Remote ischemic conditioning

Remote ischemic conditioning is a medical procedure to reduce the incidence of heart disease and stroke, the leading causes of death worldwide.[1][2] Since 1990, more people have died from cardiovascular disease than any other cause.[3] Remote ischemic conditioning (RIC) is a therapy which triggers the body's natural protection against injury (i.e. "conditions the body against injury"), and is emerging as a treatment solution for cardiovascular disease.

Remote ischemic conditioning is the deliberate, repeated, and temporary cessation of blood flow to a limb to create ischemia (lack of oxygen) in the tissue. This 'conditioning' protocol activates the body's natural protective physiology against ischemia-reperfusion injury (IRI), or simply, low oxygen levels (hypoxia or ischemia) and the damage that occurs to the tissue as a result of low oxygen levels.[4] The physiological protection produced by RIC is highly conserved across mammals.[5] RIC recapitulates the cardio-protective effects of exercise,[6] as both methods will prevent heart damage in animal models; in fact, exercise could be considered to be a form of RIC, where the stimulus or trigger (exercise) is different (remote) from the organ being protected. Remote ischemic conditioning has been termed 'exercise in a device', especially suited for those patients who are unable or unwilling to exercise.[7]

History

The phenomenon of ischemic preconditioning, (IPC) was discovered in 1986 by Murry and colleagues,[8] who made the first observation in a dog model that repeated, temporary cross-clamping of the Left Anterior Descending (LAD) artery protects the LAD territory of the heart against a subsequent prolonged ischemic event, significantly reducing the infarct size (a 75% reduction, as the infarct was 25% of the control animals). This was thought to be a local effect, and was termed local ischemic preconditioning. This ischemic preconditioning was confirmed by many other researchers, using dog, pig, mouse, and rat models.

In 1993, Karin Przyklenk and colleagues coined the term 'Remote' when they observed that performing the cross-clamping on the right side of the heart (right circumflex artery) protected the left side of the heart (LAD territory) from the ischemia, that is, the protective trigger was 'remote' from the observed effect.[9] Following this observation, other researchers confirmed this 'remote' preconditioning in experiments whereby performing the preconditioning protocol on kidney or gut tissue were also shown to provide protection to the heart.[10]

In 2002, Raj Kharbanda and Andrew Redington, working at the Hospital for Sick Children in Toronto, Canada, extended the 'remote' conditioning stimulus to the arm, and showed that non-invasively stopping and starting the blood flow in the arm provided the same protection as the invasive preconditioning stimulus on the heart.[11] This adaptation of the RIC protocol significantly improved its clinical safety and applicability, and resulted in a surge of clinical interest in this safe and easy technique to provide protection against Reperfusion injury.

Clinical trials of remote ischemic conditioning

Today, there are more than 120 clinical trials involving RIC listed on Clinical Trials with more than 10,000 patients having completed trials and another 20,000 patients in ongoing trials globally. The first human clinical trial of RIC was done by Dr. Redington at the Hospital for Sick Children in Toronto, in pediatric patients undergoing heart surgery.[12] The patients treated with RIC (study group) prior to surgery (preconditioning) exhibited less heart damage as measured by the biomarker troponin as well as a lesser need for supportive drugs. This trial of RIC was followed by many other trials, in cardiac surgery, heart attacks, cardio-thoracic intervention, heart failure, and stroke.[13]

In cardiothoracic interventions, RIC provides multi-organ protection, protecting both the heart and kidney from the damage that can occur as a result of the procedure, which includes angioplasty procedures (emergency or elective PCI) and angiography (diagnostic imaging).

RIC in heart attacks

Remote ischemic conditioning reduces infarct size in heart attack patients (STEMI) in multiple Randomized Controlled Trials (RCT) when used either in the ambulance[14] or hospital Emergency Department[15][16][17][18][19] as an adjunct therapy to primary Percutaneous coronary intervention, (PCI) or when used only with thrombolytic drugs.[20] In each these seven trials comprising 2372 STEMI patients, infarct size, a measure of damage to the heart, was significantly reduced (17 - 30% less damage), and the reduction of infarcts size was greatest (~60% reduction) in the largest infarcts. Further analysis of the Danish ambulance study (CONDI-1)[21] showed that RIC treated patients did not show a decline in myocardial salvage index (a measure of healthy heart) when they experienced system delay of treatment, while the control group experienced significant decline in salvage index.[22] The RIC treatment therefore resulted in patients effectively having an extension of the 'Golden Hour', the time during which it is important to provide medical treatment.

