A cardiomiopatia dilatada idiopática (CMD) é a segunda cardiopatia mais prevalente na espécie canina, acometendo principalmente raças grandes e gigantes, bem como o Cocker Spaniel. É uma doença que possui alta letalidade, além de comprometer substancialmente a qualidade de vida do animal. O diagnóstico definitivo é realizado por meio da ecocardiografia, onde se observam dilatação das cavidades cardíacas, mais freqüentemente do ventrículo e átrio esquerdos, e diminuição da função sistólica. Estudos realizados em seres humanos com CMD mostram que, além da sistólica, a função diastólica está comprometida, e que a análise do fluxo transmitral, importante para a detecção de alterações de relaxamento e/ou distensibilidade tem importante valor prognóstico para a sobrevida e evolução dos sintomas. O tratamento da CMD tradicionalmente baseia-se na utilização de digitálicos, diuréticos, e vasodilatadores. Contudo, nos últimos anos, visto a importância da ativação do sistema nervoso simpático sobre a fisiopatologia desta doença, os β-bloqueadores têm sido empregados. Muitos trabalhos mostram que estes fármacos melhoram a função sistólica e/ou diastólica do ventrículo esquerdo, e com isso aumentam a sobrevida e diminuindo a progressão dos sintomas. Estudaram-se 45 cães com cardiomiopatia dilatada, que foram divididos em dois grupos (A e B). O grupo A (n=25) recebeu o tratamento convencional, ou seja, digitálicos, diuréticos e vasodilatadores, e o grupo B (n=20) recebeu estes mesmos medicamentos acrescidos do carvedilol, um β-bloqueador de terceira geração. Os animais foram submetidos aos exames clínico e ecocardiográfico antes e após três, 13, 26 e 52 semanas do início do tratamento ou até o óbito. Não foram observadas diferenças nos valores dos índices de função sistólica e diastólica entre os grupos. Verificou-se que o grupo tratado com carvedilol apresentou maior tempo médio de sobrevida, porém esta diferença não foi estatisticamente significante. Quanto aos sintomas (classe funcional), observou-se que o grupo tratado com carvedilol apresentou evolução mais favorável, com maior número de animais classificados como "sintomas leves" após três meses de tratamento. Assim, embora o carvedilol tenha se mostrado benéfico, principalmente com relação aos sintomas, não se pode correlacionar esta melhora à ação do fármaco sobre as funções sistólica e diastólica / Dilated Cardiomyopathy (DCM) is the second more common heart disease in dogs, wherein large and giant breeds, as well as Cockers Spaniels, are predisposed. Such disease has a high mortality rate besides reducing the quality of life of the affected animals. The definitive diagnosis is based upon echocardiography which is characterized by dilation of cardiac chambers, mainly the left ones, and by reduced systolic function. Human medicine studies have reported that the diastolic dysfunction also plays an important role; so, an abnormal transmitral flow pattern, which represents the ventricular diastolic filling, has a great prognostic value in terms of survival and symptoms status (heart failure functional class) The management of DCM traditionally consists of digitalis, diuretics and vasodilators, however, in the late years, some attention has being paid to the importance of the sympathetic nervous system on the pathophysiology of this disorder; being so, β-blockers have been included in the therapy. Many authors have reported that these drugs improve the left ventricle systolic and diastolic function, and so they increase the survival rate and reduce the symptoms progression. Forty-five dogs with idiopathic dilated cardiomyopathy, divided into two groups (A and B), were studied. The group A (n=25) consisted of dogs that were put on the traditional therapy (digitalis, diuretics and vasodilators) and the group B (n=20) included those who were treated with all these drugs plus carvedilol, a third