Detailed map of the heart provides new insights into cardiac health and disease

In a new study, published today (12 July) in Nature, researchers have produced the most detailed and comprehensive human Heart Cell Atlas to date, including the specialised tissue of the cardiac conduction system -- where the heartbeat originates.

The multi-centre team is led by the Wellcome Sanger Institute and the National Heart and Lung Institute at Imperial College London, and has also presented a new drug-repurposing computational tool called Drug2cell, which can provide insights into the effects of drugs on heart rate.

This study is part of the international Human Cell Atlas* (HCA) initiative, which is mapping every cell type in the human body, to transform our understanding of health and disease, and will form the foundation for a fully integrated HCA Human Heart Cell Atlas.

Charting eight regions of the human heart, the work describes 75 different cell states including the cells of the cardiac conduction system -- the group of cells responsible for the heartbeat -- not understood at such a detailed level in humans before. The human cardiac conduction system, the heart's 'wiring', sends electrical impulses from the top to the bottom of the heart and coordinates the heartbeat.

By using spatial transcriptomics, which gives a "map" of where cells sit within a tissue, researchers were also able to understand how these cells communicate with each other for the first time. This map acts as a molecular guidebook, showing what healthy cells look like, and providing a crucial reference to understand what goes wrong in disease. The findings will help understand diseases such as those affecting the heart rhythm.

The assembly of a Human Heart Cell Atlas is key given that cardiovascular diseases are the leading cause of death globally. Around 20,000 electronic pacemakers are implanted each year in the UK for these disorders. These can be ineffective and are prone to complications and side-effects. Understanding the biology of the cells of the conduction system and how they differ from muscle cells paves the way to therapies to boost cardiac health and develop targeted treatments for arrhythmias.

The team also presents a new computational tool called Drug2cell. The tool can predict drug targets as well as drug side effects. It leverages single-cell profiles and the 19 million drug-target interactions in the EMBL-EBI ChEMBL database.

Unexpectedly, this tool identified that pacemaker cells express the target of certain medications, such as GLP1 drugs, which are used for diabetes and weight loss and are known to increase the heart rate as a side-effect, the mechanism of which was unclear. This study suggests that the increase in heart rate might be partly due to a direct action of these drugs on pacemaker cells, a finding the team also showed in an experimental stem cell model of pacemaker cells.

Dr James Cranley, joint first author, a cardiologist specialising in heart rhythm disorders and PhD student at the Wellcome Sanger Institute, said: "The cardiac conduction system is critical for the regular and coordinated beating of our hearts, yet the cells which make it up are poorly understood. This study sheds new light by defining the profiles of these cells, as well as the multicellular niches they inhabit. This deeper understanding opens the door to better, targeted anti-arrhythmic therapies in the future."

Dr Kazumasa Kanemaru, joint first author and Postdoctoral Fellow in the Gene Expression Genomics team at the Wellcome Sanger Institute, said: "The mechanism of activating and suppressing pacemaker cell genes is not clear, especially in humans. This is important for improving cell therapy to facilitate the production of pacemaker cells or to prevent the excessive spontaneous firing of cells. By understanding these cells at an individual genetic level, we can potentially develop new ways to improve heart treatments."

The study unearthed an unexpected discovery: a close relationship between conduction system cells and glial cells. Glial cells are part of the nervous system and are traditionally found in the brain. They have been explored very little in the heart. This research suggests that glial cells are in physical contact with conduction system cells and may play an important supporting role: communicating with the pacemaker cells, guiding nerve endings to them, and supporting their release of glutamate, a neurotransmitter.

Another key finding of the study is an immune structure on the heart's outer surface. This contains plasma cells, which release antibodies into the space around the heart to prevent infection from the nearby lungs. The researchers also identified a cellular niche enriching for a hormone that could be interpreted as an early warning sign of heart failure.

Dr Michela Noseda, senior Lecturer in Cardiac Molecular Pathology at the National Heart and Lung Institute, Imperial College London, a Coordinator of the Human Cell Atlas Heart BioNetwork and a lead author, said: "We often don't fully know what impact a new treatment will have on the heart and its electrical impulses -- this can mean a drug is withdrawn or fails to make it to the market. Our team developed the Drug2cell platform to improve how we evaluate new treatments and how they can affect our hearts, and potentially other tissues too. This could provide us with an invaluable tool to identify new drugs which target specific cells, as well as help to predict any potential side-effects early on in drug development."

