Volume 4, Issue 1 2009 The Beat™ A Compendium of Information About the University of Ottawa Heart Institute

HIGHLIGHTS

“The concept of using cell-based to rebuild blood vessels in and around the heart is proving to be the next frontier in cardiac . This landmark devel­ opment clearly represents a major step forward in adding to our ability to cure heart failure.”

– Dr. Marc Ruel, Director, Cardiac Surgery Laboratory, UOHI (from A “Smart” Way to Repair Damaged Tissue, pages 1–3)

“What we are trying to do is to figure out which genetic pathways are lost or activated as we age to see if that capacity for repair can be recreated in the adult heart.”

– Patrick Burgon, UOHI researcher (from Regenerative Medicine, page 3)

The Heart Institute’s Ottawa Model for Smoking Cessation is considered the most advanced approach in for identifying and treating tobacco addiction. Researchers at the University of Ottawa Heart Institute have developed a smart scaffold that one day may help repair damaged heart tissue following a heart attack. In this image of tissue from a rat’s hind limb, progenitor cells have been recruited to form new blood vessels to  (from Playing a Pivotal Role: support the growth of muscle tissue. The Heart Institute Leads New Approaches to Clinical Care, page 3)

The electron microscopy expertise of the Stewart Whitman Histology Core Laboratory is generating a lot of A “Smart” Way to outside interest and paying clients.

(from Canada Beats a Path to Heart Institute Core Pathology, page 4) Repair Damaged Tissue

A heart attack is an emergency event, but carried towards the heart until it hits a Surgery Laboratory, Erik Suuronen and once the immediate danger has passed, the narrowing in the artery. The plaque his Heart Institute colleagues have developed damage can be long-lasting. Heart tissue becomes lodged and, suddenly, the flow of a way to support and enhance the heart’s may die, compromising cardiac function, oxygen-rich blood to the heart is blocked. innate capacity to regenerate itself. IN THIS ISSUE while the scar tissue that forms as a result doesn’t conduct electrical signals the What we’ve just witnessed is the onset of a There are two aspects to regenerating lost P. 1–3 A “Smart” Way to Repair way healthy muscle does. This can lead heart attack. The lack of oxygen, known tissue. One is to regrow muscle that will Damaged Tissue to potentially dangerous arrhythmias. as ischemia, damages the tissue normally contract like normal heart tissue. But for Researchers at the University of Ottawa P. 3 Playing a Pivotal Role: The Heart Institute Heart Institute have developed a smart Leads New Approaches biomaterial that promises to help the body UOHI researchers have developed a way to Clinical Care repair tissue damaged by impaired blood flow associated with heart attacks and to support and enhance the heart’s innate P. 4 Canada Beats a Path to Heart other conditions such as diabetes. Institute Core Pathology capacity to regenerate itself. The Beat is published by the University of Ottawa Let’s take a look, for a moment, inside the Heart Institute (UOHI). Comments or questions chest of a person with coronary artery fed by the blocked blood vessel. Muscle that to happen, you also need new blood about The Beat should be directed to Jacques Guérette, Vice President, Communications, disease. Among other things, we can see cells start to die and heart tissue can be vessels to feed that growing tissue. While at 613-761-4850 or [email protected]. that there are yellowy patches in the permanently lost. The heart has a main­ research is underway to effectively regrow For more information about UOHI, please visit arteries. These are plaque deposits that tenance system for replacing cells that muscle, studies have shown that generating www.ottawaheart.ca. have accumulated in the artery walls over regularly die off, but the amount of new blood vessels — a process known as © 2009 University of Ottawa Heart Institute many years. As we watch, a piece of plaque damage caused by a heart attack over­ revascularization — on its own helps The Beat is a trademark of the University breaks free from one of these deposits. whelms that system. Working with of Ottawa Heart Institute. It tumbles along in the bloodstream Dr. Marc Ruel, Director of the Cardiac (continued on page 2) 2

Repairing Damaged Muscle: A) A collagen matrix containing sialyl Lewisx is injected at the site of damaged muscle tissue, where it gels to form a smart scaffold. B) The presence of sialyl Lewisx attracts progenitor cells to the site and binds with their L-selectin receptors. The progenitor cells take up residence in the scaffold, where they begin to differentiate and form new blood vessels. C) The new vessels provide oxygenated blood to growing muscle tissue, repairing the damage caused by ischemia.

