La fonction du ventricule droit est un déterminant majeur de la capacité fonctionnelle et du pronostic dans l’hypertension pulmonaire. La survenue dans ce contexte d’une insuffisance cardiaque droite requérant un support inotrope est associée à un taux de mortalité supérieur à 40%. Les déterminants cellulaires et moléculaires du découplage entre le coeur droit et la circulation artérielle pulmonaire sont méconnus, d’autant qu’il existe une grande hétérogénéité fonctionnelle parmi les patients soumis au même niveau de résistances vasculaires pulmonaires.Dans une première étude expérimentale, nous avons mis évidence à partir d’un modèle porcin d’hypertension pulmonaire chronique que les indices fonctionnels systoliques du ventricule droit mesurés en échocardiographie sont davantage corrélés au couplage ventriculo-artériel qu’à la performance contractile propre du ventricule droit. La réponse du ventricule droit à l’exercice ou à un stress pharmacologique a été peu documentée jusqu’à présent dans l’hypertension pulmonaire. Apartir de notre modèle porcin, nous avons montré que l’altération de la réserve contractile du ventricule droit est fortement associée au découplage ventriculo-artériel. La réserve contractile pourrait être un marqueur sensible et précoce de dysfonction ventriculaire droite. Dans une troisième étude, nous montrons la relation forte entre le couplage ventriculo-artériel et la plasticitéhémodynamique, fonctionnelle et moléculaire du ventricule droit dans un contexte de surcharge de pression chronique. Les variations d’expression de l’isoforme β de la chaîne légère de la myosine cardiaque pourraient déterminer l’efficacité du travail cardiaque droit. Nous avons par ailleurs constaté expérimentalement chez le rat que le remodelage géométrique et fonctionnel du ventricule droit en condition de surcharge barométrique chronique est associé à une infiltration macrophagique dumuscle cardiaque droit.Nos résultats physiopathologiques pourraient permettre une meilleure stratification des patients souffrant d’hypertension pulmonaire chronique. Ces mécanismes pourraient par ailleurs constituer autant de cibles thérapeutiques pour optimiser la fonction cardiaque droite lorsque la postcharge du ventricule droit n’est pas complètement corrigée, d’autant que les thérapies vaso-actives pulmonaires usuelles auraient des effets directs controversés sur le remodelage du ventricule droit. / Right ventricular function is a major determinant of functional capacity and prognosis in pulmonary hypertension. Right heart failure related to pulmonary hypertension is associated with a mortality rate up to 40% when inotrope support is necessary. Cellular and molecular determinants of right ventricular-pulmonary arterial coupling are misunderstood, while a wide functional range is remarkable among patients sharing the same degree of pulmonary vascular resistance.In a first experimental study, we showed from a porcine model of chronic pulmonary hypertension that usual non-invasive indices of right ventricular function are rather associated with ventricular-arterial coupling than with contractility. Right ventricular response to exercise or to pharmacological stress has been poorly reported in pulmonary hypertension. In our piglet model, we showed that impairment of right ventricular contractile reserve is strongly associated with ventricular-arterial uncoupling. Rightventricular reserve might be a sensitive marker of early ventricular dysfunction. In a third study, we highlighted that a strong relationship between ventricular-arterial coupling and functional and molecular plasticity of the pressure overloaded right ventricle. Gene expression of the beta-myosin heavy chain may be related to right heart efficiency. We also oberved experimentally in rats that structural and functional remodeling of the pressure overloaded right ventricle is associated withmacrophagic infiltration in the myocardium.Our pathophysiologic results could improve patient’s stratification in chronic pulmonary hypertension.These mechanisms may represent innovative targeted therapies to improve right ventricular function despite persistent elevated afterload.

L’hypertension pulmonaire (HP) est définie par une élévation de la pression artérielle pulmonaire moyenne (PAPm) au-delà de 25 mm de mercure (Hg) au repos en raison de l’augmentation progressive et soutenue des résistances vasculaires pulmonaires, menant à l'insuffisance cardiaque droite. La dysfonction endothéliale pulmonaire associée à l'HTAP est maintenant considérée comme un mécanisme pathogénique clé qui pourrait être préjudiciable à la fois pour la susceptibilité et le développement du remodelage vasculaire pulmonaire. Au niveau des cellules endothéliales (CE), la fixation du facteur inhibiteur de la migration des macrophages (MIF), un des plus anciens médiateurs immunologiques connus, sur le CD74 va initier une cascade de signalisation intracellulaire clef pour la prolifération, la survie cellulaire et la production de différents facteurs inflammatoires. C’est pourquoi, ces travaux de doctorat ont visés à : 1) Etudier l’importance de la voie MIF/CD74 dans l'acquisition/maintien d’un phénotype pro-inflammatoire des CE pulmonaires dans l'HTAP ; 2) Tester l’efficacité de nouveaux antagonistes de MIF, synthétisés et brevetés par la société MIFCARE, contre ce phénotype endothélial et le développement d’HP expérimentales.Nos données mettent en lumière le rôle critique de la voie MIF/CD74 pour le phénotype aberrant des CE pulmonaires HTAP et soulignent son importance comme nouvelle cible thérapeutique prometteuse pour lutter contre le remodelage vasculaire pulmonaire. Cette meilleure compréhension du rôle de la voie MIF/CD74 dans le phénotype endothélial aberrant, nous a permis l’identification d’une nouvelle molécule à forte affinité, administrable par voie orale, capable de ralentir la progression d’HP expérimentales (brevet européen en soumission). Cependant, des études plus poussées, en cours de réalisation, sont encore nécessaires avant de pouvoir transférer ces connaissances vers une utilisation clinique de ces nouveaux candidats « médicaments ». / Pulmonary arterial hypertension (PAH) is a severe progressive cardiopulmonary disorder characterized by vascular proliferation and remodeling of the small pulmonary arteries. These can lead to a progressive increase in pulmonary vascular resistance and ultimately to right ventricular failure and death. Pulmonary endothelial dysfunction and pro-inflammatory phenotype associated with PAH are now considered as a key pathogenic mechanism that could be detrimental to both the susceptibility and development of the pulmonary vascular remodeling.In pulmonary endothelial cells (EC), the binding of the immune mediator MIF (Macrophage Migration Inhibitory Factor), to its receptor CD74 initiates an intracellular signaling cascade leading to cell proliferation, cell survival and the secretion of various inflammatory mediators. Therefore, the present work seeks to: (1) Determine the importance of the MIF/CD74 signaling pathway in the acquisition of an abnormal pro-inflammatory EC phenotype in PAH; (2) Test the efficacies of MIF inhibitors, synthesized and patented by MIFCARE, on this abnormal pro-inflammatory EC phenotype and on the development of experimental pulmonary hypertension (PH).Our data highlight the critical role of the MIF/CD74 axis in the endothelial dysfunction and pro-inflammatory phenotype of pulmonary EC in PAH. In addition, our data emphasize its importance as a promising new therapeutic target to prevent the pulmonary vascular remodeling associated to this disorder. Furthermore, we were successful in identifying an agent from a novel class of MIF antagonists optimized for in vivo use that have the ability to partially reverse established PH in rats and to partially inhibit the pro-inflammatory EC phenotype observed in PAH.Collectively, we demonstrated the importance of the MIF/CD74 axis and that its inhibition with MIF antagonist agents could represent a promising strategy for the treatment of PAH (under patent). However, further studies are still needed before transferring this knowledge to clinical use of these new candidates.

