Determinamos o comportamento destes mediadores em pacientes com insuficiência aórtica crônica importante ( IAo ). Materal e métodos:Analisamos 89 portadores de Insuficiência Aórtica crônica importante, média etária de 33,6±11,5 anos, 84,6% sexo masculino, 60% assintomáticos, todos de etiologia reumática . Os pacientes foram submetidos a avaliação clínica e ecocardiográfica. Os valores médios foram: diâmetro diastólico (DD ) do ventrículo esquerdo ( VE ) de 71,9±8,3mm e o diâmetro sistólico ( DS ) do VE de 50,4±9,3mm, e a fração de ejeção ( FE ) do VE de 0,64±0,11. Realizamos a dosagem de Fator de Necrose Tumoral ( TNF ), seus receptores solúveis tipo I e II ( sTNFRI e sTNFR II ) , Interleucina-6 ( IL-6 ), seu receptor ( IL-6R), interleucina 1-beta ( IL-1beta ) , seu antagonista ( IL1-RA ) e endotelina-1 ( ET-1 ). Comparamos com níveis séricos de controles saudáveis. Conjuntamenete analisamos o polimorfismo genético do gene do TNF, localizado a -308 pares de bases do sítio de iniciação. Resultados: Os níveis séricos de TNF forma significativamente maiores em pacientes com IAo do que em controles normais ( 92,65±110,24 pg/ml contra 1,67±1,21 em controles normais, p < 0,001 ). Tiveram comportamentos similares os níveis séricos de sTNFRI ( 894,75±348,87pg/ml vs 521,42±395.13pg/ml em controles, p=0,007 ) e IL-6 ( 7,17±7,78pg/ml vs 0,81±0,38pg/ml, p=0,0001 ). Observamos correlação significativa entre níveis de sTNFRII e DDVE ( r=-0,329, p=0,038 ) e DSVE ( r=-0,352, p=0,027). Não observamos relação de níveis séricos de citocinas com sintomas. As outras citocinas não guardaram relação com parâmetros de gometria e função ventricular. A presença do alelo 2 do polimorfismo genético do TNF associou-se a paciente assintomáticos com IAo. Conclusão: Demonstramos níveis elevados de citocinas proinflamatórias em pacientes com IAo em relação a controles normais. Os níveis de sTNFRII diminuem com o aumento dos diâmetros ventriculares. A presença do alelo 2 do polimorfismo -308 do TNF associa-se a pacientes assintomáticos com IAo / Background - Proinflamatory cytokines are implied in the phisiopatology of heart failure secoundary to ischaemic or idiophatic dilated cardiomiopathy, but there are few studies regarding these mediators in valular heart disease. We determined the behaivour of proinflamatory cytokines and their antagonists in patients with chronic severe aortic regurgitation ( IAo ) Methods - We analised 89 patients with IAo mean age 33.6±11.5 years, 84.6% male, 60% asymptomatic, all of rheumatic etiology. Patients were evaluated clinnicaly and by echocardiography. Mean values were : left ventricular ( LV ) diastolic diameter ( DD ) 71.9±8.3mm, LV systolic diameter ( SD ) 50.4±9.3mm and ejection fraction 0.64±0.11. We made the plasma dosages of tumor necrosis factor-alpha ( TNF ), its soluble receptors type I and II ( sTNFRI and sTNFR II ) , Interleukin 6 ( IL-6 ) and its receptor ( IL-6R ), Interleukin 1-beta ( IL-1beta ) , its antagonist ( IL1-RA ) and endothelin-1 ( ET-1 ). Plasma levels were compared to healthy controls. We also analysed the TNF gene polimorphism, located at - 308 base pairs from the initation site. Results - Plasma TNF levels were significantly increased in IAo patients in telation to normal controls (92.65±110.24 pg/ml vs 1.67±1.21 pg/ml in controls, p < 0.001 ). Similar behaivour was observed with IL-6 (7.17±7.78pg/ml in IAo patients vs 0,81±0,38pg/ml in controls , p=0.0001 ) and sTNFRI (894.75±348.87pg/ml vs 521.42±395.13pg/ml in controls, p=0,007 ). We observed and significant relation between sTNFRII levels and LVDD ( r=-0,329, p=0,038 ) e LVSD ( r=-0,352, p=0,027). Levels of cytokines were similar in asymptomatic and sympromatic patients and the other cytokines had no relation to ventricular diameters or function. Presence of the alele 2 of the -308 TNF polimorphism was associated to asymptomatic patients. Conclusion - We showed increased plasma levels of proinflamatory cytokines in patients with IAo in relation to normal controls. There was an decrease of sTNFRII levels with increase in ventricular diameters. The presence of the alele 2 of the -308 TNF polimorphism was associated to asymtomatic patients

Evidências sugerem que o carvedilol diminui a atividade nervosa simpática muscular (ANSM) nos pacientes com insuficiência cardíaca (IC), mas não melhora o fluxo sangüíneo muscular (FSM) e a capacidade funcional nestes pacientes. Por outro lado, o treinamento físico reduz a ANSM, além de melhorar o FSM e a capacidade funcional nos pacientes com disfunção ventricular que não utilizam -bloqueadores. O objetivo deste estudo foi investigar o efeito do treinamento físico sobre a ANSM, FSM e capacidade funcional em pacientes com IC em uso de carvedilol. Foram estudados vinte e sete pacientes com IC, tratados com carvedilol, CF II-III, FE<35%, VO2 pico <20 ml/Kg/ min. Os pacientes foram randomizados em dois grupos: treinamento físico (n-15) e não treinamento (n-12). A ANSM foi medida diretamente pela colocação de um microeletrodo no nervo fibular. O FSM foi medido pela técnica de pletismografia de oclusão venosa. O treinamento físico foi realizado três vezes na semana, em cicloergômetro, durante 60 minutos, entre o limiar anaeróbio e 10% do ponto de compensação respiratório, por 4 meses. Antes do período experimental, todos os parâmetros avaliados eram semelhantes entre os grupos. O treinamento físico reduziu significativamente a ANSM (-14 ± 3 impulsos/100batimentos, p<0,01) e aumentou o FSM (0,6 ± 0,1 ml.min-1.100ml-1, p<0,01). Adicionalmente, ocorreu um aumento significativo