Current theories and therapies relating to acute myocardial infarction and reperfusion injury

llllortiw and Critiixd Con Nuniq ( 1992) 8, IO4- I I2 CQ Longman Group UK Ltd 1992

Current theories and therapies relating to acute myocardial infarction and reperfusion injury

Simon Stewart

Acute myocardial infarction (AMI) was previously treated with conservative strategies that allowed the process of ischaemia to proceed uninterrupted. The resultant myocardial necrosis and reduced ventricular function were accepted outcomes. The emergence of thrombolytic agents such as streptokinase and tissue plasminogen activator (tPA) revolutionised the management of coronary artery occlusion, yet the spectre of further myocardial necrosis and ventricular dysfunction remains. The concept of ‘reperfusion injury’, an acute process described as occurring after thrombolysis of a coronary artery occlusion and referring to an unexpected loss of ventricular function, has been extensively researched. Current research papers describing the mechanisms involved appear either to emphasise those processes that occur within the actual myocytes, or those events within the coronary vasculature. In most papers however, oxygen free radicals (OFRs) are accepted as mediators of cellular injury; despite the debate surrounding their primary source. Efforts to minimise the effects of primary ischaemia and subsequent ‘reperfusion injury’, appear to be focused upon restoring cardioprotection against the increased levels of these damaging molecules. Scavenging agents such as N-acetylcysteine (NAC) which can also assist in dilating coronary vessels as well as preventing further platelet aggregation, when combined with glyceryl trinitrate (GTN), are being closely scrutinised. Despite the advances made, the processes within the myocardium remain somewhat a mystery and the search continues for more effective strategies to ensure myocardial viability and long-term function. Critical care nurses need not only to be aware of the aim of these new strategies, but should also be conscious of their effect on the patients receiving them.

INTRODUCTION following the administration of thrombolytic

therapy for acute myocardial infarction (AMI),

The proliferation of research articles that exam- has provided critical care nurses with a wide

ine the process of myocardial reperfusion range of theories as to the possible mechanisms

involved. Despite this extensive body of

Simon Stewart BA, CCRN, Nurse Educator, School of research, myoc&dial reperfusion is still a poorly

Nursing, The Queen Elizabeth Hospital, Woodville, understood process (Naslund et al, 1990). One

South Australia reason for the uncertainty is the difficulty in

(Requests for offprints to SS)

Manuscript accepted 23 January 7992

104

comparing the results achieved in animal studies, which make up the bulk of research

INTENSIVE AND CRITICAL CARE NURSING 105

Atherosclerosis

I I Decreased EDRF Increased Turbulence

1 Exposed Collagen

Vasoconstriction + Platelet Aggregation

Vessel Occlusion

Fig. 1 Events within a coronary artery that can cause AMI

performed, with the processes that take place in human hearts (Blaustein et al, 1989). During an AMI, the person’s well-being takes precedence over any invasive or experimental investigation, whilst most theories describe microcellular events and responses that are difficult to repro- duce in an experimental environment.

The purpose of this article is to examine the various issues, theories and therapies relating to AMI and the frequently referred to concept of reperfusion, in an attempt to translate them into a constructive framework of reference within which a nurse can evaluate the current practices and treatments of AMI in a clinical environment, and identify nursing implications.

ACUTE MYOCARDIAL INFARCTION

The process of AMI in the majority of cases is thought to occur when the presence of gradually occlusive atherosclerotic lesions in a coronary artery cause a precursory decrease in vascular response to the natural vasoactive mediators, therefore reducing the vessel’s radius and its ability to dilate. During the precursory stages of infarction the diseased endothelium is acutely aggravated, releasing chemotaxic mediators that initiate vasoconstriction and create an environment favourable to platelet aggregation and subsequent thrombus formation which occludes the artery (Fig. 1).

The ‘wavefront’ model of ischaemia refers to the pattern of ischaemia and irreversible necrosis that can follow coronary vessel occlusion;

from the subendocardial layer to the subperi- cardial layer (Black et al, 1990; Johnson et al, 1990; Maza & Frishman, 1987). The completion of a full transmural infarction is thought to take anywhere between 4-36h (Larner 8c Conway, 1989). The pattern of ischaemia depends on many variables, including the position of the occlusion and the normal variance in coronary anatomy. The individuality of cardiac anatomy results in a variable amount of either retrograde or collateral blood flow, providing oxygenated blood distal to an occlusion and reducing the extent of ischaemic damage.

