Protecting the Ischaemic and Reperfused Myocardium in Acute Myocardial Infarction: Distant Dream Or Near Reality?

Heart 2000;83:381–387 381

REVIEW

Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality?

D M Yellon, G F Baxter

Acute coronary occlusion is the leading cause after the onset of ischaemia but before of morbidity and mortality in the Western therapeutic reperfusion. world, and according to the World Health Organisation will be the major cause of death in TREATMENT BEFORE ISCHAEMIA ONSET the world as a whole by the year 2020.1 Treatment of patients before the onset of Although the management of this epidemic will coronary occlusion may be possible in some centre on the development of eVective primary circumstances. For example patients with prevention programmes, the impact of these unstable angina may be at risk of myocardial strategies may be limited, particularly in the infarction during the subsequent hours, weeks, developing countries. There is an urgent need and months. Such patients could be treated for eVective forms of secondary prevention with a cardioprotective agent in addition to and, in particular, treatments which will limit various antithrombotic treatments, etc. Identi- the extent of an evolving myocardial infarction fication of patients who do not have unstable during the acute phase of coronary occlusion— angina but who have coronary disease and the death of myocardium represents a cata- other risk factors predisposing to a future myo- strophic event since dead myocytes are not cardial infarction is a more diYcult issue. replaced by division of surviving myocytes. Ideally, if all patients at risk of myocardial Preserving the viability of ischaemic myocar- infarction could be reliably identified they dium therefore presents a therapeutic target. could be treated chronically with a cardio- Although appreciated for many years, this con- protective agent, the aim of such treatment cept has so far failed to produce a clinically being to sustain the viability of the myocardium useful agent capable of protecting the ischae- in the event of sudden coronary occlusion. mic myocardium from infarction. The term Ultimately these patients would still require “cardioprotection” has been used loosely reperfusion treatment (thrombolysis, angio- during the last few decades to describe various plasty or coronary artery bypass grafting therapeutic approaches, including antiarrhyth- (CABG)), but hopefully the progression of inf- mic, antianginal, antihypertensive, and an- arction would be delayed suYciently by the tiplatelet treatments. In the present discussion, cardioprotective pretreatment to reduce long we apply the term “cardioprotection” very spe- term morbidity and mortality. cifically to describe interventions that preserve or enhance the viability of myocardium during TREATMENT AFTER ISCHAEMIA ONSET BUT ischaemia and reperfusion and thus limit the BEFORE REPERFUSION extent of acute myocardial infarction. It is our Patients who present with severe chest pain contention that in the light of current under- already have coronary occlusion. The eYcacy standing of the mechanisms of cell injury dur- of protective manoeuvres which modify ischae- ing both ischaemia and reperfusion, we are well mic injury would therefore be dependent on placed to identify molecular targets which may the degree of residual flow through the infarct provide the foundation on which rational related artery or the extent of coronary collat- therapeutic approaches can be based. eral opening. Under these circumstances, it is conceivable that a drug given as adjunctive The Hatter Institute, Department of treatment either before or in combination with Academic & Clinical Who needs cardioprotection and when? thrombolytics might “buy time” before reper- Cardiology, University The prerequisite for salvage of myocardium fusion patency, provided that there was some College London under threat of infarction is the return of residual flow through the infarct related artery Hospitals & Medical coronary flow to the tissue as quickly as or a developed collateral circulation. Of equal School, Grafton Way, possible.23 The major clinical approach to interest, agents given after the onset of London WC1E 6DB, reperfusion is the use of thrombolytics. How- UK coronary occlusion might also be useful ever, fibrinolysis is not instantaneous and while adjuncts to reperfusion treatment if they could Correspondence to: the coronary thrombus is lysing, the subtended modify reperfusion injury. Professor Yellon myocardium continues to undergo injury, email: which is ultimately irreversible. The adminis- [email protected] Reperfusion injury tration of injury modifying manoeuvres could Although reperfusion is the prerequisite for tis- Accepted 6 January 2000 occur either before the onset of ischaemia, or sue salvage there is a price to pay in terms of 382 Yellon,Baxter

