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Dr. Jose Jalife

AF Symposium 2015: Surprising Research on Fibrosis Using Sheep

Dr. Jose Jalife of the University of Michigan

Dr. Jose Jalife of the University of Michigan

A-Fib produces fibrosis (tissue that has fiber-like characteristics. Over time it makes the heart stiff, less flexible and weak). When Dr. Jose Jalife of the University of Michigan in Ann Arbor, MI, paced sheep into A-Fib, their hearts became fibrotic within a very short time and increased progressively as the sheep went from paroxysmal to persistent A-Fib.

Next, Dr. Jalife gave his sheep the a Gal-3 (protein) inhibitor. Learn the surprising results…Read more of my 2015 AF Symposium Report−>

AF Symposium 2015 Brief Reports by Steve S. Ryan, PhD

20th Annual AF Symposium

by Steve S. Ryan, PhD

This overview should give you a sense of the topics floating through the three days in Orlando and the over sixty presentations by fifty A-Fib experts and researchers. (Most recent brief reports listed first)

AF Symposium: My Brief Reports

 The Novel Oral Anticoagulants: Xarelto Best Seller; Dr. Daniel Singer
 Stimulating the Front Ear Flap Inhibits A-Fib—Research by Dr. Warren Jackman
 Dr. Ruskin Asked: Can Anyone in A-Fib Really Be Asymptomatic?
 The Rhythmia 3-Dimensional Mapping System (Live from Leipzig via Satellite) 
 LAA Occlusion Devices: Is the Watchman Device Dead in the Water?
 FDA ‘Easy Feasibility Study’ (EFS 
 Reversal Agents for the New Anticoagulants (NOACs)? 
 Female Gender: Is it a Risk Factor for Stroke?
 Living in A-Fib More Dangerous Than Having an Ablation
 Rotors! Rotors! Rotors! Sizzling Topic but No Consensus
 Holistic Approach to Health: Great Results Dealing with Obesity
 Atrial Esophageal Fistula: A Case Study
 Anticoagulation Case Study: Dilemma for 92-year-old With Paroxysmal A-Fib
 Ablation Without X-Ray or Fluoroscopy (Live via Satellite)
 From Beijing: Strange Chinese Case (Live via Satellite)
 Ablation & Closing Off the Left Atrial Appendage in the Same Procedure (Live via Satellite)
 Contact Force Sensing and Jet Ventilation (Live Satellite Presentation)
 Non-Invasive Electrocardiographic Imaging—ECGI—CardioInsight
 Fibrosis and A-Fib: Continuing Research on Sheep

The Rhythmia 3-Dimensional Mapping System (Live from Leipzig via Satellite)

Rhythmia 3-Dimensional Mapping image

Image from Rhythmia 3-Dimensional Mapping system by Medtronic

Live Via Satellite TV icon(Please be advised that the Symposium organizers go to great lengths not to identify or unfairly publicize one device over another. When writing these reports I often have to do a good deal of research to correctly identify and describe particular devices that are demonstrated, as a service to readers. But this in no way implies or suggests that one device is superior to another.)

Dr. Gerhard Hindricks of the University of Leipzig in Germany gave a dynamic presentation of a catheter ablation of a 46-year-old female with paroxysmal A-Fib using the Rhythmia 3-dimensional multipolar mapping system by Boston Scientific. Along with his colleagues Drs. Andreas Bollmann and Jedrzej Kosiuk, they used the Rhythmia special basket catheter to generate a 3-D map of electrogram voltages and activation times. To me it seemed amazingly fast. The eight-splined bidirectional catheter produced 1,000 data points per minute. In what seemed like only a few passes, they produced a 3-D color reconstruction of the patient’s left atrium.

The actual ablation was routine. They terminated the A-Fib into sinus rhythm without having to use Electrocardioversion. But they found that the PV isolation was incomplete. Using the same Rhythmia 3-D mapping catheter, they were easily and quickly able to locate the gap in the Left Superior PV and ablate it.

LAA Occlusion Devices: Is the Watchman Device Dead in the Water?

Dr. Vivek Reddy from Mount Sinai School of Medicine in New York City gave a very well referenced and persuasive presentation on the Watchman device which closes off the Left Atrial Appendage to prevent clots and strokes. The theory behind the Watchman device is that most A-Fib clots originate in the Left Atrial Appendage (LAA). The Watchman closes off the LAA where 90-95% of A-Fib strokes come from. It’s a very low risk procedure that takes as little as 20 minutes to install. Afterward, you would usually not need to be on blood thinners. (For more, see my article, The Watchman Device: The Alternative to Blood Thinners).

Dr. Reddy certainly persuaded me that the FDA should approve the Watchman device. Dr. Reddy, earlier in Washington, had made the same persuasive arguments before the FDA.

Dr. Andrew Farb from the FDA took the bull by the horns and gave his perspective on the various LAA Closure (Occlusion) Devices. But as one would expect, he didn’t indicate how the FDA would rule on the Watchman device, since deliberations were still ongoing.

