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SPOTLIGHTS
Mapping the Intricacies of the Heart
by Deborah Seah

Cardiovascular disease is one of the leading causes of death worldwide, representing 31 percent of all global deaths. Heart disease is one contributing factor to these statistics. To guide more in-depth research of the heart and the development of disease, scientists have set out to chart cellular and genetic maps of the human heart.

A quick Google search on the word “mapping” will give you multiple definitions of the word. One most applicable to our current topic would be; to record in detail the spatial distribution of [something]. Much like drawing out maps of cities, scientists have tapped into this concept to make progress in the field of research. An example of scientists creating a “map” would be the completion of the human genome project. This international effort started in 1990 and completed in 2003 brought together many researchers to achieve a complete sequence and map of all the human genes. In turn, their work helped to guide the research and development of genetics and how it can be applied to developing tools and increase understanding disease mechanisms. Another organ that scientists have been trying to map is the human brain. As a major step towards this effort, researchers from Janelia Research Campus, part of the Howard Hughes Medical Institute announced the successful mapping of all the neurons in an adult drosophila central brain.

One main goal of mapping is to have a better look into how each component occupies space and relates to the next. Having a detailed map would guide the paths towards analysing how each part of the organ works together and how they are affected by stress or disease. This was what scientists set out to achieve when mapping the human genome and the brain. This would also apply when scientists began work on mapping the human heart. Charting out these intricate components of the heart will therefore help researchers to navigate their way in understanding what goes wrong in disease for better targeted treatments.

Within an individual’s lifetime, the human heart is capable of generating an average of two to three million life-sustaining heartbeats in the human body, pumping blood for the delivery of essential nutrients and removal of waste products to and from the rest of the body for survival. Each heartbeat follows a complex synchronized sequence of events that involves various types of cells and molecular pathways in different parts of the heart. Disruption in any part of these events can result in cardiovascular disease.

Cardiac Mapping

At the macro-level, cardiac mapping refers to the process of identifying the temporal and spatial distributions of electrical potentials of heart muscle during a particular heart rhythm. Cardiac mapping uses medical devices such as the electrocardiogram (EKG) or by an invasive catheter mapping procedure. These methods will provide information on the heart’s electrical activity, or even allowing for the mapping of the location of any heart rhythm disorders or cardiac arrhythmias.

Mapping of the heart at the macro-level is therefore limited as it does not dive deeper into the cellular and molecular mechanisms that would go awry during cardiovascular disease.

Cellular and Molecular Map of the Heart

Zooming in to the cellular and molecular level, a recent work published shows a highly-detailed map of the human heart.

Scientists from different research institutes which include Harvard Medical School, Brigham and Women's Hospital, the Wellcome Sanger Institute, Max Delbrück Center for Molecular Medicine (MDC) in Germany, Imperial College London and other global collaborators recently published their work on developing an atlas of all the human heart cells, the Heart Cell Atlas. This research was part of the Human Cell Atlas initiative to map every cell type in the human body.

Akin to creating an encyclopaedia of all the heart cells, this work will help to propel detailed appreciation of the molecular processes inside the cells of a healthy human heart. This work is vital when researching on the mechanisms behind the pathogenesis of heart disease. The scientists suggested that creation of the human heart atlas will generate knowledge of improvements in treatment strategies for various types of cardiovascular disease.

"Millions of people are undergoing treatments for cardiovascular diseases. Understanding the healthy heart will help us understand interactions between cell types and cell states that can allow lifelong function and how these differ in diseases," said study co-senior author Christine Seidman, professor of medicine in the Blavatnik Institute at Harvard Medical School and a cardiovascular geneticist at Brigham and Women's.

“Ultimately, these fundamental insights may suggest specific targets that can lead to individualized therapies in the future, creating personalized medicines for heart disease and improving the effectiveness of treatments for each patient,” Seidman said.

The team of scientists used nearly 500,000 individual cells and cell nuclei from six different regions of the heart obtained from 14 healthy donated hearts. They then applied a combination of single-cell analysis, machine learning and imaging techniques to examine further into the workings of the genes in each cell. The team also discovered that each area of the heart had specific subsets of cells – pointing to different developmental origins and providing insight on how these cells could respond to treatment.

“This project marks the beginning of new understandings into how the heart is built from single cells, many with different cell states,” said study co-first author Daniel Reichart, research fellow in genetics at Harvard Medical School.

“With knowledge of the regional differences throughout the heart, we can begin to consider the effects of age, exercise and disease and help push the field of cardiology toward the era of precision medicine.” He added.

Sarah Teichmann of the Wellcome Sanger Institute, co-senior author of the study and co-chair of the Human Cell Atlas Organising Committee described this collaborative effort like creating a “Google map” of the human body.

The scientists also analysed in detail the blood vessels of the heart and added this information to the atlas for a better view of how cells in these blood vessels adapt to changes in their microenvironment at different locations.

The atlas of the human heart is now provided freely through a website, available for all researchers and those who are interested. Further to the current work, the team will also be looking to determine whether heart cells can be induced for self-repair.

In another effort to identify important molecular interactions involved in heart disease, Professor Roger Foo of the Department of Medicine, NUS Yong Loo Lin School of Medicine and Senior Consultant at the National University Heart Centre, NUH led a research team to develop the first heart genomic map. This map would include all the genes in the human heart and the mechanisms that control them.

The genomic map developed by the team from the National University of Singapore, Yong Loo Lin School of Medicine demonstrated the locations of particular “switches” that could play key roles in the control of genes in heart disease.

“Our genomic map would help to make sense of the human genome by highlighting the sections and interactions that are relevant for various organs, such as the heart. This could make it possible to analyse the functions of the entire genome someday,” said Professor Foo.

Added Asst Prof Anene-Nzelu that, “Using the genomic map, we were also able to identify new genes associated with heart disease. These could serve as targets for the development of novel treatments for these diseases.”

Generating a cellular and molecular map of the human heart will therefore accelerate the understanding of the complex intricacies of how the heart works. A better analysis into the workings of a healthy heart from a comprehensive map can help researchers plot and identify key mechanisms during the pathogenesis of cardiovascular disease at the cellular and molecular levels. This could pave the way for more precise and targeted treatments for cardiovascular disease based on the cell type and genes involved.

References:

  1. World Health Organization, Cardiovascular disease fact sheet. (17 May 2017). Retrieved from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

  2. Toga, A. W., Clark, K. A., Thompson, P. M., Shattuck, D. W., & Van Horn, J. D. (2012). Mapping the human connectome. Neurosurgery, 71(1), 1–5. https://doi.org/10.1227/NEU.0b013e318258e9ff

  3. Litviˇnuková, M., Talavera-López, C., Maatz, H., Reichart, D., et. al. (2020). Cells of the adult human heart. Nature. https://doi.org/10.1038/s41586-020-2797-4

  4. Human Cell Atlas, Heart Cell Atlas. (n.d). Retrieved from: https://www.heartcellatlas.org/#
 
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