Les films de simulations qui accompagnent le document ont été réalisés avec Pymol. / Les protéines accomplissent leur fonction dans la cellule grâce à leur faculté de changer de forme. Chaque classe de protéines peut se caractériser par une structure spécia- lisée partagée par ses membres avec un certain degré de variabilité. Tel est le cas des protéines à motifs mains-EF, qui se transforment en liant et déliant l ’ion calcium. Ce motif permet à la Troponin C de s’ouvrir et se refermer afin de moduler le mécanisme de contraction des fibres musculaires. Un mécanisme similaire permet à la Calmoduline de gérer l’activité de divers canaux cellulaires. Les techniques de simulations numériques peuvent aider à comprendre les trajectoires de ces transformations. Le projet principal de cette thèse consistait à développer une méthode informatique multi-échelle permettant de simuler des mouvements complexes à l’intérieur d ’une protéine. La représentation multi-échelle développée peut changer et s’adapter en cours de simulation. La méthode, ART holographique, explore l’espace en générant des basculements d’ensembles atomiques, selon des champs de force atomistiques non biaisés indiquant à tout moment comment les ensembles doivent pivoter. La méthode réduit le calcul des fluctuations locales mais conserve une représentation spatiale complète. La représentation multi-échelle est combinée à une technique de recherche de passages de transition énergétiquement favorables, ART nouveau, qui conduit la trajectoire moléculaire d ’étape en étape. Appliquée à plusieurs protéines, dont la Calmodulin et la Troponin C, ART holographique génère des trajectoires de transformation entre des conformations distantes de celles-ci, déjà connues grâce aux techniques de RMN ou de cristallographie. L’usage d ’une représentation spatiale complète tout au long de la simulation favorise le discernement de certains détails des mécanismes. Le rôle, l’ordre d ’intervention, ainsi que la coopérativité de certains résidus et structures impliqués dans le mécanisme des paires main-EF ont été explorés plus en détail et un état intermédiaire est proposé. / Proteins accomplish their function inside cells by means of conformational changes. Each protein class may be characterized by a specialized structure shared by its members with some variability. EF-hands proteins present a special motif which transforms itself while binding or unbinding the calcium ion. This structure allows Troponin C domains to open and close as it modulates the muscular fibers contraction. A similar mechanism allow Calmodulin to manage the activity of a diversity of protein channels. Computational techniques may help discover how these transformations occur. The main project of this thesis was the development of a multi-scale computational method for the simulation of complex motions inside a protein. The multi-scale approach is designed to adapt and change all along the simulation. The method, holographic ART, explore conformational space by generating swiveling and rotation of atomic ensembles, leaded by non biased atomistic forcefields. This determines at each step the overall motion, keeping a complete spatial representation, but with minimal local fluctuations computation. The multi-scale representation is combined with a unbiased open ended algorithm for identifying transitions states, ART nouveau, which guides the molecular trajectory from state to state. Applied to several proteins, the method was able to generate transforma- tion trajectories between distant conformations known from NMR and crystallography techniques. The use of a complete spatial representation throughout the simulation allows the method to capture atomistic details of each event. The purpose, the intervention order, as well as cooperativity between some residues and sub-structures involved in the EF-hand pair mechanism have been explored more in detail and an intermediate state is proposed.

Introdução: O tratamento quimioterápico com antraciclina está associado à cardiotoxicidade. Sua prevenção primária com o uso de beta-bloqueadores permanece controversa. O objetivo do presente estudo é avaliar o papel do carvedilol na prevenção da cardiotoxicidade relacionada ao tratamento com antraciclina. Métodos: estudo randomizado, duplo-cego, placebo controlado que incluiu 200 pacientes com câncer de mama, fração de ejeção ventricular esquerda (FEVE) preservada e uso de doxorrubicina (240 mg/m²) para receber carvedilol ou placebo até a conclusão da quimioterapia em proporção 1:1. O desfecho primário foi a redução > 10% da FEVE em seis meses. Os desfechos secundários foram o efeito do carvedilol nos marcadores de injúria miocárdica, troponina I (TnI) e peptídeo natriurético cerebral (BNP), e na disfunção diastólica. Resultados: O desfecho primário ocorreu em 14 (14,5%) pacientes do grupo carvedilol e em 13 (13,5%) do grupo placebo (p=1,0). Não houve diferença nos valores da FEVE durante o tratamento quimioterápico ou nos valores de BNP entre os grupos. Houve diferença significativa entre os grupos na distribuição dos níveis de TnI ao longo do tempo, com menor pico de TnI no grupo carvedilol (p=0,003). Além disso, houve menor incidência de disfunção diastólica no grupo carvedilol (p=0,039). Foi observada tendência para menor aumento do diâmetro diastólico do ventrículo esquerdo do início do tratamento até o final da quimioterapia no grupo carvedilol em relação ao placebo, respectivamente, 44,1+3,64 a 45,2+3,2 