October 2023

With A-Fib on the Rise, Researchers Work to Fine-Tune Treatments

Atrial fibrillation is an electrical malfunction. But what triggers it remains a mystery.

The Heart Issue

  • by Catherine Caruso
  • 13 min read
  • Audio available 🎧

Some patients with atrial fibrillation describe the feeling as that of a fish flip-flopping in their chest. Others say it’s like the flutter of a butterfly’s wings, an effect modeled in this image.

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Reading by Gracia Cameron

A stuttering heart. A fluttering heartbeat. A racing pulse. Through the ages, writers have reserved such phrases for the dramatic moments of their stories, when the main character is overcome with passionate love or overwhelmed by intense anger or fear. 

Yet despite what centuries of literature may suggest, a change in heartbeat isn’t necessarily tied to a profound emotional shift. Sometimes, it is simply a physiological quirk that transforms the usual, evenly spaced thumps into an erratic pattern of beats that speed up and slow down of their own accord. And often, such chaotic beating is the result of a condition called atrial fibrillation.

When a heart enters atrial fibrillation, an electrical malfunction causes the top half to beat rapidly, while the bottom half maintains a slower rhythm. In an instant, the heart becomes a dancer whose top and bottom halves are performing to music with wildly different tempos: arms jerking in time to an upbeat pop song, while legs keep pace with a classical ballet.

The result can be an uncomfortable burst of rapid beats that flutter inside a person’s chest like a butterfly’s wings, leaving the individual dizzy and gasping for air. Or a person can feel nothing at all, remaining completely unaware of the change. The atypical rhythm can start and end quickly, a brief burst that happens frequently or from time to time. Or, it can persist for weeks, months, or even years. But what exactly is atrial fibrillation? What causes it? Who experiences it? And what’s the best way to treat it? These are the questions that researchers and clinicians are grappling with, their work becoming only more urgent as the number of people confronting the condition swells.

An age-old condition

The human fascination with the heartbeat stretches back to ancient times. And for as long as people have known that there is a heartbeat, they’ve understood that sometimes, it becomes abnormal. Physicians in ancient China, Egypt, and Greece regularly recorded irregular pulses in their patients, realizing that a chaotic heartbeat could be a harbinger of other health problems.

However, it wasn’t until the early 1900s that physicians had the knowledge and technology to identify atrial fibrillation.

In 1901, a Dutch physician named Willem Einthoven invented the electro-cardiogram to measure electrical activity in the heart. The 600-pound instrument — an intricate setup of buckets of salt water, wires, microscope lenses, a glass recording plate, a timer, and a string galvanometer — translated the electrical impulses of the heartbeat into a spiky black line of ink on graph paper. He began using the instrument to make recordings of healthy and unhealthy human hearts.

Normally, every upper chamber beat has a corresponding lower chamber beat, to create the lub-dub of the heartbeat.

At the same time, multiple groups of scientists around the world were closing in on the idea of atrial fibrillation, as they began to suspect that the irregular heartbeats they were observing in animals during experiments might also exist in humans. However, their tools were limited to “tracings” of veins and arteries that captured only heart contractions.

Einthoven’s electrocardiogram provided undeniable evidence.

Tucked away among twenty-six recordings he published in 1906 was one labeled “pulsus inaequalis et irregularis,” or “uneven and irregular pulse”: the first documented case of atrial fibrillation. Suddenly, scientists could measure and record the electrical perturbations that drove the condition. Before long they had confirmed that atrial fibrillation existed in humans and was, in fact, common.

With that, the condition known as atrial fibrillation was born, and physicians began studying it in earnest, while also trying to figure out how to help people who had it.

An electrical malfunction

Unlike a heart attack, which stems from a blockage in the coronary artery, atrial fibrillation is an electrical problem in which the heart’s two upper chambers, or atria, start beating out of sync with its two lower chambers, or ventricles.

In a healthy heart, each beat is initiated by a cluster of specialized myocardial cells, called pacemaker cells, that make up the sinus node in the right atrium. Every time the cells fire, the sinus node produces an electrical signal that causes both atria to contract. The signal then flows through the narrow atrioventricular node in the center of the heart into the ventricles to make them contract.

