Developing personalized anti-arrhythmic drug therapy for atrial fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disorder. With an aging population, the number of people with AF is expected to rise dramatically. People with AF are twice as likely to die, are five times more likely to have a stroke, can develop worsening heart muscle function, and have a lower quality of life. We have learned that a person's genetic makeup, or DNA, has a major impact on their risk of developing AF; but we have a limited understanding of why, or how to use this information to treat people in a safer and more effective way. People with AF first receive drugs to control their irregular heart rhythm. Even people who have procedures to treat AF are also prescribed drugs. This is particularly important in the group of patients who have persistent AF, who require electrical or chemical therapy to change their heart rhythm, as the success of surgical procedures in this population is well below 50%. Unfortunately our current drugs are generally ineffective, and can be unsafe, with little progress in drug development over the last two decades.

With these challenges in mind, the first goal of my research program is to identify and understand the genes that play a role in the development and progression of AF, and determine which are most common and most important in the Canadian population. To do this, I am gathering a biobank of AF patients and performing the largest scale detailed genetic testing in this population to date. I am also focused on understanding the effect that genes can have on the safety and efficacy of rhythm controlling drugs, and have already started a trial, funded by the Canadian Cardiovascular Society, that will link a person's genetic makeup to these important outcomes. I will then be able to take this large clinical and genetic data set to the laboratory where we have developed the unique ability to generate patient-specific stem cell disease models of AF. The ultimate goal of my research program is to directly tailor therapy for AF patients based on their genetic makeup, using information from clinical research and personalized disease modeling.


Addressing morbidity, mortality and health care costs among patients evaluated for addiction care in acute care settings

Substance use disorders account for a significant burden of disease among Canadians and place an enormous burden on the acute care system. The annual cost of harms associated with substance use in Canada is estimated to be approximately $40 billion, with health care being the single largest contributor. In British Columbia (BC) there is clear urgency to address this challenge, given the recent steady increase in hospitalization rates due to substance use and the unprecedented number of drug overdose deaths prompting the recent declaration of a public health emergency.

While in hospital, individuals with a substance use disorder often have access to evidence-based addiction care, though successfully transitioning these individuals from acute to community settings remains a key clinical and research challenge. Specifically, this patient population often leaves hospital against medical advice, may be non-adherent to addiction care recommendations and often requires costly repeat hospital readmissions. Addressing these circumstances is critical, given the enormous cost implications and opportunity for more effective addiction services to dramatically reduce morbidity and mortality.

Specifically, investigating acute substance use needs and long-term solutions in acute care through after-care environments presents an urgent clinical health research priority given the frequent intersection between individuals with a substance use disorder and hospital environments. To address this, the proposed research project will establish a prospective cohort study of hospitalized individuals with a substance use disorder who are assessed for treatment of their addiction. Individuals will complete a one-time questionnaire and provide consent to the use of their personal identifiers for linkage to a variety of health care databases to allow for ongoing community follow-up over a five-year period. Creation of this study will offer the unique opportunity to identify patient characteristics of individuals accessing addiction care in the hospital setting, evaluate patient flow and predictors of outcome between hospital and community settings and determine subsequent health outcomes and health care utilization. In doing so, this research platform will generate evidence that will contribute to future interventions and knowledge advancement, and help inform best practices for the optimal delivery of addiction treatment to this population with high morbidity and mortality.

Understanding the spatial and contextual inequities of health access and use by people living with or vulnerable to HIV in British Columbia

Access to health care services is critical to improving the health and well-being of people living with or vulnerable to HIV. Factors such as density of services or neighbourhood violence play a substantial role as barriers or facilitators to health care access in broader populations, but limited research is available to show that this is also true for people living with or vulnerable to HIV. This study will investigate, within BC:

  1. The distribution of access and use of health services, especially health services in HIV testing and treatment.
  2. The barriers and facilitators related to access.
  3. How to develop a rigorous methodology to capture, quantify and analyze data on access and use of health services.

The proposal will draw data from several large, multi-year studies conducted by the BC Centre for Excellence in HIV/AIDS and will link to external datasets for the development of key measures. This project will focus on analyzing data regarding health care services utilization across different regions in BC over time. The proposal aims to improve access to services for earlier diagnosis and improved treatment for people living with HIV.

