Remote ischaemic preconditioning: is it a flag on the field?

Abstract

Ischaemic preconditioning is one of several different techniques that have been proposed to render the heart more resistant to ischaemia/reperfusion injuries. A significant reduction of troponin release is ‘proof of concept’, however, whether ischaemic preconditioning leads to improved clinical outcomes is still to be proven. Moreover, the exact mechanism of action still remains unknown since very few studies have investigated the signal transmission in humans.

Keywords

ischaemia/reperfusion injury preconditioning (cardiac)

Introduction

Ischaemic conditioning of the myocardium is a generic term that refers to different cardio-protective interventions during which the heart is exposed to relatively short bursts of ischaemia and reperfusion. Examples of conditioning protocols are preconditioning (PreC), perconditioning (PerC) and postconditioning (PostC). Preconditioning is normally used to refer to a phenomenon that occurs before a potentially lethal ischaemic event and it is thought to protect certain organs from ischaemic insult itself and from subsequent reperfusion injury. Perconditioning² refers to a conditioning stimulus applied during an ischaemic event and postconditioning refers to a phenomenon that occurs after ischaemic events.³ The ‘conditioning’ definition can also be categorized depending on different triggers. The stimulus can often be cycles of ischaemia/reperfusion, or pure nociceptive, i.e., ‘trauma preconditioning’.⁴ The conditioning phenomenon (either pre, per or post) can be carried out centrally or remotely, depending on the organ targeted.

Ischaemic preconditioning (IP)

Ischaemic preconditioning was first discovered by Reimer and Murry in the 1980s.¹ In a pioneering experiment, they interrupted the flow in coronary arteries four times in anaesthetized dogs for 5 minutes each and each interruption was followed by a period of reperfusion. The result observed was that the ‘preconditioned’ hearts were more resistant to a subsequent potentially lethal episode of ischaemia-reperfusion. Not long after this first experiment, Yellon et al. provided the first clinical evidence of central ischaemic preconditioning (CIP) in patients undergoing cardiac surgery.⁵ They preconditioned the heart by inducing transient non-lethal ischaemia, interrupting the blood flow with the aid of an aortic cross-clamp and each interruption was followed by a period of reperfusion. Troponin T level and adenosine triphosphate (ATP) depletion in preconditioned heart biopsies were significantly lower compared to the control group.

Perconditioning (PerC)

Perconditioning strictly refers to a stimulus applied during ischaemia and before reperfusion; however, its difference with early PostC is probably not well defined. It was first described in pigs² in which intermittent peripheral tissue ischaemia during coronary ischaemia reduced myocardial infarction through a KATP-dependent mechanism. Perconditioning and early PostC may be considered as equivalent phenomena: trials investigating the benefit of remote PostC in STEMI patients are referring to a ‘perconditioning phenomenon’, because the stimulus is applied during the ischaemia and before the vessel is re-opened (reperfusion). In terms of translation into a clinical ground, CONDI2 (effect of remote ischaemic conditioning (RIC) on clinical outcomes in STEMI patients undergoing primary percutaneous coronary intervention (PCI)) is currently the largest trial on PerC in patients with STEMI undergoing PCI.

Postconditioning (PostC)

The structural difference with preconditioning is that PostC may play a role just in the reduction of reperfusion injury since ischaemic injury has already happened. Although Na and colleagues first coined the definition of postconditioning in 1996 when they demonstrated that ventricular, premature, beat-driven, intermittent reperfusion may protect against reperfusion-induced ventricular fibrillation,⁶ the importance of a ‘gentle’ reperfusion after ischaemia to reduce the I/R injury had already been described by Okamoto in 1986.⁷ However Zhao and colleagues were the first to describe PostC in a structured scientific model. They occluded the left anterior descending artery of dogs for 60 minutes, allowing 3 hours of reperfusion. In the intervention group, reperfusion was anticipated by cycles of occlusion and reperfusion. They reported a significant reduction in infarct size and preserved endothelial function.³ Kerendi et al. described remote PostC with a single 5-min period of renal artery occlusion just before reperfusion as reducing myocardial infarct (MI) through an adenosine-mediated pathway in a rat model.⁸ Staat and colleagues reported the first translation into clinical practice.⁹ They performed four 1-minute cycles of angioplasty balloon inflation, each interrupted by 1-minute periods of deflation and initiated within the first minute after re-opening the culprit coronary artery. They reported a reduced infarct size of 34%. In terms of molecular signal, Heusch et al. demonstrated a reduction of infarct size by ischaemic PostC along with more markedly increased tyrosine705 phosphorylation of STAT3 in myocardial biopsies of pigs.¹⁰ Although different algorithms have been proposed in order to validate PostC, no optimum protocol has been defined, yet; however, intervention should be preferably done during the first few minutes of reperfusion.¹¹ Most studies about PostC included patients with STEMI undergoing PCI and virtually no trials have been done in patients undergoing CABG.¹¹