generation β-blocker. The animals went through clinical and echocardiographic assesment before and 3, 13, 26 and 52 weeks after starting the treatment or until death. The variables of systolic and diastolic function were not statistically different between the two groups. The median survival time of the dogs treated with carvedilol was higher, but the difference was not statistically significant. Concerning to the symptoms (heart failure funcional class), dogs who were put on carvedilol had a better progression, as more of them were classified as "mild symptoms" after three months of therapy. In conclusion, despite the beneficial effects of carvedilol on the symptoms, these can not be correlate with the systolic and diastolic functions

A cardiomiopatia dilatada (CMD) é uma das cardiopatias mais frequentes em cães, sendo a redução da contratilidade miocárdica uma de suas principais características. Dentre as raças predispostas, destaca-se o Cocker Spaniel Inglês. O diagnóstico baseia-se nos achados da ecocardiografia convencional. Todavia, as recentes técnicas ecocardiográficas de Doppler tecidual, como a determinação das velocidades miocárdicas, o registro da deformação (Df) e da taxa de deformação (TDf) miocárdicas, podem identificar padrões característicos de disfunção, antes mesmo do surgimento de anormalidades na ecocardiografia convencional. Com o objetivo de investigar os padrões de disfunção miocárdica ventricular, por meio das técnicas retro-mencionadas, foram incluídos 32 cães da raça Cocker Spaniel Inglês, sendo 16 com diagnóstico de cardiomiopatia dilatada e 16 considerados hígidos, para fins de grupo controle. O estudo Doppler tecidual possibilitou a identificação de disfunção miocárdica ventricular sistólica e diastólica, em ambos os ventrículos dos cães com CMD. No ventrículo esquerdo encontrou-se disfunção miocárdica longitudinal e transversal, caracterizada por menor velocidade miocárdica sistólica, retardo eletromecânico, contrações pós-sistólicas longitudinais, redução na Df e TDf sistólicas, além de distúrbio no relaxamento miocárdico. Por sua vez, diminuição da Df miocárdica sistólica longitudinal e retardo no relaxamento miocárdico caracterizaram a disfunção ventricular direita. O presente estudo identificou, de maneira inédita, padrões de disfunção miocárdica, obtidos por meio de Doppler tecidual, em uma população de cães da raça Cocker Spaniel Inglês com CMD. / Dilated cardiomyopathy (DCM) is one of the most common heart diseases in dogs and its main feature is reduced contractility. English Cocker Spaniel is among predisposed breeds. Diagnosis is based on conventional echocardiographic findings. However, recent tissue Doppler echocardiographic techniques, such as myocardial velocities determination and recordings of myocardial strain (St) and strain rate (SR), can identify characteristic patterns of dysfunction, even before the onset of abnormalities in conventional echocardiography. In order to investigate the patterns of ventricular myocardial dysfunction by means of retro-mentioned techniques, 32 English Cocker Spaniels were studied, being 16 diagnosed with DCM and 16 considered healthy for control purpose. Tissue Doppler study allowed identification of systolic and diastolic ventricular myocardial dysfunction in both ventricles of dogs with DCM. Left ventricular findings included longitudinal and transversal myocardial dysfunction, characterized by lower systolic myocardial velocity, electromechanical delay, longitudinal post systolic contractions, reduced systolic St and SR, and myocardial relaxation disturbance. In turn, reduced longitudinal systolic myocardial St and delayed myocardial relaxation characterized right ventricular dysfunction. The present study identified, in an unprecedented way, patterns of dysfunction, obtained by tissue Doppler, in a dog population of English Cocker Spaniels with DCM.

