Angina

Angina

1. Angina Pectoris
Dr Amira Badr

2. Heart O2 Supply

3. Supply Demand

5. The2maincoronaryarteriesaretheleftmainand
rightcoronaryarteries.
•Leftmaincoronaryartery(LMCA).Theleftmain
coronaryarterysuppliesbloodtotheleftsideofthe
heartmuscle(theleftventricleandleftatrium).Theleft
maincoronarydividesintobranches:
•Theleftanteriordescendingarterybranchesoff
theleftcoronaryarteryandsuppliesbloodto
thefrontoftheleftsideoftheheart.
•Thecircumflexarterybranchesofftheleft
coronaryarteryandencirclestheheartmuscle.
Thisarterysuppliesbloodtotheoutersideand
backoftheheart.
•Rightcoronaryartery(RCA).Therightcoronaryartery
suppliesbloodtotherightventricle,therightatrium,
andtheSA(sinoatrial)andAV(atrioventricular)nodes,
whichregulatetheheartrhythm.Therightcoronary
arterydividesintosmallerbranches,includingtheright
posteriordescendingarteryandtheacutemarginal
artery.Togetherwiththeleftanteriordescendingartery,
therightcoronaryarteryhelpssupplybloodtothe
middleorseptumoftheheart.

6. Angina
A characteristic sudden, severe, pressing
chest pain radiating to the neck, jaw, back
and arms

10. Pathogenesis of Angina
Fromametabolicpointofview,myocardialischaemia
resultsinanaerobicglycolysiswithaconsequent
increasedconcentrationandreleaseofH
+
,K
+
,and
lactateinthevenousblooddrainingtheischaemic
territory.
Theresultingacidosiscompetewithcalciumionsand
freezemovementsthroughthesarcolemmaand
sarcoplasmicreticulum,thuscausingthewell-known
“ischaemia–inducedregionalhypokinesiaor
akinesia

11. Intheclinic,existenceofmetabolicischaemiais
documentedbyadropofpHinthevenouscoronary
sinusbloodconcomitantwithareleaseoflactatefrom
theischaemicmyocytes
Thesebiochemicalalterationsprecedetheactual
occurrenceoftheclassicalECGchangesandofthe
chestpain,aswellastheregionalalterationof
contractility.Itisimportanttoemphasizethatin
patientswithanginathesechangesaretransientand,
normally,requireatrigger(i.e.,exercise,stress,
exposuretocooltemperature,etc.)whichcreatesthe
metabolicmismatch.

12. Adenosine,likemanyothermediators,isreleasedin
largequantitiesduringmyocardialischaemiainthe
interstitialspaceand,throughtheadenosineA1
receptors,modulatestheactivitiesoftheefferent
neurons,thuscausingpain[43].
Recently,ithasbeensuggestedthatinflammation
mayalsoplayaroleandtreatmentwithcanakinumab
inpatientswithchronicischaemiahasledtoa
reductionofmortality[14].Conversely,noneofthe
antianginaldrugs(withthepossibleexceptionof
nicorandil)havebeenproventoreduce
cardiovascularmortalityormyocardialinfarction,

13. ARTERIES
OF THE
HEART
Normal Angina
Pectoris
Myocardial
Infarction

16. the pathophysiology of coronary
microvascular dysfunction
Thereareseveralhypothesesforthepathophysiology
ofcoronarymicrovasculardysfunction[67].
Perhapsthemostacceptedoneisadysfunctionofthe
endothelialcellsofthemicrovascularnetwork.
Itisknownthatunderphysiologicalconditionsthe
endotheliumproducesanumberofmediatorswith
vasorelaxing,antiproliferative,anti-apoptotic,and
antithromboticeffects.Inaddition,endothelialcells
alsoregulatethecontractilefunctionof
cardiomyocytesbyinfluencingtheactivityofthegap
junction.

17. Thecauseofendotheliumdysfunctionseemstobe
linkedtoincreasedoxidativestresswithconsequent
releaseofthromboxaneA2,prostaglandinH2,and
superoxide,thusconvertingthedilatorresponseto
differentstimuliintoaconstrictiveresponse.
Endothelium dysfunction also activates
inflammatoryresponseswiththeexpressionof
chemokineandadhesionmoleculeswhich,inturn,
affectthemicrocirculation.
Inthepresenceofcoronaryendothelialdysfunction,
responsestoα-adrenergicactivationisaugmented,
causingvasoconstrictionofthemicrovessels,able
toinducemyocardialischaemia.Againstthis
hypothesis,however,isthefindingthattheefficacy
ofα-adrenergicantagonistsis,atbest,uncertain

18. Drugs Used in Angina
Angina pectoris is the medical term for chest pain or discomfort
due to coronary heart disease.
It occurs when the heart muscle doesn't get as much blood as
it needs.
This usually happens because one or more of the heart's
arteries is narrowed or blocked, also called ischemia.
Types of Angina -Knowing the types of angina and how they
differ is important.

19. Drugs Used in Angina
Angina pectoris is the medical term for chest pain or discomfort
due to coronary heart disease.
It occurs when the heart muscle doesn't get as much blood as
it needs.
This usually happens because one or more of the heart's
arteries is narrowed or blocked, also called ischemia.
Types of Angina -Knowing the types of angina and how they
differ is important.

