Pulmonell hypertension (PH) är en sjukdom med flera olika etiologier som bidrar till ett förhöjt tryck i lungkretsloppet. PH definieras som ett medelartärtryck i lungpulsådern   25mm Hg i vila uppmätt vid högersidig hjärtkateterisering (RHC). De olika orsakerna till PH delas in i fem grupper. Denna studie fokuserar på grupp I, som utgörs av pulmonell arteriell hypertension (PAH). PAH bidrar till en tryckbelastning av högerkammaren där högerkammaren måste arbeta mot ett högre tryck. Detta leder till en nedsatt högerkammarfunktion. I nuläget används right ventricular stroke work index (RVSWI) inom RHC, för att mäta högerkammarens arbete. Syftet med studien var att jämföra RVSWI beräknat med ekokardiografi och RHC. Detta för att finna ytterligare ett mått vid bedömning av högerkammarfunktion med ekokardiografi hos patienter med PAH. RVSWI beräknades med två ekokardiografiska metoder (RVSWIEKO1= 90 - (0,62 x pulmonalisflödets accelerationstid (PAT) x slagvolymindex (SVIEKO)), RVSWIEKO2= ((0,61 x maximala gradienten över tricuspidalisinsufficiensen (TRmaxPG)) + medeltrycket i höger förmak (mRAP) + 2) x SVIEKO). Båda metoderna påvisade statistisk signifikant skillnad (p <0,001) i absoluta värden mot RVSWI erhållet med RHC.  En av metoderna (RVSWI EKO2) påvisade en måttlig korrelation mot RHC, medan RVSWI EKO1 hade en försumbar korrelation mot RHC. Studien visade att ekokardiografiskt beräknat RVSWI kan användas, som ett ytterligare mått vid bedömning av högerkammarens funktion. Det krävs dock fler studier för att parametern ska kunna användas kliniskt. / Pulmonary hypertension (PH) is a disease with many different etiologies contributing to an increased pressure in the pulmonary circulation. PH is defined as a mean arterial pressure in the pulmonary artery ≥ 25mm Hg at rest measured by right heart catheterization (RHC). The different causes of PH are divided into five groups. This study focuses on group I, which consists of pulmonary arterial hypertension (PAH). PAH contributes to a pressure overload of the right ventricle. The right ventricle must work at a higher pressure, which leads to a reduced right ventricular function. Currently, right ventricular stroke work index (RVSWI) by right heart catheterization (RHC) is a measure of right ventricular workload. The purpose of the study was to compare RVSWI calculated with echocardiography to RVSWI by RHC. And to find an additional measure for assessing right ventricular function by echocardiography in patients with PAH.  RVSWI was evaluated with two echocardiographic methods (RVSWIEKO1= 90 - (0,62 x pulmonary acceleration time (PAT) x stroke volume index (SVIEKO)), RVSWIEKO2= ((0,61 x tricuspid regurgitant maximum pressure gradient (TRmaxPG)) + mean right atrial pressure (mRAP) + 2) x SVIEKO). Both the echocardiographic methods showed a statistically significant difference (p <0.001) in absolute values ​​compared to RVSWI by RHC. One of the echocardiographic methods (RVSWI EKO2) showed a moderate correlation with RHC, while RVSWIEKO1 showed a negligible with RHC. The study has shown that RVSWI evaluated with echocardiography can be used as an additional measure, when assessing right ventricular function. However, more studies are needed until the parameter can be used clinically.

Background: Right ventricular failure is a serious complication after left ventricular assist device placement. Case Presentation: A 70-year-old male in decompensated heart failure with right ventricular failure after the placement of a left ventricular assist device. A single dual-lumen PROTEKDuo cannula was inserted percutaneously via the internal jugular vein to draw blood from the right atrium and return into the pulmonary artery using the CentriMag system, by passing the failing ventricle. The patient was successfully weaned from right ventricular assist device. Conclusions: In comparison to two-cannula conventional procedures, this right ventrivular assist device system improves patient rehabilitation and minimizes blood loss and risk of infection, while shortening procedure time and improving clinical outcomes in right ventricular failure.

Right ventricular dysfunction is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in failing right ventricular tissue remain incomplete. In the present dissertation we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Two different rat models of RV hypertrophy were studied. The model of right ventricular failure (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor- coactivator-1α, peroxisome proliferator- activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor- coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor- coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in right ventricular failure tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from right ventricular failure tissue had a significantly reduced ADP- stimulated (state 3) rate for complex I. Conversely, functional right ventricular hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor- coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-right ventricular tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated right ventricular pressure-overload. We conclude that right ventricular dysfunction, but not functional right ventricular hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.

