JACC Vol. 27, No. ‘7 June 19964577-85

1577

MYOCARDIAL ISCHEMA

Myocyte Degeneration and Cell Death in Hibernating Human Myucardium ERNST R. SCHWARZ, MD, JUTTA SCHAFER, MD,* JUERGEN VOM DAHL, MD, CARSTEN ALTEHOEFER, MD, BEATE GPOHMANN, TA,* FRiEDRICH SCHOENDUBE, MD, MS, FLORENCE H. SHEEHAN, MD.t RAINER UEBIS, MD, UDALRICH BUELL, MD, BRUNO J. MESSMER, MD, FACC, WOLFGANG SCHAPER, MD,* PETER HANRATH, MD, FACC Aachen am-l Bad Nauheim, Germany; and Seattk, Washington

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O&etives. Tbe aim of this study wns to analyze the morpho- logic characteristics of myocyte degeneration ieadiag to replete- q eot ftbrosis in hibernating myocardium by use of electron microscopy and immunobistochemkai tecimiques.

Baekgtwmd. Data on tbe uitrastructure aad the cytoskeieton of

or deiayed tkmctionai recovery might be due to a variable degree of cardiomyoeyte degeneration in hiberaating mywardium.

Me&oak In 24 patients, regionai waii motion abaonuaiities were analyzed by use of the cwtteriine method before and 6 f 1 months after coronary artery bypass surgery. Preoperative tecimetium-9Pm sestamibi uptake was measured by singi~photoa emission computed tomograpay for assessing regjonat perfkufion. Fiuorinel8 Buorodeoxvvu~se uptake was measured by positron emission tomography to assess giwose metabolism. Transmwal biopsy specimeiii were taken during cownary artery bypuss surgery tkom the center of the hypocuntrac4iie aRp of the anterior wuii.

Resuk. ‘lRe myocytes showJ varying signs of mild-to-severe degenerative changes and an increased degw of tlbrosis. Immu-

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Long-term reduction of coronary blood flow is associated with reduced contraction and altered cellular metabolism but with improved or normalized regional dysfunction after successful revascularization, termed myocardiul hibernation (l-3). Im- provement of wall motion in hibernating myocardium can be achieved by coronary revascularization hy either angioplasty (4-7) or coronary artery bypass surgery (8 -1 I). Preoperative metabolic imaging hy positron emissnn tomography has rc-

etai proteins titia a& aipita-actinin. Eiectroi microsc&of the ceil organeiies and immunoldetochemlral aaaiysis of the eytasimi- etonsbowedasimilarityintbedegweofd aiteNuone. Group 1(0 = 11) replusellted patients with ouiy aliuor atrucwai dterations, whereas group 2 (II = W) showed severe morpitkgk degeuerative cboges. Wall motion abnormalities shrewd pastup emtive improv~ets, and msdaar imaghg mealed a per&&m metabolism mismatch wit&out signllkmt di&- between the PUPS.

tbe siveti&of morpi&gk nor the functionai outcome ailer revawkktbm. IBe insu4k dent aet ot wifqresefvatloa ia hibernating myocaniinm aiay lead toeprolyesbivcStnrttUrsidcOMDlPUoaattb~ttlrumpletePaJ detayfd reawery of function nfter rmtorntion of bioad flaw.

(JAm Cop Cd&d 1%36;29:1599-83

ccntiy been shown to predict recovery of regional wall motion and \hus maintain mykardiai viability (4,9,12-14). That con- tractile tunction can resume rather quickly (15) or can be delayed after blood flow has been restored indiites a time dependence of structural remodeling to rebuild energy stores and cellular contractile material (16). Histologic studies are scarce and show moderate morphologic alterations and a slight increase of connectke tissue (17-U). In the present study, morphologic characteristics of myocardiai hibernation were sassed by electron microscopy and immunohistochemical techniques.

