Abstract
Myocardial reperfusion injury has been identified as a key determinant of myocardial infarct size in patients undergoing percutaneous or surgical interventions. Although the molecular mechanisms underpinning reperfusion injury have been elucidated, attempts at translating this understanding into clinical benefit for patients undergoing cardiac interventions have produced mixed results. Ischemic conditioning has been applied before, during, or after an ischemic insult to the myocardium and has taken the form of local induction of ischemia or ischemia of distant tissues. Clinical studies have confirmed the safety of differing conditioning techniques, but the benefit of such techniques in reducing hard clinical event rates has produced mixed results. The aim of this article is to review the role of ischemic conditioning in patients undergoing percutaneous and surgical coronary revascularization.
Highlights
- •
There are a multitude of techniques for conditioning.
- •
Conditioning has been utilized in percutaneous coronary intervention and cardiac surgery.
- •
There is a lack of consistency in the techniques utilized and outcomes that have been measured.
- •
The results of studies to date lack a consistency in the benefits of conditioning.
1
Ischemia–reperfusion injury
Myocardial injury may occur in response to compromised blood flow to the heart as occurs with acute coronary occlusion or aortic cross clamping during coronary artery bypass grafting (CABG). Cellular death and ultimately a decrease in myocardial performance begin immediately after such an insult. In the case of acute coronary artery occlusion leading to ST-elevation myocardial infarction (STEMI), the gold standard intervention is reperfusion by either primary percutaneous coronary intervention (PPCI) or thrombolytic therapy . Injury to cardiac myocytes also occurs upon reperfusion of the myocardium so that overall infarct size is determined by both the original ischemia-induced necrosis and further cell necrosis secondary to reperfusion. Limiting both the original ischemic insult and the subsequent reperfusion injury is a vital strategy to improve outcomes and prevent the adverse sequel of myocardial ischemia.
2
Acute ischemic injury
Acute occlusion of a coronary artery results in myocardial ischemia and subsequent cell death. Myocyte necrosis proceeds in a “wave-front” manner beginning within the subendocardium and extending toward the subepicardium in direct relationship to the duration of the ischemic insult . The process of injury is caused by a succession of biochemical changes instigated by the anoxia causing cellular anaerobic respiration that ultimately leads to decreased myocyte contractile function .
2
Acute ischemic injury
Acute occlusion of a coronary artery results in myocardial ischemia and subsequent cell death. Myocyte necrosis proceeds in a “wave-front” manner beginning within the subendocardium and extending toward the subepicardium in direct relationship to the duration of the ischemic insult . The process of injury is caused by a succession of biochemical changes instigated by the anoxia causing cellular anaerobic respiration that ultimately leads to decreased myocyte contractile function .
3
Reperfusion injury
The concept of cell injury following reperfusion of ischemic myocardium was first postulated in the 1960s and is now accepted as a key contributor to the overall size of a myocardial infarction (MI) with four main classifications: reperfusion-induced arrhythmias, myocardial stunning, microvascular occlusion and myocardial reperfusion injury .
Reperfusion arrhythmias are a reversible type of reperfusion injury. Patients receiving PPCI post STEMI are particularly at risk whereupon a ventricular arrhythmia may arise upon reperfusion of an ischemic region. The underlying mechanisms are related to oxygen free radicals and alterations in the activity of a variety of membrane electron transfer molecules such as the sodium–calcium transporter .
Myocardial stunning is a retrospective definition given to regions of myocardium that improve in function following reperfusion in the setting of an acute ischemic insult. The underlying molecular mechanisms are similar to those involved in the phenomenon of reperfusion arrhythmias .
Reperfusion injury defines the death of cardiomyocytes that were potentially viable at the termination of the ischemic insult . This is the main target of strategies aimed at reducing reperfusion injury, and as such the main target of ischemic conditioning techniques. This is mediated by a combination of factors including oxidative stress, intracellular calcium overload and mitochondrial permeability transition pore (mPTP) opening .
4
Ischemia–Reperfusion injury & microcirculatory dysfunction
Microvascular dysfunction is frequently observed in the setting of acute coronary syndromes, especially following reperfusion of acute MI and is the pathophysiological consequence of an ischemia–reperfusion injury. Despite establishing angiographic patency of the infarct-related epicardial artery, myocardial blood flow can remain inadequate, a phenomenon known as “no-reflow” . No-reflow occurs in up to 30% of patients, and is thought to be a consequence of microemboli and subsequent microvascular obstruction . The severity of microvascular dysfunction post infarction has been demonstrated to be an important correlate of left ventricular functional recovery, cardiovascular morbidity and mortality and is proportionate to infarct size . The histological manifestations of microvascular obstruction include endothelial cell swelling, protrusions, and decreased pinocytic vesicles and are thought to be mediated through the production of reactive oxygen species following necrotic plaque particulates being showered distally into the myocardium as a consequence of plaque rupture or coronary interventional procedures .
