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Breaking the Code: Diagnostic and Therapeutic Potential of RNA

Ribonucleic acid, or RNA, is one of the three major biological macromolecules that are, along with DNA and proteins, essential for all known forms of life. Recently, types of RNA called microRNAs (miRNA) and long-non-coding RNAs (lncRNAs) have been found to play important roles in gene regulation, capturing international scientific attention for their potential as markers of heart health, as well as possible treatments for cardiovascular disease.

A Boston-based research team is now working to identify microRNA molecules that can serve as biomarkers to help predict outcomes in patients with heart disease.

Complications from heart attacks contribute to more than 550,000 cases of heart failure and 300,000 cases of sudden cardiac arrest. Both of these conditions are closely related to a process known as remodeling, in which the structure and function of the heart changes—or remodels—after a heart attack.

By using RNA sequencing technology, the researchers have identified characteristics in extracellular RNAs in plasma that might enable them to better predict patient outcomes following a heart attack. Their ultimate goal is to use miRNA-based tests to predict which patients might be at risk of complications related to heart remodeling. As a result, doctors would be able to more aggressively monitor their patients’ conditions and intervene with medications or implantable devices if needed.

The team has already identified a number of microRNA biomarker candidates. One of these molecules, miRNA-30d, is an important predictor of beneficial cardiac remodeling and outcomes in patients with heart failure. Additionally, miRNA-30d plays a functional role in preventing cell death. The scientists are now incorporating this new discovery into studies in mice to see if miRNA-30d can serve as a new therapy to protect against heart disease.

A 2016 study reported that lncRNA could serve as a drug target for cardiac hypertrophy, a heart disease in which the cardiac muscle thickens, often leading to heart failure and death. German researchers identified CHAST, short for cardiac hypertrophy-associated transcript, and they believe it may contribute to cardiac hypertrophy. They found that CHAST was specifically up-regulated in the heart muscle cells of mice with heart failure. When CHAST was overexpressed, it triggered hypertrophic growth of the heart muscle cells in culture, whereas when it was silenced it reduced abnormal growth.

Experiments suggest that the lncRNA may drive cardiac hypertrophy by blocking the normal degradation of heart muscle cells. Treating mice with an inhibitor known as an antisense oligonucleotide that targeted CHAST, both prevented and treated cardiac hypertrophy, while simultaneously improving heart function. These findings have set the stage for years to come for developing CHAST inhibitors and other lncRNAs to treat heart failure in patients.

Scientists are also exploring the therapeutic potential of RNA in the treatment of atrial fibrillation, a condition in which the patient’s irregular and often rapid heart rate can increase the risk of stroke, heart failure and other heart-related complications. Upwards of six million Americans suffer from this common type of arrhythmia, and doctors typically treat it with a variety of ablation procedures. By interfering with the transmission of the electrical impulses responsible for the arrhythmia, ablation procedures can successfully restore a regular heartbeat. For some, however, multiple ablation procedures are required, leading to scarring and fibrosis outside of the veins, sometimes affecting both of the upper heart chambers. This often results in recurrences of the erratic heartbeats after the ablation.

Now, researchers in Salt Lake City are reporting that certain circulating miRNA molecules can impact the inflammation and fibrosis, and are associating these molecules with the recurrence of atrial fibrillation. The team found low levels of three of the microRNA molecules associated with atrial scarring in a group of patients whose atrial fibrillation came back after ablation. They now believe that in the future these molecules could be used as blood-based screening tools to help determine which patients will benefit from atrial fibrillation therapies.

Over the years, scientists have come to see the important role RNA plays in a myriad of biological and physiological processes, and with extraordinary progress being made in such a short period, novel heart diagnostics and innovative drug therapies will be available within the next decade that can help transform the treatment of cardiac disease.