Table Of ContentPathophysiology and Rational PharmacotherapyofMyocardialIschemia
Gerd Heusch (Ed.)
Pathophysiology and
Rational Pharmacotherapy
of Myocardial Ischemia
With contributions by
P. B. Corr .J. Dirschinger . K. Egstrup . K. P. Gallagher
B. D. Guth· J.Herlitz -B. Heusch· G. Heusch· A. Hjalmarson
Th. Hohlfeld .J. C. Kaski ·M.Kobayashi· F.Kraus ' A.Malliani
A. Maseri· H. A.McCann .L. H. Opie . S.M. Pogwizd
W. Rafflenbeul· G. Reiniger-J. Ross,Jr..W. Rudolph· J. Schaper
W. Schaper- R. J.Schott ·K.Schrör·M.Schwaiger' F.Waagstein
H. G. Wolpers
Springer-Verlag Berlin Heidelberg GmbH
The Editor:
Prof. Dr.med. GerdHeusch
Abteilungfür Pathophysiologie
Zentrumfür InnereMedizin
UniversitätsklinikumEssen
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CIP-TitelaufnahmederDeutschenBibliothek
Pathophysiologyandrationalpharmacotherapyormyocardialischemia1GerdHeusch(ed.),With
contributionsbyP.B. Corr... - Darmstadt:Steinkopff;NewYork:Springer,1990
ISBN978-3-642-54135-3 ISBN978-3-642-54133-9(eBook)
DDI 10.1007/978-3-642-54133-9
NE:Heusch,Gerd[Hrsg.];Corr,PeterB. [Mitverf.]
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Copyright©1990bySpringer-Verlag BerlinHeidelberg
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Foreword
Ischemieheart diseaseisstillthe mostfrequent causeofdeathinthewesternworld.
There have beensignificantachievements indiagnosticprocedures aswellasinthe
medical, invasive,andsurgiealtreatmentofischemieheartdiseaseinrecentyears.A
varietyofdrugsareavailableforthepharmacotherapyofischemieheartdisease,par
ticularly nitrates, ß-blockers, and calcium-antagonists which are used as mono
therapyor invarious combinations.However, the selection ofpatientsforacertain
treatment, as weIl as the optimization of an individual treatment are still largely
empirical. On the other hand, the recent advances in experimental cardiology
emphasize the extremely complex and dynamie scenario ofischemicheart disease,
involving endothelial damage, coagulation processes, metabolie and morphologie
derangements, coronary constrictor mechanisms, blood flow redistribution,
arrhythmogenesis, contraetile dysfunction during ischemia and reperfusion, and
finallylack or presenceofpain perception.Therefore, it appearsdesirable to close
the gap between experimental and clinical cardiology and, thus, to provide a
pathophysiologiealbasisfor rationalcliniealdecisionswithrespect todiagnostic and
therapeuticprocedures.
The idea for thisbook arose during the preparationofaseminarserieson experi
mentalcardiology, when Ifound itdiffieulttocollectthepertinentinformationfrom
textbooksofcardiology,physiology,pathology, and pharmacology, aswellasfrom
numerousreviewandoriginal artieiesonspecifictopies.Iamnowverygrateful that
expertcliniealandexperimentalcolleaguesfromaroundtheworldhavejoinedmein
the effort to provide a comprehensivetextbookon the pathophysiologyofmyocar
dialischemiaand itsrationalpharmacotherapy.
Finally,Iwouldliketothankthepublisher,inpartieularMs.SabineMüllerforthe
pleasantcooperationand constructive supportineditingthisbook.