Introdução: A fração de ejeção do ventrículo direito (FEVD) é um importante fator prognóstico em pacientes com hipertensão pulmonar (HP), porém a sua medida é complicada e demorada devido à complexidade anatômica do ventrículo direito (VD). O TAPSE (Tricuspid Annular Plane Systolic Excursion) é um bom índice da FEVD, mas ele avalia apenas o componente longitudinal da contração ventricular direita. A RVFAC (Right Ventricular Fractional Area Change) parece ser um melhor índice da FEVD por incluir os componentes longitudinal e transversal da contração ventricular direita. O objetivo deste estudo foi avaliar a performance da RVFAC de acordo com a gravidade do acometimento hemodinâmico em dois grupos distintos de pacientes portadores de HP pré-capilar: hipertensão arterial pulmonar (HAP) e tromboembolismo pulmonar crônico hipertensivo (TEPCH). Métodos: 62 pacientes realizaram cateterismo cardíaco direito e ressonância magnética cardíaca em ±72h. As áreas sistóica e diastólica finais do ventrículo direito (ASFVD, ADFVD), a área diastólica final do ventrículo esquerdo (ADFVE) e o TAPSE foram medidos nas imagens de quatro cavidades. A RVFAC (ADFVD-ASFVD/ADFVD) e a relação entre as áreas diastólica finais ventriculares (ADFVD/ADFVE) foram calculadas. Os diâmetros entre as paredes livre e septal (dL-S) e antero-posterior (dA-P) do ventículo esquerdo (VE) foram medidos nas imagens em eixo curto e o índice de excentricidade do VE (IE) foi calculado (=dA-P/dL-S). A FEVD foi calculada a partir de imagens consecutivas de 6mm no eixo curto. . Resultados: A população tinha 58 anos em média, a maioria era do sexo feminino e estava em classe funcional III, 23 tinham HAP e 39 TEPCH. A FEVD apresentou correlações fracas com as medidas hemodinâmicas de sobrecarga e de função do VD. A RVFAC apresentou melhor correlação (R2=0,65, p < 0,001) do que o TAPSE (R2=0,35, p<0,001) com a FEVD e melhor capacidade para estimar FEVD<35% do que o TAPSE (TAPSE: AUC 0,73 e RVFAC: AUC 0,93, p=0,0065). Dividimos a população pela mediana da resistência vascular pulmonar (RVP) e observamos que no grupo com maior gravidade hemodinâmica essa diferença se acentuou: no grupo com RVP<8,5UW (RVFAC: R2=0,66, p<0,001 e TAPSE: R2=0,30, e p=0,002) e no grupo com RVP>8,5UW (RVFAC: R2=0,51, p<0,001 e TAPSE: R2=0,14, e p=0,041). O grupo com RVP>8,5UW apresentou maior ADFVD/ADFVE e maior IE. As correlações da RVFAC e TAPSE com FEVD foram semelhantes entre os grupos HAP e TEPCH. Conclusão: A RVFAC se correlacionou melhor com a FEVD do que o TAPSE tanto no grupo com menor como no grupo com maior gravidade hemodinâmica. No grupo com maior gravidade as correlações da RVFAC com a FEVD foram ainda mais significativas, não havendo diferenças na performance da RVFAC entre os pacientes com HAP e TEPCH. A RVFAC foi um melhor índice da FEVD talvez por incluir o movimento transversal da contração ventricular / Introduction: The right ventricular ejection fraction (RVEF) is a surrogate marker in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The TAPSE (Tricuspid Annular Plane Systolic Excursion) is a good index of RVEF, though it measures only the longitudinal component of right ventricular contraction. The RVFAC (Right Ventricular Fractional Area Change) seems to be a better index of RVEF because it takes into account the longitudinal and the transversal components of right ventricular contraction. The aim of our study was to evaluate the RVFAC performance according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methos: Sixty-two patients with PAH and CTEPH underwent right heart catheterization and cardiac MR in a 72-hour delay. The right and left ventricle end diastolic areas (RVEDA, LVEDA), the right ventricle end systolic area (RVESA) and TAPSE were measured in the four chamber view. The RVFAC (=RVEDARVESA/RVEDA) and the RVEDA/LVEDA relationship were calculated. The diameter between the left ventricle (LV) free wall and the septum (dF-S) and the diameter between the LV anterior and posterior walls (dA-P) were measured and the LV eccentricity index (EI) was calculated (=dA-P/dF-S). The RVEF was calculated by using 6 mm RV short axis cines. Results: The population had mean age of 58 years with female majority, most of the patients were in functional class III, 23 had