“Normally, every upper chamber beat has a corresponding lower chamber beat, to create the lub-dub of the heartbeat,” explains Usha Tedrow, MD ’97, an HMS associate professor of medicine at Brigham and Women’s Hospital, director of the hospital’s Clinical Cardiac Electrophysiology Fellowship Program, and clinical director of its Ventricular Arrhythmia Program.

Usha Tedrow stands, leaning on a pole, in a brightly lit room
Usha Tedrow

Like the conductor of an orchestra, the sinus node keeps the heart beating at the right rhythm and pace and tells it when to speed up or slow down. Typically, a healthy heart beats about once per second at rest, and up to 150 beats per minute during physical activity.

In a heart with atrial fibrillation, this coordinated process breaks down. Suddenly, spontaneous electrical impulses fire throughout the atria, like cameras flashing from different spots in a dark room. Each impulse sets off a new heartbeat, causing the upper chambers to beat up to 400 to 500 times per minute. Fortunately, the atrioventricular node prevents all of those beats from reaching the lower chambers, but the result is an out-of-sync heart and a rapid, irregular heartbeat.

“The hallmark of atrial fibrillation is a pulse that is irregularly irregular — there’s no pattern to the irregularity of the rhythm,” says Peter Zimetbaum, the Richard A. and Susan F. Smith Professor of Medicine in the Field of Cardiovascular Medicine at HMS and the clinical director and associate chief of cardiology at Beth Israel Deaconess Medical Center.

When someone goes into atrial fibrillation, “the first thing they may notice is that their chest doesn’t feel right,” Tedrow says, adding that patients have described the sensation as “like a fish is flip-flopping around in their chest.” The condition is often diagnosed by the modern version of Einthoven’s electrocardiogram, commonly known as an ECG or EKG.

Symptomatically, atrial fibrillation is mystifyingly heterogeneous. Tedrow’s patients often fall into two broad groups: younger patients who experience such intense symptoms that they may go to the emergency department during their first episode and older patients with so few symptoms that they may not know they are in atrial fibrillation until it’s picked up during a routine physical.

Officially, there are three main types. In paroxysmal atrial fibrillation, episodes start and stop on their own. Patients tend to be younger, sometimes athletes, and often have the most noticeable symptoms — which can include dizziness, chest pain, shortness of breath, and fatigue. In persistent atrial fibrillation, which Tedrow estimates is the most prevalent type, episodes last for more than a week, and the heart must be shocked back into normal rhythm. In permanent or chronic atrial fibrillation, the heart cannot be brought back to normal rhythm.

The three types of atrial fibrillation, Tedrow notes, also represent how the disease often progresses in an individual. Triggers for the condition include lack of sleep, dehydration, and stress. “I always tell people, that’s not what makes you have atrial fibrillation in general, but that may be why you have it today,” she says.

A growing coronary risk

It’s no exaggeration to say that atrial fibrillation is all around us, hiding in plain sight. It is the most common type of sustained, irregular heartbeat, and it is expected to become more common. In a 2013 paper in the American Journal of Cardiology, researchers estimated that U.S. cases would jump from 5.2 million in 2010 to 12.1 million in 2030. “Almost everybody knows somebody who has it,” Zimetbaum emphasizes.

Atrial fibrillation is so common that Tedrow regularly sees patients who first detect it with a heart rate monitor on their smartwatch or other wearable device — a screening strategy that she thinks could become broadly useful. “There are a lot of ongoing clinical trials that may demonstrate the benefits more, but for some patients, these devices really offer the opportunity to make a diagnosis in a way that we couldn’t before,” Tedrow says.

Risk factors for atrial fibrillation include diabetes, structural heart issues such as blockages or leaky valves, high blood pressure, alcohol consumption, and obesity. Fortunately, some of these can be modified. A 2020 paper in the New England Journal of Medicine (NEJM) showed that moderate drinkers with atrial fibrillation who stopped drinking alcohol for six months had significantly fewer episodes than those who continued drinking. In a 2015 study in the Journal of the American College of Cardiology, people with atrial fibrillation and conditions of overweight or obesity and had a sustained weight loss over a long period, spent less time in atrial fibrillation and more time in sinus rhythm. However, perhaps the biggest risk factor is one that cannot be counteracted: aging. “For every decade of life, the likelihood of developing atrial fibrillation increases,” Tedrow says. “We often say that if we lived to be 130, we’d all be in atrial fibrillation.”