(A “Smart” Way to Repair Damaged Tissue, continued) restore cardiac function. Suuronen’s work the regeneration process. This combined focuses on the revascularization process. effort greatly increases the extent of EPC The key, he has found, is helping mobilization. Sialyl Lewisx also improves progenitor cells do their job. EPC survivability so the cells have more The results showed that the rats time to fully engraft and differentiate. One of the cell types that replenish blood The biomaterial is liquid when cool, vessels is known as endothelial progenitor making it easily injectable at the damaged receiving the smart scaffold had a cells (EPCs). They are undifferentiated site. It then gels at body temperature to cells originating in bone marrow that the form the stable scaffold. 90 per cent increase in blood flow to body calls on when damage occurs. Signals go out to attract EPCs to a damaged site. To test their creation, the researchers Once they arrive, the progenitor cells can induced ischemia in thigh muscle in the the damaged tissue compared with become or stimulate the growth of new hind limbs of rats. They then treated some blood vessels, supplying oxygen to support rats with the smart scaffold and gave new muscle growth. Unfortunately, EPCs others collagen alone. The results showed the collagen-only rats. are not abundant, so by itself, the body that the rats receiving the smart scaffold can accomplish only so much repair. had a 90 per cent increase in blood flow to the damaged tissue compared with the One hope of scientists has been to give the collagen-only rats. The treated rats also system a boost by externally introducing had improved functioning after two weeks progenitor cells to increase their numbers. and showed no increase in inflammatory To date, the results of these cell response. These results were published have been less successful than originally online in January by The FASEB Journal expected. Instead of introducing cells (Erik Suuronen et al., FASEB J. 2009 from the outside, the biomaterial devel­ Jan 9. [Epub ahead of print]). oped by Suuronen’s group expands the capacity of the body’s own regenerative The success of this approach opens the door process. “Our goal,” Suuronen explained, to a variety of applications. Because the “is to develop safe and effective treatments smart scaffold enhances the body’s natural for coronary artery disease by helping the regenerative process, it could be paired body rebuild blood vessels and improve with several current and future inter­ heart function.” ventional strategies to increase their impact. These include angioplasty, cell Three things need to happen for EPCs to transplant therapies, and the transplan- become new blood vessels. They need to tation of heart muscle tissue grafts. be called into action and released into the ErikErik Suuronen,Suuronen, PhDPhD bloodstream through cell signalling; they “The concept of using cell-based therapy need to be recruited to and retained at the to rebuild blood vessels in and around the damaged site; and they need to be kept heart is proving to be the next frontier in alive and active long enough to transform cardiac medicine. This landmark devel­ into new vascular tissue. opment clearly represents a major step forward in adding to our ability to cure The new biomaterial addresses each of heart failure,” said Dr. Ruel. these issues. It consists of a collagen matrix “Our goal is to develop safe and effective treatments that has been modified to increase its Added Suuronen, “We see this as a for coronary artery disease by helping the body strength and longevity. Collagen is the breakthrough that may also positively main component of connective tissue in impact diseases such as diabetes, some rebuild blood vessels and improve heart function.” the body. The matrix provides a scaffold disorders of the liver and chronic brain where EPCs can reside while they go ischemia.” This close collaboration between • Scientist, Division of Cardiac Surgery, University of Ottawa Heart Institute through the process of differentiation. scientist and cardiac surgeon is indicative of the Heart Institute’s integration of • Research Investigator, Molecular Function & Imaging Program, A carbohydrate molecule known as sialyl research and clinical practice. As this work University of Ottawa Heart Institute x Lewis puts the “smart” in the scaffold. progresses, the partnership will help • Associate Professor, Department of Surgery; cross-appointment with the This molecule binds and retains EPCs translate successful research into patient Department of Cellular and Molecular Medicine, University of Ottawa where they are needed. In turn, the therapies more quickly. j progenitor cells then release protein • Research interests: treatment of cardiac injury and disease using tissue engineering and cell-based approaches; stem cell response to heart messengers called cytokines that travel tissue damage j through the circulatory system and to the bone marrow. These act as homing signals that call other cells to join them in 3

