no reflow phenomenon (54)
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 accompany the 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 surrounding myocytes occlude capillaries.The in?ltration and activation of neutrophils and platelets and the deposition of ?brin also play an important role in reperfusion-induced microvascular damage and obstruction.In addition to these 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 ?ow af-ter reperfusion is spatially and temporally complex.Regions of hyperemia,impaired vasodilatory ?ow reserve and very low ?ow coexist and these perfusion patterns vary over time as a result of reperfusion injury.The MVO ?rst appears centrally in the infarct core extending toward the epicardium over time.Accurate detection of MVO is 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 used clinically 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)?2010by the American College of Cardiology Foundation
Timely reperfusion in patients with acute myocardial infarc-tion (AMI)salvages myocardium and reduces mortality (1).However,successful restoration of epicardial coronary artery patency after prolonged occlusion does not always lead to adequate reperfusion at the microvascular level.This phe-nomenon of no-re?ow or microvascular obstruction (MVO)is observed both experimentally as well as clinically (2,3).Accurate detection and quanti?cation of MVO is impor-tant,because previous studies have shown that MVO is independently associated with adverse ventricular remodel-ing and patient prognosis (2,4–7).The “open epicardial artery hypothesis”should thus be shifted downstream to an “open micro-vessel hypothesis”for re?ecting optimal reper-fusion (8).
Although both the clinical as well as the experimental setting of ischemia-reperfusion share important underlying pathophysiologic aspects,the experimental models of coro-nary occlusion and reperfusion are lacking certain aspects frequently present in the clinical situation.For instance,
distal coronary microembolization of atherosclerotic debris or thrombotic material might be responsible for a substan-tial part of clinically observed MVO,which is not simulated in standard animal models of ischemia and reperfusion (6).Imaging techniques play an important role in the devel-opment and evaluation of future cardioprotective interven-tions (9).However,a “gold standard”for the detection of MVO has not been established,and several techniques measuring slightly different biological parameters are being used clinically and experimentally.The sensitivity and spec-i?city of all these techniques is as yet undetermined.Following a clinical case presentation,we review the underlying patho-physiology of myocardial ischemia with an emphasis on MVO and review current techniques to detect MVO.Case Presentation
A 49-year-old woman with a history of smoking presented to the emergency department after 3h of crushing retro-sternal chest pain.The electrocardiogram (ECG)showed ST-segment elevation in leads V 1to V 4,indicating acute transmural anteroseptal ischemia (Fig.1A).She was treated with aspirin 300mg,clopidogrel 600mg,weight-adjusted
From the *Department of Cardiology,Maastricht University Medical Center,Maastricht,the Netherlands;and the ?CVPath Institute,Inc.,Gaithersburg,Maryland.Manuscript received July 14,2009;revised manuscript received November 18,2009,accepted December 16,2009.
Journal of the American College of Cardiology
Vol.55,No.16,2010?2010by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00Published by Elsevier Inc.doi:10.1016/j.jacc.2009.12.037
low-molecular weight heparin,ni-troglycerine,a beta-blocker,and a glycoprotein IIb/IIIa inhibitor.
Coronary angiography showed an occlusive thrombus in the mid left anterior descending artery at the bifurcation of the second di-agonal branch (Figs.2A and 2B).Subsequently and approximately 4h after symptom onset,percu-taneous coronary intervention (PCI)with thrombosuction and stenting was performed (Fig.2C).Despite an angiographically optimal result without residual
stenosis,antegrade epicardial ?ow was only partially restored to Thrombolysis In Myocardial
Infarction (TIMI)?ow grade 2,even after intracoronary adeno-sine injection (Fig.2D).In the Intensive Cardiac Care Unit,her chest pain completely subsided.Despite signi?cant ST-segment resolution (STR ?70%),
persistent ST-segment elevation in leads V 1to V 3was still present 40
min after PCI (Fig.1B).The peak creatine kinase level of 900U/l was reached 12h after admission.Cardiovascular magnetic reso-nance imaging (MRI)on day 4demonstrated antero-septal akine-sia,a left ventricular (LV)end-diastolic volume of 149ml,LV stroke volume of 67ml,and ejec-tion fraction (EF)of 45%.Early
contrast-enhanced cardiovascular MRI performed 2min after contrast injection showed a central hypointense area in the anteroseptal wall corresponding to MVO (Fig.3A,arrows).Late gadolinium-enhanced cardiovascular MRI (LGE-CMR)10min after contrast injection showed an anteroseptal myo-cardial infarction (Fig.3B,arrowheads)with a central zone of MVO (Fig.3B,arrows).