Ziel der Studie war es, den Einfluss des Geschlechts auf die Klinik, die medikamentöse Therapie und den Gebrauch von Interventionen bei Patienten mit terminaler dilatativer Kardiomyopathie (DCM) nach Vorstellung zur Herztransplantation zu untersuchen. Es wurden 702 konsekutive DCM-Patienten (110 Frauen, 592 Männer) rekrutiert, die sich am Deutschen Herzzentrum Berlin zur Herztransplatation vorstellten und während eines Zeitraumes von im Mittel 4,3 Jahren beobachtet wurden. Die Diagnose DCM wurde durch Herzkatheter bestätigt. Etwa 300 Variablen zu Basisparametern, medikamentöser Therapie, Interventionen und Outcome wurden pro Patient analysiert. Der kombinierte Endpunkt wurde als das Auftreten eines von drei Ereignissen definiert: Tod auf der Warteliste, Herztransplantation oder Implantation eines Assist-Device. Die Ereignisanalyse wurde mittels multivariater Regression und Kaplan-Meier-Statistik durchgeführt. Bei Erstvorstellung zeigten Frauen und Männer keine Unterschiede in Alter, LVEF und LVEDD (% der Norm, für Alter und BSA korrigiert), aber bei Symptomatik, RVEF, linksatrialem Durchmesser, Vorhofflimmern und Beta1-Autoantikörpern. Frauen wurden signifikant früher transplantiert als Männer (112,3 +/- 117,5 vs. 340,7 +/- 332,1 Tage auf der Warteliste; p = 0,0001). Stärkste unabhängige Prädiktoren für Ereignisse bei beiden Geschlechtern waren korrigierter LVEDD und RVEF. Bei Frauen erhöhte Vorhofflimmern das Ereignisrisiko 3fach (2,905; CI: 1,406 - 6,001), wohingegen das Outcome bei Männern durch Vorhofflimmern nicht beinflusst wurde. Alter bei Erstvorstellung, Belastungsdyspnoe und Immunadsorption waren zusätzliche Prädiktoren bei Männern. Zusammenfassung: Geschlechterunterschiede bei klinischen Basisparametern können Behandlung und Outcome von DCM-Patienten beeinflussen. Vorhofflimmern ist bei männlichen Patienten nicht mit einem schlechteren Outcome assoziiert, bewirkt jedoch eine 3fache Erhöhung des Ereignisrisikos bei weiblichen Patienten. / The goal of this study was to determine the influence of gender on clinical parameters, on medical treatment and use of interventions in patients with end-stage dilated cardiomyopathy (DCM) presenting for heart transplantation. We enrolled 702 consecutive patients (592 men and 110 women) with DCM who presented at the German Heart Institute Berlin for heart transplantation and were followed for an average time of 4.3 years. Diagnosis of DCM was confirmed by cardiac catheterization. About 300 variables of baseline characteristics, medical treatment, interventions, and outcome per patient were analysed. The combined end point was defined as the occurrence of one of three events: death on the waiting list, heart transplantation or cardiac assist device implantation and was analyzed by multivariate regression and Kaplan- Meier-statistics. At presentation women and men did not differ in age, LVEF and LVEDD (% of normal, corrected for age and BSA) but in symptoms, RVEF, left atrial size, atrial fibrillation, and beta-adreno-receptor auto-antibodies. Women were transplanted significantly earlier than men (mean 112.3+/-117.5 vs 340.7+/- 332.1 days on the waiting list; p value 0.0001). Strongest independent predictors for events in both sexes were corrected LVEDD and RVEF. In women, AF increased the risk for events 3fold (2,905; CI: 1.406 – 6.001) whereas in men AF did not predict outcome. Age at first presentation, dyspnoea, and immunoadsorption were additional predictors in men. In patients with DCM, gender differences in baseline characteristics may influence management and outcome. Atrial fibrillation is not associated with a poorer outcome in men but threefold increases the risk in women.

Os efeitos da utilização da terapia de ressincronização cardíaca (TRC) em pacientes com cardiopatia chagásica (CCC) são pouco conhecidos. O objetivo desse trabalho foi comparar o efeito dessa terapia em pacientes com CCC e não-chagásica. Foram estudados, retrospectivamente, todos os pacientes submetidos à ressincronização cardíaca, associados ou não ao cardioversor-desfibrilador implantável (CDI) no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo no período de julho de 2007 a dezembro de 2017. Para comparar a mesma variável em dois momentos diferentes foi utilizado Teste de Wilcoxon. Para a comparação de proporções foi utilizado o teste exato de Fisher. A análise de sobrevida foi feita utilizando-se o método de Kaplan-Meier com o \"Long rank test\" para comparar a sobrevida entre os