Macrophages Found to be the Source of a Ripple Effect in the Development of a Life-Threatening Heart Condition

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A new study published in the Journal of Experimental Medicine from the Nahrendorf lab in the Center for Systems Biology at Massachusetts General Hospital shows a classic real-life example of the ripple effect.

Like a pebble thrown into a still body of water, immune cells called macrophages – white blood cells primarily known for removing cellular debris, pathogens and other unwanted materials – cause a series of responses in the heart that can eventually compromise the organ’s ability to provide enough oxygenated blood to the body.

These new findings advance understanding of macrophages’ role in the development of a type of heart condition known as heart failure with preserved ejection fraction, or HFpEF, and provide new insight into how to prevent development of this life-threatening disease.

What is HFpEF?

Heart failure is a condition in which the heart muscle is unable to pump enough blood to meet the body’s needs. The volume of blood pumped by the heart is determined by two factors:

  1. Contraction of the heart, which sends blood to the rest of the body, and
  2. Relaxation of the heart, which allows it to fill with blood

In the case of HFpEF, the heart contracts normally but is unable to relax and allow blood to flow into the left ventricle, thus reducing the amount of blood available to pump into the aorta.

The hearts of patients with HFpEF pump a limited amount of blood with each beat which can result in symptoms like decreased exercise tolerance, fatigue, and the accumulation of blood/fluid in the lungs, veins and tissues of the body. Fluid backs up into these areas because the heart is not able to process fluids effectively. The buildup of fluid in the lungs can result in shortness of breath while fluid in the legs causes swelling.

HFpEF accounts for around half of all human heart failure cases and has a high mortality rate — the 5-year survival of HFpEF is 35%, which is worse than most cancers.

Because HFpEF is difficult to treat and carries a poor prognosis once patients start showing symptoms, preventing HFpEF and limiting disease progression is critical.

Macrophages in the heart

Macrophages play an important role in normal cardiac function. Recent research from the Nahrendorf lab found that these white blood cells help heart muscle cells maintain a steady heartbeat.

Macrophages can also be found in high numbers around inflamed or diseased hearts to help heal tissue. They are given a helping hand by cells called fibroblasts, which generate connective tissue and collagen to help repair and remodel cardiac tissue.

However, too many fibroblasts can do more harm than good, at least when it comes to heart repair. An overabundance of fibroblasts can cause the tissue to stiffen and reduce the heart’s ability to relax and refill properly. For that reason, fibroblasts are considered a major contributor to the development of HFpEF.

Despite this known role for fibroblasts, it has remained unclear if and how macrophages are involved in the development of HFpEF.

Discovery of a ripple effect

In their most recent study, a research team from the Nahrendorf lab led by Maarten Hulsmans, PhD, a research fellow in the Center for Systems Biology, sought to further define macrophages’ role in the hopes of identifying a new therapeutic target to prevent HFpEF.

The team examined cardiac macrophages in two mouse models that had developed a similar impaired relaxation of the heart muscle as seen in human patients with HFpEF. They discovered a ripple effect that stemmed from an increased number of macrophages in the mice’s left ventricles.

These macrophages had elevated levels of an anti-inflammatory agent called IL-10, which was activating a surplus of fibroblasts and stimulating an overproduction of collagen, both of which led to increased stiffness and impaired heart relaxation.

Tissue biopsies from human patients with HFpEF also had increased levels of cardiac macrophages and circulating monocytes, which are precursors of macrophages, suggesting that the same ripple effect is occurring in humans as well.

The researchers discovered that removing IL-10 in macrophages in one mouse model reduced the numbers and activation of cardiac fibroblasts, and improved the heart’s ability to relax. If researchers can develop a drug that can limit the production of IL-10 in macrophages, they may be able to subsequently reduce the activation of fibroblasts and reduce the chances of patients developing HFpEF.

“These findings put macrophages on the map when it comes to HFpEF therapy and open up previously unexplored treatment options,” says Hulsmans. “Our identification of the central involvement of macrophages should give us a new focus for drug development,” added Matthias Nahrendorf, MD, PhD, Weissman Family MGH Research Scholar, investigator in the Center for Systems Biology and senior author of this study.

