Research Location: St Paul's Hospital

The effects of dietary nitrate supplementation on exercise tolerance in patients with fibrotic interstitial lung disease

Health Research BC is contributing matching funds to support the CANTRAIN-CTTP & Michael Smith Health Research BC Doctoral Studentship 2023 Award Program. Olivia Ferguson is a Ph.D. student at the University of British Columbia. Olivia will be conducting a clinical trial in patients with chronic lung conditions under the supervision of Dr. Jordan Guenette at the Cardiopulmonary Exercise Physiology Laboratory at St. Paul’s Hospital in Vancouver, BC.  

 

Interstitial lung disease (ILD) is a chronic progressive lung disease of either known or unknown cause, with a mean survival of only three years. ILD leads to progressive scarring of the lungs and debilitating reductions of exercise tolerance and functional abilities, which is strongly associated with reduced quality of life and mortality. Breathlessness and severely low oxygen levels in the blood are the hallmark features of ILD, which worsen with exercise. Unfortunately, very few effective and safe pharmacological therapies that target the lungs are available for ILD. Thus, preserving or enhancing muscle and heart function is essential to offset the progressive decline in lung health and for maintaining quality of life and independence. It is strongly advised that individuals with ILD undergo pulmonary rehabilitation, which is a structured exercise program; however, this may not be suitable for individuals who may not be able to handle strenuous exercise that can enhance muscle and heart function. Using nitrate in the form of concentrated beetroot juice, a safe and commercially available dietary supplement, may improve the delivery and efficiency of oxygen use at the site of exercising muscles. Orally ingesting dietary nitrate may improve the use of diminished oxygen availability rather than relying on external sources of supplemental oxygen, a common practice in ILD, which lacks real-world practicality. This novel therapeutic may allow individuals with ILD to reach exercise intensities sufficient for improving their overall exercise tolerance. If successful, it would enable them to sustain their functional abilities and engage in regular daily tasks, promoting independence and improved quality of life.

Advancing Cardiac Care Unit-based Rapid Assessment and Treatment of hypErcholesterolemia (ACCURATE)

Health Research BC is providing match funds for the Master’s Studentship 2023 Award, supported by the Canadian Consortium of Clinical Trial Training Platform (CANTRAIN). As part of my work, I will be conducting the Advancing Cardiac Care Unit-based Rapid Assessment and Treatment of hypErcholesterolemia (ACCURATE) study. The ACCURATE, BC-based study is also funded by Genome British Columbia and Vancouver Coastal Health Research Institute (VCHRI).  

Familial hypercholesterolemia (FH) is one of the most common genetic diseases, affecting 1 in 250 individuals and elevating the risk of early onset heart disease. About 1 in 14 individuals who have a heart attack under 60 years old have FH, but 99% of them were not aware of it before their heart attack. In British Columbia, over 85% of individuals with FH remain undiagnosed due to the lack of genetic testing, leading to missed opportunities for early intervention.  

The ACCURATE study aims to investigate how genetic testing for patients hospitalized with acute coronary syndrome (ACS) can improve the diagnosis of FH, influence physicians’ treatment approaches, patients’ medication use, and ultimately reduce the disease burden for these patients.  

The outcomes will contribute to understanding how genetic diagnosis influences patient care in acute cardiac settings, with the hope of influencing healthcare practices in the entire province. This will improve the health of British Columbians and enhance the reputation of BC as a leader in genomic clinical care. 

 

 

End of Award Update – December 2024

 

Results

The ACCURATE study found that 8% of young acute coronary syndrome (ACS) patients with untreated LDL-C >4 mmol/L had a genetic diagnosis of Familial Hypercholesterolemia (FH). This is a prevalence 24 times higher than in the general population. Importantly, genetic testing reclassified 88% of these patients initially categorized as “unlikely” or “possible” FH to a confirmed diagnosis of “definite” FH. These findings show that genetic testing can identify FH in patients who would otherwise be missed using traditional clinical criteria alone. Additionally, 24% of patients were identified as having polygenic hypercholesterolemia. These patients did not carry variants in the known FH-causing genes but had a high LDL polygenic risk score (PRS), indicating that other genetic factors contribute to their elevated cholesterol and heart disease risk. Altogether, our current results highlight the value of both genetic testing and polygenic risk scoring in detecting, diagnosing and understanding FH in young high-risk patient populations.  

