Prediction of cardiovascular mortality in patients with coronary artery disease using plasma and genetic markers of oxidative stress

Coronary artery disease (CAD) is the leading cause of death worldwide. The consequences of CAD severely burden the Canadian health care system, and expensive therapeutic solutions have only limited capacity for preventing or reversing the disease. Oxidized low density lipoprotein particles (oxLDL) contribute to the progression of CAD. OxLDL are a harmful byproduct produced by oxidative stress, which occurs when the production of free radicals in the body exceeds the body’s ability to neutralize and eliminate them. The environmental factors that increase the risk of CAD, such as poor nutrition, smoking, obesity, and low physical activity, are the same factors that increase oxidative stress levels in the body. Claire Heslop is studying the influence of oxidative stress on long-term survival among people with CAD, and investigating genetic differences that contribute to this relationship. She is evaluating whether markers of oxidative stress in the blood, as well as markers of inflammation, can predict risk of death from cardiovascular disease in individuals with CAD. She will also investigate oxidative stress genes to determine how inherited differences affect oxidative stress in the blood, the risk of CAD, and the risk of cardiovascular death. As part of this project, the relationships between CAD, oxidative stress markers and various physiological, lifestyle and socioeconomic risk factors will also be examined. Heslop’s work will contribute to our understanding of the role oxidative stress plays in coronary artery disease. This study may inspire the creation of new tools for diagnosing CAD and predicting long-term risk.

Economic studies of seniors at high risk of falls

Falls are a major public health problem in BC and around the world. Every year, approximately one third of adults in the community aged 65 years and older will fall. In BC, falls are responsible for 85 per cent of the $211 million annual direct cost of unintentional injuries. In New Zealand, a physiotherapist-initiated, progressive, home-based strength and balance training program reduced falls by 35 per cent; it proved cost-effective in persons aged 80 years and older. This program is currently undergoing a randomized clinical trial in BC for high-risk seniors. However, no economic outcomes have been published for any intervention to prevent falls in Canada. Jennifer Davis was previously funded by MSFHR for her early PhD work with the Falls Prevention Clinic at Vancouver General Hospital. Her current studies use economic data from the BC fall prevention trial to determine the cost implications of this program. Comparing this new program with the current standard of care, she will calculate the dollar cost per fall avoided, and the dollar cost per Quality Adjusted Life Year (a measure of disease burden, including both the quality and the quantity of life lived). She aims to perform cost-effectiveness and cost-utility analyses of the possible benefit of various types of exercise interventions compared with usual care. Davis’ long term research goal is to pioneer the improved economic evaluation of the burden of falls among seniors in Canada. This work will provide essential data for policy makers allocate health care resources in the most effective way.

The Role of Granzyme B in Aortic Aneurysms

An aneurysm is a permanent dilation, or ballooning, of a blood vessel or an artery to 1.5 times its normal diameter. It is usually a complication of atherosclerosis, a form of cardiovascular disease where the interior walls of blood vessels are blocked by a fatty substance called plaque. While most aneurysms are small, slow growing and rarely rupture, some are large, fast growing and at higher risk of rupturing. Aneurysm formation can result in hemorrhaging and death if not immediately repaired – the mortality rate after a rupture is 80-90 per cent. Aneurysms in the brain (cerebral aneurysms) can rupture and cause bleeding within the brain, resulting in a stroke. Ciara Chamberlain is studying a protease, Granzyme B, which is made and released by certain types of immune cells. Granzyme B may play a role in aortic aneurysms by breaking down structural proteins and causing thinning of the blood vessel wall. Building upon work in this area already conducted at the James Hogg iCAPTURE Centre, this research seeks to provide definitive evidence about the therapeutic potential for Granzyme B inhibition for the prevention of aneurysms in patients with mild or advanced atherosclerosis.

The Role of Ubiquitin/Proteasome System in Heart Failure

Heart failure is a disorder in which the heart loses its ability to pump blood efficiently. Despite recent advances in treatment, heart failure remains the leading cause of death in Canada. One in four Canadians suffers from heart disease, and more than 70,000 Canadians die from heart diseases each year. Treatment of heart failure is a major economic and social burden. The proteasome is a large multiprotein complex found in all cells, which breaks down unwanted or damaged proteins that have been “tagged” for elimination with a small protein called ubiquitin. The ubiquitin/proteasome system contributes to many cellular functions, including cell division, quality control of newly-produced proteins, and immune defense. Impairment of this system has been linked to several diseases, including cancer, Alzheimer’s and Parkinson’s diseases. It may also play a role in the development of heart failure. Tse Yuan Wong’s research is exploring the contribution of the ubiquitin/proteasome system to heart failure. This involves examining the functional changes of this system in heart failure and determining how it is regulated. He will also explore how disturbed proteasome function affects the progression of heart failure. This study will provide valuable insights into the mechanisms of heart failure, which could lead to novel therapeutic strategies that could have a huge impact on health care in Canada.