MethOdS Patids. Twenty-four patients (21 men, 3 women; mean

[-SD] age 60 2 8 years, range 43 to 71) underwert coronary angiography and biplane ieft ventricular angiography. Patientb prospectively recruited fulfilled the following inclusion criteria:

1578 SCHWARZ ET AL. STRUCTURAl. DEGENERATtON IN tllRF.RNATtNG MYOC‘ARI~IUM

JACC Vd. 27. No. 7 ,““a’ 1996: 1577-t@

1) anterior wall motion abnormiilities; 2) stenosis (>7OQ) or occlusion of the left anterior descending coronary arlcry; 3) angina pectoris symptoms and objective clectrocardio- graphic (ECG) criteria for ischemia at rest or during exercise: 4) clinical indication for coronary revascuiarization; 5) coro- nary anatomy suitable for coronary artery bypass surgery; 6) persistent R waves in the anterior leads of the ECG; 7) absence of any history or ECG changes for previous anterior transmu- ral infarction; 8) evidence for reduced perfusion but main- tained viability of the anterior wall by nuclear imaging.

The study pro!ocol had been dpproved by the institutional ethical review board, and patients gave written informed consent before participation.

Coronary and left ventricular ao&,rapby and regional wall mation analysis. Cardiac cathelcrization was performed by use of Judkins technique, and angiograms were recorded on 35mm tine lilm with SO frames/s for further quantitative analysis. Left ventricular angiogrlphy at baseline and at follow-up was obtained ia the 30” right anterior oblique and 6cp left anterior oblique view using 40 ml iopamidol (612 mg/ml) injected at 15 ml/s. Quantitative analysis of the ventriculograms, without knowledge of clinical or nuclear data in randomized order, was performed at the Cardiovascular Training and Research Center, University of Washington, Seattle, Lashington. Left ventricular volume and global ejec- tion fraction were calculated by the area length method (24). Regional wall motion in the distribution territory of the left anterior descending corona? artery was analyzed from the right anterior oblique projection using the centerline method and is expressed in units of standard deviation of the normal mean (25,26). Wall molnm was computed as the mean motion of chords lying in the mos1 abnormally contracting region (Icft anterior descending coronary artery center), whcrcas wall motion of the remaining left anterior descending coronary artery territory was deIined aa left anterior dcxcnding coro- nary artcry pcriphcry.

Nuclrrrr irn&rg. Nuclear imaging of myocardial perfusion and mclabolism followed standard promcols at our institution (27.28). Imaging was performed 2 z 2 weeks after coronary angiography and 2 + 2 weeks before bypass surgery.

Single-photon emission computed tomography (SPECT). Pa- tients were studied at rest after injection of 10 mCi of technetium (Tc)-99m sestamibi (Cardiolite, DcPont). Imaging was initiated 1 to 2 h later after a light meal to reduce gastrointestinal activhy. Data were acquired using a Gamma- uuucs KO’l A double-head cnmora (Siemcns) equipped with a low-cncrgy all-purpou: collimator allowing a simultaneous Ml” rotation (18(P for each camera head) with 2 X 30 steps 01 (i’ each. TranUxial slices (h.?S-mm thickness) were recon- \trucIcd using :I Rutterw~~rth liltcr third order and a cuboff frcyucncy of 0 5 on a MaxDelta computer 5ysIcm (Sicmcnc. Gcrmanyl.

