Researchers at the USF Health Morsani College of Medicine were awarded $5.6 million of expected funds for a 4-year study from the U.S. Department of Defense to examine why many people with Friedreich’s Ataxia (FA) go on to also develop heart disease, a major cause of death for those with FA.

Principal investigator for the USF study is Thomas McDonald, MD, professor in the Department of Internal Medicine (Division of Cardiology) and the Department of Molecular Pharmacology and Physiology in the USF Health Morsani College of Medicine. Dr. McDonald is also a researcher in the USF Health Heart Institute and director of the USF Health Cardiogenetics Clinic.

“We still don’t have a full understanding of the genetic mutation for Friedrich’s ataxia to determine why so many patients go on to get heart disease – we need to know,” Dr. McDonald said. “The physiology is not well characterized. This study will help us gain a better understanding of the basic mechanisms of the gene that carries FA, and help identify clinical predictors of the FA-associated heart disease.”

The new study dovetails with current work taking place in Dr. McDonald’s lab, including an R56 grant from the National Institutes of Health, which focuses on the fundamental mechanisms of LMNA-associated heart disease passed from one generation to the next — and what can be done to help prevent disease and its consequences.

This FA-heart disease study will follow FA patients and their parents over four years, and will involve careful clinical monitoring of heart health, examination of biomarkers, whole genome sequencing, stem cell modeling of heart tissue, and mitochondrial function studies.

From left, Dr. Kami Kim, Dr. Aarti Patel, Dr. Thomas McDonald, and Dr. Theresa Zesiewicz. Not pictured is Sami Noujaim, PhD.

Spearheading the work in the DoD study is a multidisciplinary team of USF Health experts representing cardiology, genetics, neurology, molecular pharmacology, cardiac electrophysiology and predictive modeling. The diverse expertise will help distinguish the clinical, genetic, and biological factors that contribute to cardiac disease in FA patients. Data from FA families and basic science models will be integrated with clinical data to identify unique factors in the heart that influence the cardiac phenotype and separate cardiac-specific traits from those influencing the neurological phenotype.

“Study results could lead to tools used in patient care settings to identify those FA families most at risk for cardiomyopathy and allow for potential intervention and treatment that could help delay onset of the heart disease,” Dr. McDonald said.

The USF Health interdisciplinary team for the study includes:

• Thomas McDonald, MD: clinical cardiology, molecular pharmacology and cardiogenetics (Division of Cardiology, Department of Internal Medicine, MCOM)
• Aarti Patel, MD: neurocardiogenetics and cardiac imaging (Division of Cardiology, Department of Internal Medicine, MCOM)
• Sami Noujaim, PhD: molecular pharmacology and cardiac electrophysiology (Department of Molecular Pharmacology and Physiology, MCOM)
• Kami Kim, MD: machine learning and clinical predictive modeling (Division of Infectious Diseases, Department of Internal Medicine, MCOM; Center for Global Health Infectious Diseases Research, COPH)
• Theresa Zesiewicz, MD, clinical neurology (Department of Neurology, MCOM)

Dr. Zesiewicz, professor in MCOM and director of the USF Health Ataxia Research Center, has specialized in clinical research and patient care for ataxias and other movement disorders’ for more than 20 years and is recognized as an international expert and leader in the field of hereditary ataxias. Her movement disorders clinic supports the evaluation of over 3,000 patients per year, likely the busiest in the world.

“Dr. Zesiewicz will play a vital role in recruiting research participant and in overseeing neurological assessments of patients as they are longitudinally followed in this study,” Dr. McDonald said.

The funding for the study came from the DoD through its Congressional Directed Medical Research Programs (CDMRP), a section of DoD that funds novel approaches to biomedical research. Link: https://cdmrp.health.mil/

The team will begin recruiting study participants next month.

Photo by Ryan Rossy, USF Health Communications

Scientific research is often a low-key exercise, with fastidious people peering into microscopes and working under the radar. Seldom are they described as rising stars, but Jiajia Yang may have broken the mold.

