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CLINICIAN UPDATE

Fundamentals of Reperfusion Injury for the
Clinical Cardiologist
Subodh Verma, MD, PhD; Paul W.M. Fedak, MD; Richard D. Weisel, MD;
Jagdish Butany, MD; Vivek Rao, MD, PhD; Andrew Maitland, MD; Ren-Ke Li, MD, PhD;
Bikramjit Dhillon, BSc; Terrence M. Yau, MD
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C
ase presentation: S.B. is a 48-year-old man who reperfusion. Indeed, such transient periods of ischemia are
suffered an acute anterior myocardial infarction and encountered in the clinical situations of angina, coronary
received fibrinolytic therapy. The patient died ⬇12 vasospasm, and balloon angioplasty, and are not associated
hours after reperfusion. K.R. is a 68-year-old diabetic woman with concomitant myocyte cell death.1,2 With increasing
who underwent conventional coronary artery bypass graft duration and severity of ischemia, however, greater cardio-
surgery and developed low output syndrome after reperfusion myocyte damage can develop, with a predisposition to a
postoperatively. V.A. is a 55-year-old man who developed a spectrum of reperfusion-associated pathologies, collectively
stunned myocardium after percutaneous coronary reperfu- called reperfusion injury.3 Reperfusion injury results in myo-
sion. What is reperfusion injury, and why is it important? cyte damage through myocardial stunning, microvascular and
Reperfusion of coronary flow is necessary to resuscitate endothelial injury, and irreversible cell damage or necrosis
the ischemic or hypoxic myocardium. Timely reperfusion (termed lethal reperfusion injury; Figure 1).3,4
facilitates cardiomyocyte salvage and decreases cardiac mor- Myocardial stunning is the best-established manifestation
bidity and mortality. Reperfusion of an ischemic area may of reperfusion injury.5,6 It is defined as “prolonged postische-
result, however, in paradoxical cardiomyocyte dysfunction, a mic dysfunction of viable tissue salvaged by reperfusion,”1,2,7
phenomenon termed “reperfusion injury.” Modalities for and was initially described by Heyndrickx et al in 1975.8 In
reperfusion include not only thrombolysis, but also percuta- this scenario, reperfusion of either a globally or regionally
neous coronary intervention (PCI), coronary artery bypass ischemic myocardial tissue results in a period of prolonged,
grafting (CABG), and cardiac transplantation. Reperfusion yet reversible, contractile dysfunction. The myocardium is
injury has been observed in each of these situations. We
essentially “stunned” and requires a prolonged period of time
discuss here the fundamental principles of reperfusion injury
before complete functional recovery. The clinical correlate of
from a mechanistic and pharmacological standpoint.
a stunned myocardium can be found after reperfusion of a
globally ischemic myocardium (cardiac arrest during cardiac
What is reperfusion injury, and why is
surgery), or in the setting of regional ischemia and reperfu-
it important? sion (PCI, thrombolysis, unstable angina, and stress- or
The myocardium can tolerate brief periods (up to 15 minutes)
exercise-induced angina).1,2,5
of severe and even total myocardial ischemia without result-
Microvascular dysfunction is another manifestation of
ant cardiomyocyte death. Although the cardiomyocytes suffer
reperfusion injury.9 –11 Reperfusion causes marked endotheli-
ischemic injury, the damage is reversible with prompt arterial
al cell dysfunction, which results in vasoconstriction, platelet
and leukocyte activation, increased oxidant production, and
From the Division of Cardiac Surgery, University of Toronto, Toronto, increased fluid and protein extravasation (discussed below).
Canada.
Correspondence to Richard D. Weisel, MD, FRCSC, Professor of Although rare, severe microvascular dysfunction may limit
Surgery, Chair, Division of Cardiac Surgery, EN 14-215, 200 Elizabeth adequate perfusion after reperfusion, a phenomenon termed
St, Toronto General Hospital. Toronto, Ontario, Canada, M5G 2C4. “no-reflow”.
E-mail richard.weisel@uhn.on.ca
(Circulation. 2002;105:2332-2336.)
