Atrial Fibrillation: Bench to Bedside

Jeffrey Goldberger, MD, Medical Director, Cardiac Electrophysiology Section, and Medical Director, Center for Atrial Fibrillation, Bluhm Cardiovascular Institute of Northwestern Memorial Hospital, Chicago, Il; Patrick T. Ellinor, MD, PhD, Director, Arrhythmia/Step Down Unit, Massachusetts General Hospital; and Teresa Tsang, Professor of Medicine, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

This session focused on the current state of practice for atrial fibrillation (AF) ablation; the pathophysiology of AF, including genetics, atrial structure, and neurologic input; and clinical and epidemiological insights into imaging AF substrate.

Dr. Ellinor began the session by saying "the biggest thing we've learned" recently is that AF is inheritable. In fact, those who have parents with atrial fibrillation are at a risk that is double of that of the general population for developing AF. Also, people who have first-degree relatives with AF under age 60 years have a risk of AF that is five times that of the general population, according to results of the "Iceland study." Further, the concordance rate of AF in monozygotic versus dizygotic twins was 22% versus 12%, with an estimated inheritability of 62%, according to results of the "Danish Twin study."

The presenter moved on, noting that ion channel mutations are rare in lone AF and that variants of chromosome 4q25 are strongly associated with AF. "How do they lead to AF?" he asked rhetorically. His answer: "non-coding variants in the genomic desert, the closest gene is PITX2, and one strong candidate gen is Pitx2c, which is critical for left/right asymmetry, including specification of the left atrium and pulmonary myocardium; it also suppresses a default program for sinoatrial node formulation in the left atrium.

Ellinor next discussed the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) AF Consortium, which looked at early-onset AF, community AF, and PR interval. They determined that the three genetic loci for AF are KCNN3, PITX2, and ZFHX3. "What do we know about ZFHX3?" Ellinor again asked rhetorically. It regulates myogenic and neuronal differentiation, it is a tumor suppressor gene in multiple cancers, and it's attached to susceptibility to Kawasaki disease. Unfortunately, its function in cardiac tissue is unknown.

The presenter explained that although the genes connected to familial AF have been found, much work is needed to understand their mechanisms. What is known is that:

• For chromosome 1q21 locus, variants are within the KCNN3 or SK3 gene
• There are three susceptibility signals for F at 4q25; if you put the together, you can look at if they really give increased risk for AF
• New SNPs are protective for AF
• Three SNPs identify patients at high risk for AF

Future work, said Ellinor, should focus on replication of other loci that didn't meet genome-wide significance in early-onset and community AF populations; examine GEI interactions for SNP age, sex, and HTN; determine if identified variants are associated with outcomes like stroke, heart failure, and death; and develop animal models of identified genes for AF.

Ellinor's key take-away point was that AF, and particularly lone AF, is heritable.

Tsang continued the session, first emphasizing that AF is an epidemic and has been labeled as such for quite some time. In fact, recent research shows that with aging, there are major increases of prevalence for both men and women, in part believes Tsang, "because we're living longer. The life expectancy now is about 80 years, compared with 40 years in 1900."

Currently, the lifetime risk of AF is one in four for both men and women who live beyond age 40 years, explained Tsang. Though she's not surprised by study results that show overall prevalence increased over three decades, she was surprised to see that these increases also occurred within specific age groups, a finding she thinks might be fueled by the rising prevalence of obesity. From 1990-2007, the prevalence went from below 20% in all 50 states to over 20% in all states but Colorado. The connection is emphasized by the knowledge that a greater body mass equals a greater risk for progression from paroxysmal to persistent/permanent AF.

Other key points Tsang made were as follows:

• From 1995-2000, there was a substantial decrease of stroke as an AF outcome, but no improved survival after fist diagnosis of AF.
• There was a marked increased in hospital utilization at an increase of 2.5% per year from 1980-2000.
• We don't know enough about silent/unrecognized AF; but if you look at studies using higher technology, they found it better than those using lower technology (regular ECG, paper charts).
• LV ER does not change significantly with aging.
• A strong relationship exists between diastolic function and first non-valvular AF.
• To determine the role of LA function in the first AF development, you can look at LA reservoir function, LA conduit function, and LA pump function using relatively simple equations.
• People with poorer LA function are at high risk for developing AF.
• You can decrease LA volume with treatment.

"So, what's on the horizon?" asked Tsang. "Looking at echo strain will be key with regard to degree of stretching or deformation; strain/strain rate imaging provides information about the regional and global function of LA."

Tsang closed by stating that "AF is a major public health problem" and that "echocardiography is non-invasive and highly effective in early detection of disease."

Before moving on to Dr. Goldberger, an attendee asked Tsang if she thinks the field will be moving away from imaging to blood testing. Tsang said that she does believe there is a role. "With ECG, you have a great tool, but it is more foreseeable to have simple test for diagnosis right in the office. We're not there yet, but it is foreseeable in the future that that can be done; it would have to be extremely simple and reproduceable, which handheld echo currently is."

Batting cleanup for the session was Dr. Goldberger, who began by noting that a 2006 study of 23,626 patients showed that ablation for AF takes well over 3 hours on average, many patients have to have it redone, the cure rate averages 63%, and many complications occur, at rate of about 8%.

There is a strong need to differentiate atrial fibrillation from atrial flutter, Goldberger stressed. It is also important to know who should have AF ablation, yet there is no clear answer to this question. Also, "What are the clinical benefits of AF ablation: symptoms, survival, stroke?" asked the speaker, adding that there would hopefully be more data on this coming on in the next few years.

Other things cardiologists who treat AF need to consider, according to Goldberger are the use of things like the hybrid Maze (explained below), how to choose among the many techniques for AF ablation, and what role new technologies should play. Cardiologists are left to largely figure these answers out on their own, as Goldberger explained that when it comes to AF ablation, no level A evidence exists for guidelines. However, a 90% success rate can be expected for ablation of atrial flutter versus 70% for atrial fibrillation, with complications for ablation of flutter at <1% and complication for ablation of AF at 1-2%.

After showing three ECG readings, for which audience members were mixed about 50/50 in determining whether they showed atrial fibrillation or atrial flutter, Goldberger explained that to differentiate the two, one should ask "Are there F waves in limb leads and is the ventricular response regular or regularly irregular. If you answer yes to both, the diagnosis is atrial flutter. Otherwise, it's AF. Carefully review and consider many override criteria. There are exceptions to this, but it will work 99% of the time."

Goldberger next explained, quickly, the hybrid maze, which includes stage I pulmonary vein isolation and removal of the LAA. He stated that LAA removal is important for stroke prevention and that after using this technique, about 30% of patients will still have Atrial fibrillation.

The speaker closed his talk and the session with a brief review of Coumadin use post-ablation. "Though rhythm control is used for treatment, many who get it have silent AF, and using it doesn't mean the patient doesn't have AF," he explained "If you can't determine if they have silent or symptomatic AF, why keep the patient on Coumadin? There is no consensus and no good answer for why you would."