Myocardial structure is compromised after myocardial infarction (MI) in vertebrates, resulting in a significant decrease in cardiac output. Pro-proliferative compounds, such as ALK5 inhibitors and p38 inhibitors, are promising in increasing cardiac function after MI, but are only beginning to be functionally evaluated. Zebrafish larvae suffering cardiac arrest in severe acute hypoxia (1 kPa for ~18-20 min) are an effective model for studying how these compounds affect MI. I investigated the effects of ALK5i and p38i on cardiac function after cardiac injury. Several concentrations (0.03 – 100 µmol) administered in four different times of exposure (6, 12, 18, and 24 h) were used. Videos of heartbeat were recorded at three different time points: before hypoxic exposure, 48 h, and 72 h after treatment. For ALK5 inhibition, heart rate (fH) decreased in different groups from 0.03-30 µmol. For p38 inhibition, low concentrations (0.1-1 µmol) during intermediate times increased cardiac function. The concentration 0.3 µmol increased stroke volume by 134%, with no changes in fH. Overall, cardiac output increased significantly (P<0.001) by 144% following p38 inhibition. Behavioral effects caused by a simulated heart attack in 7 dpf zebrafish larvae were tested one and two weeks after simulated heart attack. A control group, a cardiac injury group, and a group with cardiac injury + p38 inhibition (0.3 µmol) were evaluated for anxiety-like behavior and boldness when placed in a novel environment. Larvae with cardiac injury + p38 inhibition spent significantly more time in the thigmotaxis zone compared to larvae with cardiac injury alone, suggesting an increase in anxiety-like behavior (P=0.0395). Boldness was decreased in the cardiac injury group compared to controls, because they spent a shorter time in the novel object zone at two weeks after cardiac arrest (P=0.04). Growth was impaired in both cardiac injury groups, regardless of pharmacological inhibition, with a significant increase in growth compared to controls. Further studies of cardiac function and behavior need to be performed with a holistic approach, to understand the effects of pro-proliferative compounds from molecular to organism level.

published_or_final_version / abstract / Community Medicine / Doctoral / Doctor of Philosophy

Myocardial infarction results in tissue necrosis, leading to cell loss and ultimately to cardiac failure. Implantation of immature progenitor cells into the scar area may compensate for the cell loss and provides a new therapeutic avenue for infarct treatment. Premature myoblasts derived from skeletal muscle are one of the best candidates for this therapeutic purpose, because biopsies used for autologous cell therapy can be accessed easily, the isolated myoblasts can proliferate well in vitro, and the skeletal and cardiac muscles are structurally and functionally similar. In this study we investigated the survival and differentiation of the implanted skeletal myoblasts in the non-cryoinjured myocardium and the myocardial scar, using a syngeneic Lewis rat model. A therapeutic dose of 4x106 skeletal myoblasts/animal was implanted into the non-cryoinjured and scar tissue, and the fate of the implant was monitored at 12, 28 and 56 days after implantation by immunohistochemistry. We detected fast myosin heavy chain (fMHC) expression at each time point but significantly fewer positive cells in the scar than in the non-injured tissue. This was consistent with the staining patterns of slow myosin heavy chain (sMHC) and myogenin that overlapped with fMHC positive areas. Although the implanted myoblasts differentiated into skeletal muscle cells, they did not transdifferentiate into cardiac muscle, demonstrated by the absence of cardiac troponin I expression. During this analysis we developed a model, which could be useful to test new strategies for myoblast implantation (dosage, genetic modification, new injection technique etc.) designed to promote better engraftment of cultured myoblasts in the myocardial scar.

<p>Myocardial infarction (MI) causes high morbidity and mortality worldwide and for effective prevention and treatment MIs have to be adequately detected. </p><p>The existence of clinically unrecognized MIs (UMIs) has been known for the past hundred years, but an ultimate tool for their detection has not yet been found. Using persistent Q waves on electrocardiography as a sign of MI, it has been estimated that UMIs constitute at least ¼ of all MIs and have mortality rates similar to those of recognized MIs (RMIs). These estimates are misleading, however, since persistent Q waves do not necessarily represent MIs.</p><p>The late enhancement technique in magnetic resonance imaging (LE MRI) has been developed over the past decade and accurately determines myocardial viability. The aim of this research was to investigate the prevalence and impact of UMI and RMI in a population-based sample of 70-year-olds, assessed with MRI.</p><p>Cardiac function and viability were examined with MRI in 259 randomly selected 70-year-old subjects (127 women, 132 men) participating in a larger population-based study (PIVUS). Information on other parameters of cardiovascular disease was obtained and related to the findings.</p><p>Three methods for segmentation of the left ventricular mass were used in the first 100 subjects; these differed in accuracy and led to differences in systolic function values. In the subsequent 159 examinations one of the segmentation methods was used. </p><p>The viability images were assessable in 248 subjects (123 women, 125 men). Among these, the prevalence of UMI, 19.8%, definitely exceeded the expectations and UMIs constituted 4/5 of all MIs. The prevalence of RMI was 4.4%. MRI-detected UMIs differed from RMIs in several respects; they were smaller, frequently located inferolaterally, did not appear to be associated with atherosclerosis, and displayed increased collagen turnover. The pathogenesis of these UMIs remains to be investigated, but our observations suggest that they are caused by ischemia. Subjects with UMI showed increased cardiac morbidity, a decreased ejection fraction and an increased left ventricular mass, indicating an increased cardiovascular risk.</p><p>It is thus important to detect these UMIs, and this is adequately achieved by LE MRI. However, to decide upon prevention and treatment of these UMIs we need to know more about their pathogenesis and prognosis.</p>