20. Types of Angina
Classic Angina
Atherosclerotic angina
Angina of effort
Chronic angina
Angina that is precipitated by exertion, i.e.
increase O2 demand that can not be met because
of irreversible atherosclerotic obstruction of
coronary arteries
The principle way to relieve the pain of classic
angina is to decrease cardiac oxygen demand

21. .
Unstable angina:
•Also called “Crescendo angina” (INCREASE BY TIME).
•It has at least one of these three features:
1.Severe and acute of onset.
2.Occurs at rest.
3.rapidly progressing increase in frequency and severity of anginal

22. Types of Angina (cont.)
Unstable Angina
rapidly progressing increase in
frequency and severity of anginal
attack, especially pain at rest
It is thought to be the immediate
precursor of a myocardial infarction
and is treated as a medical emergency

23. Types of Angina (cont.)
Variant Angina
Vasospastic angina
Prinzmetal’s angina
Angina precipitated by reversible
spasm of coronary vessels
NOatherosclerosis
The principle way to relieve the pain of
variant angina is to increase cardiac
oxygen supply
Ca channel blockers with vasodilator
effects are best.
ß-blockers are contraindicated

24. Treatment strategies of Angina
Either by ↓ cardiac workOR ↑O2 supply
We need treatment for
Acute attack to relieve the spasm & pain
Prophylaxis to prevent further attack

25. 1-Decrease oxygen consumption or demand by the
followings:
a-decrease heart rate and contractility
-ßblocker
-cardioselective calcium channel blockers such as
Diltiazem and Verapamil.
b-Decrease preload (veinodilator) organic nitrate.
c-Decrease cardiac muscle stiffness onlyby inhibition
late sodium current (INaL)such as Ranolazine.
2-Dilate or open coronary artery (increase oxygen supply)
Drugs: such as organic nitrate calcium channel blockers
(amlodipine and others)
Strategy for treating Angina

26. Inthecurrentguidelines,drugsareclassifiedasbeing
first-choice(β-blockers,calciumchannelblockers,
andshort-actingnitrates)
orsecond-choice(ivabradine,nicorandil,ranolazine,
trimetazidine)treatment,withtherecommendationto
reservesecond-linemodificationsforpatientswho
havecontraindicationstofirst-choiceagents,donot
toleratethem,orremainsymptomatic.
However,suchacategoricalapproachiscurrently
questioned.
Inaddition,currentguidelinesprovidefew
suggestionstoguidethechoiceofdrugsmore
suitableaccordingtotheunderlyingpathologyorthe
patientcomorbidities.
Currentguidelinesrecommendantianginaltherapyto
controlsymptoms,priortoconsideringcoronary
arteryrevascularization.

27. Drug Classes
Organic Nitrates
β-BlockersCa Channel Blockers

28. Organic nitrates

30. Organic nitrates (cont.)
They are nitric & nitrous acid esters of glycerol
e.g. Amyl nitrite, glyceryltrinitrate (nitroglycerin),
5-isosorbid mononitrate & dinitrate
Mechanism of action:
Generation of NO with activate guanylate
cyclase and ↑cGMP
cGMP induces relaxation by :↓Ca influx, ↑Ca
sequestration in sarcoplasmic reticulum &
myosin light chain dephosphorylation

31. Organic nitrates (cont.)
Cardiovascular Effects:
VD occurs in three vascular beds
[1] Veins→ ↓preload, ↓ ventricular filling pressure → ↓ cardiac
work & O2 demand
The decreasein CO will reduce Bp and reflex tachycardia
[2] Arteries→ ↓ afterload, ↓ cardiac work
[3] Coronaries→ ↑ O2 supply to ischemic area & relieve spasm
Tolerance: The BV become desensitized to vasodilation as a
result of exhaustion of the nitric oxide pool at the membrane

32. Organic nitrates (cont.)
Tolerance is limited by ACEI, Ag
blockers & β-blockers
Skin batches should be removed for at
least 10-11hrs each day, and take a
holiday day for oral


33. Organic nitrates (cont.)
Pharmacokinetics:
Glyceryltrinitrate:
well absorbed from GIT but exposed to 1
st
pass metabolism
Given by one of the following routes:
sublingual, aerosol spray, chewable tablets
& IV for short duration & transdermal for
stable blood conc. For 24hr
These are considered the drugs of choice
during acute angina pectoris, while long-
acting preparations are used for prophylaxis
of angina

34. Organic nitrates (cont.)
Isosorbid dinitrate:
Metabolized to mononitrate (longer
duration of action)
Isosorbid mononitrate:
Not metabolized
Taken orally

35. Organic nitrates (cont.)
Side Effects:
Venodilation → Postural hypotension,
reflex tachycaria, dizzness & syncope
Arteriodilation → Throbbing headache
& flushing
Methaemoglobinaemia

36. Aswithdihydropyridines,theeffectsonpre-and
afterloadareoftenpartlyoffsetbyanincreaseof
heartrateandmyocardialcontractilitydueto
reflexsympatheticactivity.
Thus,combiningnitrateswithβ-blockersand
ivabradinemightbeusefultoblocktachycardia.
Nitratesimproveanginasymptoms,
butthisclassisineffectiveinimprovingquality
oflifeduetotheriskofadverseevents,which
includeheadache,flushing,palpitations,and
hypotension

37. β-Blockers & Ca Channel Blockers
Ca
2++

38. β-Blockers
Cardiovascular Effects:
β-blockers reduce anginal pain by ↓ cardiac O2
demand
This is accomplished primarily through
blockade of β
1receptors & so ↓ force of
contraction & so O2 demand
β-blockers can reduce O2 demand further by
causing a modest reduction in arterial pressure
(↓ afterload)
Used for exercise angina, NOT vasospastic angina
e.g. propranolol, atenolol & metoprolol