grupos. Para a análise das variáveis associadas à mortalidade pós-implante utilizou-se a análise de regressão de Cox. Noventa e oito pacientes foram incluídos e divididos em três grupos de cardiopatia: chagásica (CCC) com 42 pacientes (42,9%); isquêmicos (ISQ) com 13 (13,3%) e nãoisquêmico não-chagásico (NINC) com 43 (43,9%). Os pacientes que receberam implante de TRC foram 71,4% e TRC associado ao CDI foram 28,5%. Não havia diferença estatisticamente significativa entre os grupos na avaliação das características clínicas, exceto pela predominância de pacientes do gênero masculino no grupo ISQ. Em relação aos bloqueios de condução intraventriculares, havia menor quantidade de bloqueio de ramo esquerdo (BRE) espontâneo e maior quantidade de BRE induzido no grupo CCC. As demais características eletrocardiográficas e ecocardiográficas eram semelhantes entre os grupos. A sobrevida de pacientes que recebem a TRC foi baixa após 48 meses de implante, independentemente do tipo de miocardiopatia e a despeito da melhora significativa da classe funcional e estreitamento do QRS dos pacientes. Todavia, a sobrevida em pacientes chagásicos foi significativamente menor quando comparada as demais miocardiopatias. Ademais, a melhora da fração de ejeção do ventrículo esquerdo (FEVE) e a redução do diâmetro diastólico final do ventrículo esquerdo (DDFVE) ocorreram significativamente apenas no grupo NINC. O aumento da idade, FEVEreduzida, presença de atraso da condução intraventricular não especificada (ACINE) e de bloqueio de ramo direito (BRD) e baixa classe funcional estão associadas a maior risco de morte após implante. As taxas de complicações cirúrgicas foram baixas em todos os grupos. A taxa de óbito cirúrgico é compatível com a gravidade desses pacientes. Conclui-se que a CCC apresenta resposta clínica à TRC, mas a mortalidade após 48 meses é maior que em outras cardiopatias. / The effects of using cardiac resynchronization therapy (CRT) in patients with Chagas\' heart disease (CCC) are poorly understood. The objective of this study was to compare the effect of this therapy in patients with CCC and non-Chagas\' disease. We retrospectively studied all patients submitted to cardiac resynchronization associated or not with the implantable cardioverter defibrillator (ICD) at the Clinical Hospital of Ribeirão Preto Medical School at the São Paulo University from July 2007 to December 2017. We use Wilcoxon\'s test to compare the same variable in two different times. Fisher\'s exact test was used to compare proportions. Survival analysis was done using the Kaplan-Meier method with the Long rank test to compare survival between groups. Cox regression analysis was used to analyze the variables associated with post-implantation mortality. Ninety-eight patients were included and divided into three groups: cardiopathy: chagasic (CCC) with 42 patients (42.9%); ischemic (ISQ) with 13 patients (13.3%) and non-ischemic non-chagasic (NINC) with 43 (43.9%). The patients who received CRT implantation were 71.4% and CRI associated CRT were 28.5%. There was no statistically significant difference between the groups in the assessment of clinical characteristics, except for the predominance of male patients in the ISQ group. In relation to intraventricular conduction blockades, there was a lower amount of spontaneous left bundle branch block (LBBB) and greater amount of LBBB induced in the CCC group. The other electrocardiographic and echocardiographic characteristics were similar between groups. The survival of patients receiving CRT was low after 48 months of implantation, regardless of the type of cardiomyopathy and despite significant improvement in functional class and QRS narrowing of patients. However, survival in chagasic patients was significantly lower when compared to other cardiomyopathies. In addition, the improvement of left ventricular ejection fraction (LVEF) and the reduction of the left ventricular end-diastolic dimension (LVEDF) occurred significantly only in the NINC group. Increased age, reduced LVEF, presence of unspecified intraventricular conduction delay and left bundle branch block, and low functional class are associated with a higher risk of death after implantation. Therates of surgical complications were low in all groups. The surgical death rate is compatible with the severity of these patients. It is concluded that CCC presents a clinical response to CRT, but mortality after 48 months is higher than in the other cardiopathies.