PAH and 39 CTEPH. The RVEF was weakly correlated to the hemodynamic variables of RV afterload and function. The RVFAC was more strongly correlated to RVEF (R2=0.65, p<0.001) than TAPSE (R2=0.35, p<0.001). RVEF<35% was better predicted by RVFAC than TAPSE (TAPSE: AUC 0.73 and RVFAC: AUC 0.93, p=0.0065). We divided the population by the median of the pulmonary vascular resistance (PVR) and we observed that in the group with worse hemodynamic severity this difference increased: in the group with PVR<8,5WU (RVFAC: R2=0.66, p<0.001 and TAPSE: R2=0.30, p=0.002) and in the group with PVR>8,5 WU (RVFAC: R2=0.51, p<0.001 and TAPSE: R2=0.14, p=0.041). The group with PVR>8,5WU had an increased RVEDA/LVEDA and an increased EI. There was no differences in the RVEF relationships between the groups of PAH and CETPH. Conclusion: The RVFAC was better correlated to RVEF than TAPSE in the groups with less severe and more severe hemodynamics. In patients with increased hemodynamic severity RVFAC perfomed even better, there was no difference in the performance of RVFAC in PAH or CTEPH. RVFAC was a better index of RVEF possibly because it takes into account the transversal component of right ventricular function

Introdução: A falência do ventrículo direito (VD), durante o emprego de dispositivos de assistência circulatória do ventrículo esquerdo (DAVE), pode resultar em severo compromisso hemodinâmico com altas taxas de mortalidade. Objetivo: Este estudo avaliou o desempenho hemodinâmico e as alterações miocárdicas decorrentes do emprego de dispositivo de assistência ventricular esquerda, associado ou não à descompressão do ventrículo direito (VD) através de derivação cavo-pulmonar.Estes achados foram comparados com o emprego de assistência circulatória esquerda isolada e com a assistência circulatória biventricular, em modelo experimental de falência cardíaca. Métodos: O suporte ventricular esquerdo foi instalado por meio de bomba centrífuga em vinte e um suínos (25-32 kg) com falência biventricular severa obtida pela indução de ritmo de fibrilação ventricular (FV). Os animais foram randomizados em três grupos. No grupo Controle, foi implantado apenas o DAVE. No grupo Derivação, além do DAVE foi realizada a cirurgia de Glenn modificada, com anastomose de tubo de Politetrafluoroetileno expandido (PTFE) n° 16, entre a veia cava superior e o tronco da artéria pulmonar. No grupo Biventricular, foram instaladas duas bombas centrífugas em paralelo, uma do lado esquerdo e outra do lado direito do coração. Foram monitoradas as pressões intracavitárias no momento prévio à indução de FV e a cada 30 minutos de assistência até o limite de 180 minutos. Lactato venoso e dosagens de citocinas inflamatórias também foram coletados em momentos distintos no inicio da FV e a Intervalos regulares de uma hora até o final do experimento Amostras do endocárdio dos dois ventrículos foram coletadas e analisadas por meio de microscopia óptica e eletrônica Resultados: manutenção do ritmo de FV foi responsável por detenoração hernodinâmica Importante no grupo Controle e no grupo Derivação A diferença observada entre o fluxo do DAVE nos grupos Derlvação e Controle (+55±14 ml/kg/mln p=O 072) não foi significativa ao passo que o fluxo no grupo Biventricular for significativamente maior (+93±17 ml/kg/mln p=0.012) e se manteve estável durante o experimento A PAM se manteve constante apenas no grupo Biventricular (p<O 001) que também apresentou diminuição significativa da pressão venosa central (p=O 043). Não houve diferença nos níveis de citocinas inflamatórias entre os grupos enquanto que os níveis de lactato sérico revelaram-se significativamente menores no grupo Biventricular (p=0,014). Na análise ultraestrutural notou-se uma presença menor de edema celular na parede livre do VD no grupo Biventricular (p=0017). Conclusão: Os resultados apresentados demonstram que o desempenho hemodinâmicos da assistência ventricular esquerda associada a derivação cavopulmonar, neste modelo experimental, não foi superior ao observado com a assistência de VE isolada e não substitui a assistência biventricular de maneira efetiva. Os níveis de citocinas séricas não sofreram alterações significativas no período estudado. O grupo biventricular apresentou menor quantidade de edema