Cardiomiopatia dilatada (CMD) é uma doença miocárdica caracterizada por dilatação cardíaca e redução da contratilidade da parede do ventrículo esquerdo ou de ambos os ventrículos, sendo a etiologia de origem genética ou desconhecida. Em suínos existem raros relatos de CMD, sendo frequentemente relacionados com intoxicações por ionóforos ou gossipol. Surtos de CMD de etiologia desconhecida em suínos de rebanhos comerciais no Brasil sugeriram a existência de nova etiologia, possivelmente nutricional. Este estudo teve como objetivo investigar as possíveis causas dos surtos de CMD em suínos, a partir de análises macroscópicas, microscópicas, bioquímicas, cromatográficas, moleculares, imuno-histoquímica (IHQ) e reprodução experimental. E teve como resultado 2 artigos científicos. O primeiro artigo descreve os achados clínicos, patológicos, químicos e toxicológicos de três surtos de CMD em suínos de crescimento, além da reprodução experimental desta condição utilizando a ração de uma das propriedades afetadas. Para o estudo experimental utilizou-se 9 animais divididos em 3 grupo; Grupo 1 recebendo ração suspeita, Grupo 2 metade ração suspeita mais metade de ração controle e o grupo 3 recebeu ração controle. Dois suínos do grupo 1 apresentaram condições clínicas e patológicas semelhantes aos casos naturais após 8 dias de consumo da ração suspeita. Os principais sinais clínicos observados eram tosse e dispneia grave. Na necropsia foram constatados dilatação cardíaca bilateral acentuada, hidrotórax, hidropericárdio, edema pulmonar, ascite e fígado com aspecto de noz moscada. O segundo artigo teve como objetivo fazer a caracterização histológica, histoquímica e imuno-histoquímica das lesões cardíacas em 8 suínos com CMD e compara-las com dois suínos controles. As principais lesões evidenciadas foram atrofia de cardiomiócitos, vacuolização sarcoplasmática, ruptura de miofibras e fibras com padrão ondulado evidenciadas nas colorações de hematoxilina e eosina (HE), Tricrômico de Masson e Picrosírius. Na análise imuno-histoquímica utilizando o anticorpo anti-desmina houve uma imunomarcação reduzida ou inexistente em áreas com lesões histopatológicas. A imuno-histoquímica anti-desmina demonstrou ser uma importante ferramenta diagnóstica para caracterização de lesões de CMD em suínos. / Dilated cardiomyopathy (DCM) is a myocardial disease characterized by cardiac dilatation and reduced contractility of the left ventricular wall or both ventricles, the etiology of which is genetic or unknown. In pigs there are rare reports of DCM and are often related to ionosphere or gossypol poisoning. DCM outbreaks of unknown etiology in swine from herds in Brazil suggested the existence of a new, possibly nutritional, etiology. This study aimed to investigate the possible causes of DCM in pigs through macroscopic, microscopic, biochemical, chromatographical, molecular and immunohistochemical (IHC) evaluations, as well as the experimental reproduction of the disease. The project resulted in 2 scientific papers. The first article describes the clinical, pathological, chemical and toxicological findings of three DCM outbreaks in grower pigs, in addition to the experimental reproduction of this condition using the ration of one of the affected farms. For the experimental trial, 9 animals were divided into 3 groups; Group 1 received suspected ration only, Group 2 was fed a diet composed of half suspected ration plus half control ration, and group 3 received control ration only. Two pigs from group 1 presented clinical and pathological conditions similar to the natural cases after 8 days of consumption of the suspected ration. The main clinical signs observed were cough and severe dyspnea. At necropsy, bilateral cardiac dilatation, hydrothorax, hydropericardium, pulmonary edema, ascites and liver with the appearance of nutmeg were observed. The second article aimed to perform the histological, histochemical and immunohistochemical characterization of the cardiac lesions in 8 pigs with DCM and compare it with two control pigs. The main lesions evidenced were cardiomyocyte atrophy, sarcoplasmic vacuolization, rupture of myofibers and fibers with corrugated pattern evidenced in the staining of hematoxylin and eosin (HE), Masson's trichrome (MT) and Picrosírius (PS). Immunohistochemistry analysis using the anti-desmin antibody showed reduced or non-existent immunostaining in areas with histopathological lesions. The anti-desmin IHC proved to be an important tool for the diagnosis and characterization of DCM lesions in pigs.