Posirnm emi.uictn rc~nic*+~ A transmission an wita pc;formcd bcforc metabolic imaging to correcI for tissue phoIon rt1muation u&g a retratiabk germanium-611 wurce. After oral glunne loading with 50 g of CxIrcx~, 6 to I mC‘i of

: 22

B. RCA

Figure 1. The “polar target” of the left ventricle from apex (center region. I) IO base (outer circle region, 4). The upper part represents the anterior wall, the lcrwer part the posterior wall, with the septal lefI and the lateral wall of the left ventricle at the dght side. Regional uptake of technetium-99m sestamibi by SPEC.. and fluorine-M Iluoru- deoxyglucosc by positron emission tomography was exyl<ssed as percent to the rrgion of maximal perfusion (100%). For this study, only data in the Icfi anterior descending coronary (LAD) territory were assessed with exclusion of Ihe scptal region. RCA = right coronary artery; RCX 7 circumflex artery.

fluorodcoxyglucose (Department of Radiochemistry, Nuclear Research Center, Juelich, Germany) were injected intrave- nousiy as a slow bolus. After the tracer was injected, static ungated imaging was initiated 30 tn 45 min using an ECAT 953/15 scanner (Siemens) and lasted for 30 to 40 min. Because of the one-block ring configuration of the scanner providing 15 transaxial slices over a S-cm field of view, at least two adjacent bed positions were necessary to cover the entire heart. Trans- axial images were reconstructed with a Hanning filter (cutoff frequency 0.4) in a 64 X 64 matrii and a defined zoom factor of 1.2446 to ;lbtain the same in-plane pixel size m the conespondine S?ECT images. Consecutive pairs of positron emission tomographir slices were combined to achieve an identical axial pixel size for positron emission tomography and SPECS imaging.

An&k of SEC’T imaging and posittvn emission tomo- gaphic data. The tramaxial positron emission tomographic image files were converted to the str’;cturc cI’ the SPECT imaging files and transferred to the MuDelta sys!:m using a local area network. Regional Tc-99m sestamibi and F-18 lluorodeoxyglucose uptake were expressed in percent of the uptake in the region with maximal sestamibi uptake (27) (Fig. I). A concordant sestamibi reduction <SO% and fluorodeoxy-

glucose uptake <5(14/n was defined as a scar, whereas reduced scstdmibi upldkc but preserved fbJorodeoxyglucose activity (270%) rcprcscntcd a perfusion/metabolism mismatch (28).

Coronary revascularizatioa. Coronary artery bypass sur- gery was performed by use of sIandard techniquei under cardioplcgic condibon with internal mammary anery grafting to the Icft anterior deycnding u)ronary artely, Surgeons attempud to perform complete rcvasculariition if Iechnifally feasible. The interval between coronary angiography and sur- gical revascularization WIZI 4 2 2 weeks.

MydardU biopsy ssapiing. Trammural needle biopsy qxhnens weve ubtailm; during coronary artery b sur+

JACC Vol. 27. No. 7 Jane 1996~1577-85

SCHWAB2 ET AL. 1579 Sl’RllCTURAL DEOENERATION IN HIBERNATINO MYOCARDIUM

Table I. Morphologic Group Characteristics

Group I (n = II)

Qmup 2 (n = 13)

Conlrwtilc mat&l Number reduced Number and nomMl pattern severely altered

Titin and alpha-actinin Slightly reduced Significantly reduced

t-tubular system Normal Dilated Shape of nuclei Normal Invaninations.

itclnaions Si of nuclei Normal Enlarged Milochondria Majority normal Anercd sire, cristac

red&on Gl&TlgClt Modcat amounts large amounts Vacaola; myelin figures, Chxasional tindinga Overall increased

lipofoacin. fat droplets Fibrotic tissue Modestly enhanced severely augmented

(al%) Pm)

Group 1 = patients with only minor degenerative changes: (iroop 2 = pattents with severe dogenerativc deterioration of the cell architecture.

gery using a Tru-Cut needle 2N 27004T (Travenol Laborato- ries, Inc.). The region of iuferest for the intraoperative biopsy sampling was preoperatively defined from left ventricular angiograms. Two biopsy specimens per patient were taken with a total wet weight of 10 to 40 mg after the heart was suspended in a pericardial cradle and just before induction of cardiac arrest by cardioplegic solution. Biopsy specimens were taken only from the center of the wall motion abnormality.

