systolic and diastolic function
Brinke, E.A. ten
Citation
Brinke, E. A. ten. (2011, September 29). Hemodynamic folluw-up after heart failure surgery : systolic and diastolic function. Retrieved from
https://hdl.handle.net/1887/17886
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/17886
Note: To cite this publication please use the final published version (if
applicable).
&+$37(5
&OLQLFDODQGIXQFWLRQDOHIIHFWVRI
UHVWULFWLYHPLWUDODQQXORSODVW\
DWPLGWHUPIROORZXSLQ
KHDUWIDLOXUHSDWLHQWV
(OOHQ$WHQ%ULQNH 5REHUW-.ODXW]
6YHQ$7XOQHU +DUULHWWH)9HUZH\
-HURHQ-%D[
9LFWRULD'HOJDGR (GXDUG5+ROPDQ 0DUWLQ-6FKDOLM (UQVW(YDQGHU:DOO -HUU\%UDXQ
0LFKLHO,9HUVWHHJK 5REHUW$'LRQ 3DXO6WHHQGLMN
$QQ7KRUDF6XUJ'HF
$%675$&7
%DFNJURXQG 5HVWULFWLYH PLWUDO DQQXORSODVW\ 50$ LV LQFUHDVLQJO\ DSSOLHG WR WUHDW
IXQFWLRQDOPLWUDOUHJXUJLWDWLRQ05LQKHDUWIDLOXUHSDWLHQWV3UHYLRXVVWXGLHVLQGL
FDWHGEHQHÀFLDOFOLQLFDOHIIHFWVZLWKORZ05UHFXUUHQFHUDWHV+RZHYHUWKHXQGHUO\LQJ
SDWKRSK\VLRORJ\LVFRPSOH[DQGRXWFRPHLQWHUPVRIOHIWYHQWULFXODUIXQFWLRQLVQRW
ZHOONQRZQ:HLQYHVWLJDWHGFKURQLFHIIHFWVRI50$RQYHQWULFXODU IXQFWLRQLQUHODWLRQWRFOLQLFDORXWFRPH
0HWKRGV+HDUWIDLOXUHSDWLHQWVQ ZLWKVHYHUH05VFKHGXOHGIRU50$ZHUHDQD
O\]HGDWEDVHOLQHSUHVXUJHU\DQGPLGWHUPIROORZXSE\LQYDVLYHSUHVVXUHYROXPH
ORRSVXVLQJFRQGXFWDQFHFDWKHWHUV&OLQLFDOSHUIRUPDQFHZDVHYDOXDWHGE\1HZ<RUN
+HDUW$VVRFLDWLRQFODVVTXDOLW\RIOLIHVFRUHDQGPLQXWHKDOOZDONWHVW
5HVXOWV $OO SDWLHQWV ZHUH DOLYH ZLWKRXW UHFXUUHQFH RI 05 DW IROORZXS
PRQWKV&OLQLFDOSDUDPHWHUVLPSURYHGVLJQLÀFDQWO\DOOS*OREDOFDUGLDFIXQF
WLRQ DVVHVVHG E\ FDUGLDF RXWSXW VWURNH YROXPH DQG VWURNH ZRUN GLG QRW FKDQJH
DIWHU 50$ 5HYHUVH UHPRGHOLQJ ZDV GHPRQVWUDWHG E\ GHFUHDVHG HQGV\VWROLF DQG
HQGGLDVWROLF YROXPHV DQG ERWK S 6\VWROLF IXQFWLRQ LPSURYHG
HYLGHQFHGE\LQFUHDVHGHMHFWLRQIUDFWLRQWRS DQGOHIW
ZDUGVKLIWRIWKHHQGV\VWROLFSUHVVXUHYROXPHUHODWLRQ(69WRP/
S 'LDVWROLF IXQFWLRQ KRZHYHU GHPRQVWUDWHG LPSDLUPHQW E\ LQFUHDVHG 7DX
WRPVSDQGVWLIIQHVVFRQVWDQWWR
P/S
&RQFOXVLRQ50$VLJQLÀFDQWO\LPSURYHGFOLQLFDOVWDWXVZLWKRXWUHFXUUHQFHRI05DW
PLGWHUP IROORZXS LQ SDWLHQWV ZLWK KHDUW IDLOXUH +HPRG\QDPLF DQDO\VHV GHPRQ
VWUDWHGVLJQLÀFDQWUHYHUVHUHPRGHOLQJZLWKXQFKDQJHGJOREDOIXQFWLRQDQGLPSURYHG
V\VWROLFIXQFWLRQEXWVRPHVLJQVRIGLDVWROLFLPSDLUPHQW2YHUDOO50$DSSHDUVDQ
DSSURSULDWHWKHUDS\IRUSDWLHQWVZLWKGLODWHGFDUGLRP\RSDWK\DQGIXQFWLRQDO05
&+$37(5
,1752'8&7,21
)XQFWLRQDOVHFRQGDU\PLWUDOUHJXUJLWDWLRQ05RFFXUVLQWRRIWKHSDWLHQWV
