the structure and the role of microvasculature has been progressively clarified in this last decade ( 1 , 2 ) . we now have adequate information on the time course and percentage occurrence of microvascular obstruction ( mo ) . we know that the venules are the site of leukocyte adhesion during inflammation and that their endothelial surfaces express a number of adhesion molecules , whose production is significantly up - regulated after the onset of tissue injury ( 3 ) . similarly we know that about one fifth to one third of patients with timi grade 3 flow after mechanical or pharmacological reperfusion show evidence of mo ( 4 , 5 ) which , in turn , seems the basis of intracardiac hemorrhage ( 6 , 7 ) and of the development of myocardial wall rupture ( 8) . in patients with acute coronary syndromes undergoing pci , aspiration of the coronary artery has revealed thrombus with or without plaque components in 1550% of the patients ( 911 ) . this means that in a large percentage of cases , 5085% , mo is a dynamic phenomenon which begins gradually and progressively develops after the occluded vessel has been reopened ( 12,13 ) . it then persists for at least 1 month after reopening of the epicardial coronary artery , predicting worse scar thinning , infarct expansion , poor survival , and ultimately annulling the effect of pci ( 1416 ) . this explains all efforts made to prevent mo with mechanical devices ( 17,18 ) or with pharmacological strategies ( 1933 ) . the rational of focusing downstream the open artery hypothesis may be further emphasized by considering that all cardiac ruptures , likely the main cause of death in the in - hospital course of myocardial infarction , seem to lag behind mo which represents a significant , and in all probability the principal independent predictor of cardiac rupture ( 34 , 35 ) magnetic resonance imaging ( mri ) has proved to be of great value in detecting and monitoring mo after occlusion and reopening of the coronary artery , both in experimental and in vivo studies ( 3646 ) . it also provides evidence of its value in recognizing myocardial hemorrhage and impending wall rupture , thus allowing a window of interventional opportunity in this often catastrophic event ( 8 , 38 , 4755 ) . the aim of this study was to evaluate , by means of mri , in subacute myocardial infarction , if the different pharmacological strategies of gusto v reperfusion protocol i.e. full dose reteplase vs half dose reteplase plus full dose abciximab ( r+abcx ) , display different effects on volumes and function of the left ventricle ( lv ) , as well as on miocardial infarct size ( misz ) and mo ( 29 ) . from the list of consecutive patients randomized in the gusto v study at our institution , 20 male patients , mean age 58 years range 3775 , were addressed , after written consent , to mri study in the 4 day of myocardial infarction . although selected from a progressive list , in agreement with the criteria of gusto v ( 29 ) , the grid of mri studies was created to fulfil the following criteria : age matched patients affected by anterior and posterior myocardial infarctions , age matched patients treated with reteplase or r+abcx . the grid was thus composed of : 5 anterior treated with reteplase , 5 anterior treated with r+abcx , 5 inferior treated with reteplase , 5 inferior treated with r+abcx . examinations were performed on a somatom vision 1.5 t scanner ( siemens erlangen germany ) and analyzed with the built - in numaris cardiac software . after initial ecg triggered turbo - flash scouts in axial and in double oblique direction , stir t2 breath hold 10 mm thickness images , were obtained in four chambers and in consecutive contiguous short axis views ( sax ) , encompassing the whole lv from the base to the apex . a complete three dimensional ( 3d ) stir t2 study was then created by assembling all base to apex slices in a 3d package , from which lv end diastolic volume ( edv ) and lv end diastolic mass could be calculated . stir t2 hyperintense signal was then manually outlined in each sax slice and subsequently 3d reconstructed to obtain myocardial infarct size ( misz ) , representative of ischemic / infarcted myocardium . 1 ) . in order to quantify the degree of hypersignal level , a circular region of interest ( roi ) of 0.5 cm diameter was positioned in the center of stir t2 hyperintense area and the value was compared with a similar roi positioned in a region remote from the site of infarction . a dimensionless value , stir intensity ratio , was obtained to represent the signal intensity on myocardial infarction . 1- from base ( a ) to apex ( f ) stir t2 contiguous slices . endocardial and epicardial contours define the myocardial slice area from which a 3d quantification of lv mass can be obtained . similarly contour of hypersignal area ( a ) applied to all slices , creates the misz , expressed in % of lv mass . 