39. β-Blockers (cont.)
Side Effects:
β2 blocking → bronchospasm (asthma)
→ Insulin dependent
diabetes are susceptible
to hypoglycemic coma
↑ TG & ↓ HDL
Never stop suddenly → perception of
unstable angina & myocardial infarction

40. Theyhaveseveralsideeffects,includingbradycardia,
hypotension,bronchospasm,fatigue,andbluntingof
thetachycardiaresponsetohypoglycaemia.
Thesesideeffectsarelessevidentinβ1-selective
blockers,suchasmetoprolol,atenolol,andespecially
bisoprolol.
Otheragentsareselectivefortheβ1-receptorsandalso
possessesα-blockingactivity,resultinginvasodilation.
Thesearelabetalolandcarvedilol.
Finally,nebivololisaselectiveβ1-antagonistwith
vasodilatoryeffectsthroughnitricoxideproduction
.

41. Ca Channel Blockers
Cardiovascular Effects:
[1] Arteriolar dilation→ ↓PR & afterload
Dihydropyridine
Short acting dihydropyridine → rapid ↓BP & reflex
tachycardia………contraindicated
Long acting & sustained release → Slow ↓ BP with NO reflex
tachycardia
[2] Coronaries vasodilation→ Spasm relief
Deltiazem
[3] -ve chronotropic(↓SA node firing & ↓AV conduction)
& -ve inotropic(↓ Ca entry)
Verapamil

42. Diltiazem
increasemyocardialbloodflow,andreducemyocardial
oxygendemandandcardiacworkload.However,it
differsfromothercalciumantagonistsinitsmild
negativeinotropicandmoderatenegativedromotropic
effects,withoutapparentstimulationofcardiac
performanceorcontractility.Inaddition,itinhibits
plateletaggregation,decreasescatecholaminerelease,
diminishescoronary toneand blocksthe
vasoconstrictiveactionsofendothelin-1.
Thisappearstotranslateintoabeneficialeffecton
ischemia, thrombolysis, arrhythmias, infarct
parameters, atherosclerosisand hypertension.
Diltiazemhasarelativelyfavourablesafetyand
tolerabilityprofile,andisavailableinaonce-daily
dosageform.

43. Dihydropyridine Calcium
Channel Blockers
Calciumchannelblockersareclassified,according
totheirstructure,asdihydropyridinesornon-
dihydropyridines.(thedihydropyridinesinparticular)
inhibitcalciuminfluxthroughthehigh-voltage-
activatedL-typecalciumchannel,locatedinthesmooth
muscleofthearterialwall,leadingtosmoothmuscle
relaxation[93].
Dihydropyridineshavehighselectivityandaffinity
forL-typechannelsofthevasculaturewithadecrease
ofcoronaryandsystemicvascularresistance.Itfollows
thattheyreducecardiacafterloadand,therefore,
oxygenneedandimproveoxygendeliveryby
improvingcoronarydilatation.

44. Areflextachycardiamightoccurafteradministrationof
dihydropyridinescalciumblockers.Inthiscase,a
concomitantuseofaβ-blockermightbeusefultoblunt
thereflexandallowanadditionalanti-ischaemiceffect.
Whilecalciumchannelblockersareeffectiveinthe
treatmentofvasospasticanginaandimprovesymptoms
of“classic”angina,noneofthemimprovethesurvivalof
patientswithanginawithorwithoutmyocardialinfarction
orleftventriculardysfunction.

45. Ca Channel Blockers (cont.)
In classic angina:Ca channel blockers reduce
anginal pain by decreasing cardiac oxygen demand
–Decrease heart rate and contractility
–Decrease arterial pressure (afterload)
In variant angina:Ca channel blockers promote
relaxation of coronary artery spasm, thereby
increasing cardiac O2 supply

46. Ca Channel Blockers (cont.)
Side Effects
Arterial dilation → headache, flushing, hypotension
& peripheral edema, bradycardia
So short acting dihydropyridines should be avoided
in coronary artery disease
Verapamil & diltiazem are extensively metabolized by the
liver, care must taken to adjust the dose in patientswith
liver dysfunction
Diltiazem & verapamil affect digoxin serum level
Heart Block (especially with β-blockers & digoxin)
Reduce myocardial contractility
Constipation

47. thecombinationofβ-blockersorivabradinewith
verapamilordiltiazemisrelativelynotsafe.
Verapamilanddiltiazemaremetabolizedintheliver
toalessactivemetabolitebycytochromeP-450
CYP3A4,whichalsometabolizesivabradine.It
followsthatitshouldneverbecombinedwith
ivabradineduetotheriskofseverebradycardia.
Verapamilanddiltiazemshouldnotbeusedin
patientswithanginaandleftventriculardysfunction
and/orheartfailureastheymighthavedeleterious
effectsonoutcomes

48. Ivabradine
exertsitsactionthroughtheinhibitionoftheso-
called“I
fchannel,”where“f”meansfunny.
Thesechannelsarelocatedinthesinusnode
atrialcell.
ByinhibitingtheI
fcurrent,ivabradinereduces
heartrate.
Theeffectsofivabradineare“usedependent”
asitbindspreferentiallytothechannelsthatare
intheopenstate.Itfollowsthattheeffectsof
ivabradineonheartrateisgreaterwhenthe
heartrateishighandlowerwhentheinitialheart
rateislow.

