published_or_final_version / abstract / Anaesthesiology / Master / Master of Philosophy

Acute myocardial infarction (AMI) triggers the mobilization of stem/progenitor cells from bone marrow (BMSPCs) into peripheral blood (PB). The underlying mechanisms orchestrating this mobilization and subsequent homing of BMSPCs to the myocardium are poorly understood. While the role of traditional chemokines in the mobilization and homing of hematopoietic stem cell (HSCs) to BM niches is undisputed, their role in directing BMSPCs to the highly proteolytic environment of the ischemic myocardium is debatable and other redundant mechanism may exist. Based on our observation that bioactive lipids, such as sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P), play an important role in regulating trafficking of HSCs; we explored if they also direct trafficking of BMSPCs in the setting of myocardial ischemia. While BMSPCs expressed S1P receptors regardless of the source, the expression of S1P receptor 1 (S1PR1) and receptor 3 (S1PR3), which are responsible for migration and chemotaxis, was elevated in BMSPCs in naïve BM cells and was reduced following mobilization. This expression correlated to differential response of BMSPCs to S1P in chemotaxis assays. By employing flow cytometry analyses, we observed an increase in circulating PB CD34+, CD133+ and CXCR4+ lineage negative (Lin-)/CD45- cells that are enriched in non-HSCs (P < 0.05 vs. controls). This corroborated our mass spectrometry studies showing a temporal increase in S1P and C1P plasma levels. At the same time, plasma obtained in the early phases following AMI strongly chemoattracted human BM-derived CD34+/Lin- and CXCR4+/Lin- cells in Transwell chemotaxis assays in an S1P dependent fashion. We examined other mechanisms that may contribute to the homing of BMSPCs to the infarcted myocardium due to the reduction of S1PRs upon mobilization. We observed that hypoxia induced higher expression of cathelicidins in cardiac tissues. Indeed, PB cells isolated from patients with AMI migrated more efficiently to low, yet physiological, gradient of SDF-1 in Transwell migration assays compared to SDF-1 alone. Together, these observations suggest that while elevated S1P plasma levels early in the course of AMI may trigger mobilization of non-HSCs into PB, cathelicidins appear to play an important role in their homing to ischemic and damaged myocardium.

<p>Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs). </p><p>In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes.</p><p>Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.</p>

<p>Vetskapen om att hjärtinfarkt till stor del kan förebyggas genom en hjärtskyddande livsstil gör området mycket intressant.</p><p><strong>Syfte:</strong> Att göra en undersökning över tid angående livsstilskunskap och beteende hos patienter som haft hjärtinfarkt med fokus på fysisk aktivitet, stresspåverkan, intag av frukt och grönsaker, samt rökning.</p><p><strong>Metod:</strong> Enkätutskick gjordes till två patientgrupper, som haft hjärtinfarkt för 2-4 månader sen (grupp 1, n = 35) respektive för ca 2 år sedan (grupp 2, n = 32). Svarsfrekvensen uppgick till 83 %. </p><p><strong>Resultat:</strong> Kunskapsmässigt framgick det att båda grupperna hade överlägset bäst kunskaper gällande rökning och stress. Störst osäkerhet rådde inom området frukt/grönsaker. Efter två år såg man att samtliga områden hade minskat i sin betydelse, dock marginellt inom fysisk aktivitet. Ett relativt gott hjärtskyddande beteende kan konstateras i patientgrupperna inom samtliga områden förutom stresshantering, vilket skilde sig markant från de övriga. En förändring till något sämre beteende över tid såg man inom rökning och marginellt rörande fysisk aktivitet. Gällande intag av frukt och grönt hade förändring skett både till det sämre och till det bättre. En förändring till ett bättre beteende sågs dock beträffande stresshanteringen. Beträffande hur kunskap stämde överens med beteende ses samma mönster för båda grupperna, d v s att det inom rökningen är bäst överensstämmelse, följt av fysisk aktivitet, intag av frukt och grönt, samt sist området stress. En minskning angående överensstämmande kan konstateras i grupp 2 i följande ordning, frukt/grönsaker, fysisk aktivitet och sist rökning. Inom stressområdet ökade istället överensstämmandet mellan kunskap och beteende över tid.</p><p><strong>Slutsats:</strong> Denna kartläggning antyder att koronarpatienters kunskaper och beteende är relativt tillfredsställande på kort och lång sikt, men kunskapsmässigt är det främst inom området frukt/grönsaker det finns utrymme för ytterligare förbättringar och beteendemässigt inom stresshantering, vilket bör främjas genom större vårdinsatser inom respektive område. </p>