four distinct reperfusion associated pathologies to limit infarction in the coronary care unit. which pose a direct threat to the myocardium: The experimental literature of the 1970s and reperfusion induced arrhythmias; myocardial 1980s is replete with conflicting and inconsist- stunning; reversible microvascular injury (en- ent studies of â blockers, calcium channel dothelial stunning); and irreversible cell blockers, anti-inflammatory drugs, inhibitors damage.4–7 This latter form of lethal reperfusion of neutrophil adhesion, and nitrates. Not injury, distinct from, but additional to, lethal surprisingly, none of these agents produce inf- ischaemic injury, may be amenable to modifi- arct limitation in clinical studies. cation by cardioprotective agents. Recent Agents which, in experimental models, con- advances in our understanding of cell death sistently limit infarct size if given before ischae- during both ischaemia and reperfusion impli- mia, but do not consistently limit infarct size cate two forms of cell death in the pathology of when given only at reperfusion, are unlikely to myocardial infarction, namely necrosis and be protective when used as clinical adjuncts to apoptosis (programmed cell death, cell sui- reperfusion. Adenosine is a good example of cide). We have hypothesised that the apoptotic such an agent. When given before experimental component of tissue death may be particularly coronary occlusion it limits infarct size notably relevant at reperfusion and as such might be and reliably (see the discussion on precondi- regarded as a target for intervention to limit tioning below). However, when given during lethal reperfusion injury, discussed in more reperfusion in experimental animals its eVects detail below. Accordingly, a further indication on infarction are not consistently reproducible. for the use of certain cardioprotective agents Thus the scientific rationale for its use as an would be the prevention of lethal reperfusion adjunct to thrombolysis in the AMISTAD trial injury. The timing of cardioprotective treat- is weaker than one would like. ments will thus be determined by the form of Thirdly, those experimental agents which cell death which is targeted, in addition to the modify lethal reperfusion injury when given mechanism of action of the particular agent during the first moments of reperfusion, but and the time at which the patient presents. are not protective when their administration is delayed, must also be given during early reper- Assessing pharmacological approaches to fusion in clinical studies. In relation to this, we cardioprotection would say that there has been much discussion Over a number of years, many therapeutic of the opposing findings of the LIMIT-2 and manoeuvres have been proposed which might ISIS-4 magnesium trials. This issue has not confer protection beyond that ascribable to been completely resolved. Experimental stud- reperfusion. None has been adopted in routine ies show that magnesium administration either clinical practice as a cardioprotective interven- before coronary occlusion or during the earliest tion. Well known examples include magnesium moments of reperfusion can limit infarct size. If treatment, which was the subject of two large magnesium administration is delayed until and conflicting clinical trials (LIMIT-2 and after reperfusion, there is, as one might predict, ISIS-489). Glucose–insulin–potassium treat- no benefit. In the LIMIT-2 study magnesium ment for acute myocardial infarction was first was administered before thrombolysis and was proposed more than 30 years ago, but has not protective. In the larger ISIS-4 trial, magne- been adopted routinely despite evidence of sium was administered after thrombolysis and benefit in several trials and a subsequent was not protective. Considered together these meta-analysis.10 Antineutrophil interventions trials provide confirmation of the principles have been proposed to ameliorate some aspects established in the laboratory, although it is sur- of reperfusion injury such as the no-reflow prising that a potentially useful treatment has phenomenon, but no positive clinical trial has been largely abandoned on the basis of the yet been reported. Adenosine has been evalu- ISIS-4 findings. ated recently as an adjunct to reperfusion in the We have illustrated how much of the AMISTAD trial. This small trial provides disappointment and confusion with clinical evidence of anterior infarct size limitation but infarct size limitation to date may be ascribed no evidence of morbidity/mortality benefit. to failure to design clinical studies in the light The design of clinical trials to assess the inf- of sound experimental studies. Ultimately, the arct limiting potential of agents is a complex selection of agents for clinical assessment (and costly) area of clinical science. There are should be driven by developments in basic sci- important issues of patient recruitment, ran- ence. As our understanding of the basic patho- domisation, selection of control treatments, physiological mechanisms of ischaemic injury, choice of end point, and statistical power which adaptation to ischaemia (preconditioning), and are beyond the scope of this review. However, it reperfusion injury have advanced during the is our belief that the sine qua non of clinical last 5–8 years, it has become possible to trial design in this area of investigation must be identify ways in which the myocardium might a complete appreciation of the scientific princi- be protected (fig 1). ples of infarct limitation and a thorough and rational interpretation of the preceding experi- Advances in understanding of ischaemic mental literature relating to the agent in ques- injury: sodium–hydrogen exchange tion. There are, regrettably, examples of large inhibitors clinical trials being undertaken to assess inter- An important advance during the last few years ventions without full recognition of experimen- has been the understanding of the detrimental tal studies. Interventions that do not limit role played by the sodium–hydrogen exchange infarction reliably in the laboratory are unlikely mechanism in the cardiac myocyte.12 13 During Protecting the myocardium in acute infarction 383