5
Techniques for ischemic conditioning
5.1
Ischemic preconditioning
The concept of ischemic preconditioning (IPR) was first noted in 1986 when it was demonstrated that periods of ischemia followed by reperfusion conferred some benefit to the myocardium from a further prolonged ischemic insult . A number of animal studies were used to demonstrate a reduction in infarct size using a protocol of repetitive occlusion and reperfusion prior to a prolonged ischemic insult . This observation was tested in a randomized study of patients undergoing CABG, where IPR with 1-minute aortic cross clamping followed by five minutes of reperfusion was shown to enhance post-operative cardiac function and reduce the need for inotropic support . Although IPR has not been tested widely in the setting of an acute MI, it has been suggested that it may result in a reduction in post-procedural troponin release in patients undergoing elective PCI .
5.2
Ischemic postconditioning
Ischemic postconditioning (IPO) emerged from the need to provide clinically applicable techniques in reducing reperfusion injury. IPO uses transient, repetitive coronary occlusion during early reperfusion of MI with the aim of reducing infarct size. IPO was first described in a dog model, where a protocol of reocclusion and reperfusion following 60 minutes of coronary occlusion was shown to reduce reperfusion injury . IPO was subsequently tested in a randomized study of patients presenting with STEMI and demonstrated favourable outcomes with regards to peak creatinine phosphokinase (CK) release, myocardial segment contraction and myocardial blush grade .
The impact of IPO may be mediated through the minimization of reperfusion injury. Clinically, this is seen as the angiographic absence of no-reflow and/or absence of reperfusion arrhythmias . Whilst the most important factor in preventing myocyte death is restoration of flow, a variety of metabolic pathways are activated and are causal in myocardial injury during reperfusion, including the activation of pro-oxidants, neutrophil adherence to the endothelium and endothelial dysfunction .
5.3
Remote ischemic conditioning
Remote ischemic conditioning (RIC) is potentially the most attractive and safest ischemic conditioning technique as it avoids the target lesion and non-culprit coronary vessels that may cause further myocardial injury. RIC uses brief ischemia and reperfusion of a distant organ to protect the myocardium. Both ischemic preconditioning and postconditioning involved manipulation of the culprit coronary lesion that has initiated the acute MI, and as such carries the risk of coronary microembolisation leading to additional microvascular and myocardial injury .
RIC was first demonstrated using a protocol of four cycles of 5 minutes ischemia and 5 minutes reperfusion in the left anterior descending coronary artery to reduce infarct size in the territory of the left circumflex coronary artery . Such protection-at-distance was subsequently extended from cardiac to non-cardiac tissue, and reduction of infarct size has been elicited from several organs including the brain, kidney, intestine, skin, and skeletal muscle. The precise mechanism of transfer of the cardioprotective signal from the distant organ is unclear, and the optimum organ and protocol remain to be defined . A number of investigators have postulated a neuronal transmission as protection is abolished by ganglionic blockade with hexamethonium, whilst others have suggested humoral transmission as hexamethonium fails to abrogate protection. RIC has been applied in patients undergoing cardiac surgery, as well as those undergoing elective and emergency PCI .
6
Other conditioning techniques
Techniques that do not involve episodes of ischemia for protection against myocardial reperfusion injury have been developed in animal models but have not yet undergone large-scale investigation in humans. One such technique, “remote preconditioning of trauma” (RPCT), emerged from the observation that non-ischemic trauma such as surgical incision could be cardioprotective . Investigators noted that abdominal incision to the level of the cutaneous nociceptor sensory nerves prior to a period of myocardial ischemia reduced infarct size in mice . It has been postulated that peripheral bradykinin mediated nociceptor stimulation actives cardiac sensory nerves providing a protective benefit without central nervous system involvement . The role of bradykinin, as well as other agents such as epoxyeicosatrienoic acids, has been supported in other studies where specific antagonists were used to block the cardioprotective effects of these agents .
