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

Cardiac pacemaker cells exhibit spontaneous, rhythmic electrical excitation, termed automaticity. This automatic initiation of action potentials requires spontaneous diastolic depolarisation, whose rate determines normal rhythm generation in the heart. Pacemaker mechanisms have been split recently into: (i) cyclic changes in trans-sarcolemmal ion flows (termed the 'membrane-clock'), and (ii) rhythmic intracellular calcium cycling (the 'calcium-clock'). These two 'clocks'undoubtedly interact, as trans-sarcolemmal currents involved in pacemaking include calcium-carrying mechanisms, while intracellular calcium cycling requires trans-sarcolemmal ion flux as the mechanism by which it affects membrane potential. The split into separate 'clocks' is, therefore, somewhat arbitrary. Nonetheless, the 'clock' metaphor has been conceptually stimulating, in particular since there is evidence to support the view that either 'clock'could be sufficient in principle to set the rate of pacemaker activation. Of course, the same has also been shown for sub-sets of 'membrane-clock' ion currents, illustrating the redundancy of mechanisms involved in maintaining such basic functionality as the heartbeat, a theme that is common for vital physiological systems. Following the conceptual path of identifying individual groups of sub-mechanisms, it is important to remember that the heart is able to adapt pacemaker rate to changes in haemodynamic load, even after isolation or transplantation, and on a beat-by-beat basis. Neither the 'membrane-' nor the 'calcium-clock' do, as such, inherently account for this rapid adaptation to circulatory demand (cellular Ca²⁺ balance changes over multiple beats, while variation of sarcolemmal ion channel presence takes even longer). This suggests that a third set of mechanisms must be involved in setting the pace. These mechanisms are characterised by their sensitivity to the cyclically changing mechanical environment, and--in analogy to the above terminology--this might be considered a 'mechanics-clock'. In this review, we discuss possible roles of mechano-sensitive mechanisms for the entrainment of membrane current dynamics and calcium-handling. This can occur directly via stretch-activation of mechano-sensitive ion channels in the sarcolemma and/or in intracellular membrane compartments, as well as by modulation of 'standard' components of the 'membrane-' or 'calcium-clock'. Together, these mechanisms allow rapid adaptation to changes in haemodynamic load, on a beat-by-beat basis. 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.