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Remote and automated ischaemic conditioning

Remote ischaemic conditioning is a low-risk, low-cost procedure, and the available data in the context of percutaneous coronary intervention studies are largely positive
Rajesh Kharbanda MD
Oxford Radcliffe Hospitals NHS Trust
Oxford, UK
Andrew Redington MD
The Hospital for Sick Children
Toronto, Canada

Percutaneous coronary intervention (PCI) procedures treat coronary stenosis by mechanical disruption of the coronary plaque by balloon angioplasty and subsequent implantation of a coronary stent or scaffold that supports the vessel while healing occurs. PCI has evolved significantly over the decades with major technical improvements in the equipment, pharmacology and adjuvant devices to assess and treat lesions. The safety of PCI has improved with these advances. 
However, there has been a gradual shift in the populations being treated by PCI: primary angioplasty is now the recommended emergency treatment for ST-elevation myocardial infarction (STEMI), and early angiography and revascularisation are recommended in patients with other acute coronary syndromes (ACS).(1,2) Advanced coronary disease may be treated by PCI rather than surgery in an ageing population with co-morbidity due to prohibitive surgical risks, and the ability to treat more complex lesions such as calcified stenosis and chronic total occlusions by PCI have all served to focus attention on how best to optimise outcomes and balance the benefits in these higher-risk cases. 
Peri-procedural myocardial injury in PCI? 
In ACS there is occlusion of the blood supply to the heart and, depending upon the degree and duration of obstruction, this causes death of an area of heart muscle. In STEMI the vessel occlusion is complete and prompt primary PCI can reduce the extent of damage by restoring blood flow, but not completely prevent injury. In non-STEMI ACS there is usually transient vessel occlusion, with lesser myocardial injury. However, in both cases, the major determinant of short- and longer-term outcome is the remaining function of the left ventricle.(3) Thus, even small amounts of injury in patients with reduced ventricular function can have an adverse impact. PCI in ACS is more complex than elective PCI for stable coronary disease. Complex elective coronary intervention for stable disease, however, is also necessarily associated with some degree of myocardial injury.(4) 
The mechanisms of myocardial injury in ACS are related to the underlying pathology, but the PCI itself is more complex due to the presence of thrombus and recent myocardial injury and the PCI procedure itself can also exaggerate injury due to loss of small side branches of distal propagation of plaque material.(5)
There remains considerable debate about the prognostic relevance of cardiac injury that occurs around the time of PCI.(6) In elective PCI, troponin I and T have been demonstrated to provide prognostic information on injury and mortality both via baseline and post-procedural elevation. Furthermore, in patients undergoing PCI, Troponin I was determined to be a stronger predictor than CK-MB for increased in-hospital major complications.
In a meta-analysis of 20 studies including 15,581 patients undergoing elective PCI, Neinhuis and colleagues(7) reported that troponin I or T elevation post-PCI was significantly associated with increased mortality (p=0.001). These results were further confirmed with a more recent meta-analysis of 22 studies with 22,353 patients collectively.(8) Troponin I and T levels following non-emergent PCI are indicative of all-cause mortality (p<0.01) and of all-cause mortality and MI combined (p<0.01).
Furthermore, Milani and colleagues(9) have demonstrated that any detectable troponin release following PCI is predictive of myocardial injury and the incidence of death. In their 2272-patient study, the incidence of death alone was higher in patients with troponin- detectable release as compared with patients with non-detectable troponin release: 22.8% (>99th percentile URL), 21.4% (detectable but <99th percentile URL), and 17.7% (non-detectable). Additionally, the combined end point of death and MI also had a higher rate in the groups with detectable troponin release as compared with the group with non-detectable troponin release (51.9% of 372 patients and 50.3% of 587 patients versus 35.6% of 1313 patients).
Measurement of troponin is a very sensitive method to detect myocardial injury. The situation is made more complicated by the fact, that in high-risk ACS patients, a small amount of myocardial injury related to the PCI may confer longer-term advantages which may not be the case in those at low-risk (for example, stable) patient. Despite these issues, the new universal definition of myocardial infarction defines PCI-related MI as five-times the upper reference limit, and minimising the extent of injury would seem to be beneficial.(10)
What is conditioning? 
Cardioprotection refers to a range of strategies that aim to limit heart muscle injury resulting from ischaemia-reperfusion (IR).(11) In the basic science laboratory, ‘conditioning’ the heart reduces the extent myocardial injury. ‘Conditioning’ can be achieved by brief periods of ischaemia or pharmacological methods. 
The most powerful ‘conditioning’ stimulus is a series of short period of non-lethal cardiac ischaemia prior to the prolonged IR event.(12) This local ischaemic pre-conditioning was described in 1986 but has failed to find clinical application primarily due to difficulty in rendering the human heart ischaemic. In 2003, the concept of local post-conditioning was described, where reperfusion interrupted by a series of short periods of ischaemia also reduced myocardial infarction.(13) With the advent of primary angioplasty to treat STEMI, this has been translated rapidly to the clinical setting.(14) Although several proof-of-principle studies have reported positive effects, there is no large outcome study, and the procedure is itself invasive.(15)
What is remote conditioning?