This month, Dr. Yang became the first person to earn a PhD from USF through a new degree program within the newly opened USF Health Heart Institute.

The 30-year-old earned her degree in medical sciences from the USF Health Morsani College of Medicine, with a focus on heart disease, specifically genetic arrhythmia and cardiomyopathy gene mutations within a family.

The Heart Institute is housed within the new Morsani College of Medicine + Heart Institute building in the Water Street Tampa district of downtown Tampa. The facility, which also includes the MD degree program, opened in January 2020.

“You can’t imagine how excited I am,’’ Dr. Yang said of her degree and new career. “The most exciting part for me is that our research is really translational for patients. This isn’t just bedside to bench, but bench to bedside.’’

Originally from a small village in rural China, Dr. Yang attended medical school in Shanghai, then won a scholarship in 2015 at Descartes University in Paris. While there, she earned her Masters and learned to speak French ─ adding to her verbal portfolio of Chinese and English.

Dr. Thomas McDonald with Dr. Jiajia Yang.

After a year, she accepted a position as a research assistant at the USF Health Morsani College of Medicine and quickly showed promise as a fast and inquisitive learner, said Thomas McDonald, MD, professor in the Department of Molecular Pharmacology & Physiology. He would later work with Dr. Yang on a variety of heart-related research projects, including the role of patient-specific induced pluripotent stem cells.

“This is all technically difficult and she overcame so many obstacles,’’ Dr. McDonald said. “She really laid the ground work to help this take off.’’

During her time at USF, Dr. Yang published five research papers in peer-reviewed journals, including new findings on using patient-specific stem cells to study disease in human tissue.

“That had not been on the map at USF until now,’’ Dr. McDonald said. “Jiajia’s papers were the first.’’

Dr. Yang wasn’t shy about sharing her love for discovery.

“I don’t think I’ve ever run across anyone as enthusiastic about her work,’’ Dr. McDonald added. “She was literally jumping up and down in the hallways screaming (about the stem cells) ‘They’re beating! They’re beating!’ Her enthusiasm was contagious.’’

Armed with her degree, Dr. Yang accepted a job as resident physician in internal medicine at the University of New Mexico School of Medicine in Albuquerque. She expects to be there at least three years, but could stay longer if needed: Heart disease is the leading cause of death in New Mexico, according to the state’s Department of Health. When not working, Dr. Yang will devote time to her other passions: cooking, hiking and biking, tennis, and working out at the gym.

Dr. McDonald expects big things from his former colleague, and has no reservations about asking her to return to Tampa: “I’d like to see her career blossom and recruit her to come back to USF.’’

For more on the USF Heart Institute, visit: https://health.usf.edu/medicine/heart-institute

Written by Kurt Loft

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USF Health has established a Neurocardiogenetics Clinic focused on improving the quality of life for patients with hereditary neuromuscular disorders who are at risk for or already experiencing cardiac complications. Innovative genetic research is a central component of the new clinic.

The multidisciplinary clinic teams faculty and staff with clinical expertise in cardiology, genetics and neurology. The clinic is directed by Aarti Patel, MD, assistant professor of cardiology and director of the Cardiac Imaging Fellowship Program at USF Health in collaboration with Thomas McDonald, MD, professor of cardiology and molecular pharmacology and physiology, and a member of the USF Health Heart Institute, and Theresa Zesiewicz, MD, professor of neurology and director of the USF Health Ataxia Research Center. Patients receive a complete cardiac examination and testing along with a comprehensive family genetic evaluation from providers familiar with their neurological history.

“Combining all that information, we are able to come up with a personalized treatment plan,” Dr. Patel said.

