Metabolic syndrome (MetS) is a conglomeration of several risk factors for cardiovascular disease, with obesity currently being one of the common causes of disability and death in the United States.1 Underlying the obesity, however, there is metabolic imbalance that could be exacerbating the issue of metabolic syndrome.2 Approximately 34% of adults over 20 years old matched the criteria for metabolic syndrome.3 The risk factors for cardiovascular disease (CVD) associated with metabolic syndrome can, over time, lead to severe CVDs, such as heart failure (HF).4 Metabolic syndrome can also lead to developing metabolic heart disease over time. Understanding the development of cardiac hypertrophy and fibrosis in diet-induced metabolic heart disease allow development of an early treatment of metabolic heart disease (MHD) and HF. This study looked at one potential mediator and its role in cardiac hypertrophy and fibrosis, follistatin-like 3 (FSTL3). FSTL3 is an extracellular antagonist of members of the TGF-β superfamily. The goal of our study was to determine the effect, if any, a knockout of FSTL3 would have on the development of cardiac hypertrophy and fibrosis after a high-fat, high-sucrose diet for five months. FSTL3 knockout mice were given a high-fat, high-sucrose (HFHS) diet for five months. These mice were then sacrificed and their hearts were analyzed for cardiac myocyte hypertrophy and interstitial fibrosis using histological methods. After five months on the HFHS diet, wild-type (WT) mice had cardiac hypertrophy. In FLRG KO mice the diet-induced cardiac hypertrophy was attenuated. WT HFHS-fed mice developed interstitial fibrosis, and FLRG KO HFHS developed more accentuated interstitial fibrosis than WT HFHS diet fed mice. This study is useful in suggesting that FTSL3 contributes to the pathogenesis of cardiac hypertrophy in MHD. FTSL3 may be a useful biomarker for cardiac hypertrophy in patients with suspected MHD, and may be a viable target for therapeutic interventions aimed at decreasing pathologic myocardial hypertrophy.

Bibliography: p. 137-154. / 154 p. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis details a series of studies in patients, in human volunteers and in large animals. Haemodynamics and left ventricular systolic and diastolic mechanics are reported during lactic acidosis, during therapies for lactic acidosis, and during hyperdynamic and hypovolemic shock. The study has the unifying hypothesis that cardiac dysfunction is important in hyperdynamic and hypovolemic shock and is not caused by lactic acidosis. / Thesis (M.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1997?

