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UCSF Cardiology
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Department of Medicine

Preventing Stroke in Atrial Fibrillation: Left Atrial Appendage Closure

The UCSF Division of Cardiology is pioneering a way to reduce the risk of stroke in patients with atrial fibrillation, the most common abnormal heart rhythm.

About 2.6 million Americans suffer from atrial fibrillation, which is caused by disorganized electrical activity in the upper chambers, or atria, of the heart. Instead of pumping in an orderly coordinated way, the heart quivers and contracts rapidly and irregularly – reducing the flow of blood to the body.

In addition to symptoms such as fatigue, palpitations and shortness of breath, the most severe consequence of atrial fibrillation is an increased risk of stroke. Because blood is moving more sluggishly than usual, it can become stagnant and start to form clots. If these clots end up in the brain, they can block blood flow and cause a stroke.

Researchers believe that up to 90 percent of these clots form in the left atrial appendage, a hollowed-out, fingerlike outpouching attached to the left atrium, one of the upper chambers of the heart. Usually patients with atrial fibrillation are prescribed blood thinners such as warfarin to prevent these clots from forming. But not all patients can tolerate blood thinners, which can cause severe bleeding – a risk that increases with age. If atrial fibrillation patients are not on blood thinners, their risk of stroke also increases as they age: 15 percent of all strokes are caused by atrial fibrillation, but in patients 70 years and older, more than 20 to 25 percent of strokes are caused by atrial fibrillation.

Creating New Solutions

“The UCSF Electrophysiology Section, and UCSF in general, has a long track record of being innovative in meeting the needs of patients and giving them options with new clinical procedures and tools,” said Dr. Randall Lee, a UCSF electrophysiologist. “We are very oriented towards patient care and striving for solutions to improve their overall medical care.”

Dr. Lee has been a leader in developing a solution for atrial fibrillation patients at high risk of embolic stroke who are unable to take blood thinners: closing off the left atrial appendage using a minimally invasive approach that does not leave any devices in the body.

Left atrial appendage closure has been performed for decades through surgical techniques, but was highly invasive, requiring open heart surgery to either clip the appendage or tie a knot around it to close it off. The delicate heart tissue could sometimes tear if handled roughly. The far end of the appendage has rod-like formations, similar to the ridges on a banana peel; tying off the appendage too far from the mouth could leave spaces beneath the ridges for blood to get stuck, clot and eventually travel to the brain. Also, since blood was temporarily diverted from the heart and pumped by a heart-lung machine during surgery, it was not possible for surgeons to check whether the closure had leaks.

More recently, occlusion devices have been developed that can be inserted through catheters. One of these, called the WATCHMAN® Device, opens like an umbrella to cover the opening of the left atrial appendage, and uses hooks to anchor itself into the appendage. However, such devices can potentially perforate the heart, or work their way loose and then migrate through the body.

How it Works

Since 2007, Dr. Lee has worked with a Redwood City-based company, SentreHeart, to develop tools and a new procedure for closing the left atrial appendage without surgery or an implanted device. (Full disclosure: Dr. Lee currently serves as a consultant to SentreHeart, and has equity in the company.)

The process involves inserting a catheter into the chest, carefully puncturing the sac around the heart, called the pericardium. Then a magnet-tipped wire is advanced through the catheter until it touches the tip of the outside of the finger-shaped left atrial appendage. Another such wire is inserted through the femoral artery in the groin, threaded up into the heart, and into the far end of the interior of the left atrial appendage. The two magnets – one inside the tip of the left atrial appendage, one on its surface – snap together, and their attached wires form a “guide rail” which holds the appendage steady, even while the heart continues to beat.

The LARIAT® snare – made of polyester surgical thread and shaped like a lasso, with a slipknot tied at the end – is then slipped along the guide rail to the base of the appendage. Because the electrophysiologist cannot see the left atrial appendage directly and relies on various imaging tools to perform the procedure, he or she inflates a balloon catheter inside the appendage which is easily visible through imaging. The balloon serves as a landmark, ensuring that the LARIAT® snare encircles the mouth of the appendage, rather than leaving space for blood to later pool and clot. The slipknot is tightened, the balloon is deflated and removed, and the LARIAT® snare is cinched tight to completely close off the appendage. A thread cutter snips off the excess thread near the knot. Once all the equipment is removed, all that remains in the body is the tiny slipknot.

Preclinical data shows that the tied-off appendage eventually atrophies and shrivels up, further reducing the chance that blood could pool and form clots.