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Cell-based therapies involving adipose-derived stem cells (ASCs) have shown promise in stimulating cardiovascular regeneration, including in the treatment of myocardial infarction (MI) and ischemic heart disease. However, previous studies involving the delivery of ASCs following MI have indicated that therapeutic efficacy has been limited by low survival and/or poor retention of the transplanted cells at the site of injury. To address these limitations, the goal of this thesis was to develop a more effective delivery strategy incorporating an injectable biomaterial combined with chemotactic growth factor delivery to enhance ASC retention within the gel. Working towards future in vivo analysis in a rat model, multilineage characterization studies confirmed that ASCs isolated from the epididymal fat pad of male Wistar rats could differentiate in vitro along the adipogenic, osteogenic, and chondrogenic lineages. Subsequently, the chemotactic response of the rat ASCs (rASCs) to varying concentrations of stromal derived factor-1 α (SDF-1α) and hepatocyte growth factor (HGF) was analyzed using a modified Boyden chamber assay. The results demonstrated that SDF-1α and HGF, at 20, 50, and 100 ng/mL elicited significant migratory responses under normoxic (21%) and hypoxic (5%) culture conditions. RT-PCR analysis was conducted to assess the expression of the two chemotactic growth factors and their associated receptors in the rASCs, and secreted SDF-1α protein expression was quantified by ELISA. Moving towards the development of the biomaterials-based delivery approach, the viability of rASCs encapsulated by photopolymerization in methacrylated glycol chitosan (MGC) hydrogels modified with various degrees of arginine-glycine-aspartic acid (RGD)-peptide modification was examined. More specifically, rASCs were encapsulated in MGC hydrogels with 0%, 4%, and 7% RGD modification and cultured for up to 14 days. Viability staining results indicated that rASC viability was enhanced in the 4% and 7% RGD-modified MGC hydrogels in comparison to the MGC hydrogels with no peptide modification. Pre-loading the gels with 50 ng/mL of SDF-1α had no significant effects on cell viability over 14 days. Overall, the results demonstrate that peptide modification to promote cell adhesion within the MGC hydrogels is key to improving cell viability and thereby improving the therapeutic potential of ASCs. / Thesis (Master, Chemical Engineering) -- Queen's University, 2012-10-24 23:54:37.126

Forskningen gällande hjärt-kärlsjukdom har tidigare utgått från män och överförts till kvinnor trots att det finns skillnader i sjukdomsförlopp och påverkan på livssituationen mellan kvinnor och män. Studiens syfte var att beskriva kvinnors upplevelser av hjärtinfarkt utifrån ett transitionperspektiv. Metoden var en deskriptiv litteraturstudie där tio artiklar med kvalitativ metod ingick. Fyra rubriker med tillhörande kategorier togs fram. Första rubriken Hälsa omfattar kategorierna Diffusa fysiska symptom före den akuta fasen, Sjukdomsupplevelse i den akuta fasen och Fysisk försämring i återhämtningsfasen. Andra rubriken Livsförändring omfattar rubrikerna Svårigheter med att förstå vad som hänt i den akuta fasen, Oro inför anpassningen till ett nytt liv i återhämtningsfasen, Livsstilsförändringar i återhämtningsfasen och En ny mening med livet i omvärderingsfasen. Tredje rubriken Relationer omfattar kategorierna Vill inte vara en börda i den akuta fasen och i återhämtningsfasen, Behovet av stöd i återhämtningsfasen och En förändrad roll i familjen i omvärderingsfasen. Fjärde rubriken Omgivning omfattar kategorierna Stöd från rehabiliteringsgruppen i återhämtningsfasen och Att börja arbeta igen i återhämtningsfasen. Författarna drar slutsatsen att när kvinnor drabbas av hjärtinfarkt genomgår de en transition inom flera områden, så som identitet, relationer, kroppslig kapacitet och beteendemönster i samband med att deras hälsostatus förändras. / Cardiovascular research was originally based on men and applied on women, despite differences in disease course and effect on life between women and men. The study’s aim was to describe women’s experience of myocardial infarction from a transition perspective. The method was a descriptive literature study and ten qualitative articles were included. Four titles with associated categories were found. The first title Health included the categories Diffuse physical symptoms before the acute phase, Illness experience in the acute phase and Physical deterioration. The second title Life change included the categories Difficulties with understanding what happened, Concern regarding the adaptation to a new life, Life style changes and A new meaning with life. The third title Relations included the categories Not wanting to be a burden, Need for support and A changed role in the family. The fourth title Environment included Support from the rehabilitation and Back to work. The authors concluded that when women experience a myocardial infarction, they experience a transition in several areas such as identity, relations, physical capacity and behavioral patterns as their health status change.

