Harvard Medicine magazine, Autumn 2023 by Harvard Medical School

medicine HARVARD

SPRING2023 2023 AUTUMN

SLEEP [The Heart]

a sense of place Researchers in the Department of Cell Biology in the Blavatnik Institute at HMS work to unravel the mysteries of cellular mechanisms with the goal of identifying ways to repair or prevent malfunctions that contribute to the development of diseases such as cancer. In this photo, a scientist works with a tissue culture containing three types of normal human epithelial cells that carry cancer-associated mutations. The aim: study the process that initiates tumor development, then look for ways to thwart it. Basic science research such as this is crucial to developing new treatments and possibly methods for preventing cells from becoming perturbed in the first place.

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GRETCHEN ERTL

H A R VA R D M E D I C I N E

PATTERNS: The branchings of this

COVER: MATTIAS PALUDI

river exemplify fractal patterning, a complex geometric form that seems irregular but actually repeats itself in a self-similar manner at different scales. Fractal formations are abundant in the natural world, including in our bodies. The pattern formed by the cardiovascular system, for example, is a fractal one, as is the complex and varying pattern of beats produced by a healthy heart.

contents Autumn 2023 | Volume 96 | Number 2

SPECIAL REPORT THE HEART

DEPARTMENTS

10 From Comforting Beat to Chaotic Flutter by Catherine Caruso

A letter from the dean

Researchers and clinicians continue to perfect treatments for atrial fibrillation. 16 Internal Review by Stephanie Dutchen Hospitals are waking up to their climate change culpability and the mandate to act.

4 Commentary

5 Discovery Research at Harvard Medical School 9 Noteworthy News from Harvard Medical School 40 Five Questions by Ekaterina Pesheva

18 Shared Experience by Elizabeth Gehrman

Haider Warraich on bringing advances in cardiology to all people and on writing as a path to engendering empathy

The health of the heart is linked to the health of the brain — and vice versa.

41 Roots by Catherine Caruso

24 Collateral Damage by Charles Schmidt

Nanette Wenger on upending dogma by proving women are at risk for cardiovascular disease

Researchers increasingly find that the effects of infection by SARS-CoV-2 extend to the heart. 30 Unwavering Purpose by Ann Marie Menting A physician-researcher has spent his career advocating for better cardiovascular care for Black people. 34 Heart Felt by Molly McDonough

48 Student Life by Elizabeth Gehrman and Molly McDonough Masters and MD candidates on their career aspirations and roles as class leaders 51 Rounds Alumni on the exciting scientific or medical innovations that have occurred during their careers

TEMIZYUREK/E+/GETTY IMAGES

In addition to helping others, kindness can benefit one’s health. FEATURE 42 Up on the Roof A photo essay of research infrastructure.

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COMMENTARY

medicine HARVARD

Our Relentless Work to Stem Cardiovascular Disease ACCORDING TO A 2023 REPORT from the World Heart Federation, prog-

ress against cardiovascular disease has stalled. Although the report notes that when standardized for age, the death rate has declined by one-third since 1990, it also says that in 2021 alone, 20.5 million people died from a cardiovascular condition. Furthermore, improved outcomes are flagging globally, including in the United States. The U.S. Centers for Disease Control and Prevention echoes the federation’s report. In 2021, heart disease remained the leading cause of death in the nation with one in five deaths the result of a heart condition. In addition, each year about 805,000 people have a heart attack, nearly 20 percent of which are silent, tissue-damaging events that can increase the risk of heart failure by 35 percent. It can be difficult to understand how a disease that has plagued humans for millennia continues to exert such a hold. In part, discerning the mechanisms behind the various cardiovascular conditions has been challenging. But innovative, multidisciplinary research, including exciting work being done by HMS alumni and by our faculty, is illuminating how and why our hearts can fail. Alumni who are advancing research in cardiology and cardiac care include cardiologist Gary Gibbons, MD ’82, director of the National Heart, Lung, and Blood Institute, which supports more than 1,200 principal investigators whose research focuses on the prevention and treatment of such diseases. Other alumni focus on teasing out how cardiovascular disease singularly affects diverse populations. For example, Karol Watson, MD ’89, directs the UCLA Women’s Cardiovascular Health Center and the UCLA-Barbra Streisand Women’s Heart Health Program, while C. Noel Bairey Merz, MD ’81, directs the Barbra Streisand Women’s Heart Center and the Linda Joy Pollin Women’s Heart Health Program at the Cedars-Sinai Smidt Heart Institute. Through his work on the landmark Jackson Heart Study and, more recently, as the director and endowed professor of the Cardiovascular Research Institute at Morehouse School of Medicine, Herman Taylor, MD ’80, has been a leader in multidisciplinary research aimed at identifying the molecular bases of heart disease in Black populations. HMS researchers are making significant contributions to our understanding of the biology and pathophysiology of heart disease. A recent collaboration between the labs of Sean Megason, in the Department of Systems Biology in the Blavatnik Institute at HMS, and Adam Cohen, in the Department of Chemistry and Chemical Biology at Harvard, has described the mechanism that causes heart cells in zebrafish to start beating in synchrony, a finding that may one day shed light on how arrhythmias develop in humans. Other landmark work includes genetic studies by Christine Seidman at HMS and Brigham and Women’s Hospital and Jonathan Seidman at HMS, which found that hypertrophic cardiomyopathy can be traced to a host of gene mutations that predispose an individual to sudden cardiac death. It is the most common cause of sudden death in athletes. Ours is a community passionately dedicated to discovery and committed to care. Whether for cardiovascular disease or any condition that plagues global populations, HMS alumni and faculty remain relentlessly focused on deciphering mechanisms and developing treatments that will improve health and well-being for all.

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Associate Editor Molly McDonough Design Director Paul DiMattia Senior Copyeditor & Editorial Coordinator Susan Karcz Designer Maya Rucinski-Szwec Contributors Catherine Caruso, Stephanie Dutchen, Elizabeth Gehrman, Ekaterina Pesheva, Charles Schmidt Editorial Board JudyAnn Bigby, MD ’77; Emery Brown, MD ’87 PhD ’88; Rafael Campo, MD ’92; Elissa Ely, MD ’87; Timothy G. Ferris, MD ’92; Alice Flaherty, MD ’94; Atul Gawande, MD ’94; Donald Ingber, PhD; Sachin H. Jain, MD ’08; Perri Klass, MD ’86; Jeffrey Macklis, MD ’84; Victoria McEvoy, MD ’75; Barbara McNeil, MD ’66 PhD ’72; Lee Nadler, MD ’73; James J. O’Connell, MD ’82; Nancy E. Oriol, MD ’79; Mitchell T. Rabkin, MD ’55; Eleanor Shore, MD ’55 Dean of Harvard Medical School George Q. Daley, MD ’91 Executive Dean for Administration Lisa Muto Chief Communications Officer Laura DeCoste Harvard Medical Alumni Association Louise Aronson, MD ’92, president Chasity Jennings-Nuñez, MD ’95, vice president John F. Cramer III, MD ’74; Sitaram Emani, MD ’97; Kalon Ho, MD ’87; Jessica Ann Hohman, MD ’13; Elbert Huang, MD ’96; Timothy Jenkins, MD ’92; Kristy Rialon, MD ’08; Michelle Rivera, MD ’92; Nancy Petersmeyer, MD ’80; Kirstin Woody Scott, MD ’20; Nancy Wei, MD ’06; Laura Torres, MD ’88; Douglas Zipes, MD ’64 Chair of Alumni Relations A. W. Karchmer, MD ’64 Harvard Medicine magazine is published two times a year, with online editions appearing monthly. PUBLISHERS: Harvard Medical Alumni Association

and Harvard Medical School © The President and Fellows of Harvard College EMAIL: harvardmedicine@hms.harvard.edu WEB: magazine.hms.harvard.edu

ISSN 2152-9957 | Printed in the U.S.A.

RANDY GLASS

George Q. Daley Dean of Harvard Medical School

Editor Ann Marie Menting

ON CAMPUS

I DISCOVERY AT HARVARD MEDICAL SCHOOL

This color-enhanced abdominal X-ray shows an aorta that has a calcified region (red), which developed as a result of atherosclerotic artery disease.

Bone Deep

SCOTT CAMAZINE/SCIENCE SOURCE

A ROUTINE BONE DENSITY SCREENING TEST for osteopo-

rosis can also gauge the risk of a heart attack by detecting calcium in the aorta. But reading these images is time-consuming and requires careful training. Now, researchers from a group of institutions, including HMS and Hebrew SeniorLife, have developed algorithms that can calculate an abdominal aortic calcification test score quickly using machine learning, without the need for a person to grade the scans. Researchers evaluated the assessment, called ML-AAC-24, in a real-world setting using a registry study of 8,565 older men and women. They found that greater ML-AAC-24 scores were associated with substantially higher cardiovascular disease risk. Sharif N et al., eBioMedicine, August 2023

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DISCOVERY AT HARVARD MEDICAL SCHOOL

GERONTOLOGY

Older adults can build resilience against loneliness

Missing Link

LONELINESS IS COMMON among older adults

Liu J et al., American Journal of Geriatric Psychiatry, August 2023

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Using a mouse model, researchers at HMS have defined five distinct subtypes of sensory neurons in the colon that send signals to the brain. The neurons (shown in green in the above image of a mouse’s colon wall) have different functions; some respond to gentle forces such as stretching, while others respond to more intense stimuli, like pain. The study is the first to provide critical insight into the basic neurobiological mechanisms of colon sensation. If confirmed in humans, the findings could help scientists develop more effective therapies to treat gastrointestinal problems that may arise when the gut-brain sensing system goes awry. Wolfson R et al., Cell, August 2023

ONCOLOGY

Tool decodes brain cancer’s DNA during surgery A MULTI-INSTITUTION COLLABORATION led by HMS

researchers has developed a tool that uses artificial intelligence to rapidly decode a brain tumor’s DNA during surgery to determine its molecular identity. Currently, it can take days to weeks to obtain this critical genetic information. An accurate molecular diagnosis that details DNA alterations in a cell could help a neurosurgeon decide how much brain tissue to remove. Removing too much tissue when a tumor is less aggressive can affect a patient’s neurologic and cognitive function. Likewise, removing too little tissue when a tumor is highly aggressive may leave malignant tissue that can grow and spread.

Nasrallah MP et al., Med, July 2023

COURTESY OF RACHEL WOLFSON

— particularly during periods of social isolation. And the phenomenon is associated with an increased likelihood of chronic disease, depression, and other health issues. A new study from a multi-institution collaboration, including HMS and Hebrew SeniorLife, explores the links between loneliness and older adults’ health. The paper identifies several risk factors that help explain why older adults experienced loneliness during the COVID-19 pandemic, including advanced age, inability to complete daily activities, vision impairment, depression, and anxiety. The authors identified what they call resilience factors — having large social networks, using technology, and participating in social and physical activities — that helped mitigate some negative effects of loneliness on physical health during the pandemic. In addition, they found that social and physical activities also lessened the effects of loneliness on mental health. Researchers used data collected before and during the pandemic from 238 participants of the Successful Aging after Elective Surgery study. Participants in the study have been completing interviews with Hebrew SeniorLife for approximately 10 years. Interviews completed between July and December 2020 collected data on loneliness, social network size, technology use, activity engagement, and more. Outcomes that were measured included self-rated health, physical and mental health, and physical functioning in everyday activities. The authors suggest that older adults get involved in senior centers, participate in volunteer activities, and increase access to and knowledge of modern technological devices that allow for virtual social connection — practical interventions that can decrease the detrimental health effects of social isolation.

The standard intraoperative diagnostic approach currently involves removing brain tissue, freezing it, and examining it under a microscope. However, freezing the tissue tends to alter the appearance of cells under a microscope and can interfere with the accuracy of clinical evaluation. And the human eye cannot reliably detect subtle genomic variations on a slide. The new tool, called CHARM (Cryosection Histopathology Assessment and Review Machine), may overcome these challenges. It was developed using 2,334 brain tumor samples from 1,524 people with glioma, the most aggressive and most common type of brain tumor. When tested on a never-before-seen set of brain tumor samples, CHARM distinguished tumors with specific molecular mutations at 93 percent accuracy and successfully classified three major types of gliomas with distinct molecular features that carry different prognoses and respond differently to treatments. The tool also captured visual characteristics that signal more aggressive glioma types in tissue surrounding the malignant cells. And it pinpointed clinically important molecular alterations in a subset of low-grade gliomas, which are less aggressive and therefore less likely to invade surrounding tissue. This ability to assess the broader context around the tumor renders the model more accurate and represents a closer approach to how a human pathologist would visually assess a tumor sample. Scientists have already designed AI models to profile other types of cancer, but gliomas remain challenging due to their molecular complexity and the huge variation in the shape and appearance of the tumor’s cells. While this new model was trained and tested on glioma samples, researchers suggest it could be successfully retrained to identify other brain cancer subtypes.

HM INDEX: ABOUT 40 PERCENT OF U.S. ADULTS, OFTEN THOSE UNDER 65 YEARS OF AGE, HAVE A GUT-BRAIN INTERACTION DISORDER

Food for Thought A STUDY LED BY HMS IMMUNOLOGISTS sheds light on a

WIRESTOCK/ISTOCK/GETTY

critical intermediary between food and health — the gut bacteria that are part of our microbiome. Research in mice found that gut bacteria feed on common fatty acids such as linoleic acid, converting it to conjugated linoleic acid. This conversion launches a biological cascade that ultimately spurs a specific type of immune system to develop in the small intestine, one that protects the mice from a common foodborne pathogen. The study, which brings to light one of the intricate pathways linking diet, microbes, and the immune system, is a step toward understanding how microbiomes keep us healthy — and how to intervene when they don’t. Song X et al., Nature, June 2023

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DISCOVERY AT HARVARD MEDICAL SCHOOL

A new tool integrates histologic and molecular information obtained from biopsies of tumor tissue. In this image, the same cells from a tumor sample are shown as an immunofluorescent image that details their molecular characteristics and as a histologic preparation that provides structural information (circular overlay).

Double Take A NEW TOOL COULD IMPROVE the way pathologists see

Lin JR et al., Nature Cancer, June 2023

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COURTESY OF SANTAGATA AND SORGER LABS

and evaluate tumors. Developed by a team led by HMS pathologists and pharmacologists, the tool, called Orion, uses digital imaging to integrate information from traditional histology and molecular imaging, offering insight into a tumor’s type, behavior, and likely response to treatment. Researchers tested Orion on tumor samples from more than 70 patients with colorectal cancer and found that it provided complementary histological and molecular information about each sample and identified biomarkers common in patients with serious disease. The work is a critical step in creating a tool that can be used in the clinic to improve cancer diagnosis and treatment.

ON CAMPUS

I NEWS FROM HARVARD MEDICAL SCHOOL

noteworthy

RANDY GLASS

New leader for Global Health and Social Medicine Vikram Patel, Paul Farmer Professor and Chair of Global Health (fig. 1) and a wellknown expert in global mental health, became the new chair of the HMS Department of Global Health and Social Medicine on September 1. Patel succeeds Paul Farmer, MD ’90 PhD ’90, who led the department until his death in February 2022. In his letter to the HMS community announcing the appointment, Dean George Q. Daley, MD ’91, described Patel as a venerable and charismatic educator who shares Farmer’s philosophy that academic engagement is key to delivering quality and equitable health care to all. “I am deeply honored to serve as the chair of the department,” Patel said. “I am conscious that I follow not only in Paul’s monumental footsteps, but also in those of some of the most influential scholars in global health and social medicine. I am motivated by the potential of this role at this critical juncture in the long and storied history of a department committed to the goal of health equity in this country and globally.” “Since Vikram joined the department,” said Anne Becker, MD ’90 PhD ’90, dean for clinical and academic affairs and the Maude and Lillian Presley Professor of Global Health and Social Medicine at HMS, “he has been a vital source of intellectual energy and team building, two qualities that will serve him well as leader of the department and, in turn, will serve our community of faculty and learners very well.” Patel’s appointment comes at a time of increasing awareness of a growing mental health crisis around the world, Daley noted, adding that Patel’s “energy, determination, and drive to find solutions will be invaluable as the HMS community responds to the crisis and acts on the goals outlined in the department’s new strategic plan.” Daley also pointed out that Patel’s deep knowledge of the complexities of

mental health will complement the HMS community’s strength in neuroscience and neurobiology.

