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Secrets of the coupled clock behind the heart's natural pacemaker cells

Study points to potential new therapies that could replace implanted pacemakers

A new study gives insights into the complex synchronization of two cellular clocks that help regulate the human heartbeat, pointing toward new potential therapeutic mechanisms for heart rhythm disorders that require the implantation of artificial pacemakers.

The findings by a team led by Dr. Edward Lakatta, chief of the NIA IRP's Laboratory of Cardiovascular Science, were published in the June 12 issue of Science Signaling.

Our hearts are always exercising, even when our bodies are at rest, and automatically pump harder and faster during strenuous activity. In a healthy heart, a specialized group of cells in the wall of the right atrium called the sinoatrial node (SA node) spontaneously produce electrical impulses that travel through the organ's conduction system to make it contract regularly. Thus, the SA node acts as the body's natural pacemaker, setting the rhythm of a normal beat.

Malfunctions in the SA node's electrical signaling network can lead to abnormal conditions such as sick sinus syndrome, a too-slow or irregular heartbeat, which are typically treated by installing an artificial, permanent pacemaker. SA node problems are more common in the elderly as the cardiac system's conductive network scars and degenerates with age.

The dearth of research regarding cardiac pacemaking using human cells has precluded the development of a next-generation, device-free, and more cost-efficient treatment that may replace the artificial electrical pacemaker implantation.

While most research in this area has used animal heart cells, this team used human sinoatrial nodal pacemaker cells (SANC) from donated heart tissue. They found that a calcium (Ca 2+) clock was coupled to the SANC's natural surface membrane molecules' electric producing clock (M clock).A chart of the synchronized beats of pacemaker cells.

The researchers demonstrated that cyclic adenosine monophosphate (cAMP)—a derivative of adenosinetriphosphate (ATP) important in intracellular signaling—enhances the function of M and Ca2+ clocks by protein kinase A-mediated phosphorylation. This cAMP boost then directly accelerates the speed of the Ca2+ clock's ticking.

The team went on to show that the stimulation of Beta-adrenergic (Beta-AR)–receptors—receptors important in binding with adrenaline and epinephrine for processes like muscle relaxation and bronchial dilation—play an essential role in the heart's pacemaking by regulating the intracellular cAMP production. Beta-AR receptors were also found to accelerate the SANC's spontaneous electrical impulse generation via enhancing the coupling between the Ca2+ and M clocks.

The scientists then looked at other SANC samples that mimicked an arrested, or stopped heartbeat, and found that by increasing cAMP concentrations with the Beta-AR stimulation, they could restore the spontaneous rhythms and electric charges required to resume normal heartbeats.

This work unveils the complex and highly interdependent mechanisms of the heartbeat and shows promise for new cellular-level therapeutic targets that could someday offer alternatives to artificial pacemaker treatment in people with heart rhythm disorders.

Reference:

Tsutsui K, Monfredi OJ, Tagirova-Sirenko SG, Maltseva LA, Bychkov R, Kim MS, Ziman BD, Tarasov KV, Tarasova YS, Zhang J, Wang M, Maltsev AV, Brennan JA, Efimov IR, Stern MD, Maltsev VA, Lakatta EG. A coupled clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Science Signaling. 11, eaap7608(2018)