Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 2006. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 66-80).

Thesis (M.S.)--University of Michigan, 2006. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 66-80).

Background: The early non-invasive discrimination of Type 2 versus Type 1 Myocardial Infarction (T2MI, T1MI) is a major unmet clinical need. We aimed to externally validate a recently derived clinical score (Neumann) combing female sex, no radiating chest pain, and high-sensitivity cardiac troponin I (hs-cTnI) concentration ≤40.8 ng/L. Methods: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. The final diagnoses of T2MI and T1MI were centrally adjudicated by two independent cardiologists using all information including cardiac imaging and serial measurements of hs-cTnT/I according to the fourth universal definition of MI. Model performance for T2MI diagnosis was assessed by formal tests and graphical means of discrimination and calibration. Results: Among 6684 enrolled patients, MI was the adjudicated final diagnosis in 1079 (19%) patients, of which 242 (22%) had T2MI. External validation of the Neumann Score showed a moderate discrimination (C-statistic 0.67 (95%CI 0.64–0.71)). Model calibration showed underestimation of the predicted probabilities of having T2MI for low point scores. Model extension by adding the binary variable heart rate >120/min significantly improved model performance (C-statistic 0.73 (95% CI 0.70–0.76, p < 0.001) and had good calibration. Patients with the highest score values of 3 (Neumann Score, 9.9%) and 5 (Extended Neumann Score, 3.3%) had a 53% and 91% predicted probability of T2MI, respectively. Conclusion: The Neumann Score provided moderate discrimination and suboptimal calibration. Extending the Neumann Score by adding heart rate >120/min improved the model’s performance.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O infarto agudo do miocÃrdio (IAM), definido como a morte do mÃsculo cardÃaco decorrente de isquemia, à um dos diagnÃsticos mais comuns em pacientes hospitalizados nos paÃses industrializados. Para se estudar efeitos de drogas sobre a injÃria miocÃrdica decorrente de IAM, um dos modelos experimentais bastante utilizado à a induÃÃo de infarto do mocÃrdio (IM) com administraÃÃo de isoproterenol em ratos, uma vez que esta substÃncia causa uma lesÃo miocÃrdica semelhante a observada em IAM nos humanos. Nesse estudo o Ãleo essencial de Alpinia zerumbet, na dose de 100 mg/kg de peso, administrado por catroze dias consecutivos, foi avaliado no infarto do miocÃrdio induzido por isoproterenol (150 mg/kg de peso do animal) em ratos wistar. A injÃria miocÃrdica induzida pelo isoproterenol foi indicada pela elevaÃÃo de marcadores de injÃria miocÃrdica, como TGO e troponina I, reduÃÃo dos nÃveis de catalase e glutationa, bem como por alteraÃÃes histopatolÃgicas avaliadas no Ãpice do ventrÃculo esquerdo. Avaliou-se ainda a mortalidade, os nÃveis de hemoglobina, contagem de leucÃcitos e neutrÃfilos e nÃveis de marcadores da funÃÃo renal. O prÃ-tratamento com o Ãleo essencial de Alpinia zerumbet apresentou efeitos protetores no infarto do miocÃrdio induzido por isoproterenol em ratos, uma vez: atenuou as elevaÃÃes de TGO e troponina I; atenuou a elevaÃÃo do nÃmero de neutrÃfilos; preservou os nÃveis de catalase no miocÃrdio e preservou os nÃveis de glutationa no miocÃrdio. No entanto, nÃo exerceu efeitos sobre: mortalidade, variaÃÃo do peso dos animais; nÃveis sÃricos de TGP; nÃveis sÃricos de hemoglobina e contagem de leucÃcitos; nÃveis sÃricos de marcadores da funÃÃo renal; alteraÃÃes histopatolÃgicas no Ãpice do ventrÃculo esquerdo. Os provÃveis mecanismos de aÃÃo responsÃveis pelos efeitos benÃficos deste Ãleo em reduzir o grau de injÃria miocÃrdica neste modelo experimental podem estar relacionados a propriedades antioxidantes e em aumento dos nÃveis de Ãxido nÃtrico. / O infarto agudo do miocÃrdio (IAM), definido como a morte do mÃsculo cardÃaco decorrente de isquemia, à um dos diagnÃsticos mais comuns em pacientes hospitalizados nos paÃses industrializados. Para se estudar efeitos de drogas sobre a injÃria miocÃrdica decorrente de IAM, um dos modelos experimentais bastante utilizado à a induÃÃo de infarto do mocÃrdio (IM) com administraÃÃo de isoproterenol em ratos, uma vez que esta substÃncia causa uma lesÃo miocÃrdica semelhante a observada em IAM nos humanos. Nesse estudo o Ãleo essencial de Alpinia zerumbet, na dose de 100 mg/kg de peso, administrado por catroze dias consecutivos, foi avaliado no infarto do miocÃrdio induzido por isoproterenol (150 mg/kg de peso do animal) em ratos wistar. A injÃria miocÃrdica induzida pelo isoproterenol foi indicada pela elevaÃÃo de marcadores de injÃria miocÃrdica, como TGO e troponina I, reduÃÃo dos nÃveis de catalase e glutationa, bem como por alteraÃÃes histopatolÃgicas avaliadas no Ãpice do ventrÃculo esquerdo. Avaliou-se ainda a mortalidade, os nÃveis de hemoglobina, contagem de leucÃcitos e neutrÃfilos e nÃveis de marcadores da funÃÃo renal. O prÃ-tratamento com o Ãleo essencial de Alpinia zerumbet apresentou efeitos protetores no infarto do miocÃrdio induzido por isoproterenol em ratos, uma vez: atenuou as elevaÃÃes de TGO e troponina I; atenuou a elevaÃÃo do nÃmero de neutrÃfilos; preservou os nÃveis de catalase no miocÃrdio e preservou os nÃveis de glutationa no miocÃrdio. No entanto, nÃo exerceu efeitos sobre: mortalidade, variaÃÃo do peso dos animais; nÃveis sÃricos de TGP; nÃveis sÃricos de hemoglobina e contagem de leucÃcitos; nÃveis sÃricos de marcadores da funÃÃo renal; alteraÃÃes histopatolÃgicas no Ãpice do ventrÃculo esquerdo. Os provÃveis mecanismos de aÃÃo responsÃveis pelos efeitos benÃficos deste Ãleo em reduzir o grau de injÃria miocÃrdica neste modelo experimental podem estar relacionados a propriedades antioxidantes e em aumento dos nÃveis de Ãxido nÃtrico. / O infarto agudo do miocÃrdio (IAM), definido como a morte do mÃsculo cardÃaco decorrente de isquemia, à um dos diagnÃsticos mais comuns em pacientes hospitalizados nos paÃses industrializados. Para se estudar efeitos de drogas sobre a injÃria miocÃrdica decorrente de IAM, um dos modelos experimentais bastante utilizado à a induÃÃo de infarto do mocÃrdio (IM) com administraÃÃo de isoproterenol em ratos, uma vez que esta substÃncia causa uma lesÃo miocÃrdica semelhante a observada em IAM nos humanos. Nesse estudo o Ãleo essencial de Alpinia zerumbet, na dose de 100 mg/kg de peso, administrado por catroze dias consecutivos, foi avaliado no infarto do miocÃrdio induzido por isoproterenol (150 mg/kg de peso do animal) em ratos wistar. A injÃria miocÃrdica induzida pelo isoproterenol foi indicada pela elevaÃÃo de marcadores de injÃria miocÃrdica, como TGO e troponina I, reduÃÃo dos nÃveis de catalase e glutationa, bem como por alteraÃÃes histopatolÃgicas avaliadas no Ãpice do ventrÃculo esquerdo. Avaliou-se ainda a mortalidade, os nÃveis de hemoglobina, contagem de leucÃcitos e neutrÃfilos e nÃveis de marcadores da funÃÃo renal. O prÃ-tratamento com o Ãleo essencial de Alpinia zerumbet apresentou efeitos protetores no infarto do miocÃrdio induzido por isoproterenol em ratos, uma vez: atenuou as elevaÃÃes de TGO e troponina I; atenuou a elevaÃÃo do nÃmero de neutrÃfilos; preservou os nÃveis de catalase no miocÃrdio e preservou os nÃveis de glutationa no miocÃrdio. No entanto, nÃo exerceu efeitos sobre: mortalidade, variaÃÃo do peso dos animais; nÃveis sÃricos de TGP; nÃveis sÃricos de hemoglobina e contagem de leucÃcitos; nÃveis sÃricos de marcadores da funÃÃo renal; alteraÃÃes histopatolÃgicas no Ãpice do ventrÃculo esquerdo. Os provÃveis mecanismos de aÃÃo responsÃveis pelos efeitos benÃficos deste Ãleo em reduzir o grau de injÃria miocÃrdica neste modelo experimental podem estar relacionados a propriedades antioxidantes e em aumento dos nÃveis de Ãxido nÃtrico. / Acute myocardial infarction (AMI), defined as death of the cardiac muscle after an ischemic process, is worldwide known for its frequent diagnosis within hospitalized patients in modern industrialized countries. Myocardial infarction induced by isoproterenol (ISO) in rats is a very useful assay to study the effect of drugs on myocardial injury as a result of AMI, once its administration is responsible for a post-infarction human-like myocardial lesion. In this study, essential oil of Alpinia zerumbet (EOAZ), at a dose of 100 mg / kg, administered for fourteen consecutive days, was assessed in myocardial infarction induced