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Submitted by Jonathan Barbosa (jon_crf@hotmail.com) on 2012-02-14T17:03:17Z No. of bitstreams: 1 Borojevic4.2009.pdf: 698028 bytes, checksum: 86151947ffa804d5f04fdf87847645f9 (MD5) Approved for entry into archive by Regina Mello(mrmello@inmetro.gov.br) on 2012-06-26T17:14:30Z (GMT) No. of bitstreams: 1 Borojevic4.2009.pdf: 698028 bytes, checksum: 86151947ffa804d5f04fdf87847645f9 (MD5) Made available in DSpace on 2012-06-27T17:48:52Z (GMT). No. of bitstreams: 1 Borojevic4.2009.pdf: 698028 bytes, checksum: 86151947ffa804d5f04fdf87847645f9 (MD5) Previous issue date: 2009 Fundamento: Diversos estudos foram publicados sobre a ação de células tronco da medula óssea no ventrículo esquerdo, ao atuarem no remodelamento pós-infarto agudo do miocárdio. Os resultados, no entanto, têm se mostrado controversos. Objetivo: Avaliar através do ecocardiograma a função sistólica de pacientes com infarto agudo do miocárdio após o Transplante Autólogo de Células Mononucleares da Medula Óssea (TACMMO) através de duas vias injeção: intracoronariana e intravenosa. Métodos: Estudo aberto, prospectivo, randomizado. Foram incluídos pacientes admitidos por infarto agudo do miocárdio (IAM) com supradesnivelamento do segmento ST e submetidos à reperfusão mecânica ou química, dentro de 24 horas após o início dos sintomas, que apresentavam ao ecocardiograma redução da contratilidade segmentar e defeito fixo da perfusão relacionada à artéria culpada pelo IAM. A medula óssea autóloga foi aspirada da crista ilíaca posterior sob sedação e analgesia, nos pacientes randomizados para o grupo tratado. Após manipulação laboratorial, 100 milhões de células mononucleares foram injetadas por via intracoronariana ou intravenosa. Utilizamos o ecocardiograma (Vivid 7) para avaliar a função ventricular antes e após três e seis meses da infusão de células. Resultados: Foram incluídos trinta pacientes, 14 no grupo arterial (GA), dez no grupo venoso (GV) e seis no grupo controle (GC). Não houve diferença estatística dos parâmetros ecocardiográficos estudados entre os grupos. Conclusão: O transplante autólogo de células mononucleares da medula óssea não demonstrou melhora dos parâmetros ecocardiográficos da função sistólica. (Arq Bras Cardiol 2009; 93(3) : 374-379) 6 p. : il.

O implante de celulas para o tratamento de doencas cardiovasculares encontra-se sob investigacao em varios centros no mundo. Varias linhagens celulares, de celulas-tronco bem caracterizadas a fracoes contendo diferentes tipos de celulas, tem sido investigadas em modelos animais. Apesar dos avancos obtidos na ultima decada, na area de ciencia basica, com relacao a esta nova modalidade terapeutica, diversas questoes permanecem sem resposta. Pouco ainda se sabe sobre os mecanismos atraves dos quais a terapia celular possa gerar resultados efetivos. Adicionalmente, a melhor via para o transplante, o numero total e a concentracao de celulas, e o melhor tipo celular permanecem questoes importantes, ainda sem definicao. E fato de que diversas celulas da medula ossea exercem seus efeitos atraves de mecanismos paracrinos e de que existe um complexo mecanismo de interacao, contato e liberacao de sinais entre essas celulas e as outras populacoes celulares nos orgaos lesados. Atualmente, a maioria dos estudos em humanos se concentra em celulas de origem adulta e autologa, em oposicao ao uso de celulas de origem embrionaria. Esta revisao analisa os principais ensaios clinicos que utilizaram celulas derivadas de medula ossea em quatro cardiopatias: doenca arterial coronariana aguda e cronica, e nas cardiomiopatias chagasica e dilatada. Os resultados desses estudos demonstram que o procedimento e seguro e exequivel, e potencialmente eficaz. Inquestionavelmente, mais estudos pre-clinicos e clinicos sao necessarios para acessar o real potencial beneficio desse novo modelo terapeutico.