Reperfusion of a severely ischemic myocardium may also
© 2002 American Heart Association, Inc. result in myocyte death and necrosis (lethal reperfusion
Circulation is available at http://www.Circulationaha.org injury). This usually occurs in cardiomyocytes that have been
DOI: 10.1161/01.CIR.0000016602.96363.36 severely injured by ischemia but also may develop in revers-
2332
Verma et al Essentials of Reperfusion Injury 2333

Oxygen Free Radicals
The production of excessive quantities of reactive oxygen
species is an important mechanism of reperfusion injury.
Molecular oxygen, when reintroduced into a previously
ischemic myocardium, undergoes a sequential reduction lead-
ing to the formation of oxygen free radicals. A landmark
study by Bolli and colleagues19 showed that potent oxidant
radicals, such as superoxide anion, hydroxyl radical, and
peroxynitrite, are produced within the first few minutes of
reflow and play a crucial role in the development of reperfu-
sion injury. Oxygen free radicals also can be generated from
sources other than reduction of molecular oxygen. These
sources include enzymes, such as xanthine oxidase, cyto-
chrome oxidase, and cyclooxygenase, and the oxidation of
catecholamines.
Reperfusion is also a potent stimulus for neutrophil acti-
vation and accumulation,17 which in turn serve as potent
stimuli for reactive oxygen species production. Oxygen-
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derived free radicals produce damage by reacting with poly-
unsaturated fatty acids, resulting in the formation of lipid
peroxides and hydroperoxides that damage the sarcolemma
and impair the function of membrane-bound enzyme systems.
Free radicals stimulate the endothelial release of platelet
activating factor, which attracts more neutrophils and ampli-
Figure 1. Mechanisms and mediators of reperfusion injury. fies the production of oxidant radicals and the degree of
Reperfusion strategies are required to resuscitate the ischemic
myocardium. In the clinical realm, these include reperfusion for
reperfusion injury. Reactive oxygen species also quench
acute myocardial infarction (AMI) and angioplasty and after nitric oxide, exaggerating endothelial injury and microvascu-
CABG surgery and exercise- or stress-induced ischemia. Reper- lar dysfunction. In addition to an increased production, there
fusion injury results from several complex and interdependent is also a relative deficiency in endogenous oxidant scaveng-
mechanisms that involve the production of reactive oxygen spe-
cies, alterations in intracellular calcium handling, microvascular ing enzymes, which further exaggerates free radical–medi-
and endothelial cell dysfunction, altered myocardial metabolism, ated cardiac dysfunction.
and activation of neutrophils, platelets and complement. Reper-
fusion injury is manifested as stunned myocardium, reversible
microvascular injury, and, rarely, lethal myocyte necrosis.
Endothelial Dysfunction and Microvascular Injury
Reperfusion results in marked endothelial cell dysfunc-
tion.9,18 Endothelium-dependent vasodilatation is impaired,
ibly injured myocytes. A disruptive type of necrosis, termed whereas the responses to endothelium-dependent vasocon-
contraction band necrosis (Figure 2), has been documented strictors are exaggerated. Increased production of potent
and is ascribed to massive myofibril contraction after vasoconstrictors, such as endothelin-1 and oxygen free radi-
reperfusion-induced calcium reentry (Figure 2). This form of cals, increases coronary vasoconstriction and reduces blood
reperfusion injury is the most severe and is clearly flow. Furthermore, endothelial dysfunction facilitates the
irreversible. expression of a prothrombotic phenotype characterized by
Evidence of stunned myocardium has been extensively platelet and neutrophil activation, important mediators of
documented after reperfusion of an acute myocardial infarc- reperfusion injury. Once neutrophils make contact with the
tion, the deflation of angioplasty balloon, cessation of exer- dysfunctional endothelium, they are activated, and in a series
cise in patients with coronary artery disease, reperfusion after of well-defined steps (rolling, firm adherence, and transmi-
cardiopulmonary bypass, and reperfusion after ischemic gration) they migrate into areas of tissue injury through
stress induced by dobutamine or dipyridamole.1,2,4 – 6,12–15 endothelial cell junctions9,17,18 (Figure 2).