DIWHU P\RFDUGLDO LQIDUFWLRQ DQG LQ RI WKH SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH 7\SLFDOO\QRVWUXFWXUDOYDOYHDEQRUPDOLWLHVDUHSUHVHQWEXW05LVFDXVHGE\OHIWYHQ
WULFXODU /9 HQODUJHPHQW DQG GHIRUPDWLRQ ,I FDXVHG E\ FKURQLF HIIHFWV RI LVFKHPLD
WKHWHUPLVFKHPLF05LVXVHGZKLFKUHSUHVHQWVDVSHFLÀFIRUPRIIXQFWLRQDO05$W
\HDUIROORZXSVXUYLYDOUDWHVRIKHDUWIDLOXUHSDWLHQWVZLWKVHYHUH05DUHWR
FRPSDUHGZLWKWRLQSDWLHQWVZLWKRXW05ZKLFKDSSHDUVWREHLQGHSHQ
GHQWRIWKHHWLRORJ\LVFKHPLFYVQRQLVFKHPLF7KHSDWKRSK\VLRORJ\RIIXQFWLRQDO05
LV FRPSOH[ DQG UHPDLQV DQ XQUHVROYHG LVVXH LQ WKH PDQDJHPHQW RI HQGVWDJH KHDUW
IDLOXUH /RVV RI FRQWUDFWLOH IXQFWLRQ DIWHU P\RFDUGLDO LQIDUFWLRQ FDXVHV FRPSHQVDWRU\
FDUGLDF GLODWDWLRQ WR JHQHUDWH PRUH VWURNH YROXPH 7KLV DGDSWDWLRQ FDXVHV D VKLIW LQ
SDSLOODU\PXVFOHVSRVLWLRQUHVXOWLQJLQWHQWLQJRIWKHPLWUDOYDOYHDWFORVXUHDQGPD\
FUHDWHOHDÁHWPDOFRDSWDWLRQ)XUWKHUPRUH/9GLODWDWLRQFDXVHVDQQXODUHQODUJHPHQW
OHDGLQJWRIXUWKHUPLWUDOLQVXIÀFLHQF\$FFRUGLQJWRWKH/DSODFHODZYROXPHRYHUORDG
LQFUHDVHVZDOOVWUHVVZKLFKZRUVHQV/9SHUIRUPDQFHOHDGLQJWRIXUWKHUKHPRG\QDPLF
DGDSWDWLRQVDQGDQXQIDYRUDEOHHQHUJ\EDODQFHRIWKH/9,QYLHZRIWKHSRRUSURJQRVLV
RIGLODWHGFDUGLRP\RSDWK\DFFRPSDQLHGE\05LWVHHPVORJLFDOWKDWVXUJLFDOFRUUHFWLRQ
ZRXOGEHEHQHÀFLDO+RZHYHUGLVFXVVLRQRQWKLVWRSLFLVRQJRLQJLQSDUWLFXODUZKHWKHU
05LVMXVWDPDUNHURISRRU/9IXQFWLRQRUWKDW05LVDPDMRUFRQWULEXWRUWRGHFUHDVHG
VXUYLYDO UDWHV 6XUJLFDO WUHDWPHQW RSWLRQV WR UHVROYH IXQFWLRQDO 05 LQFOXGH UHVWULF
WLYHPLWUDODQQXORSODVW\50$W\SLFDOO\DLPLQJDWXQGHUVL]LQJRIWKHDQQXOXVE\WZR
VL]HV$OWKRXJK50$DGGHGWRFRURQDU\DUWHU\E\SDVVJUDIWLQJ&$%*GHPRQVWUDWHG
VLJQLÀFDQW DGGLWLRQDO UHOLHI RI V\PSWRPV DQG LQFUHDVHG H[HUFLVH WROHUDQFH ORQJWHUP
LPSURYHPHQW LQ WHUPV RI VXUYLYDO UDWHV DUH VWLOO GHEDWHG ,Q DGGLWLRQ TXHVWLRQV
KDYHEHHQUDLVHGUHJDUGLQJSRVVLEOHDGYHUVHKHPRG\QDPLFHIIHFWVRI50$FRQFHUQLQJ
SRVVLEOH GHOHWHULRXV HIIHFWV RI UHOLHYLQJ WKH 05 ZKLFK ZDV UHJDUGHG DV D EHQHÀFLDO
ORZDIWHUORDGIRUWKHSRRU/9¶SRSRII·SKHQRPHQRQDQGWKHLQGXFWLRQRIIXQFWLRQDO
PLWUDOVWHQRVLV)XUWKHUPRUHZKHUHDVPXOWLSOHVWXGLHVGHPRQVWUDWHGUHYHUVH/9DQG
DWULDOUHPRGHOLQJDIWHU50$ORQJWHUPVXVWDLQHG/9UHPRGHOLQJUHPDLQVXQFOHDU /LNHZLVHDFXWHVWXGLHVLQSDWLHQWVZLWKHQGVWDJHKHDUWIDLOXUHDQG05WUHDWHGZLWK50$
GHPRQVWUDWHGQRVLJQLÀFDQWFKDQJHVLQLQWULQVLF/9IXQFWLRQEXWORQJWHUPKHPRG\
QDPLFVWXGLHVDUHODFNLQJ7KHUHIRUHWKHSUHVHQWVWXG\ZDVGHVLJQHGWRHYDOXDWHWKH
FOLQLFDODQGKHPRG\QDPLFSHUIRUPDQFHDIWHU50$E\PHDQVRIFOLQLFDOSDUDPHWHUVDQG
LQYDVLYHO\REWDLQHGSUHVVXUHYROXPHORRSVUHVSHFWLYHO\DWPLGWHUPIROORZXS