Tissue prepamfion for elecfmn microscopy. Each biopsy specimen was divided into a subendocardial and a subepicar- dial part and wi tired in cold 3% glutaraldehyde in cacody- latebuger (pH 7.4,400 mCkm). After immenton fixation, the biopsy specimens were washed in cacodylatebuffer 0.1 M plus sodium eaeodylate, 7.5% saeeharose, pH 7.4. The samples were embedded in Epon after lixation in 2% osmic acid tetroxide and were dehydrated in ethanol plus substitution by propylene oxide using an automatic tissue processor. Thin sections (50 to 60 nm) were studied by electron microscopy.

Tksue pwpamtkm for immunohisbchemical analysis. For immunohistochemical analysis, the second tissue biopsy spec- imen was immediately frozen in liquid nitrogen and stored at -80°C. Cryostate sections of 4-gm thickness were prepared, fixed in acetone and incubated in the first antibody-either titin T12, alpha-actinin (Stgma) or collagen VI (TeliosKlon A 112)--for 45 min. The second antibody, biotinylated goat antimouse or donkey antirabbit (Amersham). was then applied for 45 mitt; and finaily, fluoresceinisothiocyanat-labeled streplavidin (Amersham) was added. The sections were mounted in Mowiol (Hoechst) and studied using a Leii Aristoplan microscope equipped for fluorescence microscopy.

Motphom&i~ ana&s. ‘Sk degree of fibrosis was deter- mined by moqhometric techniques using the point counting method (29). Values are indiited as percentage of the whole hii tissue.

DeflnlBon ol the patfeat groupa. Patients were ntrospec- tively divided into two groups (Table 1) depending on the results of the morphologic analysis and on the degree of structural degeneration. Group 1 (n = 11) represented pa- tients with only minor ultrastructural changea, a normal or near-normal shape and size of intracellular organeh ordy slightly reduced amounts of contrac& material and a modest occurrence of fibrotic tissue. In group 2 (n = 13), patients showed severe. ultrastructural signs of degeneration, incmaned amounts of abnormal intracellular particles, signigcttntly re- duced and altered myolilaments and an incrensed degree of fibrosis (>30%).

Statletical analysis. All values are expressed as mean 2 SD. Statistical comparisons were made using the paired Stu- dent I test. A p value CO.05 was considered statistically significant.

Results Patlent data and dioieal follow-up. All patients had mul-

tivessel disease (21 triple-vessel, 3 double-vessel coronary artery disease) with a signiticant left anterior descending coronary artery stenosis (>70%) or occlusion. No ditTerences were found between the two groups concerning demographic and clinical data. Preoperatively, all patients had severe angina and belonged to class HI or IV of the Canadian cardiwaxuler Society (CCS) classification. At &month follow-up, angina in all patients lessened at least by one CCS grade. Symptoms of heart failure also lessened substantially at fallow-up. Accord- ing to the New York Heart Association classification, 10 patients had only mild preoperative symptoms (class II), whereas 14 patients were in class HI or IV. After coronary artery bypass surgery, all patients were either asymptomatic or in class I or II. Functional outcome did not differ between the hvo groups.

Morphalegy. The location of a small metal clip, intraoper- atively sutured at the side of tissue sampling, was compared with its location at follow-up angiog.raphy with the regional wall motion abnormality at baseline angiography and demon. strated good agreement between the biopsy locatiott and angiographically defined dysfunction.

E/ecrroa micnxco~. Viable myocytes were found in all biopsy samples born the dyscontractile regions. There was no evidence for previous transmural infarction. The cardiac myo= cytes, however, showed signs of severe degeneration with loss of myotilaments, occurrence of cellular sequestration, de- creased sires of mitochondria and cellular debris. An increased degree of extracellular fibrosis was present (Fig. 2 and 3). Ihe myayte nuclei were abnormally shaped and sired and dis- played cymplasmatic inclusions or the occurrence of fine filaments. The mitocbondria had a different appease many were small: and some showed a reduced number of cristae. Other abnormalities, such as presence of glycogen deposits, fat droplets. IipofmGn and degenerative vacuole& were common.