Preconditioning without ischaemia

There are different non-ischaemic ways to protect the heart. Hypothermia has been reported to reduce ischaemic injury in different surgical scenarios.¹² Hypothermia applied during an ischaemic event may improve tissue perfusion, metabolic and mechanical function, result in fewer arrhythmias and may reduce infarct size on reperfusion in pigs.¹³ Temperature preconditioning (TP) exerted by three cycles of short-term hypothermic perfusion interspersed by periods of normothermia significantly improved recovery of hemodynamic function and reduced ventricular arrhythmias during reperfusion after 25 min of global normothermic ischaemia in rats.¹⁴ Although hypothermia itself before an ischaemic event protects the heart and brain, it seems, at least experimentally, that repeated episodes of moderate hypothermia followed by normothermia may elicit protection from I/R injury¹⁴ rather than a single one. Pharmacological preconditioning is potentially a valid alternative to conventional I/R trigger. ATP-sensitive potassium channel openers used before procedures that involve a potentially ischaemic insult may render the heart more resistant to ischaemia itself.¹⁵ Tachycardia that does not lead to ischaemia has been experimentally proposed in animal models as a mechanism that may mimic effects similar to preconditioning through modifications of the sarcoplasmic reticulum and mitochondrial ATP-sensitive potassium channels.¹⁶ Among non- ischaemic ways, pain may induce preconditioning from a distance in rats¹⁷ with a mechanism known as remote trauma preconditioning, although the same mechanism has not been demonstrated yet in humans.

Remote ischaemic preconditioning (RIPC)

The definition of RIPC was first proposed by Przyklenk and colleagues in 1993 as an extension of Reimer and Murry’s experiment. They showed that brief episodes of ischaemia in one vascular bed protected remote, virgin myocardium from subsequent sustained coronary artery occlusion in a canine model. In essence, they demonstrated that the occlusion of the circumflex artery could protect the myocardium supplied by the ‘remote’ left anterior descending artery.¹⁸ In the same year, McClanahan showed, in animal models, that non-lethal I/R injury to other non-cardiac organs, such as the kidney, could protect the heart. Some years later, the same conclusions were described by Gho who reported that non-cardiac tissue (intestine) I/R non-lethal injuries could protect the heart.¹⁹ In 1996, Jenkins’ group reported similar favourable outcomes in a group of 33 patients undergoing coronary artery bypass grafting (CABG).²⁰

Despite the positive results, the CIP method proposed by Yellon⁵ and the RIPC proposed by Przyklenk¹⁸ were too invasive and only applicable by direct intervention on the heart. This spurred the scientific communities to look for easier, less-invasive and reproducible methods of CIP/RIPC. The answer to this was remote ischaemic preconditioning (RIPC), performed using brief cycles of I/R in one of the limbs with the purpose of making the heart (considered a remote organ) or other organs more resistant to I/R injury than a non-protected one. In 1997,²¹ Birnbaum reported that briefly restricting blood flow to a lower limb of a rabbit model could reduce the extent of a provoked MI after artery occlusion. He called this phenomenon ‘ischaemic preconditioning at a distance’. In 2006, Cheung reported the first clinical application in humans, in a context of children undergoing paediatric cardiac surgery.²² Sometime later, Hausenloy reported the first application of RIPC in patients undergoing CABG.²³ More recently, similar results were reported by Thielman and by Li and Wu who investigated the effect of RIPC in patients undergoing CABG²⁴ and aortic and mitral valve replacement, respectively.^25,26

RIPC was now a simple, inexpensive technique that was attracting the attention of researchers worldwide. Most recently, Kottemberg’s trial²⁴ reported a better outcome in preconditioned hearts and was structured to be statistically powered to provide this information. Larger, randomized, clinical trials with clinical primary endpoints were designed and, in 2010, the RIP heart-study (remote ischaemic preconditioning study) started the recruitment of 2070 patients undergoing cardiac surgery and it is expected to publish the findings in 2016.²⁷ In 2012, the ERICCA Trial (Effect of Remote Ischaemic preConditioning on clinical outcomes in patients undergoing Coronary Artery bypass graft surgery) started recruiting high-risk patients (CABG ± Valve) and is expected to report in 2015.²⁸