vs 44,9+3,6 a 46,4+4,0 mm (p=0,057). Conclusão: A incidência de cardiotoxicidade com o uso de doses contemporâneas de ANT foi menor do que relatado previamente com doses mais elevadas. Neste cenário, a administração de carvedilol resultou em redução significativa da injúria miocárdica avaliada pelos níveis de troponina I e pelo aparecimento da disfunção diastólica. No entanto, essa redução não teve impacto na disfunção sistólica relacionada à cardiotoxicidade (NCT01724450) / Background: Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Its prevention with beta-blockers remains controversial. The aim of this prospective, randomized, double-blind, placebo-controlled study was to evaluate the role of carvedilol in the prevention of early onset ANT cardiotoxicity. Methods: We randomized 200 patients with breast cancer and normal left ventricular ejection fraction (LVEF) referred for doxorubicin (240 mg/m²) to receive carvedilol or placebo until completion of chemotherapy. The primary end-point was a reduction > 10% in LVEF at six months. Secondary outcomes were the effects of carvedilol on troponin I (TnI), BNP and diastolic dysfunction. Results: Primary end-point occurred in 14 (14.5%) patients in the carvedilol and in 13 (13.5%) in the placebo (p=1.0). No difference in changes of LVEF or BNP was noted between groups. There was a significant difference between groups on the TnI levels over time, with lower TnI levels in carvedilol group (p=0.003). Additionally, a lower incidence of diastolic dysfunction was seen in carvedilol group (p=0.039). A trend towards less pronounced increase in LV end-diastolic diameter during follow up was noted in the carvedilol group, respectively 44.1+3.64 to 45.2+3.2 vs 44.9+3.6 to 46.4+4.0 mm (p=0.057). Conclusion: In this largest clinical trial of ?-blockers for prevention of early onset cardiotoxicity under contemporary doses of ANT, we noted a lower incidence of cardiotoxicity than higher doses. In this scenario, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction. However, this reduction had no impact on the incidence of cardiotoxicity-related myocardial systolic dysfunction (NCT01724450)

O complexo troponina-tropomiosina regula a contração muscular esquelética e cardíaca. A ligação do cálcio nos sítios regulatórios localizados no domínio N-terminal da troponina C (TnC) induz uma mudança conformacional que remove a ação inibitória da troponina I (TnI) e inicia a contração muscular. Nós usamos fragmentos recombinantes da TnI e uma série de mutantes da TnC para estudar as interações estruturais e regulatórias das diferentes regiões da TnI com os domínios da TnC, TnT e actina-tropomiosina. Nossos resultados indicam que a TnI é organizada em regiões que apresentam funções estruturais e regulatórias e que se ligam de modo antiparalelo com os correspondentes domínios estruturais e regulatórios da TnC. Estudos funcionais mostram que a região inibitória (aminoácidos 103-116) em combinação com a região C-terminal da TnI (TnI103-182) pode regular a atividade ATPásica da acto-miosina de maneira dependente de Ca2+. A regulação não é observada com a região inibitória em combinação com a região N-terminal (TnI116) Estudos de ligação mostram que a região N-terminal da TnI (TnI1-98) interage com o domínio C-terminal da TnC na presença e na ausência de Ca2+ e também interage com a TnT. A região inibitória/C-terminal da TnI (TnI103-182) interage com o domínio N-terminal da TnC de maneira dependente de Ca2+. Baseados nestes resultados, propomos um modelo para a mudança conformacional induzida pelo Ca2+. Neste modelo, a região N-terminal da TnI está ligada fortemente com o domínio C-terminal da TnC na presença ou na ausência de Ca2+. As regiões inibitórias e C-terminal da TnI ligam-se à actina-tropomiosina na ausência de Ca2+ e nos domínios N-terminal e C-terminal da TnC na presença de Ca2+. / The troponin-tropomyosin complex regulates skeletal and cardiac muscle contraction. Calcium binding to the regulatory sites in the N-terminal domain of troponin C (TnC). induces a conformational change which removes the inhibitory action of troponin I (TnI) and initiates muscular contraction. We used recombinant TnI fragments and a series of TnC mutants to study the structural and regulatory interactions between different TnI regions and the domains of TnC, TnT and actin-tropomyosin. Our results indicate that TnI is organized into regions with distinct structural and regulatory functions which bind, in an antiparallel manner, with the corresponding structural and regulatory domains of TnC. Functional studies show that a fragment containing the inhibitory and C-terminal regions of TnI (TnIl03-182) can regulate the actomyosin ATPase in a Ca2+- dependent manner. Regulation was not observed with a fragment containing the N-terminal and inhibitory regions (TnIl-116). Binding studies show that the N-terminal region of TnI (TnI1-98) interacts with the C-terminal domain of TnC in the presence of Ca2+ or Mg2+. The inhibitory/C-terminal region of TnI (TnI103-182) binds to the N-terminal domain of TnC in a Ca2+-dependent manner. Based on these results, we propose a model for the Ca2+ -induced conformational change. In this model the N-terminal region of TnI is bound strongly to the C-terminal domain of TnC in the presence or absence of Ca2+. The inhibitory and C-terminal regions of TnI bind to actin-tropomyosin in the absence of Ca2+ and to tne N- and C-terminal domains of TnC in the presence of Ca2+.

