Introduction to the compendium on atrial fibrillation, and a few thoughts along the way…

As I sat to write this introduction to the compendium on atrial fibrillation (AF), I thought about beginning with the statistics on AF with which we are all familiar, but instead decided to take a somewhat more personal approach. These stories will hopefully provide a bit of color on the topic.

It is hard to believe that I began my research work on atrial fibrillation nearly 20 years ago. As I was training in cardiology, it would have been fair to say that I had absolutely no idea what I was going to do with myself, or what the focus of my research would be. Given my graduate work on the structure and function of ion channels, I was naturally drawn to cardiac electrophysiology, and also had a longstanding interest in genetics. It was perhaps only good luck that one of my colleagues mentioned a large family with atrial fibrillation while we were sitting around the fellow’s room--my interest was piqued. With the help of my co-fellow, Calum MacRae, these threads coalesced, and we began a research study on early-onset atrial fibrillation. I spent the next several years building a cohort of patients largely enrolled from the EP lab at MGH, although there were occasional field trips to hotels, motels, and spare bedrooms throughout the U.S. to enroll families with AF. In the years since, I have had the privilege to be able to continue to blend my clinical interests in cardiac electrophysiology with research work on the genetics of atrial fibrillation. From that nascent work on AF genetics, the current pace of human genetic discovery with routine sequencing of genomes, was simply unimaginable.

Early in my career, I had the opportunity to meet with Emelia Benjamin to discuss collaborating on the genetics of AF. By this time, Emelia was already a rather legendary figure who had published the seminal paper on risk factors for AF out of the Framingham Heart Study.[1] I was basically a nobody with only a handful of published papers on AF. Shortly into the conversation, Emelia pointedly asked, “are you a jerk?” She then explained that she had a “no-jerks rule” for collaborators – a lesson that I have since found broadly helpful when considering any new project or collaboration. After I assured her that I was not, to the best of my knowledge, a jerk, Emelia and I put together our first grant on AF genetics, a project that has continued for the last 15 years. Emelia has become a trusted friend, colleague, and mentor, so it is perhaps fitting that her contribution, with her stellar protégé Renate Schnabel, leads off this compendium. They have provided a terrific description of the risk factors, methods, and emerging directions in the epidemiology of AF.[2]

In the next article, we provide an overview on the latest in the field of AF genetics with an eye towards the future applications.[3] It was a delight have the chance to work with Carolina Roselli, an incredibly talented computational biologist in our group, and an old friend, Michiel Rienstra on this effort. Michiel is a former fellow in the lab, current mentor for Carolina, and his own work on the RACE trials and other translational studies on AF continues to push our field forward.

Current work on human genetics essentially requires a collaborative framework, since any individual site or project is unlikely to have enough sample size or power to make a meaningful contribution on its own. Similarly, science in general has increasingly benefited from bringing together investigators with different skills; some of the most fascinating projects emerge at the intersection of disciplines. In the spirit of this team-based approach, each of the reviews in this compendium are authored by the members of at least two different laboratories.

One particularly enjoyable collaboration has been in the framework of our Leducq Network on AF. The funding provided by the Leducq Foundation is truly unique, as it successfully manages to facilitate multidisciplinary teamwork while continuing to prioritize the development of emerging trainees and junior faculty. Over the last five years, I have had the pleasure of getting to know and work with Jim Martin, Wouter de Laat, Paulus Kirchhof, Ivan Moskowitz, Vincent M. Christoffels and a multitude of fantastic students, postdocs, fellows, and junior faculty members in their labs. The accompanying manuscript on the epigenetic and transcriptional networks underlying AF highlights some of the many great collaborations that have arisen from this effort.[4]

A terrific example of partnership in science is reflected in the contribution by Stan Nattel, Dobromir Dobrev and colleagues. Stan and Dobri’s work emerged from their own Leducq network and has continued to push the frontiers of translating our understanding of the molecular mechanisms underlying AF.[5] This is followed by the fascinating work of Na Li and Bianca Brundel on their respective laboratories’ work on inflammasomes and proteostasis as novel molecular mechanisms for AF.[6]

A major challenge in our field has been the lack of an animal model that faithfully captures features of AF that we observe clinically. This topic has been deftly handled by two prior fellows, Bill Hucker and Sebastian Clauss, and by my dear friend Stefan Kääb.[7] Although a small price to pay in light of the current madness in the world, it looks like our next barbeque on the roof deck with the family will have to wait another year.

