promising though not yet proven: emerging strategies to promote myocardial salvage

11
Basic Science Review Promising Though Not Yet Proven: Emerging Strategies to Promote Myocardial Salvage David G. Rizik, * MD, FACC, Kevin J. Klassen, MD, FACC, Denise A. Dowler, MSNP , Bernard J. Villegas, MD, FACC, and Simon R. Dixon, MBCHB, FRACP , FACC Remarkable advances in our ability to achieve early and sustained culprit vessel patency in acute myocardial infarction have been satisfying, but our enthusiasm must be tempered by the knowledge that the overall treatment strategy often leaves an inadequate long term clinical result. Early success of percutaneous therapy as judged at angiography does not ensure recovery of normal left ventricular function, the most important determinant of sur- vival in acute myocardial infarction. That congestive heart failure and death still compli- cate apparently successful percutaneous procedures underscores the need to develop novel therapies which salvage jeopardized myocardium, limit infarct size and preserve left ventricular function. An ever-increasing body of data demonstrates a multifactorial mech- anism of myocyte injury and microvascular collapse and also demonstrates that these injuries seem to have a profound impact on long-term outcomes. Given these findings, microvascular protection during the acute event has become the focus of a variety of emerging technologies. The goal of these mechanical and pharmacologic therapies is the restoration of normal metabolic function at the myocyte level. The acute pathologic mechanisms which contribute to sustained left ventricular dysfunction despite angio- graphically successful revascularization will be reviewed as will be several strategies being developed to counter these pathologic mechanisms. ' 2006 Wiley-Liss, Inc. Key words: acute coronary syndrome; percutaneous coronary intervention; angiography- coronary INTRODUCTION Despite advances in our ability to achieve early and sustained culprit vessel patency in acute myocardial in- farction (MI), shortcomings in the overall treatment strategy remain [1–4]. Apparent success of percutane- ous therapy does not guarantee restoration of normal left ventricular function, the most important determi- nant of survival in acute MI [5–7]. This recognized potential for the development of congestive heart fail- ure and even death following revascularization under- scores the need to develop novel therapies that salvage potentially jeopardized myocardium, limit infarct size, and preserve left ventricular function. There has been growing interest in a variety of emerg- ing technologies designed specifically for microvascular protection during the acute event, with the potential ben- efit of restoration of normal metabolic function at the myocyte level [8–10]. Since there is a burgeoning body of data demonstrating that the mechanism of myocyte injury and microvascular collapse are multifactorial and have a potentially profound impact on acute revasculari- zation efforts and long-term results [11], a variety of technologies are in the development and testing stages, both mechanical and pharmacologic, the basis of all being the critical importance of limiting infarct size, thereby enhancing long-term outcome [9]. The following discussion is intended to be a review of the acute pathologic mechanisms contributing to sus- tained left ventricular dysfunction despite apparently successful revascularization, as well as several strategies currently in the development and testing stages to coun- terbalance these deleterious effects. Scottsdale Heart Group, Scottsdale Healthcare Hospital, Scottsdale, Arizona. *Correspondence to: David G. Rizik, MD, FACC, Director of Inter- ventional Cardiology, Scottsdale Heart Group, Scottsdale Healthcare Hospital, Suite A-100, 9755 N 90th Street, Scottsdale, AZ 85258. E-mail: [email protected] Received 11 April 2006; Revision accepted 18 June 2006 DOI 10.1002/ccd.20892 Published online 12 September 2006 in Wiley InterScience (www. interscience.wiley.com). ' 2006 Wiley-Liss, Inc. Catheterization and Cardiovascular Interventions 68:596–606 (2006)

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Page 1: Promising though not yet proven: Emerging strategies to promote myocardial salvage

Basic Science Review

Promising Though Not Yet Proven: Emerging Strategiesto Promote Myocardial Salvage

David G. Rizik,* MD, FACC, Kevin J. Klassen, MD, FACC, Denise A. Dowler, MSNP,Bernard J. Villegas, MD, FACC, and Simon R. Dixon, MBCHB, FRACP, FACC

