Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and... Remote ischaemic conditioning (RIC) is a promising method of cardioprotection, with numerous clinical studies having demonstrated its ability to reduce myocardial infarct size and improve prognosis. On the other hand, there are several clini- cal trials, in particular those conducted in the setting of elective cardiac surgery, that have failed to show any benefit of RIC. These contradictory data indicate that there is insufficient understanding of the mechanisms underlying RIC. RIC is now known to signal indiscriminately, protecting not only the heart, but also other organs. In particular, experimental studies have demonstrated that it is able to reduce infarct size in an acute ischaemic stroke model. However, the mechanisms underlying RIC-induced neuroprotection are even less well understood than for cardioprotection. The existence of bidirectional feedback interactions between the heart and the brain suggests that the mechanisms of RIC-induced neuroprotection and cardioprotec- tion should be studied as a whole. This review, therefore, addresses the topic of the neural component of the RIC mechanism. Keywords Remote ischaemic conditioning · Cardioprotection · Neuroprotection Introduction percutaneous coronary intervention (PCI)—scenarios when the onset and the duration of ischaemia are carefully con- It is almost 25 years since the phenomenon of remote ischae- trolled (Fig. 1). mic preconditioning (RIPre) was discovered by Przyklenk Twelve years after the discovery of RIPre, it was shown et al. [106]. They demonstrated in a canine model that a in a rat model that remote ischaemic conditioning (RIC) series of brief, alternating episodes of ischaemia and reper- could be applied to a limb during myocardial ischaemia, and fusion, applied to one area of the left ventricle (LV) myocar- reduce infarct size by 50% [77]. This phenomenon became dium, protected a remote myocardial territory of the same known as remote ischaemic preconditioning (RIPer). The heart from a subsequent prolonged ischaemic insult followed next step in the study of RIC came with the demonstration by by reperfusion, limiting infarct size by almost 70%. In the Andreka et al., that RIC could be successfully administered same year, McClanahan et al. [94] achieved a similar infarct- simultaneously with the onset of myocardial reperfusion— limiting effect in rabbits by applying a single 10-min episode a phenomenon named as remote ischaemic postcondition- of ischaemia to a kidney prior to 30-min occlusion of the ing (RIPost) [1]. Taking this one step further, Basalay et al. left anterior-descending coronary artery. However, since the demonstrated in a rat model of acute myocardial infarction RIPre stimulus must, by definition, be applied before the that RIPost applied after a 10-min delay following the onset onset of ischaemia, it is clear that the only possible clinical of reperfusion was still able to reduce infarct size similarly niche for the RIPre phenomenon in cardioprotection could to RIPre [5]. Notably, the results included in this study were be in the setting of either elective cardiac surgery or elective obtained in three research centres, using identical protocols [5]. The success of this procedure, termed ‘delayed RIPost’, was unexpected, in view of the prevailing hypothesis that * Derek M. Yellon the majority of myocardial reperfusion cell death is due to d.yellon@ucl.ac.uk the opening of mitochondrial permeability transition pores The Hatter Cardiovascular Institute, University College (mPTP), thought to occur during the first few minutes of London, 67 Chenies Mews, London WC1E 6HX, UK reperfusion [29, 46]. However, a series of studies demon- Department of Cardiology, Karolinska University Hospital, strated implication of non-mPTP/necrosis mechanisms in 171 76 Stockholm, Sweden Vol.:(0123456789) 1 3 25 Page 2 of 15 Basic Research in Cardiology (2018) 113:25 Fig. 1 Schematic time lines representing the concepts of remote ischaemic pre-, per-, post- and delayed postcondition- ing, and the clinical scenarios in which they may be relevant. STEMI ST-elevated myocar- dial infarction. Asterisk—the evidence for the existence of the delayed remote ischaemic postconditioning phenomenon is currently limited having only been demonstrated in one experimental study myocardial death [59] including pyroptosis [147], necrop- both on the large number of successful experimental studies tosis [12, 127], and, more controversially, apoptosis [67]. [17] and the fact that it satisfied all the recommendations for We appreciate that the Basalay study is the only one to-date preclinical trials on cardioprotection [53, 56, 59, 86, 87]. reporting the benefit of delayed RIPost [5 ], and is, there- The majority of clinical studies to date have demonstrated fore, still awaiting independent confirmation. Nonetheless, the infarct-limiting effect of RIC [15, 21, 28, 36, 105, 141] the clinical potential of this cardioprotective phenomenon and improved outcome [40, 125] as a result of this procedure can be significant, as it potentially broadens the time frame in patients with STEMI. The one exception is a recent study during which myocardial injury can be prevented. Moreover, with neutral results, however, no long-term outcome data the possibility to protect myocardium beyond the first few are currently available from this study [135]. In the setting minutes of reperfusion has also been supported by studies of elective cardiac surgery, a single-centre trial involving from the groups of Ovize, Marbán and others [4, 27, 38, 71, 329 patients with isoflurane, used for the maintenance of 116], which have demonstrated cardioprotection with inter- anesthesia, suggested that RIPre provided perioperative ventions applied up to the 20th min (rats, isolated rat hearts) myocardial protection [133] and improved the prognosis [27, 38], 30th min (minipigs, mice) [71, 116] or 45th min over 1.54 years [133] and 5 years, respectively [81]. Another (rats) [4] of myocardial reperfusion. small-scale clinical study on patients undergoing elective Though RIPre first emerged as a laboratory phenomenon, aortic valve replacement, demonstrated that RIPre reduced the cardioprotective potential of RIC strategies has subse- myocardial injury if applied on a background of sevoflurane, quently drawn the attention of numerous clinical research but not propofol anesthesia [9, 10]. Two, large, multicentre groups [15, 28, 31, 36, 40, 82, 96, 105, 133, 135, 141]. In clinical trials on cardiac surgery patients using propofol for contrast to the repeated failures to translate cardioprotection anesthesia [31, 96], and one small clinical study with periop- from animal studies to clinical practice [42, 51, 59], RIC still erative anesthesia restricted to sevoflurane and fentanyl [99] appears to be a promising candidate for clinical use based failed to show any benefits of using RIPre. Bearing in mind 1 3 Basic Research in Cardiology (2018) 113:25 Page 3 of 15 25 the success of the previous (proof of concept) clinical trials C-fiber afferents by topical capsaicin application limits myo- both in STEMI patients and in patients undergoing cardiac cardial injury, mimicking the effect of RIPre [5 , 112]. It has surgery, these neutral results indicate the gaps in the knowl- been shown that calcitonin gene-related peptide (CGRP)— edge of the mechanisms underlying the RIC phenomena, as an important mediator of sensory neurons—mediates cardio- well as lack of the differences between the mechanisms of protection by RIPre [142]. Abrogation of protection by RIC myocardial ischaemia/reperfusion injury in these two clini- with spinal cord transection at T7–T10 level [34], or with cal settings. It is, therefore, imperative to investigate the intrathecal spinal opioid receptor blockade [143], confirmed mechanism of RIC to facilitate the translation of this simple, the involvement of the neural afferent pathway. The effec- non-invasive, low-cost intervention into patient benefit. Two tor arm of the RIPer reflex appears to involve parasympa- large-scale multicentre clinical trials on STEMI patients are thetic innervation. In the studies by Basalay et al., bilateral ongoing (NCT02342522; NCT01857414). Their results, due vagotomy in a rat model abolished cardioprotection induced in 2019, will shed more light on the effects and possible by either RIPre [5, 6] or RIPer [6]. Mastitskaya et al. went confounding factors of cardioprotection by RIC. further and directly inhibited parasympathetic motor neu- rons which are known to be located in two distinct brain- stem sites [93]. This resulted in complete abolishment of The mechanisms of cardioprotection the infarct-limiting effect of RIPre [93]. Notably, this study by remote ischaemic conditioning was the first to provide direct evidence for the involvement with regard to translational aspects of vagal efferents in RIPre-mediated cardioprotection. It is noteworthy that bilateral vagotomy in the Basalay et al. After the discovery of RIPre, two main competing hypoth- study did not attenuate the infarct-limiting effect of delayed eses evolved regarding the mechanism of signal transduction RIPost [5], which suggested that the mechanisms underly- from the preconditioned limb to the protected heart, one ing these two phenomena may be distinct. Surprisingly, in called the ‘humoral hypothesis’ and the other—the ‘neural a recent study by Buchholz et al., vagal stimulation in mice hypothesis’. The humoral hypothesis is based on the fact that reduced myocardial infarct size when applied either before RIC-induced cardioprotection can be transferred to a naïve ischaemia or at the onset of reperfusion [18]. However, this animal via whole blood