50. Furthermore,incontrasttoβ-blockersandtonon-
dihydropyridinescalciumantagonists,ivabradine
hasnonegativeinotropiceffects.
Recently,ivabradinehasalsobeenshownto
increasecoronarycollateralperfusionandthe
coronaryflowreserve.
Inaddition,ivabradineunlikeß-blockers,it
maintainsthephysiologicalcoronarydilation
duringexercise.
Forallthesereasons,ivabradineshouldbeadded
toß-blockersanytimetheheartrateremains
elevated.Whenaddedtobisoprolol,ivabradine
significantlyfurtherimprovedexercisetolerance
morethandoublingthedoseofbisoprolol

51. Thereareseveralclinicaldatainsupportofthis
concept.IntheASSOCIATEtrial,ivabradineadded
toatenololfurtherandsafelyimprovedexercise
toleranceinsubjectswithstableangina.

52. Nicorandil
Nicorandilisanitratederivativeof
nicotinamideandanadenosine-
sensitivepotassiumchannelopener
withnitricoxidedonorcapacity,
thusresultinginthedilatationofthe
coronaryarterieswithanincreaseof
myocardialbloodflow.

53. Inalarge,multicentric,controlled,outcomestudy
(IONA;theimpactofnicorandilinangina)
nicorandilreducedthecompositeofCVdeath,
non-fatalmyocardialinfarction,orunplanned
hospitaladmissionforcardiacpainatamedianof
1.6yearscomparedwithplacebo,despite40%of
patientswithdrawinginthetreatedgroup
becauseofheadache

54. Trimetazidine
theexactmechanismoftheantianginal
effectoftrimetazidineisnotknown,
Itcauseslessproductionoflacticacid
andprotonsformtheacutelyischaemic
myocytes,and increaseATP
production;modulatecardiacmetabolic
pathways.

55. Althoughtheexactmechanismoftheantianginaleffect
oftrimetazidineisnotknown,inexperimentalpreparation
itincreasescellulartolerancetoischaemiabyinhibiting
themitochondriallong-chainketoacylco-enzymeA
thiolaseand,consequently,increasestheanaerobic
glucosemetabolism.
Trimetazidinedirectspyruvateintothemitochondria,this
maintainstheflowofglucosetopyruvateinthecytosol
and,inturn,causeslessproductionoflacticacidand
protonsformtheacutelyischaemicmyocytes.
Thenetconsequencesofthetrimetazidineeffecton
cardiacsubstratesareareductionofFFAacidsoxidation
andanincreaseofanaerobicglucoseutilizationbythe
ischaemicmyocardiumwithlessproductionofprotons
andlacticacidproduction(lessacidosis)andmore
anaerobicATPproductionfromthecytosol

56. Cardiovasc Res, Volume 33, Issue 2, February 1997, Pages 243–257, https://doi.org/10.1016/S0008-6363(96)00245-3
The content of this slide may be subject to copyright: please see the slide notes for details.
Fig. 1 Schematic depiction of myocardial substrate metabolism.
Abbreviations: G 6-P, glucose 6-phosphate; TCA, ...

58. Thesemetabolicchangeshavebeenconfirmedin
clinicalsettings,wheretrimetazidinedidincrease
myocardiallevelsofhigh-energyphosphatesin
patientswithheartfailure.Inameta-analysisof
23randomizedtrials,trimetazidineimproved
anginasymptoms

59. Ranolazine
UseofRanolazine
Treatmentofchronicangina.
-RanolazineMayalsobeusedin
combinationwith,orasasubstitutefor,ß
blockers,forreliefofsymptomswheninitial
treatmentwithßblockersisnotsuccessful.

60. Mechanism of Action of Ranolazine
1-Ranolazineexertsantianginalandanti-ischemiceffects
withoutchanginghemodynamicparameters(heartrateor
blood pressure).
2-Besidethesimilarmetaboliceffectsoftrimetazidine,At
therapeuticlevels,ranolazineinhibitsthelatephaseofthe
inwardsodiumchannel(lateI
Na)inischemiccardiac
myocytes duringcardiacrepolarizationreducing
intracellularsodiumconcentrationsandtherebyreducing
calcium influx via Na
+
-Ca
2+
exchange.
3-Decreasedintracellularcalciumreducesventricular
tensionand myocardial oxygen consumption.
4-Athigherconcentrations,ranolazineinhibitstherapid
delayedrectifierpotassiumcurrent(I
Kr)thusprolonging
theventricularactionpotentialdurationandsubsequent
prolongation of the QT interval.

63. CONTRAINDICATION of Ranolazine
It is contraindicated in patients with liver cirrhosis.
Cirrhotic patients with mild to moderate hepatic impairment demonstrated a
3-fold increase QT prolongation.

64. Management of Angina
Change life style:
Weight loss
Stop smoking
Treatment of hypertension, diabetes, obesity
or hypercholesterolemia
Treat acute attack→ by sublingual glyceryltrinitrate
Prophylactic→ β-blockers or Ca antagonists
Aspirin, if allergic clopidogrel
and statins (cholesterol lowering agents

65. MYOCARDIAL
INFARCTION

66. Myocardialinfarction(MI)oracutemyocardialinfarction(AMI),
commonlyknownasaheartattack,istheinterruptionofblood
supplytopartoftheheart,causingsomeheartcellstodie.
Eitheroneofthefollowingcriteriasatisfiesthediagnosisforan
acute,evolving,orrecentmyocardialinfarction:
1.Typicalriseandgradualfall(troponin)ormorerapidriseand
fall(CK-MB)ofbiochemicalmarkersofmyocardialnecrosis
withatleastoneofthefollowing:
a.Ischemicsymptoms
b.DevelopmentofpathologicQwavesontheelectrocardiogram
c.Electrocardiographicchangesindicativeofischemia(ST
segmentelevationordepression)
d.Coronaryarteryintervention(e.g.,coronaryangioplasty).