Remarkable advances in our ability to achieve early and sustained culprit vessel patencyin acute myocardial infarction have been satisfying, but our enthusiasm must be temperedby the knowledge that the overall treatment strategy often leaves an inadequate long termclinical result. Early success of percutaneous therapy as judged at angiography does notensure recovery of normal left ventricular function, the most important determinant of sur-vival in acute myocardial infarction. That congestive heart failure and death still compli-cate apparently successful percutaneous procedures underscores the need to developnovel therapies which salvage jeopardized myocardium, limit infarct size and preserve leftventricular function. An ever-increasing body of data demonstrates a multifactorial mech-anism of myocyte injury and microvascular collapse and also demonstrates that theseinjuries seem to have a profound impact on long-term outcomes. Given these findings,microvascular protection during the acute event has become the focus of a variety ofemerging technologies. The goal of these mechanical and pharmacologic therapies isthe restoration of normal metabolic function at the myocyte level. The acute pathologicmechanisms which contribute to sustained left ventricular dysfunction despite angio-graphically successful revascularization will be reviewed as will be several strategiesbeing developed to counter these pathologic mechanisms. ' 2006 Wiley-Liss, Inc.

Key words: acute coronary syndrome; percutaneous coronary intervention; angiography-coronary

INTRODUCTION

Despite advances in our ability to achieve early andsustained culprit vessel patency in acute myocardial in-farction (MI), shortcomings in the overall treatmentstrategy remain [1–4]. Apparent success of percutane-ous therapy does not guarantee restoration of normalleft ventricular function, the most important determi-nant of survival in acute MI [5–7]. This recognizedpotential for the development of congestive heart fail-ure and even death following revascularization under-scores the need to develop novel therapies that salvagepotentially jeopardized myocardium, limit infarct size,and preserve left ventricular function.There has been growing interest in a variety of emerg-

ing technologies designed specifically for microvascularprotection during the acute event, with the potential ben-efit of restoration of normal metabolic function at themyocyte level [8–10]. Since there is a burgeoning bodyof data demonstrating that the mechanism of myocyteinjury and microvascular collapse are multifactorial andhave a potentially profound impact on acute revasculari-zation efforts and long-term results [11], a variety of

technologies are in the development and testing stages,both mechanical and pharmacologic, the basis of allbeing the critical importance of limiting infarct size,thereby enhancing long-term outcome [9].The following discussion is intended to be a review

of the acute pathologic mechanisms contributing to sus-tained left ventricular dysfunction despite apparentlysuccessful revascularization, as well as several strategiescurrently in the development and testing stages to coun-terbalance these deleterious effects.

Scottsdale Heart Group, Scottsdale Healthcare Hospital, Scottsdale,

Arizona.

*Correspondence to: David G. Rizik, MD, FACC, Director of Inter-

ventional Cardiology, Scottsdale Heart Group, Scottsdale Healthcare

Hospital, Suite A-100, 9755 N 90th Street, Scottsdale, AZ 85258.

E-mail: [email protected]

Received 11 April 2006; Revision accepted 18 June 2006

DOI 10.1002/ccd.20892

Published online 12 September 2006 in Wiley InterScience (www.

interscience.wiley.com).

' 2006 Wiley-Liss, Inc.

Catheterization and Cardiovascular Interventions 68:596–606 (2006)

Page 2: Promising though not yet proven: Emerging strategies to promote myocardial salvage

