Failure of generation of automaticity and conduction of electrical activity within the heart becomes progressively more common as we age and is associated with a variety of cardiovascular and non-cardiovascular diseases. A major barrier to progress in the pacemaker field is a dearth of research in human hearts although the mouse has a resting heart rate of around 750 beats per minute while human resting heart rate is around 75. LCS Scientists built a team who are on call 24 hours/day, 7 days/week to respond with a regular supply of fresh human hearts from brain-dead donors. Similar to animals, a Ca2+ clock couples to a membrane clock to drive normal automaticity in single isolated human cardiac pacemaker cells. Clock uncoupling in human pacemaker cells as a putative mechanism of sinus node arrest, the endgame of human heart. These discoveries not only generalize the coupled-clock system paradigm from mice to humans but also led us to view clock coupling as a novel therapeutic target to develop a biological pacemaker. This cell-based therapy has a potential to reduce the necessity of conventional electrical pacemaker device implantation, which costs $24B annually in the USA alone.
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