Program in Medical Education welcomes a new dean

AI in medicine course aims to prepare leaders for change Artificial intelligence is making transformative changes in our lives and is already bringing changes to medicine. The opportunity to help shape how this transformation will play out — and shape the medical leaders who will guide these changes — has helped spur the launch of a new educational program by the Department of Biomedical Informatics in the Blavatnik Institute at HMS: the Artificial Intelligence in Medicine PhD track (fig. 2). Led by Isaac Kohane, DBMI chair, and Sebastian Schneeweiss, an HMS professor of medicine at Brigham and Women’s Hospital and a professor in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health, this interdisciplinary program aims to train future generations of academic and industry leaders on the effective coupling of real-world health data with AI methods. The curriculum emphasizes multidisciplinary collaboration, clinical immersion, and methodological expertise. Trainees will have access to curated real-world health data sets that can be used to conceptualize the tools that need to be built for the clinical ecosystems of today and tomorrow. The program is a collaboration with Boston-area hospitals and the HarvardMIT Program in Health Sciences and Technology. Teaming up with the hospitals and the HST program allows trainees to enrich their understanding of AI challenges and opportunities in health care through clinical coursework at HMS and through rotations in area hospitals alongside medical students and other PhD trainees from Harvard and MIT. The AI in Medicine program hopes to attract people who have computational or quantitative training and significant AI and machine learning research experience. Those who are interested can apply through December 1, 2023.

fig. 1

fig. 2

fig. 3

On July 31, Bernard Chang, MMSc ’05, (fig. 3) began his role as the School’s dean for medical education. In his letter to the HMS community announcing Chang’s appointment, Dean George Q. Daley, MD ’91, expressed his confidence that Chang — a noted neurologist, HMS faculty member and educator, and former advisory dean for the Francis Weld Peabody academic society — has the experience, spirit, and vision to lead the Program in Medical Education into “a new era of distinction.” “Inquiry, discovery, and scholarship will be at the heart of what we do,” Daley added, “as we cultivate a new generation of physicians, well equipped to meet the challenges of the next age of medicine and health care.” A Harvard College graduate in biochemical sciences, Chang earned his MD from the New York University School of Medicine. He completed a residency and fellowship at Beth Israel Deaconess Medical Center, where he is an HMS professor of neurology. “I am honored and humbled to be taking on this role,” said Chang following the announcement. “Medical education is my passion, and there is no better place than HMS to learn to be a doctor. I am excited to tackle our mission of preparing our students to be the next generation of physician leaders.” Daley noted that, as a society advisory dean, Chang wholeheartedly promoted the well-being of students, including those from historically underrepresented and marginalized backgrounds. Chang succeeds Edward Hundert, MD ’84, who has become senior philanthropic advisor in the HMS Office of Alumni Affairs and Development. Hundert continues to serve as the associate director of the Center for Bioethics and as a senior faculty member in the Department of Global Health and Social Medicine.

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THE HEART

I ATRIAL FIBRILLATION

Some patients with atrial fibrillation describe the feeling as that of a fish flip-flopping in their chest. Others say it’s like the flutter of a butterfly’s wings, an effect modeled in this image.

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Researchers and clinicians continue to perfect treatments needed by the growing number of patients with atrial fibrillation BY CATH ER IN E CA RUSO

From Comforting Beat to Chaotic Flutter

MATTIAS PALUDI

A STUTTERING HEART. A fluttering heartbeat. A racing pulse.

Through the ages, writers have reserved such phrases for the dramatic moments of their stories, when the main character is overcome with passionate love or overwhelmed by intense anger or fear. Yet despite what centuries of literature may suggest, a change in heartbeat isn’t necessarily tied to a profound emotional shift. Sometimes, it is simply a physiological quirk that transforms the usual, evenly spaced thumps into an erratic pattern of beats that speed up and slow down of their own accord. And often, such chaotic beating is the result of a condition called atrial fibrillation. n When a heart enters atrial fibrillation, an electrical malfunction causes the top half to beat rapidly, while the bottom half maintains a slower rhythm. In an instant, the heart becomes a dancer whose top and bottom halves are performing to music with wildly different tempos: arms jerking in time to an upbeat pop song, while legs keep pace with a classical ballet. HARVARD MEDICINE | AU T U M N 202 3

ATRIAL FIBRILLATION

he result can be an uncomfortable burst of rapid beats that flutter inside a person’s chest like a butterfly’s wings, leaving the individual dizzy and gasping for air. Or a person can feel nothing at all, remaining completely unaware of the change. The atypical rhythm can start and end quickly, a brief burst that happens frequently or from time to time. Or, it can persist for weeks, months, or even years. But what exactly is atrial fibrillation? What causes it? Who experiences it? And what’s the best way to treat it? These are the questions that researchers and clinicians are grappling with, their work becoming only more urgent as the number of people confronting the condition swells. An age-old condition

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Usha Tedrow

“Normally, every upper chamber beat has a corresponding lower chamber beat, to create the lub-dub of the heartbeat.”

JOHN SOARES

The human fascination with the heartbeat stretches back to ancient times. And for as long as people have known that there is a heartbeat, they’ve understood that sometimes, it becomes abnormal. Physicians in ancient China, Egypt, and Greece regularly recorded irregular pulses in their patients, realizing that a chaotic heartbeat could be a harbinger of other health problems. However, it wasn’t until the early 1900s that physicians had the knowledge and technology to identify atrial fibrillation. In 1901, a Dutch physician named Willem Einthoven invented the electrocardiogram to measure electrical activity in the heart. The 600-pound instrument — an intricate setup of buckets of salt water, wires, microscope lenses, a glass recording plate, a timer, and a string galvanometer — translated the electrical impulses of the heartbeat into a spiky black line of ink on graph paper. He began using the instrument to make recordings of healthy and unhealthy human hearts.

At the same time, multiple groups of scientists around the world were closing in on the idea of atrial fibrillation, as they began to suspect that the irregular heartbeats they were observing in animals during experiments might also exist in humans. However, their tools were limited to “tracings” of veins and arteries that captured only heart contractions. Einthoven’s electrocardiogram provided undeniable evidence. Tucked away among twenty-six recordings he published in 1906 was one labeled “pulsus inaequalis et irregularis,” or “uneven and irregular pulse”: the first documented case of atrial fibrillation. Suddenly, scientists could measure and record the electrical perturbations that drove the condition. Before long they had confirmed that atrial fibrillation existed in humans and was, in fact, common. With that, the condition known as atrial fibrillation was born, and physicians began studying it in earnest, while also trying to figure out how to help people who had it. An electrical malfunction

Unlike a heart attack, which stems from a blockage in the coronary artery, atrial fibrillation is an electrical problem in which the heart’s two upper chambers, or atria, start beating out of sync with its two lower chambers, or ventricles. In a healthy heart, each beat is initiated by a cluster of specialized myocardial cells, called pacemaker cells, that make up the sinus node in the right atrium. Every time the cells fire, the sinus node produces an electrical signal that causes both atria to contract. The signal then flows through the narrow atrioventricular node in the center of the heart into the ventricles to make them contract. “Normally, every upper chamber beat has a corresponding lower chamber beat, to create the lub-dub of the heartbeat,” explains Usha Tedrow, MD ’97, an HMS associate professor of medicine at Brigham and Women’s Hospital, director of the hospital’s Clinical Cardiac Electrophysiology Fellowship Program, and clinical director of its Ventricular Arrhythmia Program.

Like the conductor of an orchestra, the sinus node keeps the heart beating at the right rhythm and pace and tells it when to speed up or slow down. Typically, a healthy heart beats about once per second at rest, and up to 150 beats per minute during physical activity. In a heart with atrial fibrillation, this coordinated process breaks down. Suddenly, spontaneous electrical impulses fire throughout the atria, like cameras flashing from different spots in a dark room. Each impulse sets off a new heartbeat, causing the upper chambers to beat up to 400 to 500 times per minute. Fortunately, the atrioventricular node prevents all of those beats from reaching the lower chambers, but the result is an out-of-sync heart and a rapid, irregular heartbeat. “The hallmark of atrial fibrillation is a pulse that is irregularly irregular — there’s no pattern to the irregularity of the rhythm,” says Peter Zimetbaum, the Richard A. and Susan F. Smith Professor of Medicine in the Field of Cardiovascular Medicine at HMS and the clinical director and associate chief of cardiology at Beth Israel Deaconess Medical Center. When someone goes into atrial fibrillation, “the first thing they may notice is that their chest doesn’t feel right,” Tedrow says, adding that patients have described the sensation as “like a fish is flip-flopping around in their chest.” The condition is often diagnosed by the modern version of Einthoven’s electrocardiogram, commonly known as an ECG or EKG. Symptomatically, atrial fibrillation is mystifyingly heterogeneous. Tedrow’s patients often fall into two broad groups: younger patients who experience such intense symptoms that they may go to the emergency department during their first episode and older patients with so few symptoms that they may not know they are in atrial fibrillation until it’s picked up during a routine physical. Officially, there are three main types. In paroxysmal atrial fibrillation, episodes start and stop on their own. Patients tend to be younger, sometimes athletes, and often have the most noticeable symptoms — which can include dizziness, chest pain, shortness

of breath, and fatigue. In persistent atrial It’s no exaggeration fibrillation, which Tedrow estimates is the most prevalent type, episodes last for more to say that than a week, and the heart must be shocked atrial fibrilla- back into normal rhythm. In permanent or tion is all chronic atrial fibrillation, the heart cannot be brought back to normal rhythm. around us, The three types of atrial fibrillation, hiding in Tedrow notes, also represent how the plain sight.

disease often progresses in an individual. Triggers for the condition include lack of sleep, dehydration, and stress. “I always tell people, that’s not what makes you have atrial fibrillation in general, but that may be why you have it today,” she says. A growing coronary risk

It’s no exaggeration to say that atrial fibrillation is all around us, hiding in plain sight. It is the most common type of sustained, irregular heartbeat, and it is expected to become more common. In a 2013 paper in the American Journal of Cardiology, researchers estimated that U.S. cases would jump from 5.2 million in 2010 to 12.1 million in 2030. “Almost everybody knows somebody who has it,” Zimetbaum emphasizes. Atrial fibrillation is so common that Tedrow regularly sees patients who first detect it with a heart rate monitor on their smartwatch or other wearable device — a screening strategy that she thinks could become broadly useful. “There are a lot of ongoing clinical trials that may demonstrate the benefits more, but for some patients, these devices really offer the opportunity to make a diagnosis in a way that we couldn’t before,” Tedrow says. Risk factors for atrial fibrillation include diabetes, structural heart issues such as blockages or leaky valves, high blood pressure, alcohol consumption, and obesity. Fortunately, some of these can be modified. A 2020 paper in the New England Journal of Medicine (NEJM) showed that moderate drinkers with atrial fibrillation who stopped drinking alcohol for six months had significantly fewer episodes than those who continued drinking. In a 2015 study in the Journal of the American College of Cardiology, people with atrial fibrillation and conditions of overweight or obesity and had a sustained weight HARVARD MEDICINE | AU T U M N 202 3

ATRIAL FIBRILLATION

loss over a long period, spent less time in atrial fibrillation and more time in sinus rhythm. However, perhaps the biggest risk factor is one that cannot be counteracted: aging. “For every decade of life, the likelihood of developing atrial fibrillation increases,” Tedrow says. “We often say that if we lived to be 130, we’d all be in atrial fibrillation.” Ary Goldberger, an HMS professor of medicine and director of the Margret and H. A. Rey Institute for Nonlinear Dynamics at Beth Israel Deaconess, has spent his career studying how complicated systems in the body break down over time. His earlier research focused on fractals: complex geometric forms in nature that may seem irregular, but actually have an underlying pattern, one that repeats itself when viewed at different scales. Examples of such self-similarity abound in the natural world, including in everything from river deltas and tree branches to coastlines and cloud formations. In the 1980s, Goldberger discovered that the healthy heartbeat is fractal-like: it doesn’t beat at metronomic intervals, but rather shows complex variations across timescales ranging from minutes to hours. These hidden fluctuations can be seen on special graphical displays that capture the series of variations over time. This discovery led him and colleagues to formulate the complexity-loss theory of disease and aging, which says that pathologic changes are marked by the degradation in and ultimately the collapse of the fractal-like variations over time. When this breakdown occurs in the control of the heartbeat, it can lead to conditions like atrial fibrillation. Currently, Goldberger is collaborating with Madalena Costa, an HMS assistant professor of medicine and a researcher at Beth Israel Deaconess, to develop a predictive biomarker for atrial fibrillation. Their work is based on the construct known as heart rate fragmentation: During aging and with sub-clinical heart disease, the intervals between consecutive heartbeats lose their normal physiologic interactions. This change is not evident with “snapshot” imaging such as clinical EKGs. “The degradation is hiding in plain view,” Goldberger says. “But you have to analyze the heartbeat as a 14

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Scientists don’t know what causes heart tissue to start spontaneously firing electrical impulses.

time series using novel computational tools that are not currently part of the usual clinical assessment — and are also not a part of traditional heart rate variability measures.” The researchers think that people with more fragmentation, which occurs with aging, have a greater chance of developing atrial fibrillation. “The heartbeat is very accessible and can be recorded using wearable technology,” Goldberger says. “This seemingly mundane output of our body turns out to be a remarkably useful probe of the body’s hidden happenings, including the longstanding challenge of distinguishing between one’s biological versus chronological age.” Yet despite the ubiquity of atrial fibrillation, there are still major knowledge gaps about its basic biology. In particular, scientists don’t know precisely what causes heart tissue to start spontaneously firing electrical impulses, and why it continues to do so over time. They also don’t know why it can be so hard to restore normal heart rhythm in some patients. Given the heterogeneity of the condition, Zimetbaum suspects that atrial fibrillation will turn out to be the common end result of many different mechanisms — but he is eager for more research, especially on a cellular and genetic level. “Atrial fibrillation is extremely complicated, and the truth is that people have lots of hypotheses, but we have a profoundly primitive understanding of the condition,” he says, adding that he finds the current lack of mechanistic understanding frustrating. “Until we understand more about how this happens, we can manage it, but we’re not really going to be able to fix it.” Evolving treatment options

Although physicians identified atrial fibrillation in the early 1900s, it wasn’t until later in the century that a new wave of interest in the condition occurred. “The interest in studying atrial fibrillation and treating it in novel ways is relatively new in the course of cardiac history,” Zimetbaum says. Zimetbaum has been and remains an important part of this wave. In 1997, after realizing that there was enormous variabil-

ity in how physicians were managing atrial fibrillation, he launched an atrial fibrillation registry called FRACTAL. “The goal was to understand the basics of the experience of patients with atrial fibrillation,” he says, adding that a main focus of his career “has been trying to standardize the important parts of managing the disease.” Zimetbaum became especially concerned that in the United States people with a primary problem of atrial fibrillation were spending hours in the emergency department to undergo testing for a heart attack. He and his colleagues reported findings in a 2000 issue of the Journal of the American College of Cardiology indicating that this practice was largely unnecessary. In a 2003 paper in the American Journal of Cardiology, he showed that a new emergency department pathway for atrial fibrillation could reduce the hospitalization rate for the condition from 75 to 30 percent. Much of the renewed interest in atrial fibrillation came after a 1998 paper in NEJM that reported a pivotal finding: The pulmonary veins are a main cause of the condition. It turns out that these veins, which carry oxygen-laden blood from the lungs to the heart so it can be pumped throughout the body, can develop their own electrical activity — especially when the atria are under higher-than-normal pressure resulting from hypertension or a leaky valve. “For years, surgeons had noticed that there is a little bit of heart muscle tissue in the pulmonary veins, and the veins actually beat with the heart,” Tedrow explains. “Certain situations can turn on all the little pacemakers in those veins and trigger atrial fibrillation.” Tedrow estimates that the pulmonary veins are the trigger for up to 95 percent of patients with paroxysmal atrial fibrillation. The findings also showed that the rogue beats could be eliminated with ablation. During this procedure, a cardiac electrophysiologist inserts flexible catheters into the pulmonary veins and uses heat energy or cold energy to create tiny scars that block the problematic electrical signals. “The procedure focuses on isolating the pulmonary veins and limiting the ability

“The hallmark of atrial fibrillation is a pulse that is irregularly irregular — there’s no pattern to the irregularity of the rhythm.”

