JACC Vol. 22. No. .
: &pplement A)
October 19!&99A-105A
Viral Myocarditis: A Paradigm for Understanding the Pathogenesis
and Treatment of Dilated Cardiomyopathy
MICHAEL J. SOLE, MD, FACC, PETER LIU, MD, FACC
Toronto, Ontario. Canada
Althoughan etiologiclink betweenviral myocarditisand idio-
pathic dilated cardiomyopathyhas long been recog&ed, the
actualextentof this relationhas beenuncertain.In this review,we
examinerecent developmentsin the molecularanalysis of endo-
myocardii biopsy specimens, particularlytechniques for gene
amplification,which have unequivocallyconfirmedthis relation
and given us some insight into its significance.In addition, we
show that viral myocarditisin a murine modelis associatedwith
spasm of the coronary microvasculature,leadii to myocyte
necrosis,fibrosis,calcificationand cardiacdilation.Theselindiigs
are similar to those seen in the hearts of gene&ally cardiomyo-
patbichamsters,ratsand humanswith hypertensionand diabetes,
rats after acute brain injury and modelsof Cbagasdii.
Treatmentof microvasc~d~spasm with verapamil,captopril
Idiopathic dilated cardiomyopathy accounts for approxi-
mately 25% of the in,idence of heart failure in North
America. In contrast to the remarkable progress we have
made in the diagnosis, prevention and treatmeut of other
major etiologies of heart failure, particularly coronary artery
disease, rheumatic heart disease and hypertension, we have
had little progress in the diagnosis of early cardiomyopathy
rnd treatment has been essentially palliative.
Several investigators (l-3) have noted a possible link
between dilated cardiomyopathy and preceding viral myo-
carditis. Some patients with viral myocarditis have later had
chronic myocardial dy&mction; conversely, patients with
dilated cardiomyopathy have often related a history of an
antecedent flu-like illness (3). The estimate of the overall
incidence of viral myocarditis in dilated cardiomyopathy has
varied widely but appears to be = 10%to 20%.These studies
have rekindled an interest in viral myocarditis, which had
come to be regarded as a form of heart disease with
relatively minor public impact. This interest has been stim-
From The Centre For CardiovascularResearch, University of Toronto.
Toronto, Ontario, Canada.Dr. Sole is a DistinguishedResearchPmfessorand
Dr. Liu a Research Scholarof the Heart and Stroke Foundation of Ontario,
Toronto. These studies were supported by grants from the Heart and Stroke
Foundation of Ontario, Tne Medical Research Council of Canada, Ottawa.
Onzn; Kngdli~mrmaceuticals, Markham, Ontario and Searle Canada Inc..
. in Dallas and agreed on the pathologic criteria necessary to
ManLscriptrkived September 13. 1992;revised manuscript received
January 28,1993, accepted February 7.1993.
&tdress for e: Michael J. Sole, MD, EN 13-208.The
Toronto Hospital, 200ElizabethStreet, Toronto. Ontmio, Canada MSG2C4.
01993 by the American College of Cardiology
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99A
or alpha,-adrenergicblocking agents appears to interrupt this
patb~ay and has been shox to markedlyimpede the evolution of
dilated cardiomyopathyin the genetic hamster model and a
murhie model of qyocarditis. There is some sugge&m that
digital& though benefidalduring cardiac decompensaG~,may
actuallybe detrimentalwhenadministeredduriog the earlystages
of myocardial disease. Thm experiments have led to a new
paradii for the pathogenedsof cardiomyopathyafter viral
qyocarditis,as well as a generalbypotholrisfor the pathogenesisof
sometypesof diited cardiomyopathy.They also suggestthat the
selectionof therapeuticagents for some forms of diited cardhk
myopathy may differ signilicantly between the early and late
stagesof the die.
(J Am CoilCardi 1993;22[Suppii?meM Ajt99A-IOSA)
ulated further by the development of immunologic and
