Papel dos receptores farmacológicos AT1 e AT2 da Angiotensina II em doença periodontal induzida: aspectos moleculares / Role of pharmacological receptors AT1 and AT2 of Angiotensin II in caused periodontal disease: molecular aspects

O sistema renina angiotensina (SRA) é de grande importância para o equilíbrio hídrico e regulação da pressão arterial do organismo, além de estar associado ao estimulo de vias próinflamatórias. Seu principal peptídeo é a angiotensina II, que interage principalmente com os receptores do tipo 1 (AT1) e do tipo 2 (AT2). Foi encontrado interrelação entre as doenças cardiovasculares e a periodontite. Este estudo teve como objetivo avaliar os aspectos moleculares em camundongos submetidos a um modelo experimental de periodontite, observando a influência dos receptores de Ang II tipo 1 (AT1(-)) e Ang II tipo 2 (AT2(-)) na periodontite. Métodos: A periodontite experimental foi induzida colocando-se uma ligadura com fio de nylon 5.0 ao redor do segundo molar superior esquerdo de camundongos knockoutAT1(-), AT2(-) e selvagem (WT), subdivididos 2 grupos para cada linhagem: sem ligadura e ligadura, totalizando seis grupos: três controles e três experimentais. Após 15 dias da indução da doença os animais foram submetidos à eutanásia. Com o intuito de avaliar se as variações genéticas teriam influência sobre a periodontite foram realizadas as análises de citocinas, peptídeos e enzimas foram analisados a partir de tecidos gengivais por ELISA e RT-PCR. Resultados: Os animais WT e AT2(-) apresentaram resultados semelhantes em relação às citocinas IL-1ß, IL-6, TNF-α, com aumento dos níveis em relação aos saudáveis (p < 0,001). Houve diferenças significativas em IL-ß entre os grupo AT1(-)-L e WT-L (p < 0,05), e em IL-6 e TNF-α os grupos AT1(-)-L apresentaram diferenças significativas (p < 0,001) tanto quando comparado aos grupo WT-L quanto aos grupos AT2(-)-L. Os níveis de IL-10 foram maiores em WT-L (p < 0,01), enquanto os grupos AT2(-) e AT1(-) não apresentaram alterações significativas em relação a essa citocina. Houve diferenças significativas em Angiotensina II entre os grupos AT2(-)-NL e AT2(-)-L (p < 0,01); e em Angiotensina 1-7 entre os grupos AT1(-)-L e AT2(-)-L (p < 0,05). Para TLR2 houve diferenças entre os grupos WT-NL/WT-L (p < 0,05); AT1(-)-NL/AT1(-)-L (p < 0,01) e AT2(-)-NL/AT2(-) - L (p < 0,01). Para o receptor MAS houve diferenças entre os grupos WT-NL/WT-L (p < 0,001) e AT2(-)-NL/AT2(-)-L (p < 0,001), e também em relação ao grupo WT-L/AT1(-)-L (p < 0,001) e AT1(-)-L/AT2(-)-L (p < 0,001). Para a expressão dos peptídeos ECA e ECA2, houve diferença estatística apenas para ECA entre os tipos de grupos WT-NL/WT-L (p < 0,001). Conclusão: Os animais do grupo AT1(-) apresentaram menor inflamação que as demais linhagens doentes, assim como uma menor expressão do receptor Mas e Ang 1-7. Além disso os animais dos grupos WT e AT2(-) demonstraram resultados próximos em diversas análises, evidenciando que o bloqueio do receptor AT1, sobre os efeitos moleculares, é mais positiva (AU).

