Elevated Plasma Levels of Neuropeptide Proenkephalin A Predict Mortality and Functional Outcome in Ischemic Stroke

Study Questions:

What is the prognostic significance of neuropeptides in patients presenting with symptoms of acute cerebrovascular disease?

Methods:

In a prospective observational study, the investigators measured plasma proenkephalin A (PENK-A) and protachykinin A (PTA) concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/L (PENK-A) and 22 pmol/L (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale).

Results:

PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%), and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/L (93-160.5); transient ischemic attack 114.5 pmol/L (85.3-138.8); and nonischemic event 102.8 pmol/L (76.4-137.6; both groups vs. stroke p = 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke, as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]), and to advanced functional disability (modified Rankin Scale score 3-6 vs. 0-2: 135.1 pmol/L [99.2-174.1] vs. 108.9 pmol/L [88.6-139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/L, 4.52; 95% confidence interval [CI], 1.1-19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR, 6.65; 95% CI, 1.8-24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/L) had an increased risk of mortality (HR, 2.40; 95% CI, 1.02-5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR, 2.23; 95% CI, 1.10-4.54; p < 0.05).

Conclusions:

The authors concluded that PENK-A is a prognostic biomarker in the acute phase of ischemic stroke.

Perspective:

The present study reports that plasma concentrations of PENK-A are elevated in acute stroke patients compared to patients with TIA and with nonischemic events. The elevation of PENK-A correlated with stroke severity, as assessed by NIHSS score, and with computed tomography brain lesion size. Further, elevated PENK-A concentrations predicted 3-month outcome for all-cause mortality and for the composite endpoint of death, stroke reoccurrence, and myocardial infarction. Overall, the data suggest that PENK-A and other disruption markers of the blood-brain barrier may be promising targets for biomarker analysis in stroke. Given the small sample size, possibility of overfitting, and multicollinearity in this analysis, the results need to be confirmed in larger and independent studies.

Clinical Topics: Noninvasive Imaging, Vascular Medicine, Computed Tomography, Nuclear Imaging

Keywords: Neuropeptides, Stroke, Myocardial Infarction, Ischemic Attack, Transient, Tomography, X-Ray Computed, Tachykinins, Blood-Brain Barrier, Enkephalins, Prognosis, Immunoassay, Cerebrovascular Disorders, Biological Markers, Confidence Intervals, United States


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