Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. / Efeitos da Terapia com Anti-TNF alfa na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo.

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).

FUNDAMENTO: A citocina fator de necrose tumoral alfa (TNF-α) é elevada na hipertensão resistente (HAR), mas os efeitos dos inibidores de TNF-α nessa população ainda são desconhecidos. OBJETIVOS: O objetivo deste estudo foi avaliar se uma única dose de infliximabe controlada por placebo reduz a pressão arterial (PA) de forma aguda em pacientes com HAR. MÉTODOS: Realizamos um estudo cruzado, randomizado, duplo-cego e controlado por placebo em que pacientes com HAR receberam infliximabe ou placebo. O desfecho primário foi a alteração dos níveis de PA média em relação ao basal imediatamente após a infusão, obtida por avaliação hemodinâmica não invasiva contínua, batimento a batimento. Os desfechos secundários incluíram alterações em medidas de PA central, ambulatorial e em consultório, na função endotelial, e nos biomarcadores inflamatórios após 7 dias. O nível de significância aceito foi alfa=0,05. RESULTADOS: Foram incluídos dez portadores de HAR. O resultado do desfecho primário demonstrou uma redução aguda dos níveis de PA média (média das diferenças ± desvio padrão = -6,3 ± 7,2 mmHg, p=0,02) em relação ao basal, após o uso de infliximabe, em comparação com o placebo. Os níveis de PA diastólica (-4,9 ± 5,5 mmHg, p=0,02), mas não os níveis de PA sistólica (-9,4 ± 19,7 mmHg, p=0,16), reduziram após a infusão de infliximabe. Não foram identificadas diferenças significativas nos demais parâmetros hemodinâmicos, nem nos resultados dos desfechos secundários, com exceção dos níveis de TNF-α, que aumentaram continuamente após o uso de infliximabe. Não foram relatados eventos adversos durante o protocolo. CONCLUSÕES: Uma dose única de infliximabe reduziu os níveis de PA média e diastólica imediatamente após sua infusão, em comparação com placebo em HAR. A terapia com anti-TNF-α foi considerada segura e bem tolerada. Os resultados desse estudo prova de conceito são geradores de hipótese e precisam ser investigados em maior detalhe. (Arq Bras Cardiol. 2021; 116(3):443-451).

Efeitos da Terapia com Anti-TNF alfa na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo / Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Resumo Fundamento: A citocina fator de necrose tumoral alfa (TNF-α) é elevada na hipertensão resistente (HAR), mas os efeitos dos inibidores de TNF-α nessa população ainda são desconhecidos. Objetivos: O objetivo deste estudo foi avaliar se uma única dose de infliximabe controlada por placebo reduz a pressão arterial (PA) de forma aguda em pacientes com HAR. Métodos: Realizamos um estudo cruzado, randomizado, duplo-cego e controlado por placebo em que pacientes com HAR receberam infliximabe ou placebo. O desfecho primário foi a alteração dos níveis de PA média em relação ao basal imediatamente após a infusão, obtida por avaliação hemodinâmica não invasiva contínua, batimento a batimento. Os desfechos secundários incluíram alterações em medidas de PA central, ambulatorial e em consultório, na função endotelial, e nos biomarcadores inflamatórios após 7 dias. O nível de significância aceito foi alfa=0,05. Resultados: Foram incluídos dez portadores de HAR. O resultado do desfecho primário demonstrou uma redução aguda dos níveis de PA média (média das diferenças ± desvio padrão = -6,3 ± 7,2 mmHg, p=0,02) em relação ao basal, após o uso de infliximabe, em comparação com o placebo. Os níveis de PA diastólica (-4,9 ± 5,5 mmHg, p=0,02), mas não os níveis de PA sistólica (-9,4 ± 19,7 mmHg, p=0,16), reduziram após a infusão de infliximabe. Não foram identificadas diferenças significativas nos demais parâmetros hemodinâmicos, nem nos resultados dos desfechos secundários, com exceção dos níveis de TNF-α, que aumentaram continuamente após o uso de infliximabe. Não foram relatados eventos adversos durante o protocolo. Conclusões: Uma dose única de infliximabe reduziu os níveis de PA média e diastólica imediatamente após sua infusão, em comparação com placebo em HAR. A terapia com anti-TNF-α foi considerada segura e bem tolerada. Os resultados desse estudo prova de conceito são geradores de hipótese e precisam ser investigados em maior detalhe. (Arq Bras Cardiol. 2021; 116(3):443-451)