RIPC application in clinical trials

In more than two decades after Reimer’s initial report,¹ the interest in preconditioning has exponentially increased. On average, every year, more than five hundreds articles are published (Figure 1). To date, a basic search in Pub-Med using the simple MeSH terms ‘remote ischaemic preconditioning’ (remote AND ischaemic preconditioning OR ischaemic preconditioning) produced 53 clinical trials from phase I to IV. Although RIPC has penetrated different specialties, cardiac surgery is the one which has been experimenting potential benefits of the application the most. By adding the MeSH term ‘cardiac surgery’, we obtained, out of the 53, 37 clinical trials (in different phases) of which 31 are specifically related to cardiac surgery, both pediatric and adult. According to Clinicaltrial.Gov (which contains data from the USA and another 185 countries), there were 41 trials, including those not yet active or not yet recruiting. Despite this large volume of scientific publications, the real mechanism underlying the “conditioning” and, more specifically the RIPC, has not yet been clarified. Investigations on RIPC in patients have mainly focused on biomarkers of cardiac injury after CABG or PCI as ‘proof of concept’ and less frequently on clinical outcomes (Table 1). Also, apart from very rare exceptions, the clinical trials published so far have not been designed to investigate cellular mechanisms underlying the protection elicited by RIPC. Even the largest trials, like ERICCA²⁸ and the RIP heart-study,²⁷ have been specifically designed with the aim of investigating the effect of RIPC on clinical outcomes rather than the molecular underlying mechanisms. There is a lot of information on how the preconditioning signal is formed and transmitted in animal models and very little in humans. There are three theoretical levels of signal transduction: trigger, intra-cellular cascade and end-effectors. These three hierarchical levels rely, probably, on three parallel signalling pathways, but the vast majority of them have been validated in animal models only. It has been assumed that one of the crucial mechanisms of protection elicited by RIPC lies in the mitochondria (end-effectors). There is a general consensus coming from animal models that the infarct-sparing effect of all the forms of ischaemic conditioning involves the up-regulation of the signal transduction cascades in ischaemic, reperfused cardio-myocytes that, ultimately, serve to preserve the mitochondria. Hence, the attention has been moved towards mitochondrial permeability transition pore and delay or prevention of pore opening as the end effectors in achieving conditioning-induced cardio-protection. Only a few researchers have investigated mitochondrial respiration, using either atrial or ventricle biopsies in preconditioned and non-preconditioned human hearts. Focusing on human atrial myocardium biopsies, Slagsvold and colleagues,²⁹ in a single-centre study, have reported the preservation of mitochondrial respiration and the modified expression of microRNAs, together with attenuation in the incidence of postoperative atrial fibrillation in patients randomized to receive RIPC before coronary artery bypass graft surgery. Heusch and colleagues have reported, in a small series of human ventricle biopsies, an increase of STAT5 phosphorylation from baseline to early reperfusion only in the patients with RIPC and not in the control group³⁰ and this is the only study that demonstrated the STAT5 activation identification in left ventricular myocardium at early reperfusion after cardioplegic ischaemic arrest in response to RIPC by three cycles of arm ischaemia and reperfusion.¹¹

Table 1.

Meta-analysis on the effect of RIPC in cardiac surgery.