Essen,spring 1990 GerdHeusch
v
Contents
Foreword . v
1.ABriefHistoryofAnginaPectoris:ChangeofConeeptsandIdeas
BeateHeusch,BrianD. Guthand GerdHeusch . 1
2.MyoeardialUltrastructureinIsehemia
JuttaSchaper . 11
3.MyoeardialMetabolisminIsehemia
LionelH.Opie .. . . . . . . . . . . 37
4.MetabolieImagingofisehemieHeartDiseasebyPositronEmission
Tomography
HansGeorgWolpersandMarkusSchwaiger . 59
5.Coagulation,ThrombosisandFibrinolysisinMyoeardialIsehemia
ThomasHohlfeldandKarstenSchrör . . . . . . . . . . . . . . 83
6.RegionalMyoeardialFlow-FunetionRelationshipinIsehemia
Kim P.Gallagher . . . . . . . . . . . . . . . . . . . . . . . . .. 111
7.ElectrophysiologicandBiochemicalMechanismsUnderlyingMalignant
VentrieularArrhythmiasduringEarlyMyoeardialIsehemia
StevenM.Pogwizd andPeterB.Corr . . . . . . . . . . . . . . . . . . . 137
8.ReperfusedMyoeardium:Stunning,Preconditioning,andReperfusionInjury
WolfgangSchaper, RobertJ.SchottandMasaoKobayashi . . . . . . . . . . 175
9.CoronaryVasomotorToneinMyocardiallsehemia
GerdHeuschandBrianD. Guth . 199
10.CliniealSignifieaneeofCoronaryVasomotorToneinMyoeardialIsehemia
JuanCarlosKaski andAttilioMaseri . . . . . . . . . . . . . . . . . . . .. 217
11.TheChallengeofSilentMyoeardialIsehemia
AlbertoMalliani 231
VII
u.Exercise-InducedMyocardialIschemia:TheRoleofHeartRateReduction
inTherapeuticApproach
Brian D. Guthand GerdHeuseh . . . . . . . . . . . . . . . . . . . . . . . 247
13.TreatmentofMyocardialIschemiawithBeta-Blockers
ÄkeHjalmarson,JohanHerlitzand FinnWaagstein . . . . . . . . . . 261
14.TreatmentofMyocardialIschemiawithNitrates
WernerRudolph,GünterReiniger,JosefDirsehingerand
FelieitasKraus . . . . . . . 275
15.TreatmentofMyocardialIschemiawithCalciumAntagonists
WolfRafflenbeuI . . . . . . . . . . . . . . . . . . . . . . . 295
16.CombinationAnti-AnginalTherapy:RationaleandResults
Hugh A. McCann and John Ross,Jr . . 315
17.CombinedTreatmentofStableEtTort-InducedAnginaandMixedAngina
KennethEgstrup 331
SubjectIndex . . 349
VIII
ABrief History of Angina Pectoris:
Change of Concepts and Ideas
BeateHeusch,Brian D. Guth, and GerdHeusch
Abt. für Pathophysiologie,UniversitätsklinikumEssen and Dept. ofMedicine,
UniversityofCalifornia, SanDiego, USA
Thehistoryofanginapectorismaybeconsideredinthreedevelopmentalperiods.The
firstextendedfromantiquityintothelatemiddleagesduringwhichnumerousdescrip
tionsofclinicalsymptomsappearedthat,inretrospect,werelikelyanginapectorisbut
at the time were not associated withadisease ofthe heart. The periodfrom the late
middle agesto the early 20thcenturybroughtabout the correlationbetween angina
pectorisandapathologicalstateofthecoronaryvessels.FinaIly,sincethe1930sthere
has been the development of pathophysiological concepts of angina pectoriswhich
nowfocusonan impairedrelationbetweenthe work performedbythe heartand the
oxygensupplytothe heartthroughthecoronarycirculation.
The earliestdescriptionofadiseasewhichmaybecharacterizedasanginapectoris
isfound intheEgyptianPapyrus Ebers(Fig. 1)whichoriginatesfrom 1500B.C. The
contentofthe PapyrusEbersdates back toanevenolderdynasty (2500-2000B.C.)
[8]:"Ifyoufindaman whoseehesthurts andwhosuffers painfrom hisshoulderand
hisstornach,youshaIlsaythatdeathisapproaching". Herealreadyistheassociation
of angina-like ehest pain radiating into the shoulder with a fatal result. These
symptoms were,however,relatedtoadisease ofthestornach,consequentlyherbs to
elicitvomiting and diarrheawere the recommendedtreatment.
The term "angina" is first found in writings ascribed to the Greek physician
Hippocrates (460-370 B.C.) [10, 14]. Chest pain radiating into the shoulder and
arm, also inconnection with dyspnea, iscaIledxuvaYXtj. This term iscomposedof
xudrv (the dog) and aYXill (to narrow, to compress). Apparently Hippocrates
regarded angina pectoris and angina tonsillaris - diseases of the throat associated
with a typical "barking" voice - as the same disease. A weIl known letter trom
SenecatoLucilius(originating60-65A.D.)describes pectanginalsymptoms inhim
self, symptoms which were caIled "meditatio mortis" (preparation of death) by the
physicians. InthiscontextTacitus'sdescriptionofSeneca'ssuicideisinteresting. He
could only bleed to death after he was carried into a warm bath, because his
extremities were hardened - an indication of generalized atherosclerosis. Galen
caIledanginapectoris"Kardialgia"[25].Thedesignationofboth theupperportionof
the stornach and the heart bythe term "Kardia" isprobably not accidental. Galen
knew thatthe vagalnerves innervateboth the stornach and the heartand attributed
heart burn and tachycardia to a "sympathetic" radiation from the stomach to the
heart. Apart from the fact that Galen anticipated modern ideas about autonomous
reflexes, eventoday aclinicaldifferentialdiagnosisbetweenanacute,painfuldisease
of the stornach and an anginal attack may be difficult. This ambivalent nosological
relation between heart and stornach persists alsointo today's nomenclature, inthat
ventricle means"!ittle stornach".