Abstract 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)

A Proposed Inflammatory Score of Circulating Cytokines/Adipokines Associated with Resistant Hypertension, but Dependent on Obesity Parameters / Proposta de um Escore Inflamatório de Citocinas e Adipocinas Plasmáticas Associado à Hipertensão Resistente, mas Dependente dos Parâmetros de Obesidade

Abstract Background: There is evidence that subclinical systemic inflammation is present in resistant hypertension (RHTN). Objective: The aim of the study was to develop an integrated measure of circulating cytokines/adipokines involved in the pathophysiology of RHTN. Methods: RHTN (n = 112) and mild to moderate hypertensive (HTN) subjects (n=112) were studied in a cross-sectional design. Plasma cytokines/adipokines (TNF-alpha, interleukins [IL]-6, -8, -10, leptin and adiponectin) values were divided into tertiles, to which a score ranging from 1 (lowest tertile) to 3 (highest tertile) was assigned. The inflammatory score (IS) of each subject was the sum of each pro-inflammatory cytokine scores from which anti-inflammatory cytokines (adiponectin and IL-10) scores were subtracted. The level of significance accepted was alpha = 0.05. Results: IS was higher in RHTN subjects compared with HTN subjects [4 (2-6) vs. 3 (2-5); p = 0.02, respectively]. IS positively correlated with body fat parameters, such as body mass index (r = 0.40; p < 0.001), waist circumference (r = 0.30; p < 0.001) and fat mass assessed by bioelectrical impedance analysis (r = 0.31; p < 0.001) in all hypertensive subjects. Logistic regression analyses revealed that IS was an independent predictor of RHTN (OR = 1.20; p = 0.02), independent of age, gender and race, although it did not remain significant after adjustment for body fat parameters. Conclusion: A state of subclinical inflammation defined by an IS including TNF-alpha, IL-6, IL-8, IL-10, leptin and adiponectin is associated with obese RHTN. In addition, this score correlates with obesity parameters, independently of hypertensive status. The IS may be used for the evaluation of conditions involving low-grade inflammation, such as obesity-related RHTN. Indeed, it also highlights the strong relationship between obesity and inflammatory process.

Resumo Fundamento: Evidências indicam que a inflamação sistêmica subclínica está presente na hipertensão arterial resistente (HAR). Objetivo: Desenvolver uma medida que integra citocinas envolvidas na fisiopatologia da HAR. Métodos: Indivíduos com HAR (n = 112) e indivíduos com hipertensão leve a moderada (HT) (n = 112) foram estudados em delineamento transversal. Valores de citocinas/adipocinas plasmáticas [TNF-alfa, interleucinas (IL)-6, -8, -10, leptina e adiponectina] foram divididos em tercis, e lhes atribuído um escore variando de 1 (tercil mais baixo) a 3 (tercil mais alto). O escore inflamatório (EI) de cada participante foi calculado como a soma do escore de cada citocina pró-inflamatória da qual subtraiu-se o escore de cada citocina anti-inflamatória (adiponectina e IL-10). O nível de significância aceito foi alfa = 0,05. Resultados: O EI foi mais alto nos indivíduos com HAR em comparação a indivíduos com HT [4 (2-6) vs. 3 (2-5); p = 0,02, respectivamente]. O EI correlacionou-se positivamente com parâmetros de gordura corporal, tais como índice de massa corporal (r = 0,40; p < 0,001), circunferência da cintura (r = 0,30; p < 0,001) e massa gorda avaliada por bioimpedância (r = 0,31; p < 0,001) em todos os indivíduos hipertensos. Análises de regressão logística mostraram que o EI foi um preditor independente de HAR (OR = 1,20; p = 0,02), independentemente de idade, sexo e raça; porém, o modelo perdeu significância estatística após ajuste para os parâmetros de gordura corporal. Conclusão: Um estado de inflamação subclínica definida pelo EI incluindo TNF-alfa, IL-6, IL-8, IL-10, leptina e adiponectina está associado com indivíduos obesos com HAR. Além disso, o escore correlaciona-se com parâmetros de obesidade, independentemente do grau de hipertensão. O EI pode ser usado na avaliação de condições que envolvem inflamação subclínica, tal como HAR relacionada à obesidade. O estudo também destaca a forte relação entre obesidade e inflamação.

