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.

Time to Give Up on Cardioprotection?

“…As discussed in detail earlier, most of the studies performed to date are heterogeneous: use of (1) different clinical entities with different clinical protocols (CABG, CABG+valve surgery, cardiac surgery in children, STEMI, PCI), (2) different inclusion/ exclusion criteria even for the same clinical entity and protocol, (3) different conditioning algorithms, and (4) different methods to measure infarct size (troponin I, troponin T, creatine kinase-muscle brain, single photon emission computed tomography, magnetic resonance imaging) have all contributed to the current uncertainty on the efficacy of conditioning procedures in clinical practice. It is most disconcerting that there are several consensus papers that highlight these problems with the existing studies on cardioprotection and make detailed recommendations on how an ideal study should be conducted, 12,13,228,246,249 but then some of the authors of such consensus papers go on to publish studies that do not adhere to these recommendations.…”

“…The potential reasons for this discrepancy have been discussed in detail. [245][246][247][248] Importantly, both ERICCA and RIPHeart not only failed to find benefit from remote ischemic conditioning on mortality, myocardial infarction, and stroke at hospital discharge 38 or after 12 months, 37 but they also failed to see an acute benefit in terms of a reduction of troponin release, such that from the lack of an acute protection, no better clinical outcome was to be expected. The most likely reason for the failure to see protection in terms of troponin release and clinical outcome is the use of propofol anesthesia in 90% of ERICCA patients and all patients per-protocol in RIPHeart.…”

At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury

“…Newer strategies such as ischemic preconditioning (IPC), ischemic postconditioning, and remote IPC have been shown to condition the myocardium to IRI and thus reduce the final myocardial infarct size (7). The elucidation of underlying mechanisms in different forms of ischemic conditioning has identified novel targets for cardioprotection amenable to pharmacological manipulation, so called pharmacological conditioning (8).…”

“…However, none has been translated into clinical practice with the exception of early reperfusion (14)(15)(16). The reasons for the failure to translate pharmacologic conditioning strategies of cardioprotective effects from the bench to bedside have been extensively discussed in the literatures (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19). Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies.…”

“…Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies. Nonetheless, in the position paper which published in 2013 (3), the experts concluded that the failure was not be due to a shortage of potential cardioprotective strategies discovered in the pre-clinical experimental setting (14), but was be due to the inability to successfully translate these promising therapies into interventions that actually improved the outcomes in patients (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19).…”