Cellular Cardiomyoplasty (cell therapy for myocardial regeneration) targets the basic pathophysiology of heart failure and represents a novel technique for augmenting the function of the failing heart. Previous studies have demonstrated massive mechanical losses in the first few minutes. Thus, efforts to reduce mechanical losses may prove more beneficial than those directed against biological losses alone. We believe that "Wash-out" into the disrupted blood vessels is responsible for these early losses. / In the first part of this study we hypothesized that by increasing the size of the injectate, the amount of immediate losses can be reduced achieving better retention. Using Alginate-poly-L-lysine-Alginate (APA) miscrocapsules of two different sizes (200mum&400mum) and comparing retention with bare microspheres (10mum) of similar size to MSCs, we demonstrated that immediate retention rate increased by four folds. The retention rate for group 1 (microspheres only) was 4.28+/-3.46% which was significantly lower than that for groups 2 (microspheres in 200mum microcapsules) at 16.45+/-12.66% and group 3 (microspheres in 400mum microcapsules) at 12.93+/-6.28% for Group (p<0.05). There was no difference between group 2 and 3. / In the second part, we investigated the potential of gradually increasing the cell load on functional improvement and engraftment using conventional intramuscular delivery. Five groups of rats received escalating doses of MSCs after surgically induced ischemia (gp1 no cells, gp2 0.5x 10 6, gp3 1.5x106, gp4 3x106,gp5 5x106 MSCs). At 7 weeks, we observed significant improvement in cardiac function in groups 3 to 5 compared to post-infarction baseline. This was not observed in groups 1 & 2. However, in groups 3 to 5, we observed no functional advantage for increasing the cell load beyond a minimal therapeutic dose. This is consistent with our hypothesis that small cells are washed out into the circulation. / We also showed the ability of Alginate-Poly-l-lysine-Alginate (APA) microcapsules to sustain the viability of encapsulated MSCs in-vitro. Finally, the ability of encapsulated MSCs to improve the function of the heart in-vivo was tested.

No description available.

BACKGROUND Adult bone marrow derived MSCs had been explored to treat myocardial infarction (MI) and heart failure, for which various beneficial paracrine effects had been suggested. Since MSCs in vitro express anti-inflammatory cytokines, we tested the hypothesis that changes in the pro-/anti-inflammatory cytokine ratio in the infarct microenvironment may provide such a paracrine mechanism to improve early cardiac function following acute coronary occlusion. / Methods Rats (n=88) underwent acute left coronary artery ligations and were randomized into groups M and C and then injected with culture media or MSCs, respectively. These rats underwent blinded echocardiography to evaluate left ventricular ejection fractions (LVEF). Real Time PCR was used to compare cytokine gene expression for IL-1beta, IL-6, IL-8 (pro-inflammatory) and IL-10 (anti-inflammatory) at various times. Extra-cellular matrix (ECM) deposition and inflammatory cell infiltration were also analyzed. / Results As early as 12 hours, the ratio of pro-/anti-inflammatory cytokine gene expression in group C was significantly lower than group M. Similar results were found at 24 hours, 1 and 2 weeks, respectively. LVEF improved significantly in group C (M=62% vs C=68% at 12 hours* , M=66% vs C=75% at 24 hours*, M=57% vs C=75% at 1 week *, and M=52% vs C=70% at 2 weeks*, *p<0.01). The ratio of MMP-2/TIMP1 levels was lower in the Group C at all time frames, reaching significance at 12 and 24 hours and 2 weeks. In group C, histopathological analysis revealed significantly less ECM deposition (M=1.95% vs C=0.75% at 24 hours*, M=19.30% vs C=9.36% at 1 week*, M=24.46% vs C=7.57% at 2 weeks*, *p<0.01). This was associated with significantly decreased inflammatory cell infiltration after 24 hours. / Conclusions The current data suggests that MSCs therapy decreases the pro-/anti-inflammatory cytokine ratio in the infarct microenvironment. This is associated with improved cardiac function, reduced ECM deposition, and decreased inflammatory cell infiltration. This paracrine mechanism of MSCs therapy may explain the early functional improvement after MI before cell transdifferentiation or other mechanisms takes place.

No description available.

