Microvascular Obstruction

TtHpaniAtiia“f

spnf

FM

2

Journal of the American College of Cardiology Vol. 55, No. 16, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00P

STATE-OF-THE-ART PAPER

Microvascular ObstructionUnderlying Pathophysiology and Clinical Diagnosis

Sebastiaan C. A. M. Bekkers, MD,* Saami K. Yazdani, PHD,† Renu Virmani, MD,†Johannes Waltenberger, MD, PHD*

Maastricht, the Netherlands; and Gaithersburg, Maryland

Successful restoration of epicardial coronary artery patency after prolonged occlusion might result in microvas-cular obstruction (MVO) and is observed both experimentally as well as clinically. In reperfused myocardium,myocytes appear edematous and swollen from osmotic overload. Endothelial cell changes usually accompanythe alterations seen in myocytes but lag behind myocardial cell injury. Endothelial cells become voluminous,with large intraluminal endothelial protrusions into the vascular lumen, and together with swollen surroundingmyocytes occlude capillaries. The infiltration and activation of neutrophils and platelets and the deposition offibrin also play an important role in reperfusion-induced microvascular damage and obstruction. In addition tothese ischemia-reperfusion-related events, coronary microembolization of atherosclerotic debris after percutane-ous coronary intervention is responsible for a substantial part of clinically observed MVO. Microvascular flow af-ter reperfusion is spatially and temporally complex. Regions of hyperemia, impaired vasodilatory flow reserveand very low flow coexist and these perfusion patterns vary over time as a result of reperfusion injury. The MVOfirst appears centrally in the infarct core extending toward the epicardium over time. Accurate detection of MVOis crucial, because it is independently associated with adverse ventricular remodeling and patient prognosis. Sev-eral techniques (coronary angiography, myocardial contrast echocardiography, cardiovascular magnetic reso-nance imaging, electrocardiography) measuring slightly different biological and functional parameters are usedclinically and experimentally. Currently there is no consensus as to how and when MVO should be evaluated af-ter acute myocardial infarction. (J Am Coll Cardiol 2010;55:1649–60) © 2010 by the American College ofCardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.12.037

doti

otMmuiapa

C

AtsSt

imely reperfusion in patients with acute myocardial infarc-ion (AMI) salvages myocardium and reduces mortality (1).

owever, successful restoration of epicardial coronary arteryatency after prolonged occlusion does not always lead todequate reperfusion at the microvascular level. This phe-omenon of no-reflow or microvascular obstruction (MVO)

s observed both experimentally as well as clinically (2,3).ccurate detection and quantification of MVO is impor-

ant, because previous studies have shown that MVO isndependently associated with adverse ventricular remodel-ng and patient prognosis (2,4–7). The “open epicardialrtery hypothesis” should thus be shifted downstream to anopen micro-vessel hypothesis” for reflecting optimal reper-usion (8).

Although both the clinical as well as the experimentaletting of ischemia-reperfusion share important underlyingathophysiologic aspects, the experimental models of coro-ary occlusion and reperfusion are lacking certain aspectsrequently present in the clinical situation. For instance,

rom the *Department of Cardiology, Maastricht University Medical Center,aastricht, the Netherlands; and the †CVPath Institute, Inc., Gaithersburg, Maryland.

wManuscript received July 14, 2009; revised manuscript received November 18,

009, accepted December 16, 2009.

istal coronary microembolization of atherosclerotic debrisr thrombotic material might be responsible for a substan-ial part of clinically observed MVO, which is not simulatedn standard animal models of ischemia and reperfusion (6).

Imaging techniques play an important role in the devel-pment and evaluation of future cardioprotective interven-ions (9). However, a “gold standard” for the detection of

VO has not been established, and several techniqueseasuring slightly different biological parameters are being

sed clinically and experimentally. The sensitivity and spec-ficity of all these techniques is as yet undetermined. Following

clinical case presentation, we review the underlying patho-hysiology of myocardial ischemia with an emphasis on MVOnd review current techniques to detect MVO.

ase Presentation

49-year-old woman with a history of smoking presentedo the emergency department after 3 h of crushing retro-ternal chest pain. The electrocardiogram (ECG) showedT-segment elevation in leads V1 to V4, indicating acuteransmural anteroseptal ischemia (Fig. 1A). She was treated
ith aspirin 300 mg, clopidogrel 600 mg, weight-adjusted

ccaL1cM

caA(Md

M

Ta

aatflsgstNlicaiiA

I

Iaspsiociofa“

asmiTnwndnmm

pmmiwate

1650 Bekkers et al. JACC Vol. 55, No. 16, 2010Microvascular Obstruction April 20, 2010:1649–60

low-molecular weight heparin, ni-troglycerine, a beta-blocker, and aglycoprotein IIb/IIIa inhibitor.

Coronary angiography showedan occlusive thrombus in the midleft anterior descending artery atthe bifurcation of the second di-agonal branch (Figs. 2A and 2B).Subsequently and approximately4 h after symptom onset, percu-taneous coronary intervention(PCI) with thrombosuction andstenting was performed (Fig.2C). Despite an angiographicallyoptimal result without residualstenosis, antegrade epicardialflow was only partially restoredto Thrombolysis In MyocardialInfarction (TIMI) flow grade 2,even after intracoronary adeno-sine injection (Fig. 2D).

In the Intensive Cardiac CareUnit, her chest pain completelysubsided. Despite significant ST-segment resolution (STR �70%),persistent ST-segment elevation inleads V1 to V3 was still present 40min after PCI (Fig. 1B). The peakcreatine kinase level of 900 U/l wasreached 12 h after admission.

Cardiovascular magnetic reso-nance imaging (MRI) on day 4demonstrated antero-septal akine-sia, a left ventricular (LV) end-diastolic volume of 149 ml, LVstroke volume of 67 ml, and ejec-tion fraction (EF) of 45%. Early

ontrast-enhanced cardiovascular MRI performed 2 min afterontrast injection showed a central hypointense area in thenteroseptal wall corresponding to MVO (Fig. 3A, arrows).ate gadolinium-enhanced cardiovascular MRI (LGE-CMR)0 min after contrast injection showed an anteroseptal myo-ardial infarction (Fig. 3B, arrowheads) with a central zone of

VO (Fig. 3B, arrows).Her hospital course was uneventful, and she was dis-

harged on day 6 with aspirin, clopidogrel, statin,ngiotensin-converting enzyme inhibitor and beta-blocker.fter 3 months she was in New York Heart Association

NYHA) functional class III, and a repeat cardiovascularRI showed an increased LV end-diastolic volume and

ecreased EF (41%).