The effect of an uninterrupted coronary artery occlusion can therefore vary; areas of the myocardium may be permanently damaged, producing akinesis and a characteristic fibrous scar, whilst other areas (usually on the peri- pheral margins) may remain ischaemic and in various states of dyskinesis. Opinions on whether such ischaemic myocytes in limbo (not permanently damaged but susceptible to further ischaemia) can be saved by intervention using thrombolytic agents vary considerably (Maza & Frishman, 1987).

Differing emphasis has been placed upon intracellular and intravascular mediators in the proposed models of ischaemia and reperfusion, as will be discussed. In reality, the ischaemic process in AM1 may well prove to be a combination of all these factors and more, depending on an unlimited amount of anatomical and physiological variables. Figure 2 is a model of ischaemia that represents the author’s interpre- tation of this process based on the theories presented in this article.

I.C.N.- C

106 INTENSIVE AND CRITICAL CARE NURSING

Occlusion of Coronary Artery

1 Decreased

O2 + Glucose

1

Anaerobic Resp

1

Lactic Acid + co2

1 4 increased 1 Increased

PMNs + Platelets Vasoactive Mediators

1 5- + Increased OFRS - Decreased EDRF +

Vasoconstrjction

* Cell Membrane + Endothelial Membrane Permeability Increased

Fluid + Electrolyte Disturbances

+ Necrosis

Fig. 2 A model of AMI incorporating both proposed intracellular (left pathway) and extracellular (right pathway) processes leading to myocardial dysfunction

ROLE OF OXYGEN-FREE RADICALS IN THE ISCHAEMIC PROCESS

The normal production of OFRs as a result of

the cell mitochondria utilisation of oxygen during aerobic respiration is well documented

(Cotgreave et al, 1988; Maza & Frishman, 1987;

Read & Dusting, 1987; Prasad et al, 1990). What

is less understood is the role these OFRs play in

the ischaemic process: there has been a great

deal of discussion concerning the primary

source of OFRs during ischaemia, and the role

played by the natural cardioprotective enzymes

which normally buffer them. In the normal process of oxygen utilisation by

cell mitochondria 95% of the available oxygen is reduced to Hz0 without the production of harmful by-products. In the remaining 5%, the oxygen molecule, preferring incoming electrons

to enter its molecular field one at a time (uni-

valent reduction), creates a highly reactive mol-

ecule with one unpaired electron; the superoxide anion (Oz-), an OFR. This superox-

ide molecule exists for only a few milliseconds

before being rapidly scavenged by the enzyme superoxide dismutase (SOD), speeding up its

conversion to hydrogen peroxide (HzOz).

Hydrogen peroxide is another highly reactive molecule that is similarly scavenged by the

enzymes catalase and glutiathione peroxidase to

produce HZ0 and OZ. In this manner these highly reactive and destructive OFRs are rapidly

rendered harmless (Maza 8c Frishman, 1987).

Figure 3 shows a simplified version of the reactions mediated by these cardioprotective

enzymes. In an ischaemic heart the reduction of blood

flow and therefore available 02, glucose and other essential molecules, causes a transfer to

02- + OS- + 2H+ - Superoxide dismutase + H202 + 02

Hz02 - Catalase + Glutiathione + Hz0 + 02

Fig. 3 Pathways of OFR scavenging by cardioprotective enzymes (Adapted from Maza 81 Frishman. 1967. p. 206)


anaerobic respiration by the myocyte mitochondria. This not only increases the ratio of adeno- sine triphosphate (ATP) utilised, but increases lactic acid and H+ ion concentrations. This intracellular environment favours the univalent of OFR producing reduction of Oz. The changes described are reflected in increased Oz- concentrations and a cascading production of OFRs, accompanied by an inverse depletion of the protective enzymes. As a result of less SOD, catalase and glutiathione peroxidase, more OFRs are produced, including the highly destructive hydroxyl radical (OH-), a product of increased HsOz. The hydroxyl radical, in turn, reacts with a range of metallic and lipid molecules to form a further cascade of OFRs; hastening cell dysfunction and causing their ultimate destruction (Thompson & Hess, 1986). The OFRs produced readily react with the lipid-based cell membrane causing its destruction. The consequential loss of cell integrity causes a rapid shift in the electrolyte balance, with associated osmolar swelling in the intracellular and extracellular compartments.

