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rIC: Beyond traditional acute cardioprotection

Automated remote ischaemic conditioning (rIC) aims to replicate preclinical data suggesting post-MI remodelling benefits from chronic rIC
Andrew Vanezis BSc MB ChB MRCP
Department of Cardiovascular Sciences, University of Leicester, UK
Nilesh Samani BSc MB ChB MD FRCP
Head of Department of Cardiovascular Sciences; Director Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, University of Leicester, UK
Traditional cardioprotection as a concept refers broadly to ‘all mechanisms and means that contribute to the preservation of the heart by reducing or even preventing myocardial damage’.(1) More recently, this term has been associated with protection afforded against acute ischaemia–reperfusion injury at the time of myocardial infarction (MI) and subsequent re-vascularisation. In particular, the use of remote ischaemic conditioning (rIC), a form of cardioprotection that involves intermittent interruption of blood flow to an organ or muscle bed distant to the heart (usually the upper arm), has been used successfully in the context of acute MI,(2,3) as well as planned coronary angioplasty,(4–7) to reduce myocardial damage and improve cardiovascular outcomes. Recent preliminary work has hinted at an additional role for rIC in positively influencing cardiac remodelling that occurs soon after an MI,(8,9) which may consequently have a profound impact in reducing the incidence and impact of heart failure that develops in a large number of patients post-MI.
Heart failure and cardiac remodelling
Heart failure is a major cause of long-term mortality and morbidity after MI. In the US, 7% of men and 12% of women under 70 years and 22% of men and 25% of women 70 years and over will develop heart failure (usually left ventricular systolic dysfunction) within five years of their first MI.(10) Heart failure that develops following an MI is usually a combination of infarcted myocardium due to the initial insult and cardiac remodelling that occurs in the weeks and months after the event. Remodelling is the process of reorganisation of the remaining myocardium in order to compensate for that which has been lost and no longer contributes to cardiac output. The degree of remodelling that occurs is roughly proportional to the degree of necrotic muscle infarction11 with the changes occurring at a cellular level, where cellular homeostasis and signalling is modified, and at a whole-organ level, where heart dimensions and haemodynamics are altered.
This process is initially compensatory, but over time, this process ultimately becomes detrimental. The level of remodelling and its progression is a powerful predictor for both heart failure and death following MI, with prognostic implications for further MIs, cerebral vascular accidents (CVA) and cardiac arrest.(12,13)
Remote ischaemic conditioning
Murry et al first described an endogenous cardioprotective mechanism called ischaemic preconditioning in an animal model, whereby intermittent occlusion and reperfusion of a coronary artery territory prior to sustained occlusion significantly reduced final infarct size.(14) Evolution of this technique has seen it applied after an acute ischaemic event in the clinical setting (postconditioning)(15–18) and subsequently, remotely from the target organ (rIC) in a non-invasive fashion affording protection to the heart,(2,3,19) as well other organs such as the brain 
and kidney.(20,21) 
Expanding the paradigm
Thibault et al demonstrated that the effects of post-conditioning post-MI also have a positive influence on more chronic markers such as final infarct size and myocardial contractility. They demonstrated a 7% increase in left ventricular ejection fraction after one year compared with the control group.(18) Similarly, Munk et al showed that in MI patients with an Area At Risk (AAR) of over 35%, those who received rIC after primary percutaneous coronary intervention (PPCI) had a significant improvement of left ventricular ejection fraction (LVEF) after 30 days compared with the control group: 51±11% versus 46±9%, respectively.(22) Furthermore, Hoole et al, as well as demonstrating reduced levels of troponin T (a blood biomarker of cardiac damage) in patients undergoing elective PCI who received rIC compared with control, showed that the major adverse cardiac and cerebral event rate was lower in the rIC group at six months (4 versus 13 events; p = 0.018).(5)