Introdução: O tratamento quimioterápico com antraciclina está associado à cardiotoxicidade. Sua prevenção primária com o uso de beta-bloqueadores permanece controversa. O objetivo do presente estudo é avaliar o papel do carvedilol na prevenção da cardiotoxicidade relacionada ao tratamento com antraciclina. Métodos: estudo randomizado, duplo-cego, placebo controlado que incluiu 200 pacientes com câncer de mama, fração de ejeção ventricular esquerda (FEVE) preservada e uso de doxorrubicina (240 mg/m²) para receber carvedilol ou placebo até a conclusão da quimioterapia em proporção 1:1. O desfecho primário foi a redução > 10% da FEVE em seis meses. Os desfechos secundários foram o efeito do carvedilol nos marcadores de injúria miocárdica, troponina I (TnI) e peptídeo natriurético cerebral (BNP), e na disfunção diastólica. Resultados: O desfecho primário ocorreu em 14 (14,5%) pacientes do grupo carvedilol e em 13 (13,5%) do grupo placebo (p=1,0). Não houve diferença nos valores da FEVE durante o tratamento quimioterápico ou nos valores de BNP entre os grupos. Houve diferença significativa entre os grupos na distribuição dos níveis de TnI ao longo do tempo, com menor pico de TnI no grupo carvedilol (p=0,003). Além disso, houve menor incidência de disfunção diastólica no grupo carvedilol (p=0,039). Foi observada tendência para menor aumento do diâmetro diastólico do ventrículo esquerdo do início do tratamento até o final da quimioterapia no grupo carvedilol em relação ao placebo, respectivamente, 44,1+3,64 a 45,2+3,2 vs 44,9+3,6 a 46,4+4,0 mm (p=0,057). Conclusão: A incidência de cardiotoxicidade com o uso de doses contemporâneas de ANT foi menor do que relatado previamente com doses mais elevadas. Neste cenário, a administração de carvedilol resultou em redução significativa da injúria miocárdica avaliada pelos níveis de troponina I e pelo aparecimento da disfunção diastólica. No entanto, essa redução não teve impacto na disfunção sistólica relacionada à cardiotoxicidade (NCT01724450) / Background: Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Its prevention with beta-blockers remains controversial. The aim of this prospective, randomized, double-blind, placebo-controlled study was to evaluate the role of carvedilol in the prevention of early onset ANT cardiotoxicity. Methods: We randomized 200 patients with breast cancer and normal left ventricular ejection fraction (LVEF) referred for doxorubicin (240 mg/m²) to receive carvedilol or placebo until completion of chemotherapy. The primary end-point was a reduction > 10% in LVEF at six months. Secondary outcomes were the effects of carvedilol on troponin I (TnI), BNP and diastolic dysfunction. Results: Primary end-point occurred in 14 (14.5%) patients in the carvedilol and in 13 (13.5%) in the placebo (p=1.0). No difference in changes of LVEF or BNP was noted between groups. There was a significant difference between groups on the TnI levels over time, with lower TnI levels in carvedilol group (p=0.003). Additionally, a lower incidence of diastolic dysfunction was seen in carvedilol group (p=0.039). A trend towards less pronounced increase in LV end-diastolic diameter during follow up was noted in the carvedilol group, respectively 44.1+3.64 to 45.2+3.2 vs 44.9+3.6 to 46.4+4.0 mm (p=0.057). Conclusion: In this largest clinical trial of ?-blockers for prevention of early onset cardiotoxicity under contemporary doses of ANT, we noted a lower incidence of cardiotoxicity than higher doses. In this scenario, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction. However, this reduction had no impact on the incidence of cardiotoxicity-related myocardial systolic dysfunction (NCT01724450)