Regenerative Medicine

If it were possible to shift the body’s own repair mechanisms into high gear or to grow Investigator Alexandre Stewart and his PhD student Alan Teng work in the Ruddy replacement tissues, we could avoid the risks of invasive surgeries or rejection issues Canadian Cardiovascular Genetics Centre. They are exploring gene and cell therapies and long waits on transplant lists. This is the promise of regenerative medicine, a to treat the damage caused by heart attacks. It is recognized that patients recovering rapidly expanding area of medical research. from a heart attack grow new blood vessels, but the mechanisms that govern this process are not understood. Many of the relevant genes have been identified, but not The work of Erik Suuronen and Dr. Marc Ruel highlights one promising approach the various factors that turn them on and off. (see A “Smart” Way to Repair Damaged Tissue). Other University of Ottawa Heart Institute researchers are attacking the problem of tissue regeneration in different ways. Vascular endothelial growth factor (VEGF) is well known as a key player in influencing blood vessel formation. Stewart’s group recently identified a novel factor Patrick Burgon comes at regenerative medicine from a developmental perspective. that greatly increases production of the VEGF protein in the heart. This is the kind “The heart of a newborn has a great capacity to repair itself, but this capacity is lost of groundwork that is essential for the development of new regenerative therapies shortly after birth,” he explained. This is why congenital defects of the heart are more in the future. frequently corrected today through in utero surgery. The fetus can heal with little or no scar tissue formation. These and other groups at the Heart Institute, such as the positron emission tomography (PET) imaging group, are highly collaborative. They share expertise “What we are trying to do,” he continued, “is to figure out which genetic pathways and interim findings to spur innovation and facilitate progress in this burgeoning are lost or activated as we age to see if that capacity for repair can be recreated in area. This approach has proved to be remarkably productive. As Burgon puts it, the adult heart.” Burgon and his graduate student, Lara Kouri, are currently in the “The interface of collaboration is where you get the greatest discoveries.” j process of identifying these genes and pathways.

Playing a Pivotal Role: The Heart Institute Leads New Approaches to Clinical Care