/mmu&ruc#remtiu/ u~lysts. Fitin and alpha-actinin staining was used to study alterations of the contractile appa

1580 SCHWARZ ET AL !STRtJCtlJRAL DEGENERATtON IN HtBERNATtNG MYOCARDIUM

Fl~ure 2. A, Lack of contractile material in a peripheral part of a myccyte fiiled with giycogcn (GL). The cxtraccllular space is widened and contains maniphages (M) and cellular debris (CD). An endothe- ha1 cell is present in the upper part (End). X2,9tlO, reduced by 35%. B, Alterations of a cardiomyocyte in hibernating myocardium. The con- tractile material (CM) is diminished and replaced hy nonspecific gtoplasm (NCj, and the nucleus (N) exhibits a multilobular shape. ~4,300, reduced by 35%,.

ratus of the cardiomyocytes. These prfncins closely connect with myosin and artin, respectively, and represent changes of the myofiltamcnts. The most obvious finding was the loss of strxturcs representing these contractilt proteins, which con- firms the ultrar;tructt~rai findings of myofilament reduction. Thcsc dciccts WC of different degrees of severity, and the citanges were graded as either slight or severe (Fig. 4 and 5). The occurrence of small parts of atrophied cells or of cellular debris could also be demonstrated by staining for these intra-

JAtX Vat. 11. No. 7 June 19%:tS77-63

Fi~trre 3. A, Sequestration of cellular particles (CP) hum myccyms into the extracellular space, leading to final atrophy of the cefls. X21.500, reduced by 35%. B, Atrophied cardiimyccyte containiig minimal amounts of contractb material (CM), abnormal mitochon- dria and multiple vacuoles. The cellular debris is surrounded by fibrotic material. ~6,450, reduced hy 35%.

cellular proteins. Staining for collagen VI was used as an indicator of the degree of fibrosis. The degree of fibrosis also was graded as slight versus severe alterations (Fig. 6).

Morphomerry. The amount of fibrosis, as assessed by mor- phomettic quantitative analysis, was 21 2 9% in group I compared with 45 C 15% in group 2 (p < O.O!Q In both groups, the occurrence of fibrosis was significantly higher in the subendocardial than in the subepicardial specimen (36 f 17% vs. 22 2 II%, p < 0.05).

Loss of contractile material and the severity of fibrosis assessed by immunohistochemical staining paialfeled the de-

gree of degeuerative changes detected by electron w in each patient. Those patients with most severe ultra&u&& alterations diiyed most degenerative changea when irnnm- nohistochemical stainiig was used, indicating a good correla- tion between both methods.

AngIqm@e results. Seventeen of 24 patients (71%) bad significant left anterior descending coronary artery stenosis (>70% dieter reduction). The remaining seven patients (29%) had total occlusion of the left anterior descending coronary artery with angiographii visible collateral chan- nels. Baseline ejectiin fraction was 44 2 12% (range 26% to 59%) All patients had hypokinesia or akinesia of the anterior wall including the septum and apex (Table 2). The severity of coronary stenosis did not correlate with the ultrastructural tindings. In particular, those patients with occluded vessels dii sslwmeres. sevenil cell8 are hylxm+M (uppsr I& earn@; othsrs

not demon:trale more severe degenerative chunges or more are slender snd atrophied (hmw part). X530, wx&uJ by 3Q9b.

disruption of the q&skeleton. Also, the severity of wall motion abnormalities neither correlated with the angiopaphic degree stenosed left anterior descending comaary artery (n = 17, of stenosis nor with structural changes. sestamibi uptake 55 f. 5%) and for those with left anterior

