Coronary Heart Disease - University of California, Los Angeles...Coronary Heart Disease (CHD) •...
Transcript of Coronary Heart Disease - University of California, Los Angeles...Coronary Heart Disease (CHD) •...
MitochondrialImplicationsin
CoronaryHeartDisease(Pre-Ischemia)
ArterioscleroticVascularDisease(ASVD)• ASVDisthebuildupofplaque
alongarterialwalls.• Plaqueiscomposedof
cholesterol,fat,calcium,andothersubstancesfromtheblood.
• Plaquebuildupleadstonarrowingofthearteries,andconsequentlybloodclots.
• WhenASVDoccursinthecoronaryarteries,itisclassifiedasCoronaryHeartDisease.
CoronaryHeartDisease(CHD)• Coronaryarteriesareresponsiblefor
thesupplyofoxygenatedbloodtotheheartitself.
• Thecoronaryarteriesdivergefromtheaortaalmostimmediatelyafteritbranchesofffromtheleftventricleoftheheart.
• Theleftcoronaryarteryfurtherdivergesintotheleftcircumflex(LCX)andtheleftanteriordescending(LAD),whiletherightcoronaryarteryhasonlyonemajorbranch.
• Whenatherosclerosisoccursinanyofthecoronaryarteries,bloodsupplytotheheartisslowedorblocked.
StagesofCHD
SymptomsofCHD• Angina(chestpain)• Shortnessofbreath• Fatigue
Thedecreasedefficiencyofthebloodflowcausesthemuscletobeeasilyexhausted,oftenresultinginatight,squeezingsensationinthechest,neck,arms,stomach,orupperback.Paintypicallyworsenswith(butisnotlimitedto)physicalactivityandemotions,andsubsideswithrestandtreatmentwithnitroglycerin.
HeartAttack!(Ischemia)
• Whenbloodflowisseverelyorentirelycutoff,aheartattackoccurs.
• Duringaheartattack,theheartmuscleisdeprivedofoxygen,thisiscalledischemia.
• Ischemicinjury(damageordeathtotheheartmuscle)isaresultofMyocardialInfarction(MI).
ArterioscleroticVascularDiseaseInheritance
Pathogenesis:• Thediseasecanoccurbybehavioralinduction.• Thereisalsoastronghereditarycorrelation,thoughtheexactgeneticcontributingfactorsarenotunderstoodintheirentirety.
• Themitochondrialgenome(mtDNA)hasbeenimplicatedasamaternallyinheritedpredispository factor.
MitochondrialImplications• Reactiveoxygenspecies(ROS)formedduringoxidativephosphorylationcauseoxidativestress.OxidativestresselevatesmitochondrialDNA(mtDNA)damageandmutationlevels.
• ExcessivemitochondrialdamageinbothproteinsandDNAdecreasesefficiencyandcanalsoresultinapoptosis,amitochondrialmediatedprogrammedcelldeath.
• Thedecreasedefficiencyandapoptosisinsmoothmusclecellsarecontributorstoplaqueprogression.
• Mutations/damageinDNAalsoshowadirectcorrelationwiththepresenceofCHD.
EvidenceofImplicationsIntheexperimentalexaminationoftissuefromatheroscleroticcoronaryplaque,thefollowingobservationsweremade:
1) Themeanlevelofheteroplasmy inaspecificsetoffivemitochondrialgeneswassignificantlyhigherinthediseasedtissue1.
2)Presenceofmolecularmarkersspecifictoapoptosiswassignificantlyhigherintheatherosclerotictissue6.
3)Vasoactivemarkersthatcontrolapoptosisinthesmoothmusclecellsandendothelialcellswerealteredduringtheprogressionofatherosclerosis6.
4)Theabundantpresenceofmatrixmetalloproteinases intheatherosclerotictissuecausedlotsofcellularstresssometimesfollowedbyapoptosis11.
Mitochondria:MainFunctions
• OxidativePhosphorylation• RegulationofCellularMetabolism• Apoptosis• CalciumSignaling• LipidTransfer
NormalOxidativePhosphorylationinaMitochondrion
ReactiveOxygenSpecies
• Formation:0.4-4.0%ofalloxygenconsumedinoxphos isconvertedintoasuperoxideradical.Thisoccurswhenoxphosmalfunctionsandreducesoxygen,formingasuperoxideradical.Thesuperoxideradicalisthenconvertedintohydrogenperoxidebyasuperoxidedismutaseenzyme,andthenthehydrogenperoxideisconvertedintowaterbyaglutathioneperoxidaseenzyme.Iftheenzymesdonotcatalyzethechangesadequatelyorefficientlyenough,aROSisformedcausingoxidativestress.
• ReactiveoxygenspeciesarecapableofdamagingbothproteinandDNA.mtDNAisespeciallysusceptibleduetoitslackofhistones,likenuclearDNA.
