Reversible and Irreversible Injury in the Reperfused Myocardium by klutzfu50

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									                                                                                                                                                                      Cardiac                          Radiology
      Maythem               Saeed,         DVM,          PhD             Michael
                                                                     #{149}             F. Wendland,                    PhD              Yasuo
                                                                                                                                     #{149}              Takehara,            MD          Charles
                                                                                                                                                                                      #{149}               B. Higgins,               MD




      Reversible        and Irreversible                                                                                               Injury
      in the Reperfused           Myocardium:                                                                                                              Differentiation
      with     Contrast     Material-enhanced                                                                                                                   MR Imaging’


Thrombolytic                agents        ane being          used              T      HE current                treatment                of acute                    used    in a rat model                of reperfused
with increasing                frequency             to pro-                            myocardial                  infarction              frequently               myocardial        ischemia              to differentiate
duce repenfusion                  of acute myocandi-                          involves            the use of thrombolytic                                            between      reversible               and irreversible
al infarction            in humans.             This study                    agents,         which           in many               instances                        myocardial        injury.
was designed               to assess        the potential                     causes         reperfusion                  of the ischemic
of a magnetic              resonance           (MR) con-                      myocardium.                   Early          reperfusion                 re-
                                                                                                                                                                       MATERIALS                       AND         METHODS
tnast agent,          the manganese                  chelate                  mains         the most              effective            way of re-
of N,N’-bis(pynidoxal-5-phosphate)                                            ducing          infarct          size and improving
                                                                                                                                                                     Animal           Preparation
ethylenediamine-N,N’-diacetic                                  acid           ventricular               function.              Consequently,
(DPDP),         in differentiating                   between                  determination                     of myocardial                    status                  Twenty         adult      Sprague-Dawley               rats
reversible          and irreversible                 myocar-                  during          reflow           is important                  for assess-             (Charles         River Laboratories,              Wilmington,
dial injury          during          reperfusion.             Isch-           ing short-             and long-term                       clinical                    Mass)      of both sexes, weighing                    250-340        g,
                                                                                                                                                                     were anesthetized                 with sodium           pentobar-
emia was produced                      in rats by occlu-                      prognosis              (1) and for evaluating                              in-
                                                                                                                                                                     bital (Nembutal;               Anthony         Products,        Arca-
sion of the left coronary                       artery        for             terventions                designed               to limit          the ex-
                                                                                                                                                                     dia, Calif) (50 mg/kg                  of body weight             ad-
either      15 minutes             (n       10) or 2 hours                    tent of myocardial                         infarction.               An im-
                                                                                                                                                                     ministered           intraperitoneally),             intubated
(I’ = 10), followed                 in both cases by                          aging        technique                 that could              document                through         a cervical        tracheostomy,            and
30 minutes            of repenfusion.                Signal                   successful              reperfusion                 and also dis-                      ventilated         with use of a Harvard                  respira-
intensity         (SI) was measured                     before                tinguish           reversibly                from         irreversibly                 tor. Left lateral           thoracotomy           was per-
and after (every                15 minutes             for 1                  injured          myocardium                     might          be useful               formed,        and     a 6-0 silk suture          was intro-
hour)      the administration                    of Mn-                       for these            therapeutic                 approaches.                           duced       into the myocardial                wall (intramu-
DPDP.        Prior to intravenous                       injec-                     Contrast            material-enhanced                             mag-            ral stitch)       of the pulmonary               cone and
tion of the contrast                  agent,       no signif-                 netic      resonance                 (MR)         imaging             is a             brought         to the surface           at a point      near the
                                                                                                                                                                     middle        of the line connecting                 the pulmo-
icant difference               in SI was observed                             new       diagnostic                technique                that has
                                                                                                                                                                     nary     cone with the insertion                   of the left
between         normal           and reversibly                or             potential             usefulness               in the noninva-
                                                                                                                                                                     atnial appendage               (12,13).      Both suture          ends
irreversibly           injured          myocardium.                           sive detection,                   localization,                 and                    were then threaded                   through      a 1.5-inch
Mn-DPDP              produced            greater         en-                  quantitation                of acutely                injured          myo-            (3.8-cm)       Teflon      tube     to form       a snare       loop
hancement             of SI of the irreversibly                               cardium            (2-10).           In the first hours                      af-       around      the artery;      the 1oop was closed            by
injured       region         compared            with nor-                    ter coronary                occlusion,                infarcted                        pulling      the free ends of the suture.            To test
mal myocardium.                    There       was no dif-                    myocardium                   may not be discernible                                    the occluder,       the snare was pulled            for 1
ferential        enhancement                of the revers-                    from       normal            myocardium                      without                   minute,       and occlusion      was confirmed             by
ibly injured            region        compared             with               the use of contrast                        media.           A recent                   the development            of myocardial       cyanosis
normal        myocardium.                 Thus,       Mn-                     report        demonstrated                      that       contrast-en-                and     lack of contractility      in the ischemic
                                                                                                                                                                     zone. In cases of arrhythmia              during       re-
DPDP        is useful         in discriminating                               hanced           MR imaging                     can be used                 to
                                                                                                                                                                     flow, lidocaine        (1 mg/kg)      (Elkins-Sinn,
reversible          from irreversible                   injury                distinguish               between               occlusive             and
                                                                                                                                                                     Cherry      Hill,  NJ) was injected         via the tail
in reperfused              myocardium.                                        reperfused                myocardial                 infarctions                       vein.