Her hospital course was uneventful,and she was dis-charged on day 6with aspirin,clopidogrel,statin,angiotensin-converting enzyme inhibitor and beta-blocker.After 3months she was in New York Heart Association (NYHA)functional class III,and a repeat cardiovascular MRI showed an increased LV end-diastolic volume and decreased EF (41%).
Mechanisms of Ischemic Myocardial Injury The anatomic and biochemical events of ischemic cell injury and death have been well-described (9,10).Under normal
aerobic conditions cardiac energy is acquired from fatty acids,which supply 60%to 90%of the energy for adenosine triphosphate (ATP)synthesis.The remaining energy comes from oxidation of pyruvate formed from glycolysis and lactate oxidation.Sudden occlusion of a coronary artery shifts aerobic or mitochondrial metabolism to anaerobic glycolysis within seconds.Reduced aerobic ATP formation stimulates glycolysis and increases myocardial glucose up-take and glycogen breakdown.A decrease in ATP inhibits Na ?/K ?-ATPase,increasing intracellular Na ?and Cl ?,leading to cell swelling.Derangements in transport systems in the sarcolemma and sarcoplasmic reticulum increase cytosolic Ca 2?,inducing activation of proteases and alter-ations in contractile proteins.Pyruvate is not readily oxidized in the mitochondria,leading to production of lactate,fall in intracellular pH,reduction in contractile function,and greater ATP requirement to maintain Ca 2?hemostasis (11).Infarct Region and Reperfusion
Infarct size is directly related to the duration of coronary artery occlusion.In animal models,coronary artery occlu-sion of 15to 20min followed by reperfusion completely prevents myocardial cell necrosis,whereas 40min of occlu-sion results in focal or diffuse subendocardial necrosis involving 28?5%of the coronary bed at risk (12).At 3h of occlusion,myocardial necrosis involves 70?5%of the coronary bed,and an additional 3h results in an increase of infarct size to 72?6%,similar to permanent coronary occlusion rates (79?3%).To achieve bene?t from reper-fusion,as learned in animal models,it is reasonable to administer all therapeutic interventions within the 3-h “window.”
In ischemic but reversibly injured myocardium,myocytes are edematous and swollen from osmotic overload.The cell size is increased with decreased glycogen content (3).The myocyte ?brils are relaxed and thinned;I-bands are prom-inent secondary to noncontracting ischemic myocytes (13).The nuclei show mild condensation of chromatin at the nucleoplasm.The cell membrane (sarcolemma)is intact with no breaks.The mitochondria are swollen with loss of normal dense mitochondrial granules or granular ?occulent densities.Irreversible injured myocytes contain shrunken nuclei with marked chromatin margination.The 2hall-marks of irreversible injury are cell membrane breaks and mitochondrial presence of small osmophilic densities (3).Endothelial cell (EC)changes of ischemia usually accom-pany the alterations seen in the myocytes but lag behind myocardial cell injury (14).In a canine model,EC abnor-malities are not seen until 60min.These abnormalities include focal EC swelling with loss of pinocytotic vesicles,which are observed in 20%of ECs (14).As ischemia advances,the number of affected ECs increases (40%at 90to 180min).Moreover,as ischemia prolongs,greater endothelial changes result,including clumping and margin-ation of nuclear chromatin,marked swelling of the
cyto-
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plasm,formation of intraluminal blebs,and even disruption of EC borders,hemorrhage,and?brin deposition(Fig.4) (14–16).The microvasculature can also be obstructed by extravascular compression from myocyte edema.Overall,it seems that microvascular damage lags behind myocardial cell injury,ultrastructurally,and is probably not the primary cause of myocyte injury until reperfusion occurs(14,17). The“No-Re?ow”Phenomenon
or Microvascular Obstruction
A balance exists between the bene?ts of reperfusion to reduce infarct size and reperfusion injury,which depends on the duration of occlusion.In general,if ischemic myocar-dium is reperfused early,the degree of myocardial salvage greatly exceeds damage from free radicals and calcium-loading caused by reperfusion.These positive functional consequences of reperfusion are most bene?cial within the initial12h after occlusion in humans.