Esse estudo descreve casos de “morte súbita” em bovinos associados com a ingestão de Amorimia (Mascagnia) exotropica em seis propriedades rurais localizadas na região metropolitana de Porto Alegre e da serra gaúcha. Os bovinos intoxicados foram encontrados mortos sem história de sinais clínicos prévios, ou apresentaram tremores musculares, quedas bruscas, movimentos de pedalagem, opistótono, respiração ofegante e decúbito lateral, quando induzidos ao movimento poucos minutos antes da morte. Registrou-se maior número de casos entre os meses de maio e agosto. Nove bovinos foram necropsiados e os principais achados macroscópicos observados foram mucosa oral levemente cianótica (3/9), hidropericárdio leve a moderado (3/9), petéquias e equimoses no epicárdio (5/9), coágulo no interior do ventrículo esquerdo (4/9), edema pulmonar (5/9) e mucosas vermelhas no abomaso e no intestino delgado (6/9). Histologicamente havia necrose de coagulação no miocárdio (9/9) caracterizada por retração celular, aumento da eosinofilia do citoplasma com perda das estriações, núcleos em picnose e ocasionais núcleos em cariorrexia e cariólise. No coração, edema intersticial (3/9) e infiltrado inflamatório intersticial, predominantemente, mononuclear (7/9) também foram observados. Nos rins de três bovinos havia degeneração hidrópicovacuolar multifocal das células epiteliais dos túbulos contorcidos distais associada com núcleos picnóticos deslocados para periferia da célula. As lesões cardíacas desses bovinos foram demonstradas através da imuno-histoquímica para troponina cardíaca C (cTnC). Nos corações dos bovinos intoxicados ocorreu diminuição acentuada de cTnC no citoplasma de grupos dos cardiomiócitos com características microscópicas de degeneração e necrose e, em algumas áreas havia perda total de imunomarcação. Raras fibras musculares cardíacas sem alteração histológica apresentaram perda de imunomarcação. Nos demais cardiomiócitos dos bovinos intoxicados sem lesões histológicas observou-se intensa marcação citoplasmática. / This study describes cases of sudden death in cattle that were associated with the consumption of Amorimia (Mascagnia) exotropica and occurred in six ranches located in the mountainous region of Rio Grande do Sul and the metropolitan region of Porto Alegre, Brazil. Affected cattle were found dead with no history of previous clinical signs, or showed muscular tremors, falls, paddling, opistotonus, panting, and lateral recumbence after being induced to move, few minutes before death. Most cases were recorded between May and August. Nine cattle were necropsied and main gross findings were oral mucosa slightly cyanotic (3/9), mild to intermediate hydropericardium (3/9), epicardial petechiae and ecchymoses (5/9), clot within the left ventricle (4/9), lung edema (5/9), apart of abomasal and small intestinal reddened mucosa (6/9). Histologically, there was myocardial coagulation necrosis (9/9), which was characterized by cellular retraction, enhanced cytoplasmic eosinophilia, lack of cytoplasmic striations and occasional nuclear karyorrhexis and karyolysis. There also were interstitial edema (3/9) and interstitial inflammatory infiltrate (mainly mononuclear) (7/9) in the heart. Apart of multifocal vacuolar-hydropic degeneration in the epithelial cells of the distal convoluted tubules associated with pyknotic and eccentric nuclei in the kidneys of three cattle. The cardiac lesions of these cattle were demonstrated by immunohistochemistry for cardiac troponin C (cTnC). In the hearts of cattle intoxicated was severe reduction of the cTnC in the cytoplasm of cardiomyocytes groups with microscopic features of degeneration and necrosis, and in some areas with complete loss of immunoreactivity. Rare cardiac muscle fibers showed no histological abnormality loss of immune-marking. In the remaining cardiomyocytes in cattle poisoned histological lesions were absent, but an intense cytoplasmic staining in these cells was observed.

