub 2016 Apr 5.

Cardiovascular Pharmacology Laboratory, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address:

Confirmation of medication adherence is a challenge in clinical practice and essential for the accurate diagnosis of resistant hypertension. Although it is well established that drug adherence is critical for controlling blood pressure, there are still difficulties applying a simple, inexpensive, and reliable assessment of adherence in the clinical setting. We aimed to test a simple method to assess adherence in resistant hypertensive (RH) patients. A pilot study with normotensives or mild/moderate hypertensive subjects was performed to provide a fluorescence cutoff point for adherence. After that, 21 patients referred to the Resistant Hypertension Clinic had triamterene prescribed and were monitored for a 30-day period. We conducted two unannounced randomly selected home visits for urine collection to test drug intake that day. Office, home and 24-hour ambulatory blood pressure, biochemical data, and the 8-item Morisky Medication Adherence Scale (MMAS-8) were systematically acquired. According to adherence indicated by urine fluorescence, subjects were divided into adherent and nonadherent groups. We found 57% of nonadherence. No differences were found between groups regarding baseline characteristics or prescribed medications; Kappa's test showed concordance between adherence through MMAS-8 items and fluorescence (kappa = 0.61; 95% confidence interval: 0.28-0.94; P = .005). Nonadherent patients had higher office (81 ± 11 vs. 73 ± 6 mm Hg, P = .03), 24-hour ambulatory blood pressure monitoring (75 ± 9 vs. 66 ± 7 mm Hg, P = .01), and home blood pressure measurement (77 ± 9 vs. 67 ± 8 mm Hg, P = .01) diastolic blood pressure than their counterparts. Nonadherence to antihypertensive therapy is high in patients with RH, even when assessed in clinics specialized in this condition. Fluorometry to detect a drug in the urine of RH patients is safe, easy, and reliable method to assess adherence.
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http://dx.doi.org/10.1016/j.jash.2016.03.194DOI Listing
June 2016

Deregulation of Soluble Adhesion Molecules in Resistant Hypertension and Its Role in Cardiovascular Remodeling.

Circ J 2016 Apr 13;80(5):1196-201. Epub 2016 Apr 13.

Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences, University of Campinas.

Background: Resistant hypertension (RHTN) and target organ damage are linked to increased inflammatory biomarkers, which may regulate adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1); and the platelet (P-selectin) and endothelial (E-selectin) selectins. We investigated a previously unknown relationship between soluble P-selectin (sP-selectin), E-selectin (sE-selectin), ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) with RHTN and target organ damage.

Methods and results: We included 110 subjects diagnosed for true RHTN and 112 mild-moderate hypertensive (HTN) patients. Blood pressure parameters, pulse wave velocity and left ventricular mass index (LVMI) were measured. Adhesion molecules were measured on ELISA. Both sP-selectin and sE-selectin were increased; in contrast, sICAM-1 was reduced in RHTN compared with HTN patients, while similar sVCAM-1 was noted in the groups. sP-selectin and sVCAM-1 were elevated in the presence of arterial stiffness (sP-selectin: 104±47 vs. 89±45 ng/ml, P<0.05; sVCAM-1: 1,189±411 vs. 1,060±412 ng/ml, P<0.05) and cardiac hypertrophy (sP-selectin: 105±51 vs. 88±43 ng/ml, P<0.05; sVCAM-1: 1,170±433 vs. 1,040±383 ng/ml, P<0.05) in all HTN patients. sP-selectin was associated with target organ damage after adjustment for age and BP. Apart from potential confounders, sE-selectin was a significant indicator of RHTN.

Conclusions: The adhesion molecule sP-selectin plays a role in cardiovascular damage, and sE-selectin in resistance to antihypertensive therapy. (Circ J 2016; 80: 1196-1201).
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http://dx.doi.org/10.1253/circj.CJ-16-0058DOI Listing
April 2016

Immune activation caused by vascular oxidation promotes fibrosis and hypertension.

J Clin Invest 2016 Jan 23;126(1):50-67. Epub 2015 Nov 23.

Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.
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http://dx.doi.org/10.1172/JCI80761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701546PMC
January 2016

Vascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial Cells.

Biomed Res Int 2015 4;2015:631594. Epub 2015 Oct 4.

Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences, University of Campinas, 13084971 Campinas, SP, Brazil.

Inflammatory cytokines have been associated with the pathophysiology of hypertension and target organ damage (TOD). Resistant hypertensive patients (RHTN) are characterized by poor blood pressure control and higher prevalence of TOD. This study evaluated the relationship between plasma levels of TNF-α and arterial stiffness (pulse wave velocity-PWV) in 32 RHTN and 19 normotensive subjects. Moreover, we investigated the effect of TNF-α inhibition on human endothelial cells (HUVECs) incubated with serum from RHTN and normotensive subjects. HUVECs containing serum obtained from normotensive (n = 8) and hypertensive (n = 8) individuals were treated with TNF-α inhibitor (infliximab). Cell suspensions were used for measurement of DNA fragmentation and reactive oxygen species (ROS) content. RHTN patients showed higher levels of TNF-α compared to normotensive subjects, as well as higher PWV. Positive correlation was found between TNF-α levels and PWV measures in the whole group. HUVECs incubated with serum from RHTN showed increased cell apoptosis and higher ROS content compared to normotensive subjects. Infliximab attenuated the apoptosis of HUVECs incubated with serum from RHTN, but no effect in ROS production was observed. Our findings suggest that TNF-α might mediate, at least in part, vascular damage in resistant hypertension.
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http://dx.doi.org/10.1155/2015/631594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609371PMC
August 2016

Defined daily dose (DDD) and its potential use in clinical trials of resistant hypertension.

