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Year : 2018  |  Volume : 3  |  Issue : 1  |  Page : 21-29

Protection of coronary circulation by remote ischemic preconditioning: An intriguing research frontier

1 Department of Geriatric-Rehabilitative, Italian National Research Center on Aging, Fermo, Italy
2 Department of Geriatrics, Biomedical Campus University, Rome, Italy

Date of Web Publication16-May-2018

Correspondence Address:
Elpidio Santillo
Department of Geriatric-Rehabilitative, Italian National Research Center on Aging, Contrada Mossa 2, Fermo, 63900
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cp.cp_9_18

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Ischemic preconditioning is a protective phenomenon, by which brief ischemic stimuli in a vascular bed are able to counteract the damage from a longer subsequent ischemia. Preconditioning may also confer protection from ischemia to distal tissues and organs. In this case, ischemic preconditioning is known as remote ischemic preconditioning (RIPC). RIPC can be safely and easily reproduced in clinical settings. Indeed, over the past years, its protective actions have been tested in various clinical settings, including cardiac surgery and elective percutaneous coronary interventions. However, translational studies on RIPC have provided conflicting results on reduction of mortality. Recently, studies in humans have investigated the effects of RIPC on coronary circulation, showing that RIPC could have a protective effect on coronaries. This recent area of research may offer innovative insights for designing translational studies on RIPC, unveiling new mechanisms by which RIPC protects the heart. The aims of the present manuscript are to summarize the available clinical evidence on RIPC efficacy for cardioprotection and to review studies assessing the effects of RIPC on coronary circulation in humans.

Keywords: Cardioprotection, cardiovascular diseases, coronary circulation, ischemic preconditioning

How to cite this article:
Santillo E, Antonelli-Incalzi R. Protection of coronary circulation by remote ischemic preconditioning: An intriguing research frontier. Cardiol Plus 2018;3:21-9

How to cite this URL:
Santillo E, Antonelli-Incalzi R. Protection of coronary circulation by remote ischemic preconditioning: An intriguing research frontier. Cardiol Plus [serial online] 2018 [cited 2020 May 31];3:21-9. Available from: http://www.cardiologyplus.org/text.asp?2018/3/1/21/232554

  Introduction Top

Recent development of new anti-ischemic drugs and optimization in the management of reperfusive heart strategies have provided clinicians with new options for treating of coronary heart disease (CHD).[1],[2] However, at present, CHD remains a major problem for health-care systems worldwide.[3] The research and validation of novel anti-ischemic procedures are essential matters of investigation in cardiology.

Ischemic preconditioning is an innate phenomenon, by which brief, nonlethal cycles of ischemia/reperfusion applied to a tissue or organ confer tolerance to a subsequent more protracted ischemic event.[4] The capability of ischemic preconditioning to exert protection from ischemia was initially shown in animal models.

In 1986, for the first time, Murry et al. described ischemic preconditioning in a canine model. In this pioneering study, preconditioning protocol provided four cycles of 5 min of ischemia followed by 5 min of reperfusion of the circumflex coronary. Then, the circumflex coronary artery was occluded for 40 min. Authors observed a significant reduction of infarct size (−25%; P < 0.001) in the group of preconditioned dogs compared to controls which underwent only 40 min of circumflex coronary occlusion.[4]

In 1993, Przyklenk et al. extended the concept of ischemic preconditioning through the discovery of remote ischemic preconditioning (RIPC). The authors showed that cycles of transitory ischemia/reperfusion which were exerted in a vascular bed, protected distal tissues from a later sustained ischemia. In a canine model, preconditioning of the circumflex coronary artery was able to significantly reduce the size of myocardial infarcts induced by 1-h occlusion of the left descending coronary artery. Differences in collateral flow, hemodynamic parameters, and area at risk between preconditioned and control group were excluded. Thus, it was argued that during short cycles of ischemia/reperfusion, protective humoral factors could be transported throughout the body rendering remote myocardial districts more resistant to a longer ischemia.[5]

In cardiovascular research, the great interest in studying RIPC derives mainly from its potential to offer an innovative and cost-effective solution for treatment of CHD. In fact, RIPC is easily reproducible in clinical context through the cyclic inflation of a blood pressure cuff applied to a limb, until obtaining a transient blood flow occlusion in the brachial or femoral arteries.[6]

Coronary circulation is the fundamental vascular district for CHD pathogenesis, and at the same time, it is implied in protection from RIPC.[7] Indeed, recent human studies have shown that remote preconditioning stimuli might act favorably on the coronary vascular bed. We aimed to review the available human studies of the effects of RIPC on coronary circulation. Before discussing this topic, we will also concisely summarize the molecular mechanisms of RIPC and the main evidence on RIPC efficacy for cardioprotection in humans.