Ary Goldberger, an HMS professor of medicine and director of the Margret and H. A. Rey Institute for Nonlinear Dynamics at Beth Israel Deaconess, has spent his career studying how complicated systems in the body break down over time. His earlier research focused on fractals: complex geometric forms in nature that may seem irregular, but actually have an underlying pattern, one that repeats itself when viewed at different scales. Examples of such self-similarity abound in the natural world, including in everything from river deltas and tree branches to coastlines and cloud formations.

In the 1980s, Goldberger discovered that the healthy heartbeat is fractal-like: it doesn’t beat at metronomic intervals, but rather shows complex variations across timescales ranging from minutes to hours. These hidden fluctuations can be seen on special graphical displays that capture the series of variations over time. This discovery led him and colleagues to formulate the complexity-loss theory of disease and aging, which says that pathologic changes are marked by the degradation in and ultimately the collapse of the fractal-like variations over time. When this breakdown occurs in the control of the heartbeat, it can lead to conditions like atrial fibrillation.

A birds'-eye view of a river delta in Turkey shows a fractal-like pattern of streams against the sand
The branchings of this river exemplify fractal patterning, a complex geometric form that seems irregular but actually repeats itself in a self-similar manner at different scales. Fractal formations are abundant in the natural world, including in our bodies. The pattern formed by the cardiovascular system, for example, is a fractal one, as is the complex and varying pattern of beats produced by a healthy heart. 

Currently, Goldberger is collaborating with Madalena Costa, an HMS assistant professor of medicine and a researcher at Beth Israel Deaconess, to develop a predictive biomarker for atrial fibrillation. Their work is based on the construct known as heart rate fragmentation: During aging and with sub-clinical heart disease, the intervals between consecutive heartbeats lose their normal physiologic interactions. This change is not evident with “snapshot” imaging such as clinical EKGs. “The degradation is hiding in plain view,” Goldberger says. “But you have to analyze the heartbeat as a time series using novel computational tools that are not currently part of the usual clinical assessment — and are also not a part of traditional heart rate variability measures.”

The researchers think that people with more fragmentation, which occurs with aging, have a greater chance of developing atrial fibrillation. “The heartbeat is very accessible and can be recorded using wearable technology,” Goldberger says. “This seemingly mundane output of our body turns out to be a remarkably useful probe of the body’s hidden happenings, including the longstanding challenge of distinguishing between one’s biological versus chronological age.”

Yet despite the ubiquity of atrial fibrillation, there are still major knowledge gaps about its basic biology. In particular, scientists don’t know precisely what causes heart tissue to start spontaneously firing electrical impulses, and why it continues to do so over time. They also don’t know why it can be so hard to restore normal heart rhythm in some patients.

Given the heterogeneity of the condition, Zimetbaum suspects that atrial fibrillation will turn out to be the common end result of many different mechanisms — but he is eager for more research, especially on a cellular and genetic level.

“Atrial fibrillation is extremely complicated, and the truth is that people have lots of hypotheses, but we have a profoundly primitive understanding of the condition,” he says, adding that he finds the current lack of mechanistic understanding frustrating. “Until we understand more about how this happens, we can manage it, but we’re not really going to be able to fix it.”

Evolving treatment options

Although physicians identified atrial fibrillation in the early 1900s, it wasn’t until later in the century that a new wave of interest in the condition occurred. “The interest in studying atrial fibrillation and treating it in novel ways is relatively new in the course of cardiac history,” Zimetbaum says.

Zimetbaum has been and remains an important part of this wave. In 1997, after realizing that there was enormous variability in how physicians were managing atrial fibrillation, he launched an atrial fibrillation registry called FRACTAL. “The goal was to understand the basics of the experience of patients with atrial fibrillation,” he says, adding that a main focus of his career “has been trying to standardize the important parts of managing the disease.”

Zimetbaum became especially concerned that in the United States people with a primary problem of atrial fibrillation were spending hours in the emergency department to undergo testing for a heart attack. He and his colleagues reported findings in a 2000 issue of the Journal of the American College of Cardiology indicating that this practice was largely unnecessary. In a 2003 paper in the American Journal of Cardiology, he showed that a new emergency department pathway for atrial fibrillation could reduce the hospitalization rate for the condition from 75 to 30 percent.

