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<p>Background: Genome wide association studies (GWAS) performed in Caucasian populations have identified several single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD), although their cumulative impact in other ethnicities is unknown. Using a genetic risk score (GRS), we examined the impact of CAD related SNPs on myocardial infarction (MI) in a multi-ethnic population.</p> <p>Methods: We included 4083 MI cases and 4473 controls from the INTERHEART case: control study, stratified by six ethnic groups: European, South Asian, other Asian, Arab, Latin American, and African. We created a GRS comprised of 25 SNPS, and tested its association with MI in individual ethnicities using logistic regression, and across ethnic groups through meta-analyses. Results were adjusted for age, sex, and modifiable risk factors.</p> <p>Results: The GRS was significantly associated with MI in Europeans (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04-1.12 per risk allele), South Asians (OR = 1.09, 95% CI 1.05-1.14), other Asians (OR = 1.09, 95% CI 1.04-1.15), and Arabs (OR = 1.07, 95% CI 1.03-1.12). In Latin Americans and Africans the GRS was not significant. Meta-analysis of ethnic groups demonstrated a 1.06 (95% CI 1.03-1.09) increase in the odds of MI with the GRS per risk allele. Significant heterogeneity was observed, which was reduced by exclusion of Latin Americans (I2=63% to 0%). Above clinical risk factors, the GRS modestly increased population attributable risk (PAR) (0.92 to 0.94), concordance statistic (0.73 to 0.74), net reclassification improvement (0.14), and integrated discriminatory improvement (0.007).</p> <p>Conclusions:<strong> </strong>The GRS was associated with a significant increase in the odds of MI in multiple ethnic groups. Improvements in PAR, discrimination and reclassification were modest above clinical factors.</p> / Master of Science (MSc)

Neutrophils are thought to orchestrate myocardial remodeling during the early progression to cardiac failure through the release of reactive oxygen species, antimicrobial peptides, and proteases. Although neutrophil activation may be beneficial at early stages of disease, excessive neutrophil infiltration detrimentally leads to cardiomyocyte death and tissue damage. The neutrophil-derived serine protease cathepsin G (CG) has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis1. However the role of inflammatory serine proteases in cardiac remodeling and cardiac regeneration in-vivo is still unknown. We showed that cardiac injection of neutrophil derived protease led to early cardiac dilatation and dysfunction characterized by an increase in matrix metalloprotease (MMP) activation and extracellular matrix degradation along with an increase in myocyte death by apoptosis. To assess the role of these serine proteases, we used mice lacking dipeptidyl peptidase I (DPPI), an enzyme involved in major inflammatory protease activation. DPPI deficient mice demonstrated a more robust functional recovery after ischemia reperfusion (IR) and myocardial infarction (MI) injury, as well as significantly reduced myocyte apoptosis, cardiac dilatation, infarct size and mortality rate. Meanwhile, our data showed increased groups of cardiac stem cells and proliferating cardiac cells in the MI 7-days DPPI knockout mice. We also found enhanced DPPI expression in response to pathological stress stimuli in mice. These findings reveal an unrecognized role of DPPI as a key mediator of post-ischemia cardiac injury and show that inflammatory derived proteases may contribute to the pathological cardiac remodeling and cardiac regeneration, and may be considered as novel target for future therapies. / Physiology

Rationale: Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but has only offered limited functional improvements. Finding the optimal stem cell type best suited for cardiac regeneration remains a key goal toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone stem cells (CBSCs) and cardiac-derived stem cells (CDCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=57), CDCs (n=31) or saline (n=57). Cardiac function was monitored using echocardiography with strain analysis. EGFP+ CBSCs in vivo were shown to express only 2/8 factors tested (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC and CDC therapy improved survival, cardiac function, attenuated adverse remodeling, and decreased infarct size relative to saline-treated MI controls. CBSC treated animals showed the most pronounced improvements in all parameters. By 6 weeks post-MI, EGFP+ cardiomyocytes, vascular smooth muscle cells and endothelial cells could be identified on histology in CBSC-treated animals but not in CDC-treated animals. EGFP+ myocytes isolated from CBSC-treated animals were smaller, more frequently mononucleated, and demonstrated fractional shortening and calcium currents indistinguishable from EGFP- myocytes from the same hearts. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling more so than CDCs and this occurs through two mechanisms: 1) secretion of the proangiogenic factors bFGF and VEGF (which stimulates endogenous neovascularization), and 2) differentiation into functional adult myocytes and vascular cells. / Physiology

In cellular MRI, micrometer-sized iron oxide particles (MPIO) are a more sensitive contrast agent for tracking inflammatory-cell migration compared to ultra-small superparamagnetic iron oxide particles (USPIO). Inflammation, which promotes adverse tissue remodeling, is known to occur in the viable myocardium adjacent to the necrosed area after a myocardial infarction (MI). This study investigated the temporal relationship between inflammatory cell infiltration and cardiac function during tissue remodeling post-MI using MPIO-enhanced MRI. The MPIO were injected into 7 C57Bl/6 mice (MI+MPIO group) via intravenous administration. The MI was induced 7 days post-MPIO injection. As control groups, 7 mice (Sham+MPIO group) underwent sham-operated surgery without myocardial injury post-MPIO injection and another 6 mice (MI-MPIO group) underwent MI surgery without MPIO injection. MRIs performed post-MI showed a significant signal attenuation at the MI zone in the MI+MPIO group compared to the control groups. The findings suggested that the inflammatory cells containing MPIO infiltrated into the myocardial injury site. Cardiac function was also measured and correlated with the labeled-cell infiltration at the MI site. This study demonstrated a noninvasive technique for monitoring inflammatory cell migration using the MPIO contrast agent. This MPIO-enhanced MRI technique could provide additional insight concerning cardiac disease progression that would improve therapeutic treatment for MI patients.

"The Relationship Between the Effect of Uncertainty and Perceived Support Role Performance in Spouses of PostMyocardial Infarction Clients."Little understanding of the relationship between the illness of a family member and family functioning is provided in recent studies.Studies have indicated that recovery from an illness crisis can be influenced by support from the family. The purpose of this study was to examine spouses of myocardial infarction patients for the relationship between perceived support role performance and the uncertainty regarding the illness of the patient. The population studied consisted of a convenience sample of 36 spouses of patients currently enrolled in Phase II of a cardiac rehabilitation program in a community hospital. Human subjects rights were protected. The hypothesis examined was that "uncertainty has a direct negative relationship to perception of support role performance. Study findings also did not indicate any relationships between the variables of age, gender, support role performance, and uncertainty. The results of the study could be used in planning support groups for spouses of myocardial infarction patients and to provide opportunities for the patient and spouse to form attitudes and acquire skills to master the changes in psychological, social, and physical status. The hospital course of individuals having experienced an acute coronary event is frequently characterized by emotional distress. Nurses can assist family members to identify emotional stresses and intervene to decrease emotional stress. Uncertainty is one factor that can play a role in the perception of illness-related events. / School of Nursing

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 6 uppsatser.