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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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

Background: Increased arterial stiffness is an important determinant of cardiovascular disease risk. In addition, it has been recognized that arterial stiffness has familial aggregation; however, there are no studies involving Brazilian families. Thus, the aim of this study was to evaluate the heritability of arterial stiffness in a Brazilian population., Methods: In this study, 1675 eligible individuals (both sexes and aged 18-102 years) were distributed in 125 families resident in the municipality of Baependi, a city located in the southeast of Brazil. Carotid-femoral pulse wave velocity (PWV) was measured with a noninvasive automatic device (Complior; Artech Medical, Pantin, France). Variance component approaches, implemented in the SOLAR computer package (San Antonio, Texas, USA), were applied to estimate the heritability of the studied phenotype under different statistical models., Results: Heritability estimates for carotid-femoral PWV stratified by age ranging from 11 to 35% (higher in individuals aged ≤45 years and lower in individuals aged 18-102 years). Age and hypertension showed significant effects on the PWV trait and significantly affect heritability estimates in all models., Conclusion: We conclude that the heritability of carotid-femoral PWV in a Brazilian population is intermediate, and therefore genetic studies evolving arterial stiffness phenotypes should be encouraged.

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., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Resistant hypertension (RHTN) is a multifactorial and polygenic disease, frequently associated with obesity. Low plasma adiponectin levels, a hormone produced by the adipose tissue, were associated with RHTN. Single nucleotide polymorphisms (SNPs) -11377C/G (rs266729) and +276G/T (rs1501299) in ADIPOQ (adiponectin gene) were associated with hypertension. This study evaluated the association between two SNPs (-11377C/G and +276G/T) and adiponectin levels in RHTN. This study comprised 109 patients with RHTN genotyped for both polymorphisms. A cross-sectional study was designed to compare features of CC homozygous versus G allele carriers for -11377C/G and GG homozygous versus T allele carriers for +276G/T. Office and ambulatory BP measurements were similar among genotypes subgroups in both SNPs as well as the markers of target organ damage (arterial stiffness, left ventricular mass index and microalbuminuria). Adiponectin concentrations were significantly higher in CC compared to G carrier for -11377C/G (CC:7.0 (4.0-10.2) versus G allele:5.5 (2.5-7.9), p = 0.04) and lower in GG compared to T carrier for +276G/T (GG:5.3 (2.3-7.7) versus T allele:7.1 (3.6-10.5), p = 0.04). Adjusting for systolic ambulatory BP, body mass index, age, gender, race and presence of type 2 diabetes, multiple linear regression analyses revealed that the minor alleles G (β-coefficient= -0.14, SE=0.07, p = 0.03) and T (β-coefficient=0.12, SE=0.06, p = 0.04) were independent predictors of adiponectin. The -11377C/G and +276G/T SNPs in ADIPOQ were associated with adiponectin levels in RHTN individuals., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Adipokines are hormones produced by adipocytes and have been involved in multiple pathologic pathways, including inflammatory and cardiovascular complications in essential hypertension. Arterial stiffness is a frequent vascular complication that represents increased cardiovascular risk in hypertensive patients. Adipokines, such as adiponectin, leptin and resistin, might be implicated in hypertension, as well as in vascular alterations associated with this condition. Arterial stiffness has proven to be a predictor of cardiovascular events. Obesity and target-organ damage such as arterial stiffness are features associated with hypertension. This review aims to update the association between adipokines and arterial stiffness in essential and resistant hypertension (RHTN).

Background: Hypertension is the most prevalent and significant modifiable risk factor for coronary heart disease. A portion of patients with uncontrolled hypertension are considered to have resistant hypertension (RHTN). Myocardial ischemia incidence increases along with blood pressure (BP) levels. However, the prevalence of myocardial ischemia in patients with RHTN, as well as the factors associated with it, is unknown., Methods: We enrolled 129 patients with true RHTN regularly followed in our specialty hypertension clinic and evaluated then by resting and dipyridamole pharmacological stress myocardial perfusion scintigraphy. Patients were then divided into 2 groups: those with (I-RHTN; n = 36) and those without (NI-RHTN; n = 93) myocardial ischemia. Echocardiography, 24-hour ambulatory BP monitoring (ABPM), and flow mediated dilation (FMD) were also evaluated., Results: Thirty six (28%) patients had myocardial ischemia. There was no difference between groups regarding age, sex, biochemical parameters, office, and 24-hour ABPM levels. Patients in the I-RHTN group were more likely diabetic (31% vs. 11%; P < 0.05) and obese (75% vs. 40%; P < 0.001). Adjusting for age and body mass index, multiple logistic regression showed that diabetes (odds ratio (OR) = 6.5; 95% confidence interval (CI) = 1.06-40.14; P = 0.04), FMD (OR = 0.18; 95% CI = 0.07-0.41; P < 0.001), heart rate (OR = 1.23; 95% CI = 1.11-1.36; P < 0.001), left ventricular mass index (OR = 1.02; 95% CI = 1.01-1.04; P = 0.04), and microalbuminuria (OR = 1.02; 95% CI = 1.01-1.04; P = 0.002) were independent predictors of ischemia., Conclusions: In conclusion, there is a high prevalence of myocardial ischemia in patients with RHTN. Increased microalbuminuria, heart rate, endothelial dysfunction, and left ventricular mass can be useful to guide the investigation for myocardial ischemia in these high risk patients., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Obesity, arterial stiffness and high aldosterone levels can interact to cause resistant hypertension (RHTN). Lower adiponectin (APN) levels may be significantly associated with hypertension. However, the importance of hypoadiponectinemia as a complicating factor in the lack of blood pressure (BP) control in individuals with RHTN has not been demonstrated. Ninety-six RHTN patients were classified into uncontrolled (UCRHTN, n = 44) and controlled (CRHTN, n = 52) subgroups. Their APN and aldosterone levels, office and ambulatory BP (ABPM) measurements, endothelium-dependent brachial artery responses (flow-mediated dilation (FMD)), left ventricular mass index (LVMI) and pulse wave velocity (PWV) were evaluated. The UCRHTN subgroup had increased aldosterone levels, as well as higher LVMI and PWV. In addition, lower APN levels and impaired FMD response were found in this subgroup. The brachial and ABPM pulse pressures were inversely associated with the APN levels (r = -0.45, P = 0.002; r = -0.33, P = 0.03, respectively), as were the aldosterone levels and the PWV (r = -0.38, P = 0.01; r = -0.36, P = 0.02, respectively) in UCRHTN patients. The PWV was only significantly influenced by the APN level in the UCRHTN subgroup in the multivariate regression analysis. None of the correlations mentioned above were observed in the CRHTN subgroup. Hypoadiponectinemia and high aldosterone levels may therefore be implicated in resistance to antihypertensive therapy related to arterial stiffness.

Purpose: Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)-inhibiting cGMP breakdown-reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses., Methods: Subjects (n = 26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined., Results: Mean arterial pressure and total peripheral resistance decreased in all patients (84.17 ± 21.04 to 75 ± 17.21 mmHg; 1149 ± 459.7 to 1037 ± 340 dyn.s/cm(-5), respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25 ± 5.8 to 20 ± 4.4; IVRT: 104 ± 19.33 to 88 ± 15.22; E/e' septal: 9.7 ± 3.8 to 7.9 ± 2.9; E/e' lateral: 7.7 ± 3.4 to 6.4 ± 3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i., Conclusion: Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.