JOHN SOARES

Peter Zimetbaum

of those little sparks to make their way into the atria and ignite full-blown arrhythmia,” Zimetbaum explains. In around 70 to 80 percent of cases, ablation helps reduce atrial fibrillation and its symptoms. The shift toward ablation has been a major one. Before 1998, physicians typically treated patients with antiarrhythmic drugs, which come with side effects and compliance challenges, or they left patients in atrial fibrillation and used medication to control their heart rate. Over the past decade, newer research — including a 2020 paper in NEJM — has suggested that patients with atrial

fibrillation fare better when their normal heart rhythm is restored. Meanwhile, ablation has become faster, more precise, and more effective. In 2023, another NEJM paper showed that patients who underwent the procedure had better outcomes than those treated with antiarrhythmic drugs or left in atrial fibrillation. “We’ve gotten a lot more aggressive because we can do ablation pretty safely, and there’s more and more evidence that patients do better if they’re in sinus rhythm,” Zimetbaum says. New advances promise to make ablation even faster and safer. Although it is

In around 70 to 80 percent of cases, ablation helps reduce atrial fibrillation and its symptoms.

not a cure, it is a tool that physicians can use to help patients. Another vital part of the picture, Tedrow and Zimetbaum emphasize, is minimizing stroke risk. During atrial fibrillation, the mismatch in beating between the atria and ventricles can cause blood to pool in the atria, increasing the risk of blood clots that can block blood flow to the brain and cause a stroke. The American Heart Association estimates that atrial fibrillation causes one in seven strokes in the United States. Typically, patients with a high risk of stroke take blood thinners daily, regardless of how much atrial fibrillation they experience — but the drugs come with their own risks and side effects. Zimetbaum is trying to make treatment for stroke prevention more targeted: He is an investigator on the REACT-AF trial, which is exploring whether patients can start and stop the drugs based on when they are in atrial fibrillation. “If this tailored approach turns out to be a safe and effective way to manage blood thinners for some patients, then I think it would be an enormous advance,” Zimetbaum says. Even as treatments improve, managing atrial fibrillation will continue to require nuanced and in-depth conversations with patients to help physicians understand what the best course of action may be based on the patient’s own experience and goals. Usually, patients are most concerned about being able to work, exercise, travel, and generally live their lives. For patients with frequent atrial fibrillation, this may mean actively trying to return their hearts to a normal rhythm. “I had a patient come to clinic wearing a T-shirt that said ‘I want to be in sinus rhythm,’ ” Tedrow recalls. For other patients, this may mean few interventions. “It’s a partnership,” Tedrow says. Zimetbaum agrees. “It requires working together with patients,” he says. “It’s incredibly rewarding to get patients to a place where atrial fibrillation is not dominating their consciousness.” Catherine Caruso is a science writer in the HMS Office of Communications and External Relations. HARVARD MEDICINE | AU T U M N 202 3

THE HEART

I CLIMATE IN THE CLINIC

Internal Review Hospitals are waking up to their climate change culpability and the mandate to act BY STE PHANIE DUTCHEN

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alking about climate change and health care usually involves recognizing how extreme weather events and shifting climate patterns harm people and threaten practitioners’ ability to provide care. But another facet of the issue has been gaining attention: how the health care industry itself contributes to climate change, and what can be done about it without compromising care. Data suggest that the global health care sector belches out between 4.4 and 5.2 percent of the world’s greenhouse gas emissions. Aviation, by comparison, is estimated to contribute 2 to 5 percent. In a landmark 2019 report, the group Health Care Without Harm calculated that the United States produces the greatest share of the world’s health care emissions and has the highest per-capita health care climate footprint. Those statistics alarm increasing numbers of U.S. practitioners and administrators as they realize that the systems they work in can run counter to the principle of doing no harm. Such alarm can paralyze — or spur action. “It’s an ethical imperative for health care to take this seriously and transform the way it does things,” says Anand Bhopal, a PhD research fellow at the University of Bergen focusing on health care decarbonization and a recent Takemi Associate in International Health at the Harvard T.H. Chan School of Public Health. “By sorting out our own house, we can inspire the global movement toward zero emissions to go ever faster.”

DTIMIRAOS/ISTOCK/GETTY IMAGES

Making changes, planning for more

First come awareness and quantification. Medical specialties and hospital and department teams are gauging their contributions, from estimating emissions to doing trash audits. Physicians are pushing for low-carbon alternatives when appropriate, such as telemedicine and virtual professional meetings. Statisticians are breaking down emissions within health care — supply chains, pharmaceutical production, ambulance and employee travel, energy use in buildings, anesthesia — to better understand what needs tackling. Next come creation and assessment of mitigation strategies. Some motivation trickles down from the top as organizations draft plans to achieve net-zero carbon emissions by 2050, per recommendations from the United Nations Intergovernmental Panel on Climate Change. Leaders include the U.N. and the World Health Organization, the National Academy of Medicine’s Action Collaborative on Decarbonizing the U.S. Health Sector, and the White House/U.S. Department of Health and Human Services’ Health Sector Climate Pledge. The Joint Commission, the health care accrediting organization, almost joined them when it proposed earlier this year that

carbon reduction practices become part of the rubric for accrediting hospitals, but it later made such practices voluntary. Significant change also can come from the bottom up. So-called easy wins include reducing greenhouse gases in anesthesia and inhalers and identifying where disposable materials can be replaced with recyclable or reusable ones. Some labs are experimenting with slightly raising subzero freezer temperatures to save energy without damaging biological samples. Jonathan Slutzman, an HMS assistant professor of emergency medicine and medical director for environmental sustainability at Massachusetts General Hospital, and colleagues laid out dozens of practical steps that emergency medicine and other departments can take in a 2020 Annals of Emergency Medicine article. Institutions are rising to the occasion. Mass General cut its energy use by 36 percent in the past 15 years by ramping up use of cogeneration technology, which produces electricity and usable heat at the same time; installing solar panels; and buying more of its power from local wind farms. Teams that find success — including the hospital’s Center for the Environment and Health — share what they learn with others. “We want to create processes that make it easy to do the right thing,” says Slutzman, who directs the center. “If we find things that are good for the environment, save money, and improve or are neutral for patient care, why not offer those solutions to other hospitals in this country?” Advocates for decarbonizing health care find allies in many arenas. Economically, cutting carbon often cuts costs. For employers, sustainability can improve staff morale and retention. Slashing emissions in wealthy nations supports global health equity by making space for low- and middle-income countries to strengthen their care infrastructure. Striving for net-zero emissions aligns with efforts to incentivize prevention over treatment in U.S. health care; healthy people, after all, require fewer medical resources. “The best way to decarbonize health care is to not use health care,” Aaron Bernstein, who was then interim director of the Harvard Chan School’s Center for Climate, Health, and the Global Environment, said at a March 2023 webinar. It can be hard to imagine incorporating climate considerations into day-to-day care when practitioners are already battling time constraints and pandemic burnout. But keeping people healthy requires a healthy planet, and most clinicians want to be part of the solution, says Slutzman. “Every clinician can play a role,” he says. “We have the technology. The question is, do we have the will.” Stephanie Dutchen is the manager of feature content and multimedia in the HMS Office of Communications and External Relations. HARVARD MEDICINE | AU T U M N 202 3

THE HEART

I CORONARY-COGNITIVE LINKS

The health of the heart is linked to the health of the brain — and vice versa

Shared Experience

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COURTESY MUSÉE DU LOUVRE, DÉPARTEMENT DES PEINTURES

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For centuries, folklore from every corner of the globe has held that a person’s psychological state can affect their physical health, sometimes suddenly and fatally. Apocryphal tales of death from fright or heartbreak abound, from the biblical account of Ananias and Sapphira both keeling over lifeless after being accused of lying to the Holy Spirit to Romeo and Juliet’s Lord Montague recounting how his wife’s “grief of my son’s exile hath stopp’d her breath.” BY EL IZAB ETH G EH R M A N

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CORONARY-COGNITIVE LINKS

Linked in heath and illness

to explore this phenomenon was Walter Bradford Cannon, Class of 1900, who was chair of the Department of Physiology at HMS. He coined the term “fight or flight” in 1915 and in 1942 published a paper in American Anthropologist presenting reports of so-called voodoo death recounted by explorers in South America, Africa, Australia, New Zealand, and the Caribbean since the 1500s. Cannon reviewed several cases in which an apparently healthy, vibrant individual began to languish after being accused of misdeeds by a powerful tribal leader and died within one to four days. He also noted one incident in which a shaman came to the bedside of a young man named Rob and said, oops, it had all been a mistake. “The relief,” Cannon writes, “was almost instantaneous. That evening Rob was back at work, quite happy again, and in full possession of his physical strength.” Cannon proposed, iconoclastically, that these incidents were not the work of dark magic as was supposed, but instead resulted from the “sympathetico-adrenal complex” constricting the blood vessels in response to “shocking emotional stress.” He pointed out that toward “the victim’s last gasp” one might find low blood pressure, rapid and thready pulse, and clammy skin — all associated with heart failure. 20

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There’s no longer any doubt that Cannon was right: Our thoughts and emotions can affect our heart health, and what happens to the heart, likewise, can influence the health of the brain. Solid research now links PTSD, anxiety, depression, Parkinson’s disease, bipolar disorder, and schizophrenia to increased risk of cardiovascular disease (CVD), and studies associate CVD with impaired cognition, white-matter damage, cerebrovascular disease, and dementia. According to the Alzheimer’s Association, postmortem studies show that as many as eight in ten patients with Alzheimer’s also have heart problems. These comorbidities don’t just make for an interesting pathology to untangle. The World Health Organization calls heart disease the number-one cause of death worldwide and depression the “single largcontributor to global disability.” In the Eighty years est United States alone, chronic diseases cost after Cannon $37 trillion a year, or almost 20 percent of first posited the nation’s GDP, in direct expenses and lost the existence productivity. “Both mental health and heart disease make up a large share of that,” says Jill of a brainheart connec- Goldstein, an HMS professor of psychiatry and medicine and founder and executive tion, the director of the Innovation Center on Sex science Differences in Medicine at Massachusetts remains in General Hospital. “And when they co-occur, the cost increases even further. These disorits infancy. ders are also major risk factors for Alzheimer’s disease and the aging brain,” adding, “So if we do not target them early to prevent what’s coming down the road for our aging population, they could tank our economy.” Eighty years after Cannon first posited the existence of a brain-heart connection, the science remains in its infancy, largely because skepticism lingered for decades. In 1985 in the New England Journal of Medicine, then editor Marcia Angell, now a corresponding member of the faculty of the Department of Global Health and Social Medicine in the Blavatnik Institute at HMS, wrote an editorial noting that research had not shown a link between psychology and physiology though she acknowledged that “most Americans” believed in one. “She basically said, Wouldn’t it be great if this

were true, but it’s not,” says Laura Kubzansky, a behavioral sciences professor at the Harvard T.H. Chan School of Public Health who has studied the link. “You can find arguments like this into the 2000s. Part of the reason is that historically it was hard to get research funded, which meant the studies weren’t very good. It’s still underresourced compared with many topics.” Terms like cardioneurology, neurocardiology, and psychocardiology all arose in the 1960s to describe aspects of this emerging interdisciplinary field, yet even today, no major medical body — not the U.S. Centers for Disease Control and Prevention, the National Institutes of Health, or the American Heart Association — lists psychological troubles as a risk factor for cardiovascular disease. The tide may be slowly turning, though; all three organizations at least address stress and other mental health disorders on their websites, and in 2021 the AHA issued a scientific statement, signed by Kubzansky and thirteen others, affirming that one’s mental state can play a role in heart health. “For something to be elevated to the status of risk factor,” Kubzansky says, “there has to be a lot of evidence. In the past two decades the quality of evidence has become increasingly rigorous and convincing, and it’s getting harder to dismiss.” The link also tends to get short shrift from clinicians, in part, says Goldstein, because medicine has grown up siloed by organ systems and separate diseases. “Although physicians specialize, given all the technological advances in certain fields,” she notes, “it is also important to look at commonalities among organ systems.” Understanding shared causal pathways is an important first step. “The vagus nerve is probably the most-researched channel through which the heart and mind talk,” says Kubzansky. The vagus nerve highway

Among the longest nerves in the human body, the vagus controls autonomic functions like breathing, heart rate, and blood pressure, as well as reflexes like coughing and survival behaviors like eating and drinking.

“The vagus nerve is a bidirectional inforFor many neurons it’s mation highway,” says molecular neurosciunclear what entist Stephen Liberles, a professor of cell biology in the Blavatnik Institute at HMS initiates the and a Howard Hughes Medical Institute communica- Investigator. “It has sensory neurons that tion between take information from the body to the brain and motor neurons that go in the opposite body and direction.” Liberles explains that though we brain.