Infarct size is a predictor or future cardiovascular events as well as mortality,[23] and researchers doing long term follow-up of STEMI patients treated with RIC showed that this reduction in heart damage at the time of the heart attack resulted in clinical improvement at 4 years of follow-up: MACCE (Major Adverse Cardiovascular and Cerebrovascular Event) rates were reduced by 47% (13.5% vs 25.6%, p=0.018).[24] This improvement in event-free survival resulted in mean cumulative cardiovascular medical care costs that were €2763 lower in the RIC-treated group than in the control group (€12,065 vs. €14,828)[25] for savings of approximately 20%.

There are currently two large randomized controlled trials of RIC treatment in STEMI patients ongoing in Europe,[26][27] both of which will examine the benefit of RIC treatment on coronary death and hospitalization for heart failure at one year.

RIC clinical trials in angioplasty (stenting)

Remote ischemic conditioning significantly reduced heart damage (measured by troponin elevations) in four Randomized Controlled Trials in 816 Elective (non-emergency) PCI patients.[28][29][30][31] The myocardial damage and troponin elevations observed in elective PCI are less than that in the emergency STEMI patient, because there is a lesser amount of acute reperfusion injury, and damage instead results from distal embolization and side-branch occlusions.[32] Nevertheless, myocardial damage during elective PCI remains a significant predictor of morbidity and mortality, as patients exhibiting any increase in troponin are at a significantly increased risk of future events.[33] At Papworth Hospital in Cambridge, UK, Dr. Hoole and colleagues conducted the first large study treating elective PCI patients (the CRISP study)[28] and showed that patients treated with RIC prior to stenting (preconditioning) showed a 62% reduction in troponin (a biomarker of heart damage) levels, less chest discomfort, and reduced 6 month hospitalization. Long-term follow-up of the CRISP[34] study showed that this one RIC preconditioning treatment resulted in a 35% Reduction in 6 year MACCE (Major Adverse Coronary and Cerebrovascular Event) rate.[35] This reduction resulted mainly from reduced hospitalization among the treated patients.

RIC clinical trials in angiography (cardiac imaging)

Contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury (CI-AKI) is a serious complication resulting in patients being given contrast media during imaging or invasive procedures such as angioplasty or TAVR, where the physician needs to visualize the vasculature. The incidence of CIN is 13% in an unselected population, and is increased in patients with poor kidney function and congestive heart failure, who suffer the adverse consequences of the toxic contrast media in as much as 57% of cases.[36] The development of CIN after percutaneous coronary intervention is independently associated with an increased risk of short- and long-term ischemic and hemorrhagic events.[37]

Remote ischemic conditioning has been shown to reduce kidney damage from contrast media, showing statistically significant benefit in five randomized clinical trials comprising 480 patients. The first report of the benefit of RIC on kidney injury was in an observational study of US patients,[38] and the first randomized clinical trial to show a benefit in patients at extremely high risk of injury (stage 3/4 kidney disease, diabetic, with heart failure) was done in Germany[39] where Er and colleagues showed a reduction in the incidence of CIN from RIC treatment (reduced 70%, from 40% to 12%, p=0.002), with no patients in the treated arm needing to have in-hospital dialysis treatment (14% vs 0%), and reduced 6 week readmission (60% reduction, from 36% to 14%). These results were subsequently confirmed in other clinical trials of cardiac patients [40] j.[18][41] The protection of RIC was also recently extended to patients undergoing cancer imaging (CECT, Contrast Enhanced Computer Tomography), which showed a 35% reduction in CIN across the population,[42] while the patients as highest risk (stage 3/4 kidney disease) benefitted the most, with a 60% reduction in the incidence of CIN.

These results confirm that RIC can protect the kidneys as well as the heart, providing multi-organ protection in the setting of cardiac angiography as well as oncology imaging.

RIC clinical trials in coronary surgery

The clinical study of RIC began in coronary surgery, reflecting the reality that coronary surgery was the setting in which ischemic preconditioning was first studied, and those researchers continued their investigations using RIC rather than IPC as the trigger for preconditioning. As a result, there are many trials of RIC in cardiac surgery, and it is the area in which the data are mixed (some positive, some neutral) regarding the benefit of RIC in cardiac surgery. Yetgin and colleagues conducted a systematize review and analysis of RIC in cardiac surgery,[43] examining thirteen trials with 891 patients, showing that RIC treatment reduced troponin levels in a range of 21 to 49%. In addition, the authors concluded that while the data of RIC benefit in cardiac surgery were heterogeneous across the trials, upon closer analysis, trials in which the primary endpoint was a validated biomarker (e.g. 72 hr cardiac troponin AUC) [44] showed a benefit of RIC treatment, while trials in which a non-validated biomarker was the primary endpoint (e.g. 24 hr troponin AUC), did not show a benefit. In the first prospectively designed trial to examine the benefit of RIC on clinical outcomes in coronary artery bypass surgery (CABG), Thielmann and colleagues showed that RIC treatment reduced troponin levels and improved long-term morbidity and mortality.[45] Patients who were treated with the anaesthetic isoflurane showed a benefit from RIC treatment, while the anaesthetic propofol blocked the effect of RIC.[46] Investigations in Gerd Heusch's lab showed that propofol abolishes the phosphorylation of STAT5,[47] a key survival molecule in the cell and which is activated by RIC.