echanisms of Ischemic Myocardial Injury

he anatomic and biochemical events of ischemic cell injury

Abbreviationsand Acronyms

ATP � adenosinetriphosphate

CTFC � correctedThrombolysis In MyocardialInfarction frame count

EC � endothelial cell

ECG � electrocardiogram/electrocardiography

EF � ejection fraction

FPP-CMR � first-passperfusion cardiovascularmagnetic resonanceimaging

IRA � infarct-related artery

LGE-CMR � lategadolinium-enhancedcardiovascular magneticresonance imaging

LV � left ventricle/ventricular

MCE � myocardial contrastechocardiography

MRI � magnetic resonanceimaging

MVO � microvascularobstruction

PCI � percutaneouscoronary intervention

STR � ST-segmentresolution

TIMI � Thrombolysis InMyocardial Infarction

TMP � Thrombolysis InMyocardial Infarctionmyocardial perfusion

nd death have been well-described (9,10). Under normal a

erobic conditions cardiac energy is acquired from fattycids, which supply 60% to 90% of the energy for adenosineriphosphate (ATP) synthesis. The remaining energy comesrom oxidation of pyruvate formed from glycolysis andactate oxidation. Sudden occlusion of a coronary arteryhifts aerobic or mitochondrial metabolism to anaerobiclycolysis within seconds. Reduced aerobic ATP formationtimulates glycolysis and increases myocardial glucose up-ake and glycogen breakdown. A decrease in ATP inhibitsa�/K�-ATPase, increasing intracellular Na� and Cl�,

eading to cell swelling. Derangements in transport systemsn the sarcolemma and sarcoplasmic reticulum increaseytosolic Ca2�, inducing activation of proteases and alter-tions in contractile proteins. Pyruvate is not readily oxidizedn the mitochondria, leading to production of lactate, fall inntracellular pH, reduction in contractile function, and greaterTP requirement to maintain Ca2� hemostasis (11).

nfarct Region and Reperfusion

nfarct size is directly related to the duration of coronaryrtery occlusion. In animal models, coronary artery occlu-ion of 15 to 20 min followed by reperfusion completelyrevents myocardial cell necrosis, whereas 40 min of occlu-ion results in focal or diffuse subendocardial necrosisnvolving 28 � 5% of the coronary bed at risk (12). At 3 hf occlusion, myocardial necrosis involves 70 � 5% of theoronary bed, and an additional 3 h results in an increase ofnfarct size to 72 � 6%, similar to permanent coronarycclusion rates (79 � 3%). To achieve benefit from reper-usion, as learned in animal models, it is reasonable todminister all therapeutic interventions within the 3-hwindow.”

In ischemic but reversibly injured myocardium, myocytesre edematous and swollen from osmotic overload. The cellize is increased with decreased glycogen content (3). Theyocyte fibrils are relaxed and thinned; I-bands are prom-

nent secondary to noncontracting ischemic myocytes (13).he nuclei show mild condensation of chromatin at theucleoplasm. The cell membrane (sarcolemma) is intactith no breaks. The mitochondria are swollen with loss oformal dense mitochondrial granules or granular flocculentensities. Irreversible injured myocytes contain shrunkenuclei with marked chromatin margination. The 2 hall-arks of irreversible injury are cell membrane breaks anditochondrial presence of small osmophilic densities (3).Endothelial cell (EC) changes of ischemia usually accom-

any the alterations seen in the myocytes but lag behindyocardial cell injury (14). In a canine model, EC abnor-alities are not seen until 60 min. These abnormalities

nclude focal EC swelling with loss of pinocytotic vesicles,hich are observed in 20% of ECs (14). As ischemia

dvances, the number of affected ECs increases (40% at 90o 180 min). Moreover, as ischemia prolongs, greaterndothelial changes result, including clumping and margin-
tion of nuclear chromatin, marked swelling of the cyto-

po(escc

To

Artdglci

pdoadCtcim

b

rbacsmccvtiabf(d

fppRps(etaacr

1651JACC Vol. 55, No. 16, 2010 Bekkers et al.April 20, 2010:1649–60 Microvascular Obstruction

lasm, formation of intraluminal blebs, and even disruptionf EC borders, hemorrhage, and fibrin deposition (Fig. 4)14–16). The microvasculature can also be obstructed byxtravascular compression from myocyte edema. Overall, iteems that microvascular damage lags behind myocardialell injury, ultrastructurally, and is probably not the primaryause of myocyte injury until reperfusion occurs (14,17).

he “No-Reflow” Phenomenonr Microvascular Obstruction

balance exists between the benefits of reperfusion toeduce infarct size and reperfusion injury, which depends onhe duration of occlusion. In general, if ischemic myocar-ium is reperfused early, the degree of myocardial salvagereatly exceeds damage from free radicals and calcium-oading caused by reperfusion. These positive functionalonsequences of reperfusion are most beneficial within thenitial 12 h after occlusion in humans.

Reperfusion injury is defined as reperfusion-related ex-ansion or worsening of ischemic cardiac injury leading toecreased contractility, an increased arrhythmogenic thresh-ld, conversion of reversible to irreversible myocyte injury,nd microvascular dysfunction (3). At the time of myocar-ial reperfusion, there is an abrupt increase in intracellulara2�, leading to a disturbance in the normal mechanisms

hat regulate Ca2� in the cardiomyocyte, known as thealcium paradox (18). This intracellular Ca2� overloadnduces death by causing hypercontracture of myocytes and

itochondrial permeability transition pore opening (9,18).Microvascular obstruction in the heart was first described

Figure 1 Electrocardiogram on Admission and After Interventio

(A) The ST-segment elevation in leads V1 to V4 indicating acute transmural ischemST-segment elevation, persistent ST-segment elevation in leads V2 to V3 (1 to 2 m

y Kloner et al. (3) and consists of explosive EC swelling on a

eperfusion of an ischemic bed (19). Endothelial protrusiony cell swelling together with neutrophils, red blood cells,nd platelets cause capillary obstruction (Fig. 4) (3). Mi-rovessels ultimately rupture, with fibrin and platelet depo-ition and red and white blood cell extravasation. Further-ore, surrounding myocardial cells swell, potentially

ompressing capillaries. These changes in the capillary bedan result in poor perfusion of the surrounding potentiallyiable myocytes with resultant cell death (10,20). The failureo reperfuse viable, severely ischemic myocytes (reversiblenjury) with resultant myocyte cell death (irreversible injury)t the time of reperfusion (the no-reflow phenomenon) haseen described after 90 min in a canine model (3). Reper-usion, therefore, as described by Braunwald and Kloner21) is a “double-edged” sword, because it can result in theeath of potentially salvageable myocardium.Neutrophils have also been implicated in causing reper-

usion injury in the myocardium and other organs. Neutro-hils are activated early during myocardial ischemia andrecede the appearance of histological tissue injury (17).eperfusion markedly enhances the infiltration of neutro-hils into the ischemic region (22). The essential initiatingtep involves interaction of neutrophils with vascular ECsadhesion). This is followed by activation, diapedesis, andxtravascular migration into surrounding myocytes. Produc-ion of additional chemoattractants by activated neutrophilsmplifies the initial inflammatory response. Neutrophilctivation causes a greatly enhanced oxygen uptake by theell, resulting in the production of large quantities ofeactive oxygen species that might lead to disruption of EC

the anterior wall. (B) Despite �70% resolution of initialstill present 40 min after percutaneous coronary intervention.

n

ia ofm) is

nd inactivate antiproteases present in the plasma (23).