The heart as an immunologic organ: Cardiac myocytes in innate immunity

It’s well established that severe infection in critically ill patients can result in heart damage, but what causes this damage is unclear. One possibility is that heart muscle recognizes and responds to infectious pathogens and their products, triggering events within heart cells that ultimately lead to heart failure. Dr. John Boyd is researching the link between serious infection and cardiac dysfunction. The immune system uses Toll-like receptors to recognizes infectious products. Boyd aims to establish the role and function of Toll-like receptors in the heart, and what response occurs in heart muscle cells when incubated with infectious pathogens that are known to activate these receptors. Because Toll-like receptors also recognize and respond to tissue damage arising from ischemic heart disease (when there is a decrease in the blood supply to the heart caused by constriction or obstruction of the blood vessels) and heart transplant rejection, the research could have relevance beyond cardiac response to acute infection. Ultimately, Boyd aims to provide novel insights into the connection between the heart and immunity, which could lead to the development of new strategies to improve outcomes in diseases that involve inflammatory responses of the heart.

Estimating current and future direct medical costs associated with HIV/AIDS in British Columbia using an integrated model of clinical disease history and population transmission dynamics

HIV/AIDS continues to be a major health issue in Canada, twenty-five years after the first cases were reported. About 58,000 Canadians, including 13,000 BC residents, are infected with HIV (the human immunodeficiency virus that leads to AIDS), and the incidence appears to be rising. A rough estimate sets the medical costs of caring for people with HIV/AIDS at more than $800 million a year. But rapid treatment advances make medical costs a moving target. Karissa Johnston is using the computer simulation model she developed in her earlier MSFHR-funded research to more accurately estimate the annual and lifetime medical costs of treating people infected with HIV. Johnston has designed a series of modules to measure the amount of HIV virus in peoples’ bloodstream (called the viral load) over their lifetime, their initiation and adherence to antiretroviral medications, their use of health services, and their survival time with different treatment regimes. As new treatments or data become available, individual modules can be updated without affecting the others. This information can help health care providers assess the costs and effectiveness of different treatment options. For example, antiretroviral medications successfully suppress viral load, reducing the risk of passing the infection during a sexual encounter. Even though the medications are costly, this tool will show if they ultimately result in costs savings due to a reduction in new infections.

The Genetics of Asthma, Atopy and Allergic Diseases

My research focuses on trying to identify why some children get asthma and others do not. By identifing specific environmental and genetic risk factors and determining how they work together to predispose children to developing asthma and other allergic diseases we can design better treatments. Studies have found a 1-in-5 risk of developing asthma if one parent has asthma. The odds rise to 2 out of 3 if both parents have asthma. However, in itself, a genetic predisposition does not ensure that asthma will develop. Asthma and allergic disease are the result of both genetics and the environment. The interaction between a genetic disposition and environmental factors is key in the development of – or in protecting against- asthma. I will use information from 250 French Canadian Asthma Families and two additional birth cohorts, and information from the town of Busselton Australia in my research. Home visits were conducted for all the families and children to collect information on environmental factors such as family history, number of children, parental occupations, daycare, pets, dust samples, infections, hospitalizations and medication usage. After reviewing the literature we have found 162 genes which may predispose children to developing asthma and we will be looking at these genes in conjuction with other environmental factors to try and better understand why some children develop asthma and others do not. Using statistical models we will look at what genetic and environment factors best explain why some children develop asthma and others do not. We will then do further laboratory experiments to try and identify these factors work together.

Mechanisms and consequences of aberrant repair in the lung

The World Health Organization estimates that between 100 million and 150 million people worldwide suffer from Asthma. The disease places a huge burden on the health-care system, with economic costs greater than of TB and HIV/AIDS combined. While less common than Asthma, Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease since there is no cure or effective therapy. In North America and Canada there are over 200,000 patients with this disease. Of these more than 40,000 die annually. This is the same number of people that die from breast cancer annually. Currently we think that the pathology of both diseases follows a pathway similar to normal wound healing, although there is progression of the disease because the normal «braking» mechanisms do not function properly. As a consequence, too much connective tissue is produced. My research focuses on the cells that line the airways, called the epithelium and the cells that produce the connective tissue, called fibroblasts. Epithelial cells are important since they are the first cell in the lung that interacts with the air and are therefore most likely to be injured. We think that if the epithelium does not repair properly, it will signal the fibroblasts to continue making connective tissue inappropriately.

Characterizing the role of granzyme B in atherosclerosis and hair loss in apolipoprotein E knockout mice

Cardiovascular disease is the leading cause of death in Canada. Atherosclerosis is a cardiovascular disease, in which the inside of blood vessels contain fatty growths known as plaques. Over time, these plaques become unstable and can break, resulting in blockage of blood vessels. This can lead to heart attacks, strokes and limb loss. Wendy Boivin’s research explores what makes a plaque develop, grow, and become less stable. She is focusing on a protein called Granzyme B, which is known to cause plaques. What is unknown is which of two possible approaches Granzyme B uses to induce plaque formation and atherosclerosis: either by entering blood vessel cells and killing them, or by breaking down structural proteins in the blood vessel. Wendy Boivin is studying the role of perforin, a protein that is required for Granzyme B to enter into blood vessel cells. By conducting a study that observes what happens when perforin is removed from blood vessels, she can pinpoint the pathway Granzyme B uses to cause atherosclerosis. Ultimately, this study may contribute to new therapeutic targets for combating this disease.