Introdução: A hipertensão arterial pulmonar (HAP) é uma doença grave da circulação pulmonar, cujo diagnóstico e cuja avaliação funcional dependem do cateterismo cardíaco direito. A tomografia de dupla energia (TCDE), por meio da técnica de decomposição de materiais, permite obter um mapa de Iodo do parênquima pulmonar, que pode ser avaliado de forma qualitativa e quantitativa, e pode ser útil na avaliação da HAP. Objetivos: Avaliar a distribuição de Iodo no parênquima pulmonar, comparando com marcadores hemodinâmicos, marcadores de gravidade e com grupo-controle normopressórico. Métodos: Pacientes com HAP, acompanhados na Unidade de Circulação Pulmonar (InCor-HCFMUSP), foram avaliados por angiotomografia das artérias pulmonares (angioTC) como parte de sua rotina diagnóstica, em modo de dupla energia. O grupo-controle foi composto por pacientes com suspeita clínica de tromboembolismo pulmonar (TEP), com angioTC negativa para TEP e com ecocardiograma normal. Foram avaliadas as concentrações de Iodo no pulmão (mg/mL) por meio de 8 regiões de interesse redondas com 1 cm2 de área, distribuídas ao longo do eixo ântero-posterior do pulmão direito, em 3 níveis predeterminados. Foram obtidas, também, as medidas do ventrículo direito (VD), ventrículo esquerdo (VE), razão VD/VE, diâmetros da aorta (AO) e artéria pulmonar (AP). O realce da artéria pulmonar por meio da TCDE (PAenh) também foi obtido. Os resultados foram comparados entre os grupos, e correlacionados no grupo HAP com parâmetros hemodinâmicos invasivos e marcadores de gravidade. Resultados: O grupo HAP foi composto por 21 pacientes, com idade média de 42 anos, 47,6% em classe funcional I/II. Houve diferença significativa nos diâmetros da AP (p<0,01), VD (p<0,01), e VE (p=0,01), entre os grupos HAP e controle. Também demonstraram diferenças significativas às relações entre os diâmetros AP/AO (p < 0,01) e VD/VE (p < 0,01), entre os grupos. Calibre da artéria pulmonar maior do que 2,9 cm e relação AP/AO maior do que 1,1 cm demonstraram sensibilidade de 90,5% e 87,5%, e especificidade de 100% para o diagnóstico de HP. A PAenh não demonstrou diferenças significativas entre os grupos HAP e controle, contudo se correlacionou significativamente com a medida do débito cardíaco no grupo HAP (r=-0,661, p=0,01). A PAPm demonstrou correlação com a relação AP/AO (r=0,676) e, também, com a relação VD/VE (r=0,679), ambas com p < 0,01. A concentração de Iodo no parênquima foi significativamente menor no grupo HAP em todos os segmentos analisados. O mapa de Iodo demonstrou gradiente progressivo da concentração de Iodo no parênquima pulmonar, de caráter ântero-posterior, em ambos os grupos, de magnitude significativamente menor no grupo HAP. Usando-se o valor de PAenh para correção das medidas de concentração de Iodo, deixa de haver diferença entre os grupos HAP e controle. Conclusões: A TCDE, além das medidas anatômicas obtidas pela técnica convencional, permitiu demonstrar a manutenção do gradiente ântero-posterior da concentração de Iodo em pacientes com HAP, sugerindo que sua menor magnitude seja determinada pelo baixo débito cardíaco / Background: Pulmonary arterial hypertension (PAH) is a severe disease of the pulmonary circulation. Right heart catheterization (RHC) is crucial for diagnosis and management of these patients. High-resolution computed tomography (CT) and CT angiography play a crucial role in the diagnostic work-up of pulmonary hypertension. Dual energy computed tomography (DECT) is a technique of acquisition of modern CT scanners that allows obtaining a computed tomography of the pulmonary arteries with low iodine dose, and providing an estimation of iodine distribution in the lungs. Although the search for non-invasive methods for evaluation of PAH is developing, data concerning application of DECT on PAH patients remain scarce. Objectives: To evaluate the iodine distribution in the lungs obtained by DECT in PAH patients and a control group and compare to the hemodynamic profile, and prognostic markers of PAH patients. Methods: 21 patients followed at the Pulmonary Circulation Unit (InCor-HCFMUSP) and submitted to CT angiography were evaluated by DECT. A matched control group was composed by patients routinely referred to CT angiography to rule out pulmonary embolism with negative results and also a normal echocardiogram obtained at the same day. Eight circular 1cm2 ROIs were placed along the anteroposterior axis, at the middle of the right lung and at predetermined levels to measure the Iodine concentration in the lungs. Measurements of the pulmonary artery (PA), ascending aorta (AO), right ventricle (RV) and left ventricles (LV) were obtained, as well as enhancement of the PA (PAenh). Results were compared to the control group, and correlated with hemodynamic parameters in the PAH group. Results: PAH patients averaged 42 y/o, female/male ratio of 7/1, NYA functional classes I/II. Statistically significant differences between PAH patients and controls were found regarding measurements of PA (p < 0,01), RV (p < 0,01), LV (p=0,01), PA/AO (p < 0,01) and RV/LV (p < 0,01). PA diameter greater than 2,9 cm and PA/AO ratio greater 1,1 were diagnostic for pulmonary hypertension with sensitivity/specifity of 90,5%/100% and 87,5%/100%. PAenh showed no statistical difference between PAH patients and controls . A characteristic anteroposterior Iodine concentration gradient was found in all subjects, both PAH patients showed lower Iodine concentration diffusely (p < 0,01). When corrected by PAenh, Iodine gradients showed no statistical difference between PAH patients and controls. PAenh correlates with cardiac output (r=-0,661), and mPaP correlates with PA/AO ratio (r=0,676), RV/LV ratio VD/VE ratio (r=0,679), and p<0,01. Conclusion: Anteroposterior Iodine concentration gradient is preserved in PAH in comparison with controls, but with lower magnitude. This difference was corrected through the multiplication of individual Iodine measurements by PAenh, suggesting that this could be explained by lower blood flow to the lungs of PAH patients. PAenh correlates with cardiac output, mean pulmonary arterial pressure correlates with PA/AO and RV/LV in PAH patients. DECT provided conventional anatomic measurements and allowed the characterization of preserved anteroposterior Iodine gradients in PAH patients, with decreased magnitude in comparison with controls, that could be atributed to a lower CO of these patients