molecular tools for the investigation of viral disease and by
the establishment of a National Institutes of Health-
sponsored trial examining the efficacy of immunosuppres-
sive therapy for patients with viral myocarditis.
In this report we describe a sensitive technique using
recombinant deoxyribonucleic acid (DNA) technology for
the diagnosis of viral myocarditis and unequivocally estab-
lish a link between viral myocarditis and some cases of
dilated cardiomyopathy. In addition, we show that viral
infection of the myocardium leads to spasm and reperfusion
at the level of the coronary microcirculation, resulting in
myocardial necrosis, fibrosis and calcification. Treatment of
this microvascular spasm with some specific vasoactive
agents appears to interrupt this pathway, precluding the
evolution of chronic heart disease. Finally, we generalize
these findings to present a contemporary view of thepatho-
genesis and treatment of dilated cardiomyopathy.
Diagnosis
Until a few years ago, an assessment of the incidence of
myocarditis or its relation to dilated cardio,;E;jropathy
was
problematic because of the absence of a uniformly aC=Pt@i
diagnostic standard. In 1984,a group of pathologists (4) met
establish a diagnosis by endomyocardial biopsy. The diag-
nosis of active myocarditis required an inflammatory infil-
trate (lymphocytes) with necrosis, disruption or damse of
0735.10!47/93/55.00
 SOLE AND LIIJ
1OOA
VIRAL MYOCARDITIS AND DILATED CARDIOMYOPATHY
adjacent myocytes. Wide acceptanceof the Dahas trite-
ria markedlyimprovedcomparisonof data among Idma-
tories amI alloweddevelopmentof multicentertriak ih~
ever, sign&ant inteobserver variability remained with
respectto interpretationof biopsy specimens.For example.
inexperiencedpathologistsmay misinterpretcrush, tea&
fixation or sectioningartifacts as myocardiil necrosis or
fibrosis. Furthermore,myocarditisappears to be a focal
disease,withpatchesoflymphocyte inllltrationand myocar-
dial necrosisinvolvingperhapsonly 5%of the myocardium;
thus, the likelihoodof establishinga diagnosisdependson
the numberof biopsy specimenstaken (5.6).Finally, Iym-
phocytic infiltrationalso may be seen in immunologicor
granulomatousdisease, drug-inducedhypersensitivityor
even in normalspecimens(7-9).
hybridization studies. In the last severalyears, the mo-
lecular structureof the viruses usuallyresponsiblefor the
etiology of viral myocarditishave been reasonably well
characterized(10-12).The familyof enterovirusesappearto
be the major pathogensresponsible,with HO% of human
cases attributed to coxsackie B virus (13).These viruses
have no envelopeand their genomeis encodedby a single
strand of ribonucleicacid (RNA). Thus, it appeared that
hybridizationstudiesdesignedto detectviralgenomicmate-
rial in endomyocardialbiopsyspecimensmay be fruitful.
The IIrst demonstrationof a viral signal in myocardial
tissue using molecularhybridizationwas reportedby Zahr-
inger et al. (14) in reovirus-infectedbaby mice. Subse-
quently, the successfulanalysis of humanendomyocardla!
biopsyspecimenswas reportedby Kandolfet aI. (IS) using
in situ hybridizationand by Bowles et al. (16). using a
radiolabeledprobederivedfrom a coxsackieB virus cDNA
clone and slot blot methodology.These investigatorswere
able to demonstratea viral signal in patients with dilated
cardiomyopathyand no demonstrableinflammatorydisease
on biopsy and thus conIIrmedthe clinicalimpressionthat
viral myocarditiswas a precursor to dilatedcardiomyopa-
thy. Furthermore,the study of Bowleset aI. (16)and its
subsequentextension(17)suggestedthat the frequencyof
coxsackievirusin humanpatientswith either myocarditisor
dilatedcardiomyopathymay be as highas 50%.
If coxsackievhusaccountsfor approximately50%of all
cases of viral myocarditisand approximately50% of the
cases of dilatedcardiomyopathyexhibitthe virus, does this