A Proposed Inflammatory Score of Circulating Cytokines/Adipokines Associated with Resistant Hypertension, but Dependent on Obesity Parameters.

BACKGROUND: There is evidence that subclinical systemic inflammation is present in resistant hypertension (RHTN). OBJECTIVE: The aim of the study was to develop an integrated measure of circulating cytokines/adipokines involved in the pathophysiology of RHTN. METHODS: RHTN (n = 112) and mild to moderate hypertensive (HTN) subjects (n=112) were studied in a cross-sectional design. Plasma cytokines/adipokines (TNF-alpha, interleukins [IL]-6, -8, -10, leptin and adiponectin) values were divided into tertiles, to which a score ranging from 1 (lowest tertile) to 3 (highest tertile) was assigned. The inflammatory score (IS) of each subject was the sum of each pro-inflammatory cytokine scores from which anti-inflammatory cytokines (adiponectin and IL-10) scores were subtracted. The level of significance accepted was alpha = 0.05. RESULTS: IS was higher in RHTN subjects compared with HTN subjects [4 (2-6) vs. 3 (2-5); p = 0.02, respectively]. IS positively correlated with body fat parameters, such as body mass index (r = 0.40; p < 0.001), waist circumference (r = 0.30; p < 0.001) and fat mass assessed by bioelectrical impedance analysis (r = 0.31; p < 0.001) in all hypertensive subjects. Logistic regression analyses revealed that IS was an independent predictor of RHTN (OR = 1.20; p = 0.02), independent of age, gender and race, although it did not remain significant after adjustment for body fat parameters. CONCLUSION: A state of subclinical inflammation defined by an IS including TNF-alpha, IL-6, IL-8, IL-10, leptin and adiponectin is associated with obese RHTN. In addition, this score correlates with obesity parameters, independently of hypertensive status. The IS may be used for the evaluation of conditions involving low-grade inflammation, such as obesity-related RHTN. Indeed, it also highlights the strong relationship between obesity and inflammatory process.

Metabolic Syndrome-Related Features in Controlled and Resistant Hypertensive Subjects.

BACKGROUND: Metabolic syndrome (MetS) is widespread among hypertensive patients. Clinical features and potential biomarkers of MetS in the presence of hypertension and resistant hypertension (RHTN) represent a great area of interest for investigation. OBJECTIVE: The purpose of this study was to evaluate the prevalence of MetS and the clinical features associated with it in resistant and mild to moderate hypertensives. METHODS: This cross-sectional study included 236 patients, (i) 129 mild to moderate hypertensive patients and (ii) 107 patients with RHTN. We measured blood pressure (BP) and adipokines levels, and performed bioelectrical impedance analysis. Microalbuminuria (MA), cardiac hypertrophy and arterial stiffness were also assessed. The significance level of alpha = 0.05 was adopted. RESULTS: We found a MetS prevalence of 73% in resistant and 60% in mild-to-moderate hypertensive patients. In a multiple regression analysis, MA (odds ratio = 8.51; p = 0.01), leptin/adiponectin ratio (LAR) (odds ratio = 4.13; p = 0.01) and RHTN (odds ratio = 3.75; p = 0.03) were independently associated with the presence of MetS apart from potential confounders. CONCLUSIONS: Our findings suggest that both resistant and controlled hypertensive subjects have a high prevalence of MetS. In addition, MetS-related metabolic derangements may cause early renal and hormonal changes. Finally, LAR may be useful as a reliable biomarker for identifying those hypertensive subjects who are at risk for developing MetS.

Metabolic Syndrome-Related Features in Controlled and Resistant Hypertensive Subjects / Características Relacionadas à Síndrome Metabólica em Indivíduos com Hipertensão Controlada e Hipertensão Resistente

Abstract Background: Metabolic syndrome (MetS) is widespread among hypertensive patients. Clinical features and potential biomarkers of MetS in the presence of hypertension and resistant hypertension (RHTN) represent a great area of interest for investigation. Objective: The purpose of this study was to evaluate the prevalence of MetS and the clinical features associated with it in resistant and mild to moderate hypertensives. Methods: This cross-sectional study included 236 patients, (i) 129 mild to moderate hypertensive patients and (ii) 107 patients with RHTN. We measured blood pressure (BP) and adipokines levels, and performed bioelectrical impedance analysis. Microalbuminuria (MA), cardiac hypertrophy and arterial stiffness were also assessed. The significance level of alpha = 0.05 was adopted. Results: We found a MetS prevalence of 73% in resistant and 60% in mild-to-moderate hypertensive patients. In a multiple regression analysis, MA (odds ratio = 8.51; p = 0.01), leptin/adiponectin ratio (LAR) (odds ratio = 4.13; p = 0.01) and RHTN (odds ratio = 3.75; p = 0.03) were independently associated with the presence of MetS apart from potential confounders. Conclusions: Our findings suggest that both resistant and controlled hypertensive subjects have a high prevalence of MetS. In addition, MetS-related metabolic derangements may cause early renal and hormonal changes. Finally, LAR may be useful as a reliable biomarker for identifying those hypertensive subjects who are at risk for developing MetS.

