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General Overview Coronary artery disease is the build up of plaque on the
inner walls of the coronary arteries reducing blood flow
to the heart
Aliases: atherosclerotic heart disease, coronary heart
disease, or ischemic heart disease (IH!
It is a catalyst for "yocardial infarction (Heart attac#!
coronary arteries are occluded due to a blood clot for acertain period of time that leads to myocyte death due to
o$ygen starvation
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"Global facts & map on ischaemic heart diseases." World Heart Federation. N.p., n.d. Web. 7 Mar.2014. http!###.#orld$heart$federation.or%cardioasc'lar$health%lobal$facts$map%lobal$facts$map$
on$ischaemic$heart$diseases(.
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Prevalence of coronary heart disease by age and se$ (%ational Health and %utrition&$amination 'urvey: ))*+))!-
Go A S et al.Circulation
. 2014;129:e28-e292
Copyright American Heart Association, Inc. All rights reserved.
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Treatment "ethods leading to
.eperfusion.eperfusion: .estoration of o$ygenated blood flow to the
Ischemic region of the heart
- Coronary artery bypass graft: grafting of a foreign blood
vessel
- Coronary angioplasty: Catheter / balloon guided by 01
ray to occlusion/ "ost effective
2- Thrombolysis: destruction of the plaque hardening
protein
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.eperfusion In3ury 4After a period of ischemia or lac# of o$ygen tissue damage
occurs upon the return of blood supply to the tissue-
The flash of o$ygen rich blood following a temporary
deficiency in O$ygen and nutrients from blood during the
ischemic period results in:! inflammation
! o$idative damage through the induction of o$idative
stress rather than restoration of normal function2! Hyper1contracture
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The Two Types of Contracture
Implicated:
")ardiom*oc*te H*percontract're." Courses. N.p., n.d. Web. 12 +pr. 2014.http!co'rse.-'.ed'.cn/2st'd*reso'rcepdf)ardiom*oc*te20h*percontract're.ppt
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Causality Chain:
Manifestations of Reperfusion Injury
Contracture development (rigor contracure and
)a2oerload$ind'ced contract're ,
Contracture development (rigor contracure and
)a2oerload$ind'ced contract're ,
Cause Mechanical stiffness, Tissue necrosis(Myocytedeath/infarction) and Microvascular damage (o!
Reflow)
Cause Mechanical stiffness, Tissue necrosis(Myocytedeath/infarction) and Microvascular damage (o!
Reflow)
Tissue necrosis/ autolysis leads to the release ofintracellular material into the e"tracellular mediumTissue necrosis/ autolysis leads to the release ofintracellular material into the e"tracellular medium
Resulting in an inflammatory responseResulting in an inflammatory response
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Reduction of Ischemia/Reperfusion Inur! "ith #enda$ia% a&itochondria-'ar(etin( )!toprotecti$e *eptide
by Robert A. Kloner, Sharon L. Hale, Wangde Dai, Robert C. Gorman, Takashi
Shuto, Kevin . Koomalsingh, ose!h H. Gorman, Ruben C. Sloan, Chad R. "rasier,Corinne A. Watson, #hilli! A. $ostian, Alan #. Ky!son, and David A. $ro%n
#resented by&
'd%ard 'idad "arha
ahaoa(olume )*+&-une , /)
2012 by Lippincott Williams & Wilins
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Treatments
- .adical scavengers: 'upero$ide dismutase and Catalase-
5imits:
cell permeability concerns
very high doses (of nonspecific scavengers! for efficacy to be seen
supero$ide dismutase mimetics scavenge only supero$ide anion-
- irect permeability transition pore bloc#ers: CyclosporinA
5imits: narrow therapeutic window,
nonspecific effects on other cellular cyclophilins6calcineurin
reports of cyclosporin1induced vasoconstriction-
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Reduction of #"idative $tress via
$tealth %eptidesThe Szeto-Schiller (SS) peptides
small water-soluble molecules
freely cross cell membranes due to similarstructural motif of alternating basic and aromatic
residues.
Concentrate in inner mitochondrial membrane.
E.g. Bendavia
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Hypothesis of Current $tudy
Bendavia protects the myocardium by
reducing no reflow and myocardial
infarction especially during high !"S
production.