Dr. Lee coauthored a recent paper in the Journal of the American College of Cardiology which studied 89 patients in Poland who underwent the procedure. Electrophysiologists were able to successfully close the left atrial appendage for 96 percent of patients. Only 3.3 percent of patients had procedure-related complications, which were caused by the catheterizations rather than the LARIAT® snare itself. After one year, 98 percent of patients who were available for follow-up still had complete closure of their appendage.

UCSF was one of the first centers to offer the procedure in the United States, and has performed about 30 since 2011. Dr. Lee has trained cardiologists from more than two dozen centers, coaching them as they perform the procedure for the first time.

Big potential

“Dr. Lee did a lot of the initial preclinical work, has really pioneered the whole procedure and is now training others how to do it,” said Dr. Edward P. Gerstenfeld, chief of the Cardiac Electrophysiology and Arrhythmia Service at UCSF Medical Center and the Melvin M. Scheinman Endowed Chair in Cardiology. “It’s good to have him at UCSF, because he’s been a leader in developing this technology.

“For people who just cannot take blood thinners, because they have too much bleeding from them, this can help eliminate or significantly reduce the stroke risk from atrial fibrillation,” said Dr. Gerstenfeld. “Even though there is always some cost and risk to having a procedure done, the hope is that it will improve the quality of life for people afterwards. It will have to be looked at more to see if the risk/benefit ratio is good enough to warrant it being offered to patients as an alternative to blood thinners. You’d have to show that it’s as safe as the [anticoagulation] drugs. But if it works and is safe, it would have big implications for many patients with atrial fibrillation.

“There is a huge number of people with atrial fibrillation – it’s 6.5 percent of the population over the age of 60, and 10 percent of the population over the age of 80,” said Dr. Gerstenfeld. “If this turns out to be an effective therapy that could be applied to a large percent of the population with atrial fibrillation who are at risk of stroke, it would have a big impact.”

Studying the Procedure

“The procedure clearly meets an unmet need for a very large population,” said Dr. Gregory Marcus, also a UCSF electrophysiologist. “It’s a very innovative approach, and SentreHeart and Dr. Lee have done a great job doing some preliminary work to demonstrate that it’s feasible and likely safe. The next step, which we are now taking, is to really rigorously study it.”

Dr. Marcus is principal investigator of the coordinating center for the Permanent Ligation Approximation Closure Exclusion III (PLACE III) study, which has received a grant from SentreHeart to perform a multi-center trial. Dr. Marcus is working in partnership with the San Francisco Coordinating Center, a nonprofit research organization with expertise in conducting multicenter studies and clinical trials; it is comprised of researchers from the UCSF Department of Epidemiology and Biostatistics and the California Pacific Medical Center Research Institute. He is also the chairman of the PLACE III Steering Committee, a group of experts in electrophysiology and interventional cardiology from around the country that will oversee the study.

The plan is to enroll more than 100 patients at 11 sites in the U.S. and two sites in Europe. Patients will be closely followed for a year to determine the safety and efficacy of the procedure. At one day, 30 days, three months and one year after they undergo left atrial appendage closure using the LARIAT® snare, they will receive transesophageal echocardiograms, which involve inserting a small probe through the mouth and down the esophagus to get a close look at the heart.

These images will be sent to the core echocardiography lab at UCSF, directed by Dr. Elyse Foster. She, along with Dr. Atif Qasim, a recently recruited faculty member, will help review all of these echocardiograms in detail. Any patients who experience serious adverse events, such as death, stroke, or a heart-related hospitalization, will have a team of independent physicians review their charts to determine whether these were related to the procedure.

Beyond learning whether the procedure is safe and effective, researchers will also have an opportunity to discover more about heart function, atrial fibrillation and other diseases. In addition to supporting the follow-up imaging, the grant is funding the collection of serum and plasma from patients during each visit. These biosamples will be sent to UCSF; if Dr. Marcus is able to raise additional funds, these samples will be analyzed to discover more about heart function and disease.

“This will be a very rich data set,” said Dr. Marcus. “It’s rare to have transesophageal echocardiograms done multiple times in the same patient, according to a preset protocol. We’ll also have a repository of data samples from this selected, very high-risk population.”

For example, researchers could examine whether eliminating the left atrial appendage affects clotting behavior throughout the body. “It’s likely that clots that form in the left atrial appendage are in communication with the rest of the blood pool,” said Dr. Marcus. “When you turn on a clotting factor, that tells the blood, ‘Hey! It’s time to clot now.’ It could be that those leak out and systematically affect clotting. There is some data to suggest that atrial fibrillation patients are more prone to clot, even in peripheral blood (such as blood drawn from the arm). It would be very interesting to see if we can reduce that if we get rid of the appendage. Because we’re going to have serial samples from the same people, we will be able to look at changes in those clotting factors.