Twenty of 24 patients (83%) had follow-up angiography 6 ? descending coronary artery occlusion (n = 7, sestamibi 1 months after coronary artery bypass surgery. Postoperative uptake = 50 t 7). Quantitative assessment of the nom&zed ejection fraction (Table 2) improved in all patients from 44 2 positron emission tomographic data showed a mismatch be- 12% to 54 t 9% (p < 0.05). Wall motion abnormslrty in the tween perfusion and metabolism in all patients in the anterior left anterior descending coronary artery center improved from wall. Average F-M dcozzyglucose uptake in the anterior wall -2.1 t 0.7 to - I.3 t 0.6 (p < 0.05) (Fig. 7). liuvx?e:, the measured 87 t II% in group I and w( t 9% in group 2,

degree of functional recovery at folhnv-up did not correlate indicating persistent viability (Fig. X). with the ultrastructural Rndings.

N&ear per&lw and metabolism imegbg. Nuclear im- aging did no1 reveal significant differences between the two Disclassioa groups defined by mdrphologii alterations. Al! patients had lhe presented results indicate that myocardirl hibema- perfusiin defects in the anterior wall &oup 1: 54 + 6%; group tion--defined from postrevascularization functional recovery 2: 56 f 6%) without a significant difference for those with a of previously dyscontractile myocardi~m and fmm preopera-

1582 scHurARzmAL J9CC ht. Z7, No. 7 StWJCPJUAL DEGENERATtoN IN HI&RNATl?VG MYWAJCDfUM J,ISG 1%1571-85

isticf~nrl.x210,reduced$~.B,Asignifican~~ amount of dagen M is bxawd between myocyts. separating them fmn each her. This is a severe alterauon. asrb atvzm represer!~ myoqtes in both A and B. X2iO. reduced by -XX%.

tive viability imaging-47 not represent a uniform morpho- logic appearance.

Vittias degrees of degenerative changes and loss of con- tractife mar&al were associated with similar preoperative perfusion and metabolic alterations and functional outcome Gter restoration of blood flow Even in patients with severe structural abnormalitb. fucctiona~ reccwery can be achieved if the myocardium is still hibernating. On the other hand. fxtctional abnornutities do not dist@#sh .between moderate and severe degenerative alterations of the ~myocardium as proved by histologic and immunohistochemical analyses.

In the prtveot study. al! patients with S~KXW$UI reu~~&~ izatioo of the left anterior dex-ettdii curona@ artety showed preopmtiw wall mu?& abnormalities red& corcma~ MiP:ti Rtlw !%I g!mii.!ent glucuce lq9take and functitmf reSzu -

cry after revascu&zation. One group of patients demott- stmted only slight or moderate ‘;legelnrative alterations and Ggbtlyredttcedcontmetileproteitts,ttorn3lc&htlarorganelies andthepreseaceofottlyamoderate&greeoffibro&Inthe siecmd group of patients, severe scmchd 3lcer3cions were present including degenerative changes of the myocytes, atrcF phy, occurrem of sequestered cefb~Iar particks. severe d&r- ganizttiot?ofthecytoskektottwithdareasedanttractikpro- CC&S its the extraceUular space and the presence of more were filwok

Compared with previo&y published studies on morph &+c changes itt tnyoca&i hibematiott (18,22,23), the prrsent tudytid 3ppro3ch classifies for the first time, patiettii into two gtwps depending on the morphologic t?ttdittg~ ?ltzse

died a varied a&.lpmeofstnacturaldeZewm- p3rtiedar myocardii area with regio4 hypAine&.

Because the dieraces in structutal a g3peameoftbe’biopsy spechneos were M that is. .& morphologjc appear- atsee or slight v5sus severe alterations, the dii into two group seemed reasottabk.