Introdução: O benefício da restrição hidrossalina em pacientes internados por insuficiência cardíaca (IC) descompensada não está bem estabelecido. Objetivo: Comparar o efeito de uma dieta com restrição hídrica de 800 ml e 800 mg de sódio adicional/dia (grupo intervenção: GI) com uma dieta sem restrição hidrossalina (grupo controle: GC) na redução do peso e na estabilidade clínica em três dias em pacientes internados por IC aguda descompensada. Delineamento: Ensaio clínico randomizado que incluiu pacientes adultos com IC aguda descompensada, disfunção sistólica e admissão hospitalar k 36 horas. Avaliou-se diariamente o estado congestivo por meio do Escore Clínico de Congestão (ECC); a sensação de sede por meio da escala visual analógica (escala 0-10), até k sete dias de internação. As readmissões foram avaliadas em 30 dias. Resultados: Incluídos 75 pctes (GI: 38; GC: 37), predominantemente homens com fração de ejeção média de 26±8,7%, 22% com etiologia isquêmica. Os grupos não foram diferentes nas características basais. O delta do peso (GI: -4,42±2,85 e GC: -4,67±5,6/ P=0,82) e o delta do ECC (GI: - 4,03±3,3 e GC: - 3,44±3,35/ P=0,47) no terceiro dia não foram diferentes entre os grupos. A sede foi significativamente maior no GI durante o período do estudo (P=0,002). Readmissão em 30 dias foi semelhante entre o GI 11(28,9%) e GC 7 (18,9%), (P=0,41). Conclusão: A intervenção agressiva de restrição hidrossalina não teve impacto na redução do peso e na estabilidade clínica em três dias. Além disso, foi responsável por significativo aumento da sensação de sede. / Introduction: The benefits of fluid and sodium restriction in patients hospitalized with acute decompensated heart failure (HF) are unclear. Objective: To compare the effects of a fluid-restricted (800 mL/day) and sodium additional-restricted (800 mg/day) diet (intervention group, IG) versus a diet with no such restrictions (control group, CG) on weight loss and clinical stability over a 3-day period in patients hospitalized with acute decompensated HF. Methods: Randomized clinical trial of adult patients with acute decompensated HF, systolic dysfunction, and a length of stay k36 hours. Congestion was assessed daily by means of a clinical congestion score (CCS). Perceived thirst was assessed with a 10-point visual analog scale. Patients were followed until the 7th hospital day. Readmissions were assessed at 30 days. Results: Seventy-five patients were enrolled (38 allocated to intervention, 37 to the control group). Most were male; ischemic heart disease was the predominant cause of HF (22%), and the mean ejection fraction was 26±8.7%. Both groups were homogeneous in terms of baseline characteristics. There were no between-group differences in weight loss (IG, -4.42±2.85 kg; CG, -4.67±5.6 kg; P=0.82) or change in CCS (IG, -4.03±3.3; CG, -3.44±3.35; P=0.47) at 3 days. Thirst was significantly worse in the IG during the study period (P=0.002). There were no between-group differences in the readmission rate at 30 days (IG, 11 patients [28.9%]; CG, 7 patients [18.9%]; P=0.41). Conclusion: Aggressive fluid and additional sodium restriction had no impact on weight loss or clinical stability at 3 days, and was associated with a significant increase in perceived thirst.