A cardiomiopatia dilatada idiopática (CMD) é a segunda cardiopatia mais prevalente na espécie canina, acometendo principalmente raças grandes e gigantes, bem como o Cocker Spaniel. É uma doença que possui alta letalidade, além de comprometer substancialmente a qualidade de vida do animal. O diagnóstico definitivo é realizado por meio da ecocardiografia, onde se observam dilatação das cavidades cardíacas, mais freqüentemente do ventrículo e átrio esquerdos, e diminuição da função sistólica. Estudos realizados em seres humanos com CMD mostram que, além da sistólica, a função diastólica está comprometida, e que a análise do fluxo transmitral, importante para a detecção de alterações de relaxamento e/ou distensibilidade tem importante valor prognóstico para a sobrevida e evolução dos sintomas. O tratamento da CMD tradicionalmente baseia-se na utilização de digitálicos, diuréticos, e vasodilatadores. Contudo, nos últimos anos, visto a importância da ativação do sistema nervoso simpático sobre a fisiopatologia desta doença, os β-bloqueadores têm sido empregados. Muitos trabalhos mostram que estes fármacos melhoram a função sistólica e/ou diastólica do ventrículo esquerdo, e com isso aumentam a sobrevida e diminuindo a progressão dos sintomas. Estudaram-se 45 cães com cardiomiopatia dilatada, que foram divididos em dois grupos (A e B). O grupo A (n=25) recebeu o tratamento convencional, ou seja, digitálicos, diuréticos e vasodilatadores, e o grupo B (n=20) recebeu estes mesmos medicamentos acrescidos do carvedilol, um β-bloqueador de terceira geração. Os animais foram submetidos aos exames clínico e ecocardiográfico antes e após três, 13, 26 e 52 semanas do início do tratamento ou até o óbito. Não foram observadas diferenças nos valores dos índices de função sistólica e diastólica entre os grupos. Verificou-se que o grupo tratado com carvedilol apresentou maior tempo médio de sobrevida, porém esta diferença não foi estatisticamente significante. Quanto aos sintomas (classe funcional), observou-se que o grupo tratado com carvedilol apresentou evolução mais favorável, com maior número de animais classificados como "sintomas leves" após três meses de tratamento. Assim, embora o carvedilol tenha se mostrado benéfico, principalmente com relação aos sintomas, não se pode correlacionar esta melhora à ação do fármaco sobre as funções sistólica e diastólica / Dilated Cardiomyopathy (DCM) is the second more common heart disease in dogs, wherein large and giant breeds, as well as Cockers Spaniels, are predisposed. Such disease has a high mortality rate besides reducing the quality of life of the affected animals. The definitive diagnosis is based upon echocardiography which is characterized by dilation of cardiac chambers, mainly the left ones, and by reduced systolic function. Human medicine studies have reported that the diastolic dysfunction also plays an important role; so, an abnormal transmitral flow pattern, which represents the ventricular diastolic filling, has a great prognostic value in terms of survival and symptoms status (heart failure functional class) The management of DCM traditionally consists of digitalis, diuretics and vasodilators, however, in the late years, some attention has being paid to the importance of the sympathetic nervous system on the pathophysiology of this disorder; being so, β-blockers have been included in the therapy. Many authors have reported that these drugs improve the left ventricle systolic and diastolic function, and so they increase the survival rate and reduce the symptoms progression. Forty-five dogs with idiopathic dilated cardiomyopathy, divided into two groups (A and B), were studied. The group A (n=25) consisted of dogs that were put on the traditional therapy (digitalis, diuretics and vasodilators) and the group B (n=20) included those who were treated with all these drugs plus carvedilol, a third generation β-blocker. The animals went through clinical and echocardiographic assesment before and 3, 13, 26 and 52 weeks after starting the treatment or until death. The variables of systolic and diastolic function were not statistically different between the two groups. The median survival time of the dogs treated with carvedilol was higher, but the difference was not statistically significant. Concerning to the symptoms (heart failure funcional class), dogs who were put on carvedilol had a better progression, as more of them were classified as "mild symptoms" after three months of therapy. In conclusion, despite the beneficial effects of carvedilol on the symptoms, these can not be correlate with the systolic and diastolic functions