This literature review posits that the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an attractive candidate therapeutic target in the setting of acute myocardial infarction (AMI). This transcription factor binds to antioxidant response elements (ARE) in the promoter region of a battery of genes that collectively encode an array of antioxidant, phase II drug metabolism, metabolically stabilizing, and overall cytoprotective enzymes, facilitating their transcription at basal levels and increasing transcription in response to various cellular stressors. Following a brief background tutorial on normal cardiac myocyte cellular physiology, key events that occur early in ischemia and reperfusion are outlined and integrated. These include ionic and metabolic dysregulation, electron transport chain uncoupling, mitochondrial depolarization, and the generation of reactive oxygen species (ROS). Abrupt changes in response to ischemia prime opening of the mitochondrial permeability transition pore (MPTP) and cardiac myocytes to generate a burst of ROS upon reperfusion–two key events that contribute to the umbrella term ischemia-reperfusion injury (IRI). How ROS damage cells is then outlined, and through a ROS-centric viewpoint, a case will be made as to how exogenous upregulation of Nrf2 could protect and/or salvage at-risk tissue immediately subjected to infarction and neighboring tissue in the peri-infarct zone (PIZ). The history of how Nrf2 came to be known as the "master regulator of oxidative stress" is reviewed, as well as the discovery of the canonical mechanism of Nrf2 regulation via Kelch-like ECH-associated protein 1 (Keap1) and other alternative mechanisms of endogenous Nrf2 regulation. Finally, compiling interdisciplinary evidence from research publications around the world, the benefits of therapeutically targeting Nrf2 are considered given the timescale and context of acute MI. Drug delivery methods, potential challenges, and limitations are then considered. Cardiac tissue is a dynamic substrate that exhibits changes for up to 90 days after AMI and patient outcomes are directly related to the extent of tissue lost following infarction/reperfusion. Targeting Nrf2 addresses an unmet need, as current clinical therapies focus on precluding occlusions and prompt reperfusion of infarcted tissue, but do not explicitly target at-risk tissue following infarcts and/or present-day reperfusion methodologies.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / BACKGROUND: In order to improve the quality and efficacy of healthcare while reducing the overall cost to deliver that healthcare, it has become increasingly important to manage utilization of services for populations of patients. Healthcare systems are aggressively working to identify patients at risk for hospital readmissions. Although readmission rates have been studied before, parameters for identifying patients at risk for readmission appear to vary depending the patient population. We will examine existing Electronic Health Record (EHR) data at Banner Health to establish what parameters are clinical indicators for readmission risk. Three conditions were identified by the CMS to have high and costly readmissions rates; heart failure (HF), acute myocardial infarction (AMI), and pneumonia. This study will focus on attempting to determine the primary predictive variables for these three conditions in order to have maximum impact on cost savings. METHODS: A literature review was done and 68 possible risk variables were identified. Of these, 30 of the variables were identifiable within the EHR system. Inclusion criteria for individual patient records are that they had an index admission secondary to AMI, heart failure, or pneumonia and that they had a subsequent readmission within 30 days of the index admission. Pediatric populations were not studied since they have unique factors for readmission that are not generalizable. Logistics regression was applied to all data including data with missing data rows. This allowed all coefficients to be interpreted for significance. This model was termed the full model. Variables that were determined to be insignificant were subsequently removed to create a new reduced model. Chi square testing was then done to compare the reduced model to the full model to determine if any significant differences existed between the two. RESULTS: Several variables were determined to be the significant predictors of readmission. The final reduced model had 19 predictors. When analyzed using ROC analysis, the area under the curve (AUC) was 0.64. CONCLUSION: Several variables were identified that could be significant contributors to readmission risk. The final model had an AUC on it ROC of 0.64 suggesting that it would only have poor to moderate clinical value for predicting readmission.

Heart failure (HF) is one of the leading causes of death and impacts millions of people throughout the world. Recently, injectable hydrogels have been developed as a potential new therapy to treat myocardium infarction (MI). This dissertation is focused on two main topics: 1) to gain a better understanding the transmural contractility in the healthy left ventricle (LV) wall and 2) investigate the efficacy of the hydrogel injection treatment on LV wall stress and function. The results indicate that a non-uniform distribution of myocardial contractility in the LV wall provide a better representation of normal LV function. The other important study explored the influence altering the stiffness of the biomaterial hydrogel injections. These results show that a larger volume and higher stiffness injection reduce myofiber stress the most and maintaining the wall thickness during loading. The computational approach developed in this dissertation could be used in the future to evaluate the optimal properties of the hydrogel. The last study used a combination of MRI, catheterization, finite element (FE) modeling to investigate the effects of hydrogel injection on borderzone (BZ) contractility after MI. The results indicate that the treatment with hydrogel injection significantly improved BZ function and reduce LV remodeling, via altered MI properties. Additionally, the wall thickness in the infarct and BZ regions were significantly higher in the treated case. Conclusion: hydrogel injection could be a valuable clinical therapy for treating MI.