Introdução: O benefício da restrição hidrossalina em pacientes internados por insuficiência cardíaca (IC) descompensada não está bem estabelecido. Objetivo: Comparar o efeito de uma dieta com restrição hídrica de 800 ml e 800 mg de sódio adicional/dia (grupo intervenção: GI) com uma dieta sem restrição hidrossalina (grupo controle: GC) na redução do peso e na estabilidade clínica em três dias em pacientes internados por IC aguda descompensada. Delineamento: Ensaio clínico randomizado que incluiu pacientes adultos com IC aguda descompensada, disfunção sistólica e admissão hospitalar k 36 horas. Avaliou-se diariamente o estado congestivo por meio do Escore Clínico de Congestão (ECC); a sensação de sede por meio da escala visual analógica (escala 0-10), até k sete dias de internação. As readmissões foram avaliadas em 30 dias. Resultados: Incluídos 75 pctes (GI: 38; GC: 37), predominantemente homens com fração de ejeção média de 26±8,7%, 22% com etiologia isquêmica. Os grupos não foram diferentes nas características basais. O delta do peso (GI: -4,42±2,85 e GC: -4,67±5,6/ P=0,82) e o delta do ECC (GI: - 4,03±3,3 e GC: - 3,44±3,35/ P=0,47) no terceiro dia não foram diferentes entre os grupos. A sede foi significativamente maior no GI durante o período do estudo (P=0,002). Readmissão em 30 dias foi semelhante entre o GI 11(28,9%) e GC 7 (18,9%), (P=0,41). Conclusão: A intervenção agressiva de restrição hidrossalina não teve impacto na redução do peso e na estabilidade clínica em três dias. Além disso, foi responsável por significativo aumento da sensação de sede. / Introduction: The benefits of fluid and sodium restriction in patients hospitalized with acute decompensated heart failure (HF) are unclear. Objective: To compare the effects of a fluid-restricted (800 mL/day) and sodium additional-restricted (800 mg/day) diet (intervention group, IG) versus a diet with no such restrictions (control group, CG) on weight loss and clinical stability over a 3-day period in patients hospitalized with acute decompensated HF. Methods: Randomized clinical trial of adult patients with acute decompensated HF, systolic dysfunction, and a length of stay k36 hours. Congestion was assessed daily by means of a clinical congestion score (CCS). Perceived thirst was assessed with a 10-point visual analog scale. Patients were followed until the 7th hospital day. Readmissions were assessed at 30 days. Results: Seventy-five patients were enrolled (38 allocated to intervention, 37 to the control group). Most were male; ischemic heart disease was the predominant cause of HF (22%), and the mean ejection fraction was 26±8.7%. Both groups were homogeneous in terms of baseline characteristics. There were no between-group differences in weight loss (IG, -4.42±2.85 kg; CG, -4.67±5.6 kg; P=0.82) or change in CCS (IG, -4.03±3.3; CG, -3.44±3.35; P=0.47) at 3 days. Thirst was significantly worse in the IG during the study period (P=0.002). There were no between-group differences in the readmission rate at 30 days (IG, 11 patients [28.9%]; CG, 7 patients [18.9%]; P=0.41). Conclusion: Aggressive fluid and additional sodium restriction had no impact on weight loss or clinical stability at 3 days, and was associated with a significant increase in perceived thirst.

Orientador: Maria Jose D'Elboux Diogo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T13:45:31Z (GMT). No. of bitstreams: 1 Scattolin_FatimaAyresdeAraujo_M.pdf: 3632683 bytes, checksum: bde26611a4b6901024154e3d00c11a6f (MD5) Previous issue date: 2006 / Resumo: Este estudo teve como objetivo investigar a Qualidade de Vida relacionada à Saúde (QVRS), a independência funcional e as relações destes conceitos em idosos portadores de Insuficiência Cardíaca (IC). Fizeram parte do estudo 146 idosos com IC em tratamento ambulatorial, que responderam ao The Minnesota Living with Heart Failure Questionnaire (MLHFQ) e à Medida de Independência Funcional (MIF). As análises estatísticas foram conduzidas utilizando: o Teste Mann-Whitney e o Teste Kruskal-Wallis para comparar os escores do MLHFQ e da MIF e variáveis sociodemográficas e clínicas; o Coeficiente de Correlação de Spearman para verificar a correlação entre as medidas de QVRS e MIF e a análise de Regressão Univariada e Múltipla, para identificar os preditores da QVRS e da independência funcional. A QVRS foi relacionada ao gênero, presença de sintomas (dispnéia, fadiga e edema), classe funcional- New York Heart Failure (CF-NYHA) e prática de atividade física. Foram observados mais baixos níveis de QVRS e independência funcional nas classes funcionais mais avançadas. A dispnéia e a CF-NYHA foram as variáveis preditoras da QVRS, explicando 42,0% da variabilidade da medida, enquanto, a idade superior ou