Stanley Nattel

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Stanley Nattel, Paul-David Chair in Cardiovascular Electrophysiology, Professor of Medicine, University of Montreal, Canada, and Director of the Electrophysiology Research Program in the Montreal Heart Institute Research Center, spoke to Cardiac Rhythm News about his career, the challenges facing electrophysiology, and the future of the research on drugs for arrhythmias.

When did you decide you wanted a career in medicine?


I considered a lot of careers in high school and college, including theoretical physics, astronomy and history. In my first year of college, I finally settled on medicine because I felt it provided the best combination of human-contact work and scientific potential.

Why did you decide to specialise in cardiac electrophysiology and pharmacology?
Early in medical school, I became fascinated by cardiac electrophysiology, arrhythmia mechanisms and arrhythmia therapy. There were other areas of cardiovascular therapeutics that interested me as well, however. I decided to focus on cardiac electrophysiology and pharmacology during my residency training because of the dynamic nature of arrhythmia care and the depth of potential scientific rigor applicable to arrhythmia mechanisms and therapeutics.

 

Who have been your greatest influences?


Paradoxically, one of my greatest influences was a negative one – an early academic mentor whom I respected enormously, and who when I asked him for suggestions of appropriate sites for research training told me I did not have a research mind. He even illustrated that by asking me to try to explain a hypothetical observation. When I answered, he stated that I had gotten it wrong and gave me the “right” answer (it turned out later that this “right” answer was in fact incorrect). In any case, that response was hurtful and I felt unjustified. I think it motivated me both to try to achieve my best in academic medicine, and to try never to write off the potential of a junior colleague who came to me for advice or encouragement.


I did have some significant positive influences. Dr Richard Ogilvie at McGill was my mentor in clinical pharmacology, and taught me a lot both about the discipline and care needed in scientific research and the value of collaboration with industry. He and Dr John Ruedy inspired me always to seek a rational basis for therapeutics and never to accept dogma unquestioningly just because it is widely believed. Dr Douglas Zipes in Indianapolis was a major mentor in cardiac electrophysiology. Although we sometimes clashed (in retrospect, it was healthy clashing of two strong-minded individuals passionate about medical science and electrophysiology), Zipes created a model of multidisciplinary bench-to-bedside electrophysiology research that has remained with me throughout my subsequent career. He also taught me always to look for underlying mechanisms. In addition, I was inspired by great scientists in my area, particularly Dr Michiel Janse of Amsterdam, who was an outstanding research pioneer but also an outstanding leader and man of principle, whom I admired (and continue to admire) as a model of human values, sincerity and humility, and Dr Michael Rosen of Columbia University in New York, who always did stimulating and important research and I think loved (and loves) it more than anyone else I know. Rosen is also an outstanding model of humility and human decency.

 

What have been your proudest moments?


Tough question. Restricting the answer to medicine (because I have plenty of proud moments with and in my family), I guess my proudest moments were when my lab discovered and reported fundamental mechanisms of clinical importance, that were later demonstrated to be both true and significant by other investigators. I have come to realise over the years that sometimes the most significant discoveries are ones that within a few years become such accepted principles that nobody remembers who first identified them, and they seem so correct and accepted they must always have been known. I think that really fine scientists have to lose the desire to be recognised for individual greatness, but rather derive satisfaction from having contributed to improving medical science and practice in a broad way. I have seen scientists with enormous contributions who were very much recognised and praised when they were active, but were virtually forgotten within a few years after they retired. That could be construed quite negatively, but the lack of popular awareness in the medical community in no way negates the actual enormous importance of their contributions.

 

What do you think are the biggest challenges facing cardiac electrophysiology today?


Despite enormous research and clinical advances, sudden cardiac death and atrial fibrillation remain major unresolved problems.


Sudden death was a widely researched topic in the 1970s and 1980s, but since the failure of class I and III antiarrhythmic drugs to prevent it, and since the development and wide use of implanted devices, interest has greatly waned. The problem remains enormous, however, and I am sure we will see a renewal of efforts to develop new methods to identify at-risk individuals (particularly with genetic/genomic approaches) and to develop new mechanism-based preventive approaches.


