Postcardioplegia acute cardiac dysfunction and reperfusion injury

Postcardioplegia

Acute Cardiac Jakob

Vinten-Johansen,

Dysfunction PhD, and Katsuhiko

In cardiac surgery, an obligatory period of ischemia is imposed in order to provide a convenient operative field. Brief periods of ischemia produce systolic and diastolic abnormalities related to pathology occurring during ischemia per se (ischemic injury) or expressed after the onset of reperfusion (reperfusion injury). In the surgical setting, ischemia may be encountered preoperatively with preexisting coronary disease, hypotension, or ventricular fibrillation, between intermittent infusions of cardioplegia solutions, or as a result of maldistribution of cardioplegia solution. The potential for reperfusion injury exists not only at the time of cross-clamp removal, but also with each infusion of cardioplegia solution. Infusion of cardioplegic solution is, in fact, a form of reperfusion to previously ischemic myocardium. lschemic injury and repetfusion injury are intimately linked in that the severity of ischemia sets the stage for and determines, in part, the extent of reperfusion injury. Mild-to-moderate systolic dysfunction, which may be called “postcardioplegia stunning,” remains a significant complication after cardiac surgery. More significant postoperative functional depression may occur in hearts with severe preoperative dysfunction, and in operations requiring long cross-clamp times. In addition, the failure to adequately distribute cardioplegic solution to all areas of the myocardium because of coronary stenoses, high coronary resistance or inadequate delivery pressure-flow relations, contributes to postcardioplegia dysfunction. However, the cardioplegic solution itself may also contribute to postcardioplegic dysfunction by creating temporary ionic and metabolic abnormalities. In addition, systemic hypocalcemia or hyperkalemia resulting from using large doses of

T

HE EXPEDITIOUS and successful conduct of cardiac surgery requires a quiescent heart and a bloodless field. Current techniques used to achieve this surgical environment include cardiopulmonary bypass, infusion of cardioplegia solutions with intervening periods of ischemia, and reperfusion of the previously ischemic myocardium after cross-clamp removal. These techniques provide obvious benefits to the convenient performance of the operation, but also adversely affect postoperative ventricular performance. For example, intermittent ischemia interposed between infusions of chemical cardioplegia solutions raises the potential for myocardial damage despite the modified conditions of delivery and additives designed to reduce or avoid the injury. Furthermore, this ischemic damage may be further exaggerated by activation of the complement cascade by the extracorporeal circuit, “reoxygenation injury” or “reperfusion injury” after removal of the aortic cross-clamp, or premature or excessive administration of inotropic agents. It is paradoxical that the very techniques invoked to avoid intraoperative and postopera-

From the Department of Cardiothoracic Surgery, The Bowman Gray School of Medicine, Winston-Salem, NC. Address reprint requests to Jakoh Vinten-Johansen, PhD, Department of Cardiothoracic Surge?), The Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. Copyright o I993 by W.B. Saunders Company 1053-0770/9310704-0203$03.OOlO

6

and Reperfusion Nakanishi,

Injury

MD

cardioplegic solution may temporarily aggravate postcardioplegic mechanical dysfunction. Current formulations and strategies for delivery of cardioplegia solutions are designed to address the various contributors to both ischemic and reperfusion injury that may impact on postoperative mechanical performance. lschemic injury is avoided by reducing myocardial oxygen demand by engaging immediate arrest and cooling the heart to approximately 10 degrees centigrade, and intermittently infusing solution to reoxygenate the myocardium, maintain hypothermia, and wash out accumulated metabolites. Reperfusion injury may be avoided by infusing hyperosmotic solutions at moderate pressures, and by incorporating oxygen radical scavengers or inhibitors to reduce membrane lipid peroxidation, myocellular and microcirculatory (endothelium) damage. Calcium accumulation during ischemia or reperfusion or both may be avoided by using hypocalcemic cardioplegic solutions. In addition, neutrophils may be scavenged specifically from cardioplegic solutions, or inhibitors of neutrophil activation used to limit neutrophil-mediated injury. Therefore, the concept of cardioplegic solutions has expanded from its original use as a method of inducing mechanical quiescence, to a vehicle for delivery of target-specific pharmacologic agents aimed at the multiplicity of factors contributing to ischemic-reperfusion injury. The use of cardioplegic solutions has contributed greatly to avoiding postcardioplegic dysfunction. Copyright t‘ 1993 by W. B. Saunders Company KEY WORDS: ventricular dial stunning

dysfunction,

cardioplegia,

myocar-

tive injury may themselves be contributory to these complications. Postoperative ventricular dysfunction after cardiac surgery requiring cardioplegia is commonly encountered clinica11y’-5and observed experimentally.h-x The frequency of its occurrence and the importance of both left ventricular and right ventricular function in successfully discontinuing bypass makes postcardioplegia dysfunction a realistic problem rather than a laboratory curiosity.” Postoperative myocardial dysfunction may be similar to myocardial “stunning,” which is defined as postischemic systolic (and diastolic) dysfunction that is unassociated with morphologic injury (necrosis), and is reversible after a period of convalescence. After cardiac surgery, postischemic dysfunction may be relatively transient in preoperatively normal hearts2,3,s,i” but can be protracted in cases of severe preexisting left ventricular dysfunction. I ‘I Although originally observed in regionally ischemic myocardium after reversible coronary occlusion.” postsurgical “stunning” after cardiac surgery encompasses both regional’3-‘h and global dysfunction since regional wall motion abnormalities may impact on global performancch,’ The phenomenon of postcardioplegia dysfunction or “stunning” may be observed in a wide spectrum of surgical conditions in which cardioplegic arrest and surgical ischemia have been imposed, including coronary artery bypass grafting (CABG),‘,4 valve repair, and transplantation. In contrast to regional stunning, which is largely unilateral, postsurgical stunning may involve both right and

Journalof CardvXhoracic and VascularAnesthesia, Vol7, No 4, Suppl 2 (August), 1993: pp 6-18 Sponsored by Sanofi Winthrop

7

ACUTE CARDIAC DYSFUNCTION

left ventricles.zJJr Because surgical ischemia after cardioplegic arrest may contribute to postoperative dysfunction, and may furthermore superimpose on any preexisting injury secondary to disease pathology, the phenomenon of postcardioplegia dysfunction merits considerable attention when strategies of myocardial protection are discussed and designed. The need for some form of protection is clearly demonstrated by postischemic contractile dysfunction (Fig 1A) and loss of compliance, or “stone heart,” observed after naive surgical ischemia. However, the attributes that constitute an ideal form of protection or cardioplegic solution remain elusive. The purposes of this review are to (1) discuss the etiology, expression, and avoidance or re-

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versa1 of regional and global myocardial dysfunction; and (2) outline the strategies designed to attenuate postcardioplegia dysfunction in cardiac surgery requiring cardioplegiainduced arrest, “protected global ischemia,” and reperfusion. SURGICAL ISCHEMIC

INJURY AND REPERFUSION

INJURY

The heart undergoing surgery requiring chemical cardioplegia is subjected to both ischemia and reperfusion at multiple points during the operation. Hence, the heart may be vulnerable to both reversible and irreversible injury due to both ischemia and reperfusion. Acute perioperative ischemic injury may be encountered (1) as part of the disease process for which the surgery is being conducted (ie, coronary occlusive disease), (2) as an unfortunate event before the institution of cardiopulmonary bypass (severe hypotension secondary to pump failure, tachycardia, ventricular fibrillation, failed angioplasty with dissection or reocclusion), (3) partial obstruction of the graft lumen at points of anastomosis, (4) with incompletely resolved stenotic lesions, (5) or inadequate delivery of cardioplegic solution globally or to individual grafts. Perioperative reperfusion injury may be encountered (1) during resuscitation from prebypass misadventures, (2) during each delivery of cardioplcgic solution. or (3) after release of the aortic crossclamp. In contrast to established concepts on the pathogencsis of ischemic injury, the very existence of a separate “reperfusion injury” has been avidly debated. Consequently. the nature of the linkage between ischemic injury and reperfusion injury, and the pathophysiological mechanism(s) involved are incompletely understood. The following section briefly encapsulates the pathophysiology of ischemic injury and reperfusion injury as they pertain to cardiac surgery. Pathophysiology of Ischemic Injury

IO

30

50

70

90

LV VOLUME (ml) Fig 1. Examples of postischemic dysfunction. Canine hearts subjected to 45 minutes of global ischemia without cardioplegic protection demonstrate profound postischemic contractile dysfunction characterized by a downward shlft in the Frank-Starling relationship (A). Adequate protective strategies can prolong the tolerable ischemic time to 4 hours with postfschemic dysfunction avoided. Inadequate myocardial protaction in hearts suffering severe preoperative ischemia fails to completely avoid postischemic dysfunction (6). characterized by a decrease in systolic performance (decrease in slope of the end-systolic pressure-volume relation) and left ventricular dilatation (rightward shift in position of the pressure-volume loops). (Data in A from Rozenkranzm)