67. Irreversibledamagetothemyocardiumcanbeginasearlyas
20to40minutesafterinterruptionofbloodflow.
Thedynamicprocessofinfarctionmaynotbecompleted,
however,forseveralhours.
Necrosisoftissueappearstooccurinasequentialfashion.
Reimerandassociatesdemonstratedthatcellulardeath
occursfirstinthesubendocardiallayerandspreadslikea
“wavefront”throughoutthethicknessofthewallofthe
heart.
Usingdogs,theyshowedthattheshorterthetimebetween
coronaryocclusionandcoronaryreperfusion,thegreater
theamountofmyocardialtissuethatcouldbesalvaged.
PathophysiologicalPrinciples

68. asubstantialamountofmyocardialtissuecanbe
salvagedifflowisrestoredwithin6hoursafterthe
onsetofcoronaryocclusion.
ThecellularchangesassociatedwithaMIcanbe
followedby:
1.thedevelopmentofinfarctextension(new
myocardialnecrosis),
2.infarctexpansion(adisproportionatethinningand
dilationoftheinfarctzone),or
3.Ventricularremodeling(adisproportionatethinning
anddilationoftheventricle).
PathophysiologicalPrinciples

69. Severalfactorsdeterminethesizeoftheresulting
MI.
Thesefactorsincludetheextent,severity,and
durationoftheischemicepisode;thesizeofthe
vessel;theamountofcollateralcirculation;the
statusoftheintrinsicfibrinolyticsystem;vascular
tone;andthemetabolicdemands ofthe
myocardiumatthetimeoftheevent.
MIsmostoftenresultsindamagetotheleft
ventricle,leadingtoanalterationinleftventricular
function.
Infarctionscanalsooccurintherightventricleor
inbothventricles.
SIZE OF THE INFARCTION

70. HISTORY
patients with MI describe a heaviness, squeezing,
choking, or smothering sensation.
Patients often describe the sensation as “someone
sitting on my chest.”
The substernalpain can radiate to the neck, left arm,
back, or jaw.
Unlike the pain of angina, the pain of an MI is often
more prolonged and unrelieved by rest or sublingual
nitroglycerin.
Associated findings on history include nausea and
vomiting, especially for the patient with an inferior
wall MI.
These gastrointestinal complaints are believed to be
related to the severity of the pain and the resulting
vagalstimulation.
Assessment

72. (A)ST segment elevation
without T-wave inversion.
(B) ST segment elevation with
T-wave inversion.
The elevated ST segments have
a downward concave or coved
shape and merge unnoticed
with the T wave.

73. Q waves indicate tissue necrosis and are permanent. A pathologic Q wave is one
that is greater than 3 mm in depth or greater than one-third the height of the R
wave.

74. Laboratory Tests
Creatine Kinase
CK-MB appears in the serum in 6 to 14 hours,
peaks between 14 and 28 hours, and returns to
normal levels in about 72 to 96 hours.
Serial samplings are performed every 4 to 6 hours
for the first 24 to 48 hours after the onset of
symptoms
Creatine Kinase Isoforms: CK-MB1 is the isoform
found in the plasma, and CK-MB2 is found in the
tissues. In the patient with an MI, the CK-MB2
level rises, resulting in a CK-MB2 to CK-MB1 ratio
greater than one

75. Myoglobin:Myoglobinisanoxygen-binding
proteinfoundinskeletalandcardiacmuscle.
Myoglobin’sreleasefromischemicmuscle
occursearlierthanthereleaseofCK.
Themyoglobinlevelcanelevatewithin1to2
hoursofacuteMIandpeakswithin3to15
hours.
Becausemyoglobinisalsopresentinskeletal
muscle,anelevatedmyoglobinlevelisnot
specificforthediagnosisofMI.Onsequently,
itsdiagnosticvalueindetectinganMIislimited

76. Troponin. (troponin T and troponin I):
Troponin I levels rise in about 3 hours,
peak at 14 to 18 hours, and remain
elevated for 5 to 7 days.
Troponin T levels rise in 3 to 5 hours
and remain elevated for 10 to 14 days

77. Release of cardiac markers after
acute myocardial infarction(AMI).

78. EARLY MANAGEMENT
The patient’s history and 12-lead ECG are the
primary methods used to determine initially the
diagnosis of MI.
The ECG is examined for the presence of ST segment
elevations of 1 mV or greater in contiguous leads.
1. Administer aspirin, 160 to 325 mg chewed.
2. After recording the initial 12-lead ECG, place the
patient on a cardiac monitor and obtain serial ECGs.
3. Give oxygen by nasal cannula.
Management

79. 4. Administer sublingual
nitroglycerin(unlessthesystolic
bloodpressureislessthan90mm
Hgortheheartrateislessthan50or
greaterthan100beats/minute).
5.Provideadequateanalgesiawith
morphinesulfate.

