Positron emission tomography provides quantitative measurements of radio-tracer concentrations in vivo to study physiological and molecular processes with radio-labelled compounds of biological affinity. Its application in Cardiology includes the measurement of myocardial blood flow. Quantification of regional blood flow across the myocardium may provide insight in the understanding of the physiological mechanisms involved in ischaemia. However, such measurements are restricted by scanner resolution and sensitivity and the influence of organ motion during data acquisition. Significant improvements in sensitivity in 3D mode of acquisition allow the exploitation of the inherent spatial resolution of the latest generation of PET tomographs. In addition, the acquisition of individual events in list mode makes possible the implementation of motion correction schemes. The problem of obtaining accurate attenuation correction factors, in the absence of septa, was addressed by using single photon transmission measurements and an image segmentation technique, the Local Threshold Segmentation of the attenuation coefficients. This approach was found to provide accurate attenuation coefficients and a scheme for generating attenuation correction factors for absolute quantification could be defined. The influence of motion on the spatial resolution on a current generation 3D PET scanner was assessed with experimental measurements at typical levels of respiration- related motion and was found to be significant for quantitative imaging of the myocardium. Simultaneous electrocardiographic and respiratory gating of list-mode data was implemented and validated. This dual gating approach can be used in data of high counting statistics for the elimination of motion within a single image frame. For count-limited measurements of myocardial blood flow, a method for compensating for respiratory motion, at no loss of total counts, was presented. Validation results showed a generally good accuracy and the technique was applied to 18FDG and C15O patient data. Improvement in the recovery coefficient for accurate tracer concentration assessed against well-counter measurements of blood sample tracer concentration was found for the C15O data.

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Objective Increases in the number of CD34+ stem cells and progenitor cells in blood and infarcted areas after acute myocardial infarction (AMI) are a documented phenomenon. However, no study has yet reported on the dynamic changes in specific populations of adult stem cells, such as c-kit +Lin- cells or ckit + Lin - Sca1 + (KLS cells), following AMI. This study investigated the dynamic changes in these cells in multiple systems/organs following MI in mice. Methods The C57BU6J mice received either no surgery (normal control, n=6) or surgical ligation of the left anterior descending coronary artery to create AMI (n=24). On day-1 (n=7), -3 (n=5), -6 (n=6), and -12 (n=6) after AMI, mononuclear cells were isolated from theblood, spleen, and bone marrow, and stained with Lineage-PEcy7, c-kit-PE, and Sca1-APC antibodies. The c-kit +Lin - cell and KLS cell populations in the mononuclear cells were analyzed by FACS flowcytometry. Results The pattern of changes in the c-kit + Lin - cells was very similar to that in the KLS cells in the bone marrow, circulating blood, and spleen following AMI. There was a significant increase in these cells on day-3 in the bone marrow (c-kit +Lin- cells: 1.470 ± 0.094% vs control 1.127 ± 0.019%, and KLS cells: 0.365 ± 0.012 % vs control 0.1848 ± 0.019%, p<0.05), which then slowly declined from day-6 to -12. In the blood, these cells, particularly the KLS cells, decreased slightly from day-1 to -12. On day-3, -6, and -12 the cells increased continuously and significantly in the spleen, (on day 3, c-kit +Lin-cells: 0.253 ± 0.0107 % vs control 0.1305 ± 0.014 %; it was 0.3212 ± 0.028 % on day-6). (on day-6 KLS cells: 0.1078 ± 0.076 % vs control 0.0425 ± 0.0064 % while on day 12 it was 0.1174 ± 0.035 % p<0.05). Conclusion This study provides for the first time the longest observation of the dynamic changes of specific sub-groups of adult stem cells (c-kit +Lin- cells and KLS cells) in multiple systems following AMI. The study demonstrates that AMI results in significant changes, or mobilization, of these cells in the bone marrow, spleen, and blood. Significant and continuous accumulation of the cells in the spleen occurs following AMI, despite the decreased level of the cells in the blood. The role of the spleen in stem cell mobilization after AMI is unclear and requires further investigation. / Surgery, Department of / Medicine, Faculty of / Graduate