The renin angiotensin system (RAS) is of great importance for water balance and regulation of blood pressure in the body, in addition to being associated with the stimulation of proinflammatory pathways. Its main peptide is angiotensin II, which interacts mainly with type 1 (AT1) and type 2 (AT2) receptors. An interrelationship was found between cardiovascular diseases and periodontitis. This study aimed to evaluate the molecular aspects in mice subjected to an experimental model of periodontal disease, observing the influence of Ang II type 1 (AT1(-)) and Ang II type 2 (AT2(-)) receptors on periodontitis. Methods: Experimental periodontitis was induced by placing a ligature with 5.0 nylon thread around the upper left second molar of AT1(-), AT2(-) and wild-type (WT) knockout mice, subdivided into 2 groups for each strain: without ligation and ligation, totaling six groups: three controls and three experimental. After 15 days of disease induction, the animals were euthanized. In order to evaluate whether genetic variations would have an influence on periodontal disease, analyzes of cytokines were carried out, peptides and enzymes were analyzed from gingival tissues by ELISA and RT-PCR. Results: WT and AT2(-) animals showed similar results in relation to the cytokines IL-1ß, IL-6, TNF-α, with increased levels compared to healthy ones (p < 0.001). There were significant differences in IL-ß between the AT1(-)-L and WT-L groups (p < 0.05), and in IL-6 and TNF-α the AT1(-)-L groups showed significant differences (p < 0.001) both when compared to the WT-L and AT2(-)-L groups. IL-10 levels were higher in WT-L (p < 0.01), while the AT2(-) and AT1(-) groups did not show significant changes in relation to this cytokine. There were significant differences in Angiotensin II between the AT2(-)-NL and AT2(-)-L groups (p < 0.01); and in Angiotensin 1-7 between the AT1(-)-L and AT2(-)-L groups (p < 0.05). For TLR2 there were differences between the WT-NL/WT-L groups (p < 0.05); AT1(-)-NL/AT1(-)-L (p < 0.01) and AT2(-)-NL/AT2(-)-L (p < 0.01). For the MAS receptor there were differences between the WT-NL/WT-L (p < 0.001) and AT2(-)-NL/AT2(- )-L (p < 0.001) groups, and also in relation to the WT-L group /AT1(-)-L (p < 0.001) and AT1(-)-L/AT2(-)-L (p < 0.001). For the expression of ACE and ACE2 peptides, there was a statistical difference only for ACE between the types of WT-NL/WT-L groups (p < 0.001). Conclusion: The animals in the AT1(-) group showed less inflammation than the other diseased lines, as well as a lower expression of the Mas and Ang 1-7 receptor. Furthermore, animals from the WT and AT2(-) groups demonstrated similar results in several analyses, showing that the blockade of the AT1 receptor, on molecular effects, is more positive (AU).

Hipertensión arterial sistémica posterior a COVID-19 / Systemic arterial hypertension after COVID-19

Introducción: un nuevo tipo de coronavirus que se nombró SARSCoV-2, responsable de la enfermedad por COVID-19, tuvo esparcimiento rápido en el mundo, por alta transmisión que resultó en pandemia. Se registraron 2'397,216 casos confirmados, con 162,956 defunciones en el mundo, de acuerdo con la Organización Mundial de la Salud (OMS), en abril de 2020. Sin embargo, la hipertensión afecta a 40% de adultos, lo que significa que alrededor de 250 millones de personas padecen de presión alta. La OMS, de acuerdo con sus reportes, refiere que la hipertensión es el factor de riesgo número uno de muerte. Uno de cada cuatro mexicanos padece hipertensión arterial. Objetivos: establecer la incidencia de la hipertensión arterial sistémica posterior a padecer COVID-19 en pacientes de la Unidad de Medicina Familiar (UMF) No. 48. Material y métodos: es un estudio transversal, observacional y descriptivo, conformado por 3,238 pacientes con diagnóstico de COVID-19 positivo, de ambos sexos, con edades entre 18 y 70 años. Por medio de la fórmula para poblaciones infinitas se obtiene una muestra de 348 pacientes. Se realizó revisión de expedientes en el Sistema de Información de Medicina Familiar, versión 6.2, para obtención de la información correspondiente. Resultados: 27 pacientes diagnosticados con hipertensión arterial posterior al diagnóstico de COVID-19, 52% del sexo masculino y 48% del femenino, con media de edad de 39 años, 74% correspondió a enfermedad leve por COVID-19 y 26% a enfermedad moderada. Se documenta mediana de ocho días por periodo de infección por COVID-19. En el círculo femenino el promedio de la aparición de hipertensión arterial fue de 13 meses y en el masculino la media de desarrollo de hipertensión arterial posterior a COVID-19 fue de seis meses (AU)