                                                                              (11). However,                     it is not clear                whether
Index     terms:      Heart,      infarction,          51 1 .771 .            reversibly              injured           myocardium                     can
Heart,     MR studies,        511.1214             Magnetic
                                               #{149}           reso-         be differentiated                       from        irreversibly                       Experimental                 Protocol
nance     (MR), contrast         media            Myocardium,
                                              #{149}                  in-     injured          myocardium                     during           reperfu-                  Two groups          of animals      were prepared.
farction,     511.771       Myocardium,
                         #{149}                       MR studies,             sion.                                                                                  Group     1 (reversible         myocardial      injury)
511.1214
                                                                                   In the current                   study         we examined                        rats (n = 10) were subjected               to a brief pe-
                                                                              whether            paramagnetic                      contrast            me-           riod (15 minutes)            of left coronary       artery
Radiology         1990;    175:633-637
                                                                              dia might              enhance              irreversibly                in-            occlusion      followed        by 30 minutes         of re-
                                                                              jured      (infarcted)         myocardium               to a                           flow before        acquisition       of the first image.
                                                                              different          degree      than      reversibly          in-                       Group     2 (irreversible         myocardial       injury)
                                                                                                                                                                     rats (n = 10) were subjected               to occlusion
                                                                              jured      myocardium              and might           thereby
    1 From   the Department             of Radiology,         Box             allow       differentiation            between           the
0628, University         of California,         San Francisco,                two types           of injury.       In this study            a
San Francisco,        CA 94143.         Received      October       26,       new       paramagnetic             contrast         medium,                            Abbreviations:           DPDP           N,N’-bis(pyridoxal-
1989; revision       requested         December        15; revision                                                                                                  5-phosphate)     ethylenediamine-N,N’-diacetic
                                                                              the manganese               chelate         of N,N’-bis-
received    February        19, 1990; accepted           February                                                                                                    acid; DTPA     = diethylenetriaminepentaacetic
23. Address      reprint       requests       to C.B.H.                       (pyridoxal-5-phosphate)                       ethylenedia-                             acid; SI = signal      intensity;       TTC        triphenyl-
    C RSNA,     1990                                                          mine-N,N’-diacetic                  acid (DPDP),              was                      tetrazolium    chloride.


                                                                                                                                                                                                                                          633
for 2 hours     followed      by 30 minutes                        of re-
flow. It has been found           that 2 hours                      of oc-
clusion   induces      myocardial      infarction
(14).


MR       Imaging

    Copper      needle         leads were inserted                     sub-
cutaneously          into a forelimb                 muscle         and
an abdominal            muscle,         filtered          to avoid        ra-
dio-frequency            interference,               and connect-
ed to a patient          electrocardiographic                        (ECG)
monitor       (Accusync-6L;               Advanced              Medical
Research,       Milford,          Conn)        to provide             an R-
wave signal          for triggering              the MR pulse
sequence.        Rats were positioned                        supine       in-
side a 6-cm-diameter                  bird-cage             imaging              hours      after      occlusion           of the      left   coronary
coil. An oil phantom                  was included                 as a          artery   to allow complete           development             of
standard       reference           for intensity              during             any possible       myocardial        infarction        (14).
the course        of each study.              Single-section                     Hearts     from groups        1 and 2 were excised
transaxial       MR images             were obtained                  on a       and evaluated        histochemically            with the
GE-CS!      2-T system            (GE Medical                Systems,            use of triphenyltetrazolium                chloride
Milwaukee)           operating           at a proton             fre-            (TTC)    to determine        the presence          or ab-
quency       of 85.6 MHz.             ECG-gated               spin-              sence of infarction.         Each heart was cut
echo images           were acquired                 with an echo                 into four or five slices (2-3-mm                 thickness)
time of 20 msec, a repetition                          time equal           to   parallel     to the atrioventricular            groove.
one R-R interval              (about        170-240            msec),            Tissue    slices were immersed               in 2% TTC
 128 phase-encoded                 steps,      four excitations                  for 15 minutes        at 37#{176}C. Viable      myocytes
per step, and a block size of 512 complex                                        were stained       brick red, whereas             necrotic
data points.         Single-section               images          were           tissue     remained           unstained             (14).    Stained
obtained.       Total acquisition                  time for each                 heart slices were photographed,         and the
image      was approximately                    2 minutes.             A         photographs     were compared     with MR im-
coronal      image       was acquired                 to locate        the       ages to document     the site of infarction.