  - from base ( a ) to apex ( f ) stir t2 contiguous slices . endocardial and epicardial contours define the myocardial slice area from which a 3d quantification of lv mass can be obtained . similarly contour of hypersignal area ( a ) applied to all slices , creates the misz , expressed in % of lv mass . a bolus of 0.2 mmol gd - dtpa per kg body weight ( magnevist , schering - ag , berlin , germany ) was then injected . the same sax positions of the stir study were repeated with 2d - flash cine sequences ( 2d - fl ) . by assembling base to apex contiguous sax 2d - fl cineloops , a new 3d study was created from which edv and ejection fraction ( ef ) were calculated as habitually done in cardiac mri procedure . as all t1 sequences , also 2d - fl is fit to visualize myocardial signal void in the presence of mo with the limitation of less contrasted images compared to more dedicated t1 sequences , but with the advantage of being able to follow the mo dynamically during systole ( 8) . in order to visualize only persistent mo , 2d - fl acquisition started five minutes after gd injection . since delineation and quantification of small mo was practically unfeasible , mo was visually estimated and classified as : not present ( group 1 ) , small subendocardial ( group 2 ) , and large or transmural ( group 3 ) . due to the limited time allowed for each patient , potentially unstable in day four after myocardial infarction , to the limited contrast gain in late enhancement imaging of our present scanner , to the main goal of this study i.e. to discover differences in volumes and ef , and also to the still incomplete standardization of this technique for quantification of infarct size , ( 56 ) late enhancement quantification of infarct size was not performed . thus each study could be contained in 30 minutes , the time allowed by the ethical committee of our hospital for the study of this type of patients . the list of patients , treatment and measurement performed is reported in table i. 
 table i- list of patients with individual measurementsnameagemidrugstir3d misz % 2d - fl3d ef % stirintensity ratio2d - fl3d edv ml2d - flmo 1 - 2 - 3g.p.48ant.r+abcx31361.571731a.g.c.71ant.r+abcx73561.271311o.e.67ant.r+abcx13501.61202b.g.62ant.r+abcx11671.871151l.c.a.60ant.r+abcx14541.71361s.m.53ant.reteplase19441.651452n.m.75ant.reteplase41262.21042f.g.45ant.reteplase26351.822371f.l.59ant.reteplase24441.8762m.e.72ant.reteplase24431.51871m.c.57inf.r+abcx36341.982251p.d.53inf.r+abcx39601.671491a.u.73inf.r+abcx17421.961323g.g.51inf.r+abcx35561.392212s.g.66inf.r+abcx20531.94932g.f.48inf.reteplase22431.642123c.a.63inf.reteplase22451.751603p.s.37inf.reteplase19521.621403s.m.37inf.reteplase17491.931421s.s.65inf.reteplase36311.51283 examinations were performed on a somatom vision 1.5 t scanner ( siemens erlangen germany ) and analyzed with the built - in numaris cardiac software . after initial ecg triggered turbo - flash scouts in axial and in double oblique direction , stir t2 breath hold 10 mm thickness images , were obtained in four chambers and in consecutive contiguous short axis views ( sax ) , encompassing the whole lv from the base to the apex . a complete three dimensional ( 3d ) stir t2 study was then created by assembling all base to apex slices in a 3d package , from which lv end diastolic volume ( edv ) and lv end diastolic mass could be calculated . stir t2 hyperintense signal was then manually outlined in each sax slice and subsequently 3d reconstructed to obtain myocardial infarct size ( misz ) , representative of ischemic / infarcted myocardium . 1 ) . in order to quantify the degree of hypersignal level , a circular region of interest ( roi ) of 0.5 cm diameter was positioned in the center of stir t2 hyperintense area and the value was compared with a similar roi positioned in a region remote from the site of infarction . a dimensionless value , stir intensity ratio , was obtained to represent the signal intensity on myocardial infarction . 1- from base ( a ) to apex ( f ) stir t2 contiguous slices . endocardial and epicardial contours define the myocardial slice area from which a 3d quantification of lv mass can be obtained . similarly contour of hypersignal area ( a ) applied to all slices , creates the misz , expressed in % of lv mass . 
