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. Recently we discovered a long-range correlation between periodicity of cardiac pacemaker cell clocks, heart rate and body mass: from mice to humans. Specifically, integrated local Ca2+ releases of Ca2+ clock during action potential (AP) ignition in single SAN cells, isolated from diverse species (ranged from mouse to humans) not only scales linearly to the diverse range of AP cycles across species in these cells, but also to EKG RR intervals in vivo, and furthermore scales allometrically to the broad range of body masses across species, revealing novel layers of long-range universal scaling that links microscopic subcellular mechanisms to macroscopic structural properties among diverse mammals.
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