Reperfusion injury is de?ned as reperfusion-related ex-pansion or worsening of ischemic cardiac injury leading to decreased contractility,an increased arrhythmogenic thresh-old,conversion of reversible to irreversible myocyte injury, and microvascular dysfunction(3).At the time of myocar-dial reperfusion,there is an abrupt increase in intracellular Ca2?,leading to a disturbance in the normal mechanisms that regulate Ca2?in the cardiomyocyte,known as the calcium paradox(18).This intracellular Ca2?overload induces death by causing hypercontracture of myocytes and mitochondrial permeability transition pore opening(9,18). Microvascular obstruction in the heart was?rst described by Kloner et al.(3)and consists of explosive EC swelling on reperfusion of an ischemic bed(19).Endothelial protrusion by cell swelling together with neutrophils,red blood cells, and platelets cause capillary obstruction(Fig.4)(3).Mi-crovessels ultimately rupture,with?brin and platelet depo-sition and red and white blood cell extravasation.Further-more,surrounding myocardial cells swell,potentially compressing capillaries.These changes in the capillary bed can result in poor perfusion of the surrounding potentially viable myocytes with resultant cell death(10,20).The failure to reperfuse viable,severely ischemic myocytes(reversible injury)with resultant myocyte cell death(irreversible injury) at the time of reperfusion(the no-re?ow phenomenon)has been described after90min in a canine model(3).Reper-fusion,therefore,as described by Braunwald and Kloner (21)is a“double-edged”sword,because it can result in the death of potentially salvageable myocardium. Neutrophils have also been implicated in causing reper-fusion injury in the myocardium and other organs.Neutro-phils are activated early during myocardial ischemia and precede the appearance of histological tissue injury(17). Reperfusion markedly enhances the in?ltration of neutro-phils into the ischemic region(22).The essential initiating step involves interaction of neutrophils with vascular ECs (adhesion).This is followed by activation,diapedesis,and extravascular migration into surrounding myocytes.Produc-tion of additional chemoattractants by activated neutrophils ampli?es the initial in?ammatory response.Neutrophil activation causes a greatly enhanced oxygen uptake by the cell,resulting in the production of large quantities of reactive oxygen species that might lead to disruption of EC and inactivate antiproteases present in the plasma(23).
1Electrocardiogram on Admission and After Intervention
ST-segment elevation in leads V1to V4indicating acute transmural ischemia of the anterior wall.(B)Despite?70%resolution of initial
ST-segment elevation,persistent ST-segment elevation in leads V2to V3(1to2mm)is still present40min after percutaneous coronary intervention.1651
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In addition to these ischemia-reperfusion-related events,distal coronary microembolization of atherosclerotic debris or thrombotic material is responsible for a substantial part of clinically observed MVO (6,24)(Fig.5).Microemboli are histopathologically associated with MVO,myocyte necrosis and edema,and EC sloughing within the intramyocardial capillaries (25,26).The rate of coronary microembolization is highest in documented epicardial coronary thrombosis,reaching 30%to 54%(27,28)and even higher (79%)in AMI patients (29).Few data compare acute plaque rupture versus acute plaque erosion;however,the authors have noted a higher rate of thrombotic microembolization with plaque erosion.In hearts with acute coronary thrombi,evidence of distal embolization was more frequent in ero-sions than ruptures.These thrombi were associated with focal myocardial necrosis.Other potential sources of distal embolization include primary PCI,PCI of diseased (ath-erosclerotic)saphenous vein grafts,and thrombolysis.The reported incidence of distal embolization due to soft friable atherosclerotic plaque and adherent thrombus,after PCI of bypass grafts ranges from 2%to 42%(30–32).Angiographic evidence of distal embolization in patients treated with primary PCI has been shown to occur in approximately 15%to 19%(33,34)(Fig.6).