do VO2 pico (20 ± 6%, p=0,05) no grupo treinamento físico. ANSM, FSM e pico do VO2 não se alteraram nos pacientes com IC que permaneceram sedentários. Conclui-se que o treinamento físico reduz significativamente a ANSM em pacientes com IC em uso de carvedilol. Adicionalmente, os benefícios do treinamento físico sobre o FSM e a capacidade funcional são mantidos nestes pacientes. / Evidence suggests that carvedilol decreases muscle sympathetic nerve activity (MSNA) in patients with heart failure(HF) but carvedilol fails to improve forearm vascular resistance and overall functional capacity. Exercise training in HF reduces MSNA and improves forearm vascular resistance and functional capacity. The aim of study was to investigate whether exercise training in the presence of carvedilol maintains its beneficial effects on MSNA, forearm blood flow and functional capacity. Twenty seven HF patients, Functional Class II III(NYHA), EF<35%, peak VO2 <20ml/kg/min, treated with carvedilol were randomly divided into two groups: exercise training(n=15) and untrained(n=12). MSNA was recorded by microneurography. Forearm blood flow(FBF) was measured by venous occlusion plethysmography. The four-month training program consisted of three 60-min exercise/week on cycloergometer. Baseline parameters were similar between groups. Exercise training reduced MSNA (-14 ± 3.3bursts/100HB, p<0.01) and increased FBF (0.6 ± 0.1 ml.min-1.100ml-1, p<0.01) in HF patients on carvedilol. In addition, exercise training improved peak VO2 in HF patients (20 ± 6%, p=0.05). MSNA, FBF and peak VO2 were unchanged in untrained HF patients on carvedilol. In conclusion, exercise training reduces MSNA in heart failure patients treated with carvedilol. In addition, the beneficial effects of exercise training on muscle blood flow and functional capacity are still realized in patients on carvedilol.

by Yeung Yuk-Ching. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 119-129). / Abstracts in English and Chinese. / Abstract in English --- p.ii / Abstract in Chinese --- p.v / Glossary --- p.viii / Acknowledgements --- p.x / Publications Arising From this Thesis --- p.xii / List of Tables --- p.xviii / List of Figures --- p.xix / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Definition of Heart Rate Variability --- p.1 / Chapter 1.2 --- Physiology --- p.1 / Chapter 1.2.1 --- Review of Autonomic Nervous System and Influence of Heart Rate --- p.1 / Chapter 1.2.2 --- The Role of Baroreceptors in the Control of Circulation --- p.4 / Chapter 1.2.3 --- The Control and Physiological Importance of Heart Rate --- p.7 / Chapter 1.2.3.1 --- Normal Heart Rate --- p.7 / Chapter 1.2.3.2 --- Autonomic Control of Heart Rate --- p.8 / Chapter 1.2.3.2.1 --- Sympathetic Effects --- p.8 / Chapter 1.2.3.2.2 --- Vagal Effects --- p.8 / Chapter 1.2.3.3 --- Reflexes Influencing Heart Rate --- p.9 / Chapter 1.2.3.3.1 --- Baroreceptors --- p.10 / Chapter 1.2.3.3.2 --- Chemoreceptors --- p.10 / Chapter 1.2.3.3.3 --- Atrial Receptors --- p.11 / Chapter 1.2.3.3.4 --- Coronary Chemoreflex --- p.11 / Chapter 1.2.3.3.5 --- Other Reflexes --- p.12 / Chapter 1.2.3.4 --- Influence of Complex Events on Heart Rate --- p.12 / Chapter 1.2.3.4.1 --- Respiratory Influence --- p.12 / Chapter 1.2.3.4.2 --- Effects of Decreases in Venous Return --- p.13 / Chapter 1.2.3.4.3 --- Exercise --- p.13 / Chapter 1.2.3.5 --- Physiological Importance of Heart Rate --- p.14 / Chapter 1.3 --- Spectral Analysis of Blood Pressure and Heart Rate Variability in Evaluating Cardiovascular Regulation --- p.14 / Chapter 1.4 --- Clinical Relevance --- p.15 / Chapter 1.4.1 --- Increased Sympathetic Activity --- p.15 / Chapter 1.4.2 --- Reduced Parasympathetic Activity --- p.15 / Chapter 1.4.3 --- Low Heart Rate Variability --- p.16 / Chapter 1.4.4 --- Depressed Baroreflex Sensitivity --- p.17 / Chapter 1.4.5 --- Prognostic Value of Heart Rate Variability in Disease States --- p.17 / Chapter 1.4.6 --- Abnormality of Autonomic Nervous System in Heart Failure --- p.17 / Chapter 2 --- METHODS FOR ASSESSING HEART RATE VARIABILITY --- p.20 / Chapter 2.1 --- Time Domain Analysis of Heart Rate Variability --- p.20 / Chapter 2.1.1 --- Statistical Methods --- p.21 / Chapter 2.1.2 --- Geometric Methods --- p.22 / Chapter 2.2 --- Spectral Analysis of Heart Rate Variability --- p.23 / Chapter 2.3 --- "Nonlinear Indices (fractal, entropy, chaos theory)" --- p.27 / Chapter 3 --- HEART FAILURE --- p.28 / Chapter 3.1 --- Heart Rate Variability in Heart Failure --- p.28 / Chapter 3.2 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability Analysis in Heart Failure --- p.34 / Chapter 3.3 --- Effect of Respiratory Rates on Baroreceptor Function in Heart Failure --- p.34 / Chapter 3.4 --- Effect of Treatment on Heart Rate Variability in Heart Failure Patients --- p.35 / Chapter 4 --- AIMS --- p.39 / Chapter 4.1 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability --- p.39 / Chapter 4.2 --- Effect of Slow Breathing --- p.39 / Chapter 4.3 --- Effect of Therapeutic Interventions in Chronic Heart Failure --- p.39 / Chapter 4.3.1 --- A Comparison of Celiprolol with Metoprolol --- p.39 / Chapter 4.3.2 --- A Comparison of Carvedilol with Metoprolol --- p.40 / Chapter 5 --- STUDIES --- p.41 / Chapter 5.1 --- Impact of Changes in Respiratory Frequency and Posture on Power Spectral Analysis of Heart Rate and Systolic Blood Pressure Variability in Normal Subjects and Patients with Heart Failure --- p.41 / Chapter 5.1.1 --- Subjects --- p.41 / Chapter 5.1.2 --- Recording Technique and Protocol --- p.42 / Chapter 5.1.3 --- Signal Acquisition --- p.42 / Chapter 5.1.4 --- Power Spectral Analysis --- p.43 / Chapter 5.1.5 --- Statistical Analysis --- p.46 / Chapter 5.1.6 --- Results --- p.46 / Chapter 5.1.7 --- Discussion --- p.52 / Chapter 5.1.8 --- Summary --- p.56 / Chapter 5.2 --- Slow Breathing Increases Arterial Baroreflex Sensitivityin Patients with Chronic Heart Failure --- p.57 / Chapter 5.2.1 --- Subjects --- p.57 / Chapter 5.2.2 --- Assessment of Baroreflex Sensitivity --- p.57 / Chapter 5.2.3 --- Statistical Analysis --- p.58 / Chapter 5.2.4 --- Results --- p.59 / Chapter 5.2.5 --- Discussion --- p.62 / Chapter 5.2.6 --- Summary --- p.63 / Chapter 5.3 --- β-Blockers in Heart Failure: a Comparison of a Vasodilating β- Blocker with Metoprolol on Heart Rate Variability by 24 Hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.65 / Chapter 5.3.1 --- Trial Design --- p.65 / Chapter 5.3.2 --- Study Patients --- p.65 / Chapter 5.3.3 --- Study Measurements --- p.66 / Chapter 5.3.4 --- Statistical Analysis --- p.67 / Chapter 5.3.5 --- Results --- p.67 / Chapter 5.3.6 --- Discussion --- p.80 / Chapter 5.3.7 --- Summary --- p.81 / Chapter 5.4 --- Effect of β-Blockade on Baroreceptor and Autonomic Function in Heart Failure-Assessment by Short Term Spectral Analysis --- p.83 / Chapter 5.4.1 --- Trial Design and Study Patients --- p.83 / Chapter 5.4.2 --- Recording Technique and Protocol --- p.83 / Chapter 5.4.3 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.83 / Chapter 5.4.4 --- Reproducibility --- p.84 / Chapter 5.4.5 --- Statistical Analysis --- p.84 / Chapter 5.4.6 --- Results --- p.84 / Chapter 5.4.7 --- Discussion --- p.93 / Chapter 5.4.8 --- Summary --- p.97 / Chapter 5.5 --- β-Blockade in Heart Failure: A Comparison of Carvedilol with Metoprolol on HRV by 24 hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.98 / Chapter 5.5.1 --- Trial Design and Patient Demographics --- p.98 / Chapter 5.5.2 --- Study Measurements --- p.98 / Chapter 5.5.3 --- Statistical Analysis --- p.99 / Chapter 5.5.4 --- Results --- p.99 / Chapter 5.5.5 --- Discussion --- p.105 / Chapter 5.5.6 --- Conclusions --- p.107 / Chapter 5.6 --- Comparison of Carvedilol and Metoprolol on Baroreceptor Gain in Heart Failure by Short Term Spectral Analysis --- p.108 / Chapter 5.6.1 --- Study Design --- p.108 / Chapter 5.6.2 --- Study Patients --- p.108 / Chapter 5.6.3 --- Recording Technique and Protocol --- p.108 / Chapter 5.6.4 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.108 / Chapter 5.6.5 --- Statistical Analysis --- p.109 / Chapter 5.6.6 --- Results --- p.109 / Chapter 5.6.7 --- Discussion --- p.112 / Chapter 5.6.8 --- Summary --- p.112 / Chapter 6 --- "GENERAL DISCUSSION, LIMITATIONS & CONCLUSIONS" --- p.113 / Chapter 6.1 --- Discussion --- p.113 / Chapter 6.2 --- Conclusions --- p.117 / Chapter 7 --- REFERENCES --- p.119

Background: Heart failure is a chronic disease, when a person is diseased, this also affects family, friends and the network around the person. Heart failure varies greatly related to day shape. Difficulties for families to understand the disease and its course of action are described. Experience with relatives highlights basic factors that can help to manage when a loved one is suffering from heart failure. Furthermore, related persons, patients and health care personnel are described, which together form a care team. Aim: To describe the patient experiences of living with heart failure. Method: A systematic literature study with a qualitative approach. Results: The result describes two themes and four sub-themes that treat patients' experiences of needs such as support and knowledge about the disease. Furthermore, consequences of the disease are described, such as limited autonomy and concern for changes in the future. It emerged that symptoms affect patients in everyday life and that knowledge is an important factor in being able to conduct self-care in the disease. Inadequate self-care increases the risk of symptoms which impair the disease and reduce the quality of life. Conclusion: People with heart failure experience suffering both mentally and physically. Relatives support and commitment play an important role in patients' vitality, this promotes self-care and daily routines can be carried out. Nursing staff play a major role in the disease process when the need for support and knowledge about the disease is desired. Key Words: Needs, Heart failure, Experiences, Systematic literature study, Qualitative / Bakgrund: Hjärtsvikt är en kronisk sjukdom, då en person drabbas påverkar detta även familj, vänner och nätverket runt omkring den insjuknade. Hjärtsvikt varierar kraftigt relaterat till dagsformen. Svårigheter för familjer att förstå sjukdomen och dess förlopp beskrivs. Erfarenheter hos anhöriga belyser grundläggande faktorer vilka kan vara behjälpliga för att hantera situationer när en närstående drabbas av hjärtsvikt. Vidare beskrivs närstående, patient och vårdpersonal vilka figurerar tillsammans som ett vårdteam. Syfte: Att beskriva patienters upplevelse av att leva med hjärtsvikt. Metod: En systematisk litteraturstudie med kvalitativ ansats. Resultat: Resultatet beskriver två teman och fyra subteman vilka behandlar patienters upplevelser av behov såsom stöd och kunskap kring sjukdomen. Vidare beskrivs konsekvenser av sjukdomen såsom begränsad autonomi och oro för förändringar i framtiden. Det framkom att symtom påverkar patienter i vardagen samt att kunskap utgör en viktig faktor för att kunna bedriva egenvård i sjukdomen. Undermålig egenvård ökar risker för symtom vilka försämrar sjukdomen och minskar livskvalitén. Slutsats: Personer med hjärtsvikt upplever lidande både psykiskt och fysiskt. Närståendes stöd och engagemang har en betydelsefull roll för patienters livskraft, detta främjar egenvård och dagliga rutiner går att utföra. Vårdpersonal spelar en stor roll i sjukdomsprocessen då behovet av stöd och kunskap kring sjukdomen önskas.   Nyckelord: Behov, Hjärtsvikt, Kvalitativ, Systematisk litteraturstudie, Upplevelse

