“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”
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?
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 “http://europace.oxfordjournals.org/content/early/2013/02/28/europace.eut038.full.pdf” )
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 A-Fib.com. 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 “http://europace.oxfordjournals.org/content/early/2013/02/28/europace.eut038.full.pdf” )
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Last updated: Friday, August 28, 2015
Renal Sympathetic Denervation (RSDN) for A-Fib?
Report by Steve S. Ryan, PhD Dr. Vivek Reddy of Mount Sinai School of Medicine, NY gave a presentation entitled “Renal Denervation for AF—Physiology, Mechanisms of Action and Rational in AF.”
RSDN Found Ineffective, Symplicity HTN-3 Trial
Background: (Before reading this report, it is recommended to first look at the our 2014 BAFS satellite presentation “Renal Denervation and Pulmonary Vein Isolation for PAF.)
Earlier in the Symposium, the results of the Medtronic Symplicity HTN-3 trial were announced and discussed. Medtronic’s renal denervation system was found to be basically no better than a sham procedure for reducing systolic blood pressure through six months.
Dr. Reddy described how previous surgical interventions (Thoracolumbar Surgical Sympathectomy—destroying some of the sympathetic nerve trunk) did reduce blood pressure by affecting the Sympathetic Nerves (Smithwick et al. JAMA 1953;152(16);1501-4). And the clinical trial Symplicity HTN-2 did work—84% of patients had a 10 mmHg or greater decrease in Systolic Blood Pressure (Esler et al. Lancet 2010;376(9756): 1903-9)
Then why was Symplicity HTN-3 a negative study? Was the catheter not properly employed? (Dr. Reddy described a new method of performing RSDN by using External Ultrasound Energy which has a minimal effect on the arterial wall.) Is refractory hypertension not primarily “sympathetically-driven?”
Does RSDN do anything?—Mechanistic Data
• In a small study of patients with refractory high blood pressure (HBN) that couldn’t be lowered by drugs and other methods, RSDN did significantly lower high blood pressure (Brandt et al. JACC 59:901 ).
• In another study RSDN lowered blood pressure and Muscle Sympathetic Nerve Activity (MSNA) (Achlaich et al. NEJM 36:932-934 )
• In another study RSDN lowered renal hormones like Aldosterone, Metanephrine and Normetanephrine (Ahmed H/Neuzil P/Reddy VY: JACC-CV Interv 5:758-65 )
• RSDN improved heart rate variability (F. Himmel et al. J.Clin.HTN 14:654 }
Supporting Evidence for RSDN Helping A-Fib
• Experimental studies of sheep show that high blood pressure (hypertension) produces fibrosis (interstitial collagen) and remodeling of the atria. (Heart Rhythm 2010;7:1282-1290)
• In the ARIC study of nearly 15,000 people followed for 17 years, high blood pressure accounted for 20%-25% of all A-Fib cases (other factors were Obesity, Diabetes, Smoking and Prior Cardiac Disease). (Huxley et al Circulation 123:1501-1508 )
• Hypertension was the most significant predictor of recurrence after A-Fib ablation (Takigawa et al. JRAS, DOI: 10.1177/1470320312446212 )
• Sympathetic Nervous System overactivity predicted A-Fib recurrence (Arimoto et al. JCE )
• In Dr. Pokushalov’s work described under 2014 BAFS Satellite Presentations-Siberia, PVI with RSDN had much less recurrence than just a PVI (Pokushalov et al. JACC )
But What About A-Fib Patients without High Blood Pressure—Would RSDN Help Them?
• In a small experimental study using dogs, RSDN kept the dogs from going into A-Fib and reduced renal hormones (Q.Zhao et al. JICE [2012; DOI 10.1007/s10840-012-9717-y).
• In another dog study, RSDN ameliorated pacing-induced changes in hormones and tissue structure (X.Wang et al. PloS ONE 8(5): e64611 )
• In a study of Obstructive Sleep Apnea in pigs, RSDN helped blood pressure and reduced A-Fib when the pigs had induced sleep apnea.(Linz et al. Hypertension 62:767 )
Renal Sympathetic Denervation as Upstream Therapy in A-Fib?
Dr. Reddy described a multi-center randomized study of A-Fib and Hypertension. Patients with A-Fib and hypertension will have a catheter ablation procedure (PVI). Then some will be in the placebo group and others will have a RSDN procedure. Follow-up will measure A-Fib recurrence. (H Ahmed/MA Miller/VY Reddy, JCE 25:503-9 ). The rational for this study is that Renal Denervation can dramatically affect sympathetic tone, is technically simple to do, and has minimal safety issues. In an earlier study, Renal Denervation significantly reduced blood pressure after three months (Ahmed H / Neuzil P / Reddy VY: JACC-CV Interv 5:758-65 )
Dr. Reddy’s Final Thoughts
• RSDN is a novel approach to modulate the sympathetic nervous system (one of several)
• Many animal studies demonstrate the electrophysiological effects of RSDN
• Potential Role for RSDN in A-Fib—Reduce A-Fib recurrence
In spite of the preliminary results of Symplicity HTN-3, Renal Denervation is not dead in the water. The full results of Symplicity HTN-3 haven’t been released and examined yet. And the new multi-center randomized study Dr. Reddy described may yet prove the effectiveness of RSDN.
Renal Denervation, in addition to helping people with high blood pressure and A-Fib, may benefit anybody with A-Fib. Because Renal Denervation is easy to do and relatively safe, RSDN may become another treatment option for A-Fib.
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Last updated: Wednesday, September 2, 2015