Glucocorticoid production by the adrenal gland is regulated by hypothalamicpituitary- adrenal (HPA) axis activity. Within cells, glucocorticoid levels are modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD), which interconverts active and intrinsically inert glucocorticoids. Glucocorticoids have widespread physiological effects and, in the cardiovascular system, they play a crucial role in heart development and maturation, blood pressure control, and myocardial calcium cycling. Mice which are unable to regenerate the physiological glucocorticoid, corticosterone, from 11-dehydrocorticosterone due to deletion of the type 1 11β-HSD isozyme (11β-HSD1) have previously been shown to have smaller, lighter hearts but unaltered systolic function. Moreover, a single nucleotide polymorphism (SNP) in the Hsd11b1 gene has been associated with reduced left ventricular mass in humans, suggesting a role for 11β-HSD1 in regulating cardiac size. After myocardial infarction (MI), 11β-HSD1 deficient mice have an augmented inflammatory response, increased numbers of pro-reparative alternatively-activated macrophages in the heart, enhanced peri-infarct angiogenesis and improved cardiac function compared to C57BL/6 controls. However, the role of ‘cardiovascular’ 11β-HSD1 in the development of these phenotypes, both basally and after MI, is unknown. It was hypothesised that ‘cardiovascular’ 11β-HSD1 deficiency would result in smaller hearts, and that this selective deletion would lead to altered calcium handling protein expression and diastolic abnormalities. Furthermore, it was hypothesised that ‘cardiovascular’ 11β-HSD1 deletion would reproduce the beneficial post-MI phenotype previously seen in global 11β-HSD1 deficient mice. The first aim was to characterise the cardiac phenotype of mice with global deletion of 11β-HSD1 (DelI mice), and mice in which deletion is restricted to cardiomyocytes and vascular smooth muscle cells (SMAC mice). SMAC mice have ‘floxed’ 11β- HSD1 alleles and a Cre recombinase transgene inserted into the Sm22α gene. Sm22α is expressed in vascular smooth muscle cells, and transiently in cardiomyocytes during development. Thus, Cre expression in these cells results in deletion of exon three of the Hsd11b1 gene and gives rise to a non-functional protein. Controls for DelI mice were C57BL/6 mice, and controls for SMAC mice were their Cre- littermates. DelI, but not SMAC, mice have smaller, lighter hearts, which may be explained by their shorter cardiomyocytes measured following isolation using a Langendorff preparation. Cardiomyocyte cross-sectional area is unchanged. In vivo measurement of cardiac function using ultrasound imaging showed systolic function is comparable between DelI mice and SMAC mice and their respective controls. However, there is mild diastolic dysfunction in both DelI and SMAC mice, characterised by reduced E wave deceleration and an increased mitral valve deceleration time. This phenotype occurred following pharmacological inhibition of 11β-HSD1, by administration of UE2316, a selective 11β-HSD1 inhibitor, to adult C57BL6/SJL mice. While ventricular collagen content is unaltered in DelI, SMAC and UE2316-treated mice compared to their respective controls, expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) is reduced, suggesting that altered calcium handling, rather than changes in stiffness, may underlie this phenotype. The second aim was to determine whether the beneficial acute outcomes seen previously in 11β-HSD1 deficient mice after MI could be reproduced by selective cardiovascular deletion of the enzyme. Seven days after MI, compared to Cre- littermate controls, SMAC mice have similar peri-infarct angiogenesis, total macrophage and alternatively-activated macrophage infiltration into the heart, infarct size, ventricular dilatation and systolic function. This suggests 11β-HSD1 deletion in another cell type, or types, is responsible for the phenotype seen in global 11β-HSD1 deficient mice. The final aim was to assess the impact of global 11β-HSD1 deficiency and ‘cardiovascular’ 11β-HSD1 deletion on the development of heart failure, using magnetic resonance imaging to determine structure and function. Eight weeks after MI, mice globally deficient in 11β-HSD1 have attenuated expression of ANP and β- MHC, RNA markers of heart failure, and show attenuated pulmonary oedema, reduced chamber dilatation, preserved systolic function and smaller infarcts compared to control. None of these parameters are altered in SMAC mice relative to control. In conclusion, the data presented in this thesis shows that cardiovascular 11β-HSD1 influences physiological cardiac function, potentially through regulation of calcium handling. 11β-HSD1 in other cells influences cardiomyocyte length, resulting in smaller hearts in its absence. Despite this, global 11β-HSD1 deficiency prevents heart failure development after MI, suggesting that pharmacological inhibition of 11β-HSD1 may be of benefit in treating this condition. Cardiovascular 11β-HSD1 does not, however, account for the changes in infarct healing or remodelling associated with this beneficial outcome, therefore these effects must be related to 11β-HSD1 deficiency elsewhere, such as fibroblasts or myeloid cells.