INTRODUÇÃO: A hipertensão pulmonar (HP) é comorbidade frequente em pacientes com insuficiência cardíaca (IC) e está associada ao pior prognóstico no pós-transplante cardíaco (TC). O teste de reatividade pulmonar realizado no préoperatório de TC avalia a reversibilidade da HP aos vasodilatadores, uma vez que a HP reversível tem melhor prognóstico. O nitroprussiato de sódio (NPS) é o vasodilatador mais utilizado, porém é associado a elevados índices de hipotensão arterial sistêmica, disfunção ventricular do enxerto transplantado e elevadas taxas de desqualificação para o TC. O sildenafil (SIL) é um inibidor seletivo da fosfodiesterase tipo 5 e utilizado no tratamento da HP idiopática, sem promover efeitos sistêmicos negativos. Neste estudo, objetivou-se avaliar os efeitos hemodinâmicos agudos do SIL e NPS sobre a HP de candidatos ao TC e seus efeitos sobre o remodelamento cardíaco reverso, definido como redução dos diâmetros ventriculares e melhora da função cardíaca, por meio da análise ecocardiográfica, hemodinâmica e bioquímica. MÉTODOS: Os pacientes foram submetidos, simultaneamente, ao cateterismo cardíaco direito para medida das pressões pulmonares, ao ecocardiograma, à dosagem sanguínea de BNP e à gasometria venosa, prosseguindo no estudo caso preenchessem os critérios de inclusão previamente estabelecidos. Os pacientes selecionados foram randomizados a receber NPS (1 - 2 ?g/Kg/min) ou SIL (100mg, dose única, via oral) e, após o período de tempo predeterminado, procedeu-se à nova avaliação hemodinâmica, ecocardiográfica e bioquímica. RESULTADOS: NPS e SIL reduziram significativamente a pressão sistólica da artéria pulmonar (NPS: 64,7 vs. 57mmHg, p = 0,002; SIL: 61,07 vs. 50mmHg, p < 0,001), porém o grupo que recebeu NPS apresentou redução acentuada da média da pressão arterial sistêmica (85,2 vs. 69,8mmHg, p < 0,001). Do ponto de vista ecocardiográfico, ambas as medicações promoveram redução da área ventricular direita (NPS: 29,2 vs. 25,7mm, p = 0,003; SIL: 29,4 vs. 23,8mm, p < 0,001) e elevação da fração de ejeção ventricular esquerda (NPS: 23,5 vs. 24,8 %, p = 0,02; SIL: 23,8 vs. 26 %, p < 0,001). Por outro lado, o grupo que recebeu SIL, ao contrário do NPS, apresentou melhora no índice de saturação venosa de oxigênio, medido pela gasometria venosa (SIL: 49,2 vs. 58,9%, p < 0,001). Os vasodilatadores não interferiram de forma significativa nos níveis séricos de BNP. CONCLUSÃO: Sildenafil e nitroprussiato de sódio reduziram significativamente a hipertensão pulmonar de pacientes com IC avançada. Ambos estiveram associados ao remodelamento cardíaco reverso, com diminuição da área ventricular direita e melhora da função cardíaca, medidos por parâmetros hemodinâmicos, ecocardiográficos e bioquímicos. O NPS, ao contrário do SIL, esteve associado à significativa hipotensão arterial sistêmica e piora do índice de saturação venosa de oxigênio. / INTRODUCTION: Pulmonary hypertension (PH) is a common comorbidity in heart failure (HF) patients and is associated with poor post heart transplant (HT) prognosis. The pulmonary reactivity test performed pre-operatively to the HT evaluates the reversibility of the PH to the vasodilators, since a reversible PH has a better prognosis. Sodium nitroprusside (SNP) is the most widely used vasodilator, but is associated with higher rates of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and higher rejection rates of the HT. Sildenafil (SIL) is a selective phosphodiesterase type 5 inhibitor and is used in the treatment of idiopathic PH, without producing negative systemic effects. This study aimed to evaluate the acute hemodynamic effects of SIL and SNP on the PH of HT candidates and their effects on reverse cardiac remodeling, defined as a reduction in ventricular diameter and improvement of cardiac function, through echocardiographic, hemodynamic and biochemical analysis. METHODS: The patients simultaneously underwent: right cardiac catheterization, to measure the pulmonary pressure, echocardiogram and blood dosage of BNP and venous gas analysis, continuing in the study if the previously established inclusion criteria were met. The selected patients were randomly given SNP (1 - 2 ?g/Kg/min) or SIL (100mg, single dose, orally) and after a predetermined period of time went for a new hemodynamic, echocardiographic and biochemical evaluation. RESULTS: SNP and SIL significantly reduced the systolic pulmonary artery pressure (SNP: 64.7 vs. 57mmHg, p = 0.002; SIL 61.07 vs. 50mmHg, p = 0.001). However the group which received SNP showed a marked reduction in mean systemic blood pressure (85.2 vs. 69.8mmHg, p < 0.001). From the point of view of the echocardiography, both the medications produced a reduction in right ventricular size (SNP: 29.2 vs. 25.7mm, p = 0.003; SIL 29.4 vs. 23.8mm, p < 0.001) and an increase of the left ventricular ejection fraction (NPS: 23.5 vs. 24.8 %, p = 0.02; SIL: 23.8 vs. 26 %, p < 0.001). On the other hand, the group which received SIL, unlike the SNP, showed improvements in the rate of oxygen venous saturation, measured by venous gas analysis (SIL: 49.2 vs. 58.9%, p < 0.001). Neither group significantly affected the serum levels of BNP. CONCLUSION: Sildenafil and sodium nitroprusside significantly reduced pulmonary hypertension in patients with advanced HF. Both were associated with reverse cardiac remodeling, with a reduction in right ventricular area and improvement of the cardiac function, measured by hemodynamic, echocardiographic and biochemical parameters. SNP, unlike SIL, was associated to significant systemic arterial hypotension and worsening of the rate of venous oxygen saturation.