RIPC Trialists’ Group³⁴ (2014)	23 RCTs (2200 pts)	Not reported	No differences in clinical outcomes	Perioperative MI reduced in the RIPC group but not statistically significant
Yasin NA³¹ (2014)	17 RCTs (1001 pts)	Cardiac biomarkers significantly reduced in RIPC group	No differences in clinical outcomes	No statistical difference in short-term clinical outcomes
Yang L³² (2013)	19 RCTs (1235 pts)	Troponin (I and T) significantly reduced in the RIPC group	No differences in clinical outcomes	Mixed population paediatric cases included
Heusc G¹¹ (2013)	20 RCTs (1239 pts)	Majority of studies reported reduced cardiac biomarkers release in RIPC group	No clinical outcomes reported	Small studies sample size
Zhou C³³ (2013)	15 RCTs (1.155 pts)	Troponin significantly reduced in RIPC group	No clinical outcomes reported	Significant heterogeneity were β-blockers and volatile anaesthetics; protection more significant in valve
Pilcher JM³⁴ (2012)	10 RCTs (693 pts)	Troponin significantly reduced in RIPC group	No clinical outcomes reported	Studies with incomplete or no blinding demonstrated a larger estimate of effect
D’Ascenzo F³⁵ (2012)	9 RCTs (704 pts)	Troponin significantly reduced in RIPC group	No difference in terms of length of in-hospital stay	Difference held true after excluding cross-clamp fibrillation, OPCAB CABG /and flurane as anaesthetic agent
Yetgin T³⁶ (2012)	13 RCTs (891 pts)	Troponin significantly reduced in RIPC group	No clinical outcomes reported	High heterogeneity across studies
Brevoord D³⁷ (2012)	15 RCTs (1166 pts)	Troponin and MI significantly reduced in RIPC group	No differences in clinical outcomes	No mortality nor MACE incidence reduced
Alreja G³⁸ (2012)	13 RCTs (814 pts)	Cardiac biomarkers and MI significantly reduced in the RIPC groups	No differences in clinical outcomes	Significant heterogeneity of results
Takagi H³⁹ (2011)	5 RCTs (252 pts)	Cardiac biomarkers and MI significantly reduced in the RIPC groups	No differences in clinical outcomes	No mortality nor post-procedural MI reduced in the RIPC group
Takagi H⁴⁰ (2008)	4 RCTs (184 pts)	Cardiac biomarkers and MI significantly reduced in the RIPC groups	No clinical outcomes reported	Pediatric cases included/no between-study heterogeneity of results

More trials specifically focused on human heart samples are definitely needed in order to attempt to identify the intracellular signalling pathways elicited by the RIPC since the vast majority of the RIPC studies have been carried out on mice and there is always the possibility of translational gaps from animals to humans.

RIPC: Rationale for new trials

According to clinicaltrial.gov, there are 16 trials in different phases (or completed, but not published) investigating the effect of RIPC on adult cardiac surgery (Table 2). The majority of them have, as primary outcome, biomarker change. Some of them include, in the secondary outcome, clinical figures, such as MACCE or length of stay while a few contemplate atrial or ventricle biopsies for intracellular assessment.

Table 2.

Trial currently running (or completed, but not yet published) on RIPC and adult cardiac surgery.