After his presentation, I asked him several pointed questions about this, but he was, of course, careful not to comment about current FDA deliberations. My guess? If body language, momentum, mood of the presentations, and more importantly recent research indicate anything, the Watchman device probably will not be approved by the FDA.

There was a palpable sense of sadness at the end of these presentations. The attendees realized that the game may be over for the Watchman device. I hope I am wrong, since the Watchman device would be an important tool to help A-Fib patients. Once the FDA rules and the current clinical trials of the Watchman device end, you will probably have to go to Canada or overseas to get a Watchman device installed.

(Happily I was wrong on this prediction. Update: The U.S. Food and Drug Administration (FDA) approved Boston Scientific’s WATCHMAN™ LAA closure technology for use in the U.S. on March 13, 2015. It has been available internationally since 2009. The FDA approval of the WATCHMAN device is based on the clinical program which consists of numerous studies, with more than 2,400 patients and nearly 6,000 patient-years of follow-up. The Watchman device will be available first at U.S. centers where it has been used in clinical studies.)

Watchman May Win FDA Approval

In my earlier brief reports on the Orlando AF Symposium, based on the recent research and the FDA presentation, I said the Watchman device probably won’t be approved in the US. I’m happy to say that I am most likely wrong.

At the LAA Symposium 2015 in Marina del Rey, CA, it was suggested that the Watchman device may be approved by the middle of this year. One presenter described how the FDA chairman talked with several people who were going to Canada to have the Watchman device installed. He seemed embarrassed that the Watchman was available everywhere in the world but not in the US and said that it has to be approved.

Other doctors I talked with at the LAA Symposium were of the same opinion. Presenters described how clinical trials for other LAA closure devices were on hold so that they could get approved in comparison to the Watchman (Non-Inferiority Trials). Dr. Dhanunjaya Lakkireddy of the University of Kansas Medical Center said that we are at a “tipping point” for the (A-Fib) industry.

FDA ‘Easy Feasibility Study’ (EFS)

As everyone, including the FDA, is well aware, A-Fib innovations usually start in Europe where they are more easily approved. Then only later do they move to the US for FDA approval, since the FDA generally requires more data than European regulators.

Drs. Jun Dong and Andrew Farb from the FDA described the FDA’s ‘Easy Feasibility Study’ (EFS) program where medical device innovations could be evaluated  in the US without having to go to Europe first. He encouraged researchers and attendees to take advantage of the new EFS program. This is major news and may make the development of A-Fib innovations much easier to accomplish in the US.

For further information, contact: Andrew Farb, Email: Andrew.farb@fda.hss.gov. 301-796-6317

Reversal Agents for the New Anticoagulants (NOACs)?

Dr. Luigi Di Biase from the Albert Einstein College of Medicine in the Bronx, NY and Dr. Daniel Singer from Massachusetts General Hospital in Boston each described potentially great developments in reversal agents for apixaban (Eliquis) and rivaroxaban (Xarelto).

Dr. Di Biase described studies where leaving people on uninterrupted rivaroxaban and apixaban before, during and after an ablation dramatically reduced the amount of silent thromboembolic lesions and were as safe as warfarin with regards to stroke and TIAs. (This didn’t work with dabigatran [Pradaxa].) But if patients develop bleeding or effusion during the ablation, they are in trouble because there is no direct reversal agent as there is for warfarin. He has used Factor IV as an indirect reversal agent. Dr. Singer also described how Factor IV was used as a reversal agent for apixaban.

But there are new reversal agents for apixaban and rivaroxaban which promise to completely reverse the effects of these two drugs in less than four minutes. The FDA is speeding up studies on these reversal agents. But one never knows when or if the FDA will approve them.

Female Gender: Is it a Risk Factor for Stroke?

Dr. John Day of the Intermountain Heart Institute in Murray, UT (and recently elected president of the Heart Rhythm Society) may be the first A-Fib leader to publicly question whether women should be given one point on the stroke risk CHA2DS2-VASc scale just because of their gender. Many doctors have said this in a circumspect way. Dr. Eric Prystowsky in a presentation at last year’s AHS meeting thought that most doctors would agree with Dr. Day, “as long as there wasn’t a camera focused on them.” He gave the example of a 45-year-old woman in good health and a 45-year-old man with hypertension who according to current guidelines should both be given one point on the stroke risk CHA2DS2-VASc score.

Editor’s Comments:
As readers of A-Fib.com, you know that’s been my opinion ever since the original European guidelines came out. Women in their child-bearing years are much less at risk of stroke because of the blood-thinning effect of losing blood each month. And even after menopause women have less risk of stroke. But eventually they do have more strokes. But not because of an innate inferiority, but because women live longer than men. Stroke is age related. An observational Danish registry study documents this.
For more, see The Denmark Study: Women in A-Fib Not at Greater Risk of Stroke Contrary to CHA2DS2-VASc Guidelines!) (Be advised that the original European guidelines were written by doctors with major conflicts of interest.) These guidelines may be a not so very subtle form of gender bias.