GRETCHEN ERTL

Stephen Liberles

“You know you’re nervous when you get butterflies in your stomach, but is the brain making the butterflies or are they already there and then you perceive them?”

know “a dizzying array” of neurons innervate essentially every major organ in the body, for many neurons it’s unclear what initiates the communication between body and brain. “You know you’re nervous when you get butterflies in your stomach,” he says, “but is the brain making the butterflies or are they already there and then you perceive them? We have no idea what neurons in the circuit are firing or how they send signals deeper into the brain.” Liberles studies neural populations in the vagus nerves of mice “with exquisite control” by introducing genes for lightsensitive proteins. “We can precisely measure the roles of particular neurons in physiology and behavior,” he says, “by activating or eliminating them and then observing the response.” When you trigger a specific neuron, does the animal become stressed? Does it eat more? Does its heart rate increase? The catch, of course, is that scientists don’t always know for sure what a mouse is thinking or feeling, and they can’t do similar experiments on people because of the ethical issues around manipulating human genomes. But the electrical pathway isn’t the only connection. The immune, metabolic, vascular, and hormonal systems mediate interactions between the heart and brain, and there also has been a recent explosion of articles on the genetic traits shared by cardiometabolic diseases, depression, and CVD. The influence of stress

“We know there are sex differences in the development of the brain and body, including the heart, beginning in fetal development,” says Goldstein. While fetal development is not deterministic, there are effects during this period that can set the HARVARD MEDICINE | AU T U M N 202 3

CORONARY-COGNITIVE LINKS

stage for health across the life span, even though the effects can vary due to life experiences and exposures.” Studies have shown that men and women have different stress reactions, too, which affect the brain and heart. In women, stress can increase lipid imbalance and platelet aggregation and decrease glucose regulation and the flow of blood to the heart, whereas men tend to experience greater spikes in blood pressure, heart rate, and adrenocorticotropic hormone, which controls the production of cortisol. This is particularly concerning because 84 percent of U.S. residents who responded to a 2022 survey by the research organization ValuePenguin reported feeling stressed “weekly,” and in that same year, the American Psychological Association found that a third of its frazzled survey respondents considered their stress “overwhelming.” Antonia Seligowski, an HMS assistant professor of psychology and director of Massachusetts General Hospital’s Neurocardiac Effects of Stress and Trauma Lab, says, “the research is clear that chronic, debilitating stress is more likely to bring about a heart condition.” PTSD, for example, is associated with a 27 percent increase in CVD events and cardiac-specific mortality, according to a meta-analysis reported in 2021 in JAMA Cardiology. “When we experience stress,” Seligowski explains, “our sympathetic nervous system triggers an immune response that releases cytokines in the blood, which inflame the arteries over time and promote the plaque that produces atherosclerosis, the main underlying cause of heart disease.” A picture of those at risk

Stress may also be one reason for health inequities among various populations in the United States. While death rates from CVD have declined significantly in the past fifty years — from 1,034 to 327 per 100,000 people — numerous studies have shown that people of color have increased risk of heart problems and poorer outcomes once they do occur. “A lot of people are looking at why,” Kubzansky says. “Stress may be one reason, but there’s a paradox: Black people, for example, may seem 22

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to have more physical health difficulties, but Takotsubo they appear to have similar or lower rates of was initially mental health problems than white people, implicated even accounting for other social factors like in the death income or education. So more data is defiof the actor nitely needed to better understand the role of stress in health disparities.” Debbie Stress effects also differ by sex. StatisReynolds one tics from the National Center for PTSD day after her show that twice as many women as men daughter, will have the disorder at some point in their Carrie Fisher, lives. In part, says Seligowski, that’s because died from car- “women experience more interpersonal assault, which leads to PTSD more often diac arrest.

than other types of experiences, like a car accident, for example.” Women are more inclined to report symptoms and seek treatment, too, which may contribute to their higher diagnosis rate. Nearly all cases of takotsubo cardiomyopathy, a weakening of the blood-pumping left ventricle in healthy individuals experiencing sudden stress, occur in women; in fact, research indicates that up to 5 percent of women suspected of having a heart attack actually have this disorder instead. Also known as broken heart syndrome, takotsubo was named after the ballooning left ventricle’s resemblance to a type of octopus trap used in Japan, where the malady was first described in 1990. “There’s a greater propensity to develop takotsubo if there’s preexisting stress anxiety or underlying anxiety,” says Seligowski, who is working with a research group that found greater activity in the amygdala, a brain region involved in emotional processing, in patients with takotsubo. The disorder was initially implicated in the death of the actor Debbie Reynolds one day after her daughter, Carrie Fisher, died from cardiac arrest, though Reynolds’s official death certificate blames stroke. The jury is still out on Lady Montague. Disposition may be key

Just like those butterflies in the stomach, the stress effect runs both ways. “An emerging area of research that we know much less about is how cardiac events can result in PTSD,” says Seligowski. But negative emotions are only part of the equation.

In 2001, Kubzansky co-authored one of the first epidemiologic studies reporting that optimism is associated with a lowered risk of developing cardiovascular events, including angina, myocardial infarction, and death, adding these to a long list of other clinical outcomes that appear to be improved by an optimistic outlook, including cognitive decline, respiratory illnesses, infections, and even some cancers. And Kubzansky and her colleagues learned the effect of having a positive outlook can be even stronger than the negative effect of pessimistic thinking, in part because it may help mitigate the stress response. “Optimistic individuals,” the study points out, “... may experience fewer stressors, or they may have more resources with which to deal with stress.” From a clinical standpoint, why does this matter? “We spend a lot of time in medicine and public health looking at risk factors and deficits,” Kubzansky says, “but not nearly as much time looking at assets and resources. We can’t mitigate or remove all the environmental factors that can contribute to disease, but if we can identify a strength to add to the mix, it might improve overall health and reduce the disease burden rather than constantly trying to pick up the pieces after a disease has already developed or been set in motion.” A key point for patients is that optimism is 25 to 35 percent heritable, Kubzansky says. “That means there’s a lot of room to modify it.” Educational and socioeconomic factors have been linked with higher optimism; while these may not be easily altered, studies have shown that regular physical activity, mindfulness, and an active social life can all help cultivate an optimistic outlook — and are within an individual’s power to change. “These are correlations,” Kubzansky points out, “so it’s hard to say for sure whether they’re precursors to optimism or the results of it.” Greater social connectedness, for example, could promote optimism because problem-solving is easier when you’re not alone, she contends. Or maybe optimists are just more fun to be around, so they develop a larger social network. “Either way,” Kubzansky notes, “the qualities that

correlate with optimism are worth striving for in themselves.”

JOHN SOARES

“The research is clear that chronic, debilitating stress is more likely to bring about a heart condition.”

The search for early warning signs

While interventions made later in life are helpful for preventing CVD, a life span perspective is absolutely critical, according to Goldstein. “There are naturalistic windows of opportunity for studying sex differences, specifically fetal development and puberty, and, in women, pregnancy and menopause,” she says. “During these windows, sex differences emerge as the body and brain are each differentially flooded with or depleted of gonadal hormones.” Goldstein explains that these naturalistic windows can be used to understand the early origins of diseases that may occur later in life. “For example,” she says, “we know that there are developmental origins of disorders of the brain, like depression, and of the heart, like CVD. And we know that some of these early, even fatal, origins are shared between the brain and the heart.” Understanding the shared roots, Goldstein says, “allows you to target one disorder, like depression, that onsets earlier than CVD in order to potentially help prevent the other,” adding that CVD typically occurs later than depression. By studying fetal and early childhood antecedents and how major disorders occur at different periods across the life span, Goldstein maintains, “we can focus our therapeutics earlier and identify early resiliencies to either attenuate disability or prevent future disease.” Which, of course, is the ultimate goal. “Cardiologists and neurologists usually don’t see people until they’re either sick or almost sick,” Kubzansky says. “But that could start to change if clinicians look at health as a constellation and remember that mind and body are not separate. If you ignore what’s going on from a mental health perspective or ignore the heart health of patients with brain disorders, you’re going to miss a lot of opportunities to improve outcomes.” Antonia Seligowski

Elizabeth Gehrman is a Boston-based writer. HARVARD MEDICINE | AU T U M N 202 3

THE HEART

I THE EFFECTS OF SARS-CoV-2

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Researchers increasingly find that the effects of infection by SARS-CoV-2 extend to the heart

collateral damage DUNG HOANG

BY CHARLES SCHM IDT

AS THE COVID-19 PANDEMIC was getting underway in early 2020, doctors in Wuhan, China, began to report that many patients hospitalized with the disease had cardiac injuries. Heart attacks were frequent, especially in patients with underlying risk factors, and there were numerous cases of myocarditis, which occurs when the heart’s muscle layers become inflamed. Roughly a quarter of patients with severe COVID-19 had elevated blood levels of troponin, a protein marker for cardiac damage. n This evidence altered how COVID19 was viewed; previously considered primarily a form of pneumonia, it now took on a coronary dimension. “We began to understand that it’s also a cardiovascular disease,” says Peter Libby, the Mallinckrodt Professor of Medicine at HMS and a cardiologist at Brigham and Women’s Hospital. HARVARD MEDICINE | AU T U M N 202 3

THE EFFECTS OF SARS-CoV-2

ospitalizations and deaths from COVID-19 have since fallen off, the result of widespread vaccinations and the population’s growing immunity against severe disease. But SARS-CoV-2, the coronavirus that causes COVID-19, is still with us, along with the risk it poses to heart health, especially in people with blocked arteries, hypertension, diabetes, and other predisposing factors. Millions of people who recover from COVID-19 have gone on to develop lingering cardiovascular symptoms, including abnormal heartbeats, dizziness, and shortness of breath. The number of COVID-19 cases is once again spiking — and the coronavirus continues to evolve. The latest omicron variant, BA.2.86, has more than thirty mutations that could allow it to evade the immune system’s defenses. Given the ongoing threat, research into COVID-19’s cardiovascular effects “remains vitally important,” says Anne-Marie Anagnostopoulos, a cardiologist and an HMS instructor in medicine at Beth Israel Deaconess Medical Center. “We need a greater understanding of the associated pathophysiology to develop better treatments.” Heart ills resulting from COVID

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JOHN SOARES

In most people — especially those who’ve been vaccinated — COVID-19 produces flulike symptoms that typically resolve within a few days or weeks. But other people progress to a second, and more dangerous, phase of the disease, as pro-inflammatory proteins called cytokines proliferate in the blood. During this so-called cytokine storm, the immune system becomes hyperactive, “causing a different set of problems,” says Dara Lee Lewis, MD ’92, an HMS instructor in medicine at Brigham and Women’s and director of noninvasive testing and co-director of the Women’s Cardiology Program at the Lown

Anne-Marie Anagnostopoulos

JOHN SOARES (FACING PAGE)

Cardiology Group in Boston. “Patients can develop weakened heart muscles, low oxygen levels, blood clots, fluid in the lungs — problems that may require hospitalization.” More importantly, pre-existing cardiac risk factors, such as coronary artery disease and obesity — which can predispose patients to metabolic inflammation — raise the likelihood for poor outcomes. People with vulnerable hearts, Lee Lewis explains, are more likely to succumb to COVID-19 complications than others who do not have these risk factors. In a worst-case scenario, patients could experience a type 1 myocardial infarction, which is a heart attack caused when a blood clot blocks flow in the arteries. But COVID-19 patients are also unusually prone to a different type of heart attack called a type 2 myocardial infarction. In these cases, the problem isn’t a blockage in the arteries, but rather a mismatch between oxygen supply and oxygen demand. Fever and inflammation accelerate heart rate and increase metabolic demands on many organs, including the heart. If infected lungs are incapable of effectively exchanging oxygen and carbon dioxide, then stressed hearts might suffer damage due to insufficient oxygen. Lee Lewis says that early in the pandemic, myocarditis was also a major concern, especially for student athletes. “These kids didn’t need to just go back to work and life,” she says. “They needed to get back to competitive play.” Some students she cared for who had been sick with COVID-19 showed up with chest pain, racing hearts, shortness of breath, and evidence of myocarditis on magnetic resonance imaging. Studies from around the world were reporting that up to one-third of patients who had recovered from COVID-19

also showed evidence of asymptomatic myocarditis on imaging studies. This was troubling, since post-viral myocarditis is a known cause of sudden cardiac death in athletes. “We worried that many of our student athletes would be unable to return to competitive play,” Lee Lewis says. Fortunately, the asymptomatic cases turned out to be uneventful, and the affected students made full recoveries. “Asymptomatic myocarditis wasn’t as big an issue as we initially feared it would be,” Lee Lewis adds. “So, we stopped doing MRIs on everyone who walked in the door.”

Autopsies of susceptible to the coronavirus spike protein. patients who The spike protein is key to the virus’s infectivity. Once the spike protein is docked to died from cell-based receptors, it acts to allow SARSCOVID-19 re- CoV-2 to enter a cell. vealed clots Respiratory epithelial cells are considered throughout to be key targets of infection, as are pericytes, the body and which are cells that wrap around capillaries. When infected by the virus, these cells release evidence cytokines that, in turn, act on other cell types of multiple that collectively form the interior lining of all organ failure. blood vessels in the body. This lining, known

A push to understand SARS-CoV-2

That COVID-19 could be so closely associated with heart health wasn’t entirely unexpected. Scientists already knew that other types of infections, such as flu and bacterial sepsis, can amplify cardiac risk factors. It’s not uncommon for older people to have inactive plaques in coronary arteries. The plaques can be destabilized by a localized inflammatory response to remote infections. COVID-19 put a spotlight on these connections and led to greater awareness of the interplay between infections and cardiac disease. But as an unknown virus, SARS-CoV-2 raised many new questions. One example — whether the virus infects myocytes, the cells responsible for heart contractions — “was initially a big issue,” Libby says. Research has since shown that myocytes for the most part escape infection. Instead, SARS-CoV-2 damages the heart indirectly by unleashing inflammatory reactions that affect cardiovascular functioning. Upon invading the body, SARS-CoV-2 latches onto cells studded with receptors that are

“We need a greater understanding of the associated pathophysiology to develop better treatments.”

as the vascular endothelium, “can be thought of as an organ in and of itself,” Lee Lewis says. “The endothelium has a huge job in preventing inappropriate blood clots and allowing blood vessels to constrict and dilate when they normally should.” Normally, the endothelium keeps blood flowing in a liquid state. But when cytokines activate endothelial cells, the cells transition to a defensive posture: they mobilize macrophages and other immune cells and release molecules that promote blood clotting. “Cytokines speak to cells throughout the body,” explains Jeremy Luban, a professor at UMass Chan Medical School who also serves on the executive committee of the Massachusetts Consortium on Pathogen Readiness, an HMS-led multi-institutional effort to slow the spread of COVID-19 and prepare for future pandemics. “And among the cells that may be listening are endothelial cells, which constantly have to monitor for coagulation and tissue damage states and induce actions like clotting to stop bleeding and other measures to prevent harm to tissues.” But blood clots can be lethal. They can, for instance, obstruct arteries feeding the brain. During the pandemic’s early months, arterial blockages were implicated in strokes in numerous patients, even in young people without predisposing risk factors. Autopsies of patients who died from COVID-19 revealed clots throughout the body and evidence of multiple organ failure. Up to one-third of patients hospitalized with COVID-19 were shown to have myocardial injuries that Libby attributes to microvascular clots and endothelial dysfunction, among other conditions. HARVARD MEDICINE | AU T U M N 202 3

THE EFFECTS OF SARS-CoV-2

POTS and viral infection

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Severe initial disease is still the best predictor of long-term symptoms.

often feel dizzy, fatigue easily, have trouble exercising, and are prone to fainting. “POTS is something that we as cardiologists, friends, and neighbors need to be on the lookout for,” Lee Lewis says. “Many people suffer with it for weeks or months before getting a diagnosis.” POTS affects up to three million people in the United States, most of them women between the ages of 15 and 50, and often begins after pregnancy, trauma, or a major surgery. A family history of POTS also boosts the risk. But, according to Lee Lewis, POTS cases associated with COVID-19 can affect men or women. At this time clinicians are unsure what the prognosis will be for these patients. How does virally triggered POTS develop in the first place? Mounting evidence points to inflammatory effects on nerves that control blood flow and heart rate. Apart from acting directly on the endothelium, inflammation targets small nerve fibers that dictate when blood vessels should dilate or constrict. Impulses sent through the sympathetic nervous system, for instance, normally tell blood vessels to constrict and the heart rate to increase during standing in order to maintain adequate blood pressure to the brain. However, in people with POTS, the blood vessels may not constrict appropriately. Instead, the heart rate must rise even more than normal to compensate for the “lazy” blood vessels, says Lee Lewis. Conversely, the parasympathetic nervous system kicks in when the body rests, instructing blood vessels to dilate and instructing the heart to beat more slowly so the blood pressure goes down. When people stand, blood moves to the lower extremities. To counter this drop, the brain triggers the release of a burst of norepinephrine, which signals the sympathetic nervous system to cause vessels to constrict and the heart to beat faster, moving the blood back to the brain and torso. In someone with POTS, that normal response “gets thrown out of whack,” Lee Lewis says. The vessels don’t constrict and blood stays pooled in the legs, yet the heart rate speeds up and stays elevated. Lee Lewis often works with Peter Novak, an associate professor of neurology at