Microvascular ?ow within the reperfused bed is both spatially and temporarily complex.Apparently,blood ?ow in the area of structural MVO is not completely absent but rather very low,ranging between 0.13and 0.37ml/g/min,which is ?50%of baseline blood ?ow (35,36).Microvas-cular obstruction ?rst appears centrally in the infarct core extending toward the epicardium over time.Different myo-cardial regions can be distinguished (Fig.7)(37).In the noninfarcted region,microvasculature is intact and blood ?ow is normal.In the noninfarcted (stunned)area-at-risk,microvasculature is structurally and functionally still intact.The infarcted region has outer zones of intact microvasculature with co-existing areas of hyperemia,low re?ow,and impaired ?ow reserve,depending on the degree of capillary damage.
Myocardial blood ?ow in certain areas of MVO is hyperemic during the ?rst 2min of reperfusion but progres-sively decreases within 2to 3h after reperfusion,resulting in a 2-fold increase of MVO (35,38).A further increase in
Coronary Angiogram
anterior descending artery (LAD)(A)(arrow).After introduction of the ?rst guidewire,intraluminal thrombus diagonal branch (*)can be seen (B).After thrombosuction and stenting followed by kissing balloon in?ation (C)Infarction ?ow grade 2,despite an angiographically optimal result (D).
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MVO size has been demonstrated up to48h after initiation of reperfusion(39).This progression of MVO is presumably related to reperfusion injury.Therefore,therapeutic inter-ventions trying to attenuate MVO are likely to be most successful when initiated early after reperfusion. Diagnosis of MVO
Coronary angiography.After the recognition that com-plete thrombotic coronary occlusion caused AMI and that early reperfusion with thrombolytic agents increased myocardial salvage and reduced mortality,there was a need to angiographically assess the quality of reperfusion (40).Successful reperfusion is de?ned by assessing ante-grade angiographic epicardial blood?ow,graded as TIMI ?ow;TIMI?ow grade0:absent antegrade?ow;TIMI ?ow grade1:partial contrast penetration beyond an occlusion with incomplete distal?lling;TIMI?ow grade 2:patent epicardial artery with opaci?cation of the entire distal artery(however,contrast?lling or washout is delayed);TIMI?ow grade3:patent epicardial artery with normal?ow.
Early studies using this angiographic assessment found that mortality was signi?cantly lower in patients with TIMI?ow grade3than in those with other TIMI?ow grades(4%vs.8%,p?0.01),and importantly,TIMI ?ow grade2was not associated with a signi?cant survival advantage compared with TIMI?ow grades0or1(41).A TIMI?ow grade?2without a residual obstructive lesion has been generally regarded as the“angiographic no re?ow”(42).Although angiographic assessment of reperfusion is still useful in daily clinical practice,the clinician should be aware that TIMI?ow grade3is not always synonymous with optimal tissue reperfusion,be-cause MVO can be demonstrated in a substantial number of these patients(2).
Because the TIMI?ow grading system is semi-quantitative and subjective,a more objective angiographic marker of tissue perfusion was developed.The corrected TIMI frame count(CTFC)assesses the number of cine frames required for contrast to?rst reach standardized distal coronary landmarks in the culprit artery.A higher CTFC and thus slower epicardial?ow90min after administration of a thrombolytic agent is associated with increased mortal-ity and composite end points and adds prognostic informa-tion even in patients with TIMI?ow grade3(43). Coronary blood?ow velocity patterns.In patients with substantial MVO the coronary blood?ow velocity pattern is characterized by a reduction in systolic antegrade?ow,the appearance of abnormal retrograde?ow in early systole (?10cm/s),and a rapid deceleration of diastolic?ow velocity(?600m/s),which was found to be highly associ-ated with TIMI?ow grade2(44,45).
These distinct coronary?ow velocity patterns are associ-ated with a decreased recovery of LV function over time and
Cardiovascular MRI
short-axis images with a single breathhold3-dimensional inversion recovery gradient-echo pulse sequence.(A)Early
cardiovascular magnetic resonance imaging(MRI)showing a central hypoenhanced area corresponding to microvascular early MVO).(B)Late gadolinium-enhanced cardiovascular MRI(10min after contrast injection)showing hyperenhancement infarction(arrowheads)with a central zone of MVO(arrows,late MVO).Note that the extent of late MVO is smaller Cardiovascular MRI section).1653
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seem accurate predictors of long-term cardiac events in reperfused AMI (46).These altered coronary blood ?ow velocity patterns are believed to be related to an increased microvascular impedance as a consequence of profound microvascular damage and obstruction.