Introduction: a new type of coronavirus that was named SARSCoV-2, responsible for the COVID-19 disease, with rapid spread in the world, due to high transmission that resulted in pandemic. There were 2'397,216 confirmed cases, with 162,956 deaths in the world, according to the WHO in April 2020. However, hypertension affects 40% of adults and means that around 250 million people suffer from high blood pressure. The WHO, according to its reports, refers that hypertension is the number one risk factor for death. One in four Mexicans suffers from high blood pressure. Objectives: to establish the incidence of systemic arterial hypertension after suffering from COVID-19 in patients of the UMF No. 48. Material and methods: it is a cross-sectional, observational and descriptive study, consisting of 3,238 patients with a positive COVID-19 diagnosis of both sexes, aged 18-70 years. Through the formula for infinite populations a sample of 348 patients is obtained. Will proceed with review of files in the Family Medicine Information System, version 6.2, to obtain the corresponding information. Results: 27 patients diagnosed with hypertension after the diagnosis of COVID-19, 52% of the male sex and 48% of the female sex, with a mean age of 39 years; 74% corresponds to a mild illness by COVID-19 and 26% to moderate disease. A median of 8 days per period of infection by COVID-19 is documented. In the female circle, the average onset of hypertension was 13 months and as for the male sex, the mean development of hypertension after COVID-19 was six months (AU)

Bloqueo del eje renina angiontensina aldosterona (RAAS) en la enfermedad renal diabética. Más allá del control de la hipertensión arterial / Renin angiotensin aldosterone system (RAAS) and its suppression in diabetic kidney disease. Control of arterial hypertension and beyond

La enfermedad renal diabética (ERD) es una comorbilidad con alta prevalencia a nivel mundial, siendo una de las complicaciones más frecuentes de la diabetes mellitus (DM). La ERD se relaciona con complicaciones cardiovasculares y progresión de la enfermedad renal crónica (ERC), por ello la identificación de factores modificables, como el control de la presión arterial, es uno de los pilares más importantes en el manejo integral. En esta revisión hacemos un recorrido sobre el papel de la hipertensión y el bloqueo del eje renina angiotensina aldosterona (RAAS) en el curso de la ERD y las estrategias terapéuticas orientadas a la reducción de la presión arterial (PA), el bloqueo RAAS y el impacto en resultados renales y cardiovasculares. El objetivo de este artículo es hacer una revisión de las intervenciones más importantes que actúan bloqueando el eje renina angiotensina aldosterona (RAAS) y determinar si estas medidas en los pacientes con ERD, solo tienen impacto en el control de la presión arterial o si también son estrategias de nefro y cardio-protección. Conclusión: La ERD es una de las complicaciones más frecuentes de la diabetes mellitus (DM). El control de la PA sigue siendo un pilar fundamental para lograr estos objetivos. Los bloqueadores del RAAS (iECAS y BRAs) son los antihipertensivos de elección con efecto terapéutico por el bloqueo RAAS y esto les permite tener además del control de la PA, efectos nefroprotectores y cardioprotectores importantes en pacientes con ERD, sobre todo cuando hay la presencia de albuminuria. Evaluamos que además de los inhibidores de la enzima convertidora de angiotensina (iECAs) y los bloqueadores del receptor de angiotensina (BRAs), vienen tomando importancia los antagonistas selectivos del receptor mineralocorticoide (ARM) como Finerenona.

Diabetic kidney disease (DKD) is a comorbidity with a high worldwide prevalence, and one of the most frequent complications of diabetes mellitus (DM). CKD is related to cardiovascular complications and the progression of chronic kidney disease (CKD), therefore the identification of modifiable factors, such as blood pressure control, is one of the most important pillars in comprehensive management. In this review, we will analyze the role of hypertension and the renin-angiotensin-aldosterone system (RAAS) and its suppression in the course of CKD, and therapeutic strategies aimed at reducing blood pressure (BP), RAAS blockade, and the impact on renal and cardiovascular outcomes. The objective of this article is to review the most important interventions that act by blocking the renin-angiotensin-aldosterone system (RAAS) and to determine if these measures in patients with CKD only have an impact on blood pressure control or if they are also nephron and cardio-protective strategies. Conclusion: DKD is one of the most frequent complications of diabetes mellitus (DM). BP control continues to be a fundamental pillar to achieve these objectives. RAAS blockers (iECAS and ARBs) are the first-line antihypertensive with a therapeutic effect due to RAAS blockade and this allows them to have, in addition to BP control, important nephroprotective and cardioprotective effects in patients with CKD, especially when there is albuminuria. We evaluated that in addition to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), selective mineralocorticoid receptor antagonists (MRA) such as Finerenone are gaining importance.