meanthat almostall casesof idiopathicdilatedcardiomyop-
athy are viral in origin?An examinationof data fromBowIes
et aI. (16)reveaIedthat their viralprobehybridized,although
with dilferentintensities,to all samplesof myocardid RNA
examined.To interpretthe results, the hybridizationsignals
on slot blot, usingthe coxsackievirusB probe, were com-
pared by densitometrywith those obtainedfor the same
sample with a cDNA probe for the ubiquitous cellular
Protein beta-tubulin.Samples that hybridizedmore than
twice as stronglyto the viral probe werearbitrarilyconsid-
ered to be positive.The cDNAprobe used in the study of
Bowleset aI. (16)was said to be specificfor coxsackie-
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JACC Vol. 22, No. 4 (SupplementA)
October 19939!JA-105A
viruses;however,becauseonly short regionsof the coxsack-
ievirusgenomeare conservedamongdifferentserotypes,the
developmentof such a universal coxsackieviruscDNA
probedoes not appearpossible.
Initial studies in our laboratory,using similarmethodol-
ogy and biopsy specimensfrom patients with hypertrophic
cardiomyopathy and other nonmyocarditic conditions,
showedpositivesignalsof varyingintensityin all specimens
examined,confirmingcross-hybridizationbetweenviral and
humangenomicsequences.No signalswere detectedwhen
highly stringent conditionswere used (18).Thus, another
approachto moleculardiagnosiswas necessary.
Thepalymerasechainreaetlontechnique. Thistechnique,
whichresultsin the rapidgeometricreduplicationof specific
DNAsequencesof interest (19)is ideal for the analysisof
smallbiopsy specimensin which low copy numbersof the
viral genomemay be present. Using the polymerasechain
reaction. our laboratory analyzed the endomyocardialbi-
opsy samplesfrom 48 patients presentingwith idiopathic
dilated cardiomyopathyof recent or acute origin (18). In
these studies, we used short synthetic DNA sequences
designedto be complementaryto cDNAsequenceshomol-
ogousamonga broadrangeof enteroviruses,particularlythe
coxsackieviruses,whichappear to be the etiologyof most
casesof myocarditis.
Fiveof our 48 patientsdemonstratedpositiveenteroviral
signalsusing the polymerasechain reaction and high strin-
gency;hybridizationsignalsdid not showa gradedresponse
but wereeither positiveor negative.Two of the patientshad
myocarditisby the Dallascriteria, whereasthe other three,
althoughtest results werejudged Dallas-negative,had a
very compatiblehistory. In one patient whoseinitialbiopsy
result was positive by both the polymerasechain reaction
and Dallas criteria, we obtained 6 months after the initial
analysis a repeat biopsy, in which the polymerasechain
reactionfindingswere still positivewhereashistopathologic
findingshad alreadyturnednegative.In anotherbiopsyat 1
year the polymerasechainreactionresultsalso had become
negative.
These studies strongIysupport the hypothesisthat viral
myocarditiscan be a precursorto dilated cardiomyopathy.
We also demonstratedthat the viral RNA may persist in
myocardialcells in the absenceof or after the Mammatory
response; the integrity and virulence of this viral RNA
remainsto be determined.
The use of the polymerasechain reaction promisesto
yield considerableinsight into the relation between viral
infection and dilated cardiomyopathy.Studies evaluating
viral content and persistence using a quantitative poly-
merasechain reactionand the cIinicaIcourse have recently
beeninitiated.Whetherthe problemof sampleheterogeneity
is as limitingfor polymerasechain reaction analysisas for
iistopathologicresults needs to be detemined. Probesfor
viraletiologiesof myocarditis,outside of the coxsackieand
echoviruses (for example, influenza, adenovirus, herpes
simplexand zoster), also need to be developed.With the
 JACC Vol. 22. No. 4 (Supplement A)
October 199399A-105A VIRAL MYOCARDITIS
SOLE AND LIU
AND DILATED CARDIOMYOPATHY
WA