Pediatrician Engages Communities to Make a Lasting Impact on Child Health

Elsie Taveras, MD, MPH

Ofer and Shelly Nemirovsky MGH Research Scholar

Chief of General Pediatrics at MassGeneral Hospital for Children

Executive Director of the Kraft Center for Community Health

Imagine you are a pediatric clinician in an urban community health center. You notice that the majority of your patients have the same triad of conditions – obesity, asthma and behavioral health problems.

You can encourage your patients to lose weight, prescribe asthma medication or connect them with psychiatric services, all of which may help the symptoms, but not the root cause. What can you do in the short time you have with each patient to address the determinants of these conditions?

This is the question Elsie Taveras, MD, MPH, Ofer and Shelly Nemirovsky MGH Research Scholar, chief of General Pediatrics at MassGeneral Hospital for Children, and Executive Director of the Kraft Center for Community Health, confronted while completing her pediatric residency in a Boston clinic serving inner-city youth.

“I started realizing that, although much of my work was providing one-on-one patient care for these conditions, so many of the determinants of the health and well-being of the children I cared for had more to do with their social and environmental conditions and not their clinical care,” says Taveras.

These experiences guided her decision to focus on a combination of clinical and community-based research approaches to address the causes of childhood health problems and reduce health disparities. While working in community settings presents a unique set of challenges, Taveras says the relationships that she has built and the potential to have a long-term impact make the work incredibly rewarding.

Engaging Diverse Stakeholders

Taveras has found that conducting research within a community requires an understanding of context and who the stakeholders are, what matters most to them, and the best ways to engage them in the research process.

“In the same way that we wouldn’t build a home without a blueprint from an architect, you can’t design an intervention for families without families’ voices to inform the work,” says Taveras.

Other stakeholders can range from youth-based organizations and public health practitioners to school administrators and representatives from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). These stakeholders are an integral part of their communities and understand the barriers to proper health and health care.

Mass General’s Focus on Community Research

At a local level, Taveras is encouraged to see how the hospital has elevated community health as a key component of its mission under the leadership of President Peter L. Slavin, MD. Mass General is one of the few academic medical centers in the country to incorporate a commitment to the community in its mission statement.

“I’m thrilled by Mass General’s national leadership in community health and the opportunity to serve disadvantaged populations through the Kraft Center,” says Taveras. “I’m optimistic about the changes that I’ve seen and how that reflects our institutional support for community health.”

Between Taveras’ individual efforts and those of Mass General and the Kraft Center, they may be able to address the root causes of health issues in the urban communities in Massachusetts—and extrapolate those results to other communities nationally.

“Tremendous inequities in health exist, largely attributable to poor access to high quality care as well as social and economic factors that are distributed unevenly based on income, race and ethnicity,” says Taveras. “We can transform the health of children and their families by increasing access to care, investing in bold new solutions that improve social and environmental conditions, and supporting the training of clinicians and researchers who want to improve outcomes for medically underserved communities.”

Weekend Links

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We’ve hand-picked a mix of Massachusetts General Hospital and other research-related news and stories for your weekend reading enjoyment:

A Painful Bruise Wouldn’t Heal. It Took Several Hospital Visits to Discover Why. – A 39 year old woman had been sick for months. She had seen many doctors and had been given a variety of diagnoses, but no one could tell her exactly what was wrong. Mass General physicians Vivek Naranbhai and Leigh Simmons put together a number of clues to find the answer.

Into the Depths – One measure of medicine’s progress is how far inside a living human body the physician can peer. Before X-rays and other imaging technologies, that job fell to ingenious devices and the naked eye. One of the most significant advances happened when a series of 19th-century innovations encountered the services of a professional sword swallower.

New ways scientists can help put science back into popular culture –  How can science integrate with the rest of human culture to intertwine with things like art, music, theater, film and even religion?

Scientists Aim To Pull Peer Review Out Of The 17th Century – The technology that drives science forward is forever accelerating, but the same can’t be said for science communication. The basic process still holds many vestiges from its early days — that is the 17th century. Some scientists are pressing to change that critical part of the scientific enterprise.

