TopTen-Generic-V3-02Editor’s note: This is the 10th in a 10-part series detailing the top scientific research of 2014, as determined by the American Heart Association’s volunteer and staff leaders.


Two innovative models to study and test how specific genes affect the heart and blood vessels are leading to successful experimental treatments, opening a new frontier in medicine.

These innovative models were among the top scientific research developments of 2014, according to the American Heart Association.

‘Heart on a chip’

Researchers pioneered a “heart on a chip” model to learn how a single mutation affects the heart cells of children with Barth syndrome. The rare genetic condition leads to heart failure at a young age. Researchers found that delivering a healthy version of a mutated gene corrected the cell problems, according to a study published in Nature Medicine.

A mutant gene in Barth syndrome patients affects the mitochondria, the energy-generators of the cells, and the study helped demonstrate how it translated into heart weakness. Researchers created a model using a rubbery “chip,” about two centimeters square, overlaid with a protein blueprint and the stem cells they converted from skin cells. They cut tiny flaps in the chip to see how the cells contracted. Strong tissue contracts a lot; weak tissue does not.

From the model, they found the mitochondria of the Barth syndrome cells were producing excessive oxidants that prevented strong heart contractions. Replacing the defective gene with a healthy version fixed the problem.

The use of the heart on a chip model to genetically correct irregular heart contractions in the cells derived from Barth syndrome patients was significant, according to study author William Pu, M.D., associated professor at Harvard Medical School in Boston, Massachusetts. “Since we can reverse disease on a chip, the hope is you could transfer the gene into a patient,” Pu said.

Experts agree that it may lead to a shorter-term treatment.

“Everyone wants a cure but it’s much harder to cure than to treat. There are still many patients who desperately want treatment before we can find a cure,” said Yuk Law, M.D., director of Cardiac Transplant and Heart Failure Service at Seattle Children’s Hospital and associate professor in the Department of Pediatrics at the University of Washington School of Medicine. “This offers to me hope in the smaller steps of treating the disease.”

The heart on a chip model could give researchers more insight into how heart cells function and react to treatments in other diseases, according to Megan McCain, Ph.D., a co-author of the study who did the research as a post-doctoral fellow at Harvard.

“What’s great about this is that we can test drugs without touching the patient, so we take a small piece of their skin but the drug testing happens on the bench and it’s patient-specific,” said McCain, now an assistant professor of biomedical engineering at the University of Southern California in Los Angeles.

‘Big data’ leads to stent discovery

Taking another innovative approach to medicine, researchers used big data — huge amounts of complex information that can be analyzed to reveal patterns of information — to discover that a cancer drug may be a powerful way to prevent blood vessel disease triggered by stents, the tiny mesh scaffolds used to prop open blocked heart blood vessels.

Although useful at clearing dangerous plaque build-up in arteries, stents can also damage the inner lining of the artery, leading to smooth muscle overgrowth in the middle layer that can re-narrow the passageway as the vessel wall thickens. Clogged or blocked vessels can lead to chest pain and heart attacks.

“We used human tissue to identify novel mediators of disease using the computational biology approach — the ‘big data’ approach,” lead study author Ziad Ali, MD, PhD, said. Early in the study, Ali was a cardiovascular fellow at Stanford Medical Center in California; he’s now associate director of translational medicine at Columbia University Medical Center. “The computational biology approach can give you a good hypothesis, but then you need to prove it in the lab,” he said. “The marriage of the two is what makes this study really special.”

Mining data from previous studies of coronary artery disease, researchers identified the GPX-1 gene as one involved in the unhealthy remodeling of blood vessels that can occur after a stent procedure to treat atherosclerosis; it can narrow the vessel again. They confirmed its effect in a mouse study.

They continued to search medical literature for how genes interacted in people who had received stents that could help cause this unhealthy remodeling. This led to identifying another gene, ROS1, which appeared to affect GPX-1. That led to testing of crizotinib, a chemotherapy drug used to inhibit ROS1.

After giving the drug to mice with heart stents, they found the drug stopped the unhealthy blood vessel remodeling without harming the healthy growth and healing of the blood vessel lining.

“This could have major clinical impact,” said Euan Ashley, M.D., senior study author and associate professor of cardiovascular medicine and of genetics at Stanford. “Down the road, patients who receive drug-eluting stents with this new drug may no longer be required to take blood thinners after their procedure.”

Big data also has the potential to be applied directly to patients and help redefine how clinical trials are performed, Ashley said. “Can you imagine if you can combine the medical records of one billion patients around the world? We can combine data from the electronic medical records for millions of people across many years and ask the questions in real time.”