 

Impact

The ACCURATE study has addressed a significant gap in care by diagnosing FH-positive patients in an acute cardiac care setting where genetic testing is not currently performed and therefore, these patients would likely remain undiagnosed. By providing treating physicians with genetic test results within 1 month of their patients’ ACS event, this study has raised awareness of the genetic basis underlying their patients’ premature cardiovascular events. While it is too early to measure changes in long-term outcomes, this approach ensures physicians are better informed to consider these insights in real-time clinical decision making and follow-up care. The rationale for conducting this research and the early results from ACCURATE has also inspired conversations with policy makers, industry experts, and healthcare providers in BC about the importance of integrating clinical FH genetic testing in the province. 

 

Potential Influence 

This study has the potential to change the standard of care for young patients with heart attacks by making FH genetic testing routine, especially for those with high LDL levels. This would lead to earlier detection of FH and may also highlight the importance of tailoring treatment intensity based on genetic findings, thus allowing physicians to identify those who may require more aggressive interventions to achieve lipid targets and prevent further cardiovascular events. Over time, this approach could help lower the rates of heart attacks and other cardiovascular events caused by undiagnosed or undertreated FH in British Columbia. Beyond its local impact, the study may provide a clear model for integrating genetic testing into acute cardiac care that can be adopted nationally and internationally.  

 

Next Steps

ACCURATE is ongoing as patients in the Active Testing Phase are still being followed to assess outcomes including treatment intensification, lowest LDL-C achieved, guideline lipid target attainment at 15-months post ACS, and the rate of recurrent cardiovascular events. Next steps include assessing how these genetic results for FH impact physicians and their patients, particularly how they are integrated into clinical care. For this reason, we plan to conduct a survey to explore physicians’ reactions to and concerns regarding FH genetic results, assess the influence on clinical workflow, changes in treatment plans, and identify ways to support physicians in better diagnosing FH and delivering optimal care for patients. Additionally, exploring genetic testing for first-degree relatives may be a future direction to help identify more individuals with FH, therefore extending the reach and impact of the study.  

Investigating psychomotor response to L-DOPA challenge as a biomarker for clinical outcomes in late-life depression: A pilot feasibility trial

Major depressive disorder (depression) is a common condition affecting older adults, also called late-life depression (LLD). Depression later in life can negatively impact overall health, including increasing the risk of developing dementia. With Canada’s aging population, it is important to develop more effective ways of managing this condition.  

 

LLD is frequently associated with a phenomenon called psychomotor slowing, which is a decrease in the speed of both physical movements and information processing. The presence of psychomotor slowing can signify more severe illness and a risk of worse outcomes in LLD. Psychomotor slowing in LLD is related to the abnormal functioning of dopamine, a neurotransmitter that influences motivation, reward, and pleasure in the brain. This slowing may be reversible by taking a dopamine-like medication called levodopa (L-DOPA). However, we do not know whether there is a link between psychomotor slowing, reversibility by L-DOPA, and treatment outcomes in LLD. 

 

I am a geriatric psychiatrist at St. Paul’s Hospital and a postdoctoral research fellow at the University of British Columbia. My study, which is supported by the CANTRAIN-CTTP & Michael Smith Health Research BC Post-Doctoral Studentship Award and conducted at St. Paul’s Hospital in Vancouver BC, will invite participants to receive two weeks of treatment with a drug called Levocarb which contains L-DOPA (an L-DOPA “challenge”). We will measure participants’ walking speed, overall speed of movements, and cognitive function before and after the challenge.  

 

The goal of this study is to evaluate whether psychomotor slowing in LLD changes in response to changes in brain dopamine levels, and whether this change can predict improvements in depression symptoms and cognitive function following standardized antidepressant treatment. These data will improve our understanding of the biology of LLD and may enhance our ability to predict which treatments will be most helpful for older adults suffering from depression. 

