Botox reduces AF burden for up to a year after cardiac surgery


Botulinum toxin injected into epicardial fat pads during coronary artery bypass graft (CABG) surgery reduced the incidence of postoperative atrial fibrillation (AF) compared with placebo, with substantial suppression persisting after one year, a pilot study has found.

Jonathan Steinberg (The Valley Health System, New York, USA) presented the findings at a late-breaking clinical trials session of the Heart Rhythm Society (HRS) 36th Annual Scientific Sessions (13–16 May, Boston, USA).

Steinberg said the objectives of the analysis were: “To determine the effects of botulinum toxin on AF burden over an extended follow-up, and to assess the autonomic effects of botulinum toxin by serial measurements of heart rate variability.” The results of a primary analysis of up to 30 days postoperatively were presented last year at the Heart Rhythm Society Scientific Sessions and subsequently published in the Journal of the American College of Cardiology.

AF is a common complication after cardiac surgery and occurs in approximately 30–40% of patients. The autonomic nervous system plays an important role in the initiation and maintenance of AF and, as botulinum toxin interferes with neurotransmitter release, the researchers tested the hypothesis that it could prevent the development of atrial tachyarrythmias postoperatively in patients undergoing CABG surgery. The study design was a prospective randomised double blind parallel group two-centre trial.

Steinberg told delegates: “Patients were enrolled in the study if they had preoperative history of paroxysmal AF and if they had conventional criteria to undergo CABG surgery. They were excluded if they had prior ablation of any type or were seriously ill with other conditions. All the patients underwent conventional CABG procedures. When that portion of the procedure was completed the surgeon was instructed to inject either botulinum toxin or normal saline into each of the four major epicardial fat pads visible to the surgeon. An implantable loop recorder (ILR) was then implanted on the day of the surgical procedure in all patients [to capture subsequent AF events]. The data were collected throughout 30 days and then again at three, six, nine and 12 months. Heart rate variability was evaluated by time and frequency domain techniques, before surgery and after CABG, at three, six, nine and 12 months.”

The two randomised groups were very similar in clinical characteristics, and there were no statistical differences in relevant medical background or in any of the surgical data.

Between the primary analysis at 30 days and the 12-month follow-up examination, seven of the 30 patients (27%) in the placebo group had recurrent AF, compared with none of the patients in the botulinum group (p=0.002). In the placebo group, six of the 30 patients (20%) developed clinically frequent AF during the year following the procedure, and required additional drug therapy, and two patients (7%) required catheter ablation for persistent AF. None of the patients in the botulinum toxin group required additional drug treatment or catheter ablation and none evolved to persistent AF. In addition, there were no strokes or other serious clinical events observed in either group during the one-year follow-up.

The results of the primary analysis, presented last year, found that the incidence of early postoperative AF within 30 days after CABG was 7% in the botulinum toxin group, and 30% in the placebo group (p=0.024).

Steinberg said: “The potential implications of these findings are that botulinum toxin can be viewed as a neuromodulator, and thus differs from the neurodestructive effects of other forms of ablation. The favourable reduction of AF burden outlasted the anticipated and observed botulinum toxin effects on autonomic nervous system activity, perhaps by reverse atrial remodelling or discordance between effects on sinus node function in AF vulnerability.”

But he cautioned: “The study findings should be interpreted in light of its limitations – specifically, a small number of enrolled patients, and the denervation effect was not confirmed by objective testing during surgery or after.” In addition, he pointed out, the study did not confirm the precise mechanisms of functional atrial remodelling or whether it actually occurred. And, the AF burden of each patient before the procedure was not available.

Lead author Evgeny Pokushalov (State Research Institute of Circulation Pathology, Novosibirisk, Russian Federation) predicted that botox injections may become an alternative to the use of radiofrequency ablation in CABG. He said: “Atrial fibrillation begets atrial fibrillation. Injecting botulinum toxin just ruins this vicious cycle and the patient has enough time for reverse remodelling.”

John D Day (Intermountain Medical Centre, Salt Lake City, USA), chair of the session presenting the findings, described the results as “huge”. He said: “This study could have dramatic implications in cardiac surgery. This is not just for CABG – this could be valve surgeries, this could be anything. We have focussed on something that helps [pulmonary vein isolation] but maybe the ultimate Holy Grail is neuromodulation.”

Pokushalov pointed out that the procedure has important safety characteristics, because fat pads have an essential function. “This result clearly demonstrates this therapy is safe because we did not see any differences between the placebo group and the group after botulinum toxin injection. [Fat pads are] not a useless structure, that is why our injection is just a temporary block. This is a big feature of that.”

He continues, “This therapy can prevent atrial fibrillation recurrences not only in the early period after the operation but during 12 months also. Frankly speaking we were very surprised. We know from plastic surgery that botulinum toxin works for not such a long time, just maybe three to six months, not more.”

Steinberg agreed: “It was surprising. We were expecting to demonstrate dissipation of the AF benefits by around three to six months.”

He speculated on possible reasons for the findings: “These patients have fixed structural remodelled effects but there is also an element of an electrical phenomenon, or an autonomic phenomenon, that may fuel progressive remodelling that perhaps we stall by introduction of botulinum toxin so that there can be a stabilisation of AF burden over time. The other possibility is maybe some of the drug effect outlasts what we had anticipated from the pure pharmacologic effect of botulinum toxin.”

Day suggested: “Maybe these nerve bodies in these fat pads are far more important than we think they are, and injecting botox, maybe it has some sort of a permanent change to these ganglionic plexi, or these nerves within the fat pad – or at least at one year. There is something that we do not understand about the brain-heart connection that might be very important – we are just starting to understand that there is something there and there is a whole neuromodulation field. 

In conclusion Steinberg said: “A further large-scale study will be required to confirm these findings and to assess the potential value of botulinum toxin and neuromodulation on post-operative AF and in other clinical settings. Is it these particular patients or can we extend the findings and observations to other similar patients? And it does suggest a different avenue for interventionists, that does not involve the traditional ablation modes. There may be 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 have used to accomplish that.”