A cardiomiopatia dilatada (CMD) é uma das cardiopatias mais frequentes em cães, sendo a redução da contratilidade miocárdica uma de suas principais características. Dentre as raças predispostas, destaca-se o Cocker Spaniel Inglês. O diagnóstico baseia-se nos achados da ecocardiografia convencional. Todavia, as recentes técnicas ecocardiográficas de Doppler tecidual, como a determinação das velocidades miocárdicas, o registro da deformação (Df) e da taxa de deformação (TDf) miocárdicas, podem identificar padrões característicos de disfunção, antes mesmo do surgimento de anormalidades na ecocardiografia convencional. Com o objetivo de investigar os padrões de disfunção miocárdica ventricular, por meio das técnicas retro-mencionadas, foram incluídos 32 cães da raça Cocker Spaniel Inglês, sendo 16 com diagnóstico de cardiomiopatia dilatada e 16 considerados hígidos, para fins de grupo controle. O estudo Doppler tecidual possibilitou a identificação de disfunção miocárdica ventricular sistólica e diastólica, em ambos os ventrículos dos cães com CMD. No ventrículo esquerdo encontrou-se disfunção miocárdica longitudinal e transversal, caracterizada por menor velocidade miocárdica sistólica, retardo eletromecânico, contrações pós-sistólicas longitudinais, redução na Df e TDf sistólicas, além de distúrbio no relaxamento miocárdico. Por sua vez, diminuição da Df miocárdica sistólica longitudinal e retardo no relaxamento miocárdico caracterizaram a disfunção ventricular direita. O presente estudo identificou, de maneira inédita, padrões de disfunção miocárdica, obtidos por meio de Doppler tecidual, em uma população de cães da raça Cocker Spaniel Inglês com CMD. / Dilated cardiomyopathy (DCM) is one of the most common heart diseases in dogs and its main feature is reduced contractility. English Cocker Spaniel is among predisposed breeds. Diagnosis is based on conventional echocardiographic findings. However, recent tissue Doppler echocardiographic techniques, such as myocardial velocities determination and recordings of myocardial strain (St) and strain rate (SR), can identify characteristic patterns of dysfunction, even before the onset of abnormalities in conventional echocardiography. In order to investigate the patterns of ventricular myocardial dysfunction by means of retro-mentioned techniques, 32 English Cocker Spaniels were studied, being 16 diagnosed with DCM and 16 considered healthy for control purpose. Tissue Doppler study allowed identification of systolic and diastolic ventricular myocardial dysfunction in both ventricles of dogs with DCM. Left ventricular findings included longitudinal and transversal myocardial dysfunction, characterized by lower systolic myocardial velocity, electromechanical delay, longitudinal post systolic contractions, reduced systolic St and SR, and myocardial relaxation disturbance. In turn, reduced longitudinal systolic myocardial St and delayed myocardial relaxation characterized right ventricular dysfunction. The present study identified, in an unprecedented way, patterns of dysfunction, obtained by tissue Doppler, in a dog population of English Cocker Spaniels with DCM.

No description available.

The main function of the heart is to pump blood throughout the cardiovascular system by generating pressure differences created through volume changes. Although the main purpose of the heart and vessels is to lead the flowing blood throughout the body, clinical assessments of cardiac function are usually based on morphology, approximating the flow features by viewing the motion of the myocardium and vessels. Measurement of three-directional, three-dimensional and time-resolved velocity (4D Flow) data is feasible using magnetic resonance (MR). The focus of this thesis is the development and application of methods that facilitate the analysis of larger groups of data in order to increase our understanding of intracardiac flow patterns and take the 4D flow technique closer to the clinical setting. In the first studies underlying this thesis, a pathline based method for analysis of intra ventricular blood flow patterns has been implemented and applied. A pathline is integrated from the velocity data and shows the path an imaginary massless particle would take through the data volume. This method separates the end-diastolic volume (EDV) into four functional components, based on the position for each individual pathline at end-diastole (ED) and end-systole (ES). This approach enables tracking of the full EDV over one cardiac cycle and facilitates calculation of parameters such as e.g. volumes and kinetic energy (KE). Besides blood flow, pressure plays an important role in the cardiac dynamics. In order to study this parameter in the left ventricle, the relative pressure field was computed using the pressure Poisson equation. A comprehensive presentation of the pressure data was obtained dividing the LV blood pool