Atherosclerosis is characterized by a chronic inflammation, involving autoimmune components, in the arterial wall. An increase in proinflammatory activity relative to anti-inflammatory activity is considered to cause a progression of the disease towards plaque instability and risk of atherothrombotic events, such as acute coronary syndrome (ACS). Cortisol, the end product of the hypothalamus-pituitary-adrenal (HPA) axis, is a powerful endogenous anti-inflammatory mediator. Disturbances in the HPA axis have been reported in chronic inflammatory/autoimmune diseases, like rheumatoid arthritis. The aim of this thesis was to study various markers of systemic inflammation in patients with acute and stable conditions of coronary artery disease (CAD) and relate these findings to the cortisol response. Both patients with ACS and patients with stable CAD had high levels of C-reactive protein (CRP), interleukin (IL)-6 and IL-1 receptor antagonist, compared with healthy controls. In addition, patients with stable CAD had significantly more neutrophil-platelet aggregates than controls, as a possible indicator of neutrophil activation. The cortisol response was determined in two different cohorts of CAD patients; one consisting of patients with a first-time myocardial infarction and one consisting of patients with long-term stable CAD. From the acute phase to 3 months, the patients with a myocardial infarction showed a higher 24-h cortisol secretion and a flattened diurnal slope caused by higher cortisol levels in the evening, as compared with healthy controls. The patients with long-term stable CAD showed similarly high levels of cortisol in the evening. The levels of evening cortisol were strongly correlated with CRP and IL-6. When exposed to acute physical or acute psychological stress at 3 months, the ACS patients showed a markedly blunted cortisol response compared with healthy controls. Following the stress tests, a significant increase in CRP was observed in the patients but not in the controls, indicating a failure of the HPA axis to compensate for stress-induced inflammation in CAD. In the ACS patients, the time course of matrix metalloproteinases (MMPs) and their tissue inhibitor TIMP-1 was determined during the 3 months follow-up. A major finding was that the MMP-9 and TIMP-1 levels remained significantly higher in the patients at all time points compared to the controls. MMP-9 and TIMP-1, but not MMP-2, MMP-3 or MMP-7, were related to inflammatory activity, as assessed by CRP and IL-6. MMP-9 and TIMP-1 showed significant correlation with evening cortisol, even after adjustment for CRP and IL-6, lending further support for a link between ´high´ flat cortisol rhythm and systemic inflammatory activity. The activation status of neutrophils in stable CAD was further examined by measuring the expression, affinity state and signalling capacity of b2-integrins and the innate production of reactive oxygen species (ROS). However, the neutrophils in patients were not more activated in vivo than were cells in healthy controls, neither were they more prone to activation ex vivo. The data rather indicated an impaired function of neutrophils in stable CAD. The neutrophils in CAD patients showed a significantly lower number of total glucocorticoid receptors (GRs) and a lower GRa:GRb ratio compared to healthy controls, indicating a chronic over activation of the HPA axis and, possibly, a state of glucocorticoid resistance. Moreover, the evening cortisol levels in patients were associated with an overexpression of annexin-1, the ´second messenger´ of glucocorticoid action. In contrast to neutrophils in controls, the neutrophils in patients also showed a hyper responsiveness to exogenous annexin-1 resulting in impaired neutrophil function. To conclude, clinically stable CAD was associated with a systemic inflammatory activity, involving a high MMP-9:TIMP-1 ratio and an increased inflammatory response to acute stress but not any activation of neutrophils. This inflammatory activity was associated with a dysregulated cortisol secretion, defined by a flat diurnal rhythm and a blunted cortisol response to stress. Although the clinical relevance remains to be verified, an intriguing hypothesis is that a hyporesponsive HPA axis favours the development towards plaque instability. / On the day of the defence date the title of article III was: "A sustained elevation of serum matrix metalloproteinase-9 is associated with diurnal salivary cortisol in patients with acute myocardial infarction-a 3-month follow-up".

The incidence of stroke and re-infarction is noticeably high in the first few days following acute myocardial infarction. This finding has raised questions whether the systemic inflammatory reaction secondary to myocardial necrosis is involved. The inflammation might affect the activation of platelets leading to insufficient effect of the antiplatelet treatment given. Furthermore, the importance of platelet reactivity and inflammation in terms of long-term prognosis is not fully understood. The prognostic importance of C-reactive protein (CRP) in relation to clinical variables also needs to be clarified. The present studies are aimed at describing the dynamics of platelet function during the first days of an acute myocardial infarction, in relation to diabetes and inflammation. We also investigated whether increased platelet reactivity or the increased concentration of CRP in blood were related to a worse outcome. Finally, we examined if CRP levels contributed to a predictive model using clinical variables known to affect outcome in patients with AMI.  We used two novel platelet function tests to measure platelet reactivity; the PA-200 (a laser light aggregometer) and the PFA-100 (measures primary haemostasis in whole blood). Platelet aggregation increased during the initial course of an acute myocardial infarction. The increase in platelet aggregation was most pronounced in diabetics and in patients showing higher systemic inflammatory reaction, assessed by measuring the concentration of CRP in blood. The pronounced platelet aggregation occurred despite ongoing antiplatelet and antithrombotic treatment. There was a significant association between the levels of CRP and the degree of platelet reactivity. However, while the CRP levels were associated with a worse outcome (AMI, stroke and death), the results of the platelet function tests were not. The importance of CRP in predicting prognosis depended on which adjustments were made for confounding factors. CRP and prognostic variables in a statistical model predicting death, however, showed that CRP was excluded. Thus CRP did not predict outcome beyond clinical prognostic variables. The results of these studies reinforce the importance of clinical variables such as heart failure, age, atrial fibrillation, smoking status, diabetes and impaired kidney function - all of which were associated with worse prognosis in multivariable analysis.