While great progress has been made on the discovery of many genes and genetic loci for AF, how this data will be applied clinically remains an open question. Dan Roden, Marco Perez, and colleagues have teamed up to discuss the potential applications of genetics to the clinical care of AF.[8] I have always been incredibly grateful to Dan for his mentorship, guidance, and friendship. His thoughtful approach to science and mentorship has been a role model for many of us. Ultimately, if we end our careers only a fraction as successful as Dan has been, we will have accomplished quite a lot.

We then turn to Eric Ding, Greg Marcus, and Dave McManus⁹ who provide a comprehensive review of the ever-expanding technologies to identify AF. Dave is a unique blend of inventor, scientist, and electrophysiologist, and as such is ideally positioned to lead us through the plethora of new devices on the horizon.

Far and away the best parts of my career in academia have been the chance to work with an incredibly talented group of students, postdoctoral fellows, and junior faculty. The creativity, dedication and enthusiasm that they bring to the group are the highlight of many days, and any success that we have had is largely due to their tireless efforts. I distinctly remember my first conversations with Steve Lubitz, when he was finishing his clinical training as a cardiology fellow and planning to move to Boston for his research time. It was in the early days of the lab, and we were both interested in the prospect of him joining us. However, there was a small problem - I didn’t have enough money to cover his salary.

Fortunately, Steve didn’t let that deter him; he tracked down a T32 fellowship training program in the epidemiology of CVD at the Brigham. I have been grateful to Paul Ridker ever since for taking a chance on the two of us and welcoming Steve into his training program. It has been a tremendous honor to be along for the ride as Steve has seamlessly transitioned from postdoctoral training through a junior faculty position to become an established scientist. In turn, he is mentoring the future generation of scientists such as Shaan Kurshid. In the next article in the series, Steve and Shaan partnered with Jeff Healey and William McIntyre to provide an overview of the exciting developments in population-based screening for AF¹⁰.

An intriguing line of recent investigation has been the application of deep learning models to the electrocardiogram to improve risk prediction of AF and other cardiovascular diseases. The teams from Mayo and the Broad Institute, led by Peter Noseworthy and Anthony Philippakis respectively, have provided a view of the future where we can imagine these methods changing the care of our patients with AF. [11]

Catheter ablation remains the mainstay of treatment for symptomatic AF patients, yet many challenges are inherent with any invasive procedure. With this in mind, Pierre Jais, Vivek Reddy, and colleagues provide an assessment of the emerging methods for safer and more efficient approaches to pulmonary vein isolation.[12] One of my favorite memories of Vivek from his time at MGH was when I walked by his office late one evening and he was frantically searching for a textbook. When I asked what he was doing, he explained that he had to take the EP boards the next day and had forgotten to study. Although thinking back to when I took the EP boards is still unsettling, Vivek’s frenetic genius has clearly continued to serve him well.

To round out the articles, I am grateful for the contribution by the teams of Sap Haldar and Jörg Hüser from Amgen and Bayer. As the leads for cardiovascular development in their respective companies, they have unique perspectives on the emerging potential therapeutic targets and approaches for AF.[11] It remains humbling that despite all of our progress on AF in the past twenty years, it has been more than a decade since the approval of our last antiarrhythmic medication for AF.

Research in AF continues to advance rapidly - in 2019 alone, there were over 6,800 manuscripts that mentioned AF. As a result, it would be impossible to cover every aspect of the many interesting threads of AF-related work in this compendium. Hopefully, the current series of articles will provide the reader a timely assessment of the state of the art in AF research and act as a starting point for a deeper evaluation of the primary manuscripts.

Finally, in this time of great uncertainty in the world, I would like to extend my best wishes to each of you and your families. I look forward to reconnecting with friends and colleagues again in person once the world reopens, but in the meantime, please stay safe and take care.