Setting the pace – looking at the first heartbeat and beyond

The heart is the first organ to form during embryonic development. It’s key role in providing proper blood supply to the developing embryo relies on the coordinated contraction of cardiomyocytes. The timing of the contractions is dependent on pacemaker and conductive cells, which arise much later in fetal development. However, we know that cardiomyocytes can spontaneously generate calcium currents and contract before any of the pacemaker cells are present, both in vivo and in vitro. 

Jia et al have shown, using a combination of zebrafish embryos and mathematical modelling, that the heart undergoes a transition from stochastic contraction of individual cardiomyocytes to a synchronised beat. The authors used transgenic lines to visualise calcium activity in the embryonic heart, then applied high-speed microscopy to measure these calcium waves. They found that in the developing heart tube, there’s initial transient release of calcium, followed by the start of an irregular heartbeat that then transitions to a more regular heartbeat, with rhythmicity taken over by pacemaker cells later in development.

Through mathematical modeling, they were able to generate a model that closely mimicked the observed Calcium dynamics, which they then tested by loss-of-function analyses using chemical rather than genetic approaches. Furthermore, they proved that electrical depolarisation of the plasma membrane of cardiomyocytes precedes calcium release, and even more interestingly, that they could ectopically depolarise and induce calcium waves earlier in development. This shows that cardiomyocytes are already electrically coupled before the first calcium wave, and that the first wave sets up an oscillatory loop that converges on a specific periodicity.

Finally, the authors shows that there’s no pre-defined region of initiation of the calcium waves, and that upon inhibition of calcium in those cells, a new region of initiation would spontaneously arise. Surprisingly, in the complimentary experiment where a second group of cells was induced to initiate calcium waves, only when this secondary group of cells was pacing at a higher frequency than the initial group of cells, would the secondary calcium waves take over heartbeat pacing. 

The painstaking description of these process at both the cellular and bioelectrical levels opens a myriad new questions: how conserved is this process? Several species have different heart topologies, how would this process work in those? What determines the first depolarisation in cardiomyocytes? Is the system indeed self-organising from an early, noise-rich state? Are there any advantages to this process?