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Upstream Therapy

“Upstream Therapy” Concept: Alternative Therapies for A-Fib? 2014 Boston AF Symposium

Boston AF Symposium 2014

Dr Eric Prystowsky

Dr Eric Prystowsky

“Upstream Therapy” Concept: Alternative Therapies for A-Fib?

Report by Steve S. Ryan, PhD

Dr. Eric Prystowsky of The Care Group in Indianapolis, IN introduced the thought-provoking concept of “Upstream Therapy” in his presentation Alternative Therapies for Atrial Fibrillation.

Up to now, most A-Fib research has been focused on meds or devices to stop or control A-Fib. But can we find ways to stop A-Fib from developing in the first place? Dr. Eric Prystowsky lectured on the concept of “Upstream Therapies”

Dr. Eric Prystowsky Slide 1

Dr. Eric Prystowsky Slide 1: Concept of “upstream” therapies.

What is Upstream Therapy?

An example of an Upstream Therapy is the Galectin-3 inhibitor which prevents fibrosis from developing in the heart thereby also preventing A-Fib from developing or progressing. (See Dr. Jalife’s 2014 presentation: The Holy Grail: Preventing A-Fib by a GAl-3 Inhibitor)

We know, for example, that High Blood Pressure (HBP) often triggers or causes A-Fib, probably because of the pressure and strain HPB puts on the Pulmonary Vein openings in the Left Atrium.

Can therapies like Angiotensin Receptor Blockers, Ace Inhibitors or Hypertensive Therapy (Upstream Therapies) lower HPB and keep someone from developing A-Fib?

Dr. Eric Prystowsky slide 2

Dr. Eric Prystowsky Slide 2: Can “upstream” therapies like Angiotensin Receptor Blockers and Ace Inhibitors help patients “steer clear” of A-Fib?

six Potential Upstream Therapies

Dr. Prystowsky discussed six potential Upstream Therapies which might show promise in A-Fib.

1.  ACE-I/ARBs. ACE Inhibitors and Angiotensin Receptor Blockers may potentially prevent A-Fib by:

• Limiting Substrate Modification such as dilation, fibrosis and conduction velocity slowing

• Improve Hemodynamic Function by lowering atrial and blood pressure and reducing heart failure

• Reducing Initiators of A-Fib by decreasing stretch-activated ion channels Dr. Prystowsky showed how in one study the angiotensin II receptor blocker Irbesartan lowered A-Fib recurrence. But other studies (ACTIVE I) were not so conclusive.

2.  Statins. In one study Atorvastatin significantly lowered the rate of recurrence of A-Fib. But other studies didn’t show statins having much effect on A-Fib.

3.  PUFAs (Polyunsaturated Fatty Acids). He discussed two studies in which PUFAs weren’t very effective.

4.  Acupuncture. In one study persistent A-Fib patients after Electrical Cardioversion were randomized to acupuncture or sham acupuncture for 10 sessions of 15/20 minutes weekly starting 48 hours after the cardioversion. Acupuncture was effective, but the sham acupuncture wasn’t (no placebo effect). This indicates the acupuncturist must be very knowledgeable, experienced and hit the right spots for acupuncture to be effective.

5.  Renal Denervation. In a small study PVI combined with Renal Ablation resulted in less recurrence than just a PVI. (See also: the disappointing news about Renal Denervation in the satellite case Renal Denervation and Pulmonary Vein Isolation for PAF from Siberia, Russia in which it was announced that the Medtronic Symplicity HTN-3 trial didn’t reduce blood pressure)

6.  Tarantula Peptide Inhibits A-Fib.

Alternative Therapies for Atrial Fibrillation

Dr. Prystowsky offers scientists and researchers the thought-provoking concept of “Upstream Therapy”. Divert the contributing factors that contribute to Atrial Fibrillation. What a worthy goal.  Stop A-Fib from developing in the first place!  (See also, Dr. Jalife’s presentation at this year’s Symposium “ )

Editor’s Comments:
In addition to upstream therapies which reduce high blood pressure, we might also consider therapies that:
reduce or cure sleep apnea which is a trigger or cause of A-Fib
reduce or cure diabetes, another trigger or cause of A-Fib
• keep people from excessive alcohol consumption “holiday heart” which triggers A-Fib.
In a limited study acupuncture was effective to some extent, but right now we don’t have enough data to say acupuncture can make people A-Fib free like a successful catheter ablation. More scientific studies need to be made of acupuncture. And effective acupuncturists need to be identified and listed in a directory similar to the listings of EPs (and surgeons) in Acupuncturists need to go through a certification process to verify they can effectively treat A-Fib patients.
For A-Fib patients today, statins, polyunsaturated fatty acids, and Renal Denervation aren’t very effective.
The most promising, exciting upstream therapy for A-Fib is the Galectin-3 inhibitor which prevents fibrosis from developing in the heart and reduces fibrosis already in the heart (See Dr. Jalife’s presentation at this year’s Symposium” )

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Last updated: Tuesday, April 18, 2017 

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:

Preventing and Reversing Fibrosis!

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.

Gal-3 Inhibitors May Stop A-Fib Progression and Reduce Fibrosis

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.

Can Gal-3 Inhibitors “Cure” A-Fib? Galectin Therapeutics

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.

Modified Citrus Pectin

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.

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Last updated: Saturday, April 8, 2017 

Footnote Citations    (↵ returns to text)

  1. former brand name Davanat
  2. Brechka, Nicole (2009). “Putting the Squeeze on Cancer”. Better Nutrition. August 2011.
  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;  doi: 10.1371/journal.pone.0075361. eCollection 2013.

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