A degeneração valvar crônica mitral (DVCM) é uma cardiopatia de alta prevalência na clínica médica de pequenos animais e acomete principalmente cães idosos de raças de pequeno porte. A fim de se acompanhar a evolução da insuficiência cardíaca (IC), a galectina-3 (Gal-3) vem sendo utilizada como um biomarcador na identificação de doenças cardíacas pré-clínicas, progressão e descompensação em pacientes humanos. O objetivo deste estudo clínico foi estabelecer intervalos de referência da Gal-3 na população canina estudada e determinar a utilidade desse novo biomarcador sérico, isoladamente ou em associação com o pró-peptídeo natriurético tipo B (NT-proBNP) e a troponina cardíaca I (cTnI), para estimativa de prognóstico em curto prazo em cães com IC decorrente de DVCM. O delineamento fundamentou-se em um estudo clínico observacional transversal prospectivo com braço longitudinal. A amostra foi composta por 139 cães distribuídos em cinco grupos criteriosamente selecionados de acordo com o estadiamento da DVCM (Grupo controle: estágio A- composto por 60 cães hígidos de raças de pequeno porte com predisposição à DVCM, 28 cães em estágio B1, 20 cães em B2, 20 cães em estágio C e 11 cães em estágio D), advindos da rotina do Serviço de Cardiologia do VCM, Hospital Veterinário da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo. Os grupos B1, B2, C e D foram avaliados em um segundo momento, aos 60 dias. Foram dosados Gal-3 humana e canina, NTproBNP e cTnI. Os valores de referência mensurados no grupo A para Gal-3 humana foram de 7,548 ng/mL (P25%-75%=8,933-10,960). A recuperação da concentração de Gal-3 em cães clinicamente saudáveis, obtida com kit canino, foi significativamente mais baixa, com baixa repetibilidade e reprodutibilidade, em comparação com o kit humano, sugerindo assim menor sensibilidade do kit canino utilizado. Ainda, a magnitude e a variação nas concentrações de Gal-3 humana e canina não permitiram a detecção de diferenças entre os estágios da DVCM e também não foram capazes de identificar pacientes em IC. Conclui-se, portanto, que diferentemente dos demais marcadores avaliados, NT-proBNP e cTnI, já consagrados na IC para a espécie canina, a Gal-3 não se constitui em um biomarcador adequado para avaliar a IC secundária à DVCM em cães / Chronic mitral valve degeneration (CMVD) is a highly prevalent heart disease in small animal internal medicine seen mainly in older small breed dogs. In order to follow the progression of heart failure (HF), galectin-3 (Gal-3) has been applied as a biomarker to identify pre-clinical cardiac diseases, progression and decompensation in human patients. This study aimed to establish reference intervals for Gal-3 in a canine population, and to determine the utility of this new biomarker, isolated or in association with Type B natriuretic pro-peptide (NT-proBNP) and cardiac troponin I to estimate short term prognosis in dogs with HF caused by CMVD. It was designed as an observational prospective cross-sectional clinical study with a longitudinal arm. One hundred thirty nine dogs were distributed among five groups with rigorous selection criteria, according to ACVIM CMVD staging (Control group: stage A- 60 healthy small breed dogs, predisposed to CMVD; 28 dogs in stage B1, 20 dogs in stage B2, 20 dogs in stage C and 11 dogs in stage D), recruited from the Cardiology Service from the Veterinary Teaching Hospital, School of Veterinary Medicine, University of São Paulo. Groups B1, B2, C and D had a second blood sampling at day 60. Measurements were obtained for human and canine Gal-3, NT-proBNP and cTnI. Reference values obtained for group A for human Gal-3 were 7.548 ng/mL (P25%-75%=8.933-10.960). Gal-3 concentration recovery for healthy dogs obtained with canine kit was significantly lower, with low repeatability and reproducibility, compared to the human kit, suggesting lower sensitivity of the canine Gal-3 kit used. We concluded that the magnitude and variation observed in human and canine Gal-3 did not allow for detection of differences between stages of CMVD nor were capable of identifying patients in HF, compared to the other measured biomarkers, NT-proBNP and cTnI, already established for canine HF evaluation

Objetivo: Avaliar a relação entre os parâmetros da cardiotocografia computadorizada (cCTG) e da dopplervelocimetria com a lesão miocárdica fetal e com a ocorrência de acidemia no nascimento, em gestações com insuficiência placentária. Métodos: Estudo prospectivo com 49 gestações complicadas pela insuficiência placentária (Doppler de artéria umbilical anormal - índice de pulsatilidade [IP] > p95) diagnosticada entre 26 e 34 semanas. Todas as pacientes foram avaliadas pelo Doppler de artéria umbilical, artéria cerebral média e ducto venoso e pela cCTG (Sonicaid FetalCare, versão 2.2, por 30 minutos). Foi analisada a última avaliação fetal até 48h antes do parto e anterior à corticoterapia. Foi analisado o sangue de cordão umbilical no parto, para detectar a acidemia no nascimento (pH < 7,20) e a lesão miocárdica fetal (Troponina