Kharbanda’s group took this concept a step further in humans by applying rIC during an ongoing MI. They applied a rIC protocol using a blood pressure cuff to the forearm of ST segment elevation MI (STEMI) patients during their ambulance journey to receive PPCI. Conditioned patients with a large MI showed a significantly improved myocardial salvage index (MSI), a radiographic marker of cardiac damage, than unconditioned subjects.(2,19) A smaller study by the same group was undertaken in STEMI patients where rIC was applied to the forearm just after PCI. With the addition of morphine, there was a significant reduction of troponin T levels in the conditioned group compared with the control group, although there was little effect of conditioning without the addition of morphine.(3)
In all the studies to date, the rIC stimulus was implemented on a one-off basis, either pre- or immediately post-MI. Tantalisingly, one rodent study recently hinted that the progression to heart failure can be averted (or at least delayed) by serial bouts of rIC soon after an ischaemic event. Wei et al demonstrated the greatest improvement in LV chamber size, LV function and haemodynamic changes post-MI in the group that received repeated remote conditioning every day for 28 days compared with a control group and two groups receiving one-off applications of rIC either before ischaemia (pre-conditioning) or during (peri-conditioning). The benefit appears to be in addition to the initial improvement seen due to reduction in scar size. The study highlighted a variety of ways in which repeated rIC may work, including a reduction in oxidative stress, attenuation of the expression of genes associated with fibrosis and hypertrophy, and blunting of the inflammatory response with reduced levels of neutrophil and macrophage infiltration in the myocardium and reduced cytokine signalling.(8) Complementary work by Shimzu et al also demonstrated the important role neutrophils play in chronic rIC.(9)
Automated rIC
The autoRIC™ Device, developed by CellAegis Devices Inc, automates the process of rIC. The device automatically inflates to 200mmHg for five minutes interspersed with five minutes of deflation for a total of four cycles. This device enables trial participants to automate rIC in their own home with little or no input from a healthcare professional after first use. Prior to the implementation of the autoRIC™ Device, the authors administered rIC for trial purposes using a manual sphygmomanometer. For some studies where daily rIC was needed after the participant was discharged from hospital, this required visits to participants’ homes, which were time-consuming and incurred significant travel costs. The feedback received from trial participants to date is that the autoRIC™ Device is simple to use and gives a sense of empowerment as they are, to a degree, responsible for their own treatment.
Current trials
At the present time there are two trials underway with the hypothesis that chronic rIC use in the post-STEMI period can positively influence cardiac remodelling and reduce the incidence of and progression to heart failure: DREAM (Daily REmote Conditioning in Acute Myocardial Infarction; and CRIC (Chronic Remote Ischemic Conditioning to Modify Post-MI Remodelling; Both trials are utilising the autoRIC™ Device.
The DREAM study is a UK based randomised control trial recruiting individuals who have suffered a STEMI and have had successful PPCI. Inclusion criteria includes having a post-STEMI LVEF on transthoracic echocardiography of <45% on a background of a previously documented normal myocardium. The study aims to recruit 72 patients. Primary outcome data are obtained from baseline and four-month cardiac magnetic resonance imaging (cMRI) to assess EF, left ventricular end diastolic volume (LVEDV) and systolic volume (LVESV), infarct size and oedema.
CRIC will recruit from a similar patient population in Canada with a recruitment aim of 82. CRIC differs from DREAM in that the investigators will recruit only left anterior descending (LAD) territory infarcts only, will not screen post-STEMI LVEF on echo and will exclude diabetic individuals. Furthermore, primary outcome will be obtained by comparing cMRI at baseline and 28 days to compare LVEDV. Both trials aim to complete recruitment by early 2015. It is hoped that once these trials are complete, we will be in a better position to assess the role of chronic rIC in remodelling and whether this technique merits investigation with larger Phase III, randomised, controlled trials (RCTs).
rIC is only now beginning to reach its translational potential with regards to protection from ischaemic/reperfusion injury. It is yet to be established whether early preclinical data suggesting that chronic rIC use in the context of post-MI remodelling will be borne out in the trial data, but it hoped that results of both the DREAM and CRIC trials will go some way to answering this question and potentially open the door for larger RCTs to follow.
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