celular na parede livre do ventrículo direito. / Background Right ventricular (RV) failure durinq left ventricular assist device (LVAD) support can result in severe hernodynarnic cornpromise with hiqh mortality. Objective: This study investiqated the acute effects of cavopulmonary anastomosis on L VAD performance and riqht ventricular myocardial compromise in comparison with isolated LVAD support and biventricular circulatory support in a model of severe cardiac failure. Methods: LVAD support was performed by means of centrituqa pump implantation in 21 anesthetized guinea piqs (25-32 kg) with severe biventricular failure achieved by ventricular fibrillation (VF) induction. Animais were randomized in three groups In the Control group, isolated LVAD support was performed In the Cavopulmonary group, cavopulmonary anastomosis was established by connecting the superior vena cava ano pulmonary main artery with a short segment of expanded politrafluorotylen no. 16 (rnodified Glenn shunt). In the Biventricular group, biventricular assist device support was established by means of two parallel centrifugal: pumps, one of them on the riqht-hand side of the heart and the other on the left-hand side. They were maintened under circulatory support and hemodynamic monitoring for 3h. Blood sample was collected before VF and in intervals of 30 minutes until the end of the surgery. Venous lactate and cytokines serum levels derterminations were also obtained, before VF and each hour. Endocardium samples of the septum and two ventricles were collected and analyzed by optics and electronic in microscopy. Results: Ventricular fibrillation maintenance was responsible for acute LVAD performance impairment after mino in the Control and Cavopulmonary groups. Cavopulmonary anastomosis resulted in non-significant improvement of LVAD pump flow in relation to control group (+55±14 ml/kg/min, p=0.072), while animais under biventricular support maintained higher LVAD flow performance (+93±17 ml/kg/min, p=0.012). Mean arterial pressure remained constant only in biventricular group (p<0.001), which also presented significant decrease of right atrial pressure (p=0,043). Similar increases in cytokine levels were observed in the three groups while the serum lactate presented lower level only in the Biventricular group (p=0,014). Ultrastructural analysis documented the presence of lower levels of myocardial cellular swelling in right ventricle in the Biventricular group . (p=0.017). Conclusion: The concomitant use of cavopulmonary anastomosis during LVAD support in a pig model of severe biventricular failure resulted in non-siqnificant improvement of hemodynamic performance and it did not effectively replace the use of biventricular support. Cytokine levels were similar in three groups. The Biventricular group showed lower levei of cellular swelling in the right ventricle.

La fraction d'éjection du ventricule droit (FEVD) est un marqueur de survie en cas d'hypertension pulmonaire (PH), mais sa mesure est compliquée et fastidieuse. Le TAPSE (Tricuspid Annular Plane Systolic Excursion) est un bon indice de la FEVD mais il ne mesure que la composante longitudinale de la contraction ventriculaire droite. La fraction de variation surfacique du ventricule droit RVFAC (Right Ventricular Fractional Area Change) semble être un meilleur indice de FEVD car il prend en compte le sens longitudinal et transversal des éléments de la contraction du ventricule droit. Le but de notre étude était d'évaluer la performance RVFAC fonction de la sévérité hémodynamique chez les deux groupes de patients atteints de PH:l'hypertension artérielle pulmonaire (HAP) et l'hypertension pulmonaire thromboembolique chronique (CTEPH).Methodes: Soixante-deux patients atteints d'HTAP et CTEPH ont bénéficié d’un cathétérisme cardiaque droit et d’une IRM cardiaque dans un délai de 72 heures. Les surfaces ventriculaires droite et gauche a la fin de la diastole (RVEDA, LVEDA), la surface du ventricule droit a la fin da la systole (RVESA) et TAPSE ont été mesurés dans la vue quatre cavités. Le RVFAC (RVFAC=RVEDA-RVESA/RVEDA) et le rapport RVEDA/LVEDA ont été calculés. Le diamètre entre la paroi libre et le septum (DF-S) et le diamètre entre les parois antérieure et postérieures du ventricule