Introdução: A hipertensão arterial pulmonar (HAP) é uma doença grave da circulação pulmonar, cujo diagnóstico e cuja avaliação funcional dependem do cateterismo cardíaco direito. A tomografia de dupla energia (TCDE), por meio da técnica de decomposição de materiais, permite obter um mapa de Iodo do parênquima pulmonar, que pode ser avaliado de forma qualitativa e quantitativa, e pode ser útil na avaliação da HAP. Objetivos: Avaliar a distribuição de Iodo no parênquima pulmonar, comparando com marcadores hemodinâmicos, marcadores de gravidade e com grupo-controle normopressórico. Métodos: Pacientes com HAP, acompanhados na Unidade de Circulação Pulmonar (InCor-HCFMUSP), foram avaliados por angiotomografia das artérias pulmonares (angioTC) como parte de sua rotina diagnóstica, em modo de dupla energia. O grupo-controle foi composto por pacientes com suspeita clínica de tromboembolismo pulmonar (TEP), com angioTC negativa para TEP e com ecocardiograma normal. Foram avaliadas as concentrações de Iodo no pulmão (mg/mL) por meio de 8 regiões de interesse redondas com 1 cm2 de área, distribuídas ao longo do eixo ântero-posterior do pulmão direito, em 3 níveis predeterminados. Foram obtidas, também, as medidas do ventrículo direito (VD), ventrículo esquerdo (VE), razão VD/VE, diâmetros da aorta (AO) e artéria pulmonar (AP). O realce da artéria pulmonar por meio da TCDE (PAenh) também foi obtido. Os resultados foram comparados entre os grupos, e correlacionados no grupo HAP com parâmetros hemodinâmicos invasivos e marcadores de gravidade. Resultados: O grupo HAP foi composto por 21 pacientes, com idade média de 42 anos, 47,6% em classe funcional I/II. Houve diferença significativa nos diâmetros da AP (p<0,01), VD (p<0,01), e VE (p=0,01), entre os grupos HAP e controle. Também demonstraram diferenças significativas às relações entre os diâmetros AP/AO (p < 0,01) e VD/VE (p < 0,01), entre os grupos. Calibre da artéria pulmonar maior do que 2,9 cm e relação AP/AO maior do que 1,1 cm demonstraram sensibilidade de 90,5% e 87,5%, e especificidade de 100% para o diagnóstico de HP. A PAenh não demonstrou diferenças significativas entre os grupos HAP e controle, contudo se correlacionou significativamente com a medida do débito cardíaco no grupo HAP (r=-0,661, p=0,01). A PAPm demonstrou correlação com a relação AP/AO (r=0,676) e, também, com a relação VD/VE (r=0,679), ambas com p < 0,01. A concentração de Iodo no parênquima foi significativamente menor no grupo HAP em todos os segmentos analisados. O mapa de Iodo demonstrou gradiente progressivo da concentração de Iodo no parênquima pulmonar, de caráter ântero-posterior, em ambos os grupos, de magnitude significativamente menor no grupo HAP. Usando-se o valor de PAenh para correção das medidas de concentração de Iodo, deixa de haver diferença entre os grupos HAP e controle. Conclusões: A TCDE, além das medidas anatômicas obtidas pela técnica convencional, permitiu demonstrar a manutenção do gradiente ântero-posterior da concentração de Iodo em pacientes com HAP, sugerindo que sua menor magnitude seja determinada pelo baixo débito cardíaco / Background: Pulmonary arterial hypertension (PAH) is a severe disease of the pulmonary circulation. Right heart catheterization (RHC) is crucial for diagnosis and management of these patients. High-resolution computed tomography (CT) and CT angiography play a crucial role in the diagnostic work-up of pulmonary hypertension. Dual energy computed tomography (DECT) is a technique of acquisition of modern CT scanners that allows obtaining a computed tomography of the pulmonary arteries with low iodine dose, and providing an estimation of iodine distribution in the lungs. Although the search for non-invasive methods for evaluation of PAH is developing, data concerning application of DECT on PAH patients remain scarce. Objectives: To evaluate the iodine distribution in the lungs obtained by DECT in PAH patients and a control group and compare to the hemodynamic profile, and prognostic markers of PAH patients. Methods: 21 patients followed at the Pulmonary Circulation Unit (InCor-HCFMUSP) and submitted to CT angiography were evaluated by DECT. A matched control group was composed by patients routinely referred to CT angiography to rule out pulmonary embolism with negative results and also a normal echocardiogram obtained at the same day. Eight circular 1cm2 ROIs were placed along the anteroposterior axis, at the middle of the right lung and at predetermined levels to measure the Iodine concentration in the lungs. Measurements of the pulmonary artery (PA), ascending aorta (AO), right ventricle (RV) and left ventricles (LV) were obtained, as well as enhancement of the PA (PAenh). Results were compared to the control group, and correlated with hemodynamic parameters in the PAH group. Results: PAH patients averaged 42 y/o, female/male ratio of 7/1, NYA functional classes I/II. Statistically significant differences between PAH patients and controls were found regarding measurements of PA (p < 0,01), RV (p < 0,01), LV (p=0,01), PA/AO (p < 0,01) and RV/LV (p < 0,01). PA diameter greater than 2,9 cm and PA/AO ratio greater 1,1 were diagnostic for pulmonary hypertension with sensitivity/specifity of 90,5%/100% and 87,5%/100%. PAenh showed no statistical difference between PAH patients and controls . A characteristic anteroposterior Iodine concentration gradient was found in all subjects, both PAH patients showed lower Iodine concentration diffusely (p < 0,01). When corrected by PAenh, Iodine gradients showed no statistical difference between PAH patients and controls. PAenh correlates with cardiac output (r=-0,661), and mPaP correlates with PA/AO ratio (r=0,676), RV/LV ratio VD/VE ratio (r=0,679), and p<0,01. Conclusion: Anteroposterior Iodine concentration gradient is preserved in PAH in comparison with controls, but with lower magnitude. This difference was corrected through the multiplication of individual Iodine measurements by PAenh, suggesting that this could be explained by lower blood flow to the lungs of PAH patients. PAenh correlates with cardiac output, mean pulmonary arterial pressure correlates with PA/AO and RV/LV in PAH patients. DECT provided conventional anatomic measurements and allowed the characterization of preserved anteroposterior Iodine gradients in PAH patients, with decreased magnitude in comparison with controls, that could be atributed to a lower CO of these patients