The continuing challenges for women in STEMM – Senior levels of science are male dominated, but work is underway to restore the balance

A Single Psychedelic Drug Trip Can Change Your Personality for Years – Researchers have found that individuals who took even a single dose of psychedelic drugs like LSD, “magic” mushrooms and ayahuasca could experience sustained personality changes that lasted several weeks, months or even years — but oftentimes, these changes were for the better.

 -top photo courtesy of Proto Magazine

Martinos Center Researcher Receives Award to Explore Anesthesia and Sleep

Researcher profile Lewis.pngThe Society for Neuroscience recently named Mass General researcher Laura Lewis, PhD, a recipient of the Peter and Patricia Gruber International Research Award. Supported by The Gruber Foundation, the award recognizes young neuroscientists for outstanding research and educational pursuit in an international setting and includes $25,000 for each recipient.

We asked Dr. Lewis, an investigator at the MGH Martinos Center for Biomedical Imaging and a junior fellow in the Harvard Society of Fellows, about her research and how this award will help advance her work.

What problem(s) are you addressing with your research?

My goal is to understand what happens in the brain during sleep and anesthesia. Sleep is essential for healthy brain function, but we still know surprisingly little about how it works. Why do we become unconscious during sleep, and how is this different from losing consciousness during anesthesia? Why do we dream and why is our cognition impaired when we haven’t slept enough?

Ultimately, we’d like to answer these questions by studying the human brain. However, noninvasively measuring human brain activity is very challenging, so I also work on developing new techniques for imaging and analyzing brain function.

What methods are you using?

I use a combination of methods. Most recently, I’ve been working on developing noninvasive imaging approaches that combine functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to measure human brain activity at high resolution. I’m collaborating with physicists and engineers to translate new, accelerated imaging methods into use for neuroscience. With these methods, we can scan people as they fall asleep inside the MRI and image small brain regions during sleep.

I also use intracranial electrocorticography (recordings from electrodes placed directly onto the surface of the brain during a surgery). These recordings are only obtained in patients who are receiving these electrodes for clinical reasons, such as epilepsy. They provide extremely high resolution recordings of the electrical activity of the human brain.

What results have you found thus far and what are the implications for clinical care?

Our anesthesia studies discovered a pattern of activity that appears at the moment people become unconscious. Networks of different brain regions begin to break down, so information can’t be transferred from one brain region to the next. Finding these signatures of unconsciousness can help both with monitoring patients under anesthesia, and with designing the next generation of anesthetic drugs.

Our imaging studies have recently shown that we can noninvasively measure neural activity throughout the whole brain much faster than previously thought: on timescales of hundreds of milliseconds. These imaging tools could be used for a broad range of neuroscience applications, as they enable fast, precise, and noninvasive measurements of brain activity.

Our sleep studies have discovered that activity in a specific brain region predicts transitions between sleep and wake – signaling the moment of awakening, or slow drifts into drowsiness. In the long term, I hope these studies will help inform clinical research of the diverse neurological and psychiatric conditions associated with sleep disturbances.

How will the Gruber International Award help advance your research?

I’m really honoured to have received the Gruber Award and I’m very grateful for the foundation’s support. My research is interdisciplinary, as it draws from many different areas and requires integrating many techniques, so the award is really beneficial for advancing this multidisciplinary research direction.

Could Controlling Inflammation Improve Cystic Fibrosis Therapies?

Today, February 28th, is the 11th annual International Rare Disease Day. This is a day for every member of the rare disease community—patients, caregivers, and researchers—to join together on behalf of all of those suffering with a rare disease. In this blog post we highlight one Massachusetts General Hospital researcher who is tackling rare disease.

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Fifty years ago, a cystic fibrosis (CF) diagnosis was like receiving a death sentence. Most children with CF did not live past the age of 10.

Thanks to heavy investment and advancements in medical research, children diagnosed with CF after the year 2000 are expected to live into their 50s. However, more research is needed to cure this disease, starting with a better understanding of the mechanisms that cause the infection and inflammation associated with CF.

