NSG 533 Path Exam 3 Notes, Exams of Molecular biology

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NSG 533 Path Exam

3 Notes

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W e k 8 :CoronaryHeartDisease& Hypertension

Introductions Prevalence

• Almost 1 in2adultshavesomeformofCVD
• Hypertension–> 116 mi l ion( 46 %)
• Coronaryheartdisease– 18. 2 mi l ion( 6. 7 %) CoronaryHeartDisease
• LeadingcauseofdeathinAmericanmenandwomen
• 365 , 914 U.S.deathsin 2017 (~ 1 ofevery 7 deaths)
• From 2007 to 2017 ,theannualdeathratea t ributabletoCHDdeclinedby 28. 1 %.
• Approximately 35 % ofpeoplewhohaveacoronaryeventinagivenyearwi l dieofit.
• In-hospitalmortalityishigherinwomenthaninmenwithSTEMI( 7. 4 % versus 4. 6 %)and NSTEMI( 4. 8 % versus 3. 9 %).
• Inthepastdecade,therehasb e namarkeddeclineinSTEMI(from 133 to 50 casesper 100000 person-years). SocialDeterminantsAffectSurvivalandLifeExpectancyPostMI
• InastudyusingdatafromtheCooperativeCardiovascularProject,survivalandlifeexpectancy afterAMIwerehigherinwhitesthaninblacks( 7. 4 % versus 5. 7 %). o WhitepatientslivinginhighSESarea s howedthelongestlifeexpectancy.
• AmongpatientshospitalizedforSTEMIbetw e n 2003 and 2014 ,lackofhealthinsurance(OR,

1. 77 [ 95 % CI, 1. 72 – 1. 82 ]; P < 0. 001 )andbelow-medianincome(OR, 1. 08 [ 95 % CI, 1. 07 – 1. 09 ]; P < 0. 001 )wereindependentpredictorsofin-hospitalmortality.

• Comparedwithnonparticipants,participantsintheSupplementalNutritionA s istanceProgram havetwicetheriskofCVDmortality,whichlikelyreflectsdifferencesinsocioeconomic, environmental,andbehavioralcharacteristics. CardiovascularDisease(CVD)MortalityTrendsforMales& Females
• Usetobemorefemaledeathsandtheninmales o Thisi s omewhatduetohormonetreatment ▪ OncerealizedHRTaffects,weeducatedwomen&onlythosewhotrulyn e dedit gotit ▪ Thiscausedastepdecreaseinfemalesdeathsmakingitle s thanmales
• Wesawadecreaseindeaths&after 2000 itplateauedoffandthenbegantoincreaseagain o Canbeduetolifestyle CHDRiskFactors RiskFactorNote
• Riskfactoridentification&modification(preventivecardiology)isbasedonthepremisethat exposuretocertainhostandenvironmentalfactorsincreasesaperson’ s tatisticalriskfor developingcoronaryheartorarterydisease
• Whenwealtertheseconditions,riskshouldbereduced

- GeneticStudies o ElevatedLDLlinkedtoCHDinpersonswithgeneticformsofhypercholesterolemia o DecreasedLDLremovalrelatedtodefectiveo r educednumberofLDLreceptors ▪ OnthesurfaceoftheliverthereareLDLreceptors - Thesereceptorsresponsibleforclearingandremovingcholesterolfrom circulation ▪ Peoplewhohavefewerordefectivereceptorshaveageneticformsof hypercholesterolemia - FH=familialhypercholesterolemia o Unle s treatedataveryyoungage(sometimespheresis)itincreases risk o FH→ significantatherosclerosisandprematureCADintheabsenceofothe r iskfactors ▪ HomozygousFH - Familialhypercholesterolemia - BumpsofskinaredepositsofcholesterolderivedfromLDL - Skyhighcholestero l evelsataveryyoungage OtherRiskFactors - Smoking o Weknowit’stheleadingcauseofpreventabledeathsinUS ▪ Wewo r yaboute-cigare t euse o 1 / 3 indeathswithCADarefromsmoking o Detrimentalaffects ▪ DecreaseHDL-C ▪ Reducedcoronaryflow ▪ Increasesriskforvasospasms ▪ Adverselyaffectsendothelialfunction,fibrinogenlevel,&plateleta g regation