The physiological and clinical considerations of centrifugal and axial pumps as ven- tricular assist devices (VADs) demands limitations on the power, size and geometry of the impellers. A typical pump design method is to rely on the characteristics of previously designed pumps with known performance using empirical equations and nondimensional parameters based on uid dynamics similarity law. Such data are widely available for industrial pumps operating in Reynolds number region of 108. VADs operate in Re < 106 and therefore the similarity concept does not apply between the industrial diagrams and the medical application of small pumps. The present dissertation employs a parametric approached analytical model to in- vestigate more than 150 axial and centrifugal pumps. The design parameters are optimised using the response surface methodology. The effect of different design parameters on the performance, force analysis and hemocompatibility of the pumps is thoroughly investigated by modelling the haemolysis through a power-law equation. The results show an explicit and consistent relationship between the number of blades, outlet width, outlet angle and the hemocompatibility of the device. Centrifu- gal pumps showed signi cantly lower probability of blood complications compared to axial pumps. The evaluation of the design characteristics helps pump designers to select their parameters accordingly for a low probability of blood complications. Furthermore, experimental techniques are employed to test more than 70 pumps in different conditions of flow, pressure and rotational speed. The experimental results validate the numerical simulations and create a database of empirical equations and data points for small axial and centrifugal pumps. The specifi c speed and speci fic diameters of the pumps are plotted on an ns − ds diagram to enable preliminary design of small pumps for VADs suitable for different stages of congestive heart failure (CHF).

A necessidade de buscar novos tratamento para a Insuficiência Cardíaca (IC) crônica levanta o questionamento da eficácia e segurança de drogas que não foram adequadamente testadas ou que ainda não tiveram sua eficácia aceita pela comunidade científica. O sildenafil é um vasodilatador com potencial eficácia na redução da pressão sistólica da artéria pulmonar (PSAP), mas com pequenos estudos e sem demonstração de impacto em desfechos duros. Os diuréticos de alça são utilizados rotineiramente em pacientes com IC sem sinais de congestão e tal prática não está recomendada nas diretrizes terapêuticas, desconhecemos sua eficácia e segurança neste cenário. No intuito de elucidar estas questões, foram desenvolvidos I) revisão sistemática com metanálise para estudo uso de sildenafil. II) revisão sistemática com metanálise para estudo uso de diurético de alça, III) Delineamento e execução em andamento de ensaio clínico randomizado multicêntrico testando a retirada de diurético de alça. I e II) Métodos e resultados: Ambas revisões sistemáticas foram realizadas no Pubmed, Embase e Cochrane, e termos relacionados à insuficiência cardíaca crônica diurético de alça e sildenafil foram utilizados, respectivamente. Após avaliação de texto completo, apenas estudos em humanos foram incluídos na metanálise. A droga sildenafil foi avaliada em 9 estudos randomizados contra placebo e demonstrou redução de hospitalização (RR 0.29, 95% C.I 0.11 to 0.78) e melhora progressiva em parâmetros funcionais e hemodinâmicos O uso de diurético de alça foi testado em 7 ensaios clínicos e não mostrou significância em piora da função renal, distúrbio eletrolítico e mudança de peso. III) Métodos e resultados: Em um estudo duplo-cego randomizado, de não inferioridade, multicêntrico compara-se o a segurança e tolerabilidade da retirada de furosemida de pacientes com IC crônica e estável com disfunção ventricular. Com início da coleta em setembro de 2015, até o momento 96 pacientes foram randomizados. Conclusão: Quanto ao sildenafil, já temos evidências que apontam para um efeito benéfico e progressivo na melhora da capacidade funcional, perfil hemodinâmico e redução de hospitalização em pacientes com IC com disfunção ventricular e pressão da artéria pulmonar elevada A recomendação para uso de diurético de alça em pacientes estáveis com IC permanece uma incógnita e o ensaio clínico em andamento nos trará uma resposta de importante impacto clínico na tomada de decisão para manutenção do uso de diurético. / The challenges and promises of new treatments for chronic heart failure (CHF) raises the question of the efficacy and safety of drugs that have not been properly tested or that have not yet had their efficacy accepted by the scientific community. Sildenafil is a vasodilator with potential efficacy in reducing pulmonary artery systolic pressure (PSAP), but with small studies and no demonstration of impact on hard outcomes. Routinely, Loop diuretics are used in patients with HF without signs of congestion and such practice is not recommended in the therapeutic guidelines, we do not know its efficacy and safety in this scenario. In order to elucidate