Many patients initially seen at the Neurocardiogenetics Clinic have been diagnosed with Friedreich’s ataxia (FA), a rare, debilitating and life-shortening neuromuscular disorder that usually strikes in childhood. At some point in their lives 55 to 60-percent of FA patients develop some form of cardiac disease. The most devastating of these is cardiomyopathy, a heart muscle disease that limits blood pumped to the rest of the body and increases risk for heart failure and abnormal heart rhythms.

“FA is a multisystem disease that affects many different parts of the body, including the heart,” Dr. Zesiewicz said. “And one of its most sinister complications is cardiomyopathy, an enlarged heart.”

The Neurocardiogenetic clinic offers patients and their families the opportunity to participate in ongoing genetic studies exploring potential links between heart disease and neuromuscular diseases like FA and certain types of other ataxias and muscular dystrophies.

Dr. Aarti Patel (left), assistant professor of cardiology, collaborates with Dr. Thomas McDonald, professor of molecular pharmacology and physiology, at the new USF Health Neurocardiogenetics Clinic. Dr. Theresa Zesiewicz. professor of neurology (not pictured), is another collaborator.

While a deficiency in the frataxin protein can lead to fibrosis and scarring of heart muscle tissue in FA, competing theories exist about how a genetic mutation may actually result in heart problems in this particular ataxia and other neuromuscular disorders.

Dr. McDonald’s research team is searching for answers to many questions, including how different genetic variations may lead to cardiac abnormalities and affect the severity of heart disease.

Small blood samples are collected from patient volunteers with different inherited neuromuscular and/or cardiac disorders, as well as family members who are unaffected genetic carriers of neuromuscular diseases. In laboratory cell culture dishes, USF Health researchers genetically reprogram the blood cells into pluripotent stem cells that can grow into any cell type. Then they induce these stem cells — containing the same genetic make-up as the patient who provided blood — to become nerve cells and heart muscle cells.

The goal is to work out at a molecular level how FA or other inherited neuromuscular diseases damage the heart muscle. Once that is achieved, Dr. McDonald said, the “disease in a dish” can be used to identify potential drug targets and test treatment options on the patient’s own cells.

“With stem cell technology and disease-in-a-dish modeling, we’re looking for the earliest changes in either a heart or a nerve cell (that lead to disease),” he said. “A big unanswered question is whether the molecular or cellular process happening in the nerve is the same as that damaging the heart muscle. By using stem cell-based research we hope to be able to determine if there is a connection between the nerve and the heart – or whether it’s a separate, independent process but based upon the same genetic defect.”

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The collaborative research builds upon robust data collected by doctors in the clinic, including the wide range of symptoms seen in patients with hereditary neurological disorders involving cardiac complications.

Ultimately, that can help improve understanding of why genetic variations in certain neuromuscular diseases cause cardiac complications, Dr. McDonald said. “Having a clear clinical picture of each research participant will help us correlate the genetics and function of cells we see in the laboratory with how that translates to disease progression in the individual.”

“With careful clinical surveillance and novel biomarkers, our hope is that we will be able to predict which patients and their family members are at highest risk for cardiovascular disease so we can intervene early with effective treatment,” Dr. Patel said. “We’re hoping to identify patients even before they develop cardiac symptoms, so we can prevent heart disease.”

-Video and photos by Allison Long, USF Health Communications and Marketing

In the laboratory and the clinic, Dr. Thomas McDonald focuses on inherited heart diseases that can lead to potentially deadly heart rhythm disturbances

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Sudden cardiac death most often makes the news when athletes in peak physical condition collapse and die while exercising or competing.  This spring, Zeke Upshaw, 26, a basketball player for the Grand Rapids Drive, a G-league affiliate of the Detroit Pistons, collapsed face-down on home court during the final minute of a game and later died at the hospital. A medical examiner ruled that he had suffered sudden cardiac death.

“Sudden cardiac death is when someone, usually otherwise healthy and often young, tragically drops dead – without any warning,” said Thomas V. McDonald, MD, a professor in the USF Health Department of Cardiovascular Sciences.