Living in A-Fib More Dangerous Than Having an Ablation

Living in A-Fib is more dangerous than having an ablation, according to Dr. Josef Kautzner from Prague, the Czech Republic. Studies have documented that the adverse effects of living in A-Fib, having to take A-Fib drugs and anticoagulants for life are both pragmatically and statistically worse than having an ablation. Dr. Kautzner discussed how A-Fib can cause or is associated with silent brain lesions and dementia. Any time you go into a hospital is a risk. And no one would say that a catheter ablation is a walk in the park. But an ablation is a low risk procedure, though not risk free. The risk is similar to having your tubes tied. The possible adverse effects of an ablation procedure (like bleeding at the groin) are generally temporary, unlike the lasting, permanent damage you can do to your heart, body and brain by living in A-Fib for years.

Rotors! Rotors! Rotors! Sizzling Topic but No Consensus

The most hotly discussed topic at this year’s symposium was rotors. The opinions expressed about rotors were at times very heated, more than I had ever seen at an AF Symposium. Dr. Shih-Ann Chen of Taipei, Taiwan disagreed with Dr. Sanjiv Narayan of Stanford, CA about the basic concepts of rotors and how they should be defined. Dr. Ravi Mandapati of UCLA and Loma Linda University disagreed with Dr. Narayan which was all the more striking in that he had worked with Dr. Narayan when he was at UCLA. Dr. Pierre Jais of Bordeaux, France said that the FIRM mapping system misses 40% of the atrium area.

Drs. Haissaguerre and Jais from Bordeaux and Dr. Sebastien Knecht of Brussels, Belgium gave presentations on how they were using the CardioInsight body surface mapping vest to perform ablations of “drivers” at many different centers, while Dr. Karl-Heinz Kuck from Hamburg, Germany using a different body surface mapping system said that he couldn’t ablate rotors. Dr. Narayan says the FIRM system finds a maximum of 2-3 rotors in the atria, while other systems find as many as seven. The FIRM system says rotors are usually relatively stable and can last as long as 30 seconds while others say they rotate in one fixed spot for only one or two rotations, that they tend to migrate within a certain area.

The presenters obviously didn’t share a consensus of basic concepts of what rotors are, how they work, their importance in A-Fib, how they should be correctly identified, used, and ablated. (It seems to me the Bordeaux group has the best understanding and pragmatic use of rotors. They refer to “rotors” and focal sources as “drivers.”) But the CardioInsight system Bordeaux uses isn’t currently available or isn’t being tested in the US.

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Holistic Approach to Health: Great Results Dealing with Obesity

Obesity was one of the most often discussed topics. There is a growing consensus among EPs that it isn’t enough to just give obese patients a catheter ablation while not dealing with their obesity. If the obesity isn’t dealt with, their A-Fib is very likely to re-occur. A-Fib will develop in other spots that haven’t been ablated. The condition (obesity) that triggered or caused the A-Fib will trigger or cause it again, if it isn’t taken care of.

Dr. Prashanthan Sanders of Adelaide, Australia described the great results he is getting in his clinic which includes a weight loss program and counseling. He convinces his overweight patients to buy into the program, lose weight, and keep it off. The program works so well that just by losing weight patients become A-Fib free. This program is a holistic approach to health and also is developed to work for diabetes, sleep apnea, hypertension, binge drinking and smoking.

Dr. Sanders foresees a world where some patients become A-Fib free simply by changing their life style, where they don’t have to have a catheter ablation to become A-Fib free.

Many other doctors commented that A-Fib treatment at many centers today includes or should include much more than A-Fib ablation and drugs. A-Fib centers should have nutritionists, exercise therapists, sleep apnea specialists, etc. as part of their A-Fib program.

Atrial Esophageal Fistula: A Case Study

Dr. John Day of the Intermountain Heart Institute in the Challenging Cases Discussion described his experience with the dreaded Atrial Esophageal Fistula. Though very rare, this is one of the few possible complications of a catheter ablation that can kill you. An ablation, if not done with caution, can irritate and damage the esophagus which often lies right next to the heart. Over 2-3 weeks stomach acid can eat through this damaged area to produce a hole or fistula from the esophagus into the heart.

As soon as Dr. Day saw this patient, he knew it was a fistula and immediately called surgeons and a GI doctor. All the surgeons were doing operations and didn’t want to do the surgery in the EP lab. Dr. Day described how he and his colleagues ran down the hospital hallway to the operating room while giving the patient a transfusion and at the same time pumping out the blood escaping from his heart.

The GI doctor got there first and put in a stent in the esophagus to plug the hole. There was lots of discussion as to whether this was the best approach, but it worked. The patient survived but had to spend a month in the hospital.

