Does remote ischaemic conditioning reduce inflammation? A focus on innate immunity and cytokine response

Abstract

The benefits of remote ischaemic conditioning (RIC) have been difficult to translate to humans, when considering traditional outcome measures, such as mortality and heart failure. This paper reviews the recent literature of the anti-inflammatory effects of RIC, with a particular focus on the innate immune response and cytokine inhibition. Given the current COVID-19 pandemic, the inflammatory hypothesis of cardiac protection is an attractive target on which to re-purpose such novel therapies. A PubMed/MEDLINE™ search was performed on July 13th 2020, for the key terms RIC, cytokines, the innate immune system and inflammation. Data suggest that RIC attenuates inflammation in animals by immune conditioning, cytokine inhibition, cell survival and the release of anti-inflammatory exosomes. It is proposed that RIC inhibits cytokine release via a reduction in nuclear factor kappa beta (NF-κB)-mediated NLRP3 inflammasome production. In vivo, RIC attenuates pro-inflammatory cytokine release in myocardial/cerebral infarction and LPS models of endotoxaemia. In the latter group, cytokine inhibition is associated with a profound survival benefit. Further clinical trials should establish whether the benefits of RIC in inflammation can be observed in humans. Moreover, we must consider whether uncomplicated MI and elective surgery are the most suitable clinical conditions in which to test this hypothesis.

RIC in COVID-19—a Clinical Trial to Investigate Whether Remote Ischemic Conditioning (RIC) Can Prevent Deterioration to Critical Care in Patients with COVID-19

“…Two of the largest clinical trials to measure cytokines in patients who had been administered RIC (with n = 65, n = 90 participants) demonstrated cytokine attenuation in the treatment group undergoing RIC prior to off-pump CABG and colorectal surgery, respectively. In the latter study, levels of IL-1β and TNF-α were significantly reduced [13].…”

“…The primary aim of this study is to investigate the effect of RIC on cytokine production and inflammatory responses in COVID-19. Several animal studies have shown that RIC suppresses cytokine induction via downregulation of NF-κB, a central transcription factor mediating proinflammatory gene induction in both innate and adaptive immune cells, and myeloperoxidase (MPO) pathways (reviewed in [13]). Two of the largest clinical trials to measure cytokines in patients who had been administered RIC (with n = 65, n = 90 participants) demonstrated cytokine attenuation in the treatment group undergoing RIC prior to off-pump CABG and colorectal surgery, respectively.…”

“…The above observations that cytokine storm contributes to COVID-19 morbidity and mortality and that RIC can suppress the inflammatory response led us to propose that RIC could provide benefit in patients with COVID-19 [4,13]. The rationale of this study is thus that RIC will supress cytokine induction in patients with COVID-19, leading to less cytokine-induced cardiac injury.…”

“…Remote ischemic conditioning (RIC) is a simple, non-invasive procedure in which a blood pressure cuff is applied to the upper arm for repeated cycles of inflation and deflation (typically 3-5 cycles of 5 min each) [10,11]. This process activates pro-survival mechanisms in the body to protect vital organs and improve the immune system [11][12][13][14]. Therefore, we believe it represents a promising strategy to protect organs against reduced blood flow and heightened immune response, as seen in patients with COVID-19 infections [13].…”

“…This process activates pro-survival mechanisms in the body to protect vital organs and improve the immune system [11][12][13][14]. Therefore, we believe it represents a promising strategy to protect organs against reduced blood flow and heightened immune response, as seen in patients with COVID-19 infections [13]. Several studies suggest that RIC can suppress cytokine induction in the setting of cardiac surgery or sepsis [12,13,15,16].…”