1
Fig.1.PapyrusEbers
Until the late middle ages medicine was committed to Galen's ideas, including
thoseaboutanginapectoris. However,graphicsbyLeonardoda Vinci (1452-1519)
(Fig. 2) andAndreasVesalius(1514-1564) provethattheanatomyoftheheartand
the coronary vessels were known in great detail. According to the prevailingidea,
however, thecoronaryveins functionedto bringnutritivebloodfromtheliverto the
heart [22].
This conceptpersisteduntil1628whenW.Harveypublishedhis"ExercitatioAna
tomicade MotuCordiset Sanguinis" (Fig. 3), inwhichhenot only describedthecir
culation of blood through the lungs and the body, but also described the supply of
bloodtotheheartbythecoronaryarteries.Thus,theinitialperiodintheunderstand
ing of angina pectoris endedwith a knowledge of its symptomsbut ideas aboutthe
genesis ofthis diseaseanditsrelationto theheartremainedunclear.
In1761,Morgagnicharacterizedthepathologyoftypicalcoronaryatherosclerosis
at autopsy. Progressintheunderstandingof anginapectorisexceedingthe morpho
logy of coronary atherosclerosis was provided by British clinicians in the late 18th
century. The surgeon lohn Hunter suffered from angina pectoris and studied the
symptoms carefully in himself. He noticed the provocation of anginal attacks by
physical exercise. In 1793 he died during an anginal attack after he became very
excitedin adiscussionduringroundsinSt.George'sHospital. lohnHunteris, thus,
aclassicexamplefor theacuteprecipitationofanginapectorisbyphysicalandmental
stress.Athisautopsyamarkedossificationofthecoronaryarterieswasrevealed[1].
In1768W. Heberdengave hisclassiclectureon anginapectoristo theRoyalCollege
of Physicians which was published 4 years later. On the basis of numerous clinical
observations,he describedthetypicalpainsensation,the provocationofanginapec
toris by physicalexercise andopulent meals, and the higherincidence in men, par
ticularlyin thoseolderthan50years.Heberden,whosenameisused todayto desig
nate the poststenoticmyocardial ischemia on the basis of coronary atherosclerosis,
2
Fig.2.Illustrationofthe heartbyLeonardodaVinci
consideredcoronaryspasm asthe causeofangina pectoris. Consequently,herccom
mendedopiumand alcohol for therapy.
In 1809A.Bumswasthe firsttodevelopapathophysiologicalconceptforthe rela
tion between the clinical anginal symptoms and the coronary atherosclerosis at
autopsy. He argued that the diseased heart, like an extremity with a tourniquet,
could not increaseitsfunction withoutan adequateincreaseinbloodflow, and that
cardiac failure would result from the excessive demand. This concept remained
hypotheticaluntil itwaslaterconfirmedbyexperimentalinvestigationsinthe course
ofthenineteenthcentury. In 1881the GermanpathologistsCohnheimandv.Schult
heiss-Rechberg, using animal experiments, characterized the coronary arteries as
functional end-arteries,suchthattheirocclusion leads to irreversible lossofthe per
fused myocardialarea.Theyattributedthe lossofcardiacfunction and the initiation
ofventricularfibrillationaftercoronaryligation,not tothe lackofoxygen, buttothe
accumulationofmetaboliebyproductsdue to the lackofwashout.
Crucial for the developmentofmore preciseideas aboutmyocardialischemia was
the development of appropriate experimental models.In 1912Morawitzand Zahn
[16]developed a coronary sinus cannulawhich first permitted the measurement of
coronary blood flow in situ. Progress in the diagnosis and therapy of the clinical
symptomsoccuredin 1867asL. Bruntonfirst describedin"Lancet"the therapeutic
3