  Molecular Mechanisms of Ischemic Preconditioning Top

In the last two decades, many studies have examined the molecular pathways which are implicated in ischemic preconditioning.[8] However, mechanisms responsible for cardioprotection from ischemic preconditioning are not fully clarified, and to some extent, are still debated. Various circulating mediators (including adenosine, opioids, bradykinin, and nitric oxide [NO]), which are released in response to short ischemic stimuli, have been proposed as trigger molecules of tissue protection from RIPC [Figure 1]. Interestingly, recent evidence suggests that even microRNA, a class of small noncoding RNAs, participates in the genesis of RIPC signaling.[9],[10] When trigger substances bind to their receptors, a downstream cascade of intracellular signals is generated through recruitment of various cross-talking protein kinases such as protein kinase C, extracellular-regulated kinase, and phosphatidylinositol 4-5-biphosphate 3 kinase/protein kinase B.[8]
Figure 1: Mechanisms of remote ischemic preconditioning. In the humoral pathway model, brief peripheral ischemic stimuli cause the release of circulating mediators which act as triggers of tissue protection. After, receptor binding provokes cascade signaling of cross-talking protein kinases which interact with mitochondria. Cardioprotection is obtained through recruitment of mitochondrial effectors such as mito-KATP channels, mitochondrial permeability transition pore, and connexin 43. In the neural pathway model, brief peripheral ischemic stimuli provide heart protection through the modulation of the autonomous nervous system. Moreover, humoral mediators may be released in consequence of the stimulation of neural pathway. ERK ½: Extracellular-regulated kinase; JAK-STAT: Janus kinase-signal transducers and activators of transcription pathway; PKC: Protein kinase C; mito-KATP: Mitochondrial ATP-sensitive K+ channel; mPTP: Mitochondrial permeability transition pore PI3K/Akt: Phosphatidylinositol 4-5-biphosphate 3 kinase/protein kinase B; RISKs: Reperfusion injury salvage kinase group; SAFE survivor activating factor enhancement pathway

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The reperfusion injury salvage kinase group and the survivor activating factor enhancement pathway have been identified as interacting molecular pathways which convey the preconditioning stimulus to the mitochondria.[11],[12] Structural components of mitochondria have been shown to play a key role in protection by ischemic preconditioning. In particular, the mitochondrial adenosine triphosphate-sensitive K+ (mito-KATP) channels and mitochondrial permeability transition pore (mPTP) have been identified as important effectors of protection from RIPC. It has been observed that activation of mito-KATP channels could reduce mitochondrial calcium overload, while inhibition of mPTP is implicated in molecular pathways which counteract cellular necrosis.[13],[14]

Another key role in protection seems to be played by connexin 43, a protein located in subsarcolemmal cardiomyocyte mitochondria and gap junctions.[15] It has been shown that RIPC preserves the phosphorylation of connexin 43. As a consequence, the permeability and conductance of gap junction decrease, which promotes the mechanical stability of cardiomyocytes.[16],[17]

The sequential activation of cytosolic and mitochondrial effectors provides tolerance to prolonged ischemic events through the modulation of protein translation and through the expression of genes involved in survival signaling, autophagy, and apoptosis.[8]

In humans, it has been also demonstrated that the proteomic response to remote preconditioning stimuli in peripheral blood is characterized by an increment of proteins involved in the acute-phase response and the regulation of cellular function.[18]

Notably, protection from ischemic preconditioning occurs in two distinct temporal windows. They have been, respectively, named the “early” and “late” window of protection. The early window of protection approximately manifests at 4 h after preconditioning, while the late window occurs 24 h after preconditioning.[19]