“We’re also interested in the cause-and-effect relationship between inflammation and atrial fibrillation,” said Dr. Marcus. “We and others have contributed to this literature, showing that inflammation can cause atrial fibrillation, and atrial fibrillation can also increase inflammation. We also know that inflammation seems to be important in many other diseases – not only cardiovascular diseases such as myocardial infarctions (heart attacks), but also probably cancer and diabetes. So if you can reduce inflammation, perhaps that can lead to other benefits that would not otherwise be expected.”

Dr. Marcus and the rest of the steering committee will review proposals from other researchers at UCSF and around the world who would like to access the PLACE III data to conduct their own research. “This is a very valuable collection, and will be a fruitful repository for other investigations,” said Dr. Marcus.

In addition to the PLACE III study, Dr. Marcus and Dr. Lee are establishing a national registry, and will invite all patients in the U.S. and Europe who undergo the LARIAT® procedure to enroll. Dr. Marcus hopes to have several thousand patients sign up to track long-term success, complications and outcomes of the procedure.

Pioneering a Combined Procedure

UCSF is also leading the way in studying whether pairing the left atrial appendage closure with another procedure can lead to improved outcomes. While some atrial fibrillation patients go in and out of normal heart rhythm, most remain in atrial fibrillation all the time.

The body’s natural pacemaker is located in the right atrium, and emits the electrical signal that initiates each heartbeat and causes the heart muscle to contract in a smooth, coordinated manner. However, “rogue” electrical signals can originate from other locations in the heart, including both atria, the pulmonary veins – which carry blood from the lungs to the left atrium – and the left atrial appendage. These disruptive electrical signals wreak havoc, causing the heart to move in a disorganized, ineffectual manner.

“The gold standard for eliminating atrial fibrillation is the Cox-Maze procedure,” said Dr. Nitish Badhwar. This is a surgical procedure that involves cutting and sewing the atria in a maze-like pattern. Because the scar tissue which forms on the heart from this procedure does not conduct electricity well, it interrupts the flow of disruptive electrical signals. The procedure has an 80 to 90 percent success rate in curing atrial fibrillation. “With the Cox-Maze procedure, the removal of the left atrial appendage is an integral part of the procedure,” said Dr. Badhwar, since abnormal electrical signals can also originate in the appendage.

As catheter-based procedures have improved, they offer an effective, less invasive way to treat atrial fibrillation. Dr. Melvin M. Scheinman, the Walter H. Shorenstein Endowed Chair in Cardiology, performed the first catheter ablation in humans at UCSF in 1981, and the use of this procedure to treat atrial fibrillation was first described in 1998.

Electrophysiologists insert a catheter through the groin, arm or neck, and thread tiny devices up to the heart. After identifying where “rogue” electrical signals are originating in the heart, they use radiofrequency energy or other methods to strategically ablate, or destroy, heart tissue. Similar to the Cox-Maze procedure, catheter ablation electrically isolates “rogue” signals, creating a line of scar tissue that does not conduct electricity. However, ablating the left atrial appendage can be risky, since the tissue is more delicate than the rest of the heart, and ablation can sometimes perforate it.

Left atrial appendage closure offers what could be a better solution. Since 2011, Dr. Badhwar and Dr. Lee have begun offering a two-part combined procedure for patients with persistent atrial fibrillation. They first perform the left atrial appendage closure using the LARIAT® procedure. Because the appendage atrophies, it no longer emits “rogue” electrical signals that can contribute to atrial fibrillation. About a month later, Drs. Badhwar and Lee then perform catheter-based ablation of the left atrium, reducing or eliminating “rogue” signals originating in the pulmonary veins or atria.

So far, they have performed this combined procedure in about 10 patients at UCSF, as well as another 10 patients at other centers in the U.S. “Ideally, I would like to see outcomes at one year, but preliminary results look very good,” said Dr. Badhwar. “More than half of patients are staying in normal rhythm, which for this group would not be expected if they just had the ablation or the appendage closure.”

The main reasons that patients would not be good candidates for either this combined procedure or the LARIAT® procedure by itself would be because they had previous open heart surgery – the resulting scar tissue makes it difficult to insert a catheter through the pericardium – or patients whose left atrial appendage is located in a difficult-to-reach position. “But anytime you’re considering doing any procedure on patients with persistent atrial fibrillation, I think they would be candidates for doing this combined procedure,” said Dr. Badhwar. “Our hope is that if we can replicate the Cox-Maze procedure through catheter-based methods, then we can have similar kinds of results, with a less invasive procedure.”