gauche (DA-P) ont été mesurés et l'indice d’excentricité LV (IE) a été calculé (= DA-P / DF-S). Le RVEF a été calculée à l'aide de coupes jointives de 6 mm en petit axe du ventricule droit.Résultats: La population avait un âge moyen de 58 ans avec une majorité des femmes, la plupart des patients étaient en classe fonctionnelle III, 23 avaient des HAP) et 39 des CTEPH. La RVEF était faiblement corrélée aux variables hémodynamiques de la post-charge et de la fonction VD. Le RVFAC était plus fortement corrélée à FEVD (R2 = 0,65, p <0,001) que TAPSE (R2 = 0,35, p <0,001). Une FEVD <35% était mieux prédite par un RVFAC bas que par une diminution de TAPSE (TAPSE: AUC 0,73 et RVFAC: AUC 0,93, p = 0,0065). Nous avons divisé la population par la médiane de la résistance artérielle pulmonaire (RAP) et nous avons observé que dans le groupe avec la pire sévérité hémodynamique, cette différence a augmenté: dans le groupe avec PVR < 8,5 UW (RVFAC: R2 = 0,66, p <0,001 et TAPSE: R2 = 0,30, p =0,002) et dans le groupe avec PVR > 8,5 UW (RVFAC: R2 = 0,51, p <0,001 et TAPSE: R2 = 0,14, p = 0,041). Le groupe avec PVR> 8,5 WU avait un rapport RVEDA/LVEDA augmenté et une augmentation de l`indice excentricité. Les relations RVEF-RVFAC n’étaient pas différentes entre les groupes de HAP et CETPH.Conclusion: La fraction de variation surfacique du ventricule droit RVFAC fournit un reflet simple et fiable de la FEVD peut-être parce que contrairement à TAPSE qui ne prend en compte que le raccourcissement longitudinal, RFVAC prend également en compte la composante transversale de la fonction ventriculaire droite. / The right ventricular ejection fraction (RVEF) is a surrogate marker in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The TAPSE (Tricuspid Annular Plane Systolic Excursion) is a good index of RVEF, though it measures only the longitudinal component of right ventricular contraction. The RVFAC (Right Ventricular Fractional Area Change) seems to be a better index of RVEF because it takes into account the longitudinal and the transversal components of right ventricular contraction. The aim of our study was to evaluate the RVFAC performance according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolicpulmonary hypertension (CTEPH).Methos: Sixty-two patients with PAH and CTEPH underwent right heart catheterization and cardiac MR in a 72-hour delay. The right and left ventricle end diastolic areas (RVEDA, LVEDA), the right ventricle end systolic area (RVESA) and TAPSE were measured in the four chamber view. The RVFAC (RVFAC=RVEDA–RVESA/RVEDA) and the RVEDA/LVEDA relationship werecalculated. The diameter between the left ventricle (LV) free wall and the septum (dL-S) and the diameter between the anterior and posterior walls (dAP) were measured and the LV eccentricity index (EI) was calculated (EI=dAP/dL-S). The RVEF was calculated by using 6 mm RV short axis cines.Results: The population had mean age of 58 years with female majority, most of the patients were in functional class III, 23 had pulmonary arterial hypertension (PAH) and 39 had chronic thromboembolic pulmonary hypertension (CTEPH). The RVEF was weakly correlated to the hemodynamic variables of RV afterload and function. The RVFAC was morestrongly correlated to RVEF (R2=0.65, p<0.001) than TAPSE (R2=0.35, p<0.001). RVEF<35% was better predicted by RVFAC than TAPSE (TAPSE: AUC 0.73 and RVFAC: AUC 0.93, p=0.0065). We divided the population by the median of the pulmonary vascular resistance (PVR) and we observed that in the group with worse hemodynamic severity this difference increased: inthe group with PVR<8,5WU (RVFAC: R2=0.66, p<0.001 and TAPSE: R2=0.30, p=0.002) and in the group with PVR>8,5 WU (RVFAC: R2=0.51, p<0.001 and TAPSE: R2=0.14, p=0.041). The group with PVR>8,5WU had an increased RVEDA/LVEDA and an increased EI. There was no differences in the RVEF relationships between the groups of PAH and CETPH.Conclusion: The RVFAC was better correlated to RVEF than TAPSE in the groups with less severe and more severe hemodynamics. In patients with increased hemodynamic severity, with no difference in the performance in theHAP or CTEPH groups. RVFAC was a better index of RVEF possibly because it takes into account the transversal component of right ventricular function.