The myocardium is a functionally aerobic tissue. While synthesis of ATP is adequate to meet the high metabolic demands of the normally perfused myocardium, the rate of ATP produced by anaerobic glycolysis is extremely low and is insufficient to support viability of the myocardium during ischemia, let alone support contractile activity and ion pump function. The classical definition of ischemia reflects the central role occupied by oxygen deficiency: an imbalance between myocardial oxygen and substrate supply versus the demand. However, not only the inadequacy of oxygen and substrate delivery but also the accumulation of tissue metabolites (lactate. CO?, H+) must be considered as factors contributing to the extent of contractile, metabolic and morphologic abnormalities occurring during ischemia. Ischemia may therefore be more broadly defined as a nutrient supply or rate of metabolite washout that is inadequate to sustain steady-state metabolism at a given level of cardiac performance.r7 In the early seconds following interruption of coronary blood flow, oxidative phosphorylation is reduced and

8

VINTEN-JOHANSEN

metabolism is converted to the more inefficient anaerobic metabolism. Intracellular levels of ATP decrease and metabolic products including AMP, adenosine, inosine, and hypoxanthine incrcasc. H+ and lactate also accumulate and progressively inhibit glycolytic flux and further limit ATP production. The decline in ATP production and ATP content contributes to impaired function of energydependent ion pumps within myocardium. Impaired Ca++ATPasc function results in reduced efflux of Ca++ from the cytosol, while reduced Nat-K+-ATPase activity induces a loss of K+ from the cytosol and a rise in intracellular Na+ conccntration.rx Moreover, the gain in intracellular Na+ may be further enhanced through the Na+/H+ exchange, which is driven by accumulation of intracellular H+ .I’) Those factors that influence the severity of surgically imposed ischemic injury are briefly listed in Table I. As the duration of the ischemic period increases, the potential for reversible myocardial injury to develop into irreversible damage increases. The perpetrator(s) of this lethal transition are not fully identified, but may be related to Ca’ ’ accumulation. Accumulation of Ca++ in the cytosol can activate proteases and phospholipases, leading to ccl1 membrane damage. At the same time, the activity of endogenous free-radical scavengers (catalase, superoxide dismutase, glutathione peroxidase) decreases. Thus, the appearance of oxygen-derived free radical species, including superoxide anion (.02), hydrogen peroxide (H202), and hydroxyl radical (.OH) may overwhelm surviving endogenous scavengers and cause lipid peroxidation leading to destruction of membrane structures and organelles. However, substrate levels of molecular oxygen sufficient to generate the oxyradical species may not appear until reoxygenation or reperfusion. Puthophysiology of Repe@sion Injuty Although the myocardium must be reperfused after ischemia to survive, recent studies have demonstrated that injury may be accelerated or extended by events specific to Table 1. Factors Influencing the Pathogenesis of Ischemia-Reperfusion

AND NAKANISHI

the reperfusion phase.:” Some question the existence of this so-called “rcpcrfusion injury”; however, cvidcncc dcscribing its characteristics, time course and mechanisms is accumulating. Furthermore, rcpcrfusion injury can be modified (cithcr cxtcnsion or regression) by interventions initiated at the time of reperfusion. I?.. li.:l-25 ln this artictc, reperfusion injury is defined as pathology that is cxtcnded. acccleratcd, or cxprcsscd dc novo from the profile observed during ischemia, resulting from events occurring after the onset of reperfusion. A second, more pragmatic and optimistic definition may be offered: tissue injury manifested or developed after reperfusion (including infusion of cardioplegic solutions) that can bc altcrcd (reduced or incrcascd) by modifying cithcr the conditions of repcrfusion or the composition of the perfusatc (ic. cardioplcgic solution). In this regard, the infusion of cardioplegic solution to an ischemic myocardium or myocardial segment can be considered a stage of rcpcrfusion. Several factors contributing to rcperfusion injury have been proposed and arc briefly rcvicwed below. The Severity qf‘lschemia The severity of preceding ischemia predetermines the magnitude of the subsequent injury after reperfusion. Longer periods or greater severity of ischemia with lower collateral flow will accelerate and exaggerate the reperfusion injury, as well as extend the postrcperfusion recovery time.*” Ca ++ Accumulation The phenomenon of excessive intracellular Ca++ accumulation after repcrfusion is widely observed. The Na+/Ca++ exchange system is suspected of being a major route of Ca++ influx, fueled by the accumulation of intracellular Na+ during ischemia. I’).?7 At the time of reperfusion, Na+/Ca++ exchange is reactivated by resynthesis of ATP and washout of H+ (an inhibitor of the exchange mechanism),Ix and may favor Ca ++ influx with extrusion of Na+ accumulated in myocardium.

Injury in the Surgical Setting

Neutrophils and Oxygen Free Radicals

lschemia I. Preischemic

physiology

catecholamines nutrition hormones presenting

disease (coronary

hypertrophy,

occlusion,

etc.)

II. Duration antecedent cross-clamp

“unprotected” (ischemic

ischemia

period)

ill. Collateral blood supply noncoronary

(minor)

coronary incomplete IV. Adequacy

cross-clamping

of protection

immediate

arrest

hypothermia composition

of solution

adequacy/frequency

of delivery

Previous studies have shown that reperfusion is accompanied by rapid neutrophil accumulation into the ischemic burst of oxygen free myocardiumZ9 with a subsequent radicals.“’ Ncutrophils, activated by chemotactic factors and cytokines such as complement fragments CSa, leukotriene B4, and platelet activating factor, may be the main sources of oxygen radical production, although oxyradicals may also be generated by the vascular endothelium, the cytosol, and mitochondria.sr Activated neutrophils produce .02 and H202 from molecular oxygen by the membranebound enzyme NADPH oxidase. Although .Oz and Hz02 are cytodestructive, these species also provide substrate for formation of the highly toxic .OH via the iron catalyzed Fenton or Harber-Weiss reaction. Furthermore, the oxidant hypochlorous acid is formed by the neutrophil granule enzyme myeloperoxidase. Another potential source of oxygen free radicals is the xanthine oxidase system localized

9

ACUTE CARDIAC DYSFUNCTION

within the vascular endothelium. Xanthine dehydrogenase normally present in the endothelium is converted to xanthine oxidase with the accumulation of Ca++ during ischemia. At the time of reperfusion, molecular oxygen (02) reacts with hypoxanthine accumulated from degradation of ATP during ischemia with xanthine oxidase as catalyst, which then forms xanthine and uric acid with the production of .02. However, the presence of xanthine oxidase in vascular endothelium is somewhat species-specific, and its abundance, function, and contribution to the oxyradical pool in man are unclear. 32 Activation of neutrophils also enhances degranulation and release of proteases such as collagenase and elastase, which may cause cellular damage. In addition, activated neutrophils may adhere firmly to microvascular endothelium or embolize in the microcirculation, resulting in impaired microvascular perfusion and postischemic “no-reflow phenomenon.“33

Endothelial Dysfunction It is now clear that neutrophil adhesion to coronary endothelium is a prerequisite for their activation and accumulation in myocardium. Neutrophil adherence to endothelium involves the binding of adhesion molecules on the surface of the neutrophil (CDll/CD18 complex) to complementary adhesion sites on the vascular endothelium and myocyte. Under normal conditions, endothelial cells secrete the vasoactive autacoid endothelium-derived relaxing factor (EDRF) or nitric oxide (N0),s4 which may prevent neutrophils from adhering to the vascular endotheha1 cell~.~~Ischemia-reperfusion results in endothelial dysfunction expressed as reduced vasorelaxation with an endothelium-dependent vasodilator due to attenuated production and/or release of EDRF from coronary endothelial cells.36,37 Reduction of EDRF impairs the NO-induced portion of vasodilation in the overall coronary autoregulatory mechanisms, but more importantly implies a loss of the capability of endothelial cells to control neutrophil adherence, resulting in an unbridled neutrophil-mediated cascade of injury. Moreover, the endothelium may be the primary site of complement activation and C5a production, which upregulates the expression of CDll/CD18 complex on the neutrophi1 surface and enhances neutrophil-endothelium interaction. EDRF elaboration by vascular endothelial cells may be further decreased by direct interaction with .02, resulting in effective neutralization of NO. Consequently, loss of NO release by the coronary vascular endothelium may play a large role in the pathogenesis of ischemia-reperfusion injury.23.25.38

This scheme of injury is applicable to surgical ischemia and reperfusion. Coronary artery EDRF-related function is not affected by 45 minutes of severe normothermic global ischemia, although longer periods of ischemia may compromise EDRF production or release.3g However, damage to coronary artery endothelium in the ischemic myocardium occurs predominantly after reperfusion with normal blood (Fig 2) possibly secondary to oxyradical-induced injury.25,38 The use of hyperkalemic, hypothermic blood cardioplegia does not prevent this endothelial injury, but it does prevent

ACh

.