level of the heart.              Transaxial             images        3
mm thick were then obtained                               at the mid-
dle of the left ventricle                  over a 60 X 60-                       Data        Analysis
mm field of view.                Heart       rates were 250-
                                                                                     All data are presented       as mean     ± stan-                          Figure         1.      Representative          images      of revers-
350 beats/minute.                Mn-DPDP                 (400 zmol/
                                                                                 dard error of the mean.        The statistical      sig-                      ible     injury   acquired     before      (top left) and 15
kg) was injected             during         a 3-minute              period                                                                                     (top right), 30 (bottom             left),   and 60 (bottom
                                                                                 nificance    of the difference      between     the SI
via the tail vein (130 mol/kg                             per mm-                                                                                              right)    minutes        after the intravenous        admin-
                                                                                 of normal     myocardium       and that of revers-
ute). A total of six images                    were acquired,                                                                                                  istration    of Mn-DPDP            (400 mol/kg).
                                                                                 ibly     or irreversibly           injured          myocardium
one before         the administration                     of the con-
                                                                                 (SI ratio) was determined               with an un-
trast agent and one each at 3, 15, 30, 45,
                                                                                 paired      Student      t test.  The significance        of
and 60 minutes             after the injection.
                                                                                 differences         between      SI values     obtained
                                                                                                                                                               values       of both       regions        increased            sim-
                                                                                 before      and after administration              of con-
                                                                                                                                                               ilarly     (182%       ± 6% of control               and
                                                                                 trast    material        within       each         group       was eval-
Analysis             of MR           Images                                                                                                                    193% ± 14% at 3 minutes,                        respective-
                                                                                 uated     with        a repeated-measure                     analysis    of
    Signal      intensity       (SI) values        were ob-                      variance      followed     by the Tukey   test. A                             ly) and did not change                     significantly
tamed       from a rectangular              cursor-defined                       probability        value  of less than .05 was con-                           during        a 60-minute           period         (Table).
region       of interest      with operator-adjust-                              sidered     to be significant.                                                The enhancement                   of the myocardium
able dimensions              and position.           The size of                                                                                               was homogeneous                    and uniform                (Fig
each region          of interest        was 6-12 pixels,                                                                                                        1, Table),       with      no differential               en-
each pixel being             0.23 X 0.23 mm. SI mea-                                                         RESULTS
                                                                                                                                                               hancement             observed          between            the re-
surements          were obtained            at several       posi-
                                                                                                                                                               versibly        injured       myocardium                 and the
tions on each image:                interventricular           sep-              Reversible                 Myocardial                 Injury
                                                                                                                                                               normal         myocardium              during         the hour
turn (representing              normal        myocardiurn),
anterolateral           wall (representing             revers-                       Representative           MR                images          ob-            after    the Mn-DPDP                 injection          (Fig 3).
ibly or irreversibly             injured       myocardium),                      tamed      before        and 15,              30, and          60 mm-         No change            in SI ratio         was produced
skeletal       muscle,      and oil phantom.              All SI                 utes after       injection    of               Mn-DPDP                (400    by administration                 of the contrast                me-
values      were standardized               to the SI of the                     mol/kg)           are shown                  in Figure            1 . Pri-    dium       (Fig 3), and the jeopardized
oil phantom.            The position          of the region                      or to the administration               of Mn-                                 zone      could       not be defined.               Postmor-
of interest        remained         fixed for analysis            of             DPDP,        the reperfused         reversibly      in-                       tern TTC staining              revealed        no evi-
SI of control          and subsequent             images.                        jured      zone    could    not be visually                                   dence       of infarction         in these        hearts
Contrast        between        injured      and normal           re-                                                                                           (all hearts       were     uniformly           stained
                                                                                 identified        on MR images           (Fig 1). Fig-
gions was determined                   with use of the ra-
                                                                                 ure 2 shows          the time     course       of                             brick     red, which         is characteristic           of
tio of the SI of reversibly                or irreversibly
                                                                                 changes         in SI after    the injection      of                          noninfarcted            myocardium).
injured       myocardium            to that of normal
myocardium.                                                                      Mn-DPDP.            There    was no significant
                                                                                 difference           in SI values          between         nor-               Irreversible                      Myocardial            Injury
                                                                                 mal myocardium                  (interventricular
Postmortem                   Documentation                                       septum)         and reversibly              injured       myo-                    MR images      from      a representative
   After completion       of image   acquisition,                                cardium          (anterolateral           wall)     (0.38     ±               study   are shown       in Figure         4. As was
group    1 animals   were removed        from the                                0.04 [n = 10] vs 0.47 ± 0.06 [n                             10]).             the case with     reversible         injury,    there
magnet     and maintained      for a total of 3                                  After      injection         of Mn-DPDP,              the SI                  was       no        significant          difference         in SI


634        Radiology
        #{149}                                                                                                                                                                                                           June     1990
                                                                            hTevenlbIe      injury
                                                                   -
                                                                                                                             2.5                                                                 -          Irreversible             Injury
                                                                                                                                                                                                                                              ference    between     the percentage           of
     400                                                       -   4   -    reversible   Injury               .                                                                         -        4-         reversible           Injury
                                                                                                                                                                                                                                              change     in SI of skeletal       muscle     and
                                                                                                                                                                                                                                              the SI of normal      myocardium           was
                                                                                                                                                                                                                                              noted   for 1 hour    after     the administra-
                                                                                                                                                                                                                                              tion of the contrast        agent     (Fig 5, Ta-
                                                                                                                                                                                                                                              ble).
