Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA: Rationale and Study Design for the RIC-AFRICA Trial

Purpose Despite evidence of myocardial infarct size reduction in animal studies, remote ischaemic conditioning (RIC) failed to improve clinical outcomes in the large CONDI-2/ERIC-PPCI trial. Potential reasons include that the predominantly low-risk study participants all received timely optimal reperfusion therapy by primary percutaneous coronary intervention (PPCI). Whether RIC can improve clinical outcomes in higher-risk STEMI patients in environments with poor access to early reperfusion or PPCI will be investigated in the RIC-AFRICA trial. Methods The RIC-AFRICA study is a sub-Saharan African multi-centre, randomized, double-blind, sham-controlled clinical trial designed to test the impact of RIC on the composite endpoint of 30-day mortality and heart failure in 1200 adult STEMI patients without access to PPCI. Randomized participants will be stratified by whether or not they receive thrombolytic therapy within 12 h or arrive outside the thrombolytic window (12–24 h). Participants will receive either RIC (four 5-min cycles of inflation [20 mmHg above systolic blood pressure] and deflation of an automated blood pressure cuff placed on the upper arm) or sham control (similar protocol but with low-pressure inflation of 20 mmHg and deflation) within 1 h of thrombolysis and applied daily for the next 2 days. STEMI patients arriving greater than 24 h after chest pain but within 72 h will be recruited to participate in a concurrently running independent observational arm. Conclusion The RIC-AFRICA trial will determine whether RIC can reduce rates of death and heart failure in higher-risk sub-optimally reperfused STEMI patients, thereby providing a low-cost, non-invasive therapy for improving health outcomes.

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1–17.1)% of LV mass; control: 11.1 (7.0–17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial.

Remote ischaemic conditioning in ST elevation myocardial infarction: a registry-based randomised trial

ObjectivesRemote ischaemic conditioning (RIC) has been tested as a possible strategy for mitigating reperfusion injury in ST elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PPCI). However, surrogate outcomes have shown inconsistent effects with lack of clinical correlation.MethodsWe performed a registry-based randomised study of patients with STEMI allocated to RIC (4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min of ischaemia followed by 5 min of reperfusion) or standard of care (SOC) during PPCI. We examined the associations of RIC on core laboratory measurements of myocardial perfusion, infarct size (IS), left ventricular (LV) performance and clinical outcomes.ResultsA total of 252 patients were enrolled. The median age was 61 (IQR: 55–70) years and 72.8% were male. Sum ST segment deviation resolution ≥50% was similar between RIC and SOC (65.2% vs 55.7%, p=0.269). In those with 3-day cardiovascular MRI (n=88), no difference in median (25th, 75th percentiles) IS (14.9% (4.5%, 23.1%) vs 16.1% (3.3%, 22.0%), p=0.980), LV dimensions (LV end-diastolic volume index: 78.7 (71.1, 91.2) mL/m2 vs 79.9 (71.2, 88.8) mL/m2, p=0.630; LV end-systolic volume index: 48.8 (35.7, 51.4) mL/m2 vs 37.9 (31.8, 47.5) mL/m2, p=0.551) or ejection fraction (50.0% (41.0%–55.0%) vs 50.0% (43.0%–56.0%), p=0.554) was demonstrated. Similar results were observed with 90-day cardiovascular MRI. At 1 year, the clinical composite of death, congestive heart failure, cardiogenic shock and recurrent myocardial infarction was similar in RIC and SOC (21.7% vs 13.3%, p=0.110).ConclusionsIn a contemporary registry-based randomised study of patients with STEMI undergoing PPCI, adjunctive therapy with RIC did not improve myocardial perfusion, reduce IS or alter LV performance. Consequently, there was no difference in clinical outcomes within 1 year.Trial registration numberNCT03930589.

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9–39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

Remote ischaemic conditioning for stroke: unanswered questions and future directions

Remote ischaemic conditioning (RIC) refers to a process whereby periods of intermittent ischaemia, typically via the cyclical application of a blood pressure cuff to a limb at above systolic pressure, confers systemic protection against ischaemia in spatially distinct vascular territories. The mechanisms underlying this have not been characterised fully but have been shown to involve neural, hormonal and systemic inflammatory signalling cascades. Preclinical and early clinical studies have been promising and suggest beneficial effects of RIC in acute ischaemic stroke, symptomatic intracranial stenosis and vascular cognitive impairment. Through systematic searches of several clinical trials databases we identified 48 active clinical trials of RIC in ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage. We summarise the different RIC protocols and outcome measures studied in ongoing clinical trials and highlight which studies are most likely to elucidate the underlying biological mechanisms of RIC and characterise its efficacy in the near future. We discuss the uncertainties of RIC including the optimal frequency and duration of therapy, target patient groups, cost-effectiveness, the confounding impact of medications and the absence of a clinically meaningful biomarker of the conditioning response. With several large clinical trials of RIC expected to report their outcomes within the next 2 years, this review aims to highlight the most important studies and unanswered questions that will need to be addressed before this potentially widely accessible and low-cost intervention can be used in clinical practice.

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

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.