NHE inhibitors via the sodium–calcium exchanger mechanism, resulting in intracellular calcium overload and H+ Na+ cell death. One of the exciting developments over the NHE NCE last few years is the recognition that inhibiting the sodium–hydrogen exchange mechanism is + Na a powerful means of delaying cell death during – ischaemia. In experimental studies, these + 2+ H accumulation Intracellular Ca inhibitor compounds have proved to be con- during anaerobic overload sistently eVective in limiting infarct size when metabolism administered before the onset of ischaemia.14–16 This therapeutic promise has been investigated

Other signals in a large trial (11 500 patients) of cariporide, 17 Free radicals "Growth" factors the GUARDIAN trial. The importance of Bax this trial is that it is the first large clinical trial of (pro-apoptotic) – a cardioprotective agent, whose primary mech- Damaged mithochondria anism of action is prevention of tissue necrosis. Caspase cyt-c cascade Death receptors We view the trial as an example of how failure (fas ligand and TNFa) to recognise the message of the preclinical data – Bcl-2 can result in the design of an ambiguous clini- (anti-apoptotic) Apoptosis cal trial. Reduction in the primary end point Caspase inhibitors (death plus myocardial infarction at 36 days) Preservation of failed to reach significance. ATP generation?? GUARDIAN was a combined phase 2 and 3 trial with assessment of three diVerent caripo- + ride dosages. The combination of three patient mt-K ATP KATP channel openers subgroups in diverse clinical settings (unstable angina, high risk coronary angioplasty, and Kinase cascade CABG) was ambitious. In the preclinical evalu- ation of cariporide there was clear evidence that pre-ischaemic administration was protective, but there was no unanimity that administration ACE B2 δ A3 A1 – after the onset of ischaemia was cardioprotec- inhibitors + + + + ACE tive. As such it is not surprising that the early Inactive δ peptides NEP agonist A3 agonist A1 agonist subgroup analysis reveals CABG as being the Bradykinin NEP – only setting in which cariporide treatment was inhibitors protective—that is, administration was before the commencement of a scheduled ischaemic Endothelial cell event. Analysis is still under way but protection Figure 1 Modification of several molecular targets presents new therapeutic possibilities for was observed only in the CABG group at high limitation or delay of myocyte death during ischaemia and/or reperfusion. The figure dose; because there were no serious adverse summarises three promising approaches to infarct limitation during ischaemia and/or eVects at any dose used, this suggests that there reperfusion. To p Intracellular accumulation of protons during ischaemia leads to the activation of the sarcolemmal sodium–hydrogen exchanger (NHE). Consequent is the possibility of using higher doses to achieve intracellular sodium overload causes the activation of the sarcolemmal sodium–calcium protection in the correct setting. exchanger (NCE) and predisposes to intracellular calcium overload. Inhibitors of NHE attenuate this mechanism of injury and can limit infarct size in experimental models. Bottom Preconditioning is an endogenous adaptive response in myocytes. Mediators Advances in understanding of adaptation released in ischaemic tissue include adenosine, noradrenaline, bradykinin, and opioid to ischaemia: preconditioning mimetic peptides. These mediators act via seven transmembrane G-protein coupled receptors on agents myocytes, (adenosine A and A receptors, ä-opioid receptors, and bradykinin B receptors) 1 3 2 During the last decade there has been a major and initiate a complex kinase signalling cascade, which opens the KATP channel in the mitochondrial inner membrane (mt-KATP). These channels are the likely end eVector of advance in our understanding of how myocar- preconditioning. Opening of the channel enhances myocyte viability during ischaemia dium can adapt to transient ischaemia. Brief through a mechanism that is likely to involve preservation of mitochondrial integrity and periods of sublethal ischaemia precondition the ATP generating capacity. There are several possibilities for exploitation of pharmacological heart to withstand a longer period of lethal preconditioning (“preconditioning mimetics”). Adenosine A1 and A3 receptor agonists and ä-opioid receptor agonists activate the preconditioning signal cascade and limit infarct size ischaemia, slow the rate of tissue injury, and in experimental models. Potentiation of endogenously generated bradykinin during limit infarct size.18–21 Experimentally this pro- ischaemia is possible with angiotensin converting enzyme (ACE) inhibitors and neutral endopeptidase (NEP) inhibitors. These agents prevent the breakdown of bradykinin and tection has been shown to aVord the myocar- augment its protective eVects on myocytes. Centre The predominant pathological feature of dium a potent form of cardioprotection.21 infarction is myocyte death by necrosis. However, apoptosis is now recognised as an There are two phases to this adaptive response: additional mechanism of cell death which may be activated, particularly during reperfusion. Regulation of apoptotic pathways is extremely complex and incompletely understood, but an early acute form of protection lasting inhibition of apoptosis may be a therapeutic route to salvage myocytes during ischaemia approximately two hours; and a “second and/or reperfusion. Caspase inhibitors and counter regulatory growth factors limit infarct window” or delayed form of protection which size when administered during the early reperfusion period. develops over several hours, and lasts approximately three days. The molecular mechanisms ischaemia, myocyte intracellular pH decreases underlying each form of preconditioning are owing to the accumulation of protons. The incompletely understood but we now have the sodium–hydrogen antiport mechanism in car- potential to use drugs which can induce diac myocytes is activated to extrude these preconditioning like responses. protons in exchange for sodium. In turn, intra- During brief periods of ischaemia, a number cellular sodium accumulation leads to reduced of endogenous cardioprotective substances are calcium eZux and/or increased calcium influx released from ischaemic cardiac myocytes and 384 Yellon,Baxter