• Hypertension o Mostprevalentcardiovasculardisease o Directrelationbetw e nelevatedbloodpre s ure&incidenceofCAD/stroke - Physicalinactivity o Adults 18 yoorolderonly 24. 3 % metbothfederalguidelineforaerobicexercise& musclestrength o Physicalactivitydoestheoppositeofsmoking ▪ ItincreasesHDL&decreasetriglycerides ▪ Facilitateoptimalbodyweight ▪ Decreaseinsulinresistance ▪ IncreasemaximalCO - Diabetesme l itus o 26 mi l ionadultshavediagnosed o 9. 4 mi l ionhaveundiagnosed o 92 mi l ionhavepre-diabetes o CADisamajorcomplicationofdiabetes

o Increasesplateleta g regation o Promote s moothmuscleproliferation&cholesterolco l ectiononarterialwa l

- Obesity o 35 cmforwomen& 40 cmformen Non-ModifiableRiskFactors

• Familyhistory
• Age o MI ▪ You r iskisgreaterifyourfatherhadanMIat 40 comparedtoifhehadanMIat 75 o Overa l ,theriskincreaseswithage
• Gender o Symptomsare 10 yearsearlierinmenthanwomen o Coronarydiseaseriskevensoutoncethewomanreachesmenopauseage NovelRiskFactors - Elevatedlipoprotein(a) o GeneticparticlesimilartoLDL o LipoproteinAisliketheclo t ingfactorplasminogen ▪ Itmovestoreducedfibrinolysis o Tendstobea s ociatedwithatherosclerosis,increasecoronarydiseaseevents&stroke o Measuredbyasimplebloodtest - ElevatedhighsensitivityC-reactiveprotein(hs-CRP) o Inflammatorymarker ▪ Inflammationispartnerswithatherosclerosis - Elevatedfibrinogen o Inflammatorymarker - ElevatedLDLparticlenumber o CholesterolconcentrationintheLDLparticles ▪ Therecouldbemoreorle s cholesterolineachparticlewedon’tknow o ThenumberofparticlesofLDLthemselvesismoreindicativeofriskthantheLDL-C - Sma l ,denseLDL o Moreatherogenic PathogenesisofAtherosclerosis
• Progre s ivediseaseproce s thatgenera l ybeginsinchildhood o However,clinicalmanifestationso c urinmiddletolateadulthood
• Multifactorialproce s
• Variablecompositionoflesions o Somearedense&fibrous o Somecontainlargeamountsoflipids&bloodproductdebris
• Lesionsarelikelytodevelopfo l owingendothelialinjury o Areasofincreasedshearwa l stre s areespecia l yvulnerable

Advanced(Complicated)Lesion

• Smoothmusclece l s,numerousmacrophages,Tce l s,oftena s ociatedwithlipidcoreand necroticmaterial - Coveredbyafibrouscap o Smoothmusclece ls u r oundedbyconnectiveti s uematrix o Thickcap ▪ Thismeansthereisalotofconnectiveti s ue&isdesnse ▪ Provide s tabilitytothelesion o Thin,non-uniformcap,macrophage-rich ▪ Lesionisunstable - Thisispronetorupture - ThisrupturingiswhatcausesamajorityofMIs o Ifinheadorneckcancausestroke - Maycausethrombosis,hemo r hage,and/orcalcification - Usua l ywhiteinappearandprotrudesup - Itmayormaynotaffectbloodflow - AnatomyofAtheroscleroticPlaque - o Smoothmuscleismovedintotheintima o Wes e t-lymphocytes&macrophagesarepresent

o Lipidladenfoamce l sarepresent o Lipidcoreiscoveredbyacap ▪ Doesn’tshowifthickorthin Atherosclerosis:AProgre s iveProce s