dochacirAvnpesfeerab

ept

sirwcecnflmicr

hs


In addition to these ischemia-reperfusion-related events,istal coronary microembolization of atherosclerotic debrisr thrombotic material is responsible for a substantial part oflinically observed MVO (6,24) (Fig. 5). Microemboli areistopathologically associated with MVO, myocyte necrosisnd edema, and EC sloughing within the intramyocardialapillaries (25,26). The rate of coronary microembolizations highest in documented epicardial coronary thrombosis,eaching 30% to 54% (27,28) and even higher (79%) inMI patients (29). Few data compare acute plaque rupture

ersus acute plaque erosion; however, the authors haveoted a higher rate of thrombotic microembolization withlaque erosion. In hearts with acute coronary thrombi,vidence of distal embolization was more frequent in ero-ions than ruptures. These thrombi were associated withocal myocardial necrosis. Other potential sources of distalmbolization include primary PCI, PCI of diseased (ath-rosclerotic) saphenous vein grafts, and thrombolysis. Theeported incidence of distal embolization due to soft friabletherosclerotic plaque and adherent thrombus, after PCI of

Figure 2 Acute Coronary Angiogram

Proximal occlusion of the left anterior descending artery (LAD) (A) (arrow). After inLAD (arrow) and second diagonal branch (*) can be seen (B). After thrombosuctioto Thrombolysis In Myocardial Infarction flow grade 2, despite an angiographically

ypass grafts ranges from 2% to 42% (30–32). Angiographic a

vidence of distal embolization in patients treated withrimary PCI has been shown to occur in approximately 15%o 19% (33,34) (Fig. 6).

Microvascular flow within the reperfused bed is bothpatially and temporarily complex. Apparently, blood flown the area of structural MVO is not completely absent butather very low, ranging between 0.13 and 0.37 ml/g/min,hich is �50% of baseline blood flow (35,36). Microvas-

ular obstruction first appears centrally in the infarct corextending toward the epicardium over time. Different myo-ardial regions can be distinguished (Fig. 7) (37). In theoninfarcted region, microvasculature is intact and bloodow is normal. In the noninfarcted (stunned) area-at-risk,icrovasculature is structurally and functionally still intact. The

nfarcted region has outer zones of intact microvasculature witho-existing areas of hyperemia, low reflow, and impaired floweserve, depending on the degree of capillary damage.

Myocardial blood flow in certain areas of MVO isyperemic during the first 2 min of reperfusion but progres-ively decreases within 2 to 3 h after reperfusion, resulting in

tion of the first guidewire, intraluminal thrombus (haziness) at the bifurcation ofstenting followed by kissing balloon inflation (C), flow was only partially restoredl result (D).

troducn and

optima

2-fold increase of MVO (35,38). A further increase in

Morvs

D

Cptmn(gflflo2ddw

tTgfla

Alnrcaco

qmTfcaoitCsca(va


VO size has been demonstrated up to 48 h after initiationf reperfusion (39). This progression of MVO is presumablyelated to reperfusion injury. Therefore, therapeutic inter-entions trying to attenuate MVO are likely to be mostuccessful when initiated early after reperfusion.

iagnosis of MVO

oronary angiography. After the recognition that com-lete thrombotic coronary occlusion caused AMI andhat early reperfusion with thrombolytic agents increasedyocardial salvage and reduced mortality, there was a

eed to angiographically assess the quality of reperfusion40). Successful reperfusion is defined by assessing ante-rade angiographic epicardial blood flow, graded as TIMIow; TIMI flow grade 0: absent antegrade flow; TIMIow grade 1: partial contrast penetration beyond ancclusion with incomplete distal filling; TIMI flow grade: patent epicardial artery with opacification of the entireistal artery (however, contrast filling or washout iselayed); TIMI flow grade 3: patent epicardial arteryith normal flow.Early studies using this angiographic assessment found

hat mortality was significantly lower in patients withIMI flow grade 3 than in those with other TIMI flowrades (4% vs. 8%, p � 0.01), and importantly, TIMIow grade 2 was not associated with a significant survival

Figure 3 Cardiovascular MRI

A set of 2 corresponding short-axis images with a single breathhold 3-dimensionaltion) contrast-enhanced cardiovascular magnetic resonance imaging (MRI) showinganteroseptal region (arrows, early MVO). (B) Late gadolinium-enhanced cardiovascanteroseptal myocardial infarction (arrowheads) with a central zone of MVO (arrowtrast penetration over time (see Cardiovascular MRI section).

dvantage compared with TIMI flow grades 0 or 1 (41). a

TIMI flow grade �2 without a residual obstructiveesion has been generally regarded as the “angiographico reflow” (42). Although angiographic assessment ofeperfusion is still useful in daily clinical practice, thelinician should be aware that TIMI flow grade 3 is notlways synonymous with optimal tissue reperfusion, be-ause MVO can be demonstrated in a substantial numberf these patients (2).Because the TIMI flow grading system is semi-

uantitative and subjective, a more objective angiographicarker of tissue perfusion was developed. The correctedIMI frame count (CTFC) assesses the number of cine

rames required for contrast to first reach standardized distaloronary landmarks in the culprit artery. A higher CTFCnd thus slower epicardial flow 90 min after administrationf a thrombolytic agent is associated with increased mortal-ty and composite end points and adds prognostic informa-ion even in patients with TIMI flow grade 3 (43).

oronary blood flow velocity patterns. In patients withubstantial MVO the coronary blood flow velocity pattern isharacterized by a reduction in systolic antegrade flow, theppearance of abnormal retrograde flow in early systole�10 cm/s), and a rapid deceleration of diastolic flowelocity (�600 m/s), which was found to be highly associ-ted with TIMI flow grade 2 (44,45).

These distinct coronary flow velocity patterns are associ-

ion recovery gradient-echo pulse sequence. (A) Early (2 min after contrast injec-tral hypoenhanced area corresponding to microvascular obstruction (MVO) in theRI (10 min after contrast injection) showing hyperenhancement indicating anMVO). Note that the extent of late MVO is smaller than early MVO, due to con-

inversa cen

ular Ms, late

ted with a decreased recovery of LV function over time and

srvmmMgflmgdsmdtbdTm

tT3u

hh

Trbdwce

vaaetsaMt(tmawm

ta


eem accurate predictors of long-term cardiac events ineperfused AMI (46). These altered coronary blood flowelocity patterns are believed to be related to an increasedicrovascular impedance as a consequence of profoundicrovascular damage and obstruction.yocardial blush grading. The assessment of TIMI flow

rade and CTFC and the identification of distinct coronaryow velocity patterns only indirectly reflect the status of theicrocirculation. Perfusion can also be assessed angio-

raphically with a semi-quantitative description of myocar-ial contrast density on the final angiogram after reperfu-ion, described as TIMI myocardial perfusion (TMP) oryocardial blush grade (47,48). The TMP flow grades are