THERAPEUTIC COOLING

There is a growing body of evidence demonstratingthat temperature modification during experimental myo-cardial injury may beneficially alter myocyte metabo-lism and limit infarct size [12,13]. Moreover, recentstudies have suggested that infarct size reduction maystill be possible when relatively mild hypothermic con-ditions are employed even after experimental injury isinduced [14].Certainly, the strategy of temperature modulation as a

neuroprotective mechanism has been an accepted prac-tice for several decades. It has been used therapeutically

for organ protection in cardiovascular and neurosurgery,

as well as in transplant surgery for allograft preservation

during organ procurement. Moreover, endovascular hy-

pothermia has been recently demonstrated to benefit the

highest risk patients in the setting of acute myocardial

injury; specifically, in those patients experiencing out-

of-hospital cardiac arrest, hypothermia may confer a sur-

vival advantage. Two previously published trials [15,16]

have clearly established an early and sustained survival

benefit when cardiac arrest patients were exposed to

hypothermic conditions relative to their normothermic

counterparts. In the smaller of these two randomized

Fig. 1. Myocardial temperature curve demonstrating early and sustained hypothermia for3 hr following revascularization procedure. Target Temp is the intended hypothermia targetfor this patient. Set Point Temp is the actual measured temperature during the course ofcooling. The intended hypothermia target is actually achieved (i.e. Set Point Temp) in about20 min from the onset of cooling.

Fig. 2. Myocardial perfusion scan 30 days after acute anterior MI complicated cardiogenicshock. Myocardial perfusion imaging at 30 days postintervention revealed a defect involvingthe mid to distal anteroseptal areas. Defect intensity is mild to moderate. The extent of thedefect is 5% of the left ventricle. The gated images reveal an end-diastolic volume of 120 ml,an end-systolic volume of 53 ml, and an ejection fraction of 56%.

Strategies to Promote Myocardial Salvage 597

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trials, Bernard and Gray showed that treatment with mildtherapeutic hypothermia imparted nearly a twofold sur-vival advantage in patients with cardiac arrest [16].There has also been a steadily growing anecdotal ex-

perience in the form of published case reports [17]. Inone recent report, a 50-year-old man suffering an ante-rior MI complicated by nearly 20 min of refractory,pulseless, ventricular fibrillation underwent inductionof hypothermia during the performance of emergencyroom cardiopulmonary resuscitation (CPR) and intuba-tion. The target temperature of 338C (918F) wasachieved in *20 min (Fig. 1). Several days followingsuccessful reperfusion involving primary stenting of theleft anterior descending (LAD), he was extubated andenjoyed complete neurologic recovery. Myocardial per-fusion imaging (Fig. 2) at 30-days postinterventionrevealed a defect involving the mid to distal anteroseptalareas. Defect intensity was mild to moderate. The extentof the defect was 5% of the left ventricle. The gatedimages revealed an end-diastolic volume of 120 ml, anend-systolic volume of 53 ml, and an ejection fraction of56%.The rather typical appearing myocardial temperature

curve for this patient is shown in Fig. 2. Hypothermicconditions can be rapidly achieved, generally being

maintained for *3 hr following coronary revasculariza-tion. The point emphasized in this specific case is theneed to rapidly cool patients to at least a temperature of358C prior to coronary intervention (without delayingdoor-to-balloon time) if this therapy is going to be ofmaximal benefit; a concept to be further explored inmore detail here.The rationale for endovascular hypothermia in ST

segment elevation MI is partially based on the under-standing that the infarct size may be favorably altered by*10% for every 18C reduction in body temperature[12,13]. In one of the initial landmark studies [18] oftherapeutic cooling performed in human size pigs, Daeet al. showed infarct size reduction in the hypothermia

group relative to those maintained at normothermicconditions [(9 6 6)% vs. (45 6 8)%, P < 0.0001]. Thatmild temperature therapy theoretically exerts a beneficialeffect on myocyte metabolism and prevents microcircu-latory collapse was suggested not only by the triphenyl-tetrazolium chloride (TTC) staining but also by the con-firmatory sestamibi autoradiographic studies performed

in these studies (Fig. 3).Although it is tempting to simplify the mechanism by

which hypothermia benefits ischemic tissue, the mecha-nisms are both complex and incompletely understood.It is clear that there is a substantial diminution in themetabolic requirements of jeopardized or ischemic myo-cardium under hypothermic conditions and this may, in

part, explain the overall benefit. It has also been shownin multiple animal models that there are preserved myo-cardial adenosine triphosphate stores, resulting in preser-vation of cell membrane integrity [19,20].Two relevant clinical trials are worth mentioning. In