transfusion [32]. Conversely, Gho study also revealed the difference in cardioprotective mecha- et al. demonstrated that the neural blocker, hexamethonium, nisms of these two time-periods of vagal stimulation: the abolished cardioprotection by brief mesenteric artery occlu- first activated the Akt/GSK-3β muscarinic pathway, while sion [43], suggesting the important role for the autonomic the second activated α7nAChR and JAK-2, independently of ganglia in RIPre. However, in a later study by Weinbren- the cholinergic anti-inflammatory pathway [18]. The results ner et al., hexamethonium failed to inhibit the protection of these studies [5, 18] raise the possibility that additive afforded by RIPre, performed as infrarenal occlusion of the benefit could be achieved by combining different types of aorta [140]. This result, as well as the necessity for a reper- RIC. A recent study by Kleinbongard et al. confirms the fusion period interspaced between the RIPre and myocardial neuronal transfer of the protective signal during RIC [78]. ischaemia, during which time the humoral factor could travel In this study, RIC was demonstrated to attenuate ischaemia- to the heart, were viewed as reasons to exclude the hypoth- induced ST-segment elevation on the ECG during ongoing esis of a neuronal signal transmission from the remote area coronary artery occlusion [78]. to the heart [140]. Yellon’s group were the first to demonstrate the involve- In 2010, Gourine et  al. proposed the existence of a ment of both neural and humoral pathways in RIPre [89]. ‘remote preconditioning reflex’—a neural pathway of car - They found that in an RIPre model of femoral artery occlu- dioprotection which is recruited by RIPre and protects the sion in mice, the absence of venous blood return from the heart against ischaemia and reperfusion injury [44] (Fig. 2). preconditioned limb, or combined femoral and sciatic nerve This idea was supported by the data indicating the pres- resection, completely abolished the infarct-limiting effect. ence of all the components necessary for the realization of Moreover, resection of only one nerve—either femoral a classical reflex in the pathway mediating cardioprotection or sciatic—only partially abolished this effect [89]. In an by RIPer: sensory (afferent) C-fiber neurons, an integration elegant study, Jensen et al. confirmed the requirement for centre in the central nervous system, and motor (efferent) both the neural and humoral pathways in RIPre-mediated vagal neurons. In this regard, it has been demonstrated in cardioprotection by testing whether human plasma dialysate a rat model of myocardial ischaemia/reperfusion injury, obtained after RIC could reduce infarct size and improve that cardioprotection by RIPre is completely abolished by hemodynamic recovery in isolated rabbit hearts [64]. They denervation of the limbs performed as either mechanical showed that the plasma dialysate was protective if obtained transection of nerves [5, 130] or blocking afferent C-fibers from healthy subjects or diabetic subjects without peripheral by neonatal capsaicin treatment [5]. Similarly, stimulation of neuropathy, but when obtained from diabetic patients with 1 3 25 Page 4 of 15 Basic Research in Cardiology (2018) 113:25 Fig. 2 Neural mechanisms of remote ischaemic preconditioning. centration in the myocardium mediates the cardioprotective effects A diagram of connections (both known and controversial) between of remote preconditioning. It is also unclear which of the abdominal n. vagus fibres—afferent or efferent—are involved in this phenom- the neural and humoral mechanisms of remote ischaemic precondi- enon. The known humoral factors that have the closest relationship tioning of the heart and the brain. The core of this mechanism is the with neural mechanisms are GLP-1 and nitrite. However, the source ‘remote preconditioning reflex’ comprising afferent somatic nerves, of their release in response to remote ischaemic stimulus is not clear. integration centre/centres in the central neural system, and efferent GLP-1 glucagon-like peptide-1, ACh acetylcholine vagal nerves, innervating the heart and other organs, specifically, the intestine. However, it is not certain whether the increase in ACh con- neuropathy it was not protective. These findings further indi- infarct size in naïve isolated hearts subjected to ischaemia cate that the mechanism of a humoral factor release involves and reperfusion. However, the plasma was no longer cardio- neural pathways [64]. protective if collected from vagotomised animals, or if the Because the initial studies investigating the role of the ganglionic blocker hexamethonium or muscarinic antagonist autonomic ganglia in RIPre-mediated cardioprotection had atropine were applied to isolated hearts [103]. This led to been controversial [43, 140], this question was re-visited by the conclusion that release of a protective factor following Yellon’s group in 2016 [102, 103]. They demonstrated that RIC is dependent on prior activation of the vagus nerve. In plasma dialysate obtained from RIPre-treated rats reduced addition, the factor appears to induce cardioprotection via 1 3 Basic Research in Cardiology (2018) 113:25 Page 5 of 15 25 recruitment of intrinsic cardiac ganglia. Their subsequent with vagal sensory fibers innervating the viscera [58]. The study, demonstrating that coronary effluent from a precon- molecular weight of GLP-1 is 3.3 kDa thereby satisfying the ditioned isolated heart could protect another isolated heart, key criteria of the humoral preconditioning factor (including but not isolated cardiomyocytes, also contributed to the molecular weight of less than 8 kDa), suggested by Lang and hypothesis of the importance of intrinsic cardiac ganglia in colleagues on the basis of the proteomic analysis of blood the mechanisms of direct ischaemic preconditioning [102]. samples obtained from experimental animals receiving the Since the first demonstration of the possibility to trans- RIPre stimulus [85]. Studies conducted in animal models by fer ischaemic preconditioning cardioprotection with blood the Yellon group [13, 14], and subsequently by others [111], [32], the attention of several research groups has focused demonstrated potent cardioprotection by GLP-1 receptor on identifying the humoral factor responsible for RIPre. (GLP-1R) activation. The efficacy of GLP-1R agonists in Several candidate humoral factors of RIC have been pro- limiting infarct size has also been shown in clinical trials on posed, including stromal cell-derived factor-1 [30], nitrite/ STEMI patients [90, 144]. Later, Basalay et al. showed that nitric oxide [110], interleukin-1α [41], interleukin-10 [19], GLP-1 mediates cardioprotection by RIC, and demonstrated microRNA-144 [88], apolipoprotein A-I [57], alpha-ketoglu- that cardioprotection induced by GLP-1R activation is medi- tarate-dependent dioxygenase Egln1 [101] and glucagon-like ated by a mechanism involving M3 muscarinic receptors [7, peptide-1 (GLP-1) [7, 8]. However, for the purpose of this 8]. The location of these M3 muscarinic receptors, mediat- review, we focus on two of the proposed humoral media- ing the infarct-limiting effect of RIPre, is not yet established. tors that are most relevant to the ‘neural hypothesis’ of RIC, The main extracellular signaling molecules that namely nitrite/nitric oxide [110] and GLP-1 [7, 8]. have been shown to be involved in cardioprotection by Using an in  vivo mouse model, Rassaf et  al.  demon- RIPre  include opioids, bradykinin and adenosine [79]. strated that shear stress-dependent stimulation of endothe- Opioid peptides can be secreted from cardiac nerves lial nitric oxide (NO) synthase within a femoral artery by or produced in the cardiomyocytes themselves [107]. RIPre yields a substantial release of NO. This NO is subse- Shimizu et al. demonstrated that the protective effect of quently oxidized to nitrite and transferred humorally to the dialysate from a donor limb subjected to RIC, on isolated myocardium, where it reduces infarct size caused following cardiomyocytes is blocked by pre-treatment of the car- 30-min myocardial ischaemia and 24-h reperfusion [110]. diomyocytes with the opiate receptor blocker naloxone In addition, a series of experiments in which plasma from [122]. These results suggest that opioid receptors involved healthy volunteers subjected to RIPre was perfused through in RIC are located in cardiomyocytes and not connected isolated mouse hearts, identified plasma nitrite as the car - with neural activation. On the other hand, in another dioprotective agent [110]. Similarly, in a recent study by study, hexamethonium abolished the protection provided Hauerslev et al., scavengers of NO attenuated RIPre-induced by intramesenteric bradykinin infusion [119]. Regard- protection in rat hearts [47]. Previously, it had been shown ing bradykinin, it is worth mentioning that it is degraded that either stimulation of cervical vagal nerves or perfusion rapidly by angiotensin-converting enzyme (ACE) [136], with acetylcholine is associated with NO release in an iso- while ACE inhibitors and angiotensin-1 receptor antago- lated rabbit heart via the neuronal isoform of NO synthase nists [63] mimic its cardioprotective effects. The role of [16]. Interestingly, in an earlier study, bilateral vagal nerve adenosine in RIC cardioprotection is still controversial, stimulation in rabbits was followed by an increase in nitrite being confirmed in a mouse model [ 120], but not a porcine formation at the level of the stomach and the colon [62]. model [48]. In terms of planning future clinical studies on the effect of Analysis of the concentrations of metabolites in plasma RIC, it is important to keep in mind that