Botulinum Toxin Long-Term Benefit Against Post-CABG AF Intrigues, Baffles

May 18, 2015

BOSTON, MA — Seen a certain way, standard antiarrhythmic agents are poisons. But an actual poison that has changed the face of some other clinical specialties could be more than just a new wrinkle in cardiology's continuing search for a way to suppress an arrhythmia that has mostly resisted drug therapy.

In a small randomized pilot study, the burden of atrial fibrillation (AF) after CABG surgery fell precipitously after intraoperative injections of botulinum toxin into the epicardial fat pads[1].

The injections' impressive effects within the first month have already been published and were in line with expectations[2]. But what happened thereafter out to 1 year was perplexing and potentially game-changing: AF still seemed to be suppressed long after the toxin's effect should have worn off and after it actually had worn off by some other measures.

The 60 patients, 30 who received botulinum toxin injections and 30 who were injected with saline, all wore implantable loop recorders (ILRs) and were further valuated at 3, 6, 9, and 12 months. After 30 days, "We were expecting to demonstrate dissipation of the AF benefits by around 3 to 6 months," said Dr Jonathan S Steinberg (University of Rochester School of Medicine and Dentistry, NY), when presenting the study's long-term results here at the Heart Rhythm Society 2015 Scientific Sessions.

But AF burden by ILR criteria was significantly less in the active-therapy than placebo group at 3, 9, and 12 months and trended less (P=0.06) at 6 months. In fact, Steinberg said, AF burden in the actively treated group was "consistently very low," without any apparent attenuation of the effect out to 1 year.

The epicardial fat pads secrete proinflammatory cytokines and harbor ganglionic plexi that support vagal innervation and are sometimes targeted during surgical AF ablation. Injecting them with botulinum toxin, in this study at least, seemed to have an unexpectedly profound effect on the arrhythmia.

"In the vast majority of patients, at each one of those time points, they did not meet our conventional ILR criteria of 0.5% per month AF burden," according to Steinberg. For perspective, he said, had the patients shown those results after catheter ablation instead, "most would have been considered full responders at each of those time-point comparisons."

Other Effects More Transient, as Expected

Monitoring of heart-rate variability (HRV) told a different story. At 1 month, both the botulinum-toxin group and the placebo group showed significant changes in HRV, as conventionally measured both by high- and low-frequency domains and by the standard deviation of NN intervals (SDNN). Those changes "suggested reduction of both parasympathetic and sympathetic activity," according to Steinberg.

But the HRV effect went away after 1 month in the placebo group and between 3 and 6 months in the active-treatment group, so that by 6 months HRV had returned to baseline on both groups.

In other words, he said, "The favorable reduction of AF burden outlasted the anticipated and observed botulinum-toxin effects on autonomic nervous system activity." But he can only speculate as to why that happened.

Botulinum toxin injections are a neuromodulating ablation, not "neurodestructive" as are other ablation techniques for AF, even those that target the ganglionic plexus, observed Steinberg. By all rights their effects should be predictably reversible. But there is also "an autonomic phenomenon that may fuel progressive [atrial] remodeling, that perhaps we stalled by introduction of botulinum toxin—so that there was stabilization of AF burden over time. That's one possibility."

Or, he proposed, perhaps the toxin's effect on the ganglionic plexus "is more long-lived than we had anticipated, and maybe some of the drug effect, or damage induced by the drug, outlasted what we had anticipated from the pure pharmacologic effect of botulinum toxin."

"Simple Intervention, Huge Implications"

According to Dr John D Day (Intermountain Medical Center, Salt Lake City, UT), "The implications here are huge." Speaking from the panel after Steinberg's presentation, Day pointed out that all the patients had paroxysmal AF before surgery, making them higher risk for the postop arrhythmia. Yet those who received what was "basically Botox [Allergan]" had some early AF the first month but essentially no AF recurrence thereafter. "We've never seen an ablation trial or drug trial that basically has close to a 100% success rate."

It's hard to tell whether the treatment has downsides or how much it might add to the cost of surgery, "but this is a simple intervention," Day told heartwire from Medscape, noting that the injections added only a mean of 11 minutes to surgery time.

Colchicine, beta-blockers, and conventional antiarrhythmics like amiodarone have been tried for prevention of postop AF, Day noted, but their success has been limited or entirely elusive. "Nothing compares to this Botox data he presented."

The 60 patients had been randomized at two centers to receive epicardial fat-pad injection of either botulinum toxin type A (Xeomin, Merz) as 50 U/mL or a placebo of 1 mL of 0.9% normal saline per fat pad, along with CABG. The two groups of 30 didn't differ significantly in number or type of grafts, how many surgeries were performed off-pump, aortic cross-clamp time, duration of intubation, or time in the intensive-care unit.

During the first 30 days, the rate of postop AF was 7% in actively treated patients and 30% in controls (P=0.024). From then out to 12 months, there were no further instances of AF in the botulinum-toxin group but 27% of control patients developed AF recurrences (P=0.002). AF burden by ILR from baseline to 12 months averaged 0.07% and 1.5%, respectively (P <0.001).

Steinberg acknowledged that the AF burden in actively treated patients might have turned out higher had other criteria for AF been used, but by accepted ILR definitions "they did extremely well."

If the 12-month results are borne out in other studies, he said, "it does suggest that there may be a new paradigm that we need to pursue both experimentally and in clinical investigations to understand why [this neuromodulation] intervention has such a profound effect."

It may be, he said, that there is "some potent effect of interfering with autonomic effects that fuel AF that we perhaps have underestimated in the past by virtue of the tools we've used to accomplish it."

Neither Steinberg nor Day had relevant financial relationships. Disclosures for the coauthors are listed in the abstract.

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