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

Jul 30, 2012   |  

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Editor's Note: Based on Doehner W, von Haehling S, Suhr J, et al. Elevated Plasma Levels of Neuropeptide Proenkephalin A Predict Mortality and Functional Outcome in Ischemic Stroke. J Am Coll Cardiol 2012; 60:346-354.

Article Summary

Background: Stroke is one of the leading causes of death in modern society being on third position behind heart disease and cancer in the United States1 and even on first position in some Eastern European countries.2 Early differentiation between transient ischemic attack (TIA) and stroke remains challenging and the diagnosis of TIA remains biased by subjective judgement.3 Moreover, the prognosis may vary, although they share pathophysiological mechanisms and their therapeutic consequences have assimilated.4 Development of novel biomarkers may have a prevalent potential to facilitate the diagnosis of ischemic stroke distinguishing from intracerebral hemorrhage, TIA, and other stroke mimics.5

Recent studies identified stable precursor fragments of the neuropeptides enkephalin (proenkephalin-A , PENK-A) and substance P (protachykinin-A, PTA) as potent markers of BBB integrity.6,7 Both mature neuropeptides are active as neurotransmitters and are involved in nociception and immune stimulation. They have been implicated in the pathophysiology of certain neuropathologies including Parkinson's disease, Alzheimer's disease, and severe head injury.8 Elevated plasma levels of methionine-enkephalin in patients after acute cerebral infarction have been reported.9 The role of enkephalins in stroke is, however, incompletely understood as both, presence and absence of a neuroprotective effect of opioid receptor stimulation have been described.10,11

The aim of the present study was to evaluate PENK-A and PTA in patients presenting with symptoms of acute cerebrovascular disease in relation to stroke severity and to outcome.

We hypothesized that PENK-A and PTA may be associated with a poorer outcome.

Methods: In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients, who were admitted to with symptoms for acute stroke. The median time between symptom onset and hospital admission was 4.5 hours (interquartile range [IQR] 1.3-19.8 hours). Patients with symptom onset >24 hours before initial assessment on hospital admission were not considered as acute stroke patients and were therefore excluded.

All patients underwent cranial computed tomography (CT; Siemens Somatom Sensation16, Erlangen,Germany) within 90 minutes after hospital admission. The scans were performed on a Siemens scanner using 4.5mm slices.

Plasma concentrations were determined by sandwich immunoassay, lower detection limits were 15.6pmol/L (PENK-A) and 22pmol/L (PTA). Intra- and interassay coefficients of variation were <10% and <15% for PTA and <12% and <13% for PENK-A, respectively. The normal range of PENK-A is from 41.8-131pmol/L (median:62.3pmol/L) and for PTA from 30.8-179.2pmol/L (median:98.7pmol/L). Normal ranges are not dependent on age or gender. Clinical outcome was assessed at three months for mortality, major adverse cerebro-/cardiovascular events (MACCE), and functional outcome (modified Rankin Scale;mRS).

Results: PENK-A was significantly elevated in patients with ischemic stroke (n=124;65.6%) compared to patients with transient ischemic attack (TIA) (n=16;8.5%) and to patients with non-ischemic (NI) events (n=49;25.9%) (median[interquartile range;IQR] stroke: 123.8pmol/L[93-160.5];TIA:114.5pmol/L[85.3-138.8];NI:102.8pmol/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 (mRS score 3-6 vs.0-2:135.1pmol/L[IQR;99.2-174.1] vs.108.9pmol/L[IQR;88.6-139.5];p=0.014). After adjusting for age, NIHSS and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio for log-10 PENK-A in pmol/L[HR]:4.52;95%confidence interval[CI]:1.1-19.0;p<0.05) and MACCE (HR:6.65;95%CI:1.8-24.9;p<0.05). Patients in the highest quartile of PENK-A (cutoff>153pmol/L) had an increased risk of mortality (HR:2.40;95%CI:1.02-5.40;p<0.05) and of MACCE (HR:2.23;95%CI:1.10-4.54;p<0.05).

The added value for higher PENK-A and PTA values as compared to the clinical model with three risk categories provided for all-cause death a net reclassification improvement (NRI)=20.2% (PENK-A;p=0.026) and an NRI=6.0% (PTA;p=0.439), and for composite endpoint an NRI=29.2% (PENK-A;p=0.006) and an NRI=22.5% (PTA;p=0.002)

Conclusion: PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of the cerebral injury, and may have prognostic value for fatal and nonfatal events.

Commentary/Perspective: PENK-A and other disruption markers of the BBB may be promising targets for biomarker analysis in stroke. Future studies with larger collectives should substantiate PENK- A as a disease marker in ischemic stroke.

References

  1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics–2011 Update: A Report From the American Heart Association. Circulation 2011;123:e18-e209.
  2. Bejot Y, Benatru I, Rouaud O, et al. Epidemiology of stroke in Europe: geographic and environmental differences. J Neurol Sci 2007;262:85-8.
  3. Castle J, Mlynash M, Lee K, et al. Agreement regarding diagnosis of transient ischemic attack fairly low among stroke-trained neurologists. Stroke 2010; 41:1367-70.
  4. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Circulation 2006;113: e409-49.
  5. Saenger AK, Christenson RH. Stroke biomarkers: progress and challenges for diagnosis, prognosis, differentiation, and treatment. Clin Chem 2010; 56:21-33.
  6. Ernst A, Kohrle J, Bergmann A. Proenkephalin A 119–159, a stable proenkephalin A Precursor fragment identified in human circulation. Peptides 2006; 27:1835-1840.
  7. Ernst A, Suhr J, Kohrle J, Bergmann A. Detection of stable N-terminal protachykinin A immunoreactivity in human plasma and cerebrospinal fluid. Peptides 2008; 29:1201–1206.
  8. Ernst A, Buerger K, Hartmann O, et al. Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation. J Neuroimmunol 2010; 221:62-7.
  9. Kobari M, Ishihara N, Yunoki K. Increase of plasma methionine-enkephalin levels in patients at the acute stage of cerebral infarction. Neurol Res 1988; 10:120-2.
  10. Yang L, Wang H, Shah K, Karamyan VT, Abbruscato TJ. Opioid receptor agonists reduce brain edema in stroke. Brain Res 2011; 1383:307-16.
  11. Iwata M, Inoue S, Kawaguchi M, et al. Delta opioid receptors stimulation with [D-Ala2, D-Leu5] enkephalin does not provide neuroprotection in the hippocampus in rats subjected to forebrain ischemia. Neurosci Lett 2007; 414:242-6.

Keywords: Alzheimer Disease, Biomarkers, Cerebral Hemorrhage, Heart Diseases, Stroke, Neuroprotective Agents, Neurotransmitter Agents


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