by ISO (150 mg / kg bodyweight) in Wistar rats. The myocardial injury induced by ISO was indicated by elevated markers of myocardial injury, such as AST and troponin I, reduced levels of catalase and glutathione, as well as histopathological changes evaluated at the apex of the left ventricle. It was also evaluated mortality, hemoglobin levels, leukocyte and neutrophil counts and levels of markers of renal function. Pretreatment with the EOAZ showed protective effects on myocardial infarction induced by isoproterenol in rats, as attenuated the elevation of AST, Troponin I, attenuated the increased number of neutrophils; preserved the levels of catalase in the myocardium and preserved glutathione levels in the myocardium. However, do not exert any effects on mortality, weight variation of animals, serum ALT, serum levels of hemoglobin and white blood cell count, serum markers of renal function, histopathological changes in left ventricular apex. The probable mechanisms of action responsible for the beneficial effects of this oil in reduce the degree of myocardial injury in this experimental model may be related to antioxidant properties and increased levels of nitric oxide. / Acute myocardial infarction (AMI), defined as death of the cardiac muscle after an ischemic process, is worldwide known for its frequent diagnosis within hospitalized patients in modern industrialized countries. Myocardial infarction induced by isoproterenol (ISO) in rats is a very useful assay to study the effect of drugs on myocardial injury as a result of AMI, once its administration is responsible for a post-infarction human-like myocardial lesion. In this study, essential oil of Alpinia zerumbet (EOAZ), at a dose of 100 mg / kg, administered for fourteen consecutive days, was assessed in myocardial infarction induced by ISO (150 mg / kg bodyweight) in Wistar rats. The myocardial injury induced by ISO was indicated by elevated markers of myocardial injury, such as AST and troponin I, reduced levels of catalase and glutathione, as well as histopathological changes evaluated at the apex of the left ventricle. It was also evaluated mortality, hemoglobin levels, leukocyte and neutrophil counts and levels of markers of renal function. Pretreatment with the EOAZ showed protective effects on myocardial infarction induced by isoproterenol in rats, as attenuated the elevation of AST, Troponin I, attenuated the increased number of neutrophils; preserved the levels of catalase in the myocardium and preserved glutathione levels in the myocardium. However, do not exert any effects on mortality, weight variation of animals, serum ALT, serum levels of hemoglobin and white blood cell count, serum markers of renal function, histopathological changes in left ventricular apex. The probable mechanisms of action responsible for the beneficial effects of this oil in reduce the degree of myocardial injury in this experimental model may be related to antioxidant properties and increased levels of nitric oxide. / Acute myocardial infarction (AMI), defined as death of the cardiac muscle after an ischemic process, is worldwide known for its frequent diagnosis within hospitalized patients in modern industrialized countries. Myocardial infarction induced by isoproterenol (ISO) in rats is a very useful assay to study the effect of drugs on myocardial injury as a result of AMI, once its administration is responsible for a post-infarction human-like myocardial lesion. In this study, essential oil of Alpinia zerumbet (EOAZ), at a dose of 100 mg / kg, administered for fourteen consecutive days, was assessed in myocardial infarction induced by ISO (150 mg / kg bodyweight) in Wistar rats. The myocardial injury induced by ISO was indicated by elevated markers of myocardial injury, such as AST and troponin I, reduced levels of catalase and glutathione, as well as histopathological changes evaluated at the apex of the left ventricle. It was also evaluated mortality, hemoglobin levels, leukocyte and neutrophil counts and levels of markers of renal function. Pretreatment with the EOAZ showed protective effects on myocardial infarction induced by isoproterenol in rats, as attenuated the elevation of AST, Troponin I, attenuated the increased number of neutrophils; preserved the levels of catalase in the myocardium and preserved glutathione levels in the myocardium. However, do not exert any effects on mortality, weight variation of animals, serum ALT, serum levels of hemoglobin and white blood cell count, serum markers of renal function, histopathological changes in left ventricular apex. The probable mechanisms of action responsible for the beneficial effects of this oil in reduce the degree of myocardial injury in this experimental model may be related to antioxidant properties and increased levels of nitric oxide.