INTRODUÇÃO: Apesar dos avanços nas técnicas cirúrgicas e cuidados intensivos, o infarto do miocárdio perioperatório (IMPO) ainda é uma complicação da cirurgia de revascularização miocárdica (CRM), de difícil diagnóstico. Nessa situação, os parâmetros clínicos habitualmente utilizados para o seu reconhecimento têm limitações, podendo estar alterados pelo trauma cirúrgico. A ressonância magnética cardiovascular (RMC), por sua vez, detém alta acurácia para a detecção de necrose miocárdica. OBJETIVOS: Avaliar a detecção de IMPO pela RMC, comparando-a com os critérios de diagnóstico clínico (DC) e com a cintilografia miocárdica, com pirofosfato de tecnécio-99m (SPECT), assim como investigar a repercussão das áreas de IMPO visualizadas à RMC sobre a função sistólica ventricular esquerda. MÉTODOS: Entre agosto de 2003 e março de 2006, foram estudados 24 pacientes adultos, portadores de doença arterial coronária crônica, com indicação de CRM. Eles foram submetidos a RMC, com técnicas de cine-ressonância e realce tardio, antes e depois da cirurgia, analisando-se o surgimento de novas áreas de necrose miocárdica (IMPO) e/ou disfunção contrátil ventricular esquerda. Também foram realizados: eletrocardiogramas (ECG) seriados, visando detectar o surgimento de novas ondas Q patológicas, depois da cirurgia; dosagens seriadas de marcadores bioquímicos de lesão miocárdica (CKMB e troponina I), para determinar o pico de sua elevação, depois da cirurgia; e SPECT, pré e pós-operatória, analisando-se a presença de novas áreas de hipercaptação do radiofármaco. O DC foi feito com base nos achados de ECG, contração segmentar do ventrículo esquerdo e níveis séricos dos marcadores bioquímicos. Os pacientes foram acompanhados por, pelo menos, 6 meses, depois da cirurgia e submetidos a uma terceira RMC, ao final deste período, para reavaliação da função ventricular. RESULTADOS: A RMC detectou IMPO em significativamente mais pacientes do que o DC (8 [33%] x 1 [4%], p=0,016). Em sua maioria, as áreas de necrose miocárdica visualizadas à RMC foram de pequena extensão (massa média de 5,7±10,2g) e padrão focal. Apesar disto, nos pacientes com IMPO à RMC, houve significativa redução pós-operatória da fração de ejeção ventricular esquerda (de 50±18 para 43±18%, p=0,044), que se manteve após 6 meses, e elevação maior do que 10 vezes o nível sérico normal dos marcadores bioquímicos, após a CRM, o que não ocorreu no grupo sem IMPO. Houve moderada correlação entre a massa de IMPO, medida pela RMC e o pico de elevação sérica dos marcadores bioquímicos (CKMB: r=0,705, p<0,001; troponina I: r=0,625, p=0,003). Observou-se moderada concordância diagnóstica entre a RMC e a SPECT para a detecção de necrose miocárdica perioperatória (Kappa=0,46). As características clínicas e cirúrgicas foram semelhantes entre os dois grupos, com exceção do perfil lipídico e a dose média de estatina (sinvastatina), em uso pelos pacientes, antes da cirurgia (significativamente menor no grupo com IMPO à RMC). CONCLUSÕES: A RMC revelou-se um método útil para o diagnóstico de IMPO, que foi subestimado pelo DC. O achado de necrose perioperatória à RMC associou-se a significativa diminuição da função sistólica ventricular esquerda e grande elevação sérica dos marcadores bioquímicos de lesão miocárdica. / INTRODUCTION: Despite advances in surgical technique and intensive care, perioperative myocardial infarction (POMI) remains a complication of coronary artery bypass graft surgery (CABG) with a challenging diagnosis. In this condition, clinical parameters usually utilized in the detection of POMI have limitations, since they can be affected by surgical trauma. Cardiovascular magnetic resonance imaging (CMRI), on the other hand, provides highly accurate detection of myocardial necrosis. OBJECTIVE: To evaluate POMI findings on CMRI and compare them to clinical diagnosis (CD) and technetium-99m pyrophosphate myocardial scintigrams (SPECT), as well as investigate the impact of POMI areas detected by CMRI on left ventricular systolic function. METHODS: Between August 2003 and March 2006, 24 adult patients with stable coronary artery disease, referred for CABG surgery, were studied. CMRI with cine and delayed-enhancement techniques was performed, before and after