Andréa Rodrigues Sabbatini

Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers

Abstract Background. Increased levels of inflammatory biomarkers such as interleukin-6 (IL-6), 10 (IL-10), 1β (IL-1β), tumor necrosis factor-α (TNF-α) high-sensitivity C-reactive protein (hs-CRP) are associated with arterial stiffness in hypertension. Indeed, resistant hypertension (RHTN) leads to unfavorable prognosis attributed to poor blood pressure (BP) control and target organ damage. This study evaluated the potential impact of inflammatory biomarkers on arterial stiffness in RHTN. Methods. In this cross-sectional study, 32 RHTN, 20 mild hypertensive (HTN) and 20 normotensive (NT) patients were subjected to office BP and arterial stiffness measurements assessed by pulse wave velocity (PWV). Inflammatory biomarkers were measured in plasma samples. Results. PWV was increased in RHTN compared with HTN and NT (p < 0.05). TNF-α levels were significantly higher in RHTN and HTN than NT patients. No differences in IL-6 levels were observed. RHTN patients had a higher frequency of subjects with increased levels of IL-10 and IL-1β compared with HTN and NT patients. Finally, IL-1β was independently associated with PWV (p < 0.001; R2 = 0.5; β = 0.077). Conclusion. RHTN subjects have higher levels of inflammatory cytokines (TNF-α, IL-1β and IL-10) as well as increased arterial stiffness, and detectable IL-1β levels are associated arterial stiffness. These findings suggest that inflammation plays a possible role in the pathophysiology of RHTN.

High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension

Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility and sympathetic nerve activation, the relationship between leptin and blood pressure (BP) in resistant hypertension (RHTN) is unknown. We aimed to assess the correlation of plasma leptin and aldosterone levels with BP in uncontrolled controlled RHTN (UCRHTN) and CRHTN patients. Plasma leptin and aldosterone levels, office BP, ambulatory BP monitoring and heart rate were measured in 41 UCRHTN, 39 CRHTN and 31 well-controlled HTN patients. No differences were observed between the three groups regarding gender, body mass index and age. The UCRHTN group had increased leptin when compared with CRHTN and well-controlled HTN patients (38.2±21.4, 19.6±8.7 and 20.94±13.9 ng ml−1, respectively; P<0.05). Aldosterone levels values were also statistically different when comparing RHTN, CRHTN and well-controlled HTN patients (9.6±3.8, 8.1±5.0 and 8.0±4.7 ng dl−1, respectively; P<0.05). As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients (86.2±7.2, 83.5±6.7 and 83.4±8.5, respectively; P<0.05). Plasma leptin positively correlated with systolic (SBP) and diastolic BP (DBP), and aldosterone (r=0.43, 0.35 and 0.47, respectively; all P<0.05) in UCRHTN, but neither in the CRHTN nor in the HTN group. Simple linear regression showed that SBP, DBP and aldosterone may be predicted by leptin (r2=0.16, 0.15 and 0.19, respectively; all P<0.05) only in the UCRHTN subgroup. In conclusion, UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with CRHTN and HTN subjects.

Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension

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.

Deregulation of adipokines related to target organ damage on resistant hypertension

Resistant hypertension (RHTN) includes patients with controlled blood pressure (BP) (CRHTN) and uncontrolled BP (UCRHTN). In fact, RHTN patients are more likely to have target organ damage (TOD), and resistin, leptin and adiponectin may affect BP control in these subjects. We assessed the relationship between adipokines levels and arterial stiffness, left ventricular hypertrophy (LVH) and microalbuminuria (MA). This cross-sectional study included CRHTN (n=51) and UCRHTN (n=38) patients for evaluating body mass index, ambulatory blood pressure monitoring, plasma adiponectin, leptin and resistin concentrations, pulse wave velocity (PWV), MA and echocardiography. Leptin and resistin levels were higher in UCRHTN, whereas adiponectin levels were lower in this same subgroup. Similarly, arterial stiffness, LVH and MA were higher in UCRHTN subgroup. Adiponectin levels negatively correlated with PWV (r=−0.42, P<0.01), and MA (r=−0.48, P<0.01) only in UCRHTN. Leptin was positively correlated with PWV (r=0.37, P=0.02) in UCRHTN subgroup, whereas resistin was not correlated with TOD in both subgroups. Adiponectin is associated with arterial stiffness and renal injury in UCRHTN patients, whereas leptin is associated with arterial stiffness in the same subgroup. Taken together, our results showed that those adipokines may contribute to vascular and renal damage in UCRHTN patients.