a feasibility study using one of the earliest endovascu-

lar hypothermia devices, Dixon et al. demonstrated that

such a technology could be successfully integrated into

an interventional treatment pathway without delaying

door-to-balloon time [8]. This was the first human trial

in which patients were cooled to 338C. It was generallyconsidered safe and well tolerated; equally important,

the shivering suppression protocol (forced air warming

blanket, with intravenous meperidine and oral buspirone

loading, a 5-HT1A partial agonist) was invariably effec-

tive. In this study, not powered to show a statistical dif-

ference in infarct size, there was a noticeable trend to-

ward reduction in infarct size in the cooled group. Initial

thrombolysis in myocardial infarction (TIMI) 0/1 flow

was associated with a larger median infarct size than

Fig. 3. Myocardial perfusion and viability in experimentallyinfarcted human size pig specimens demonstrated throughsestamibi studies on pathologic specimens (top panel). Imageon the upper right panel demonstrates the effect on viabilityof hypothermia. Bottom panel shows the results of triphenyl-tetrazolium chloride staining (TTC) after therapeutic tempera-ture modulation in experimental infarction. The left lowerpanel shows a large segment of infarcted myocardium relativeto the area at risk (AAR) under normothermic conditions. Theright lower panel shows myocardial preservation under hypo-thermic conditions.

598 Rizik et al.

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those with a patent culprit vessel and brisk TIMI flow(P ¼ 0.047).This led to the pivotal COOL MI trial [21], in which

400 patients were randomized at 26 investigational sitesworldwide. However, unlike the trend suggesting myo-cardial salvage in the phase I trial, the primary efficacyendpoint of a 30% reduction in infarct size as determinedby SPECT imaging at 30 days was not met in the largerrandomized study. There was no difference in overallinfarct size between the control arm (13.8%, infarct size)and the temperature therapy arm (14.1%, P ¼ 0.834).This may have been a result of the study design withinclusion of ‘‘all-comers,’’ including relatively smallMIs in which it is historically more difficult to demon-strate infarct size reduction. Moreover, unlike the feasi-bility study, in the pivotal trial there was a significantlylonger door-to-balloon time in the hypothermia treat-ment group when compared with that in the control arm(92 6 47 min vs. 110 6 41 min, P ¼ 0.0003). Thismay also have contributed to the lack of benefit of hypo-thermia.Does the time to therapeutic cooling matter if signifi-

cant myocardial salvage is to be achieved? Table I, a sub-group analysis of anterior infarcts only from the COOLMI I pivotal trial, shows the potential for salvage if thetarget temperature is reached prior to definitive catheter-ization laboratory intervention and restoration of flow inthe infarct-related artery. For those anterior MIs whosebody temperature was at or below 358C at the time ofmechanical revascularization, there was a significantimprovement in mean and median infarct size. However,the numbers are sufficiently small and this concept mustbe further validated prospectively in a larger study.Armed with these lessons learned from the first large-

scale trial, an additional study is currently enrollingwhich will include only anterior MIs, with a priority onearlier induction of the cooling process. To this end,

there is also emphasis on emergency room deploymentof the Reprieve Cooling System (Radiant Medical,Redwood City, CA) in order that target temperature isreached earlier. Also, the cooling apparatus has beenimproved to provide much greater cooling power, poten-tially allowing the target temperature of 338C to beachieved within 15–20 min. If in fact the target temper-ature can be achieved in 30 min or less, one can envi-sion the initiation of endovascular hypothermia beingreadily integrated into the emergency room protocolwithout the risk of delaying definitive revascularization.However, the bottom line on endovascular temperaturetherapy in acute myocardial infarction (AMI) is the needto actually confirm its theoretical benefits in a random-ized controlled trial.