igual a 80 anos, escolaridade e CF-NYHA foram preditoras da independência funcional, explicando 35,0% da variabilidade dos escores da MIF. Foram constatadas correlações significantes de moderada magnitude entre as dimensões física e emocional do MLHFQ e as sub escalas motora e total da MIF, respectivamente. Os resultados evidenciam que a QVRS e a independência funcional são conceitos correlacionados e influenciados pela CF-NYHA. Além disso, a MIF foi também associada à idade avançada e à escolaridade. Portanto, recomenda-se que intervenções voltadas para a melhora da QVRS em idosos portadores de IC, considerem ações específicas para grupos de idade mais avançada e baixa escolaridade, visando otimizar a independência funcional, bem como os sintomas relacionados à IC / Abstract: The main purpose of this study was to investigate the Heath-related Quality of Life (HRQL), the Functional Independence and their relations in elderly with Heart Failure (HF). One hundred and forty-six elderly outpatients completed the Minnesota Using with Heart Failure Questionnaire (MLHFQ) and the Functional Independence Measure (FIM). Analyses were conducted: to compare the MLHFQ, FIM scores, and Socio-Demographic and clinical variables using Mann-Whitney and Kruskal-Wallis Tests, Spearman coefficient to test the correlation between HRQL and FIM scores and Univariate and Multiple Regression Analyses were used to identify the predictors of QoL and FIM. HRQL was related to gender, presence of symptoms (dyspnea, fatigue, and edema), New York Heart Failure (NYHA) class and physical activity. It was observed lower level of HRQL and functional independence in the more advanced NYHA classes. The dyspnea and the NYHA class were HQRL variable predictors, explaining 42,0% of the variance of the measure, whereas the age over 80 years old, education and NYHA class were predictors of the functional independence, explaining 35,0% of the variance of the FIM scores. It was found significant correlations of moderate strength between the scores of the physical and emotional MLHFQ dimensions and the motor and total FIM sub-scales, respectively. It was concluded that the quality of life and functional independence in the elderly are correlated concepts influenced by the functional class of HF. Moreover, Functional Independence Measure was influenced also by aging and schooling. Then, it is interesting that intervention designed to improve the HRQL in the elderly consider specified actions to older groups with low level of schooling, concerned to optimizing the Functional Independence as well as the HF related symptoms / Mestrado / Enfermagem e Trabalho / Mestre em Enfermagem

Abstract Intrauterine infections apparently cause about 85% of preterm deliveries at less than 28 weeks of gestation. Infection and inflammation play an important role in morbidity and mortality during perinatal period. The inflammatory mechanisms and pathophysiological consequences of intrauterine infection are poorly understood. According to current evidence from animal studies, the phenotypes of fetal inflammatory response are variable, ranging from spontaneous preterm birth to fetal death. The fetus is rather well protected against infectious agents by both structural and functional barriers. Toll-like receptors (TLR) are a part of innate immune system. Binding of bacterial or viral component to TLR induces inflammatory response in the host. The present study addressed the hypothesis that the effects of bacterial lipopolysaccharide (LPS) on the fetus, depends on the route by which it reaches the fetus. In this experimental study we hypothesized that an acute inflammation within the amniotic cavity may cause an innate immune response in the fetus consequently leading to cardiovascular distress. Secondly the role of the placenta in protecting the fetus from acute infectious challenges was evaluated. Additionally, the role of gestational age in the fetal immune response was studied. In the present study, LPS from Gram-negative bacteria caused an acute intrauterine inflammation in mice as indicated by the elevated levels of inflammatory mediators (e.g. cytokines) in amniotic fluid. The fetal heart revealed mRNA and protein expression of TLR4, which recognizes LPS. Moreover, the data showed a cytokine response in the fetal heart and severe cardiac dysfunction. In contrast, intraperitoneal LPS administered to the mother did not cause an acute cytokine response in the fetus. After intraperitoneal LPS the placenta showed severe blood congestion and a cytokine response. The data suggest that TLRs play roles in regulating the acute inflammatory responses in the placenta. Despite the absence of a fetal immune response, the placental lesions caused a