An A*STAR-led study into heart failure, the largest ever conducted in Singapore, is revealing new ways to predict death or admission to hospital for people who have suffered heart failure, as well as opening potential new avenues to reduce the risk of heart failure occurring.
It’s all part of the Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT), a million government-backed initiative that for the first time has brought together leading cardiologists and heart disease researchers from A*STAR, the National University of Singapore (NUS), the Duke-NUS Medical School and two national heart institutions (National University Heart Centre and National Heart Centre Singapore). Also involved are Singapore's Khoo Teck Puat Hospital, Tan Tock Seng Hospital, Changi General Hospital and Singapore General Hospital. Together, this all-star cast is throwing the weight of Singapore’s scientific expertise and resources at heart disease, one of the country’s biggest killers, responsible for roughly 30% of all deaths.
“ATTRaCT is the first integrated platform for translational cardiovascular research that leverages Singapore’s competitive advantages to identify and validate novel targets in heart disease progression,” says Carolyn Lam, a professor at the Duke-NUS Medical School and senior consultant cardiologist at the National Heart Centre Singapore, who is leading the program.
Launched in 2015, ATTRaCT builds on previous Singapore-led initiatives such as the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry, an 11-nation study of more than 6,000 heart failure patients. However, ATTRaCT goes much further, using advanced cardiac imaging, genetic and molecular studies to look at the root causes of heart diseases in patients and animal models.
Heart of the matter
The linchpin of the program is a nationwide prospective study involving Singaporeans with heart failure and healthy controls. Over three years, each of the trial’s 1,200 participants undergoes a battery of sophisticated diagnostic tests. These include magnetic resonance imaging to view the heart’s anatomy and the health of its tissues. Blood samples are also examined for novel molecular and immunologic indicators of disease. Also, geneticists are decoding the full genome sequence of each individual.
The clinical part of the study is yielding a wealth of data, so much that leaders of the A*STAR Bioinformatics Institute were enlisted to help with its management and analysis. Those clinical findings were then fed into the program’s more basic discovery efforts.
The goal, says Lam, is to better understand the mechanisms underlying disease progression so researchers can identify molecular pathways that can be targeted to prevent heart failure. The ATTRaCT investigators also hope to develop new imaging modalities or blood-based tests for detecting early signs of pre-symptomatic disease, as well as reveal the genetic factors responsible for predisposing people to heart issues.
An unmet medical need
The study is the first large-scale trial in Asia that seeks to unravel differences in the two distinct forms of heart failure, each of which is defined by the amount of blood pumped out of the heart with each beat.
For about half of patients with heart failure, the blood volume is reduced, causing what is known as heart failure with reduced ejection fraction, or HFrEF, a problem that can be treated with drugs that help maintain fluid balance in the body. The other half maintain what seems like normal blood volumes, but the heart muscle thickens and becomes stiff, limiting its capacity to meet the body’s needs.
This is known as heart failure with preserved ejection fraction, or HFpEF, and it has no effective remedies — in part because so little is known about what drives this muscle thickening and why, for instance, women are more predisposed to HFpEF than men. “Fundamentally,” says Roger Foo of the A*STAR Genome Institute of Singapore, “we still need to understand what the biology of that disease is.”
Foo is one of ATTRaCT’s leaders, in charge of all research related to genetics and epigenetics. Other leaders include Patrick Cozzone, executive director of the A*STAR Singapore Bioimaging Consortium, who runs the imaging track of the study, and Mark Richards, a cardiologist who directs the NUS Cardiovascular Research Institute and is heading efforts to discover blood biomarkers of disease. The ATTRaCT network additionally collaborates with several of the largest pharmaceutical companies in the world.
“It’s an impressive research team—multi-national, multi-disciplinary and multi-institutional,” says John McMurray, a cardiologist at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences in Scotland, who serves on the external scientific review committee for ATTRaCT. “I’ve reviewed initiatives like this in other countries, but this one is special, helped by charismatic, strong and focused leadership, and sympathetic and supportive government oversight.”
ATTRaCT is only just past the halfway mark, but has already spurred a number of seminal discoveries. For example, the study investigators have filed to patent a new imaging technique that can track metabolism in the heart muscle like never before.
They’ve also pinpointed a molecule circulating in the bloodstream of patients that predicts outcomes specifically in women with HFpEF, potentially shedding light on the female predisposition to the disease.
Notably, the discovery of a molecule in the blood of patients with HFpEF, known to be the target of a drug that’s already widely used for other types of diseases, suggests that the same drug could conceivably be repurposed to help deal with the unique pathology of HFpEF.
Foo and his colleagues also recently identified an RNA molecule (pictured right, in red) involved in regulating the heart’s response to stress. This molecule, they reported in the journal Nature Communications, is active in diseased heart tissue from patients, and blocking it helped promote heart repair and regeneration in mice.1 Currently, notes Foo, no known therapies can do that—all existing heart medications merely slow disease progression. Now, he says, “the question is: can we heal the heart and cause recovery and reverse disease in patients?”
By mid-2019, when ATTRaCT has run its course, Lam hopes the platform will transform from an observational one for target discovery, to an interventional one for precision trials in heart disease. At the point, novel and repurposed drugs discovered in the first phase of the program should be ready for clinical testing in patients. “To achieve this,” she says, “continued strong partnership among the clinical and research institutions, as well as between academia and industry, are essential.”
The A*STAR-affiliated researchers contributing to this research are from Asian neTwork for Translational Research and Cardiovascular Trials program and are also affiliated with the Singapore Bioimaging Consortium, the Genome Institute of Singapore, the Singapore Immunology Network, the Institute of Molecular and Cell Biology and the A*STAR-NUS Clinical Imaging Research Centre.
See, K., Tan, W.L.W., Lim, E.H., Tiang, Z., Lee, L.T., et al. Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo. Nature Communications 8, 225 (2017) | article