T cardíaca [cTnT] >= 0,09 ng/mL). A cTnT foi obtida em 38 casos e o pH em 46 casos. Resultados: Quinze (39,5%) recém-nascidos apresentaram cTnT >= 0,09 ng/ml e 20 (43,5%) pH < 7,20. Os fetos que evoluíram com acidemia apresentaram menor número de movimentos por hora na cCTG (mediana 2 vs. 15, p=0,019). Houve correlação positiva entre o pH e o número de movimentos fetais por hora (rho=0,35; P=0,019) e com a frequência cardíaca fetal basal (rho 0,37, P=0,011), e correlação negativa entre o pH e o escore zeta do IP para veias (IPV) do ducto venoso (rho= -0,31, P=0,036). A regressão logística identificou o escore-zeta do IPV do ducto venoso (P=0,023) e a frequência cardíaca fetal basal (P=0,040) como variáveis independentes associadas com a acidemia no nascimento. A ocorrência de lesão miocárdica fetal, quando comparada ao grupo com cTnT normal, apresentou associação significativa com o escore zeta do IP da artéria umbilical (mediana 8,8 vs. 4,0; P=0,003), IPV do ducto venoso (mediana 2,6 vs. -1,4; P= 0,007), frequência cardíaca fetal basal (mediana 146 vs. 139 bpm; P=0,033), número de acelerações entre 10-15 bpm (mediana 0 vs. 1; P=0,013), duração dos episódios de baixa variação (mediana 21 vs. 10 min; P=0,038) e a variação de curto prazo (short-term variation-STV) (mediana 3,7 vs. 6,1 ms; P=0,003). Observou-se correlação positiva entre o valor da cTnT no cordão umbilical e a frequência cardíaca fetal basal (rho=0,33; P=0,042), e correlação negativa entre a cTnT e a STV (rho= -0,37; P=0,021). A regressão logística identificou a STV como fator preditor independente para o dano miocárdico fetal (P=0,01), sendo a STV <= 4,3 ms o melhor ponto de corte para predição do evento (sensibilidade de 66,7% e especificidade de 91,3%). Conclusão: Em gestações com insuficiência placentária detectada antes da 34ª semana gestacional, o IPV do ducto venoso e a frequência cardíaca fetal basal analisada pela cCTG são os preditores independentes associados com a acidemia no nascimento; e o valor da STV avaliada pela cCTG é a variável que melhor prediz a lesão miocárdica fetal. A cCTG é ferramenta importante no manejo de fetos com insuficiência placentária, principalmente quando associada a outros métodos propedêuticos como a dopplervelocimetria / Objective: To evaluate the reliability of fetal heart rate parameters analyzed by computerized cardiotocography (cCTG) and fetal Doppler to predict myocardial damage and acidemia at birth in pregnancies complicated by placental insufficiency. Methods: Forty nine patients with placental insufficiency (abnormal umbilical artery Doppler - pulsatility index [PI] > p95) diagnosed between 26-34 weeks of gestation were prospectively studied. All patients were submitted to Dopplervelocimetry of umbilical artery, middle cerebral artery and ductus venosus and to the cCTG (Sonicaid Fetal Care, version 2.2; 30 minutes of duration). We analyzed the last fetal assessment 48h before delivery and prior to steroid therapy.Umbilical cord blood samples were collected at birth to detect acidemia (pH < 7.20) and myocardial damage (cTnT >= 0.09 ng/ml). The results of cTnT were available in 38 cases and in 46 cases we had the pH values. Results: Fifteen (39.5%) newborns had cTnT >= 0.09 ng/ml and 20 (43.5%) had a pH < 7.20. Fetuses who developed acidemia had fewer fetal movements per hour in cCTG (median 2 vs. 15, P=0.019). There was a positive correlation between pH and the number of fetal movements per hour (rho 0.35, P=0.019) and basal fetal heart rate (rho 0.37, P=0.011), and a negative correlation between pH and the zscore of pulsatility index for veins (PIV) of ductus venosus (rho= -0.31, P=0.036). The logistic regression analysis identified the z-score of PIV of ductus venosus (P=0.023) and basal fetal heart rate (P=0.040) as independent variables associated with acidemia at birth. The occurrence of fetal myocardial injury was significantly associated with z-score of PI of umbilical artery (median 8.8 vs. 4.0, P=0.003), PIV of ductus venosus (median 2.6 vs. -1.4, P=0.007), basal fetal heart rate (median 146 vs. 139 bpm, P=0.033), number of accelerations between 10-15 bpm (median 0 vs. 1, P=0.013), duration of episodes of low variation (median 21 vs. 10 min, P=0.038) and short-term variation (STV) (median 3.7 vs. 6.1 ms, P=0.003). We observed a positive correlation between the value of cTnT in the umbilical cord and basal fetal heart rate (rho=0.33, P=0.042), and a negative correlation between cTnT and STV (rho=-0.37, P=0.021). Logistic regression identified the STV as an independent predictor for myocardial damage (P=0.01), and STV <= 4.3 ms was the best cutoff to predict the event (sensitivity 66.7% and specificity of 91.3%). Conclusion: In pregnancies with placental insufficiency detected before the 34th week of gestation, the PIV of ductus venosus and basal fetal heart rate analyzed by cCTG are independent variables associated with acidemia at birth; and the STV is the parameter that best predicts fetal myocardial injury. The cCTG is an important tool in the management of fetuses with placental insufficiency, especially when associated with other diagnostic methods such as Doppler

