Faculty Spotlight: Amir Munir, MD

Connecting the Lab with the Clinic

“I tell people I have one foot in cardiology, another in oncology, a hand in immunology and another in molecular biology,” said cardiologist Amir Munir, MD, a new faculty member who cares for patients and also conducts research in cardio-oncology and immunology. “There’s so much crosstalk among these fields, and I get to be the cross-cut between them. I hear about the exciting molecular and anti-cancer therapy trials, the newest innovations in immunology technology, and the seminal clinical trials in cardiology. Getting a sneak peek into each of these worlds helps me formulate an idea of how I’ll move my science forward.” 

Born in Mesa, Ariz., Dr. Munir grew up in West Windsor, N.J. He always loved the sciences, but also really enjoyed interacting with people, which inspired him to pursue a career in medicine. While earning his bachelor’s degree in chemistry from Washington University in St. Louis, Mo., he joined the lab of Helen Piwnica-Worms, PhD, a Howard Hughes Medical Investigator and  molecular biologist. 

He worked with a postdoctoral fellow, investigating how a protein called p21 affects cell cycle checkpoints and regulations, and how to potentially inhibit or antagonize it as a treatment for cancer. “I learned core skills, like how to set up an experiment and what controls are necessary,” said Dr. Munir. “If your experiment doesn’t work, which is probably 95 percent of the time, how can you troubleshoot it and break it apart, section by section, to understand what may have gone wrong, and how to optimize it the next time around?”

During medical school at Case Western Reserve in Cleveland, Dr. Munir joined the lab of cardiologist Saptarsi Haldar, MD, MS, who was later recruited to UCSF and then went on to become a vice president of research for Amgen. “Research was fun and I enjoyed doing it, but at that point I still didn’t know if it was how I wanted to spend my life,” said Dr. Munir. “But working with Sap, for the first time I saw someone who was both a physician and a scientist. That showed me that both can be done together, and done well. Sap had an infectious energy about him. At that time he was a junior faculty member, and his lab was just two people. But what really resonated with me was how passionate he was about research, and how invested he was in his trainees.”

In the Haldar Lab, Dr. Munir helped investigate an epigenetic reader protein called JQ1. He and his colleagues found that in animal models of vascular injury such as atherosclerosis and narrowing of coronary and carotid arteries, JQ1 could rescue some of the pathological effects of vascular smooth muscle activation. “That was the experience that led me to say, ‘Maybe a career in science really is for me,’” he said.

Immersed in Science as a Sarnoff Fellow

Dr. Haldar also encouraged Dr. Munir to apply for a Sarnoff Fellowship, which allows medical students to spend an additional year during medical school engaged full-time in research at a site other than their home institution. So Dr. Munir spent a year at UT Southwestern Medical Center in Dallas in the lab of Eric Olson, PhD, a leading researcher in the key transcription factors and mechanisms underlying development and disease in cardiac and skeletal muscles.

In the Olson Lab, Dr. Munir worked with Catherine (“Cat”) Makarewich, then a postdoctoral fellow, on a new class of molecules called long noncoding RNAs. Another lab member had discovered that some of these molecules contain instructions for tiny proteins. “I manually went through huge databases of long noncoding RNAs to see if some of them had protein-coding potential, then did experiments to show they actually produced proteins,” he said. “The fun part of Eric’s lab was that you not only had to find a protein, but also figure out what it does.”

Dr. Munir helped define the function of several of these proteins, discovering that MOXI was involved in fatty acid oxidation, and that deleting it in animal models adversely affected the ability to exercise or use fatty acids as a source of fuel. Another tiny protein, mitolamban, caused severe heart failure when it was overexpressed in animal models. That damage was associated with grossly enlarged mitochondria, which are the energy factories of a cell. They found that mitolamban was an important regulator of portions of the electron transport chain, affecting how the mitochondria use oxygen to metabolize and generate sources of fuel. They also discovered yet another micropeptide, DWORF, which binds to calcium, helps the heart to beat, and was protective against heart failure when overexpressed in an animal model of dilated cardiomyopathy.

“The Sarnoff Fellowship is an immersive experience, where you’re placed in a totally new environment and work in a lab where people are excited about mentoring and science,” said Dr. Munir. “That set me on my path towards becoming a physician-scientist. I went back to Case Western and told Sap, ‘I’m going to become a cardiologist physician-scientist.’”

Cancer, the Heart and Immunology

After earning his medical degree from Case Western Reserve, Dr. Munir completed an internal medicine residency from the Brigham and Women’s Hospital in Boston, then came to UCSF for his general cardiology fellowship. “I was drawn to UCSF for the opportunity to train in three different hospitals,” he said. Those included UCSF Health, a quaternary academic center and referral center for much of Northern California, as well as San Francisco Veterans Affairs Medical Center, where he cared for veterans, and Zuckerberg San Francisco General Hospital and Trauma Center, where he served vulnerable and working poor patients. “Those first two clinical years were very rigorous, and I also got to learn from different patient populations and mentors,” he said.