efined as follows: TMP flow grade 0: failure of dye to enterhe microvasculature; TMP flow grade 1: dye slowly entersut fails to exit the microvasculature; TMP flow grade 2:elayed entry and exit of dye from the microvasculature;MP flow grade 3: normal entry and exit of dye from theicrovasculature.Myocardial perfusion grading also permits risk stratifica-

ion and adds prognostic information even in patients withIMI flow grade 3. Achievement of both TIMI flow gradeand myocardial blush grade 3 is associated with mortality

nder 1% (49).Previous studies have shown that 11% of patients who

ad established epicardial patency and TIMI flow grade 3

Figure 4 Sequential Changes in the Microvasculature After Var

At 60 min of ischemia, endothelial cells are swollen with decrease in pinocytotic vesicemia as large intraluminal protrusions (P), absent or decreased pinocytotic vesicles, mplugging are observed. With permanent coronary occlusion, intravascular protrusions aging with fibrin deposition are seen only after longer duration of ischemia. N � nucleu

ad a myocardial blush grade of 0/1, again emphasizing that r

IMI flow grading is an inaccurate marker of tissueeperfusion (50). It is believed, however, that myocardiallush only indirectly reflects microvascular status but pre-ominantly describes varying degrees of extravasation andashout of dye that is caused by a combination of increased

apillary permeability, capillary resistance, and interstitialdema (51).

The usefulness of angiographic and coronary blood flowelocity methods to detect MVO is disputable, because theyre often performed immediately after mechanical reperfusion,time point where microvascular flow is known to be hyper-

mic, and therefore they might not be an accurate reflection ofhe final microvascular damage. Experimental studies havehown that the size of MVO increases depending on the timefter reperfusion as a result of reperfusion injury (35).

yocardial contrast echocardiography. Myocardial con-rast echocardiography (MCE) uses small microbubbles�5 �m) that possess an intravascular rheology similar tohat of red blood cells and remain entirely within theicrovasculature. During constant infusion, a steady state is

chieved after approximately 2 to 3 min. After destructionith high energy pulses, the rate of microbubble replenish-ent is proportionate to blood flow.Myocardial contrast echocardiography is able to delineate

he area-at-risk for necrosis during acute coronary occlusionnd has gained tremendous insight into post-ischemic tissue

Periods of Ischemia

pillary damage (endothelial change) continues to occur with longer duration of isch-ne-bound vesicles (V), and capillary obstruction with red (R) and white (W) blood cellpronounced; however, membrane-bound vesicles and red and white blood cell plug-mitochondrium. Reproduced with permission from Virmani et al. (16).

ying

les. Caembrare lesss; M �

eperfusion (52). A persistent contrast defect despite a

pMaaw

tsvshm

bsbrit(CcA

ctiemw(p

smanctps

dpah

mMrprtacAwl1

trtOaMMiitMgpg

era(


atent epicardial artery after reperfusion correlates withVO (2). Myocardial contrast echocardiography studies

lso made clear that substantial MVO could be observed inll patients with TIMI flow grade 2 and in 16% of patientsith TIMI flow grade 3 (53).Myocardial contrast echocardiography predicted segmen-

al myocardial recovery with a sensitivity of 88% and apecificity of 74% and a positive and negative predictivealue of 83% and 81%, respectively (54). In addition, MCEtudies have shown that pericardial effusion, early congestiveeart failure, and adverse arrhythmias occur significantlyore frequently in patients with MVO (55).The technique of intracoronary injection of microbubbles

efore and shortly after coronary reflow make it less univer-ally applicable, and although intravenous methods haveecome available, several disadvantages to the use of MCEemain: moderate spatial resolution, operator dependency,ncomplete LV coverage with suboptimal visualization ofhe lateral wall, and semi-quantitative assessment of MVO54,56).

ardiovascular MRI. Two contrast (gadolinium)-enhancedardiovascular MRI techniques are used to detect MVO in

Figure 5 Obstructed Microvessels andMyocardial Reperfusion Injury

Distal platelet-rich (intramyocardial) embolus (A) when treated with thrombo-lytic therapy will result in reperfusion injury with (B) contraction bandnecrosis (arrowheads) and diffuse neutrophil and red cell infiltration in apatient with myocardial infarction secondary to epicardial coronary plaquerupture.

MI. The primary technique is first-pass perfusion cardiovas- t

ular MRI (FPP-CMR) (7,57,58). With this technique, mul-iple imaging planes are dynamically imaged to track anntravenous bolus of contrast into the myocardium. A homog-nous increase in signal intensity in normal and infarctedyocardium is observed early after contrast administration,hereas MVO is seen as an area of reduced signal intensity

hypoenhancement) in the central core of the infarct thatersists for �2 min after contrast administration (early MVO).The second technique is LGE-CMR (5,59,60). Due to

low washout and local accumulation of contrast 10 to 15in after contrast injection, the infarcted myocardium

ppears hyperenhanced or “bright” compared with normaloninfarcted myocardium (61). This hyperenhanced regionlosely corresponds to the area of necrosis as measured byriphenyltetrazolium chloride staining (62). A central hy-oenhanced region within the hyperenhanced region corre-ponds to MVO (late MVO).

FPP-CMR was found to be more sensitive for theetection of MVO compared with LGE-CMR (59). Ex-erimental studies have demonstrated that the spatial extents well as location of early MVO closely correlate withistopathological analyses (36,63).LGE-CMR, as compared with FPP-CMR, underesti-ates the extent of MVO and might miss small regions ofVO due to slow penetration of contrast into the MVO

egion over time (64). FPP-CMR is hampered by incom-lete LV coverage, low signal-to-noise ratio, and low spatialesolution interfering with MVO detection. Imaging pro-ocols that combine early imaging and complete LV cover-ge might overcome this (65). Not only the timing afterontrast administration but also the timing of imaging afterMI is important, because only persistent MVO after 1eek independently predicted adverse LV remodeling, un-

ike MVO that was present at 2 days but disappeared afterweek (58).In contrast to MCE, cardiovascular MRI allows mul-

islice imaging with high tissue contrast and high spatialesolution, enabling accurate quantification and localiza-ion of MVO and infarct size relative to the entire LV.nly one experimental study directly compared MCE

nd FPP-CMR with thioflavin-S staining and foundCE to overestimate and FPP-CMR to underestimateVO size. This can be explained by the predominantly

ntravascular sojourn of microbubbles, whereas gadolin-um as a freely diffusible tracer rapidly extravasates intohe interstitium, thereby artificially decreasing the area of

VO (63). In addition, microbubbles are larger thanadolinium molecules and might become temporarilylugged in microvessels that would allow passage ofadolinium.Cardiovascular MRI studies have shown that the pres-

nce of MVO significantly increases with infarct transmu-ality and independently predicts adverse events, includingdverse LV remodeling, congestive heart failure, and death7,55). In a recent study, the extent of MVO was not found
o be related to the change in LVEF at follow-up, suggest-

iiEprmapptmaSmibm

sa

viascmtIcstf

ag6wro


ng that MVO size might be clinically less important thants mere presence (66).