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I& Ischemia/Reperfusion Injury in
$heep Model
Male 3orsett h*brid sheep #ere 'sed.
"H*brid i%or 5heep." Hybrid Vigor Sheep. N.p., n.d. Web. 12 +pr. 2014.http!###.breedersales.com6earnH*brid$i%or$in$)attle$and$5heep$$reedersalesH*brid$i%or$5heep.html(.
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I& Ischemia/Reperfusion Injury in
$heep Model
Group 1 Vehicle
(Control)
8
'roup endavia
(*&*+ mg/g
per hour)
--
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Materials and Methods
Anesthesia was applied.
Catheter placed to observe left ventricular
pressure.
#yocardial infarction by snares leading to an
ischemic ris$ zone of %&-%' of the *.
Coronary occlusion from t+& to t+,& minutes. !eperfusion from t+,& minutes to t+%& minutes.
Treatment at t+& minutes.
/nfarct size assessed at t+%& minutes
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Left% Ischemic ris+ ,one LV)and infarct si,e ris+ ,one)in sheep eposed to in $i$oischemia/reperfusion 0 min/ h).
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
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II& o!Reflow and Infarct $i.e in Rait
Model
Ne# 8ealand White 9abbits
"'nn* reed G'ide! Ne# 8ealand White 9abbit."HubPages. N.p., n.d. Web. 12 +pr. 2014.http!b'nnie.h'bpa%es.comh'b'nn*$reed$G'ide$Ne#$8ealand$White$9abbit(.
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Materials and Methods
Anesthetized
Coronary artery occlusion (CA") for & minutes.
!eperfusion for hours.
Administration of various e0tracts with differing
dosage (concentrations were variable wrt time).
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II& o!Reflow and Infarct $i.e in Rait Model
Group # Number ofRabbits
Infusion composition
and time of
administration
- -+ *&*+ mg/g per hour ofendavia at t0* minutes
efore reperfusion
-1 *&*1+ mg/g&hr of
endavia at t0-* minsefore reperfusion for *
mins ,then *&*+ mg/g&hr
2 -1 *&- mg/g &hr of endaviaat t0 - min efore
reperfusion for * mins
then *&*+ mg/g&hr
3 -+ *&*+ mg/g&hr of saline att0* mins efore
reperfusion (control)
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II& o!Reflow and Infarct $i.e in Rait Model
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II& o!Reflow and Infarct $i.e in Rait Model
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III. Ischemia/Reperfusion Injur in Guinea
!i"s
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"aterials and "ethods
- Guinea pigs anestheti7ed
- Hearts e$cised
2- Hearts on 5angendorff Apparatus forelectromechanical functioning
i. chema of $an"endorff %pparatus (ne$t slide!
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Materials andMethodsi. $chema of 4angendorff 5pparatus
"5'therlandandHearse." SutherlandandHearse. N.p., n.d. Web. 12 +pr. 2014.http!###.so'thalabama.ed'ishrhelphearse(.
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Group # Number of
Guinea !i"s
Infusion
- -3 Control &Ischemia/Reperfusion
61 nmol/$ 'endaia t*1+
mins
2 6 1 nmol/$ 'endaiapostischemic
3 7+., -mol/$ cclosporine %
postischemic
"aterials and "ethods
8- Hearts divided into 8 groups:
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"aterials and "ethods
'- 1o-flow ischemia for %& mins.
,-!eperfusion followed for 2%& mins.
3- /nfarct size assessed.
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Infarct si,e in isolated (uinea pi( hearts eposed to (lo3al ischemia/reperfusion 20 min/2h).
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
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I8& Myocardial 9ptae of endavia
"6an%endorfher." Langendorfherz. N.p., n.d. Web. 12
+pr. 2014. http!###.her$:reisla'f$net.deinde;.php1&6=1(.