endothelial cells which trigger the early and delayed preconditioning responses. In early Trial acronyms preconditioning, these molecular triggers of AMISTAD: Adenosine as an Adjunct to adaptation include adenosine, bradykinin, and Thrombolytic Therapy for Acute Myocar- opioid peptides, acting on myocytes at the dial Infarction adenosine A /A receptors, the bradykinin B 1 3 2 CESAR-2: Second Clinical European Stud- receptor, and the ä1-opioid receptor, respec- tively. Through a complex signal transduction ies in Angina and Revascularization mechanism, the phosphorylated target protein GUARDIAN: Guard During Ischemia Against Necrosis (or “end eVector”) appears to be the KATP channel on the mitochondrial inner mem- ISIS-4: Fourth International Study of Inf- brane, opening of which is thought to be arct Survival 22 23 cardioprotective. Thus, both the endog- LIMIT-2: Second Leicester Intravenous enous triggers (adenosine, bradykinin, opioids) Magnesium Intervention Trial and the putative end eVector of preconditioning, the ATP sensitive potassium channel

(KATP), present tangible therapeutic templates for anti-ischaemic drug development. infarct size studies to support this concept at Adenosine was the first endogenous ligand present. to be identified as a trigger of the cardioprotec- In the ischaemic preconditioning response tive action of ischaemic preconditioning. Fol- the role of endogenous opioid peptides as trig- lowing an enormous amount of research it is gers of this phenomenon has also been identi- clear that the infarct limiting eVects of both fied, and it is now clear that these act through endogenous adenosine and exogenously ap- the ä-receptor subtype activating the signalling cascade of preconditioning.35–37 Selective plied analogues work via the A and/or the A 1 3 -receptor agonists37 38 have been shown to receptor subtypes in isolated cardiac ä induce cardioprotection in experimental mod- myocytes,24 animal studies,25 26 and human car- els. Many of the opiates that are used clinically diac tissue27 28. Experimental studies also show for their antinociceptive and analgesic proper- that intermittent administration of low doses of ties are non-selective opioid receptor agonists. A agonists confers cardioprotection over long 1 For example morphine will activate µ-, ê-, and periods without an adverse haemodynamic 29 30 ä-opioid receptors and has been shown to have profile. some cardioprotective properties experi- Bradykinin has been identified as another mentally.39 40 It is likely that a number of opiates important endogenous trigger of the precondi- 31 32 used in cardiac surgery and coronary care tioning response. During periods of ischae- including fentanyl, morphine, and diamor- mia considerable quantities of bradykinin are phine exert some ä-opioid receptor activity. generated by the endothelium and exert The potential cardioprotective properties of important paracrine eVects. However, the these agents, under these clinical conditions, is actions of endogenously generated bradykinin unproven at present. However, there is poten- are brief because the peptide is rapidly tial for developing selective ä-opioid receptor 33 metabolised. Exogenous administration of agonists as cardioprotective agents, particularly bradykinin induces cardioprotection but from for use in the settings of acute coronary a therapeutic perspective this has limitations syndromes and CABG, if treatment can be ini- since bradykinin has potent haemodynamic tiated before the index ischaemic event. eVects. There is an important class of agents There is a growing consensus that the distal already available and widely used, however, target or eVector of protection is the KATP which potentiate the physiological actions of channel. Initially research concentrated on the endogenous bradykinin generated during is- sarcolemmal KATP channel as the downstream chaemia by inhibiting its metabolism. These target of phosphorylation, but recent evidence are the angiotensin converting enzyme (ACE) has pointed to the mitochondrial inner mem- inhibitors, since ACE is a major route for 22 23 brane KATP channel as the eVector protein. bradykinin breakdown. It has been suggested A number of experimental KATP channel open- for many years that ACE inhibitors are ers which have been shown to be cardioprotec- “cardioprotective” through ill defined mecha- tive are non-selective and open both channels. nisms. The recognition that bradykinin is an However, two agents are of particular interest