• Pathway o Normal o Fa t ystreak o FibrousPlaque o O c lusiveatheroscleroticplague ▪ Sidenote:Thisiswhenwes e effortinducedangina o Plaquerupture/fi s ures&Thrombosis ▪ Unstableangina ▪ MI ▪ Coronarydeath ▪ Stroke ▪ Critica l egischemia

PathogenesisofAtherosclerosis

• Abnormalitiesinlipidmetabolism
• Smoking o Causesendothelialdysfunction&otherthings
• Hypertension/ve s elshearwa l stre s o Injuryinsidetheartery
• Endothelialdysfunction
• Inflammatoryandimmunologicfactors
• Plaquefi s uring/rupture o Leadstoanacutecoronaryevent

RoleofHDL

• HDLpromotesreversecholesteroltransportfromthearterialwa l ,specifica l yfromlipid-laden macrophages o Itisbringingitbacktotheliverforfurtherproce s ing
• Mayalsoprotectagainstexce s lipida c umulationintheve s elwa l byinhibitingtheoxidation ofLDL CharacteristicsofPlaquesPronetoRupture
• VulnerablePlaque o Largerlipidcore o Averythincap ▪ Whenexposedtostre s suchashypertensionortoba c osmokeitcaneasilybe injured&rupture
• Oncerupturedthereisbl e dingintothelumenwhichcausesabloodclot toform
• Thisdecreasebloodflow&ptexperiencesanacutecoronarysyndrome
• StablePlaque o Sma l erlipidcore o Mus t hickerfibrouscap o Eventhoughthelumeni s ma l eritisamorestableform ▪ Ptmostlikelyexperiencingeffortangina ▪ ProtrudemoreintoarterysomoredecreaseinBF

ARupturedAtheroscleroticPlaque

• E c entric,lipid-rich
• Fragilefibrouscap - Priorluminalobstruction< 50 % o Inthesevulnerablethereisusua l yadequatebloodflow ▪ Theymaynotobstructbloodflowsignificantly
• Visibleruptureandthrombus Degr e ofStenosisPriortoMI
• Mostcommonlythereisle s than 50 % stenosispriortoMyocardialinfarction o ~ 70 % ofptwhohadMIhadstenosis< 50 % o ~ 18 % hadstenosis 50 – 70 % o ~ 14 % hadstenosis> 70 %
• Weares e ingthatitismoremildandmoderatestenosisthatpthavethatgetMIs Response–to–InjuryHypothesis - Variou s ourceso r iskfactorsmayinducesomeformofendothelialdysfunctions - Changesinendotheliummayresultin o Alterationsinpermeability o Adhesivecharacteristics o Growth–stimulatorycharacteristics
• Thesechangesleadtomonocyte-endotheliala t achment,adherence,andtransmigration o Sothatmonocytesenterthesubendothelium,becomeactivatedasmacrophages,andare joinedbyT-ce l s
• MacrophagesandTlymphocytescomposethefirstlesionofatherosclerosis thefa t ystreak
• Activationofthesece l scanresultintheformationofmoleculesthata t ractsmoothmusclece l s tomigrateandreplicatewithinthelesion
• Throughaproce s ofco-stimulation,remodeling,andformationofa l theelementsofCTby smoothmuscleandbyendothelialce l s,fibrousplaquesultimatelyformwithafibrouscapthat coversalipidcoreandnecroticmaterial A p licationsofTherapies
• Earlydietaryinterventionforchildrenwithdyslipidemia o DecreasinglevelsofLDLcancauseregre s ionofatheroscleroticlesionsandimprove endothelialfunction o Avegandietcangreatlyreducecardiovasculardiseaserisk
• Angina o Isdefinedasischemicpainwithexercise o A g re s iveriskfactormodificationcanresultinlesionregre s ionandimprovedti s ue perfusion o Ex:plant-baseddiet
• AspirinandP 2 Y 12 inhibitors, o Exampleofp 2 y 12 inhibitorisClopidogrel o Wes e thisgivenwhensomeonecomesinwithunstableangina