INTRODUÇÃO: Após a embolia pulmonar cerca de 1 a 3% dos pacientes desenvolvem embolismo crônico seguido de elevação da pressão da artéria pulmonar e aumento da resistência vascular pulmonar (RVP) e o aumento contínuo da pressão vascular leva ao remodelamento das pequenas artérias. Considerando estes dados, o objetivo deste estudo foi avaliar o aumento da reatividade da artéria pulmonar após a inalação de óxido nítrico, após à tromboendarterectomia (PTE) em comparação ao pré-operatório. MÉTODOS: Foram inclusos neste estudo vinte pacientes com idade entre 18 e 68 anos, submetidos à tromboendarterectomia no período de janeiro de 2005 a julho de 2008. Todos os pacientes no período pré-operatório foram submetidos a cateterização cardíaca direita, com medida da pressão pulmonar, entre as duas pressões, potência cardíaca e resistência vascular pulmonar. Estes mesmos pacientes foram submetidos à inalação de óxido nítrico (NO) por dez minutos e nova medida de todas as variáveis foi realizada. Três meses após a tromboendarterectomia, treze pacientes passaram por novos exames, antes e após a inalação de NO. Foi avaliada a reatividade pela comparação estatística dos parâmetros hemodinâmicos, antes e após a inalação do NO. Nós também consideramos o teste positivo de acordo com o critério clássico (redução 20% na PAPm e PVR após inalação de NO) e redefinimos o critério (PAPm diminuindo para 40 mmHg ou menos após inalação com NO, com um redução maior que 10 mmHg). RESULTADOS: A análise estatística usada para análise dos dados paramétricos foi o teste student t e para dados não paramétricos utilizou-se o Wilcoxcon Signed Ranks. Significância estatística 5%. Considerando somente os pacientes que completaram os testes hemodinâmicos (n=13), de acordo com o critério clássico seis indivíduos apresentaram resposta positiva ao NO inalado antes PTE, enquanto nove pacientes tiveram resposta positiva após PTE. A diferença entre pré-PTE e pós-PTE não foi estatísticamente significante (p=0,375). Assim, os critérios foram redefinidos. Dois pacientes tiveram resposta positiva na pré-PTE e outros quatro foram positivos na pós-PTE. Nenhuma diferença estatística foi observada entre pré-PTE e pós-PTE respondedores (p=0,688). CONCLUSÕES: Neste estudo, não foi observado aumento da reatividade ao NO inalado em comparação aos testes pré-operatórios / INTRODUCTION: After pulmonary embolism, 1 to 3% of these patients develop a chronic embolism, with elevated pulmonary artery pressure and increased pulmonary vascular resistance (PVR). The continuous elevated pressure leads to the remodeling of the small arteries. The objective of this study is to determinate if there is an increase in the responsiveness to the inhaled nitric oxide, in the post-thromboendaterectomy test, in comparison to the preoperative test. METHODS: The study includes twenty patients, age 18 to 68, submitted to thromboendarterctomy, between January 2005 and December 2007. All patients, in the preoperative period, were submitted to right cardiac catheterization, with the measurement of the pulmonary pressures, wedge pressure, cardiac output and PVR. Afterwards, they inhaled 20 ppm of nitric oxide (NO) for ten minutes, with a new measurement of all variables. Three months after thromboendarterectomy, thirteen patients underwent a new measurement, before and after nitric oxide inhalation. We analyzed the reactivity of the pulmonary artery, considering the statistical changes in the hemodinamical parameters. We also considered a positive test according to classical criterion (reduction 20% in PAPm and PVR after NO inhalation) and redefined criterion (PAPm falling to 40 mmHg or less, after inhaled NO, with a drop higher than 10 mmHg). RESULTS:The statistical analyze used the Student-t test for parametrical data and the Wilcoxon Signed Ranks for non parametrical data. Statistical significance 5%.Regardling only the patients who complete both hemodynamic tests (n = 13), according to the classical criterion, six subjects had positive response to inhaled NO before PTE while nine patients had positive response after PTE. The difference between pre-PTE and post-PTE was not statistical significant: p = 0,375. Concernig the redefined criterion, two subjects had positive response in pre-PTE test and four subjects had positive response in post-PTE test, with no statistically significant difference between pre-PTE and post-PTE responders (p = 0,688). CONCLUSIONS: In this study, we could not find, in the postoperative test, a greater reactivity to inhaled NO, in comparison to the preoperative test

A hipertensão arterial pulmonar (HAP) é uma doença que acomete o território vascular pulmonar, gerando incapacidade funcional e falência cardíaca progressiva. Diversos marcadores de resposta têm sido desenvolvidos para a avaliação dos pacientes com HAP frente às novas modalidades terapêuticas desenvolvidas nos últimos anos, entre os quais o teste de caminhada de seis minutos é o mais utilizado. Embora seja simples, possui algumas limitações inerentes à técnica padrão, como por exemplo a necessidade de espaço físico adequado para sua realização. O objetivo deste trabalho foi elaborar e validar um protocolo de caminhada na esteira para a avaliação de pacientes com HAP. Os resultados mostraram correlação da distância caminhada em esteira com os dados hemodinâmicos, assim como com a classificação funcional e com a distância caminhada no solo. Além disso, a distância percorrida no teste em esteira apresentou correlação significativa com a sobrevida, confirmando portanto, sua correlação com a gravidade da doença. A inalação de