these questions, I) systematic review with meta-analysis were developed to study the use of sildenafil. II) systematic review with meta-analysis to study the use of loop diuretics, III) Design and execution in progress of a multicenter randomized clinical trial testing for loop diuretic withdrawal. I and II) Methods and results: Both systematic reviews were performed in PubMed, Embase and Cochrane, and terms related to chronic diuretic heart failure of the loop and sildenafil were used, respectively. After full-text evaluation, only human studies were included in the meta-analysis. The drug sildenafil was evaluated in 9 randomized placebo-controlled studies and demonstrated a reduction in hospitalization (RR 0.29, 95% CI 0.11 to 0.78) and progressive improvement in functional and hemodynamic parameters. The use of a loop diuretic was tested in 7 clinical trials and did not show significant deterioration in renal function, electrolyte disturbance and weight change. III. METHODS AND RESULTS: In a double-blind randomized, non-inferiority, multicenter study, the safety and tolerability of furosemide withdrawal from patients with chronic and stable HF with ventricular dysfunction were compared. Randomization started at September 2015, to the moment 96 patients were randomized. CONCLUSION: Regarding sildenafil, we already have evidence of a beneficial and time-related effect on the improvement of functional capacity, hemodynamic profile and reduction of hospitalization in patients with HF with ventricular dysfunction and elevated pulmonary artery pressure. The recommendation for the use of a loop diuretic in stable patients with HF remains an unknown and the ongoing clinical trial will provide us with an important clinical impact response in the decision making to maintain the use of diuretics.

Introdução: A inflamação e o estresse oxidativo estão associados à progressão do infarto agudo do miocárdio (IAM) para a insuficiência cardíaca (IC). Logo, o tratamento com metilprednisolona, um conhecido glicocorticoide com propriedades anti-inflamatórias e antioxidantes, tem o potencial de mitigar a piora da função do ventrículo esquerdo após o IAM. Entretanto, a utilização de glicocorticoides após o IAM tem apresentado resultados contraditórios que podem ser decorrentes da maneira como são aplicados. Objetivo: Verificar a influência do período de administração de acetato de metilprednisolona sobre a função cardíaca de ratos após o infarto agudo do miocárdio. Materiais e Métodos: No experimento 1, foram utilizados 29 ratos Wistar machos divididos em 3 grupos: Sham (n=14), infartado tratado com salina logo após o IAM (IAM0 n=7) e infartado tratado 7 dias pós-IAM (IAM7 n=8). A função cardíaca foi avaliada 2 e 56 dias pós-IAM pelo exame de ecocardiografia. No experimento 2 foram utilizados 45 ratos Wistar machos divididos em 4 grupos: Sham (Sham, n=13); infartado (IAM, n=14); infartado e tratado com metilprednisolona no dia da indução do infarto (IAM+M0, n=7); infartado e tratado com metilprednisolona no 7º dia após a cirurgia (IAM+M7, n=7). A cirurgia do IAM foi realizada pela oclusão da artéria coronária descendente anterior esquerda. Uma dose única de acetato de metilprednisolona (40mg/kg,i.m.) foi aplicada nos animais dos grupos IAM+M. A função cardíaca foi avaliada pela ecocardiografia e pelo cateterismo ventricular 56 dias após a indução do infarto. Dados morfométricos e de estresse oxidativo do coração foram avaliados No experimento 3, foram utilizados 16 ratos Wistar machos, sendo divididos em 2 grupos: grupo controle tratado com salina no dia 0 (C, n=5) e grupo tratado com acetato de metilprednisolona (40mg/kg. i.m.) no dia 0. A coleta de sangue ocorreu uma vez por semana durante oito semanas, para avaliação de parâmetros do soro. A função cardíaca foi avaliada pelo cateterismo ventricular 56 dias o início da administração farmacológica. Dados morfométricos e de estresse oxidativo do coração foram avaliados. Parecer CEUA/UFRGS: 30797. Resultados: Os grupos IAM e IAM+M0 e IAM+M7 apresentaram área de infarto de 50,4%, 54,8% e 55,1%, respectivamente. A fração de encurtamento e a mudança de área fracional do ventrículo esquerdo diminuíram significativamente (37% e 39%) no grupo IAM em relação ao Sham. O tratamento iniciado no 7º dia promoveu um declínio adicional na mudança da área fracional (66%) quando comparado ao IAM. Tais parâmetros foram semelhantes entre os grupos IAM e IAM+M0. Observamos um aumento de 69% na pressão diastólica final do ventrículo esquerdo (PDFVE) no grupo IAM quando comparado ao grupo Sham. O tratamento com acetato de metilprednisolona, independentemente do tempo de administração, foi capaz de atenuar a PDFVE apenas os grupos IAM e IAM+M7 apresentaram congestão pulmonar. Conclusão: Nossos resultados demonstram que o tratamento com metilprednisolona iniciado logo após o infarto agudo do miocárdio impede ou reverte o aumento da PDFVE e a congestão pulmonar. O tratamento realizado no 7º dia após o IAM também foi eficaz em atenuar a PDFVE, porém não reverteu a congestão pulmonar. Portanto, concluímos que o tratamento iniciado precocemente apresenta potencial em mitigar a transição do IAM para a insuficiência cardíaca. / Introduction: Inflammation and oxidative stress are associated with the progression of acute myocardial infarction (AMI) to heart failure (HF). Therefore, treatment with methylprednisolone, a known glucocorticoid with anti-inflammatory and antioxidant properties, has the potential to mitigate the worsening of left ventricular function after AMI. However, the use