0(7+2'6 3DWLHQWV
7KH VWXG\ JURXS FRQVLVWHG RI SDWLHQWV ZLWK FDUGLRP\RSDWK\ 1HZ <RUN +HDUW $V
VRFLDWLRQ1<+$FODVV,,,,9/9HMHFWLRQIUDFWLRQ/9()05JUDGHZKRZHUH
VFKHGXOHGIRU50$7KHPHFKDQLVPRI05ZDVEDVHGRQPDOFRDSWDWLRQGXHWR/9GLOD
WDWLRQ3DWLHQWVUHFHLYHGRSWLPDOPHGLFDOPDQDJHPHQWIRUKHDUWIDLOXUH3DWLHQWVZLWK
SULPDU\PLWUDOYDOYHG\VIXQFWLRQSURODSVHUKHXPDWLFGLVHDVHVWHQRVLVRUDELRORJLF
RUPHFKDQLFDOSURVWKHVLVLQWKHDRUWLFSRVLWLRQZHUHH[FOXGHG$GGLWLRQDOVXUJHU\ZDV
SHUIRUPHGZKHQQHFHVVDU\7KHSURWRFROZDVDSSURYHGE\RXU,QVWLWXWLRQDO(WKLFV&RP
PLWWHHDQGDOOSDWLHQWVJDYHLQIRUPHGFRQVHQW3DWLHQWFKDUDFWHULVWLFVDQGVXUJLFDOGDWD
DUHVXPPDUL]HGLQ7DEOH
7DEOH3DWLHQWVFKDUDFWHULVWLFV
%DVHOLQH 0LGWHUPIROORZXS SYDOXH
3DWLHQWVQ
0DOHIHPDOHQ
$JH\HDUV
,VFKHPLFRULJLQQ
&OLQLFDOFKDUDFWHULVWLFV
1<+$FODVV 3
PLQXWHKDOOZDONWHVWP 3
4XDOLW\RIOLIHVFRUH 3
1<+$1HZ<RUN+HDUW$VVRFLDWLRQ3YDOXHVWDLOHGZHUHREWDLQHGE\QRQSDUDPHWULF:LOFR[RQ
VLJQHGUDQNVWHVW
6WXG\SURWRFRO
%DVHOLQHKHPRG\QDPLFGDWDZHUHREWDLQHGGXULQJURXWLQHGLDJQRVWLFFDWKHWHUL]DWLRQ
SULRUWRVXUJHU\LQFOXGLQJWKHUPRGLOXWLRQFDUGLDFRXWSXWYHQWULFXORJUDSK\DQGFRUR
QDU\DQJLRJUDSK\,QDGGLWLRQD)FRQGXFWDQFHFDWKHWHU&'/H\FRP=RHWHUPHHU7KH
1HWKHUODQGVZDVSODFHGLQWKH/9DQGDWHPSRUDU\SDFLQJOHDGLQWKHULJKWDWULXPWR
REWDLQSUHVVXUHYROXPHORRSVDWÀ[HGLQFUHPHQWDOEHDWVPLQKHDUWUDWHV
&RQGXFWDQFHGHULYHG/9YROXPHZDVFDOLEUDWHGE\WKHUPRGLOXWLRQDQGK\SHUWRQLFVD
OLQHGLOXWLRQ'DWDZHUHDFTXLUHGDWOHDVWPLQXWHDIWHUFKDQJLQJWRDKLJKHUKHDUWUDWH
DQGSHULRGVRIaVHFRQGVZHUHVHOHFWHGIRURIÁLQHDQDO\VLV$OOPHDVXUHPHQWVZHUH
UHSHDWHGDIWHUVXUJHU\GXULQJUHFDWKHWHUL]DWLRQDWPLGWHUPPRQWKVIROORZ
XS&OLQLFDOGDWDLQFOXGLQJ1<+$FODVVTXDOLW\RIOLIHVFRUHDQGPLQXWHKDOOZDONWHVW
ZHUHDVVHVVHGDWWKHVDPHWLPHSRLQWV
&+$37(5
(FKRFDUGLRJUDSK\
$GGLWLRQDO WUDQVHVRSKDJHDO HFKRFDUGLRJUDSK\ 7(( ZDV SHUIRUPHG ZLWKLQ GD\V
EHIRUH VXUJHU\ RQ SDWLHQWV ZLWK PRGHUDWHWRVHYHUH 05 JUDGH VHHQ RQ WUDQV
WKRUDFLF HFKRFDUGLRJUDSK\ 77( 7(( ZDV GRQH ZLWKRXW JHQHUDO DQHVWKHVLD WR DYRLG
XQGHUHVWLPDWLRQ RI 05 6HYHULW\ ZDV JUDGHG VHPLTXDQWLWDWLYHO\ IURP FRORU'RSSOHU
HFKRFDUGLRJUDSK\LQFRQYHQWLRQDOSDUDVWHUQDOORQJD[LVDQGDSLFDOFKDPEHULPDJHV
$WIROORZXSUHSHDW77(DVVHVVHGSRVVLEOHUHFXUUHQW05$OO77(PHDVXUHPHQWVZHUH
DQDO\]HG LQ UDQGRP RUGHU E\ WZR LQGHSHQGHQW REVHUYHUV ZLWKRXW NQRZOHGJH RI WKH
FOLQLFDOVWDWXVRIWKHSDWLHQW
6XUJLFDOSURFHGXUHV
'HWDLOVRIWKHVXUJLFDOSURFHGXUHVDUHGHVFULEHGHOVHZKHUH,QVKRUWDVWULQJHQW50$
ZDV SHUIRUPHG E\ PHDQV RI DWULDO WUDQVVHSWDO DSSURDFK XVLQJ D &DUSHQWLHU (GZDUGV