Objetivo: Avaliar a relação entre os parâmetros da cardiotocografia computadorizada (cCTG) e da dopplervelocimetria com a lesão miocárdica fetal e com a ocorrência de acidemia no nascimento, em gestações com insuficiência placentária. Métodos: Estudo prospectivo com 49 gestações complicadas pela insuficiência placentária (Doppler de artéria umbilical anormal - índice de pulsatilidade [IP] > p95) diagnosticada entre 26 e 34 semanas. Todas as pacientes foram avaliadas pelo Doppler de artéria umbilical, artéria cerebral média e ducto venoso e pela cCTG (Sonicaid FetalCare, versão 2.2, por 30 minutos). Foi analisada a última avaliação fetal até 48h antes do parto e anterior à corticoterapia. Foi analisado o sangue de cordão umbilical no parto, para detectar a acidemia no nascimento (pH < 7,20) e a lesão miocárdica fetal (Troponina T cardíaca [cTnT] >= 0,09 ng/mL). A cTnT foi obtida em 38 casos e o pH em 46 casos. Resultados: Quinze (39,5%) recém-nascidos apresentaram cTnT >= 0,09 ng/ml e 20 (43,5%) pH < 7,20. Os fetos que evoluíram com acidemia apresentaram menor número de movimentos por hora na cCTG (mediana 2 vs. 15, p=0,019). Houve correlação positiva entre o pH e o número de movimentos fetais por hora (rho=0,35; P=0,019) e com a frequência cardíaca fetal basal (rho 0,37, P=0,011), e correlação negativa entre o pH e o escore zeta do IP para veias (IPV) do ducto venoso (rho= -0,31, P=0,036). A regressão logística identificou o escore-zeta do IPV do ducto venoso (P=0,023) e a frequência cardíaca fetal basal (P=0,040) como variáveis independentes associadas com a acidemia no nascimento. A ocorrência de lesão miocárdica fetal, quando comparada ao grupo com cTnT normal, apresentou associação significativa com o escore zeta do IP da artéria umbilical (mediana 8,8 vs. 4,0; P=0,003), IPV do ducto venoso (mediana 2,6 vs. -1,4; P= 0,007), frequência cardíaca fetal basal (mediana 146 vs. 139 bpm; P=0,033), número de acelerações entre 10-15 bpm (mediana 0 vs. 1; P=0,013), duração dos episódios de baixa variação (mediana 21 vs. 10 min; P=0,038) e a variação de curto prazo (short-term variation-STV) (mediana 3,7 vs. 6,1 ms; P=0,003). Observou-se correlação positiva entre o valor da cTnT no cordão umbilical e a frequência cardíaca fetal basal (rho=0,33; P=0,042), e correlação negativa entre a cTnT e a STV (rho= -0,37; P=0,021). A regressão logística identificou a STV como fator preditor independente para o dano miocárdico fetal (P=0,01), sendo a STV <= 4,3 ms o melhor ponto de corte para predição do evento (sensibilidade de 66,7% e especificidade de 91,3%). Conclusão: Em gestações com insuficiência placentária detectada antes da 34ª semana gestacional, o IPV do ducto venoso e a frequência cardíaca fetal basal analisada pela cCTG são os preditores independentes associados com a acidemia no nascimento; e o valor da STV avaliada pela cCTG é a variável que melhor prediz a lesão miocárdica fetal. A cCTG é ferramenta importante no manejo de fetos com insuficiência placentária, principalmente quando associada a outros métodos propedêuticos como a dopplervelocimetria / Objective: To evaluate the reliability of fetal heart rate parameters analyzed by computerized cardiotocography (cCTG) and fetal Doppler to predict myocardial damage and acidemia at birth in pregnancies complicated by placental insufficiency. Methods: Forty nine patients with placental insufficiency (abnormal umbilical artery Doppler - pulsatility index [PI] > p95) diagnosed between 26-34 weeks of gestation were prospectively studied. All patients were submitted to Dopplervelocimetry of umbilical artery, middle cerebral artery and ductus venosus and to the cCTG (Sonicaid Fetal Care, version 2.2; 30 minutes of duration). We analyzed the last fetal assessment 48h before delivery and prior to steroid therapy.Umbilical cord blood samples were collected at birth to detect acidemia (pH < 7.20) and myocardial damage (cTnT >= 0.09 ng/ml). The results of cTnT were available in 38 cases and in 46 cases we had the pH values. Results: Fifteen (39.5%) newborns had cTnT >= 0.09 ng/ml and 20 (43.5%) had a pH < 7.20. Fetuses who developed acidemia had fewer fetal movements per hour in cCTG (median 2 vs. 15, P=0.019). There was a positive correlation between pH and the number of fetal movements per hour (rho 0.35, P=0.019) and basal fetal heart rate (rho 0.37, P=0.011), and a negative correlation between pH and the zscore of pulsatility index for veins (PIV) of ductus venosus (rho= -0.31, P=0.036). The logistic regression analysis identified the z-score of PIV of ductus venosus (P=0.023) and basal fetal heart rate (P=0.040) as independent variables associated with acidemia at birth. The occurrence of fetal myocardial injury was significantly associated with z-score of PI of umbilical artery (median 8.8 vs. 4.0, P=0.003), PIV of ductus venosus (median 2.6 vs. -1.4, P=0.007), basal fetal heart rate (median 146 vs. 139 