Local renin angiotensin system and sperm DNA fragmentation / 亚洲男科学杂志(英文版)

The renin angiotensin system (RAS) appears to influence male fertility at multiple levels. In this work, we analyzed the relationship between the RAS and DNA integrity. Fifty male volunteers were divided into two groups (25 each): control (DNA fragmentation ≤20%) and pathological (DNA fragmentation >20%) cases. Activities of five peptidases controlling RAS were measured fluorometrically: prolyl endopeptidase (which converts angiotensin [A] I and A II to A 1-7), neutral endopeptidase (NEP/CD10: A I to A 1-7), aminopeptidase N (APN/CD13: A III to A IV), aminopeptidase A (A II to A III) and aminopeptidase B (A III to A IV). Angiotensin-converting enzyme (A I to A II), APN/CD13 and NEP/CD10 were also assessed by semiquantitative cytometry and quantitative flow cytometry assays, as were the receptors of all RAS components: A II receptor type 1 (AT1R), A II receptor type 2 (AT2R), A IV receptor (AT4R or insulin-regulated aminopeptidase [IRAP]), (pro)renin receptor (PRR) and A 1-7 receptor or Mas receptor (MasR) None of the enzymes that regulate levels of RAS components, except for APN/CD13 (decrease in fragmented cells), showed significant differences between both groups. Micrographs of RAS receptors revealed no significant differences in immunolabeling patterns between normozoospermic and fragmented cells. Labeling of AT1R (94.3% normozoospermic vs 84.1% fragmented), AT4R (96.2% vs 95.3%) and MasR (97.4% vs 87.2%) was similar between the groups. AT2R (87.4% normozoospermic vs 63.1% fragmented) and PRR (96.4% vs 48.2%) were higher in non-fragmented spermatozoa. These findings suggest that fragmented DNA spermatozoa have a lower capacity to respond to bioactive RAS peptides.

Determination of perindopril erbumine by oxidative coupling reaction using 2, 6-dichloroquinone-4-chlorimide

Abstract Perindopril erbumine (Perindopril tert-butylamine salt) is a potent angiotensin-converting enzyme (ACE) inhibitor. It is used to treat the patients with hypertension and heart failure problems. A sensitive, inexpensive and precise analytical technique has been developed for the estimation of perindopril in bulk and formulations. The procedure involves the development of colour by forming an oxidative coupling reaction between drug (PPE) and reagent such as 2, 6-dichloroquinone-4-chlorimide (DCQC). The formed colored species were measured at (max=520 nm. The developed method showed linearity within the concentration limits of 25-75 µg mL-1. The linear correlation coefficient (r) and molar absorptivity were found to be 0.9999 and 3.285 x 103 mol-1cm-1. % Recovery ± SD values were in the range of 99.69 - 100.51 (+ 0.42 - ( 0.41) (n=3) which indicates the accuracy of the developed method. The interference of other excipients that are commonly present in formulations is found to be negligible. Precision and accuracy of the proposed method were confirmed by student t-test and F-tests at 95% confidence limits with (n-1) degrees of freedom. The validity parameters of proposed method were calculated by ICH guidelines

Levels of angiotensin-converting enzyme 1 and 2 in serum and urine of children with Sickle Cell Disease / Níveis de enzima conversora da angiotensina 1 e 2 no soro e na urina de crianças com Doença Falciforme