Introduction: Cardiac cell-cell junctions play important roles in maintaining cardiac integrity linking single cardiomyocytes into a single functioning syncytium. There are three main types of cell junctions in the heart: gap junctions (GJ), desmosomes (D) and adherens junctions (AJ). Mutations in the proteins which make-up these junctions are known to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Pathological features include progressive replacement of right ventricular cardiac muscle with fibrofatty tissue. This can lead to heart failure and life threatening arrhythmias. During normal development of the mammalian heart, protein components of AJ and D gradually fuse to form composite junctions at the intercalated discs, also called areae compositae (singular, area composita, AC). In contrast, the adult heart of lower vertebrates, including the zebrafish, may have few or no AC type junctions. The detailed structure of cardiomyocyte cell-cell junctions in the adult zebrafish heart remain poorly defined and their role in normal development, growth and response to injury have yet to be studied. This thesis will examine the hypothesis that localisation and distribution of myocardial cell-cell junction proteins are crucial in normal myocardial development and in endogenous cardiac regeneration and repair following injury. This will be achieved by understanding the normal development of cell-cell junction proteins in zebrafish from embryonic to adulthood. These findings will then be analysed in comparison to cell-cell junction proteins localisation and distribution in early and late mammalian (mouse and human) myocardium. Once a normal pattern of cell-cell junction proteins will be established, the localisation of cell-cell junction proteins in plakologbin mutant zebrafish model for cardiomyopathy will be studied to understand the distribution and localisation of these proteins in disease manifestation. This model will then be used to test if localisation of cell-cell junction proteins plays an important in cardiac repair following injury by using embryonic laser injury model, this will be further tested by drug intervention study to investigate underlying pathways such as Wnt signalling pathway. Methods: Myocardial cell-cell junctions were assessed using immunohistochemistry in embryonic, juvenile and adult zebrafish hearts and in foetal and adult human hearts. The Plakoglobin mutant zebrafish line (UAS:Gal-4:Plakoglobin Naxos; named as PGNx) was characterised using various functional and morphological assessments including histology, echocardiography and MRI scanning. Similar studies were undertaken in PGNx mutants at different developmental stages. A pharmacological intervention study, using a GSK-3 inhibitor, was carried out in PGNx mutants followed by cardiac structural and functional assessments. Laser-induced cardiac trauma was used to assess the response to injury and repair in normal and PGNx embryos following treatment with the GSK3 inhibitor drug. Results: Cell-cell junction patterning in the embryonic, juvenile and adult zebrafish heart shows a characteristic pearl string appearance of desmoplakin and β-catenin labelled distinct disc shaped AJ. Human foetal heart showed small distinct D and AJ, while the adult human heart had features consistent with AC type junctions. PGNx fish showed reduced ventricle ejection fraction, dilatation of the atrium, reduced amplitude of wall motion and ventricle relaxation velocity compared to age-matched controls. Echocardiography and MRI imaging confirmed severe atrial dilatation and restrictive ventricle physiology in adult fish. The cell-cell junction proteins were over-expressed in the zebrafish PG mutant (PGNx) hearts compared to age-matched controls. Drug studies using a GSK-3β inhibitor showed complete recovery of cardiac function and partial recovery of heart structure. Cardiac injury studies, using laser, showed failure of repair in PGNx embryos compared to age-matched controls. The GSK3 inhibitor failed to improve the functional response following heart laser injury. Conclusions: Cell-cell junctions are distributed abundantly around cardiomyocytes in the zebrafish heart during early development and into adulthood. In contrast to previous studies in adult mammalian heart, there was no evidence of AC type junctions in adult zebrafish cardiomyocytes. The mutant zebrafish line showed restrictive cardiac physiology and abnormal cardiac structure confirming the key role played by plakoglobin in the normal heart development. This is further supported by evidence showing failure of repair in PGNx mutant embryos after injury. Drug treatment with a GSK-3 inhibitor highlights a potentially novel therapeutic pathway for treatment of ARVC involving Wnt signalling.