Children born with this rare genetic disease experience a thick, sticky buildup of mucus in the lungs, pancreas and other organs due to a lack of a chloride channel needed to hydrate mucus for effective transport through the body. The non-hydrated mucus clogs airways and traps bacteria, which can cause chronic lung infections and inflammation that eventually lead to permanent lung damage, respiratory failure and death.

Research from Bryan Hurley, PhD, principal investigator within the Mucosal Immunology & Biology Research Center at MassGeneral Hospital for Children, and director of the MGHfC Digestive Disease Summer Research Program, focuses on infectious and inflammatory diseases, such as CF, that disrupt mucosal surfaces of the lung and digestive tract. He is investigating how targeting neutrophils—white blood cells that attack infections—could be the key to developing improved therapies for CF patients.

Hurley-LabBench.jpg Continue reading “Could Controlling Inflammation Improve Cystic Fibrosis Therapies?”

Research Awards and Honors: February 2018

February 2018 awards honors.pngMassachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this series we highlight a few individuals who have recently received awards or honors for their achievements:

Dania DayeDania Daye, MD, PhD, a resident in the Department of Radiology, has received a Trainee Research Prize from the Radiological Society of North America in the health services policy and research category, for her research “Point of care virtual radiology consultants in primary care: A new model for patient-centered radiology.”

“This award highlights the importance of the emerging research in patient-centered care models in radiology and will further promote my efforts in this field. I was very humbled to have been chosen to receive the award. It will certainly have a positive impact on my career trajectory moving forward.” 


Leif Ellisen, MD, PhD, program director for Breast Medical Oncology at the MGH Cancer Center and Weissman Family MGH Research Scholar, and Srinivas Vinod Saladi, PhD, instructor in the MGH Cancer Center, have received the Douglass Foundation Prize for Excellence in Hematology-Oncology Laboratory Research. This award honors their research published in the journal Cancer Cell. The award is given annually recognizing the excellent scientific publication from the cancer center. Pictured from left, Nicholas Dyson, PhD, scientific director of the MGH Cancer Center; Saladi and Ellisen

“We were truly honored to receive the Douglass Family Foundation award recognizing excellence in research at the MGH Cancer Center. As a clinician-scientist, it is very rewarding to be recognized for work that yields new insights into the basic biology of cancer. It is also humbling to be singled out among all my brilliant investigator colleagues in our Cancer Center for recognition. This award is a tribute to the hard work of the lab members, and it encourages us all to strive for excellence in scientific discovery and clinical application.”

Shyamala-Maheswaran.jpgShyamala Maheswaran, PhD, associate professor and scientific director of the MGH Center for Cancer Risk Assessment, has received an Outstanding Scientist Award from the American Association of Indian Scientists in Cancer Research (AAISCR). This award recognizes outstanding, novel and significant biomedical research which has led to important contributions to the fields of basic cancer research, translational cancer research, cancer diagnosis, prevention of cancer or treatment of cancer patients. The award will be presented at the AAISCR meeting in Chicago, Illinois on April 16.

“I feel honored and happy to receive the Outstanding Scientist Award from the American Association of Indian Scientists in Cancer Research.  Important contributions to a field are never possible without the effort of a talented research team. I have been very fortunate to work with remarkable scientists, postdoctoral fellows, students and research technicians, so this award belongs to all of us.  It gives me the impetus to continue to be more productive and answer critical questions that will make a difference in the field of basic and translational cancer research.” 


Raul Mostoslavsky, MD, PhD, The Laurel Schwartz Associate Professor in the MGH Cancer Center and The Kristine and Bob Higgins MGH Research Scholar, has received the Premio Raices (Roots Prize) from the Ministry of Science and Technology in Argentina. The prize recognizes Argentinian scientists abroad for their achievements and continued collaborations with scientists in Argentina.

