The aim of this study was to determine the characteristics of the remodeling of the heart right ventricle as well as the changes in the interstitial fibrillar collagen network of myocardium during pre-infarction, acute myocardial infarction and post-infarction development stages of IHD.Indications of right ventricle remodeling are estimated in all development stages of IHD. The concentric type of the right ventricle hypertrophy develops in patients with chronic IHD yet till the first acute MI occurs, i.e. in the pre-infarction period, due to the prolonged myocardial ischemia: its mass and endocardial surface area was bigger than the same parameters of the control group. In this stage of the development of the IHD the variation of right and left ventricle geometrical (endocardial area) and mass parameters was toughly related (linear relationship, r≥0, 5, p<0,05) and irrespective from the total stenotic lesion of the coronary arteries (index of stenosis). In the periods of acute MI and post-infarction IHD these parameters did not vary significantly, i.e. the concentric type hypertrophy of the right ventricle persists. The percentage volume, perimeter, number of bundles areas of the interstitial fibrillar collagen network increase significantly in the pre-infarction period, comparing with the control group and persists in later stages of IHD.

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.

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.

Background: The right ventricular outflow tract (RVOT) is known to be the origin of potentially dangerous ventricular tachycardias (VT). Arrhythmias can occur in what are otherwise assume to be structurally normal hearts as well as in arrhythmia syndromes like Brugada syndrome, catecholaminergic polymorphic VT and arrhythmogenic right ventricular dysplasia. In adults with surgically corrected tetralogy of Fallot (ToF), VT often originates in the RVOT. Methods: To investigate potential arrhythmia substrates in the structurally normal heart, the RVOT of adult rats was investigated and compared to the right ventricle (RV). In the human, the right atrium (RA), RV and the RVOT were examined in patients free of electrical and structural disease at the time of clinically indicated surgery on the left heart. The same tissue samples were collected from adults with surgically corrected ToF at the time of pulmonary valve replacement. Real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to explore changes on the mRNA level. Antibody based techniques (immunohistochemistry and Western blot) and mass spectrometry were used to identify changes on the protein level. In the rat RVOT, fine microelectrodes were employed to investigate electrophysiological characteristics. Results: A reduction in the Na+ channel Nav1.5 was found in the structurally normal RVOT in the rat and human. In the rat, RVOT-nodal like myocytes were identified. Unlike ventricular myocytes, the myocytes did not express the gap junction channel Cx43 and the K+ channel Kir2.1, but they did express the pacemaker Ca2+ channel Cav3.2 and the transcription factor Tbx3. Ectopic pacemaker and nodal-like action potentials with phase 4 depolarization were recorded from the region of the pulmonary valve. In the RA of ToF patients, SERCA2A was found to be downregulated (mRNA and protein) as seen in heart failure and atrial fibrillation. Further widespread remodelling was found in the RA, the RV and RVOT identifying multiple changes as seen in heart failure with downregulation of K+ channels and β-receptors and an increase in inflammatory markers and extracellular matrix molecules. Multiple molecules involved in the mitochondrial respiration chain were found to be downregulated in the RVOT of ToF patients. Conclusion: This is the first study that demonstrates reduction in Nav1.5 in the RVOT of structurally normal human hearts. The changes found in the rat RVOT could explain why arrhythmias originate in the RVOT. The widespread remodelling in ToF, especially in the ECM, could form a substrate for reentry arrhythmias. Mitochondrial dysfunction could point towards potential treatment targets for heart failure in this patient group.

