2013 BOSTON ATRIAL FIBRILLATION SYMPOSIUM
By Steve S. Ryan, PhD
This report combines two basic science presentations from the BAFS 2013 dealing with fibrosis. The first by Dr. Jose Jalife shows experimentally how A-Fib induces fibrosis, while the second by Dr. Hans Kottkamp says that A-Fib, in the real world, doesn’t always seem to produce fibrosis.
“Pure Model” of A-Fib
Dr. Jose Jalife of the University of Michigan, in a very well designed experiment, described how he and his colleagues induced A-Fib in sheep by pacing their hearts. His goal was to develop a “pure model of A-Fib”—to show how sustained high frequency electrical activity produces remodeling of the heart both structurally (fibrosis) and electrically (ion channels). By use of this sheep model he is attempting to define and isolate the actual mechanisms of how A-Fib develops and progresses, and then apply this model to humans. Dr. Jalife hopes this model can be used to prevent the progression from paroxysmal to persistent A-Fib.
Dr. Jalife started by implanting pacemakers in the hearts of sheep. He then induced A-Fib by pacing for 6-30 seconds, then stopping, then pacing again, etc. He continued this till the sheep were in persistent A-Fib. Once the pacing started, it took 5.5 days for the first A-Fib episode to occur. In the next four weeks progressively more episodes of A-Fib developed, but they self-terminated (paroxysmal A-Fib). And by the 55th day the sheep were in persistent A-Fib. These sheep were compared to a control group of sheep matched by gender, size, weight, etc. These sheep were kept for approximately a year. They didn’t develop heart failure, because sheep have a very good AV Node which filters the A-Fib pulses from affecting the ventricles.
All heart parameters remained normal, except for the markers of fibrosis which increased progressively as the sheep went from paroxysmal to persistent A-Fib. Fibrosis appeared in the right atrium, left atrium and the posterior left atrium. This fibrosis produced collagen and scarring in the heart which is a permanent remodeling effect of A-Fib. Fibrotic tissue is scarred, immobile, basically dead tissue with reduced or no blood flow and no transport function. It results in a loss of atrial muscle mass. Over time it makes the heart stiff, less flexible and weak, overworks the heart, reduces pumping efficiency and leads to other heart problems.
Dr. Jalife showed a slide of one sheep whose dominant frequency in paroxysmal A-Fib increased to 7.3 Hz. When the sheep became persistent, the dominant frequency increased to 10.3 Hz. After four months the dominant frequency increased, then remained constant at 11.3 Hz. The other sheep had similar electrical progressions, though they differed slightly from each other. A-Fib shortened the atrial refractory period and the action potential duration. Rotor frequencies were increased. Sodium and calcium heart electrical currents were lowered, while potassium and IK1 currents were increased. These electrical changes were associated with gene expression changes.
In a question and answer session, Dr. Jalife thought that electrical remodeling might be reversed, but not structural remodeling. Once fibrotic collagen and scarring occur, they currently are permanent.
Fibrosis in the Real World
Dr. Hans Kottkamp of the Heart Center Hirslanden in Switzerland, discussed several studies including some from his own facility which indicated that A-Fib doesn’t seem to always produce fibrosis. In particular he cited the work of Dr. Nassir Marouche whose MRI studies of fibrosis (see MRI [MAGNETIC RESONANT IMAGING] APPLIED TO A-FIB in the 16th Annual Boston Atrial Fibrillation Symposium, 2011 reports) found that someone with a lot of fibrosis (Utah Stage 4, 35% fibrosis) may only be in paroxysmal A-Fib and may have had A-Fib for only a short time. While someone with little fibrosis may have been in A-Fib for a long time.
In Dr. Kottkamp words, “if structural remodeling was a consequence of arrhythmia, there would be a clear, step-wise increase in fibrosis with increased duration of the arrhythmia… One would see a decrease in fibrosis when comparing paroxysmal and persistent A-Fib patients.” He cited several studies where there was great variability in the degree of fibrosis, where some patients in persistent A-Fib had low collagen and fibrosis, while other patients with paroxysmal A-Fib had high levels of fibrosis. (I have written Dr. Kottkamp to obtain the bibliographic references for the studies he cited and will publish them when they arrive.)
So, who’s right—Dr. Jalife or Dr. Kottkamp? They are both “right.”
The beauty of Dr. Jalife’s work in developing a “Pure Model” of A-Fib is it isolates the actual mechanism of how A-Fib develops and shows, for example, how it produces fibrosis. For most of the Symposium attendees, the question of whether A-Fib produces fibrosis was definitively answered by Dr. Jalife’s data. Dr. Jalife’s work is ground-breaking and provides doctors and researchers with a model to study and develop strategies to cure A-Fib.
But in the real, messy world described by Dr. Kottkamp, it isn’t as easy and clear how to isolate the mechanisms that produce fibrosis.
Let’s take a theoretical patient “A” who has a lot of fibrosis (Stage 4) but who is only in paroxysmal A-Fib. Many other factors in addition to A-Fib may produce fibrosis. Patient “A” may have a diseased heart with a lot of fibrosis, but may have only developed A-Fib recently and still be paroxysmal.
In contrast, patient “B” may have very little fibrosis but be in persistent A-Fib for some time. Other factors may slow the progression of fibrosis. He may lead a very healthy life style, take medications or supplements that inhibit fibrosis, or just be genetically blessed with a heart that resists fibrosis.
What this Means for Patients
As patients with A-Fib, we have to base our medical decisions on the conclusion that A-Fib produces fibrosis; that if we stay in A-Fib over a significant period of time, we will progressively develop fibrosis which is currently irreversible. However, as Dr. Kottkamp points out, it isn’t inevitable that everyone will develop fibrosis to an equal extent. Further research may identify why some people don’t develop fibrosis as much as others. Further research may also find the means or medications to hinder the progressive development of fibrosis.
Last updated: Saturday, January 30, 2016