exogenous NO [98] samples of patients subjected to RIC revealed an increase and nitroglycerin [35, 50, 148, 155] have been shown to be in glycine concentration following RIC [23]. This is rel- able to reduce infarct size, and may therefore, potentially evant to the current review, as glycine is known to be an interfere with RIC. inhibitory neurotransmitter in the central nervous sys- The results obtained by Mastitskaya et al. [92] suggest tem, and specifically, in parasympathetic nuclei [22, 131, that visceral organs, innervated by the posterior gastric 132]. In the above-mentioned study, the injection of gly- branch of the vagus nerve, are the likely source of a humoral cine mimicked the protective effects of RIC in rats [23]. factor (or factors) of RIC cardioprotection. This finding is García-Dorado’s group demonstrated that glycine exerts interesting as it provides the first potential mechanism unit- cross-species cardioprotection against infarction through ing the ‘neural’ and ‘humoral’ hypotheses of RIC. Apart glycine receptor activation [66]. The potential involvement from nitric oxide [62], GLP-1 appears to be the most likely of glycine signalling in RIC-induced cardioprotection candidate for this role. Its release from the L-cells of the should be borne in mind when planning clinical trials, as intestine is modulated by vagal efferent (motor) activity certain drugs, such as Ketamine [137], can inhibit glycine [58, 115] and there is also evidence that GLP-1 may interact neurotransmission to cardiac vagal neurons. 1 3 25 Page 6 of 15 Basic Research in Cardiology (2018) 113:25 The importance of understanding the mechanism of situations with patients suffering from peripheral polyneu- RIC cardioprotection is clearly demonstrated by the neutral ropathies of different etiologies, or exposed to drugs with results of two recent multicentre trials—ERICCA and RIPH- vagolytic effects, these results allow us to predict a lack eart, in which the majority of the patients were given propo- of cardioprotective benefit from RIPre in these cohorts of fol as part of the anesthesia protocol [31, 96]. Importantly, it patients. On the other hand, delayed RIPost could potentially had previously been shown that propofol inhibits neurotrans- be more effective in the same patients, being less susceptible mission to cardiac vagal neurons in the nucleus ambiguous to innervation impairments, though no clinical trials demon- [138]. On the other hand, propofol had been shown to cause strating this have been completed so far. the enhanced nitrite production in cultured myocytes [146], The other missing part in our knowledge is the mecha- whereas nitrite is known as one of the humoral mediators of nism of vagally mediated RIPre cardioprotection. The feasi- RIPre [110]. The results of small-scale clinical trials com- bility of vagally mediated cardioprotection (i.e., RIPre) in a pleted in 2012 and 2014 confirmed the importance of the left ventricle, which is known to be only sparsely innervated, anesthetic regime, showing that RIPre during isoflurane but can be explained by the observation that there is a local ace- not during propofol anesthesia decreased myocardial damage tylcholine (ACh) synthesis system in the myocardium [37, in patients undergoing CABG surgery [82] or elective aortic 69, 109]. This system is positively modulated by cholinergic valve replacement [9, 10]. A recent experimental study also stimuli [69]. Conversely, atropine reduces the basal ACh clearly demonstrated that propofol, but not sevoflurane, abol- content [69]. It has been shown that either bilateral vagot- ished the infarct-limiting effect of RIPre in rats in vivo [ 11]. omy [5] or direct inhibition of the parasympathetic motor In a more recent single-centre study with a neutral effect of neurons in the central nervous system [93], or atropine treat- RIC in CABG patients, propofol was purposefully avoided ment [34] abolishes the infarct-limiting effect of RIPre. Yet, [99]. However, in this study, the anesthetic protocol included it is not clear whether it is the increase of acetylcholine con- fentanyl, which has been shown to inhibit neurotransmission centration that mediates the cardioprotective effect of RIC. to cardiac vagal neurons in the nucleus ambiguous [45]. It There are a number of experimental observations relevant to could also be argued, however, that fentanyl or sufentanil the assumption that it is indeed acetylcholine which medi- did not abolish RIC-induced cardioprotection in other clini- ates RIPre. First, in support of this hypothesis, the hearts cal studies [9, 133]. Although there are multiple possible from transgenic mice overexpressing choline acetyltrans- reasons for the lack of protection in these studies, as has ferase (ChAT)—the main ACh-synthesizing enzyme in car- been extensively discussed [25, 39, 55], the suppressed vagal diomyocytes—are more resistant to ischaemia–reperfusion system is likely to have contributed. injury than wild-type hearts [70]. And second, RIC increases The effect of an anesthetic protocol on RIC efficacy was both ChAT expression and ACh content in mice hearts [68, revealed in a Bayesian network meta-analysis of 55 rand- 100]. However, there are also experimental data that con- omized trials, which included 6921 patients undergoing car- tradict this hypothesis. In this regard, it has been shown that diac surgery. The use of volatile agents and the combination acute myocardial ischaemia provoked an increase of ACh of volatile agents with remote preconditioning were found concentration in an ischaemic myocardium, and vagotomy to be associated with a reduction in mortality at the longest did not affect this increase [76], while on the other hand, follow-up time available, when compared to total intrave- vagotomy abolished the infarct-limiting effect of RIPre [5 ]. nous anesthesia [151]. Furthermore, it was observed that This indicates that the loss of RIPre-mediated cardioprotec- the combination of RIC with volatile agents was associated tion in vagotomised rats [5] might be caused by some other with a reduction in mortality when compared to RIC with factors rather than a decrease in ACh concentration. Another total intravenous anesthesia [151]. indirect argument suggesting that ACh concentration may not be of critical importance for ischaemic precondition- ing is that vagotomy abolishes the myocardial interstitial Unresolved questions and discrepancies ACh release induced by brief myocardial ischaemia [75]. on the mechanisms of cardioprotection On the other hand, bilateral vagotomy does not attenuate the by remote ischaemic conditioning infarct-limiting effect of direct ischaemic preconditioning [5], which indicates that ACh concentration in the myocar- Although the degree of cardioprotection conferred by RIPre dium does not correlate with the degree of cardioprotection. and delayed RIPost is similar, the underlying mechanisms Currently, there are no data revealing whether RIPre causes seem to be distinct [5]. In the Basalay et al.’s study (2012), further increase of ACh concentration in the ischaemic myo- the infarct-limiting effect of delayed RIPost was not affected cardium in comparison to the myocardial ischaemia itself, by either vagotomy or peripheral denervation, as opposed to and whether vagotomy prevents this additional increase. The the effect of RIPre [5 ]. As peripheral or especially parasym- answer to this question is even more difficult, as the degree pathetic denervation, can potentially represent real clinical of ACh increase during myocardial ischaemia varies from 1 3 Basic Research in Cardiology (2018) 113:25 Page 7 of 15 25 study to study, depending on the animal species, samples and electrical stimulation of right [3, 18, 20, 72, 73], left [123, techniques used, as well as on the duration of the ischaemic 124] or both vagal nerves [134] limited myocardial infarct episode [74, 76, 102]. size when started either before [18, 20, 72] or during [3, Despite the lack of experimental data that would unequiv- 73, 123, 124, 134] myocardial ischaemia, or at the onset of ocally answer the question of myocardial ACh concentration reperfusion [18]. In a clinical study by Yu et al., low-level in RIC-mediated cardioprotection, there are several observa- transcutaneous stimulation of the vagal branch within the tions that may shed some light on this aspect. In this respect, area of the right tragus, in patients presenting with STEMI, it was demonstrated that cardiomyocytes of adult, but not was followed by the reduction of the incidence of reper- neonatal rats, are able to synthesize, transport and excrete fusion-related ventricular arrhythmia, the area under curve ACh in the heart [109]. The expression level of ChAT and for creatine kinase-MB and myoglobin over 72 h, and blood the amount of ACh excreted were also significantly down- levels of inflammatory markers [52, 150]. In the study by regulated in cardiomyocytes of old animals [109]. If ACh Basalay et al., the activity of only one vagal nerve—either concentration in myocardium determines the potency of pro- right or left—was sufficient and contributed equally to medi- tection by RIC, we may expect that RIC would be less effec- ate cardioprotection established by RIPre. On the other hand, tive in children and aged people. Indeed, RIPre was actually functional integrity of both nerves was required to establish shown to impair ventricular function and increase infarct size cardioprotection when the remote conditioning stimulus was in an isolated neonatal rabbit heart [118]. An earlier, small- applied during myocardial ischaemia [6]. However, the dif- scale clinical study had demonstrated myocardial-protective ferences in the mechanisms of RIPre and RIPer