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International Journal of Stroke 19(3)
Cardiovascular disease
The concept of RIC was first developed investigating possible
interventions for coronary artery occlusion and its
review in this space is beyond the scope of this article.
Nonetheless, differences in stroke and cardiac populations
are vital to consider if we are to learn from RIC in other
conditions. The definitive " CONDI-2/ERIC-PPCI " study65
found that a single session of RIC prior to primary percutaneous
coronary intervention did not improve cardiac death
or hospitalization with heart failure 12 months after ST
elevation MI, despite several prior phase II studies indicating
that RIC was cardio protective.66,67 A possible explanation
is that patients with ischemic heart disease may be
pre-conditioned through effective cardiac treatments. In a
rat model of myocardial infarction, rats were treated with
opiates, heparin, and a platelet inhibitor. RIC did not confer
any additional benefit when given alongside these treatments.
Therefore, in the setting of ischemic heart disease,
medications that are not routinely used in stroke could
attenuate the effects of RIC.68
Future directions
There is still a great deal of uncertainty regarding the effective
" dose " of RIC. Strategies can be broadly divided into
acute RIC, where RIC is given in a single session around
the time of cerebrovascular event, or chronic RIC, where
RIC is given in multiple sessions over a longer period.
Numerous studies are currently in progress with a wide
variety of RIC protocols used, ranging from a single episode
of RIC to RIC twice daily for a week. These are summarized
in Supplementary Table 2. Furthermore, the
Remote Ischaemic Conditioning in Stroke Collaboration
(RISC) aims to complete an individual participant metaanalysis
to understand potential differences in RIC delivery
and population subgroups (PROSPERO registration
CRD42020197351).
Determining an optimal RIC dose is difficult without an
adequate biomarker. RIC can modulate several proteins
involved in lipid metabolism, coagulation, immuno-inflammatory
responses and endovascular homeostasis;69 though
more work in larger clinical populations and correlated
with outcomes is needed to confirm whether proteomic
regulation provides a candidate biomarker. Furthermore,
RIC has been shown to induce changes in vascular dynamics
in stroke patients, such as flow-mediated dilatation18
and cerebral blood flow;49,70 offering potential alternative
biomarkers of effect.
Compliance has been variably reported across different
studies and there is a clear divide between compliance with
RIC protocols that last a matter of days compared with
those requiring the participant to carry on the intervention
for months or even years. When RIC is delivered for a
period of 2 weeks or less, compliance has been reported as
International Journal of Stroke, 19(3)
78-97%,32,33,71,72 although the exception to this is the
RECAST-2 trial, which found a significant decline in compliance
at 48 h in both RIC and sham when patients were
transferred from hospital to a rehabilitation facility.35 This
may reflect differing healthcare practices in different countries.
Even if we find an effective dose of RIC, it is of no
use if the protocol is so demanding that patients cannot
comply with it. Future work should focus on finding the
minimum effective dose and monitoring compliance with
this regime.
Conclusion
The paradigm of IC is a promising intervention in the field
of cytoprotection. The fear is, that like so many previous
neuroprotective strategies, RIC will fail to translate from
pre-clinical studies to beneficial outcomes in clinical trials.
However, recent evidence from the RICAMIS and RICA
trials is encouraging. Further study of this cheap and easily
applicable intervention is, therefore, warranted. Despite
this, there remain large gaps in our understanding of the
mechanisms and therefore the optimum dose and delivery
of RIC. Research for a reliable biomarker of RIC efficacy
to help determine the ideal RIC strategy should be promoted.
Furthermore, we must ensure RIC is tolerable to the
populations in whom it shall be applied.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: Prof
T England is the Chief Investigator for the Remote Ischaemic
Conditioning after Stroke Trial 3 (RECAST-3) funded by the
National Institute for Health and Care Research (NIHR) Efficacy
and Mechanism Evaluation (EME) Programme.
ORCID iD
Timothy J England
https://orcid.org/0000-0001-5330-8584
Supplemental material
Supplemental material for this article is available online.
References
1. Murry CE, Jennings RB and Reimer KA. Preconditioning
with ischemia: a delay of lethal cell injury in ischemic myocardium.
Circulation 1986; 74: 1124-1136.
2. Przyklenk K, Bauer B, Ovize M, Kloner RA and Whittaker P.
Regional ischemic " preconditioning " protects remote virgin
myocardium from subsequent sustained coronary occlusion.
Circulation 1993; 87: 893-899.
https://www.orcid.org/0000-0001-5330-8584
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