Other techniques that have been proposed for their cardioprotective effects have included acupuncture, electro-acupuncture and transcutaneous electrical nerve stimulation (TENS). The application of electro-acupuncture for several days prior to an ischemic insult has been shown to reduce infarct size . This effect was blocked by beta-blocker therapy, indicating a beta-adrenergic mediated pathway, although other studies have indicated that humoral mechanisms may also play a role . In a randomized trial of patients undergoing valve replacement, a program of electro-acupuncture was shown to reduce postoperative troponin release .
TENS is the most recent stimulus to be examined for cardioprotection . The application of TENS to a rabbit model as well as humans has been shown to reduce infarct size. It has been postulated that opioid receptor dependent pathways may mediate the cardioprotective effects of TENS since naloxone can be used to counter the effects of TENS.
7
Mechanisms underpinning ischemic conditioning
The two major signalling pathways that have been implicated in the cardioprotection offered by ischemic conditioning are the reperfusion injury salvage kinase (RISK) pathway and the survival activating factor enhancement (SAFE) pathway . Both pathways are recruited at the time of the ischemic insult and mediate their effects through mitochondrial stabilization.
The RISK pathway is characterized by a group of pro-survival protein kinases including Akt and ERK 1/2 that confer cardioprotection at the time of myocardial reperfusion through the mPTP. Preclinical studies have demonstrated that the impact of such agents as cardiotrophin-1, atorvastatin and bradykinin may be mediated through activation of the RISK pathway . This pathway has also been implicated in mediating the beneficial effects of both ischemic pre and post-conditioning .
The SAFE pathway, which includes activation and recruitment of tumour necrosis factor alpha (TNF-α) and signal transducer and activator of transcription-3 (STAT-3), is recognized as a RISK-free pathway that confers cardioprotection in ischemic preconditioning. Cardioprotection mediated through this axis involves the binding of TNF-α to TNF receptor-2, activation of STAT-3, and activation of mPTP .
The activation of both the RISK and the SAFE pathway has their end points at the level of the mPTP . mPTP is a mitochondrial membrane channel that opens in response to conditions that occur during cell ischemia and reperfusion, such as raised intracellular calcium and phosphate and in the presence of reactive nitrate and oxygen species . Opening of the pore allows large molecules to diffuse freely into the mitochondria causing organelle swelling, rupture and ultimately the release of proteins that lead to cellular necrosis .
Although RIC is likely to be mediated through the above pathways, a number of investigators have proposed the presence of an alternative, neurologically mediated pathway. This has been based upon the observation that drugs that inhibit nerve conduction may attenuate protection conferred by ischemia in a distant tissue .
8
Cardioprotection in patients with STEMI
As the aim of therapy in STEMI is rapid restoration of coronary perfusion, studies have focused on IPO and RIC as means of improving patient outcomes ( Tables 1 and 2 ). These studies have in large confirmed the safety of cardioprotection but the question regarding its efficacy remains debatable.
| Author | Number of patients | Technique | End point | Effect(s) of IPO |
|---|---|---|---|---|
| Staat et al. | 30 | 4 × 1 minute occlusion post PCI | CK release; blush grade | Reduced CK and increased blush grade |
| Laskey et al. | 24 | 2 × 90 seconds occlusion post PCI | ST segment resolution; CK release | More rapid ST segment resolution and reduced CK |
| Thibault et al. | 38 | 4 × 1 minute occlusion post PCI | Infarct size and LV function | Reduced infarct size and improved LV function |
| Lonborg et al. | 118 | 4 × 30 seconds occlusion post PCI | Infarct size, peak trop and HF prevalence | Reduced infarct size, lower NYHA grade II–IV HF, no difference in peak trop |
| Sorensson et al. | 76 | 4 × 1 minute occlusion post PCI | Infarct size, LV function, trop rise, TIMI flow | No difference |
| Freixa et al. | 79 | 4 × 1 minute occlusion post PCI | Infarct size, LV function, myocardial salvage | No difference in infarct size or LV function. Reduced myocardial salvage |
| Tarantini et al. | 78 | 4 × 1 minute occlusion post PCI | Infarct size | Trend toward larger infarct size |
| Thuny et al. | 50 | 4 × 1 minute occlusion post PCI | Myocardial odema, infarct size, CK release | Reduction in odema, infarct size, and CK release |
| Hahn et al. | 700 | 4 × 1 minute occlusion post PCI | ST segment resolution, TIMI flow, myocardial blush, stent thrombosis, TVR, MACE | No difference |
| Author | Number of patients | Technique | End point | Effect(s) of RIC |
|---|---|---|---|---|
| Botker et al. | 333 | 4 × 5 minutes arm ischemia | Myocardial salvage | Higher salvage index |
| Munk et al. | 333 | 4 × 5 minutes arm ischemia | LV function | No difference |
| Rentoukas et al. | 96 | 3 × 4 minutes arm ischemia | ST segment resolution, percentage reduction in ST deviation, peak trop | Higher resolution in ST segments, lower peak trop |
The impact of IPO in the STEMI population was first examined in a cohort of 30 patients randomized to either four re-occlusions of 1-minute duration separated by 1-minute of reperfusion or placebo following PCI . This study demonstrated a 36% reduction in the release of creatinine kinase-MB (CK-MB) over a 72-hour period, inferring a reduction in the total size of the MI in the IPO group. This was a small study, with no clinical follow-up, therefore data relating to the apparent reduction in infarct size and likely positive remodelling in the post-conditioned arm could not be correlated with cardiovascular morbidity or mortality end points. Furthermore, the surrogate of infarct size, and coronary and myocardial flow were not the most accurate methods of assessment, and may have been better served by non-invasive assessment with late-gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) and Doppler-pressure flow derived indices of flow and microvascular resistance, respectively.