Brigham and Women’s and a specialist in long COVID. He describes POTS as one of many dysautonomias resulting from imbalances in the autonomic nervous system, which includes the sympathetic and parasympathetic systems. The autonomic nervous system controls involuntary physiological processes; not just heart rate and blood pressure, but also breathing, digestion, and sexual arousal. Novak estimates that 60 to 80 percent of patients with long COVID have symptoms of autonomic dysfunction, with POTS being the most common. Treatments for long COVID

Levy describes long COVID as a postpandemic pandemic. “Something like sixty-five million people worldwide have been affected,” he says, adding that long COVID profoundly affects people’s ability to work, go to school, or both. The COVID Recovery Center at Brigham and Women’s currently sees up to 150 patients each month and has a waiting list of four to six weeks. About 10 percent of the roughly four thousand patients seen so far were evaluated for cardiovascular problems. But that’s probably an underestimate, Levy says, since patients with POTS and other cardiovascular symptoms are likely to be referred directly to cardiology and not the recovery center for initial evaluation and treatment. According to Anagnostopoulos, therapeutic strategies for patients with long COVID and a POTS-like syndrome or exercise intolerance and tachycardia emphasize light exercise and structured endurance training. The goal is to ward off a “deconditioning spiral” that might cause the original problem to worsen. Similar to POTS, if patients remain sedentary for too long, Anagnostopoulos says, they could develop cardiac atrophy; decreased stroke volume, meaning that the heart doesn’t pump enough blood out of the left ventricle during contraction; or compensatory tachycardia, characterized by resting heart rates that exceed 100 beats per minute. “It’s important to acknowledge that these patients are suffering,” Anagnostopoulos says. “Many of them are young and unac-

JOHN SOARES

Microvascular damage has also been implicated in the long-term symptoms that now constitute a growing focus of COVID-19 research. “Even five months after the acute phase of the illness, we can detect these disturbances,” Libby says. He adds that answers to the mystery of what causes long COVID may be found in microvascular dysfunction. Bruce Levy, the Parker B. Francis Professor of Medicine at HMS and a co-founder of Brigham and Women’s COVID Recovery Center, agrees. The fact that microvessels are present throughout the body, Levy says, might explain why long COVID has been associated with more than 200 symptoms affecting nearly every organ. Brain fog and the confusion and forgetfulness that attends it, for instance, might result from inflammation’s effects on blood vessels in the central nervous system, while long-term cardiovascular symptoms might arise from inflammation in the small vessels leading to and surrounding the heart. A paper that appeared in August 2023 in Nature Medicine reported an extensive analysis of health care data collected by the U.S. Department of Veterans Affairs during a two-year follow-up of veterans who survived the first thirty days of a SARS-CoV-2 infection and data from a control cohort that had not shown evidence of infection. The study looked at risk of death, hospitalization, and pulmonary and nonpulmonary sequelae. Its findings showed that cardiovascular problems sometimes linger even in people who were never hospitalized for COVID-19. Levy, however, points out that severe initial disease is still the best predictor of long-term symptoms. Among the more common lingering problems — affecting up to one-third of all patients with long COVID — is postural orthostatic tachycardia syndrome (POTS), which causes the heart to beat abnormally fast. POTS can be diagnosed if a patient’s standing heart rate test measures a sustained increase of at least 30 beats per minute that persists for ten minutes or more after a patient stands. In many patients with POTS, standing heart rates exceed 120 beats per minute. People who have the condition

“POTS is something that we need to be on the lookout for. Many people suffer with it for weeks or months before getting a diagnosis.”

Dara Lee Antonia Lewis Seligowski

customed to being sick or held back in any way from what they want to do. They often feel they haven’t been taken seriously. And what they want to know is that the doctor sitting with them is developing a plan for improvement.” Anagnostopoulos points to a 2022 report on long COVID in adults by the American College of Cardiology, which cautions against starting treatment for tachycardia or POTS with upright exercise such as power walking or jogging. According to the report, these activities might “worsen fatigue, resulting in post-exertional malaise.” The report’s authors recommend instead a preliminary strategy of recumbent and semirecumbent exercises, such as stationary biking and rowing, with increasing intensity as a patient regains functional capacity. Researchers are also making headway on how best to approach cardiovascular threats in acutely ill patients with COVID-19. Given a high prevalence of clotting disorders, it might be assumed that anticoagulants and antiplatelet treatments would improve outcomes. But some clinicians caution that bleeding risks from those drugs may outweigh their potential benefits. Advances are also being made in the use of anticytokines, such as glucocorticoids and monoclonal antibodies, to counter systemic inflammation. Libby emphasizes that future trials investigating COVID-19’s cardiovascular effects need to be better coordinated. An initial rush to respond to the pandemic produced a flood of observational and non-randomized studies in this area, he says, which spread more confusion than illumination. Although the pandemic seems to be receding, Luban cautions against complacency. Cardiovascular disease remains a leading killer and, after declining for years, deaths from heart attack and stroke rose again as SARS-CoV-2 spread worldwide. Fortunately, the virus has not yet evolved to a more virulent form, he says, adding that “it’s heartening that vaccine protection against hospitalization and severe disease seems to be hanging in there. But who knows what will happen? This virus has surprised us every step of the way.” Charles Schmidt is a writer based in Maine. HARVARD MEDICINE | AU T U M N 202 3

THE HEART

I DISPARITIES IN CVD CARE

Herman Taylor

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A physician-researcher has spent his career advocating for better cardiovascular care for Black people

BY ANN MARIE MENTING

GREGORY MILLER

Unwavering Purpose

COMMUNITY RECURS AS A THEME in the life of Herman Taylor, MD ’80. Early on, it came to him by chance, for he was part of a family and a church that were close and supportive. Later, as a first-year student at HMS, it came to him by circumstance in the form of lifelong friendships, forged during anatomy classes, with three Black classmates. Still later, it came to Taylor by choice, drawn from his commitment to being a physician, cardiologist, researcher, and advocate who seeks to improve health and research equity for Black people. This chosen path led him into established communities where he worked to become a trusted member by involving community members in health intervention studies and educating them on cardiovascular risk factors, all the while partnering with governmental, academic, and philanthropic institutions to ensure that the fruits of U.S. medical research and clinical advances would be available to all people. The clinical foundation for Taylor’s career began with an internship at Mount Auburn Hospital in Cambridge, Massachusetts. A subsequent three-year tour with the National Health Service Corps in Miami’s Liberty City enclave brought Taylor face-to-face with myriad health issues of both the area’s Black residents and members of its Haitian and Cuban refugee communities. After Liberty City, Taylor began an internal medicine residency at the University of North Carolina at Chapel Hill, then pursued an interventional cardiology fellowship at the University of Alabama at Birmingham, where he became a member of the faculty and the founding medical director of the UAB Hospital Cardio-Pulmonary Rehabilitation Service.

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DISPARITIES IN CVD CARE

In 1998, Taylor joined the Jackson Heart Study as its principal investigator and founding director while also holding professorships at the University of Mississippi Medical Center (UMMC), Jackson State University, and Tougaloo College, each affiliated with the study. The study remains the most significant epidemiological study of cardiovascular disease in Black people. In 2014, Taylor became the endowed professor and director of the Cardiovascular Research Institute at Morehouse School of Medicine, where he continues to be a lead investigator on several cardiovascular studies supported by the National Institutes of Health. Taylor has received numerous awards and recognitions for his work as a clinician, researcher, and mentor. He also has testified about cardiovascular disease prevention and health equity in hearings convened by the U.S. House and Senate and in meetings of the U.S. Civil Rights Commission. Taylor spoke with Harvard Medicine magazine about his career. An edited version of that conversation follows. Let’s start with Princeton and HMS. Why did you choose those two schools?

My path to Princeton began with my sincere wish to leave the South and see what was out there. Now, my father had asked me to apply to the University of Alabama. He said that since we had to pry George Wallace out of the doors of UA so that we could attend, I needed to apply. I did, but I also applied to Princeton. Although I wanted to leave Alabama, I did want to return, and I said so in my application: I wanted to get the best credentials possible to work in the South in medicine and to do whatever good I could there. When Princeton said yes and provided me the means to attend, I accepted. When applying to medical schools, I set my sights on HMS because I knew the best preparation in medicine would be found there. I applied to a robust list of medical schools, but Harvard was the obvious choice in my mind. When you arrived, did you feel you had made the right decision?

I did! From the first day, the excitement was just incredible. Some of the brightest people you’d ever hope to meet were in your classes. If we go down a list of what they’re doing now, that would prove true. And the lecturers, particularly in the first couple of years, were incredible. They were inspiring to be around. The best of them integrated humanity into the clinical question at hand and showed how the science of the day could be brought to bear in resolving a human problem. These were important, informative experiences for me. My journey is an incredible odyssey, from growing up in the shadow of the steel mills in Bessemer, Alabama, and breathing air polluted by iron ore to walking the Quadrangle at HMS. Incredible. So tell me, why medicine, why cardiology?

Well, those decisions have interesting stories. The decision to pursue cardiology grew out of a summer research experience I had 32

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I wanted to get the best credentials possible to work in the South in medicine and to do whatever good I could there.

during my undergraduate years. This summer research fellowship program, held at what is now the Weill Cornell Medical College in New York City, was designed for minority students who were thinking about attending medical school. It was highly competitive. One of its courses was a medical school-level course in cardiovascular physiology. I took it, and I immediately fell in love with the discipline. I said, ‘I’m going to be a cardiologist.’ And when I became aware of the great disparities in cardiovascular health between Black and white populations, my interest was further fueled. But I was in college, and, like many college students, my intentions would waver. Even though I had declared my interest in medicine and cardiology, I also liked architecture, or thought I liked it. I was wondering which career would satisfy me over a lifetime. One Sunday after church, I was sitting on my grandmother’s porch and talking to her about my indecision. She was rocking back and forth, but she stopped rocking and said, ‘Junior’ — that’s me — ‘you know health is the first blessing.’ That brought it all together. One of the activities you were involved in early in your career brought together cardiology and the power of the Black church, right? Heart to Heart?

That program was a not-for-profit I founded in the early 1990s. I had completed my cardiology fellowship at the University of Alabama at Birmingham, and had started as an instructor on the cardiology faculty there, when I traveled to Kenya to attend an annual conference of the former International Society on Hypertension in Blacks. When these conferences ended, attendees had a tradition of performing a day of community work, so this time we went to a rural clinic outside Nairobi. At the end of the day, a woman came to us with her 10-year-old daughter who she said was having a hard time getting around. We determined the girl had a congenital heart condition. Her mother asked us for help, and I found myself saying yes. Six months later, with help from the president of UAB and Al Pacifico, then the director of the Division of Cardiothoracic Surgery at the university, the girl, her mother, and a local medical care provider flew to Alabama so she could have surgery. The plane fare was arranged by my mother, who was then the president of the AME Missionary Society in our Episcopal district. She marshaled all the women in the group and took care of the social side of things, including securing a donation for the plane ticket. The intervention for that young girl — her name was Faith — was the beginning of Heart to Heart. During the decade or so that I led the organization, we performed more than one hundred surgeries on kids from five different continents. Each time, we involved a local medical care provider and provided them with intensive medical education that they could take back home and pass along. We considered it the ripple effect of good. When I left to take the helm of the Jackson Heart Study, the leadership of the Heart to Heart program went to people at Children’s Hospital in Birmingham.

The Jackson Heart Study also relies on community involvement and trains doctors and health care workers, doesn’t it?

It does. This was to be a holistic approach to improving health through community interventions that would make a difference for Black people for generations to come. You need to remember that in the final half of the twentieth century, there was a 40 percent or so drop in deaths from cardiovascular disease across the U.S. Unfortunately, that promising statistic failed to capture what was happening in Black communities. If you looked at data from Mississippi anytime between 1970 and 2000, there was pretty much a flat line in terms of change in cardiovascular deaths among Black people. It was a disparity that was increasing but was not being explained. This study offered the chance to take a hard look at the cardiovascular epidemic among Black Americans in what was pretty much its epicenter, Mississippi. Although I hadn’t been thinking of leaving my faculty position at UAB, the notion that this study focused on Black people, not as an afterthought or as an addition to another study, appealed to me. I also realized this was really kind of a dream job for me: I could continue my cardiology practice and be a part of the founding of a study that would be comparable to the Framingham Heart Study; in fact, people were already calling it the Black Framingham. It was largely an epidemiological study, of course. But by the very nature of studying a problem, you change it. Then they said they hoped to involve UMMC, Jackson State, and Tougaloo, and I said ‘tell me more.’ Was it important to you to have affiliations with academic institutions and their students?

Very much so. Especially since two of the schools were historically Black schools — HBCUs. The mission of the study was to build a legacy of health. This meant that we felt it was vital to establish a pipeline of trainees who would have a transgenerational impact on health, an impact that would continue long after our time was done. This priority was equal to our work to advance scientific knowledge. You’ve written about how important it was to secure the trust of community members because the history of medicine is filled with atrocities perpetrated on Black people. How did the Jackson Study work to establish trust?

We began by bringing community members into the process of helping us decide how we were going to build the study. This was critical. But even before we talked with people about how we should do the study, we did everything we could to show people that we cared about them. We held information sessions, town hall-type meetings, and presentations in churches and schools and at sporting events and political venues. We talked about why the study was necessary, why people should be concerned about cardiovascular disease and its risk factors. Community engagement became community mobilization. We trained residents to understand traditional cardiovascular disease risk factors and behavioral interventions to mitigate or minimize those risks. We

Between 1970 and 2000, there was pretty much a flat line in terms of change in cardiovascular deaths among Black people.

involved high school students in summer science, language, and math enrichment programs; we took young scholars who were studying ethics, research design, and epidemiology at Tougaloo and had them shadow physicians and other investigators, so they could learn the practical side of the academics; and we trained graduate students at Jackson State who were working on degrees in public health and epidemiology. We even involved residents and cardiology fellows from UMMC. We also reached beyond Jackson. We sensitized members of Mississippi’s congressional delegation to the work of the study. Some of those people got to be very senior in Congress, and they knew about us, our activities, and our challenges. I think the Jackson study educated our populace and our power structure. And because of the study’s collaborations with the NIH, the data it gathers is incrementally expanding and diversifying the database that will train precision medicine algorithms. Your move to Morehouse’s Cardiovascular Research Institute expands efforts at data gathering to include genetic, epigenetic, and bioinformatic investigations. Is there an effort that you find especially promising or groundbreaking?

That’s hard because they are all so promising. But I am excited by what members of our multidisciplinary team have found in their analysis of data from our MECA study, an investigation of the role of resilience in health and well-being. The initial work on this was funded by the American Heart Association, and the investigation is now expanding, thanks to support from NIH. The study asks why so many Black people in the United States — people who continually face so many challenges because of race and who statistically face higher risks for cardiovascular disease — survive so well in the face of adversity, or even thrive. There is growing evidence that individual and communal resilience may play a role, possibly a big role, in this seeming contradiction. In addition to contextual factors, the study will look for genetic, metabolomic, and other “omic” signatures of resilience that may help explain this phenomenon. If such signatures are found, they could be used to design new approaches to resolving disparities and to assess interventions. Is there any advice you would offer physicians who care for Black patients? Is there a tenet you follow in your practice?