leading to effects of RIPre in children [26]. However, in a more recent this difference [6 ] have not been explained. Another aris- clinical trial performed on 299 children (aged neonate to ing question is—whether electrical vagal nerve stimulation 17 years), RIPre was not associated with important improve- can completely mimic all aspect of RIC, which include the ments in clinical outcomes and physiological markers after indirect stimulation of the release of humoral factors [52]. cardiac surgery [95]. It should be noted, however, that there While the importance of the activation of parasympa- was no standardized protocol of anesthesia in this study, thetic efferents in RIC-mediated cardioprotection is now and more than half the patients were exposed to propofol unambiguous, the role of the sympathetic nervous system [95]. The effect of RIC in elderly patients (> 70 years) was in this phenomenon has not been described clearly. How- investigated in the CONDI trial, and found to be equally ever, it has been demonstrated that beta-blockers reduce as protective as in younger patients [126]. Similarly, in the infarct size in STEMI patients undergoing PCI [61], and LIPSIA CONDITIONING trial, the combination of RIC and this group of drugs is currently included in the guidelines local ischaemic postconditioning was effective in both age for the management of these patients [60]. It has been shown groups—under and over 65 years old [36]. Similar results that beta-adrenoreceptors are involved in the mechanisms of were obtained after the analysis of confounders of RIPre myocardial infarct-limiting effect of remote pre- and post - cardioprotection in patients undergoing coronary artery conditioning of trauma [128, 129]. The existence of some bypass grafting [80]. In a recent experimental study by common, inherent mechanisms, such as the activation of Heinen et al., plasma of young male volunteers, subjected C sensory fibers and the K(ATP) channels for both remote to RIC, reduced infarct size in isolated hearts from aged rats preconditioning of trauma [65] and RIPre/RIPer [5, 83, 117], [49]. However, RIC plasma of aged male volunteers had no may be an argument to suggest that sympathetic beta-adren- protective effect in young rat hearts [49]. This indicates that ergic activation is involved in the mechanisms of RIC car- aging affects the RIC-induced release of a humoral factor, dioprotection. On the other hand, it has been demonstrated but not the susceptibility of myocardium to the protective in rats that exercise training, which shares some molecular effect of this phenomenon. mechanisms with RIC [108, 121], augments the dynamic One of the main purposes for investigating the mecha- heart rate response to vagal but not sympathetic stimula- nisms of endogenous cardioprotective phenomena is the tion [97]. Moreover, it is known that sympathetic nervous potential to develop pharmacological therapy or electronic response to ischaemia–reperfusion injury is altered with devices that can fully mimic its positive effects. These could RIPre [84]. In the CONDI trial, the infarct-limiting effect have the advantage of being able to be applied or admin- of RIC was preserved in beta-blocker users [126]. Although istered significantly more quickly than the RIC procedure, there are no available data on the effect of beta-blockers which requires up to 40 min. As RIPre/RIPer cardioprotec- on the efficacy of RIC in other clinical trials with STEMI tion is mediated by the activation of vagal efferents [5 , 93], patients, the fact that remote conditioning was able to reduce it is logical to assume that vagal nerve stimulation could infarct size in the clinical study, where almost all the patients potentially reproduce the effects of RIC. The obvious were taking beta-blockers [36], reinforced the CONDI question arising here is whether monolateral vagal nerve results (Table 1). Similarly, medication with beta-blockers stimulation can achieve this goal. In experimental studies, was not a significant confounder of RIPre cardioprotection 1 3 25 Page 8 of 15 Basic Research in Cardiology (2018) 113:25 Table 1 The use of beta1- First author Year Country Number of Beta-blockers use RIC effect Endpoints blockers in clinical studies patients (RIC/control, %) on the effect of remote ischaemic conditioning in Bøtker HE 2010 Denmark 333 15/15 Yes MSI (SPECT) patients undergoing primary Rentoukas I 2010 Greece 96 99/100 n.s. Peak TnI percutaneous coronary Crimi G 2013 Italy 100 13/20 Yes AUC CK-MB interventions Eitel I 2015 Germany 696 96/98 Yes MSI (MRI) Verouhis D 2016 Sweden 93 10/15 No MSI (MRI) Gaspar A 2018 Portugal 258 14/16 Yes Progression of heart failure RIC remote ischaemic conditioning, MSI myocardial salvage index, SPECT single-photon emission-com- puted tomography, TnI troponin I, AUC ar ea under curve, CK-MB creatine kinase-muscle/brain, MRI mag- netic resonance imaging in patients undergoing cardiac surgery [80]. In contrast, a including the possible involvement of endogenous opioids meta-analysis of 15 clinical trials, including 1155 patients [113, 154] and CGRP [113]. On the other hand, in one randomised to treatment with or without RIPre, showed study, local electrical stimulation enhanced the neuropro- an attenuated effect of this intervention in cardiosurgery tective effect of RIPost in a rat stroke model [145], which patients on perioperative beta-blocker treatment [153]. might suggest that the mechanisms underlying the thera- peutic effects of these interventions are different. Pigna - taro et al. demonstrated that the neuronal isoform of nitric Remote ischaemic conditioning of the brain oxide synthase takes part in the neuroprotective effect of RIPost [104]. Further investigation of the neuroprotec- In addition to protecting the heart, RIC is potentially able tive mechanism of RIC is important to establish the most to protect any other organ or tissue. It has been shown in a effective and safe implementation of this phenomenon to series of experimental studies that RIPre, RIPer, RIPost and clinical practice. delayed RIPost reduce brain infarct size in a rodent model of The activity of the cardiovascular system is continu- acute focal ischaemia/reperfusion brain injury [24]. Interest- ally modulated by the central nervous system, ensuring ingly, the reperfusion ‘time-window’, during which delayed coordination and regulation of regional cardiac electri- RIPost was effective, seems to be longer in an ischaemic cal, mechanical and metabolic indexes throughout each stroke model [104, 114] than in a STEMI model [4, 5]. In cardiac cycle [2]. This fine regulation is provided by the this regard, in a rat model with 100-min focal brain ischae- neuronal elements, which are distributed from the level of mia, RIPost was able to reduce infarct size when initiated the insular cortex to the intrinsic cardiac nervous system, within 30 min of reperfusion [104]. Impressively, when sub- and are in constant communication with one another [2]. ject to 30-min brain ischaemia, RIPost was effective up to In this regard, both ischaemic and haemorrhagic strokes 3 h of reperfusion [114]. A meta-analysis of 13 randomized can cause abnormalities in autonomic nervous system controlled trials, which included a total of 794 study partici- activity, followed by functional imbalance within the car- pants who either suffered from, or were at risk from brain diovascular system, and in certain situations—even by ischaemia and reperfusion injury, suggested that RIPost can irreversible cardiomyocyte damage, determined as serum offer cerebral protection for stroke patients [152]. Compared troponin elevation [33]. On the other hand, nociceptive with controls, RIPost was shown to be able to reduce the sensory inputs arising from the ischaemic heart represent a recurrence of stroke or transient ischaemic attacks, levels of stimulus that can evoke discord within and among different National Institutes of Health Stroke Scale score, modified levels of the hierarchy of the neuronal elements connecting Rankin Scale score and high-sensitivity C-reactive protein heart, brain and central nervous system [2, 54]. Bearing in [152]. mind the existence of these bidirectional feedback interac- The studies on the mechanisms of RIC-induced neuro- tions between the heart and brain [2], and specifically the protection are quite scarce in comparison with the amount involvement of brain subcortical structures in ‘remote pre- of studies on the mechanisms of RIC-induced cardiopro- conditioning reflex’ [44, 93], more detailed understanding tection. Similar to RIC-induced cardioprotection, there is of the mechanisms of RIC-induced neuroprotection would evidence for the involvement of the neural pathway in the shed more light on the mechanisms RIC-induced cardio- mechanism of RIC of the brain [91, 104, 114, 139, 149], protection and myocardial ischaemia/reperfusion injury. 1 3 Basic Research in Cardiology (2018) 113:25 Page 9 of 15 25 Open Access This article is distributed under the terms of the Crea- Conclusions tive Commons Attribution 4.0 International License (http://creat iveco mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Investigating the mechanisms of RIC is the essential step on tion, and reproduction in any medium, provided you give appropriate the road to its translation to patient benet fi , and specic fi ally to credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. the discovery of therapies or electronic devices, which would be able to mimic the beneficial effects of this phenomenon. 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Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

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Medicine & Public Health; Cardiology