Nam2

.

Fig 2. Endothelium-dependent vasorelaxation to acetylcholine (ACh) in in vitro vascular ring preparation is a standard bioassay for NO release by the coronary artery endothellum. NO released by acid&d NaNO* directly relaxes the vascular smooth muscle independent of the endothelium. Hearts subjected to 46 minutes of normothermic ischemia without reperfusion of any kind damonstrated no endothelium-dependent dysfunction. However, roperfusion with normal blood (REP group) produced approximately 30% depression in endothelium-dependent vasorelaxatfon. Blood cardiopfegia-induced arrest for an additional hour after the normothermlc period of ischemia did not prevent this endothelial dysfunction, but dfd prevent additional injury from occurring during the period of arrest. IBCH, ischemia; REP, ischemia plus unmodified blood reperfuaion; BCP, ischemia plus 1 hour blood cardiopfegic arrest and reperfusion; ?? P c 0.05 versus other groups. 0, ISCH; El, REP; W, BCP.

further injury that may occur over the additional intermittent protected ischemia. MANIFESTATION

hour of

OF POSTCARDIOPLEGIA

CONTRACTILE

DYSFUNCTION

As mentioned previously, postsurgical ventricular dysfunction is a common clinical occurrence.2~3~5JoClinically, postcardioplegia dysfunction shares characteristics similar to experimental myocardial stunning resulting from brief coronary occlusion. Cardiac dysfunction, assessed as cardiac output, cardiac index, or ejection fraction, is most marked early after surgery, with a gradual time course to partial or complete recovery over the ensuing 24 to 48 hours.2,3J,40 During this period, complete recovery can be achieved in patients with relatively normal to mildly depressed preoperative ejection fractions (> 0.50).2,3Jo,40However, in patients with more severe preoperative ventricular dysfunction, (ejection fraction <0.45), the time course of recovery is more prolonged and the ultimate extent of recovery achieved is significantly less.” Therefore, the clinical presentation of postsurgical patients bears a striking resemblance to other clinical and experimental situations in which myocardial stunning is expressed. Postsurgical ventricular mechanical dysfunction involves abnormalities in both systolic and diastolic performance. From experimental studies,6,7,41systolic elastance and preload-recruitable stroke work, both assessed by time-varying pressure-volume relations, are depressed postischemically

10

VINTEN-JOHANSEN

relative to their respective preischemic values (Fig 1B). This postsurgical dysfunction, assessed by preload-indepcndent and afterload-independent indices, would seem to corroborate clinical reports of dysfunction using load-sensitive indices such as ejection fraction, stroke work, stroke work in some index and cardiac output,-- ‘.x~” despite attempts studies to analyze data at comparable left ventricular filling and mean arterial pressures and heart ratc.‘Clinical studies using the load-insensitive pressure-volume indices have not corroborated the temporarily reversible postsurgical mcchanical depression, 42.43although alterations in the degree of postcardioplegia dysfunction due to treatment effects (ic, types of solution used and additives incorporated) have been demonstrated, indicating that such dysfunction can indeed be modulated.” Experimentally, diastolic dysfunction (loss of compliance) is a well-recognized consequence of ischemia-reperfusion injuryZ” in spite of well-formulated cardioplegic solutions. h.7.44The acute nature of these experimental studies precludes drawing any conclusion on whether this diastolic dysfunction resolves or becomes exaggerated over time. Clinical studies confirm the loss of immediate postsurgical compliance,4? and suggest that diastolic dysfunction may deteriorate during the first 2 to 4 hours postoperative recovery period. As suggested by Little and Applegate (article this journal), this loss of compliance may create a filling defect contributing significantly to depressed pump function. Loss of chamber compliance may bc due to a number of factors including direct injury to the myocardium (ic, edema, loss of Ca++ homeostasis), increased pulmonary vascular resistance or right ventricular dysfunction, resulting in right ventricular dilatation and septal shift toward the left ventricle. Regional Dysfunction Globul Dysfunction

Contributes to Overall

In the surgical setting, postcardioplegia dysfunction involves depression of not only global ventricular performance, but also of regional performance. This is particularly relevant to surgical revascularization of acute evolving myocardial infarction. The immediate or even delayed recovery of regional contraction of previously hypokinetic or dyskinetic segments contributes to counteracting depression of overall global performance. Because surgical global ischemia is superimposed onto regional ischemia in surgical revascularization of evolving myocardial infarction, correction of regional stunning may contribute to less postsurgical global dysfunction, particularly if multiple vessels are revascularized. Although the possible presence of necrosis may disqualify the revascularized segment for being “stunned,” postsurgical regional dysfunction will still contribute to global cardiac dysfunction.

genie factors. The causes of postsurgical ventricular “stunning” arc summarized in Table 2. The factors arc neither mutually cxclusivc, nor arc they indicative of a “final common pathway” mechanism of contractile dysfunction. Mechanical factors in Table 2 primarily produce defects in ventricular filling. The disease pathology presented at the time of surgery includes not only global disease (congestive heart failure), but coronary discasc with significant amounts of myocardium involved. Preexisting ischemic disease is vulnerable to superimposed damage occurring during surgical ischemia, which in turn may predispose the myocardium to ischemia-reperfusion injury during the procedure (intra-operative damage). Furthermore, iatrogenic factors arising from the nature of myocardial protection itself may contribute to early postsurgical dysfunction. Because current cardioplegia solutions arrest the heart by depolarizing doses of potassium, persistent systemic hyperkalemia may contribute significantly to postcardioplegia dysfunction. 45 In addition, systemic hypocalccmia originating from cumulative citrate levels from hypocalcemic blood cardioplegic solutions may produce temporary dysfunction postbypass. This iatrogenic dysfunction may be reversible with inotropic therapy or Ca+ + correction after a brief period of rcperfusion on total vented bypass.’ Mechanisms qf Contractile Dysfimction to Ischemia-Reperfkion lnjur?,

Secondmy

Dysfunction originating from preexisting disease and ischemia-reperfusion injury represents a significant contributor to postcardioplegia dysfunction. There are numerous mechanisms proposed to explain postischemic contractile dysfunction attributable to ischemia-reperfusion injury (Table 3). The mechanism(s) are not exclusive of the other factors listed in Table 2, but may interact with other factors to extend postsurgical contractile dysfunction. For example. dysfunction arising from ischemia-reperfusion injury encountered after removal of the cross-clamp may superimpose onto filling defects resulting from left ventricular hypertrophy. Most strategies devised to protect the heart arc based, in part, on the pathophysiology of ischemia-reperfusion Table 2. Causes of Postcardioplegia Systolic Dysfunction I, Mechanical factors hypertrophy pericardial/thoracic

constraints

Il. Disease pathology acute/chronic

failure

resolution of chronic MVI coronary disease III. Intra-operative factors duration of cross-clamp time adequacy of myocardial protection delivery edema

CAUSES AND MECHANISMS

OF POSTCARDIOPLEGIA

DYSFUNCTION

Postsurgical myocardial dysfunction results from a number of factors that can broadly be categorized under mechanical factors, pathophysiological factors related to ischemia and reperfusion injuries, intraoperative and iatro-

AND NAKANISHI

formulation IV. latrogenic factors persistent hyperkalemia persistent hypocalcemia hypothermia Abbreviation: MVI, mitral valve insufficiency.

11

ACUTE CARDIAC DYSFUNCTION

Table 3. Mechanisms Leading to Contractile Dysfunction Related to Ischamia-Reperfusion

Injury

Depressed ATP levels Impaired blood flow Calcium overload Reduced sensitivity to intracellular Cat+ Ca++-related sarcoplasmic-reticular

dysfunction

Oxygen-derived free radicals

injury and the avoidance of these pathogenetic mechanisms. The mechanisms resulting in contractile dysfunction pertinent to ischemia-reperfusion injury specifically are summarized below. Reduced A TP Availability

ATP levels in the myocardium are severely depressed during normothermic ischemia. Hypothermic cardioplegia retards this loss of high-energy phosphates, but does not entirely prevent it, particularly with long periods of aortic cross-clamp.46 The hypothesis is that postischemic contractile dysfunction may result from an insufficient energy supply (ie, ATP turnover rate) secondary to depletion of adenine nucleotide precursors or impaired mitochondrial phosphorylation capacity, or depletion of energy reserves (ie, tissue ATP levels). However, recent data have not confirmed the energy-depletion hypothesis.47 First, while ATP depletion correlates closely with other markers of ischemia in the absence of reperfusion, this correlation, especially with postischemic function, is lacking in reperfused myocardium. 47 Secondly, normal levels of creatine phosphate, and normal to mildly depressed oxygen consumption values in postischemic myocardium,48,49 indicate an intact phosphorylation capacity. Thirdly, postischemic myocardium is responsive to both inotropic stimuiation50.51 and Starling mechanisms,49%5Z-54despite reduced ATP levels, suggesting that depressed ATP levels are not imposing limitations on contractile performance. Impaired Myocardial Blood Flow