In terms of heart health, of course it’s crucial to follow the guidelinedirected approaches that we follow with any patient. But communication and trust are the cornerstones of an effective therapeutic relationship. As a profession, we have not consistently been trustworthy or communicative with Black patients. To break that barrier, the most powerful attribute a physician can bring to a patient encounter is humility. By humility I mean keeping the patient central to the encounter, assuming nothing but that the human being before you has deep concerns, legitimate perceptions and feelings, people who love them, and a story to tell in their own words. Ann Marie Menting is the editor of Harvard Medicine magazine. HARVARD MEDICINE | AU T U M N 202 3

THE HEART

I ALTRUISM

In addition to helping others, kindness

In this scene from the Book of the Dead, an ancient Egyptian collection of funerary spells (circa 1250 BC), Ani (standing to the left of the upright support of the balance, center) is being judged on his worthiness to enter the afterlife. His heart has been placed on a pan to determine its weight. If it is heavy, it will be consumed by a monster (lower right), and Ani will be denied entry to the afterlife. If it is as light as the feather resting in the opposite pan, Ani will be welcomed into the beyond. The test is being overseen by jackal-headed Anubis, the guide to the afterlife. Thoth, scribe to the gods, has taken on a human form and stands behind Anubis, poised to register the results.

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can benefit one’s health

Heart Felt

BY MOLLY MCDONOUGH

FROM WHERE IN THE BODY might kindness

flow? Folklore and belief systems far and wide point to the heart. Ancient Egyptian mythology, for example, maintained that the leap to the afterlife required a test. Before the deceased could enter, their heart had to be weighed, placed on a balance under the watchful eyes of the gods.

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ALTRUISM

The chemistry of kindness

THE DEAD PERSON’S HEART WASN’T BEATING

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Dopamine is released when we give to others. Scientists have actually witnessed this in the lab.

Best known for its role in inducing contractions during childbirth and in mother-infant bonding, oxytocin is closely linked to empathy and altruistic behavior. Oxytocin receptors are found throughout the cardiovascular system, including in the heart. The hormone can cause blood vessels to widen, encouraging blood flow and lowering blood pressure. And it’s been shown to counteract oxidative stress and inflammation, both of which can contribute to atherosclerosis, heart attack, and stroke — a hint of how the transient mood boost one gets from helping others may relate to longer-term health. Survival of the selfish?

The molecules rewarding good deeds with good feelings are linked to ancient deeprooted instincts. Perhaps their release is an evolutionary nod that whatever we are doing — including giving — is good for us. But this possibility raises a paradox that has irked evolutionary theorists dating back to Darwin: If the natural world has been shaped by cutthroat competition, what explains our drive to share limited resources with others? When Stephen Post was a high school student in the late 1960s, there was a focus on the brutishness of human nature. Trendy books like Lord of the Flies and The Territorial Imperative emphasized people’s more selfish and violent tendencies. “There was a bias toward cynicism that I feel was unfounded,” recalls Post, who, in addition to directing the Center for Medical Humanities, Compassionate Care, and Bioethics at Stony Brook University, heads the board of directors for the Institute for Research on Unlimited Love, a nonprofit that disseminates research on the health benefits of kind giving. “To be kind was to be deluded. The thinking was, as the French philosopher Sartre argued, if anybody looks at you with kindness, watch out, because they’re after your wallet. But you really can’t explain an awful lot of human behavior with that model in mind.” Since then, Post says, science has helped “rewrite the story” by highlighting the ubiquity of altruism across cultures throughout human history. For example, researchers

JOHN SOARES (FACING PAGE)

but it wasn’t considered dead weight; it held proof of virtue. If the person had lived a life of goodness, their heart would be light as a feather — and the gates to the afterlife would swing open. But if their life had been filled with greed, their heart would be heavy. For this person, there would be no welcome to the afterlife; instead, their heart was fed to Ammit, a soul-devouring goddess with the forequarters of a lion, the hindquarters of a hippo, and the head of a crocodile. This ancient tale is just one example of the heart’s symbolic link to goodness. Christian art depicts Jesus’s heart aglow, sacred and filled with benevolence. Hindu and Buddhist traditions consider the heart chakra the center of compassion. And in Dr. Seuss’s tale, the Grinch’s heart is two sizes too small. With advances in our understanding of anatomy and physiology over the past few centuries, science has shifted the focus for our actions and emotions from the heart to the brain. Yet, in a sense, the ancient Egyptians may have been on to something. Emerging evidence suggests that good deeds can become etched into our bodies, including the cardiovascular system — and that our hearts and our health benefit when we are kind to others.

In his book The Healing Power of Doing Good, nonprofit leader Allan Luks quoted survey respondents attempting to articulate the feelings they experienced when doing volunteer work. “It makes you explode with energy,” one said. Others described “a relaxation of muscles that I didn’t even realize had been tensed” and a “euphoric” feeling of being “zapped by an energy bolt.” Luks coined the term “helper’s high” to describe these feelings. This sensation has physiological origins. Gregory Fricchione, the Mind/Body Medical Institute Professor of Psychiatry at HMS and director of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, describes it as a release of “chemical juice.” When we help others, he says, neurotransmitters flow up in a tight bundle of axons called the medial forebrain bundle through the subcortex with “exit ramps to many of the important structures of the brain” — the fear-conditioning amygdala, the memory-forming hippocampus, and the motivation-moderating medial prefrontal cortex. Among these neurotransmitters is dopamine. This feel-good chemical is linked to the brain’s reward center. And it’s released when we give to others. Scientists have actually witnessed this in the lab. A few years ago, a small study from an international research collaboration that included scientists from the National Institutes of Health used magnetic resonance imaging to measure brain activity associated with making a charitable donation. The findings, reported in PNAS, suggested that this action engages the mesolimbic system of the brain, triggering a euphoric rush of dopamine in much the same way that anticipating a reward, like money, does. Numerous other processes may be implicated in the helper’s high, says Fricchione: pain-reducing endogenous opioids, endorphins, and perhaps even the neuromodulating chemicals that make up the endocannabinoid system. Then there’s oxytocin, the so-called affiliation hormone, which has plentiful receptors in the amygdala, where it helps suppress fear and anxiety.

Gregory Fricchione

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ALTRUISM

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Nicholas Christakis

JOHN SOARES

have identified an intrinsic propensity in toddlers as young as fourteen months to help others with tasks without being influenced by rewards, encouragement, or threats. Fricchione sees altruistic pro-social behavior as a logical extension of fundamental mammalian behaviors — the drive to nurture offspring and attach to caregivers. “It would be strange if evolution only provided us with a brain reward-motivation circuitry that supported ‘gimme, gimme,’” he says. “Of course, we know individuals like that, and they make us angry and frustrated, because we feel they aren’t behaving as good mammals. Evolution has provided us with the structures and functions that remind us that we survive better by cooperating as a group — not only when we’re seeking social support, but when we’re giving it.” Post agrees that the key is in community. “Group selection theory says that a certain amount of our evolution occurred in groups,” he says. “So, my group is going to do better to the degree that it exhibits compassion and helping behavior.” In 2010, Nicholas Christakis, MD ’89, a sociologist-physician who then held faculty positions at HMS and Harvard University, attempted to map out how groups could become kind. Analyzing data from a series of experiments that used a “public goods game,” in which participants could dole out money, in the form of tokens, to strangers who were also participants in the experiments, he found that those who received funds from others were more likely to give money to other strangers in a future game. An individual’s generosity caused a chain reaction that reverberated out, extending to three degrees of separation. Capturing the pay-it-forward phenomenon in the lab, these findings, published in PNAS, drew widespread interest. “How two people treat each other in one part of the city may relate to how two other people treat each other in another part of the city,” says Christakis, who now directs the Human Nature Lab at Yale University. In other words, he says, “altruism is contagious.” The kindness of individuals cascades, ultimately creating a stronger group that is better equipped to survive.

Christakis sees kindness as one of several pro-social tendencies we’ve evolved because they are key to maintaining social cohesion, a thesis he describes at length in his 2019 book, Blueprint: The Evolutionary Origins of a Good Society. The flip side of this, he adds, is that we find it stressful to be antagonistic or to be alone. Isolation from a group “causes wear and tear on our body,” explains Christakis. Indeed, according to the American Heart Association, loneliness and social isolation are associated with a 29 percent increased risk for heart attack or premature death, while emotions like anger and hostility are also considered to be coronary disease risk factors. To Christakis, those health threats are “the kind of inverse of evolution’s way of telling us to be kind. We have to be kind to other people so they’ll want to be in our group, and we have to support the group so that the whole is greater than its parts.” While the health benefits of kindness are probably not incidental, Christakis adds, they are multifaceted. It’s not as straightforward as saying that kindness can completely prevent or cure a disease. “Pro-social behaviors like kindness are probably exceedingly complex physiologically, acting upon our bodies in multiple ways, not all of which are understood.”

EVAN MANN (FACING PAGE)

Sense of purpose

How does this complex mix play out in the modern world? One way to find out is to examine the health outcomes of people who complete measurable acts of altruism. In a 2013 randomized controlled trial published in JAMA Pediatrics, a group of teens was assigned to complete volunteer work. After two months of weekly volunteering, the young people displayed significant decreases in risk factors for cardiovascular disease — systemic inflammation, total cholesterol levels, and BMI — compared to their nonvolunteering peers. Other research has found lower risk of early death among those who volunteer. A 2020 American Journal of Preventive Medicine study of nearly thirteen thousand volunteers over age 50 who were assessed over a fouryear period revealed that those who spent more than a hundred hours per year volunteering had a 44 percent lower risk of mortal-

ity compared to those who did not volunteer, even after controlling for factors like stress, health behaviors, and personality traits. One of the authors of that study is Eric Kim, an affiliate scientist at the Lee Kum Sheung Center for Health and Happiness at the Harvard T. H. Chan School of Public Health. Kim acknowledges that the physiological mechanisms linked to the helper’s high could drive health benefits, but he also highlights additional drivers. Volunteers tend to get more exercise, use preventive health services more often, and experience better social cohesion, for example. Kim, who is also an assistant professor of psychology at the University of British Columbia, argues that one of the most important effects of volunteering is that it contributes to a person’s sense of purpose. “If you have a will to live, that will to live will help push you past all kinds of barriers that emerge when you’re trying to enact positive health behaviors,” he says. In a study of nearly fourteen thousand retired adults published in 2020 in Preventive Medicine, Kim and colleagues found that those with a higher sense of purpose in life had a lower likelihood of becoming physically inactive, having sleep problems, or developing an unhealthy BMI. Similarly, a 2016 meta-analysis in Psychosomatic Medicine described a lower relative risk for cardiovascular events among people with a higher sense of purpose, even after controlling for variables like conventional cardiovascular risk factors and psychological distress. “People often ask me how they might increase their sense of purpose,” says Kim. “The answer is, it’s very difficult. But one of the most scalable ways, that is kind of on the easier side, is volunteering.”

Researchers found that those who volunteered for self-oriented reasons had a similar mortality risk to those who didn’t volunteer at all.

Giving from the heart

Yet even if it’s relatively easy to get into volunteering, it’s not just about going through the motions. Kim points to a 2012 study in Health Psychology that found a lower risk for premature mortality among volunteers — but there was a caveat. Surveying participants about their motivations, researchers found that those who volunteered for self-oriented reasons had Antonia Seligowski a similar mortality risk as those who didn’t

volunteer at all. And in the JAMA Pediatrics paper on teen volunteers, the cardiovascular benefits of volunteering were greater among those individuals whose survey responses displayed an uptick in empathy, defined as caring about what happens to other people. Acts of altruism can also burden the body. Caregiving, for example, can become an immense stressor contributing to myriad health issues. That’s why Post doesn’t think that altruism itself is the best medicine. “Altruism really conveys an action; it can be habitual, routinized, or externalized,” he says. “It doesn’t get to the kindness. It doesn’t get to the heart.” Rather, intentional acts of kindness that do not become a burden are key. Post describes what he calls “kind giving” or “kind altruism,” an idea related to the Buddhist concept of loving-kindness that meditation works to finesse. “It’s not how much you do for others, but the kindness you pour into it,” he adds. Christakis points out that a propensity for kindness, like any evolved tendency, varies between individuals. But there are ways to cultivate it. He remembers a radio interview he listened to during a drive from Cambridge to the Longwood campus thirty-five years ago. The interviewee, a Buddhist monk, was asked how he might maintain his state of Zen instead of succumbing to road rage if a driver cut him off on the streets of Boston. “I recall that, without missing a beat, the monk said he would imagine that in that car, there’s a woman in the back, and the man is driving desperately because she’s pregnant and going into labor,” says Christakis. “So, the monk had trained himself to reframe what was happening around him in the most positive and favorable light.” Post echoes the importance of cultivating a kind disposition that pervades one’s life — whether you’re donating money, volunteering, or just stuck in a traffic jam. “The science bears this out. It’s how you can actually de-stress. It’s how you can be visionary. And it’s how you can experience joy and happiness,” he says. “It’s actually pretty simple,” Post adds with a shrug. “I mean, you can just be kind.” Molly McDonough is the associate editor of Harvard Medicine magazine. HARVARD MEDICINE | AU T U M N 202 3

FIVE QUESTIONS

I HAIDER WARRAICH

A conversation with Haider Warraich, HMS assistant professor of medicine, Division of Cardiovascular Medicine, Brigham and Women’s Hospital; author of State of the Heart: Exploring the History, Science, and Future of Cardiac Disease

Why medicine, why cardiology?

The part of the world where I grew up — Pakistan and South Asia in general — is home to some of the highest rates of heart disease in the world. I felt there was so much happening in the world of cardiology that wasn’t being told. There were many advances and there were so many wins that we were achieving through our work. I wanted to be the person to witness those stories and, perhaps, even change how they ended. The heart is one of the most intensely studied organs. What are some of the mysteries it still harbors?

We understand the heart probably better than any other organ, yet one of the biggest gaps in our understanding and treatment of heart disease is our inability to reverse damage. In a literal way, the heart is not good at healing, and we have very few means to help it recover function. This represents a vast frontier.

Although we have more tools to help prevent and treat heart disease than we have for almost any other condition, most people who need the therapies aren’t getting them. Those people are more likely to belong to groups vulnerable to poor outcomes. Women are less likely to receive evidence-based therapies for heart disease. Black Americans are less likely to receive evidence-based therapies for heart disease. The same is true if you live in a rural area, if you are living in poverty, if you don’t speak English. Heart disease is increasingly more an economic condition than a medical one. 40

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Among historical thinkers, I am perhaps most inspired by Leonardo da Vinci. He was able to work across disciplines, to be an artist, a storyteller, a physicist, an astronomer, and to bring them together in a way that moved our understanding of being in a powerful way. People like Leonardo used all their faculties to advance our understanding of what it means to be a human being, what it means to be here on Earth as part of nature. This is what I try to do in my books. If we try to isolate things too much, we become blind to the truth. What does the writer Haider Warraich teach the physician Haider Warraich?

The writer teaches me to always observe and take note of the details, to inhabit the moment that I share with my patient and to see what that moment means in their life. I think this type of broad view engenders empathy, and empathy is the core of not just what I feel helps me become a better writer, but what helps me be a better physician and a better teacher. Writing has allowed me to be more present for my patients, more curious as a physician, and more empathetic as a teacher. Writing has allowed me to find greater meaning in my work. — Ekaterina Pesheva

JOHN SOARES (THIS PAGE); GREGORY MILLER (FACING PAGE)

What are we still getting wrong about the heart and heart disease despite all the great advances in cardiology?