o Anemia

• Increasedforceofmyocardialcontraction o Exercise IschemiaisRelatedtoMyocardialOxygenSu p ly& Demand MyocardialStu n ing
• Fo l owingabriefepisodeofsevereischemia,prolongedmyocardialdysfunctiono c urs,thena gradualreturnofcontractileactivity
• InAMI,stunnedmyocardiumliesadjacen t oinfarctedmyocardium o Stunnedmyocardiumisrightnex t othedeadti s ue
• Canbecausedby o Transientcalciumoverloadofmyocytesimmediatelyafte r eperfusion o Excitationcontractionuncouplingduetodysfunctionofthesarcoplasmicreticulum o Generationofoxygenderivedfr e radicals HemodynamicConsequencesofMyocardialIschemia
• Declineinmyocardialoxygentensionandlo s incontractility
• Regionaltoglobaldepre s ioninLVfunction
• ReductionsinSV(strokevolume),CO(cardiacoutput),andEF(ejectionfraction)
• ElevationsinLVEDV(leftventricularenddiastolicvolume)andP(pre s ure)
• Increasedresistancetoventricularfi l ing
• ClinicalevidenceofHF(heartfailure)whencontractionceasesin 20 - 25 % oftheLV
• Note:thiswholeproce s happenswithinsecondsofcoronaryarteryo c lusion

o Thisisbecausethehearthasnooxygenstores o Itaffectsbothcontractilityandfi l ing EffectsofIschemiaonMyocardialMetabolism

• Declineinproductionofhighenergyphosphates(ATP,CP)anddeclineinti s uestores o RememberinhypoxiathereisnoATPgenerationratherlactateisproduced - ATP> 60 % control–ti s ueisreversiblyinjuredbyischemia o Ce l ularsignsofischemiaarepresent ▪ Glycogenlo s , ▪ Nuclearchromatinclumping, ▪ Intermyofibri l aredema, ▪ Mitochondrialswe l ing - ATP< 20 % control–ce l scannotregeneratehighenergyphosphateormaintainphysiologic ionicgradients o Ce l swe l ing o Sarcolemmaldamage ▪ Damagetoce l ularmembrane
• Ventriculartachydysrhythmiascausedbyenhancedautomaticity,r e ntry,ortri g eredactivity
• MarkedreductioninRMP,APamplitude,rateofupstrokeofphase 0 ,andtheAPduration o RMPisusua l y- 90 canbecloserto- 70 o Decreaseinrateofrise o Na r owingofactionpotential o
• ReductioninATPstoresinterfereswithtran s arcolemmalNa-Kexchange
• Intrace l ularNa+andCa + elevate
• LowerATPstoresreduceCa + uptakebytheSRandextrusionofCa + fromce l s
• Increasedintrace l ularCa + causesmitochondrialCa + overload,decreasingATPproduction further Na/CAOverloadandIschemia

o Cla s I :Newonset,severeora c eleratedangina o Cla s II: Anginaatrest,subacute ▪ Subacute=anginaatrestwithintheprecedingmonth,notwithinthepreceding 48 hours o Cla s III: Anginaatrest,acute ▪ Acute=anginaatrestwithinthepreceding 48 hours o Physicalexammayinclude ▪ Transien t hirdandfourthheartsounds

• S 4 :atrialcontractionagainstastiffventricleisresponsibleforit
• S 3 :increaseinfi l ingphase,oftenheardwithHF ▪ Transientsystolicmurmurofmitralregurgitation NSTEMI
• NoSTelevatedMI
• Moresevereplaquedamage
• Morepersisten t hrombotico c lusion(upto 1 hour)
• Plaquerupture
• EKG&LabFindings o InitialECGdoesnotshowelevatedSTsegment;STdepre s ionand/orinvertedTwaves arepresent o EarlypeakCKlevel o STEMI
• STelevationMI
• Largeplaquefi s ures
• Fixedandpersisten t hrombus
• Ce s ationofmyocardialperfusionfor> 1 hour
• Transmuralnecrosisofinvolvedmyocardium
• ClinicalFeatures o Mayhaveprodromalsymptoms:unstableangina,generalmalaise,exhaustion o Painisvariableinintensity,quality,andlocation o Painlastslongerthanangina,unrelievedbyrestandNTG o Maypresenta s ymptomsofacuteLVfailure,weakne s ,orsyncope(elderly)