3K\VLRULQJ(GZDUGV/LIHVFLHQFHV,UYLQH&$86$5LQJVL]HZDVGHWHUPLQHGE\PHD
VXULQJWKHVL]HRIWKHDQWHULRUPLWUDOOHDÁHW$ULQJWZRVL]HVVPDOOHUWKDQWKHPHDVXUHG
VL]HZDVLPSODQWHG:KHQLQGLFDWHGDGGLWLRQDO&$%*ZDVSHUIRUPHG,PPHGLDWHO\DIWHU
VXUJHU\7((ZDVUHSHDWHGWRH[FOXGHUHVLGXDO05WRPHDVXUHWKHWUDQVPLWUDOGLDVWROLF
SUHVVXUHJUDGLHQWE\FRQWLQXRXVZDYH'RSSOHUDQGWRGHWHUPLQHWKHOHQJWKRIFRDS
WDWLRQRIWKHDQWHULRUDQGSRVWHULRUOHDÁHWVE\WZRGLPHQVLRQDO7((DWWKH$3OHYHO 'DWDDQDO\VLV
+HPRG\QDPLFLQGH[HVZHUHFDOFXODWHGXVLQJFXVWRPPDGHVRIWZDUHDVWKHPHDQRIDOO
EHDWVGXULQJDVWHDG\VWDWHSHULRGRIaVDWHDFKSDFHGKHDUWUDWHOHYHO/9IXQFWLRQ
ZDVTXDQWLÀHGE\FDUGLDFRXWSXW&2/9HMHFWLRQIUDFWLRQ/9()VWURNHYROXPH69
HQGGLDVWROLFDQGHQGV\VWROLFYROXPH('9(69DQGSUHVVXUH('3(63DQGPD[LPDO
DQGPLQLPDOUDWHRI/9SUHVVXUHFKDQJHG3GW0$;G3GW0,16WURNHZRUN6:ZDVFDO
FXODWHGDVWKHSUHVVXUHYROXPHORRSDUHD$IWHUORDGHIIHFWLYHDUWHULDOHODVWDQFH($ZDV
FDOFXODWHGDV(63697KHHQGV\VWROLFSUHVVXUHYROXPHUHODWLRQ(6395ZDVGHWHUPLQHG
E\VLQJOHEHDWDQDO\VLVDQGTXDQWLÀHGE\LWVVORSH((6HQGV\VWROLFHODVWDQFHDQGYRO
XPHLQWHUFHSWDWPP+J(69DVGHWDLOHGHOVHZKHUH7KHWLPHFRQVWDQWRIUHOD[
DWLRQ7DXZDVGHWHUPLQHGE\SKDVHSORWDQDO\VLV7KHHQGGLDVWROLFSUHVVXUHYROXPH
UHODWLRQ('395ZDVGHULYHGIURPWKHÀOOLQJSKDVHWUDMHFWRU\RIWKHSUHVVXUHYROXPH
ORRSLQFOXGLQJDOOGDWDSRLQWVEHWZHHQWKHPRPHQWVRIPLQLPDOSUHVVXUHDQGPD[LPDO
YROXPH/9GLDVWROLFVWLIIQHVV(('ZDVGHWHUPLQHGDVWKHOLQHDUVORSHRIWKH('395WKH
VWLIIQHVVFRQVWDQW.('IURPDQH[SRQHQWLDOÀW('3 $ÃH[S.('Ã('9('395SRVLWLRQ
ZDVGHÀQHGE\WKHLQWHUFHSWDWPP+J('9/9PHFKDQLFDOG\VV\QFKURQ\'<66
ZDVGHWHUPLQHGIURPWKHVHJPHQWDOFRQGXFWDQFHVLJQDOV,QDGGLWLRQZHFDOFXODWHG
LQWHUQDOÁRZIUDFWLRQ,))WRTXDQWLI\WKHLQHIIHFWLYHVKLIWLQJRIEORRGYROXPHZLWKLQWKH
/9GXHWRQRQXQLIRUPFRQWUDFWLRQDQGUHOD[DWLRQ
6WDWLVWLFDODQDO\VLV
:HXVHGDOLQHDUPL[HGHIIHFWVPRGHOZLWKSDWLHQWVLQFOXGHGDVUDQGRPHIIHFWVDQGFRQ
GLWLRQV EDVHOLQH IROORZXS SDFLQJ EHDWVPLQXWH DQG WKHLU LQWHUDFWLRQ
DVÀ[HGHIIHFWV7KLVPRGHODFFRXQWVIRUFRUUHODWLRQEHWZHHQUHSHDWHGPHDVXUHPHQWV
$OO GDWD DUH SUHVHQWHG DV PHDQV VWDQGDUG GHYLDWLRQ 'LIIHUHQFHV EHWZHHQ FOLQLFDO
SDUDPHWHUV DW EDVHOLQH YHUVXV IROORZXS ZHUH DVVHVVHG ZLWK QRQSDUDPHWULF :LOFR[RQ
VLJQHGUDQNVWHVWV$SUREDELOLW\YDOXHZDVFRQVLGHUHGVWDWLVWLFDOO\VLJQLÀFDQWLQ
DOODQDO\VHV
5(68/76
6XUJLFDODQGFOLQLFDOGDWD
:HHQUROOHGSDWLHQWVZLWKKHDUWIDLOXUHPDOHIHPDOH\HDUV$OOSDWLHQWV
XQGHUZHQW50$PHGLDQULQJVL]HUDQJH(LJKWSDWLHQWVZHUHGLDJQRVHGZLWK
LVFKHPLFFDUGLRP\RSDWK\RIZKLFKXQGHUZHQWDGGLWLRQDO&$%*RQHZDVDOUHDG\UH
YDVFXODUL]HG&$%*LQWKHSDVWDQGRQHKDGSURYHQLUUHYHUVLEOHLVFKHPLD,QSDWLHQWV