Introdução: A fração de ejeção do ventrículo direito (FEVD) é um importante fator prognóstico em pacientes com hipertensão pulmonar (HP), porém a sua medida é complicada e demorada devido à complexidade anatômica do ventrículo direito (VD). O TAPSE (Tricuspid Annular Plane Systolic Excursion) é um bom índice da FEVD, mas ele avalia apenas o componente longitudinal da contração ventricular direita. A RVFAC (Right Ventricular Fractional Area Change) parece ser um melhor índice da FEVD por incluir os componentes longitudinal e transversal da contração ventricular direita. O objetivo deste estudo foi avaliar a performance da RVFAC de acordo com a gravidade do acometimento hemodinâmico em dois grupos distintos de pacientes portadores de HP pré-capilar: hipertensão arterial pulmonar (HAP) e tromboembolismo pulmonar crônico hipertensivo (TEPCH). Métodos: 62 pacientes realizaram cateterismo cardíaco direito e ressonância magnética cardíaca em ±72h. As áreas sistóica e diastólica finais do ventrículo direito (ASFVD, ADFVD), a área diastólica final do ventrículo esquerdo (ADFVE) e o TAPSE foram medidos nas imagens de quatro cavidades. A RVFAC (ADFVD-ASFVD/ADFVD) e a relação entre as áreas diastólica finais ventriculares (ADFVD/ADFVE) foram calculadas. Os diâmetros entre as paredes livre e septal (dL-S) e antero-posterior (dA-P) do ventículo esquerdo (VE) foram medidos nas imagens em eixo curto e o índice de excentricidade do VE (IE) foi calculado (=dA-P/dL-S). A FEVD foi calculada a partir de imagens consecutivas de 6mm no eixo curto. . Resultados: A população tinha 58 anos em média, a maioria era do sexo feminino e estava em classe funcional III, 23 tinham HAP e 39 TEPCH. A FEVD apresentou correlações fracas com as medidas hemodinâmicas de sobrecarga e de função do VD. A RVFAC apresentou melhor correlação (R2=0,65, p < 0,001) do que o TAPSE (R2=0,35, p<0,001) com a FEVD e melhor capacidade para estimar FEVD<35% do que o TAPSE (TAPSE: AUC 0,73 e RVFAC: AUC 0,93, p=0,0065). Dividimos a população pela mediana da resistência vascular pulmonar (RVP) e observamos que no grupo com maior gravidade hemodinâmica essa diferença se acentuou: no grupo com RVP<8,5UW (RVFAC: R2=0,66, p<0,001 e TAPSE: R2=0,30, e p=0,002) e no grupo com RVP>8,5UW (RVFAC: R2=0,51, p<0,001 e TAPSE: R2=0,14, e p=0,041). O grupo com RVP>8,5UW apresentou maior ADFVD/ADFVE e maior IE. As correlações da RVFAC e TAPSE com FEVD foram semelhantes entre os grupos HAP e TEPCH. Conclusão: A RVFAC se correlacionou melhor com a FEVD do que o TAPSE tanto no grupo com menor como no grupo com maior gravidade hemodinâmica. No grupo com maior gravidade as correlações da RVFAC com a FEVD foram ainda mais significativas, não havendo diferenças na performance da RVFAC entre os pacientes com HAP e TEPCH. A RVFAC foi um melhor índice da FEVD talvez por incluir o movimento transversal da contração ventricular / Introduction: The right ventricular ejection fraction (RVEF) is a surrogate marker in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The TAPSE (Tricuspid Annular Plane Systolic Excursion) is a good index of RVEF, though it measures only the longitudinal component of right ventricular contraction. The RVFAC (Right Ventricular Fractional Area Change) seems to be a better index of RVEF because it takes into account the longitudinal and the transversal components of right ventricular contraction. The aim of our study was to evaluate the RVFAC performance according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methos: Sixty-two patients with PAH and CTEPH underwent right heart catheterization and cardiac MR in a 72-hour delay. The right and left ventricle end diastolic areas (RVEDA, LVEDA), the right ventricle end systolic area (RVESA) and TAPSE were measured in the four chamber view. The RVFAC (=RVEDARVESA/RVEDA) and the RVEDA/LVEDA relationship were calculated. The diameter between the left ventricle (LV) free wall and the septum (dF-S) and the diameter between the LV anterior and posterior walls (dA-P) were measured and the LV eccentricity index (EI) was calculated (=dA-P/dF-S). The RVEF was calculated by using 6 mm RV short axis cines. Results: The population had mean age of 58 years with female majority, most of the patients were in functional class III, 23 had PAH and 39 CTEPH. The RVEF was weakly correlated to the hemodynamic variables of RV afterload and function. The RVFAC was