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. Author manuscript; available in PMC: 2020 Apr 20.
Published in final edited form as: Cond Med. 2019 Aug;2(4):164–169.

Chronic remote ischemic conditioning for cardiovascular protection

Jun Chong 1,2,3,*, Heerajnarain Bulluck 2,4,*, Andrew FW Ho 3,5,6, William A Boisvert 7,8, Derek J Hausenloy 2,3,9,10,11,12
PMCID: PMC7169952  NIHMSID: NIHMS1050561  PMID: 32313876

Abstract

New treatments are needed to prevent adverse left ventricular remodelling following acute myocardial infarction (AMI), in order to prevent heart failure and improve clinical outcomes following AMI. Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been reported to reduce myocardial infarct (MI) size in AMI patients treated by primary percutaneous coronary intervention, and whether it can improve clinical outcomes is currently being investigated. Interestingly, repeated daily episode of limb RIC (termed ‘chronic remote ischemic conditioning’, or CRIC) has been shown in experimental and clinical studies to confer beneficial effects on post-AMI cardiac remodelling and chronic heart failure. In addition, the beneficial effects of CRIC extend to vascular function, peripheral arterial disease and stroke. In this review article, we focus on the therapeutic potential of CRIC as a strategy for cardiovascular protection and for improving clinical outcomes in patients with cardiovascular disease.

Introduction

Acute myocardial infarction (AMI) and the heart failure (HF) that often follows, are among the leading causes of mortality and morbidity worldwide. As such new treatments are needed to reduce myocardial infarct (MI) size, in order to prevent resultant adverse left ventricular (LV) remodelling, and prevent the onset of HF.(Hausenloy et al., 2017) In this regard, the heart can be protected against acute lethal ischemia/reperfusion injury (IRI) by subjecting the myocardium to brief cycles of alternating ischemia and reperfusion, a phenomenon termed ‘ischemic preconditioning’ (IPC).(Murry et al., 1986) However, IPC requires the intervention to be applied before the onset of acute myocardial ischemia (which is not possible in AMI patients), and for it to be applied to the heart directly (making the intervention invasive). Interestingly, the ‘conditioning’ stimulus can be applied to an organ or tissue away from the heart, either prior to ischemia, during ischemia, or at the onset of reperfusion, thereby lending itself to clinical application in AMI patients - a phenomenon referred to as ‘remote ischemic conditioning’ (RIC).(Przyklenk et al., 1993) Crucially, the RIC stimulus can be applied both simply and non-invasively, by inflating and deflating a pneumatic cuff placed on the upper arm or thigh to induce 3 to 4 cycles of brief ischemia and reperfusion to the limb.(Kharbanda et al., 2002;Hausenloy & Yellon, 2008) A single RIC stimulus applied to the limb has been shown to reduce peri-operative myocardial injury in patients undergoing coronary revascularization by either PCI(Hoole et al., 2009) or CABG(Hausenloy et al., 2007), and has been demonstrated to reduce MI size in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI),(Botker et al., 2010;White et al., 2015) although not all studies have been positive. However, in large clinical outcome studies, a single limb RIC stimulus was shown to not improve clinical outcomes in CABG patients.(Hausenloy et al., 2015;Meybohm et al., 2015) Interestingly, emerging data suggests that repeated daily episodes of limb RIC, termed chronic remote ischemic conditioning (CRIC), may have beneficial effects over and above a single RIC stimulus following AMI(Wei et al., 2011) and in stroke.(Meng et al., 2012)

In this review article we focus on the therapeutic potential of CRIC as a strategy for cardiovascular protection. The reader is referred to other articles investigating the use of CRIC as a strategy for neuroprotection.(Khan et al., 2018;Hess et al., 2015)

CRIC and post-infarct remodelling

The first study to introduce the concept of CRIC, was by Shimizu et al(Shimizu et al., 2010) in a small study, who demonstrated in 5 healthy volunteers that repeated daily episodes of limb RIC (3×5 min cycles of inflations and deflations of cuff on upper arm) for 10 days reduced neutrophil adhesion and activation. This finding confirmed that the anti-inflammatory effects observed with a single limb RIC stimulus could be extended to CRIC. Based on these findings and the knowledge that excessive oxidative stress and inflammation contributes to post-AMI adverse LV remodelling, Redington’s group(Wei et al., 2011) went on to investigate the effect of CRIC on subsequent post-AMI adverse LV remodelling in a rat model. They found that CRIC (3×5 min cycles of unilateral hindlimb ischaemia and reperfusion) applied either daily or every 3 days for 28 days prevented post-AMI adverse LV remodelling (preserved LV function, less LV dilatation, and attenuated LV hypertrophy and myocardial fibrosis), and improved survival, in a dose-dependent manner at 12 weeks, and to a greater extent than a single limb RIC stimulus applied prior to reperfusion.(Wei et al., 2011) The beneficial effects of CRIC were shown to be associated with less oxidative stress and inflammation (reduced leucocyte accumulation, less NF-kB activation, and attenuated expression of pro-inflammatory cytokines, IL-1β and TNF-α).(Wei et al., 2011) The findings from this study suggested that CRIC applied after AMI mediate distinct benefits on post-AMI LV remodelling when compared to a single limb RIC stimulus given at the time of AMI.