conclusion of these studies, the applicationof the poly- pathogeneticimportancefor hamster heart disease. These
merasechain reactionto endomyocardialbiopsy specimens investigatorsperfusedjuvenile normaland cardiom~D~c
for the routinediagnosisof viral myocauiitisby the clinical (before the phenotypicexpression of the disease) hamster
laboratoryshould become a reality. heartsin vivo with liquidsilicone rubber(MIcrofil)and were
able to demonstratethat the onset of the cardiomyopathy
was associatedwith numerousareas of microvascularm&n-
PathogelWis
strictionor spasm. These abnormalties dii not represent
The evolutionof myocardii damagein viralmyocarditis fixedanatomicaltemtionsofthese microvessels;rather,they
occurs in two phases (13,20). The acute phase, which lasts appearedto be potentialsites of ischemiaand reperfusion.
approximatelyI week in the mouse, is characterizedby viral Boththe cardiomyopathy andthe vasculardisordercould be
invasion of the myocardium,wit? viralreplicationand cell preventedby treatingthe animals with verapamil(31) or
lysis. Neutralizingantibodiesareformedand vinrjlis cleared praxosin(32).
or attentuatedby macrophagesand naturalkillercells. After Ourlaboratoryandothershave extendedthese studies:a
this stage, the myocardiumis intiltratedby inflammatory similarpathologicand microvascularpictureis seen in the
cells and thereis activationof the immunesystem, including heartsof rats and humanswith hypertensionand diabetes
the productionof heart-reactiveantibodies;this phase lasts (33,34), after acute brain injury in the rat (35) and in the
several weeks or months and is associated with varying
murinemodel of chagasicmyocarditis(36).
degrees of myocauM damege-fmm minimalto devastat-
Enterovirusespredominantlyassuciatedwith viral myo-
ing. Typicalpathologicfindingsin the murinemodel include
carditismay infect endothelialceils (37.38),and antiendo-
multiplefocal areasof myocyte loss, sheets of fibrosisand
thelial antibodieshave been identifiedin viral myocarditis
calcifted deposits diffusely distributedacross all cardiac
(39). These findingssuggest that microvascularspasm also
muscle layersand chambers.
may be relevantto the pathophysiologyof myocatW dam-
AUtuimmuWuIigkl0fdibltedeardionyopathy~viral
age associated with myocarditis.Our Momtory (40) and
i&ctiou. This understandingof the pathogenesis of the
that of Silver and Kowalczyk(41), using the Micd tech-
diseae has led to the hypothesisthatthe evolution ofdilated
nique.recentlydemonstratedthe associationof microvascu-
cardiomyopathy afk viral infection is predominantly auto-
lar spasm with the onset of murine myocarditis,thereby
immune in origin, resulting from either sharedantigens or
supportingthis hypothesis. Although the etUogy of the
molecular mimicry. Several observations in the murine
model supportthis hypothesis: 1) susceptiblemouse strains microvascularabnormalityin myocarditisis uncertain, it
exhibit highlevels of viremia.delayedproductionof oeutral- would seem likely to originatefrom the immunologicre-
ixing antibodyand delayed clearanceof virus (2I); 2) cyto sponseto or endothelialdamagefromthe viralinfection.The
toxic T-lymphocytesfrom the spleens of virally infected possible role or roles of endothelialor leukocytemediators
mice can lyse myocytes in culture (22,23);and 3) autoanti- such as endothelin,nitricoxide, ptostaglandins,cytokines
bodies directedagainstspecific myocauliaiproteinsappear and lymphokinesawaitfuturestudy.
in susceptiblemurinestrains and in patientswith postviral NeWlu&tf4U These exper&nts have led
myocarditisand idiopathiccardiomyopathy(24-26). How- to the development of a new model for the pathogenesisof
ever, there is also gatheringevidence r&Uis nonsupportive dilated cardiomyoputhy occurring after viral myocardG
of the autoimmuneorigin of myocaubalinjury: I) athymic (Fii. 1). Such a model also providesa rational explanation
mice still get viral qyocarditis (27); 2) mice with severe for the detrimentaleffects of exercise in acute myocarditis
combinedimmuuodef&ncy develop extensive myocarditis (13). It may also accout for the markedearlydepressionof
(20);and 3) immunosuppressivetherapyaggravatesmyocar- ventricularfunction on the basis of stunningin these pa-
ditis in the murinemodel(28-30) andis not ofproved benefit tients.
in humans(MasonJ, personalcommunication).This appar- Our understandingof microvascularSpasmalso has al-
ent paradoxbegs us to consideralternativemechanismsthat lowed us to develop (with Kubota et al. WI)an~@II
may also play a role in the pathogenesisof cardiomyopathy strategy for the diagnosis of such types of myocardial
aftermyocaulitis. disease using a branchedchain fatty acid aaalogrceW-
PemdbIeruh!uf~~ orspasm. The piodophenyl)3$ diiethylpentadecanoic acid @MIpp).
pathologicappeamnceofmurine myucarditisalso character- Cat&c imagesobtainedwith DMIPPin hamstersprone to
izes other pa&gms ofdilated cat&myopathy. For exam- but before the onset of cardiomyopathyexhiiit a marked
ple, these pathologicIWings ate exhibited by the cardiomy- hity; this p~ttem could be completelyrestoredto