Abstract Introduction: Sickle cell nephropathy begins in childhood and presents early increases in glomerular filtration, which, over the long term, can lead to chronic renal failure. Several diseases have increased circulating and urinary angiotensin-converting enzyme (ACE) activity, but there is little information about changes in ACEs activity in children with sickle cell disease (SCD). Objective: We examined circulating and urinary ACE 1 activity in children with SCD. Methods: This cross-sectional study compared children who were carriers of SCD with children who comprised a control group (CG). Serum and urinary activities of ACE were evaluated, as were biochemical factors, urinary album/creatinine rates, and estimated glomerular filtration rate. Results: Urinary ACE activity was significantly higher in patients with SCD than in healthy children (median 0.01; range 0.00-0.07 vs median 0.00; range 0.00-0.01 mU/mL·creatinine, p < 0.001. No significant difference in serum ACE activities between the SCD and CG groups was observed (median 32.25; range 16.2-59.3 vs median 40.9; range 18.0-53.4) mU/m`L·creatinine, p < 0.05. Conclusion: Our data revealed a high urinary ACE 1 activity, different than plasmatic level, in SCD patients suggesting a dissociation between the intrarenal and systemic RAAS. The increase of urinary ACE 1 activity in SCD patients suggests higher levels of Ang II with a predominance of classical RAAS axis, that can induce kidney damage.

Resumo Introdução: A nefropatia falciforme começa na infância e apresenta aumentos precoces na filtração glomerular, que, em longo prazo, podem levar à insuficiência renal crônica. Várias doenças têm aumentado a atividade da enzima conversora da angiotensina (ECA) urinária e circulante, mas há pouca informação sobre alterações na atividade das ECAs em crianças com doença falciforme (DF). Objetivo: Examinamos a atividade da ECA-1 circulante e urinária em crianças com DF. Métodos: Este estudo transversal comparou crianças que eram portadoras de DF com crianças que compunham um Grupo Controle (GC). As atividades séricas e urinárias da ECA foram avaliadas, assim como os fatores bioquímicos, a relação albumina/creatinina urinária e a taxa de filtração glomerular estimada. Resultados: A atividade urinária da ECA foi significativamente maior em pacientes com DF do que em crianças saudáveis (mediana 0,01; intervalo 0,00-0,07 vs mediana 0,00; intervalo 0,00-0,01 mU/mL·creatinina, p < 0,001. Não foi observada diferença significativa nas atividades séricas da ECA entre os grupos DF e GC (mediana 32,25; intervalo 16,2-59,3 vs mediana 40,9; intervalo 18,0-53,4) mU/mL·creatinina, p < 0,05. Conclusão: Nossos dados revelaram uma alta atividade urinária da ECA-1, diferente do nível plasmático, em pacientes com DF, sugerindo uma dissociação entre o Sistema Renina Angiotensina Aldosterona (SRAA) intra-renal e sistêmico. O aumento da atividade urinária da ECA-1 em pacientes com DF sugere níveis mais elevados de Ang II com predominância do eixo clássico do SRAA, que pode induzir lesão renal.

Interactions amongst inflammation, renin-angiotensin-aldosterone and kallikrein-kinin systems: suggestive approaches for COVID-19 therapy

Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.(AU)

Genomics and epidemiology of the P 1 SARS-CoV-2 lineage in Manaus, Brazil

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

Factores moleculares implicados en insuficiencia cardiaca / Molecular factors involved in heart failure

La insuficiencia cardiaca se define como un síndrome caracterizado por la incapacidad de proveer las necesidades metabólicas del organismo, presentando disnea y fatiga. Hasta ahora, se ha descrito la participación de varias moléculas involucradas en los mecanismos de señalización intracelular que conducen a la insuficiencia cardiaca y estimulan la síntesis de algunas proteínas, como colágeno, la cual induce a una hipertrofia cardiaca(AU)

Heart failure is defined as a syndrome characterized by the inability to meet the metabolic needs of the organism, causing dyspnea and fatigue.Descriptions are available of the involvement of several molecules in cell signaling mechanisms which lead to heart failure and prompt the synthesis of some proteins, such as collagen, inducing cardiac hypertrophy(AU)

Informe diário de evidências COVID-19: busca referente aos dias 11, 12 e 13 de julho de 2020 / COVID-19 daily evidence report: search for July 11, 12 and 13, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos.