Myocardial blush grading.The assessment of TIMI ?ow grade and CTFC and the identi?cation of distinct coronary ?ow velocity patterns only indirectly re?ect the status of the microcirculation.Perfusion can also be assessed angio-graphically with a semi-quantitative description of myocar-dial contrast density on the ?nal angiogram after reperfu-sion,described as TIMI myocardial perfusion (TMP)or myocardial blush grade (47,48).The TMP ?ow grades are de?ned as follows:TMP ?ow grade 0:failure of dye to enter the microvasculature;TMP ?ow grade 1:dye slowly enters but fails to exit the microvasculature;TMP ?ow grade 2:delayed entry and exit of dye from the microvasculature;TMP ?ow grade 3:normal entry and exit of dye from the microvasculature.
Myocardial perfusion grading also permits risk strati?ca-tion and adds prognostic information even in patients with TIMI ?ow grade 3.Achievement of both TIMI ?ow grade 3and myocardial blush grade 3is associated with mortality under 1%(49).
Previous studies have shown that 11%of patients who had established epicardial patency and TIMI ?ow grade 3had a myocardial blush grade of 0/1,again emphasizing that TIMI ?ow grading is an inaccurate marker of tissue reperfusion (50).It is believed,however,that myocardial blush only indirectly re?ects microvascular status but pre-dominantly describes varying degrees of extravasation and washout of dye that is caused by a combination of increased capillary permeability,capillary resistance,and interstitial edema (51).
The usefulness of angiographic and coronary blood ?ow velocity methods to detect MVO is disputable,because they are often performed immediately after mechanical reperfusion,a time point where microvascular ?ow is known to be hyper-emic,and therefore they might not be an accurate re?ection of the ?nal microvascular damage.Experimental studies have shown that the size of MVO increases depending on the time after reperfusion as a result of reperfusion injury (35).
Myocardial contrast echocardiography.Myocardial con-trast echocardiography (MCE)uses small microbubbles (?5?m)that possess an intravascular rheology similar to that of red blood cells and remain entirely within the microvasculature.During constant infusion,a steady state is achieved after approximately 2to 3min.After destruction with high energy pulses,the rate of microbubble replenish-ment is proportionate to blood ?ow.
Myocardial contrast echocardiography is able to delineate the area-at-risk for necrosis during acute coronary occlusion and has gained tremendous insight into post-ischemic tissue reperfusion (52).A persistent contrast defect despite a
Sequential Changes in the Microvasculature After Varying Periods of Ischemia
ischemia,endothelial cells are swollen with decrease in pinocytotic vesicles.Capillary damage (endothelial change)continues to occur with longer intraluminal protrusions (P),absent or decreased pinocytotic vesicles,membrane-bound vesicles (V),and capillary obstruction with red (R)and With permanent coronary occlusion,intravascular protrusions are less pronounced;however,membrane-bound vesicles and red and deposition are seen only after longer duration of ischemia.N ?nucleus;M ?mitochondrium.Reproduced with permission from Virmani et 1654
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patent epicardial artery after reperfusion correlates with MVO(2).Myocardial contrast echocardiography studies also made clear that substantial MVO could be observed in all patients with TIMI?ow grade2and in16%of patients with TIMI?ow grade3(53).
Myocardial contrast echocardiography predicted segmen-tal myocardial recovery with a sensitivity of88%and a speci?city of74%and a positive and negative predictive value of83%and81%,respectively(54).In addition,MCE studies have shown that pericardial effusion,early congestive heart failure,and adverse arrhythmias occur signi?cantly more frequently in patients with MVO(55).
The technique of intracoronary injection of microbubbles before and shortly after coronary re?ow make it less univer-sally applicable,and although intravenous methods have become available,several disadvantages to the use of MCE remain:moderate spatial resolution,operator dependency, incomplete LV coverage with suboptimal visualization of the lateral wall,and semi-quantitative assessment of MVO (54,56).
Cardiovascular MRI.Two contrast(gadolinium)-enhanced cardiovascular MRI techniques are used to detect MVO in AMI.The primary technique is?rst-pass perfusion cardiovas-
technique,mul-
to track an
A homog-
and infarcted
administration,
signal intensity
the infarct that
(early MVO).