In a follow-up study by the same research group, Rohailla et al(Rohailla et al., 2014) went onto to show in a murine AMI model that CRIC (4×5 min cycles of unilateral hindlimb ischaemia and reperfusion) daily for 9 days reduced MI size to a level similar to that with a single RIC stimulus, and this beneficial effect was associated with downregulation of mTOR and subsequent upregulation of pro-autophagy proteins. Whether this effect of CRIC on autophagy signalling contributes to the beneficial effects of CRIC on post-AMI remodelling is not known and remains to be determined. In a subsequent study, Yamaguchi et al(Yamaguchi et al., 2015) investigated in a rat AMI model the effects of CRIC (5×5 min cycles of bilateral hindlimb ischaemia and reperfusion) daily for 28 days, initiated 4 weeks following AMI, thereby testing the effects of CRIC in the chronic phase of AMI. They found less oxidative stress and improved LV remodelling (preserved LV function, less LV dilatation and attenuated myocardial hypertrophy) in CRIC-treated hearts compared to control, suggesting beneficial effects of CRIC in the chronic phase of AMI healing.(Yamaguchi et al., 2015) Interestingly, the effects of CRIC were associated with upregulation of miR-29a and miR-30a (negative regulators of fibrosis) in myocardial tissue and circulating exosomes.(Yamaguchi et al., 2015)

The first clinical study to test the effects of CRIC in AMI patients as a strategy to prevent adverse LV remodelling was by Vanezis et al. in 2018.(Vanezis et al., 2018) They randomised 73 STEMI patients treated by PPCI with LV ejection fraction <45% to receive either CRIC (4×5 min cycles of upper arm cuff inflation and deflation) initiated 3 days post-STEMI and applied daily for 28 days or sham. Unfortunately, they found no effects of CRIC on post-AMI remodelling at 4 months post-AMI in terms of LV chamber size or function assessed by cardiac MRI. The reasons for failure of CRIC to have beneficial effects post-STEMI are not clear but may be due to delaying the application of CRIC to 3 days’ post-infarction, a critical period when inflammation and oxidative stress contribute to adverse LV remodelling. In the original experimental study reporting beneficial effects of CRIC in a rat model of AMI, a single RIC stimulus was given prior to reperfusion and CRIC was initiated the next day.(Wei et al., 2011) This issue should be addressed by the ongoing Chronic Remote Ischemic Conditioning to Modify Post-MI Remodeling (CRIC-RCT) study ( NCT01817114), which is testing the effect of a single limb RIC stimulus applied prior to reperfusion followed by CRIC (4×5 min cycles of upper arm cuff inflation and deflation) applied daily for 28 days on post-AMI LV remodelling. In addition, the ongoing Comprehensive Remote Ischemic Conditioning in Myocardial Infarction (CORIC-MI) study is investigating the effect of a comprehensive CRIC protocol comprising RIC (5×5 min cycles of bilateral thigh cuff inflation and deflation) applied both prior to and immediately following PPCI, and repeated daily for 28 days on post-STEMI LV remodelling assessed by cardiac MRI at 28 days.(Song et al., 2018)

In summary, CRIC has been shown in experimental animal studies to prevent post-AMI adverse LV remodelling, but whether it is effective in AMI patients is currently being tested.