Orientador: Wilson Nadruz Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T14:00:02Z (GMT). No. of bitstreams: 1 Mesquita_RobertoFredianiDuarte_M.pdf: 944774 bytes, checksum: f0d61f73994f5a8b3eb32209a538bfa3 (MD5) Previous issue date: 2014 / Resumo: Evidências prévias mostram que o desenvolvimento de hipertensão arterial sistêmica (HAS) na gravidez se associa ao aumento do risco cardiovascular ao longo da vida. Cerca de 20% das mulheres que desenvolvem HAS na gravidez podem persistir com níveis elevados de pressão arterial, e portanto com HAS crônica. Porém não se sabe se há diferenças a longo prazo entre mulheres que desenvolveram HAS a partir da gravidez (HAG) em comparação com mulheres cuja HAS não se iniciou neste período (HANG). O objetivo deste estudo foi avaliar as possíveis diferenças clínicas, metabólicas e ecocardiográficas entre estes grupos. Foram avaliadas 50 mulheres do grupo HAG e 100 mulheres do grupo HANG, acompanhadas em ambulatório de um hospital terciário universitário, por meio de história clínica, exame físico, exames laboratoriais e ecocardiografia. Os grupos foram pareados por tempo de hipertensão (tempo médio: 15 anos). Os resultados estão apresentados como média ± erro padrão e a significância estatística foi considerada quando p<0,05. O grupo HAG apresentou idade menor que o grupo HANG (46,6±1,4 vs. 65,3±1,1 anos; p<0,001), porém maiores valores de pressão arterial sistólica (159,8±3,9 vs. 148,0±2,5 mmHg; p=0,009) e pressão arterial diastólica (97,1±2,4 vs. 80,9±1,3 mmHg; p<0,001), apesar de fazer uso de maior número de classes de anti-hipertensivos (3,4±0,2 vs. 2,6±0,1, p<0,001). Os grupos apresentaram valores similares de índice de massa do ventrículo esquerdo (VE), porém o grupo HAG apresentou maior espessura relativa do VE (0,457±0,010 vs. 0,421±0,007; p=0,006) e maior prevalência de geometria concêntrica do VE (50 vs. 33%; p=0,044) do que o grupo HANG, embora estas diferenças não se mantiveram estatisticamente significativas após ajuste por pressão arterial. Estes resultados indicam que o grupo HAG apresenta pior controle de pressão arterial e remodelamento ventricular esquerdo desfavorável em comparação com o grupo HANG, sugerindo que o grupo HAG pode compor uma população de mulheres hipertensas com predisposição a desenvolver pior controle clínico e maior risco cardiovascular em longo prazo / Abstract: Up to 20% of women with hypertensive pregnancy disorders might persist with high blood pressure levels, thus developing chronic hypertension. This study evaluated whether hypertensive women whose hypertension began as hypertensive pregnancy disorders and persisted afterwards (PH group) exhibited long-term clinical and echocardiographic differences in comparison with hypertensive women whose diagnosis of hypertension did not occur during pregnancy (NPH group). A total of 150 women (50 PH and 100 NPH; median duration of hypertension = 15 years) who were referred to a university hospital outpatient clinic were cross-sectionally evaluated by clinical and laboratory examination, blood pressure measurement and echocardiography. The PH and NPH groups were matched by duration of hypertension. In comparison with the NPH group, PH women exhibited lower age (46.6±1.4 vs. 65.3±1.1 years; p<0.001), but presented higher systolic (159.8±3.9 vs. 148.0±2.5 mmHg; p=0.009) and diastolic (97.1±2.4 vs. 80.9±1.3 mmHg; p<0.001) blood pressure, although used a higher number of antihypertensive classes (3.4±0.2 vs. 2.6±0.1, p<0.001). The samples showed similar left ventricular (LV) mass index, but the PH group presented higher relative wall thickness (0.457±0.010 vs. 0.421±0.007; p=0.006) and increased prevalence of LV concentric geometry (50 vs. 33%; p=0.044) than the NPH one, albeit such differences did not remain statistically significant after adjustment for blood pressure levels. In conclusion, this study showed that PH women may exhibit worse blood pressure control and adverse left ventricular remodeling compared to NPH ones. These findings suggest that PH subjects might be a subgroup of hypertensive women at increased cardiovascular risk / Mestrado / Clinica Medica / Mestre em Clinica Medica

Idiopathic ventricular tachycardias, which occur in patients without structural heart disease, are a common entity, representing up to 10% of all ventricular tachycardias evaluated by cardiac electrophysiology services. Pregnancy can increase the incidence of various cardiac arrhythmias. Factors that can potentially promote arrhythmias in pregnancy include the effects of hormones, changes in autonomic tone, hemodynamic perturbations, hypokalemia, and underlying heart disease. Ventricular arrhythmias in pregnancy are repetitive monomorphic ventricular premature complexes and couplets that frequently originate at the right ventricular outflow tract. New onset symptomatic repetitive right ventricular outflow tract ventricular tachycardia during pregnancy has been inadequately reported in the literature. We present a case of symptomatic repetitive right ventricular outflow tract tachycardia that started during pregnancy and continued in the postpartum period, requiring curative treatment with electrophysiology study and radiofrequency ablation.