Recently, there were two large trials in CABG surgery (ERICCA [48] and RIP-HEART [49]) which reported neutral results for the clinical benefit of RIC; unfortunately, both of those trials used propofol as the initiating anaesthetic, and thus, based on the previously reported interference by propofol on RIC, were not entirely unexpected. In a viewpoint letter that followed the publication of the ERICCA and RIP-HEART trials, Drs Gerd Heusch and Bernard Gersh commented that the use of propofol rather than volatile anaesthesia appears to be a common denominator of all studies that failed to see protection with RIC.[50]

Another recent trial in high-risk CABG patients showed a reduced incidence of surgical acute kidney injury (AKI) in RIC treated patients (37.5% vs 52.5% p=0.02), fewer RIC patients received dialysis, and also showed reduced stay in the intensive care unit.[51] The clinical investigators of this study did not use propofol as the anaesthetic, and in 3 month follow up reported that RIC treatment improved clinical outcomes among these patients [52]

Emerging applications

Clinician researchers are seeking to expand the clinical benefit of RIC beyond a single application in cardiovascular indications, and this includes the multiple, repeated use of RIC (chronic conditioning) in chronic disease states to aid recovery or prevent additional disease progression. Because RIC modifies the expression of genes involved in inflammation, coagulation and complement pathways,[53] researchers believe that this treatment could modify the existing disease processes. The areas of research that are most advanced are in heart failure and stroke/stroke recovery.

Heart failure

Despite advances in the treatment of heart attacks, survivors are at a significant risk of progression to heart failure and risk of death within 5 years, resulting from adverse remodelling processes in the heart.[54][55] The acute inflammatory process that occurs early after a heart attack is necessary for healing and scar formation,[56] but can be negative if the inflammatory processes continue. Continued oxidative stress results in an inflammatory state, the death of heart cells, fibrosis of the ventricles, and hypertrophy (enlargement) of the heart,[57] progressing to heart failure. Repeated daily remote ischemic conditioning leads to significant downregulation of neutrophil activation and proinflammatory responses in humans,[58] and could prove beneficial in improving the post-myocardial infarction inflammatory state. In rodent post-MI models of heart failure, repeated RIC treatment (once daily for 28 days) resulted in reduced markers of inflammation (including TGF-B), improved ventricular function, and resulted in improved survival (over 100 days) of treated animals compared to non-treated animals, in a dose-dependent manner.[59] This study provided the scientific rationale for the CRIC-RCT clinical trial, NCT01817114 which investigates the effect of such repeated RIC treatment in patients following heart attacks. There are currently two other ongoing randomized controlled trials of chronic conditioning in heart failure patients: NCT01664611, and NCT02248441.

Stroke and other Neurological Indications

In addition to its efficacy in cardiological settings, RIC is also thought to remotely recruit neuroprotective pathways, and its safety, feasibility and low cost gives it high potential for translation to a wide variety of neurological conditions;[7] see reference for a comprehensive and recent review. However, just as has been seen in the heart, the brain has the ability to self-protect, and can adapt to stress and injury (e.g. hypoxia, ischemia) by triggering activation of cellular protective pathways.[60] Not only does RIC confer protection against ischemia-reperfusion injury, RIC also increases cerebral blood flow, which might be an important factor in the neuroprotective effect.[61]

The first trial of RIC in acute stroke was done by Hougaard and colleagues in Denmark.[62] Patients with an acute ischemic stroke were randomized to RIC treatment (preconditioning) versus usual treatment. RIC preconditioning increased tissue survival after 1 month and also a reduced risk of infarction in tissue that would be expected to have a high likelihood of infarction. Possible confounders of the study include: not all patients received the full dose of RIC treatment.