opathicS~hamster,age4teticaUytransmitted(autosomal nornnu after tmatment with veqamil. using thaumm-ZM

recessive) mode) of myocardkJdilation and failure (31). scintigraphy,IWin-Net0 et al. (43)demonstratedrcyersible
Factor et al. (31) noted the resemblancebetween the my@ and paradoxic perfusion abmnmahties in patients with
cardial Gons of hamster cardiomyopathyand those ob chronic&gas disease.These studiessuggestthatresearch
served after reperfusioninjury and suggestedthat reperfu- examiningnew imagingstrategiesfor the earlydiasnogisand
sion injury at a microcirculatory level may be of assessmentoftmatmentofviral myocarditismaybe fitful

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 JACC Vol. 22. No. 4 C3umhm A)
10% SOLBANDLIU octaba 1993:99ArlWA
vIRALMrocARDITIs
ANDDILATEDcARDIomPAm

captqd is ofbenefit inthehamsterqo&l;however,neither

nhbdipii nordiltiaxemappearsto be eEective(45).
Recently,our laboratory has extendedthesebenefitsof
VcrapBmil andalpha,-adrenergic an@umists(doxaxosin) to
the qyocarditismodelproducedby encephalomyocarditis
infectiooin the mouse.Vempamil or doxaxosinwereelk-
tive whetheradministered as preuWmentor afterpeak
viremiaat4daysafterviralinoculation(4O,andunpublished
bserWk~).Theseagentsabolishedevidenceofmicrovas-
Lr spasm(Microfil),dramatically reducedmyocatdial
i&nunation,aecrosisandfi~cationandbc~cially
akeredthe&icalcourseofthedisease.otherlabomtories
have demonstrated similarresults after treatment(com-
mencingat viral inoculation)with captopril(47) or the
beta-adteneqic blockercarte0101(48);however,metoprolol
thegtpyhas an adversea&t on the courseof the disease
.

Condusions
DmlophgrpardipI#tht~and~
ddlu!d~. Theseresuits haveailowedus to
extendthe or&l hypothesisof Factorand %nnenblick
(49)for the pathophysiology of someformsof dilatedcar-
diomyopathy (Fii. 2): Myocardiidamageanddii car-
diomyopathy mayhavea varietyofetiologies. Although the
initialstimulimay dik, the pathogenesisof myocarGal
damaee~~hoftbeseconditionsappearstoresideinthei
shareddevelopmentof microvascular spasmwithinthe
myocardium. Thisspasmresultsin repetitivecyclesofsmall
vesselobstruction andrep&i&m, whichleadto the disso-
Ihmmmppnmive m. The therapeuticapproach hrtionofmyocardial matrixanda diffusefocallossofcardii
ofviral my&is hasreflectedthefocus musclemass. These in turnresult in qyo6berslippage,
to the treatment
onanimmunoh@cpa&ogenesis.Awidevarietyof~ cardiacdilationandhypertrophy ofthe remainingmyocytes.
suppressivere@uenshave been employedin bothanimal Uhimately,this chainofevents exhaustsbothbiochemical
modelsandluuuanswithnoclearevidenceofbene6t- andmechanical compensatory mechanisms andcubninates
huleedpamdoxkexa&Mmdthediseasehasbeenseen in myocardklfake.
in the murhtemale1afkerpredniwloneand cyclosporin Thereis supportforthishypothesisin humans.Treasure
therapy(28-30).Theumxutainty gene&d by smallclinical et al. (50) have demonstrated a decreasein endothelhun-
studiesandthestrongsupportfWheimmunehypothesisled dependent vawdikr reserveofthe coronarymicrovascu-
tothee&bli&MlttdaN8tionalInfititutesdHeelth laturein patientswithdii cardiomyopathy. Toussaintet
sponsoredmuhicenteredtrial(IuasonJ,personalcommuni- al. (51) were able to obtaindirect electronmkrosqic
cdfiw)toeWhHte immunosuppressive therapyin viral evidenceformi cnnmscular spasmandmyocardial ischemia
myocWditis.Thistlialwasrecentlyconcludedandagabtwas in biopsyspecimenstahenfromthe rightventricleof a
unableto clearlyestablishthe e&acy of inununosuppres- U-yearold patientwith dilatedcatdiomyopathy. Finally,
sive therapy. pisuuaet al. (52)reporkdthatlong-termdiltiW!em therapy
lkatmmtwiulcaldumdmnnd~alpha,-and had a benef&l elkct on hemodynamics, morbidityand
~Idodrar,Wverttn#caqnar~ mortality inpatientswithidiopathic diited cardiomyopathy.
hibttmx.Thedemonstration thatmim spasmmay Theselatterdatawntmstwithmanystudiesthatreport
uuderktheevoh&nofviralmyocarditistodiicardio- detrimental elects ofcalchunchannelblockersin ischemic
myopathyprovidestheopport&yfornewtherapemk myocardial dysfunction orin patientswithcongestivefailure
appu=hes. vempamilandthe alpba,gdrenersic antagonist tiOIllheartdiseapeOfvariouSarigins.
pmxosinhavebeenshowntoreveFseiIkowMk Tmtwntordik?deordiomJopdbyinenrlyverSuSlate
and markedlyamekate both hamstercardiomy~~ stagsuTheinsightsgainedfiomthesestudiesarealsod
OW,44,49 andthe cat&myopathyassociatedwithCha- genemlimporknceforthetlWmentofpatientswithdilated
8as dii 0. Recent reports(47) also suuge!St that cardiomyopathy. Inrecentyears,ourundersuuulitg ofneu-