Cardiac troponins are released into the circulation following myocardial injury with measurement of serum troponin concentration integral to the diagnosis of myocardial infarction. The next generation of high-sensitivity cardiac troponin assays have enhanced precision at very low concentrations and for the first time permit troponin concentrations to be reliably quantified outwith acute coronary syndromes. My aim was to evaluate the impact of more sensitive troponin assays on the diagnosis of myocardial infarction and to determine the potential for novel applications in stable cardiovascular diseases. In 2,929 consecutive hospitalised patients with myocardial injury I assessed the impact of implementing a contemporary sensitive troponin assay and a lower diagnostic threshold, on the incidence, management and outcome of patients with primary (type 1) and secondary (type 2) causes of myocardial infarction. Lowering the threshold improved outcomes in patients with type 1 myocardial infarction, but disproportionately increased the diagnosis of type 2 myocardial infarction, and identified a group of patients who remained at high-risk of death over the next 12 months. In 1,126 consecutive patients with suspected acute coronary syndrome I evaluated the impact of a high-sensitivity cardiac troponin I assay and sex-specific diagnostic thresholds on the diagnosis of myocardial infarction. Whilst having little effect in men, the use of sex-specific diagnostic thresholds would double the diagnosis of myocardial infarction in women, identifying those at increased risk of recurrent events. In a second cohort of 4,870 patients, I evaluated the optimal threshold to rule out myocardial infarction. The negative predictive value for myocardial infarction or cardiac death at 30 days was evaluated for a range of troponin concentrations. Troponin concentrations < 5 ng/L on presentation identified half of all patients with suspected acute myocardial infarction as low risk. Implementation of this assay and approach would markedly reduce hospital admissions and improve the diagnosis of myocardial infarction, particularly in women. High-sensitivity cardiac troponin assays may help us to manage patients with chronic cardiovascular diseases, such as aortic stenosis or stable angina pectoris. In patients with aortic stenosis, cardiac troponin was associated with an advanced hypertrophic response on electrocardiography and the presence of myocardial fibrosis on cardiac magnetic resonance imaging. Furthermore, cardiac troponin concentrations were a strong independent predictor of cardiovascular death or aortic valve replacement. In patients with stable angina, cardiac troponin was associated with transient ST-segment depression on ambulatory monitoring, suggesting that troponin concentrations may be modified by silent myocardial ischaemia. My findings suggest that high-sensitivity troponin assays have major potential to improve the assessment, treatment and outcome of patients with suspected acute coronary syndrome. The potential for cardiac troponins to improve risk stratification and monitoring of disease progression in patients with chronic cardiovascular disease now needs to be evaluated in prospective cohort studies.