óxido nítrico(NO) durante o teste de caminhada levou a variações compatíveis com as variações hemodinâmicas frente à mesma dose de NO, sugerindo que o protocolo em questão possa refletir intervenções terapêuticas. Conclui-se que o protocolo de caminhada na esteira é um marcador funcional e prognóstico para pacientes com HAP, constituindo-se em um instrumento útil na avaliação de rotina de pacientes com HAP. / Pulmonary arterial hypertension (PAH) is a disease affecting the pulmonary arterial territory leading to progressive functional impairment and heart failure. Many different surrogate markers have been studied to evaluate PAH patients under the different treatment strategies that have been developed during the last decade. Among these markers, the six-minute walk test is the most used one. Although simple, many limitations exist mainly related to the need of appropriate physical area to perform the test properly. The aim of this study was to develop and validate a treadmill six-minute walk test for PAH patients evaluation. The developed protocol well correlated with other markers of disease severity as invasive hemodynamic data, functional class and even the distance walk at the hallway six minute walk test. Furthermore, the treadmill walked distance was associated to survival thus strengthening its ability to reflect disease severity. Nitric oxide (NO) inhalation during the treadmill walk test led to a variation in the walked distance proportional to the hemodynamic changes induced by the same dose of inhaled NO, suggesting that the developed protocol may be able to reflect at least acute therapeutical interventions. We conclude that the treadmill six minute walk test is a useful prognostic and functional marker for the routine evaluation of PAH patients.

A condição de hipertensão pulmonar é definida como a presença de pressão arterial pulmonar média acima de 25 mmHg em repouso. Esta é a resultante hemodinâmica de vários processos nosológicos que acometem a circulação nos pulmões, notadamente os pequenos vasos pré e intraacinares. A microcirculação pulmonar pode se alterar na presença de enfermidades cardíacas, pulmonares, tromboembólicas, infecto-parasitárias e do tecido conectivo, entre outras. Na ausência dessas condições, o diagnóstico de hipertensão arterial pulmonar idiopática se impõe. Com respeito especificamente à doença cardíaca levando a alterações vasculares pulmonares, temos as situações que acarretam aumento de fluxo sangüíneo pulmonar (cardiopatias congênitas que cursam com defeitos de septação das câmaras ou dos grandes vasos) ou dificuldade de drenagem venosa (disfunção sistólica ou diastólica do ventrículo esquerdo, valvopatia mitral e doenças do átrio esquerdo ou veias pulmonares). As alterações vasculares pulmonares que ocorrem nessas circunstâncias podem dificultar ou impedir o reparo cirúrgico de um defeito congênito de septação cardíaca, ou o encaminhamento de pacientes com doença miocárdica para o transplante. Por essas razões, a avaliação de pacientes com defeitos septais cardíacos ou miocardiopatia deve ser criteriosa. Na maioria das vezes a avaliação não invasiva é suficiente para o planejamento terapêutico. Entretanto, em pacientes com cardiopatia congênita e suspeita clínica de hipertensão pulmonar, assim como naqueles portadores de miocardiopatia candidatos ao transplante, a medida direta da resistência vascular pulmonar, através de procedimento invasivo, se faz necessária. Nas últimas décadas, tem havido interesse progressivo de se ampliar a indicação da avaliação não invasiva, omitindo-se a invasiva, sobretudo com o uso de parâmetros avaliados pela ecocardiografia com Doppler e pela ressonância magnética. O uso dessas medidas, na prática clínica, ainda é restrito, mas tende a ampliar-se. O presente estudo foi idealizado no sentido de se verificar, em portadores de defeitos septais cardíacos ou de miocardiopatia na faixa etária pediátrica, se dados ecocardiográficos poderiam ser preditivos de determinadas condições hemodinâmicas, a ponto de isentar certos pacientes da avaliação invasiva pré-operatória. Esta verificação foi feita nos dois grupos de indivíduos (cardiopatias congênitas ou miocardiopatia), com o exame ecocardiográfico realizado simultaneamente ao cateterismo cardíaco. Foram estudados 30 pacientes com defeitos septais cardíacos (idade entre 0,41 a 58,2 anos) e 23 pacientes com miocardiopatia candidatos a transplante (idade entre 0,40 a 15 anos). Para avaliação comparativa entre o ecocardiograma e o cateterismo foram utilizadas várias medidas. Do ponto de vista ecocardiográfico procurou-se analisar variáveis derivadas do fluxo pulmonar ao Doppler: tempo de aceleração (TAc), tempo de ejeção (TEj), período pré-ejetivo (PPE), integral velocidade-tempo do fluxo sistólico da via de saída do ventrículo direito (VTIVSVD) e índices envolvendo essas variáveis). Além disso, avaliou-se a integral velocidade-tempo do componente sistólico e diastólico da veia pulmonar superior direita (VTIVP) e a razão entre o fluxo pulmonar e o sistêmico (Qp/Qs). Do ponto de vista do cateterismo foram obtidas medidas de pressões, razão entre fluxos pulmonar e sistêmico (Qp/Qs) e razão entre a resistência vascular pulmonar e sistêmica (RVP/RVS). No grupo de indivíduos com cardiopatias congênitas, fundamentalmente foram observadas associações: entre a razão PPE/TEj e a pressão arterial pulmonar diastólica, assim como o índice RVP/RVS; entre a razão PPE/VTIVSVD e RVP/RVS; entre as razões Qp/Qs pelos dois métodos; entre a variável VTIVSVD e a razão das resistências; entre a variável VTIVP e a razão das resistências. No grupo de indivíduos com miocardiopatia foram observadas associações: entre a razão PPE/VTIVSVD e a pressão arterial pulmonar sistólica; entre a razão PPE/TEj e a pressão arterial pulmonar diastólica; entre a variável TAc e a pressão arterial pulmonar média e razão das resistências. Apesar de ter sido possível o desenvolvimento de modelos preditivos para dados hemodinâmicos a partir destas variáveis ecocardiográficas, a