THE POTENTIAL ROLE FORPHOSPHOINOSITIDE 3-KINASE g INHIBITION

The acute phase of a MI and resulting tissue hypoxiadirectly induces cardiomyocyte apoptosis as well as theupregulation of proinflammatory mediators such as vas-cular endothelial growth factor (VEGF) and platelet-activating factor (PAF) [22–24]. Of immediate concernis ischemia-induced cardiomyocyte apoptosis and necro-sis, as both unfold within minutes [25]. Although con-siderable information has been gathered on cardiomyo-cyte death, for example in the general field of ischemicpreconditioning, this data has not translated into effec-tive MI therapies. This was to some degree predictable,as ischemic injury generally evolves prior to patientpresentation at an interventional setting, rendering thepatient inaccessible during times when an antiischemicinjury therapy would be most needed [26].Reperfusion injury by contrast unfolds after reestab-

lishment of flow in culprit artery irrespective of the re-vascularization modality (percutaneous intervention orthrombolysis). Reperfusion generates damage in largepart by fostering myocardial inflammation [27,28]. Assuch, its mode of action centers on the vascular compart-ment (leukocytes and endothelium) as opposed to thecardiomyocyte directly, and the microvasculature flowrather than epicardial flow. Once again, although at-tempts have been made to therapeutically limit reperfu-sion injury, for example through the use of leukocyte ad-hesion molecule antagonists [28,29], these too have metwith limited clinical success.Leukocyte recruitment is a key component of nascent

inflammatory reactions; so too are leukocyte activationand vascular edema. Furthermore, these events areclosely interrelated, with activated leukocytes releasingfactors that compromise the endothelial barrier and fur-ther drive edema. A therapeutic approach that seeks tomore broadly block the pathogenesis of MI might there-

TABLE I. Infarct Size (%LV) in Subset COOL MI Patients withAnterior Infarctions

Control Test

Test <358Cat time

of PCI

Test �358Cat time

of PCI

Number 59 61 16 38

Mean 6 SD 18.2 6 16.5 17.9 6 17.1 9.3* 6 11.5 21.9 6 18.1

Median 15.0 11.0 5.0* 16.5

This demonstrates the relationship between degree of cooling and myo-

cardial salvage potentially achieved in anterior myocardial infarction

subset of COOL MI patients. Infarct size is expressed as % LV. Those

patients with an anterior myocardial infarction whose body temperature

was below 358C at the time percutaneous revascularization was per-

formed demonstrated significantly smaller infarct size by myocardial per-

fusion scan.*P < 0.05 when compared with control.

Strategies to Promote Myocardial Salvage 599

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fore prove more suited to limiting infarct development.The challenge of such an approach lies in the widenumber of proinflammatory/proedema agents generatedduring ischemia/reperfusion injury. These include VEGF[30], PAF [31–33], cytokines such as interleukin-1 (IL-1)and tumor necrosis factor (TNF) [34], eicosanoids suchas thromboxanes and leukotrienes [35,36], histamine[37], thrombin [38], and complement factors such asC5a [39]. Clearly this diversity makes for blockade atthe receptor level unfeasible. Inhibition at the subre-ceptor level, however, might be reasonable if a commonsignaling element were identifiable.Phosphoinositide 3-kinase (PI3K) could represent this

gatekeeper, lying downstream of both receptor tyrosinekinases (RTKs) as well as G protein-coupled receptors(GPCR), two receptor classes encompassing the ligandslisted earlier (Fig. 4). The g isoform, in particular, isknown to play key roles in regulating inflammation, asPI3Kg knockout mice show markedly reduced edema[40] and inflammatory responses (including neutrophil,platelet, macrophage, and mast cell activation) [41–48].Hearts of PI3Kg knockout mice are also protected fromnegative inotropic effects of PAF [43]. PI3Kd knockoutmice are similarly resistant to edema and inflammation[49,50]. By contrast, PI3Ka and b, two broadly ex-pressed isoforms, apparently play more fundamental bio-logic roles (such as mitogenesis and organogenesis),since genetic deletion of either of these isoforms is lethal