FUNDAMENTO: A injeção de células-tronco no contexto do infarto agudo do miocárdio (IAM) tem sido testada quase exclusivamente pela via anterógrada intra-arterial coronariana (IAC). A via retrógrada intravenosa coronariana (IVC) pode ser uma via adicional. OBJETIVO: Comparar o padrão de distribuição e retenção celular nas vias anterógrada e retrógrada. Investigar o papel da obstrução microvascular pela ressonância magnética na retenção de células pelo tecido cardíaco após a injeção de células mononucleares da medula óssea (CMMO) no IAM. MÉTODOS: Estudo prospectivo, aberto, randomizado. Foram incluídos pacientes com IAM que apresentassem: (1) reperfusão mecânica ou química com sucesso em até 24 horas do início dos sintomas e (2) infarto acometendo mais de 10% da área do ventrículo esquerdo (VE) pela cintilografia miocárdica. Cem milhões de CMMO foram injetadas na artéria relacionada ao infarto pela via IAC ou veia, pela via IVC. Um por cento das células injetadas foi marcado com Tc99m-hexametil-propileno-amina-oxima(99mTc-HMPAO). A distribuição das células foi avaliada 4 e 24 horas após a injeção da cintilografia miocárdica. Ressonância magnética cardíaca foi realizada antes da injeção de células. RESULTADOS: Trinta pacientes foram distribuídos aleatoriamente em três grupos. Não houve eventos adversos graves relacionados ao procedimento. A retenção precoce e tardia das células marcadas foi maior no grupo IAC do que no grupo IVC, independentemente da presença de obstrução da microcirculação. CONCLUSÃO: A injeção pela abordagem retrógrada mostrou-se viável e segura. A retenção de células pelo tecido cardíaco foi maior pela via anterógrada. Mais estudos são necessários para confirmar esses achados. BACKGROUND: The injection of stem cells in the context of acute myocardial infarction (AMI) has been tested almost exclusively by anterograde intra-arterial coronary (IAC) delivery. The retrograde intravenous coronary (IVC) delivery may be an additional route. OBJECTIVE: To compare the cell distribution and retention pattern in the anterograde and retrograde routes. To investigate the role of microvascular obstruction by magnetic resonance imaging in cell retention by cardiac tissue after the injection of bone marrow mononuclear cells (BMMC) in AMI. METHODS: This was a prospective, open label, randomized study. Patients with AMI who presented: (1) successful chemical or mechanical reperfusion within 24 hours of symptom onset and (2) infarction involving more than 10% of the left ventricle (LV) at the myocardial scintigraphy were included in the study. One hundred million BMMC were injected into the infarction-related artery through IAC route, or vein through the IVC route. One percent of the injected cells were labeled with 99mTc-hexamethyl-propylene-amine-oxime (99mTc-HMPAO). Cell distribution was evaluated at 4 and 24 hours after the myocardial scintigraphy injection. Cardiac magnetic resonance imaging was performed before cell injection. RESULTS: Thirty patients were randomized into three groups. There were no serious adverse events related to the procedure. The early and late retention of labeled cells was higher in the IAC group than in IVC group, regardless of the presence of microcirculation obstruction. CONCLUSION: The injection using the retrograde approach was feasible and safe. Cell retention by cardiac tissue was higher using the anterograde approach. More studies are needed to confirm these findings.

Background Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The St udy O f Trial P olicy Of I nterim T runcation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. Methods/Design We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation. Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. Discussion A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.

The objective of this study was to investigate safety and feasibility of autologous bone marrow mononuclear cells (BMMNC) transplantation in ST elevation myocardial infarction (STEMI), comparing anterograde intracoronary artery (ICA) delivery with retrograde intracoronary vein (ICV) approach. An open labeled, randomized controlled trial of 30 patients admitted with STEMI was used. Patients were enrolled if they 1) were successfully reperfused within 24 h from symptoms onset and 2) had infarct size larger than 10% of the left ventricle (LV). One hundred million BMMNC were injected in the infarct-related artery (intra-arterial group) or vein (intravenous group), 1% of which was labeled with Tc99m-hexamethylpropylenamineoxime. Cell distribution was evaluated 4 and 24 h after injection. Baseline MRI was performed in order to evaluate microbstruction pattern. Baseline radionuclide ventriculography was performed before cell transfer and after 3 and 6 months. All the treated patients were submitted to repeat coronary angiography after 3 months. Thirty patients (57 ± 11 years, 70% males) were randomly assigned to ICA ( n = 14), ICV ( n = 10), or control ( n = 6) groups. No serious adverse events related to the procedure were observed. Early and late retention of radiolabeled cells was higher in the ICA than in the ICV group, independently of microcirculation obstruction. An increase of EF was observed in the ICA group ( p = 0.02) compared to baseline. Injection procedures through anterograde and retrograde approaches seem to be feasible and safe. BMMNC retention by damaged heart tissue was apparently higher when the anterograde approach was used. Further studies are required to confirm these initial data.

Age 76 (65-83) 76 (64-84) 76 (67-82) 0.382 Gender (% Female) 51.6 52.4 49.3 !0.01 Race (% Caocasion) 76.4 74.3 82.0 !0.01 Ishcemic etiology 45.7 45.0 47.7 !0.01 Atrial arrhythomia 30.8 30.0 32.9 !0.01 Pulmonary HTN 6.3 5.3 8.7 !0.01 Renal insufficiency 19.6 19.3 20.4 !0.01 Dyspnea at rest 43.8 42.5 47.1 !0.01 BNP 804 (407-1670) 835 (425-1720) 735 (360-1540) !0.01 Troportin (Abnormal) 21.0 21.4 20.1 !0.01 Discharge beta blocker 67.9 70.2 62.7 !0.01 Discharge ACE-imbioitor 56.0 57.6 52.3 !0.01

Background Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. Methods A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 × 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). Implications Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required. Trial Register This trial is registered at the NIH registry under the number NCT00350766.