A second challenge is atrial fibrillation, which is increasing its prevalence and adverse impact on population health. A variety of new approaches are being developed, but their value and effectiveness remain to be established.


Cell and gene therapies have enormous potential, but their practical application remains a major challenge. There is enormous enthusiasm and activity around them, but we seem still far from specific practical applications.


Another major challenge results from an embarrassment of riches. Enormous advances are being made every day over a wide range of highly specialised fields that have been opened by explosions in knowledge and technology: molecular biology and biophysics, genetics, genomics, proteomics, sophisticated mathematical modeling, breakthroughs in bioengineering, nanotechnology and ablation techniques, to name only a few. We will have to work increasingly in highly-sophisticated multidisciplinary teams to be sure that this potential is exploited optimally and translated as efficiently as possible into improved diagnostic and therapeutic practices.

 

How has electrophysiology evolved since you began your career? Where do you see this field going in the next ten years?


The revolution in electrophysiology since I began to practice medicine and do research in the early 1970s has been breathtaking.


At the clinical level, we have evolved from treating PVCs and APCs to targeting defined arrhythmia mechanisms. Ablation has moved from causing controlled intracardiac explosions with direct current shocks to create atrioventricular block (in the early 1980s) to targeted ablation of critical vulnerable structures with a range of potential energy sources under detailed imaging guidance. Devices have moved from non-programmable VVI pacemakers to sophisticated units that can detect and treat arrhythmias with great precision, and at the same time provide arrhythmia logs or be used for electrophysiology testing. The management of ventricular arrhythmias related to acute myocardial ischaemia has moved from intravenous lidocaine in the CCU to early on-site defibrillation, coronary intervention to prevent the enormous myocardial scars that were so often the cause of debilitating heart failure and ventricular tachyarrhythmias, and implanted devices that greatly reduce the risk of arrhythmic death in high-risk patients. The management of atrial fibrillation has not advanced as much. We know the risks of antiarrhythmic drug therapy better and recognise the importance of anticoagulation in stroke prevention. We have a lot of new ideas about upstream therapy and atrial-selective antiarrhythmic drugs, but the practical value of these ideas remains to be demonstrated. AF ablation procedures are now widely practiced and are helping many individuals, but remain plagued by recurrences, complications, limited effectiveness in a range of chronic atrial fibrillation populations, and practical limitations in terms of application to the potentially enormous AF population.


At the basic level, molecular electrophysiology has provided detailed insights into ion-channel composition and electrophysiological properties in different tissues and in response to a variety of cardiac conditions. Molecular genetics has already provided breathtaking breakthroughs into clinical pathophysiology, and may eventually allow for individualised therapy approaches based on genetic signatures and determinants of arrhythmia. The future is very exciting and I suspect that as much as the field of clinical electrophysiology has been revolutionised at both the basic and clinical levels over the past 30 years, it is likely to go through even more dramatic changes over the next 30.

 

How far do you think it is possible to go regarding advances on drugs for arrhythmias?


It is possible to go extremely far. There is an enormous amount to learn about the genetic determinants of arrhythmias, the underlying molecular electrophysiology and pathophysiology, and the basis for clinical evolution of arrhythmia syndromes, but knowledge is being acquired at an extremely rapid rate. Advances in medicinal chemistry, drug design and drug screening will likely allow industry to design drugs for almost any target, provided they know its molecular composition. Advances in simulation and analysis methods will eventually allow scientists to determine fundamental arrhythmia mechanisms non-invasively and predict their response to drugs by in silico analysis before beginning expensive animal experimentation and clinical investigation. Advances in genomics may allow for truly personalised therapy approaches.


One enormous obstacle that should not be underestimated is the cost of new drug development. We may be reaching the point that some true breakthroughs are possible but do not happen because of the prohibitive costs of drug development and the financial risks involved. Some major drug companies have simply abandoned research in the cardiovascular area. Issues of drug development costs, the economics and politics of drug development scrutiny, patent protection and so on may have to be seriously re-evaluated in the future if we want the enormous potential that exists to be realised.

 

What are your current areas of research?