dispersão dos valores foi considerável, não permitindo recomendar a adoção dos modelos para a predição pontual na prática clínica. No entanto, os dados mostraram ser possível, a partir da avaliação não invasiva, estimar, com especificidade adequada, valores de Qp/Qs, ao cateterismo, acima de 3,0. Isto foi possível a partir, de valores de Qp/Qs igual ou superiores a 2,89 no exame ecocardiográfico. Alem disso, as variáveis VTIVSVD (igual ou superior a 22 cm) e VTIVP (igual ou superior a 20 cm), para o grupo de pacientes com cardiopatia congênita, mostraram-se capazes de predizer a ocorrência de RVP/RVS 0,1 (cateterismo), com especificidade superior a 0,80. No grupo dos pacientes com miocardiopatia, a variável TAc (igual ou superior a 95 ms) mostrou-se capaz de predizer a ocorrência de RVP/RVS 0,1 (cateterismo) com especificidade também acima de 0,80. Assim sendo, nesses pacientes, o ecocardiograma pôde ser útil na identificação de um subgrupo de indivíduos em situação mais favorável com respeito à hemodinâmica pulmonar, para os quais o cateterismo cardíaco poderia ser considerado desnecessário. Futuros estudos serão importantes para se avaliar os resultados tardios (notadamente pós-operatório) nos pacientes avaliados de forma não invasiva, reforçando, a adequação desse tipo de avaliação. / Pulmonary hypertension is defined as a mean pulmonary arterial pressure of > 25 mmHg registered at rest, during cardiac catheterization. A number of conditions have been demonstrated to cause pulmonary hypertension, including congenital (septal defects) and acquired heart diseases, chronic lung disease, connective-tissue disease, thromboembolic disorders, schistosomosiasis, HIV infection, use of anorexigens, etc. In the absence of all these conditions, a diagnosis of idiopathic pulmonary arterial hypertension is established. In the specific setting of the cardiac disorders, either increased pulmonary blood flow (congenital cardiac septal defects) or altered pulmonary venous drainage ( left ventricular systolic or diastolic dysfunction, mitral valve disease, abnormalities of the left atrium) can cause pulmonary vascular abnormalities leading to pulmonary hypertension. Moderate to severe pulmonary vascular abnormalities lead to increased risk of postoperative complications and/or poor long-term outcomes in patients with septal defects undergoing surgical repair or those with cardiomyopathy undergoing heart transplantation. Thus, for these patients, preoperative measurement of pulmonary vascular resistance by cardiac catheterization is mandatory. In general, those with a pulmonary vascular resistance index of > 6 Wood units·m2 (pulmonary to systemic vascular resistance ratio of > 0,3) are not assigned to operation. In the last decades, there has been growing interest on the development of noninvasive methods/parameters that could allow for decision about the therapeutic strategies without cardiac catheterization. In this way, several parameters derived from Doppler-echocardiographic analysis or magnetic resonance has been used to predict hemodynamic data. In the present study, we used echocardiographic parameters to determine which patients with congenital cardiac septal defects or cardiomyopathy could theoretically be assigned to surgical treatments without catheterization. In order to correlate echocardiographic information with data derived from cardiac catheterization, both procedures were carried out simultaneously. Catheterization was performed as part of the routine evaluation, not specifically for research purposes. Thirty consecutive patients with congenital septal defects (aged 0,41 to 58,2 years) and 23 consecutive patients with cardiomyopathy (aged 0,40 to 15 years) were enrolled Doppler-echocardiographic evaluation consisted of flow analysis at the right and left ventricular outflow tract and pulmonary vein. The following parameters were recorded: right ventricular ejection time (RVET), acceleration time (AcT); right ventricular pre-ejection period (RVPEP); velocity time integral of the right ventricular systolic flow (VTIRVOT); velocity time integral of pulmonary venous flow (VTIPV); indexes involving these variables (AcT/RVET, RVPEP/RVET, RVPEP/VTIRVOT); pulmonary to systemic blood flow ratio (Qp/Qs). The parameters derived from cardiac catheterization included pulmonary and systemic pressures, blood flow and vascular resistance. Blood flow and vascular resistance were expressed as ratios Qp/Qs and PVR/SVR, respectively pulmonary to systemic blood flow and vascular resistance ratios). In patients with congenital septal defects, a Qp/Qs of 2,89 by Doppler-echocardiographic analysis was predictive of Qp/Qs > 3,0 by cardiac catheterization, with specificity > 0.78. For values of 4.0 (echocardiography), the specificity was > 0.91. A VTIRVOT of 22 cm or VTIPV 20 cm could predict PVR/SVR ratios 0.1 with specificity > 0.81. For values of 27 cm and 24 cm respectively, the specificity was > 0.93. In patients with cardiomyopathy, a AcT of 95 msec was predictive of PVR/SVR 0.1 with specificity > 0.85. Doppler-echocardiographic parameters could not predict absolute values of hemodynamic variables with acceptable accuracy. Based on these results we conclude that Doppler-echocardiographic analysis can be used to identify patients with low levels of pulmonary vascular resistance (those with septal defects or cardiomyopathy) and increased pulmonary blood flow (septal defects).These patients could be safely assigned surgical treatments with no need for invasive evaluation. In view of the relatively low levels of sensitivity that we observed (< 0.65), some patients with favourable pulmonary hemodynamics would still be assigned to catheterization in case of adoption of the cut-off levels used in the study. Prediction of absolute values of hemodynamic parameters was not considered sufficiently accurate for decision making. Further studies are obviously necessary to evaluate long-term outcomes in patients treated on the basis of noninvasive evaluation only.

