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Be still my beating heart

Study is the first to enable biochemical reactions in the heart to be seen with MRI using a novel contrast agent

About six weeks into a pregnancy, the steady heartbeat of a fetus can be detected via ultrasound. From the earliest moments of life until death, the heart toils unceasingly to pump life-giving blood around the body. Perhaps unsurprisingly, this fist-sized workhorse has the greatest energy demands of all the body’s organs.

To do its job of beating 100,000 times daily, our hearts need to make a chemical fuel called adenosine triphosphate (ATP)—and lots of it. (An adult heart makes about six kilograms of ATP—35 times its weight—daily.)

Until relatively recently, doctors weren’t able to measure how much of an energy source, such as fatty acids and glucose, was consumed by the human heart. In the early 2000s they began using positron emission tomography (PET) to study glucose metabolism in cardiac patients. This technique relies on radiotracers to show uptake of glucose or fatty acids that are used to make ATP. A missing link remained, however: what happens to those substrates once they enter the heart’s cells? Pioneering work in medical imaging led by Dr. Charles Cunningham, a senior scientist at Sunnybrook Research Institute (SRI), is unraveling this mystery. Cunningham and colleagues are the first in the world to demonstrate noninvasive metabolic MRI of the human heart using a contrast agent called hyperpolarized carbon-13-labelled pyruvate. Put simply, this contrast agent is a byproduct of glucose that is prepared in a strong magnetic field and injected into a person undergoing MRI. A process called dynamic nuclear polarization increases the signal from the pyruvate 10,000-fold. A higher intensity signal increases image brightness, enabling biochemical reactions occurring within the heart to be seen. The study was published in Circulation Research; images from the paper landed the team the cover of the journal’s November 2016 issue.

The contrast agent may prove useful in heart failure, where the heart is unable to meet the body’s pumping needs. It could help establish metabolism as a biomarker of heart failure, opening the door to earlier diagnosis and care that is specific to each patient. “The progression of heart failure is very likely preceded by metabolic changes, so if you could image those and tell which people are going down that path, you could treat them more aggressively or tailor the treatment,” says Cunningham, who is also an associate professor of medical biophysics at the University of Toronto.

Researchers do not fully understand the metabolic shifts that occur in heart failure, but they do know that there are abnormalities in how the heart makes ATP. Normally, pyruvate, which is made from glucose, goes into the TCA (tricarboxylic acid) cycle, the metabolic cycle that creates ATP within cells. When the heart starts to fail, however, it relies more on fat as the main fuel, says Dr. Kim Connelly, a co-author of the study and a cardiologist at St. Michael’s Hospital in Toronto, Canada. At a later stage of heart failure, the heart reverts to using more glucose. “It’s not a static process. [Metabolism] changes depending on how bad your heart failure is and what the cause of the heart failure is. Before this, we never had a good technique that could help tease out exactly what’s going on in terms of the heart taking up glucose and taking up fats, and what happens to them once they enter the cells in the heart and get broken down,” says Connelly.

It could help establish metabolism as a biomarker of heart failure, opening the door to earlier diagnosis and care that is specific to each patient.

Hyperpolarized carbon-13 MRI could elucidate those changes, as well as the mechanisms behind them. Early on in heart failure, when the heart stops using glucose properly, seeing how much pyruvate is used to make ATP could be quite telling. “Bicarbonate is produced when pyruvate is converted into acetyl coenzyme A, which enters the TCA cycle. So high bicarbonate means lots of carbs going in, and low bicarbonate means that flux is downregulated. When it’s decreased that could be the marker that we’re after,” says Cunningham.

The technique offers advantages over PET, which images metabolism to show differences between healthy and diseased tissue. First, PET only shows the uptake of a molecule, whereas hyperpolarized carbon-13 MRI shows what happens after the heart takes up glucose. “The big thing with this is you see the conversion of one thing into another,” says Cunningham. Second, the contrast agent is safe, making possible long-term studies in patients. The use of ionizing radiation in PET however, restricts the number of scans people can have.

Chuck

Dr. Charles Cunningham led the world’s first study demonstrating noninvasive metabolic MRI of the human heart using a contrast agent called hyperpolarized carbon-13-labelled pyruvate.

Photo: Nation Wong

Moreover, carbon-13 metabolic MRI could easily be integrated with regular cardiac MRI, which assesses the heart’s size and function, and analyzes scarring. It would only add 10 minutes to the procedure. “It’s done at the same time as the MRI, so it’s perfectly spatially coregistered to the MRI; [this means] on a pixel-by-pixel basis, you could compare metabolism to other parameters,” says Cunningham.

He plans to study metabolic imaging in people with enlarged hearts, a condition that puts them at increased risk of heart failure. By following them and looking at outcomes he hopes to learn whether glucose metabolism can be used as a biomarker to predict disease. “I think that will answer the question as to whether it’ll be useful clinically,” he says.

The current focus is on cardiac applications, but Connelly says metabolic imaging would be useful in other clinical domains. “There’s no reason why we can’t measure [metabolism] in the liver or kidneys, and use it to gain really valuable insight into what happens to people with kidney diseases or liver diseases, and also to tailor-make drugs. This is potentially much, much broader,” he says.

It has been more than a decade since Cunningham began working on this technique. His lab had to engineer hardware to pick up the signal, and create software to switch the MR scanner to do metabolic imaging while retaining the capacity to see anatomy in the same frame of reference. He says most of their efforts were aimed at making the contrast agent safe. To ensure sterility, it was prepared with pharmacist oversight in SRI’s good manufacturing practice facility, which guarantees quality control for patients.

So, how did it feel to finally see it work clinically after so many years of research and development?

“It was a good day,” Cunningham says, smiling. “It was a huge step forward. I was happy.”

Cunningham’s research was supported by the Canada Foundation for Innovation, Canadian Institutes of Health Research, Heart and Stroke Foundation, and Ontario Institute for Cancer Research.