Commentary on: Lipoprotein(a), remote ischemic conditioning, and stroke recurrence in patients with symptomatic intracranial atherosclerotic stenosis

Stroke is a common cause of morbidity and mortality worldwide and a huge healthcare burden [1,2]. Only a small percentage of stroke patients qualify for intravenous thrombolysis or mechanical thrombectomy due to strict criteria, especially due to their narrow therapeutic windows [[3], [4], [5]]. Despite extensive research, these reperfusion options remain the only approved treatments for stroke [[6], [7], [8]]. Some subtypes of stroke, such as intracranial atherosclerotic stenosis (ICAS), are prone to recurrence despite the best available treatment. ICAS is a leading cause of ischemic stroke, particularly in the Asian population where it contributes to 30–50 ​% of strokes [[9], [10], [11]]. Patients with symptomatic ICAS have a significantly higher risk of recurrent stroke, up to 25 ​% per year, despite optimal medical therapy [[12], [13], [14]]. Unlike extracranial carotid stenosis, where carotid endarterectomy or stenting is effective, the management of ICAS remains challenging, with medical therapy being the primary approach [15,16]. Thus, treatment strategies focusing on reducing stroke recurrence are urgently needed for high-risk ICAS patients.

Remote ischemic conditioning (RIC), first developed in 1986 as a cardioprotective treatment for myocardial infarction, represents a technique using brief episodes of non-lethal ischemia in one body part to protect against lethal ischemia in a distant organ [17,18]. The first application of RIC in stroke was conducted in Mongolian gerbils, showing that two episodes of brief global ischemia can protect the hippocampus from delayed injury due to lethal ischemia, highlighting the therapeutic benefits of RIC in stroke [19]. There are multiple protocols for RIC in stroke; it can be induced before, during, or after stroke, referred to respectively as remote ischemic preconditioning, remote ischemic perconditioning, and remote ischemic postconditioning [19]. RIC entails the inflation of a blood pressure cuff to supra-systolic pressures in one or multiple limbs, generally for 5 ​min, followed by a reperfusion period [18]. Administration can be a single episode around the time of stroke or multiple episodes, referred to as chronic RIC [18].

While the exact mechanism of RIC in neuroprotection is uncertain, it may involve humoral signaling, peripheral nerve activation, and immune modulation [19,20]. Remote organ signaling is initiated by limb ischemia, releasing autacoids such as adenosine, bradykinin, and calcitonin gene-related peptide, which either stimulate afferent neural pathways or pass through the blood brain barrier to directly affect the brain. Other RIC-associated circulating factors include stromal cell-derived factor 1 (SDF1 or CXCL12), interleukin-10, microRNA-144, and nitrite [19]. Exosomes play a crucial role in RIC, with circulating exosomes derived from the plasma of RIC-treated animals exhibiting similar protective effects [21]. Mitochondria are the primary target of RIC. RIC triggers G-protein coupled receptors, leading to ATP-dependent potassium channel activation, preventing mitochondrial permeability transition pore formation, and reducing apoptosis induced by cytochrome C release [22,23]. In addition, RIC confers neuroprotection by enhancing leptomeningeal collateral circulation, improving oxygen supply by 2,3-biphosphoglycerate-rich erythrocytes, modulating metabolism, and decreasing inflammatory gene expression [[24], [25], [26]].

Accumulating clinical trials demonstrate that RIC can improve functional outcomes after stroke and prevent recurrent strokes, including in the ICAS population. For example, in a single-arm phase II study (PICNIC-One study), chronic RIC adjuvant to routine secondary stroke prevention reduced stroke recurrence with minor complications [27]. In another randomized controlled phase II trial, RIC twice daily for 2 weeks before carotid artery stenting substantially reduced the incidence of new ischemic lesions and decreased lesion volumes in patients with severe carotid artery stenosis [28]. In patients with symptomatic ICAS, RIC significantly improved cerebral blood flow and cerebral glucose metabolism when performed twice a day for 3 months [29]. However, in the RICA trial (chronic RIC in patients with symptomatic ICAS), there was no difference between RIC and sham control in lowering the risk of stroke in patients with symptomatic ICAS, potentially due to poor compliance [30]. As RIC effectively prevents stroke recurrence when applied consecutively for at least 180–300 days, large-scale clinical trials with long-term adherence are needed to validate the efficacy of RIC in patients with symptomatic ICAS [31].

The diagnosis of stroke currently relies on imaging which has limited availability and may delay treatment [32]. Biomarkers will enable rapid, low-cost, blood-based diagnosis, reducing time to intervention. A reliable biomarker may help differentiate stroke subtypes quickly in emergency settings, especially in cases with normal or ambiguous neuroimaging findings [[32], [33], [34]]. Certain biomarkers (e.g., inflammatory markers, endothelial dysfunction indicators) could identify high-risk individuals, valuable in primary and secondary stroke prevention [[32], [33], [34]]. In addition, biomarkers can serve as objective measures of treatment response to therapies like thrombolysis, thrombectomy, or neuroprotective agents, tailoring treatments based on individual pathology and severity [[35], [36], [37], [38]]. Moreover, biomarkers related to neuroinflammation, neurogenesis, and angiogenesis can help predict recovery potential, aiding in habilitation [37,38].

In this issue of Neurotherapeutics, the study by Wu et al. analyzed 1286 patients from the RICA trial and revealed that elevated lipoprotein(a) levels correlate with increased stroke recurrence rate in patients with symptomatic ICAS [39]. While the RICA trial showed no change in stroke risk in patients receiving chronic RIC, subgroup analysis revealed that chronic RIC significantly benefits participants with high lipoprotein(a). Utilizing biomarkers to stratify risk and to monitor response may help in tailoring treatment for ischemic stroke, highlighting the need for additional investigation in this field. Lipoprotein(a) is a low-density lipoprotein–like particle synthesized by the liver that consists of an apolipoprotein B100 linked to a large glycoprotein apolipoprotein(a) [40]. While the exact physiological role of lipoprotein(a) remains uncertain, it has been documented to enter the arterial intima and promote atherosclerosis [41,42]. Moreover, significantly increased levels of lipoprotein(a) are associated with elevated risk of ischemic stroke, especially in young stroke patients, suggesting lipoprotein(a) as a predictive biomarker for stroke risk [[43], [44], [45], [46]]. A preclinical study in adult rhesus monkeys showed that RIC modulates lipid metabolism as early as two weeks after RIC, advancing the use of lipoprotein(a) for predicting therapeutic responsiveness [47]. Utilizing biomarkers to stratify risk and to monitor response may help tailor treatment for ischemic stroke, highlighting the need for additional investigation in this field.

A biomarker for RIC remains elusive. The present study demonstrates that lipoprotein(a) independently correlates with increased risk of recurrent ischemic stroke in patients with symptomatic ICAS and may serve as an enrichment biomarker for RIC therapy, providing a significant advance in the field of stroke diagnostics [39]. Further investigations on how lipoprotein(a) is incorporated in the protective mechanisms of RIC will enhance the safety and effectiveness of RIC in stroke.

Author Contributions

NP wrote the initial draft with support from JYL. CVB edited and provided input on the main points of the Commentary and supervised the entire writing process. All authors read and approved the final manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.