Jose Jalife, MD

2014 Boston AF Symposium

Experiments in Atrial Remodeling in Sheep and the Transition From Paroxysmal to Persistent A-Fib

By Steve S. Ryan, PhD

Dr. Jose Jalife of the Center for Arrhythmia Research of the University of Michigan described his experiments inducing A-Fib in sheep by pacing their hearts. He is trying to discover the mechanisms underlying the transition from paroxysmal to persistent A-Fib.

Background: Some patients remain paroxysmal (usually with anti-arrhythmic therapy), while a large proportion progress to persistent A-Fib. (In a study of 5,000+ A-Fib patients, 54% of those on rate control meds went into permanent A-Fib in one year.)¹

Previous presentation summary: This talk was a continuation of Dr. Jalife’s 2013 Boston A-Fib Symposium presentation on his experimental studies with sheep. (See A-Fib Produces Fibrosis—Experimental and Real-World Data.) He implanted pacemakers in the hearts of sheep; then induced A-Fib by pacing for 6-30 seconds, then stopped, then paced again, etc. He continued this sequence until the sheep were in persistent A-Fib. He left them in A-Fib for about a year. Dr. Jalife also had a control group of sheep who were monitored but not paced into A-Fib.

Pacing Sheep into A-Fib

Once pacing started in the sheep, it took around 5.5 days to produce the first A-Fib episode. It took around 7-9 weeks of pacing for the sheep to move from Paroxysmal to Persistent A-Fib. At that point the sheep stayed in Persistent A-Fib without any further need of pacing. Dr. Jalife’s sheep developed two major types of atrial remodeling:

• Structural Remodeling (Fibrosis)
• Electrical Remodeling (ion channel expression changes)

(In humans, remodeling usually also results in atrial dilation. Dr. Jalife’s sheep once in A-Fib also developed significant Atrial Dilation compared to a control group of sheep.)

Unlike humans, the sheep didn’t develop heart failure, left ventricle dilation and dysfunction, or tachycardia-induced cardiomyopathy despite being in A-Fib for more than a year. This is possibly because sheep have a very good AV Node (unlike most humans) which filters the A-Fib pulses from affecting the ventricles and keeps the ventricular rate low.

Genetic Differences in Sheep

But there were differences in the sheep. Some sheep transitioned into persistent A-Fib fast (<40 days) while others needed more pacing to transition into persistent A-Fib (>40 days). Sheep from the same herd would have the same diet, environment, etc. But genetically they must have been different in their ability to hold out from transitioning into persistent A-Fib.)

Structural Remodeling

All ventricular parameters remained normal in the paced sheep, except for atrial dilation and 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 was the result of collagen deposition in the atria which is a permanent remodeling effect of A-Fib.

Dr. Jalife showed slides of a normal pig’s heart compared to a pig in persistent A-Fib. Well over ½ the atria seemed fibrotic.

Mechanisms of Electrical Remodeling

As expected, sustained A-Fib shortened the atrial action potential duration and refractory period. Also, rotor frequencies were increased. For example, in one sheep the dominant frequency of the first episode of paroxysmal A-Fib was 7.3 Hz, but increased progressively to 10.3 Hz during the transition to persistent AF. When AF in that sheep became persistent, the dominant frequent had stabilized at 11.3 Hz and remained constant for up to a year.

Graphic used with permission

In perhaps the most important findings of Dr. Jalife’s experiments, the rate of increase in dominant frequency correlated strongly with the time at which AF stabilized. In other words, although the progression from paroxysmal to persistent A-Fib varied from one animal to another, the rate of dominant frequency increase could be used to forecast the time at which AF became persistent.

 In other words, although the progression from paroxysmal to persistent A-Fib varied from one animal to another, the rate of dominant frequency increase could be used to forecast the time at which AF became persistent.

Dr. Jalife and his team also identified the mechanisms of electrical remodeling in sheep, which ion channels in the heart are responsible for transitioning sheep from paroxysmal to persistent A-Fib. 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 the alpha subunits of the L-type calcium (CACNA1C) and sodium (SCNSA) channel protein.”