80. Thrombolyticdrugslysecoronarythrombiby
convertingplasminogentoplasmin.
Thrombolytictherapyprovidesmaximalbenefitifgiven
withinthefirst3hoursaftertheonsetofsymptoms.
Significantbenefitstilloccursiftherapyisgivenupto
11hoursafteronsetofsymptoms.
Contraindications
■Previoushemorrhagicstrokeatanytime;otherstokes
orcerebrovasculareventswithin1year
■Knownintracranialneoplasm
■Activeinternalbleeding(doesnotincludemenses)
■Suspectedaorticdissection
Thrombolytic Therapy

81. Cautions/Relative Contraindications
■Severeuncontrolledhypertensiononpresentation(blood
pressure>180/110mmHg)
■Historyofpriorcerebrovascularaccidentorknownintracerebral
diseasenotcoveredincontraindications
■Currentuseofanticoagulantsintherapeuticdoses(international
normalizedratio[INR]≥2:3);knownbleedingdiathesis
■Recenttrauma(within2–4weeks),includingheadtrauma
ortraumaticorprolonged(>10minutes)cardiopulmonary
resuscitation(CPR)ormajorsurgery(<3weeks)
Thrombolytic Therapy

82. ■For streptokinase/anistreplase: prior
exposure (especially within 5 days to 2
years) or prior allergic reaction
■Pregnancy
■Active peptic ulcer

83. (PTCA)isaneffectivealternativetoreestablishbloodflow
toischemicmyocardium.
PrimaryPTCAisaninvasiveprocedureinwhichthe
infarct-relatedcoronaryarteryisdilatedduringtheacute
phaseofanMIwithoutprioradministrationofthrombolytic
agents.
PrimaryPTCAmaybeanexcellentreperfusionalternative
forpatientsineligibleforthrombolytictherapy.
Thenursemustcarefullymonitorthepatientafteraprimary
PTCAforevidenceofcomplications.
Thesecomplicationscanincluderetroperitonealor
vascularhemorrhage,otherevidenceofbleeding,early
acutereocclusion,andlaterestenosis.
Primary PercutaneousTransluminal
Coronary Angioplasty (PTCA)

84. Hemodynamic Monitoring
Use of a pulmonary artery catheter for
hemodynamic monitoring is indicated
in the patient with MI who has severe or
progressive congestive heart failure or
pulmonary edema, cardiogenic shock,
progressive hypotension, or suspected
mechanical complications.
Additional Diagnostic Tests:
Radionuclide Imaging
Echocardiogram
Stress Test

85. Prophylacticantidysrhythmicsduringthefirst24hoursof
hospitalizationarenotrecommended.
IVnitroglyceriniscontinuedfor24to48hours.
Dailyaspiriniscontinuedonanindefinitebasis.
Clopidogrelmaybeusedforpatientswhoareintolerantof
aspirin.
IVβblockertherapyshouldbeadministeredwithinthe
initialhoursoftheevolvinginfarction,followedbyoral
therapyprovidedtherearenocontraindications.
βblockersareoneofthefewpharmacologicalagentsthat
havebeenshowntoreducemorbidityandmortalityinthe
patientwithanMI.
Theyreduceoxygendemandbydecreasingtheheartrateand
contractility.
Theyalsoincreasecoronaryarteryfillingbyprolonging
diastole.
INTENSIVE AND
INTERMEDIATE
CARE MANAGEMENT

86. Calciumchannelblockersmaybegiventopatientsin
whomβblockertherapyisineffectiveorcontraindicated.
Angiotensin-convertingenzyme(ACE)inhibitorsare
administeredtopatientswithanteriorwallMIandto
patientswhohaveanMIwithheartfailureintheabsence
ofsignificanthypotension.
ACEinhibitorshelppreventventricularremodeling
(dilation)andpreserveejectionfraction.
Heparinisgiventopatientsundergoingpercutaneousor
surgicalrevascularizationandforthosereceiving
thrombolytictherapywithalteplase.

INTENSIVE AND
INTERMEDIATE
CARE MANAGEMENT

87. Complications
Vascular Complications
Recurrent ischemia
Recurrent infarction
Mechanical Complications
Left ventricular free wall
rupture
Ventricular septal rupture
Papillary muscle rupture
with acute mitral
regurgitation
Myocardial Complications
Diastolic dysfunction
Systolic dysfunction
Congestive heart failure
Hypotension/cardiogenic
shock
Right ventricular
infarction
Ventricular cavity dilation
Aneurysm formation (true,
false)

88. Complications
Pericardial Complications
Pericarditis
Dressler’s syndrome
Pericardial effusion
Thromboembolic
Complications
Mural thrombosis
Systemic
thromboembolism
Deep venous thrombosis
Pulmonary embolism
Electrical Complications
Ventricular tachycardia
Ventricular fibrillation
Supraventricular
tachydysrhythmias
Bradydysrhythmias
Atrioventricular block
(first, second, or third
degree)

89. Management of Myocardial Infarction
Acute Management
Pain Relief Thrombolysis
-Nitrates (sublingual or IV)
-Diamorphine (opioid analgesics, IV)
-β-blockers to ↓ cardiac work,
but there is no sign of heart failure
-IV thrombolytic agents to
limit the size of infarct
-e.g. streptokinase, recombinant
tissue plasminogen activator &
antistreplase

90. Angioplasty,alsocalledpercutaneous
coronaryintervention(PCI),isa
procedureusedtoopenblocked
coronaryarteries(causedbycoronary
arterydisease)andrestorebloodflow
totheheartmusclewithoutopen-heart
surgery.
CoronaryArteryBypassGraftSurgery
(CABG) isasurgicalprocedureto
restorenormalbloodflowtoan
obstructedcoronaryartery.