This cautionary and very dramatic tale certainly got the attention of all the attendees. No matter how rare a fistula is, every EP and A-Fib center must have an established protocol in place to deal with it. I remember Dr. Hugh Calkins in a previous Symposium advising, “There are only two kinds of EPs—those who have not had an Atrial Esophageal Fistula and those who have!” (Dr. Calkins’ patient with fistula also survived.)

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Anticoagulation Case Study: Dilemma for 92-year-old With Paroxysmal A-Fib

Dr. Peter Kowey of Lankenau Hospital in Winnewood, PA described a case that illustrates the kind of dilemma both doctors and patients often have to face. A 92-year-old woman with paroxysmal A-Fib who had been treated for many years with warfarin had some bruising and nuisance bleeding, but never anything major.

Dr. Kowey thought that ethically he should tell her about the different new anticoagulants which may be superior to warfarin, then see if she wanted to change. She went with apixaban (Eliquis), then six months later had a stroke even though she was taking apixaban properly and conscientiously. Happily, she made an almost full recovery. She returned to warfarin which had worked for her in the past and which she was comfortable using.

Editor’s Comments:
One of the reasons Dr. Kowey discussed the new anticoagulants with his 92-year-old patient was because warfarin is considered more apt to cause bleeding in older patients. The newer anticoagulants in clinical trials caused less bleeding. But we don’t have much data from the clinical trials on people over 90 years old.
Can we say that apixaban didn’t work or was ineffective? No. Anticoagulants reduce but do not totally eliminate the risk of an A-Fib stroke. Just because she had a stroke doesn’t mean apixaban didn’t work.
Dr. Jeremy Ruskin pointed out that there has never been and probably never will be a head-to-head comparison of the three new anticoagulants. But in my opinion apixaban (Eliquis) appears to have tested better and is safer than the others
For more, see my 2013 BAFS articles, The New Anticoagulants (NOACs) and Warfarin vs. Pradaxa and the Other New Anticoagulants.

Ablation Without X-Ray or Fluoroscopy (Live via Satellite)

Live Via Satellite TV iconIn the satellite case live presentations, Drs. Rodney Horton and Amin Al-Ahmad from the Texas Cardiac Arrhythmia Institute in Austin, TX surprised us by doing an ablation without wearing the standard lead aprons to prevent fluoroscopy exposure. Even more surprising was one of the lab assistants who was pregnant. She could work on the ablation because no fluoroscopy was used. The doctors did the whole ablation using ICE (Intracardiac Echo) and 3D mapping. They showed for example how ICE can be used to thread the catheter up into the heart and into the left atrium. Dr. Horton said that not having to wear those heavy lead aprons would probably add 5-10 years to his ablation career.

(They didn’t wear surgical masks during the ablation which was surprising to me. I will write them for an explanation.)

From Beijing: Strange Chinese Case (Live via Satellite)

Live Via Satellite TV iconThe live satellite case from Beijing, China was technically flawless and probably a first of its kind. But it wasn’t much of a learning experience for the attendees. The Chinese EPs only used one catheter and had to frequently pull out the mapping catheter and replace it with the ablation catheter, etc. When the expert panel asked them questions, the Chinese EPs either didn’t understand or simply didn’t answer them. They seemed very uncomfortable. It seemed like a throwback to ablation techniques of 20 years ago.

Ablation and Closing Off the Left Atrial Appendage in the Same Procedure (Live via Satellite)

Live Via Satellite TV iconDrs. Claudio Tondo, Gaetano Fassini, Massimo Moltrasio, and Antonio Dello Russo from Milan, Italy showed how they do a catheter ablation for A-Fib and install the Watchman device in the same procedure, when it’s needed. They do the ablation procedure first. Then when the patient is in sinus rhythm, they install the Watchman device. (This can’t be done in the US, because the Watchman device hasn’t received FDA approval. In later discussions including representatives of the FDA, there was an all too real possibility that the Watchman will never receive FDA approval.)

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Contact Force Sensing and Jet Ventilation (Live Satellite Presentation)

Image of the TactiCath Quartz irrigated ablation catheter with EnSite Contact Force Module (Photo St. Jude Medical, Inc.)

TactiCath Quartz irrigated ablation catheter with EnSite Contact Force Module (Photo St. Jude Medical, Inc.)

Live Via Satellite TV icon Drs. Kevin Heist and Moussa Mansour from Massachusetts General in Boston showed in a live case how they used a Contact Force Sensing catheter combined with Jet Ventilation. (There are two Contact Force Sensing catheters approved by the FDA—the ThermoCool Smart Touch device by Biosense Webster (approved Feb. 24, 2014) and the TactiCath Quartz Contact Force Ablation Catheter by St. Jude Medical (approved Oct. 27, 2014). This live case used the TactiCath catheter but didn’t imply or suggest it is superior to the ThermoCool catheter. For a description of each, see my 2014 AF Symposium report The New Era of Catheter Ablation Technology: Force Sensing Catheters.

This combination of Force Sensing Catheter with Jet Ventilation for RF ablation probably represents the most advanced RF ablation strategy available today. Jet Ventilation doesn’t stop the heart from beating as in bypass surgery. But to this observer it seemed to put the heart in a type of slow motion with a lot less movement than when the heart is beating in normal sinus rhythm. You could really see a difference when they turned the Jet Ventilation off and on. Slowing down the heart like this helps the ablation doctor make lesions in hard-to-access areas and makes it easier to hold the catheter steady and apply the right contact pressure.

Non-Invasive Electrocardiographic Imaging—ECGI—CardioInsight

Drs. Michel Haissaguerre and Pierre Jais from Bordeaux/LYRIC gave presentations on the ECGI system. The day before their ablation, the patient lies down on his/her back and a technician places a vest-like device with 256 electrodes over his/her chest and stomach. These electrodes combine with rapid CT (Computed Tomography) scans to produce a very detailed 3D color map of the heart. (For a detailed description and discussion of the ECGI system, see 2013 BAFS: Non-Invasive Electrocardiographic Imaging [ECG]) The system automatically detects rotors and foci and computes them into a “Cumulative Map” or movie. These driver regions are ranked, based on statistical prevalence.

Then, Dr. Sebastien Knecht from CHU Brugmann, Brussels, Belgium, described the AFACART trial design and preliminary results using the CardioInsight ECGI system. Many centers in Europe including four in Germany are now using the CardioInsight. Requiring very little training, technicians and EPs using the CardioInsight system are getting similar great results like the Bordeaux group. Though these studies just started, it looks like the CardioInsight ECGI mapping and ablation system is poised to revolutionize the way EPs map and perform ablations.

Fibrosis and A-Fib: Continuing Research on Sheep

Dr. Jose Jalife of the University of Michigan in Ann Arbor, MI, continued his exciting research on fibrosis and A-Fib. In previous Symposiums Dr. Jalife demonstrated how A-Fib produces fibrosis. When he paced sheep into A-Fib, their hearts became fibrotic within a very short time. The markers of fibrosis (collagen and scarring) increased progressively as the sheep went from paroxysmal to persistent A-Fib. (See A-Fib Produces Fibrosis—Experimental and Real-World Data.)

Fibrosis is tissue that has fiber-like characteristics which develop in place of the normal smooth walls of the heart. 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. Fibrosis, up to now, was considered permanent and irreversible. But Dr. Jalife gave his sheep a Gal-3 inhibitor GM-CT-01 that actually prevented and reduced fibrosis! (For his previous presentations, see 2014 BAFS: The Holy Grail: Preventing A-Fib by a GAL-3 Inhibitor.)

In his continuing studies of sheep, Dr. Jalife found that fibrosis predicts recurrence, and that fibrosis can not be reversed if it is well established, even with GAL-3 Inhibitors.

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Last updated: Friday, November 18, 2016 

Fibrotic Atrial Cardiomyopathy (FACM) – 2014 Boston AF Symposium

2014 Boston AF Symposium

Hans Kottkamp MD

Hans Kottkamp MD

Fibrotic Atrial Cardiomyopathy (FACM)

By Steve S. Ryan, PhD

Dr. Hans Kottkamp of the Hirslanden Hospital in Zurich, Switzerland presented the concept of “Fibrotic Atrial Cardiomyopathy (FACM)” in his talk entitled “Fibrotic Atrial Cardiomyopathy – Implications for Catheter Ablation of AF.”

TYPES OF A-FIB substrates

Dr. Kottkamp discussed two types of substrates (or genotypes) of how A-Fib develops:

  • “Focal” A-Fib with the trigger as the only driver and with no (or very limited) structural atrial remodeling over time (even decades or “forever”).
  • A-Fib due to a severe underlying structural heart disease, e.g., mitral stenosis which causes significant structural remodeling.

Then he proposed a third type:

  • A-Fib as a manifestation of a pre-existing “Fibrotic Atrial Cardiomyopathy (FACM)” which can be mild (I), moderate (II), or severe (III). FAMC involves structural remodeling in a potentially progressive disease process. FAMC may explain what was characterized as “Lone” A-Fib with no previously identifiable cause in an otherwise healthy patient.

(Cardiomyopathy is a heart condition or disease in which the heart muscle is weakened and the heart’s ability to pump blood is impaired. For example, fibrous tissue may partially replace the heart muscle, disabling the heart so that it no longer functions properly and blood no longer moves efficiently. Cardiomyopathy is often accompanied by atrial fibrillation. Dr. Kottkamp’s concept of “atrial cardiomyopathy” isn’t the same thing as normal cardiomyopathy in which the ventricles are impaired.) 