CRIC in chronic heart failure

The first study to investigate the effect of limb RIC in chronic heart failure patients was by MacDonald et al(McDonald et al., 2014) who found that a single limb RIC stimulus had no salutatory effects on peak VO2 during peak exercise in 20 chronic heart failure patients (LVEF<40% with heart failure symptoms). Experimental animal studies have suggested beneficial effects with CRIC applied following AMI either in the acute period(Wei et al., 2011) or 4 weeks post-AMI(Yamaguchi et al., 2015) suggesting that CRIC may have beneficial effects in chronic heart failure. The first clinical study to test the effects of CRIC in chronic heart failure patients was by Kono et al(Kono et al., 2014) who found that CRIC (4×5 min cycles of bilateral upper arm cuff inflation and deflation) applied twice daily for 7 days resulted in a modest increase in coronary flow reserve (CFR), assessed by transthoracic Doppler echocardiography, as a physiological index of coronary microcirculation in both healthy subjects (N=10) and patients with chronic HF with reduced LVEF (N=10, ischemic cardiomyopathy in six patients, and idiopathic dilated cardiomyopathy in four patients). However, there were no differences in circulating inflammatory markers or cardiac size or function (assessed by echocardiography) with CRIC.(Kono et al., 2014)

Pryds et al(Pryds et al., 2017b) investigated the effect of CRIC (4×5 min cycles of upper arm cuff inflation and deflation) applied daily for 28 days in 22 chronic ischemic heart failure patients and 21 aged-matched controls. CRIC was shown to have no effect on either LVEF or global longitudinal strain assessed by cardiac MRI in both heart failure and control patients, although it did improve GLS in patients with highest NT-proBNP plasma levels. CRIC also had no effect on peak cardiopulmonary exercise capacity or disease-related quality of life, although it did increase skeletal muscle power in both heart failure and control patients.(Pryds et al., 2017b) This latter finding suggests that CRIC may be used to prevent the decrease in skeletal muscle function arising from cardiac cachexia. Interestingly CRIC did reduce plasma NT-proBNP levels in heart failure patients but not in control patients, and lowered systolic blood pressure in heart failure patients but not in control patients.(Pryds et al., 2017b) The mechanism underlying the beneficial effects of CRIC on both NT-proBNP and GLS is not clear but may relate to less myocardial wall stress, caused by reduction in afterload (as evidenced by lowered systemic blood pressure), and this may due to the release of known vasodilatory mediators of RIC such as adenosine and nitric oxide.(Pryds et al., 2017b) In a further study, using the same CRIC protocol demonstrated a mild anti-inflammatory effect with modest reductions in C-reactive protein and calprotectin in patients with chronic ischemic heart failure when compared to control patients.(Pryds et al., 2019)

Interestingly, a randomised controlled trial by Chen et al(Chen et al., 2018) has demonstrated beneficial effects of CRIC (4×5 min cycles of upper arm cuff inflation and deflation) applied twice daily for 6 weeks in patients with chronic ischemic heart failure randomised to receive either CRIC (N=23) or standard therapy (N=24). CRIC was reported to improve LVEF (from 39.2% to 43.4%, assessed by echocardiography), increase exercise capacity (assessed by 6 minute walk test), reduce NYHA class, and lower levels of plasma BNP, when compared to control.(Chen et al., 2018) Of note, the beneficial effects of CRIC were associated with correction of cardiac autonomic dysfunction in heart failure patients with increased parasympathetic and reduced sympathetic activity, as assessed by heart rate variability.(Chen et al., 2018) Although, the beneficial effects of CRIC in this study were impressive, it must be noted that no sham control was used.

Prior experimental and clinical studies have demonstrated that a single limb RIC stimulus may reduce platelet activation(Pedersen et al., 2011;Lanza et al., 2016) and inhibit thrombus formation,(Ropcke et al., 2012) suggesting that it may be useful in the setting of chronic heart failure, a condition associated with increased risk of thrombotic events.(Lip et al., 2012) Pryds et al(Pryds et al., 2017a) have investigated the effect of CRIC (4×5 min cycles of upper arm cuff inflation and deflation) applied daily for 28 days on platelet function in 16 chronic ischemic heart failure patients and 21 matched patients with no ischemic heart disease. CRIC was shown to have no effect on platelet aggregation in response to collagen or arachidonic acid in either heart failure or control patients or platelet turnover. This differs from the effects of a single limb RIC stimulus that was reported to reduce platelet activation.(Pedersen et al., 2011;Lanza et al., 2016) However, CRIC did increase fibrinolysis in both heart failure and control patients, suggesting it may reduce the risk of thrombosis.(Pryds et al., 2017a) However, this finding differs again from a single limb RIC stimulus that had no effect on haemostasis in healthy volunteers.(Kristiansen et al., 2016)

In summary, CRIC has been shown to confer beneficial effects in patients with stable ischemic heart failure, as evidenced by improvements in cardiac function, exercise tolerance and lowering of plasma BNP levels. Whether CRIC can improve clinical outcomes such as re-hospitalisation for heart failure needs to be tested in a large randomised controlled trial.