CG. In patients treated with thrombolytic therapy, com-lete STR (�70%) is a highly accurate predictor of infarct-elated artery (IRA) patency and is associated with lowerortality (67–69). However, up to 50% of patients with

bsence of complete STR (STR �70%) might still have aatent IRA and TIMI flow grade 3 (68,70). After successfulrimary PCI and establishment of TIMI flow grade 3, 30%o 50% of patients have incomplete STR, indicating thaticrocirculatory perfusion might be impaired (71,72). Onlylimited number of studies have directly related incompleteTR to MVO by coronary Doppler flow velocity measure-ents, cardiovascular MRI, and MCE (66,73,74). The

nterpretation of STR data should be done cautiously,ecause methodologies, definitions, and time points ofeasuring STR differ between studies.Most studies have used the sum of STR method from

tandard 12-lead ECG, in which ST-segment deviation in

Figure 6 Representative Micrographs of Distal Microembolizati

(A) Low-power (Movat’s pentachrome) view of rupture site (arrow) showing luminanonocclusive thrombus composed of necrotic core material. (C) High-power imageylin and eosin). (D) High-power image of intramural coronary artery atheroemboluspatient who underwent percutaneous coronary intervention for acute myocardial in

ll leads is summed and compared before and after inter- o

ention. Single lead STR �50% in the lead with maximumnitial ST-segment elevation is a simple, universally avail-ble alternative that predicts TIMI flow grade 3 with 70%ensitivity and 54% specificity (75). Single lead STR isomparably accurate in predicting outcome as sum STReasurements (76). Minimal absolute ST-segment devia-

ion after thrombolytic therapy can also be used to predictRA patency (77). Because ST-segment elevation and STRan behave dynamically over time, continuous instead oferial ECG assessment might provide additional informa-ion on epicardial patency and quality of myocardial reper-usion (78).

Other electrocardiographic changes have been describeds signs of successful angiographic reperfusion (TIMI flowrades 2 or 3). Terminal T-wave inversion was observed in0% of patients, and a patent coronary artery was associatedith an increased number of accelerated idioventricular

hythms in small studies (79–81). These markers, however,nly reflect IRA patency and have not been validated against

Plaque Material From Ruptured Atheroma

and cholesterol clefts. (B) Adjacent distal segment to rupture site demonstratesnstrating cholesterol clefts (arrows) with superimposed thrombus (Th) (hematox-ting of cholesterol clefts (arrows) and surrounded by healing myocardium in a

n.

on of

l fibrindemoconsis

farctio

ther measures of MVO.

M

Dlaacec

rieow

eSsmcmw(

fsfac

C

F


anagement of No-Reflow

espite major advances in the understanding of the under-ying pathophysiology of MVO, many different mechanicalnd pharmacologic therapeutic approaches to prevent orttenuate MVO have revealed very different and, in part,ontradictory results. Interventions that were effective in thexperimental setting did not show significant effects clini-ally, and vice versa.

The use of a microcirculatory protection device effectivelyetrieved embolic debris during PCI in AMI but failed tomprove microvascular flow, reduce infarct size, or result innhanced event-free survival (32). Although the aspirationf thrombus significantly improved reperfusion comparedith conventional PCI, a substantial number of patients still

Figure 7 Different Regions of Microvascular Flow After Reperfu

Schematic short-axis presentation showing the different regions of microvascular fl

linical Methods to Detect MVOTable 1 Clinical Methods to Detect MVO

Technique

Invasive

Coronary angiography

TIMI flow grade

Corrected TIMI frame count

Coronary blood flow patterns

Systolic retrograde flow

Diastolic flow velocity deceleration

Myocardial blush grade

TMP grade

Noninvasive

Myocardial contrast echocardiography Contras

Cardiovascular magnetic resonance imaging

Early contrast enhancement Central�2 m

Late contrast enhancement Centralusua

Electrocardiography

ST-segment resolution (60–90 min after reperfusion)

ST-segment deviation (90 min after reperfusion) 1 mm fo

PP � first pass perfusion; MI� myocardial infarction; MVO � microvascular obstruction; TIMI � Thromb

xperienced low myocardial blush grades and incompleteTR (82). Likewise, intra-aortic balloon counterpulsationignificantly reduced MVO experimentally, but a recenteta-analysis of clinical studies using intra-aortic balloon

ounterpulsation in the setting of ST-segment elevationyocardial infarction suggested that this is not associatedith a change in LVEF and increased survival at follow-up

83,84).A range of pharmacologic adjunctive measures of reper-

usion have been evaluated. Glycoprotein IIb/IIIa inhibitionignificantly improved microvascular flow and reduced in-arct size in a dog model of coronary occlusion/reperfusionnd significantly increased the rate of complete STR,oronary artery patency, and CTFC in clinical trials

reperfused acute myocardial infarction.

Generally Accepted as MVO Ref. #

�2 (42)

�40 (49)

�10 cm/s (44,45)

�600 m/s (44,45)

�1 (47,50)

t within area at risk despite angiographic reperfusion (2,53)

hancement within the infarcted area that persistser contrast injection during FPP (early MVO)

(7,57,58)

hancement within the area of hyperenhancement,15 min after contrast injection (late MVO)

(5,59,60)

�30% (67,70,74)

ior MI, 2 mm for anterior MI (77)

sion

ow in

t defec

hypoenin aft

hypoenlly 10–

r infer

olysis In Myocardial Infarction; TMP � TIMI myocardial perfusion.

(acopcccc

vd(ppaan

tml(sftIt

ms

C

TipisiTvomSlfts

RbICt

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2


85–88). Possibly by reversing microvascular spasm, thedministration of intracoronary verapamil after PCI de-reased no-reflow zones leading to a better functionalutcome in first AMI patients (89). The extent of MVO isroportional to the number of polymorphonuclear leuko-ytes present in the infarcted area. The inhibition ofomplement pathways decreased polymorphonuclear leuko-yte free radical generation and enhanced the recovery oforonary flow in an isolated rat heart model (90,91).

Circulating levels of endothelin, a potent and long-actingasoconstrictor, are low in normal individuals but increaseduring ischemia, with a further increase during reperfusion16). Endothelin-mediated vasoconstriction, neutrophillugging, and microvascular permeability play a role in theathogenesis of MVO. The significant reduction of MVOnd infarct size in a canine model after the administration ofn endothelin A-receptor antagonist after 90 min of coro-ary occlusion supports this concept (92).Selective administration of intracoronary adenosine at-

enuated functional and structural abnormalities of theicrovasculature, leading to improved regional ventricu-

ar function as compared with placebo in a canine model93). In the clinical setting, however, although infarctize was reduced, a 3-h infusion of adenosine in reper-used ST-segment elevation myocardial infarction pa-ients failed to show an improved outcome in the AMISTADI (Acute Myocardial Infarction STudy of ADenosine)rial (94).