The normally tight coupling between blood flow, oxygen consumption and contractile function makes impaired perfusion an attractive hypothesis for the etiology of postischemit dysfunction. Although some studies of cardioplegic arrest and reperfusion demonstrate better perfusion and varying oxygen consumption profiles in postischemic hearts,55.5h perfusion deficits are rarely demonstrated. In fact, a persistent postischemic reactive hyperemia is often observed. These observations would contradict impaired perfusion being a primary player in the etiology of postcardioplegia global dysfunction. In regionally ischemic-reperfused segments, however, blood flow deficits are more demonstrable and may play a more important role in determining regional postischemic dysfunction. In briefly ischemic ( < 1.5 minutes) segments, postischemic blood flow is normal to supranormal,4s but with a loss of vasodilator reserve.57 However, with ischemia of longer duration, blood flow deficits are observed specifically in the subendocardium. The immediate response upon

reperfusion is a reactive hyperemia even in areas ultimately destined for necrosis.21,58,59However, perfusion deteriorates progressively after this initial hyperemia to levels well below baseline, consistent with a “no-reflow” or more appropriately a “low-reflow” phenomenon.*’ These “lowreflow” zones are limited to necrotic tissue. The contrast between low blood flows in necrotic areas and normal or supranormal blood flows in non-necrotic areas within the same area at risk would support the concept that postischemit blood flow deficits are a manifestation of reperfusion injury. However, whether this progressive low-reflow plays an active role in producing either necrosis or contractile dysfunction awaits further study. However, the findings that (1) avoiding normal coronary perfusion pressures during the first 30 minutes of reperfusion avoids this no-reflow phenomenon while reducing both infarct size and postischemit dysfunction,*’ and (2) surgically modified reperfusion also reduces infarct size and postischemic dysfunctioni4Jb.*z suggest that there may be a cause and effect relationship between progressive postischemic blood flow deficits and necrosis or contractile dysfunction in reperfused segments. The contribution of the ischemic-reperfused segment to global contractile performance makes this an important point. Calcium Overload

Calcium (Ca++) is strongly implicated in postischemic injury.18,6t6i The observations that Ca++ accumulates in ischemic-reperfused tissue’8,60 makes the Ca++-overload hypothesis attractive as a major factor in producing postcardioplegia dysfunction.62 Extracellular Ca++ may enter the cell through membrane disruptions, facilitated entry via cu-adrenergic receptor activity, or via the Na+-Ca++ antiport mechanism working in reverse (ie, Ca++ influx, Na+ efflux). Ca+ + may also accumulate secondary to an impaired uptake of Ca ++ by the sarcoplasmic reticulum.63 Finally, Ca++ from the mitochondria represents an important reservoir from which Ca++ can be mobilized into the cytosol. Ca++ accumulation may then trigger further ATP depletion by activating Ca++-sensitive ATPases, Ca++sensitive phospholipases or oxyradical-producing xanthine oxidase or by uncoupling oxidative phosphorylation. The plethora of data demonstrating attenuated postischemic injury with hypocalcemic cardioplegic solutions64.h5 and calcium channel blockers65-67would certainly lend support to Ca++ overload (either as a direct mechanism or indirectly) playing an important role in the etiology of postcardioplegia dysfunction. Impaired Myojibrillar Sensitivityto Calcium

The observation that intracellular Ca++ may be elevated after ischemia and reperfusion and contractile responses remain obtunded raises the possibility that the responsiveness of the contractile apparatus (myofilaments) is impaired. This possibility was confirmed by the observation by Kusuoka et aVj8that Ca++ transients were not reduced in the globally stunned myocardium. Therefore, attenuated Ca++ influx and subsequent triggering were not likely the

VINTEN-JOHANSEN

12

primary mechanisms of postischemic contractile dysfunction. That the myofilaments themselves were rendered less sensitive to intracellular Ca++ concentration during systole is consistent with data reported earlier by Hess et aP9 that maximal Ca+ +-activated myofibrillar ATPase activity and Ca++ sensitivity of the ATPase were both depressed in the ischemic heart. The direct mechanism producing myofibrillar desensitization to intracellular Ca++ is not clear, but may be secondary to Ca++ overload during reperfusion.6i Whether alterations in Ca++ overload is a benefit provided by hypocalcemic cardioplegia solutions, and whether loss of myofibrillar sensitivity can be avoided by cardioplegic adjuvants are not clear. Dysfunction of the Sarcoplasmic Reticulum In a series of studies, Krause and colleagues6sx70 reported that sarcoplasmic reticulum isolated from “stunned” myocardium demonstrated reduced Ca++ transport, accumulation, and Ca++-Mg++-ATPase activity. These studies implicated the sarcoplasmic reticulum as-a possible organelle in which damage caused excitation-contraction uncoupling and subsequent postischemic dysfunction. A reduction in the uptake of Ca++ by the sarcoplasmic reticulum, in combination with possible changes in the kinetics of the Ca-release channels, would allow less Ca++ to be released after transarcolemmal Ca++ influx during systole. Less Ca++ is therefore available for cycling to the contractile apparatus. The effect of this attenuated Ca++-trigger Ca++ release from sarcoplasmic reticulum stores on the strength of contraction may be compounded by the decreased sensitivity of the postischemic myolilaments to ambient cytosolic Ca++ concentrations. Oxygen-Detived Free Radical-Induced I#q As described in the previous section on “Pathophysiology of Reperfusion Injury,” oxygen radical species are thought to be key participants in postischemic injury. In the surgical setting, oxygenated crystalloid or blood cardioplegia solutions may provide sufficient substrate (Oz) for oxygenderived free radical generation. Numerous studies have suggested that oxyradicals are particularly involved in the etiology of postischemic and postcardioplegia dysfunction.52,63,70-74 Although most of the data incriminating oxyradicals in the pathogenesis of dysfunction are indirect by using purported scavengers or inhibitors, direct quantitation of oxyradical “bursts” during reperfusion have recently been provided by Bolli and colleagues,72 Garlick et al,75 and Zweier et aL30 These studies and others confirm that (1) oxyradicals are generated as a burst during reperfusion, (2) there is a positive correlation between the duration or severity of ischemia and the quantity of oxyradicals generated, (3) the burst of radicals occurs at early reperfusion coincident with arrhythmias, coronary vascular endothelial injury, and the functional deterioration leading to postischemit “stunning.” Assuming (cautiously) that various oxyradical scavengers and inhibitors are devoid of other effects that may alter postischemic dysfunction, it is reasonable to venture that targeting oxyradicals in cardioplegic solu-

AND NAKANISHI

tions may counteract their generation or accumulation during infusions of oxygenated crystalloid or blood-based solutions,52.73,74x76and thereby attenuate postcardioplegia dysfunction. The several mechanisms involved in ischemia-reperfusion discussed above are undoubtedly not mutually exclusive. In fact, these mechanisms may be called into action at various times and to various extents, depending on the degree of preceding ischemic injury. For example, oxyradical generation may alter sarcolemmal and sarcoplasmic reticular morphology, leading to abnormal Ca++ homeostasis, Ca++ accumulation, damage to Ca++ binding sites on the myofilaments, and abnormal Ca++ transport and storage by the sarcolemma. This cascade of effects would ultimately lead to postischemic dysfunction. By the same token, Ca++ accumulation may promote further oxygen radical production via conversion of Ca+ +-sensitive xanthine dehydrogenase to xanthine oxidase, or needlessly depleting ATP levels through activation of Ca++-sensitive ATPases. The initiator of the sequence of events leading to postischemic and postcardioplegic dysfunction has not been definitively identified, but is suspected to be oxyradical generation, from which other manifestations of injury emanate as shown in Fig 3. STRATEGIES

FOR AVOIDING

POSTCARDIOPLEGIA

DYSFUNCTION

Principles of myocardial protection during cardiac surgery reflect the complexity and multiplicity of factors contributing to the pathogenesis of postischemic dysfunction. Therefore, a “multi-tasking” approach has evolved over time as the pathogenetic components of injury have been identified. In accomplishing the most appropriate protection for a given heart, the cardioplegic solution used is key because it is the vehicle of delivery of therapy directed toward the various components of ischemicreperfusion injury, but it also is the potential instrument for

POSTCARDIOPLEGIA

DYSFUNCTION

Radicals 4 E-C Coupling SRDysfunction Impaired

+ Efficiency

+

-

Sensitivity

1

Calcium

I J “STUNNING”

/’ Perfusion

+Siy>th

Overload

-

ATP +

Neural

Fig 3. A scheme of mechanisms leading to postischemic dysfunction in hearts damaged by is&hernia-reperfusion injury. In this scheme, the generation of oxygen-derived free radicals is the initiating event that triggers abnormalities in Ca++ homeostasis and kinetics of contraction leading to dysfunction. Other perturbations may develop and extend the degree of dysfunction, and therefore era secondary pathogeneticfactors. E-C, excitation-contraction coupling; SR, sarcoplasmic reticulum; Sympath Neural, sympathetic neural activity.

