Have you ever worried about your blood pressure or cholesterol? Unfortunately, high blood pressure (hypertension), high cholesterol, diabetes, and other risk factors for heart disease are very common in our society.
Even if your blood pressure and cholesterol are fine, you probably know friends, neighbours, relatives, or colleagues who have these risk factors. It’s not surprising that the older we become, the more we tend to worry about developing cardiovascular disease.
Fortunately, many excellent scientists and physicians in Alberta are working hard in this area, and their efforts to better understand the workings of the heart and blood vessels will enable them to better prevent and treat cardiovascular disease, helping us to live longer and better.
Improving healthcare for patients with heart disease
At the University of Calgary, Heritage Population Health Investigator Dr. Kathryn King has drawn on her clinical and research experience in cardiology and cardiac surgery to develop a new study looking at how Canadians make decisions about their health. Dr. King is particularly interested in how gender and culture can affect heart patients’ decisions regarding their care. For instance, our cultural background may influence eating habits or health beliefs, and gender issues can have an impact on recovery following cardiac surgery and rehabilitation. Dr. King is hoping her four-year study in risk management decision-making will one day lead to practical improvements in healthcare delivery for people with heart disease.“We want to take a fresh look at appropriate models of care for cardiac patients. Ultimately, our goal is to be able to develop a decision-making model of care that is sensitive to both gender issues and ethnocultural affiliations,” she explains. “Our existing models don’t capture the essence of gender and culture as well as they could in today’s society. It’s important to try to understand a person’s culture, and to work with it, both physically and from the psychosocial perspective.”
Over the next few years, Dr. King’s team of researchers will survey a thousand Canadians of all ages, from across Canada. The interviewees will include urban and rural Euro-Canadians and French Canadians, Chinese immigrants from Hong Kong, Sikhs, and aboriginal people living on reserves.
The risk for heart disease
Heritage Scholar Dr. Todd Anderson heads a Calgary research group that’s investigating how to best assess and then address an individual’s risk of heart disease. Dr. Anderson’s team focuses specifically on the endothelium, the single-cell lining of blood vessels. They’re looking at endothelial function in the coronary circulation (the movement of blood to heart muscle cells through the arteries) and the peripheral circulation (the movement of blood from the heart to various organs and limbs) in patients at risk for atherosclerosis (clogged arteries). He hopes that better knowledge of the evaluation and treatment of the risk factors for cardiovascular disease will lead to better prevention.“We now know that the endothelium is important. It plays an integral part in the control of whether someone gets atherosclerosis or not,” explains Dr. Anderson. “You can measure endothelial function, both in animals and in humans. Over the last two decades, we’ve discovered that endothelial function responds abnormally if cholesterol builds up in the artery, or even if an individual has risk factors like diabetes, high blood pressure, or smoking.”
Current research studies in this area are focusing on improving vascular function, particularly in patients with diabetes, kidney failure, or high levels of cholesterol or atherosclerosis. For instance, Dr. Anderson and his colleagues are assessing the impact of demographic, biochemical, and genetic risk factors and how these factors interrelate, as well as how various new medications improve endothelial function.
It’s a dynamic process, he explains. The physician can improve endothelial function by prescribing medication to lower cholesterol, blood pressure medication (such as ace inhibitors), or anti-platelet drugs, or by modulating insulin resistance (with a drug called metformin).
Dr. Anderson is also the principal investigator in the ongoing “Firefighters and their endothelium” (FATE) clinical trial. About 1600 middle-aged male firefighters from Calgary and three other centres are participating in this eight-year study to assess the clinical usefulness of endothelium function tests in predicting whether an individual is at risk for a heart attack or stroke. One day you may go to your doctor’s office to have your endothelial function assessed along with your blood pressure and cholesterol.
Working toward reducing stroke injury
Heritage Medical Scientist Dr. Paul Kubes is studying how and why white blood cells are recruited to sites of inflammation. One day his research could lead to ways to reduce the initial brain injury caused by stroke.“Normally white cells fight infection,” explains Dr. Kubes, Chair of the University of Calgary Immunology Research Group. “If you get a paper cut or an infection in your lungs, the white cells come, destroy the bacteria, and life goes on.” However, in certain situations where there is reduced blood flow (ischemia), as in a stroke or heart attack, a flood of white cells will appear even though there is no infection. When blood flow returns to normal, the white cells recognize that the tissue is different. They decide to remove it and start anew. In the case of brain or heart tissue, this action results in significant injury.