[51]. It would therefore be wisest to direct prospectiveanti-PI3K-based MI therapies toward g/d but away froma/b isoforms. This would not only help maximize thepotential therapeutic index but also prevent inhibition ofbeneficial repair mechanisms such as angiogenesis whichoccur during infarct remodeling.Indeed, nonspecific inhibitors of all PI3K isoforms may

be detrimental if used as a cardioprotective therapy,since PI3K activity is generally regarded as antiapoptotic(or procardiomyocyte survival) [52–63]. For example,the nonspecific PI3K inhibitor wortmannin has been re-ported to eliminate the cardioprotective effects of eryth-ropoietin [64], IGF-I [52], insulin [65], adrenomedullin[66], opioids [67], bradykinin [68], atorvastatin [69],carbon monoxide [70], and ischemic preconditioning[71–73]. Furthermore, although wortmannin reducedneutrophil infiltration in isolated hearts exposed to ische-mic/reperfusion injury [56] it failed to reduce infarct sizewhen delivered postreperfusion, as did LY294002, an-other nonspecific PI3K inhibitor [57]. Both wortmanninand LY294002 broadly inhibit PI3K isoforms, and there-fore their anticardioprotective effects may well derivefrom blockade of PI3Ka or PI3Kb rather than PI3Kg.Targeting specific PI3K isoforms (g and d) that spe-

cifically mediate inflammation represents a more ration-ale approach to promote myocardial salvage. A specificinhibitor of PI3Kg would be expected to inhibit leuko-cyte activation, platelet activation, edema, and may pre-

Fig. 4. Signaling pathways leading to loss of endothelial bar-rier function. Phosphorylation of tight junction proteins suchas VE-cadherin and b-catenin disrupts endothelial cell-to-cellapposition, with the resulting increase in paracellular perme-ability, which then leads to tissue edema. These events can betriggered through either receptor tyrosine kinase or G protein-coupled receptor signaling (e.g., VEGF or PAF and histamine,

respectively). PI3K forms a common signaling event down-stream of both these receptor classes, leading through kinasecascades that include Akt, mTOR, CKII, and GSK3-b to phos-phorylation of junctional proteins. Akt is the most used name;however, protein kinase B (PKB) is an alternative; mTOR,mammalian target of rapamycin; CKII, casein kinase II; andGSK-b, glycogen synthase kinase-3b.

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vent the negative inotropic effects of inflammatory cyto-kines. TG100-115 (TargeGen, San Diego, CA), a smallmolecule selective inhibitor of PI3Kg and PI3Kd, is ableto reduce inflammation in preclinical species induced byPAF [74]. Furthermore, TG100-115 reduces infarct sizein both rodent and porcine models of MI when deliveredfollowing reperfusion [74]. These results indicate thattargeting pathologic events such as edema and inflam-mation that occur relatively late in infarct developmentis a valuable myocardial salvage strategy. On the basisof a strong molecular rationale and encouraging preclin-ical results, TG100-115 is being studied in acute MIpatients [75].

SUPERSATURATED OXYGEN AND ACUTEMYOCARDIAL INJURY

Hyperbaric oxygen has been shown to reduce tissueinjury during ischemia and reperfusion in a variety ofexperimental models [76–81]. Although the precisemechanisms underlying these beneficial effects are notwell elucidated, hyperbaric oxygen decreases tissueedema, reduces formation of lipid peroxide radicals,alters nitric oxide synthase expression, and inhibits leu-kocyte adherence and plugging in the microcirculation.

In models of acute MI, administration of hyperbaric oxy-gen during ischemia or early after reperfusion was asso-ciated with a reduction in final infarct size [82–84]. Thisserved as the rationale for attempting to integrate thisinto a treatment strategy for patients with acute MI.In the early 1990s, Fluosol, a perflurochemical emul-

sion, was used in an attempt to reduce reperfusion injuryand possibly also enhance oxygen delivery to the micro-vasculature [85,86]. Although initial studies appearedpromising, in a larger randomized trial, patients receiv-ing Fluosol had no improvement in left ventricle (LV)function, as well as a higher incidence of pulmonaryedema and congestive heart failure. It is important tonote that although Fluosol has a high oxygen-carryingcapacity, the substance does not achieve regional hyper-oxia, and therefore this therapy differs markedly fromhyperbaric oxygen therapy per se.Use of hyperbaric oxygen has been evaluated in a

small randomized trial of patients receiving thrombolysis[87]. Patients treated with hyperbaric oxygen were foundto have a smaller peak creatine kinase and improved leftventricular ejection fraction at discharge when comparedwith controls; however, these differences were not statis-tically significant. One of the major limitations of thisstrategy is that use of hyperbaric oxygen chambers isimpractical for most patients with evolving MI.