of glucocorticoids after AMI has presented contradictory results that may be due to the way they are applied. Aim: To verify the influence of the period of administration of methylprednisolone acetate on the cardiac function of rats after acute myocardial infarction. Materials and Methods: In the experiment 1, 29 male Wistar rats were divided into 3 groups: Sham (n = 14), infarcted treated with saline immediately after AMI (AMI0 n = 7) and infarcted treated 7 days after AMI n = 8). Cardiac function was assessed 2 and 56 days post AMI by echocardiography. In the experiment 2, 45 male Wistar rats were divided into 4 groups: Sham (Sham, n = 13); infarcted (AMI, n = 14); infarcted and treated with methylprednisolone on the day of infarction induction (AMI+M0, n = 7); infarcted and treated with methylprednisolone on the 7th day after surgery (AMI+M7, n = 7). The AMI surgery was performed by occlusion of the left anterior descending coronary artery. A single dose of methylprednisolone acetate (40 mg / kg, i.m.) was applied to animals in the AMI-M groups. Cardiac function was assessed by echocardiography and ventricular catheterization 56 days after infarction induction. Morphometric and oxidative stress of the heart were evaluated. In the experiment 3, 16 male Wistar rats were divided into 2 groups: control group treated with saline at day 0 (C, n = 5) and group treated with methylprednisolone acetate (40mg / kg, im) at day 0 Blood collection occurred once a week for eight weeks for evaluation of serum parameters. Cardiac function was assessed by ventricular catheterization 56 days after initiation of pharmacological administration. Morphometric data and oxidative stress of the heart were evaluated. CEUA / UFRGS opinion: 30797. Results: The AMI and AMI+M0 and AMI+M7 groups presented an infarct area of 50.4%, 54.8% and 55.1%, respectively. The fraction of shortening and the change in fractional area of the left ventricle decreased significantly (37% and 39%) in the AMI group in relation to Sham. The treatment started on day 7 promoted an additional decline in the fractional area change (66%) when compared to AMI. These parameters were similar between the AMI and AMI + M0 groups. We observed a 69% increase in left ventricular end-diastolic pressure (LVEDP) in the AMI group when compared to the Sham group. Treatment with methylprednisolone acetate, irrespective of the time of administration, was able to attenuate LVDEP only the AMI and AMI+M7 groups presented pulmonary congestion. Conclusion: Our results demonstrate that treatment with methylprednisolone initiated shortly after acute myocardial infarction prevents or reverses the increase in LVEDP and pulmonary congestion. Treatment on the 7th day after AMI was also effective in attenuating LVEDP, but did not reverse pulmonary congestion. Therefore, we conclude that the treatment started early has the potential to mitigate the transition from AMI to heart failure.

INTRODUÇÃO: Estudos prévios demonstram que pacientes com insuficiência cardíaca (IC) podem apresentar redução dinâmica na capacidade inspiratória (CI) durante o exercício associada à redução da capacidade aeróbia. Poucas informações estão disponíveis atualmente sobre se esta redução está relacionada a anormalidades da mecânica ventilatória ou à disfunção muscular inspiratória. OBJETIVOS: Comparar a atividade muscular inspiratória e a intensidade da dispneia durante o exercício em pacientes com IC estável que apresente (Grupo 1) ou não (Grupo 2) redução da CI durante o exercício. MÉTODOS: Foram avaliados 16 pacientes com IC clinicamente estáveis (11 homens, 30 ± 5% de fração de ejeção) e não obesos tratados de acordo com diretrizes baseadas em evidências, sem outras doenças sistêmicas ou evidência espirométrica de obstrução do fluxo aéreo (VEF1/CVF = 83 ± 5%). Os pacientes realizaram teste de exercício cardiopulmonar incremental com medidas seriadas de CI, percepção de dispneia (Borg) e monitoramento contínuo das pressões esofágica (Pes) e gástrica (Pga). A pressão transdiafragmática (Pdi) foi obtida a partir de Pga–Pges. As manobras de Sniff e pressão inspiratória máxima (PImax) foram comparadas em repouso e imediatamente após o exercício. RESULTADOS: Quatro pacientes (25%, Grupo 1) apresentaram redução da CI durante o exercício (-0,18 ± 0,01 vs 0,28 ± 0,05L, p < 0,05). Não houve diferença significativa entre os grupos na função pulmonar e variáveis ecocardiográficas, exceto por uma menor capacidade residual funcional no Grupo 1 (72 ± 9 vs 97 ± 17%; p < 0,05) e menor PImax no Grupo 2 (-101± 25 vs 67 ± 24 cmH2O, p < 0,05). Pes,Sniff (Grupo 1: -77,9 ± 8,7 a -79,6 ± 8,8; Grupo 2: -63,3 ± 4,8 a -66,3 ± 3,8 cmH2O) e Pdi,Sniff (Grupo 1: 116,3 ± 13,9 a 118,3 ± 14,2; Grupo 2: 92,3 ± 5,6 a 98,0 ± 6,0 cmH2O) não diminuíram significativamente com o exercício, assim como Pes,PImax (Grupo 1: -90,5 ± 6,2 a 90,0 ± 9,7; Grupo 2: -64,5 ± 7,3 a 62,3 ± 7,5 cmH2O) e Pdi,PImax (Grupo 1: 140,0 ± 14,0 a 129,3 ± 15,1; Grupo 2: 102,1 ± 15,4 a 90,4 ± 11,4 cmH2O). Apesar de Pga e Pdi terem reduzido ao longo das manobras seriadas de CI durante o exercício no Grupo 1, a Pes não diferiu entre os grupos. A dispneia também foi semelhante entre os grupos. Por fim, o Grupo 1 apresentou volume de reserva inspiratório menor que o Grupo 2 somente no pico do exercício (0,90 ± 0,08 vs 1,47 ± 0,21L; p <0,05). CONCLUSÃO: A redução da CI durante o exercício em alguns pacientes com IC parece ser acompanhada por queda da força diafragmática que é totalmente compensada pelos músculos inspiratórios acessórios. O Grupo 1 apresentou