RESUMO
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.
Assuntos
Hipertensão/genética , Metaloproteinase 2 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Idoso , Brasil , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Pacientes AmbulatoriaisRESUMO
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 [ß = 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.
Assuntos
Resistência a Medicamentos , Hipertensão/sangue , Hipertrofia Ventricular Esquerda/sangue , Metaloproteinase 9 da Matriz/sangue , Obesidade/sangue , Remodelação Vascular , Estudos Transversais , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-1/sangueRESUMO
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.
Assuntos
Hipertensão/sangue , Hipertensão/enzimologia , Metaloproteinase 2 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Rigidez Vascular , Remodelação VentricularRESUMO
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.
Assuntos
Vasoespasmo Coronário/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Hipertensão/fisiopatologia , Fator de Necrose Tumoral alfa/farmacologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular , Vasoespasmo Coronário/epidemiologia , Estudos Transversais , Células Endoteliais/citologia , Feminino , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/epidemiologia , Infliximab/farmacologia , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
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 (ß-coefficient= -0.14, SE=0.07, p = 0.03) and T (ß-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.
Assuntos
Adiponectina/sangue , Adiponectina/genética , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Resistência a Medicamentos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de RiscoRESUMO
BACKGROUND: Increased levels of inflammatory biomarkers such as interleukin-6 (IL-6), 10 (IL-10), 1ß (IL-1ß), 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-1ß compared with HTN and NT patients. Finally, IL-1ß was independently associated with PWV (p < 0.001; R(2) = 0.5; ß = 0.077). CONCLUSION: RHTN subjects have higher levels of inflammatory cytokines (TNF-α, IL-1ß and IL-10) as well as increased arterial stiffness, and detectable IL-1ß levels are associated arterial stiffness. These findings suggest that inflammation plays a possible role in the pathophysiology of RHTN.
Assuntos
Proteína C-Reativa/metabolismo , Citocinas/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Mediadores da Inflamação/sangue , Rigidez Vascular , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Hipertensão/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Dinoprosta/análogos & derivados , Resistência a Medicamentos , Endotélio Vascular/patologia , Hipertensão/sangue , Hipertensão/patologia , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Dinoprosta/sangue , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Rigidez Vascular/efeitos dos fármacosRESUMO
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.
Assuntos
Albuminúria/diagnóstico , Isquemia Miocárdica/diagnóstico , Hipertensão do Jaleco Branco/diagnóstico , Adulto , Idoso , Albuminúria/tratamento farmacológico , Albuminúria/etiologia , Albuminúria/fisiopatologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Determinação da Pressão Arterial , Monitorização Ambulatorial da Pressão Arterial , Índice de Massa Corporal , Estudos Transversais , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Prognóstico , Hipertensão do Jaleco Branco/complicações , Hipertensão do Jaleco Branco/tratamento farmacológico , Hipertensão do Jaleco Branco/fisiopatologiaRESUMO
PURPOSE: Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes. METHODS: We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels. RESULTS: No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo. CONCLUSION: The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.
Assuntos
Carbolinas/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Pressão Sanguínea/efeitos dos fármacos , Carbolinas/farmacologia , Estudos Cross-Over , GMP Cíclico/sangue , Diástole/efeitos dos fármacos , Resistência a Medicamentos , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Nitritos/sangue , Inibidores da Fosfodiesterase 5/farmacologia , Método Simples-Cego , Tadalafila , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
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.
Assuntos
Adiponectina/sangue , Pressão Sanguínea/efeitos dos fármacos , Hiperaldosteronismo/sangue , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Fatores Etários , Análise Química do Sangue , Monitorização Ambulatorial da Pressão Arterial , Índice de Massa Corporal , Estudos Transversais , Progressão da Doença , Resistência a Medicamentos , Ecocardiografia , Endotélio Vascular/fisiologia , Feminino , Humanos , Hipertensão/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
A hipertensão arterial sistêmica (HAS) é uma síndrome que tem alta prevalência e baixas taxas de controle no mundo ocidental. Atualmente, os mecanismos que contribuem para o desenvolvimento de HAS e suas complicações estão mais elucidados. Por exemplo, hoje se sabe que pacientes hipertensos apresentam mais frequentemente resistência à insulina/hiperinsulinemia, dislipidemia, micro albuminúria e obesidade do que normo tensos. Embora classicamente a associação entre obesidade e hipertensão tenha sido atribuída a alterações hemodinâmicas, sabe-se que inúmeras alterações interferem no desenvolvimento desse quadro, como a disfunção endotelial, o aumento da atividade do sistema renina-angiotensina-aldosterona (SRAA) e do sistema nervoso simpático (SNS)...
Hypertension has a high prevalence and low rates of control worldwide. Nowadays, the mechanisms that contribute to the development of hypertension and its complications are better understood. For example, it is well known that hypertensive patients frequently have insulin resistance/hyper insulinemia, dyslipidemia, obesity and micro albumiria compared to normotensive subjects. Classically, the association between obesity and hypertension has been attributed to hemodynamic alterations but more recently other factors such as endothelial dysfunction, aldosterone--angiotensin-renin system (AARS) and sympathetic nervoussystem activity (SNS)...