Myocardial infarction (MI) causes high morbidity and mortality worldwide and for effective prevention and treatment MIs have to be adequately detected. The existence of clinically unrecognized MIs (UMIs) has been known for the past hundred years, but an ultimate tool for their detection has not yet been found. Using persistent Q waves on electrocardiography as a sign of MI, it has been estimated that UMIs constitute at least ¼ of all MIs and have mortality rates similar to those of recognized MIs (RMIs). These estimates are misleading, however, since persistent Q waves do not necessarily represent MIs. The late enhancement technique in magnetic resonance imaging (LE MRI) has been developed over the past decade and accurately determines myocardial viability. The aim of this research was to investigate the prevalence and impact of UMI and RMI in a population-based sample of 70-year-olds, assessed with MRI. Cardiac function and viability were examined with MRI in 259 randomly selected 70-year-old subjects (127 women, 132 men) participating in a larger population-based study (PIVUS). Information on other parameters of cardiovascular disease was obtained and related to the findings. Three methods for segmentation of the left ventricular mass were used in the first 100 subjects; these differed in accuracy and led to differences in systolic function values. In the subsequent 159 examinations one of the segmentation methods was used. The viability images were assessable in 248 subjects (123 women, 125 men). Among these, the prevalence of UMI, 19.8%, definitely exceeded the expectations and UMIs constituted 4/5 of all MIs. The prevalence of RMI was 4.4%. MRI-detected UMIs differed from RMIs in several respects; they were smaller, frequently located inferolaterally, did not appear to be associated with atherosclerosis, and displayed increased collagen turnover. The pathogenesis of these UMIs remains to be investigated, but our observations suggest that they are caused by ischemia. Subjects with UMI showed increased cardiac morbidity, a decreased ejection fraction and an increased left ventricular mass, indicating an increased cardiovascular risk. It is thus important to detect these UMIs, and this is adequately achieved by LE MRI. However, to decide upon prevention and treatment of these UMIs we need to know more about their pathogenesis and prognosis.

Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains x, 121 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 84-118).

Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains xii, 263 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 233-242).

published_or_final_version / Medicine / Master / Doctor of Medicine

Hjärtinfarkt är den dominerande dödliga sjukdomen i Sverige, vilket fler kvinnor än män avlider i. Kvinnor insjuknar senare i livet och upplever fler och mer diffusa symptom än män. Stress är en vanlig förekommande riskfaktor, vilket kan skapas från samhällets förväntningar på kvinnor. Det finns förväntningar om omsorgsfulla kvinnor som samtidigt ska prestera bra både på arbetet och i hemmet, vilket genererar stress. Förväntningar från samhället och kroppens biologi skiljer sig mellan män och kvinnor. Män har historiskt sett representerat normen för människan i forskning och därför är det viktigt att uppmärksamma kvinnors erfarenheter. Syftet med studien var att belysa kvinnors erfarenheter av livet efter hjärtinfarkt. En litteraturstudie användes som metod, vilket genererade tio vetenskapliga artiklar som resulterade i tre teman och nio kategorier. Kvinnornas erfarenheter visade att hjärtinfarkt medförde ett avbrott i livet och med hjälp av närstående samt egna reflektioner lärde kvinnorna känna sig själva igen. En ny prioriteringsordning skapades med fokus på kvinnornas hälsa och liv. Studien visar att stress är en stor faktor i kvinnors erfarenheter efter hjärtinfarkt och att kvinnors erfarenheter behöver uppmärksammas för att vårdpersonal ska kunna ge adekvat vård. Det hade varit betydelsefullt om framtida forskning hade uppmärksammat hur stress skiljer sig mellan könen vid hjärtinfarkt, eftersom stress är en riskfaktor.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.