Most of the 200,000 to 450,000 sudden cardiac deaths each year in United States are caused by heart rhythm disturbances  provoked by certain strenuous activities, prescription medications, recreational drugs, or other triggers. “Sometimes it just happens in your sleep.  The most severe and earliest form would be sudden infant death, or SIDS,” Dr. McDonald said.

Physician-scientist Thomas McDonald, MD, a professor in the USF Health Department of Cardiovascular Sciences and member of the USF Health Heart Institute, with his laboratory team.

Dr. McDonald was recruited to the USF Health Heart Institute in October 2017 from Albert Einstein College of Medicine in New York City, where he was a professor of both cardiology and molecular pharmacology. He also co-directed the thriving Montefiore-Einstein Clinic for CardioGenetics, the first such interdisciplinary clinic in metropolitan New York for families at risk of sudden cardiac death from arrhythmias.

At USF Health his laboratory continues to focus on the fundamental causes of heart conditions passed from one generation to the next — and what can be done to help prevent disease and its consequences.  The hereditary conditions he studies include those affecting the heart’s electrical system to cause arrhythmias, like long QT syndrome and Brugada syndrome, and those affecting heart muscle, such as hypertrophic cardiomyopathy and dilated cardiomyopathy.  While rare, these conditions can substantially increase an individual’s risk for sudden cardiac death and devastate families.

In long QT syndrome, the heart takes longer than normal to recharge between beats. This electrical disturbance, called a prolonged QT interval, can often be seen on an electrocardiogram (ECG) like the one pictured here.

Dr. McDonald has also started a USF Health Cardiogenetics Clinic, modeled after the Montefiore-Einstein center he co-founded, to evaluate and treat families in which members succumb to unexplained sudden cardiac death or SIDS, or where suspicion of an underlying, hereditary heart rhythm disturbance exists.

His work bridging the laboratory and clinic has implications for a much larger population than people with relatively rare inherited cardiac disorders.  Dr. McDonald points to growing evidence of the interplay between genetics and environmental factors like diet, exercise and stress.

“By studying these rare or uncommon cardiac diseases,” he said, “we may uncover more generalizable biochemical pathways that could be influenced to harm the heart given the wrong environment — even in genetically unaffected families.”

 Studying uncommon (inherited) heart diseases to gain better insight into more common ones.

Dr. McDonald lifts a container including pluripotent stem cells from storage in liquid oxygen. Alexander Bertalovitz, PhD, (right) an assistant professor of cardiovascular sciences who helps manage the cardiogenetics laboratory, followed Dr. McDonald to USF Health from Albert Einstein College of Medicine in New York City.

Pinpointing the meaning of genetic variants of “unknown significance”

Dr. McDonald analyzes genetic changes, or mutations, which may lead to malfunctioning of ion channels that create electrical signals in the heart.

His team has spent the last few years characterizing the function of 1,000 different mutations found in cardiac ion channel genes associated with hereditary rhythm conditions such as long QT syndrome and Brugada syndrome. The researchers recreate the genetic variations in a cellular model and use automated electrophysiology techniques to analyze how the mutations affect the ion channel’s ability to correctly generate each heartbeat. All these variations have been cited in published scientific literature; however, it is still largely unclear which ones truly increase the risk of abnormal rhythms leading to palpitations, seizures, fainting or sudden death – and which are benign.

The research project is supported by a five-year, $1.7 million R01 grant from the NIH’s National Health, Lung and Blood Institute.

“Our ultimate goal is to work with other investigators to create a NIH-curated public database that physicians and genetic counselors could access to find out whether a genetic variant is likely, or unlikely, to cause a potentially life-threatening heart rhythm disturbance in a patient or their family members,” Dr. McDonald said.

As genetic testing is becomes more common, a growing challenge is that lab reports of people referred for DNA sequence testing often come back listing many “variants of unknown significance,” Dr. McDonald said. “That drives physicians and patients crazy because they don’t know what that means… what do they do with that information?”