 

 

End of Award Update – February 2025

 

Results

My pilot clinical trial has provided some of the first-ever data on the psychiatric, psychomotor, and cognitive effects of levodopa (L-DOPA) in depressed older adults. So far, we are observing significant improvements in psychomotor speed, working memory, and depressive symptoms in response to a 2-week administration of L-DOPA. 

 

Impact

This clinical trial has provided, to my knowledge, the first BC-based opportunity to participate in clinical interventional research for older adults living with depression. This research is providing access to a novel treatment approach which will benefit health outcomes for older adults in BC and, possibly in the future, the rest of Canada and beyond. 

 

Potential Influence

This clinical trial is the first in a planned sequence of studies to investigate the usefulness of L-DOPA as a challenge medication to help predict response to other medications in late-life depression. If successful, this research will lead to a practical clinical tool that enables us to provide personalized, evidence-based treatment options for older adults with depression. 

 

Next Steps

Early results from this study are being prepared for publication and will be presented at upcoming conferences. A follow-on study with a randomized component is currently being planned, which will build off our promising pilot data. 

Bridging the gap: screening for fontan associated liver disease (FALD)

One in 3,000 children is born with one, instead of two, heart pumps, and as a result of a surgery called the “Fontan”, survive well into into adulthood. This surgery creates an artificial path that collects blood low in oxygen from the veins and sends to the lungs (instead of using a right heart pump) to pick up oxygen; leaving the single pump to send blood with oxygen to the body. We are learning these patients are developing many issues in adulthood including liver disease. The best way of identifying significant liver disease is through a liver biopsy, but it is not reasonable to perform biopsies regularly. We do not know the best way to easily identify and monitor liver disease in the Fontan population, yet this knowledge is critical to maintaining Fontan liver health, reducing co-morbidities ultimately benefiting our health care system. The first part of the study will be undertaken at St.Paul’s Hospital and Mazankowski Heart Center in Edmonton. We will perform a number of liver related blood tests/imaging to determine the best combination that identifies significant liver disease as diagnosed by liver biopsy. The second part will take place at five adult sites across Canada and will confirm our findings from the first part.

Familial hypercholesterolemia patient engagement forum: Family care and women’s health

Familial Hypercholesterolemia (FH) is the most common inherited disorder, with a prevalence of 1 in 250 Canadians, characterized by lifelong elevation in blood cholesterol leading up to 22-fold increased risk for heart disease. Despite this, in BC alone, more than 85 percent of cases are undiagnosed and only a minority receive appropriate treatment. A key component for improving care for this population is by increasing awareness through patient education, engagement and dissemination of recent FH research results. The purpose of this proposal is to organize an updated educational forum on FH, focusing specifically on family-based care and women’s health, including lectures by patients, physicians, dietitians and genetic counsellors, and interactive group sessions including patients’ testimonials. This forum will provide an opportunity for patients to learn about new developments in diagnosis and treatment of FH, including management in special populations, such as pregnant women and children. The goal is to empower patients to become advocates for the FH community by increasing awareness of the disease and recognizing the importance of screening their families for early identification, treatment and ultimately heart disease reduction.

Team members: Iulia Iatan (UBC, Centre for Heart and Lung Innovation); Nancy Pratt-Najera (St. Paul’s Hospital); Lubomira Cermakova (St. Paul’s Hospital, Healthy Heart Program Prevention Clinic); Durhane Wong-Rieger (Canadian Organization for Rare Diseases).

Determination of the optimal SARS-CoV-2 vaccination strategy to achieve a robust and long-lasting immune response

Global COVID-19 vaccine distribution has been inequitable, with high-income countries afforded widespread access to vaccines and boosters, while among the low-income countries only 2 percent of individuals are vaccinated. Consequently, over 50 percent of the world’s population remains unvaccinated. Fortunately, however, data from vaccinated cohorts can inform the most efficient and effective community-level vaccination strategies for the unvaccinated populations. Currently approved mRNA vaccines were initially tested with dosing intervals of 21-28 days; however, this may lead to suboptimal immunity. Further, data informing the optimal timing and frequency of booster doses is lacking. This project will answer critical questions regarding the optimal vaccination strategies to achieve a robust long-lasting immune response. In this study I will employ data from a prospective national cohort of adult paramedics, providing sociodemographic data and serum blood samples. I will identify the optimal vaccination strategies to achieving a robust immune response at 12, 18 and 24 months, including examining differences between sex, race, and age. These data will inform ongoing global vaccination efforts, to maximize efficiency and long-term protection.