fetal cardiovascular compromise. In addition, the present data indicate that the fetal expression of TLR4 is tissue specific and developmentally regulated. Present study provides new insights into the acute inflammatory mechanisms in maternal and fetal compartments and the pathophysiological changes in fetal cardiovascular hemodynamics. / Tiivistelmä Hyvin ennenaikaisen, alle 28. raskausviikolla tapahtuneen synnytyksen taustalta löytyy usein kohdunsisäinen infektio (IUI). Kohdunsisäisen infektion aiheuttama synnytys on suurimpia sikiön vammautumiseen tai kuolemaan johtavia syitä. Tulehdukselliset mekanismit, jotka johtavat synnytykseen tai sikiön vammautumiseen ovat huonosti tunnettuja. Tollin kaltaiset reseptorit (TLR) ovat osa synnynnäisen immuniteetin puolustusjärjestelmää. Niiden tarkoitus on tunnistaa nopeasti elimistölle vieraat, usein bakteeri- tai virusperäiset rakenteet ja käynnistää tulehdusvaste tuottamalla tulehdusvälittäjäaineita. Nämä välittäjäaineet säätelevät tulehdusprosessia, toisaalta niiden liiallinen tuotto voi aikuisilla johtaa elinvaurioihin kuten sydämen toimintahäiriöön. On esitetty että tulehdusvälittäjäaineet käynnistäisivät myös ennenaikaisen synnytyksen IUI:ssa. TLR-reseptorien merkityksestä sikiön tulehdusvasteessa tai synnytyksen käynnistymisessä on vain vähän tietoa. Väitöskirjatyössä tutkittiin kokeellisen hiirimallin avulla bakteeriperäisen lipopolysakkaridin (LPS) kykyä aiheuttaa sikiön tulehdusvaste, sekä muutoksia sikiön sydämen ja verenkierron toiminnassa, riippuen LPS:n reitistä sikiöön. Toisaalta kokeellisella mallilla tutkittiin istukan kykyä suojata sikiötä voimakkaalta tulehdusreaktiolta. Tarkoituksena oli tutkia myös sikiön kehitysasteen vaikutusta LPS:n aiheuttamaan tulehdusvasteeseen. Tutkimuksessa havaittiin LPS:n aiheuttavan kohdunsisäisen tulehduksen kun sitä annettiin suoraan lapsiveteen. Sikiön sydämessä todettiin TLR4 lähetti-RNA:n ja proteiinin ilmentyminen sekä nopea sytokiinien tuotannon lisääntyminen kuvastaen äkillistä tulehdusprosessia. Samanaikaisesti ultraäänitutkimuksessa todettiin sikiön sydämen vaikea toimintahäiriö. Toisaalta, jos LPS annettiin kantavalle emolle vatsaonteloon, tulehdusvälittäjäaineiden tuotannon lisääntymistä sikiössä ei havaittu. Sen sijaan istukassa todettiin akuutti verentungos ja tulehdusvaste. Edellä kuvattu istukan toimintahäiriö johti myös sikiön sydämen ja verenkierron toiminnan vaikeutumiseen huolimatta siitä, ettei sikiön sydämessä havaittu tulehduksellista vastetta. Lisäksi sikiöstä ja istukasta saadut tulokset viittaavat siihen, että TLR-reseptorit ovat mukana LPS:n tunnistamisessa ja äkillisen tulehdusvasteen käynnistymisessä. Tutkimus antaa uutta tietoa raskauden aikaisista tulehduksellisista mekanismeista sekä sikiön sydämen toiminnan äkillisistä muutoksista voimakkaan tulehduksen aikana.

Fundamento: Na descompensação da insuficiência cardíaca, pode ocorrer o baixo débito cardíaco, nessa situação o uso de inotrópico pode ser necessário. Se o acesso venoso for periférico, a infusão venosa prolongada de inotrópicos pode levar à flebite. Por outro lado, o acesso venoso central pode apresentar complicações. O Cateter Central de Inserção Periférica (PICC) pode ser uma opção nessa situação. O objetivo do presente estudo foi avaliar a incidência de flebite com o uso do PICC em comparação ao acesso venoso periférico. Métodos: em estudo clínico randomizado foram selecionados pacientes com insuficiência cardíaca congestiva avançada, em uso de inotrópico endovenoso; plaquetas >= 50.000/mm3 e fração de ejeção do ventrículo esquerdo (FEVE) < 0,45. Os pacientes foram randomizados para receberem o PICC ou manter o acesso venoso periférico. O desfecho principal foi à ocorrência de flebite. Os dados foram analisados pela regressão logística. Resultados: Foram incluídos 40 pacientes no Grupo PICC e 40 pacientes no grupo controle. A mediana da idade foi de 61,5 (IQR=16) anos, a FEVE foi de 24,0 (IQR= 10) % e a dose da dobutamina foi de 7,73 (IQR = 5,3) mcg/kg*min. No Grupo PICC a ocorrência de flebite foi de 2,5 % (1 paciente) enquanto no grupo controle foi de 95% (38 pacientes), com razão dos riscos (HR) de 0,1% (IC 95%: 0,0 a 1,6%, P < 0,001). Conclusões: O uso de PICC foi associado a redução da incidência de flebite durante a infusão endovenosa contínua de dobutamina em pacientes com baixo débito cardíaco durante internação por insuficiência cardíaca descompensada / Background: During decompensated heart failure, the use of intravenous inotropes can be necessary. With peripheral venous access, prolonged infusions can cause phlebitis. However, traditional central venous catheters have possible complications. Peripherally inserted central catheters (PICCs) may be an alternative to traditional