Dr. McDonald with Jiajia Yang, a PhD student in the Department of Molecular Pharmacology and Physiology.

An important step toward improving the guidance that doctors offer individuals with inherited heart disorders would be the ability to more precisely distinguish between disease-causing mutations and mutations with little or no harmful physiological effects through a resource like a scientifically validated database, he added.

Recommended treatment options for long QT are life-long and vary, including regular cardiac monitoring, taking medication such as beta blockers, restricting strenuous sports activities, or sometimes implanting pacemakers or defibrillators to help control abnormal heartbeats.  So, for example, if DNA testing of a child or young adult revealed a long QT genetic variation characterized as having little risk of leading to sudden cardiac death, prescribing beta blockers and routine cardiac monitoring might be the best preventive therapy – avoiding the long-term management and small, but real, lifetime risk of complications from an implantable device.

 Dr. McDonald comments on the focus of his laboratory’s research on genetic variations.

Opening Tampa Bay region’s first CardioGenetics Clinic

The twice-monthly Cardiogenetics Clinic, which opened in March, is held at USF Health Cardiology’s Armenia Avenue location. The new clinic is staffed by a team with the expertise to address the diverse medical, psychological, social and ethical issues arising when evaluating genetic heart conditions that predispose patients to sudden cardiac death.

Dr. McDonald — with certified genetic counselor Melissa Racobaldo (far left) and clinical geneticist Christopher Griffith, MD — leads a comprehensive discussion of family medical history with a patient and his mother referred to the USF Health Cardiogenetics Clinic.

“When I arrived there was no formal cardiogenetics program in the greater metropolitan area of Tampa Bay where 4 million people live — so the prospect of building one from scratch was very attractive,” said Dr. McDonald, who specializes in adult cardiology. He leads the clinic working with USF Health faculty members Christopher Griffith, MD, assistant professor of pediatrics and a clinical geneticist; and Melissa Racobaldo, a genetic counselor; as well as Gary Stapleton, MD, a pediatric interventional cardiologist from Johns Hopkins All Children’s Hospital. USF College of Public Health students specializing in genetic counseling are expected to join the clinic in coming months.

Many with congenital cardiac conditions have no signs or symptoms. Patients and their families referred to the clinic typically have experienced a history of arrhythmias or other cardiac events, or suffered the unexpected death of a loved one.

During the initial visit, families meet with team members for a cardiac history and examination, review of medical records and/or autopsy reports, and baseline tests that include an electrocardiogram and echocardiogram.  Based on the family’s medical history, a tree-like chart known as the DNA pedigree is created to identify familial genetic patterns and sudden unexpected deaths linked to cardiac disorders.  “The most important genetic test is still a complete family history,” Dr. McDonald said.

Certified genetic counselor Melissa Racobaldo consults with Dr. McDonald about a patient.

DNA testing is usually only recommended when the team discerns that the pattern of cardiac-related events is highly likely to be genetic rather than environmental.  For instance, a family history indicating that a few relatives died from heart disease in their 80s might be considered environmental.

If a mutation is found in one of the genes known to be associated with a dangerous cardiac arrhythmia, then the first (affected) patient who got tested receives immediate counseling by a cardiologist, and genetic testing and counseling will be offered to all at-risk relatives. Different heart rhythm genetic mutations have different effects on ion channels, so individualized remedies are required.

“Genetics is still quite complex to most people, so we try to make our explanations understandable and not so scary,” said Dr. McDonald, who has co-authored several articles on how patients are affected by cardiogenetic testing, including in the journals Qualitative Health Research and Personalized Medicine.

“Our dominant message is ‘we’re here to provide information, which gives you knowledge, and knowledge gives you power to manage your life and to help the next generation.”

A pedigree, which depicts the relationship between individuals and relevant facts about their medical histories, can be used to help understand the transmission of genes within the family. Dr. McDonald points to a square indicating the presence of a particular genetic trait in a male.