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 JACC Vol. 22. No. 4 Gupphmt A)
&t&r 1993:9!&-IWA
SOLE AND LIU
VIRAL MYOCARDITISAND DILATED CARDIOMYOPATHT
103A

F&are 2. bticrovascularspasmaud the pathogenek of

dilated cardiomyopathy.

rohumora!dystegulationand pump function in congestive These data suggest that the selection of therapeutic
heart faihue has broughtabout a varietyof new therapeutic agentsfor the treatmentof some forms of dilatedcardiomy-
strategiesfor the relief of these patients.However,despite opathy should take into consideration the s&p of the
our advances, the underlyingheart disease is relentlessly disease. Duringthe late stagesof congestiveheartfailure,it
progressivein ahnost all patients and the e&t to preserve is appropriatethattherapybe dbected towardhemdynamic
cardiac function during the end stages tdtimately proves and neurohumoralissues. Drugssuch as digitalis,angioten-
fruitless.Cliniciansare thus initiatingtreatmentearlierin the sin-converting enzyme inhibitors or other vasodihuors
course of the disease.In doing so, they have assumedthat shouldbe used,whereascalciumchannelblockersor alphat-
agentsthathaveprovedtobesuccessfidintheamelioration adreneqgicblockersmaynotbeofbene&.DutingtheearIier
of symptoms during the late stages of Wure would he stagesof myocatdkldysfunction,at least in viralmyocardi-
similarlye&a&us whengiven early and, conversely,that tis and in selectedcasesof dilatedcardiomyopathy,it would
drugsthat were ineffectivelate wouldnot be of use if given appearthat the focusoftherapy shouldbe dkectedto active
earlier. processeswithinthe myocatdiumitself, particuhuiymicro-
The validityofthese clinicalassumptionsis not sustained vascularspasm and the resultant remodelingof the heart.
by the expetimentalevidence. For example,althoughVera- Experimentidatawouldsuggesttheuseofagentssuchas
patnil or alpha,-adrenergicantagonistsit of no use (or, in an angiotens~~verting enxyme inhibitors (particuhuly
the case of verapan& contraindicated)when given during captoptil), alpha+lrenergic blockers, vempamiland per-
the decompensatedstage of heart failure, our experiments haps vasodiing beta-blocks. The role of diitalis is
suggestthat there may be very real benefitto the myocar- uncetUin.
diutnandthecourseofthediseaseinsomecasesofdilated Futurestudks.Itshotddberecogkdthattheconcepts
cardiomyopathywhenthese agentsare administeredduring we have outIhted have been derived &otn the rest&s of
eatlier s-s bektx qyocardkl tktion becomespenna- experiments in animalmodels. The evolutiond myocardkl
tlently compromised. diseaseand the courseofdilatedcardiomyopathyin humans
The use ofdigitalisis of partictdarinterestin this regatd. cannotbeasckarly demarcatedintostagesbycontempo-
When digitoxin is given late in hams*- cardiomyopathy tary diagnostictechniquesas it can be in animals.Thus,
(whentheheartisGbrosedanddhatedwithiittieevidenceof CO~tiOllOftheCliniCalUtiiityOf~canceptsWehave
on@ng necrosk), it is of some therapeuticbeneth (53); presented here will have to await the developmentuf im-
however,digitoxingiven duringthe early phase (character- proveddiitic strategiesand the resultsoffuture
clinical
ixedbymicrovasctdarspastn)hasamarkedlyadverseeikct, studies.
keasiqg mortalityand congestionand acceleratingmy*
cardial de&no&m (53), thereby support& the expecta-
don that di&dis may aggravatemicrovasctdarspasm.Dig-
italisalsoappearstohaveanadverseekctonthecourseof
acute viral myocarditisin a rabbit model(54).In addition,
there is a widespreadimpressionthat patientswith myocar-
ditis ate particularlysensitiveto digi@ (55).

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