Title	Type of operation	Primary Outcome	Secondary Outcome	Status	RIPC dose	Anaesthesia	Cardioplegia	Biopsies
RIPC on Human myocardium (120 pts) Marek Deja, Medical University of Silesia (Poland) Start 11/2013	CABG	Troponin T levels	CK-MB/ oxygen metabolic assessment and creatinine clearance/ Resistance of isolated right atrial pectinate muscle trabeculae to simulated hypoxia-reperfusion/ apoptosis induction/ state of mitochondria (electron microscopy)/ Alveolar-arterial gradient/ S100 concentration, NGAL and zonulin concentration	Phase 2 Final data collection date for primary outcome measure on February 2015	Three cycles of 5 min left upper arm ischaemia	NS	NS	Atrial
Transfer of Cardioprotection During RIPC (332 pts) University Hospital, Essen (Germany) Start 08/2013	CABG (±reparative valve surgery)	Cumulative postoperative troponin I release	All-cause mortality/MACCE/renal function/Cardio-protective factors released into circulating blood	Phase 2/3 Final data collection date for primary outcome measure September 2015	Three cycles of 5 min left upper arm ischaemia	NS	NS	No
RIPC on Patients Undergoing Heart Surgery (120 pts) University of Campinas (Brazil) Start 07/2013	CABG / Valve surgery	Molecular pathway activation/Inflammatory response	All cause of mortality	Phase 1 Final data collection date for primary outcome measure August 2015	Four cycles of 5 min left upper arm ischaemia	NS	blood cardioplegia	Ventricle
RIPC on RISK Signalling Pathway (72 pts) Yonsei University (Korea) Start 06/2013	AVR	Activation of RISK pathway by comparison of the phosphorylation of the PI3K-Akt and Erk 1/2	Assessment of RIPC-induced release of HMGB1 by comparison of serum HMGB1 level by ELISA	Phase 4 Final data collection date for primary outcome measure April 2015	Three cycles of 5 min ischaemia (250mmHg inflation) & 5 min reperfusion	NS	NS	Ventricles
Delayed RIPC on Myocardial Injury (160 pts) Seoul National University Hospital (Korea) Start 05/2013	Valve Replacement Surgery	Troponin I change	Serum creatinine changes	Phase 1 Final data collection date for primary outcome measure on December 2014	24-48 hr. before surgery 4 cycle 5 minutes limb ischaemia and reperfusion	NS	NS	No
RIPCON trial (100 pts) Heinrich-Heine University, Duesseldorf+multicentric (Germany) Start 05/2012	CABG (On-Off pump)	Myocardial injury as measured by cardiac troponin T serum release over 72 hours after coronary bypass surgery	All-cause mortality (30 days / 1 year)/MACCE/Myocardial infarction/Renal function/circulating microparticles after coronary bypass surgery	Phase 1 Final data collection date for primary outcome measure on June 2015	Three cycles of 5 min left upper arm ischaemia	Avoided use of propofol Drugs: isoflurane + sufentanil anaesthesia	Cross-clamp fibrillation or blood cardioplegia for myocardial protection vs off-pump	Ventricle (molecular analysis non otherwise specified)
RIP-valve (100 pts) University Hospital, Angers (France) Start July 2011	AVR	Infarct size as assessed by 72 hours area under curve serum troponin-I	NS	Completed Final data collection date for primary outcome measure on October 2012	Three cycles of 5 min left upper arm ischaemia	NS	NS	No
Remote IMPACT (250 pts) McMaster University+ multicentric (Canada) Start March 2011	Patients undergoing cardiac surgery	Peak post operative creatine kinase (MB)	Change in serum creatinine/All-cause mortality/Need for Dialysis/LOS/Incidence of pneumonia/Incidence of stroke/Peak CK-MB/Peak CK-MB within 24 hours after surgery	Completed	300 mmHg inflation of thigh pneumatic tourniquet for three cycles of 5 minutes each with 5 minutes of no inflation between cycles	NS	NS	No
ERICCA trial (1612 pts) (Multicentric UK) Start 04/2011	CABG±Valve high risk pts (Euro>5)	MACCE at 12 months	30 days MACCE/ All cause death/ Peri-operative myocardial and renal injury/ Length of ITU stay/Inotrope score/Hospital stay/6 minute walk test/ Quality of life/Echo sub study	Enrolment completed Follow-up will be ongoing until the middle of March 2015	Three cycles of 5 min left upper arm ischaemia	NS	Blood cardioplegia	No
TRIMRIPC trial (60 pts) Norwegian University+ multicentric (Norway) Start 01/2011	CABG (or Heart Transplantation)	Mitochondrial respiration	NS	Completed	NS (+exercise training?)	NS	NS	Ventricle or atrial
RIPC in type II BM patients undergoing CABG (200 pts) University College London Hospitals (UK) Start 12/2010	CABG	Troponin-T release over the perioperative 72-hour period	NS	Phase 1 Final data collection date for primary outcome measure on July 2012	simultaneous 2 x 5- minute cycles of forearm and lower leg ischaemia	NS	NS	No
RIPC on Incidence of AF (410 pts) Baystate Medical Center Start 10/2010	CABG	Post-op atrial fibrillation	Stroke	Phase 3 Final data collection date for primary outcome measure December 2014	Four cycles of 5 min left upper arm ischaemia	NS	NS	No
RICO Trial (660 pts) Academisch Medisch Centrum (The Netherlands) Start 01/2010	CABG	Post-operative atrial fibrillation	MACCE/LOS	Phase 2 Final data collection date for primary outcome measure January 2012	Three cycles of 5 min left upper arm ischaemia	NS	NS	No
Effect of RIPC in cardiac surgery (1200 pts) Seoul National University Hospital+ multicentric Start 10/2009	Off-pump CABG and VALVE	MACCE/ GI complication	Length of ICU stay/Length of postoperative hospital stay	Phase 1 Final data collection date for primary outcome measure on September 2010	Three cycles of 5 min left upper arm ischaemia	NS	NS	No
RIPC on Acute Kidney Injury After Cardiac Surgery (120 pts) Maine Medical Center Research Institute Start 11/2008	CABG	Incidence of acute kidney injury after surgery	Oliguria/elevation in NGAL	Phase 1 Final data collection date for primary outcome measure March 2010	Three cycles of 5 min left upper arm ischaemia	NS	NS	No
RIPC in CABG with cold crystalloid Cardioplegic Arrest University Hospital Essen Start 06/2008	CABG	Troponin I levels	All-cause mortality/MACCE/MI/renal function	Phase 3 Final data collection date for primary outcome measure on October 2012	Three cycles of 5 min left upper arm ischaemia	isoflurane+ sufentanil anaesthesia	Crystalloid Cardioplegic	No

ERICCA : Effect of Remote Ischaemic Preconditioning on Clinical Outcome.