  - from base ( a ) to apex ( f ) stir t2 contiguous slices . endocardial and epicardial contours define the myocardial slice area from which a 3d quantification of lv mass can be obtained . similarly contour of hypersignal area ( a ) applied to all slices , creates the misz , expressed in % of lv mass . a bolus of 0.2 mmol gd - dtpa per kg body weight ( magnevist , schering - ag , berlin , germany ) was then injected . the same sax positions of the stir study were repeated with 2d - flash cine sequences ( 2d - fl ) . by assembling base to apex contiguous sax 2d - fl cineloops , a new 3d study was created from which edv and ejection fraction ( ef ) were calculated as habitually done in cardiac mri procedure . as all t1 sequences , also 2d - fl is fit to visualize myocardial signal void in the presence of mo with the limitation of less contrasted images compared to more dedicated t1 sequences , but with the advantage of being able to follow the mo dynamically during systole ( 8) . in order to visualize only persistent mo , 2d - fl acquisition started five minutes after gd injection . since delineation and quantification of small mo was practically unfeasible , mo was visually estimated and classified as : not present ( group 1 ) , small subendocardial ( group 2 ) , and large or transmural ( group 3 ) . due to the limited time allowed for each patient , potentially unstable in day four after myocardial infarction , to the limited contrast gain in late enhancement imaging of our present scanner , to the main goal of this study i.e. to discover differences in volumes and ef , and also to the still incomplete standardization of this technique for quantification of infarct size , ( 56 ) late enhancement quantification of infarct size was not performed . thus each study could be contained in 30 minutes , the time allowed by the ethical committee of our hospital for the study of this type of patients . the list of patients , treatment and measurement performed is reported in table i. 
 table i- list of patients with individual measurementsnameagemidrugstir3d misz % 2d - fl3d ef % stirintensity ratio2d - fl3d edv ml2d - flmo 1 - 2 - 3g.p.48ant.r+abcx31361.571731a.g.c.71ant.r+abcx73561.271311o.e.67ant.r+abcx13501.61202b.g.62ant.r+abcx11671.871151l.c.a.60ant.r+abcx14541.71361s.m.53ant.reteplase19441.651452n.m.75ant.reteplase41262.21042f.g.45ant.reteplase26351.822371f.l.59ant.reteplase24441.8762m.e.72ant.reteplase24431.51871m.c.57inf.r+abcx36341.982251p.d.53inf.r+abcx39601.671491a.u.73inf.r+abcx17421.961323g.g.51inf.r+abcx35561.392212s.g.66inf.r+abcx20531.94932g.f.48inf.reteplase22431.642123c.a.63inf.reteplase22451.751603p.s.37inf.reteplase19521.621403s.m.37inf.reteplase17491.931421s.s.65inf.reteplase36311.51283 table i sets out the list of patients with individual measurements ; in table ii the descriptive statistics in both types of treatment ; and in table iii the descriptive statistics divided by drug regimen and site of myocardial infarction . table ii- descriptive statistics in both types of treatmentsdrugminimummaximummeanstdr+abcxage487360.88.5stir 3d misz % 117328.918.72d - fl 3d ef346750.810.5stir intensity ratio1.2721.70.22d - fl 3d edvml93225149.544reteplaseage377555.413.6stir 3d misz % 1741257.72d - fl 3d ef265241.28.1stir intensity ratio1.502.201.750.22d - fl 3d edvml76237153.148.3 
 table iii- descriptive statistics divided by drug regimendrugmiagestir 3d misz % 2d - fl 3d efstirintensity ratio2d - fl3d edv mlr+abcxantmean61.628.452.61.6135std8.726.211.20.222.8infmean6029.4491.8164std9.310.110.70.357.6totalmean60.828.950.81.7149.5std8.518.710.50.244.reteplaseantmean60.826.838.41.8149.8std12.68.37.90.364.3infmean5023.2441.7156.4std13.67.58.10.233.1totalmean55.42541.21.8153.1std13.67.78.10.248.3 
  tables from iv to vii show the results of paired t - test ( 2 tailed significance ) for the two different regimens of therapy . table iv- infarct size ( misz% ) as % of the whole , three dimensionally ( 3d ) calculated , myocardial massstir3d misz % meanstandard deviationsig . ( 2-tailed)r+abcx28.918.720.586reteplase25.07.70 
 table v- from contiguous base to apex cine 2d - flash slices , three dimensional ( 3d ) ejection fraction ( ef ) is calculated in both drug regimens2d - fl3d efmeanstandard deviationsig . ( 2-tailed)r+abcx50.8010.510.035reteplase41.208.08 
 table vi- ratio between intensity values obtained with stir images , in infarct area and in normal myocardium , in both drug regimensstirintensity ratiomeanstandard deviationsig . ( 2-tails)r+abcx1.690.250.653reteplase1.740.22 