• mtDNA,whenfunctional,repairsthedamagebymolecularremodeling.However,mutationsanddamagestillaccumulateovertime.Damagemayultimatelyresultinapoptosis.
O2→O2-→ H2O2→ H2O
OxidativeStressEffects• ROSshavealsobeenimplicatedin:aging,schizophrenia,bipolardisorder,
dementia,Alzheimer’s,epilepsy,chronicmigraines,strokes,neuropathicpain,Parkinson’s,ataxia,transientischemicattack,cardiomyopathy,chronicfatiguesyndrome,fibromyalgia,diabetes,HepatitisC,etc…aswellasCHD.
Prevention• HealthyBalancedDiet:
-lowintakeofsaturatedandtrans-fat-highfiber-fruits&vegetables-wholegrain-someunsaturatedfat:avocado,oilyfish,nutsandseeds…
• PhysicalActivity:LowerBMIandBloodPressure• Reducedrinking…Giveupsmoking…• ManageStress!
Screening
Detectionmethodsinclude:
• Exercisestresstest• HeartCTscan• Nuclearstresstest• Echocardiogram stresstest• Electrocardiogram (ECG)• Coronaryangiography- aninvasivetestthatevaluatesthe
heartarteriesunderx-ray• Electron-beamcomputedtomography(EBCT)tolookfor
calciumintheliningofthearteries-- themorecalcium,thehigheryourchanceforCHD
Prognosis
• Outcomesdifferbyseverityandindividual.Withearlydetection,lifestylechangescanbeadequatetreatment.
Inmoresevereandadvancedcases,surgery(bypass,stentplacement,angioplasty)ordeatharepossibleoutcomes.
Conclusion• BehavioralhabitscontributetotheriskofArterioscleroticCoronaryHeartDisease.
• Still,manyindividualsarehereditarilypredisposedthroughboththemitochondrialgenomeaswellasthenucleargenome.
• TherearemultiplefactorsthatcontributetotheproductionofROSsandtheinductionofapoptosis,bothsymptomsandcausesofCHD.
• Lifestylechangesindiet,exercise,smoking,etc.canaidinboththepreventionandcombatofcoronaryheartdisease.
Sources1. Sobenin,IgorA.,MargaritaA.Sazonova,AntonY.Postnov,YuriV.Bobryshev,andAlexanderN.Orekhov.
"Abstract."NationalCenterforBiotechnologyInformation.U.S.NationalLibraryofMedicine, 11Sept.2012.Web.15Aug.2013.
2. "WhatIsAtherosclerosis?"- NHLBI,NIH.N.p.,1July2011.Web.15Aug.2013.<http://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis/>.
3. "heteroplasmy – Dictionarydefinitionofheteroplasmy |Encyclopedia.com: FREEonlinedictionary."Encyclopedia.com|FreeOnlineEncyclopedia.N.p.,n.d. Web.15Aug.2013.<http://www.encyclopedia.com/doc/1O6-heteroplasmy.html>.
4. Board,A.D.A.M.Editorial."CoronaryHeartDisease." CoronaryHeartDisease.U.S.NationalLibraryofMedicine,22June2012.Web.15Aug.2013.<http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004449/>.
5. Jia,Z.etal."ResultFilters."NationalCenterforBiotechnologyInformation.U.S.NationalLibraryofMedicine,14June2013.Web.15Aug.2013.
6. Best,PatriciaJ.etal."Apoptosis."Apoptosis:BasicConceptsandImplicationsinCoronaryArteryDisease.N.p.,n.d. Web.15Aug.2013.
7. Corral-Debrinski,M.etal."AssociationofMitochondrialDNADamagewithAgingandCoronaryAtheroscleroticHeartDisease."NationalCenterforBiotechnologyInformation.U.S.NationalLibraryofMedicine, Sept.1992.Web.15Aug.2013.
8. Ballinger,S.W."MitochondrialDysfunctioninCardiovascularDisease."NationalCenterforBiotechnologyInformation.U.S.NationalLibraryofMedicine, 15May2005.Web.15Aug.2013.
9. Pieczenik,SteveR.,andJohnNeustadt. "MitochondrialDysfunctionandMolecularPathwaysofDisease."NBIHealth.N.p.,18Jan.2007.Web.14Aug.2013.
10. Davies,M.J."Reactive OxygenSpecies,Metalloproteinases, andPlaqueStability."ReactiveOxygenSpecies,Metalloproteinases,andPlaqueStability.N.p.,n.d. Web.15Aug.2013.
11. Watanabe,N.,andU.Ikeda."MatrixMetalloproteinases andAtherosclerosis."NationalCenterforBiotechnologyInformation.U.S.NationalLibraryofMedicine, 6Mar.2004.Web.15Aug.2013.
Acknowledgements
Thankyou!Fromthebottomofmyheart.• Dr.Peipei Ping• CaitlinBlackandAmandaLin• Dr.DavidLiem• Dr.JunZhang• AllthemembersofthePinglab!