Science Translational Medicine: Could Gene Therapy Replace Pacemakers?

A new study in dogs reveals two genes responsible for controlling heartbeat rhythm and re-coordinating the action of the heart’s right and left ventricles. These genes may be part of the molecular pathway affected by pacemakers, researchers report in the 14 September issue of the journal Science Translational Medicine.

Using gene therapy or drugs to activate these genes in heart failure patients may help people who cannot use a pacemaker—or possibly replace pacemakers altogether, the study authors propose.

“We have demonstrated that an existing clinical pacemaker therapy is also inducing very unique changes in the heart muscle itself, and in this sense is as complex as any drug, gene, or cell therapy might be,” said David Kass, senior author of the study and professor of cardiology at Johns Hopkins University.

Like rowers in unison, the human heart works most efficiently when its two ventricles contract together simultaneously to pump blood into circulation. In some patients with heart failure, the ventricles beat out of sync, sloshing blood from one side of the heart to the other rather than pumping blood out to the body— an added burden on an already damaged heart.

 

 

 

Video illustration of the failing heart. Electrical activity (left illustration) starts on the right side of the heart and spreads from cell to cell. In a normal heart, the entire ventricle would be activated (turn blue) virtually at the same time. Mechanical motion (right illustration) of the heart’s left ventricle shows shortening starting on the right side of the chamber (blue) and stretching (yellow) on the opposite side that has not been activated.The motion sloshes blood across the heart without ejecting it to the body.

[Video © Science/AAAS]

Soon after its development, researchers realized that an implanted pacemaker, known as CRT therapy, could resynchronize the ventricles and make the heart work better. Today, it is well known that hearts treated with CRT are stronger and healthier. Although CRT is used worldwide, researchers remain in the dark as to what causes the heart to fail in the first place, and why CRT is so effective.

Given the unusual success of CRT, researchers thought perhaps the pacemaker was altering molecular pathways in the heart—and maybe these changes could be translated into another type of heart failure treatment, such as a drug or a gene therapy.

Nuclear scan imaging of right and left heart ventricles in a patient who received successful CRT therapy. Both sides of the left ventricle are moving inward together and the volume inside the heart gets smaller. This result is more ejection of blood to the body.

Mimicking the actions of a pacemaker, Kass and colleagues resynchronized the heartbeats of dogs with heart failure and discovered that restoring regular heartbeat rhythm and rebuilding heart tissue depended on the action of two genes: RGS2 and RGS3. These genes control a set of receptor proteins in the heart.

 

 

 

Nuclear scan imaging of right and left heart ventricles in a patient who received successful CRT therapy. Both sides of the left ventricle are moving inward together and the volume inside the heart gets smaller. This result is more ejection of blood to the body.

The results highlight a key mechanism that potentially explains how CRT works, and is a stepping stone toward developing new approaches to fix the failing heart.

“I think of this process like the Benjamin Button story—it is research done in reverse. Instead of bench to bedside, we started in the clinic with a therapy that works, and are trying to figure out why,” said Kass.

“The work is one of several aspects of CRT that we currently pursuing, but is the furthest along in revealing a molecular mechanism, and the closest to clinical translation.”

Links

Read the abstract, “G?s-Biased ?2-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart,” by David Kass and colleagues.