 table vii- end diastolic volume ( edv ) , expressed in milliliters(ml ) obtained from cine 2d - flash ( 2d - fl ) sequences , in both drug regimens2d - fl 3d edvmlmeanstandard deviationsig . ( 2-tailed)r+abcx149.544.030.842reteplase153.148.36 
  as evident , mean values of misz , ef , intensity ratio and edv , were not statistically different in patients treated with reteplase and in those treated with r+abcx . neither a further grouping for site of myocardial infarction provided additional differences . in spite of this , mean value of ef in abciximab was only slightly depressed but clearly higher than that of the reteplase group . so when a correlation was attempted with ef and the other measures evaluated , it became clear that the linear regression between ef and misz was strongly significant in the reteplase group . this clear and expected correlation was no longer present in r+abcx group with ef completely unrelated to misz ( fig . 2- inverse linear regression between infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) in both drug regimens . details in the text . 
  - inverse linear regression between infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) in both drug regimens . similarly , mo also showed a powerful relation to ef , with the strongest correlation in group 3 of patients , those with the greatest mo areas ( fig . 3 ) . 
 figure 3relationship between microvascular obstruction ( 2d - fl mo ) infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) . relationship between microvascular obstruction ( 2d - fl mo ) infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) . large mo ( group 3 ) was present in 25% of patients : i.e 5 out of 20 . four of these patients were in the reteplase group whereas small subendocardial ( group 2 ) mo , were uniformly distributed in r+abcx groups : see table i. of note , two patients of this study died : c.a . and p.s . both for wall rupture , both in the reteplase group and with severe ( group 3 ) mo . the first patient who died in day five , was the object of a previous publication ( 8) . finally , no significant correlations could be found when patients were grouped according to the site of myocardial infarction ( fig . 4 - inverse linear regression between infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) according to the site of myocardial infarction : anterior ( ant . ) or inferior ( inf . ) . details in the text . 
   - inverse linear regression between infarct size ( misz% ) ad ejection fraction ( 2d - fl 3d ef ) according to the site of myocardial infarction : anterior ( ant . ) or inferior ( inf . ) . as already known , mri 3d reconstruction of the lv carries a small variability so that also a limited population can be sufficient to disclose differences not revealed by echocardiography ( 5762 ) . this is also the case of this 20 patient study , in which mean ef in r+abcx patients was clearly higher , though with weak significance , compared to the reteplase group . this occurred despite similar misz and intensity ratio , indicating that different degrees of cell damage may be represented by similar stir t2 signal , which thus seems unable to distinguish irreversible necrotic from reversible viable myocardium . the traditional onion configuration of myocardial ischemia and infarction suggests that the outer layers are less damaged than the inner myocardium . under these circumstances with increasing misz a progressive impairment of the lv with lowering ef all this happened , as represented by the clear inverse relation between misz and ef . this was the result of epicardial fibrinolysis , which though successful , could not prevent the development of mo . this was related , in our study with equivalent pain to treatment time between groups ( 63 ) to the extent of misz more than the success of epicardial trombolysis . the above considerations were furthermore confirmed by the opposite behaviour observed in r+abcx patients where not only epicardial but also microvascular vessels were pharmacologically preserved . in these patients despite unchanged misz compared to reteplase , the inverse relationship of figure 2 was completely lost and almost no mo occurred . almost contemporaneously some years ago , two different works indicated that t2 weighted ( 64 ) and t1 weighted sequences ( 39 ) were able to define infarct areas with good correspondence with the infarct size expressed by thallium irreversible defect . in experimental comparison however ( 65 ) , infarct areas seemed more accurately represented by t1 compared to those , slightly