L’hypertension pulmonaire est une pathologie rare et grave résultant d’une obstruction des artères pulmonaires et provoquant une dysfonction cardiaque droite, caractérisée par une ischémie. C’est cette dysfonction cardiaque qui conditionne la survie des patients.L’objectif de ce travail de thèse était de mettre au point une thérapie cellulaire permettant de soutenir le ventricule droit et ainsi de prolonger la survie des patients.Une thérapie cellulaire à base de cellules endothéliales progénitrices, capables d’induire et de participer à l’angiogénèse, a été administrée par voie intracoronaire, intracardiaque et par l’intermédiaire d’un patch chez un modèle porcin d’hypertension pulmonaire.Nous avons mis en évidence une amélioration de la fonction cardiaque droite, une augmentation de la densité capillaire et une diminution de l’hypertrophie suite à l’administration intracoronaire. En revanche, les injections de cellules dans le ventricule droit ont révélé une augmentation de la densité capillaire de manière localisée mais n’ont pas permis d’améliorer la fonction cardiaque. Enfin, l’administration par patch n’a pas permis la migration cellulaire dans le ventricule droit. En conclusion, l’injection intracoronaire donne des résultats pré-cliniques encourageants en améliorant la fonction du ventricule droit chez un modèle animal d’hypertension pumonaire. Ces résultats sont à confirmer sur d’autres modèles et sont à compléter par des études mécanistiques approfondies. / Pulmonary perturbation is a rare and serious pathology resulting from obstruction of the pulmonary arteries and causing right cardiac dysfunction, characterized by ischemia. It is this cardiac dysfunction that conditions the survival of patients.The goal of this thesis work was to develop a cell therapy to support the right ventricle and thus prolong the survival of patients.Cell therapy with endothelial progenitor cells, capable of inducing and participating in angiogenesis, has been administered intracoronally, intracardiacally and via a patch in a porcine model of pulmonary hypertension.We found improvement in right heart function, increased capillary density, and decreased hypertrophy following intracoronal administration. In contrast, injections of cells into the right ventricle revealed an increase in capillary density in a localized manner but failed to improve cardiac function. Finally, patch administration did not allow cell migration into the right ventricle. In conclusion, intracoronal injection gives encouraging preclinical results by improving the function of the right ventricle in an animal model of pulmonary hypertension. These results are to be confirmed on other models and are to be completed by detailed mechanistic studies.

No / We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.

Background: The twisting motion of the left ventricle (LV), with clockwise rotation at the base and counter clockwise rotation at the apex during systole, is a vital part of LV function. Even though LV rotation has been studied for decades, the rotation pattern has not been described in detail. By the introduction of speckle tracking echocardiography measuring rotation has become easy of access. However, the axis around which the LV rotates has never before been assessed. The aims of this thesis were to describe the rotation pattern of the LV in detail (study I), to assess RV apical rotation (study II), develop a method to assess the rotation axis (study III) and finally to study the effect of regional ischemia to the rotation pattern of the LV (study IV). Methods: Healthy humans were examined in study I-III and the final study populations were 40 (60±14 years), 14 (62±11 years) and 39 (57±16 years) subjects, respectively. In study IV six young pigs (32-40kg) were studied. Standard echocardiographic examinations were performed. In study IV the images were recorded before and 4 minutes after occlusion of left anterior descending coronary artery (LAD). Rotation was measured in short axis images by using a speckle tracking software. By development of custom software, the rotation axis of the LV was calculated at different levels in every image frame throughout the cardiac cycle. Results: Study I showed significant difference in rotation between basal and apical rotations, as well as significant differences between segments at basal and mid ventricular levels. The rotation pattern of the LV was associated with different phases of the cardiac cycle. Study II found significant difference in rotation between the LV and the RV. RV rotation was heterogeneous and bi-directional, creating a ´tightening belt action´ to reduce it circumference. Study III indicated that the new method could assess the rotation axis of the LV. The motion of the rotation axes in healthy humans displayed a physiological and consistent pattern. Study IV found a significant difference in the rotation pattern, between baseline and after LAD occlusion, by measuring the rotation axes, but not by conventional measurements of rotation. AV-plane displacement and wall motion score (WMS) were also significantly changed after inducing regional ischemia. Conclusion: There are normally large regional differences in LV rotation, which can be associated anatomy, activation pattern and cardiac phases, indicating its importance to LV function. In difference to the LV, the RV did not show any functional rotation. However, its heterogeneous circumferential motion could still be of importance to RV function and may in part be the result of ventricular interaction. The rotation axis of the LV can now be assessed by development of a new method, which gives a unique view of the rotation pattern. The quality measurements and results in healthy humans indicate that it has a potential clinical implication in identifying pathological rotation. This was supported by the experimental study showing that the rotation axis was more sensitive than traditional measurements of rotation and as sensitive as AV-plane displacement and WMS in detecting regional myocardial dysfunction.