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Abstract

Remote ischaemic conditioning (RIC) is a promising method of cardioprotection, with numerous clinical studies having demonstrated its ability to reduce myocardial infarct size and improve prognosis. On the other hand, there are several clini- cal trials, in particular those conducted in the setting of elective cardiac surgery, that have failed to show any benefit of RIC. These contradictory data indicate that there is insufficient understanding of the mechanisms underlying RIC. RIC is now known to signal indiscriminately, protecting not only the heart, but also other organs. In particular, experimental studies have demonstrated that it is able to reduce infarct size in an acute ischaemic stroke model. However, the mechanisms underlying RIC-induced neuroprotection are even less well understood than for cardioprotection. The existence of bidirectional feedback interactions between the heart and the brain suggests that the mechanisms of RIC-induced neuroprotection and cardioprotec- tion should be studied as a whole. This review, therefore, addresses the topic of the neural component of the RIC mechanism. Keywords Remote ischaemic conditioning · Cardioprotection · Neuroprotection Introduction percutaneous coronary intervention (PCI)—scenarios when the onset and the duration of ischaemia are carefully con- It is almost 25 years since the phenomenon of remote ischae- trolled (Fig. 1). mic preconditioning (RIPre) was discovered by Przyklenk Twelve years after the discovery of RIPre, it was shown et al. [106]. They demonstrated in a canine model that a in a rat model that remote ischaemic conditioning (RIC) series of brief, alternating episodes of ischaemia and reper- could be applied to a limb during myocardial ischaemia, and fusion, applied to one area of the left ventricle (LV) myocar- reduce infarct size by 50% [77]. This phenomenon became dium, protected a remote myocardial territory of the same known as remote ischaemic preconditioning (RIPer). The heart from a subsequent prolonged ischaemic insult followed next step in the study of RIC came with the demonstration by by reperfusion, limiting infarct size by almost 70%. In the Andreka et al., that RIC could be successfully administered same year, McClanahan et al. [94] achieved a similar infarct- simultaneously with the onset of myocardial reperfusion— limiting effect in rabbits by applying a single 10-min episode a phenomenon named as remote ischaemic postcondition- of ischaemia to a kidney prior to 30-min occlusion of the ing (RIPost) [1]. Taking this one step further, Basalay et al. left anterior-descending coronary artery. However, since the demonstrated in a rat model of acute myocardial infarction RIPre stimulus must, by definition, be applied before the that RIPost applied after a 10-min delay following the onset onset of ischaemia, it is clear that the only possible clinical of reperfusion was still able to reduce infarct size similarly niche for the RIPre phenomenon in cardioprotection could to RIPre [5]. Notably, the results included in this study were be in the setting of either elective cardiac surgery or elective obtained in three research centres, using identical protocols [5]. The success of this procedure, termed ‘delayed RIPost’, was unexpected, in view of the prevailing hypothesis that * Derek M. Yellon the majority of myocardial reperfusion cell death is due to d.yellon@ucl.ac.uk the opening of mitochondrial permeability transition pores The Hatter Cardiovascular Institute, University College (mPTP), thought to occur during the first few minutes of London, 67 Chenies Mews, London WC1E 6HX, UK reperfusion [29, 46]. However, a series of studies demon- Department of Cardiology, Karolinska University Hospital, strated implication of non-mPTP/necrosis mechanisms in 171 76 Stockholm, Sweden Vol.:(0123456789) 1 3 25 Page 2 of 15 Basic Research in Cardiology (2018) 113:25 Fig. 1 Schematic time lines representing the concepts of remote ischaemic pre-, per-, post- and delayed postcondition- ing, and the clinical scenarios in which they may be relevant. STEMI ST-elevated myocar- dial infarction. Asterisk—the evidence for the existence of the delayed remote ischaemic postconditioning phenomenon is currently limited having only been demonstrated in one experimental study myocardial death [59] including pyroptosis [147], necrop- both on the large number of successful experimental studies tosis [12, 127], and, more controversially, apoptosis [67]. [17] and the fact that it satisfied all the recommendations for We appreciate that the Basalay study is the only one to-date preclinical trials on cardioprotection [53, 56, 59, 86, 87]. reporting the benefit of delayed RIPost [5 ], and is, there- The majority of clinical studies to date have demonstrated fore, still awaiting independent confirmation. Nonetheless, the infarct-limiting effect of RIC [15, 21, 28, 36, 105, 141] the clinical potential of this cardioprotective phenomenon and improved outcome [40, 125] as a result of this procedure can be significant, as it potentially broadens the time frame in patients with STEMI. The one exception is a recent study during which myocardial injury can be prevented. Moreover, with neutral results, however, no long-term outcome data the possibility to protect myocardium beyond the first few are currently available from this study [135]. In the setting minutes of reperfusion has also been supported by studies of elective cardiac surgery, a single-centre trial involving from the groups of Ovize, Marbán and others [4, 27, 38, 71, 329 patients with isoflurane, used for the maintenance of 116], which have demonstrated cardioprotection with inter- anesthesia, suggested that RIPre provided perioperative ventions applied up to the 20th min (rats, isolated rat hearts) myocardial protection [133] and improved the prognosis [27, 38], 30th min (minipigs, mice) [71, 116] or 45th min over 1.54 years [133] and 5 years, respectively [81]. Another (rats) [4] of myocardial reperfusion. small-scale clinical study on patients undergoing elective Though RIPre first emerged as a laboratory phenomenon, aortic valve replacement, demonstrated that RIPre reduced the cardioprotective potential of RIC strategies has subse- myocardial injury if applied on a background of sevoflurane, quently drawn the attention of numerous clinical research but not propofol anesthesia [9, 10]. Two, large, multicentre groups [15, 28, 31, 36, 40, 82, 96, 105, 133, 135, 141]. In clinical trials on cardiac surgery patients using propofol for contrast to the repeated failures to translate cardioprotection anesthesia [31, 96], and one small clinical study with periop- from animal studies to clinical practice [42, 51, 59], RIC still erative anesthesia restricted to sevoflurane and fentanyl [99] appears to be a promising candidate for clinical use based failed to show any benefits of using RIPre. Bearing in mind 1 3 Basic Research in Cardiology (2018) 113:25 Page 3 of 15 25 the success of the previous (proof of concept) clinical trials C-fiber afferents by topical capsaicin application limits myo- both in STEMI patients and in patients undergoing cardiac cardial injury, mimicking the effect of RIPre [5 , 112]. It has surgery, these neutral results indicate the gaps in the knowl- been shown that calcitonin gene-related peptide (CGRP)— edge of the mechanisms underlying the RIC phenomena, as an important mediator of sensory neurons—mediates cardio- well as lack of the differences between the mechanisms of protection by RIPre [142]. Abrogation of protection by RIC myocardial ischaemia/reperfusion injury in these two clini- with spinal cord transection at T7–T10 level [34], or with cal settings. It is, therefore, imperative to investigate the intrathecal spinal opioid receptor blockade [143], confirmed mechanism of RIC to facilitate the translation of this simple, the involvement of the neural afferent pathway. The effec- non-invasive, low-cost intervention into patient benefit. Two tor arm of the RIPer reflex appears to involve parasympa- large-scale multicentre clinical trials on STEMI patients are thetic innervation. In the studies by Basalay et al., bilateral ongoing (NCT02342522; NCT01857414). Their results, due vagotomy in a rat model abolished cardioprotection induced in 2019, will shed more light on the effects and possible by either RIPre [5, 6] or RIPer [6]. Mastitskaya et al. went confounding factors of cardioprotection by RIC. further and directly inhibited parasympathetic motor neu- rons which are known to be located in two distinct brain- stem sites [93]. This resulted in complete abolishment of The mechanisms of cardioprotection the infarct-limiting effect of RIPre [93]. Notably, this study by remote ischaemic conditioning was the first to provide direct evidence for the involvement with regard to translational aspects of vagal efferents in RIPre-mediated cardioprotection. It is noteworthy that bilateral vagotomy in the Basalay et al. After the discovery of RIPre, two main competing hypoth- study did not attenuate the infarct-limiting effect of delayed eses evolved regarding the mechanism of signal transduction RIPost [5], which suggested that the mechanisms underly- from the preconditioned limb to the protected heart, one ing these two phenomena may be distinct. Surprisingly, in called the ‘humoral hypothesis’ and the other—the ‘neural a recent study by Buchholz et al., vagal stimulation in mice hypothesis’. The humoral hypothesis is based on the fact that reduced myocardial infarct size when applied either before RIC-induced cardioprotection can be transferred to a naïve ischaemia or at the onset of reperfusion [18]. However, this animal via