catheters. Our objective was to compare the incidence of phlebitis between PICCs and catheters used to achieve peripheral venous access. Methods: In a randomized clinical trial, 40 patients were randomized to the PICC group and 40 patients were randomized to thecontrol group. The inclusion criteria were advanced heart failure, ejection fraction < 0.45, and platelets > 50,000/mm3. The patients were randomly assigned to receivea PICC or keep their peripheral venous access. The primary endpoint was the occurrence of phlebitis. Results: We included 40 patients in the PICC group and 40 patients in the control group. The median age was 61.5 (interquartile range [IQR]=16) years, the ejection fraction was 0.24 (IQR=0.10), and the dobutamine dose was 7.73 (IQR=5.3) mcg/kg*min. Phlebitis occurred in 1 patient (2.5%) in the PICC group and in 38 patients (95.0%) in the control group, with a hazard ratio of 0.1% (95% confidence interval [CI]: 0.0%-1.6%, P < 0.001). Conclusion: PICCs were associated with a lower incidence of phlebitis in patients hospitalized for decompensated heart failure with low cardiac output during intravenous dobutamine infusions

Congestive heart failure (CHF) is associated with a significant economic burden that includes frequent emergency department visits, hospitalizations, and readmissions. The purpose of this study was to examine the differences, if any, between hospital readmission rates and insurance reimbursement rates for non-Hispanic Black and White CHF patients in California. The theoretical framework was Bandura's social cognitive theory. Secondary data for this quantitative study were obtained from the Office of Statewide Health Planning and Development and State Inpatient Databases from Healthcare Cost and Utilization for calendar year 2014-2016. A t-test and Levene's test for equality of variance were conducted on a sample of 11,905 patient records from 675 hospitals in California; the readmission discharge data and insurance reimbursement rates were analyzed by ethnicity and payer type. The results indicated that there was not a statistically significant difference between non-Hispanic Blacks as compared to non-Hispanic Whites in relation to readmission rates (M = 49.6, SD = 38.28) or insurance reimbursement rates (M = 50.88, SD = 36.52). Non-Hispanic Blacks had a higher readmission rate (36%) as compared to Whites (29%), and although these results are not significant, they support the need for healthcare professionals to develop programs that meet the needs of the community. The results of this study contribute to positive social change by providing information that healthcare professionals may be able to use to decrease CHF readmissions and improve access to care for non-Hispanic Blacks and other vulnerable patient groups.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal. / ACE inhibitors reduce the mortality rates for congestive heart failure and myocardial infarction. This has been shown to occur both in patients and in animal post-myocardial infarction (MI) models. Background Inflammatory cytokines have been shown to be activated post-MI and in congestive heart failure (CHF), and to contribute to ventricular dysfunction and remodeling. Angiotensin converting enzyme (ACE) inhibitors have been shown to be beneficial post-MI and in CHF, and we hypothesised that one of the mechanisms by which they exert their beneficial effects is by reducing cardiac expression of cytokines. Methods and results In order to verify this, 402 rats had a MI created by coronary artery ligation. In order to evaluate the benefit of ACE inhibitors started early post-MI, rats were separated into 3 treatment groups and followed 28 days: (1) MI no therapy; (2) quinapril started day 1; and (3) quinapril started day 25. In order to evalute the effects of ACE inhibitors once CHF had developed, 3 more groups were started and followed for a total of 84 days. Following the initiation of CHF (28 days post-MI), rats were randomised to (l) MI no therapy; (2) quinapril started on day 28; (3) quinapril started on day 81. In the early post-MI group, quinapril improved cardiac hemodynamics and prevented the increase in cardiac cytokine expression (tumor necrosis factor-α, interleukin 1β, 5 and 6), regardless of when it was started. Only when quinapril was started on day 1 did it improve ventricular remodeling. In the CHF group (84 days), quinapril had no effect on cardiac hemodynamics or ventricular remodeling. Quinapril, whether started on day 28 or 81, prevented the rise in cardiac cytokine expression. Conclusions In this post-MI model of CHF, ACE inhibitors have more beneficial effects on cardiac hemodynamics and ventricular remodeling when started early post-MI, rather