Fig. 5. Diagram of the TherOx1 Aqueous Oxygen System.

Strategies to Promote Myocardial Salvage 601

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The introduction of a catheter-based system to pro-vide hyperbaric oxygen therapy directly to ischemic tis-sue was a major advance in the field. This innovativesystem uses aqueous oxygen (AO) to deliver hyperbariclevels of oxygen on a regional basis using a smallextracorporeal circuit (TherOx, Irvine, CA) (Fig. 5). Thetechnological breakthrough allowing for the ability todeliver intracoronary AO was described nearly a decadeago [88]. Because oxygen is not readily soluble in water,bubble formation is ordinarily encountered when the dis-solved gas partial pressure greatly exceeds hydrostaticpressure. In order to overcome this propensity for bubbleformation, Spears et al. developed a catheter-basedmethod for infusion of O2, dissolved in a crystalloid so-lution at extremely high concentrations (i.e., 1–3 ml, O2

g�1) into blood without bubble nucleation. The technol-ogy is now being developed commercially (TherOx). Inthis way, AO, a liquid phase combination of water andmedical grade oxygen, can be mixed with blood atambient pressure. When exposed to oxygen-deprived tis-sues, AO is able to correct hypoxemia or produce hyper-oxemia (as in the case of ischemic myocardium), withsmall amounts of carrier solution. Regional organ or tis-sue perfusion is achieved using a blood loop, permittingprecise control of the pO2 when AO is mixed with arte-rial blood in the circuit [76–81].In experimental models of MI, AO hyperoxemic ther-

apy after coronary reperfusion has been associated withless myocardial injury and preservation of ventricularfunction [89–91]. Spears et al. studied the effect of

hyperoxemic reperfusion with AO on left ventricularfunction and infarct size in a porcine model of MI [89].Following a 60-min balloon occlusion of the left anteriordescending coronary artery, hyperoxemic perfusionwas performed for 90 min after a 15-min period ofnormoxemic autoreperfusion. Hyperoxemic reperfusionwith either AO or a hollow fiber oxygenator (HFO) wasassociated with a significant improvement in left ven-tricular function at 90 min when compared with nor-moxemic perfusion. This improvement persisted aftertermination of hyperoxemic therapy. Infarct size andother measures of myocardial injury, including the meanhemorrhage score and myeloperoxidase levels, were sig-nificantly lower in the AO-treated animals, but not inthe HFO group or normoxemic controls (Fig. 6). Elec-tron microscopy revealed that control animals had moreprominent endothelial edema, myocyte hypercontrac-ture, and capillary luminal narrowing when comparedwith AO-treated animals (Fig. 7). In a further study, AOhyperoxemic reperfusion in a canine model was shownto improve microvascular flow and left ventricular ejec-tion fraction [90]. More recently, Spears et al. demon-strated that late administration of AO therapy might alsobe beneficial. In this study, animals treated with AO24 hr after reperfusion had a significant improvement inLV ejection fraction and a smaller infarct size whencompared with controls [91].Subsequently, a pilot study of hyperoxemic reperfu-