IE               __________                                                                                                           ___________
           ,‘        ‘.,.‘.,,‘.,.                                                                                 ia          .o                  .
                                                                                                                                                                                                                                                                        DISCUSSION
                                                                                                                                      control             3              15                 30              45              60
                control             3       15            30           45         60
                                        time     (mlii)                                                                                                       time        (mlii)                                                              Toxicity              of Contrast                    Media
2.                                                                                                                3.
                                                                                                                                                                                                                                                  The acute    median        lethal     dose                             of
Figures    2, 3. (2) Effect of Mn-DPDP                on SI in reversible     and irreversible       myocardial      lesions.
                                                                                                                                                                                                                                              Mn-DPDP       in mice        is 4.8 mmol/kg
There is a significant      difference         in the pattern     of enhancement      between       the two lesions.       The
                                                                                                                                                                                                                                              (15), a toxic   dose     that    is higher                               than
difference     in enhancement          persisted      for at least 1 hour after the administration            of Mn-
DPDP. No significant          difference         in SI values was observed       between       the two groups      before                                                                                                                     that of ionic    iodinated         contrast                               media
the injection     of Mn-DPDP.         * indicates       P < .05 as compared      with   precontrast      SI; t indicates      P                                                                                                               on a molar                 basis        but is less than                    that
< .05 as compared                        with        SI of reversible                    myocardial            in ratio injury.              (3) Time-course                        changes                                                   of Gd-DTPA                    (5.6 mmol/kg).                         Biodis-
of SI of reversible      and irreversible       injury to SI of normal     myocardium        before and after the                                                                                                                             tribution             and excretion                       of Mn-DPDP
administration        of Mn-DPDP.        * indicates   P < .05 for comparison       of control     SI ratio value      to
                                                                                                                                                                                                                                              have       been          determined                     via Mn-54                 ra-
that obtained      after injection     of contrast    media; t indicates     P < .05 for comparison         of values
                                                                                                                                                                                                                                              diolabeling                 and compared                        with        those
of reversible   to irreversible    injury.  Note that there is a significant    difference       between     the
two lesions   for 60 minutes     after injection    of Mn-DPDP.     Acute infarction       caused    no signifi-                                                                                                                              of manganese                      (54Mn)             chloride            (oral
cant increase    in SI ratio in the absence      of the contrast agent on Ti-weighted           images.                                                                                                                                       communication,                           Scott         Rocklage,             Salu-
                                                                                                                                                                                                                                              tar, Sunnyvale,                      Calif,          June        1988).         It
                                                                                                                                                                                                                                              was found                 that 0.17%                 ± 0.05%             of the
                                                                                                                       180                                                          -                 hreversibly            injured          injected            Mn-54            DPDP              per gram             of tis-
                                                                                                                                                                               -    e        -        reverlibly           Injured
                                                                                                                                                                                                                                              sue was present                        in the heart                  30 mm-
                                                                                                                                                                                                                                              utes after             injection               and that             0.01%          ±
                                                                                                      g                140                                                                                                                    0.005%           (similar            to background                        val-
                                                                                                          U
                                                                                                      ,                120
                                                                                                                                                                                                                                              ues) was present                          at 7 days            after       injec-
                                                                                                                                                                                                                                              tion.      In contrast,                   1.24%          ± 0.35%            of the
                                                                                                                       100
                                                                                                                                                                                                                                              injected            54MnC12               was present                  in the
                                                                                                                                                                                                                                              heart        after        30 minutes                   and 0.48%                ±
                                                                                                                                   control            3           15           30                     45            60
                                                                                                                                                                                                                                              0.02%         was present                     after       7 days.