Two innovative conferences brought Another event organized by the Heart Fourteen joined the Heart hundreds of physicians and nurses to the Institute early in 2009 was the First Institute’s smoking cessation network doorstep of the University of Ottawa Heart Ottawa Conference on Smoking Cessation, in December alone. Institute early in 2009. Both events offered where top tobacco addiction experts from some dramatic new lessons in managing across North America came to advise These include hospitals within the coronary artery disease. physicians and other health professionals River Valley Health Authority in New on preventive strategies. Brunswick, institutions within Vancouver In late 2007, the Heart Institute, working Coastal Health (VCH) in British Columbia, with The Ottawa , opened The Heart Institute’s own smoking St. Joseph’s Healthcare in Hamilton, and the first multidisciplinary Pulmonary cessation network has now grown to six prominent hospitals in the Toronto Hypertension Clinic in Canada. The 50 Canadian hospitals and medical centres area, such as St. Michael’s Hospital and clinic provides patients with access to the since the program began in 2004. Each has Sunnybrook Health Sciences Centre. Institute’s full diagnostic, treatment and been mentored by Institute personnel in Other recently partnered hospitals include research resources. In January of this the Ottawa Model for Smoking Cessation. Regina General Hospital in Saskatchewan, year, the country’s leading physicians, To date, some 6,000 Canadians are smoke- Hospital in , researchers and professionals free after being identified and treated and Boundary Trails Health Centre in presented a day-long series of lectures through the Heart Institute-developed Winkler, Manitoba. at a national Pulmonary Hypertension Ottawa Model, which is considered the Symposium organized and hosted by most advanced approach in Canada for At the conference, Dr. Pipe, Canada’s the Heart Institute. identifying and treating tobacco addiction. leading researcher on new approaches to Dr. Richard N. Channick, of the University of Close to 50 per cent of participants remain the prevention of cardiovascular disease, California, San Diego, was the keynote speaker at the Pulmonary Hypertension Symposium. Most of the speakers represented smoke-free at the 12-month mark. repeated and refuted many of the common He presented on “Classification, Diagnosis expertise from the clinic, including misconceptions about quitting smoking. and Treatment of Pulmonary Hypertension: Dr. Lisa Mielniczuk, Medical Director of “Tobacco addiction is the most funda­mental Within the Ottawa Model, all nurses A Practical Approach for Clinicians.” the Pulmonary Hypertension Program, preventive health issue in Canada. Smokers and physicians are trained about tobacco and Dr. George Chandy, the program’s understand why they shouldn’t smoke and addiction, how to address patients about talk, is becoming known as a renaissance Co-Director. Prominent invited guests very much welcome assistance in quitting tobacco addiction, and how to use nicotine drug thanks to various confusing included Dr. Richard N. Channick, smoking,” said Dr. Andrew Pipe, Medical replacement therapy to help patients quit studies that have shown that it improves Division of Pulmonary and Critical Director of the Institute’s Minto Prevention for good. concentration, decreases hunger, and can Care, University of California, San Diego and Rehabilitation Centre. “Through our relieve depression and anger. Medical Center, and Dr. John T. Granton, programs, we are developing a group of Dr. Richard Hurt, of the Mayo Clinic’s Program Director, Critical Care Medicine, clinical leaders who will introduce a very Nicotine Dependence Center, and an Further, nicotine offers the perfect reward University of Toronto. successful smoking cessation program — the internationally respected authority on to smokers because in many places and Ottawa Model — to hospitals across Canada. issues of tobacco control and smoking compared with other drugs, cigarettes are Pulmonary hypertension, a disease of the The conference was another demonstration cessation, provided a secondary viewpoint relatively acceptable, carry no immediate blood vessels that affects the lungs, carries of the Heart Institute’s leadership in on smoking as a global epidemic. Tobacco side effects, and are easily obtained. a serious prognosis, particularly among preventive medicine.” companies, he said, are targeting the Dr. Hughes went on to discuss the clear young women. It generally claims the lives Asian market, and China is the world’s biological mechanisms that kick in with of patients within two years of diagnosis. Just as important is how the Heart Institute largest producer of cigarettes. Dr. Hurt, smoking and how abstinence may cause a is using its leadership to help other hospitals an admitted three-pack-a-day smoker relapse of prior alcoholism and depression Researchers are not yet certain why young recast their role in preventive medicine. until he quit in 1975, is no stranger to in a minority of smokers. women are affected, noted Dr. Ross Davies, Robert Reid, Associate Director of the the world of smoking addiction. He said Administrative Director of the Heart Prevention and Rehabilitation Centre, about 60 per cent of Chinese men smoke. The Heart Institute continues to take a Institute’s Pulmonary Hypertension Program. said, “The Heart Institute is playing a This means that the number of smokers in leadership role and expand its professional Further, it is a complex illness that can be pivotal role in educating hospitals and China is larger than the entire population education activities. Other new symposia difficult to diagnose. The Heart Institute clinicians on new approaches to medical of the United States. conducted in the past year include: program delivers what Dr. Davies calls a care and research.” Reid’s research has • Heart Failure; “one-stop service” for patients, providing resulted in several highly effective new Dr. John Hughes, a psychiatrist and Direc- • Small Animal Imaging; and access to cardiologists, respirologists and programs in heart health education. tor of the Human Behavior Pharmacology • Molecular Function and Imaging: nurses at the Institute and from The Ottawa Laboratory at the University of Vermont Cardiovascular Metabolism. j Hospital. The clinic has served 265 patients The Ottawa Model has received wide in Burlington, is a leading researcher on since it opened, and the annual number of recognition as an efficient but personal issues relating to mental health and tobacco patients is expected to grow. approach to helping patients quit smoking. addiction. Nicotine, he explained in his 4 Canada Beats a Path to Heart Institute Core Pathology