“What we’re trying to figure out is how the white cells get into these tissues and if we can come up with strategies to prevent them getting there,” he explains. “Part of the problem is that we really don’t have a clear understanding how the white cells get out of the blood vessels. They move at incredibly high speeds, and then they suddenly stop.” He adds that since different organs use very different mechanisms of white cell recruitment, a better understanding of the heart’s recruitment process is needed before those white cells can be targeted and studied.
Trying to prevent sudden death
Calgary cardiologist and Heritage Clinical Investigator Dr. Derek Exner has a special interest in the risk factors and therapies for serious heart rhythm problems. Dr. Exner is involved in a variety of cardiovascular clinical trials investigating why heart attack patients are more likely to die from sudden cardiac death due to heart rhythm problems than those who have not had a heart attack. Based on studies elsewhere, it’s estimated about 3000 to 3500 Albertans fall prey to sudden cardiac death annually. Many will have had a prior heart attack.Dr. Exner is assessing how a heart attack affects the heart’s electrical system and the autonomic nervous system that controls the heart, as well as the impact of depression on the autonomic nervous system. He hopes that one day the results of his research will help identify people at risk before they start to develop problems, so that measures can be taken to lower their risk and prevent deaths.
In May 2001, Dr. Exner and colleagues at teaching and community hospitals in Calgary and Edmonton began recruiting 350 Albertans to participate in a four-year clinical trial. They’re enrolling heart-attack survivors, aged 30 to 90, who have some measurable damage to the heart muscle. The study aims to identify which patients will develop heart rhythm problems, and to determine when and how often testing should be undertaken following a heart attack. Each participant will undergo three different sets of tests, during which researchers will measure any impact on the patient’s autonomic nervous system and whether the electrical system of the participant’s heart was affected by the heart attack.
Currently, these tests for heart patients are invasive and only available in major centres. Dr. Exner aims to develop a more widely applicable, non-invasive way of undertaking cardiac assessments so that patients in smaller centres can also be tested. He estimates that all the patients will be enrolled in this study by July 2003, and the final results will be published in 2005.
Dr. Exner points out that one of the major challenges has been to find patients with obvious heart damage, given the high quality of care for patients with a heart attack. “Cardiology in Alberta is certainly comparable to anywhere else in North America and probably superior to many sites,” he says.
Discovering who is likely to have a stroke early in life
Heritage Scholar Dr. Sarah Childs is investigating the genes involved in angiogenesis, the process by which new blood vessels develop. In several diseases, angiogenesis is increased, while in others it can be impaired. Other studies related to this topic suggest that knowledge of the genes controlling blood-vessel growth may lead to new treatments for various health problems, including stroke and cancer.“We’re trying to identify the genes that specifically influence the way blood vessels develop,” says Dr. Childs, a member of the University of Calgary Smooth Muscle Research Group. “For instance, we would like to identify the genes that predispose infants to have strokes. With all the information we now have from genome projects, we’re just on the edge of being able to discover a lot of connections that have been really difficult to make before. We now need to focus on what’s the best question to ask.”
Dr. Childs is using the zebrafish, a small, tropical fish, to investigate early growth of blood vessels. Zebrafish have a number of advantages for her research: their cardiovascular system is very similar to that of mammals; they produce a large number of eggs each week; and their embryos are transparent. This transparency allows her to observe the embryos’ blood vessels and blood cells by microscopy to learn more about the earliest stages of development of blood vessels. It also allows Dr. Childs to perform very detailed screens for subtle genetic defects affecting vessel development.
