Kim Ryun Drasbek

Ischemic heart disease remains a major global health burden, with ischemia-reperfusion injury representing a critical determinant of myocardial damage. Remote ischemic conditioning (RIC) and differentiated physical exercise regimens have emerged as potential preconditioning strategies enhancing myocardial resilience, and increasing evidence suggests that these cardioprotective effects may, in part, be mediated by targeted delivery of extracellular vesicle (EV)-carried microRNAs (miRNAs). RIC induces rapid alterations in circulating EV cargo, including miRNAs known to promote cell survival, attenuate oxidative stress, and modulate inflammation. This transient yet pronounced miRNA response to RIC indicates a rapid EV-associated molecular change that may be relevant to early signaling events underlying remote organ preconditioning. EV-miRNA content also changes acutely in response to exercise. These changes are associated with vascular remodeling, anti-apoptotic signaling, and metabolic adaptations, suggesting that exercise-induced EVs provide both immediate and sustained cardioprotection, although temporal dynamics remain incompletely defined. Consequently, RIC and exercise elicit distinct yet overlapping EV-miRNA signatures that may affect myocardial preconditioning. Here, we review whether EV-delivered miRNAs elicited by RIC and exercise may contribute to cardioprotection and may be therapeutically exploited in clinical settings such as heart failure and ischemic disease.

Objective: Acute ischemic stroke (AIS) is one of the leading causes of death and disabilities, and as such, it is of utmost importance to identify novel treatment options. Remote ischemic conditioning (RIC) is a promising non‐invasive treatment that is thought to activate the body's own protective mechanisms against damaging ischemia. Here, we study the transcriptomic impact of microRNAs (miRNAs) that are upregulated by RIC. Methods: Using RNA sequencing, we investigated the transcriptional changes in human brain microvascular endothelial cells (HBMECs) transfected with four selected RIC‐upregulated miRNAs (RIC‐miRNAs), miR‐16‐5p, miR‐144‐3p, miR‐182‐5p, and miR‐451a, under oxygen and glucose deprivation (OGD) and reoxygenation—mimicking the initial stages of AIS. Results: Pronounced transcriptional changes were present after RIC‐miRNA transfection, with 149 unique downregulated and 212 upregulated differentially expressed genes in HBMECs after OGD and RIC‐miRNA transfection compared to all other conditions. These genes were involved in pathways of energy metabolism and cell cycle regulation. Conclusion: Our study suggests that the selected RIC‐miRNAs regulate pathways that may facilitate endothelial cell survival, recovery, and remodeling events from ischemic damage, adding to the knowledge of the pathways affected by RIC during stroke.

BACKGROUND: Reperfusion therapies for ischemic stroke are a cornerstone of acute treatment, though only available for a subset of patients due to a narrow time window. Other supplementary treatment is warranted, as only half of the patients reach functional independence. GLP-1 RA (glucagon-like peptide-1 receptor agonists) are associated with decreased cardiovascular disease, mainly driven by reduced stroke risk, and have gained interest as therapeutic agents for stroke recovery in experimental stroke models. This review aims to evaluate the current data on the effect and safety of GLP-1 RA in nondiabetic patients with ischemic stroke and in animal models of cerebral ischemia. We will describe its potential neuroprotective mechanisms. METHODS: On June 20, 2024, keyword-based literature searches were conducted in PubMed and Embase and repeated on March 6, 2025. Records evaluating GLP-1-based therapies in animals and patients with ischemic stroke who did not have diabetes were included. RESULTS: In total, 35 studies, 31 preclinical and 4 clinical, applying 9 different GLP-1 therapies were reviewed. GLP-1 RA improved functional outcome and induced a marked infarct volume reduction compared with vehicle (placebo) in preclinical animal stroke models. The proposed mechanisms include reduced oxidative stress, hypoxia-triggered cell death, and inflammatory response following acute ischemic stroke. Despite these neuroprotective effects observed in stroke models, evidence for improved clinical outcomes in humans remains limited. Recent randomized trials have not shown a significant effect on stroke incidence or neurological recovery in patients without diabetes who are treated with GLP-1 RA. GLP-1 RA appears safe and well-tolerated in both acute and chronic settings. CONCLUSIONS: GLP-1 RA improves functional outcome and reduces infarct volume in preclinical animal stroke models without diabetes. Translating these promising preclinical findings into clinical benefits remains a key challenge and a critical opportunity for future research.

