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Decoding Heart-Brain Talk to Prevent Sudden Cardiac Deaths

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Deeptankar DeMazundar in a white doctor's coat
Credit: Colleen Kelley/UC Creative + Brand

As a cardiac electrophysiologist, Deeptankar DeMazumder has worked for years with people at risk for sudden cardiac arrest (SCA). Despite the latest medical advances, less than 10 percent of individuals stricken with an SCA will survive this highly dangerous condition in which irregular heart rhythms, or arrhythmias, cause the heart suddenly to stop beating.

In his role as a physician, DeMazumder keeps a tight focus on the electrical activity in their hearts, doing his best to prevent this potentially fatal event. In his other role, as a scientist at the University of Cincinnati College of Medicine, DeMazumder is also driven by a life-saving aspiration: finding ways to identify at-risk individuals with much greater accuracy than currently possible—and to develop better ways of protecting them from SCAs. He recently received a 2020 NIH Director’s New Innovator Award to pursue one of his promising ideas.

SCAs happen without warning and can cause death within minutes. Poor heart function and abnormal heart rhythms are important risk factors, but it’s not possible today to predict reliably who will have an SCA. However, doctors already routinely capture a wealth of information in electrical signals from the heart using electrocardiograms (ECGs). They also frequently use electroencephalograms (EEGs) to capture electrical activity in the brain.

DeMazumder’s innovative leap is to look at these heart and brain signals jointly, as well as in new ways, during sleep. According to the physician-scientist, sleep is a good time to search for SCA signatures in the electrical crosstalk between the heart and the brain because many other aspects of brain activity quiet down. He also thinks it’s important to pay special attention to what happens to the body’s electrical signals during sleep because most sudden cardiac deaths happen early in the waking hours, for reasons that aren’t well understood.

He has promising preliminary evidence from both animal models and humans suggesting that signatures within heart and brain signals are unique predictors of sudden death, even in people who appear healthy [1]. DeMazumder has already begun developing a set of artificial intelligence algorithms for jointly deciphering waveform signals from the heart, brain, and other body signals [2,3]. These new algorithms associate the waveform signals with a wealth of information available in electronic health records to improve upon the algorithm’s ability to predict catastrophic illness.

DeMazumder credits his curiosity about what he calls the “art and science of healing” to his early childhood experiences and his family’s dedication to community service in India. It taught him to appreciate the human condition, and he has integrated this life-long awareness into his Western medical training and his growing interest in computer science.

For centuries, humans have talked about how true flourishing needs both head and heart. In DeMazumder’s view, science is just beginning to understand the central role of heart-brain conversations in our health. As he continues to capture and interpret these conversations through his NIH-supported work, he hopes to find ways to identify individuals who don’t appear to have serious heart disease but may nevertheless be at high risk for SCA. In the meantime, he will continue to do all he can for the patients in his care.

References:

[1] Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Circ Res. 2018;123(3):356-371.

[2] Entropy of cardiac repolarization predicts ventricular arrhythmias and mortality in patients receiving an implantable cardioverter-defibrillator for primary prevention of sudden death. DeMazumder D, Limpitikul WB, Dorante M, et al. Europace. 2016;18(12):1818-1828.

[3] Dynamic analysis of cardiac rhythms for discriminating atrial fibrillation from lethal ventricular arrhythmias. DeMazumder D, Lake DE, Cheng A, et al. Circ Arrhythm Electrophysiol. 2013;6(3):555-561.

Links:

Sudden Cardiac Arrest (National Heart, Lung, and Blood Institute/NIH)

Deeptankar DeMazumder (University of Cincinnati College of Medicine)

DeMazumder Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: National Heart, Lung, and Blood Institute; Common Fund


All of Us: Partnering Together for the Future of Precision Medicine

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All of Us Research Program
Credit: All of Us Research Program

Over the past year, it’s been so inspiring to watch tens of thousands of people across the country selflessly step forward for vaccine trials and other research studies to combat COVID-19. And they are not alone. Many generous folks are volunteering to take part in other types of NIH-funded research that will improve health all across the spectrum, including the more than 360,000 who’ve already enrolled in the pioneering All of Us Research Program.

Now in its second year, All of Us is building a research community of 1 million participant partners to help us learn more about how genetics, environment, and lifestyle interact to influence disease and affect health. So far, more than 80 percent of participants who have completed all the initial enrollment steps are Black, Latino, rural, or from other communities historically underrepresented in biomedical research.

This community will build a diverse foundation for precision medicine, in which care is tailored to the individual, not the average patient as is now often the case. What’s also paradigm shifting about All of Us is its core value of sharing information back with participants about themselves. It is all done responsibly through each participant’s personal All of Us online account and with an emphasis on protecting privacy.

All of Us participants share their health information in many ways, such as taking part in surveys, offering access to their electronic health records, and providing biosamples (blood, urine, and/or saliva). In fact, researchers recently began genotyping and sequencing the DNA in some of those biosamples, and then returning results from analyses to participants who’ve indicated they’d like to receive such information. This first phase of genotyping DNA analysis will provide insights into their genetic ancestry and four traits, including bitter taste perception and tolerance for lactose.

Results of a second sequencing phase of DNA analysis will likely be ready in the coming year. These personalized reports will give interested participants information about how their bodies are likely to react to certain medications and about whether they face an increased risk of developing certain health conditions, such as some types of cancer or heart disease. To help participants better understand the results, they can make a phone appointment with a genetic counselor who is affiliated with the program.