PREVIOUS STUDIES OF FIBROSIS

At last year’s Boston A-Fib Symposium (see BAFS 2013: A-Fib Produces Fibrosis—Experimental and Real-World Data), Dr. Kottkamp cited several studies which indicated that A-Fib doesn’t seem to always produce fibrosis, where there is a great variability in the degree of fibrosis.1 This is in contrast with Dr. Jose Jalife’s experimental studies of sheep where A-Fib clearly produces fibrosis (see BAFS 2013: A-Fib Produces Fibrosis—Experimental and Real-World Data). In the real, messy world it isn’t always as easy and clear how to isolate the mechanisms that produce or limit fibrosis. As Dr. Kottkamp points out, sheep are not humans. Fibrosis may work differently in humans compared to animal models like sheep. (Of course it would be unethical to experimentally produce A-Fib and fibrosis in humans as one can in animal models.)

HISTOLOGICAL DATA

Dr. Kottkamp cited his and other researchers’ histological data and showed slides of heart cell tissue which showed in his analysis that:

  • The hypothesis that fibrosis progresses systematically from paroxysmal to persistent A-Fib was not confirmed.
  • While there was a tendency of increased mean fibrosis level in patients with persistent vs paroxysmal A-Fib, the variation within the two groups was very high.
  • No correlation at all could be detected between patient age and increase in the extent of fibrosis or fatty changes in atrial tissue.2
  • Atrial samples taken from age-matched A-Fib-free patients contained negligibly low amounts of fibrofatty tissue despite similar clinical high-risk profiles.3

Similar to Dr. Nassir Marrouche’s Utah Stages I-IV, Dr. Kottkamp showed slides of paroxysmal patients with No Fibrosis (no FACM), Mild Fibrosis (FACM I), Moderate Fibrosis (FACM II), Severe Fibrosis (FACM III).

WHAT DR. KOTTKAMP’S RESEARCH MEANS FOR A-FIB PATIENTS

According to Dr. Kottkamp, what FACM means for patients:

  • In patients with “Focal” paroxysmal A-Fib (no or almost no fibrosis [No FACM], PV isolation can (almost) be considered curative. Though there are relatively rare cases of extra-PV foci in these cases.
  • In patients with  FACM I AND II (similar to Utah Stages II and III) the ablation cannot really “cure” the underlying disease FACM. However, in many of these cases, ablation can effectively treat the arrhythmia A-Fib which in many patients is the only clinical manifestation of the FACM disease.
  • While patients in FACM III (similar to Utah Stage IV) are very hard or impossible to cure with today’s standard catheter mapping and ablation techniques.

CONCLUSIONS

Dr. Kottkamp’s conclusions:

  • Circumferential PV isolation is a cornerstone treatment for most patients with paroxysmal A-Fib.
  • The concept of FACM as a primary atrial disease explains recurrences of paroxysmal or even persistent A-Fib after a period of stable Sinus Rhythm after a previous PV isolation by the potentially progressive nature of the FACM disease (which is independent of the arrhythmia).
  • In patients with A-Fib recurrence after durable PV isolation, the ablation strategy can be targeted to the individual substrate localization.
  • In patients with more advanced substrates (FACM II-III), additional substrate modification may be reasonable in patients with persistent A-Fib already in the first ablation session.
Editor’s Comments:
Dr. Kottkamp’s concept of Fibrotic Atrial Cardiomyopathy may become important in our understanding of A-Fib, though it needs further studies to determine how it develops and progresses, how it differs from fibrosis measurements like Utah Stages I-IV, how best to quantify and measure it, etc.
Dr. Kottkamp’s concept that Lone A-Fib may come from Cardiomyopathy, that “Lone” A-Fib isn’t really lone or idiopathic but may come from a form of Atrial Cardiomyopathy may be an important thesis for future research. It may explain why some paroxysmal A-Fib patients have extensive fibrosis, while others don’t. (Though there are other factors which may produce fibrosis as well as Cardiomyopathy.)
Dr. Platonov’s finding that age doesn’t relate to fibrosis is certainly good news for patients. It indicates that just because we are getting older, our hearts aren’t automatically developing fibrosis. (Though we do know that A-Fib is associated with aging of the heart. As patients get older, the prevalence of A-Fib increases, roughly doubling with each decade.4 This suggests that A-Fib may be related to degenerative, age-related changes in the heart.)
Contrary to Dr. Jalife’s experimental studies with sheep which showed that A-Fib produces fibrosis, Dr. Kottkamp’s studies indicate that in the real world fibrosis doesn’t progress systematically from paroxysmal to persistent A-Fib. But his studies did show that there was more fibrosis in persistent vs. paroxysmal A-Fib patients. And that people without A-Fib compared to age-matched patients with A-Fib, had “negligibly low amounts of fibrofatty tissue (fibrosis) despite similar clinical high-risk profiles.”
Even though animal models like sheep aren’t perfect, studies like Dr. Jalife’s are scientifically sound and very convincing. Sheep hearts seem very similar to human hearts for all practical purposes. As patients with A-Fib, we have to base our medical decisions on the conclusion that A-Fib produces fibrosis (Dr. Kottkamp disagrees with this conclusion); 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. This is consistent with Dr. Jalife’s studies in which even sheep with the same environment, diet, similar gene pool, etc. did differ in how fast they developed fibrosis.