In your books, you explore themes that are scientific and medical but also social and philosophical. What inspires this work?

ALUMNI

I ROOTS I NANETTE WENGER, MD ’54

The Power of Persistence ON HER FIRST DAY OF MEDICAL SCHOOL, Nanette Wenger remembers learning

that “the secret of the care of the patient is in caring for the patient.” More than seven decades later, that tenet remains central to her medical practice. During her career as a cardiologist, spent mostly at Emory University School of Medicine and Grady Memorial Hospital in Atlanta, Wenger has devoted herself to caring for patients, conducting research, teaching, and mentoring younger physicians — all while doggedly working to bring much-needed attention to cardiac disease in women. “One of the lessons I’ve learned is if I believe what I am doing is necessary and important, I should persist and endeavor to enroll others in my vision,” Wenger says. When Wenger attended HMS, women were accepted only on a trial basis; there were a mere ten women in her class. Yet, she looks back on her experience fondly, recalling strong camaraderie with classmates and mentors. Wenger found standout mentors in cardiologists Herrman Blumgart, Class of 1921, and Louis Wolff, Class of 1922, at what was then Beth Israel Hospital.Their early mentorship motivated her to become a mentor herself: Wenger estimates that she has trained thousands of young physicians, including, in several instances, three generations within one family. After completing her cardiology training at Mount Sinai Hospital in New York City,Wenger joined the faculty at Emory and Grady.There, she noticed that many women were coming into the hospital with chest pain and heart attacks. Yet she’d been taught that heart disease was a man’s disease. A literature search turned up nothing about heart disease in women, so Wenger began approaching national cardiology organizations. She was initially met with resistance, along with insistence that women don’t have heart disease. But, she persisted. Eventually what is now the National Heart, Lung, and Blood Institute agreed to organize a conference on the topic, which she co-chaired. She co-authored a seminal paper in the New England Journal of Medicine that summarized recommendations from the conference, including how to treat women with heart disease, and what research on the topic was needed. “The emerging information and knowledge deficits interested clinicians and scientists in the subject,” she says. Wenger spent decades studying and raising awareness about heart disease in women — work that has elevated her to rock star status in the cardiology community and culminated in more than 1,700 scientific publications, as well as several awards named in her honor. Yet, “we’ve just begun the journey,” she cautions, noting that women who have heart disease still don’t fare as well as men. Fortunately, Wenger shows no sign of slowing down; she continues to see patients, carry out research, and train young physicians with the same dedication and enthusiasm she had during her first years in medicine. “Perhaps the most the important things I’ve done are to ask questions and to continue to translate research into equitable cardiovascular care,” she says. —Catherine Caruso

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THE HEART

I PHOTO ESSAY

“Although many research projects have been slowed, as a research institution, we are up and running.” —HMS DEAN GEORGE Q. DALEY, MD ’91, TOWN HALL ADDRESS, 4.10.20

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Up on the Roof The sleek, solid structures crouched around the HMS Quadrangle may be considered by some to represent the School’s imposing community of investigators. For others, numbers may serve to describe the sweep of biomedical inquiry on campus: $317 million in research grants and contracts in FY23 supporting the work of 193 faculty and 669 research fellows and postdocs. There is, however, another indicator of the School’s intellectual activity: the vast infrastructure of ducts, fans, sensors, and systems that regulate the environments of the research buildings, keeping conditions safe and holding them steady for researcher and research alike. The images that follow bring that infrastructure to the fore. They expose, even celebrate, the intricate rooftop mechanisms that ceaselessly circulate the air and fluids critical to maintaining conditions that support the lifeblood of the scientific enterprise at HMS. by Ann Marie Menting photography by John Soares HARVARD MEDICINE | AU T U M N 202 3

PHOTO ESSAY

Large condenser fans (previous pages) ensure steady temperatures in rooms that house heat-generating equipment, such as computer servers. The fans draw the warm inside air over a network of copper piping through which flows a water-glycol mixture that cools the air. If outside temperatures make the liquid too cold, sensors trigger the fans to shut off so the heated air may passively escape. The system functions like a compressor for a residential air-conditioning unit. The tall stacks in the above photo send air from laboratory fume hoods to heights where it can dissipate quickly and safely. The height of the stacks also keeps vented air away from personnel working on rooftop systems. Other rooftop units remove moisture from air flowing into lab areas that require low humidity.

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Building laboratory spaces for new faculty and changing existing research spaces means modifying exhaust and supply airflow requirements. Sometimes equipment is added to accommodate these needs, and sometimes existing equipment is put out of service. The photo at right shows a vent that has been capped and rendered inactive. It may have been kept in place because its ductwork runs through several floors, making it costly to extract, or as a hedge for future changes that would benefit from linking with an existing system.

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PHOTO ESSAY

Equipment atop the building in the above image shows a good deal of bright ductwork connected to large air-handling units in the lower left. These units pull in outdoor air to allow for the six complete air changes per hour required for laboratory spaces. The cone-shaped tops of the khaki-colored stacks in the center of the photo can hurl air even higher than the stacks shown on previous pages. For any given building, the height that vented air must reach is carefully calculated by engineers who know the environmental and safety specifications for tightly built areas such as HMS. Rooftop temperature and pressure gauges (right) are off much of the time. The physical properties they measure can be monitored by remote sensors linked to laptops. If a worker is on the roof without a monitoring device, the gauges can be activated and measurements taken. An architectural collage (far right) captures older and newer buildings’ profiles and color palettes. Just as the older and newer mix of equipment on the roofs of Quadrangle buildings can be remade to meet the changing needs of the research community, these structures can be modified to allow for the evolving needs of the HMS academic and administrative communities.

“It is in times of crisis that the highest ideals of perseverance, generosity, spirit, creativity, and grit reveal themselves.”

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STUDENT LIFE

I CLASS LEADERS

Student Life Aya Awwad

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JOHN SOARES (THIS AND FACING PAGE)

AS A CHILD, Aya Awwad, a Palestinian Israeli who grew up in Tamra, Israel, had a love-hate relationship with the small bookstore her parents owned. “I borrowed the books,” she says, “but I had to help out in the shop to get the other things they sold, like toys. As a third grader, that was annoying, but it taught me you need to work to achieve things.” She was introduced to medicine in seventh or eighth grade through both the school for gifted children she attended and the NIR School of the Heart, an experiential program that brings together students from several Middle Eastern countries to learn about the systems of the body, especially the cardiovascular system, and about one another’s traditions and beliefs. “I found medicine fascinating early on because it’s not an exact science,” Awwad says. “The clinical presentation of the patients can vary, but through that uncertainty we try to find a way to lead our decision-making, so it’s an art as well.” After high school she got her MD from Technion – Israel Institute of Technology in Haifa. In her sixth year she spent a month at Brown University studying infectious disease. “That was my first exposure to medicine outside of Israel,” she says. She found learning in another culture exciting. “Working and talking with people with different backgrounds, perceptions, and approaches to things increases your understanding and tolerance. You realize how big the world is and become more open.” When she returned to Israel she started searching for a way to continue her studies abroad, and discovered the master of medical sciences in clinical investigation program at HMS. “I want to be a clinician and do research,” she says, “and back home, medicine is structured around clinical work, so I need to develop the skills that will allow me to dedicate time to both.” A Fulbright scholarship helped her come back to New England, where she joined the lab of Sahir Kalim, an assistant professor of medicine at Massachusetts General Hospital. There, she’s conducting translational research in chronic and end-stage kidney disease, studying the mechanisms that underpin the morbidity and mortality seen in patients with the disease, and finding new biomarkers and possible therapeutic interventions. For her next steps, Awwad recognizes that “nothing is guaranteed,” but she is optimistic, in part because Kalim and her other colleagues in the lab have been so supportive. “Even though I’m just starting they have been a great help to me, improving my research skills and pushing me forward to increase my curiosity.” She admits she has missed clinical work, though. It’s one reason she joined the Master’s Student Council. “I like to work with people,” she says. “The council gives me a way to positively affect the social life of students in the University and sharpens my skills for creating a community wherever I am.” —Elizabeth Gehrman

Geraldine (Gerry) Serwald GERRY SERWALD UNDERSTANDS the importance of leading by example. When she

was an undergraduate at Washington University in St. Louis, she’d toyed with the idea of pursuing premed — but it wasn’t until she attended a meeting of the Minority Association of Pre-Medical Students that those plans solidified. During that meeting a photo of Ebony Carter, a Black OB-GYN, appeared on screen during a presentation. “I got goosebumps. I had never seen a Black female physician before,” says Serwald. “You know what they say about ‘If you can see it, you can be it and achieve it’? It is so true.” Serwald’s parents, who emigrated from Ghana to Chicago before she was born, also believed she could do whatever she set her mind to. Their confidence rubbed off on her. Growing up, she became increasingly aware of how significant their encouragement was in a society that often failed to instill confidence in women. “I decided I want to bring that empowerment to the societal level for marginalized communities, harnessing medicine as a tool for self-agency, empowerment, and social justice,” Serwald says. After college she spent a few years working in a maternal-fetal medicine research group at St. Louis’s Barnes-Jewish Hospital. There she witnessed the interdisciplinary aspects of medicine, connected directly with labor and delivery patients, and affirmed her desire to apply to medical school. She chose HMS because of the “robust resources and incredibly inspiring people. HMS has the best network for any path I pursue.” Once she arrived, she was also “enamored with and in awe of” her richly diverse community of classmates. The desire to build that community drew Serwald to the HMS and HSDM Student Council. In September of her first year, she was elected president of her class. “Medicine is extraordinary. But it will inevitably be challenging. I wanted to make sure we built a strong community, so that when times get tough, we can comfort and support each other,” she says. During her tenure as president, Serwald has emphasized “follower-based leadership,” giving her fellow council members the agency, encouragement, and autonomy to thrive. She’s proud of how they have brought their own skills and ideas to planning successful community-building events and to establishing a longitudinal relationship with the School’s Office for Community Centered Medical Education to work with local organizations serving the people of Boston. As her second year of medical school gets underway, Serwald is busy starting rotations and is excited to experience the different specialties. Regardless of what she decides to pursue, she knows that female and women’s health will always be paramount in her practice. And she’ll continue as president of her class, with a leadership outlook that hearkens back to her upbringing. “With a supportive community as our home base, she says, “we’re all empowered to pursue our interests and effect positive change within the HMS community and beyond.” —Molly McDonough

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CLASS LEADERS

Michael Elnemais Fawzy MICHAEL ELNEMAIS FAWZY BELIEVES EVERYONE’S LIFE has many

turning points. His first one came when, as a child, he discovered Aragoz, the hand puppet character traditional in his native Egypt. He became so enthralled that he joined his neighborhood puppet theater, doing everything from working the stage door to scriptwriting. “I started asking why some people are the good guys of the story and some are the bad guys,” he says. “I realized if we help people, we will decrease the number of bad guys.” Another turning point in his early life arose when he saw the movie The Street Player, about a talented Egyptian football player who, in the final scene, says “I will play with the losers” — a reference, says Elnemais Fawzy, to “people who have lost their way.” A third critical moment was when one of his fellow students dropped out of medical school. “She was talented,” he says, “but no one paid attention to her problems.” These and other influences led him to study medicine, specifically psychiatry. “I love to hear people’s stories,” he says, “and doctors can change people’s lives.” His focus on mental health eventually led him to human rights, and once he began to “combine all the pieces of my puzzle,” he started the Taqet Amal Foundation. Founded in 2014, it works with medically underserved Egyptians who are at high risk for mental illness. The foundation helps them adapt to adverse circumstances by improving their resilience and psychological well-being. Early on, the group worked with children, partly through puppet theater, but it has since expanded to reach more than 12,000 people in eight governorates. In 2016 Elnemais Fawzy spent a month at Boston Children’s Hospital to “see how mental health services for children were built. Research is needed to explore Egypt’s national health system and to study human rights in psychiatry,” he says. The Master’s Student Council is just another way for him to help others find their voice. “American culture is based on diversity,” he says, “but some international students may feel they are not represented enough.” Elnemais Fawzy, who will graduate in May, is now serving as a consultant psychiatrist at Al-Abbassia Mental Health Hospital in Cairo. “My ultimate dream is to start a program for young researchers in Egypt,” he says, “so they can create collaborations between low-income countries in Africa. If we empower clinical researchers there, we can open a small window for hope.” —Elizabeth Gehrman

JOHN SOARES JOHN SOARES

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ALUMNI

I ROUNDS

This colorized scanning electron micrograph shows a T-cell (pink) that has been modified to target cancer cells, in this case, a prostate cancer cell. This therapeutic approach, called CAR T therapy, is being used to treat certain blood cancers, including lymphomas.

STEVE GSCHMEISSNER/SCIENCE SOURCE

DETAILS, UPDATES, AND OBSERVATIONS FROM ALUMNI

Which scientific or medical development has excited you the most during your career? HARVARD MEDICINE | AU T U M N 202 3

ROUNDS

Jorge Casas-Ganem, MD ’98

As a sarcoma surgeon, the improvement in diagnosis and the development of targeted therapies have improved outcomes and survival for my patients. On the reconstructive side, 3D printing techniques for patient-specific custom implants have been a game changer. We are now reconstructing bony defects that previously could not be reconstructed. John Welch, MD ’68

Beginning in the early 1990s with laparoscopic cholecystectomy, the explosive development of laparoscopic surgery made possible by advances in instrumentation revolutionized the field of general surgery. New leaders in the field rapidly gained prominence in academic surgical societies, and the public and insurance companies embraced small-incision operations and early hospital discharges. Benjamin Chaska, MD ’83

The identification of the cause of AIDS together with the treatments developed. The use of mRNA technology to develop vaccines for SARS-CoV-2 and the further exploration of that technology to develop vaccines against other infectious agents. The monoclonal antibody revolution. The vast numbers of new and efficacious treatments for heart disease and cancer. Stephen Smith, MD ’63

Jane Liebschutz, MD ’91

Changes in treatment for addiction have been life-changing for so many individuals with opioid use disorder, in particular, office-based treatment with buprenorphine. This has expanded the capabilities for treatment outside of stigmatized and hard-toaccess methadone programs.

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Charles Epstein, MD ’73

Linda Leum, MD ’86

I consider CRISPR-Cas9 to be one of the more exciting scientific developments.

Too many to list. My dear friend and HMS classmate, Jeannie Bennett, MD ’86, developed the first FDA-approved gene therapy for a type of childhood blindness.

Esteban Mezey, MD ’62

The completion of the human genome sequence. It is revolutionary for the diagnosis, prevention, and treatment of disease. Petros Giannikopoulos, MD ’06

It’s hard to narrow this down to just one, so I will go with three: large-scale genomics, including whole-genome sequencing, RNA sequencing, single-cell sequencing, and spatial multiomics; CRISPR-based genomic editing; and artificial intelligence. Kenneth Franklin, MD ’78

Invasive cardiology, such as coronary artery angioplasty, has been an important innovation.

Peter Liebert, MD ’61

The development of total parenteral nutrition. Elizabeth Kaufman, MD ’85

If anyone had told me how far pacemaker and defibrillator technology would advance during my career, I would have thought they were writing science fiction. Keeping up with the new developments, both intellectually and from a skill set standpoint, is exciting. It is always fun to be on a learning curve.

RAMON ANDRADE 3DCIENCIA/SCIENCE SOURCE

As an endocrinologist, I have been excited and gratified regarding the opportunity to implement GLP-1 agonist therapy for treatment of certain patients with type 2 diabetes. For many patients this class of medication is superior to insulin and other pharmaceutical options.