dispneia similar em relação ao grupo 2, provavelmente, pelo fato de o exercício ter sido interrompido antes de os pacientes atingirem limiares ventilatórios críticos para expansão do volume corrente. / BACKGROUNG: It has been described that patients with chronic heart failure (CHF) may present with dynamic reduction in inspiratory capacity (IC), which was associated with low peak aerobic capacity. Little information is currently available about whether this reduction is related to respiratory mechanics abnormalities or to impaired inspiratory muscle function. OBJECTIVE: To compare inspiratory muscle activity and intensity of dyspnea during exercise in stable patients with CHF presenting (Group 1) or not (Group 2) with dynamic reduction in IC. METHODS: We studied 16 clinically stable, non obese patients with CHF (11 males, 30 ± 5% ejection fraction) treated according to current evidence-based guidelines with no other systemic diseases or spirometric evidence of airflow obstruction (FEV1/FVC = 83 ± 5%). They performed incremental cardiopulmonary cycle exercise test with serial measurements of IC, dyspnea rating (Borg), and continuous monitoring of esophageal (Pes) and gastric (Pga) pressures. Transdiaphragmatic pressure (Pdi) was obtained from Pga–Pes. Sniff and maximal inspiratory pressure (MIP) maneuvers were compared at rest and immediately post exercise. RESULTS: Four patients (25%, Group 1) showed IC reduction during exercise (-0.18 ± 0.02 vs 0.28 ± 0.19L; p<0.05). There were no significant between-groups differences in lung function and echocardiographic variables, except for a lower functional residual capacity (72 ± 9 vs 97 ± 17%; p < 0.05) in Group 1 and a lower MIP (-101 ± 25 vs 67 ± 24 cm H2O; p < 0.05) in Group 2. Pes,Sniff (Group 1: -77.9 ± 8.7 to -79.6 ± 8.8; Group 2: -63.3 ± 4.8 to -66.3 ± 3.8 cmH2O) and Pdi,Sniff (Group 1: 116.3 ± 13.9 to 118.3 ± 14.2; Group 2: 92.3 ± 5.6 to 98.0 ± 6.0 cmH2O) did not significantly decrease with exercise. Despite Pga and Pdi felt along successive IC maneuvers in Group 1, Pes did not differ between groups. Dyspnea was also similar between groups. Finally, inspiratory reserve volume was lower in Group 1 only at peak exercise (0.90 ± 0.08 vs 1.47 ± 0.21L; p <0.05). CONCLUSIONS: Decrements in exercise IC in some patients with CHF seems accompanied by a dynamic impairment in diaphragm strength that is fully compensated by other inspiratory rib cage muscles. Group 1 presented similar dyspnea compared to Group 2 probably because they stopped exercise before reaching critical ventilatory constraints to tidal volume expansion.

Orientador: Aparecido Antônio Camacho / Banca: Evandro Zacché Pereira / Banca: Maria Lucia Gomes Lourenço / Banca: Antonio Sergio Ferraudo / Banca: Aureo Evangelista Santana / Resumo: Cães com degeneração mixomatosa da válvula mitral (DMVM) estadiados na classe II-ISACHC da insuficiência cardíaca congestiva apresentam diversas alterações dentro do estágio clínico. Evidenciando-se um ou mais sinais clínicos, aumento de câmaras cardíacas, alterações no ritmo e frequência cardíaca, bem como variabilidade da frequência cardíaca, relacionando-se ao maior ou menor predomínio do sistema nervoso autonômico parassimpático. O objetivo deste estudo foi determinar a possível existência de subclasses dentro da classe II e conhecer as variáveis que diferenciariam estas subclasses. Foram utilizadas vinte e duas variáveis na análise multivariada de 15 cães pertencentes à classe II-ISACHC da ICC. Por meio da análise de agrupamento pelo método hierárquico e não hierárquico, foram determinadas três subclasses excludentes (subclasse S1, subclasse S2 e subclasse S3). Foi possível relacionar a subclasse S1 com as variáveis de variabilidade da frequência cardíaca (e.g. NNm, PNN>50%), a subclasse S3 com as variáveis de remodelamento cardíaco (e. g. AE/Ao, DIVEd/Ao, FE%) e a subclasse S2 com câmara ventricular direita (e.g. DIVDd/Ao). Posterior à análise exploratória de fatores foram determinados três fatores (PSNA, RCFS e VDST) que relacionam as variáveis inclusas em cada fator com as subclasses. O PSNA incluiu as variáveis de variabilidade da frequência cardíaca e frequência cardíaca, o RCFS incluiu as variáveis de remodelamento cardíaco e função sistólica e o VDST integra a câm... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The dogs with myxomatous mitral valve degeneration (MMVD) staged in class II-ISACHC of congestive heart failure (CHF) have several changes within the clinical stage. Evidencing one more clinical signs, increased heart chambers, changes in heart rate and rhythm, changes in heart rate variability relating to the greater or lesser prevalence of the parasympathetic autonomic nervous system. The objective of this study was to determine the possible existence of subclasses within class II and to know the variables that would differentiate these subclasses. Twenty-two variables were used in the multivariate analysis of 15 dogs, class II of CH. Using hierarchical and non-hierarchical clustering, three exclusive subclasses (S1, S2 and S3) were determined. It was possible to relate subclass S1 to heart rate variability variables (e.g. NNm, PNN>50%), subclass S3 with cardiac remodeling variables (e.g. LA/Ao, LVDd/Ao, EF%) and subclass S2 with right ventricular chamber (e.g. RVDd/Ao). After analysis of factors were determined three factors (PSNA, RCFS and VDST) that relate the variables with the subclasses. The PSNA included variables of heart rate and heart rate variability, the RCFS contained the variables of cardiac remodeling and systolic function and the VDST enclosed the right ventricular chamber. The analysis of variance of the factors compared by subclasses determined that subclass S1 has higher values of PSNA when compared to subclasses S2 and S3. The subclass S3 had higher val... (Complete abstract click electronic access below) / Doutor