Tltent@important6ttdittgwasthataUbiopsyspxirnetts showed signs of long-term degener4tioo, most pro&My due to isdtem&witbolxeviderKeoftransmttralinfaretion.~,

malities of long-term hypoperfused myoaxdittm catt be presentinthe3hsettceofseveretisattein~.lR~~ the adaptation process, as d&ted in the earlier dexriiptiom, is sumparable with the situation of short h&em&ion known from animal experiments (3031). Active downregttlatiott of tbr contractile function due to a dowttregulation of myocardia! oxygen consumption (3.2) may txstu in these patiertt~ and probably represents the early stage of bibemation. This em cas may invoive repetitive stunning. but this is 3hnost irr+- sible to clarify in the human heart. Mjofilamettts are stiff present, but they are not active iii cotxtractiot~ This promo might invotve altered Ca’ ’ i!uxes or potassitmt pomp activity (33). It is 3fso possible that in fmt&mally &~~~~gttkted tnyxyia mRNA smtheslr rate for cortttactik proteitts is nu ch iower than that in ttotmJIy contracting mychytes, as was shrnvn in vascular smooth muscle cells (3-Q which may kad CO

changes in contra&e ptoteitt enzyme activity (35). The more severe structmal alteratitnts in the -xcottd grwp

may represent 3 more advanced stage of the disease. that is. a partial e.xhau&on of the celtular adaptatixt causing hiherna- tion and the occurrence of degeneratiott and final ccl death. to contrast a recent study by Flameng and Siv3lkx (36) de- wrihed end-stage hibet-tutiott LT pat&a without fuoctional receve~ after revassh. Howe~cr, strttetttraf and fmtc- iiod end st3ge ofchmnic i!s&emi3 3&l the Lxan cirwpch of no return of fun&m du+z :c :he kxss of dowttregtdatiori capacitks may owrbp an! canm* be dishpished by iltdiml imaging rL*nyues

JACCVd27.NO.7 YHWARZETAL 1583 k 199&15~-85 !3lRUCtLX4L DEGENERATION 1% AIBERNATlK MW3CARVtUM

fuxtion (4.40). If so. hibem :tiq myocudium may represent an adaptive press itlsupicient to maintain all integrity for the entire bgopfmd mywardium. ?U all myswdial celk can survive. and ftmchd recovery is partially incomplete or delay4 or huh.

Thatpat.ientwithslightnrorphQlogicchangesakoshowd ordyprtialreaweryofxgimalfimtionsupportstiKexis- teup of diCerent states of longterm Apt&ion in the same heart. Long-term otmvations may result in further reuwer)l as it has heen ckwr&xd by serial evaluation after either c-v -9 (4) of coronary artery bvpass wrgel?r

1584 SCHWARZ ET AL. JACC Vol. 27, No. 7 STRUCIIJRAL DEGENERATION IN HIBERNATING MYOCARDIUM hne lw6:1577-85

(40). However, evahtation of the time-course of this degener- ation was not part of this study design and may vary substan- tially among patients.

The findings from transmural biopsy specimens did not demonstrate .my predictive power for a therapeutic strategy. Furthermore, nuclear imaging techniques cannot distinguish between mild and severe structural damages in dyscomractile but viable tissue.

!3ndy limitations. Our data were obtained from a rela- tively small number of patients with evidence for hibernating myocardium. Owing to logistic redsons, Iye were not able to provide data on absolute myocardial blood flow without an on-site cyclotron. However, from the clinical point of view, perfusion imaging using Tc-9% sestamibj in combination with semiquantitative SPECT imaging analysis is a widely accepted method (41).

Conelnsfons. The protective mechanisms of hibernating myocardium seem to be insufficient in the presence of persis- tent underperfusion or with the occurrence of multiple isch- emit episodes. Cardiac structure deteriorates, finally leading to cell death and fibrosis. This seems to he a progressive and probably time-dependent process or may even reflect different conditions of the myocytes. Thus, early coronary revascular- ization might be the only therapeutic strategy that could avoid structural degeneration or that could even result in functional and morphologic restitution.

We &dtdty acbm’dedge the helpful comments of Bharati Shivalkar, .MD, university of Lcwen. Belgium.

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