Investigation of aging-related pathways associated with an increased risk of emphysema in HIV-infected patients

Because antiretroviral therapy has enabled people to live longer, those with HIV now face a growing epidemic of age-related chronic diseases such as chronic obstructive pulmonary disease (COPD). The reason for this increased risk, however, remains unknown. Compelling evidence suggests that HIV infection triggers an inflammatory process which causes the premature aging of inflammatory and structural cells due to cell exhaustion from repeated divisions and oxidative stress. This concept of “inflamm-aging” (coined by Claudio Franceschi) applies fittingly to the development of COPD as well, where the primary trigger is cigarette smoke.

Given the dual pro-inflammatory states of HIV and COPD, Dr. Leung hypothesizes that the accelerated development of emphysema in HIV is driven in part by inflammation-induced cell aging related to the HIV infection and potentiated in the lungs by cigarette smoke. Dr. Leung's laboratory has found peripheral leukocyte telomere lengths, a marker of cell senescence, are shorter in HIV-infected patients who also have COPD compared to HIV-infected patients without COPD. Those with the most severe airflow obstruction on spirometry and those with the greatest extent of emphysema as visualized on CT scanning also appear to have the shortest telomere lengths. The laboratory group is now exploring whether similar relationships hold in lung cells obtained from HIV-infected patients.

Physical activity in individuals with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a lung condition that affects more than 75,000 British Columbians. People with COPD have a shortness of breath, chronic cough, and can experience difficulties with the activities of daily life, such as showering, walking, and social activities. Many people with COPD have regular flare-ups, or exacerbations, of their lung condition. These exacerbations result in a severe shortness of breath and overall weakness and fatigue and sometimes lead to long hospital stays. These flare-ups and long hospital stays can cause severe problems with activity tolerance, which then further increases the risk of future flare-ups.

The objective of Dr. Pat Camp's research program is to investigate how physical activity can improve the health outcomes of people who are hospitalized with a COPD flare-up. This research program will include a systematic literature review to summarize the current state of knowledge, validating tools to measure activity in hospitalized COPD patients, and determining if exercise programs for hospitalized patients can improve their quality of life and health outcomes. In addition, Dr. Camp's research program will include projects that incorporate patient input about what activities are important to them, which will indicate the level and type of activity that is necessary in order for these patients to be discharged safely from the hospital.

By developing a thorough understanding of how exercise leads to increased health in COPD patients, this research program aims to improve the quality of life and overall health of patients hospitalized with acute COPD flare-ups. Future work will extend these innovations to other chronic lung disease populations, such as patients with lung transplants or interstitial lung disease.

Innate immunity and its influence on cardiovascular function

In Canada, severe infection, or sepsis, is the most common acute illness causing death. Patients with severe infections can go into shock as a result of progressive cardiac collapse and can die within 24 to 48 hours. The mortality rate of sepsis is 40%. The fact that this rate has not changed in the last 30 years illustrates that very little is known about how infection causes cardiovascular dysfunction and that very little is known about the best ways to prevent this from occurring.

Dr. John Boyd's research program is using a two-pronged approach to understand how sepsis causes progressive cardiac collapse. The objective of his clinical research program is to identify prognostic factors and to characterize the cardiac response to infection in patients with sepsis. Specifically, he is focusing on very early enrollment of acutely ill patients with infection presenting to the St. Paul's Hospital emergency department in order to identify prognostic factors such as new biomarkers and the presence of emerging infections. He will characterize their cardiovascular response to infection using a bedside cardiac ultrasound. Although previous work in this area has been done, patients were recruited from critical care units 24 to 36 hours following admission, too late to identify prognostic markers and intervene to improve outcome.

As a complementary approach, Dr. Boyd's pre-clinical (basic) research program is taking a molecular approach and using the immune system as a tool in the fight against cardiovascular collapse. He has identified a "counter-regulatory" receptor which appears able to reverse the heart damage induced by other receptors in the same family. The identification of this receptor will hopefully lead to the development of a targeted intervention for sepsis-related cardiovascular dysfunction. Dr. Boyd's clinical research program aims to answer simple but as-yet unstudied questions such as the optimal volume of IV fluid and how one can reliably diagnose infection. Although the results of his laboratory work are not yet close to reaching the bedside, they may potentially lead to therapies in the future.