COVID-19, ACE -inhibitors and angiotensin receptor blockers: The need to differentiate between early infection and acute lung injury / COVID-19, y IECA -inhibidores y bloqueadores de los receptores de angiotensina: la necesidad de diferenciar entre una infección temprana y una lesión pulmonar aguda

SARS-CoV-2, along with SARS-CoV and MERS-CoV, forms part of the three highly pathogenic coronaviruses identified since the start of the millennium.1,2 While SARS-CoV was identified on 2003 and MERS-CoV on 2012, the initial reports of SARS-CoV-2 (the etiological agent of COVID-19) were first released at the end of December 2019.3,4 Now, after less than four months, the virus has distributed globally and has become the focus of extensive medical research, as the number of cases keeps rising.A significant part of the investigative effort has been directed to the search for an effective therapy or intervention that could stop the spread of the disease or be used to effectively treat infected patients. Likewise, potential predisposing factors to develop a more severe clinical presentation are progressively being identified. Some of the more relevant are older age and the presence of certain comorbidities, such as cerebrovascular and coronary heart disease, hypertension and diabetes.5­8 It is important to highlight that the last two are chronic conditions commonly treated with ACE-inhibitors and angiotensin II type-I receptor blockers.9­11 However, the evidence suggests that these medications can upregulate the expression of angiotensin converting enzyme 2 (ACE2), the cellular receptor for both SARS-CoV and SARS-CoV-2.11­16 Thus, a group of researchers hypothesized that ACE2-increasing drugs could raise the risk of infection and prompt a more severe clinical course or a fatal outcome in diabetic and hypertensive patients.

Menores niveles circulantes del péptido vasoactivo y cardioprotector angiotensina-(1-9) en pacientes con hipertension arterial pulmonar / Lower circulating levels of angiotensin-(1-9), a vasoactive and cardio-protective peptide in patients with pulmonary artery hypertension

RESUMEN: Introducción: La vía clásica del sistema renina-angiotensina (SRA) está activado en pacientes con hipertensión arterial pulmonar (HAP). Previamente, hemos encontrado que en la disfunción ventricular post infarto al miocardio experimental la activación del eje clásico del SRA, dado por la enzima convertidora de angiotensina I (ECA) y angiotensina (Ang ) II se correlaciona negativamente con el eje paralelo del SRA dado por la ECA homóloga (ECA2) y el péptido vasoactivo y cardioprotector Ang-(1-9). Resultados preclínicos muestran la eficacia de la administración de Ang-(1-9) en el tratamiento del remodelamiento cardiovascular patológico. Hasta la fecha no existen antecedentes de los niveles circulantes de Ang-(1-9) en pacientes con hipertensión arterial pulmonar comparados con sujetos sanos. Objetivo: Determinar los niveles circulantes del péptido vasoactivo y cardiprotector Ang-(1-9) en pacientes con HAP y compararlos con sujetos sanos pareados por edad y sexo. Métodos: Estudio comparativo transversal en pacientes con HAP (grupo I, OMS) con presión de arteria pulmonar media (mPAP) ≥25 mmHg bajo tratamiento con furosemida (40%), espironolactona (53%), Acenocumarol/Warfarina (47%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) y digoxina (13%). Los sujetos controles correspondieron a sujetos asintomáticos sanos sin enfermedad cardiovascular, cardiopatía estructural ni pulmonar (n=14). En todos los pacientes se determinó mPAP, proBNP, resistencia vascular pulmonar (RVP, WU), presión capilar pulmonar (PCP, mmHg), gasto cardíaco (L/min), capacidad funcional por test de caminata 6 minutos (TC6M), cambio del área fraccional del ventrículo derecho VD (FAC, %). Se utilizó prueba t de Student y programa estadístico SPSS10.0. Un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: Los pacientes ingresados al estudio mostraron: etiología de la HAP, idiopática (86,7%), VIH (13,3%), capacidad funcional I (6,2%), II (68,3) y III (25%) y promedio mPAP 51,3±1,9. Pacientes con HAP (grupo I, OMS) versus sujetos sanos mostraron disminución significativa de FAC, actividad plasmática de la ECA2 y niveles circulantes de Ang-(1-9). En la vía clásica del RAAS pacientes con HAP mostraron mayor actividad plasmática de ECA y niveles circulantes e Ag II. Correlaciones significativas se encontraron entre niveles de Ang-(1-9) y mPAP (r = -0.701, p < 0,001) y Ang-(1-9) vs FAC (r = 0.549, p < 0,01). Conclusiones: En pacientes con HAP (grupo I, OMS), los niveles circulantes de Ang-(1-9) están significativamente disminuidos y se asocian inversamente con la PAP, severidad del remodelamiento y disfunción del ventrículo derecho. El uso terapéutico de Ang-(1-9) como agente vasodilatador y cardioprotector podría ser relevante y potencialmente útil, desde una perspectiva clínica, en la HAP. Ang-(1-9) podría reducir la PAP y mejorar el remodelamiento vascular y del ventrículo derecho en la HAP. Por lo tanto, este péptido podría ser útil como blanco terapéutico en la HAP.