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Materials and Methods
% separate "roup of "uinea pi"s (n)
earts 0ere perfused constantl 0ith 1 nmol/$ 'endaia
amples collected at
1. 'aseline (,+ minutes before "lobal no*flo0 ischemia)
,. 2er 13 minutes for the first hour of reperfusion
%t each time point4 , samples of perfusate 0ere obtained (1 m$ of each)
Input perfusate from the buffer before entr into the perfusion cannula
5utput from the pulmonar (arter) cannula
$tandard formulation:
Organ uptake (%) = Input(nmol/L) Output(nmol/L) -**
Input(nmol/L)
'endaia Concentration
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'endaia Concentration 6etermination
i"h !erformance $i7uidChromato"raph
Mass pectrometr
Mass $pectrometry& (n&d&)& Mass Spectrometry& Retrieved March -*,*-3, from http://www&mhhe&com/physsci/chemistry/
;554
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Upta+e of #enda$ia 3! the m!ocardium 3efore ischemia #aseline)and durin( reperfusion.
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
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V- "yocyte Hypo$ia6.eo$ygenation
&$periments- "yocytes isolated from * G-Pigs-
- Placed in perfusion chamber-
"Perfusion Chamber with Field Stimulation (RC-49MFS)." Warner Instruments -. N.p. n.d. !eb. Mar. #$4.
%https&''www.warneronline.om'produtinfo.fm*id+44,.
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V- "yocyte Hypo$ia6.eo$ygenation
&$periments
endavia
Treated 'roup
BluorescentR#$ proe
Dm TMRMproe
o fluorescent
proe
Control 'roup
BluorescentR#$ proe
Dm TMRMproe
o fluorescentproe
%urpose:
-& Cell $urvival& R#$ production
2& Change inMitochondrialmemrane potential
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-* minutes
Treated group4 2 nmol5 Bendavia in perfusion chamber.
Control group 4 no Bendavia administered.
+ minutes
Baseline superfusion.
* minutes
Tyrode6s solution (2&& Argon)--7 8ypo0ia.
Ma" 2* minutesor until Cell Eeath
Tyrode6s Solution (normo0ic).
Remar& Cell death assessed b/ transition from rod-shaped to rounded
V- "yocyte Hypo$ia6.eo$ygenation
&$periments
' i l l t f t i th t d d t h i d
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- 'urvival plot for myocytes in the study e$posed to hypo$ia andreo$ygenation-
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
Cellular .O' production during hypo$ia6reo$ygenation
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- Cellular .O' production during hypo$ia6reo$ygenation-
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
2 "itochondrial membrane potential (m! in myocytes during cellular
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2- "itochondrial membrane potential (m! in myocytes during cellularhypo$ia6reo$ygenation-
lonerRet al. ahaoa 2012;1:-
2012 by Lippincott Williams & Wilins
=ffects of Reperfusion Injury
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+bo'$5leiman et al. Nature Reviews Neuroscience 7, 207?21@ AMarch 200> B doi!10.10/Cnrn1C>C
=ffects of Reperfusion Injury
)*lophilin 3
Mit. 5#ellin% )a2 effl';
9elease apopto%enicfactors e;. )*t c,procaspases
endavia possile Mechanism of
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endavia possile Mechanism of
5ction Bendavia does notappear to be a direct bloc#er of the
mitochondrial permeability transition pore (mPTP!
It appears to inhibit initiation and cascade .O'
production or by "itochondrial .O' scavenging
As such it indirectly causes the closure of the mPTP and
the subsequent maintenance of myocyte energetics (the
preservation of the membrane potential!
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Conclusion
Bendavia reduces infarct si7e in rabbits guinea pigs and
sheep
The upta#e of Bendavia in constant throughout
reperfusion and before it
Bendavia is most efficient when applied after the onset of
ischemia and when targeting larger at ris# 7ones
Bendavia sustains mitochondrial membrane potential
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$tudy 4imitations
.educes infarct si7e but other drugs show greaterdecrease in infarct si7e as opposed to Bendavia
5ow statistical significance in cases due to small samplesi7es
&ven if the cells have been saved from cell death they
remain stunned for days to wee#s To determine whetherBendavia improves cardiac function we need a long termstudy-
9e did not study whether Bendavia limits calciumoverload, a critical component of ischemia reperfusionin3ury-
Bendavia does not target receptors hence there is room for
better the upta#e-
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Buture Implications
Treating neurodegenerative diseases li#e
Par#insons disease, Huntingtons disease, andAl7heimers disease-
Ophthalmological diseases li#e diabeticretinopathy, macular degeneration, and cataractformation-
Paves way for the development and enhancementof targeted peptides-