whole blood transfusion [32]. Conversely, Gho study also revealed the difference in cardioprotective mecha- et al. demonstrated that the neural blocker, hexamethonium, nisms of these two time-periods of vagal stimulation: the abolished cardioprotection by brief mesenteric artery occlu- first activated the Akt/GSK-3β muscarinic pathway, while sion [43], suggesting the important role for the autonomic the second activated α7nAChR and JAK-2, independently of ganglia in RIPre. However, in a later study by Weinbren- the cholinergic anti-inflammatory pathway [18]. The results ner et al., hexamethonium failed to inhibit the protection of these studies [5, 18] raise the possibility that additive afforded by RIPre, performed as infrarenal occlusion of the benefit could be achieved by combining different types of aorta [140]. This result, as well as the necessity for a reper- RIC. A recent study by Kleinbongard et al. confirms the fusion period interspaced between the RIPre and myocardial neuronal transfer of the protective signal during RIC [78]. ischaemia, during which time the humoral factor could travel In this study, RIC was demonstrated to attenuate ischaemia- to the heart, were viewed as reasons to exclude the hypoth- induced ST-segment elevation on the ECG during ongoing esis of a neuronal signal transmission from the remote area coronary artery occlusion [78]. to the heart [140]. Yellon’s group were the first to demonstrate the involve- In 2010, Gourine et  al. proposed the existence of a ment of both neural and humoral pathways in RIPre [89]. ‘remote preconditioning reflex’—a neural pathway of car - They found that in an RIPre model of femoral artery occlu- dioprotection which is recruited by RIPre and protects the sion in mice, the absence of venous blood return from the heart against ischaemia and reperfusion injury [44] (Fig. 2). preconditioned limb, or combined femoral and sciatic nerve This idea was supported by the data indicating the pres- resection, completely abolished the infarct-limiting effect. ence of all the components necessary for the realization of Moreover, resection of only one nerve—either femoral a classical reflex in the pathway mediating cardioprotection or sciatic—only partially abolished this effect [89]. In an by RIPer: sensory (afferent) C-fiber neurons, an integration elegant study, Jensen et al. confirmed the requirement for centre in the central nervous system, and motor (efferent) both the neural and humoral pathways in RIPre-mediated vagal neurons. In this regard, it has been demonstrated in cardioprotection by testing whether human plasma dialysate a rat model of myocardial ischaemia/reperfusion injury, obtained after RIC could reduce infarct size and improve that cardioprotection by RIPre is completely abolished by hemodynamic recovery in isolated rabbit hearts [64]. They denervation of the limbs performed as either mechanical showed that the plasma dialysate was protective if obtained transection of nerves [5, 130] or blocking afferent C-fibers from healthy subjects or diabetic subjects without peripheral by neonatal capsaicin treatment [5]. Similarly, stimulation of neuropathy, but when obtained from diabetic patients with 1 3 25 Page 4 of 15 Basic Research in Cardiology (2018) 113:25 Fig. 2 Neural mechanisms of remote ischaemic preconditioning. centration in the myocardium mediates the cardioprotective effects A diagram of connections (both known and controversial) between of remote preconditioning. It is also unclear which of the abdominal n. vagus fibres—afferent or efferent—are involved in this phenom- the neural and humoral mechanisms of remote ischaemic precondi- enon. The known humoral factors that have the closest relationship tioning of the heart and the brain. The core of this mechanism is the with neural mechanisms are GLP-1 and nitrite. However, the source ‘remote preconditioning reflex’ comprising afferent somatic nerves, of their release in response to remote ischaemic stimulus is not clear. integration centre/centres in the central neural system, and efferent GLP-1 glucagon-like peptide-1, ACh acetylcholine vagal nerves, innervating the heart and other organs, specifically, the intestine. However, it is not certain whether the increase in ACh con- neuropathy it was not protective. These findings further indi- infarct size in naïve isolated hearts subjected to ischaemia cate that the mechanism of a humoral factor release involves and reperfusion. However, the plasma was no longer cardio- neural pathways [64]. protective if collected from vagotomised animals, or if the Because the initial studies investigating the role of the ganglionic blocker hexamethonium or muscarinic antagonist autonomic ganglia in RIPre-mediated cardioprotection had atropine were applied to isolated hearts [103]. This led to been controversial [43, 140], this question was re-visited by the conclusion that release of a protective factor following Yellon’s group in 2016 [102, 103]. They demonstrated that RIC is dependent on prior activation of the vagus nerve. In plasma dialysate obtained from RIPre-treated rats reduced addition, the factor appears to induce cardioprotection via 1 3 Basic Research in Cardiology (2018) 113:25 Page 5 of 15 25 recruitment of intrinsic cardiac ganglia. Their subsequent with vagal sensory fibers innervating the viscera [58]. The study, demonstrating that coronary effluent from a precon- molecular weight of GLP-1 is 3.3 kDa thereby satisfying the ditioned isolated heart could protect another isolated heart, key criteria of the humoral preconditioning factor (including but not isolated cardiomyocytes, also contributed to the molecular weight of less than 8 kDa), suggested by Lang and hypothesis of the importance of intrinsic cardiac ganglia in colleagues on the basis of the proteomic analysis of blood the mechanisms of direct ischaemic preconditioning [102]. samples obtained from experimental animals receiving the Since the first demonstration of the possibility to trans- RIPre stimulus [85]. Studies conducted in animal models by fer ischaemic preconditioning cardioprotection with blood the Yellon group [13, 14], and subsequently by others [111], [32], the attention of several research groups has focused demonstrated potent cardioprotection by GLP-1 receptor on identifying the humoral factor responsible for RIPre. (GLP-1R) activation. The efficacy of GLP-1R agonists in Several candidate humoral factors of RIC have been pro- limiting infarct size has also been shown in clinical trials on posed, including stromal cell-derived factor-1 [30], nitrite/ STEMI patients [90, 144]. Later, Basalay et al. showed that nitric oxide [110], interleukin-1α [41], interleukin-10 [19], GLP-1 mediates cardioprotection by RIC, and demonstrated microRNA-144 [88], apolipoprotein A-I [57], alpha-ketoglu- that cardioprotection induced by GLP-1R activation is medi- tarate-dependent dioxygenase Egln1 [101] and glucagon-like ated by a mechanism involving M3 muscarinic receptors [7, peptide-1 (GLP-1) [7, 8]. However, for the purpose of this 8]. The location of these M3 muscarinic receptors, mediat- review, we focus on two of the proposed humoral media- ing the infarct-limiting effect of RIPre, is not yet established. tors that are most relevant to the ‘neural hypothesis’ of RIC, The main extracellular signaling molecules that namely nitrite/nitric oxide [110] and GLP-1 [7, 8]. have been shown to be involved in cardioprotection by Using an in  vivo mouse model, Rassaf et  al.  demon- RIPre  include opioids, bradykinin and adenosine [79]. strated that shear stress-dependent stimulation of endothe- Opioid peptides can be secreted from cardiac nerves lial nitric oxide (NO) synthase within a femoral artery by or produced in the cardiomyocytes themselves [107]. RIPre yields a substantial release of NO. This NO is subse- Shimizu et al. demonstrated that the protective effect of quently oxidized to nitrite and transferred humorally to the dialysate from a donor limb subjected to RIC, on isolated myocardium, where it reduces infarct size caused following cardiomyocytes is blocked by pre-treatment of the car- 30-min myocardial ischaemia and 24-h reperfusion [110]. diomyocytes with the opiate receptor blocker naloxone In addition, a series of experiments in which plasma from [122]. These results suggest that opioid receptors involved healthy volunteers subjected to RIPre was perfused through in RIC are located in cardiomyocytes and not connected isolated mouse hearts, identified plasma nitrite as the car - with neural activation. On the other hand, in another dioprotective agent [110]. Similarly, in a recent study by study, hexamethonium abolished the protection provided Hauerslev et al., scavengers of NO attenuated RIPre-induced by intramesenteric bradykinin infusion [119]. Regard- protection in rat hearts [47]. Previously, it had been shown ing bradykinin, it is worth mentioning that it is degraded that either stimulation of cervical vagal nerves or perfusion rapidly by angiotensin-converting enzyme (ACE) [136], with acetylcholine is associated with NO release in an iso- while ACE inhibitors and angiotensin-1 receptor antago- lated rabbit heart via the neuronal isoform of NO synthase nists [63] mimic its cardioprotective effects. The role of [16]. Interestingly, in an earlier study, bilateral vagal nerve adenosine in RIC cardioprotection is still controversial, stimulation in rabbits was followed by an increase in nitrite being confirmed in a mouse model [ 120], but not a porcine formation at the level of the stomach and the colon [62]. model [48]. In terms of planning future clinical studies on the effect of Analysis of the concentrations of metabolites in plasma RIC, it is important to keep in