“I was truly moved when I heard I received this award (and happy to know that my parents, who attended the award ceremony, will be proud!). We, as scientists, work tirelessly for the sake of understanding nature, for the possibility of discovery something new, with the hope that one day, one of these discoveries may benefit a patient. Not for awards. But receiving a recognition like this made me feel that I’m contributing my grain of sand to advance science, that I may be doing something right, and for this I was both flattered and thankful.”

Sabrina Paganoni.jpgSabrina Paganoni, MD, PhD, of the Department of Physical Medicine and Rehabilitation, has received the 2017 Clinician Scientist Development Three-Year Award in ALS sponsored by the American Academy of Neurology and the American Brain Foundation. Paganoni is nationally recognized as a leader in cutting-edge research in ALS. Throughout the past three years, she has obtained funding to conduct four Phase 2 clinical trials for ALS. These trials include promising biomarkers to measure target engagement of various compounds in patients with ALS.

“This Career Development Award comes at a critical time in my career when I am starting new projects, generating data, and applying for funding to become an established investigator with expertise in ALS clinical research. This award will allow me to dedicate the next few years to ALS clinical trials, while still continuing to see ALS patients in the clinic.”

Weekend Links

bouquet of flowersWe’ve hand-picked a mix of Massachusetts General Hospital and other research-related news and stories for your weekend reading enjoyment:

How to wake up in a good mood every day – The Society of American Florists, in conjunction with Nancy Etcoff, an investigator at Mass General, conducted a six-month study into how keeping flowers in the home can affect your mood and found that a simple bouquet can help kick start your day.

Why Activism Is Good For Teens — And The Country – opinion piece written by Gene Beresin, executive director of the MGH Clay Center for Young Healthy Minds

Big dogs on campus – A report from Harvard Med School suggests that having a dog offers health and social benefits, including reducing stress and becoming more active

Look at this: Google AI can predict heart disease by checking eyes

The Struggle to Keep Science Reporting Scientific


What’s Next for Cardiac Research and Clinical Care?

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The American Heart Association hosted its annual Scientific Sessions in November. This week-long event provided an opportunity for clinicians, basic scientists, and researchers to discuss what’s new and what’s next for cardiac research and clinical care.

Here’s what Massachusetts General Hospital researchers and cardiologists found most interesting from this year’s sessions:

New guidelines for high blood pressure

Previous guidelines had considered blood pressure below 140/90 to be normal. The announcement at AHA that 130/80 is the new 140/90 came as big news to cardiologists. “We struggle on a daily basis with the management of patients with hypertension. So hopefully these guidelines will help us deliver better care recommendations,” said Malissa Wood, MD, Co-Director of the Women’s Heart Health Program.

Focus on personalization of care

Precision medicine, which takes into account individual variability in genes, environment, and lifestyle, has become a new area of focus. The discussions around precision medicine at this year’s AHA provided insight into how personalized care can be applied in the field of cardiac care. “The precision medicine summit gives me a good sense of where the field is and where the field is going over the next few years,” – said Steven Lubitz, MD, MPH, cardiac electrophysiologist at Mass General.

Issue of whether an individual can get too much exercise

There was much discussion around the impact of strenuous exercise on heart health. “Whether something that we know is inherently good for you can be overdone and actually start causing harm – this continues to be both a scientific and clinical topic that many of us are wrestling with,” – said Aaron Baggish, MD, Director of the Cardiovascular Performance Program.

Check out the full video:

Remembering the Legacy of a Mass General Neurophysiologist and Pioneer in Race Relations at Harvard

Black History Month is an annual celebration in February of achievements by African Americans. This year, we’re commemorating the life and legacy of S. Allen Counter, a Professor of Neurology at Harvard Medical School, a neurophysiologist at Massachusetts General Hospital and the founding director of the Harvard Foundation for Intercultural and Race Relations. Although Counter passed away in July of 2017 at the age of 73, the many impacts he made live on.

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S. Allen Counter (photo courtesy of The Harvard Gazette)

Research contributions

Allen Counter came to Harvard in 1970 as a postdoctoral fellow and assistant neurophysiologist at Mass General and Harvard Medical School. After brief stints serving on the National Advisory Mental Health Council at what is now called the Department of Health and Human Services, and teaching inmates at the Massachusetts Correctional Institution in Concord, Counter returned to Boston.