more strongly correlated to RVEF (R2=0.65, p<0.001) than TAPSE (R2=0.35, p<0.001). RVEF<35% was better predicted by RVFAC than TAPSE (TAPSE: AUC 0.73 and RVFAC: AUC 0.93, p=0.0065). We divided the population by the median of the pulmonary vascular resistance (PVR) and we observed that in the group with worse hemodynamic severity this difference increased: in the group with PVR<8,5WU (RVFAC: R2=0.66, p<0.001 and TAPSE: R2=0.30, p=0.002) and in the group with PVR>8,5 WU (RVFAC: R2=0.51, p<0.001 and TAPSE: R2=0.14, p=0.041). The group with PVR>8,5WU had an increased RVEDA/LVEDA and an increased EI. There was no differences in the RVEF relationships between the groups of PAH and CETPH. Conclusion: The RVFAC was better correlated to RVEF than TAPSE in the groups with less severe and more severe hemodynamics. In patients with increased hemodynamic severity RVFAC perfomed even better, there was no difference in the performance of RVFAC in PAH or CTEPH. RVFAC was a better index of RVEF possibly because it takes into account the transversal component of right ventricular function

An accumulation of sudden unexpected cardiac deaths (SUCD) occurred in young Swedish orienteers, most of whom were elite athletes. From 1979 to 1992 the incidence in 18 to 34 year old male elite orienteers ranked on the national level the same year as death was calculated to 30 (per 100,000), which represents a 20 to 40 fold increase from the expected rate. From 1989 to 1992, the incidence was 50. There were, however, no indications on any similar clusters of SUCD in other sports. A special program to alter behaviour in orienteers was implemented in 1992-1993, after which there have been no more cases of SUCD in orienteers below 35 years of age. A histopathological re-evaluation of 16 cases of SUCD revealed myocarditis in 75% of these cases. In parallel, four of those cases also had changes mimicing arrhythmogenic right ventricular cardiomyopathy (ARVC). The combination of an increased incidence and myocarditis suggested that infection may be a pathogenetic factor. A broad search for different microorganisms in archival sera from five cases and tissues from the autopsies in two of those cases revealed the only common finding that all had antibodies to Chlamydia pneumoniae. DNA from C. pneumoniae was detected in the lung and heart in one of two cases. The intimate contact with nature of orienteers suggested possible zoonotic/vectorborne pathogens. Bartonella is such a pathogen and known to cross-react with C. pneumoniae. The use of PCR to test for DNA from the gltA gene of Bartonella in the two formerly mentioned cases of SUCD, and in three additional cases, gave positive bands from the hearts in four cases and the lung in a fifth case. The PCR products were sequenced and found to be identical to B. henselae in three cases and almost identical to B. quintana in the remaining two cases. Four of the five cases had antibodies to Bartonella when using micro immunofluorescence test with the antigens B. henselae, B. quintana, and B. elizabethae. The total prevalence of antibodies to Bartonella was 31% in 1,136 elite orienteers vs. 6.8% in 322 healthy blood donors (p&lt;0.001), suggesting widespread exposure in the elite. It is hypothesized that subacute or reactivated Bartonella infection has a pathogenetic role in SUCD in orienteers, and may be involved in the development of ARVC-like disease.

Chronic neonatal pulmonary hypertension (PHT) frequently presents with rightventricular (RV) dysfunction. In neonatal rats exposed to chronic hypoxia, RV dysfunction is reversed by sustained rescue treatment with a Rho-kinase (ROCK) inhibitor – the caveat being systemic hypotension. We therefore examined the reversing effects of pulmonary-selective ROCK inhibition. Rat pups were exposed to air or hypoxia from birth for 21 days and received sustained rescue treatment with aerosolized Fasudil (81 mg/ml t.i.d for 15 min) or i.p. Y27632 (15 mg/kg b.i.d) from days 14-21. Inhaled Fasudil normalized pulmonary vascular resistance, and reversed pulmonary vascular remodeling but did not improve RV systolic function. Systemic, but not pulmonary-selective, ROCK inhibition attenuated increased RV ROCK activity. Our findings indicate that RV dysfunction in chronic hypoxic PHT is not merely a result of increased afterload, but rather may be due to increased activity of ROCK in the right ventricle.