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ST-segment elevation myocardial infarction (STEMI) is a common presentation of acute myocardial infarction, constituting approximately 30% of all cases. Based on the highest level of evidence for improvement in both morbidity and mortality in these patients, clinical guidelines from around the world support the prolonged use of secondary preventative medications (e.g., acetylsalicylic acid, second antiplatelet [clopidogrel, prasugrel, and ticagrelor], statin, beta-blocker, and angiotensin blocker). While in-hospital and discharge prescription rates for these essential life-saving medications is excellent, adherence is known to decline within weeks of hospital discharge. This decline in evidence-based medication use was confirmed in a population of patients with coronary artery disease in Ontario (Chapter 3). Furthermore, it was demonstrated that this decline was consistent across all medication classes and subgroups of patients. We developed a protocol (Chapter 4) for a cluster-randomized controlled trial evaluating the impact of repeated reminders sent by mail to the family physician and the patient, starting one month after the STEMI. The fifth chapter highlights the results of the cluster-randomized controlled trial, which demonstrates suboptimal persistence to all 4 of 4 cardiac medication classes at 12-months. There was no significant difference compared to usual care in the use of guideline-recommended medications post-STEMI when participants (and their family physicians) receive repeated postal reminders.

Changing the temperature, frequency of stimulation and calcium concentration altered the dose-response curves for isoproterenol and histamine on guinea pig and rabbit papillary muscles. Basal developed force, maximal developed force and sensitivity to the agonists were all affected. Increasing the temperature stepwise from 25° to 42° resulted in a progressive decrease in BDF and sensitivity to the agonists. The response of MDF was different in the guinea pig and rabbit. In the guinea pig, MDF was not affected by changing the temperature, and the size of the response to isoproterenol and histamine was similar. In the rabbit, the largest MDF response was seen at 37.5° when the calcium concentration was maintained at 2.2 mM. At this calcium concentration the response to histamine was less than that to isoproterenol at each temperature, although the difference was not significant. Increasing the frequency of stimulation stepwise from 0.5 to 4 Hz in the guinea pig, and 0.2.to 3 Hz in the rabbit affected the dose-response curves in a slightly different manner. In both species, BDF was reduced by low frequency stimulation. At other frequencies BDF was not changed. With isoproterenol, the MDF was only reduced by high frequency stimulation, and the sensitivity increased stepwise with increasing frequency. With histamine, the MDF was reduced by both low and high frequency stimulation. In the rabbit the response to histamine was consistently less than that to isoproterenol. The sensitivity to histamine was not affected by changing the frequency in the guinea pig, but was increased by high frequency stimulation in the rabbit. Increasing the calcium content stepwise from 1.5 to 8 mM in the guinea pig, and 0.5 to 6 mM in the rabbit resulted in a progessive increase in BDF, MDF and sensitivity. In both species, the increase in MDF appeared to reach a maximum between 2.2 and 6 mM calcium. In the rabbit this effect was less noticeable in situations where the frequency or temperature was also reduced. The response to histamine was reduced compared to that of isoproterenol. We postulate that the response to histamine is reduced in rabbit papillary muscles due to stimulation of H₁- receptors in this tissue. It has been shown that stimulation of β and H₂- receptors results in an increase in cyclic AMP, while stimulation of H₁- receptors has no effect on cyclic AMP. The increase in cyclic AMP may enhance calcium binding by the SR resulting in an augmented response.. In the guinea pig papillary muscle which contains β- and H^- receptors, the inotropic responses to isoproterenol and histamine are similar, while in the rabbit papillary muscle which contains 3- and H₁- receptors, the response to histamine is reduced compared to that of isoproterenol. This difference may be due to the lack of cyclic AMP involvement in the response to histamine in this tissue. Use of the calcium antagonist D600 produced a decrease in the sensitivity of rabbit papillary muscles to isoproterenol, but did not depress the MDF. There was no difference in the sensitivity to histamine. D600 therefore could not distinguish any difference in dependence on extracellular calcium between isoproterenol and histamine in this tissue. Isoproterenol stimulated an increase in ⁴⁵Ca content of rabbit right ventricle strips at 2 minutes after administration. No effect could be detected at any other time, nor when histamine was used. It is sugges- ted that at times greater than 2 minutes any increase in ⁴⁵Ca content induced by isoproterenol was masked by a "pool saturation" phenomenon, and that this increase which was detected is consistent with a difference in the mechanism of action of isoproterenol and histamine in rabbit ventricular muscle. / Pharmaceutical Sciences, Faculty of / Graduate