Stunning also may be an important causative factor in the
development of ischemic cardiomyopathy, wherein repeated Alterations in Calcium Handling
episodes of myocardial ischemia and reperfusion may lead to Changes in intracellular calcium homeostasis play an impor-
tant role in the development of reperfusion injury.16 Ischemia
the development of heart failure.5
and reperfusion are associated with an increase in intracellu-
lar calcium; this effect may be related to increased sarcolem-
What are the mediators of reperfusion injury? mal calcium entry through L-type calcium channels or may
Several mechanisms and mediators of reperfusion injury have be secondary to alterations in sarcoplasmic reticulum calcium
been described. The most frequently cited include oxygen cycling. In addition to intracellular calcium overload, alter-
free radicals, intracellular calcium overload, endothelial and ations in myofilament sensitivity to calcium have been
microvascular dysfunction, and altered myocardial implicated in reperfusion injury. Activation of calcium-
metabolism.9 –11,16 –18 dependent proteases (calpain I) with resultant myofibril
2334 Circulation May 21, 2002

Figure 2. A, Left ventricular free wall from a
48-year-old male who received fibrinolysis for acute
anterior myocardial infarction and died ⬇12 hours
after reperfusion. The left ventricular myocardium
showed dark brown discoloration in the papillary
muscle and free wall consistent with reperfusion-
related hemorrhage (RI). B, Histological section of
myocardium from the same patient showing acute
ischemic changes with margination of polymorpho-
nuclear leukocytes (PMN) and interstitial edema
(white arrow). In addition, myofibrils show thinning
and wavy pattern consistent with reperfusion injury
(black arrow). C, High-power representation of the
box in B showing neutrophil “tethering” and trans-
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migration (arrowhead). Neutrophil activation plays a
prominent role in reperfusion injury. D, Histological
section from left ventricular myocardium demon-
strating extensive contraction band change (black
arrows) and extensive extravasation of red blood
cells (arrowhead). Figure courtesy of Dr F. Schoen,
Brigham and Women’s Hospital, Boston, Mass. E,
Histological section of left ventricular myocardium
after acute myocardial infarction without reperfu-
sion. Extensive PMN infiltrate consistent with an 24-
to 48-hour-old infarct.

proteolysis has been suggested to underscore reperfusion the rapid recovery of aerobic metabolism and left ventricular
injury, as has proteolysis of troponin I.20,21 function after post– cardiac surgery reperfusion.25

Altered Myocardial Metabolism Endogenous Protective Mechanisms
Reperfusion of an ischemic myocardium results in altered The myocardium is the source of endogenous protective
myocardial metabolism, which in turn may contribute to mechanisms that are stimulated during reperfusion. These
delayed functional recovery. For example, cardioplegic arrest endogenous cardioprotective strategies serve to counter the
and aortic cross-clamping during cardiac surgery induce deleterious mechanisms described above. In many instances,
anaerobic myocardial metabolism with a net production of however, they are insufficient to prevent reperfusion injury.
lactate.22 Importantly, lactate release persists during reperfu- The most important endogenous protective mechanisms are
sion, suggesting a delayed recovery of normal aerobic me- adenosine production, opening of ATP-sensitive potassium
tabolism.22 Persistent lactate production after reperfusion channels (KATP), and release of NO.26 Although the details of
predicts postoperative ventricular dysfunction requiring intra- endogenous cardioprotection are beyond the scope of this
aortic balloon pump support.22 Likewise, the activity of update, it is important to note that these mechanisms have
mitochondrial pyruvate dehydrogenase (PDH) is inhibited by been exploited from pharmacological and therapeutic stand-
40% after ischemia and remains depressed for up to 30 points (discussed below).
minutes after reperfusion.23,24 In addition, the recovery of
postischemic myocardial function is dependent on the recov- What is the influence of cardiovascular risk
ery of PDH activity. These results suggest that persistent factors on reperfusion injury?