).Due to
10to15
myocardium
with normal
region
as measured by
).A central hy-
region corre-
for the
(59).Ex-
the spatial extent
correlate with
underesti-
small regions of
into the MVO
by incom-
and low spatial
Imaging pro-
LV cover-
the timing after
of imaging after
MVO after1 week independently predicted adverse LV remodeling,un-like MVO that was present at2days but disappeared after 1week(58).
In contrast to MCE,cardiovascular MRI allows mul-tislice imaging with high tissue contrast and high spatial resolution,enabling accurate quanti?cation and localiza-tion of MVO and infarct size relative to the entire LV. Only one experimental study directly compared MCE and FPP-CMR with thio?avin-S staining and found MCE to overestimate and FPP-CMR to underestimate MVO size.This can be explained by the predominantly intravascular sojourn of microbubbles,whereas gadolin-ium as a freely diffusible tracer rapidly extravasates into the interstitium,thereby arti?cially decreasing the area of MVO(63).In addition,microbubbles are larger than gadolinium molecules and might become temporarily plugged in microvessels that would allow passage of gadolinium.
Cardiovascular MRI studies have shown that the pres-ence of MVO signi?cantly increases with infarct transmu-rality and independently predicts adverse events,including adverse LV remodeling,congestive heart failure,and death (7,55).In a recent study,the extent of MVO was not found to be related to the change in LVEF at follow-up,suggest-
Figure5Obstructed Microvessels and
Myocardial Reperfusion Injury
Distal platelet-rich(intramyocardial)embolus(A)when treated with thrombo-lytic therapy will result in reperfusion injury with(B)contraction band necrosis(arrowheads)and diffuse neutrophil and red cell in?ltration in a patient with myocardial infarction secondary to epicardial coronary plaque rupture.1655
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ing that MVO size might be clinically less important than its mere presence (66).
ECG.In patients treated with thrombolytic therapy,com-plete STR (?70%)is a highly accurate predictor of infarct-related artery (IRA)patency and is associated with lower mortality (67–69).However,up to 50%of patients with absence of complete STR (STR ?70%)might still have a patent IRA and TIMI ?ow grade 3(68,70).After successful primary PCI and establishment of TIMI ?ow grade 3,30%to 50%of patients have incomplete STR,indicating that microcirculatory perfusion might be impaired (71,72).Only a limited number of studies have directly related incomplete STR to MVO by coronary Doppler ?ow velocity measure-ments,cardiovascular MRI,and MCE (66,73,74).The interpretation of STR data should be done cautiously,because methodologies,de?nitions,and time points of measuring STR differ between studies.
Most studies have used the sum of STR method from standard 12-lead ECG,in which ST-segment deviation in all leads is summed and compared before and after inter-vention.Single lead STR ?50%in the lead with maximum initial ST-segment elevation is a simple,universally avail-able alternative that predicts TIMI ?ow grade 3with 70%sensitivity and 54%speci?city (75).Single lead STR is comparably accurate in predicting outcome as sum STR measurements (76).Minimal absolute ST-segment devia-tion after thrombolytic therapy can also be used to predict IRA patency (77).Because ST-segment elevation and STR can behave dynamically over time,continuous instead of serial ECG assessment might provide additional informa-tion on epicardial patency and quality of myocardial reper-fusion (78).
Other electrocardiographic changes have been described as signs of successful angiographic reperfusion (TIMI ?ow grades 2or 3).Terminal T-wave inversion was observed in 60%of patients,and a patent coronary artery was associated with an increased number of accelerated idioventricular rhythms in small studies (79–81).These markers,however,only re?ect IRA patency and have not been validated against other measures of MVO.
Representative Micrographs of Distal Microembolization of Plaque Material From Ruptured Atheroma
pentachrome)view of rupture site (arrow)showing luminal ?brin and cholesterol clefts.(B)Adjacent distal segment composed of necrotic core material.(C)High-power image demonstrating cholesterol clefts (arrows)with superimposed image of intramural coronary artery atheroembolus consisting of cholesterol clefts (arrows)and surrounded percutaneous coronary intervention for acute myocardial infarction.
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Management of No-Re?ow
Despite major advances in the understanding of the under-lying pathophysiology of MVO,many different mechanical and pharmacologic therapeutic approaches to prevent or attenuate MVO have revealed very different and,in part,contradictory results.Interventions that were effective in the experimental setting did not show signi?cant effects clini-cally,and vice versa.
