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Randomized Controlled Trial
. 2025 May 20;14(10):e040787.
doi: 10.1161/JAHA.124.040787. Epub 2025 May 13.

Effect of Remote Ischemic Conditioning and Red Blood Cells Biomarkers on Outcomes in Patients With Acute Stroke

Rolf Ankerlund Blauenfeldt  1   2 , Jennifer L Waller  3 , Kim Ryun Drasbek  4 , Jesper Nørgaard Bech  2   5 , Anne-Mette Hvas  6 , Julie Brogaard Larsen  2   6 , Morten Nørgaard Andersen  2   7 , Marlene Christina Nielsen  6 , Maria Kjølhede  1 , Mathilde Kjeldsen  5 , Martin F Gude  2   8 , Mohammad Badruzzaman Khan  9 , Babak Baban  9 , Grethe Andersen  1   2 , David C Hess  9
Affiliations
Randomized Controlled Trial

Effect of Remote Ischemic Conditioning and Red Blood Cells Biomarkers on Outcomes in Patients With Acute Stroke

Rolf Ankerlund Blauenfeldt et al. J Am Heart Assoc. .

Abstract

Background: Remote ischemic conditioning (RIC) is a simple and low-cost intervention that is thought to increase collateral blood flow through the vasodilatory effects of nitric oxide (NO) produced by the endothelium and red blood cells (RBCs). The aim of this study was to investigate whether RBC form and function are associated with short- and long-term outcomes in patients with acute ischemic stroke, and whether RIC treatment modified this effect.

Methods and results: This is a predefined substudy to the RESIST (Remote Ischemic Conditioning in Patients with Acute Stroke Trial) randomized clinical trial conducted in Denmark. RIC was started in the ambulance and continued at the hospital for 7 days. RBC deformability and erythrocyte aggregation rate were assessed using ektacytometry, NO using flowcytometry, and nitrite content using ozone chemiluminescence. Logistic regression and mixed effect models were used. Out of 1500 prehospital randomized patients, and between July 28, 2020 and November 11, 2023, 486 patients had blood samples taken. Of these 249 (51%) had acute ischemic stroke and were included in this study. In the acute phase, higher levels of RBC deformability, aggregation, and RBC NO content were associated with worse clinical outcome if patients were treated with RIC compared with sham. Similar results were found at 24 hours, except for a potential effect on early neurological improvement in RIC-treated patients with an increased deformability level at 24 hours.

Conclusions: RIC may have time-dependent and biomarker-specific effects on stroke outcomes, and detrimental interactions between increasing biomarker levels and RIC were observed. This may explain previous failures to translate RIC into an effective neuroprotective therapy in the hyperacute phase.

Keywords: deformability; ischemic stroke; nitric oxide; nitrite; outcome; red blood cell; remote ischemic conditioning.

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Conflict of interest statement

Dr Blauenfeldt reports lecture fees from Bayer, Pfizer, and Novo Nordisk outside the submitted work. Dr Hess reports receiving grants from the National Institutes of Health biomarker substudy of the parent clinical trial during the conduct of the study; personal fees from Athersys Inc's scientific advisory board outside the submitted work; holding a patent for multipotent stem cells in neurological disease issued to the Medical College of Georgia–Augusta University by Athersys Inc.

Dr Larsen reports lecture fees from Bristol‐Myers Squibb (paid to her institution), lecture fees from Merck (paid to her institution), and travel support from Bayer outside the submitted work. The other authors have no disclosures.

Figures

Figure 1
Figure 1. Mixed model regression lines by time points and the association with early neurological improvement on NIHSS.
A, EI max, (B) aggregation pressure, (C) aggregation time, (D) NO in RBCs, (E) nitrite concentration. EI indicates elongation index; mPa, millipascal; NIHSS, National Institutes of Health Stroke Scale; NO, nitric oxide; and RBCs, red blood cells.
See this image and copyright information in PMC

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