surgery, in order to evaluate the occurence of new areas of myocardial necrosis (POMI) and/or left ventricular systolic disfunction. Additional procedures included: serial electrocardiograms (ECG), to assess the appearance of new pathologic Q waves after surgery; serial measurements of biochemical markers of myocardial injury (CKMB and troponin I), to determine their peak serum levels after surgery; and SPECT, before and after surgery, in order to analyse the occurence of new areas of radionuclide increased uptake. CD was based on ECG findings, left ventricle regional contraction results and serum levels of biochemical markers. Patients were followed for, at least, 6 months after surgery, and a third CMRI scan was then repeated, in order to reassess ventricular function. RESULTS: CMRI revealed POMI in significantly more patients than CD (8 [33%] x 1 [4%], p=0.016). In most cases, areas of myocardial necrosis detected by CMRI were small (mean mass of 5.7±10.2g) and had focal distribution. Notwithstanding, patients who presented with POMI on CMRI had a significant decrease in postoperative left ventricular ejection fraction (from 50±18 to 43±18%, p=0.044), which persisted after 6 months, and a more than ten-fold increase in serum levels of biochemical markers after CABG. There was a moderate correlation between POMI mass measured by CMRI and peak serum levels of biochemical markers (CKMB: r=0.705, p<0.001; troponin I: r=0.625, p=0.003). Also, there was a moderate diagnostic agreement between CMRI and SPECT for the detection of perioperative myocardial necrosis (Kappa=0.46). Patient clinical and surgical characteristics were similar between groups, except for plasma lipid profile and mean statin (simvastatin) dosage before surgery (which was significantly lower in the group with POMI on CMRI). CONCLUSIONS: CMRI was found to be a useful tool in the diagnosis of POMI, which was underestimated by CD. Detection of perioperative myocardial necrosis by CMRI was associated with a significant decrease in left ventricular systolic function and high serum levels of biochemical markers of myocardial injury.

INTRODUÇÃO: Apesar dos avanços nas técnicas cirúrgicas e cuidados intensivos, o infarto do miocárdio perioperatório (IMPO) ainda é uma complicação da cirurgia de revascularização miocárdica (CRM), de difícil diagnóstico. Nessa situação, os parâmetros clínicos habitualmente utilizados para o seu reconhecimento têm limitações, podendo estar alterados pelo trauma cirúrgico. A ressonância magnética cardiovascular (RMC), por sua vez, detém alta acurácia para a detecção de necrose miocárdica. OBJETIVOS: Avaliar a detecção de IMPO pela RMC, comparando-a com os critérios de diagnóstico clínico (DC) e com a cintilografia miocárdica, com pirofosfato de tecnécio-99m (SPECT), assim como investigar a repercussão das áreas de IMPO visualizadas à RMC sobre a função sistólica ventricular esquerda. MÉTODOS: Entre agosto de 2003 e março de 2006, foram estudados 24 pacientes adultos, portadores de doença arterial coronária crônica, com indicação de CRM. Eles foram submetidos a RMC, com técnicas de cine-ressonância e realce tardio, antes e depois da cirurgia, analisando-se o surgimento de novas áreas de necrose miocárdica (IMPO) e/ou disfunção contrátil ventricular esquerda. Também foram realizados: eletrocardiogramas (ECG) seriados, visando detectar o surgimento de novas ondas Q patológicas, depois da cirurgia; dosagens seriadas de marcadores bioquímicos de lesão miocárdica (CKMB e troponina I), para determinar o pico de sua elevação, depois da cirurgia; e SPECT, pré e pós-operatória, analisando-se a presença de novas áreas de hipercaptação do radiofármaco. O DC foi feito com base nos achados de ECG, contração segmentar do ventrículo esquerdo e níveis séricos dos marcadores bioquímicos. Os pacientes foram acompanhados por, pelo menos, 6 meses, depois da cirurgia e submetidos a uma terceira RMC, ao final deste período, para reavaliação da função ventricular. RESULTADOS: A RMC detectou IMPO em significativamente mais pacientes do que o DC (8 [33%] x 1 [4%], p=0,016). Em sua maioria, as áreas de necrose miocárdica visualizadas à RMC foram de pequena extensão (massa média de 5,7±10,2g) e padrão focal. Apesar disto, nos