Resumo Fundamentos: A síndrome metabólica (SM) é comum em pacientes hipertensos. As características clínicas e os potenciais biomarcadores da SM na presença de hipertensão e hipertensão resistente (HR) representam uma ampla área de interesse a ser investigada. Objetivo: O objetivo deste estudo foi avaliar a prevalência de SM e as características clínicas associadas à síndrome em indivíduos com hipertensão resistente e leve a moderada. Métodos: Este estudo transversal incluiu 236 pacientes, (i) 129 pacientes com hipertensão leve a moderada e (ii) 107 pacientes com HR. Medimos a pressão arterial (PA), parâmetros bioquímicos e os níveis de adipocinas dos pacientes, além de microalbuminúria (MA), hipertrofia cardíaca e rigidez arterial. Foi adotado o nível de significância de alfa 0,05. Resultados: A SM esteve presente em 73% dos pacientes com HR e 60% daqueles com hipertensão leve a moderada. Na análise de regressão múltipla, a MA (odds ratio = 8,51; p = 0,01), a razão leptina/adiponectina (RLA) (odds ratio = 4,13; p = 0,01) e a HR (odds ratio = 3,75; p = 0,03) foram independentemente associadas com a presença de SM, excluindo-se potenciais fatores de confusão. Conclusões: Nossos resultados sugerem que tanto hipertensos resistentes como hipertensos controlados apresentam alta prevalência de SM. Além disso, distúrbios metabólicos relacionados à SM podem causar alterações precoces renais e hormonais, e a RLA parece ser útil como biomarcador confiável para identificar indivíduos hipertensos em risco de desenvolverem SM.

Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients with Resistant Hypertension / Papel da MMP-2 e MMP-9 na Resistência à Terapia Medicamentosa em Pacientes com Hipertensão Arterial Resistente

AbstractBackground: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.

ResumoFundamento:A despeito da crescente evidência do importante papel das metaloproteinases da matriz extracelular (MMP-9 e MMP-2) na fisiopatologia da hipertensão, o perfil dessas moléculas na hipertensão arterial resistente (HAR) permanece desconhecido.Objetivo:Comparar os níveis plasmáticos de MMP-9 e MMP-2 e seus inibidores teciduais (TIMP-1 e TIMP-2, respectivamente), assim como as suas razões MMP-9/TIMP-1 e MMP-2/TIMP-2, entre pacientes com HAR controlada (HARC, n = 41) e HAR não controlada (HARNC, n = 35). Além disso, a associação desses parâmetros com as características clínicas, pressão arterial (PA) de consultório e rigidez arterial (determinada pela velocidade da onda de pulso) foi avaliada nesses subgrupos.Métodos:Este estudo incluiu 76 indivíduos com HAR submetidos a exame físico, eletrocardiografia e exames laboratoriais para a avaliação de parâmetros bioquímicos.Resultados:Valores semelhantes de MMP-9, MMP-2, TIMP-1, TIMP-2, e razões MMP-9/TIMP-1 e MMP-2/TIMP-2 foram encontrados nos subgrupos HARNC e HARC (p > 0,05). Observou-se uma correlação significativa entre PA diastólica (PAD) e razão MMP-9/TIMP-1 (r = 0,37; p = 0,02) e PAD e MMP-2 (r = -0,40; p = 0,02) no subgrupo HARNC. Por outro lado, não se observou correlação no subgrupo HARC. Os modelos de regressão logística demonstraram que MMP-9, MMP-2, TIMP-1, TIMP-2 e suas razões não se associaram com a falta de controle da PA.Conclusão:Esses achados sugerem que MMP-2 e MMP-9 não afetem o controle da PA em indivíduos com HAR.

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

BACKGROUND: Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP­2) 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.