The role of the airway epithelium NLRP3 inflammasome in asthma pathogenesis

Asthma is a respiratory disease that afflicts more than two million Canadians. Asthmatics experience both airway inflammation and changes in the airway structure, called airway remodeling, when they inhale allergens, pollutants and other insults, and this leads to an exacerbation. The airway epithelium is the first site of contact for inhaled substances and has been shown to be different in asthmatics than in non-asthmatics. In specific cells of the body, including the airway epithelium, a danger sensor called the “inflammasome” can signal as part of the immune system to produce inflammation in response to an insult. Currently, we do not know if this airway epithelium danger sensor functions differently in asthmatics than in members of the general population and if this contributes to the development and progression of asthma.

Dr. Jeremy Hirota's hypothesis is that if the airway epithelium danger sensor is present, it increases airway inflammation and contributes to development and progression of asthma. His research goal is to determine the specific mechanisms responsible for airway epithelium danger sensor activation and to find out if it is more active in asthmatics. He is using three distinct approaches for his proposed research: 1) Using lungs that have been donated for medical research, he will compare the danger sensor between non-asthmatics and asthmatics. 2) Using the same donated lungs, he will grow human airway epithelial cells and expose them to an allergen or mechanical wound and then measure the resulting inflammation. 3) He will explore the role of the airway epithelium danger sensor during periods of allergen exposure by comparing normal mice to mice with a dysfunctional danger sensor.

The increasing prevalence of asthma in Canada demonstrates a requirement for a greater understanding of mechanisms leading to disease development and for new approaches to prevent or treat this disease. This research has the potential to highlight new therapeutic targets to control both excessive airway inflammation and the development of asthma.

Fostering cultural safety in nursing practice with people experiencing problematic substance use

The purpose of this project is to generate new knowledge that will foster understanding of what constitutes safe nursing care in acute care settings for people who are experiencing problematic substance use and social disadvantage. The target audience will be practicing nurses who provide care to people experiencing substance use, as well as health care administrators, nursing leaders and policy makers. The key research question is: What is culturally safe care from the perspective of patients and nurses in acute care settings and what supports the delivery of culturally safe care?

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The role of Apical Junction Complex in airway epithelial repair and differentiation in asthma

Asthma is a serious global health problem, affecting over 300 million people worldwide. The disease is predominantly an inflammatory disorder of the conducting airways, and can be treated or controlled using current therapies. However, un-controlled asthma leads to continual inflammation and damage, resulting in permanent scaring which is termed airway remodeling. Airway remodeling can be defined as changes in the composition, content and organization of cellular and molecular constituents of the conducting airways. One of the structural changes that occurs as a result of airway remodeling is detachment of the cells that line the surface of the airways, called the epithelium. In normal airways, the epithelium forms a barrier against the inhaled external environment which includes aero allergens, viruses and particulate matter, through the formation of apical junction complexes (AJCs). In asthma, part of the abnormal response to inhaled allergens is thought to be due to impaired barrier function caused by damage to the airway epithelium and loss of AJCs. Emerging evidence suggests that AJCs are able to influence other aspects of epithelial function such as release of inflammatory mediators and mechanisms of epithelial repair. Building on earlier work in this area, Dr. Tillie-Louise Hackett’s current research is designed to determine whether AJCs play an important role in normal airway epithelial repair and if the mechanisms involved are altered in asthmatic patients. The results of her research will provide scientists and clinicians with a better understanding of the pathological mechanisms that contribute to multiple respiratory diseases. In addition, Dr. Hackett’s findings will open avenues for the development of new therapeutics to improve the lung health of Canadians living with obstructive lung diseases, such as asthma and Chronic Obstructive Pulmonary Disorder.

Utilization of an Interactive Internet-based Platform for Managing Chronic Diseases at a Distance

Chronic diseases represent an increasing burden for both the patient and healthcare system. Many people also now have more than one chronic disease. For those people with chronic diseases living in rural areas, the risk for hospitalization is more than 60% greater. These patients and their primary care providers face an enormous challenge in meeting their day-today health needs that patients with chronic diseases have.

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