Charles Antzelevitch is professor and executive director of the cardiovascular research program at the Lankenau Institute for Medical Research in Pennsylvania, and a professor of medicine and pharmacology and experimental therapeutics at Sidney Kimmel Medical College in Philadelphia, Pennsylvania. He tells Cardiac Rhythm News about his extensive contributions to electrophysiology, and their impact on everyday practice, and shares his thoughts on the future priorities for research in the field.
Why did you decide to become a doctor, and why did you choose to specialise in cardiac electrophysiology?
I was intent on becoming a scientist since early childhood, always curious as to how things worked. Initially, I studied to be a biochemist but switched to cardiac electrophysiology after visiting an electrophysiology lab and being mesmerised by the electrocardiographic signals bouncing up and down on the oscilloscope screen.
Who were the biggest influences on your early career?
My mentor, Gordon K Moe, one of the fathers of cellular electrophysiology and the director of research at the Masonic Medical Research Laboratory (MMRL), was the biggest influence in my early career. He recruited me to his research laboratory in Utica, New York, in 1977. I agreed to come for a two-year postdoctoral fellowship and wound up staying 37 years, taking over as the director of the institute upon his retirement in 1984.
What has been the biggest development in electrophysiology during your career?
The past 40 years have witnessed numerous incredible advances in electrophysiology. The most meaningful and exciting for me are the advances in molecular genetics, which opened the floodgates of knowledge, permitting us to peer into mechanisms of cardiac function in health and disease that were previously out of view.
What has been the biggest disappointment in electrophysiology—an advance that you hoped would change practice, but failed to do so?
My biggest disappointment is that having demonstrated the remarkable efficacy of the combination of ranolazine and dronedarone in producing atrial-selective inhibition of sodium channel activity, thus very effectively suppressing the development of atrial fibrillation (AF), big pharma failed to move forward with it. Despite a very successful phase II clinical trial called Harmony, the drug combination was not advanced to phase III. There remains a dire need for a safe and effective pharmacological agent to combat atrial fibrillation.
You have extensive experience in the area—what do you consider to be the key unanswered questions?
Despite tremendous progress in recent years, we continue to lack a full understanding of the mechanisms underlying the development of many forms of cardiac arrhythmia. It is unfortunate that the National Institutes of Health (NIH) funding needed to delve more deeply into this and many other medical problems is so woefully inadequate.
You have performed a lot of research on sudden cardiac death—what have been your key findings?
My contributions, and that of my tremendously talented team members, to the scientific literature, include >550 original papers and reviews, and seven books. A major achievement includes the discovery and characterisation of reflected re-entry, phase II re-entry, and late phase III early afterdepoliarisations (EADs) as mechanisms of extrasystolic activity capable of precipitating life-threatening ventricular tachycardia and fibrillation. We have also performed pioneering work demonstrating electrical heterogeneity within ventricular myocardium, particularly transmural dispersion of repolarisation and discovery of a unique population of cells, that we named M cells, opening new doors to our understanding of electrophysiology and pharmacology of the heart and arrhythmogenic mechanisms. Other findings include delineation of the cellular and ionic basis for the long QT, Brugada, and short QT syndromes, as well as catecholaminergic ventricular tachycardia (VT), and design of novel approaches to therapy of these syndromes. We have worked on the cellular and ionic basis for the J wave and T wave of the ECG uncovered the genetic basis for Brugada, short QT, long QT, and early repolarisation syndromes, and designed novel therapeutic modalities. Additionally, we discovered a novel therapy for atrial fibrillation using atrial-selective sodium channel blockers, and novel therapeutic approaches for the Brugada and early repolarisation syndromes.
Which of these has had the biggest impact on daily practice?
Our team has a long history of involvement and interest in the Brugada and early Repolarisation syndromes. The product of this work has contributed to the daily practice of medicine. We suggested the use of quinidine to prevent sudden death associated with these syndromes in 1999, which is today used all over the world. A few years later, we suggested the use of quinidine for short QT syndrome, which is widely used as well. We were among the first to coin the term J wave syndromes to encompass both of these sudden death syndromes. In 2004, we convened a consensus conference in upstate New York, from which emanated the second expert consensus conference report dealing with Brugada syndrome (Antzelevitch et al. Circulation and Heart Rhythm, 2005) as well as the first book dedicated to Brugada syndrome. In 2015, Gan-Xin Yan and I convened another consensus conference in Shanghai, China, from which emanated the first expert consensus statement dealing with the J wave syndromes (Antzelevitch et al, Heart Rhythm, Europace-EP, and Journal of Arrhythmia, 2016), and the first book dedicated to the J wave syndromes.