anaerobic metabolism may be an important contributor to Cardiovascular risk factors, including hypercholesterolemia,
inadequate postoperative ventricular function; improving the diabetes, and hypertension, have been reported to increase
recovery of aerobic myocardial metabolism during reperfu- reperfusion injury. Although the exact mechanisms remain
sion may serve as an important target for reperfusion injury. unclear, one recurring theme is that increased oxidative stress
Interventions that improve the transition from anaerobic to and endothelial cell dysfunction may underlie risk factor–
aerobic myocardial metabolism (insulin, adenosine) facilitate mediated exacerbation of reperfusion injury.9
Verma et al Essentials of Reperfusion Injury 2335

Which pharmacological strategies attenuate PCI, or surgical revascularization). Although the primary end
reperfusion injury? points of death and myocardial infarction were similar be-
Over the past 2 decades, ⬇1000 interventions have been tween groups, patients subjected to surgical revascularization
studied as potential cardioprotective agents in ischemia and exhibited a trend (P⫽0.06) toward improved left ventricular
reperfusion injury. We limit our discussion to some of the function in the cariporide group. These data suggest that
more contemporary approaches. Na⫹–H⫹ inhibition may be beneficial in attenuating myocar-
dial stunning after CAGB surgery.
Inotropic Stimulation of the Reperfused
Stunned Heart Stimulating Endogenous Cardioprotectants
It is important to note that the stunned reperfused myocardi- As discussed above, adenosine is an endogenous cardiopro-
um is sensitive to inotropic stimulation.1,2,26 As discussed tectant released during ischemia that exerts its beneficial
above, reperfusion injury results in significant desensitization effects via opening of mitochondrial KATP channels through
of the myofibrils to calcium; this phenomenon likely is interaction with the A1 and A3 receptors on cardiomyo-
overcome during inotropic stimulation, augmenting contrac- cytes.30 Despite marked beneficial effects of adenosine ther-
tility. Although inotropic stimulation is not the ideal strategy apy in experimental models of ischemia and reperfusion, the
to counter reperfusion injury, it is effective and is not clinical experience has been limited. Preliminary results of a
associated with a worsening of ultimate functional recovery phase-II clinical trial suggested that adenosine treatment may
or tissue necrosis. Indeed, transient inotropic support rou- reduce the requirement for inotropic and/or mechanical sup-
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tinely is used for a stunned reperfused myocardium in a port in patients undergoing cardiac surgery.31
variety of settings. Accumulating evidence suggests that endogenous myocar-
dial protection may be mediated via opening of mitochondrial
Antioxidants KATP channels. Pharmacological agents that open KATP chan-
The central role of oxygen free radicals in the development of nels are being evaluated as potential cardioprotective
reperfusion injury led to a widespread interest in the use of interventions.3
antioxidant therapy to attenuate reperfusion injury. Antioxi- Decreasing reperfusion injury via modulation of nitric
dants have been tested in several experimental and clinical oxide bioavailability is an active area of research.32 Nitric
models with mixed success.26 Despite positive observations oxide may serve to diminish reperfusion injury through
in classic models of experimental ischemia and reperfusion, improving endothelial function, decreasing platelet and neu-
clinical experience with antioxidants has been disappointing. trophil activation, and augmenting coronary flow. NO also
Indeed, therapy with human recombinant superoxide, de- may exert direct beneficial effects on cardiomyocyte survival
signed to attenuate angioplasty-induced reperfusion injury, (independent of endothelial cells) and may achieve this
demonstrated no beneficial effects.27 Although this may be through the opening of KATP channels.33 It is important to
related to cell impermeability, this study cast a shadow on the point out that these cardioprotective effects may depend on
development of antioxidant strategies for reperfusion injury. the magnitude of NO production; excessive NO production
It is important to note that the major antioxidant for the may exert marked deleterious effects on functional recovery.
cardiomyocyte is glutathione peroxidase, not superoxide Careful dose-ranging studies will be required before devel-
dismutase. Vitamin E (alpha tocopherol) is the major lipid- oping NO donors for patients receiving reperfusion treatment.