sion employing AO was performed in 29 patients withacute MI [10]. This demonstrated that the technique wassafe and feasible after mechanical reperfusion therapy.Hyperoxemic reperfusion was well tolerated and no he-modynamic or electrical instability was observed duringthe infusion. Importantly, an early improvement inregional wall motion was observed in the infarct zone,which was greater than expected from historical con-trols. Promising clinical results were obtained in anobservational study at Centro Cardiologico Monzino,Milan, Italy [92]. Twenty-seven consecutive patientswith anterior wall infarction were treated with hyperoxe-mic reperfusion after LAD stenting. Compared with ahistorical control cohort, patients treated with AO werefound to have an earlier peak creatine kinase, more com-plete ST-segment resolution, and greater improvementof left ventricular function at 6 months. In anotherrecent study of patients with anterior wall infarction,AO therapy was also shown to improve LV remodeling[93].The AMIHOT randomized trial was designed to deter-

mine whether hyperoxemic reperfusion would improveventricular function or limit infarct size after primarypercutaneous coronary intervention (PCI). Two hundredand sixty-nine patients with acute anterior or large infe-rior MI presenting up to 24 hr from symptom-onset were

Fig. 6. Infarct size at 3 hr of reperfusion in swine. % AN/AR,percent (area of necrosis)/(area at risk); AO RP, AO hyperoxe-mic reperfusion of the LAD; auto RP, passive reperfusion;Norm RP, active normoxemic reperfusion; HFO, hyperoxemicreperfusion with a hollow fiber oxygenator.

602 Rizik et al.

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randomized to receive hyperoxemic reperfusion aftersuccessful PCI or normoxemic blood autoreperfusion.Hyperoxemic reperfusion was performed for 90 min.The trial had three coprimary endpoints, including ST-segment resolution, infarct size at 14 days, and Dregional wall motion score index of the infarct zone at3 months. At 30 days, the incidence of major adversecardiac events was similar between the control and AOgroups. There was no significant difference in the inci-dence of the primary endpoints between the studygroups. In post hoc analysis, anterior MI patients reper-fused <6 hr from symptom-onset who were treated withAO had a greater improvement in regional wall motion(DWMSI ¼ 0.54 in control group vs. 0.75 in AO group,P ¼ 0.03), smaller infarct size (median infarct size ¼23% of the LV in control group vs. 9% in AO group,P ¼ 0.04), and improved ST-segment resolution whencompared with normoxemic controls. Overall, these re-sults suggest that hyperoxemic reperfusion is safe andwell tolerated after PCI for acute MI. The AMIHOT-2trial is currently in progress and will evaluate the effi-cacy of AO therapy in patients with anterior MI reper-fused within 6 hr of symptom-onset.

CONCLUSION

Our knowledge of the exact mechanism of myocar-dial injury, though embryonic, has provided the evolu-tionary basis for the development of newer therapies

directed at myocardial salvage in acute MI. Many ofthese technologies hold great promise, requiring furtherrefinement as well as scientific scrutiny in the form ofrandomized clinical trials in order to prove safety andefficacy. Irrespective of whether it is a catheter-basedtherapy proven to be the optimal adjunct to mechanicalreperfusion or the development of a pharmacologic ap-proach, any modality will be deemed successful only ifit is integrated into the reperfusion strategy with consis-tency and ease.

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Fig. 7. The top TEM photomicrograph (a) shows a represen-tative endothelial cell and associated capillary lumen crosssection in the infarct zone for a control animal; as noted bythe arrow in the figure, prominent endothelial cell edema per-sists in the autoreperfusion control at 3 hr postreperfusion(time of histological examination); numerous intramitochon-drial inclusion bodies and myocyte hypercontracture wereobserved in the control animals as well. In contrast, TEM pho-tomicrograph (b), taken from Aqueous Oxygen (AO)-treatedmyocardium, depicts a capillary lumen that is more widely

patent, with no associated observation of endothelial celledema and myocyte hypercontracture. The proposed mecha-nism of action for AO Therapy is to restore microvascular flowpost-AMI at the cellular level, starting with reversal of endo-thelial edema as a response to hypoxia. Reduced EC edemawould lead to improved perfusion, and in turn enable betterpenetration of oxygen into vulnerable myocardium in a classictransport model. These histological data support this pro-posed mechanism. (a) ‘‘Open artery,’’ and (b) ‘‘Open artery’’combined with AO therapy.

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