L’objectif de mon travail de thèse était d’une part, de mieux comprendre le rôle des différentes familles de phosphodiestérases (PDEs) dans la régulation de la signalisation dépendante de l’AMPc (PDE-AMPc) dans les cellules musculaires lisses vasculaires (CMLVs), et d’autre part, d’évaluer leur implication fonctionnelle dans la réactivité vasculaire et leur altération potentielle dans un modèle physiopathologique, l’insuffisance cardiaque (IC). Mon travail s’est articulé autour de deux modèles de muscle lisse vasculaire : (1) des CMLVs isolées en culture ayant acquis un phénotype synthétique sur lesquelles une approche d’imagerie en temps réel (FRET : Transfert d’Energie de Fluorescence par Résonance) a été appliquée afin de visualiser in situ la dynamique spatiotemporelle des signaux dépendants de l’AMPc. Nos résultats indiquent que, dans ces cellules, l’augmentation des niveaux d’AMPc provoquée par la stimulation β-adrénergique (β-AR) implique différents récepteurs suivant le compartiment intracellulaire considéré (β1- et β2-ARs dans le cytosol et seulement β2-ARs dans le compartiment sous-membranaire). Nous avons par ailleurs observé que l’expression des ARNm des différentes isoformes de PDE-AMPc et la contribution fonctionnelle de ces enzymes dans la régulation des signaux AMPc intracellulaires étaient dépendantes de la densité des CMLVs en culture.(2) des anneaux d’artères intactes issues de deux lits vasculaires différents (aorte et artère mésentérique) isolées à partir de rats sains et IC, permettant d’étudier leur fonction contractile et donc la régulation de celle-ci par la voie de l’AMPc. Nous avons montré que les familles de PDE-AMPc contribuent de façon différente au contrôle du tonus vasculaire dans l’aorte thoracique (PDE3 = PDE4 sans participation de la PDE2) et dans l’artère mésentérique (PDE4 > PDE2 sans participation de la PDE3), l’endothélium exerçant un rôle essentiel dans la régulation de l’activité de ces PDEs musculaires lisses, notamment par le biais de la production de NO. Nous avons également mis en évidence des altérations de la réactivité vasculaire, et notamment de son contrôle par la voie de l’AMPc/PDE, dans notre modèle de rat IC. Dans l’aorte, la dysfonction endothéliale liée à l’altération de la voie du NO est à l’origine d’une augmentation de l’activité PDE3 masquant l’activité PDE4 et la relaxation β-adrénergique. Dans l’artère mésentérique des rats IC, dont la fonction endothéliale apparaît préservée, les PDE2, 3 et 4 restent fonctionnelles.L’ensemble de nos travaux souligne le rôle essentiel des PDEs dans la régulation de la signalisation AMPc vasculaire, et montre que l’activité et la fonction des différentes familles de PDE-AMPc sont finement modulées par de nombreux paramètres (phénotype et densité cellulaire des CMLVs) ou situations physio-pathologiques (nature du lit vasculaire, présence de l’endothélium, situation d’IC). / The aim of my thesis was to investigate the role of cyclic nucleotide phosphodiesterases (cAMP-PDEs) in the regulation of cAMP-dependent signaling in vascular smooth muscle cells (VSMCs), and to assess their functional involvement in vascular reactivity and their potential alteration in a pathophysiological model of heart failure (HF). My work was based on two models of vascular smooth muscle:(1) Isolated VSMCs in culture having acquired a synthetic phenotype, in which an approach of real-time imaging (FRET: Fluorescence Resonance Energy Transfer) was applied in situ to visualize the spatiotemporal dynamics of cAMP-dependent signals. Our results indicate that, in these cells, increased levels of cAMP induced by β-adrenergic stimulation (β-AR) involve different β-ARs subtypes according to the intracellular compartment considered (β1-and β2-ARs in the cytosol and only β2-ARs in the submembrane compartment). We also observed that the mRNA expression of cAMP-PDEs isoforms and the functional contribution of these enzymes in the regulation of intracellular cAMP signals were dependent on the VSMCs seeding density in culture.(2) Arterial blood vessels from two different vascular beds (aorta and mesenteric artery) isolated from healthy and HF rats, to study their contractile function and thus the regulation by the cAMP pathway. We showed that cAMP-PDE families contribute differently to the control of vascular tone in the thoracic aorta (PDE3 = PDE4, no PDE2) and mesenteric artery (PDE4 > PDE2, no PDE3), endothelium exerting a crucial role in the regulation of their functional activities, especially through the production of nitric oxide (NO). We also demonstrated alterations in vascular reactivity during HF, including its control through the cAMP-PDEs. In the aorta, endothelial dysfunction associated with the alteration of the NO pathway leads to an increase in PDE3 activity which masks PDE4 activity and β-AR relaxation. In mesenteric artery from HF rats, endothelial function is preserved and PDE2, 3 and 4 are functional.This study underlines the importance of PDEs in regulating vascular cAMP signaling, and shows that the activity and function of different cAMP-PDE families are tightly modulated by many parameters (VSMCs phenotype and seeding density) and/or physiopathological situations (vascular bed, endothelium and HF).