13

ACUTE CARDIAC DYSFUNCTION

paradoxically aggravating injury. In this regard, the composition of the solution and the appropriate conditions of delivery are of paramount importance. The general tenets of myocardial protection and the more target-specific components are summarized in Table 4 and discussed below. Table 4 presents the principles and components of surgical myocardial protection in terms of targeting &hernia or reperfusion. The constituents of a blood cardioplegic formulation used clinically and experimentally at the authors’ institution are summarized in Table 5.

Table 5. Composition of Amino Acid-Enhanced Csrdioplwk Principle

Solution

Component

Oxygenation

Blood

Buffer acidosis

Tromethamine

Appropriate pH Substrates

Rapid chemically induced arrest, ventricular decompression, and hypothermia remain the most fundamental principles of surgical myocardial protection. Infusion of hypothermic (4-10°C) hyperkalemic cardioplegic solution to the heart on vented cardiopulmonary bypass collectively reduces the myocardial 02 demands by greater than 90%. By reducing Or demands to this level, the metabolic supply: demand mismatch that determines the severity of ischemia is substantially offset, thereby increasing the myocardium’s tolerance to ischemia and prolonging the period of tolerable ischemia. A multidose infusion of cardioplegic solution (ie, every 20 to 30 minutes during arrest) reoxygenates the heart, replenishes metabolic substrates and target-specific agents (ie, oxyradical scavengers), washes out metabolites, restores hypothermia that is invariably offset by ambient

Table 4. Principles of Myocardial Protection Reduced lschemic Injury Method

Hypothermia

Mechanism

Potassium

Depolarization

Procaine

Block depolarization

Adenosine (?)

Hyperpolarize

Perfusion

Decrease metabolic

Cardioplegia

Rate

Topical Substrates

Glucose

Increase glycolysis

Glutamate, aspartate

Increase Krebs, M-A

Oxygen

Shunle Increase oxygen Metabolism

Buffer acidosis

THAM, Histidine

Decrease H+-loading

Bicarbonate

Enzyme activity

Reduce Reperfusion Injury Prevent Ca++ accumulation

Citrate (CPD)

Direct hypocalcemia

Ca++ channel

Cat+-influx

blockers Low Na+ Avoid edema

Hyperosmolarity Glucose, K+,

Decrease NA+/CA++ exchange Altered starling forces

Mannitol Low pressure Target-specific therapy (ie, neutrophils) Oxygen free radicals

0.028 2 0.067 @ 4-8°C

Glutamate, aspartate

Reduce calcium

CPD chelation

Avoid edema

Low pressure

13 mM each 0.80 + 0.02 mEq 50 mmHg 381 ? 3 mOsm

Reduce O2 demands

Asystole and Hypothermia

Immediate arrest

c.02 11.84 + 0.4 Hct 17.6 + 1.2

Hyperosmolarity

Principle

Vallles

Filters

Reduce presence

Immediate

Hyperkalemia

Hypothermia

22.1 + 2.3 mEq K+ 4-8°C delivery

Abbreviations: C.Oz, arterial O2 content; Hct, hematocrit.

heating, and replenishes the cardioplegic solution that may have been washed out by noncoronary collateral blood flow. Although hypothermia has several potentially deleterious effects, the net balance is evidently protective. One potentially deleterious consequence of hypothermia is the reduction of the reparative rate as well as the general metabolic rate. However, the decrease in reparative processes caused by hypothermic cardioplegic solution during induction can be offset by preceding the hypothermic infusion with a normothermic infusion of cardioplegic solution.8x77 This allows a brief period in which metabolic demands of cardiac work are minimized while the metabolic rate of repair can be maximized. This period of “active resuscitation” improves postischemic function in preoperatively depressed hearts. Hypocalcemia

The importance of Ca++ abnormalities in postischemic contractile dysfunction is the impetus for attempting to control calcium influx during arrest and reperfusion. Since a major source of intracellular calcium is transarcolemmal influx from the extracellular space, calcium chelating agents (ie, citrate found in citrate-phosphate-dextrose solutions) are used to lower ionized calcium (especially in blood cardioplegic solutions).@ Two caveats must be issued with regard to calcium levels in cardioplegic solutions: (1) the “ideal” calcium content differs between blood and asanguineous cardioplegic solutions, ranging between 0.1-0.3 mEq/L for blood-based solutions”Jj5 to 1.2 mM/L in St. Thomas’ Hospital crystalloid solution,76 and (2) profoundly hypocalcemic or Ca++-free solutions may precipit2Ne the “calcium paradox,” particularly in myocardium with antecedent ischemia, resulting in severe postischemic dysfunction or contracture. The benefits of hypocalcemia in cardioplegic solutions may depend on the presence of hyperkalemia since hypocalcemia alone was found to exaggerate postischemit injury.24

Complement inhibitors Reduce activation Monoclonal antibodies

Reduce adherence

Neutrophil-Related

Allopurinol

Inhibitor

Therapy

SOD, catalase

Degraders

MPG, DMSO

Scavengers

,The activation and dhemotaxis of neutrophils produced by extracorporeal circulation79 and myocardial ischemia and reperfusion are the rationale for reducing neutrophil

14

VINTEN-JOHANSEN

population or inhibiting their activation or adherence to the vascular endothelium. Therapy can be directed specifically toward attenuating neutrophil generation, endothelial cell dysfunction, microvascular embolization, and interstitial infiltration. The interposition of a white cell filter in the cardioplegic line is an effective method for controlling neutrophil delivery to the myocardium specifica11y.7y Possible therapy that awaits further development and testing includes inhibitors or antagonists of both chemotactic factors and cytokines. Tissue-specific inhibitors of endothelial and myocyte adhesion molecules may also occupy an important position in the surgical armamentarium against neutrophil-mediated injury. Therapy Against Coronary Vascular Endothelial Injury Since the coronary vascular endothelium is the primary interface responsible for neutrophil-related injury, it is a logical approach to attenuate damage to the vascular endothelium. Studies demonstrating that endothelial damage occurs principally upon reperfusion make the cardioplegic solution an ideal vehicle in which to introduce endothelium-sparing therapy.“” Endothelial dysfunction after cardioplegic arrest and reperfusion may be one of the mechanisms underlying abnormalities in postischemic perfusion, increased coronary vascular tone, edema, and neutrophil accumulation. In addition, these studies suggest that this endothelial damage may be counteracted by precursors of NO synthase*’ or efficient organic NO donors, Fig 4A.71 Enhancing blood cardioplegia with an exogenous source of NO provided by an NO-donor compound, prevents this cndothelial injury. As shown in Fig 4B, endothelial dysfunction may contribute to postcardioplegia dysfunction. Preservation of postisch-

AND NAKANISHI

emit coronary artery function related to NO is paralleled by improvement of postischemic left ventricular pcrformancc. Although the current consensus is that NO may bc cardioprotective in ischemia and reperfusion, some cvidence suggests that NO may be deleterious in reoxygen ation injury after hypoxia (not ischemia), which may be encountered with surgical correction of infant malformations. In these cases, therapy directed toward recruiting or enhancing production of NO by the L-argininc pathway may be contraindicated. However, this issue needs to be investigated before concrete conclusions can be drawn. Bufering c$ Tissue Acidosis Hydrogen ions and lactate build up during surgical ischemia; this buildup inhibits glycolysis upon which the ischemic myocardium is dependent, and activates Na+/H+ exchange resulting in further Na+ accumulation and Ca++accumulation by the Na+/Ca++ antiport system. Buffering H+ buildup in the cytosol is therefore beneficiaLhJ and can be accomplished by several buffering agents in the cardioplegic solution, including tromethamine (THAM), histidine and bicarbonate. Studies have shown that a slightly alkaline solution relative to the neutrality point of water at the temperature delivered is an appropriate pH in contrast to a solution constrained to a pH of 7.4 (measured at 37”C).x’j Edema Myocardial edema is a manifestation of reperfusion injury2” that can be attenuated by appropriately adjusting both the osmolality of the cardioplegic solution and the delivery pressure. Severe global or regional ischemia may predispose to edema,14~2”~21which may lead to loss of compliance and subsequent diastolic filling defects, and to

B

A 120 100 80 60 40 20 0 ACh

VEH

SPM-L

SPM-H

Fig 4. (A) Vasorelaxation responses to the endothelium-dependent stimulation of NO, ACh in epicardial coronary vessels from ischemic hearts. Vessels in the organ bath preparation were preconstricted wlth U45319, a thromboxane A2 mimetic. After 30 minutes of normothermic global ischemia, cardioplegia was maintained for 1 hour using hypothermic, hyperkalemic blood cardioplegia without additives (VEH), with 1 PM of the NO-donor compound SPM-5185 (SPM-L) or 10 PM SPM (SPM-H). Standard blood cardioplegia in VEH did not avoid postischemic endothelial dysfunction. In contrast, the SPM-H group showed complete avoidance of this endothelial dysfunction. ?? , VEH; 5%SPM-L; ? ,?SPM-H (6): Baseline (Base) versus postischemic (REP) left ventricular performance was measured in the same hearts as shown in Panel A. Blood cardioplegia unenhanced with the NO-donor (VW group] demonstrated significant postischemic dysfunction. In contrast, the NO-donor SPM-5185 avoided postcardiopkgia dysfunction in a dose-dependent manner. These data suggest that NO may protect the vascular endothellum and attenuate reperfusion injury mechanisms involved in postcardioplegia stunning. 0, BASE; ?,?REP. LV, left ventricle; ESPVR, end-systolic pressure-volume relationship. ?? P < 0.05 versus Baseline measurement (B) or versus VEH and SPM-L groups (A).