                                                                                                                                                                  time
                                                                                                                                                                                                                                              Whole-body                    clearance                 and cumula-
                                                                                                      Figure 5. Effect of Mn-DPDP     (400 imol/
                                                                                                      kg) on the skeletal muscle. Note that the in-                                                                                           tive excretion                    studies             of Mn-54
                                                                                                      crease                       in SI is less              than   that in the heart                                           (cf          DPDP            in rats yielded                      43% renal              ex-
                                                                                                      Fig 2). * indicates                                     P  < .05 for comparison                                              of         cretion           (all within                 6 hours)             and 47%
                                                                                                      precontrast    and                                  postcontrast                           values.                                      hepatic            excretion               by 7 days.               Six per-
                                                                                                                                                                                                                                              cent      of the injected                       dose        remained                 in
                                                                                                                                                                                                                                              the body.               In contrast,                  free 54MnCl2
                                                                                                      earliest         measurement,                and maximum                                                                                yielded            no renal               excretion,              with         50%
Figure           MR images
                4.                of irreversible      injury                                         contrast          was obtained               15 minutes                af-                                                              hepatic            excretion               and 50% whole-
obtained      before (top left) and 15 (top right),
                                                                                                      ter Mn-DPDP                  injection.          Figure           3                                                                     body         retention              at 7 days               after       injec-
30 (bottom       left), and 60 (bottom          right) mm-
utes after the administration              of Mn-DPDP                                                 demonstrates                the difference                  in the                                                                      tion      (16). These                 data suggest                   that       Mn-
00     imol/kg).        Increase    in SI with Mn-                                                    profile        of the contrast               of reversible                                                                              54 DPDP               or its metabolites                          mostly
OPDP administration              is demonstrated.                                                     and irreversible                 injury.                                                                                                clear       the heart,               while            nearly         40% of
                                                                                                           TTC staining               produced             the brick                                                                          the free 54MnCl2                          remains             present            af-
                                                                                                      red coloration                on the posterior                    wall                                                                  ter 7 days.
between            the irreversibly           injured                                                 and interventricular                      septum             of the                                                                          The partial                 excretion               of Mn-DPDP
myocardium              (0.35     ± 0.05) and the                                                     left ventricle             indicative            of normal                                                                              by the liver,                 along            with        the myocar-
normal          myocardium            (0.27      ± 0.03)       be-                                    myocardium,                 whereas           the anterola-                                                                             dial retention                    of radiolabeled                       Mn-
fore      the administration                of Mn-DPDP.                                               teral     wall       remained            unstained,               mdi-                                                                  DPDP,            suggests               that       the composition
Signal        arising     from      slowly        flowing                                             dating        the presence              of myocardial                   in-                                                             of this compound                             may be altered                      in
blood        along     the inner         wall     of the left                                         farction.          All rats from             this group                                                                                 vivo,        liberating                free manganese                        ions.
ventricle           was evident.         After       injection                                        demonstrated                 transmural              infarct         in at                                                              Consistent                 with          this idea,            White           et al
of Mn-DPDP,                  the SI of normal                myo-                                     least     three        or four slices             (2-3-mm                                                                               (16) reported                   that        increasing                the ratio
cardium            increased          to 254%         ± 20% of                                        thickness).                                                                                                                             of ligand             to metal               concentration                     from
control          and showed              no further                                                        The effects            of Mn-DPDP                   adminis-                                                                       2,000        to 1 17,000                in tracer            experiments
change           for 60 minutes              (Table).        En-                                      tration        on skeletal            muscle          SI were                                                                           increased               renal         clearance               from         22% to
hancement               in irreversibly              injured                                          similar         for the two groups                     (Fig 5).                                                                         60%. However,                        myocardial                   toxicity
myocardium                 was significantly                 great-                                   Peak       SI enhancement                   of 165% ± 7%                                                                                has not been                   observed                 in studies              de-
er (323%            ± 29% of control,                P < .05)                                         of the control               value       was noted               at 3                                                                   signed           to test for it. In an isolated
than       that      in normal           myocardium.                                                  minutes           after     administration,                    fol-                                                                     heart        preparation,                     no evidence                  of
This       difference           persisted         for 60 mm-                                          lowed         by a steady            decline.           Interest-                                                                       myocardial                  depression                   was found                 at
utes      (Table,        Fig 2) and provided                    clear                                 ingly,       the increase             in the SI of skele-                                                                               higher           Mn-DPDP                     concentrations
delineation              of the injured             zone.       Dif-                                  tal muscle            (from       0.21 ± 0.02 to 0.34 ±                                                                                 than       those           used         for imaging                  (17).
ferential           enhancement               is demonstrat-                                          0.04) was less than                   that observed                  in                                                                      It should              be noted                that      the biodis-
ed in Figure              3, where          a significant            in-                              normal           myocardium               (from          0.27 ±                                                                         tribution             and excretion                       studies          of
crease        in the SI ratio             is evident          at the                                  0.03 to 0.66 ± 0.09).                   A significant                 dif-                                                              Mn-54            DPDP            do not indicate                       defi-


Volume               175               Number
                                    #{149}                     3                                                                                                                                                                                                                                   Radiology                     635
                                                                                                                                                                                                                                                                                                                              #{149}
nitely       the form         of the excreted              Mn-54                      dium     in regions      of irreversible         inju-                             Gd-DTPA-albumin                 to rats subjected
DPDP.          However,          they      do clearly                                 ry; (b) increased       interstitial       water     vol-                          to 15 or 30 minutes             of myocardial
show        that   the biodistribution,                   espe-                       ume    caused     by edema           in the injured                                ischemia.         However,       animals       subject-
cially      in the heart,           and the excretion                                 zone,    so that    the distribution          volume                               ed to 60 and 90 minutes                 of ischemia
characteristics             of Mn-DPDP              are sub-                          for the         contrast           medium      is increased                        followed         by reflow      showed       signifi-
stantially        different          from     those       of free                     relative         to the         total   volume      of myo-                        cant    increase      in SI in the ischemic
54MnC12.         On the other              hand,       they     do                    cardial     tissue;  (c) greater     accessibility                                 zone      compared         with   the normal
not exclude            the possibility            that      some                      of intracellular       water     to the contrast                                   myocardium.