Vascular effects of CRIC

The first clinical study to report beneficial cytoprotective effects with a single limb RIC stimulus (3×5 min upper arm inflation and deflation) was by Kharbanda et al(Kharbanda et al., 2002) who reported less endothelial dysfunction (assessed by flow-mediated dilatation) in the contralateral limb following a sustained episode of limb ischemia and reperfusion. Luca et al(Luca et al., 2013) were the first to investigate the effect of CRIC on endothelial dysfunction induced by acute ischemia and reperfusion. They demonstrated that healthy volunteers randomised to receive CRIC (3×5 min cycles of upper arm cuff inflation and deflation) applied daily for 7 days had improved endothelial function following acute ischemia and reperfusion, when compared to control, and to a level similar to a single limb RIC stimulus. ,(Luca et al., 2013) These findings suggest that the protective effects of RIC on endothelial function did not display tachyphylaxis, suggesting that CRIC may confer long-term cytoprotective effects against acute ischemia and reperfusion.

Beneficial effects on vascular and endothelial function have also been reported in the brachial artery and forearm microcirculation in healthy volunteers, following CRIC (4×5 min cycles of upper arm cuff inflation and deflation) applied daily for 7 days, suggesting vascular effects of CRIC, which extend from conduit arteries to the skin microvasculature.(Jones et al., 2014) These suggest that CRIC may be beneficial in patients with endothelial dysfunction such as occurs in diabetes and aging. Interestingly, the vascular effects induced by CRIC were shown to still be present 8 days after end of the intervention, suggesting a ‘memory’ vascular effect,(Jones et al., 2014) that extends beyond the usual 2–3 days observed with the ‘second window of protection’ (SWOP).(Marber et al., 1993) The current paradigm suggests that a single limb RIC stimulus elicits 2 windows of protection, the first manifesting immediately and lasting 2–3 hours, and the SWOP, appearing 12–24 hours later and lasting 2–3 days.(Hausenloy & Yellon, 2010) CRIC therefore appears to extend the window of protection to 8 days - these findings need to be confirmed in other studies, and the mechanisms underlying this protective effect need to be investigated. The SWOP has been attributed to the de novo synthesis of cardioprotective proteins, such as inducible nitric oxide synthase and cyclo-oxygenase-2.(Hausenloy & Yellon, 2010) The mechanisms underlying this memory effect are not clear, but may be due to epigenetic changes in the vasculature which can extend the protective effect beyond the SWOP.

A potential hemodynamic consequence of the vasodilatory effects induced by CRIC (7–28 days) have been confirmed in several clinical studies reporting a reduction in systemic blood pressure (of about 5mmHg) in healthy volunteers(Madias & Koulouridis, 2014;Madias, 2015a;Madias, 2015b;Kono et al., 2014) and patients with heart failure(Pryds et al., 2017b), although not all studies have been positive.(Kimura et al., 2007) Whether the effect of CRIC on lowering blood pressure has a ‘memory’ effect, i.e. persists beyond the intervention, remains to be determined. The mechanisms underlying the vascular effects of CRIC are not clear but may relate to: adaptations to shear stress, augmentation of endothelium-dependent vasodilation and production of nitric oxide,(Kimura et al., 2007) circulation of vasoactive mediators (such as, nitrite, vascular endothelial growth factor or endothelial progenitor cells),(Kimura et al., 2007) and/or systemic anti-oxidant and anti-inflammatory effects.

In summary, CRIC has been shown to confer salutatory effects on vascular and endothelial function that may be beneficial to patients with endothelial dysfunction and hypertension. Further studies are needed to elucidate the mechanisms underlying this protective effect.

CRIC in peripheral arterial disease

Peripheral arterial disease (PAD) and its complications that include wound ulcers and lower extremity amputation, exert significant morbidity and mortality, especially in diabetic patients. As such new treatments are needed to control symptoms of PAD, prevent its progression, and reduce the risk of complications. Clinical studies have shown that a single limb RIC stimulus improved exercise tolerance in patients with symptomatic PAD,(Saes et al., 2013), although not all studies have been positive.(Delagarde et al., 2015) Whether patients with symptomatic PAD are already ‘preconditioned’ may in part explain the mixed results of RIC on PAD symptoms of intermittent claudication. An additional clinical study reported that a single limb RIC stimulus could improve the ankle-brachial-index (ABI),(Shahvazian et al., 2017) the ratio of the systolic blood pressure measured at the ankle against one measured at the brachial artery, which is used to diagnose the presence of PAD.