overestimated , obtained with t2 sequences . nonetheless the same images also indicated that t2-weighted could detect subendocardial void of signal not visible in t1 sequence , indicating that two different tissue were at the same time present in that infarct area , both well detected by t2 approach . this closely calls mri experimental data which indicate that in the same infarct area , irreversibly damaged myocites with patent microcirculation and irreversibly damaged myocytes with occluded microcirculation may coexist ( 12 ) . since then , both t2 ( 6668 ) and t1 late enhancement imaging have been utilized to estimate infarct size , t1-weighted largely dominating the scene ( 36 , 39 , 6992 ) . in spite of this , some limitations suggest that beyond the clear experimental and clinical evidence of late enhancement usefulness , the exact quantification of infarct size requires further technological , procedural and methodological steps to be completely defined ( 56 , 68 , 74 ) . in addition , void of signal in t2 images most likely indicates hemorrhagic tissue , currently a prevalent domain of t2 imaging ( 9396 ) . figure 5 whose imaging of wall rupture as been object of a previous publication ( 8) and p.s . 5- short axis stir image of the left ventricle ( a ) and the corresponding macroscopic autoptic specimen ( c ) . subendocardial void of signal in a corresponds to hemorrhagic tissue in c , while hypersignal in a corresponds to edema in c. ( d ) small red cells dominate the center of hemorrhagic area ( dark subendocardium in c ) . ( b ) in the area of edema ( white area in c ) proceeding from the inner ( right - bottom ) to the outer ( left - top ) plane : the number of unbroken myocites progressively increases while the interstitial space progressively reduces . 
  - short axis stir image of the left ventricle ( a ) and the corresponding macroscopic autoptic specimen ( c ) . subendocardial void of signal in a corresponds to hemorrhagic tissue in c , while hypersignal in a corresponds to edema in c. ( d ) small red cells dominate the center of hemorrhagic area ( dark subendocardium in c ) . ( b ) in the area of edema ( white area in c ) proceeding from the inner ( right - bottom ) to the outer ( left - top ) plane : the number of unbroken myocites progressively increases while the interstitial space progressively reduces . 6- long axis images of the left ventricle in cine 2d - flash ( a ) and in stir t2 sequence ( b).both indicate the presence of mo , stir image also suggesting the hemorrhagic nature of mo . - long axis images of the left ventricle in cine 2d - flash ( a ) and in stir t2 sequence ( b ) . both indicate the presence of mo , stir image also suggesting the hemorrhagic nature of mo . stir t2 short axis slice with clear evidence of transmural hyperenhancement of the inferior wall surrounding a subendocardial void of signal ( a ) . this respectively corresponds to : oedema and subendocardial haemorrhage in the macroscopic autoptic specimen ( b ) . the histological aspect of those layers indicate subendocardial red blood cells predominance ( d ) and in ( c ) the extensive loss of myocytes in the confining zone near the hemorrhagic endocardium , progressively replaced in the outer layers by unbroken myocytes and parallel reduction of " expanded " interstitium . this last happened without a clear modification of signal intensity in hyperenhanced area of a thus similar or contiguous levels of t2 intensity , represents different degrees of cell injure as already outlined in previous mri studies on ischemia necrosis hemorrhage and healing tissue ( 97 ) in figure 6 is represented the second case of wall rupture : p.s . a long axis 2d - fl after gadolinium injection clearly demonstrate the presence of a long mo extended from the base to the subepicardial inferior distal wall . both 2d - fl ( a ) and stir t2 ( b ) images were able to identify the presence of severe mo , stir t2 also suggesting the haemorrhagic characteristics of mo , and 2d - fl allowing to follow mo dynamically during systole , thus indicating its threatening extension towards the epicardium . r+abcx prevents mo : compared to traditional fibrinolytic therapy , this allow a better lv function and most likely an improved long term survival . extensive mo was present and well recognized in 25% of all cases , 80% of which fall in the reteplase group of treatment . the combination of t1 dynamic 2d - flash cine and stir t2 sequences may allow recognition and tissue characterisation of mo also suggesting the presence of impending ruptures .