A study of 24 STEMI patients, using two cycles of 90 seconds occlusion post PCI, demonstrated a more rapid resolution of ST-segment . This study also showed that patients treated with IPO had a significant improvement in the coronary flow reserve (CFR) with the end-procedure CFR being directly proportional to the degree of ST-segment resolution. Although the IPO group also had a lower post-procedural peak serum creatine kinase release, this study was limited by virtue of its small size and should be perceived as hypothesis generating. Further randomized studies, with interrogation of more detailed invasive physiological markers such as the index of microvascular resistance (IMR) or hyperemic microvascular resistance (hMR) correlated with non-invasive imaging, such as LGE-CMR are required to determine the interaction between the perceived improvement in myocardial perfusion following PCI with long-term ventricular remodelling. In addition, the effect of IPO on clinical end points such as mortality and major adverse cardiac events remains uncertain.
The impact of IPO upon the myocardium and ventricular function was assessed with CMR in 118 STEMI patients following a postconditioning protocol of four 30 seconds balloon occlusion following PCI . In this population, postconditioning was associated with a reduction in CMR-based infarct size at 3-month follow-up. Similar beneficial effects were observed using SPECT to investigate infarct size at 6-month follow-up as well as CMR at 72 hours using a postconditioning protocol of four 1-minute balloon inflations post PCI . These studies, however, were small and non-randomized in nature, and failed to report on the clinical end points associated with the positive remodelling observed following the IPO protocols performed in the acute setting. Therefore, whilst inferring the potential of IPO in the STEMI setting, more definitive assessment is still required.
The clinical studies of IPO have not universally provided positive results. A number of smaller studies have failed to replicate the positive impact of postconditioning upon infarct size as assessed by CMR . The largest study to date, consisting of 700 participants, has failed to demonstrate any beneficial effect of a postconditioning protocol consisting of four cycles of 1-minute occlusion and 1-minute reperfusion upon the rate of ST segment resolution 30 minutes post procedure . A major drawback of all these trials have been the lack of a universal IPO protocol, inadequate statistical power, as well as the use of differing outcomes such that a definitive conclusion cannot be drawn regarding the efficacy of IPO in the STEMI population.
Three major studies have examined the impact of RIC in patients with STEMI with encouraging results. A protocol of four cycles of 5-minute upper limb ischemia prior to PCI has demonstrated higher mean myocardial salvage as assessed by myocardial perfusion imaging, and a trend toward improvements in left ventricular ejection fraction in patients with large areas of myocardium at risk in the RIC group . The impact of RIC in conjunction with and without intravenous morphine in a series of 96 patients presenting with STEMI demonstrated that the effect of RIC can be enhanced by adjunctive use of intravenous morphine with improvements in ST-segment resolution and reduced peak troponin I . The RISK pathway has been suggested to mediate the enhanced effects of morphine.
