HU and WRU Medical School Researchers discover New Target in Heart Failure

New Target in Heart Failure

Researchers from Harvard Medical School, Dana-Farber Cancer Institute and Case Western Reserve University School of Medicine have made a fundamental discovery relevant to the understanding and treatment of heart failure, a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.

In contrast to standard therapies for heart failure, JQ1 works directly within the cell’s nucleus to prevent damaging stress responses. This research lays the foundation for a new way of treating a diseased heart. The study appears in the August 1 issue of Cell. 



“So much has been learned from this molecule,” said James Bradner, HMS assistant professor of medicine at Dana-Farber and the paper’s senior author. “The fundamental similarity between the biology of cancer cell growth and heart enlargement following extraordinary stress connects these mature fields of study in new and exciting ways, of immediate relevance to drug development.”

Heart failure occurs when the organ’s pumping capacity cannot meet the body’s needs. Existing drugs, most of which block hormones such as adrenaline at the cell’s outer surface, have improved patient survival. Unfortunately, several clinical studies have demonstrated that heart failure patients taking these hormone-blocking drugs still succumb to high rates of hospitalization and death. Leveraging a new approach, the research team turned their attention from the cell’s periphery to the nucleus—the place that unleashes sweeping damage-control responses that, if left unchecked, ultimately destroy the heart.

The team found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus. Previous research linking BET bromodomains to cancer prompted researchers in Bradner’s laboratory to develop a direct-acting BET inhibitor, called JQ1. In models of cancer, JQ1 functions to turn off key cancer-causing genes, occasionally prompting cancer cells to “forget” they are cancer. In models of heart failure, JQ1 silences genetic actions causing enlargement of and damage to the heart—even in the face of overwhelming stress.


“As a practicing cardiologist, it is clear that current heart failure drugs fall alarmingly short for countless patients. Our discovery heralds a brand-new class of drugs that work within the cell nucleus and offers promise to millions suffering from this common and lethal disease,” said Saptarsi Haldar, assistant professor of medicine at Case Western Reserve, a cardiologist at University Hospitals Case Medical Center and a senior author of the paper.


Led by principal investigators Haldar and Bradner, the team studied mice that developed classic features of human heart failure, including massively enlarged hearts full of scar tissue and poor in pumping function


For one month, the scientists administered a single daily dose of JQ1 to the sick mice. The treated mice were protected from precipitous declines in heart function in a matter of days. Animals that received the compound saw a 60 percent improvement, compared to an untreated control group.

“Remarkably, at the end of the experiment, the hearts of many JQ1-treated mice appeared healthy and vigorous, despite being exposed to persistent and severe stress,” said Priti Anand, a researcher in Haldar’s lab and co-first author on the paper. “We knew we were on to something big the first time we saw this striking response.”



This collaboration started when Haldar read Bradner’s 2010 Nature paper describing the creation of JQ1 and its ability to transform cancer cells into healthy ones. Following an open-source approach to drug development, Bradner elected to make JQ1’s chemical recipe publicly available to accelerate the creation of new treatments for patients. This synergistic approach to discovery opened the door for Haldar to work with Bradner to probe the role of BET bromodomains in the heart.

“This study best exemplifies the power of open-source approaches to drug discovery,” Bradner said.

In the coming months, the team will test JQ1 in preclinical models of heart failure and other cardiovascular conditions. With the jumpstart offered by Bradner’s creation of JQ1, the research team hopes one day to move to clinical trials.

“While it’s been known for many years that the nucleus goes awry in heart failure, potential therapeutic targets residing in this part of the cell are often dubbed as ‘undruggable,’ given their lack of pharmacological accessibility,” said Jonathan Brown, HMS instructor in medicine at Brigham and Women’s Hospital and co-first author on the paper. “Our work with JQ1 in pre-clinical models shows that this can be achieved successfully and safely.”