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.

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"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!