free Mn2+          dissociates           from     the che-                            agent     caused    by cell membrane               dam-
late. To date,           no myocardial              toxicity                          age; or (d) a combination             of these        ef-
                                                                                                                                                                         Contrast-Material                        Enhancement
has been         detected          with     use of the                                fects.
                                                                                                                                                                         of Skeletal       Muscle
Mn-DPDP             complex.           More      studies                                   Irreversibly             injured        reperfused
need       to be performed                to elucidate                                myocardium                 is characterized                by ex-                       SI enhancement                    of skeletal            muscle
this important              point.                                                    plosive         cellular         swelling          and forma-                      was significantly                  less than            that     of
                                                                                      tion      of large        blebs       of cytosolic           edema                 normal         myocardium                  after       adminis-
                                                                                      beneath           the sarcolemma                  (18,19),       ad-               tration       of Mn-DPDP.                   We attribute
Contrast-Material                             Enhancement
                                                                                      celerated           structural          disintegration                of           the different             effects        of the contrast
in Myocardial                       Injury
                                                                                      the myocytes                (20), accentuated                 inter-               agent       in these         two regions                to differ-
   Previous               studies    of the               application                 stitial      edema         due to increased                 capil-                 ences      in blood           flow,       tissue        blood         vol-
of Mn-DPDP                    to myocardial                   imaging                 lary permeability                   (21), and intramyo-                            ume,      size of the extracellular                          space,
 in rats demonstrated                            that        (a) Mn-                  cardial        hemorrhage                (22). Edema             for-              and/or        permeability                 of the capillary
 DPDP         administration                        significantly                     mation         and hemorrhage                    depend           on               wall     to the agent.              Another             consider-
 increases           the contrast                  between              nor-          the     severity           and duration                    of ischemia             ation     is that some               free manganese                     is
 mal and ischemic                        zones           (17), with             the   and      reflow          (21,22).                                                  present        in the body,               and       this passes
acutely         ischemic               zone          appearing               as a          In reversible                 injury,         the lack of dif-                into     myocardial              cells      to a greater             de-
 region        of low SI; and (b) Mn-DPDP                                             ferential          enhancement                       between           the         gree     than      into      skeletal          muscle          cells.
administration                     allows            differentiation                  reversibly             injured           myocardium                   and          However,            analogous              results         have
between            occlusive               infarcts            (6-hour                the normal                myocardium                     is likely       due       been      observed            with       the use of dys-
left coronary                 artery         occlusion)                and            to complete                reestablishment                       of coro-          prosium          DTPA-bismethylamide,                               a
reperfused              infarcts            (2-hour             left coro-            nary       blood         flow        during            the reperfu-                compound              that produces                  signal       loss
nary       occlusion              followed                by 4-hour                   sion period               and insufficient                      enlarge-           on T2-weighted                   MR images                (28). This
reperfusion)                (1 1). In rats with                       occlu-          ment         of the extracellular                         space.      It has       contrast        agent        caused          greater         SI loss
sive infarcts,               three         well-defined                               been        shown           that       the most             severely               in normal           myocardium                   (18% ± 3% of
zones        were        seen:          Epicardium                   and en-          ischemic           myocytes                 remain           viable      for       the control            value)        than       in skeletal
docardium               were          enhanced,                  while         the    at least         15 minutes                if reperfusion                is        muscle        (54% ± 6% of the control
midmyocardial                       zone         was hypoin-                          reestablished                 during            this time           period         value).