15

ACUTE CARDIAC DYSFUNCTION

perfusion defects secondary to extravascular compression. Tissue edema may be avoided (or reversed) by (1) making the cardioplegic solution hyperosmotic with glucose, potassium, and/or mannitol, and (2) constraining cardioplegic delivery pressure to less than 100 mmHg in normal myocardial and 50 mmHg in myocardium with suspected ischemic injury. Substrate Enhancement Various substrates have been advocated to replenish endogenous substrates or precursors that are lost during ischemia, or to pharmacologically augment various metabolic pathways. Glucose is added to provide substrate for glycolysis without recruiting the glycogen reserve and to increase osmolality and thereby counteract edema formation. The amino acids glutamate and aspartate have been advocated as a cardioplegic supplement to replenish key Krebs cycle intermediates lost during ischemia.4yJ3J4 Glutamate enters the Krebs cycle by conversion to cu-ketoglutarate, while aspartate enters via transamination to oxaloacetate. These key Krebs cycle precursors are taken up by the ischemic myocardium and improve oxidative metabolism, maintain activity of the malate-aspartate shuttle, and directly produce ATP by substrate-level phosphorylation. These amino acids provide greater benefit in the energydepleted heart4y,s4 than in normal heart+ undergoing cardioplegic arrest and reperfusion. Oqgen Radical Tizerapy Based on the evidence supporting the active role played by species of oxygen-derived free radicals in ischemiareperfusion injury, inhibitors of oxyradical production (ie, allopurinol, oxypurinol, deferoxamine) and actual scavengers (superoxide dismutase, glutathione peroxidase, a-tocopherol) could reduce myocardial injury secondary to ischemia, cardioplegia infusions, and reperfusion. A drug targeting some aspect of oxygen-derived free radical activity could be incorporated in the solution and delivered with each infusion, thereby offsetting oxyradical-mediated injury. A number of radical scavengers and inhibitors have been evaluated both experimentally and clinically as adjuncts to cardioplegic solutions.73J1-sh The consensus to date is that superoxide dismutase used in combination with catalase offers protection beyond that provided by naive cardioplegia. The reason why superoxide dismutase plus catalase works is that the cascade of oxyradical production is interrupted in several places rather than at a single point. The xanthine oxidase inhibitor allopurinol has been found to be effective in reducing postischemic contractile dysfunction cxperimentally.73 The clinical benefits of adjuvant oxyradical therapy bear greater study, but early indications are hopeful.“” CAN POSTCARDIOPLEGIA

DYSFUNCTION

BE OVERCOME?

Postischemic contractile dysfunction is very difficult to overcome. This is true in part because the injury is a composite of ischemic pathology and reperfusion damage. Although there is little that can be done to attenuate the

antecedent ischemic injury, well-designed strategies of cardioplegic protection can intervene in both ischemic and reperfusion injury. Strict adherence to established principles of myocardial protection, and judicious incorporation of adjunctive elements, may successfully prevent postcardioplegia dysfunction. As shown in Fig 1, cold multidose blood cardioplegia used to prevent ischemic injury can prolong the ischemic time with excellent restoration of postischemic ventricular performance. More dramatically, cardioplegia solutions appropriately modified in their composition and conditions of delivery can also avoid reperfusion injury in hearts rendered vulnerable to severe damage by ischemic and reperfusion mechanisms. Therefore, in hearts subjected to either severe normothermic ischemiaX~49J4~73J7or regional ischemia,13-15J2 postischemic injury can be avoided and near-normal systolic and diastolic function restored by understanding the pathophysiologic mechanisms operative, and tailoring the composition of the cardioplegic solution to target the principal perpetrators of myocardial injury. In addition, provisions must be made to deliver cardioplegic or reperfusate solutions to the myocardium in sufficient amounts to exert protection from ischemic injury and prevention of reperfusion injury. Carz Regional L$sfunction Be Avoided By Surgical Revascularization Y A series of studies from this laboratory investigated the ability of surgical reperfusion, with its numerous modifications of reperfusate delivery conditions (pressure, volume, O2 demands) and cardioplegia compositions, to restore postischemic contractile function compared to nonsurgical (normal blood) reperfusion .14.*?In this setting, the delivery of cardioplegic solution is the first reperfusion to the previously ischemic segment. In these studies14.22 surgical reperfusion using blood cardioplegia as the initial reperfusate delivered to the ischemic segment partially restored postischemic contractile function, despite the additional 1 hour of global ischemia. In contrast, reperfusion with normal blood failed to restore any contractile function in the ischemic-reperfused segment. A later study by Cheung et al’” corroborated this restoration of postoperative segmental function with surgical reperfusion using blood cardioplegia after 7 days, but showed also that (1) regional dysfunction was worse during the early postsurgical period but improved markedly over time in agreement with clinical data for global “stunning, “*L’” (2) the better postischemic functional recovery in the surgically reperfused segments was sustained over the 7-day observation period indicating that the ultimate extent of recovery achieved as well as the rate of functional recovery was better with surgical reperfusion. Clinical studies8svX9 corroborate the experimental data of Cheung et al ” b y showing improved wall motion in patients revascularized surgically compared to a nonsurgitally recanalized cohort. Therefore, unlike its cardiology counterpart in which prevention or reversal of postischemic contractile dysfunction (stunning) has been difficult to demonstrate, postcardioplegia contractile dysfunction can be avoided, even with preexisting reperfusion injury.54 The surgical success in

16

VINTEN-JOHANSEN

eluding this phantom may owe to the multi-faceted appreach available with today’s extracorporeal techniques and target-specific adjuvants to cardioplegia solutions. Although the use of these solutions has the potential to aggravate ischemic-reperfusion injury, the opportunity to deliver agents to overcome the pathogenetic factors influencing postischemic injury provides greater benefit. Future studies will need to target the more specific causes of

AND NAKANISHI

postcardioplegia dysfunction, and delve into the molecular causes to further attenuate postcardioplegia contractile dysfunction.

ACKNOWLEDGMENT

The authors would like to thank MS Sharon Ireland for meticulous preparation of the article.