The Cardiogenetics Clinic will offer patients access to the latest clinical trials for new drugs or devices. Dr. McDonald was recently named USF site lead investigator for a world-wide Phase 3 study testing the effect on walking endurance of an investigational medication for patients with dilated cardiomyopathy caused by a rare genetic mutation. This form of heart disease, in which inadequate pumping of blood causes the heart to become weaker, can lead to heart failure.

“Heart in a dish” as a drug screening tool

Interested in drug discovery for inherited heart diseases lacking effective medications, Dr. McDonald’s lab has begun collecting blood cells from USF Health cardiomyopathy patients who provide informed consent.

The adult blood cells can be genetically reprogrammed into induced pluripotent stem cells (iPSCs) with the potential to develop into any cell type in the body, including heart cells.  The goal is to model the early stages of inherited heart disease with patient-specific cells grown in a petri dish, working out at a molecular level how the disease does its damage to heart muscle.

 On the horizon: Modeling inherited heart diseases using pluripotent stem cells

Dr. McDonald and Maliheh Najari Beidokhti, PhD, a postdoctoral associate in the Department of Cardiovascular Sciences.

“Once you do that,” Dr. McDonald said, “you can use the ‘heart disease in a cell culture dish’ to screen any number of drugs or chemical compounds for their potential therapeutic benefit.”

Dr. McDonald is also collaborating with colleagues in the USF Health Department of Neurology to look at rare genetic mutations for nervous system diseases, such as certain types of muscular dystrophy and ataxias, which can lead to severe heart damage,

Dr. McDonald received his bachelor’s degree in zoology from USF in 1977 and MD degree from the University of Florida.  He completed a residency in medicine and research fellowship in cardiology at Columbia-Presbyterian Medical Center in New York City. At Stanford University School of Medicine, he conducted fellowships in clinical cardiology and interventional cardiology, as well as a postdoctoral research fellowship. He spent 22 years as a faculty member at Albert Einstein College of Medicine before joining the USF Health Morsani College of Medicine last fall.

Continuously funded throughout his career by the NIH or the American Heart Association (AHA), Dr. McDonald has authored more than 70 peer-reviewed publications.   Among his many high-impact papers was a 2013 article published in FASEB.  The NIH-supported study was among the first to report that synonymous (silent) changes in DNA traditionally considered neutral may adversely affect the processing speed and efficiency of ion channels associated with the heart arrhythmia syndrome Long QT and alter disease severity.

Dr. McDonald has served on multiple study sections of the NIH and AHA. He was elected in 2011 as an AHA Fellow-Basic Cardiovascular Sciences Council.

Dr. McDonald says his clinical practice helps inform and complement the translational science he conducts in the laboratory.

Some things you may not know about Dr. McDonald

• During high school, he worked one year as a head cook for a restaurant in Winter Park, Fla., before entering college. “It made me realize that hard work is important, but also motivated me to study so I could make a living by using my head more than my hands.”
• Wife Kami Kim, MD, also a USF Health physician-scientist, is a professor with joint appointments in the Department of Internal Medicine and in the Department of Global Health. They met in the cardiac intensive care unit at Columbia Presbyterian Medical Center when Dr. McDonald was a resident and Dr. Kim was rounding as a medical student.  Their two sons, both studying theoretical math, are Clayton, 24, a PhD student at Boston College, and Vaughan, 20, starting his junior year at Harvard University.
• McDonald enjoys bicycling, Japanese cooking, and nearly exclusively reads fiction – “it’s another window on the human condition.” His two favorite books are One Hundred Years of Solitude, an acclaimed novel by Nobel Prize-winning Latin-American author Gabriel García Márquez, and Infinite Jest, a literary bestseller and unconventional comedy by David Foster Wallace.

-Video and photos by Torie M. Doll, USF Health Communications and Marketing