Remote ischaemic conditioning (RIC) describes the phenomenon of cardioprotection that is achieved by ischaemia in a distant organ. Originally this was ischaemia of internal organs such as gut or kidney, but in 2002 we described the effectiveness of intermittent limb ischaemia prior to ischaemia to limit experimental myocardial infarction (remote preconditioning).(16) Unlike local conditioning, remote conditioning can be applied during cardiac ischaemia (remote per-conditioning), and immediately and some time after the procedure (remote post-conditioning).(17,18) 
Thus, a blood-pressure cuff inflated to 200mmHg is used to temporarily stop the blood supply to the arm for five minutes and repeated four times. This remote conditioning stimulus has been tested in a number of small proof-of-principle clinical studies, including patients undergoing emergency and elective PCI. 
Available evidence
Two studies have investigated the effects of RIC in protecting the heart during ST-EMI. Rentoukas et al studied 96 patients and showed that those treated by RIC (n=33) had better resolution of the ECG, and less troponin release when RIC was applied with morphine (n=33), compared with control (n=33).(19) Boetker et al randomised 333 patients to receive RIC consisting of three cycles of five minutes of upper limb ischaemia or sham in the ambulance while being transferred for PPCI.(20) The end point was six-month myocardial salvage index. This reflects how much of the area at risk by the vessel occlusion is salvaged. The median salvage index in the remote conditioning group was 0.75 versus 0.55 in the control group, and RIC had positive effects on left ventricular function in those with a large area-at-risk. 
Three series published to date have shown positive effects of RIC in PCI. Recently, Luo and colleagues reported their findings of using RIC prior to elective PCI to limit peri-procedural injury in a randomised study.(21) They applied three cycles of five minutes of upper limb ischaemia less than two hours before the procedure to the treatment group and compared a single value of 16-hour post-procedure high sensitive cardiac troponin I between treatment (n=101) and control (n=104). Myocardial injury (Type 4a MI) was defined as five-times the upper limit normal according to the most recent guidelines. RIC reduced the incidence of type 4a MI from 54% in the control group to 39% in the treatment group. Hoole et al studied 242 patients and showed a reduction in median 24-hour troponin I levels (0.16 versus 0.06ng/ml, p=0.04), but no reduction in the incidence of type 4a MI (defined as three x ULN) in those treated by RIC.
Six-month major adverse cardiovascular events were reduced by RIC, and six-year follow-up of this cohort has recently been presented that confirms continued beneficial effects.(22) Ghaemian et al randomised 80 patients to two cycles of five-minute lower limb ischaemia or control one hour before PCI. This study included patients with prior Troponin elevation, with some patients undergoing multi-vessel PCI, and demonstrated a lower incidence of Troponin elevation in the RIC group.(23) Whereas comparison between cohorts is difficult, the most recent studies appear to be a more complex group, including patients with prior bypass graft surgery and left mainstem and chronic and sub-total occlusion PCI. This may account for the much higher incidence of Type 4a MI reported at 54% in the control group (despite the newer higher cut-off), compared with the CRISP stent study.
In 2006, Iliodromitis et al24 published a study in 41 patients undergoing elective PCI. In the 20 treated by RIC (three, five-minute cycles of upper limb ischaemia), the RIC group had significantly higher troponin I and CK-MB release compared with control. One other study has reported neutral effects of RIC on peri-procedural troponin release,(25) but that used a shorter time of ischaemia. 
The accumulating evidence appears to demonstrate that RIC attenuates myocardial injury after PCI, and improves the effectiveness of PPCI. 
What might the future hold? 
The clinical impact of RIC treatment is presently difficult to define. The positive studies in STEMI with improved left ventricular function, and the long-term follow up data from CRISP stent cohort provide some support for the clinical utility of RIC. The study from Luo et al(21) used contemporary definitions of type 4a MI, and demonstrates positive effects of RIC in possibly a more complex group. Additionally, there may be potential ancillary benefits of RIC such as reducing the incidence of contrast induced nephropathy. In a randomised study of 100 patients with impaired renal function, Er et al showed that RIC reduced the incidence of contrast medium induced nephropathy from 40% in the control group to 6%; this may be particularly beneficial in those undergoing complex PCI.(26) Future studies will need larger numbers of patients, multicentre involvement and should include assessment of clinical endpoints. 
Automated RIC devices 
Although RIC is easily achieved by inflation of a blood pressure cuff to render the limb ischaemic, at a practical level this would be highly resource intensive. An automated device would facilitate delivery or RIC in an accurate and timely manner, and enhance its uptake into larger clinical studies. However, there are presently no commercially available devices to deliver RIC. The autoRICTM device has received a CE Mark certification in the EU. 
At a risk–cost–benefit level, RIC is a low-risk, low-cost procedure, and the available data in the context of PCI studies are largely positive. Although elective PCI is generally a low-risk procedure, the development of myocardial infarction is largely unpredictable. A large number of patients will need to be treated to prevent an event, but the consequences of a peri-procedural MI at a population level may be important, particularly in those undergoing complex procedures with already reduced left ventricular function, and the cost-benefit equation may therefore be favourable. The finding that RIC attenuates injury in complex PCI and during PPCI is perhaps of most significance, as the incidence and extent of injury are larger, and so the benefits are likely to be most clinically important. Larger clinical studies are underway and will define where best to target RIC therapy. 
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