• PhysicalExam o Anxiousandrestle s o Coldperspirationandskinpa l or o VariableHRandBPresponses o Fourthheartsound ▪ ReductioninLVcompliance o Thirdheartsound ▪ withsevereLVdysfunction o Systolicmurmur ▪ Mitralregurgitation
• Lab&EKGFindings o ElevationofCK o ElevationofCK-MB o Elevationofmyoglobin(peak 1 - 4 hours) o Elevationoftroponin ▪ Begintoriseat 3 hoursfromonset o ElevationofLDH 1 o STsegmentelevation,Twaveinversion,Qwaves ▪ Leadsthatreflectinjuredmyocardium o o

▪ Mechanismofmyocardialinjuryiscoronaryarteryobstructioncausedby formationofanintramuralhematoma(IMH)orintimaldisruption ▪ Morecommoninyoungwomen,especia l ypregnancy-a s ociatedMIs ImpactsofMIonLV

• Immediatelyuponlo s ofbloodflow,thezoneofmyocardiumsuppliedbythatve s e l osesits abilitytoshortenandperformcontractilework
• Theremaining“normal”myocardiumbecomeshyperkineticasaresultofcompensatory mechanisms o IncreasedSNSactivity,Frank-Starling
• Survivalislowestwith3ve s eldisease o Somoreve s els=le s likelytosurvive
• ThelowertheEF( 35 % orle s )thelowerthelikelihoodtosurvive VentricularRemodeling
• Changesinma s andshapeoftheventriclethata c ompaniesdiseaseaffectingtheheart
• LVwa l thinninganddilationinareaofinfarctionpriortotheformationofafirm,fibroticscar o Reductioninnumberofmyocytes
• Infarctexpansionleadsto o DiminishedSV,CO,andEF o LVdistendsduetodyskinesis o DecreasedLVemptyingresultsinincreasedEDV(preload)
• Secondarychangeso c urinnon-infarctedti s ue o Increaseinsarcomerelength o Greate r elativeshorteningoffibers
• Overa l increaseinwa l tensionwithLVdilation o Wa l stre s servesasastimulusformyocytehypertrophy
• Neurohumoralactivationo c urstocompensateforLVdysfunction o Therearepositiveandnegativeeffects o Increaseinnorepi,atrialnatriureticfactor,vasopre s in,angiotensinII ▪ Thesemaypromoteheartfailureandhavepo s ibleinfluenceonventricular remodeling
• Ex:angiotensinIIcausesmyocytehypertrophy,vasoconstriction&release ofaldosterone o Increasesarterialwa l stre s
• Infarctexpansionislinkedtohighermortalitiesandhighernonfatalcomplication s uchasHF andventricularaneurysm
• Myocardialresponsetoischemia&infarction

o A p licationsofTherapies

• ACEinhibitors o GivenpostMI ▪ Especia l ywhenthereisanydegr e ofleftventriculardysfunction o Limitremodelingproce s o Limitventriculardilationandhypertrophy o Bluntneurohumoralresponse, o Promotesodiumexcretion
• Nitrates o Givenwhenadmi t edforunstableanginaorMI o Reduceinfarctsize o ReduceLVfi l ingpre s ure, o Reducearterialpre s ure,improveregionalmyocardialbloodflow ComplicationsofMI
• Dysrhythmias LVfailure RVinfarction
• Cardiogenicshock Papi l arymusclerupture Pericarditis
• LVaneurysm StableAnginaPectoris - Chestdiscomfortcausedbymyocardialischemia,usua l ybroughtonbyexertion o Usua l ybecauseofstableplaque
• A s ociatedwithadisturbanceinmyocardialfunction,butwithoutmyocardialnecrosis