1. “Sustained AF reduces L-type calcium (Caᵥ1.2) and sodium (Naᵥ1.5) protein expression”
2. “Sustained AF reduces the rapid sodium inward (I_Na) and L-type calcium (I_CaL) currents”
3. “Sustained AF reduces the transient outward current (I_to)”
4. “Sustained AF increases the inward rectifying potassium current (I_K1)  and protein expression of the Kir2.3 channel”

Conclusions

The sheep model explains the structural and electrical remodeling that occurs in humans.

As in humans, there is a variable progression in time from paroxysmal to persistent A-Fib.

The rate of dominant frequency increase during such a progression predicts the time at which AF stabilizes and becomes persistent, reflecting changes in Action Potential Duration and densities of I_CaL, I_K1, I_Na and I_to.

Predicting the transition from paroxysmal to persistent A-Fib is feasible, at least in some patients, by measuring the increase in dominant frequency over time.

Editor’s Comments:

A-Fib Produces Fibrosis

No one seeing Dr. Jalife’s presentation could doubt that A-Fib produces fibrosis. (Though even among sheep in the same environment, diet, etc. and with a similar gene pool, there were differences in how fast the individual sheep progressed to persistent A-Fib.) 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 and can lead to a host of other heart problems.

Added 11/7/20: In a study of dogs, it only took 30 minutes of high-rate pacing to develop electrical remodeling and to start re-wiring the heart to make it more prone to go into and remain in A-Fib.”Electrical remodeling develops quickly, is progressive, and may be persistent.” A-Fib begets A-Fib and is self-perpetuating. A-Fib causes electrophysiological changes that contribute to its progressive nature.

A common strategy today…is to leave you in A-Fib but control your heart rate by the use of beta-blockers, etc. But leaving you in A-Fib produces fibrosis which is irreversible and very damaging to the heart.

Don’t Let Your Doctor Just Leave You in A-Fib

A common strategy today for treating A-Fib is to leave you in A-Fib but control your heart rate by the use of beta-blockers, calcium-channel blockers, etc. But leaving you in A-Fib produces fibrosis which is generally irreversible and very damaging to the heart. If your doctor wants to leave you in A-Fib, Dr. Jalife’s experiments would recommend that you get a second opinion, and ASAP.

Electrical Remodeling Can Be Reversed, But Usually Not Fibrosis

One of the major advantages of a successful catheter ablation (and surgery) is it probably reverses the electrical remodeling effect of A-Fib. This makes intuitive sense. A heart beating in normal sinus rhythm (NSR) doesn’t usually produce those weird ion channel currents. But more research needs to be done before we can conclude this. However, a successful catheter ablation does not reverse fibrosis (structural remodeling), though it can reduce atrial dilation.

Mechanisms of Electrical Remodeling—Dominant Frequency

By identifying the actual mechanisms of electrical remodeling, Dr. Jalife’s ground-breaking experiments may lead to new therapies and drugs to combat not only the transition from paroxysmal to persistent A-Fib, but how to prevent patients from developing A-Fib in the first place. And using dominant frequency to predict when a patient is transitioning to persistent A-Fib, can be an invaluable tool for doctors (and reassuring for patients).

Progressing to Persisent A-Fib Can Happen Very Fast—You Don’t Have Much Time!

One of the scariest parts of Dr. Jalife’s presentation was how fast he could pace those sheep into persistent A-Fib. Obviously sheep aren’t people. But we know that for most people, there is a relatively short window of time when they progress from paroxysmal to persistent A-Fib (about a year). When you have A-Fib, you can’t count on genetics, diet, life style, environment, etc. to protect you from progressing to persistent A-Fib. Right now we just don’t know why some people stay paroxysmal for years, while most become persistent after a relatively short time. Worst case scenario, you have about a year. Act accordingly.

Goette, A. et al. Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation. Dec. 1, 1996;94(11):2968-74. https://pubmed.ncbi.nlm.nih.gov/8941128/ DOI: 10.1161/01.cir.94.11.2968