More recently, CRIC has been tested in experimental animal studies and clinical studies in PAD patients and in patients with diabetic foot ulcers. Using a critical limb ischemia rat model, comprising permanent ligation of the iliac artery and vein, Karakoyun et al(Karakoyun et al., 2014) demonstrated that CRIC (3×10 min hindlimb ischaemia and reperfusion) applied daily for variable periods of 1, 7, 14, and 30 days improved limb blood flow, reduced skeletal muscle injury and these effects were associated with increased circulating endothelial progenitor cell counts and enhanced angiogenesis. This data suggests that CRC may be a potential therapy for salvaging viable skeletal tissue in PAD patients presenting with critical limb ischemia. In a randomised controlled trial, Ahmed et al(Ahmed et al., 2019) reported that CRIC (4×5 min cycles of unilateral upper arm cuff inflation and deflation) applied once every 3–4 day weeks for 28 days resulted in significant improvements in pain-free walking distance and ABI at 30 days. Interestingly, a recent clinical study has shown CRIC (4×5 min cycles of unilateral upper arm cuff inflation and deflation) applied daily for 12 weeks to be ineffective in diabetic patients with moderate PAD (N=18) with no effect on transcutaneous tissue oxygen tension of the instep of the feet, toe brachial index, and heart rate variability when compared to sham (N=18).(Hansen et al., 2019) In this study 80% of patient had peripheral symmetric neuropathy that may in part explain the lack of efficacy of CRIC,(Hansen et al., 2019) given that requirement of a neural pathway to mediate the salutatory effects of limb RIC.(Jensen et al., 2012)

Finally, an interesting study in patients with diabetic foot ulcers has shown that CRIC (3×5 min cycles of bilateral upper arm cuff inflation and deflation) applied once every 2 weeks for 6 weeks improve wound healing in diabetic patients with foot ulcers (N=24), when compared to a sham protocol (N=16).(Shaked et al., 2015) The mechanisms underlying this healing effect of CRIC with RIC only applied once every 2 weeks, are not clear but may relate to its beneficial vascular effects (increased skin perfusion)(Jones et al., 2014) increased tolerance to hypoxia, and anti-oxidant/anti-inflammatory effects.

In summary, clinical studies investigating the effect of CRIC in PAD patients in terms of reducing symptoms and preventing complication of PAD have been mixed, with the beneficial effects of CRIC potentially being confounded by the presence of co-existing diabetic neuropathy.

CRIC in sepsis cardiomyopathy

Interestingly, it has been suggested that CRIC may have beneficial effects in sepsis cardiomyopathy, a condition that is associated with significant morbidity and mortality in acutely unwell patients. Using an experimental murine model of lipopolysaccharide (LPS)‑induced septic cardiomyopathy model, Honda et al(Honda et al., 2019) first demonstrated that a single RIC stimulus (4×5 min cycles of hindlimb ischemia and reperfusion) prevented LPS-induced cardiomyopathy as evidenced by preserved LV function, a inflammatory response, and improved survival at 7 days. They also tested CRIC (4×5 min cycles of hindlimb ischemia and reperfusion) applied daily for 5 days, and showed that the effects on survival at 7 days was greater that conferred by a single limb RIC stimulus.(Honda et al., 2019) Whether CRIC had greater benefits than a single limb RIC stimulus on cardiac function and the inflammatory response to LPS was not determined in this study. Whether CRIC is beneficial in the clinical setting of sepsis cardiomyopathy remains to be investigated.

Summary and conclusions

In summary, CRIC or repeated episodes of limb RIC applied daily for 7 to 28 days have vascular and cytoprotective effects that may benefit patients with endothelial dysfunction, hypertension, chronic heart failure, and post-AMI LV remodelling. The availability of automated pneumatic cuffs for delivering the CRIC protocol should facilitate the implementation of this intervention for patient benefit, given potential issues of compliance. Future clinical studies investigating the efficacy of CRIC in other settings should use a randomised controlled trial design and include a suitable sham protocol. Further studies are needed to elucidate the mechanisms underlying the beneficial effects of CRIC, to determine whether the beneficial effects of CRIC can be recapitulated using pharmacological agents.

FUNDING

William A. Boisvert was supported by National Institutes of Health grant HL081863. Derek Hausenloy was supported by the British Heart Foundation (CS/14/3/31002), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-021). This article is based upon work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). Part of this work was performed within the Russian Government Program of Competitive Growth of Kazan Federal University.