Intracranial atherosclerotic stenosis (ICAS) is a significant risk for stroke, and has a high risk of recurrence. Two randomized trials of RIC have been conducted in patients with ICAS. The first was a randomized trial that included 68 Chinese patients aged <80 years with intracranial arterial stenosis of 50–99% and who had experienced a stroke or TIA within the previous 30 days...[63] This study evaluated the effects of brief repetitive bilateral arm ischemic conditioning for 300 days, on stroke recurrence: ischemic conditioning reduced the incidence of recurrent stroke from 23,3% to 5% at 90 days, and 26.7% to 7.9% at 300 days, and improved the rate of recovery from the initial stroke (measured with the modified Rankin Scale). Cerebral perfusion was also improved in treated patients compared to untreated. The second clinical trial examined the effect of remote ischemic conditioning for 180 days on symptomatic ICAS in Chinese people aged 80–95 years, as invasive stenting is not always suitable for these elderly patients, and less-invasive methods are needed. Remote ischemic conditioning safely prevented stroke (statistically significant) and TIA recurrence and reduced inflammation in these patients.[64]

Delayed cerebral infarction after subarachnoid haemorrhage is a major cause of morbidity. The rationale for use of RIC in this condition is to precondition the brain and prevent delayed neurological deficits. Two Phase I trials have shown that RIC after subarachnoid haemorrhage is feasible, safe and well tolerated.[65][66]

Traumatic brain injury (TBI) shares many pathophysiological pathways with acute stroke, and ischaemic preconditioning increases brain resistance to injury.[67] Animal models of stroke (open skull model and closed skull model [68]) show that RIC preconditioning improved cerebral blood flow, reduced ischemic injury and edema, reduced cell death and improved functional outcomes. A small randomized clinical trial in severe TBI also showed that patients who received RIC had lower levels of biomarkers of brain injury than did patients who did not receive RIC.[69]

Reduced cerebral blood flow is an early finding in Vascular Cognitive Impairment (VCI). Cardiovascular risk factor control is currently the only management option for VCI, but observational studies suggest that exercise slows down cognitive decline.[70] In a mouse model which reproduced the damage seen in patients with VCI (white matter damage, cerebral hypoperfusion, inflammation, blood–brain barrier damage and cognitive deficits), daily RIC for 2 weeks increased cerebral blood flow, and this increase persisted for 1 week after cessation of conditioning. Moreover, compared with mice that did not undergo RIC, mice that underwent RIC had less inflammation, reduced white and grey matter damage, less β‑amyloid deposition and improved cognition.[71] These findings suggest that RIC is an effective treatment for lVCI, in accordance with observational data that suggest exercise reduces cognitive decline in patients with VCI.[70]

Remote ischemic conditioning: timing and protocol

The RIC stimulus can be applied to different tissues in the body, see History of remote ischemic conditioning. Either the upper or lower limb may be used as the RIC trigger; however the ease and comfort of occluding blood flow in the upper limb compared to the lower limb has resulted in the majority of clinical trials using the arm to initiate the RIC response. Researchers continue to investigate to determine the 'optimal' dosing for the RIC stimulus, leading to the following recent conclusions: the upper limb is superior to the lower limb,[72] and one limb is equivalent to two limbs in the generation of the response,[73] and maximal benefit occurs at 4-6 cycles.[73]

Pre, per, post, and chronic conditioning

The non-invasiveness and ease of application of RIC by limb ischemia has allowed this therapy to be studied in more situations that the original and invasive ischemic preconditioning, which realistically was only applicable in elective surgery situations. RIC has been studied in various indications where the therapy was applied at different times: pre-conditioning, in which RIC is applied within the hour prior to the intervention (e.g. elective cardiothoracic and surgical procedures), per-conditioning, in which RIC is applied at the time of the ischemic event (e.g. evolving heart attack, acute stroke, trauma), and chronic conditioning or chronic RIC (CRIC), in which RIC is applied once daily for a period of time after an ischemic event, for example, after a heart attack or stroke, or daily in chronic disease conditions such as peripheral vascular disease or ulcerative colitis. Post-conditioning is a term that is used to describe the short, intermittent inflations of an intra-coronary ballon at the time of reperfusion, and does not refer to remote ischemic conditioning on a limb. Delayed postconditioning is synonymous with chronic conditioning. For an excellent discussion of these concepts see the recent review by Hausenloy and Yellon [74]

Manual conditioning method

Remote ischemic conditioning on the limb has mostly been done by limb occlusion by a healthcare professional, using a manual BP cuff and a stopwatch. The 'standard' RIC protocol comprises 4 cycles of 5 minutes inflation/5 minutes deflation at 200mm Hg, and is used in the majority of the clinical protocols in investigational studies. This is the original conditioning protocol first described by Murry et al.,[75] which was based on examinations of energetic depletion of the cell.

Automated conditioning method

There is one automated device that is approved in Europe and Canada for the delivery of remote ischemic conditioning. The autoRIC Device[76] automatically delivers four cycles of, 5 minutes of inflation at 200mm Hg followed by 5 minutes of deflation, providing the repeated cycles of ischemia and reperfusion on the upper limb. This is the standard protocol that is used in the majority of clinical trials investigating the benefit of RIC.

In a comparative study of the autoRIC Device and RIC performed manually with a blood-pressure cuff and stopwatch, the autoRIC Device was shown to be much easier to use[77]

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