tense.       The enhancement                               of the endo-               (23). Recently,                  Jeremy            et al (24)
cardial        zone        was presumed                         to be                 found          that normal                 coronary             blood
                                                                                                                                                                         Contrast-Material                    Enhancement
caused         by prominent                       signal          emanat-             flow       and reserve                 are preserved                 in
                                                                                                                                                                         of Reperfused                   Myocardium
ing from           stasis         of blood              at the blood-                 dogs       subjected              to 10 minutes                   of isch-
endocardium                    interface.               However,                in    emia       followed              by reperfusion.                    Ultra-              The possibility             of reperfusion                of
rats with           reperfused                  infarcts,           the in-           structural           features             that characterize                        infarcted         myocardium                in humans
jured       area       was uniformly                        and in-                   reversible            injury          have         been        shown          to   with      the use of thrombolytic                        agents
tensely         enhanced.                                                             completely                disappear              by 20 minutes                     has aroused            intense        interest         in the
     The current                 study         addresses               the            after      reflow          (23,25).           Furthermore,                 it      evaluation           of damage            in reperfused
potential           of Mn-DPDP-enhanced                                               has been           demonstrated                       that     the pre-            myocardium.               Specifically,            it is impor-
MR imaging                  to allow               discrimination                     requisite           for complete               recovery          of                tant to determine                 myocardial              viabili-
between            cases         in which               reperfusion                   ischemic            myocardium                 is recovery           of            ty in a region            that     has been           reper-
of ischemic              myocardium                        is initiated               ultrastructural                integrity          after     20 mm-                 fused.       Detection         of acute         myocardial
sufficiently             early          to effectively                  rescue        utes      of reflow           following            brief      isch-                ischemia         and infarction                with      MR im-
jeopardized               tissue          and cases               in which            emia        (26). This          rapid       recovery          likely               aging       without         the use of contrast                    me-
permanent               damage               persists            after       re-      accounts            for the lack of definable                        ef-           dia is dependent                on differential                con-
perfusion.             This         study          demonstrates                       fects      at MR imaging                   after     30 minutes                    trast     caused       by the presence                 of re-
that an increase                     in SI of irreversibly                            of reflow            and Mn-DPDP                    administra-                    gional       edema         and perhaps              other
injured         myocardium                       after        adminis-                tion      in the current                study.       Further-                      factors,      which          require       several          hours
tration        of Mn-DPDP                       provides              the ba-         more,         this is consistent                 with     an earli-                to develop            sufficiently           to permit
sis for discrimination                             between             re-            er finding             of no difference                 in relax-                  their     detection.           Furthermore,                the dif-
versible          and irreversible                        injury.         The         ation        rates      between           normal         and                       ferential        contrast          is most        evident         on
irreversibly              injured             region            was uni-              briefly         ischemic           dog myocardium                                  T2-weighted               images        (4,7,9,10),           which
formly         enhanced                 immediately                    after          measured              in vitro        following            15 mm-                  require       long       acquisition            times        and
injection          of contrast                 agent,           with       peak       utes of left coronary                      artery       occlusion,                 are susceptible               to motion-related                   arti-
enhancement                     at 15 minutes-a                          pat-         24 hours            of reflow,           and treatment                             facts.
tern     of enhancement                           similar          to that            with       gadolinium               diethylenetriammne-                                 In vivo       studies         showed          that     Gd-
seen      in reperfused                    infarcts            after       4          pentaacetic              acid (DTPA)               (5). Wolfe          et          DTPA        did not improve                   the contrast
hours        of reflow              (11). The higher                        SI in     al (27) observed                  equal        SI enhance-                         between          normal          and infarcted                myo-
the irreversibly                    injured             zone        could             ment         within        the ischemic               and non-                     cardium          after      5 hours       of coronary              oc-
be attributed                to (a) accumulation                             of a     ischemic            regions         after      administration                      clusion       (9) but did make                   it possible           to
higher         concentration                      of contrast               me-       of the        intravascular                 contrast          agent                distinguish            reversible          from        irrevers-


636         Radiology
         #{149}                                                                                                                                                                                                                    June       1990
ible myocardial          injury       on MR images                                             with       and      without             gadolinium-DTPA.                            Ra-       18.   Jennings        RB, Reimer            KA.       Factors     in-
                                                                                               diology      1986; 158:765-769.                                                                     volved       in salvaging           ischemic         myocardi-
of the excised       heart       (5). Tscholakoff
                                                                                         6.    Peshock      RM, Malloy          CR, Buja LM, Nun-                                                  um: effect         of reperfusion            of arterial        blood.
et al (9) found       that occlusive            and re-                                        nally     KL, Parkey        RW, Willerson          JT. Mag-                                         Circulation           1983; 68:25-36.
perfused     myocardial            infarcts      could                                         netic resonance           imaging      of acute myocar-                                       19.   Jennings         RB, Reimer           KA.       Lethal     myocar-
not be consistently             discriminated          by                                      dial infarction:        gadolinium         diethylene-                                              dial ischemic           injury.      Am J Pathol           1981;
                                                                                               triamine      pentaacetic        acid as a marker       of                                           102:241-255.
means     of MR imaging               with    the use of
                                                                                               reperfusion.        Circulation        1986; 74:1434-                                         20.   Reimer        KA.       The relationship              between
Gd-DTPA         in dogs.       However,          de Roos                                       1440.                                                                                               coronary         blood      flow and reversible                and ir-
et al (29) used      the same           agent     in pa-                                 7.    McNamara          MT. Higgins          CB, Ehman       RL,                                          reversible         ischemic        injury.      In: Califf       RM,
tients   and were        able     to distinguish                                               Revel     D, Sievers       R, Brasch     RC.       MRI con-                                         Wagner         GS, eds. Acute            coronary         care:
                                                                                               trast enhancement              of acute myocardial                                                  principles         and practice.           Boston:      Martinus
occlusive           from    reperfused                infarcts                   on
                                                                                               ischemia            using         the      paramagnetic                      pharma-                Nijhoff,       1985; 9-20.