AUTHOR AGREEMENT AND STATEMENT

We certify that we are the only authors of the article, are authorized to submit the article to Conditioning Medicine, and are not in breach or violation of any other obligation by granting publication rights to Conditioning Medicine. In addition, the following statements are true: The article is original and has not been published in any other peer-reviewed journal. It is not being considered for publication by any other journal and does not violate the rights of any copyright owner. The article contains no language that is unlawful, libelous, or in violation of a contract or confidentiality agreement. To our knowledge, all factual statements in the article are true. There is no formula or procedure described in the article that, if followed precisely as described, would cause any injury, illness or damage to persons following the formula or procedure. In submitting this article to Conditioning Medicine, the authors accept the following license agreement: Anyone is free to copy, distribute, and display this article. Anyone is free to create works derived from this article. Anyone is free to make noncommercial use of this article provided that these conditions are met: a) the original authors and publisher must be clearly and fully attributed; b) with any reuse or distribution of the article, the license terms must be made clear; and c) in the event that the original authors later republish the article in other journals or publications, the authors agree to acknowledge Conditioning Medicine as a source.

Footnotes

Disclosures: None

Reference List

  • 1.Ahmed KMT, Hernon S, Mohamed S, Tubassum M, Newell M & Walsh SR. (2019). Remote Ischemic Pre-conditioning in the Management of Intermittent Claudication: A Pilot Randomized Controlled Trial. Ann Vasc Surg, 55, 122–130. [DOI] [PubMed] [Google Scholar]
  • 2.Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN & Nielsen TT. (2010). Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet, 375, 727–734. [DOI] [PubMed] [Google Scholar]
  • 3.Chen L, Zhou Q, Jin H, Zhu K, Zhi H, Chen Z & Ma G (2018). Effects of Remote Ischaemic Conditioning on Heart Rate Variability and Cardiac Function in Patients With Mild Ischaemic Heart Failure. Heart Lung Circ, 27, 477–483. [DOI] [PubMed] [Google Scholar]
  • 4.Delagarde H, Ouadraougo N, Grall S, Macchi L, Roy PM, Abraham P & Prunier F (2015). Remote ischaemic preconditioning in intermittent claudication. Arch Cardiovasc Dis, 108, 472–479. [DOI] [PubMed] [Google Scholar]
  • 5.Hansen CS, Jorgensen ME, Fleischer J, Botker HE & Rossing P (2019). Efficacy of Long-Term Remote Ischemic Conditioning on Vascular and Neuronal Function in Type 2 Diabetes Patients With Peripheral Arterial Disease. J Am Heart Assoc, 8, e011779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM & Garcia-Dorado D (2017). Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J, 38, 935–941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T & Yellon DM. (2015). Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N Engl J Med, 373, 1408–1417. [DOI] [PubMed] [Google Scholar]
  • 8.Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ & Yellon DM. (2007). Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet, 370, 575–579. [DOI] [PubMed] [Google Scholar]
  • 9.Hausenloy DJ & Yellon DM. (2008). Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res, 79, 377–386. [DOI] [PubMed] [Google Scholar]
  • 10.Hausenloy DJ & Yellon DM. (2010). The second window of preconditioning (SWOP) where are we now? Cardiovasc Drugs Ther, 24, 235–254. [DOI] [PubMed] [Google Scholar]
  • 11.Hess DC, Blauenfeldt RA, Andersen G, Hougaard KD, Hoda MN, Ding Y & Ji X (2015). Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat Rev Neurol, 11, 698–710. [DOI] [PubMed] [Google Scholar]
  • 12.Honda T, He Q, Wang F & Redington AN. (2019). Acute and chronic remote ischemic conditioning attenuate septic cardiomyopathy, improve cardiac output, protect systemic organs, and improve mortality in a lipopolysaccharide-induced sepsis model. Basic Res Cardiol, 114, 15. [DOI] [PubMed] [Google Scholar]
  • 13.Hoole S, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, Clarke SC, Shapiro LM, Schofield PM, O’Sullivan M & Dutka DP. (2009). Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation, 119, 820–827. [DOI] [PubMed] [Google Scholar]
