Mechanism of age-associated failure of the heart’s pacemaker

2017

Challenge

Failure of initiation and conduction of electrical activity within the heart increases as we age, and this is associated with a variety of cardiovascular and non-cardiovascular diseases. Treatment of such electrical failure of the heart requires implantation of an electronic pacemaker device, which is a costly and imperfect solution. Consequently, scientists are working towards the creation of a ‘biological pacemaker,’ a superior and less-invasive treatment that would reawaken the intrinsic electrical functions of the heart’s cells. However, a major barrier to progress in this field is a dearth of research in human hearts.

Advance

IRP researchers led by Edward G. Lakatta, M.D., built a team that works around the clock, seven days per week to supply researchers with fresh human hearts from brain-dead donors, allowing scientists to isolate fresh cardiac cells for their studies. This team discovered that regular, timed release of calcium ions (a ‘calcium clock’) in human cardiac pacemaker cells interacts with electrically conductive molecules on the cells’ surfaces (a ‘membrane clock’) to drive normal electrical heart rhythms. The team went on to show that uncoupling these two internal clocks in human pacemaker cells could be a potential mechanism of sinus node arrest, a pause in the heart’s rhythm that can eventually cause the heart to stop beating.

Impact

These discoveries not only confirm the human relevance of previous discoveries about the heart’s ‘coupled-clock system’ in mice, but also suggest clock coupling as a novel therapeutic target to develop a biological pacemaker. Such cell-based therapy has the potential to reduce the necessity of conventional electrical pacemaker device implantation, which costs $24 billion annually in the U.S. alone.

Publications

Tsutsui K, Monfredi O, Tagirova S, Maltseva L, Bychkov R, Kim M, Ziman B, Tarasov K, Tarasova Y, Zhang J, Wang M, Maltsev A, Brennan J, Efimov IR, Stern M, Maltsev V, Lakatta E. (2018). A coupled-clock system drives automaticity of human sinoatrial nodal pacemaker cells. Sci Signaling. 11(534).