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Last updated: Wednesday, September 2, 2015 

References    (↵ returns to text)
  1. Mahnkopk, C. et al Evolution of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm. 2010 Oct. 7(10):1475-81 http://www.ncbi.nlm.nih.gov/pubmed/20601148 doi: 10.1016/j.hrthm.2010.06.030. Epub 2010 Jul 1.
  2. Platonov, PG et al. Structural Abnormalities in Atrial Walls Are Associated With Presence and Persistency of Atrial Fibrillation But Not With Age. J Am Coll Cardiol 2011;58(21):2225-2232. Last accessed 4/1/14 http://content.onlinejacc.org/article.aspx?articleid=1147757. doi:10.1016/j.jacc.2011.05.061
  3. Ibid.
  4. Calkins, H, Berger, R. Atrial Fibrillation: Management Strategies. Scientific American Special Health Reports. Last accessed August 24, 2015. URL: http://tinyurl.com/Calkins-A-Fib-Mgmt-strategies, p. 9.

Preventing A-Fib by a Gal-3 Inhibitor -2014 Boston AF Symposium

Jose Jalife, MD

Jose Jalife, MD

2014 Boston AF Symposium

The Holy Grail: Preventing A-Fib by a GAl-3 Inhibitor

By Steve S. Ryan, PhD

Dr. Jose Jalife from the Center for Arrhythmia Research at the University of Michigan gave a second presentation aptly titled “Searching for the Holy Grail: Upstream Therapy to Prevent AF Progression.” Briefly summarizing his previously described experimental studies of pacing sheep into A-Fib, it took about seven weeks of pacing to push sheep into persistent self-sustaining A-Fib. (See BAFS 2014: Experiments in Atrial Remodeling in Sheep and the Transition From Paroxysmal to Persistent A-Fib.)

Dr. Jalife asked the question “What if I treat my sheep with a drug that prevents fibrosis? Would I be able to effectively prevent, or at least delay the transition to persistent A-Fib?”

How Fibrosis Develops

In the fibrotic sheep a marker of cardiac fibrosis, pro-collagen type III (PIIINP), was found in their serum. Explaining how sheep develop fibrosis, Dr. Jalife described how a normal heart has what are called “Fibroblasts” which make up 50-70% of cells in the heart. They provide the heart’s structural and mechanical support to the myocytes (muscle cell or muscle fiber). But in fibrosis these Fibroblasts turn into “Myofibroblasts” (activated fibroblasts) which:

  • Are unexcitable (do not contract in response to electrical stimuli)
  • Secrete profibrotic cytokines (cell signaling proteins) (e.g., TGF-ß1, PDGF)
  • Express cell adhesion proteins (e.g., n-cadherin)
  • Replace myocytes in the remodeled myocardium

Fibrosis is tissue that has fiber-like characteristics which develop in place of the normal smooth walls of the heart. 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. Fibrosis, up to now, was considered permanent and irreversible.

Dr. Jalife described Galectin-3 (Gal-3), a protein that produces (“mediates”) tissue fibrosis. (It’s also involved in inflammation, immune response, cancer, heart disease and stroke.) For you technical types, “Gal-3 pentamers bind to poly N-acetyl lactosamine (LNac) residues on TGF receptors of myofibroblasts causing cell surface retention and promoting signaling through Smad and AKT pathways and leading to fibrosis.” (For us non-technical types, all we need to know is that Gal-3 promotes fibrosis.)

When sheep are paced into A-Fib, this also produces more galectin-3. Gelactin-3 in turn promotes structural remodeling (TGF-ß1-induced atrial structural remodeling—fibrosis) and electrical remodeling, which leads to persistent A-Fib.

The Holy Grail of A-Fib—Gal-3 Inhibitors

But the Gal-3 inhibitor GM-CT-011 by Galectin Therapeutics prevents Gal-3 from producing fibrosis!!! This means it’s “a potential new upstream therapy for the prevention of persistent AF.”

