Potential new drug target found for atrial fibrillation

A mutation in the largest human protein, called titin, may point the way to new treatments to prevent stroke and heart failure in atrial fibrillation patients, according to research from the University of Illinois Chicago.

Atrial fibrillation is an irregular heart rhythm that affects more than 33 million people worldwide, increasing their risk of heart failure and stroke. While most patients develop atrial fibrillation in their 70s, often due to high blood pressure or obesity, it can also happen earlier in life, caused by inherited genetic mutations. 

Most atrial fibrillation patients get a combination of drugs to prevent stroke and heart failure. But a new study from the laboratory of Dr. Dawood Darbar, chief of cardiology and professor of medicine and pharmacology at UIC, finds that a drug that corrects the result of a small genetic change associated with familial atrial fibrillation could address both concerns.

The study, published in iScience, looked at a small genetic deletion of nine amino acids from titin. Titin is present in muscle tissue throughout the body, including the heart, and mutations in the gene encoding the protein have been associated with familial risk of cardiomyopathy, heart failure and atrial fibrillation.  

Darbar and colleagues deleted a short segment of the titin gene in zebrafish and in human stem cell-derived heart cells and examined if this change caused heart abnormalities and arrhythmia. In embryonic stages, the zebrafish mutants exhibited general heart dysfunction, but most of these resolved by birth. However, abnormal contractions in the atria remained, giving rise to atrial fibrillation in adulthood. The findings were replicated in experiments with heart cells derived from human stem cells. 

“Not only did removing only nine amino acids have such a dramatic impact in zebrafish and in stem cell-derived heart cells, but it’s also the first time we’ve shown that a genetic defect that you’re born with really doesn’t manifest until later on in life,” Darbar said. 

The researchers then found that an experimental drug could restore normal atrial contraction in the genetic mutants. Unlike the drugs currently used to treat atrial fibrillation, this effect could also potentially reduce the risk of stroke, preventing the need for blood thinner medications.  

“This could potentially be a paradigm shift in terms of how we treat patients at risk of a stroke from atrial fibrillation,” Darbar said. “It opens up new avenues to not only treat atrial fibrillation but reduce the risk of stroke with a single treatment.” 

The researchers are looking for industry partners to further test the drug’s potential clinically.  

In addition to Darbar, UIC co-authors on the paper include Xinghang Jiang, Olivia Ly, Hanna Chen, Ziwei Zhang, Beatriz Ibarra, Mahmud Pavel, Grace Brown, Arvind Sridhar, Dr. David Tofovic, Abigail Swick, Dr. Richard Marszalek, Fritz Navales, Salman Khetani, Dr. Jalees Rehman, Yu Gao and Arthur Saxena. The research was funded by the National Institutes of Health grants R01HL138737, R01HL150586, R01HL148444, 5R35GM133416 and 5T32HL139439.