The U of A Vascular Biology Research Group
Members of the University of Alberta Vascular Biology Research Group—Drs. Stephen Archer, Evangelos Michelakis, and Jason Dyck—enjoy a “translational” approach to research, taking an idea all the way from the laboratory bench to the patient’s bedside.Heritage Scientist Stephen Archer, a basic scientist as well as a cardiologist, has a special interest in pulmonary circulation and “oxygen sensing.” All mammals, including humans, are designed to live with a certain oxygen level in their blood, he explains. They all have sensors in the blood vessels that monitor oxygen levels in the lung. These sensors detect when oxygen levels alter, just as a thermostat detects temperature changes in a home. When the oxygen level falls (such as in pneumonia, altitude sickness, or a collapsed lung following surgery), the body senses that and reacts to keep the oxygen uptake normal. The lung is not the only oxygen-sensitive organ in the body. There are also oxygen sensors in the blood vessels, in the airways of the lung, in the human placenta, and in the adrenal glands of babies.
Dr. Evangelos Michelakis, a Heritage Scholar, also has expertise in both basic science and clinical research. Recruited to Edmonton after completing his internal medicine and cardiology training at Yale University and the University of Minnesota, Dr. Michelakis suggests that the strong partnership between the university and AHFMR fosters excellent bench-to-bedside research in Alberta. In the case of the Vascular Biology Research Group, researchers first investigate in animals treatments based on gene therapy or de novo drug approaches to treat pulmonary hypertension. If this preclinical animal research proves successful, they then apply these findings in clinical trials with human patients.
In 2001, Dr. Michelakis established the Cardiovascular Ion Channel Gene Therapy Unit (CIGNET) at the University of Alberta. Funded by the Canada Foundation for Innovation and the Government of Alberta’s Innovation and Science Research Investment Program, CIGNET uses cutting-edge basic science technologies to determine the role of ion channels in cardiovascular physiology.
Another member of the Vascular Biology Group is Heritage Scholar Dr. Jason Dyck, a molecular biologist. Dr. Dyck received his B.Sc. and Ph.D. from the University of Alberta, then did post-doctoral work at Baylor College of Medicine in Houston and at Dartmouth Medical School in New Hampshire before being recruited back to Edmonton. Also a member of the CIHR Cardiovascular Research Group and the Perinatal Research Centre, Dr. Dyck has expertise in gene transfer and adenoviral gene delivery techniques, and is currently studying cardiac energy metabolisms and cardiac hypertrophy, an enlargement of the heart that often precedes heart failure.“What we’re trying to do is make the heart work as efficiently as possible, to optimize its use of energy,” explains Dr. Dyck. “Our primary focus is to identify and characterize proteins that regulate cardiac energy metabolism at the cellular level.” The next step is to take the gene that codes for the specific protein and genetically engineer a virus that can efficiently deliver the gene to the heart. The virus is infused into a rat heart. Several days later, once the protein is expressed, the heart is removed and analyzed for changes in energy metabolisms.
“In this way, we can see if we have actually changed the heart’s energy preference and how well the heart functions with these changes. In addition, we can test whether the gene can protect the heart from ischemic injury that is often associated with heart attacks or open-heart surgery. If the genes that we’re interested in turn out to be beneficial, then that would be the first step on the road to a gene therapy.”
Trying to prevent premature death
Drs. Archer, Michelakis, and Dyck recently pooled their knowledge and expertise in basic science and clinical practice to develop a new treatment for pulmonary arterial hypertension (PAH). “Our research varies from quite basic (such as cloning genes and putting them into viruses) to applied research, like taking a drug (Viagra) that’s clinically available and trying to treat pulmonary hypertension,” explains Dr. Archer. PAH is a relatively rare but very serious disorder of the blood vessels of the lungs. The blood pressure in the arteries of the lung rises very high, placing a huge strain on the right chamber of the heart. PAH eventually causes heart failure and premature death.
Drs. Archer, Michelakis, and Dyck were the first to show that a single dose of sildenafil (Viagra), a drug ordinarily used to treat erectile dysfunction, significantly lowers blood pressure in PAH. Viagra seems to be a safe, effective medication for patients with this vascular disorder. It’s also less costly and is associated with fewer side effects than existing treatments for PAH. The Edmonton team is now undertaking a new clinical trial to discover if Viagra remains effective in PAH over the long term.
The Canada Foundation for Innovation has provided funding to construct a new $17 million Heart and Stroke Research Centre in Edmonton. Under the direction of Dr. Archer, this centre will enable the University of Alberta’s clinician-scientists to collaborate with basic scientists to study heart disease and stroke in a world-class facility.