Counter’s research focused on clinical and basic studies on nerve and muscle physiology, auditory physiology and neurophysiological diagnosis of brain-injured children and adults, and his research took him across the globe. He ventured to Ecuador to study the neural damage caused by lead-glazing in the village of La Victoria, and to China to study acupuncture.

But Counter’s most intriguing investigation took him to a remote Inuit village in Greenland to learn more about the descendants of a famed explorer.

Counter had been fascinated with the story of Matthew A. Henson, a black explorer who planted the US flag at or near the North Pole in 1909, when Admiral Robert E. Peary was too hobbled by frostbite to do so. During a 1986 research trip to Greenland, Counter managed to track down two eighty year old mixed race Eskimo men who were the surviving biological sons of Henson and Peary (born to two indigenous Inuit women in 1906).

In 1987, Counter was able to arrange for a military plane to fly the men to the United States to meet their American relatives for the first time. During that trip, Counter became aware of an injustice in how the two explorers had been buried and commemorated. Admiral Peary was buried in Arlington National Cemetery with a large white granite monument declaring him the “The discoverer of the North Pole,” while Henson, who reached the North Pole ahead of Peary and placed the American Flag in the ice pack, was buried in a non-descript grave in New York’s Woodlawn Cemetery.

Counter successfully petitioned President Regan to issue a Presidential Order to disinter Henson’s remains and move them to Arlington National Cemetery beside Peary, where Counter was permitted to place a monument crediting Henson as co-discoverer of the North Pole.

Counter’s Greenland expeditions also led him to discover the cause of widespread hearing loss among the Inuit of Greenland – he determined that their hearing loss was not caused by a virus, bacterial infection or diet, but rather by repeated exposure to rifle blasts that destroyed the hair cells of their inner ears.

Improving race relations

In addition to his research endeavors, Allen Counter is also remembered for his profound impact on inclusion and diversity at Harvard.

In 1981, Harvard established the Harvard Foundation for Intercultural and Race Relations, which promotes peace and education and supports civility, intercultural understanding, and racial harmony on campus. Counter was its first and had been its only director.

“Through his leadership of the Harvard Foundation, Counter advanced understanding among members of our community and challenged all of us to imagine and strive for a more welcoming University and a more peaceful world,” said Harvard President Drew Faust in an interview with the Harvard Gazette.

The Harvard Gazette article also says that Counter helped make minority students feel welcome and at home at Harvard, and  worked to foster a diverse community. He is remembered for his ability to bring people together around a cause, and his dedication to improving race relations at the university.

Parting thoughts

In a Phi Beta Kappa Oration delivered at the 2015 Harvard University commencement ceremony, Dr. Counter described the underlying philosophy that guided his teaching and research efforts over a 40+ year career.

“I have tried to share with my students some of the same values instilled in me by my grandmother: integrity, compassion, courage, tenacity, the bond of your word, and a thirst for exploration.”

“I have always believed that education should not be confined to the classroom, but must encompass real-world experiences if we are to produce learned, caring and cultured men and women prepared to tackle social issues and to solve global problems.”

Using Zebrafish Models to Study Cardiovascular Disease

Maryline-squareprofile.jpgMaryline Abrial, PhD, is a postdoctoral research fellow in the Burns Lab at the Cardiovascular Research Center at Massachusetts General Hospital. She took part in a science communication internship at the Mass General Research Institute this fall. She wrote this first-person account of her life as a researcher as part of her internship.

Background and Education

I think what drew me to the biological sciences was a passionate high school biology teacher, who was great mentor and advisor over the years of my undergraduate and graduate training.

I have always found biological processes fascinating. The complexity of them can be very challenging, but understanding and deciphering even a small part feels very rewarding when you can impact human diseases.

Since I started my graduate studies in France in University Claude Bernard in Lyon, I have focused on cardiovascular science. During my PhD, I studied myocardial infarction, which is more commonly known as a heart attack.

