Neuropeptide Y (NPY), a sympathetic cotransmitter, might provide a clue to which patients with atrial fibrillation (AF) will respond to vagal nerve stimulation to decrease AF burden, a new study suggests.
The investigators drew on data from a previous trial of neuromodulation, TREAT-AF, consisting of low-level stimulation of the tragus nerve (LLTS) — the auricular branch of the vagus nerve — which showed that the intervention reduced AF burden, compared with sham stimulation.
The current study compared levels of NPY in patients who did and did not respond to this modality.
“One of the important findings of our study was that patients with AF who have higher baseline levels of neuropeptide Y demonstrated greater responses to LLTS, compared to those with lower levels,” lead author Stavros Stavrakis, MD, associate professor, University of Oklahoma College of Medicine, Oklahoma City, told theheart.org | Medscape Cardiology.
“Our findings implicate NPY signaling and left atrial NPY receptor expression in AF progression and response to neuromodulation,” he said.
The results were published online in a research letter in the November 6 issue of JACC Clinical Electrophysiology.
LLTS is a noninvasive strategy that uses a unit similar to transcutaneous electrical nerve stimulation (TENS) to stimulate the tragus nerve, Stavrakis explained.
This intervention “has shown promising results in mitigating sympathetic signaling, since the autonomic nervous system influences AF burden,” he said. However, it is unclear which patients with AF might respond to this modality, and the mechanisms underling the efficacy of LLTS are “not well understood.”
In particular, it is “undetermined” whether biomarkers of sympathetic activity can guide patient selection for LLTS.
NPY is a biomarker of sympathetic hyperactivity after myocardial infarction (MI) and heart failure (HF) and might also be a biomarker of AF progression and LLTS response, Stavrakis said.
The researchers drew on data from their original randomized trial, called Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation (TREAT-AF), which compared stimulation of the tragus nerve, located in the outer protuberance of the ear, with stimulation of the earlobe, which contains no vagal nerves, and served as a “sham” control (n = 26 and n = 27 patients, respectively).
Participants had paroxysmal AF with a mean duration of 2 years, but structurally normal hearts (mean left ventricular ejection fraction [EF], 60% ± 5.4%). AF burden was assessed using 2-week noninvasive cardiac monitors, and NPY levels were measured using immunosorbent assay, they write.
The mean NPY level was “expectedly” lower than in patients with chronic HF, the authors note, with a baseline level that was positively correlated with age, body mass index (BMI), and heart rate.
The intervention was delivered daily for 1 hour over a 6-month period, with participants evaluated at baseline and at 3 and 6 months after randomization.
During the follow-up period, the participants who received LLTS had 14.4 fewer beats/min, (95% CI, 2.9 – 25.9) than those in the sham group (P = .014), as well as fewer episodes of ventricular response during AF (odds ratio [OR], 0.36; 95% CI, 0.18 – 0.72; P = .004).
These findings demonstrated “the efficacy of LLTS in this cohort,” the authors note.
In addition, NPY levels changed differently over time in the two groups (P = .018). In particular, the levels significantly increased at 6 months, compared with baseline (63.2 ± 5.9 vs 42.7 ± 4.7 pg/mL; P = .01) in the earlobe group.
By contrast, in the LLTS group, the 6-month NPY levels were comparable to baseline (37.1 ± 4.8 vs 39.3 ± 4.6 pg/ mL, respectively; P = .64) and significantly lower than in the earlobe group (37.1 ± 4.8 vs 63.2 ± 5.9 pg/mL, respectively; P = .008).
“Notably, in the LLTS group, NPY level was negatively correlated with change in AF burden during follow-up (r = −0.48; P = .036), indicating that higher baseline NPY level was associated with greater responses to LLTS,” the authors write.
Further Light on NPY
The researchers further sought to determine whether NPY receptor (NPYR) expression was associated with AF progression. To do so, they examined NPYR RNA abundance from left atrial tissue samples obtained from patients during open-heart surgery.
Using RNA sequencing, they studied NPY1R, NPY2R, NPY4R, and NPY5R messenger RNA in patients with paroxysmal, persistent, or long-standing AF and found that NPYR counts (except for NPY2R) were significantly greater in patients with persistent or long-standing persistent AF than in those with paroxysmal AF.
This might point to “an association between AF expression and left atrial NPYR expression,” they suggest.
“We present the first evidence of a significant association among AF progression, left atrial NPYR expression, and circulating NPY level in response to neuromodulation,” the authors summarize.
“Circulating NPY levels increased over time in patients treated with earlobe stimulation, while no change was observed with tragus stimulation,” they conclude. The findings — further corroborated by increased left atrial expression of NPYR — “implicate NPY-NPYR signaling in AF progression and response to neuromodulation.”
Commenting on the study for theheart.org | Medscape Cardiology, James Douketis, staff physician in General Internal Medicine and Clinical Thromboembolism, St. Joseph’s Healthcare, Hamilton, Ontario, Canada, called the study concept “very interesting and, I think, relatively novel.”
Nevertheless, the study is small and, at best, “hypothesis-generating,” said Douketis, who holds the David Braley-Nancy Gordon Chair in Thromboembolic Disease at McMaster University and was not involved with the study.
“I wonder whether it may be relevant for patients who develop new-onset AF that is paroxysmal after surgery, as opposed to people who have chronic or persistent AF, as a way to help distinguish the two, which would be clinically helpful,” Douketis mused.
“It may make a difference in helping to determine if you need to anticoagulate these patients if they have evidence of neuropeptide Y, and the level may be a marker of AF progression,” he suggested, adding the finding remains “very preliminary” and not yet ready for clinical application.
Stavrakis agreed. “The next step is continuing to try to find biomarkers of response to optimize autonomic modulation therapy, but at this point, it is still investigational.”
The study was funded by grants from the National Institutes of Health (NIH)/National Institute of General Medical Sciences, the National Institutes of Health/National Institute of Aging, the National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI), and the American Heart Association. Stavrakis and coauthors and Douketis report no relevant financial relationships.
J Am Coll Cardiol Clin Electrophysiol. Published online November 6, 2020. Letter