than later when chronic CHF has developed. However, ACE inhibitors attenuate the rise in cardiac cytokine expression in both conditions. This study helps to identify a new mechanism by which ACE inhibitors may exert their beneficial effects in the early and late post MI-setting. / Les inhibiteur de l'enzyme de conversion de l'angiotensine II (IECA) réduisent le taux de mortalité, chez les personnes atteintes de défaillance cardiaque congestive (DCC) et/ou victime d'un infarctus du myocarde (IM). Ceci a été démontré aussi bien chez l'humain que dans des modèles animaux. Les mécanismes responsables des effets bénéfiques observés semblent multiples et incluent des effets hémodynamiques, une réduction des effets cellulaires de l'angiotensine II et une augmentation de la production d'oxyde nitrique. Etant donné que les cytokines inflammatoires sont activées en période post IM et en DCC, et que cette augmentation contribue à l'initiation de dysfonctions ventriculaires et au remodelage, nous émettons l'hypothèse quq les effets bénéfiques observés par ces agents sont aussi la résultante de leurs capacités à réduire le stress oxidatif et l'expression cardiaque de cytokines. Un total de 402 rats ont subi un IM par ligature de l'artère coronaire gauche. Afin d'évaluer les effets des IECAs débutes précocement post IM, les rats ont été séparés en trois groupes et suivis durant une période de 28 jours : (l) IM sans traitement; (2) quinapril débuté le premier jour post IM; et (3) quinapril débuté le 25 jour post IM. De plus, afin d'évaluer les effets des EECAs durant le développement de la DCC (28 jours post IM), trois groupes additionnels ont été suivis durant une période de 84 jours; (l) IM sans traitement; (2) quinapril débuté 28 jours post IM; et (3) quinapril débuté 81 jours post IM. Précocement post IM, quinapril améliore l'hémodynamie cardiaque et prévient l'augmentation de l'expression de cytokines cardiaques (facteur de tumeur nécrosante-α, interleukine-1β, 5 et 10) indépendamment du temps de traitement. Seul le traitement au quinapril appliqué au premier jour post IM résulte en une amélioration du remodelage ventriculaire. Quand débuté plus tardivement post IM (28 jours) le quinapril n'a pas d'effet négatif ou positif sur les paramètres hémodynamiques ou le remodelage ventriculaire. Par contre, le traitement avec le quinapril débuté 28 ou 81 jours post IM, prévient l'augmentation de l'expression de cytokines cardiaques. Dans ce modèle expérimental de DCC subséquent à un IM, les lECAs ont démontré des effets supérieurs sur les paramètres hémodynamiques ou le remodelage ventriculaire lorsque le traitement est débuté tôt post IM, plutôt que tardivement lorsque la DCC est développée. Par contre, les DECAs atténuent l'augmentation de l'expression cardiaque de cytokines dans les deux situations. Cette étude identifie un nouveau mécanisme par lequel les EECAs peuvent conférer des effets bénéfiques précocement et tardivement post IM.

Thesis (M.Pharm. (Pharmacy Practice))---North-West University, Potchefstroom Campus, 2008.

A Insuficiência cardíaca (IC), síndrome clínica que afeta predominantemente os idosos, caracteriza-se por graus variados de comprometimento hemodinâmico e contínua estimulação neuro-hormonal, com conseqüente redução da capacidade funcional e elevação nas concentrações plasmáticas do peptídeo natriurético B (PNB). Diversos ensaios clínicos demonstraram os benefícios dos inibidores da ECA na atividade neuro-hormonal e na capacidade funcional de pacientes com IC, com a magnitude desses efeitos proporcional à dose desses agentes. Entretanto, a sistemática exclusão dos idosos, observada na grande maioria desses estudos, tem questionado a validação e incorporação de tais resultados na população geriátrica. O objetivo deste estudo foi avaliar os efeitos de diferentes doses de quinapril, um inibidor da ECA com meia-vida biológica >24 horas, nas concentrações plasmáticas do PNB, nas distâncias percorridas no teste da caminhada de 6 minutos (TC-6 min) e na incidência de reações adversas, em idosos com IC sistólica. Métodos: Ensaio clínico, aberto, não randomizado e prospectivo. Foram avaliados, segundo os critérios de inclusão e exclusão, 30 pacientes (76,1 ± 5,3 anos; 15 homens e 15 mulheres) com IC classe funcional II-III (NYHA), com fração de ejeção ventricular esquerda < 40% (33,5 ± 4,5%), em uso de diuréticos (30), digoxina (24) e nitratos (13). As avaliações foram realizadas no momento da inclusão (condição basal) e a cada dois meses, com a adição de 10, 20, 30 e 40 mg de quinapril, e incluíam avaliações clínicas, exames bioquímicos, análises das concentrações plasmáticas do PNB e TC-6 min. Resultados: Completados oito meses de terapêutica com inibidor da ECA, as