For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non‐invasive and virtually cost‐free therapy for protecting the myocardium against the detrimental effects of acute ischaemia‐reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia‐reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart – initially termed ‘cardioprotection at a distance’. Subsequent pre‐clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non‐invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro‐hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof‐of‐concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting.
This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia–reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 μM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia–reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 μM vs C eff = 0.04 ± 0.04 μM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia–reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.
RationaleThe intrinsic cardiac nervous system is important in our understanding of cardiac physiology. Using a pharmacological approach, we investigated the hypotheses that these nerves play a role in (1) direct ischaemic preconditioning (IPC) and (2) the cardioprotection offered by the humoral mediator of remote ischaemic conditioning (RIC).MethodsFor the IPC experiment, isolated Langendorff perfused rat hearts were subjected to one of the following conditions; (1) Control + Hexamethonium (50 µM), (2) IPC (3 × 5-min global ischaemia) + Hexamethonium, (3) IPC alone. All hearts were subjected to 35-min ischaemia followed by 60-min reperfusion. In the second study, RIC (4 × 5 min hindlimb ischaemia/reperfusion) or sham was performed on anaesthetised rats, before exsanguination and centrifugation to obtain platelet-free plasma. After dialysis across a <12–14 kDa membrane, the dialysate was perfused through a naïve isolated Langendorff rat heart prior to an ischaemia-reperfusion injury, as described above. The hearts were assigned to the following groups; (1) Sham dialysate, (2) RIC dialysate, (3) Sham+hexamethonium (50 µM), (4) RIC+hexamethonium, (5) Sham+atropine (100 nM), (6) RIC+atropine (100 nM). All hearts were analysed for infarct size using triphenyl-tetrazolium chloride staining. Data presented as mean ± SEM and analysed using analysis of variance.ResultsHexamethonium partially, but significantly, abrogated IPC-mediated cardioprotection (Control = 44.4 ± 4.0%, IPC+Hex = 31.8 ± 5.0%, p < 0.05 vs IPC = 14.2 ± 1.9%). RIC dialysate significantly protected a naïve heart from injury (RIC = 27.6 ± 2.3 vs Control = 42.9 ± 1.2, p < 0.05). Both hexamethonium (45.8 ± 2.5%) and atropine (36.5 ± 3.4%) abrogated dialysate-mediated protection.ConclusionIntrinsic cardiac nerves seem to be important in the induction of protection both in IPC and the response to the humoral RIC mediator.
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