Translating research into practice: Investigating the impact of Alzheimer’s disease diagnostics in Canada (IMPACT-AD)

Health Research BC is providing match funds for this research project, which is funded by the Brain Canada Multi-Investigator Research Initiative (MIRI) – Improving Health Outcomes and Quality of Life. Additional support is provided by UBC Faculty of Medicine, Djavad Mowafaghian Centre for Brain Health, and Women’s Brain Health Initiative. The research is also being undertaken in collaboration with the Canadian Consortium on Neurodegeneration in Aging.

 

Early and accurate diagnosis of Alzheimer’s disease is critical as timely access to health care and community services has the potential to slow disease progression and improve quality of life. Current approaches for diagnosis rely on traditional imaging tests and observation of the signs and symptoms of the disease. Adding the measure of proteins found in cerebrospinal fluid (biomarkers) has been shown to help correctly identify the disease and predict those with mild symptoms that are likely to progress to dementia; however, such testing is not readily available in Canada.

 

The IMPACT-AD study specifically addresses barriers to uptake and use of Alzheimer’s disease biomarker testing in the Canadian health care system. This Canada-wide study will develop a comprehensive understanding of how biomarkers for Alzheimer’s disease impact clinical decision making and health care costs. Collaborating with patients, caregivers, and physicians, IMPACT-AD will also investigate the effect of testing on personal decision-making. The findings of this study will lay the necessary groundwork, modernize, and improve the care available to Canadians affected by Alzheimer’s disease and related forms of dementia.

 

IMPACT-AD is led by Dr. Mari DeMarco, a clinical chemist at St. Paul’s Hospital, and a clinical associate professor in Pathology and Laboratory Medicine at UBC. DeMarco is joined by a multidisciplinary team that includes both Canadian and international laboratory medicine specialists, geriatricians, neurologists, health economists, rural/remote clinicians, ethicists, and statisticians.

 

For more information about the study and how you can get involved, visit www.impactAD.org.

Award update: December 2021

Delivery of self-management through a peer-support telehealth intervention in patients with cardiovascular disease: The Healing Circles Project

Health Research BC is providing match funds for this research project, which is funded by CIHR’s eHealth Innovation Partnership Program (eHIPP).

 

Cardiovascular disease (CVD) is a leading cause of death and disability in Canada, resulting in an estimated $22.2 billion in health care costs and lost productivity annually. Older adults are afflicted more than any other population, with many dealing with complex chronic conditions in isolation.

 

Patient self-management has been found to play a key role in improving patient health and reducing hospital admissions. Correspondingly, social and peer support, and timely access to credible information on managing CVD, are essential for patient self-management and quality of life. Over a four-year period, Dr. Scott Lear, a professor in the Faculty of Health Sciences and the Department of Biomedical Physiology and Kinesiology at Simon Fraser University, and his team based at St. Paul’s Hospital, will study the use of a new application, Healing Circles, that offers support to seniors with CVD while staying in their homes and communities.

 

Healing Circles is a private and secure peer support and self-management platform created through a partnership between university-based researchers, industry, decision-makers, clinicians and patients. The Healing Circles application, accessible on smartphones, tablets, and desktop or laptop computers, was developed by Curatio, a digital mobile health company, headquartered in Vancouver. Expansion of the use of Healing Circles by seniors with CVD builds on Lear’s pilot study of the application involving women with heart disease from across Canada. After ten weeks, the women reported being better able to manage their health through the peer support and knowledge gained.

 

Healing Circles Project participants form virtual ‘Circles’ with 8 to 10 other patients to connect with and support one another as they learn to live day-to-day with their CVD. Additionally, the 250 study participants can interact with all members of the wider Healing Circles community to share experiences. Investigators anticipate that CVD patients using the Healing Circles platform in their homes will have improved self-management skills compared to patients receiving usual care, and improved quality of life, preventing secondary complications and reducing the need for health care and hospital use.