mind that exogenous NO [98] samples of patients subjected to RIC revealed an increase and nitroglycerin [35, 50, 148, 155] have been shown to be in glycine concentration following RIC [23]. This is rel- able to reduce infarct size, and may therefore, potentially evant to the current review, as glycine is known to be an interfere with RIC. inhibitory neurotransmitter in the central nervous sys- The results obtained by Mastitskaya et al. [92] suggest tem, and specifically, in parasympathetic nuclei [22, 131, that visceral organs, innervated by the posterior gastric 132]. In the above-mentioned study, the injection of gly- branch of the vagus nerve, are the likely source of a humoral cine mimicked the protective effects of RIC in rats [23]. factor (or factors) of RIC cardioprotection. This finding is García-Dorado’s group demonstrated that glycine exerts interesting as it provides the first potential mechanism unit- cross-species cardioprotection against infarction through ing the ‘neural’ and ‘humoral’ hypotheses of RIC. Apart glycine receptor activation [66]. The potential involvement from nitric oxide [62], GLP-1 appears to be the most likely of glycine signalling in RIC-induced cardioprotection candidate for this role. Its release from the L-cells of the should be borne in mind when planning clinical trials, as intestine is modulated by vagal efferent (motor) activity certain drugs, such as Ketamine [137], can inhibit glycine [58, 115] and there is also evidence that GLP-1 may interact neurotransmission to cardiac vagal neurons. 1 3 25 Page 6 of 15 Basic Research in Cardiology (2018) 113:25 The importance of understanding the mechanism of situations with patients suffering from peripheral polyneu- RIC cardioprotection is clearly demonstrated by the neutral ropathies of different etiologies, or exposed to drugs with results of two recent multicentre trials—ERICCA and RIPH- vagolytic effects, these results allow us to predict a lack eart, in which the majority of the patients were given propo- of cardioprotective benefit from RIPre in these cohorts of fol as part of the anesthesia protocol [31, 96]. Importantly, it patients. On the other hand, delayed RIPost could potentially had previously been shown that propofol inhibits neurotrans- be more effective in the same patients, being less susceptible mission to cardiac vagal neurons in the nucleus ambiguous to innervation impairments, though no clinical trials demon- [138]. On the other hand, propofol had been shown to cause strating this have been completed so far. the enhanced nitrite production in cultured myocytes [146], The other missing part in our knowledge is the mecha- whereas nitrite is known as one of the humoral mediators of nism of vagally mediated RIPre cardioprotection. The feasi- RIPre [110]. The results of small-scale clinical trials com- bility of vagally mediated cardioprotection (i.e., RIPre) in a pleted in 2012 and 2014 confirmed the importance of the left ventricle, which is known to be only sparsely innervated, anesthetic regime, showing that RIPre during isoflurane but can be explained by the observation that there is a local ace- not during propofol anesthesia decreased myocardial damage tylcholine (ACh) synthesis system in the myocardium [37, in patients undergoing CABG surgery [82] or elective aortic 69, 109]. This system is positively modulated by cholinergic valve replacement [9, 10]. A recent experimental study also stimuli [69]. Conversely, atropine reduces the basal ACh clearly demonstrated that propofol, but not sevoflurane, abol- content [69]. It has been shown that either bilateral vagot- ished the infarct-limiting effect of RIPre in rats in vivo [ 11]. omy [5] or direct inhibition of the parasympathetic motor In a more recent single-centre study with a neutral effect of neurons in the central nervous system [93], or atropine treat- RIC in CABG patients, propofol was purposefully avoided ment [34] abolishes the infarct-limiting effect of RIPre. Yet, [99]. However, in this study, the anesthetic protocol included it is not clear whether it is the increase of acetylcholine con- fentanyl, which has been shown to inhibit neurotransmission centration that mediates the cardioprotective effect of RIC. to cardiac vagal neurons in the nucleus ambiguous [45]. It There are a number of experimental observations relevant to could also be argued, however, that fentanyl or sufentanil the assumption that it is indeed acetylcholine which medi- did not abolish RIC-induced cardioprotection in other clini- ates RIPre. First, in support of this hypothesis, the hearts cal studies [9, 133]. Although there are multiple possible from transgenic mice overexpressing choline acetyltrans- reasons for the lack of protection in these studies, as has ferase (ChAT)—the main ACh-synthesizing enzyme in car- been extensively discussed [25, 39, 55], the suppressed vagal diomyocytes—are more resistant to ischaemia–reperfusion system is likely to have contributed. injury than wild-type hearts [70]. And second, RIC increases The effect of an anesthetic protocol on RIC efficacy was both ChAT expression and ACh content in mice hearts [68, revealed in a Bayesian network meta-analysis of 55 rand- 100]. However, there are also experimental data that con- omized trials, which included 6921 patients undergoing car- tradict this hypothesis. In this regard, it has been shown that diac surgery. The use of volatile agents and the combination acute myocardial ischaemia provoked an increase of ACh of volatile agents with remote preconditioning were found concentration in an ischaemic myocardium, and vagotomy to be associated with a reduction in mortality at the longest did not affect this increase [76], while on the other hand, follow-up time available, when compared to total intrave- vagotomy abolished the infarct-limiting effect of RIPre [5 ]. nous anesthesia [151]. Furthermore, it was observed that This indicates that the loss of RIPre-mediated cardioprotec- the combination of RIC with volatile agents was associated tion in vagotomised rats [5] might be caused by some other with a reduction in mortality when compared to RIC with factors rather than a decrease in ACh concentration. Another total intravenous anesthesia [151]. indirect argument suggesting that ACh concentration may not be of critical importance for ischaemic precondition- ing is that vagotomy abolishes the myocardial interstitial Unresolved questions and discrepancies ACh release induced by brief myocardial ischaemia [75]. on the mechanisms of cardioprotection On the other hand, bilateral vagotomy does not attenuate the by remote ischaemic conditioning infarct-limiting effect of direct ischaemic preconditioning [5], which indicates that ACh concentration in the myocar- Although the degree of cardioprotection conferred by RIPre dium does not correlate with the degree of cardioprotection. and delayed RIPost is similar, the underlying mechanisms Currently, there are no data revealing whether RIPre causes seem to be distinct [5]. In the Basalay et al.’s study (2012), further increase of ACh concentration in the ischaemic myo- the infarct-limiting effect of delayed RIPost was not affected cardium in comparison to the myocardial ischaemia itself, by either vagotomy or peripheral denervation, as opposed to and whether vagotomy prevents this additional increase. The the effect of RIPre [5 ]. As peripheral or especially parasym- answer to this question is even more difficult, as the degree pathetic denervation, can potentially represent real clinical of ACh increase during myocardial ischaemia varies from 1 3 Basic Research in Cardiology (2018) 113:25 Page 7 of 15 25 study to study, depending on the animal species, samples and electrical stimulation of right [3, 18, 20, 72, 73], left [123, techniques used, as well as on the duration of the ischaemic 124] or both vagal nerves [134] limited myocardial infarct episode [74, 76, 102]. size when started either before [18, 20, 72] or during [3, Despite the lack of experimental data that would unequiv- 73, 123, 124, 134] myocardial ischaemia, or at the onset of ocally answer the question of myocardial ACh concentration reperfusion [18]. In a clinical study by Yu et al., low-level in RIC-mediated cardioprotection, there are several observa- transcutaneous stimulation of the vagal branch within the tions that may shed some light on this aspect. In this respect, area of the right tragus, in patients presenting with STEMI, it was demonstrated that cardiomyocytes of adult, but not was followed by the reduction of the incidence of reper- neonatal rats, are able to synthesize, transport and excrete fusion-related ventricular arrhythmia, the area under curve ACh in the heart [109]. The expression level of ChAT and for creatine kinase-MB and myoglobin over 72 h, and blood the amount of ACh excreted were also significantly down- levels of inflammatory markers [52, 150]. In the study by regulated in cardiomyocytes of old animals [109]. If ACh Basalay et al., the activity of only one vagal nerve—either concentration in myocardium determines the potency of pro- right or left—was sufficient and contributed equally to medi- tection by RIC, we may expect that RIC would be less effec- ate cardioprotection established by RIPre. On the other hand, tive in children and aged people. Indeed, RIPre was actually functional integrity of both nerves was required to establish shown to impair ventricular function and increase infarct size cardioprotection when the remote conditioning stimulus was in an isolated neonatal rabbit heart [118]. An earlier, small- applied during myocardial ischaemia [6]. However, the dif- scale clinical study had demonstrated myocardial-protective ferences in the mechanisms of RIPre