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, which part-funded the research with the German Centre for Cardiovascular Research (DZHK), said: "Using cutting-edge technologies, this research provides further intricate detail about the cells that make up specialised regions of the human heart and how those cells communicate with each other. The new findings on the heart's electrical conduction system and its regulation are likely to open up new approaches to preventing and treating rhythm disturbances that can impair the heart's function and may even become life-threatening."

"International collaboration is key to scientific progress. This impactful study and other discoveries from the broader Human Cell Atlas initiative are excellent examples of what can be achieved when the international research community works together across borders. Our combined efforts can ultimately produce better outcomes for patients worldwide."

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Tweaked genes borrowed from bacteria excite heart cells in live mice

Biomedical engineers at Duke University have demonstrated a gene therapy that helps heart muscle cells electrically activate in live mice. The first demonstration of its kind, the approach features engineered bacterial genes that code for sodium ion channels and could lead to therapies to treat a wide variety of electrical heart diseases and disorders.

The results appeared online February 2 in the journal Nature Communications.

"We were able to improve how well heart muscle cells can initiate and spread electrical activity, which is hard to accomplish with drugs or other tools," said Nenad Bursac, professor of biomedical engineering at Duke. "The method we used to deliver genes in heart muscle cells of mice has been previously shown to persist for a long time, which means it could effectively help hearts that struggle to beat as regularly as they should."

Sodium-ion channels are proteins in the outer membranes of electrically excitable cells, such as heart or brain cells, that transmit electrical charges into the cell. In the heart, these channels tell muscle cells when to contract and pass the instruction along so that the organ pumps blood as a cohesive unit. Damaged heart cells, however, whether from disease or trauma, often lose all or part of their ability to transmit these signals and join the effort.

One approach researchers can take to restoring this functionality is gene therapy. By delivering the genes responsible for creating sodium channel proteins, the technique can produce more ion channels in the diseased cells to help boost their activity.

In mammals, sodium channel genes are unfortunately too large to fit within the viruses currently used in modern gene therapies in humans. To skirt this issue, Bursac and his laboratory instead turned to smaller genes that code for similar sodium ion channels in bacteria. While these bacterial genes are different than their human counterparts, evolution has conserved many similarities in the channel design since multi-cellular organisms diverged from bacteria hundreds of millions of years ago.

Several years ago, Hung Nguyen, a former doctoral student in Bursac's laboratory who now works for Fujifilm Diosynth Biotechnologies, mutated these bacterial genes so that the channels they encode could become active in human cells. In the new work, current doctoral student Tianyu Wu further optimized the content of the genes and combined them with a "promoter" that exclusively restricts channel production to heart muscle cells. The researchers then tested their approach by delivering a virus loaded with the bacterial gene into veins of a mouse to spread throughout the body.

"We worked to find where the sodium ion channels were actually formed, and, as we hoped, we found that they only went into the working muscle cells of the heart within the atria and ventricles," Wu said. "We also found that they did not end up in the heart cells that originate the heartbeat, which we also wanted to avoid."

This gene therapy approach only delivers extra genes within a cell; it does not attempt to cut out, replace or rewrite the existing DNA in any way. Scientists believe these types of delivered genes make proteins while floating freely within the cell, making use of the existing biochemical machinery. Previous research with this viral gene delivery approach suggests the transplanted genes should remain active for many years.

As a proof of concept, tests on cells in a laboratory setting suggest that the treatment improves electrical excitability enough to prevent human abnormalities like arrhythmias. Within live mice, the results demonstrate that the sodium ion channels are active in the hearts, showing trends toward improved excitability. However, further tests are needed to measure how much of an improvement is made on the whole-heart level, and whether it is enough to rescue electrical function in damaged or diseased heart tissue to be used as a viable treatment.

Moving forward, the researchers have already identified different bacterial sodium channel genes that work better in preliminary benchtop studies. The team is also working with the laboratories of Craig Henriquez, professor of biomedical engineering at Duke, and Andrew Landstrom, director of the Duke Pediatric Research Scholars Program, to test the ability of these genes to restore heart functionality in mouse models that mimic human heart diseases.

Read more at Science Daily