The ischaemic environment, once established, may take a considerable period of time to resolve. The theory of ‘myocardial stunning’ refers to a proposed uncoupling of the calcium- transport-dependent sarcoplasmic reticulum contractile mechanism, secondary to the electrolyte disturbance described. This is exac- erbated by the decreased production of the high energy phosphates e.g. ATP, resulting in decreased ventricular function (Prasad et al, 1990). The associated loss of cardiac output due to ‘myocardial stunning’ may take days or weeks to resolve, depending on the severity and extent of ischaemia (Blaustein et al, 1989; Larner & Conway, 1989).

ROLE OF VASCULAR MEDIATORS

In recent years the importance of the injured vascular endothelium in determining the extent of an AMI has been focused upon. Injured or exposed endothelium stimulates thrombus formation through the mediation of prostaglandins which increase platelet aggregation and stimu-

late mast cell release of histamine. Aggregating platelets in turn release serotonin enhancing the aggregation of polymorphonuclear neutrophils (PMNs) (Maza & Frishman, 1987). The comple- ment system is similarily activated; C5a is known to interact with the receptors of circulating neutrophils, inducing a leukocyte chemotaxis, auto-aggregation and adherence to the injured endothelium. Activated and infiltrating PMNs, through the actions of various chemical mediators, are implicated in the production of OFRs including hypochlorous acid (HOCL), causing further myocyte injury (Mullane et al, 1987; Sullivan et al, 1988). Whether PMNs are responsible for 90% of OFR production as some sources have reported, is debatable (Thompson & Hess, 1986). Other sources maintain that the PMN aggregation described takes up to 624 h to occur, and is probably responsible for secondary injury or the commonly described reperfusion injury (Larner & Conway, 1989).

Micro-embolisation due to aggregating PMNs has been linked to prolongation of the ischaemic process, despite primary thrombolysis (Thomp- son 8c Hess, 1986). This process may be aggravated by the osmotic swelling in the intracellular and extracellular compartments (Maza & Frish- man, 1987). As well as infiltrating and injuring the vascular endothelium and myocytes beneath it, the activated PMNs initial respiratory burst is thought to produce OFRs that interfere with the production and effect of endothelial derived relaxing factor (EDRF), producing localised vasoconstriction (Read & Dusting, 1987; Thompson 8c Hess, 1986). It has been reported that platelets can also contribute to the presence of OFRs and may aggrevate this effect (Thomp- son and Hess, 1986). As a combination these factors may contribute to the ‘no reflow’ phenomenon, which refers to a lack of coronary

blood flow despite the thrombolysis of the primary occluding thrombus.

The inevitable result of an ongoing ischaemic process is an ever-increasing number of necrosed myocytes, with a parallel decrease in myocardial function. It is obvious that reperfus- ing the affected area will help to reverse some of the damage described, and subsequently salvage a degree of myocardial function.


AIMS OF REPERFUSION

There is some thought that readmission of coronary blood flow through a previously

occluded artery in AM1 is not necessarily benefi-

cial to the myocardium and may actually increase

the rate of necrosis (Ferrari et al, 1990). In contrast there are others who would argue that

reperfusion hastens only the death of unsal-

vageable myocytes, and benefits those myocytes that are merely ischaemic and not irreparably

damaged (Maza & Frishman, 1987). Certainly

there has been a conscious shift away from

simply aiming to open an acutely occluded

artery, towards a broader aim of ensuring max-

imal myocardial function. There is a considerable body of evidence to

support the theory that early reperfusion is

more beneficial in AMI; thrombolytic therapy

initiated within 3 h of primary signs and symp-

toms achieves greater myocardial viability and

subsequent long-term survival rates. Further

research has indicated that thrombolysis can be

beneficial even 13-24 h later (The Lancet, 1989).

REPERFUSION INJURY

Reperfusion injury has been described in a

number of experimental animal models and in

human hearts during cardiac surgery, usually following the clamping and sudden reintroduc-

tion of blood flow through the coronary vessels

during bypass operations. There are obvious

moral and ethical limitations to human studies

(of which nurses should be aware) and con- sidering the difficulties in reproducing the con- ditions that exist within the human heart during an AMI, researchers are unable to reach definite conclusions concerning the mechanisms of reperfusion injury.