into 17 pie-shaped segments based on a modification of the standard seventeen segment model. Further insight into intracardiac blood flow dynamics was obtained by studying the turbulent kinetic energy (TKE) in the LV. The methods were applied to data from a group of healthy subjects and patients with dilated cardiomyopathy (DCM). DCM is a pathological state where the cardiac function is impaired and the left ventricle or both ventricles are dilated. The validation study of the flow analysis method showed that a reliable user friendly tool for intra ventricular blood flow analysis was obtained. The application of this tool also showed that roughly one third of the blood that enters the LV, directly leaves the LV again in the same heart beat. The distribution of the four LV EDV components was altered in the DCM group as compared to the healthy group; the component that enters and leaves the LV during one cardiac cycle (Direct Flow) was significantly larger in the healthy subjects. Furthermore, when the kinetic energy was normalized by the volume for each component, at time of ED, the Direct Flow had the highest values in the healthy subjects. In the DCM group, however, the Retained Inflow and Delayed Ejection Flow had higher values. The relative pressure field showed to be highly heterogeneous, in the healthy heart. During diastole the predominate pressure differences in the LV occur along the long axis from base to apex. The distribution and variability of 3D pressure fields differ between early and late diastolic filling phases, but common to both phases is a relatively lower pressure in the outflow segment. In the normal LV, TKE values are low. The highest TKE values can be seen during early diastole and are regionally distributed near the basal LV regions. In contrast, in a heterogeneous group of DCM patients, total diastolic and late diastolic TKE values are higher than in normals, and increase with the LV volume. In conclusion, in this thesis, methods for analysis of multidirectional intra cardiac velocity data have been obtained. These methods allow assessment of data quality, intra cardiac blood flow patterns, relative pressure fields, and TKE. Using these methods, new insights have been obtained in intra cardiac blood flow dynamics in health and disease. The work underlying this thesis facilitates assessment of data from a larger population of healthy subjects and patients, thus bringing the 4D Flow MRI technique closer to the clinical setting.

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies.

Apesar dos avanços no entendimento da fisiopatologia e dos recursos terapêuticos atualmente disponíveis, a cardiomiopatia dilatada (CMD) permanece como uma condição com alta mortalidade, sendo que a disfunção microvascular é um dos mecanismos relacionados à piora da função cardíaca. Nos últimos anos, novas técnicas de ecocardiografia vêm sendo utilizadas para avaliação da disfunção microvascular, incluindo a medida de velocidade de fluxo coronário pelo Doppler da artéria coronária descendente anterior (ADA), e a análise quantitativa do fluxo miocárdico pela ecocardiografia com perfusão miocárdica em tempo-real (EPMTR). No presente estudo, avaliamos o valor prognóstico da reserva de velocidade de fluxo coronário (RVFC), obtida pelo Doppler da ADA, e da reserva de fluxo miocárdico (RFM), obtida pela EPMTR, para predizer morte e transplante cardíaco em pacientes com CMD de origem não isquêmica. Adicionalmente, avaliamos se as medidas de reserva de fluxo acrescentam valor prognóstico sobre variáveis clínicas e ecocardiográficas que já são conhecidas como preditores de eventos nesta população. Estudamos 195 pacientes com CMD (130 homens, média etária 54 ± 12 anos) que apresentavam fração de ejeção do ventrículo esquerdo inferior a 35% pelo ecocardiograma e ausência de sinais de doença arterial coronária obstrutiva por angiografia coronária invasiva ou por método não invasivo (cintilografia de perfusão miocárdica ou angiotomografia de coronárias). Foram analisados parâmetros ecocardiográficos convencionais de função sistólica e diastólica do ventrículo esquerdo em repouso. A velocidade de fluxo coronário foi determinada pelo Doppler pulsado na ADA e a dinâmica das microbolhas no miocárdio foi quantificada pela EPMTR utilizando programas computacionais específicos, tanto em repouso como durante o estresse pelo dipiridamol (0,84 mg/Kg). As RVFC, RFM e reserva de velocidade de repreenchimento de microbolhas no miocárdio (reserva ) foram obtidas pela relação entre os parâmetros de fluxo durante a hiperemia e em repouso, sendo consideradas diminuídas quando os valores estavam abaixo de 2,0. O tempo médio de acompanhamento foi de 29 meses (variando de 6 a 69 meses). Neste período, 45 pacientes (24%) apresentaram