Plasma 8-isoprostane levels are associated with endothelial dysfunction in resistant hypertension.

BACKGROUND Impaired endothelial function and arterial stiffness are associated with hypertension and are important risk factors for cardiovascular events. Reactive oxygen species reduce nitric oxide bioavailability and have a pivotal role in endothelial function. Resistant hypertension (RHTN) is characterized by blood pressure (BP) above goal (140/90mmHg) in spite of the concurrent use of ≥3 antihypertensive drugs of different classes. This study evaluated the association between 8-isoprostane levels, an oxidative stress marker, endothelial function and arterial stiffness, in RHTN. METHODS Ninety-four RHTN and 55 well-controlled hypertensive (HT) patients were included. Plasma 8-isoprostane levels were determined by ELISA. Also, flow-mediated dilation (FMD) and pulse wave velocity (PWV) were evaluated to determine endothelial function and arterial stiffness, respectively. RESULTS Levels of 8-isoprostane were markedly higher in RHTN compared to HT patients (22.5±11.2 vs. 17.3±9.8pg/ml, p<0.05, respectively). A significant inverse correlation was observed between FMD and 8-isoprostane (r=-0.35, p=0.001) in RHTN. Finally, multiple logistic regression revealed that 8-isoprostane was a significant predictor of endothelial dysfunction (FMD≤median) in RHTN group. CONCLUSION RHTN showed markedly higher oxidative stress measured by 8-isoprostane, compared to HT patients. Taken together, our findings suggest the involvement of oxidative stress in endothelial function in RHTN.

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

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.

The white-coat effect is an independent predictor of myocardial ischemia in resistant hypertension

Abstract White-coat hypertension (WCH), commonly found in pseudoresistant hypertension, does not pose higher cardiovascular risk than hypertensive status. However, when the decrease of the out-of-office blood pressure does not reach normal levels – the white-coat effect (WCE) – the repercussions are still obscure. We investigated the repercussions of the WCE in myocardial perfusion in resistant hypertension (RHTN). We enrolled 129 asymptomatic RHTN subjects – divided into WCE (n = 63) and non-WCE (n = 66) – to perform rest and stress myocardial perfusion scintigraphy and biochemical tests. Groups were equal regarding age, gender and body mass index. There was a high prevalence of WCE (49%). WCE was associated with higher prevalence of myocardial ischemia (49.2% vs 7.6%, p < 0.001), microalbuminuria (60.3% vs 36.4%, p = 0.01) and higher heart rate (72 [64–80] vs 64 [60–69], p < 0.001), compared with non-WCE patients. On an adjusted logistic regression, heart rate was considered a predictor of WCE (OR = 1.10, 95% CI 1.04–1.15; p < 0.001), but not MA (OR = 1.8, 95% CI 0.8–3.9; p = 0.15). On a second model of adjusted logistic regression, WCE was an independent predictor of myocardial ischemia (OR = 14.7, 95% CI 4.8–44.8; p < 0.001). We found a high prevalence of WCE in RHTN, and this effect may predict silent myocardial ischemia in this subset of hypertensive patients. In this group of hypertensives special attention should be given to the WCE.

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

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. METHODSANDRESULTS 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).

Adiponectin -11377C/G and +276G/T polymorphisms affect adiponectin levels but do not modify responsiveness to therapy in resistant hypertension.

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.

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