He appreciated the supportive teaching and mentoring environment. “I now tell younger trainees that though some tasks may seem insurmountable in the beginning, with the amazing teaching and collaboration here, day by day you slowly grow your competence in a very well-supported environment,” said Dr. Munir.

When considering what area of research to specialize in, he was drawn to the relatively new field of cardio-oncology, which focuses on the cardiovascular health of cancer patients and survivors. “Many patients get targeted therapies for their cancer which have revolutionized their care, but those newer therapies can also cause toxicities in the heart,” said Dr. Munir. “I wanted to help better diagnose this, discover what’s driving those toxicities, and develop better treatments – which allows me to intersect my interests as a clinician and scientist.”

Dr. Munir was part of the inaugural cohort of the newly created Cardio-Oncology Fellowship Program. It is led by Javid Moslehi, MD, founding chief of the Section of Cardio-Oncology and Immunology and the William Grossman, MD Distinguished Professor in Cardiology.

Studying Immune Checkpoint Inhibitor Myocarditis

As a cardio-oncology and immunology fellow and now as a postdoctoral scholar in Dr. Moslehi’s lab, Dr. Munir has focused on a condition called immune checkpoint inhibitor (ICI) myocarditis, a relatively rare but potentially fatal condition in which patients who receive cancer immunotherapy develop inflammation of the heart. The condition was first described by Dr. Moslehi and his collaborators in 2016, and his group has been at the forefront of discovering what causes it and how to treat it.

“T cells have brakes that tell them, ‘Hey, don’t attack,’” said Dr. Munir. “Cancer takes advantage of those brakes and put up signs that say, ‘T cells, take a breather.’ Immune checkpoint inhibitors release those brakes on T cells, directing a patient’s own immune system to attack the cancer. That’s really revolutionized how we treat patients with cancer.” But sometimes those immune checkpoint inhibitors can go too far, provoking “friendly fire” that causes the immune system to attack not only cancerous cells, but also a patient’s healthy tissue – which is what happens with ICI myocarditis.

During general cardiology fellowship, Dr. Munir cared for patients with ICI myocarditis as well as other forms of myocarditis, such as those caused by viral infection or a severe reaction to vaccines. “We can try to protect the heart by unloading it with ECMO, and we can also give steroids, which may or may not work,” he said. “But we still use steroids because we don’t know what else to do. Although we have a well-equipped arsenal to treat the vast majority of heart disease, there’s still a huge unmet need for treatment of myocarditis. Because the driver is the immune system, we need targeted therapies that are anti-inflammatory.”

Dr. Munir has been studying the effects of a more recent combination of immunotherapies: PD-1 inhibitors, a mainstay therapy, combined with a newer therapeutic called LAG-3 inhibitors. “Interestingly, patients who get LAG-3 and PD-1 combination therapy have a higher risk of myocarditis than patients who get PD-1 therapy alone, or CTLA-4 and PD-1 therapy,” he said. “It made us wonder what LAG-3 is doing.” He and his colleagues studied LAG-3 and PD-1 in a mouse model, finding that myocarditis was their cause of death. 

Dr. Munir and his colleagues are now trying to determine which T cell populations in the heart drive ICI myocarditis. “We want to understand the cardiac immune system, and tease out what are the critical markers of activated, angry T cells in the heart,” he said. “We want to use this information for diagnosis and treatment of these patients.”

Identifying specific biomarkers for these “angry” T cells which are driving myocarditis would be a gamechanger. “The way we diagnose myocarditis right now is by getting a biopsy sample of the heart and sending it to a pathologist, who classifies it based on the histology they see,” said Dr. Munir. “But it’s really hard to get heart tissue, because it’s an important organ that you don’t want to mess with, for good reason. If we can identify specific biomarkers of these ‘angry’ T cells and develop a radioisotope or radiotracer dye against those using PET tracers, we could use advanced imaging to tell us that there are activated T cells in the heart.” That non-invasive diagnostic could also be used to measure a patient’s responsiveness to therapy.

Dr. Munir is also interested in developing more precise ways to diagnose and treat myocarditis. “By using new immunoprofiling techniques and leveraging single-cell technology, we could better understand and categorize different types of cardiac inflammation,” he said. “Instead of doing that based on what we see under a slide, we could define the specific immune cell profiles in the heart. Are there more B cells, or specific types of T cells? Are there macrophages at play? Then we can tailor therapies to treat the condition, based on what cells are driving it – instead of just using steroids, a hope, and a prayer.”