In mice, protection from late RIPC is induced by systemic release of interleukin-10 whose expression in remote muscle is increased after a brief ischemic injury.[20] On the other hand, in humans, a cyclooxygenase-2 (COX-2)-dependent mechanism has been hypothesized on the basis of the late protective effect of RIPC.[21],[22] COX-2 activity stimulates the synthesis of cytoprotective prostanoids, transcriptional upregulation of COX-2 is induced by the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway. The JAK-STAT pathway also promotes the transcription of the inducible NO synthase (iNOS). iNOS contributes to the positive effects of the late phase of preconditioning against ischemic-reperfusive damage through the amplified production and bioavailability of NO.[23] Beneficial actions of NO include antioxidant effects, influx inhibition of L-type calcium channels, and antagonism of beta-adrenergic stimulation.[24]

The preservation of protection from ischemic preconditioning in aging hearts is still matter of scientific discussion. In fact, studies on senescent animals and older humans have provided inconsistent results.[25] Recent evidence suggests that protection from conditioning may be maintained in some individuals who possess a plasticity of signaling. Indeed, in geriatric age, the loss of some protective molecular pathways might be compensated by the adaptive action of other mediators which sustain tissue protection from ischemia.[26]

Remarkably, some studies have proposed an involvement of neural pathways to explain the protection from RIPC as an alternative mechanism or in concomitance with humoral pathways.[27]

Mild peripheral ischemic stress could confer cardioprotection through the positive modulation of the autonomic nervous system activity, favorably influencing heart rate, myocardial blood flow, and heart rate variability.[28] The preservation of neural pathway seems essential even for the release of humoral mediators after RIPC in diabetic humans.[29] Finally, mechanistic similarities between RIPC and the exercise-induced preconditioning have been also described.[30]

  Heart Protection from Remote Ischemic Preconditioning in Human Studies Top

The evidence of effective cardioprotection from RIPC in animal models encouraged researchers to verify the efficacy of RIPC in counteracting heart ischemic damage in humans in various clinical settings.[6] Remote preconditioning procedures are conceptually employable in heart surgery and elective percutaneous coronary interventions (PCI), before an expected procedure-related ischemic period. On the other hand, in acute coronary syndrome and primary PCI, ischemic conditioning has also been applied during ischemia, and it has been properly defined “preconditioning.”

Remote ischemic preconditioning in acute coronary syndrome and primary angioplasty

In acute coronary syndromes, proof of usefulness of remote conditioning is still limited, but encouraging. Conditioning protocol has proved to be feasible even during air medical transport of patients with ST-elevation myocardial infarction (STEMI).[31] Moreover, benefits of RIPC have been reported in various studies of patients undergoing primary angioplasty.[32],[33],[34]

In a trial of 96 patients referred for primary PCI, participants were randomized to receive RIPC, RIPC, and morphine, or to a control group. In the RIPC and morphine group, ST-segment reduction and troponin I peak were significantly better than controls.[32] The enhancement of favorable effects of RIPC in participants who were given morphine was expected since endogenous opioids are well-known mediators of RIPC-related heart protection.[35]

In 2014, Sloth et al. showed that RIPC before primary PCI-ameliorated long-term outcomes in 333 STEMI patients. In fact, over a median follow-up of 3.8 years, patients in the RIPC group exhibited a significantly lower all-cause mortality compared to controls.[33]

In 2017, a meta-analysis of eleven studies (including nine randomized controlled trials) investigating the benefits of ischemic conditioning in STEMI patients found evidence for a higher myocardial salvage index and a reduced infarct size in participants who underwent RIPC + PCI compared with the PCI group.[34]

Remote ischemic preconditioning in heart surgery

Several studies have evaluated the efficacy of RIPC for cardioprotection in a heart surgery setting, though with inconclusive results.[36],[37],[38],[39]

The enthusiasm about clinical translation of protection from RIPC in heart surgery has been recently tempered for the failure of two large multicenter trials in patients undergoing cardiac surgery. In fact, in 2015, Effect of RIPC on Clinical Outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA) and remote ischemic preconditioning for heart surgery (RIPHeart) trials showed no advantages in patients who received RIPC before heart surgery compared with controls.[40],[41] Nevertheless, it has been hypothesized that the negative results of these trials may have been caused by many confounding factors such as patients' comorbidities, the use of cardiopulmonary bypass, cardioplegia, and anesthetics. In particular, propofol, an anesthetic drug widely employed in both ERICCA and RIPHeart, can reduce or abolish the effects of RIPC.[42] Therefore, future studies' designs in cardiac surgery should consider to weigh the effects of all pharmacological and technical variables that may influence RIPC effect.