To test whether the Gal-3 inhibitor worked or not, Dr. Jalife gave some sheep the Gal-3 inhibitor and other sheep saline twice per week. The inhibitor:

  1. Lessened A-Fib-induced atrial dilation
  2. Reduced fibrosis by 50%!!!
  3. Reduced the increase in dominant frequency
  4. Prevented the shortening of action potential duration in both atria
  5. Increased the percentage of sheep spontaneously terminating their persistent A-Fib during treatment

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Dr. Jalife’s General Conclusions:

  1. Persistent A-Fib remodeling in sheep isn’t caused by other heart problems like altered LV function or other heart illnesses. (In his first presentation Dr. Jalife previously demonstrated that sustained A-Fib leads to progressive atrial dilation but doesn’t alter LV function.)
  2. Atrial remodeling results in part “from proliferation of myofibroblasts expressing α-SMA and secreting cytokines like TGF-ß1, as well as Gal-3.”
  3. Sustained A-Fib leads to atrial dilation, increased atrial collagen and fibrosis, which correlates with increased α-SMA, TGF-ß1 and Gal-3.
  4. Remodeling can be measured by the progressive increase in Dominant Frequency during the transition from paroxysmal to persistent A-Fib. This results from “differential changes in the expression and function of Naᶧ, Ca²ᶧ, and Kᶧ channels.”
  5. “Gal-3 inhibition reduces both A-Fib induced structural and electrical remodeling in the sheep model of persistent A-Fib.” Inhibiting Gal-3 by GM-CT-01 is a new, potentially powerful upstream therapy to prevent persistent A-Fib. [And the most important conclusion!]

Dr. Jalife’s last slide captured the importance of his experimental work:

There is hope for A-Fib prevention.

Added 9/15/15: The natural supplement, Pecta-Sol C (Modified Citrus Pectin), binds to Galectin-3 and is a Galectin-3 inhibitor. It may reduce or prevent structural and electrical A-Fib remodeling.3It is known as a natural detoxifier.

Editor’s Comments:
Throughout this web site I warn about the dangers of developing fibrosis (by for example leaving people in A-Fib while only controlling the heart rate). Up to now fibrosis was permanent and irreversible, and caused irreparable damage to one’s heart. There were no proven and approved therapies to reverse fibrosis. But this may no longer be the case. Dr. Jalife showed that Gal-3 inhibitors reverse fibrosis! This is tremendous news for patients and is certainly the most important finding of this year’s Boston A-Fib Symposium.
Dr. Jalife’s work demonstrated that sheep can be prevented from going from Paroxysmal to Persistent A-Fib by using Gal-3 inhibitors. This is also wonderful news for patients. All too often someone develops A-Fib and, within a year, progresses to persistent A-Fib which is harder to cure and produces more fibrosis and remodeling. But Gal-3 inhibitors stop this progression!
Let’s imagine it’s a couple of years from now. Gal-3 has been approved by the FDA (this obviously isn’t a certainty, but it looks promising). You develop paroxysmal A-Fib (as easily determined by the Dominant Frequency of your A-Fib). Your EP gives you a Gal-3 inhibitor which both keeps you from going into persistent A-Fib and reduces the amount of fibrosis in your heart.
Let’s take this a step further. Some of the sheep taking Gal-3 inhibitors went back into sinus rhythm, possibly because their fibrosis was reduced. Can Gal-3 inhibitors “cure” A-Fib? Is a Gal-3 inhibitor the magic pill we’ve been waiting for? If you develop paroxysmal A-Fib, can you simply take a Gal-3 inhibitor and be A-Fib free? This is probably an overly hopeful speculation. But perhaps this could be Dr. Jalife’s next experiment.
Even if GAl-3 inhibitors are successful and approved by the FDA, in all likelihood there will still be a need for catheter ablation (and surgery). A 50% reduction in fibrosis is great, but there’s still that other 50% which may still be permanent. In private comments to the editor, Dr. Jalife thinks fibrosis might be irreversible once it develops.
The Galectin-3 inhibitor GM-CT-01 (and GR-MD-02) by Galectin Therapeutics (Nasdaq: GALT) is moving toward FDA approval. In studies with rats these Gal-3 inhibitors “led to significantly reduced fibrosis, reversal of cirrhosis and a significant reduction in portal hypertension (cirrhosis is basically fibrosis of the liver).” GR-MD-02 is in Phase 1 clinical trial with the first human patients. It received Fast Track designation from the FDA for fatty liver disease with advanced fibrosis.2
If you are an investor, Galectin Therapeutics (Nasdaq: GALT) might be something worth looking into while it’s still relatively cheap.

Added: 9/15/15: Instead of having to wait years for possible FDA approval, you can take a natural supplement, Pecta-Sol C (Modified Citrus Pectin), that works like a Galectin-3 inhibitor to prevent and reduce the development of fibrosis and A-Fib. (Thanks to Mary LaPorte for alerting us to Modified Citrus Pectin.)


Additional reading: Martins, RP et al. Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation. Circulation, published online January 24, 2014. http://www.ncbi.nlm.nih.gov/pubmed/24463369

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Last updated: Tuesday, September 29, 2015 

References    (↵ returns to text)
  1. former brand name Davanat
  2. Brechka, Nicole (2009). “Putting the Squeeze on Cancer”. Better Nutrition. August 2011. http://www.betternutrition.com/citrus-pectin-cancer-fighter/
  3. Traber PG et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. Plus One, 2013 Oct.9;8(10):e75361 http://www.ncbi.nlm.nih.gov/pubmed/24130706;  doi: 10.1371/journal.pone.0075361. eCollection 2013.

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