eventos, sendo 43 mortes de causa cardíaca e 2 transplantes cardíacos. Na análise univariada foram preditores de eventos: etiologia chagásica, classe funcional de insuficiência cardíaca, uso de inibidores da enzima conversora de angiotensina e/ou bloqueadores dos receptores de angiotensina II (fator protetor), diâmetros ventriculares e do átrio esquerdo, volumes ventriculares, fração de ejeção, disfunção diastólica, grau de insuficiência mitral, RVFC, RFM e reserva . Na análise multivariada, foram preditores independentes de eventos o diâmetro do átrio esquerdo (razão de chances = 1,16 por unidade de aumento; intervalo de confiança 95% = 1,078 1,264; p<0,001) e a reserva diminuída (razão de chances = 3,219; intervalo de confiança 95% = 1,178 8,795; p<0,001). No modelo sequencial de predição de eventos, fração de ejeção e diâmetro do átrio esquerdo adicionaram valor prognóstico às variáveis clínicas (aumento do qui-quadrado de 15,2 para 58,5; p < 0,001). A reserva adicionou poder ao modelo (qui-quadrado de 70,2; p<0,001). Concluímos que tanto a RVFC, obtida pelo Doppler da ADA, como a RFM e reserva , obtidas pela EPMTR sob estresse pelo dipiridamol, são preditoras de morte e transplante cardíaco em pacientes com CMD não isquêmica. Entretanto, somente o diâmetro do átrio esquerdo e a reserva mostraram valor prognóstico independente e incremental sobre variáveis clínicas e ecocardiográficas que já são conhecidas como preditores de eventos nesta população / Despite advances in understanding of the pathophysiology and therapeutic approaches, dilated cardiomyopathy (DCM) remains as a condition with high mortality and one of the mechanisms involved in this process seems to be microvascular dysfunction. Recently, new echocardiographic techniques have been incorporated in the clinical practice and used for the assessment of microvascular dysfunction, including evaluation of left anterior descending coronary artery (LAD) by Doppler and quantitative analysis of myocardial flow by real-time myocardial perfusion echocardiography (RTMPE). In the present study, we evaluated the prognostic value of coronary flow velocity reserve (CFVR), obtained by transthoracic echocardiography, and parameters of myocardial flow reserve (MFR), obtained by RTMPE for predicting cardiac death and heart transplantation in patients with nonischemic DCM. In addition, we sought to detect the incremental value of flow reserve over clinical and echocardiographic parameters already known as predictors of events in this population. We studied 195 patients with DCM (130 men, mean age 54 ± 12 years) who had left ventricular ejection fraction (LVEF) less than 35% by echocardiography and no signs of obstructive coronary artery disease by invasive coronary angiography or noninvasive methods (nuclear medicine or angiography by computed tomography). We assessed conventional echocardiographic parameters of systolic and diastolic left ventricular function at rest. Coronary flow velocity was determined by pulsed Doppler in LAD and dynamics of microbubbles in the myocardium was measured by RTMPE using specific computer programs, both at rest and during dipyridamole stress (0.84 mg/kg). CFVR, MFR and the reserve of velocity of microbubbles in the myocardium ( reserve) were obtained as the ratio between parameters of flow during hyperemia and at rest, being considered abnormal when these were below 2.0. The mean follow-up was 29 months (ranging from 6 to 69 months). During this period, 45 patients (24%) had events, 43 cardiac deaths and 2 heart transplantations. In the univariate analysis, predictors of events were: Chagas disease, New York Heart Association functional class, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker (protective effect), left ventricular and atrial diameters, left ventricular volumes, LVEF, diastolic dysfunction, degree of mitral regurgitation, CVFR, MFR and reserve. By multivariate analysis, the only independent predictors of events were the left atrial diameter (OR = 1.16, 95% confidence interval = 1.078 to 1.264, p <0.001) and reserve 2.0 (OR = 3.219, confidence interval 95 % = 1.178 to 8.795, p <0.001). In the sequential model of events prediction, LVEF and left atrial diameter added prognostic value over clinical factors (chi-square from 15.2 to 58.5; p<0.001). reserve added power to the model (chi-square = 70.2, p<0.001). We concluded that CVFR, obtained by Doppler in LAD, MFR and reserve, obtained by dipyridamole stress RTMPE, are predictors of cardiac death and heart transplantation in patients with nonischemic DCM. However, only left atrial diameter and depressed reserve showed independent and incremental predictive value beyond that provided by current known prognostic clinical and echocardiographic factors