One of the major theories of reperfusion injury contends that sudden increases in oxygenated blood flow via a previously occluded coronary artery will result in a ‘respiratory burst’ by the ischaemic myocytes as they utilise the previously unavailable oxygen, producing a rapid increase in OFRs. As previously described,

the normal chemoprotective enzymes such as

SOD, catalase and glutiathione peroxidase are

depleted during primary ischaemia, leaving the

destructive cascade of OFR, production to con- tinue unabated, and even accelerated (Thomp-

son & Hess, 1986; Ferrari et al, 1990). Whether

such an accelerated ischaemic process only

destroys those myocytes that are beyond salvaging, or actually causes irreversible injury to

myocytes that were merely ischaemic and

potentially able to function once oxygenated circulation was established, is unclear. This

theory of continuing cell injury despite reintro-

duction of oxygen has been labelled the ‘oxygen

paradox’ (Maza & Frishman, 1987).

Regardless of the fact that OFRs have been

attributed to a number of mechanisms, most studies of reperfusion injury describe an unex-

pected deterioration in myocardial function

despite evidence of reperfusion.

This unexpected loss of function may be

explained by the ‘no reflow’ phenomenon pre-

viously discussed, or may be due to electrolyte

imbalance; some researchers believe this to be

the primary cause for myocardial dysfunction.

The ‘calcium paradox’ in particular is thought to

be a major mediator of dysfunction. Previously ‘myocardial stunning’ post AMi was described as

a product of the ischaemic dysfunction of the

calcium-dependent sarcoplasmic reticulum; paradoxically however, the reintroduction of

blood flow to the myocardium and associated increase in intracellular calcium is thought to

‘overload’ the sarcoplasmic reticulum, thereby

sustaining the decreased cardiac output asso-

ciated with ‘myocardial stunning’ (Allen &

Orchard, 1987). The most recognised and certainly most

dramatic consequence of reperfusion are the ‘reperfusion arrhythmias’; hence the efficacy of cardiac monitoring and defibrillation equipment at hand during AMI (Black et al, 1990; The Lancet, 1989). Figure 4 displays the rhythm strips of 2 people who received thrombolytic therapy (streptokinase) for AM1 and whose cardiac enzymes levels were consistent with early reperfusion.

Both ventricular tachycardia and accelerated idioventricular rhythm are common during

INTENSlVEANDCRlTlCALCARENURSlNG 109

Fig. 4e 4 h post-streptokinase, required emergency defibrillation

Fig. 4b 8 h post-streptokinase, resolved spontaneously

Fig. 4 Common ‘reperfusion arrhythmias’ include a) ventricular tachycardia and b) idioventricular rhythm

reperfusion. As with the other concepts discussed a variety of theories, including the presence of arrhythmogenic OFRs, catecholamine stimulation, re-entry ischaemia and electrolyte disturbances, have been proposed as mediators of this phenomena (The Lancet, 1989).

PROVIDING MYOCARDIAL PROTECTION

How can a cardiologist provide protection to viable myocytes facing further damage from reperfusion injury? The thrust of research being carried out today relies upon trying to under- stand the process of ischaemia and preventing the cascade of reactions it provokes. Recently there have been efforts to produce either direct or synthetic preparations of the intrinsic scavenging enzymes SOD, catalase and glutiathione peroxidase in order to preserve the vulnerable myocytes during ischaemia.

Trials of SOD administration in richly col- lateralised animal models produced significant salvaging of the myocardium post infarction (Naslund et al, 1990), but have a recognisable limitation in practical application to poorly col- lateralised human hearts. Collateral circulation not only provides a pathway for oxygenated blood but also the scavenging agent introduced.