  • 14.Jensen RV, Stottrup NB, Kristiansen SB & Botker HE. (2012). Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol, 107, 285. [DOI] [PubMed] [Google Scholar]
  • 15.Jones H, Hopkins N, Bailey TG, Green DJ, Cable NT & Thijssen DH. (2014). Seven-day remote ischemic preconditioning improves local and systemic endothelial function and microcirculation in healthy humans. Am J Hypertens, 27, 918–925. [DOI] [PubMed] [Google Scholar]
  • 16.Karakoyun R, Koksoy C, Yilmaz TU, Altun H, Banli O, Albayrak A, Alper M & Sener Z (2014). The angiogenic effects of ischemic conditioning in experimental critical limb ischemia. Eur J Vasc Endovasc Surg, 47, 172–179. [DOI] [PubMed] [Google Scholar]
  • 17.Khan MB, Hafez S, Hoda MN, Baban B, Wagner J, Awad ME, Sangabathula H, Haigh S, Elsalanty M, Waller JL & Hess DC. (2018). Chronic Remote Ischemic Conditioning Is Cerebroprotective and Induces Vascular Remodeling in a VCID Model. Transl Stroke Res, 9, 51–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN & MacAllister R (2002). Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation, 106, 2881–2883. [DOI] [PubMed] [Google Scholar]
  • 19.Kimura M, Ueda K, Goto C, Jitsuiki D, Nishioka K, Umemura T, Noma K, Yoshizumi M, Chayama K & Higashi Y (2007). Repetition of ischemic preconditioning augments endothelium-dependent vasodilation in humans: role of endothelium-derived nitric oxide and endothelial progenitor cells. Arterioscler Thromb Vasc Biol, 27, 1403–1410. [DOI] [PubMed] [Google Scholar]
  • 20.Kono Y, Fukuda S, Hanatani A, Nakanishi K, Otsuka K, Taguchi H & Shimada K (2014). Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure. Drug Des Devel Ther, 8, 1175–1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kristiansen J, Grove EL, Rise N, Neergaard-Petersen S, Wurtz M, Kristensen SD & Hvas AM. (2016). Effect of remote ischaemic conditioning on coagulation and fibrinolysis. Thromb Res, 141, 129–135. [DOI] [PubMed] [Google Scholar]
  • 22.Lanza GA, Stazi A, Villano A, Torrini F, Milo M, Laurito M, Flego D, Aurigemma C, Liuzzo G & Crea F (2016). Effect of Remote Ischemic Preconditioning on Platelet Activation Induced by Coronary Procedures. Am J Cardiol, 117, 359–365. [DOI] [PubMed] [Google Scholar]
  • 23.Lip GY, Piotrponikowski P, Andreotti F, Anker SD, Filippatos G, Homma S, Morais J, Pullicino P, Rasmussen LH, Marin F & Lane DA. (2012). Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Thromb Haemost, 108, 1009–1022. [DOI] [PubMed] [Google Scholar]
  • 24.Luca MC, Liuni A, McLaughlin K, Gori T & Parker JD. (2013). Daily ischemic preconditioning provides sustained protection from ischemia-reperfusion induced endothelial dysfunction: a human study. J Am Heart Assoc, 2, e000075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Madias JE. (2015a). Absence of a sustained blood pressure lowering effect of once daily remote ischemic conditioning sessions in a normotensive/prehypertensive subject. Int J Cardiol, 184, 307–309. [DOI] [PubMed] [Google Scholar]
  • 26.Madias JE. (2015b). Sustained blood pressure lowering effect of twice daily remote ischemic conditioning sessions in a normotensive/prehypertensive subject. Int J Cardiol, 182, 392–394. [DOI] [PubMed] [Google Scholar]
  • 27.Madias JE & Koulouridis I (2014). Effect of repeat twice daily sessions of remote ischemic conditioning over the course of one week on blood pressure of a normotensive/prehypertensive subject. Int J Cardiol, 176, 1076–1077. [DOI] [PubMed] [Google Scholar]
  • 28.Marber MS, Latchman DS, Walker JM & Yellon DM. (1993). Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation, 88, 1264–1272. [DOI] [PubMed] [Google Scholar]
  • 29.McDonald MA, Braga JR, Li J, Manlhiot C, Ross HJ & Redington AN. (2014). A randomized pilot trial of remote ischemic preconditioning in heart failure with reduced ejection fraction. PLoS One, 9, e105361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH & Ji X (2012). Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology, 79, 1853–1861. [DOI] [PubMed] [Google Scholar]
  • 31.Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D & Zacharowski K (2015). A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med, 373, 1397–1407. [DOI] [PubMed] [Google Scholar]