REFERENCES

1. Luu M, Stevenson LW, Brunken RC, Drinkwater DM, Schelbert HR, Tillisch JH: Delayed recovery of revascularized myocardium after referral for cardiac transplantation. Brief Communications 119:668-670,199O 2. Breisblatt WM, Stein KL, Wolfe CJ, et al: Acute myocardial dysfunction and recovery: A common occurrence after coronary bypass surgery. J Am Coil Cardiol15:1261-1269,199O 3. Mangano DT: Biventricular function after myocardial revascularization in humans: Deterioration and recovery patterns during the first 24 hours. Anesthesiology 62:571-577, 1985 4. Fremes SE, Christakis GT, Weisel RD, et al: A clinical trial of blood and crystalloid cardioplegia. J Thorac Cardiovasc Surg 88:726-741, 1984 5. Roberts AJ, Spies SM, Sariders JH, et al: Serial assessment of left ventricular performance following coronary artery bypass grafting. Early postoperative results with myocardial protection afforded by mnltidose hypothermic potassium crystalloid cardioplegia. J Thorac Cardiovasc Surg 81:69-84,198l 6. Vinten-Johansen J, Chiantella V, Johnston WE, et al: Adjuvant N-(2-mercaptopropionyl)-glycine in blood cardioplegia does not improve myocardial protection in ischemically damaged hearts. J Thorac Cardiovasc Surg 100:65-76,199O 7. Yokoyama H, Julian JS;Vinten-Johansen J, et al: Postischentic [Ca++] repletion improves cardiac performance without altering oxygen demands. Ann Thorac Surg 49:894-902,199O 8. Rosenkranz ER, Vinten-Johansen J, Buckberg GD, Okamoto F, Edwards H, Bugyi H: Benefits of normothermic induction of blood cardioplegia in energy-depleted hearts, with maintenance of arrest by multidose cold blood cardioplegic infusions. J Thorac Cardiovasc Surg 84:667-677,1982 9. Wilson IC, Gardner TJ: Stunned myocardium in cardiac surgery, in Goldhaber SZ, Bounameaux H (eds): Stunned Myocardium. Properties, Mechanisms, and Clinical Manifestations. New York, NY, Marcel Dekker, 1992, pp 379-399 10. Roberts AJ, Spies SM, Meyers SN, et al: Early and longterm improvement in left ventricular performance following coronary bypass surgery. Surgery 88:467-475,198O 11. Ballantyne CM, Verani MS, Short HD, Hyatt C, Noon GP: Delayed recovery of severely “stunned” myocardium with the support of a left ventricular assist device after coronary artery bypass graft surgery. J Am Co11Cardiol l&710-712,1987 12. Heyndrickx GR, Baig H, Nellens P, Leusen I, Fishbein MC, Vatner SF: Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol234:H653-H659, 1978 13. Vinten-Johansen J, Edgerton TA, Hansen KJ, Carroll P, Mills SA, Cordell AR: Surgical revascularization of acute (1 hour) coronary occlusion: Blood versus crystalloid cardioplegia. Ann Thorac Surg 42:247-254,1986 14. Vinten-Johansen J, Edgerton TA, Howe HR, Gayheart PA, Mills SA, Howard G, Cordell AR: Immediate functional recovery and avoidance of reperfusion injury with surgical revascularization of short-term coronary occlusion. Circulation 72:431-439,1985 15. Vinten-Johansen J, Faust KB, Mills SA, Cordell AR: Surgical revascularization of acute evdliring myocardial infarction with-

out blood cardioplegia fails to restore postischemic function in the involved segment. Ann Thorac Surg 44:66-72,1987 16. Cheung EH, Arcidi JM Jr, Dorsey LMA, Vinten-Johansen J, Hatcher Jr, CR, Guyton RA: Reperfusion of infarcting myocardium: Benefit of surgical reperfusion in a chronic model. Ann Thorac Surg 48:331-338,1989 17. Hearse J: Ischemia at the crossroads? Cardiovas Drugs Ther 2:9-15,198s 18. Nayler WG: Calcium and cell death. Eur Heart J 4:33-41, 1983 19. Tani M, Neely JR: Role of intracellular Na+ in Ca++ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts: possible involvement of H+/Na+ exchange and Na+/Ca++ exchange. Circ Res 65:1045-1056,1989 20. Vinten-Johansen J, Johnston WE, Mills SA, et al: Reperfusion injury after temporary coronary occlusion. J Thorac Cardiovas Surg 95:960-968,1988 21. Vinten-Johansen J, Lefer DJ, Johnston WE, et al: Controlled coronary hydrodynamics at the time of reperfusion reduces postischemic injury. Cor Art Dis 3:1081-1093, 1992 22. Vinten-Johansen J, Buckberg GD, Okamoto F, Rosenkranz ER, Bugyi H, Leaf J: Studies of controlled reperfusion after ischemia. V. superiority of surgical versus medical reperfusion after regional ischemia. J Thorac Cardiovasc Surg 92:525-534,1986 23. Nakanishi K, Vinten-Johansen J, Lefer DJ, Fowler WC III, McGee DS, Johnston WE: Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size. Am J Physiol263:H1650-H1658,1992 24. Nakanishi K, Lefer DJ, Johnston WE, Vinten-Johansen J: Transient hypocalcemia during the initial phase of reperfusion extends myocardial necrosis after 2 hours of coronary occlusion. Cor Art Dis 2:1009-1021,199l 25. Lefer DJ, Nakanishi K, Johnston WE, Feelisch M, VintenJohansen J: Anti-neutrophil and myocardial protecting actions of SPM-5185, a novel nitric oxide (NO) donor, following acute myocardial ischemia and reperfusion in dogs. Biol Nitric Oxide 188-190,1992 26. Gebhard MM: Myocardial protection and ischemia tolerance of’ the globally ischemia heart. Thorac Cardiovasc Surg 38:55-59,199O 27. Tani M, Neely JR: Mechanisms of reperfusion injury by low Ca*+ and/or high K+. Am J Physiol258:H1025-H1031,1990 28. Philipson KD, Bersohn MM, Nishimoto A: Effects of pH on Na+/Ca*+ exchange in canine cardiac sarcolemmal vesicles. Circ Res 50:287-293,1982 29. Engler RL, Dahlgren MD, Morris D, Peterson MA, SchmidSchonbein G: Role of leukocytes on the response to acute myocardial ischemia and reflow in dogs. Am J Physiol 251:H314H323,1986 30. Zweier JL, Flaherty JT, Weisfeldt ML: Direct measurement of free radicals gener@ed following reperfusion of ischemic myocardium. Proc Natl Acad Sci 84:1404-1407,1987 31. Lucchesi BR: Modulation of leukocyte-mediated myocardial reperfusion injury. Ann Rev Physiol52:561-576,199O

ACUTE CARDIAC DYSFUNCTION

32. Jarasch ED, Bruder G, Heid HW: Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Stand 548:39-46, 1986 33. Engler RL, Schmid-Schonbein GW, Pavelec RS: Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Path01 111:98-111,1983 34. Palmar RMJ, Ferrige AG, Moncada S: Nitric oxide release accounts for biological activity of endothelium-derived relaxing factor. Nature 327525526,1987 35. Kubes P, Suzuki M, Granger N: Nitric oxide: An endogenous modurator of leukocyte adhesion. Proc Nat1 Acad Sci 88:4651-4655,199l 36. Ku DD: Coronary vascular reactivity after acute myocardial ischemia. Science 218:576-578,1982 37. VanBenthuysen KM, McMurtry IF, Horwitz LD: Reperfusion after acute coronary occlusion in dogs impairs endotheliumdependent relaxation to acetylcholine and augments contractile reactivity in vitro. J Clin Invest 79:265-274,1987 38. Tsao PS, Aoki N, Lefer DJ, Johnson G III, Lefer AM: Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82:14021412,199O 39. Dignan RJ, Dyke CM, Abd-Elfattah AS, et al: Coronary artery endothelial cell and smooth muscle dysfunction after global myocardial ischemia. Ann Thorac Surg 53:311-317,1992 40. Bolli R, Hartley CJ, Rabinovitz RS: Clinical relevance of myocardial “stunning.” Cardiovas Drugs Ther 5:877-890,199l 41. Vinten-Johansen J, Julian JS, Yokoyama H, et al: Efficacy of myocardial protection with hypothermic blood cardioplegia depends on oxygen. Ann Thorac Surg 52:939-948,199l 42. Fremes SE, Weisel RD, Mickle DA, et al: Myocardial metabolism and ventricular function following cold potassium cardioplegia. J Thorac Cardiovasc Surg 89:531-546,1985 43. Harpole DH, Rankin JS, Wolfe WG, et al: Assessment of left ventricular functional preservation during isolated cardiac valve operations. Circulation 8O:III-l-111-9,1989 44. Mills SA, Hansen KJ, Vinten-Johansen J, Howe HR, Geisinger KR, Cordell AR: Enhanced functional recovery with venting during cardioplegic arrest in chronically damaged hearts. Ann Thorac Surg 40:566-573,1985 45. Kofsky ER, Julia P, Buckberg GD: Overdose reperfusion of blood cardioplegia solution: A preventable cause of postischemic myocardial depression. J Thorac Cardiovasc Surg 101:275-283, 1991 46. Hearse DJ: The protection of the ischemic myocardium: Surgical success v. clinical failure? Prog Cardiovasc Dis 30:381-402, 1988 47. Rosenkranz ER, Okamoto F, Buckberg GD, et al: Studies of controlled reperfusion after ischemia. II. Biochemical studies: Failure of tissue ATP to predict recovery of contractile function after controlled reperfusion. J Thorac Cardiovasc Surg 92:488-501, 1986 48. Vinten-Johansen J, Gayheart “PA, Johnston WE, Julian JS, Cordell AR: Regional function, blood flow, and oxygen utilization relations in repetitively occluded reperfused canine myocardium. Am J Physiol261:H538-H547,1991 49. Rosenkranz ER, Okamoto F, Buckberg GD, VintenJohansen J, Robertson JM, Bugyi H: Safety of prolonged aortic clamping with blood cardioplegia. II. Glutamate enrichment in energy-depleted hearts. J Thorac Cardiovasc Surg 88:402-409,1984 50. Becker LC, Levine JH, DiPaula AF, Guarnieri T, Aversano TR: Reversal of dysfunction in postischemic stunned myocardium by epinephrine and post extrasystolic potentiation. J Am Co11 Cardiol7:580-589,.1986 51. Ito BR, Tate H, Kobayashi M, Schaper W: Reversibly