ZLWKVHYHUHWULFXVSLGUHJXUJLWDWLRQDFRQFRPLWDQWUHVWULFWLYHWULFXVSLGDQQXORSODVW\ZDV
SHUIRUPHG PHGLDQ ULQJ VL]H UDQJH &DUGLRSXOPRQDU\ E\SDVV &3% WLPH
ZDV PLQXWHV ZLWK D FRQFRPLWDQW DRUWLF FURVVFODPS WLPH RI PLQXWHV
7ZRSDWLHQWVUHTXLUHGLQRWURSLFVXSSRUWGREXWDPLQH!JNJPLQXWHPRUHWKDQ
KRXUVSRVWRSHUDWLYHO\7KHPHDQVWD\RIWKHSDWLHQWVLQGHLQWHQVLYHFDUHXQLWZDV
GD\VZLWKDWRWDOKRVSLWDOVWD\RIGD\V$OOSDWLHQWVZHUHGLVFKDUJHGIURPKRVSLWDO
LQJRRGFOLQLFDOFRQGLWLRQ6XUJLFDOGDWDDUHVXPPDUL]HGLQ7DEOH
$OOSDWLHQWVZHUHDOLYHDWPLGWHUPIROORZXSDQGFOLQLFDOO\LPSURYHGDFFRUGLQJWRVLJ
QLÀFDQWO\LPSURYHGFOLQLFDOSDUDPHWHUV1<+$FODVVLPSURYHGIURPWR
S PLQXWH KDOOZDON WHVW LPSURYHG IURP WR P S DQGTXDOLW\RIOLIHVFRUHLPSURYHGIURPWRS
(FKRFDUGLRJUDSK\
$OOSDWLHQWVLQFOXGHGLQWKLVVWXG\ZHUHGLDJQRVHGSUHRSHUDWLYHO\ZLWKVHYHUH05JUDGH
RU$IWHUZHDQLQJIURP&3%LQWUDRSHUDWLYH7((VKRZHGDPHDQOHQJWKRIFRDSWDWLRQ
&+$37(5
RIPPZLWKDPHDQWUDQVPLWUDOGLDVWROLFSUHVVXUHJUDGLHQWRIPP+J
DQGQRUHVLGXDO05$WPLGWHUPIROORZXS77(ZDVUHSHDWHGDQGQRUHFXUUHQFHRI05
ZDVGHWHFWHG7DEOH +HPRG\QDPLFGDWD
+HPRG\QDPLFGDWDDUHVXPPDUL]HGLQ7DEOH7KHVWDWLVWLFDOPRGHOWHVWHGGLIIHUHQFHV
EHWZHHQFRQGLWLRQVEDVHOLQHIROORZXSHIIHFWRIKHDUWUDWHSDFLQJDQGWKHLQWHUDF
WLRQ EHWZHHQ FRQGLWLRQV DQG SDFLQJ 7KH LQWHUDFWLRQ IDFWRU WHVWHG ZKHWKHU HIIHFWV RI
SDFLQJZHUHGLIIHUHQWEHWZHHQERWKFRQGLWLRQVKRZHYHUQRQHRIWKHYDULDEOHVVKRZHGD
VLJQLÀFDQWFRQGLWLRQSDFLQJLQWHUDFWLRQ$WIROORZXSJOREDO/9IXQFWLRQZDVXQFKDQJHG
HYLGHQFHGE\XQFKDQJHG&26:DQG69(69DQG('9ZHUHVLJQLÀFDQWO\UHGXFHGERWK
S ZLWK UHVSHFWLYHO\ DQG DW EHDWVPLQXWH LQGLFDWLYH RI VXEVWDQ
WLDOUHYHUVH/9UHPRGHOLQJDIWHU50$$IWHUORDG($ZDVVLJQLÀFDQWO\LQFUHDVHG
S ZKLFKKRZHYHUGLGQRWUHVXOWLQVLJQLÀFDQWFKDQJHRIWKHYHQWULFXORDUWHULDO
FRXSOLQJ($((66\VWROLFIXQFWLRQGHPRQVWUDWHGLPSURYHGFRQWUDFWLOLW\DFFRUGLQJWRDQ
LQFUHDVHG/9()DQGUHGXFHG(69S S(DUO\DFWLYHUHOD[DWLRQVKRZHG
7DEOH6XUJLFDOGDWD 6XUJLFDOLQWHUYHQWLRQ
50$&$%*
50$
50$
5LQJVL]H50$ UDQJH
0LWUDOUHJXUJLWDWLRQJUDGH
$0VL]HPP
$0/VL]HPP
$0$0/UDWLR
/HQJWKRIFRDSWDWLRQPP
7UDQVPLWUDOJUDGLHQWPP+J
&DUGLRSXOPRQDU\E\SDVVPLQXWHV
$RUWDFURVVFODPSLQJPLQXWHV
,QWHQVLYHFDUHXQLWVWD\GD\V
+RVSLWDOVWD\GD\V
,QWUDDRUWLFEDOORRQSXPS
,QRWURSLFVXSSRUW !KUV
50$UHVWULFWLYHPLWUDODQQXORSODVW\&$%*FRURQDU\DUWHU\E\SDVVJUDIWLQJ$0PLWUDODQQXOXV$0/
DQWHULRUPLWUDOOHDÁHW'DWDDUHSUHVHQWHGDVQXPEHURISDWLHQWVLQYROYHGDQGRIWKHWRWDOJURXS
RUDVPHDQ6' 'REXWDPLQH!JNJPLQXWH
9DOXHVEHWZHHQSDUHQWKHVHVZHUHREWDLQHGLPPHGLDWHO\SRVWVXUJHU\
