9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection

Abstract

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Keywords: Apoptosis; Asprin; Autophagy; Basic research; Beta blockers; CABG; Cardiac surgery; Clinical trials; Conditioning; Cyclosporine; DNA; Infarction; Injury; Ischaemia; Ischaemic; Metoprolol; Mitochondrial transition pore; Necroptosis; Necrosis; Opiates; Postconditioning; Pre-clinical; Preconditioning; Pyroptosis; RISK pathway; Reperfusion; SAFE pathway; Statins; Valve replacement; p2y12.

Fig. 1

Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by necroptosis. Sharing features with necrosis and programmed cell death, apoptosis, necroptosis involves the recruitment of cellular pathways (typically through receptor-interacting protein kinase (RIPK)), that may be activated through the dissipation of DAMPS from neighbouring necrosed cells. Like necrosis, but unlike apoptosis, the cell membrane does not remain intact, and may lead to the release of further DAMPS. The ensuing inflammatory reaction can then lead to pryoptosis—inflammatory cytokine mediated injury. The consequence of the spreading wave of dying cells, like toppling dominos, is likely responsible for the formation of the characteristic confluent myocardial infarct. Apoptosis, in contrast, is the ordered process of cell death, through the successful completion of an ordered cellular shut-down and compartmentalisation of potentially injurious cellular contents that prevents unintended injury to neighbouring cells. Autophagy plays a role in the house keeping of healthy cells, removing senescent proteins and organelles, such as mitochondria (mitophagy). During ischemia/reperfusion injury, autophagy may be a double-edged sword: while autophagy may remove terminally injured and dangerous organelles and oxidised proteins, contributing to energy recovery in reperfusion, excess autophagy may be linked to apoptosis and excessive substrate degradation

Fig. 2

Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathway model of ischaemic conditioning. The acute ischaemic stress of non-injurious ischaemia leads to the release of multiple stress-inducible factors that may activate through G-protein coupled receptors (GCPR) or receptor tyrosine kinases (RTK) to induce the RISK cascade, or through inflammatory cytokines via the glycoprotein 130 (gp130) or tumour necrosis factor receptor (TNFR) to activate the SAFE pathway. The resulting signalling cascade then impacts upon mitochondria, potentially inhibiting the mitochondrial permeability transition pore (mPTP) and other mitochondrial proteins such as connexin-43 (Cx43), or via the nucleus to induce, through promotors, new protein synthesis. PI3K (Phosphoinositide 3-kinase), Akt [Serine/threonine kinase (protein kinase B)], eNOS (Endothelial nitric oxide synthase), ERK (Extracellular signal-regulated kinases), JAK (Janus Kinase), MEK (Mitogen-activated protein kinase kinase), NO (Nitric oxide), p70S6K (p70 S6 ribosomal protein kinase), PKC (Protein Kinase C), Ras/Raf (small GTPase proteins), STAT (Signal transducer and activator of transcription)

Fig. 3

The conditioning stimulus and the impact of co-morbidity and drug therapies. In animal and human studies, it is possible to trigger cardioprotection with conditioning strategies—particularly if the subjects are young and free from co-morbidity. However, the efficacy of a conditioning stimulus is significantly blunted when there are co-morbidities presence (age, diabetes, hypertension, hypercholesterolaemia): the conditioning stimulus that was once effective, appears suppressed, and unable to exceed a critical threshold required for triggering protection. In contrast, with the “success hypothesis”, we find that medications already in regular use in patients presenting with acute coronary syndromes are already cardioprotective in their own right and likely already attenuating infarct size. Examples of these include opiates, P2Y₁₂ inhibitors, statins, beta blockers, etc. (see text). Indeed, such a cocktail may be sufficient to trigger cardioprotection: the drugs have already exceeded the conditioning threshold, will reduce infarct size and optimise outcomes. While this makes the demonstration of efficacy of ischaemic conditioning-type strategies challenging, it represents a genuine benefit for patient outcomes. Further optimisation may, however, require targeting alternate mechanisms of cell injury