Highlights
- •Higher circulating PENK-A, an endogenous opioid neuropeptide, was independently associated with ischemic stroke risk in REGARDS
- •PENK-A's association with stroke was non-linear
- •Adjustment for established stroke risk factors did not alter the relationship between PENK-A and stroke
- •PENK-A's association with stroke may be most relevant to White men
Abstract
Objectives
The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular
risk, with prior findings relevant to heart failure, kidney disease, and vascular
dementia. Despite these findings, the association of PENK-A with ischemic stroke is
unknown, so we examined this association in a prospective cohort study and analyzed
differences by race and sex.
Materials and Methods
The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective
cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants
that developed first-time ischemic stroke over 5.9 years and 899 randomly selected
participants. Cox models adjusted for demographics and stroke risk factors were used
to calculate hazard ratios (HRs) of stroke by baseline PENK-A.
Results
PENK-A was higher with increasing age, female sex, White race, lower body mass index,
and antihypertensive medication use. Each SD higher increment of PENK-A was associated
with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding
by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly
in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men.
Conclusions
Higher baseline plasma PENK-A was independently associated with future stroke risk
in REGARDS. This association was most apparent among White men. There was little confounding
by established stroke risk factors, suggesting a possible causal role in stroke etiology.
Further research is needed to understand the role of endogenous opioids in stroke
pathogenesis.
Key Words
Abbreviations:
CI (confidence interval), ECG (electrocardiogram), eGFR (estimated glomerular filtration rate), HR (hazard ratio), IQR (interquartile range), NIHSS (National Institutes of Health Stroke Scale), PENK-A (pro-enkephalin A), SD (standard deviation), REGARDS (REasons for Geographic and Racial Differences in Stroke study), TOAST (Trial of ORG 10172 in Acute Stroke Treatment)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 10, 2021
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106237
Copyright
© 2021 Elsevier Inc. All rights reserved.
