As a young medical student caring for her first patients, Michelle O’Donoghue, MD, MPH, of the Division of Cardiovascular Medicine, considered specializing in pediatrics and often found that the clinical puzzles presented by cardiology patients intimidated her the most.
“The cardiovascular system has so many intricacies, and cardiology covers quite a broad spectrum in terms of clinical and research directions,” O’Donoghue said. But as she completed her internal medicine residency at Massachusetts General Hospital, O’Donoghue continued to encounter unanswered questions surrounding heart disease, the leading cause of death in the United States, and the breadth of the cardiology landscape soon proved alluring.
“Within cardiology, we’re spoiled to have a large number of clinical trials to help support our decision-making on prescribing different therapies, and I was drawn to that particular aspect,” she said. “The idea of questioning the evidence base for the clinical decisions that we make as doctors every day is vitally important, and the natural pathway from this realization was that I wanted to be able to contribute meaningfully to conducting research that helps shapes how we treat patients.”
In 2005, she began her fellowship in cardiovascular medicine, also at Mass General, while pursuing research alongside leading experts at the TIMI Study Group, an internationally renowned research group at the Brigham where she is now a senior investigator. Under the mentorship of Eugene Braunwald, MD, and Marc Sabatine, MD, MPH, the former and current chairs of the TIMI Study Group, respectively, O’Donoghue became captivated by the field of cardiology and jumpstarted her research career.
The first clinical trial she worked on with the group, PRINCIPLE-TIMI 44, studied the antiplatelet effects of prasugrel, which was subsequently approved by the U.S. Food and Drug Administration and today is widely used to prevent clots from forming in the coronary arteries. Since then, O’Donoghue has continued to study antiplatelet therapies as well as antithrombotic and lipid-lowering therapies, leading studies of thousands of patients worldwide. She is currently the principal investigator for two global trials and is helping lead a phase III trial in collaboration with Oxford University, ORION 4 / HPS4 / TIMI 65 trial, which is evaluating a drug called inclisiran that is designed to lower “bad” LDL cholesterol by directly targeting the synthesis of a protein involved in its removal from the blood stream.
This cutting-edge technology is used by another therapeutic O’Donoghue is currently examining in a phase II clinical trial. The drug uses small interfering RNA to target the production of lipoprotein (a), a particle that circulates in the blood and appears to drive inflammation and atherogenesis (the formation of fatty plaques in the arteries). Statins aside, therapeutics that control inflammation have only more recently begun to receive attention as promising treatment strategies, and O’Donoghue is actively probing their potential in other clinical trials.
Bringing New Perspectives to Clinical Care
When O’Donoghue pivoted into cardiology research, she immediately observed that her colleagues looked different. “Within pediatrics, I had seen more female representation, but in cardiology, women still constitute the vast minority of physicians within the field,” she said.
Likewise, when O’Donoghue began her research career she saw that female patients were frequently underrepresented in clinical trials. O’Donoghue had initially been attracted to cardiology’s rich, clinical research ecosystem. But she recognized that meaningful breakthroughs could not be claimed for all patients without diverse study populations.
“We are now only beginning to unravel the fact that the pathways that lead to heart disease in women and men may differ,” O’Donoghue said. “For all too long, the feeling was that the biology of the disease state is the same for women and men, and that women are just, on average, ‘smaller men.’ But it’s not always clear whether we should be considering alternate dosing or even alternate treatment strategies for women compared to men.”
O’Donoghue has begun to consider this question from a number of perspectives. One of her first investigations early in her career suggested that an invasive imaging technique to look at the blood vessels around the heart (angiography) could be more beneficial for men than certain low-risk women after a heart attack. She further uncovered that women are less likely to have traditional blockages in the largest heart arteries.
“Much is still not understood about whether women may have different types of heart disease that may not be well visualized on a standard coronary angiogram,” said O’Donoghue, who is also exploring how men and women may respond differently to antiplatelet therapies, lipid-lowering therapies and diabetes medications for cardiovascular disease. “This leads us to ask the question as to whether we should be considering alternate diagnostic modalities and therapies for some of our female patients”.
She notes the importance of facilitating female participation in clinical trials, citing findings that show women are approached less frequently than men to join trials and are more likely than men to discontinue a study drug. “We need to better understand what the reasons for this might be — why women may be reluctant to participate, and what barriers there might be for investigators to invite women to participate,” she said.
The Road Forward
Roughly a decade ago, O’Donoghue received a promotion at Harvard Medical School, where she is now an associate professor. Not long afterwards, she was diagnosed with multiple sclerosis.
“It was a very big turning point for me in terms of realigning my priorities,” she said. “Many people would consider facing this type of diagnosis to be devastating news, but in many ways, I found it to be one of the most important teaching lessons and opportunities in my own life. It led me to focus on the aspects of my career that are most important to me, and at the same time, focus on achieving a meaningful work-life balance.”
The field of cardiology is notoriously unforgiving of a “work-life balance,” and O’Donoghue cites this reputation as one factor that may deter women from choosing the specialty. But she believes that with careful thought, cardiologists can pursue the variety of endeavors that may be important to them. In addition to her busy work schedule, O’Donoghue is a mother and prioritizes as much time as possible with her newborn son. “I believe that all working mothers struggle to achieve work-life balance in their lives. However, I consider myself fortunate to have a research career that introduces a fair amount of flexibility.”
Beyond dividing her time on and off the hospital campus, O’Donoghue also has learned to prioritize the aspects of her career that are most meaningful to her. She is committed to teaching medical students and housestaff and continues to spend several weeks each year attending on the inpatient cardiology services at both the Brigham and Mass General.
“I have always found it quite enlightening to think about practice differences between institutions, because it forces me to take a step back and think through the evidence behind the different therapeutic decisions that we might make every day,” she said.
Probing the safety and efficacy of established clinical practices has driven some of O’Donoghue’s work, but examining new therapeutic targets remains critical for her as well.
“By shining a spotlight on unidentified pathways of disease and trying to marry this with the work we do through clinical trials, we may really be able to advance science further,” she said. “The technologies that we have available have vastly expanded over the past several years, creating so many more opportunities for discovery work. It’s exciting to think about the possibilities down the road.”