Högerkammare (RV) har en komplex anatomi, spelar en viktig roll för blodsyresättning och kan påverkas av fler patofysiologiska tillstånd. Utvärdering av RV:s funktion är viktig för överlevnad och har prognostiskt värde vid hjärt-och lungsjukdomar. Transthorakal ekokardiografi (TTE) används för RV:s storlek- och funktionsbedömning. Tricuspid annular plane systolic excursion (TAPSE) och annulus tricuspid peak systolic velocity (RVs´) är två vanliga metoder för bedömning av RV:s funktion. Båda metoderna har bra reproducerbarhet och är enkla att utföra.  Syftet med detta arbete är att utreda interobservatörvariation, sambandet och överensstämmelse mellan TAPSE och RVs´. Studien är en tvärsnittsstudie av 53 friska testpersoner 18-60 åringar. Mätningen baserades på en blind dubbelbestämning av två biomedicinska analytiker studenter. Analysen genomfördes med programmet IBM SPSS Statistics.  Interobservatörvariationsanalys visade ingen signifikant skillnad i mätosäkerheten mellan studenterna, (PTAPSE=0,568 och PRVs´=0,548). Enligt regressionsanalysen hade RVs´ något mindre mätosäkerhet än TAPSE. Ett svagt positivt samband hittades mellan RVs´ och TAPSE och 100% överenstämmelse avseende utfall påvisades, Kappavärdet blev 1. Båda metoderna har bra interobservatörvariation hos oerfarna undersökare. Hos hjärt- och lungfriska ser sambandet svagt positivt ut mellan TAPSE och RVs´. Dock kunde tidigare studier identifiera starkare positivt samband. Skillnaden i resultatet kan bero på erfarenhetsbrist hos studenterna och lågt antal deltagare. / The Right ventricle (RV) has a complex anatomy, plays an important role in blood oxygenation and can be affected by several pathophysiological conditions. Evaluation of RV function has prognostic value in heart and lung diseases. Tricuspid annular plane systolic excursion (TAPSE) and annulus tricuspid peak systolic velocity (RVs´) are two common methods for assessing RV function in Transthoracic echocardiography.  The study aimed to investigate interobserver variation, the correlation and agreement between TAPSE and RVs´. The study is a cross-sectional study of 53 healthy participants aged 18-60. The measurement was based on a blind double determination by two biomedical analyst students. The analysis was implemented with the program IBM SPSS Statistics. Interobserver variation analysis showed no significant difference between the two students, (PTAPSE =0,568 and PRVs´=0,548). Regression analysis showed RVs´ had slightly less measurement uncertainty than TAPSE. A weak positive correlation was found between RVs´ and TAPSE and 100% agreement regarding outcome was demonstrated, Kappa value was 1. Both methods have good interobserver variation in inexperienced examiners. In people with healthy heart and lungs, the relationship between TAPSE and RVs looks weakly positive. Previous studies identified stronger positive association. Differences in the results may be due to a lack of experience on the part of the students and a low number of participants.