17

injured, postischemic canine myocardium retains normal contractile reserve. Circ Res 61:834-846,1987 52. Vinten-Johansen J, Carroll PJ, Johnston WE, et al: Reversal of dyskinesis by increased and diastolic segment length in ischaemicreperfusal myocardium. Cardiovasc Res 23:810-820,1989 53. Robertson JM, Vinten-Johansen J, Buckberg GD, Rosenkranz ER, Maloney JV Jr: Safety of prolonged aortic clamping with blood cardioplegia. I. Glutamate enrichment in normal hearts. J Thorac Cardiovasc Surg 88:395-401.1984 54. Rosenkranz ER, Okamoto F, Buckberg GD, Robertson JM, Vinten-Johansen J, Bugyi HI: Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamateblood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. J Thorac Cardiovasc Surg 91:428-435,1986 55. Krukenkamp IB, Silverman NA, Levitsky S: The effect of cardioplegic oxygenation on the correlation between the linearized Frank-Starling relationship and myocardial energetics in the ejecting postischemic heart. Circulation 76:V-122,1987 56. Silverman NA, delNido P, Krukenkamp I, Levitsky S: Biological rationale for formulation of antegrade cardioplegic solutions, in Chitwood WR (ed): State of the Art Reviews. Philadelphia, PA, Hartley & Belfus, 1988, pp 181-195 57. Bolli R, Triana F, Jeroudi MO: Postischemic mechanical and vascular dysfunction (Myocardial “stunning” and microvascular “stunning”) and the effects of calcium-channel blockers on ischemia/reperfusion injury. Clin Cardiol 12:III16-111-25, 1989 58. Zhao ZQ, McGee DS, Nakanishi K, Toombs CF, Johnston WE, Ashar MS, Vinten-Johansen J: Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit. Circulation 1992 (in press) 59. Toombs CF, McGee DS, Johnston WE, Vinten-Johansen J: Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia. Circulation 86:986-994,1992 60. Nayler WG: The role of calcium in the ischemic myocardium. Am J Path01 102:262-270,198l 61. Kusuoka H, Marban E: Role of altered calcium homeostasis in stunned myocardium, in Kloner RA, Przyklenk K (eds): Stunned Myocardium: Properties, Mechanisms, and Clinical Manifestations. New York, NY, Marcel Dekker, 1993, pp 197-213 62. der Toit EF, Opie LH: Modulation of severity of reperfusion stunning in the isolated rat heart by agents altering calcium flux at onset of reperfusion. Circ Res 70:960-967,1992 63. Krause SM, Hess ML: Characterization of cardiac sarcoplasmic reticulum dysfunction during short-term normothermic global ischemia. Circ Res 55:176-184,1985 64. Follette DM, Fey K, Buckberg GD, Helly Jr, JJ, et al: Reducing postischemic damage by temporary modification of reperfusate calcium, potassium, pH, and osmolarity. J Thorac Cardiovasc Surg 82:221-238, 1981 65. Allen BS, Okamoto F, Buckberg GD: Studies of controlled reperfusion after ischemia. IX. Reperfusate composition: Benefits of marked hypocalcemia and diltiazem on regional recovery. J Thorac Cardiovasc Surg 92:564-572,1986 66. Prasad K, Bharadwaj B: Influence of diltiazem on cardiac function at organ and molecular level during hypothermic cardiac arrest. Can J Cardiol3:351-356,1987 67. Melendez J, Gharagozloo F, Sun S-C, et al: Effects of diltiazem cardioplegia on global function, segmental contractility, and the area of necrosis after acute coronary artery occlusion and surgical reperfusion. J Thorac Cardiovasc Surg 95:613-617,1988 68. Kusuoka H, Koretsune Y, Chacko VP, Weisfeldt ML, Marban E: Excitation-contraction coupling in postischemic myocar-

18

dium. Does failure of activator Circ Res 66:1268-1276, 1990

VINTEN-JOHANSEN

Ca’

’ transients

underlie

stunning?

69. Hess ML, Krause SM, Greenhelf LJ: Assessment of hypothermic, cardioplegic protection of the global ischemic canine myocardium. J Thorac Cardiovasc Surg 80:293-301, 1980 70. Krause SM, Jacobus WE, Becker LC: Alterations in cardiac sarcoplasmic reticulum calcium transport in the post-ischemic “stunned” myocardium. Circ Res 65:526-530, 1989 71. Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi BR: Canine myocardial reperfusion injury: Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res 54:277-285, lY84 72. Bolli R, Jeroudi MO, Pate1 BS, et al: Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion: Evidence that myocardial “stunning” is a manifestation of reperfusion injury. Circ Res 65:607-622, 1989 73. Vinten-Johansen J, Chiantella V, Faust KB, et al: Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 45:3lY-326, 1988 74. Chambers DJ, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: Allopurinol and oxypurinol reduce myocardial injury following ischemic arrest. Ann Thorac Surg 44:2Yl-297, 1987 75. Garlick PB, Davies MJ, Hearse DJ, Slater TF: Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ Res 61:757-760, 1987 76. Faust KB, Chiantella V, Vinten-Johansen J, Meredith JH: Oxygen-derived free radical scavengers and skeletal muscle ischemicireperfusion injury. Am J Surg 54:709-719, 1988 77. Teoh KH, Christakis GT, Weisel RD. et al: Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia. J Thorac Cardiovasc Surg Y1:888-895, 1986 7X. Yamamoto F, Braimbridge MV, Hearse DJ: Calcium and cardioplegia: The optimal calcium content for St. Thomas’ Hospital cardioplegic solution. J Thorac Cardiovasc Surg 87:908-912. 19x4 7Y. Dreyer WJ, Smith CW, Entman ML: Invited letter concerning: Neutrophil activation during cardiopulmonary bypass. J Thorat Cardiovasc Surg 102:318-320, 1991 80. Buckberg GD, Becker H, Vinten-Johansen J, Robertson JM, Leaf J, McConnell DH: Myocardial function resulting from varying acid-base management during and following deep surface

AND NAKANISHI

and perfusion hypothermia and circulatory arrest, in Kahn I-I. Prdkash 0 (eds): Acid-base Regulation and Body Temperature. Boston, MA, Martinus Nijhoff, 1985 81. Bernard M, Menasche P, Pietri S, Grousset C, Piwnica A. Cozzone PJ: Cardioplegic arrest superimposed on evolving myocardial ischemia. Improved recovery after inhibition of hydroxyl radical generation by peroxidase or deferoxamine: A 3’P nuclear resonance study. Circulation 1988: 78:III-164.III-172 (suppl3) 82. Okamoto F, Allen BS. Buckberg GD, Leaf J, Bugyi H: Studies of controlled reperfusion after ischemia X. Reperfusate composition: Supplemental role of intravenous and intracoronary coenzyme Qic, in avoiding reperfusion damage. J Thorac C’ardiovast Surg 92:573-582, 1986 83. Chambers DJ, Braimbridge MV, Hearse DJ: Free radicala and cardioplegia: Free radical scavengers improve postischemic function of rat myocardium. Eur J Cardio-Thorac Surg l:37-45, 19x7 X4. Menasche P. Grousset C, Gauduel Y, Piwnica A: A comparative study of free radical scavengers in cardioplegic solutions. Improved protection with peroxidase. J Thorac Cardiovasc Surg 921264.271. 1986 X5. Weisel RD, Mickle DAG, Finkle CD, et al: Myocardial free-radical injury after cardioplegia. Circulation X4:14-18. 1991 (suPPI 3) X6. Bical 0, Gerhardt M-F, Paumier D, et al: Comparison of different types of cardioplegia and reperfusion on myocardial metabolism and free radical activity. Circulation X4:111-375-111-379. 1991 (suppl3) 87. Vinten-Johansen J, Nakanishi K, McGee DS, Zhao ZQ: Acadesine improves surgical myocardial protection with blood cardioplegia in ischemically injured hearts. Circulation 861-104, 1992 (abstr) 88. Beyersdord F, Sarai K, Maul FD, Wendt T, Satter P: Immediate functional benefits after controlled reperfusion during surgical revascularization for acute coronary occlusion. J Thorac Cardiovasc Surg 102:856-866, 1991 XY. Allen BS, Buckberg GD. Schwaiger M, et al: Studies ol controlled reperfusion after ischemia. XVI. Early recovery of regional wall motion in patients following surgical revascularization after eight hours of acute coronary occlusion. J Thorac Cardiovasc Surg Y2:636-648, 1986 90. Rozenkranz ER, Buckberg GD: Myocardial protection during surgical coronary reperfusion. J Am Coll Cardiol 1:1235-1246, 1983