What are your current research interests?
Our current focus continues to be defining the genetic basis for inherited cardiac arrhythmia syndromes, and developing novel therapeutic approaches to treat cardiac arrhythmias, including atrial fibrillation and inherited cardiac arrhythmia syndromes. In the realm of cardio-oncology, we are working to better understand why and how agents effective in fighting cancer produce cardiac arrhythmias, and how this can be prevented. Taking advantage of the many valuable resources at the Lankenau Institute for Medical Research, we are working to better understand the electrophysiology of cancer, and how the electrical activity of cancer cells can be manipulated to treat the disease and ultimately effect a cure.
What do you consider to be the most important paper published on this topic in the past year?
The most important paper published in this field in the past couple of years from the clinical perspective is probably the 2017 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, by Al-Khatib et al (Circulation 2018; 138 (13): e272–e391).
What are the key priorities for future research in this area?
To better understand the mechanisms underlying channelopathies and cardiomyopathies, which will hopefully guide us to innovative approaches to therapy.
What is the value in this online age of attending conferences?
Didactic sessions are valuable but the one-on-one, face-to-face sidebars are invaluable.
What advice would you give to someone who was starting out in cardiovascular medicine?
A career in biomedical research is among the most intellectually stimulating and fulfilling that you can pursue. Be aware that pursuing such a career is today more difficult than ever before, because of the difficulty in obtaining grant support. However, if you have a thirst for knowledge and an insatiable curiosity about how things work, biomedical science offers an exciting challenge that promises to be rewarded by the thrill of discovery, which will more than offset the difficulties you will likely encounter in your scientific career. Do not be afraid to take the plunge.
What was your childhood dream job?
What I am doing now.
What are your hobbies and interests outside of medicine?
I enjoy hiking, swimming, biking, making music and, most of all, spending time with the grandkids.
• Professor and executive director of the cardiovascular research program, Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
• Director of research, Lankenau Heart Institute, Wynnewood, Pennsylvania
• Professor of medicine and pharmacology and experimental therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
• 2017: Professor of medicine and pharmacology and experimental therapeutics, Sidney Kimmel Medical College
• 2015: Professor and executive director of the Cardiovascular Research Program, Lankenau Institute for Medical Research, and director of research, Lankenau Heart Institute
• 1995–2016: Professor of pharmacology, SUNY Health Science Center
• 1987–2015: Gordon K Moe Scholar, chair in experimental cardiology, Masonic Medical Research Laboratory
• 1984–2015: Executive director and director of research, Masonic Medical Research Laboratory
• 1984: Senior research scientist, Experimental Cardiology, Masonic Medical Research Laboratory
• 1986–1995: Research professor, Pharmacology Department, SUNY Health Science Center
• 1983: Associate professor, Pharmacology Department, SUNY Health Science Center
• 1980: Research scientist, Experimental Cardiology, Masonic Medical Research Laboratory
• 1980: Assistant professor, Pharmacology Department, SUNY Health Science Center, Syracuse, New York
• 1977: Postdoctoral fellow, Experimental Cardiology Department, Masonic Medical Research Laboratory, Utica, New York
Professional and academic honours (selected)
• President, International Cardiac Electrophysiology Society 1996–1998
• Secretary/treasurer, International Cardiac Electrophysiology Society 1998–present
• Distinguished Scientist Award, North American Society of Pacing and Electrophysiology (NASPE, currently Heart Rhythm Society) 2002
• Excellence in Cardiovascular Science Award. NE Affiliate American Heart Association 2003
• Carl J Wiggers Award, American Physiological Society 2007
• Distinguished Scientist Award, American College of Cardiology 2011
• Distinguished Service Award, Cardiac Electrophysiology Society 2015
• Douglas P Zipes Lecture Award, Heart Rhythm Society 2016