pacientes com IMPO à RMC, houve significativa redução pós-operatória da fração de ejeção ventricular esquerda (de 50±18 para 43±18%, p=0,044), que se manteve após 6 meses, e elevação maior do que 10 vezes o nível sérico normal dos marcadores bioquímicos, após a CRM, o que não ocorreu no grupo sem IMPO. Houve moderada correlação entre a massa de IMPO, medida pela RMC e o pico de elevação sérica dos marcadores bioquímicos (CKMB: r=0,705, p<0,001; troponina I: r=0,625, p=0,003). Observou-se moderada concordância diagnóstica entre a RMC e a SPECT para a detecção de necrose miocárdica perioperatória (Kappa=0,46). As características clínicas e cirúrgicas foram semelhantes entre os dois grupos, com exceção do perfil lipídico e a dose média de estatina (sinvastatina), em uso pelos pacientes, antes da cirurgia (significativamente menor no grupo com IMPO à RMC). CONCLUSÕES: A RMC revelou-se um método útil para o diagnóstico de IMPO, que foi subestimado pelo DC. O achado de necrose perioperatória à RMC associou-se a significativa diminuição da função sistólica ventricular esquerda e grande elevação sérica dos marcadores bioquímicos de lesão miocárdica. / INTRODUCTION: Despite advances in surgical technique and intensive care, perioperative myocardial infarction (POMI) remains a complication of coronary artery bypass graft surgery (CABG) with a challenging diagnosis. In this condition, clinical parameters usually utilized in the detection of POMI have limitations, since they can be affected by surgical trauma. Cardiovascular magnetic resonance imaging (CMRI), on the other hand, provides highly accurate detection of myocardial necrosis. OBJECTIVE: To evaluate POMI findings on CMRI and compare them to clinical diagnosis (CD) and technetium-99m pyrophosphate myocardial scintigrams (SPECT), as well as investigate the impact of POMI areas detected by CMRI on left ventricular systolic function. METHODS: Between August 2003 and March 2006, 24 adult patients with stable coronary artery disease, referred for CABG surgery, were studied. CMRI with cine and delayed-enhancement techniques was performed, before and after surgery, in order to evaluate the occurence of new areas of myocardial necrosis (POMI) and/or left ventricular systolic disfunction. Additional procedures included: serial electrocardiograms (ECG), to assess the appearance of new pathologic Q waves after surgery; serial measurements of biochemical markers of myocardial injury (CKMB and troponin I), to determine their peak serum levels after surgery; and SPECT, before and after surgery, in order to analyse the occurence of new areas of radionuclide increased uptake. CD was based on ECG findings, left ventricle regional contraction results and serum levels of biochemical markers. Patients were followed for, at least, 6 months after surgery, and a third CMRI scan was then repeated, in order to reassess ventricular function. RESULTS: CMRI revealed POMI in significantly more patients than CD (8 [33%] x 1 [4%], p=0.016). In most cases, areas of myocardial necrosis detected by CMRI were small (mean mass of 5.7±10.2g) and had focal distribution. Notwithstanding, patients who presented with POMI on CMRI had a significant decrease in postoperative left ventricular ejection fraction (from 50±18 to 43±18%, p=0.044), which persisted after 6 months, and a more than ten-fold increase in serum levels of biochemical markers after CABG. There was a moderate correlation between POMI mass measured by CMRI and peak serum levels of biochemical markers (CKMB: r=0.705, p<0.001; troponin I: r=0.625, p=0.003). Also, there was a moderate diagnostic agreement between CMRI and SPECT for the detection of perioperative myocardial necrosis (Kappa=0.46). Patient clinical and surgical characteristics were similar between groups, except for plasma lipid profile and mean statin (simvastatin) dosage before surgery (which was significantly lower in the group with POMI on CMRI). CONCLUSIONS: CMRI was found to be a useful tool in the diagnosis of POMI, which was underestimated by CD. Detection of perioperative myocardial necrosis by CMRI was associated with a significant decrease in left ventricular systolic function and high serum levels of biochemical markers of myocardial injury.