These investigations could not only make cancer treatments safer and more effective, but also shed light on other forms of heart disease. “Cardio-oncology and ICI myocarditis are great ways to study the immune system of the heart, but these insights can also be applied to the broader cardio-inflammation world,” said Dr. Munir. “We’re starting to recognize that inflammation plays a role in atherosclerosis and likely in some types of heart failure. After a heart attack, inflammation is crucial for healing, but can also be maladaptive. The more granularly we can understand how maladapted immune cells affect the heart and coronary arteries, the better we can figure out ways to target them.”

Dr. Munir believes there are likely shared, common pathways across lots of different types of cardiac inflammation. “If we can develop ways to trace those [immune] cells with PET tracers, to antagonize or delete those cells with gene therapy or antibodies, the world of treating ICI myocarditis ripples outward into the larger cardiology-inflammatory sphere,” he said.

A Rising Star 

Dr. Munir is very grateful for the support he has received on his journey to become a physician-scientist. During his cardio-oncology and immunology fellowship, he was selected as a Chan Zuckerberg Biohub Physician-Scientist Fellow, which provided partial salary, a science bootcamp at the start of the program, and a longitudinal seminar curriculum on topics such as gene editing, drug development, how to write a grant, and how to give a talk. Now as a postdoctoral fellow, he receives support from the Sarnoff Scholar Award, which helps former Sarnoff Fellows as they transition to junior faculty.

“As a junior faculty, it’s a vulnerable time,” said Dr. Munir. “I’m not bringing in the large funding yet, yet I need protected time to grow. Everyone has been wildly supportive of my career, from [UCSF Cardiology Division Chief] Jeff Olgin to Javid Moslehi and near-peer mentors like Arun Padmanabhan and Alan Baik. Having the support of people who have become physician-scientists has been invaluable. The scientific and cardiology community here is second to none. And in a full circle moment, now I’m actually mentoring a Sarnoff Fellow, Alan Gutierrez, in the lab. He’s a rock star. This world is cyclical in nature.”

“Amir is a rising star in our field of cardio-oncology and cardio-immunology,” said Dr. Moslehi. “He has already made seminal contributions, with the identification of a novel chemokine receptor that mediates T lymphocyte entry into the heart during active myocarditis, an observation that has immediate therapeutic implications. Amir is also a natural leader, and I predict he will be leading his own cardio-oncology program in the near future.”  

“Amir is an outstanding colleague and physician-scientist, bringing great enthusiasm to his work,” said Dr. Baik. “He is equally passionate about cardio-immunology research and providing exceptional patient care.”

“Amir has excelled as a postdoctoral fellow and been absolutely fearless in tackling an exciting line of investigation,” said Dr. Padmanabhan. “He also possesses that additional ‘special something’ – the intellectual curiosity that drives him to stay in the lab late into the evenings and come in on the weekends, to dive into the literature and seek out the expertise of colleagues when he encounters something he doesn’t understand, to leverage his ever-expanding technical skills to assist colleagues with their science, and to continuously challenge himself to expand his knowledge base and technical proficiencies. I’m excited to see the world-class science that Amir will continue doing over the course of his career.”

‘It Takes a Community’

In addition to his research, Dr. Munir is passionate about teaching. “I have been privileged to have amazing mentors, and feel very indebted to their investment in me,” he said. “That’s why I take mentorship seriously. Becoming a physician-scientist is a long, arduous path, but if I can mentor others and get them excited, that will be my barometer of success.”

He also feels privileged to care for patients. “If someone is hospitalized, it’s often one of the most difficult days of their life,” said Dr. Munir. “I try to take time to be there for them, explain what’s happening, and answer their questions in a way that’s not rushed. Especially in cardio-oncology and immunology, there’s rarely one right answer. There are usually five or six different pathways. Hearing the patient’s stories and understanding what’s important to them is so critical in figuring out which pathway is best for them. There can be a lot of nuances in this decision-making process, and patients need to drive that. When patients understand what’s happening, they are active participants.”

Dr. Munir aspires to become an independently funded physician-scientist studying the mechanisms of cardiac inflammation, and how to better diagnose and treat it. “It takes a community for science to happen,” he said. “Scientific discovery only takes you so far – it’s the people and community that will take you the rest of the way. UCSF really sets you up for success, and the support I’ve received from my division and section has made a world of difference as I develop as a physician-scientist.”

Dr. Munir is married to Naureen Syed, FNP, a primary care nurse practitioner who works for Palo Alto Medical Foundation. Together they enjoy exploring every crevice of Golden Gate Park and admiring the ever-changing blossoms in the San Francisco Botanical Garden. 

-    Elizabeth Chur