On a more optimistic note, the combination of intravenous preparations of N-acetylcysteine (NAC) and glyceryl trinitrate (GTN) (Horowitz et al, 1988) may provide a means to ensure a degree of cardiprotection during infarction and reperfusion. Previously intravenous GTN has been administered in ischaemic events in order to reduce both coronary and systemic vasoconstriction. GTN achieves vasodilatation by providing a source of nitric oxide a labile substance that has identical biological properties to EDRF and has the added effect of reducing platelet aggregation (Johnson et al, 1990). Unfortunately, as with other biochemical mechanisms, the pathway from GTN to nitric oxide requires an essential chemical group which can become depleted. NAC in conjunction


with GTN has come to the forefront as a treatment for ischaemia due its ability to potentiate GTN by providing the necessary sulphyhydryl group and forming S-nitro-NAC a chemical that exhibits strong inhibitory effects on platelet and PMN aggregation (Horowitz et al, 1988). Earlier research into NAC suggests that not only is it able to scavenge certain OFRs directly, including hypochlorous acid, hydrogen peroxide and the hydroxyl radical, but that by donating sulphydryl groups, glutiathione peroxidase is able to return to its bioprotective status against the highly destructive hydroxyl radical, in the cycle of buffering and returning to a reduced state (Ceconi et al, 1988).

As with the other agents currently being studied, the question of whether NAC can provide adequate human cardioprotection remains unanswered. Reperfusion injury has been postu- lated to occur in the first few seconds of re-introduction of oxygenated blood flow to the myocardium (The Lancet, 1989), and the ability of these agents to reach those areas most vulnerable to the process of reperfusion, in sufficient concentrations, is still unclear.

NURSING IMPLICATIONS

What are the implications a nurse should con- sider, when nursing a patient with coronary disease, in relation to the emergence of the theories described, and the parallel develop- ment of strategies designed to exploit them? This article has touched upon a number of issues and points that are relevant to clinical practice. These include:-

Despite the spectre of reperfusion injury any patient with a high risk of occluding a coronary vessel, should be closely monitored for the purpose of early recognition of AMI, thereby ensuring the potential for minimising cardiac dysfunction through thrombolytic intervention. Following thrombolytic therapy for AMI, any nurse involved should not only anticipate and be prepared for the possibility of

3.

compromising reperfusion arrhythmias, e.g. ventricular tachycardia, but should be aware that concurrent electrocardiograph (ECG) changes such as resolving ST eleva- tion or T wave inversion may indicate that early reperfusion has occurred (Black et al, 1990). Despite evidence of early reperfusion the nurse should anticipate the consequences of decreased ventricular function as a result of reperfusion injury by vigilant monitoring of the patient’s condition. Routine nursing observations should include; - Assessing the patient’s general appear- ance for signs of cyanosis, severe vasoconstriction and excessive diaphoresis. - Noting the patient’s neurological status and degree of fatigue. - Observing vital signs at regular intervals, in order to note any precursory rise in blood pressure and heart rate before a compensatory rise in cardiac output pre- cedes a dramatic fall due to decompen- sation. - Monitoring heart and lung sounds for signs of systolic or diastolic dysfunction as well as any valvular incompetence associated with ischaemic injury; the emergence of an S3, S4, summation gallop or valvular regurgitation heart sounds may well be accompanied by the characteristic crackles of pulmonary oedema, and other signs of falling cardiac output requiring immediate intervention. - Continuous ECG monitoring may reveal an increasing trend in compromising arrhythmias that warn of impending dysfunction, associated with both electrolyte imbalance and hypoxia. - More invasive monitorings, depending on the limitations imposed by thrombolytic therapy, could include simple central venous pressure (CVP) monitoring of pre- load and an arterial line for monitoring the pulse pressure. If inserted, a pulmonary catheter will enable the pulmonary pressures (PAP) and pulmonary capillary wedge pressure (PCWP) to be monitored


for signs of left and/or right ventricular dysfunction; a rise in the left ventricular end diastolic volume (LVEDV) is a characteristic feature after AMI, however the ventricular wall usually stiffens approxi- mately 6 h following a transmural infarction and the LVEDV decreases accordingly. - If available, cardiac output studies can provide a broader view of ventricular function including vital monitoring of the cardiac index to indicate if there is a persistent loss of cardiac output.

4. A patient experiencing ‘myocardial stunning’, secondary either to primary ischaemia or ‘reperfusion injury’, may well require a longer stay in a specialised unit such as a coronary care unit. A rehabili- tation plan that includes recognition of both the psychological effects of slowed recovery and the need to limit activity so that catecholamine innervation and myocardial oxygen demand (MVOs) is mini- mised must be considered in planning the nursing care (Underhill et al, 1982).