endogenous cardioprotective substance pro- as they open mitochondrial KATP channel vides a rationale for the use of ACE inhibitors relatively selectively, namely diazoxide22 23 and in the setting of ongoing ischaemic heart nicorandil.41 Selective pharmacological open-

disease where basal bradykinin concentrations ing of mitochondrial KATP channels oVers the may be augmented to a concentration suY- potential for cardioprotection without haemo- cient to confer cardioprotection during an dynamic perturbations (owing to sarcolemmal 34 acute myocardial infarction. It may be KATP channel opening in vascular smooth mus- relevant to add that neutral endopeptidase is cle) as has been shown in recent experimental another important metabolic pathway for studies.42 43 At present the only clinically

bradykinin breakdown. Inhibitors of neutral available KATP channel opener licensed for endopeptidase, which are currently being cardiovascular use is nicorandil. This agent developed for the treatment of hypertension also possesses nitrate activity which might and chronic heart failure, may oVer a similar account for its haemodynamic proﬁle (coron- cardioprotective proﬁle although there are no ary vasodilator and blood pressure lowering). Protecting the myocardium in acute infarction 385

However, the additional KATP opening proper- injury). For the last two decades practical ties appear to account for the beneficial eVects demonstration of lethal reperfusion injury has aVorded to patients with unstable angina as proved elusive.7 The most convincing means of seen in the recent CESAR 2 study.44 It demonstrating such lethal reperfusion injury is therefore remains to be determined if the to administer agents that modify infarct size experimental promise of nicorandil will be when given during the first moments of reper- realised by a direct cardioprotective action in fusion. A number of agents have been exam- patients. However, the results from CESAR 2, ined in this setting and the outcome has been in which patients were already using nitrates, confusion and disappointment (see above). point to an action that goes beyond that of a Over the last two decades it was assumed nitrovasodilator. that the mechanism of cell death during reper- It is important to appreciate that no matter fusion was essentially a continuation or exacer- how protective preconditioning or its pharma- bation of the necrotic process initiated during cological mimetics appear, the application of the preceding ischaemia. One of the most the protective treatment should occur before the exciting developments in the last 4–5 years is episode of ischaemia. This point cannot be the recognition that apoptosis may be a patho- emphasised too strongly because there may be logical event relevant to ischaemia–reperfusion confusion when treatments linked to precondi- injury. It is likely that apoptosis occurs in addi- tioning are proposed as adjuncts to reperfusion tion to necrosis during ischaemia and reper- (as with AMISTAD). There is little evidence fusion, both in experimental models and in that preconditioning triggers such as adenosine clinical myocardial infarction.45 Because apop- or modulators such as KATP channel openers are tosed cells are phagocytosed by adjacent cells, protective when given after the onset of ischae- no inflammatory reaction occurs. Hence, mia, unless there is residual flow into the risk detection of apoptosis by conventional histo- zone. There is no consensus in the experimen- logical approaches is very diYcult. Using tal literature that they are able to limit infarct specialised techniques that detect DNA frag- size when given at the time of reperfusion. mentation, there is evidence that apoptosis occurs during ischaemia–reperfusion in addi- Can we modify reperfusion injury? tion to necrotic cell death. However, it is far The approaches discussed so far have centred from clear at what stage apoptosis occurs in on treatment administered before the onset of relation to necrosis. It is also unclear whether it myocardial ischaemia in an attempt to modify occurs predominantly during ischaemia or the ischaemic process and delay or slow the during reperfusion itself, although the balance evolution of infarction. Unfortunately the of evidence suggests that apoptosis is acceler- majority of patients with evolving myocardial ated by the process of reperfusion.46 infarction will have had no heralding event and Apoptosis may not have been previously rec- indeed may not have been identified at high ognised as a means of lethal injury during risk. Treatments which need to be adminis- reperfusion. It is possible therefore that those tered before the onset of ischaemia such as agents examined over the years to limit lethal those described above may be of limited reperfusion injury may have been unsuccessful clinical eYcacy since the majority of individu- because they did not modify this potentially als present with an ongoing ischaemic episode. important component of myocardial death, For these patients reperfusion represents the whereas specific anti-apoptotic interventions only means of limiting infarct size. However, as may be better able to ameliorate lethal mentioned above, reperfusion comes at a price reperfusion injury. This approach is currently in terms of reperfusion injury, which may more speculative than those mentioned above, include further tissue death (lethal reperfusion but recently various agents which block the