These discrepant results underscore the complex underlyingechanisms implicated in the pathophysiology of MVO and

uggest that successful therapy should be multitargeted.

onclusions

emporary coronary occlusion followed by reperfusion resultsn microvascular damage—with endothelial swelling, neutro-hil activation, and entrapment—leading to reperfusion-nduced myocardial damage. Microvascular flow after reperfu-ion is spatially and temporally complex. Regions of hyperemia,mpaired vasodilatory flow reserve, and very low flow coexist.he magnitude and spatial extent of these perfusion patterns

ary over time as a result of reperfusion injury. Microvascularbstruction is independently associated with adverse LV re-odeling and prognosis. Therefore, its detection is crucial.

everal techniques (coronary angiography, MCE, cardiovascu-ar MRI, ECG) measuring slightly different biological andunctional parameters are used clinically and experimentally forhe evaluation of MVO (Table 1). Currently, there is no consen-us on how and when MVO should be evaluated after AMI.

eprint requests and correspondence: Dr. Johannes Walten-erger, Department of Cardiology and Cardiovascular Researchnstitute Maastricht (CARIM), Maastricht University Medicalenter, Peter Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht,

he Netherlands. E-mail: [email protected].

EFERENCES

1. The GUSTO Investigators. An international randomized trial com-paring four thrombolytic strategies for acute myocardial infarction.N Engl J Med 1993;329:673–82.

2. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusionimmediately after successful thrombolysis. A predictor of poor recoveryof left ventricular function in anterior myocardial infarction. Circula-tion 1992;85:1699–705.

3. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenonafter temporary coronary occlusion in the dog. J Clin Invest 1974;54:1496–508.

4. Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstructionand left ventricular remodeling early after acute myocardial infarction.Circulation 2000;101:2734–41.

5. Hombach V, Grebe O, Merkle N, et al. Sequelae of acute myocardialinfarction regarding cardiac structure and function and their prognos-tic significance as assessed by magnetic resonance imaging. Eur Heart J2005;26:549–57.

6. Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of‘no-reflow’ after percutaneous coronary intervention. Circulation 1994;89:2514–8.

7. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance ofmicrovascular obstruction by magnetic resonance imaging in patientswith acute myocardial infarction. Circulation 1998;97:765–72.

8. Roe MT, Ohman EM, Maas AC, et al. Shifting the open-arteryhypothesis downstream: the quest for optimal reperfusion. J Am CollCardiol 2001;37:9–18.

9. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N EnglJ Med 2007;357:1121–35.

0. Buja LM. Myocardial ischemia and reperfusion injury. CardiovascPathol 2005;14:170–5.

1. Stanley WC. Cardiac energetics during ischaemia and the rationale formetabolic interventions. Coron Artery Dis 2001;12 Suppl 1:S3–7.

2. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefrontphenomenon of ischemic cell death. 1. Myocardial infarct size vsduration of coronary occlusion in dogs. Circulation 1977;56:786–94.

3. Jennings RB, Steenbergen C Jr., Reimer KA. Myocardial ischemia andreperfusion. Monogr Pathol 1995;37:47–80.

4. Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LW,Braunwald E. Ultrastructural evidence of microvascular damage andmyocardial cell injury after coronary artery occlusion: which comesfirst? Circulation 1980;62:945–52.

5. Reimer KA, Jennings RB. The changing anatomic reference base ofevolving myocardial infarction. Underestimation of myocardial collat-eral blood flow and overestimation of experimental anatomic infarctsize due to tissue edema, hemorrhage and acute inflammation. Circu-lation 1979;60:866–76.

6. Virmani R, Forman MB, Kolodgie FD. Myocardial reperfusion injury.Histopathological effects of perfluorochemical. Circulation 1990;81:IV57–68.

7. Velasco CE, Turner M, Inagami T, et al. Reperfusion enhances thelocal release of endothelin after regional myocardial ischemia. AmHeart J 1994;128:441–51.

8. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusioninjury. Cardiovasc Res 1998;38:291–300.

9. Eeckhout E, Kern MJ. The coronary no-reflow phenomenon: a reviewof mechanisms and therapies. Eur Heart J 2001;22:729–39.

0. Maxwell SR, Lip GY. Reperfusion injury: a review of the pathophys-iology, clinical manifestations and therapeutic options. Int J Cardiol1997;58:95–117.

1. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edgedsword? J Clin Invest 1985;76:1713–9.

2. Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schonbein GW. Role of leukocytes in response to acute myocardialischemia and reflow in dogs. Am J Physiol 1986;251:H314–23.

3. Babior BM. The respiratory burst of phagocytes. J Clin Invest1984;73:599–601.

4. Erbel R, Heusch G. Coronary microembolization. J Am Coll Cardiol2000;36:22–4.

5. Kawano H, Hayashida T, Ohtani H, et al. Histopathological findingsof the no-reflow phenomenon following coronary intervention for
acute coronary syndrome. Int Heart J 2005;46:327–32.
mailto:[email protected]

2

2

2

2

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

4

4

4

4

4

5

5

5

5

5

5

5

5

5

5

6

6

6

6

6

6


6. Saber RS, Edwards WD, Bailey KR, McGovern TW, Schwartz RS,Holmes DR Jr. Coronary embolization after balloon angioplasty orthrombolytic therapy: an autopsy study of 32 cases. J Am Coll Cardiol1993;22:1283–8.

7. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyo-cardial platelet aggregation in patients with unstable angina sufferingsudden ischemic cardiac death. Circulation 1986;73:418–27.

8. Falk E. Unstable angina with fatal outcome: dynamic coronarythrombosis leading to infarction and/or sudden death. Autopsy evi-dence of recurrent mural thrombosis with peripheral embolizationculminating in total vascular occlusion. Circulation 1985;71:699–708.

9. Frink RJ, Rooney PA Jr., Trowbridge JO, Rose JP. Coronary throm-bosis and platelet/fibrin microemboli in death associated with acutemyocardial infarction. Br Heart J 1988;59:196–200.

0. Hong MK, Popma JJ, Pichard AD, et al. Clinical significance of distalembolization after transluminal extraction atherectomy in diffuselydiseased saphenous vein grafts. Am Heart J 1994;127:1496–503.

1. Kaplan BM, Benzuly KH, Kinn JW, et al. Treatment of no-reflow indegenerated saphenous vein graft interventions: comparison of intra-coronary verapamil and nitroglycerin. Cathet Cardiovasc Diagn 1996;39:113–8.

2. Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protectionduring percutaneous coronary intervention in acute ST-segment ele-vation myocardial infarction: a randomized controlled trial. JAMA2005;293:1063–72.

3. Silva-Orrego P, Colombo P, Bigi R, et al. Thrombus aspiration beforeprimary angioplasty improves myocardial reperfusion in acute myocar-dial infarction: the DEAR-MI (Dethrombosis to Enhance AcuteReperfusion in Myocardial Infarction) study. J Am Coll Cardiol2006;48:1552–9.

4. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinicalsignificance of distal embolization during primary angioplasty for acutemyocardial infarction. Eur Heart J 2002;23:1112–7.

5. Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressiveimpairment of regional myocardial perfusion after initial restoration ofpostischemic blood flow. Circulation 1989;80:1846–61.

