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.

No description available.

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.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 15, 2008). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Please read the abstract in the section 00front of this document / Dissertation (MA (Psychology))--University of Pretoria, 2005. / Psychology / unrestricted

D.Litt. et Phil. (Psychology) / It has long been known that South Africans are a high risk population for the development of coronary heart disease. Cardiovascular diseases accounted for 8,7% of all deaths in this country in 1988. Despite this distressing situation, rehabilitation facilities for people who have suffered a myocardial infarction or heart attack are relatively scarce. The facilities that exist tend to focus on the biomedical aspects of cardiac rehabilitation such as exercise and diet, and tend to neglect the psychosocial factors. A review of the literature shows, however, that psychosocial factors, and in particular the Type A coronary-prone behaviour pattern are significantly related not only to the development of coronary heart disease, but also to the probability of sUffering and surviving a heart attack. In addition, Type A.behaviour has been shown to be predictive of the risk of a second infarction after an initial attack. For this reason, the proven technology of a treatment programme developed under the auspices of the Recurrent Coronary Prevention Project (Powell & Thoresen, 1986) was applied in an attempt to adapt the programme for the" South African context. The study was aimed at establishing whether the RCPP programme could successfully be employed in this country, and whether the duration could be shortened so as to be more economically viable given the limited economic resources that characterise health care in South Africa. The modified programme was administered to a group of 13 post-myocardial patients at a local cardiac rehabilitation centre. A second group of 11 patients at the same centre served as a no-treatment waiting list control group, but simultaneously underwent an aerobic exercise and cardiovascular counselling programme. Results of the study indicate that 'the modified programme is highly successful in modifying Type A behaviour and its components in South African sUbjects. Comparisons of the experimental and control groups after the intervention showed statistically significant differences on the majority of measures. It was therefore concluded that the modified programme can be used fruitfully in the local context, but it was cautioned that the present sample needs to be followed up over time to ensure that the treatment gains are maintained.