91. Secondary prophylaxis after myocardial
infarction:
Stop smoking
Exercise
Low dose of aspirin to reduce reocclusion of
vessels or alternatively warfarin if the patient
can not tolerate aspirin
β-blockers orally especially for patient who
have post infarct arrhythmia
Hypocholersterolemic drugs

92. Ischemia Reperfusion Injury
Myocardialischemia-reperfusionistheleadingcauseforthe
eventsofcardiovasculardisease,andisconsideredasamajor
contributortothemorbidityandmortalityassociatedwith
coronaryocclusion.Themyocardialdamagecausedby
ischemia-reperfusioninjuryconstitutestheprimary
pathologicalmanifestationofcoronaryarterydisease.Itresults
fromtheinteractionbetweenthesubstancesthataccumulate
duringischemiaandthosethataredeliveredonreperfusion.
Thelevelofthisdamagecanrangefromasmallinsult
resultinginlimitedmyocardialdamagetoalargeinjury
culminatinginmyocytedeath.Importantly,major
ischemia-reperfusioninjurytotheheartcanresultin
permanentdisabilityordeath.

93. HavingrecognizedthatitisabloodclotthatleadstoST-
segmentelevatedMI,thetimelyrestorationofcirculationtothe
affectedmyocardiumwasfoundtolimittheinfarctsizeand
alsoimprovemyocardialfunction(2).However,severallines
ofexperimentalandclinicalevidencesshowedthat
reperfusionoftheischemicmyocardiumcausesfurther
damageandthisisknownasischemia-reperfusioninjury(3).
AlthoughtheinstitutionofreperfusionfollowingMIledtoa
markedreductioninmortalityduetoMI-relatedheartfailure,
thereisasignificantincreaseinsurvivingpatientswithchronic
cardiacdysfunctionthatresultedfromischemia-reperfusion
injury.Indeed,prolongedischemiamayaccountforupto50%
ofthefinalMIsizeandcausesmultiplecellularmetabolicand
ultra-structuralchangesandinfact,thesizeoftheinfarctisa
majordeterminantofthetreatmentoutcomesandthusthe
primaryaimofMItreatmentapproachesistoreducethe
infarctsize.

94. Theischemia-reperfusioninjuryinducesinflammatory
response,whichisinitiallylocalizedbuteventually
becomessystemicandinducesmulti-organdysfunctionit
isimportanttounderstandthemechanismsofmyocardial
ischemia-reperfusioninjuryinordertodeveloptherapies
targetingbothischemicandreperfusiondamage,toreduce
theinfarctsize,consideringthatsmallerinfarctsizecan
leadtobettercardiacfunction,overlong-term.Despitea
significantamountofresearchaswellasencouraging
preclinicalresultswithmultipleagents,mostoftheclinical
trialstopreventreperfusioninjuryhavebeendisappointing
(7)andthusitisimportanttoidentifyanddevelop
therapiesthatpotentiallyreduceinfarctsize.

95. Initially,ischemiacausesmitochondrialoxidative
phosphorylationarrestduetoalackofsufficient
oxygen,leadingtoareductioninATPproduction.In
ordertocompensateforthis,theaffected
cardiomyocytesconductanaerobicglycolysisforATP
production,whichleadstotheaccumulationof
protonsandlactate,resultinginintracellularacidosis.

TheelevatedintracellularH+activatestheplasma
membraneNa+/H+exchanger,whichexpelsthe
H+fromthecellinexchangeforNa+,leadingtoan
increaseinintracellularNa+.

96. ReducedactivityofNa
+
/K
+
-ATPaseduetoacidand
insufficientATP,alsocontributestotheincreasein
intracellularNa
+
,whichleadstotheactivationof
sarcolemmalNa
+
/Ca
2+
exchangerandabuildupof
intracellularCa
2+
.
Followingreperfusion,respiratoryactivity,mitochondrial
potential,andATPsynthesisarerestoredandintracellular
pHisrestoredrapidlytonormallevel,whichcauses
activationofCa
2+
dependentprotease,calpain,which
degradesthecytoskeletonandthesarcolemma.The
increasedavailabilityofATPuponreperfusioninthe
presenceofincreasedCa
2+
activatessarcoplasmic
reticulum(SR)uptakeofCa
2+
,exceedingthethresholdof
ryanodinechannels,whichreleaseCa
2+
intothecytosol.

97. CyclicrepetitionofthisprocessleadstoCa
2+
oscillations
thatleadtouncontrolledmyofibrillarhypercontractionand
alsopromoteopeningofthemitochondrialpermeability
transitionpore(mPTP).
OpeningofmPTPresultsinmitochondrialmatrixswelling,
whichtriggerstheruptureofmitochondrialoutermembrane
andreleaseofmitochondrialintermembranespacecontents
suchascytochromec,intocytosol.Cytochromecsetsthe
courseofpromotingtheprogrammedcelldeathby
activatingthecaspasecascade.Theincreased
Ca
2+
oscillationsalsoenhancetheactivityofxanthine
oxidases,promotingtheproductionofROS,whichfurther
exacerbatemembranedamagebydirectlypromoting
openingofthemPTP,andthuscontributetocelldeath
duringreperfusion.

98. ROSismostlyproducedbythedifferent
typesofcellsintheischemiczone,
includingtheinjuredmyocytes,
endothelialcellsandneutrophils.
Neutrophilsenteringtheischemiczone
furtheraggravatethecellulardamage
byreleasinginflammatorymediators,
causingmicrovascularobstructionand
localand eventuallysystemic
inflammation.

99. ..

