Vanquishing an Insidious Foe

Research is targeting the varied, complex nature of cardiovascular disease

By Debora Van Brenk, BA’86, MA’87

The question is one Dr. Rob Hegele hears often: Is cardiovascular disease a product of genetics or a product of lifestyle? “The answer is … yes,” said the Robarts Research Institute scientist.

One of the world’s foremost experts on the genetic basis of cardiovascular disease, Dr. Hegele cares for more than 2,500 patients at his lipid clinic. For those individuals, he is more than a physician. By mapping the genetic basis of their high cholesterol or Type 2 diabetes, he is also able to help change their outcomes.

“We provide a glimpse into the future for them,” he said.

Dr. Hegele is one member of an ever-expanding team of researchers at Robarts focused on understanding the varied and complex natures of vascular disease.

Invisible, insidious and often devastating, vascular diseases are the leading cause of preventable death and disability in Canada. From chronic high blood pressure and stroke to heart attacks and dementia, poor vascular health impacts not only the flow of blood through the body, but also the proper function of blood vessels and vital organs such as the brain and heart.

And it often goes undetected and undiagnosed until it’s too late.

Robarts scientists are using imaging and cellular markers to detect early changes in vascular flow. They examine the microenvironment of the brain, especially as it ages, to understand the impact on blood flow and how blood vessels are formed or damaged. By understanding why these changes happen and how early, these researchers look to create the proper treatments for prevention, assessment and repair.

Cardiovascular research is at the ‘heart’ of that work at Robarts.

“We are a product of both our genes and our environment. Science and medicine have progressed to the extent we can now be much more confident of the role of genetics in the conditions that plague us,” Dr. Hegele said.

Through their studies, his laboratory has learned that about five per cent of people are so genetically hardwired to develop cardiovascular disease that almost no amount of intense diet or exercise can reverse the trend.

“There’s another five per cent who have an improbably high genetic tolerance for poor lifestyle choices. They can eat all the burgers and fries they want, and seem to be immune from disease,” he said.

But for the remaining 90 per cent of us, it’s a balance between genetic factors and lifestyle. “The good news is for most people a combination of lifestyle changes and sometimes the right medication can bend the curve of disease onset and literally be life-changers in the personal battle against cardiovascular disease,” he added.

“Genetics is important not just for diagnosis but is the first step in the process of developing the treatments of tomorrow,” he said.

Marlys Koschinsky, PhD, is working to understand the fundamentals of a particle called lipoprotein(a), known as Lp(a). Identified in clinical trials as the single most common genetically inherited risk factor for coronary heart disease, it is relatively resistant to lifestyle changes or lipid-lowering drugs.

If low-density lipoprotein (LDL) is generally known as the ‘bad’ cholesterol, elevated levels of Lp(a) can be thought of as the ‘super-bad’ cholesterol.

Koschinsky, who serves as the Scientific & Executive Director at the Institute, conducts basic science into Lp(a) and works with clinicians and laboratory scientists in trying to uncover its secrets.

“I’m always trying to help provide information about the basic aspects of Lp(a): How does it work, how does it contribute to heart disease, how does it contribute to peripheral vascular disease and stroke, what are the mechanisms at play that are different than what LDL does?

“And in people who have elevated levels of Lp(a), how do we approach developing pharmaceutical interventions?”

She is a key player in a large, Phase three clinical study of a compound being tested for its ability to block the production of Lp(a).

“In five or six years, we will know if specifically lowering Lp(a) will result in better clinical outcomes. All our data, all our evidence to date suggest, because it’s a risk factor, that lowering Lp(a) is going to be beneficial. But we need the proof,” Koschinsky said.

She is confident it can be done, with collaborations, team work, lab and clinical research, and a range of private- and public-sector partners.

That sentiment is echoed by Nica Borradaile, MSc’98, PhD’03, an Associate Professor in Physiology and Pharmacology who researches how excess fatty acids – called lipids – compromise cells in the liver and blood vessels.

“At the School and Robarts, you get to collaborate a lot. It’s a good model,” she said.

Borradaile’s research is expanding our understanding of the role of lipids in a person’s recovery from ischemic injury – that is, injury that takes place in tissues and limbs when blood flow to their cells has been restricted by vascular disease, often as a result of obesity and metabolic disease.

Most recently, she has been analyzing the effectiveness of natural compounds, such as vitamins, for their ability to mitigate lipotoxicity. So many people take vitamin supplements, she said; it’s important to know which ones may have an impact on which systems – and why that’s the case, or why not.

In the past decade, for example, some have suggested Vitamin D might improve cell function for people with metabolic syndrome that resulted in poor blood flow to a limb. Her newly published research shows the vitamin, for this purpose anyhow, may be a dead end.

“Learning what isn’t effective in improving cell function is often as instructive as learning what is effective,” Borradaile said. “We’re working in the lab on the underlying mechanisms involved.”

“Just because Vitamin D doesn’t promote blood-vessel regeneration in cardiovascular disease, doesn’t mean it’s not beneficial in other areas. It’s complicated.”

Welsh is also the holder of the endowed chair position the Cecil and Linda Rorabeck Chair in Molecular Neuroscience and Vascular Biology.

His lab is using multi-photon microscopy as a centrepiece of new technology to examine cells and tissues, including blood flow through vessels circulating to and through the brain.

Where most tissue analysis entails static, two-dimensional images, photon microscopy shows the inner workings of blood vessels in movie-like format. The wavelengths of the instrument’s light pulses ensure sharp images that don’t damage the tissues under examination.

“We see them live, in real time. What this gives us is temporal information and spatial information,” he said. “The truth is vascular disease is very heterogeneous, even within a tissue. That’s why getting this equipment gives us a more complete picture of disease through space and time. You can see the blood vessels, you can see the blood flowing through the capillaries.”

His lab also employs a novel ‘Robo-Caroline,’ which can be programmed to produce and process from a single tissue a near-infinite number of slices, which can then be stitched together into a deep, three-dimensional image that helps assess how healthy or unwell the patient’s blood vessels are.

“To us, it always seems to come back to the blood vessels. It’s one of those things that takes a beating and keeps on ticking. But when it doesn’t keep ticking, then you’re in trouble,” he said.

Making sure it keeps on ticking is researchers’ ultimate goal in preventing, diagnosing and treating cardiovascular disease.

And while in some fields of research and medicine it’s difficult to measure how successful an intervention is, Dr. Hegele has proof of success in clinical studies, in the changes that have taken place in his patients and in the number of patients he sees through life’s milestones year after year.

“For me, one long-term marker of success is that my clinic is full of people. They keep me coming back. They tell me about the trips they’ve taken and how their grandchildren are doing.”