concentrações plasmáticas do PNB foram 67,4% menores em relação à condição basal: redução de 33,3% com a dose de 10 mg em relação à condição basal, 27,1% com 20 mg em relação à dose de 10 mg, 23,6% com 30 mg em relação à dose de 20 mg e 12,5% com 40 mg em relação à dose de 30 mg de quinapril, com p<0,005 em todas as comparações. Do mesmo modo, as distâncias percorridas no TC-6 min foram, em média, 64,9% maiores no final do estudo em relação à condição basal: aumento de 22,8% com a dose de 10 mg em relação à condição basal, 13,3% com 20 mg em relação à dose de 10 mg, 12,2% com 30 mg em relação à dose de 20 mg e 5,6% com 40 mg em relação à dose de 30 mg de quinapril, com p<0,005 em todas as comparações. Reações adversas graves, como hipotensão arterial associada a sintomas de baixo débito cerebral e/ou disfunção renal, não foram observadas, o que possibilitou o emprego da dose máxima de quinapril (40 mg/dia) em todos os pacientes, incluindo-se dois octogenários e dois nonagenários. Conclusão: Os resultados deste estudo demonstraram os benefícios da terapêutica com inibidores da ECA no perfil neuro-hormonal e na capacidade funcional de idosos com insuficiência cardíaca sistólica, bem como a relação positiva entre a dose e o efeito dos inibidores da ECA. Ademais, os sucessivos aumentos nas doses de quinapril não foram associados a reações adversas, possibilitando o emprego da dose máxima em todos os pacientes, incluindo-se dois octogenários e dois nonagenários. / Heart Failure (HF), a clinical syndrome that affects specially the elderly, is characterized by varied degrees of hemodinamic compromise and continuous neuro-hormonal stimulation, with consequent reduction of the functional capacity and elevation in the plasmatic concentrations of the natriuretic peptide B (BNP). Several clinical attempts showed the benefits of the ACE inhibitors in the neuro-hormonal activity and in the functional capacity of patients with HF, with the magnitude of those effects being proportional to the dose of the agents. However, the observed systematic exclusion of the elderly in the most of studies, has questioned the validation and the incorporation of such results in the geriatric population. The objective of this paper was the evaluation of the effects caused by different doses of quinapril, an ACE inhibitor with biological half-life> 24 hours, in the plasmatic concentrations of BPN, in the distances in the walk test of 6 minutes and in the incidence of adverse reactions in elderly with sistolic HF. Methods: prospective and not randomized study. 30 patients (76,1 ± 5,3 years; 15 men and 15 women with HF - class II-III (NYHA) - were evaluated, following the criteria of enclosure and exclusion, with ejection fraction of left ventricular <40% (33,5 ± 4,5%), in use of diuretics (30), digoxina (24) and nitrates (13). The evaluations were carried out in the moment of the enclosure (basic condition) and every other month, with the addition of 10 mg, 20 mg, 30 mg and 40 mg of quinapril. It was included clinical evaluations, biochemical exams, analyses of the BNP plasmatic concentrations and walk test of 6 minutes. Results: After eight months of treatment with the ACE inhibitor, the plasmatic concentrations of BNP were 67,4% smaller than the ones in the basic condition: reduction of 33,3% with the dose of 10 mg regarding the basic condition, 27,1% with 20 mg regarding the dose of 10 mg, 23,6% with 30 mg regarding the dose of 20 mg and 12,5% with 40 mg regarding the dose of 30 mg of quinapril, with p<0,005 in all the comparisons. In the same way, the distances in the walk test of 6 minutes were, on average, 64,9% bigger in the end of the study regarding the basic condition; there was the increase of 22,8% with the dose of 10 mg regarding the basic condition; 13,3% with 20 mg regarding the dose of 10 mg; 12,2% with 30 mg regarding the dose of 20 mg and 5,6% with 40 mg regarding the dose of 30 mg of quinapril, with p<0,005 in all the comparisons. Serious adverse reactions, as arterial hypotension associated to syncope and/or kidney dysfunction, were not observed, which made possible the use of the maximum dose of quinapril (40 mg/day) in all patients, including two octogenarians and two nonagenarians. Conclusion: The results of the study showed the benefits of the treatment with ACE inhibitors in the neuro-hormonal profile and in the functional capacity of elderly with sistolic heart failure, as well as the positive relation between the dose and the effect of the ACE inhibitors. Moreover, the successive increases in the doses of quinapril were not associated to adverse reactions, making possible the use of the maximum dose in all of the patients, including two octogenarians and two nonagenarians.