Peter Zimetbaum stands in a dark suit and tie in a room with a wood-paneled wall on the right and white wall on the left
Peter Zimetbaum

Much of the renewed interest in atrial fibrillation came after a 1998 paper in NEJM that reported a pivotal finding: The pulmonary veins are a main cause of the condition. It turns out that these veins, which carry oxygen-laden blood from the lungs to the heart so it can be pumped throughout the body, can develop their own electrical activity — especially when the atria are under higher-than-normal pressure resulting from hypertension or a leaky valve.

“For years, surgeons had noticed that there is a little bit of heart muscle tissue in the pulmonary veins, and the veins actually beat with the heart,” Tedrow explains. “Certain situations can turn on all the little pacemakers in those veins and trigger atrial fibrillation.” Tedrow estimates that the pulmonary veins are the trigger for up to 95 percent of patients with paroxysmal atrial fibrillation.

The findings also showed that the rogue beats could be eliminated with ablation. During this procedure, a cardiac electro-physiologist inserts flexible catheters into the pulmonary veins and uses heat energy or cold energy to create tiny scars that block the problematic electrical signals. “The procedure focuses on isolating the pulmonary veins and limiting the ability of those little sparks to make their way into the atria and ignite full-blown arrhythmia,” Zimetbaum explains. In around 70 to 80 percent of cases, ablation helps reduce atrial fibrillation and its symptoms.

The hallmark of atrial fibrillation is a pulse that is irregularly irregular — there’s no pattern to the irregularity of the rhythm.

The shift toward ablation has been a major one. Before 1998, physicians typically treated patients with antiarrhythmic drugs, which come with side effects and compliance challenges, or they left patients in atrial fibrillation and used medication to control their heart rate. Over the past decade, newer research — including a 2020 paper in NEJM — has suggested that patients with atrial fibrillation fare better when their normal heart rhythm is restored. Meanwhile, ablation has become faster, more precise, and more effective. In 2023, another NEJM paper showed that patients who underwent the procedure had better outcomes than those treated with antiarrhythmic drugs or left in atrial fibrillation. “We’ve gotten a lot more aggressive because we can do ablation pretty safely, and there’s more and more evidence that patients do better if they’re in sinus rhythm,” Zimetbaum says.

New advances promise to make ablation even faster and safer. Although it is not a cure, it is a tool that physicians can use to help patients. Another vital part of the picture, Tedrow and Zimetbaum emphasize, is minimizing stroke risk.

During atrial fibrillation, the mismatch in beating between the atria and ventricles can cause blood to pool in the atria, increasing the risk of blood clots that can block blood flow to the brain and cause a stroke. The American Heart Association estimates that atrial fibrillation causes one in seven strokes in the United States.

Typically, patients with a high risk of stroke take blood thinners daily, regardless of how much atrial fibrillation they experience — but the drugs come with their own risks and side effects. Zimetbaum is trying to make treatment for stroke prevention more targeted: He is an investigator on the REACT-AF trial, which is exploring whether patients can start and stop the drugs based on when they are in atrial fibrillation. “If this tailored approach turns out to be a safe and effective way to manage blood thinners for some patients, then I think it would be an enormous advance,” Zimetbaum says.

Even as treatments improve, managing atrial fibrillation will continue to require nuanced and in-depth conversations with patients to help physicians understand what the best course of action may be based on the patient’s own experience and goals. Usually, patients are most concerned about being able to work, exercise, travel, and generally live their lives. For patients with frequent atrial fibrillation, this may mean actively trying to return their hearts to a normal rhythm.

“I had a patient come to clinic wearing a T-shirt that said ‘I want to be in sinus rhythm,’” Tedrow recalls.

For other patients, this may mean few interventions. “It’s a partnership,” Tedrow says. Zimetbaum agrees. “It requires working together with patients,” he says. “It’s incredibly rewarding to get patients to a place where atrial fibrillation is not dominating their consciousness.”


Catherine Caruso is a science writer in the HMS Office of Communications and External Relations.

Images: Mattias Paludi (butterfly); John Soares (Tedrow and Zimetbaum); Temizyurek/E+/Getty Images (river delta)