6. Judd RM, Lugo-Olivieri CH, Arai M, et al. Physiological basis ofmyocardial contrast enhancement in fast magnetic resonance images of2-day-old reperfused canine infarcts. Circulation 1995;92:1902–10.

7. Villanueva FS. Myocardial contrast echocardiography in acute myo-cardial infarction. Am J Cardiol 2002;90:38J–47J.

8. Reffelmann T, Kloner RA. Microvascular reperfusion injury: rapidexpansion of anatomic no reflow during reperfusion in the rabbit. Am JPhysiol Heart Circ Physiol 2002;283:H1099–107.

9. Rochitte CE, Lima JA, Bluemke DA, et al. Magnitude and timecourse of microvascular obstruction and tissue injury after acutemyocardial infarction. Circulation 1998;98:1006–14.

0. Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, FritzJK. The western Washington randomized trial of intracoronary strep-tokinase in acute myocardial infarction. A 12-month follow-up report.N Engl J Med 1985;312:1073–8.

1. Brener SJ, Moliterno DJ, Aylward PE, et al. Reperfusion after primaryangioplasty for ST-elevation myocardial infarction: predictors of suc-cess and relationship to clinical outcomes in the APEX-AMI angio-graphic study. Eur Heart J 2008;29:1127–35.

2. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflowphenomenon as a predictor of adverse long-term outcome in patientstreated with percutaneous transluminal coronary angioplasty for firstacute myocardial infarction. J Am Coll Cardiol 2000;36:1202–9.

3. Gibson CM, Murphy SA, Rizzo MJ, et al., Thrombolysis In Myo-cardial Infarction (TIMI) Study Group. Relationship between TIMIframe count and clinical outcomes after thrombolytic administration.Circulation 1999;99:1945–50.

4. Iwakura K, Ito H, Takiuchi S, et al. Alternation in the coronary bloodflow velocity pattern in patients with no reflow and reperfused acutemyocardial infarction. Circulation 1996;94:1269–75.

5. Lepper W, Hoffmann R, Kamp O, et al. Assessment of myocardialreperfusion by intravenous myocardial contrast echocardiography andcoronary flow reserve after primary percutaneous transluminal coronaryangioplasty [correction of angiography] in patients with acute myo-cardial infarction. Circulation 2000;101:2368–74.

6. Furber AP, Prunier F, Nguyen HC, Boulet S, Delepine S, Geslin P.
Coronary blood flow assessment after successful angioplasty for acute
myocardial infarction predicts the risk of long-term cardiac events.Circulation 2004;110:3527–33.

7. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMImyocardial perfusion grade to mortality after administration of throm-bolytic drugs. Circulation 2000;101:125–30.

8. van’t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ,Zijlstra F; Zwolle Myocardial Infarction Study Group. Angiographicassessment of myocardial reperfusion in patients treated with primaryangioplasty for acute myocardial infarction: myocardial blush grade.Circulation 1998;97:2302–6.

9. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV,Braunwald E. Relationship of the TIMI myocardial perfusion grades,flow grades, frame count, and percutaneous coronary intervention tolong-term outcomes after thrombolytic administration in acute myo-cardial infarction. Circulation 2002;105:1909–13.

0. Henriques JP, Zijlstra F, van’t Hof AW, et al. Angiographic assess-ment of reperfusion in acute myocardial infarction by myocardial blushgrade. Circulation 2003;107:2115–9.

1. Kaul S. Coronary angiography cannot be used to assess myocardialperfusion in patients undergoing reperfusion for acute myocardialinfarction. Heart 2001;86:483–4.

2. Villanueva FS, Glasheen WP, Sklenar J, Kaul S. Assessment of riskarea during coronary occlusion and infarct size after reperfusion withmyocardial contrast echocardiography using left and right atrial injec-tions of contrast. Circulation 1993;88:596–604.

3. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patternsrelated to thrombolysis in myocardial infarction perfusion grades aftercoronary angioplasty in patients with acute anterior wall myocardialinfarction. Circulation 1996;93:1993–9.

4. Greaves K, Dixon SR, Fejka M, et al. Myocardial contrast echocar-diography is superior to other known modalities for assessing myocar-dial reperfusion after acute myocardial infarction. Heart 2003;89:139–44.

5. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the ‘noreflow’ phenomenon. A predictor of complications and left ventricularremodeling in reperfused anterior wall myocardial infarction. Circula-tion 1996;93:223–8.

6. Porter TR, Li S, Oster R, Deligonul U. The clinical implications of noreflow demonstrated with intravenous perfluorocarbon containingmicrobubbles following restoration of Thrombolysis In MyocardialInfarction (TIMI) 3 flow in patients with acute myocardial infarction.Am J Cardiol 1998;82:1173–7.

7. Lima JA, Judd RM, Bazille A, Schulman SP, Atalar E, Zerhouni EA.Regional heterogeneity of human myocardial infarcts demonstrated bycontrast-enhanced MRI. Potential mechanisms. Circulation 1995;92:1117–25.

8. Orn S, Manhenke C, Greve OJ, et al. Microvascular obstruction is amajor determinant of infarct healing and subsequent left ventricularremodelling following primary percutaneous coronary intervention.Eur Heart J 2009;30:1978–85.

9. Nijveldt R, Hofman MB, Hirsch A, et al. Assessment of microvascularobstruction and prediction of short-term remodeling after acutemyocardial infarction: cardiac MR imaging study. Radiology 2009;250:363–70.

0. Yan AT, Gibson CM, Larose E, et al. Characterization of microvas-cular dysfunction after acute myocardial infarction by cardiovascularmagnetic resonance first-pass perfusion and late gadolinium enhance-ment imaging. J Cardiovasc Magn Reson 2006;8:831–7.

1. Simonetti OP, Kim RJ, Fieno DS, et al. An improved MR imagingtechnique for the visualization of myocardial infarction. Radiology2001;218:215–23.

2. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayedcontrast enhancement to irreversible injury, infarct age, and contractilefunction. Circulation 1999;100:1992–2002.

3. Wu KC, Kim RJ, Bluemke DA, et al. Quantification and time courseof microvascular obstruction by contrast-enhanced echocardiographyand magnetic resonance imaging following acute myocardial infarctionand reperfusion. J Am Coll Cardiol 1998;32:1756–64.

4. Lund GK, Stork A, Saeed M, et al. Acute myocardial infarction:evaluation with first-pass enhancement and delayed enhancement MRimaging compared with 201Tl SPECT imaging. Radiology 2004;232:49–57.

5. Bekkers SC, Backes WH, Kim RJ, et al. Detection and characteristics
of microvascular obstruction in reperfused acute myocardial infarction

6

6

6

6

7

7

7

7

7

7

7

7

7

7

8

8

8

8

8

8

8

8

8

8

9

9

9

9

9

K


using an optimized protocol for contrast-enhanced cardiovascularmagnetic resonance imaging. Eur Radiol 2009;19:2904–12.

6. Nijveldt R, Beek AM, Hirsch A, et al. Functional recovery after acutemyocardial infarction: comparison between angiography, electrocardi-ography, and cardiovascular magnetic resonance measures of micro-vascular injury. J Am Coll Cardiol 2008;52:181–9.