Cardiac remodeling after acute myocardial infarction (MI) is an important process that leads to progressive ventricular enlargement and heart failure. Several variables have been identified to predict an increase in left ventricular (LV) volume and a decrease of LV ejection fraction (LVEF) after an acute MI including infarct size, anterior location, cardiac enzyme level, transmurality of the infarct, patency of the infarct-related artery, end systolic volume (ESV) and mitral deceleration time, etc. / Regional disturbances of LV wall motion have long been recognized to occur in patients with cardiac diseases, such as hypertrophic cardiomyopathy, unstable angina, acute ischemia, and MI. Tissue Doppler imaging (TDI) is recently established for detecting regional contractile abnormalities and asynchrony, and can predict reverse remodeling and improved synchronicity after biventricular pacing therapy in heart failure patients. However, it is unclear whether LV asynchrony plays an important role in the evolutionary changes of LV remodeling after an acute infarction and whether it can predict the changes independently. / The identification of transmural extent of myocardial necrosis and degree of non-viability after acute MI is clinically important. TDI-derived strain rate imaging (SRI) quantifies local rate of myocardial deformation and has the potential to differentiate viable from infarcted myocardium. / Therefore, in this study we aimed to investigate: (1) Whether SRI may differentiate transmural from non-transmural MI as assessed by ce-MRI in routine patients post acute infarction, and establish practical cutoff values for identifying transmural scar tissue from non-transmural or subendocardial infarction with viable myocardium. (2) Whether LV systolic and diastolic asynchrony measured by TDI occurs early after acute MI even in the absence of widening of QRS complexes, and determine if this is explained by the site and extent of the infarction measured by ce-MRI. (3) The relationships between serial measurements of infarct size on ce-MRI and LV remodeling process after an acute infarction, and determine whether early assessment of infarct size predicts progressive ventricular enlargement and cardiac dysfunction, and whether it differs with infarct location. (4) The relationships between LV asynchrony, infarct size and LV remodeling, and determine whether early assessment of LV asynchrony by TDI compared with standard clinical correlates of LV remodeling and infarct size predicts progressive ventricular enlargement and cardiac dysfunction. (Abstract shortened by UMI.) / Zhang Yan. / "April 2005." / Adviser: John E. Sanderson. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0175. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 161-192). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, polarizes macrophages towards the reparatory phenotype. AZM has an excellent safety profile and has been approved for human use. We hypothesize that AZM reduces inflammation and improves heart function in MI. Methods and results: In our initial studies, we demonstrated that oral free AZM (160 mg/kg daily for 7 days), initiated 3 days prior to MI, enhances post-MI cardiac recovery as a result of shifting macrophages to the reparatory state. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory and an increase in reparative macrophages, decreasing the pro-inflammatory/reparative macrophage ratio. Macrophage changes were associated with a significant decline in pro- and an increase in anti-inflammatory cytokines. Additionally, AZM treatment was correlated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the reparative phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. We designed this proof of concept study using pre-MI AZM therapy to achieve steady state levels prior to injury. Therefore, in our follow-up studies we targeted inflammatory macrophages using a non-Pegylated liposomal formulation of AZM (Lazm) which has been shown in multiple studies to promote drug efficacy and minimize off-target effects. To test the hypothesis that Lazm is more effective and safer than free AZM, low doses of free/liposomal AZM (10 or 40 mg/kg, administered intravenously) were initiated immediately after MI. We observed that Lazm induces early resolution of the post-MI inflammatory response as evidenced by switching of the activation state of monocytes/macrophages towards the reparatory phenotype. Neutrophils were substantially decreased, particularly pro-inflammatory neutrophils. Cytokine profiles were also shifted to the anti-inflammatory status with Lazm therapy. Taken together, AZM treatment resulted in a significant shift in macrophage activation towards the reparatory state. The shift in inflammatory state was accompanied by a decrease in apoptosis and infarct size in the injured heart, as well as enhanced angiogenesis and LV functional recovery in our long-term studies. In addition, Lazm was protective against off-target effects of AZM on the heart. Conclusion: This is the first evidence of a novel and clinically-relevant therapeutic strategy to modulate post-MI inflammation. We found that AZM reduces cardiac inflammation and improves adverse cardiac remodeling after infarction via promoting a shift of macrophage activation state. The overarching significance of this work is the modulation of sterile inflammation, which can be a viable therapeutic target in many conditions including stroke and heart attack. Additionally, this is the first study to demonstrate the immune modulation properties of liposomal AZM, which has wide potential therapeutic applications beyond the cardiovascular field. Importantly, liposomal formulation of AZM is protective from its cardiac off-target effects. Our findings strongly support clinical trials using AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

The cell infiltration into the myocardial infarction (MI) site was studied using magnetic resonance imaging (MRI) with micrometer-sized iron oxide particles (MPIO) as cell labeling probes. MI is a leading cause of global death and disability. However, the roles of inflammatory cells and stem cells during the post-MI remodeling and repair processes are yet to be discovered. This study was to develop noninvasive MRI techniques to monitor and quantify the cellular infiltration into the MI site. MPIO can produce pronounced signal attenuation at regions of interest in MRI. Therefore, cells labeled with these particles can be detected after they are activated and home to the MI site. In the first project, MPIO of various doses were injected into the mouse blood stream 7 days before the MI surgery. Serial MRI was performed at various time points post-MI to monitor the inflammatory cell infiltration into the MI site. Significant signal attenuation caused by labeled cells, in particular macrophages, was observed at the MI site. The study suggests an optimal imaging window should be from 7 to 14 days post-MI, during which the MR signal was inversely proportional to the MPIO dose. The study also suggests an optimal MPIO dose should be between 9.1 and 14.5 µg Fe/g body weight. In the second project, mesenchymal stem cells labeled with MPIO were transplanted into the mouse bone marrow 14 days before the MI surgery. Serial MRI was performed at various time points post-MI to monitor the labeled cells, which mobilized from the bone marrow and homed to the MI site. All the MRI findings were further confirmed by histology. In addition to revealing the characteristics of cell infiltration during MI, this study also provides noninvasive MRI techniques to monitor and potentially quantify labeled cells at the pathological site. The technique can also be used to investigate the function of cells engaged in MI and to test the effect on cell infiltration caused by any treatment strategies.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 4 uppsatser.