My work focused on understanding cellular interactions and especially how non-contractile cell types can help to protect the cells in charge of contraction after an injury such as a heart attack.

After my PhD, I decided to pursue my work in the field of cardiovascular sciences in the exciting scientific environment that Boston offers. I joined the laboratory of Dr. Caroline Burns and Dr. Geoffrey Burns in the Cardiovascular Research Center at Massachusetts General Hospital.

The zebrafish as a model organism

The Burns laboratory studies heart development and regeneration in a particular animal model—the zebrafish.

Unlike humans, zebrafish can regenerate new cardiac tissue after an injury such as a heart attack, which makes them a great model to study the cellular and molecular mechanisms involved in cardiac regeneration.

The zebrafish is also a powerful vertebrate model to study cardiovascular developmental biology because of its rapid external development, the large number of eggs that can be obtained and, more importantly, its beating developing heart that can be observed only 24 hours after fertilization of the egg.

While the zebrafish heart, which is comprised of a single ventricle and atria, is a simpler version of the human heart, the mechanisms regulating its development share much in common.

Investigating aortic arch development

After joining the Burns lab, I slowly became familiarized with zebrafish, and all the genetic tools and imaging techniques that make them such an attractive research model.

I worked closely with a senior research fellow who was studying the development of the great arteries of the heart (also named Pharyngeal Arch Arteries, or PAAs) during embryonic development.

In humans, the PAAs start off symetrically, but then undergo intensive remodeling before taking their final asymetrical shape. Impaired remodeling of those PAAs during development can lead to congenital heart diseases such as Tetralogy of Fallot.

This remodeling process is similar throughout vertebrates, and the zebrafish is a great model organism to visualize and study the cellular progenitors that give rise to these specific arteries.

Using the zebrafish to perform small molecule screening, we uncovered a specific signaling pathway that is involved in the differentiation of great arteries’ cellular progenitors. Using genome-editing technologies, we engineered zebrafish lacking the function of two genes that are involved in this pathway.

Surprisingly, we found that those zebrafish embryos presented a phenotype similar to a human disease called Marfan Syndrome (MFS), a genetic disorder that affects the connective tissue.

People affected by MFS present symptoms in different parts of their bodies, but the most severe ones are linked to the cardiovascular system and include widening or aneurysm of the basis of the aorta (aortic root), which is the main artery carrying blood away from the heart.

This aneurysm can cause a dissection or a tear in the vessel, which will weaken it over time and could lead to a life threatening rupture.

We found that our zebrafish models, when engineered to lack the expression of these two genes, rapidly exhibit an impressive aortic aneurysm (in only 5 days) in a location that is anatomically equivalent to where human aortas are susceptible to developing aneurysm in MFS.

We have analyzed these zebrafish aneurysms and found several molecular hallmarks of the human disease, suggesting that the mechanisms by which zebrafish embryos develop aortic aneurysms are similar to those in Marfan patients.

The Marfan Foundation has funded my research for two years beginning in July of 2016. We are using zebrafish models in combination with genetic tools and microscopic imaging to complement ongoing work in the aneurysm field.

Although tremendous progress has been made in the past decade in the aneurysm research, several questions remain unknown regarding the drivers of the disease.

Current preventive medical therapies for Marfan patients are mainly aimed to reduce blood pressure to decrease the risk of life-threatening complications or to undergo cardiac surgery to repair the aortic root. But so far no therapy has been discovered that prevents or reverses the process of aortic dilation itself.

Because zebrafish embryos are so small and readily available, we can screen large collections of small molecules to looks for candidates that will prevent or cure aortic aneurysm in zebrafish.

In the long run, we hope that any small molecule that suppresses zebrafish aneurysm could be therefore tested in other laboratory models and eventually in humans to learn if they will prevent and/or reverse Marfan Syndrome-associated aneurysm.

The zebrafish gives us a tremendous advantage in studying the pathophysiology of cardiovascular diseases. With the progress of genome editing technologies now readily available, this model can be used to study specific cardiovascular diseases and help to further validate and understand the function of candidate genes identified in human cohorts affected by cardiovascular diseases.