ABSTRACTS: Classic renin-angiotensis pathway (RAP) is activated in patients with pulmonary artery hypertension (PAH). We have previously shown that in patients with post myocardial infarction systolic dysfunction the activation of RAP mediated by angiotensin converting enzyme (ACE) and angiotensin II (Ang II) is inversely correlated with the parallel RAP axis mediated by homologous ACE (ACE2) and by the vasoactive and cardioprotective peptide Ang-(1-9). Pre clinical studies show that administration of Ang-(1-9) leads to a favorable ventricular remodelling. At present there is no information regarding levels of Ang-(1-9) in PAH patients compared to healthy subjects. Methods: 16 PAH patients (WHO group 1), with mean PA pressure > 25mmHg being treated with furosemide (40%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) were compared with healthy subjects (n=14). mPAP, pro BNP, pulmonary vascular resistance (Wu), pulmonary capillary pressure (PCP mmHg), cardiac output (L/min), functional capacity (6 min walking test) (6mWT), and changes in right ventricular fractional area (RV FA), were measured in all subjects. Results: In HAP subjects, the eiotology of PAH was unknown in 87%, or HIV (13%). Functional class was I (6.2 %), II (68.3%) or III (25%). Mean PAP was 51.3±1.9. Compared to healthy subjects, PAH patients had significantly lower RV FA, ACE2 and Ang-(19) levels. Also they had greater ACE plasma activity and AngII circulating levels. Significant correlations were found between Ang-(1-9) and mPAP (-0.701, p < 0,001) and between Ang-(1-9) and RV FA (r = 0.549, p < 0,01). Conclusion: group I PAH subjects, circulating levels of Ang-(1-9) are significantly lower than in healthy subjects and are inversely related to PAP, severity of ventricular remodeling and right ventricular dysfunction. The use of Ang-(1-9) as a vasodilator and cardioprotector agent could be clinically useful in PAH subjects.

Influence of ACE polymorphism on echocardiographic data of patients with heart failure / Influência do polimorfismo da ECA nos dados ecocardiográficos de pacientes com insuficiência cardíaca

Background: Angiotensin converting enzyme (ACE) polymorphism has been associated with different clinical and echocardiographic parameters in patients with heart failure (HF). However, no studies have been investigated such association with HF caused by Chagas disease. Objectives: To perform a genetic study to evaluate the frequency of ACE polymorphism in patients with HF caused by Chagas disease attending a university hospital in the central-west region and its association with echocardiographic findings. Methods: Descriptive study of ACE polymorphism (I/D) and echocardiographic data of 103 patients with HF caused by Chagas disease. Echocardiographic parameters were compared between the genotypes using the ANOVA test. Results: Genotypic distribution of the ACE polymorphism was 16.5% DD, 57.3% DI and 26.2% II. There was no statistically significant difference in the distribution of genotypes between men and women. The echocardiographic findings were: left ventricular ejection fraction: 43.8 ± 14.8 (DD) vs. 42.3 ± 11.6 (ID) vs. 44.9 ± 13.0 (II), p = 0.664; left ventricular diastolic diameter: 59.2 ± 9.7 (DD) vs. 60.3 ± 7.6 (ID) vs. 59.7 ± 78.1 (II), p = 0.879; left ventricular systolic diameter: 48.6 ± 12.8 (DD) vs. 50.6 ± 9.7 (ID) vs. 49.3 ± 11.9 (II), p = 0.753; and left atrial volume: 44.9 ± 10.1 (DD) vs. 40.9 ± 9.6 (ID) vs. 38.2 ± 7.8 (II), p = 0.068. Significant correlation coefficients were found for gender, age, ethnicity, heart rate and dyslipidemia. Conclusion: ACE polymorphism was not associated with echocardiographic findings in patients with HF caused by Chagas disease

