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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Haunted-house experience scares up interesting insights on the body’s reaction to threats

The so-called fight-or-flight response is evolution's way of preparing the body to defend itself or flee from a real or perceived threat, like a lion in the tall grass or -- in modern times -- an overdue performance review.

Scientists have struggled to study the effects of genuine threats on people's mental and physical state because of ethical and practical constraints of human lab experiments.

In new research published in the journal Psychological Science, researchers used a haunted-house experience to study participants' subjective and physiological responses to perceived threats in a safe yet immersive environment.

In this haunted-house setting, which included 17 rooms with various threats that formed an uninterrupted experience, the researchers examined how the body responds to threats differently depending on the social context (whether friends were around), features of the threats (whether they were expected), and emotions (whether individuals felt afraid).

"There are a lot of factors that influence how human bodies respond to threat," said Sarah M. Tashjian, of the Division of Humanities and Social Sciences at the California Institute of Technology and lead author of the study. "We found that friend-related emotional contagion, threat predictability, and subjective feelings of fear were all relevant for the body mounting a response."

All of these factors help increase a person's ability to survive when under threat, but in the study, each had slightly different influences, which demonstrate the dynamic nature of the sympathetic nervous system.

To study the effects of frightening experiences, previous studies used scary images, mild electric shocks, or loud noises. In the current study, 156 participants went through the haunted house in small groups. During the 30-minute experience, they encountered situations that mimicked the threat of suffocation, an oncoming speeding car, and a volley of shots (with pellets) from a firing squad.

Participants wore real-time physiological-monitoring wristbands to measure their electrodermal activity, or sweat-induced changes in the skin's electrical characteristics, including skin conductance level and skin conductance response.

Before visiting the haunted house, participants rated their expected fear on a scale from 1 to 10. Afterward, they rated their experienced fear level on the same scale. From these data, four factors were examined, including group composition, threat imminence, intrapersonal factors of fear, and a "baseline orienting response," or the participant's sensitivity to threats.

Results showed a positive association between the number of friends in a group and tonic arousal, which reflects the body's overall physical response to stress or emotion. On average, the more friends that participants had with them while touring the haunted house, the higher their physical response.

"We interpreted this to reflect fear contagion -- if your friends are around, your body picks up on their signals and has a higher level of arousal even in the absence of specific scares or startles," Tashjian said. "In the lab, it is difficult to study the effects of groups on physiology."

Studies usually involve testing one person at a time or, at most, pairs of friends. In this study, the researchers had the unique opportunity to study how being in groups with different mixes of friends and strangers affected people's perceptions of threat.

The researchers also noted positive associations between unexpected attacks, subjective fear, and phasic frequency. Phasic effects are rapid changes the body experiences as it responds to an event. Individuals who felt the most afraid during the haunted house had more peaks in these responses. "If your body is more cued-in to the threatening event, you also psychologically feel more fear," Tashjian said.

Other findings revealed that participants with an initially strong response to the first room of the haunted house showed increased responses as they visited other rooms. Participants with more frequent responses in the first room showed decreased responses over time.

"From a results perspective, this study is distinct because we measure multiple aspects of skin conductance, including slow responding, rapid responding, frequency of responses, and level of responses," Tashjian explained. "Most studies use just one of these measures, which limits our understanding of how dynamic the sympathetic nervous system is and how different factors exert different influences on biology."

She added that the research is a "major advance for cognitive and social psychology," because it furthers the understanding of how "naturalistic contexts," such as the immersive haunted house experience, influence the body's response to threats. Also significant is the finding that friends amplify the physical response.

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