7DEOH+HPRG\QDPLFSDUDPHWHUVDWEDVHOLQHYHUVXVPLGWHUPIROORZXSDIWHU50$ %DVHOLQH0LGWHUPIROORZXSDIWHU50$3YDOXHVRIHIIHFWV ESPESPESPESPESPESP&RQGLWLRQ3DFLQJ,QWHUDFWLRQ *HQHUDO +5EHDWVPLQ &2/PLQ 69P/ 6:PP+JÃ/ ($PP+JP/ ($((6 6\VWROLF (69P/ (63PP+J /9() G3GW0$;PP+JV (63,62PP+J ((6PP+JP/ (69 'LDVWROLF ('9P/ ('3PP+J G3GW0,1PP+JV 7DXPV (('PP+JP/
&+$37(5
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ÁRZIUDFWLRQESPEHDWVSHU PLQXWH50$UHVWULFWLYHPLWUDODQQXORSODVW\
OHQJWKHQHG 7DX EXW G3GW0,1 ZDV VOLJKWO\ LPSURYHG S S 3DVVLYH GLD
VWROLFIXQFWLRQGHPRQVWUDWHGLPSDLUPHQWLQGLFDWHGE\LQFUHDVHG(('DQG.('RIZKLFK
WKHODWWHUUHDFKHGVLJQLÀFDQFHS )XUWKHUPRUH('9FDOFXODWHGDVWKHYROXPH
LQWHUFHSWRI('395DWPP+JZDVVLJQLÀFDQWO\UHGXFHGUHÁHFWLQJORZHURSHUDWLQJ
YROXPHV FRQVLVWHQW ZLWK D OHIWZDUG VKLIW RI WKH SUHVVXUHYROXPH ORRS '<66 GLG QRW
FKDQJHDIWHU50$ZKHUHDV,))LQFUHDVHGVLJQLÀFDQWO\SLQGLFDWLQJXQFKDQJHG
JOREDOG\VV\QFKURQ\DQGDVOLJKWO\LQFUHDVHG,))
',6&866,21
5HFHQWVWXGLHVGHPRQVWUDWHGJRRGVXUYLYDOUDWHVDIWHU50$VXUJHU\RIDSSUR[LPDWHO\
DQGDWDQG\HDUIROORZXSUHVSHFWLYHO\$OWKRXJKQRVLJQLÀFDQWGLIIHUHQFH
LQVXUYLYDOUDWHFRXOGEHGHWHFWHGZKHQFRPSDULQJ&$%*ZLWKDGGLWLRQDO50$YHUVXV
&$%*DORQHWKHHIÀFDF\RIDGGLQJ50$WR&$%*ZDVGHPRQVWUDWHGE\LPSURYHG
FOLQLFDO SHUIRUPDQFH DFFRUGLQJ WR LPSURYHG 1<+$ FODVV )XUWKHUPRUH LPSURYHG
H[HUFLVHWROHUDQFHZDVGHPRQVWUDWHGE\WUHDGPLOOVWUHVVWHVWVLQSDWLHQWVUHFHLYLQJDG
GLWLRQDO50$,QDGGLWLRQRXUJURXSKDVSXEOLVKHGRQWKHEHQHÀFLDOHIIHFWVRI50$
RQUHYHUVHUHPRGHOLQJ'HVSLWHWKHVHSURPLVLQJUHVXOWVLQWHUPVRIFOLQLFDORXWFRPH
DQG/9UHYHUVHUHPRGHOLQJWKHXQGHUO\LQJPHFKDQLVPUHPDLQVVSHFXODWLYHVLQFHOLWWOH
LQIRUPDWLRQLVDYDLODEOHUHJDUGLQJWKHKHPRG\QDPLFHIIHFWVRI50$(DUO\SRVWRSHUD
WLYHVWXGLHVGLGQRWGHPRQVWUDWHVLJQLÀFDQWDFXWHFKDQJHVLQEDVHOLQHKHPRG\QDPLFV
DQG/9V\VWROLFDQGGLDVWROLFIXQFWLRQDQGVWXGLHVRQFKURQLFHIIHFWVJLYHLQVXIÀFLHQW
PHFKDQLVWLFLQIRUPDWLRQ7KHUHIRUHZHVWXGLHGKHDUWIDLOXUHSDWLHQWVEHIRUHVXUJHU\
DQGDWPLGWHUPIROORZXSaPRQWKVDIWHU50$XVLQJSUHVVXUHFRQGXFWDQFHFDWK
HWHUVWRREWDLQLQYDVLYHORDGLQGHSHQGHQWKHPRG\QDPLFSDUDPHWHUV
9DOYXODUIXQFWLRQ
2XUÀQGLQJV7DEOHLQGLFDWHWKDWWKHPHDQSUHVVXUHGURSDFURVVWKHUHVWULFWHGPLWUDO
RULÀFHDIWHU50$ZDVOHVVWKDQPP+JLQGLFDWLQJQRRFFXUUHQFHRIIXQFWLRQDOPLWUDO
VWHQRVLV GHVSLWH WKH VWULQJHQW XQGHUVL]LQJ ,Q DGGLWLRQ QR UHFXUUHQFH RI 05 ZDV GH
WHFWHGLQRXUVWXG\JURXS
*OREDO/9IXQFWLRQ
*OREDO/9IXQFWLRQDIWHU50$GHPRQVWUDWHGQRVLJQLÀFDQWFKDQJHVZLWKUHVSHFWWR&2
69DQG6:ZKLFKLVLQOLQHZLWKRXUSUHYLRXVDFXWHPHDVXUHPHQWVDIWHU50$SHUIRUPHG