soluble antioxidant and requires prolonged and very high
levels of oral treatment to achieve cardiac concentrations that Metabolic Stimulation With Insulin
are protective from reperfusion injury. In an attempt to improve the transition from anaerobic to
aerobic myocardial metabolism, the effects of insulin on
Sodium-Hydrogen Antiport Inhibition ischemia and reperfusion injury have been studied. Insulin
Inhibition of sodium– hydrogen exchange (Na⫹–H⫹) has re- caused a marked stimulation of PDH activity and prevented
ceived much recent attention as a potential cardioprotectant the inhibition of PDH activity after reperfusion.24 Further-
factor.28 Ischemia and reperfusion result in marked intracel- more, insulin treatment reduced extracellular lactate release
lular acidosis; this in turn activates the sarcolemmal Na⫹–H⫹ after reperfusion and increased intracellular high-energy
antiport, which facilitates proton extrusion (in exchange for phosphate levels. In a randomized, controlled trial comparing
Na⫹).3,28 The intracellular hypernatremia that develops results insulin cardioplegia versus placebo, insulin produced a more
in activation of the sodium– calcium (Na⫹–Ca⫹2) exchanger, rapid recovery of aerobic metabolism and left ventricular
with resultant increases in [Ca⫹2]i. Indeed, inhibitors of function after reperfusion (cross-clamp release).25
Na⫹–H⫹ exchange have been demonstrated to exhibit marked
cardioprotection in experimental models of ischemia and What does the future hold?
reperfusion. More recently, the Na⫹–H⫹ inhibitor cariporide The past 2 decades have witnessed several pharmacological
was investigated in a large clinical trial involving 11 500 patients interventions designed to limit reperfusion injury. Unfortu-
(Guard During Ischemia Against Necrosis [GUARDIAN] nately, the success of some agents has been limited to
trial).29 The trial was designed to investigate the potential experimental models of ischemia and reperfusion. The lack of
cardioprotective effects of cariporide in a diverse group of a consistent clinical benefit may be related to a variety of
patients receiving reperfusion treatment (unstable angina, factors, including poor clinical trial design, inadequate phar-
non–ST segment elevation myocardial infarction, high risk- macokinetic/pharmacodynamic studies, and the complexity
2336 Circulation May 21, 2002

of the human in vivo model (compared with classic experi- 13. Kloner RA, Bolli R, Marban E, et al. Medical and cellular implications of
stunning, hibernation, and preconditioning: an NHLBI workshop. Circu-
mental models of reperfusion injury). It is important to
lation. 1998;97:1848 –1867.
distinguish therapeutic strategies for ischemia versus reper- 14. Ambrosio G, Betocchi S, Pace L, et al. Prolonged impairment of regional
fusion, and it is possible that a combination of agents is contractile function after resolution of exercise-induced angina: evidence
required to elicit maximum clinical benefit. The GUARD of myocardial stunning in patients with coronary artery disease. Circu-
lation. 1996;94:2455–2464.
during Ischemia Against Necrosis (GUARDIAN) trial with 15. Weisel RD. Myocardial stunning after coronary bypass surgery. J Card
cariporide provides further insight into this concept. Preclin- Surg. 1993;8(suppl 2):242–244.
ical evaluation of cariporide indicated a consistent benefit 16. Gross GJ, Kersten JR, Warltier DC. Mechanisms of postischemic con-
tractile dysfunction. Ann Thorac Surg. 1999;68:1898 –1904.
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strategy). Hence, it is not surprising that in the GUARDIAN myocardial ischemia-reperfusion injury. Cardiovasc Res. 1999;43:
trial, the only cohort that exhibited benefit was the CABG 860 – 878.
18. Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion
cohort, in which cariporide was instituted before the onset of injury. J Pathol. 2000;190:255–266.
ischemia.3 19. Bolli R, Jeroudi MO, Patel BS, et al. Direct evidence that oxygen-derived
In the future, we will witness the development and testing free radicals contribute to postischemic myocardial dysfunction in the
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Fundamentals of Reperfusion Injury for the Clinical Cardiologist
Subodh Verma, Paul W.M. Fedak, Richard D. Weisel, Jagdish Butany, Vivek Rao, Andrew
Maitland, Ren-Ke Li, Bikramjit Dhillon and Terrence M. Yau

Circulation. 2002;105:2332-2336
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doi: 10.1161/01.CIR.0000016602.96363.36
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2002 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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