Cell-accurate optical mapping across the entire developing heart

The heart has a built-in pacemaker that sets the rhythm of the heartbeat. Pacemaker cells produce electrical signals that spread across the heart in a coordinated wave. As each cell receives its signal, ion channels open in its membrane. Calcium ions rush in from the spaces around the cells, triggering the release of more calcium ions from internal stores. The rise in calcium ion levels causes the heart muscle to contract. Standard techniques for studying how the activation process spreads across the heart typically involve removing the organ from the animal. One reason for this is that no microscopy technique had been able to provide the detail needed to observe the activity of individual cells across the whole heart during its activation cycle. Zebrafish embryos have a simple heart with two chambers that can be visually explored because the embryos are transparent. Their hearts are activated in a pattern that has been maintained throughout evolution with principal similarities in many different species. These properties make fish embryos well suited for the non-invasive examination of the heart. Weber, Scherf et al. have studied genetically engineered zebrafish embryos whose heart muscle cells contained a calcium-sensitive fluorophore, using a technique called light sheet microscopy. This method illuminates the heart with a thin sheet of laser light, which causes the fluorescent dye to glow in a way that indicates changes in the concentration of calcium ions in the cells. A fast and sensitive camera detects these signals and stacks of movies are recorded and synchronized, allowing cardiac activation to be mapped in three dimensions as it spreads across the heart. Applying this new technique revealed that different parts of the heart conduct activation signals at different speeds. These speeds finely match the anatomical features of the heart, yielding planar progression of the activation signal over the increasingly complex shape of the developing heart. Weber, Scherf et al. also showed that the heart only requires a handful of pacemaker cells to reliably set the heart’s rhythm. Future modifications to the technique of Weber, Scherf et al. could help us investigate how the heart works in even finer detail. For example, it might reveal how electrical activity, calcium handling, and contraction influence one another, and how they individually and collectively respond to drug treatments. This will help us understand how the normal heart rhythm develops, how it can be modified, and how the heart adapts to changes in its environment, including damage during cardiac disease.