RIPCON : Effects of Remote Ischaemic PreConditioning in Off-pump Versus On-pump Coronary Artery Bypass Grafting.

RIP-VALVE : Remote Ischaemic Preconditioning in Aortic Valve Surgery.

REMOTE-IMPACT : Remote Ischaemic Preconditioning in Cardiac Surgery Trial.

TRIMRIPC TRIAL : Myocardial Physiology and Microanatomy In Individuals Undergoing Heart Surgery.

RICO: Remote Ischaemic Conditioning and Atrial Fibrillation After Coronary Artery Bypass Grafting.

New trials are needed in order to:

- Identify potential triggers (humoral/neuronal etc.) and investigate the pathways they rely on;

- Clarify what cascades are activated after a trigger interacts on human ventricle myocytes and other surrounding cell types;

- Investigate on what pathways the end-effectors work.

Moreover, aside from focussing on the standard three hierarchical levels, it would be advisable to:

- Determine what changes are evoked in the myocytes after RIPC, but before the ischaemic period;

- Estabilish what is the effect of RIPC in human naive myocytes and if there are differences with non-naive hearts.

‘Effect of remote ischaemic preconditioning on blood and myocardial biomarkers of stress and injury-related signalling in patients having isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass’ is a multicentric trial carried out between the National Heart and Lung Institute (NHLI), London and the Bristol Heart Institute (ISRCTN 33084113 / UKCRN ID 13672 / REC No: 12/LO/1361).

The primary outcome of this study is to determine whether RIPC reduces troponin I release. The secondary research objectives are to determine cellular changes and intracellular mechanisms elicited by a trigger after remote preconditioning, but before the ischaemic event (e.g., cross-clamp time during cardiac surgery) and after the ischaemic event (20 minutes after the discontinuation of cardiopulmonary bypass). The vast majority of the studies have investigated, primarily in animal models, the signalling pathway changes after reperfusion, which involves mainly the SAFE and the RISK pathways and the activation of intracellular kinases such as PKCϵ.⁴¹ In order to monitor the changes in the activation (phosphorylation) of cardiac proteins following RIPC with prior I/R, we will study the cardiac phospho-proteome in both subgroups of RIPC and control human hearts, using Tandem Mass Tagging (TMT). In the rest of the biopsies, we will study the standard cardiac proteomic after RIPC and after I/R. Moreover, considering the plasma will be collected at different time points, it will be possible to correlate a potential humoral trigger to a specific intracellular pathway’s activation.

Another open question is the ‘RIPC dose’. In simple words, how many times the blood pressure cuff should be inflated and deflated at the level of the limb in order to elicit cardio-protection. In our trial, we decided to follow the steps of the most representative trials,²⁸ inflating the blood pressure cuff 4 times for 5 minutes, each inflation followed by a period of 5 minutes of reperfusion. However, according to a recent trial investigating the effect of RIPC in ad hoc PCI, the cardiac protection was elicited even after a single cycle of 5 minutes blood pressure cuff inflation.⁴²

Conclusion

There seems to be a large body of evidence in the literature supporting the view that a preconditioned heart has a significantly reduced biomarker release when exposed to an ischaemic insult (Table 1). The biological validity of RIPC has been proven in animal models, but very few studies have yet investigated the signal transmission in humans. The question still unanswered is, “Does reduced troponin release leads to any better clinical outcomes?” The vast majority of the trials have been structured to detect differences in terms of troponin release and very few were able to point out benefits in terms of clinical outcomes while others have showed no benefits.⁴³ In a recent review and meta-analysis of 23 trials, RIPC did not have a significant effect on clinical end-points, with the exception of peri-operative MI which was almost half in the RIPC compared to the control arm (2.8% versus 4.9%).⁴⁴

The identification of the mechanisms underlying RIPC is still unclear.

Ischaemic preconditioning, after the first report in the mid-eighties, still remains a ‘hot topic’, with hundreds of publications produced every year and several trials active in different phases, but definitely more research is needed in order to clarify the intracellular mechanism in humans.

Understanding the intracellular mechanisms on the nature of the trigger may be needed in order to get us closer to ‘bottling the RIPC’. If RIPC was found to be of clinically beneficial, it could represent a general shift in clinical practice, easy and quick to deliver, at no extra costs, a real panacea for an ever-strapped-for-cash health service.

Footnotes

Declaration of Conflicting Interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors

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