Beat to beat Ca2+-dependent regulation of pacemaker cell rate and rhythm

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Failure of generation of automaticity and conduction of electrical activity within the heart becomes progressively more common as we age and is associated with variety of 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 heart rate is around 75. LCS Scientists build a team who are on call 24hours/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 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 cost $24B annual in the USA alone. Recently, a significant long-range power law correlation has been identified between the periodicity of cardiac pacemaker cell clocks, heart rate, and body mass across various species, ranging from mice to humans. This correlation encompasses the integrated local Ca2+ releases of Ca2+ clock self-order (synchronize) during action potential (AP) ignition in single sinoatrial node (SAN) cells. Isolated from diverse species, these cells not only exhibit linear scaling with the diverse range of frequencies across species but also with EKG RR intervals in vivo. Moreover, this scaling is allometrically related to the broad range of body masses across species. This power law behavior represents the trans-species similarity of self-ordered criticality mechanisms of pacemaker cell molecular function that governs heart rate (HR). On the tissue level, a recent discovery of cytoarchitecture resembling neurons in the sinoatrial node (SAN) pacemaker cells requires a new paradigm of impulse generation. As in the single pacemaker cells, spontaneous, stochastic local Ca2+ oscillations (LCOs), which occur heterogeneously in phase, frequency, and amplitude throughout the SAN produce periodic impulses. How these cells within the SAN tissue synchronize to create rhythmic impulses was an unsolved problem. We discovered a network of functional pacemaker cell clusters within SAN, in which LCOs substantially differed in phase. These functional clusters form a unique solution of spatiotemporal synchronization of their Ca2+ dynamics behavior via phase shift, contributing differentially to the amplitude and kinetics of the global SAN Ca2+ impulse at different times during each impulse. Autonomic receptor blockers desynchronize LCO phases among clusters, resulting in fractionation of integrated Ca2+ signal, leading to a marked increase in the mean SAN impulse intervals and its variability.