Thesis (M.S.)--Boston University

Background: Myocardial injury affects up to one in three patients undergoing non-cardiac surgery. However, very little is known about the underlying pathophysiology. In the general population, patients with elevated resting heart rate are at increased risk of cardiac events, mortality, heart failure and autonomic dysfunction, while hypertension is a well described risk factor for cardiovascular disease. I hypothesised that common abnormalities of heart rate or blood pressure were associated with myocardial injury after non-cardiac surgery. Methods: This thesis comprises a series of secondary analyses of data from five prospective multi-centre epidemiological studies of surgical patients. The main outcome of interest was myocardial injury, defined using objective measurement of cardiac troponin. I used logistic regression analysis to test for association between exposures and outcomes. Results: In a large international cohort, patients with high preoperative heart rate had increased risk of myocardial injury and patients with very low preoperative heart rate had reduced risk of myocardial injury. Patients with elevated preoperative pulse pressure had increased risk of myocardial injury, independent of existing hypertension or systolic blood pressure. High heart rate, or high or low systolic blood pressure during surgery, was associated with increased risk of myocardial injury. In a separate study, elevated preoperative heart rate was associated with cardiopulmonary and autonomic dysfunction, and reduced left ventricular stroke volume, suggestive of heart failure. Finally, autonomic dysfunction, identified using cardiopulmonary exercise testing, was associated with elevated preoperative heart rate, elevated plasma NT-Pro-BNP (indicative of heart failure) and postoperative myocardial injury. Conclusions: Elevated preoperative heart rate, autonomic dysfunction and subclinical heart failure may be part of a common phenotype associated with perioperative myocardial injury. Further research is needed to characterise the pathological processes responsible for myocardial injury, and to identify potential therapeutic targets.

A Research Report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Master of Medicine In the branch of Nuclear Medicine Johannesburg September 2013 / The use of Single Photon Emission Computed Tomography (SPECT) myocardial perfusion imaging (MPI), with Technetium – 99m (Tc-99m) Sestamibi in conjunction with either exercise, pharmacologic stress or both is an established tool for both the diagnosis and prognostication of patients with ischemic heart disease. For perfusion imaging with SPECT, Tc-99m labeled radiopharmaceuticals (Sestamibi or Tetrofosmin) are commonly used. The major metabolic pathway for clearance of Sestamibi is the hepatobiliary system which creates difficulty in both visual and quantitative interpretation of myocardial perfusion, particularly of the inferior and infero-septal walls after reconstruction. Diluted lemon juice, an acid-rich drink is an alimentary cholekinetic that facilitates Sestamibi transit through the liver. Whole milk stimulates liver clearance as well as increases peristaltic movement. The aim of the study was to determine which protocol would be the best to reduce interfering infra-cardiac activity and therefore result in an improvement in image quality. We had three groups, comparing the use of full fat milk, diluted lemon juice and a control group that had no intervention. All patients referred to our institution for MPI from November 2009 to May 2012 were enrolled in the study. A total of six hundred and thirty (630) patients who fulfilled the inclusion criteria were randomized without stratification into three groups. Group 0 (G0) were given diluted lemon juice, 246 patients; full fat milk to group 1 (G1), 313 patients and group 2 (G2); 71 patients, had no intervention. The latter was the control group. Raw data of both the stress and rest images were visually and quantitatively assessed by two Nuclear Medicine physicians for the presence of infra-cardiac activity. The physicians were blinded to the intervention received and the data were reviewed simultaneously. The administration of milk or lemon juice resulted in a significant decrease in the intensity of infra-cardiac activity compared to the control group. This improvement was even more significant in the milk group for patients done during rest myocardial perfusion imaging.

Thesis (M.S. in chemical engineering)--Washington State University, December 2009. / Title from PDF title page (viewed on Feb. 12, 2010). "School of Chemical Engineering and Bioengineering." Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 4 uppsatser.

Thesis (M. Phil.)--University of Queensland, 2002. / Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xviii, 132 p.; also includes graphics. Includes abstract and vita. Advisors: George E. Billman and Timothy E. Kirby, Dept. of Educational Services and Research. Includes bibliographical references (p. 124-132).

Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 175-192).