Meta-analyses of studies on RIPC in heart surgery have shown that RIPC is able to reduce troponin release after heart surgery [Table 1]. This result suggests that RIPC could render myocardium more resistant to ischemic-reperfusive damage during cardiac surgery.
Table 1: Meta-analyses evaluating the efficacy of RIPC for cardioprotection in heart surgery

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However, this benefit did not translate in the improvement of major clinical cardiac end-points. In fact, meta-analyses agree that RIPC before cardiac surgery has no effect in reducing hard clinical outcomes such as postoperative mortality and myocardial infarction. However, RIPC seems to reduce the incidence of acute kidney injury after cardiac surgery.[43],[44],[45],[46],[47],[48],[49],[50]

Remote ischemic preconditioning in elective percutaneous coronary interventions

Efficacy of heart protection by RIPC has also been assessed in elective PCI setting with promising results. In the Cardiac RIPC in Coronary Stenting (CRISP Stent) study, RIPC reduced the major adverse cardiac and cerebral event rate at 6 months in 192 patients who underwent PCI.[51] This benefit was preserved at long-term follow-up.[52]

A trend for lower periprocedural myocardial infarction was seen recently in the RIPC arm of EUROCrips study, a multicenter trial which evaluated 223 patients undergoing elective PCI.[53]

Notably, meta-analyses of studies showed that RIPC significantly reduced the incidence of perioperative myocardial infarction in patients undergoing elective PCI [Table 2].[54],[55],[56],[57],[58] Interestingly, the lack of effect of RIPC on C-reactive protein (CRP) levels, as evidenced in two meta-analyses, suggests that the modulation of inflammation is not the main protective mechanism of remote preconditioning.[57],[58] On the other hand, it is well known that CRP is not a sensitive marker of inflammation in patients referred for PCI. Therefore, inflammatory response in these patients should be studied by assessing the levels of more sensitive markers of inflammation such as interleukin 6 and nuclear factor-kappaB.[58] Furthermore, studies which were included in meta-analyses were often small and heterogeneous in quality and methodology. Larger and well-designed trials are needed to confirm the effectiveness of RIPC in providing clinically relevant heart protection in elective PCI.
Table 2: Meta-analyses evaluating the efficacy of RIPC for cardioprotection in elective PCI

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  Effects of Remote Ischemic Preconditioning on Coronary Circulation Top

Coronary circulation is not only a determinant of ischemic damage but can be itself the victim of ischemic injuries which cause interstitial oedema, overexpression of adhesion molecules, or microembolizations and capillary destruction.[7]

Beyond the protection of the cardiomyocytes compartment, a positive influence of RIPC on coronary circulation has been supported by a number of recent studies on animals and humans.

An increment of the flow in the left anterior descending coronary and a reduction of coronary resistance after RIPC was clearly showed in pigs.[59] In addition, in male Lewis rats, RIPC significantly raised both coronary flow and left ventricular developed pressure compared to controls.[60]

However, it is not clear if such effects were directly related to protection from preconditioning.

Both invasive techniques, such as coronary angiography and noninvasive methods, such as ultrasonography, have been used to investigate the effect of RIPC on coronary circulation in humans [Table 3].
Table 3: Studies investigating effects of RIPC on coronary circulation in humans

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Zhou et al. examined coronary flow changes after RIPC in 18 healthy human males through echocardiography. This noninvasive study showed a positive response of coronary flow to RIPC. In fact, the mean value of peak diastolic velocity increased from 28.6 ± 1.4 cm/s on baseline to 33.0 ± 1.2 cm/s after the third cycle of RIPC.[61]

In contrast, the invasive evaluation of coronary flow, in the course of percutaneous coronary procedures, did not reveal any increment after arm RIPC in 11 adult patients with single-vessel disease. Such results could be influenced by the pharmacological therapy (i.e., glyceryl trinitrate and adenosine infusion) which was administered during the PCI. However, authors of the study argued that coronary response to RIPC might be present only in some species, but absent in humans.[62]

Our group investigated the coronary flow velocity change after RIPC in 95 elderly patients with heart diseases.[63] The variation of coronary flow velocity in response to RIPC was examined noninvasively through ultrasonography and resulted in similar outcomes to those observed in the previous study by Zhou et al.[61] Moreover, we highlighted that the presence of heart failure (HF) and higher systolic pressure were able to weaken the coronary response to RIPC.[63] These findings suggest that vasodilatory effect of RIPC on coronary circulation is preserved in elderly patients with heart disease, but a comorbid condition could attenuate it.