The use of a microcirculatory protection device effectively retrieved embolic debris during PCI in AMI but failed to improve microvascular ?ow,reduce infarct size,or result in enhanced event-free survival (32).Although the aspiration of thrombus signi?cantly improved reperfusion compared with conventional PCI,a substantial number of patients still
experienced low myocardial blush grades and incomplete
STR (82).Likewise,intra-aortic balloon counterpulsation signi?cantly reduced MVO experimentally,but a recent meta-analysis of clinical studies using intra-aortic balloon counterpulsation in the setting of ST-segment elevation myocardial infarction suggested that this is not associated with a change in LVEF and increased survival at follow-up (83,84).
A range of pharmacologic adjunctive measures of reper-fusion have been evaluated.Glycoprotein IIb/IIIa inhibition signi?cantly improved microvascular ?ow and reduced in-farct size in a dog model of coronary occlusion/reperfusion and signi?cantly increased the rate of complete STR,coronary artery patency,and CTFC in clinical trials
Regions of Microvascular Flow After Reperfusion
presentation showing the
different regions of microvascular ?ow in reperfused acute myocardial infarction.
FPP ??rst pass perfusion;MI ?myocardial infarction;MVO ?microvascular obstruction;TIMI ?Thrombolysis In Myocardial Infarction;TMP ?TIMI myocardial perfusion.
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(85–88).Possibly by reversing microvascular spasm,the administration of intracoronary verapamil after PCI de-creased no-re?ow zones leading to a better functional outcome in?rst AMI patients(89).The extent of MVO is proportional to the number of polymorphonuclear leuko-cytes present in the infarcted area.The inhibition of complement pathways decreased polymorphonuclear leuko-cyte free radical generation and enhanced the recovery of coronary?ow in an isolated rat heart model(90,91). Circulating levels of endothelin,a potent and long-acting vasoconstrictor,are low in normal individuals but increased during ischemia,with a further increase during reperfusion (16).Endothelin-mediated vasoconstriction,neutrophil plugging,and microvascular permeability play a role in the pathogenesis of MVO.The signi?cant reduction of MVO and infarct size in a canine model after the administration of an endothelin A-receptor antagonist after90min of coro-nary occlusion supports this concept(92).
Selective administration of intracoronary adenosine at-tenuated functional and structural abnormalities of the microvasculature,leading to improved regional ventricu-lar function as compared with placebo in a canine model (93).In the clinical setting,however,although infarct size was reduced,a3-h infusion of adenosine in reper-fused ST-segment elevation myocardial infarction pa-tients failed to show an improved outcome in the AMISTAD II(Acute Myocardial Infarction STudy of ADenosine) trial(94).
These discrepant results underscore the complex underlying mechanisms implicated in the pathophysiology of MVO and suggest that successful therapy should be multitargeted. Conclusions
Temporary coronary occlusion followed by reperfusion results in microvascular damage—with endothelial swelling,neutro-phil activation,and entrapment—leading to reperfusion-induced myocardial damage.Microvascular?ow after reperfu-sion is spatially and temporally complex.Regions of hyperemia, impaired vasodilatory?ow reserve,and very low?ow coexist. The magnitude and spatial extent of these perfusion patterns vary over time as a result of reperfusion injury.Microvascular obstruction is independently associated with adverse LV re-modeling and prognosis.Therefore,its detection is crucial. Several techniques(coronary angiography,MCE,cardiovascu-lar MRI,ECG)measuring slightly different biological and functional parameters are used clinically and experimentally for the evaluation of MVO(Table1).Currently,there is no consen-sus on how and when MVO should be evaluated after AMI. Reprint requests and correspondence:Dr.Johannes Walten-berger,Department of Cardiology and Cardiovascular Research Institute Maastricht(CARIM),Maastricht University Medical Center,Peter Debyelaan25,P.O.Box5800,6202AZ Maastricht, the Netherlands.E-mail:j.waltenberger@mumc.nl.REFERENCES
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Key Words:diagnosis y imaging y microvascular obstruction(MVO)y myocardial infarction y pathophysiology y review.
1660Bekkers et al.JACC Vol.55,No.16,2010 Microvascular Obstruction April20,2010:1649–60