100. Ischemicpre-conditioning
Thephenomenonofischemicpre-conditioningreferstoa
therapeuticapproachwherebyrepeatedshortepisodesof
ischemiaprotectthemyocardiumagainstasubsequenttotal
occlusionofthecoronaryartery.
Thisapproachhasbeenrecognizedasthestrongestform
ofinvivoprotectionagainstmyocardialischemicinjury,since
itismostconsistentandthemagnitudeofprotection
achievedislargerthanthatfromanyotherintervention.It
hasbeensuggestedthatsuchpre-conditioninghas
significantapplicationpriortocardiacsurgery.Abriefperiod
ofischemiaprotectstheheartfrommoreprolongedepisodes
ofischemia,andreducenotonlytheinfarctsizebutalsoits
incidence,andalsominimizeseverityofreperfusion-induced
arrhythmias,preventingendothelialcelldysfunction(16).

101. Themechanismunderlyingischemicpre-conditioningis
verycomplexandisprobablyassociatedwiththeactivation
ofcertainG-protein-coupledreceptors(GPCR).
Thereisalsoevidenceindicatingthetransactivationof
receptortyrosinekinaseactivity,andthePI3K/Aktsignaling
pathway.AsbrieflyillustratedinFig.2,activationofGPCR
andPI3K/Aktleadstoelevatedactivityofnitricoxide
synthase(NOS)andnitricoxide(NO)formation,aswellas
guanylatecyclaseandproteinkinaseG(PKG).Substrates
forPKGincludetheSRregulatoryproteinphospholamban,
whichpromotesSRCa
2+
uptake,andthusreduces
cytosolicCa
2+
overloadandinhibitionofmPTP.
ActivationofAktalsoinhibitsGSK-3βandpro-apoptosis
membersoftheBcl-2proteinfamilysuchasBadandBim,
therebyinhibitingmPTPopening.

103. Ischemicpost-conditioning
Thephenomenon ofischemicpost-conditioning
encompasses introductionofbriefcyclesof
ischemia/reflowsoonafterthedamagingprolonged
ischemiafollowedbyreperfusion(17).
Ischemicpost-conditioninghasbeenshowntoreduce
infarctsize,insomecases,equivalenttothatobserved
withischemicpre-conditioning.Ingeneral,theprotection
affordedbyischemicpost-conditioningisweakorabsent
afterbriefischemicepisodesthatcausesmallinfarcts(18).
However,unlikeischemicpre-conditioning,whichdelays
thedevelopmentofinfarction,post-conditioningreduces
reperfusioninjury.Althoughnostandardoperating
procedureshavebeendefined,thepost-conditioning
interventionmustbedonewithinthefirstfewminutes
followingreperfusionafterischemia.

104. Na+/H+exchangeinhibitors
Thebuildupofintracellularcalciumresultingfromthe
inhibitionofNa
+
/K
+
-ATPaseandbythehyperactivationof
Na
+
/H
+
exchangerincardiomyocytesduringischemiaand
reperfusion,istherationalefortheuseofNa
+
/H
+
exchange
inhibitors,toprotecttheheartfromischemia-reperfusion
injury.
Cariporidehasbeenextensivelystudiedanditdemonstrated
anattenuationofreperfusioninjurycharacterizedby
improvedLVfunction(28).SM-20550,another
Na
+
/H
+
exchangeinhibitor,wascomparedwithnicorandil,a
K-channelopenerwithnitrate-likeactivity.Bothreduced
infarctsizeinadose-dependentmannerwhengivenpre-
ischemiabutonlySM-20550wasbeneficialwhengivenpost-
ischemia(29).Besidesthecardioprotectiveeffects,several
linesofevidenceindicatesthatNa
+
/H
+
exchangeinhibitionis
alsoeffectivetominimizemyocardialremodelling(3

105. Atrialnatriureticpeptide(ANP)andphosphodiesterase
5(PDE5)inhibitors
AnimalstudieshavedemonstratedthatinclusionofANP
duringreperfusionreducesinfarctsizethroughthe
activationofcGMP/PKGsignalingpathway(31),PKG,
whenactivatedbycGMP,phosphorylatesseveral
intracellulartargetproteinsthatareinvolvedinthe
regulationofvasculartone,vasorelaxationinvascular
smoothmuscleandalsoendothelialpermeability,andcell
differentiationandproliferation.

106. Targetingthispro-survivalsignalingpathwayof
cGMP/PKG forthepreventionofmyocardial
reperfusioninjuryalsohasevidencefromstudies
usinginhibitorsof(PDEenzymes,inparticularPDE5,
whichblocksthehydrolysisofcGMP.ThusPDE5
inhibitorssuchassildenafil,vardenafil,andtadalafil
havebeenshowntobeprotectiveagainstmyocardial
ischemia/reperfusioninjury,byinducingthe
expressionofNOS,andactivationofPKG-dependent
hydrogensulfidegeneration.

107. Glucose-insulin-potassium(GIK)
Glucagon-likepeptide-1(GLP-1)
Theinsulinotropicincretin,GLP-1anditsanalogue
exenatidehavebeenshowntoofferprotectionduring
ischemia-reperfusion.Thistherapeuticapproachhas
successfullybeentranslatedintotheclinicalsetting,
employingexenatideduringreperfusion.
AdenosineReceptorAgonist
Avarietyofmechanismsofactionofacardioprotective
effectforadenosinehasbeensuggested,includingapotent
vasodilatoryaction,amongothers.Inadditiontoitseffects
onthevasculatureandleukocytes,adenosineincreasesNO
availabilityviaactivationofAkt/cGMP/PKGsignaling
pathway.

108. mPTPinhibitors
Cyclosporine-Aisthefirstpharmacologicagentthat
hasbeenshowntolimitinfarctsizebyinhibitingthe
openingofthemPTP.AlthoughotherindirectmPTP
inhibitors,includingsodiumnitrite