Myocardial infarction (MI) leads to permanent loss of cardiac muscle due to the limited regenerative potential of the mammalian heart. The affected heart muscle is replaced by a fibrotic scar; however, the scar is not able to offset the increase in wall stress placed on the remaining myocardium. This distending pressure can lead to dilative remodeling of the ventricle, progressive loss of cardiac function, and heart failure. Despite current medical therapy, heart failure continues to have a high mortality rate. Therefore, there is a clinical need for treatments that can both improve cardiac function post-MI and reduce ventricular remodeling to prevent progression to heart failure. Injectable biomaterials aim to provide a scaffold to stimulate infarct repair by mimicking the healthy cardiac extracellular matrix (ECM). The ECM plays a critical role in tissue regeneration but after a MI it is pathologically modified. Injection of biomaterials post-MI can provide a scaffold that better stimulates infarct repair. In this study, hydrogels were developed from recombinant human type I and type III collagen (rHCI and rHCIII), the two most prevalent structural proteins in the cardiac ECM. Injection of rHCI and rHCIII hydrogels in a mouse model of MI improved cardiac function and reduced infarct size 28 days post-treatment. Infarcted hearts treated with rHCI exhibited improved myocardial salvage in the region bordering the scar with improved capillary density. rHCI hydrogel was also superior to rHCIII in reducing ventricular remodeling. The injection of rHCI hydrogel into the border zone post-MI resulted in an acute improvement of contractile function two days after treatment that was maintained long-term. At two days post-injection, rHCI treated animals had reduced apoptotic cardiomyocytes and lower levels of oxidative stress. Methylglyoxal modifies and crosslinks collagen in the ECM, leading to oxidative stress. Two days after injection, the rHCI hydrogel at the epicardial surface was modified by methylglyoxal, while methylglyoxal-derived advanced glycation end-product levels in the underlying myocardium were lower than in control animals. It appears that rHCI hydrogel injection is soaking up free methylglyoxal from the myocardium, reducing levels of oxidative stress in cardiac muscle and improving contractility of cardiomyocytes bordering the scar. These results suggest that rHC therapy is a promising approach to improve cardiac contractility, and limit ventricular remodeling post-MI.

Myocardial injury after noncardiac surgery (MINS) is common in patients undergoing inpatient noncardiac surgery and has been shown to adversely impact short- and long-term patient prognosis. Most MINS events are asymptomatic and systematic troponin measurement early after surgery is of paramount importance to detect these events. The largest study to determine thresholds and prognostic importance of MINS used troponin T and high-sensitivity troponin T. There is limited information on how to diagnose MINS using high-sensitivity troponin I (hsTnI). How to predict who is at higher risk of MINS and would benefit the most from troponin monitoring, and how to manage patients who suffer a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps. Chapter 2 describes the result of a large prospective cohort of patients undergoing noncardiac surgery which determined the utility of preoperative N-Terminal pro-B type Natriuretic Peptide to predict 30-day MINS and vascular death, in addition to clinical evaluation. Chapter 3 uses data collected as part of a large prospective cohort with a nested biobank to determine thresholds of hsTnI that can predict major cardiovascular events in patients who underwent noncardiac surgery and be used to diagnosis MINS using hsTnI. Chapter 4 details the methods of an international, multicentre, randomized placebo-controlled trial (MANAGE Trial) determining the impact of dabigatran, a blood thinner, and using a partial factorial design, of omeprazole, a gastric acid reducing drug, on the occurrence of major vascular and upper gastrointestinal events in patients who suffered a MINS and are followed for up to 2 years. Chapter 5 presents the results of the omeprazole component of the MANAGE Trial. Chapter 6 discusses the key findings of the thesis and future research directions. / Thesis / Doctor of Philosophy (PhD) / Damage to the heart muscle occurring after a noncardiac surgery, called myocardial injury after noncardiac surgery (MINS), occurs frequently and negatively impacts patient’s short- and long-term health and survival. Most patients who suffer a MINS do not present symptoms suggestive of heart problems. Blood tests obtained after surgery measuring troponins, a marker of heart damage, is necessary to detect which patients are having MINS. Different troponin tests are available, including a test called high-sensitivity troponin I, for which there is limited information on how to diagnose MINS using this test. How to predict who is at higher risk of MINS and how to treat patients who suffered a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps.