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Seeking a rational basis for therapeutics 

Intercontinental lecture, Stanley Nattel

Topics: Arrhythmias
Date: 24 Jun 2013
Stanley Nattel, who has dedicated his career to improving the treatment of atrial fibrillation (AF) through investigating the underlying basic mechanisms, will deliver this year’s EHRA EUROPACE Intercontinental Lecture today at 14.00 (Naxos Lecture room).

The overall guiding philosophy behind Nattel’s work has been to seek a rational basis for therapeutics and never accept dogma unquestioningly. “I had the opportunity to investigate some standard clinical practice when training, and was shocked to realise that a lot of therapeutics had a flimsy basis,” says Nattel, who is Professor of Medicine and Paul-David Chair in Cardiovascular Electrophysiology at the University of Montreal, Canada. “Since then a lot of my research has revolved around the mechanistic and etiological complexity of clinical problems and trying to devise more rational approaches to managing them.”
From the outset Nattel, who qualified in medicine from McGill University in 1974, was interested in cardiology. “It was the unanswered questions in electrophysiology (EP) that intrigued me. I appreciated the dynamic quality of this new and rapidly advancing field.”
Between 1974 and 1978 Nattel undertook his internal medicine/ clinical pharmacology training at the Royal Victoria Hospital and Montreal General Hospital, where he gained exposure to arrhythmias and their management in the Coronary Care Unit. One early experience that has proved influential in Nattel’s subsequent approach to students was when a mentor (whom he respected enormously) made the throw-away comment that he did not have a research oriented mind. “Anyone with less resilience might have been badly affected. The reality is that what may seem inconsequential to someone in authority has enormous significance to someone who looks up to them. This experience has taught me above all never to write off the potential of junior colleagues,” he said.
Between 1978 and 1981 Nattel undertook EP  and cardiology training in the US, first at Indiana University (where he studied cellular action potentials and the effects on disease states) and then at the University of Pennsylvania (where he learned in vivo research techniques in whole animal models).
Nattel returned to the Montreal General Hospital in 1981, where he combined clinical work in cardiology and internal medicine/clinical pharmacology with a basic science appointment in pharmacology at McGill University, juggling clinical work with basic research. “It was a really intense period. Mid-afternoon I’d finish in the intensive care unit, then go to the lab and work until two or three in the morning,” he remembers. This endeavour is even more heroic when you consider that at the time he had two young children at home aged two and five. “I was helped by having an amazing wife,” he said.
In 1987 Nattel moved to the Montreal Heart Institute Research Center with the explicit remit to boost basic science research. Nattel, who was director of the institute between 1990 and 2004, is widely credited with propelling the centre from a well-known and respected clinical research group into one of the most important cardiology research centres in the world. Under his leadership the size of the research centre increased three fold, funding five fold, a critical mass of basic labs was developed and a sophisticated clinical trial centre established.
Much of Nattel’s research has focused around AF, which he realised in the early 1990s was something of a ‘Cinderella’ area that had not received as much attention as ventricular arrhythmias.
His contributions have included showing that AF causes cellular calcium overload and adaptive changes in cardiac tissue that in the short term protect the heart from calcium loading, but in the long term predispose the heart to a variety of complications of ion-channel remodelling, including increased arrhythmia vulnerability and clotting-disorders/strokes. Nattel’s laboratory also helped to define the role of atrial fibrosis in AF due to hypertension, valvular heart disease, senescence and various cardiomyopathies, where excessive amounts of connective tissue are laid down in the atrium. He pioneered the notion of developing treatments targeting the substrate underlying arrhythmias, rather than merely the final electrical product.
His laboratory clarified the detailed electrophysiology of the human atrium. He identified the “ultra-rapid delayed rectifier” ion-channel, which is only present in the human atrium and plays a crucial role in controlling AF. He determined its molecular basis and clarified its role in normal heart-function and disease. His group also detailed the properties of a wide range of other ion currents in human atrium, culminating in the first complete mathematical models of the human atrial action potential. “This has allowed us to investigate the various pathologies that lead to arrhythmogenesis,” he says.
In addition to his basic science research, Nattel has always been a keen contributor to clinical trials. Among others he was involved in the Canadian Trial of Atrial Fibrillation, the AF-CHF study of rhythm versus rate control effects in patients with AF and congestive heart failure, and more recently the ADVICE study of the value of adenosine guided pulmonary vein isolation in AF. “The theories you develop through research mean little unless you can validate their clinical relevance and application,” he stressed.
Today Nattel has given up the administrative responsibilities of running the centre to focus on his own research and clinical duties. He divides his time between holding weekly general cardiology clinics, supervising his lab (he has trained at least 40 PhD students, 20 Master’s students and 50 post-doctoral fellows) and also has a hospital commitment of four weeks of emergency room responsibilities per year where he is the admitting cardiologist.
Large amounts of time are taken up with editorial responsibilities, which include being Editor-in-Chief of the Canadian Journal of Cardiology, and Associate Editor of three other journals. “I’m really sensitive that reviewers and editors should work with authors as much as possible to help communicate the significance of their findings more effectively to the scientific community” he said.
Speaking at international meetings has also become a major past time. Nattel particularly welcomes the opportunity to deliver the Intercontinental lecture at EHRA EUROPACE 2013, since he believes that building links between investigators in North America and Europe is extremely important. “While individuals can make incredible contributions to science, the reality is that most advances come through global team interactions. For this, intercontinental cross-fertilisation of ideas is crucial,” he said.
In the Intercontinental lecture Nattel will highlight a number of basic mechanisms in AF at the molecular and tissue levels, and then consider how these might contribute to the development of new clinical approaches. “One of the really fascinating things about AF is that many of the theories that were formulated in the early 20th century are still present today”. As a young faculty member, he added, he made the fascinating discovery of a review article by Walter Garrey from 1924 discussing the causes of AF as they had been postulated by various researchers of the time. “I was amazed by the variety of different mechanisms that had been thought about back then, and that we were still debating 75 years later. These self-same mechanisms form the basis of our understanding today. It was quite humbling.”
Such observations lost in the midst of time now underline to him the importance of not allowing scientific discoveries that do not have immediate clinical applications to be left behind. “It’s vital that the basic scientific enterprise is supported not only as a tool to apply in the next two to three years, but as something that is important to develop in itself,” he said.
Family life and religion have both been central to Nattel’s life. He is married, with four children aged between 22 and 33, and two grandchildren. He is also close to his parents, who moved to Canada from Poland after spending World War II in a concentration camp. “I’m a religiously observant Jew, and make sure that I study the Talmud every day, and teach a weekly class. The Bible says that God created man in his own image, which means that all human beings have elements of divinity in them. This has defined the way I deal professionally with people, whether they’re co-workers, colleagues, students or patients,” he said.