Understanding a potentially common upper airway disorder: Empty nose syndrome

Empty Nose Syndrome (ENS) is thought to be an unusual outcome of sinus surgery due to excessive loss of nasal tissues, particularly from a pair of structures called the inferior turbinates. Turbinates usually function to warm and humidify air flowing into the nose. Patients with ENS often have severe nasal symptoms and develop very poor quality of life as well as mental health problems. As a result of these mixed symptoms, ENS patients are often misdiagnosed, mismanaged, and left to their own devices.

Our research has shown that ENS patients can be identified based on specific clinical symptoms and imaging of the sinuses. We have also found that by rebuilding structures within the nasal cavity known as inferior turbinate augmentation (ITA) we can greatly improve nasal function. However, little is known about the specific changes in nasal function with ENS, how mental health problems develop, or how to best treat these patients.

Our objectives are three-fold: 1) to measure the patterns of nasal airflow and sense of smell present in ENS patients by using computer analysis and smell testing; 2) to understand how ITA might improve function in ENS patients by measuring nasal airflow and sense of smell before and after surgery; and 3) to study the impact of ENS on mental health using depression and anxiety survey scores, and then measure the change in these scores after ITA to study the relationship between the nasal and mental health problems in ENS. By studying the relationship between nasal and psychiatric symptoms in ENS we will both improve our understanding of how this syndrome develops and improve our understanding of how surgical interventions might help mend these symptoms.

Understanding the aging HIV lung from dysbiosis to cell injury

Patients with human immunodeficiency virus (HIV) are now living to older ages thanks to effective anti-HIV medicines. Despite these gains, many of them suffer from chronic lung disease that greatly impacts their ability to carry out their daily activities and impairs their quality of life. The type of lung disease they face is similar to what longtime smokers develop, a progressive narrowing of the airways and destruction of the lung. However, in HIV, the process appears to be accelerated and more severe. It’s not unusual, for instance, to see patients in their 30s and 40s develop this lung disease (which is approximately 30-40 years earlier than expected). Also, it’s not unusual for HIV patients who have never smoked before to develop this kind of disease. Unfortunately, the traditional medications we use to treat lung disease often interact with anti-HIV medicines, causing severe side effects. Management of breathing symptoms in HIV patients is therefore difficult and it is imperative that we find better agents to combat lung disease in this population. Only by understanding what causes and drives this lung injury process can this goal be achieved, though.

Multiple studies have now shown that smoking alone cannot explain the lung disease phenomenon in HIV. I believe that HIV injures the lung in a two phase process. First, the virus directly breaks down the protective layer of the airway known as the epithelium. Second, over time, as patients develop repeated lung infections due to their weakened immune systems, the bacterial community of the lung or microbiome shifts. I believe that this community disruption results in molecular changes that age the lung faster. My approach is to perform an in-depth investigation into the epithelium of the airway using two innovative methods. To explore the injury that HIV inflicts on the airway, I have created a novel model of the HIV airway using HIV-infected cells co-cultured on a cell culture model of the airway epithelium. We will use this model to see how HIV-infected cells break down the protective barrier of the lung. To explore the shifts in the microbiome, I have collected airway cells from HIV-infected and uninfected patients to not just describe what bacteria exist in the airway but also to determine what effect the community differences between the two groups have on the function of genes in the cells. We will measure how ‘old’ these cells are and compare these findings to uninfected patients.

End of Award Update: December 2022

 

Most exciting outputs

The work of my laboratory was the first to detect accelerated epigenetic aging and methylation disruptions in the HIV airway epithelium, work that has now been published in the American Journal of Respiratory and Critical Care Medicine, and eBioMedicine.

 

Impacts so far

These insights into accelerated aging in the HIV airway epithelium provide clues into why people living with HIV may be prone to developing chronic lung diseases such as Chronic Obstructive Pulmonary Disease or COPD.

 

Potential future influence

Our work highlights the importance of accelerated aging in HIV, even in patients with well controlled infection. Reversing these aging mechanisms may be critical in the prevention or attenuation of airflow obstruction in this population.

 

Next steps

We are continuing to explore mechanisms of early aging in the HIV airway using novel technologies such as magnetic resonance imaging, optical coherence tomography, and single cell sequencing.

 

Useful links