LQWKHRSHUDWLQJURRP9HQWULFXODUYROXPHVKRZHYHUGHPRQVWUDWHGVLJQLÀFDQWUHYHUVH
&+$37(5
UHPRGHOLQJDWPLGWHUPIROORZXSHYLGHQFHGE\GHFUHDVHG(69DQG('9
ZKLFKLVLQOLQHZLWKSUHYLRXVHFKRFDUGLRJUDSKLFVWXGLHV7KHYROXPHUHGXFWLRQV
ZHUHVLPLODUDOWKRXJKVOLJKWO\PRUHSURQRXQFHGLQSDWLHQWVQ ZLWK50$DQGDG
GLWLRQDO&$%*('9(69YVWKRVHQ ZLWKRXW&$%*('9(69
+RZHYHU SDWLHQW QXPEHUV ZHUH FRQVLGHUHG WRR VPDOO WR \LHOG PHDQLQJIXO VXEJURXS
DQDO\VHV&RQGXFWDQFHGHULYHGYROXPHV7DEOHFORVHO\FRUUHVSRQGHGZLWKHFKRFDU
GLRJUDSK\ LQ WKLV JURXS ('9 P/ EDVHOLQH WR P/ IROORZXS (69
P/ WR P/ )XUWKHUPRUH DIWHUORDG ($ ZDV VOLJKWO\ EXW VLJQLÀFDQWO\
LQFUHDVHG S ZKLFK KRZHYHU GLG QRW UHVXOW LQ D VLJQLÀFDQW FKDQJH LQ
YHQWULFXORDUWHULDOFRXSOLQJ($((67KHODWWHULVLQOLQHZLWKWKHUHVXOWVPHDVXUHGLQ
WKHDFXWHVHWWLQJ$SRVVLEOHH[SODQDWLRQIRUWKHFKDQJHLQDIWHUORDGFRXOGEHWKHFORVXUH
RIDORZUHVLVWDQFHUXQRIILQWRWKHOHIWDWULXP7KHLQFUHDVHGDIWHUORDGDOVRGLGQRW
UHVXOWLQGHSUHVVHGV\VWROLFIXQFWLRQEXWUDWKHUV\VWROLFIXQFWLRQLPSURYHGDVHYLGHQFHG
E\WKHLQFUHDVHG/9()DQGGHFUHDVHG(697DNHQWRJHWKHULWDSSHDUVWKDWWKHOLPLWHG
LQFUHDVHLQDIWHUORDGGLGQRWUHVXOWLQSK\VLRORJLFDOO\LPSRUWDQWHIIHFWVRQ/9IXQFWLRQ
GLVSURYLQJ WKH FRQFHSW WKDW À[LQJ WKH UHJXUJLWDQW PLWUDO YDOYH ZRXOG EH GHOHWHULRXV
IRUWKHGDPDJHG/91HYHUWKHOHVVIXWXUHUHVHDUFKRQSKDUPDFRORJLFDOORZHULQJRIWKH
DIWHUORDGDQGLPSURYLQJ($((6FRXOGEHRILQWHUHVWDQGKDYHWRSRLQWRXWLIUHGXFWLRQ
RIDIWHUORDGLVGHVLUDEOHLQWKLVSDWLHQWSRSXODWLRQ
6\VWROLFDQGGLDVWROLF/9IXQFWLRQ
:HREVHUYHGLPSURYHGV\VWROLFIXQFWLRQDIWHU50$ZLWKUHJDUGWRLQFUHDVHG/9()DQG
GHFUHDVHG(69ZKLFKLVLQOLQHZLWKSUHYLRXVUHSRUWV1RVLJQLÀFDQWHIIHFWVFRXOG
EH GHPRQVWUDWHG IRU G3GW0$; RU ((6 7KH PHDVXUHPHQWV SHUIRUPHG LQ WKHDFXWH VHW
WLQJ GHPRQVWUDWHG VLPLODU FKDQJHV DOWKRXJK QR VLJQLÀFDQFH ZDV UHDFKHG DW WKDW WLPH
SRLQW'LDVWROLFIXQFWLRQVKRZHGDSDUWO\GLIIHUHQWLDOHIIHFWRQHDUO\DFWLYHUHOD[DWLRQ
DQGRQWKHODWHSDVVLYHGLDVWROLFVWLIIQHVVLHWKHUHFLSURFDORIFRPSOLDQFH:KHUHDVG3
GW0,1LQFUHDVHGVOLJKWO\VXJJHVWLQJLPSURYHPHQWUHOD[DWLRQWLPHFRQVWDQW7DXLQFUHDVHG
LQGLFDWLQJGHSUHVVHGHDUO\UHOD[DWLRQ7KHHIIHFWVRQ7DXZHUHPRUHVXEVWDQWLDODQGWKLV
SDUDPHWHULVDOVROHVVLQÁXHQFHGE\LQWHUDFWLRQZLWKV\VWROLFIXQFWLRQ7KHODWHSDVVLYHSDUW
RIGLDVWROLFIXQFWLRQDVVHVVHGE\RSHUDWLQJVWLIIQHVV(('DQGVWLIIQHVVFRQVWDQW.('GHP
RQVWUDWHGDQRQVLJQLÀFDQWLQFUHDVHRI(('DQGDVLJQLÀFDQWO\LQFUHDVHG.('7KHVHHIIHFWV
ZHUHDOVRIRXQGLQWKHDFXWHVHWWLQJDOWKRXJKWKHDFXWHFKDQJHVGLGQRWUHDFKVWDWLVWLFDO
VLJQLÀFDQFH3RWHQWLDOO\WKHFRPELQHGHIIHFWVRIVOLJKWO\LQFUHDVHGDIWHUORDGLQFUHDVHG