Remote ischemic conditioning (RIC) has demonstrated neuroprotective effects, yet translating these effects into clinical efficacy has proven challenging. T

During the last decade, non‐invasive methods such as liquid biopsy have increasingly replaced invasive techniques for diagnosing and monitoring diseases. Liquid biopsies are easier to obtain, highly sensitive, cost‐effective per sample, and can be used for real‐time monitoring, such as tracking drug response. To uncover molecular and cellular characteristics today, blood, saliva, urine, or cerebrospinal fluid are typically analyzed. In this methodological proof‐of‐concept study, we propose that patient profiling can be facilitated by assessing surface markers on extracellular vesicles (EVs) directly in plasma without prior purification. EV composition reflects the physiological or pathological state of their parent cell, making EVs valuable tools for biomarker discovery and understanding disease mechanisms. Plasma and purified EVs from 30 ischemic stroke patients were analyzed for 17 surface markers using an in‐house protein microarray method (EV Array). The findings indicate that measurements on EVs directly in plasma and on purified EVs show similar patterns in expression of surface markers, supporting the feasibility of omitting purification in EV profiling. This knowledge can provide faster monitoring of various diseases, prevent delays in patient profiling, and optimize patient care.

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.

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). This study aims to investigate whether RIC affects RBC deformability and levels of NO and nitrite in patients with ischemic stroke. METHODS: 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 seven days. Blood samples were collected at different time points: prehospital in the ambulance, in-hospital upon arrival, 2 hours postadmission, and 24 hours postadmission. RBC deformability and erythrocyte aggregation rate were assessed using ektacytometry, NO using flowcytometry, and nitrite content using ozone chemiluminescence. RESULTS: Of 1500 prehospital randomized patients, 486 patients were included in this study between July 28, 2020, and November 11, 2023, and had blood samples taken. Of these, 249 (51%) had AIS, and here RIC treatment was not associated with increased RBC maximal deformability (RIC, 0.549; sham, 0.548; P =0.31), RBC NO (RIC, 35 301 median fluorescence intensity; sham, 34979 median fluorescence intensity; P =0.89), or nitrite (RIC, 0.036 µmol/L; sham, 0.034 µmol/L; P =0.38), but RIC treatment was associated with a significantly reduced aggregation pressure and a slower erythrocyte aggregation rate (RIC, 323.76 millipascal; sham, 352.74 millipascal; P =0.0113). CONCLUSIONS: Prehospital and in-hospital RIC significantly reduced erythrocyte aggregation rate in patients with acute ischemic stroke, while there was no change in RBC deformability, NO content, or whole blood nitrite levels. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03481777.

Acute ischemic stroke (AIS) is one of the leading causes of death and disabilities, and as such, it is of utmost importance to identify novel treatment options. Current acute treatments for AIS are limited to either thrombectomy or thrombolysis, both of which must be initiated within 4.5-6 hours of symptom onset. Remote ischemic conditioning (RIC) is a promising non-invasive treatment that is thought to activate the body’s own protective mechanisms against damaging ischemia through circulating microRNAs (miRNAs). Here, we investigate the transcriptional changes in human brain microvascular endothelial cells (HBMECs) transfected with four selected RIC-upregulated miRNAs (RIC-miRNAs), miR-16-5p, miR-144-3p, miR-182-5p, and miR-451a, under oxygen and glucose deprivation (OGD) - mimicking the initial stages of AIS. Pronounced transcriptional changes were present after RIC-miRNA transfection, with 149 unique downregulated and 212 upregulated differentially expressed genes in HBMECs after OGD and RIC-miRNA transfection compared to all other conditions. These genes were involved in cell cycle regulation, DNA replication and pathways of energy metabolism. However, we saw no direct effect on cell viability after RIC-miRNA transfection and OGD. In conclusion, our study suggests that the selected RIC-miRNAs regulate pathways that may facilitate endothelial cell recovery and remodeling events from ischemic damage, offering new therapeutic avenues for AIS.