7. Barbash GI, Roth A, Hod H, et al. Rapid resolution of ST elevationand prediction of clinical outcome in patients undergoing thrombolysiswith alteplase (recombinant tissue-type plasminogen activator): resultsof the Israeli Study of Early Intervention in Myocardial Infarction. BrHeart J 1990;64:241–7.

8. de Lemos JA, Antman EM, Giugliano RP, et al. ST-segmentresolution and infarct-related artery patency and flow after thrombo-lytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14investigators. Am J Cardiol 2000;85:299–304.

9. Schroder R, Dissmann R, Bruggemann T, et al. Extent of early STsegment elevation resolution: a simple but strong predictor of outcomein patients with acute myocardial infarction. J Am Coll Cardiol1994;24:384–91.

0. de Lemos JA, Braunwald E. ST segment resolution as a tool forassessing the efficacy of reperfusion therapy. J Am Coll Cardiol2001;38:1283–94.

1. Feldman LJ, Coste P, Furber A, et al. Incomplete resolution ofST-segment elevation is a marker of transient microcirculatory dys-function after stenting for acute myocardial infarction. Circulation2003;107:2684–9.

2. van’t Hof AW, Liem A, de Boer MJ, Zijlstra F; Zwolle Myocardialinfarction Study Group. Clinical value of 12-lead electrocardiogramafter successful reperfusion therapy for acute myocardial infarction.Lancet 1997;350:615–9.

3. Bekkers SC, Lemmert ME, Schalla S, et al. ST segment resolutionafter reperfusion therapy for acute myocardial infarction is related tomicrovascular obstruction (abstr). Circulation 2007;116 Suppl II:II425.

4. Santoro GM, Valenti R, Buonamici P, et al. Relation betweenST-segment changes and myocardial perfusion evaluated by myocar-dial contrast echocardiography in patients with acute myocardialinfarction treated with direct angioplasty. Am J Cardiol 1998;82:932–7.

5. Syed MA, Borzak S, Asfour A, et al. Single lead ST-segment recovery:a simple, reliable measure of successful fibrinolysis after acute myocar-dial infarction. Am Heart J 2004;147:275–80.

6. Zeymer U, Schroder R, Tebbe U, Molhoek GP, Wegscheider K,Neuhaus KL. Noninvasive detection of early infarct vessel patency byresolution of ST-segment elevation in patients with thrombolysis foracute myocardial infarction; results of the angiographic substudy of theHirudin for Improvement of Thrombolysis (HIT)-4 trial. Eur Heart J2001;22:769–75.

7. Cooper HA, de Lemos JA, Morrow DA, et al. Minimal ST-segmentdeviation: a simple, noninvasive method for identifying patients with apatent infarction-related artery after fibrinolytic administration. AmHeart J 2002;144:790–5.

8. Krucoff MW, Johanson P, Baeza R, Crater SW, Dellborg M. Clinicalutility of serial and continuous ST-segment recovery assessment inpatients with acute ST-elevation myocardial infarction: assessing thedynamics of epicardial and myocardial reperfusion. Circulation 2004;110:e533–9.

9. Gorgels AP, Vos MA, Letsch IS, et al. Usefulness of the acceleratedidioventricular rhythm as a marker for myocardial necrosis andreperfusion during thrombolytic therapy in acute myocardial infarc-
tion. Am J Cardiol 1988;61:231–5. m
0. Gressin V, Gorgels A, Louvard Y, Lardoux H, Bigelow R. ST-segment normalization time and ventricular arrhythmias as electrocar-diographic markers of reperfusion during intravenous thrombolysis foracute myocardial infarction. Am J Cardiol 1993;71:1436–9.

1. Wehrens XH, Doevendans PA, Ophuis TJ, Wellens HJ. A compar-ison of electrocardiographic changes during reperfusion of acutemyocardial infarction by thrombolysis or percutaneous transluminalcoronary angioplasty. Am Heart J 2000;139:430–6.

2. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspirationduring primary percutaneous coronary intervention. N Engl J Med2008;358:557–67.

3. Amado LC, Kraitchman DL, Gerber BL, et al. Reduction of “no-reflow” phenomenon by intra-aortic balloon counterpulsation in arandomized magnetic resonance imaging experimental study. J AmColl Cardiol 2004;43:1291–8.

4. Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review andmeta-analysis of intra-aortic balloon pump therapy in ST-elevationmyocardial infarction: should we change the guidelines? Eur Heart J2009;30:459–68.

5. Antman EM, Giugliano RP, Gibson CM, et al., The TIMI 14Investigators. Abciximab facilitates the rate and extent of thromboly-sis: results of the thrombolysis in myocardial infarction (TIMI) 14trial. Circulation 1999;99:2720–32.

6. de Lemos JA, Antman EM, Gibson CM, et al. Abciximab improvesboth epicardial flow and myocardial reperfusion in ST-elevationmyocardial infarction. Observations from the TIMI 14 trial. Circula-tion 2000;101:239–43.

7. Kunichika H, Ben-Yehuda O, Lafitte S, Kunichika N, Peters B,DeMaria AN. Effects of glycoprotein IIb/IIIa inhibition on microvas-cular flow after coronary reperfusion. A quantitative myocardial con-trast echocardiography study. J Am Coll Cardiol 2004;43:276–83.

8. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoproteinIIb/IIIa inhibition with coronary stenting for acute myocardial infarc-tion. N Engl J Med 2001;344:1895–903.

9. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronaryverapamil on microvascular and myocardial salvage in patients withacute myocardial infarction. J Am Coll Cardiol 1997;30:1193–9.

0. Prasad A, Stone GW, Stuckey TD, et al. Relation between leucocytecount, myonecrosis, myocardial perfusion, and outcomes followingprimary angioplasty. Am J Cardiol 2007;99:1067–71.

1. Shandelya SM, Kuppusamy P, Herskowitz A, Weisfeldt ML, ZweierJL. Soluble complement receptor type 1 inhibits the complementpathway and prevents contractile failure in the postischemic heart.Evidence that complement activation is required for neutrophil-mediated reperfusion injury. Circulation 1993;88:2812–26.

2. Galiuto L, DeMaria AN, del Balzo U, et al. Ischemia-reperfusioninjury at the microvascular level: treatment by endothelin A-selectiveantagonist and evaluation by myocardial contrast echocardiography.Circulation 2000;102:3111–6.

3. Babbitt DG, Virmani R, Forman MB. Intracoronary adenosineadministered after reperfusion limits vascular injury after prolongedischemia in the canine model. Circulation 1989;80:1388–99.

4. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. Arandomized, double-blinded, placebo-controlled multicenter trial ofadenosine as an adjunct to reperfusion in the treatment of acutemyocardial infarction (AMISTAD-II). J Am Coll Cardiol 2005;45:1775–80.

ey Words: diagnosis y imaging y microvascular obstruction (MVO) y
yocardial infarction y pathophysiology y review.

Microvascular Obstruction

Documents

Transcript of Microvascular Obstruction