  • 32.Murry CE, Jennings RB & Reimer KA. (1986). Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 74, 1124–1136. [DOI] [PubMed] [Google Scholar]
  • 33.Pedersen CM, Cruden NL, Schmidt MR, Lau C, Botker HE, Kharbanda RK & Newby DE. (2011). Remote ischemic preconditioning prevents systemic platelet activation associated with ischemia-reperfusion injury in humans. J Thromb Haemost, 9, 404–407. [DOI] [PubMed] [Google Scholar]
  • 34.Pryds K, Kristiansen J, Neergaard-Petersen S, Nielsen RR, Schmidt MR, Refsgaard J, Kristensen SD, Botker HE, Hvas AM & Grove EL. (2017a). Effect of long-term remote ischaemic conditioning on platelet function and fibrinolysis in patients with chronic ischaemic heart failure. Thromb Res, 153, 40–46. [DOI] [PubMed] [Google Scholar]
  • 35.Pryds K, Nielsen RR, Jorsal A, Hansen MS, Ringgaard S, Refsgaard J, Kim WY, Petersen AK, Botker HE & Schmidt MR. (2017b). Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure. Basic Res Cardiol, 112, 67. [DOI] [PubMed] [Google Scholar]
  • 36.Pryds K, Rahbek SM, Bjerre M, Thiel S, Refsgaard J, Botker HE, Drage OR & Ranghoj NR. (2019). Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling. Scand Cardiovasc J, 53, 183–191. [DOI] [PubMed] [Google Scholar]
  • 37.Przyklenk K, Bauer B, Ovize M, Kloner RA & Whittaker P (1993). Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation, 87, 893–899. [DOI] [PubMed] [Google Scholar]
  • 38.Rohailla S, Clarizia N, Sourour M, Sourour W, Gelber N, Wei C, Li J & Redington AN. (2014). Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling. PLoS One, 9, e111291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Ropcke DM, Hjortdal VE, Toft GE, Jensen MO & Kristensen SD. (2012). Remote ischemic preconditioning reduces thrombus formation in the rat. J Thromb Haemost, 10, 2405–2406. [DOI] [PubMed] [Google Scholar]
  • 40.Saes GF, Zerati AE, Wolosker N, Ragazzo L, Rosoky RM, Ritti-Dias RM, Cucato GG, Chehuen M, Farah BQ & Puech-Leao P (2013). Remote ischemic preconditioning in patients with intermittent claudication. Clinics (Sao Paulo), 68, 495–499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Shahvazian N, Rafiee M, Rahmanian M, Razavi-Ratki SK & Farahzadi MH. (2017). Repeated Remote Ischemic Conditioning Effect on Ankle-brachial Index in Diabetic Patients - A Randomized Control Trial. Adv Biomed Res, 6, 28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Shaked G, Czeiger D, Abu AA, Katz T, Harman-Boehm I & Sebbag G (2015). Intermittent cycles of remote ischemic preconditioning augment diabetic foot ulcer healing. Wound Repair Regen, 23, 191–196. [DOI] [PubMed] [Google Scholar]
  • 43.Shimizu M, Saxena P, Konstantinov IE, Cherepanov V, Cheung MM, Wearden P, Zhangdong H, Schmidt M, Downey GP & Redington AN. (2010). Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res, 158, 155–161. [DOI] [PubMed] [Google Scholar]
  • 44.Song L, Yan H, Zhou P, Zhao H, Liu C, Sheng Z, Tan Y, Yi C, Li J & Zhou J (2018). Effect of comprehensive remote ischemic conditioning in anterior ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: Design and rationale of the CORIC-MI randomized trial. Clin Cardiol, 41, 997–1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Vanezis AP, Arnold JR, Rodrigo G, Lai FY, Debiec R, Nazir S, Khan JN, Ng LL, Chitkara K, Coghlan JG, Hetherington SL, McCann GP & Samani NJ. (2018). Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial. Heart, 104, 1955–1962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Wei M, Xin P, Li S, Tao J, Li Y, Li J, Liu M, Li J, Zhu W & Redington AN. (2011). Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res, 108, 1220–1225. [DOI] [PubMed] [Google Scholar]
  • 47.White SK, Frohlich GM, Sado DM, Maestrini V, Fontana M, Treibel TA, Tehrani S, Flett AS, Meier P, Ariti C, Davies JR, Moon JC, Yellon DM & Hausenloy DJ. (2015). Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv, 8, 178–188. [DOI] [PubMed] [Google Scholar]
  • 48.Yamaguchi T, Izumi Y, Nakamura Y, Yamazaki T, Shiota M, Sano S, Tanaka M, Osada-Oka M, Shimada K, Miura K, Yoshiyama M & Iwao H (2015). Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. Int J Cardiol, 178, 239–246. [DOI] [PubMed] [Google Scholar]

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