9
Cardioprotection in patients undergoing elective PCI
Minimizing cardiac damage during elective PCI is an attractive target for the application of ischemic conditioning techniques . Studies investigating the role of ischemic conditioning in elective PCI are summarized in Table 3 .
| Author | Number of patients | Technique | End point | Effect(s) of RIC |
|---|---|---|---|---|
| Iliodromititis et al. | 41 | 3 × 5 minutes arm ischemia | CRP, CK-MB and trop | Elevations in CRP, CK-MB and trop |
| Hoole et al. | 242 | 3 × 5 minutes arm ischemia | Trop, MACCE | Lower trop and MACCE |
| Hoole et al. | 54 | Balloon occlusion of TV in MVD patients and 3 × 5 minutes arm ischemia in SVD patients | Coronary microvascular resistance and blood flow | No difference |
| Hoole et al. | 42 | 3 × 5 minutes arm ischemia | LV function | No difference |
| Davies et al. | 192 | 3 × 5 minutes arm ischemia | MACCE over 6 years | Lower MACCE |
| Ahmed et al. | 149 | 3 × 5 minutes arm ischemia | CRP, CK-MB and trop | Reduced trop |
| Luo et al. | 205 | 3 × 5 minutes arm ischemia | Trop | Reduced trop |
| Prasad et al. | 95 | 3 × 5 minutes arm ischemia | CRP, trop, EPCC | No difference |
A study of 242 patients undergoing elective PCI with no detectable troponin I at baseline and using transient limb ischemia prior to arrival in the catheterization laboratory demonstrated that RIC was associated with reduced troponin I release at 24 hours . At 6 years, the rate of major adverse cardiac and cerebral event (MACCE) was also lower in the RIC group . Although the positive impact of RIC using a model of transient limb ischemia upon post-procedural troponin I release has been conformed in two additional studies, a molecular mechanism by which this would translate into improved MACCE outcomes has not been established . Interestingly, a smaller study of 41 patients using an RIC protocol of double limb transient ischemia showed an increase in post-procedural troponin I and C-reactive protein . Although this was a small study, it raises the possibility that the ischemic conditioning stimulus may have a therapeutic window beyond which any additional stimulus has a deleterious effect and further investigations are required to answer this question.
As in the STEMI population, not all studies in elective PCI have confirmed the efficacy of RIC in this patient group. Studies examining the impact of RIC upon the IMR and changes in left ventricular ejection fraction have not shown any clear benefit from RIC . Similarly, RIC was not found to have any clinical efficacy in a group of 95 patients with stable and unstable angina in terms of post procedural troponin T, C-reactive protein, endothelial progenitor cell counts, or the composite rate of death, MI, and target vessel revascularization at 1 year .
It is challenging to draw comparisons amongst the aforementioned studies given their diverse patient population, RIC protocol, and the wide range of outcomes measured. The trial with the longest follow up and the largest population showed a potential clinical benefit with RIC. However, as with the IPO data, until an adequately powered randomized study is performed with the use of standard contemporary trial end points, such as major cardiovascular events and mortality, the routine use of RIC in elective PCI remains debatable.
10
Cardioprotection in patients undergoing CABG
The impact of ischemic conditioning has been widely studied in patients undergoing CABG with earlier studies focusing on IPR and later studies on RIC ( Tables 4 and 5 ).
| Author | Number of patients | Technique | End point | Effect(s) of IPC |
|---|---|---|---|---|
| Perrault et al. | 20 | Aortic cross clamping | CK-MB and lactate | Higher CK-MB |
| Cremer et al. | 14 | Aortic cross clamping | CK-MB, lactate, and trop | No difference in CK-MB or trop; higher lactate |
| Jenkins et al. | 33 | Aortic cross clamping | Trop | Reduced trop |
| Kaukoranta et al. | 30 | Aortic cross clamping | Oxygen saturation, pH, lactate, CK-MB and Trop | No difference |
| Illes et al. | 70 | Aortic cross clamping | Hemodynamic parameters, post-operative complications, inotropic n and IABP requirements | Increased cardiac index, reduced inotropic requirement, no difference in morbidity or mortality |
| Szmagala et al. | 56 | Aortic cross clamping | Trop | Reduced trop |
| Wu et al. | 40 | Aortic cross clamping | Free radical generation, cardiac index and RVEF | Improvements in all the end points analyzed |
| Teoh et al. | 30 | Aortic cross clamping | Trop | Reduced trop |
| Ghosh et al. | 120 | Aortic cross clamping | Trop | Reduced trop in off-pump patients |
| Buyukates et al. | 20 | Aortic cross clamping | NO, MDA, CK-MB, LDH, need for defibrillation, postoperative arrhythmia, LVEF | Higher NO production. Lower MDA, CK-MB, and LDH, need for electrical defibrillation, and better LVEF |
| Ji et al. | 40 | Aortic cross clamping | Trop | Reduced trop |
| Jebeli et al. | 40 | Aortic cross clamping | CK-MB, LVEF, hemodynamic parameters, inotrope requirement, ventricular arrhythmia | No difference except for a reduction in inotropic requirement |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