Int J Cardiol 2016 Jan 28;202:515-6. Epub 2015 Sep 28.

Department of Pharmacology, Faculty of Medical Sciences University of Campinas - UNICAMP, Campinas, SP, Brazil.

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http://dx.doi.org/10.1016/j.ijcard.2015.09.096DOI Listing
January 2016

Does Renal Denervation Fit All Resistant Hypertension? The Role of Genetics.

J Clin Hypertens (Greenwich) 2016 Feb 3;18(2):161-2. Epub 2015 Aug 3.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

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http://dx.doi.org/10.1111/jch.12642DOI Listing
February 2016

Association of Mineralocorticoid Receptor Polymorphism I180V With Left Ventricular Hypertrophy in Resistant Hypertension.

Am J Hypertens 2016 Feb 6;29(2):245-50. Epub 2015 Jun 6.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil;

Objectives: Genetic polymorphisms on mineralocorticoid receptor gene (NC3C2) are associated with variability of mineralocorticoid receptor (MR) function and cardiovascular implications. We sought to investigate whether I180V (rs5522) and MRc.-2G_C (rs2070951) polymorphisms in NR3C2 gene are associated with resistance to antihypertensive treatment and target-organ damage in resistant hypertensive (RHTN) patients.

Methods: One hundred and eighty-one RHTN and 122 mild to moderate hypertensive (HTN) patients were enrolled in this study. Genotypes were obtained by allelic discrimination assay using real-time polymerase chain reaction. We determined pulse wave velocity (PWV), microalbuminuria, and left ventricular mass index to assess target-organ damage. We compared clinical and laboratorial characteristics of AA vs. G carriers for rs5522 and AC vs. GG vs. CG for rs2070951.

Results: We did not found differences in allele, genotype, and haplotype frequencies for both polymorphisms between HTN and RHTN subjects. We found increased levels of aldosterone and ambulatory blood pressure (BP) in G carriers only for rs5522. Left ventricular hypertrophy (LVH) was more prevalent in G carriers than AA homozygous for rs5522 but not for rs2070951 in RHTN. On the other hand, microalbuminuria and PWV were similar among genotypes for both polymorphisms. No differences were observed between the haplotypes, except for higher aldosterone concentration in GG compared to AG and AC haplotypes.

Conclusion: Our study suggests that rs5522 polymorphism might affect cardiac remodeling and aldosterone levels in RHTN subjects.
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http://dx.doi.org/10.1093/ajh/hpv070DOI Listing
February 2016

Role of MMP-2 and MMP-9 in resistance to drug therapy in patients with resistant hypertension.

Arq Bras Cardiol 2015 Aug 2;105(2):168-75. Epub 2015 Jun 2.

Núcleo de Pós-Graduação e Pesquisa, Santa Casa de Belo Horizonte, Belo Horizonte, MG, BR.

Background: Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown.

Objectives: To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN (CRHTN, n=41) and uncontrolled RHTN (UCRHTN, n=35). In addition, the association of those parameters with clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was evaluate in those subgroups.

Methods: This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram, and laboratory tests to assess biochemical parameters.

Results: Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in the UCRHTN and CRHTN subgroups (P>0.05). A significant correlation was found between diastolic BP (DBP) and MMP-9/TIMP-1 ratio (r=0.37; P=0.02) and DPB and MMP-2 (r=-0.40; P=0.02) in the UCRHTN subgroup. On the other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9, MMP-2, TIMP-1, TIMP-2 and their ratios were not associated with the lack of BP control.

Conclusion: These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects.
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http://dx.doi.org/10.5935/abc.20150060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559126PMC
August 2015

Refractory and resistant hypertension: characteristics and differences observed in a specialized clinic.

J Am Soc Hypertens 2015 May 19;9(5):397-402. Epub 2015 Mar 19.

Faculty of Medical Sciences, Department of Pharmacology, Laboratory of Cardiovascular Pharmacology, University of Campinas, Campinas, SP, Brazil.

Resistant hypertension (RH) is defined as uncontrolled blood pressure (BP) despite the use of ≥3 anti-hypertensive drugs, or controlled requiring use of ≥4 drugs. Recently, a new definition for an extreme phenotype of RH (uncontrolled BP using at least five drugs) has emerged-the refractory hypertension (RfH). Although characteristics of RH are well established, little is known about this newly described subgroup. For this work, 116 subjects with RH were enrolled from a specialized clinic and divided into RH (n = 80) and RfH (n = 36). Subjects were submitted to echocardiography, 24-hour ambulatory BP measurement and biochemical analyses. Logistic regression analysis demonstrated that: (1) white-coat effect (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.12-9.27; P = .03), (2) black race (OR, 6.67; 95% CI, 1.99-16.16; P < .001), and (3) left ventricular mass index (OR, 1.02; 95% CI, 1.01-1.03; P = .04) were independent predictors of refractoriness. In conclusion, RfH and RH present different patient characteristics, and these phenotypic aspects can be useful for better understanding this harder-to-treat subgroup.
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http://dx.doi.org/10.1016/j.jash.2015.03.005DOI Listing
May 2015

Resistant hypertension: a volemic or nervous matter?

J Am Soc Hypertens 2015 May 9;9(5):408-9. Epub 2015 Feb 9.

Faculty of Medical Sciences, Laboratory of Cardiovascular Pharmacology, University of Campinas, Campinas, SP, Brazil.

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http://dx.doi.org/10.1016/j.jash.2015.01.014DOI Listing
May 2015
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