This week, I had the pleasure of delivering the keynote address at the All of Us Virtual Face-to-Face. This lively meeting was attended by a consortium of more than 2,000 All of Us senior staff, program leads with participating healthcare provider organizations and federally qualified health centers, All of Us-supported researchers, community partners, and the all-important participant ambassadors.

If you are interested in becoming part of the All of Us community, I welcome you—there’s plenty of time to get involved! To learn more, just go to Join All of Us.

Links:

All of Us Research Program (NIH)

Join All of Us (NIH)


Bringing Needed Structure to COVID-19 Drug Development

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SARS-Cov-2 Molecular Map
Caption: Molecular map showing interaction between the spike protein (gold) of the novel coronavirus and the peptidase domain (blue) of human angiotensin-converting enzyme 2 (ACE2). Credit: Adapted from Yan R., Science, 2020.

With so much information swirling around these days about the coronavirus disease 2019 (COVID-19) pandemic, it would be easy to miss one of the most interesting and significant basic science reports of the past few weeks. It’s a paper published in the journal Science [1] that presents an atomic-scale snapshot showing the 3D structure of the spike protein on the novel coronavirus attached to a human cell surface protein called ACE2, or angiotensin converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry.

What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19.

This new work, conducted by a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, took advantage of a high-resolution imaging tool called cryo-electron microscopy (cryo-EM). This approach involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can solve the structure of intricate macromolecular complexes in a matter of days, including this one showing the interaction between a viral protein and human protein.

Zhou’s team began by mapping the structure of human ACE2 in a complex with B0AT1, which is a membrane protein that it helps to fold. In the context of this complex, ACE2 is a dimer—a scientific term for a compound composed of two very similar units. Additional mapping revealed how the surface protein of the novel coronavirus interacts with ACE2, indicating how the virus’s two trimeric (3-unit) spike proteins might bind to an ACE2 dimer. After confirmation by further research, these maps may well provide a basis for the design and development of therapeutics that specifically target this critical interaction.

The ACE2 protein resides on the surface of cells in many parts of the human body, including the heart and lungs. The protein is known to play a prominent role in the body’s complex system of regulating blood pressure. In fact, a class of drugs that inhibit ACE and related proteins are frequently prescribed to help control high blood pressure, or hypertension. These ACE inhibitors lower blood pressure by causing blood vessels to relax.

Since the COVID-19 outbreak, many people have wondered whether taking ACE inhibitors would be helpful or detrimental against coronavirus infection. This is of particular concern to doctors whose patients are already taking the medications to control hypertension. Indeed, data from China and elsewhere indicate hypertension is one of several coexisting conditions that have consistently been reported to be more common among people with COVID-19 who develop life-threatening severe acute respiratory syndrome.

In a new report in this week’s New England Journal of Medicine, a team of U.K. and U.S. researchers, partly supported by NIH, examined the use of ACE inhibitors and other angiotensin-receptor blockers (ARBs) in people with COVID-19. The team, led by Scott D. Solomon of Brigham and Women’s Hospital and Harvard Medical School, Boston, found that current evidence in humans is insufficient to support or refute claims that ACE inhibitors or ARBs may be helpful or harmful to individuals with COVID-19.

The researchers concluded that these anti-hypertensive drugs should be continued in people who have or at-risk for COVID-19, stating: “Although additional data may further inform the treatment of high-risk patients … clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns.” [2]

Research is underway to generate needed data on the use of ACE inhibitors and similar drugs in the context of the COVID-19 pandemic, as well as to understand more about the basic mechanisms underlying this rapidly spreading viral disease. This kind of fundamental research isn’t necessarily the stuff that will make headlines, but it likely will prove vital to guiding the design of effective drugs that can help bring this serious global health crisis under control.

References:

[1] Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 27 March 2020. [Epub ahead of publication]

[2] Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer MA, Solomon SD. 30 NEJM. March 2020 [Epub ahead of Publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Transformative High Resolution Cryo-Electron Microscopy (Common Fund/NIH)

Qiang Zhou (Westlake Institute for Advanced Study, Zhejiang Province)

Scott D. Solomon (Brigham and Women’s Hospital, Boston)

NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute


Can Childhood Stress Affect the Immune System?

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Katie Ehrlich

Katie Ehrlich
Credit: Alan Flurry, University of Georgia, Athens

Whether it’s growing up in gut-wrenching poverty, dealing with dysfunctional family dynamics, or coping with persistent bullying in school, extreme adversity can shatter a child’s sense of emotional well-being. But does it also place kids at higher of developing heart disease, diabetes, and other chronic health conditions as adults?

Katherine Ehrlich, a researcher at University of Georgia, Athens, wants to take a closer look at this question. She recently received a 2018 NIH Director’s New Innovator Award to study whether acute or chronic psychosocial stress during childhood might sensitize the body’s immune system to behave in ways that damage health, possibly over the course of a lifetime.


Modeling Hypertrophic Cardiomyopathy in a Dish

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Image of cardiac fibers

Credit: Zhen Ma, University of California, Berkeley

Researchers have learned in recent years how to grow miniature human hearts in a dish. These “organoids” beat like the real thing and have allowed researchers to model many key aspects of how the heart works. What’s been really tough to model in a dish is how stresses on hearts that are genetically abnormal, such as in inherited familial cardiomyopathies, put people at greater risk for cardiac problems.

Enter the lab-grown human cardiac tissue pictured above. This healthy tissue comprised of the heart’s muscle cells, or cardiomyocytes (green, nuclei in red), was derived from induced pluripotent stem (iPS) cells. These cells are derived from adult skin or blood cells that are genetically reprogrammed to have the potential to develop into many different types of cells, including cardiomyocytes.


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