Remote ischaemic conditioning: defining critical criteria for success—report from the 11th Hatter Cardiovascular Workshop

Abstract

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2–ERIC–PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Effect of Remote Ischaemic Conditioning on the Inflammatory Cytokine Cascade of COVID-19 (RIC in COVID-19): a Randomized Controlled Trial

“…Therefore, enrolling participants in different phases of their disease may in part explain our findings. While the aforementioned limitations may not have fully unmasked a positive signal from RIC, our study has been very helpful in identifying and validating potential pitfalls for success as described by Bell et al [ 19 ] and highlights the need to further investigate the easily accessible and cost-effective benefits of RIC in patients with COVID-19. Given the involvement of ongoing inflammation with possible cytokine elevation in patients with long COVID-19 and the paucity of specific treatments for this syndrome, it may be interesting to study the potential benefit of RIC in this population [ 43.…”

“…Early repetitive or chronic RIC administration has shown benefits in reducing levels of inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) following lipopolysaccharide-induced sepsis and has been associated with a reduction in mortality in mice [17]. In recent years, RIC has grown from being an innovative strategy for cardiovascular protection [19][20][21]. This emerging field of RIC has been thought to protect organs (e.g., brain, heart, lungs, and kidneys) against the harmful effect of ischemic/reperfusion injury through activation of cell survival pathways and modulation of inflammatory responses that improve mitochondrial function [22][23][24][25].…”

Insights into research on myocardial ischemia/reperfusion injury from 2012 to 2021: a bibliometric analysis

“…As for cardioprotective strategies, experimental studies in the early years from 2007 to 2012 had revealed the essential signal transduction pathways underlying local ischemic postconditioning and remote ischemic preconditioning [ 34 ]. For example, oxidative stress after ischemia/reperfusion produces a large number of reactive oxygen and nitrogen species, leading to cardiac cell death and contractile dysfunction.…”

Non-responsiveness to cardioprotection by ischaemic preconditioning in Ossabaw minipigs with genetic predisposition to, but without the phenotype of the metabolic syndrome

“…Injury to both, cardiomyocytes, i.e., infarct size [ 82 ], and the coronary microcirculation, i.e., microvascular obstruction [ 11 ], contribute to patients’ prognosis. Whereas encouraging preclinical and clinical proof-of-concept studies demonstrated reduced infarct size by mechanical and pharmacological cardioprotection strategies [ 27 ], their translation to better clinical outcome in phase III trials in patients with acute myocardial infarction has been largely disappointing [ 1 , 4 , 25 ]. Such failure of translation has primarily been attributed to co-morbidities and co-medications of patients with acute myocardial infarction which may impair cardioprotective signalling [ 26 ].…”