Background:  The right ventricle (RV) is multi-compartmental in orientation with a complex structural geometry. However, assessment of this part of the heart has remained an elusive clinical challenge. As a matter of fact, its importance has been underestimated in the past, especially its role as a determinant of cardiac symptoms, exercise capacity in chronic heart failure and survival in patients with valvular disease of the left heart. Evidence also exists that pulmonary hypertension (PH) affects primarily the right ventricular function. On the other hand, previous literature suggested that severe aortic stenosis (AS) affects left ventricular (LV) structure and function which partially recover after aortic valve replacement (AVR). However, the impact of that on RV global and segmental function remains undetermined.  Objectives: We sought to gain more insight into the RV physiology using 3D technology, Speckle tracking as well as already applicable echocardiographic measures. Our first aim was to assess the normal differential function of the RV inflow tract (IT), apical and outflow tract (OT) compartments, also their interrelations and the response to pulmonary hypertension. We also investigated the extent of RV dysfunction in severe AS and its response to AVR. Lastly, we studied the extent of global and regional right ventricular dysfunction in patients with pulmonary hypertension of different aetiologies and normal LV function. Methods: The studies were performed on three different groups; (1) left sided heart failure with (Group 1) and without (Group 2) secondary pulmonary hypertension, (2) severe aortic stenosis and six months post AVR and (3) pulmonary hypertension of different aetiologies and normal left ventricular function. We used 3D, speckle tracking echocardiography and conventionally available Doppler echocardiographic transthoracic techniques including M-mode, 2D and myocardial tissue Doppler. All patients’ measurements were compared with healthy subjects (controls). Statistics were performed using a commercially available SPSS software. Results: 1-  Our RV 3D tripartite model was validated with 2D measures and eventually showed strong correlations between RV inflow diameter (2D) and end diastolic volume (3D) (r=0.69, p&lt;0.001) and between tricuspid annular systolic excursion (TAPSE) and RV ejection fraction (3D) (r=0.71, p&lt;0.001). In patients (group 1 &amp; 2) we found that the apical ejection fraction (EF) was less than the inflow and outflow (controls:  p&lt;0.01 &amp; p&lt;0.01, Group 1:  p&lt;0.05 &amp; p&lt;0.01 and Group 2: p&lt;0.05 &amp; p&lt;0.01, respectively). Ejection fraction (EF) was reduced in both patient groups (p&lt;0.05 for all compartments). Whilst in controls, the inflow compartment reached the minimum volume 20 ms before the outflow and apex, in Group 2 it was virtually simultaneous. Both patient groups showed prolonged isovolumic contraction (IVC) and relaxation (IVR) times (p&lt;0.05 for all). Also, in controls, the outflow tract was the only compartment where the rate of volume fall correlated with the time to peak RV ejection (r = 0.62, p = 0.03). In Group 1, this relationship was lost and became with the inflow compartment (r = 0.61, p = 0.01). In Group 2, the highest correlation was with the apex (r=0.60, p&lt;0.05), but not with the outflow tract. 2- In patients with severe aortic stenosis, time to peak RV ejection correlated with the basal cavity segment (r = 0.72, p&lt;0.001) but not with the RVOT. The same pattern of disturbance remained after 6 months of AVR (r = 0.71, p&lt;0.001). In contrast to the pre-operative and post-operative patients, time to RV peak ejection correlated with the time to peak outflow tract strain rate (r = 0.7, p&lt;0.001), but not with basal cavity function. Finally in patients, RVOT strain rate (SR) did not change after AVR but basal cavity SR fell  (p=0.04). 3- In patients with pulmonary hypertension of different aetiologies and normal LV function, RV inflow and outflow tracts were dilated (p&lt;0.001 for both). Furthermore, TAPSE (p&lt;0.001), inflow velocities (p&lt;0.001), basal and mid-cavity strain rate (SR) and longitudinal displacement (p&lt;0.001 for all) were all reduced. The time to peak systolic SR at basal, mid-cavity (p&lt;0.001 for both) and RVOT (p=0.007) was short as was that to peak displacement (p&lt;0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r=0.7, p&lt;0.001) in controls, but with that of the mid cavity in patients (r=0.71, p&lt;0.001). Finally, pulmonary ejection acceleration (PAc) was faster (p=0.001) and RV filling time shorter in patients (p=0.03) with respect to controls. Conclusion: RV has distinct features for the inflow, apical and outflow tract compartments, with different extent of contribution to the overall systolic function. In PH, RV becomes one dyssynchronous compartment which itself may have perpetual effect on overall cardiac dysfunction. In addition, critical aortic stenosis results in RV configuration changes with the inflow tract, rather than outflow tract, determining peak ejection. This pattern of disturbance remains six month after valve replacement, which confirms that once RV physiology is disturbed it does not fully recover. The findings of this study suggest an organised RV remodelling which might explain the known limited exercise capacity in such patients. Furthermore, in patients with PH of different aetiologies and normal LV function, there is a similar pattern of RV disturbance. Therefore, we can conclude that early identification of such changes might help in identifying patients who need more aggressive therapy early on in the disease process.

No description available.