Sample preparation and microscopic Previously the technical head of diagnostic “Because of the variety and specificity of The electron microscope is still a vital piece imaging are critical, if unglamorous, electron microscopy (EM) and supervisor immunohistochemical methods [antibody of equipment for researchers studying aspects of research. Consistency and pre­ of the Histopathology Laboratory at The staining or tagging] which became the biological structures underlying cell cision are the hallmarks of good histology Ottawa Hospital (Civic campus), Rippstein available in the early 1980s, EM became function. The capability has certainly and microscopy. The Stewart Whitman was recruited by the Heart Institute to less popular, particularly as a diagnostic paid dividends for Institute researchers. Histopathology Core Laboratory was establish and manage an EM facility tool,” explained Rippstein. “So over time For example, in 2008, Heidi McBride, a established as a shared resource to provide dedicated to research. That facility now EM training programs eroded, and now highly regarded expert in mitochondrial specialized equipment and expertise to resides within the Core Lab. It is Rippstein’s we find ourselves in a situation where it’s research, uncovered an unknown method researchers at the University of Ottawa EM expertise that is generating a lot of difficult to find EM expertise.” This that mitochondria use to transport waste Heart Institute. Over the years, the lab’s outside interest and paying clients from shortage of electron microscopy specialists products within cells. She credits Rippstein’s reputation for excellent work has grown, other research centres, such as the University has placed the Heart Institute facility in EM expertise with making this significant and institutions from around Ottawa of Ottawa, the Ontario Health Research great demand among Canadian scientists discovery possible. and across the country now line up for Institute, McGill University, the University wishing to incorporate EM imaging into its services. of Saskatchewan, Health Canada, and the their research. In addition to processing The origins of the Core Lab go back to National Research Council. and imaging EM samples, Rippstein 2001 when Stewart Whitman joined the Histology is the study of the anatomy provides investigators with assistance in Heart Institute as a vascular biology and structure of cells and tissues. In interpreting results. researcher. He brought with him a sub­ histology, tissue samples are prepared, stantial young investigator equipment thinly sliced, and mounted on glass slides grant from the Canada Foundation for for examination under a microscope. It Innovation. The histology equipment he is one of the workhorse processes for “The Core Lab offers the technical was able to purchase for his laboratory medical diagnostics and biological was very advanced and helpful to many of research. Preparing his­tological samples capabilities to support the histology the Institute’s scientists. Whitman decided is a labour-intensive process. For that it should reside in a shared facility immunohistochemistry-based tests (those needs of any of our researchers.” that anyone could access. that use antibodies to identify proteins in tissues), the samples are usually flash- – Peter Rippstein, Manager, Stewart Whitman “The money to buy this equipment came frozen in liquid nitrogen and sectioned Histopathology Core Laboratory, UOHI from the Canadian taxpayers,” said on a machine known as a cryostat, which Whitman. “We wouldn’t want them to think keeps them cold throughout the proce- that we’re hoarding it.” He became the dure. For structural studies, tissue samples driving force behind establishing the Core that have been chemically preserved are Lab and training technicians from other dehydrated in alcohol and ultimately Heart Institute laboratories in histological impregnated with paraffin wax, solidify- techniques, such as immunohistochemistry. ing them for cutting into sections only a few microns thick — far thinner than Whitman is an immunologist who works a human hair. in the field of atherosclerosis. His research explores how the immune response to tiny Standardization and quality control are cracks in blood vessel walls may contribute essential in preparing histological samples. to atherosclerotic plaque formation. His If the samples are handled incorrectly, presence has provided a perspective on molecular changes can occur and be heart disease that has influenced researchers mistaken for intrinsic properties of the throughout the Heart Institute. To honour tissue, obscuring or invalid­ating research his role as the founder and advocate of the results. The core facility has equipment to core facility and his varied contributions automate the entire preparation process, to research at the institution, the Heart which greatly reduces the variability that Institute recently dedicated the lab in can occur with manual sample prepara­ his name as the Stewart Whitman tion. “When I first came here, the equip­ Histopathology Core Laboratory. ment in individual labs was definitely in need of upgrading. The Core Lab offers For those interested in learning more the technical capabilities to support the about services available from the Core histology needs of any of our researchers,” Lab, please contact Peter Rippstein at said Peter Rippstein, Manager of the [email protected]. j Histopathology Core Laboratory. Peter Rippstein conducts the Heart Institute’s highly sought-after electron microscopy services and manages the Stewart Whitman Histopathology Core Laboratory. He is seen here at the electron microscope.

Stewart Whitman, PhD

“The money to buy this equipment came from the Canadian taxpayers. We wouldn’t want them to think that we’re hoarding it.”

• Co-Director, Vascular Biology Laboratory, University of Ottawa Heart Institute

• Associate Professor, Department of Pathology and Laboratory Medicine; cross-appointment with the Department of Cellular and Molecular Medicine, University of Ottawa

• Research interests: immunology and cardiovascular disease, specifically the inflammatory- immune system’s effect on atherosclerosis; bacterial pathogens and their relationship to cardiovascular disease j