and RIPer leading to effects of RIPre in children [26]. However, in a more recent this difference [6 ] have not been explained. Another aris- clinical trial performed on 299 children (aged neonate to ing question is—whether electrical vagal nerve stimulation 17 years), RIPre was not associated with important improve- can completely mimic all aspect of RIC, which include the ments in clinical outcomes and physiological markers after indirect stimulation of the release of humoral factors [52]. cardiac surgery [95]. It should be noted, however, that there While the importance of the activation of parasympa- was no standardized protocol of anesthesia in this study, thetic efferents in RIC-mediated cardioprotection is now and more than half the patients were exposed to propofol unambiguous, the role of the sympathetic nervous system [95]. The effect of RIC in elderly patients (> 70 years) was in this phenomenon has not been described clearly. How- investigated in the CONDI trial, and found to be equally ever, it has been demonstrated that beta-blockers reduce as protective as in younger patients [126]. Similarly, in the infarct size in STEMI patients undergoing PCI [61], and LIPSIA CONDITIONING trial, the combination of RIC and this group of drugs is currently included in the guidelines local ischaemic postconditioning was effective in both age for the management of these patients [60]. It has been shown groups—under and over 65 years old [36]. Similar results that beta-adrenoreceptors are involved in the mechanisms of were obtained after the analysis of confounders of RIPre myocardial infarct-limiting effect of remote pre- and post - cardioprotection in patients undergoing coronary artery conditioning of trauma [128, 129]. The existence of some bypass grafting [80]. In a recent experimental study by common, inherent mechanisms, such as the activation of Heinen et al., plasma of young male volunteers, subjected C sensory fibers and the K(ATP) channels for both remote to RIC, reduced infarct size in isolated hearts from aged rats preconditioning of trauma [65] and RIPre/RIPer [5, 83, 117], [49]. However, RIC plasma of aged male volunteers had no may be an argument to suggest that sympathetic beta-adren- protective effect in young rat hearts [49]. This indicates that ergic activation is involved in the mechanisms of RIC car- aging affects the RIC-induced release of a humoral factor, dioprotection. On the other hand, it has been demonstrated but not the susceptibility of myocardium to the protective in rats that exercise training, which shares some molecular effect of this phenomenon. mechanisms with RIC [108, 121], augments the dynamic One of the main purposes for investigating the mecha- heart rate response to vagal but not sympathetic stimula- nisms of endogenous cardioprotective phenomena is the tion [97]. Moreover, it is known that sympathetic nervous potential to develop pharmacological therapy or electronic response to ischaemia–reperfusion injury is altered with devices that can fully mimic its positive effects. These could RIPre [84]. In the CONDI trial, the infarct-limiting effect have the advantage of being able to be applied or admin- of RIC was preserved in beta-blocker users [126]. Although istered significantly more quickly than the RIC procedure, there are no available data on the effect of beta-blockers which requires up to 40 min. As RIPre/RIPer cardioprotec- on the efficacy of RIC in other clinical trials with STEMI tion is mediated by the activation of vagal efferents [5 , 93], patients, the fact that remote conditioning was able to reduce it is logical to assume that vagal nerve stimulation could infarct size in the clinical study, where almost all the patients potentially reproduce the effects of RIC. The obvious were taking beta-blockers [36], reinforced the CONDI question arising here is whether monolateral vagal nerve results (Table 1). Similarly, medication with beta-blockers stimulation can achieve this goal. In experimental studies, was not a significant confounder of RIPre cardioprotection 1 3 25 Page 8 of 15 Basic Research in Cardiology (2018) 113:25 Table 1 The use of beta1- First author Year Country Number of Beta-blockers use RIC effect Endpoints blockers in clinical studies patients (RIC/control, %) on the effect of remote ischaemic conditioning in Bøtker HE 2010 Denmark 333 15/15 Yes MSI (SPECT) patients undergoing primary Rentoukas I 2010 Greece 96 99/100 n.s. Peak TnI percutaneous coronary Crimi G 2013 Italy 100 13/20 Yes AUC CK-MB interventions Eitel I 2015 Germany 696 96/98 Yes MSI (MRI) Verouhis D 2016 Sweden 93 10/15 No MSI (MRI) Gaspar A 2018 Portugal 258 14/16 Yes Progression of heart failure RIC remote ischaemic conditioning, MSI myocardial salvage index, SPECT single-photon emission-com- puted tomography, TnI troponin I, AUC ar ea under curve, CK-MB creatine kinase-muscle/brain, MRI mag- netic resonance imaging in patients undergoing cardiac surgery [80]. In contrast, a including the possible involvement of endogenous opioids meta-analysis of 15 clinical trials, including 1155 patients [113, 154] and CGRP [113]. On the other hand, in one randomised to treatment with or without RIPre, showed study, local electrical stimulation enhanced the neuropro- an attenuated effect of this intervention in cardiosurgery tective effect of RIPost in a rat stroke model [145], which patients on perioperative beta-blocker treatment [153]. might suggest that the mechanisms underlying the thera- peutic effects of these interventions are different. Pigna - taro et al. demonstrated that the neuronal isoform of nitric Remote ischaemic conditioning of the brain oxide synthase takes part in the neuroprotective effect of RIPost [104]. Further investigation of the neuroprotec- In addition to protecting the heart, RIC is potentially able tive mechanism of RIC is important to establish the most to protect any other organ or tissue. It has been shown in a effective and safe implementation of this phenomenon to series of experimental studies that RIPre, RIPer, RIPost and clinical practice. delayed RIPost reduce brain infarct size in a rodent model of The activity of the cardiovascular system is continu- acute focal ischaemia/reperfusion brain injury [24]. Interest- ally modulated by the central nervous system, ensuring ingly, the reperfusion ‘time-window’, during which delayed coordination and regulation of regional cardiac electri- RIPost was effective, seems to be longer in an ischaemic cal, mechanical and metabolic indexes throughout each stroke model [104, 114] than in a STEMI model [4, 5]. In cardiac cycle [2]. This fine regulation is provided by the this regard, in a rat model with 100-min focal brain ischae- neuronal elements, which are distributed from the level of mia, RIPost was able to reduce infarct size when initiated the insular cortex to the intrinsic cardiac nervous system, within 30 min of reperfusion [104]. Impressively, when sub- and are in constant communication with one another [2]. ject to 30-min brain ischaemia, RIPost was effective up to In this regard, both ischaemic and haemorrhagic strokes 3 h of reperfusion [114]. A meta-analysis of 13 randomized can cause abnormalities in autonomic nervous system controlled trials, which included a total of 794 study partici- activity, followed by functional imbalance within the car- pants who either suffered from, or were at risk from brain diovascular system, and in certain situations—even by ischaemia and reperfusion injury, suggested that RIPost can irreversible cardiomyocyte damage, determined as serum offer cerebral protection for stroke patients [152]. Compared troponin elevation [33]. On the other hand, nociceptive with controls, RIPost was shown to be able to reduce the sensory inputs arising from the ischaemic heart represent a recurrence of stroke or transient ischaemic attacks, levels of stimulus that can evoke discord within and among different National Institutes of Health Stroke Scale score, modified levels of the hierarchy of the neuronal elements connecting Rankin Scale score and high-sensitivity C-reactive protein heart, brain and central nervous system [2, 54]. Bearing in [152]. mind the existence of these bidirectional feedback interac- The studies on the mechanisms of RIC-induced neuro- tions between the heart and brain [2], and specifically the protection are quite scarce in comparison with the amount involvement of brain subcortical structures in ‘remote pre- of studies on the mechanisms of RIC-induced cardiopro- conditioning reflex’ [44, 93], more detailed understanding tection. Similar to RIC-induced cardioprotection, there is of the mechanisms of RIC-induced neuroprotection would evidence for the involvement of the neural pathway in the shed more light on the mechanisms RIC-induced cardio- mechanism of RIC of the brain [91, 104, 114, 139, 149], protection and myocardial ischaemia/reperfusion injury. 1 3 Basic Research in Cardiology (2018) 113:25 Page 9 of 15 25 Open Access This article is distributed under the terms of the Crea- Conclusions tive Commons Attribution 4.0 International License (http://creat iveco mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Investigating the mechanisms of RIC is the essential step on tion, and reproduction in any medium, provided you give appropriate the road to its translation to patient benet fi , and specic fi ally to credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. the discovery of therapies or electronic devices, which would be able to mimic the beneficial effects of this phenomenon. 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Basic Research in CardiologySpringer Journals

Published: Jun 1, 2018

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