bpm, P=0.033), number of accelerations between 10-15 bpm (median 0 vs. 1, P=0.013), duration of episodes of low variation (median 21 vs. 10 min, P=0.038) and short-term variation (STV) (median 3.7 vs. 6.1 ms, P=0.003). We observed a positive correlation between the value of cTnT in the umbilical cord and basal fetal heart rate (rho=0.33, P=0.042), and a negative correlation between cTnT and STV (rho=-0.37, P=0.021). Logistic regression identified the STV as an independent predictor for myocardial damage (P=0.01), and STV <= 4.3 ms was the best cutoff to predict the event (sensitivity 66.7% and specificity of 91.3%). Conclusion: In pregnancies with placental insufficiency detected before the 34th week of gestation, the PIV of ductus venosus and basal fetal heart rate analyzed by cCTG are independent variables associated with acidemia at birth; and the STV is the parameter that best predicts fetal myocardial injury. The cCTG is an important tool in the management of fetuses with placental insufficiency, especially when associated with other diagnostic methods such as Doppler

<p>The aims of this project were to investigate the impact of perioperative myocardial damage on morbidity and mortality after coronary artery bypass grafting (CABG), to determine whether biochemical marker levels after CABG correlate to perioperative myocardial infarct size, and to assess the long-term morbidity after CABG, in particular to determine whether women do worse.</p><p>The studies were conducted in patients who had undergone isolated, primary CABG. The correlation of postoperative cardiac marker levels to early and late survival was evaluated in 4,911 consecutive patients; this showed that elevated cardiac markers implied a highly increased risk of both early cardiac death and late death. Hospital readmission for any cause and effect of gender on the readmission rate were analysed in 7,493 patients; it was found that the risk of readmission was higher in women than in men, because of greater co-morbidity and higher age. In the same patient cohort, it was clearly demonstrated that perioperative myocardial damage increased the risk of heart failure independently, and that late mortality was greatly increased in patients readmitted for heart failure. Finally, in a prospective, clinical trial, creatine kinase MB (CK-MB) and troponin I and T levels were found to correlate to infarction mass, as quantified by magnetic resonance imaging postoperatively. The findings strongly suggested that CK-MB above five times the upper normal limit was the result of perioperative myocardial infarction.</p><p>In conclusion, perioperative myocardial damage is an important adverse event with a highly negative effect on early and late survival after CABG, and also entails an increased risk of subsequent heart failure, which markedly impairs long-term survival. Gender differences may be explained by patient characteristics and risk factors and not by female sex per se. Increases in biochemical markers after CABG correspond to the amount of perioperatively infarcted myocardium. </p>

The aims of this project were to investigate the impact of perioperative myocardial damage on morbidity and mortality after coronary artery bypass grafting (CABG), to determine whether biochemical marker levels after CABG correlate to perioperative myocardial infarct size, and to assess the long-term morbidity after CABG, in particular to determine whether women do worse. The studies were conducted in patients who had undergone isolated, primary CABG. The correlation of postoperative cardiac marker levels to early and late survival was evaluated in 4,911 consecutive patients; this showed that elevated cardiac markers implied a highly increased risk of both early cardiac death and late death. Hospital readmission for any cause and effect of gender on the readmission rate were analysed in 7,493 patients; it was found that the risk of readmission was higher in women than in men, because of greater co-morbidity and higher age. In the same patient cohort, it was clearly demonstrated that perioperative myocardial damage increased the risk of heart failure independently, and that late mortality was greatly increased in patients readmitted for heart failure. Finally, in a prospective, clinical trial, creatine kinase MB (CK-MB) and troponin I and T levels were found to correlate to infarction mass, as quantified by magnetic resonance imaging postoperatively. The findings strongly suggested that CK-MB above five times the upper normal limit was the result of perioperative myocardial infarction. In conclusion, perioperative myocardial damage is an important adverse event with a highly negative effect on early and late survival after CABG, and also entails an increased risk of subsequent heart failure, which markedly impairs long-term survival. Gender differences may be explained by patient characteristics and risk factors and not by female sex per se. Increases in biochemical markers after CABG correspond to the amount of perioperatively infarcted myocardium.