CRISPR-Cas9 base editors, like the adenine base editor shown above, are used in genome engineering to cut DNA. These editors allow for nucleotide base conversions at specific points in genomic DNA.

Robert Duerr, MD ’88

Frank Seinsheimer, MD ’71

Martin-Jose Sepulveda, MD ’78

I believe the two greatest achievements in my lifetime were the invention of statins, which will soon mean that cardiovascular disease will no longer be the number one cause of death in the United States, and checkpoint inhibitors.

The advances in immunology and genetic therapy.

The recognition and disclosures of bias, discrimination, and structural racism in medicine and medical practice.

Samuel Gerber, MD ’80

Daniel Kopans, MD ’73

Conversion from open to arthroscopic procedures of the shoulder, ankle, elbow, hip, and knee.

The early detection of breast cancer has been a major advance. Screening began in the mid-1980s and the death rate, unchanged over the prior fifty years, has declined by more than 40 percent since 1990. Therapy has improved, but breast cancer is cured when treated early. I developed a guidewire that directs surgeons to lesions in the breast that appear on imaging but that cannot be felt. I believe this innovation has allowed for safe, less traumatic outpatient biopsies that can help physicians make those early diagnoses of breast cancer that improve outcomes for patients.

Lise Johnson, MD ’88

The rapid advances of genomic medicine. Morris Fisher, MD ’65

The development of molecular biology and increased clinical neurophysiological capabilities based on the ready availability of computers. Gordon Cutler, MD ’73

In fifty years, advances in molecular biology and genetics have enabled whole new classes of therapeutics, including recombinant human proteins, monoclonal antibodies, and DNA- and RNA-based treatments, which have achieved great progress in endocrinology, inflammatory diseases, oncology, cardiovascular disease, and vaccine development and hold great promise for neurology, genetic diseases, and other fields.

Bruce Parker MD ’63

Magnetic resonance imaging is an important advance.

Gregory Juarez, MD ’92

The use of ultrasound in the perioperative arena. We can provide safer and advanced blocks in the OR to improve outcomes in our patients. Also, real-time ultrasound has given us access to viewing the cardiopulmonary system to diagnose and treat acute issues. Scott Wasserman, MD ’96

Probably the validation of breast conservation and multidisciplinary therapy for the treatment of breast cancer. This change in treatment has had enormous impact on the well-being of many women.

It is hard to believe that about twenty years have passed since the sequencing of the human genome. This development, augmented by computing power, revolutionized health care and made the current biotech innovations possible. Stemming from this development, scientists and physicians can personalize treatments for cancer, identify the causes of and develop treatments for rare diseases, and develop cell and gene therapies.

Mary Flowers, MD ’78

Sylvester Sviokla, MD ’72

The notion of transplanting pig kidneys into humans to reduce the number of end-stage renal disease patients waiting for kidney transplants.

All forms of imaging in the first half of my career and the development of buprenorphine and naloxone combination drugs in the second half.

Martin Prince, MD ’85

The development of magnetic resonance imaging. Daniel Weingrad, MD ’73

Howard Kirshner, MD ’72

The development of acute stroke treatment, first in 1995 with intravenous tPA, later with mechanical thrombectomy. Many strokes are now treatable, and many more patients who would have been disabled for life are recovering well. Nneka Holder, MD ’97

Vaccines, especially those developed against human papillomavirus and SARS-CoV-2. Karen Singer, MD ’77

During a medical school research elective, my student, Russell A. Brown, developed the CT-guided stereotactic frame, which uses N-localizer technology. This development has had a major influence on modern neurosurgery and stereotactic radiotherapy — perhaps not as significant as modern genetics, but still a great contribution to improved patient care. Another exciting development, and there have been many, was endoscopic surgeries for appendectomies, hysterectomies, knee meniscus surgeries, and so many more procedures. The development of robotic surgery has advanced things even further. Fred St. Goar, MD ’84

I have had the pleasure and privilege of helping to develop some exciting cardiovascular therapeutic advances such as the MitraClip and HeartFlow imaging. But the innovation that I am most excited about, and proud of being involved with, is the JADA postpartum hemorrhage control device, which will make childbirth safer for mothers around the world.

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ROUNDS

“The development of new imaging techniques, plus microsurgery.” Stephen Grund, MD ’91

Robin Yuan, MD ’78

As a hematologist/oncologist, it’s impossible to choose just one. Unraveling the pathophysiology of thrombotic thrombocytopenic purpura, paroxysmal nocturnal hemoglobinuria, and heparin-induced thrombocytopenia and thrombosis have been important advances. I would also choose the use of all-trans retinoic acid and arsenic for acute promyelocytic leukemia and imatinib for chronic myelogenous leukemia. CAR T therapy and checkpoint inhibitors have also been exciting developments.

While the technique of microsurgery was invented much before my career began, the applications and evolution within plastic surgery blossomed during the early years of my professional life and opened a door to reconstructive possibilities that were challenging, stressful, and exciting.

Edmund Lee, MD ’96

The advent of biologic medications for skin diseases such as psoriasis.

Steven Jonas, MD ’62

The recognition of the importance of public health practice, even as politics in our nation — the only country in the developed world that does not have a national health insurance system — have diminished its scope, funding, and influence. Joseph Burnett, MD ’58

Marguerite Barnett, MD ’79

The development of genomic medicine. Michael Quinones, MD ’86

Tyrosine kinase inhibitors, by far. Small molecules treating and potentially curing cancer is a big leap from the original chemotherapy Sidney Farber, Class of 1927, used!

Christopher Baker, MD ’74

The research that has characterized systemic inflammatory response syndrome and helped clinicians prevent and treat multiple organ failure in critically injured or ill patients. William Goodson, MD ’71

The transition from opinion- and authoritybased decision-making to the wide application of prospective clinical trials, preferably randomized, to guide medical decisions. Jan Polissar, MD ’61

The development of retinoids.

Transactional analysis and the discovery of the structure of the human genome.

George Lewinnek, MD ’67

Robert Colvin, MD ’68

The discovery of the CRISPR tool has been exciting.

Advances in managing critically ill patients.

Acute stroke treatment, first with intravenous tPA, then with mechanical thrombectomy. Also the advances in imaging, including CT scans and MRI. Although these advances were exciting, I was sorry that young doctors never learned the clinical skills we once needed. There were times when the imaging missed the pathology, and because I was old enough to have learned physical diagnosis, I knew enough to keep looking.

Donald Brief, MD ’57

Craig Comiter, MD ’92

The CAT scan and minimally invasive surgery are advances I consider to be important.

The use of immunotherapy for cancer treatment has been exciting.

James MacDonald, MD ’95

James Reiss, MD ’62

The change in the treatment of many cancers from chemotherapy and radiation to immune-modulated therapies, for example, the use of Rituxan in lymphoma. Also, the growing awareness of the roots of systemic racism that is central to U.S. medicine.

The development of new imaging techniques, plus microsurgery.

Susan Haas, MD ’79

I consider the development of minimally invasive surgery and medication abortion to be important advances made during my career. Brian Lewis, MD ’69

The insights into the biology and treatment of cancer that have revolutionized oncology. Richard Schwartzstein, MD ’79

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Mitchell Rabkin, MD ’55

The insight on DNA and the exquisite technologies of biomedical investigation.

Thanks to all who shared thoughts on the scientific or medical advances that have been exciting to witness during your career. We hope you will share your thoughts on our upcoming questions: If you took time off before or during your years as an HMS student, how did you spend that time? and Who or what inspired you to become the physician or scientist you are today? Responses for these will appear in print, online, or both in the coming months. Responses can be submitted online: alumni.hms.harvard.edu/rounds; via email: hmsalum@hms.harvard.edu; or by phone: 617-384-8520.

ALUMNI

I IN MEMORIAM

In Memoriam 1940s

Dan A. Ditmore, MD April 1, 2023

1949

Arndt R. von Hippel, MD March 23, 2023

Luis Fernandez-Herlihy, MD January 23, 2023

1958

1950s

Joseph W. Burnett, MD March 2, 2023

1950

Charles S. Lipson, MD August 16, 2023

John H. Eaton, MD March 25, 2014

Anthony S. Patton, MD June 25, 2023

1951

1959

James B. Field, MD March 8, 2023

Bruce W. Steinhauer, MD May 27, 2023

Marvin L. Gordon, MD February 7, 2023 1952

Kendrick P. Lance, MD December 30, 2022 1953

George R. Smith Jr., MD February 18, 2023 1954

Arthur L. Klatsky, MD April 30, 2023 Francis Wood Jr., MD July 31, 2022 1955

Ralph A. Heising, MD May 3, 2023 Harold C. Urschel Jr., MD November 12, 2012 1956

Stanley S. Franklin, MD September 19, 2022 1957

Charles W. Daniels, MD September 17, 2022

1965

1990s

Richard Cornell, MD July 22, 2023

1994

Edward M. Hughes, MD July 14, 2023

Ann B. Sidwell, MD April 15, 2023

W. Michael Kuehl, MD April 24, 2023

1998

Andrew Mallory, MD May 2, 2023 Russell E. Martenson, PhD March 27, 2023

2010s

George R. Neeley, MD July 18, 2023

2010

1966

1960s

Joan L. Martinez (Joan M. Leary), MD May 17, 2023

1960

1967

S. Edward Davis III, MD March 24, 2023

Jonathan K. Wise, MD June 27, 2023

Jon B. Tingelstad, MD February 28, 2023

1968

1961

Alfred L. Goldberg, PhD April 18, 2023

Darrel D. Bibler, MD April 24, 2023

1970s

Allen L. Cline, MD May 23, 2023

1971

Stephen G. Edelstein, MD March 14, 2023

John T. Baker, MD August 21, 2022

Raymond C. Yerkes, MD May 31, 2020

1972

1963

Susan L. Chambers-Brennan, MD March 21, 2023

Curtis L. Hill, MD March 11, 2023 Wesley P. Peterson, MD September 20, 2022

Samuel C. Somers, MD February 26, 2023

Andrew N. Gray, PhD March 28, 2023

1974

Richard J. Stadtmiller, MD July 24, 2023

1964

Michael J. Bradford, MD August 2, 2023 Stephen B. Hulley, MD November 22, 2022

This listing of deceased alumni includes those whose notices of death were received between April 1 and August 29, 2023.

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ALUMNI

I NEWS

PRESIDENT’S REPORT

Our Continuing Dedication to HMS and Its Students “IF YOU CAN SEE IT, YOU CAN BE IT” is at the soul of the initiative to support URiM students and expand diversity at HMS. Alumni mentoring broadens students’ professional horizons and opens vistas to unforeseen career opportunities. This year, in partnership with Andrea Reid, MD ’88, associate dean in the Program in Medical Education and director of the Office of Recruitment and Multicultural Affairs, alumni greatly expanded participation in promising programs of student support and in mentoring. Students were universally enthusiastic about these programs; the office plans to sponsor additional programs for other members of our richly diverse student body. At the May 2023 Council meeting, David Nierenberg, MD ’76, chair of alumni giving, reported that because of the outstanding level of individual donations from alumni, FY23 projections would be met or exceeded. Expansion of the number of alumni donors is a key objective going forward. In his final report as chair of the slate committee, Douglas Chin, MD ’94, MMSc ’94, updated the Council on the results of the elections, which were finalized on June 2. New members of the Council include Kirstin Woody Scott, MD ’20 (first pentad), Nancy Wei, MD ’06 (fourth pentad), Timothy Jenkins, MD ’92 (seventh pentad), Kalon Ho, MD ’87 (eighth pentad), and Laura Torres, MD ’88 (councilor-at-large). Retiring Council members are Numa Perez, ’15, Coleen Sabatini, MD ’04, Margaret Liu, MD ’81, David Cohen, MD ’86 PhD ’87, and Larry Paul, MD ’90. Chasity Jennings-Nuñez, MD ’95, will serve as slate committee chair for FY24. Dean George Q. Daley, MD ’91, reviewed the continuing drive for scientific excellence at HMS, including the new Blavatnik Harvard Life Lab Longwood, which provides incubator laboratory space with dedicated technical support staff to identify and accelerate ideas by integrating therapeutics science from the earliest stage and supporting collaborative science across institutions and disciplines. He also updated Council members on efforts to explore options to reduce student debt, including debt-free medical education. While the latter will require a significant gift, likely from a major donor, the generous donations that alumni continue to make remain key to sustaining important student support programs such as the Dean’s REACH Scholarship, a need-based four-year scholarship that provides funding to a select group of incoming MD students. Finally, Louise Aronson, MD ’92, the incoming Council president, outlined her vision for a central portal to channel student and alumni engagement opportunities and to foster greater intergenerational relationships at multiple levels. This would build on ongoing work by the Council and provide a platform alumni could access to enhance their working relationships with many programs within the HMS community. As my term on the Council and as HMAA president closes, I am humbled by the dedication of HMS and its alumni to improving the student experience. The School’s commitment to continued excellence and inclusion means that HMS will remain the world’s flagship in biomedical science, health care, and education.

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Are you inspired by a peer’s dedication to the School? The Alumni Council is seeking nominations for the 2024 Distinguished Service Award for HMS Alumni. Established in 2019, this award recognizes MD alumni who have demonstrated loyalty, service, and commitment to HMS through volunteering, community building, service as an ambassador for the School, or other work supporting HMS and its mission. Submit your nomination by December 31 at alumni.hms.harvard.edu/nomination.

How Can We Reach You? The Alumni Council and the alumni engagement team take pride in keeping you informed of the latest news, exclusive benefits, invitations, reunion notices, and networking and professional events. Has your email address and/or phone number changed recently? Update your contact information at alumni.hms.harvard.edu/reconnect.

Alumni Council Welcomes Five New Members MD graduates selected five new Alumni Council members during the 2023 election. Four of those members will represent the first (classes of 2018–2022), fourth (2003–2007), seventh (classes of 1988–1992), and eighth (classes of 1983– 1987) pentads, respectively: Kirstin Woody Scott, MD ’20 (Class of 2019); Nancy Wei, MD ’06; Timothy Jenkins, MD ’92; and Kalon Ho, MD ’87. Laura Torres, MD ’88 (Class of 1987), will represent all classes as councilor-at-large. Learn more about the new representatives at alumni.hms.harvard.edu/election.

Thank You, Alumni Donors Philanthropic support from 2,246 alumni during fiscal year 2023 is helping HMS serve humanity by advancing science, medicine, and education. MD alumni can view each class’s FY 2023 Honor Roll of Donors — a list of those who made gifts between July 1, 2022, and June 30, 2023 — at alumni.hms.harvard.edu/honor-roll.

Join Your Reunion Committee Classes ending in “4” and “9” will be celebrating their reunions June 6–8. Join your Reunion Committee to help plan a personalized class event and encourage your classmates to participate in 2024 activities. For more information, contact the alumni engagement team at 617-384-8520 or hmsalum@hms.harvard.edu.

RANDY GLASS

Kenneth Bridges, MD ’76, is vice president of external affairs for Pfizer, Inc., in South San Francisco.

Nominate a Deserving Alum

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On balance In ancient Egypt, it was believed that entrance to the afterlife depended on the weight of one’s heart. The heart from an unkind person would be heavy, making them unsuitable for the afterlife, but the heart of a good and kind person would be as light as a feather; they would be welcomed into the beyond. Although scientific research does not usually take on the question of eternal life or the rebirth of the soul, studies do indicate that treating others with kindness can benefit one’s health and well-being in this life.