Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity

Additional relevance arises from the fact that mechano-sensitivity of pacemaking may help to explain pacemaker dysfunction in mechanically over- or under-loaded tissue. As the combined contributions of the various underlying oscillatory mechanisms are integrated at the pacemaker cell level into a single output - a train of pacemaker action potentials - we will not adhere to a metaphor that implies separate time-keeping units ('clocks'), and rather focus on cardiac pacemaking as the result of interactions of a set of coupled oscillators, whose individual contributions vary depending on the pathophysiological context. We conclude by considering the utility and limitations of viewing the pacemaker as a coupled system of voltage-, calcium-, and mechanics-modulated oscillators that, by integrating a multitude of inputs, offers the high level of functional redundancy that is vitally important for cardiac automaticity.