Dr. Kathryn King is a Heritage Population Health Investigator and also receives funding from the Canadian Institutes of Health Research (CIHR) and the Social Sciences and Humanities Research Council of Canada (SSHRC). She is an Associate Professor, holding a joint appointment in the Faculty of Nursing and in the Faculty of Medicine’s Department of Community Health Sciences, at the University of Calgary.
Dr. Todd Anderson is a Heritage Scholar. He also receives funding from the Heart and Stroke Foundation of Canada, CIHR, and the Canadian Diabetes Association, as well as physician-initiated grants from Pfizer Canada, Eli Lilly, GlaxoSmithKline, Aventis, and Calgary Laboratory Services. He is an Associate Professor in the Department of Medicine at the University of Calgary.
Dr. Paul Kubes is a Heritage Scientist and a Canada Research Chair. He also receives funding from CIHR, the Bayer Partnership Fund, and the Heart and Stroke Foundation of Canada. He is a Professor in the Department of Physiology and Biophysics and the Department of Medicine at the University of Calgary.
Dr. Derek Exner is a Heritage Clinical Investigator and a CIHR Clinician Scientist who also receives funding from the Heart and Stroke Foundation of Canada. He is an Assistant Professor in the University of Calgary departments of Medicine and Community Health Sciences.
Dr. Sarah Childs is a Heritage Scholar and also receives funding from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. She is an Assistant Professor in the Department of Biochemistry and Molecular Biology at the University of Calgary.
Dr. Stephen Archer is a Heritage Scientist and also receives support from CIHR, the Heart and Stroke Foundation of Alberta, and the Canada Foundation for Innovation. He is a Professor in the departments of Medicine and Physiology at the University of Alberta, Director of the Division of Cardiology, and Heart and Stroke Foundation Chair in Cardiovascular Research for Northern Alberta, NWT, and Nunavut.
Dr. Evangelos Michelakis is an AHFMR Scholar and a CIHR New Investigator. He was the Canadian Cardiovascular Society Young Investigator for 2001. He holds funding from CIHR, the Heart and Stroke Foundation, the Canada Foundation for Innovation, and the Alberta government’s Medical Services Innovation Fund. An Assistant Professor in the Department of Medicine (Cardiology), he is the Director of the University of Alberta Pulmonary Hypertension Program, as well as of the Cardiovascular Ion Channel Gene Therapy Unit (CIGNET).
Dr. Jason Dyck is a Heritage Scholar whose research is also supported by the CIHR and the Heart and Stroke Foundation of Canada. He is an Assistant Professor in the University of Alberta Department of Pediatrics and Child Health and the Department of Pharmacology; Director of the CIHR-supported U of A Viral Core Facility; and a member of the university’s Cardiovascular Research Group and the Vascular Biology Research Group.
Recent publications
King KM, Humen DP, Smith HL, Phan CL, Teo KK. Psychosocial components of cardiac recovery and rehabilitation attendance. Heart 2001 Mar;85(3):290-294.
Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. Journal of the American College of Cardiology 2001 Apr;37(5):1344-1350.
Ibbotson GC, Doig C, Kaur J, Gill V, Ostrovsky L, Fairhead T, Kubes P. Functional alpha4-integrin: a newly identified pathway of neutrophil recruitment in critically ill septic patients. Nature Medicine 2001 Apr;7(4):465-470.
Veenhuyzen GD, Singh SN, McAreavey D, Shelton BJ, Exner DV. Prior coronary artery bypass surgery and risk of death among patients with ischemic left ventricular dysfunction. Circulation 2001 Sep;104(13):1489-1493.
Childs S, Chen J-N, Garrity DM, Fishman MC. Patterning of angiogenesis in the zebrafish embryo. Development 2002 Feb;129(4): 973-982.
Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002 May;105(20):2398-2403.
Soltys C-LM, Buchholz L, Gandhi M, Clanachan AS, Walsh K, Dyck JRB. Phosphorylation of cardiac protein kinase B is regulated by palmitate. American Journal of Physiology: Heart and Circulatory Physiology 2002 283(3):H1056-H1064.