5. The plethora of emerging preparations designed to minimise the effects of AM1 and reperfusion injury requires nurses to pursue a knowledge base that will enable them to be effective patient advocates. In a critical area it is sometimes difficult to relate to a patient the advantages and disadvantages of treatment; so it is particu- larly important that nurses must under- stand the implications of administering the medication ordered and make a commit- ment to act if they have concern over any aspects of its use.

CONCLUSION

The potential for thrombolytic-induced reperfusion to instigate a cascade of harmful effects on an already compromosied myocardium must be recognised by nurses when caring for patients who are at risk of AMI. The benefits of early thrombolysis of a coronary occlusion outweigh

the risks in most cases. As primary observers of patients with AMI, and in many instances insti- gators of interventive management, nurses must be aware of those options available to minimise myocardial damage as well as the implications of using such strategies. The overwhelming con- sideration should be the patients’ welfare.

References

Allen DC, Orchard CH 1987 Myocardial contractile function during ischaemia and hypoxia. Circulation Research 60(2): 153-168

Black L, Coombs VJ, Townsend SN 1990 Reperfusion and reperfusion injury in acute myocardial infarction. Heart and Lung 19(3): 274-284

Blaustein A, Deneke SM, Stolz RI et al 1989 Myocardial glutathione depletion impairs recovery after’short neriod of ischaemia. Circulation 80(5): 1449-1457

C&oni C, Curello A, Cargoni R et al i988 The role of glutithione status in the protection against ischaemia and reperfusion damage: effects of N-acetyl cysteine. Journal of Molecular dll Cardiology 20: 5-13

Cotareave IA. Moldeus P. Orrenius S 1988 Host bt&hemicai defense mechanisms against prooxidants. Annual Review of Pharmacological Toxicology 28: 189-212

Ferrari R, Alfieri 0, Cure110 S et al 1990 Occurrence of oxidative stress during reperfusion of the human heart. Circulation 8 1 ( 1): 202-2 11

Horowitz JD, Henry CAH, Syrjanen ML et al 1988 Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 77(4): 787-794

Johnson G, Tsao P, Allan ML 1990 Synergism between superoxide dismutase and sodium nitrite in cardioprotection following ischaemia and renerfusion. American Heart lournal: 53&537

The’Lancet 1989 Reperfusion &jury after thrombolytic therapy for acute myocardial infarction. The Lancet Sept: 655-657

Larner AJ, Conway MA 1989 Free radicals in acute myocardial infarction. Quarterly Journal of Medicine 70(263): 205-2 13

Maza SR, Frishman WH 1987 Therapeutic options to minimise free radical damage and thrombogenicity in ischaemiclreperfused myocardium. American Heart Journal 114(5): 206-213

Mullane K, Hatala MA, Kraemer R, Sessa W et al 1987 Myocardial salvage induced by REV-590 1: an inhibitor and antagonist of the leukotrienes. Journal of Cardiovascular Pharmacology lO(4): 399-405

Naslund U, Haggmark S, Johansson G et al 1990 Limitation of myocardial infarct size by superoxide dismutase as an adjunct to reperfusion after different durations of coro&ry occlusion in the pig. Circulation Research 66(5): 1295-1301

Prasad K, Kalra J, Chaudhary AK et al 1990 Effect of polymorphonuclear leukocyte - derived oxygen free radicals and hypochlorous acid on cardiac function


and some biochemical parameters. American Heart Journal 3( 1): 538-550

and tumour necrosis factor on neutrophil function by

Read MA, Dusting GJ 1987 The inhibitory actions of pentoxifylline. Infection and immunity: 1722-1729

anti-oxidants on endothelium derived relaxing factor Thompson A, Hess ML 1986 The oxygen free radical

released from cultured bovine cells. Clinical and system; a fundamental mechanism in the production

Experimental Pharmacology 14: 409-414 of myocardial necrosis. Progresses in Cardiovascular Disease 28(6): 449462

Sullivan GW, Holliday TC, Novick WJ et al 1988 Underhill SL, Woods SL, Sivarjan ES 1983 Cardiac Inhibition of the inflammatory action of interleukin nursing. Philadelphia, J B Lippincott Co

Current theories and therapies relating to acute myocardial infarction and reperfusion injury

Documents

Transcript of Current theories and therapies relating to acute myocardial infarction and reperfusion injury