When does our heart first start to beat?

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Originally published at bhf.org.uk.

Until now, researchers thought that the first time our heart muscle contracted to beat was at 8 days after conception, in mice or around day 21 of a human pregnancy.

Now, a team funded by the BHF at the University of Oxford has demonstrated earlier beating of the heart in mouse embryos which, if extrapolated to the human heart, suggests beating as early as 16 days after conception

Antonio Miranda, a BHF-funded PhD student at the University of Oxford, was part of the team responsible for these new findings. Here, he tells us exactly why this work is so important to the fight against heart disease.

Having a healthy and functioning heart is not only vital during adulthood but also before birth. The heart is the first organ to form and function as the baby develops in the womb and this function is essential for the survival and formation of the foetus.

Research into how the heart forms would be useful, not only to gain a better understanding of specific types of heart tissues, but also to better understand how congenital heart disease arises.

Treating the failing heart

But learning about the tiniest of hearts is not only helpful for babies with congenital heart disease, it is also helpful for adults with heart failure, where the heart is less able to pump blood properly around the body.

While many advances have been made to treat heart attacks and save lives, there is no way to prevent or treat the damage that is left behind. This can lead to heart failure and ultimately the need for a heart transplant

Heart failure is one of the major challenges in modern medicine. Regenerative medicine, more precisely stem cell therapies, offer the promise of overcoming some of these challenges by attempting to directly repair the damage to the heart caused during a heart attack.

The trouble with mending broken hearts

Thanks to investment in the field of regenerative medicine, such as the BHF’s Mending Broken Hearts Appeal, we have greatly increased our understanding of how to best manipulate stem cells

While in other contexts there are already a few successful applications for using stem cells, the heart has proven to be a challenge.

One of the main difficulties with repairing the heart is that the new cells need to connect and synchronise their beating with the existing tissue. Just like making an origami, without having the right set of instructions it becomes a much more difficult endeavour to make a heart, or even parts of the heart, with the right form and function.

Writing the instruction manual for mending the broken heart

To overcome this hurdle, we need to uncover the ‘instructions’ necessary to transform stem cells into fully functional heart muscle cells, that resemble the ones lost in damaged areas.

Stem cell applications basically try to recreate — in a dish in a lab — steps that take place in cells during the development of an embryo. Directly studying and visualising these steps in the embryo and then trying to replicate them in a dish is the best way to push stem cell applications forward.

Just like having instructions makes it easier to make origami (top row), learning how to read the instructions to achieve each step of heart development (bottom row, stages of mouse heart development), will bring us closer to one day being able to make a heart in a dish.

Looking at heart development under the microscope

One of the main focuses of my work at the University of Oxford, under the supervision of Professor Shankar Srinivas, has been to image some of the steps involved in heart development, in order to gain as many insights as possible.

An obstacle to this has been the limited capabilities of traditional microscopes. But we’ve been able to use a technology called ‘lightsheet microscopy’ — an exciting, relatively new way of imaging that opens up new possibilities when looking at embryos. It allows us to image larger samples in great detail and from several angles, in order to build up a 3D image of the embryo.

Mouse embryonic heart at 12.5 days of gestations imaged with a lightsheet microscope. All heart muscle cells are outlined in orange, while cells of the inner layer of the heart (endocardium) are also marked in cyan.

While snapshots can provide a lot of information, filming changes happening in real-time can give us even more insights. Lightsheet microscopy is ideal for live-imaging, but it doesn’t allow us to easily image several embryos at the same time or to easily change the conditions to which the embryos are exposed.

Unlike lightsheet microscopy, a more established technique called confocal microscopy, which is slower in capturing images, allows us to image several embryos at the same time, with higher details.

Tracking calcium in the heartbeat

https://medium.com/media/8d3ca9e0aeebfa757e344e912c76a0e2/href

One of the main requirements for a heart to beat is a synchronised and reliable change in the amount of calcium inside the cells.

For a paper published in eLife, we used confocal microscopy to make movies of the first heartbeats, and changes in the amount of cellular calcium in heart muscle cells, during mouse embryo development.

Our major finding was the observation that, prior to the initiation of the heartbeat, heart muscle cells individually display slow changes in the amount of calcium. We called these changes ‘Spontaneous Asynchronous Calcium Oscillations’ or SACOs. Using pharmacological drugs, we found that impairing these SACOs not only affects the initiation of the heartbeat but also the subsequent formation of the heart.

This discovery now provides us with a system that we can use to understand how heart muscle cells synchronize for the first time in order to start a rhythmic beating. Understanding how this process works may help us get closer to discovering techniques for how to successfully incorporate stem cells into a damaged heart.

We need to understand more than the genetics

A lot of research has been done in trying to understand the genetic instructions in stem cells that allow them to become specialist cells such as heart cells. But it is important to note that genetics alone is not enough

If you blend a chicken egg, that egg is never going to form a chicken, even though all the genes are still there. Just like Humpty Dumpty, not even all the king’s horses and all the king’s men could put it back together again.

Changes in the amount of calcium inside the cells is shown with rainbow colours. Initially cells seem to behave independently from each other, but as they synchronise, the heart starts to beat rhythmically.

With the ongoing development of imaging techniques, it is becoming more feasible to investigate the processes involved in embryo development. Studies that aim to image in detail these processes complement the genetic studies in order to understand which are the signals and the 3D environments required that lead to the emergence of each cell type.

This could be useful in not just discovering strategies to repair the heart and treat heart failure, but in regenerative medicine as a whole. It is an exciting time to be in this field of research and hopefully by better understanding the origins of the first heartbeat, we can make a big contribution to the BHF’s fight for every heartbeat.

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When does our heart first start to beat? was originally published in British Heart Foundation on Medium, where people are continuing the conversation by highlighting and responding to this story.