<p>Covering the metal surface of blood-contacting cardiovascular implants (stents, ventricular assist devices) with functional endothelium may reduce the incidence of clotting and restenosis complications and also reduce the need for risky anticoagulation therapy following implantation of such devices. We developed a novel cell therapy for seeding autologous endothelium onto blood-contacting vascular stents at the point of care to reduce thrombosis and stent restenosis. The proposed research tested the following hypotheses: (1) autologous endothelial cells (ECs) can spread on titanium (Ti) tubes and reduce thrombosis on the Ti surface <italic>in vivo</italic>; (2) shear stresses on the surfaces of an implanted carotid artery stent will be conducive to EC retention and function under arterial flow; and (3) nitinol stents seeded with ECs at the point of care will remain adherent and functional after stent deployment and arterial fluid shear stress conditions <italic>in vitro</italic> and <italic>in vivo</italic>. Based on the experiments reported herein, the primary conclusions of the dissertation are as follows: (1) autologous ECs significantly reduce thrombosis on Ti surfaces implanted into the bloodstream <italic>in vivo</italic>; (2) shear stresses on stent surfaces under carotid artery flow conditions are sufficiently low to be compatible with EC retention and function; (3) ECs seeded onto nitinol stents by infusion at the point of care are retained and spread to form a functional layer following deployment and arterial flow conditions both <italic>in vitro</italic> and <italic>in vivo</italic>.</p> / Dissertation

The main treatment for myocardial infarction is early reperfusion of ischemic tissue. Ischemia and reperfusion (IR) produces reactive oxygen species that oxidize membrane phospholipids. The production of oxidized lipids and their role on cell death in cardiac IR injury is unknown. Using in vitro model of IR, our goal was to identify oxidized phosphatidylcholines (OxPC) from cardiomyocytes, to determine their bioactivity on cardiomyocyte viability and mitochondrial permeability, and using an OxPC specific EO6 antibody inhibit OxPC activity on cardiomyocytes. Rat cardiomyocytes were exposed to IR and lipid extracts underwent lipidomic analysis with HPLC-MS/MS to quantitate 82 novel OxPC species. Cell viability and mitochondrial permeability were determined in vehicle control, non-oxidized control PC, and fragmented OxPC molecules. EO6 antibody was applied and cell viability was assessed. Cardiomyocytes under IR demonstrated increased relevant OxPCs particularly fragmented species. OxPC treatment resulted in loss of cardiomyocyte viability, increased mitochondrial permeability when compared to control. EO6 antibody blocked the loss of cardiomyocyte viability. We have shown for the first time that OxPCs are generated cardiomyocytes during IR and they have detrimental effects on cardiomyocyte viability. Additionally the EO6 antibody inhibits the bioactivity of the OxPCs on cardiomyocytes and could be part of a future treatment regimen.

Mitte des Jahres 2009 wurden an 30 Tagen am neu installierten Herzkatheterarbeitsplatz der Abteilung für Kardiologie und Angiologie, der Klinik für Innere Medizin Messungen durchgeführt um die Exposition von Untersucher und assistierender Pflegekraft während koronarangiographischer und –interventioneller Prozeduren an einer der modernsten Herzkatheterarbeitsplätze zu erfassen. Dazu wurden an 8 Körperteilen des Untersuchers und Assistenzpersonals (jeweils Auge, Schulter, Handrücken und Unterschenkel beidseits) Thermolumeszenzdosimeter angebracht und diese dann nach einem Untersuchungstag ausgewertet. Bei den Ergebnissen stellte sich heraus, dass die empfohlenen jährlichen Expositionswerte unter den vorherrschenden Bedingungen nicht erreicht werden und die Arbeit an einem modernen Herzkatheterarbeitsplatz als sicher gilt. Jedoch ist das Strahlenfeld als solches sehr inhomogen und weist auch starke Schwankungen je nach Art der Untersuchung, der Erfahrung des Untersuchers und auch der Komplexität des Falles auf. Desweiteren muss beachtet werden, dass die technischen Neuerungen der letzten Jahre erheblich zur Verminderung der Exposition geführt haben und somit an älteren Anlage eine Überschreitung der jährliche empfohlenen Teilkörperdosis als wahrscheinlich gilt.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1982. / Bibliography: leaves 260-277. / Microfiche. / xiv, 277 leaves, bound ill. 29 cm

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