the basis          of substantial                 SI enhance-
                                                                                               ceutical complex  gadolinium-DTPA.                                                 Radi-      21.   McDonagh             PF, Goldman             N, Laks M.             The
ment.        Nonreperfused                    infarction            was                        ology 1984; 153:157-163.                                                                            effects     of global         myocardial          ischemia         fol-
not well           defined.           This     agent       provid-                       8.    Johnston            DL,       Liu       P, Rosen              BR.        In vivo                    lowed       by reperfusion             on trans-coronary
ed differential                enhancement                   for 30                            detection      of reperfused         myocardium          by                                         exchange          during       cardiopulmonary                by-
                                                                                               nuclear      magnetic      resonance         imaging.                                               pass. Microcirculation                  1982; 2:243-270.
minutes           (29), consistent                with        the rap-
                                                                                               Am Coil Cardiol           1987; 9:127-135.                                                    22.   Fishbein        MC,      Y-Rit     J, Lando U, Kanmat-
id renal         excretion             of this contrast               me-                9.    Tscholakoff        D, Higgins        CB, Sechtem         U,                                         suse K, Mercier              JC, Ganz W. The rela-
dium        (10,30,31).            Mn-DPDP,               similar         to                   McNamara          MT.     Occlusive        and reper-                                                tionship       of vascular         injury      and myocardial
Gd-DTPA,               enters         the extracellular                                        fused     myocardial       infarcts:    effect     of Gd-                                            hemorrhage            to necrosis         after reperfusion.
                                                                                               DTPA       on ECG-gated          MR imaging.          Radiol-                                       Circulation           1980; 62:1274-1279.
space       but is cleared                from      the myocar-
                                                                                               ogy 1986; 160:515-519.                                                                        23.   Jennings               RB,         Schaper          J,    Hill     ML,        Steen-
dium        much         more         slowly,        thus       pro-                    10.    Wesbey       GE, Higgins        CB, McNamara             MT.                                        bergen             C, Reimer                 KA.         Effect       of reperfu-
viding         a longer           effective         imaging                                    Effect of gadolinium-DTPA                   on the mag-                                             sion        late     in      the      phase         of reversible                  isch-
time      (“imaging               window”)             after      ad-                          netic relaxation        times of normal            and in-                                          emic         injury:           changes             in cell        volume,              elec-
                                                                                               farcted     myocardium.          Radiology         1984;                                            trolytes,            metabolites,                  and       ultrastructure.
ministration                of the agent             (11,15,17).
                                                                                               153:164-167.                                                                                        Circ Res 1985; 56:262-278.
     In conclusion,                 Mn-DPDP               has a po-
                                                                                        1 1.   Saeed        M,     Wagner              S. Wendland                     MF,       Deru-       24.   Jeremy    RW, Stahl L, Gillinov       M, Litt M,
tential        role in distinguishing                         be-                              gin N, Finkbeiner          WE, Higgins        CB.       Oc-                                         Aversane     TR, Becker   LC.    Preservation         of
tween         reversible             and irreversible                 in-                      clusive    and reperfused         myocardial        in-                                             coronary    flow reserve    in stunned        myocar-
jury     in the reperfused                     myocardium.                                     farcts: differentiation         with Mn-DPDP-en-                                                    dium.    Am J Physiol    1989; 256:H303-H310.
                                                                                               hanced      MR imaging.         Radiology       1989;                                         25.   Reimer             KA,        Jennings              RB,      Tatum           AH.           Pa-
Irreversibly              injured          myocardium                is
                                                                                               172:59-64.                                                                                          thology       of acute         myocardial         ischemia:
visualized             as a region            of hypermnten-                            12.    Selye H, Bajesz E, Grasso            S. Mendell        P.                                           metabolic          function        and ultrastructural
sity that can be distinguished                                 from                            Simple     technique      for the surgical        occlu-                                            studies.      Am J Cardiol             1983; 52:72A-82A.
the less enhanced                       normal        and revers-                              sion of coronary        vessels     in the rat. Angiol-                                       26.   Shaper      J, Mulch           J, Winkler       B, Shaper       W.
                                                                                               ogy 1960; 11:398-407.                                                                               Ultrastructural,             functional        and biochemi-
ibly injured              tissue.        Thus,      this agent
                                                                                        13.    Sievers    RE, Schmiedl         U, Wolfe     CL, et al.                                             cal criteria        for estimation           of reversibility
or similar           agents          may      be useful           in as-                       A model of acute regional              myocardial                                                   of ischemic          injury:      a study      on the effects
sessing         the viability               of jeopardized                                     ischemia            reperfusion                    in   the     rat.     Magn                       of global        ischemia         on the isolated           dog
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                                                                                        14.    Vivaldi      MT. Kloner       RA, Schoen         FJ. Tn-                                      27.   Wolfe      CL, Moseley             ME, Wikstrom              MG, et
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Volume           175         Number
                          #{149}                  3                                                                                                                                                                                                         Radiology                        637
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