The primary interests of the lab remain the basic mechanisms of arrhythmogenesis as they affect our understanding of clinical medicine and our ability to develop innovative therapeutic approaches. We are working hard to understand the fundamental processes that result in arrhythmogenesis, that change normal myocardium into tissue with an increased risk of developing and sustaining tachyarrhythmias. Our primary focus is on mechanisms and prevention of atrial fibrillation, which represents about 2/3 of the lab’s activities, but we are also interested in changes that predispose the heart to ventricular proarrhythmia, particularly by remodeling ventricular repolarisation. We use a broad-based multidisciplinary approach, incorporating models in isolated cells, organs and whole animals, and using methods like molecular biology, cell and membrane physiology/biophysics, optical and conventional mapping, genomics and mathematical modeling to gain new insights into arrhythmia pathogenesis and prevention.

 

Outside of medicine, what other interests do you have?


I have a wonderful family, an extremely special and precious wife, parents, four children and now one grandchild that are a constant source of joy, inspiration and preoccupation. I am a religiously observant Jew, a practice which enriches my life and provides plenty of opportunity for study, personal growth, outreach to those in need and personal challenge. I enjoy reading when I have the time, usually just before I go to sleep, but when I am lucky and get sucked into the world of a book, can fill most otherwise unoccupied moments. I also try to remain physically fit, which is not always easy but is crucially important for both body and mind.

 

Fact file

 

Birth
January 28, 1951, Canada

 

Degrees
1972 – B.Sc., McGill University (Magna cum Laude)
1974 – M.D., McGill University

 

Post-graduate training
1974 1975 – Royal Victoria Hospital (Internship in Medicine)
1975 1976 – Royal Victoria Hospital (Residency in Int. Medicine)
1976 1978 – Montreal General Hospital (Residency in Clinical Pharmacology)
1978 1980 – Indiana University (Fellowship in Cardiology)
1980 1981 – University of Pennsylvania (Fellowship in Physiology)

 

Medical certification
1981 – Quebec (Internal Medicine)
1978 – RCP&S (Internal Medecine)
1978 – American Board of Internal Medicine
1981 – RCP&S (Cardiology)
1981 – Quebec (Cardiology
1981 – American Board of Internal Medicine (Cardiology)

 

Academic appointments (past and present)
1981 – Assistant Physician, Montreal General Hospital
1981 – Assistant Professor (Pharmacology and Medicine), McGill University
1986 – Associate Physician, Montreal General Hospital
1987 – Staff Cardiologist, Montreal Heart Institute
1987 – Awarded tenure, McGill University
1987- Associate Professor (Pharmacology and Medicine), McGill University
1991 – Associate Professor (Medicine), University of Montreal
1992 – Associate Member (Pharmacology and Physiology), University of Montreal
1994 – Awarded tenure, University of Montreal
1995 – Professor (Medicine), University of Montreal
1997 – Member, Biomedical Modeling, University of Montreal Research Group

 

Memberships in scientific societies
American College of Cardiology (Fellow), American Heart Association, Council on Basic Science, American Physiological Society, American Society for Pharmacology and Experimental Therapeutics, Biophysical Society, Canadian Academy of Health Sciences (Fellow), Canadian Cardiovascular Society, Canadian Society for Clinical Pharmacology, Heart Rhythm Society (Fellow), Pharmacological Society of Canada, Royal College of Physicians of Canada (Fellow), Royal Society of Canada (Fellow), The Physiological Society

 

Numbers (past and present)
23 awards
Experience in manuscript review in 46 publications
Member of 19 editorial boards
Administrative experience at the Montreal General Hospital, Montreal Heart Institute, McGill University, University of Montreal and other institutions
External reviewer for 13 agencies
20 Scientific Review Committee Memberships
Member of 13 thesis examining committees
Service as a consultant to more than 30 companies
Member of scientific advisory boards of six companies
120 students supervised
Teaching experience in eight university courses as a lecturer and director of five
251 invited lectures
4 symposia organized
Member of the organizing committees of nine international meetings

 

Patents
Statin drugs to treat atrial fibrillation (four pending applications), Acetylcholine-dependent current as a novel ionic target for AF (three pending applications), and Bioreactor for cultured cells (one pending application)

 

Publications
398 peer-reviewed articles
27 non peer-reviewed publications
29 book chapters, letters and monographs published
359 abstracts published and 13 submitted