Table 1 Considerations for administration of infarct limiting treatments in acute myocardial infarction

Clinical scenario Treatment rationale Choice of agent Implications for trial Patient at risk of acute Pre-ischaemic pretreatment “Preconditioning” mimetics, eg, Several agents are protective if administered before coronary myocardial infarction, to limit infarct size. adenosine and selective receptor occlusion. Clinically, timing of bolus treatment would be eg, unstable angina. agonists, KATP channel openers. Other diYcult. Continuous pretreatment over an indefinite period anti-ischaemic agents, eg, Na/H before infarction is the only feasible approach. For trial exchange inhibitors. purposes, only a limited number of unstable angina patients would be available. Patient presents with (a) Intra-ischaemic Anti-ischaemic agents must have Drug access to the ischaemic risk zone would be evolving myocardial treatment to limit ongoing access to the risk zone during the early unpredictable. Some patients may benefit (eg, if there is some infarction. Reperfusion ischaemic injury is ischaemic period. residual flow) but because of inherent variability in eVective treatment is indicated. dependent on access of drug dosing of the risk zone, large numbers would be required to to the ischaemic risk zone show statistical benefit. Not an ideal scenario for a clinical through either residual flow trial. Potential benefit of adenosine in AMISTAD may be via in the infarct related artery, an anti-ischaemic eVect since experimental evidence for an a cyclical pattern of eVect at reperfusion is conflicting. thrombosis (“stuttering ischaemia”) or a degree of collateral flow, (b) Pre- or perireperfusion A few clinically tested agents, eg, Reperfusion injury may contribute 25–50% of final infarct treatment to limit insulin and magnesium, may act size. Unless treatment is very potent, large numbers would be reperfusion injury. predominantly in this mode. required to detect benefit. Reperfusion injury occurs early Experimental agents which attenuate and timing of treatment is critical. Administration after reperfusion injury include various reperfusion will reveal little or no eVect, cf magnesium in inhibitors of apoptosis. LIMIT-2 and ISIS-4 trials.

In all cases, prompt reperfusion is the prequisite for tissue salvage. In a trial, any beneﬁt would have to be beyond that attributable to reperfusion treatment alone. 386 Yellon,Baxter

complex apoptotic pathways, given at reper- 6 Opie LH. Reperfusion injury and its pharmacologic modification. Circulation 1989;80:1049–62. fusion as a means of limiting lethal tissue 7 Jennings RB, Reimer KA. Lethal reperfusion injury: fact or injury, have undergone early preclinical evalua- fancy? In: Parratt JR, ed. Myocardial response to acute injury. London: MacMillan, 1992:17–34. tion. Naturally occurring modifiers of apopto- 8 Woods KL, Fletcher S, RoVeC,et al. Intravenous sis include various “growth factors” which magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester intravenous mag- exert a counter regulatory action during devel- nesium intervention trial (LIMIT-2). Lancet 1992;339: opment. We have hypothesised that growth 1553–8. 9 ISIS-4 (Fourth International Study of Infarct Survival) Col- factors are able to reduce lethal reperfusion laborative Group. ISIS-4: a randomised factorial trial injury by inhibiting apoptosis. 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IMAGES IN CARDIOLOGY

Candle ﬂame appearance in dissection of aorta

- A 40 year old man underwent transoesopha- geal echocardiography for suspected dissection of aorta. Dissection extended from T7 vertebral level to L2 vertebral level. At the exit point of the dissection, there was a tiny opening through which a jet of blood ﬂowed from the false lumen to the true lumen. The appearance produced a candle shaped image on colour Doppler imaging (Ao, aorta). K M KRISHNAMOORTHY P K DASH VRIYER