In addition, we observed that higher serum uric acid was associated with a more pronounced coronary flow increment after RIPC. We interpreted this result in the light of the well-known antioxidants properties of uric acid, which participates in the cardioprotective purine signaling pathway.[64]

Recently, Corcoran et al. studied the effect of RIPC on the endothelium-dependent and endothelium-independent coronary vasodilation in sixty patients with stable coronary disease. They found that vasoconstriction secondary to acetylcholine infusion was reduced by RIPC. Therefore, authors supposed that an endothelium-dependent mechanism could be implicated in RIPC.[65] Although this evidence was obtained in a nonculprit coronary artery, it is particularly relevant because it strongly supports the idea that cardioprotection from RIPC involves coronary circulation.

Moreover, the endothelium-dependent coronary vasodilation after RIPC observed in this study, appeared unrelated to cytokines which modulate endothelial function. Concentrations of interleukin-6, myeloperoxidase, tissue plasminogen activator, and von Willebrand factor did not significantly differ in the RIPC group compared to controls.

Forthcoming translational studies should elucidate whether the positive influence on coronaries' endothelial function deriving from RIPC could confer relevant cardioprotection in long-term outcomes. Whether other protective mechanisms of heart circulation are associated with RIPC also remains to be explored. There is initial evidence that RIPC might favorably interfere not only with the epicardial coronary circulation but also with the cardiac microcirculatory function.[66],[67]

Of note, Kono et al. demonstrated that a 1-week course of RIPC treatment on both upper arms was effective in ameliorating coronary microcirculation in ten healthy individuals and ten patients with HF. In this study, coronary flow reserve was assessed noninvasively through transthoracic Doppler echocardiography on baseline and after 1 week of RIPC procedures. Patients with HF presented a trend in reduction of levels of tumor necrosis factor-α, interleukin-6, troponin-T, and brain natriuretic peptide, without reaching statistical significance.[66] However, the study could be underpowered to unveiling differences in concentrations of circulating markers after RIPC.

The study of coronary flow response subsequent to RIPC could gain greater interest in the event that it will be able to provide the validation of a “surrogate index” of effective cardioprotection (i.e., the magnitude of coronary flow change after RIPC). Available evidence from reported studies suggests that some variables may interfere with coronary flow response to RIPC, favoring or impairing it [Figure 2]. Therefore, future investigations should take into account the many confounders which could potentially interfere with the detection of coronary effects of RIPC. Many variables such as age, gender, medications, comorbidities, and a diseased coronary circulation might tend to attenuate the coronary response to RIPC beyond the efficacy of the cardioprotection itself.[68],[69]
Figure 2: Factors influencing coronary response to remote ischemic preconditioning

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  Conclusions Top

The study of the effects of RIPC on coronary circulation in humans is an intriguing research area for several reasons. First, the study of RIPC effects on coronary circulation could help in clarifying its mechanistic connection with drugs actions, physical exercise, aging, diet, and comorbidities.[70],[71] Second, even if RIPC appears as a feasible cardioprotective strategy, the best protocol of ischemia/reperfusion, in terms of number of cycles, tissue mass exposed, and duration and timing of application, is not yet established. Initial evidence suggests that duration and number of RIPC cycles are more important than the tissue mass exposed for the efficacy of protection from preconditioning.[72] Further studies which would include the evaluation of coronary circulation might help to confirm this hypothesis. Third, beyond the induction of cardioprotection, the analysis of coronary vasodilation after RIPC could offer prognostic information to clinicians who manage patients with heart diseases. Indeed, it cannot be excluded that participants with high coronary flow response to RIPC (high responders to RIPC) could have a better survival compared to individuals with an attenuated coronary response to RIPC (low responders to RIPC). In fact, innate cardioprotective mechanisms could be reduced or abolished in low responders to RIPC, making them more vulnerable to cardiovascular disease.

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Conflicts of interest

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