Changes of Bax, Bcl-2, CCR-2, MCP-1, and TGF-β1 genes in the left ventricle of spontaneously hypertensive rat after losartan treatment / 소아과

PURPOSE: Increased apoptosis was recently found in the hypertrophied left ventricle of spontaneously hypertensive rats (SHRs). Although the available evidence suggests that apoptosis can be induced in cardiac cells by various insults including pressure overload, cardiac apoptosis appears to result from an exaggerated local production of angiotensin in adult SHRs. Altered expressions of Bcl associated X (Bax), Bcl-2, chemokine receptor (CCR)-2, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, phosphorylated extracellular signal-regulated kinases (PERK), and connexin 43 proteins, and kallikrein mRNA were investigated to explore the effects of losartan on the SHR model. METHODS: Twelve-week-old male rats were grouped as follows: control (C), SHR (hypertension: H), and losartan (L; SHRs were treated with losartan [10 mg/kg/day] for 5 weeks). Western blot and reverse transcription polymerase chain reaction assays were performed. RESULTS: Expression of Bax, CCR-2, MCP-1, TGF-β1, PERK, and connexin 43 proteins, and kallikrein mRNA was significantly increased in the H group compared to that in the C group at weeks 3 and 5. Expression of Bax, CCR-2, MCP-1, TGF-β1, and connexin 43 proteins and kallikrein mRNA was significantly decreased after losartan treatment at week 5. PERK protein expression was significantly decreased after losartan treatment at weeks 3 and 5. Bcl-2 protein expression was significantly decreased in the H group compared to that in the C group at weeks 3 and 5. CONCLUSION: Losartan treatment reduced expression of Bax, CCR-2, MCP-1, TGF-β1, PERK, and connexin 43 proteins, and kallikrein mRNA in SHRs, along with decreased inflammation and apoptosis.

Prognostic Effect of Guideline-Directed Therapy Is More Noticeable Early in the Course of Heart Failure

BACKGROUND: There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. METHODS: Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), β-blocker, and mineralocorticoid receptor antagonist. RESULTS: In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34–0.95), mortality (HR, 0.41; 95% CI, 0.24–0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36–0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41–0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47–0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and β-blockers with composite endpoint. CONCLUSION: The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.

Angiotensin Receptor Blockers as an Alternative to Angiotensin-Converting Enzyme Inhibitors in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are the first choice for the treatment of acute myocardial infarction (AMI), and angiotensin receptor blockers (ARBs) should be considered in patients intolerant to ACEIs. Although previous studies support the use of ARBs as an alternative to ACEIs, these studies showed inconsistent results. The objective of this study was to demonstrate the clinical impact of ARBs as an alternative to ACEIs in patients with AMI undergoing percutaneous coronary intervention (PCI). METHODS: The CardiOvascular Risk and idEntificAtion of potential high-risk population in AMI (COREA-AMI) registry enrolled all consecutive patients with AMI undergoing PCI. The primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization due to heart failure. RESULTS: Of the 3,328 eligible patients, ARBs replaced ACEIs in 816 patients, while 824 patients continued to use ACEIs and 826 patients continued to use ARBs. The remaining 862 patients did not receive ACEIs/ARBs. After the adjustment with inverse probability weighting, the primary endpoints in the first groups were similar (7.5% vs. 8.0%, hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.75–1.05; P = 0.164). Composite events were less frequent in the ACEI to ARB group than no ACEI/ARB group (7.5% vs. 11.8%, HR, 0.76; 95% CI, 0.64–0.90; P = 0.002). CONCLUSION: The alternative use of ARBs following initial treatment with ACEIs demonstrates comparable clinical outcomes to those with continued use of ACEIs and is associated with an improved rate of composite events compared to no ACEI/ARB use in patients with AMI undergoing PCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02385682