SUHVVXUHGURSDFURVVWKHPLWUDORULÀFHDQGLPPRELOL]DWLRQRIWKHDQQXOXVDOWKRXJKHDFK
YHU\OLPLWHGPD\KDYHFXPXODWHGLQWKHREVHUYHGYHU\VXEWOHGLDVWROLFFKDQJHV*OREDO
GLDVWROLFIXQFWLRQUHÁHFWHGE\('3GLGQRWFKDQJHVLJQLÀFDQWO\LQGLFDWLQJWKDWWKHQHW
SK\VLRORJLFDOHIIHFWRISRVVLEO\50$LQGXFHGGLDVWROLFLPSDLUPHQWUHPDLQHGOLPLWHG
'\VV\QFKURQ\
0HFKDQLFDO G\VV\QFKURQ\ LV LQFUHDVLQJO\ UHFRJQL]HG DV DQ LPSRUWDQW IDFWRU H[SODLQ
LQJ /9 G\VIXQFWLRQ (DUOLHU VWXGLHV SHUIRUPHG LQ WKHDFXWH VHWWLQJ GHPRQVWUDWHG QR
VLJQLÀFDQWHIIHFWRQG\VV\QFKURQ\DIWHU50$:HIRXQGDOVRQRHIIHFWRQJOREDOG\V
V\QFKURQ\DQGDOWKRXJKVLJQLÀFDQWRQO\DVPDOOLQFUHDVHRI,))DWPLGWHUPIROORZXS
7KH ODWWHU FRXOG EH WKH FRQVHTXHQFH RI UHVROYLQJ WKH PLWUDO YDOYH OHDNDJH EHFDXVH
G\VV\QFKURQ\LVPRVWHYLGHQWGXULQJLVRYROXPLFFRQWUDFWLRQZKHQERWKYDOYHVDUHHI
IHFWLYHO\FORVHG
+HDUWUDWHHIIHFW
0HDVXUHPHQWV ZHUH SHUIRUPHG GXULQJ SDFLQJ WR H[FOXGH ELDV E\ DOWHUHG KHDUW UDWH
DQG WR LQYHVWLJDWH KHDUW UDWH GHSHQGHQFLHV EHIRUH DQG DIWHU 50$ 6WDWLVWLFDO DQDO\VLV
GHPRQVWUDWHG D YHU\ OLPLWHG FKURQRWURSLF UHVHUYH LQ WKHVH SDWLHQWV ZKLFK UHPDLQHG
DIWHU50$69JUDGXDOO\GHFUHDVHGDWKLJKHUKHDUWUDWHOLPLWLQJWKH&2LQFUHDVH&RQ
VLGHULQJ WKH VLJQLÀFDQW UHGXFWLRQ LQ ('9 GXULQJ SDFLQJ S LW DSSHDUV SULPDU
LO\DÀOOLQJDEQRUPDOLW\ZKLFKFDXVHVWKH69GHFUHDVH)LJXUHVKRZVWKHVFKHPDWLF
SUHVVXUHYROXPHORRSVEDVHGRQPHDQ('9(69('3DQG(63DWLQFUHPHQWDOSDFHG
KHDUW UDWHV S S S DW EDVHOLQH DQG IROORZXS )XUWKHUPRUH ZH REVHUYHG D
VLJQLÀFDQWLQFUHDVHLQGLDVWROLFVWLIIQHVVDIWHULQFUHPHQWDOKHDUWUDWH+RZHYHUWKHUHZDV
QRFRQGLWLRQSDFLQJLQWHUDFWLRQLQGLFDWLQJWKDWWKLVHIIHFWZDVQRWDOWHUHGE\50$DQG
SUHVHQWDOUHDG\EHIRUHVXUJHU\,PSRUWDQWO\LWVKRXOGEHQRWHGWKDWLQFUHDVHGKHDUWUDWH
FIGURES CHAPTER 8 Figure 1
0 50 100 150
50 100 150 200
LV Volume (mL)
LV Pressure (mmHg)
p80 p100 p120
0 50 100 150
50 100 150 200
LV Volume (mL)
LV Pressure (mmHg)
)LJXUH6FKHPDWLFSUHVVXUHYROXPHORRSVEDVHGRQPHDQHQGGLDVWROLFDQGHQGV\VWROLFSUHV
VXUHVOHIWSDQHODQGYROXPHVULJKWSDQHODWLQFUHPHQWDOSDFHGKHDUWUDWHVSSSDW
EDVHOLQHDQGIROORZXS'RWWHGOLQHLQWKHIROORZXSSDQHOUHSHDWVWKHEDVHOLQHSORRSVDVUHIHU
HQFH/9OHIWYHQWULFXODU
&+$37(5
E\SDFLQJRQO\SDUWO\PLPLFVWKHHIIHFWVRIH[HUFLVH*LYHQWKHREVHUYHGGURSLQ('3
GXULQJ SDFLQJ V\PSDWKHWLF VWLPXODWLRQ DQG YROXPH UHFUXLWPHQW GXULQJ WUXH H[HUFLVH
PD\ OHDG WR D PRUH SRVLWLYH HIIHFW RQ &2 E\ PDLQWDLQLQJ RU HYHQ LQFUHDVLQJ QRUPDO
ÀOOLQJSUHVVXUHVDQGWKXV('9DWKLJKHUKHDUWUDWH
6WXG\OLPLWDWLRQV
7KH QXPEHU RI SDWLHQWV ZDV VPDOO DQG WKH VWXG\ JURXS KHWHURJHQHRXV 7KH HIIHFWV
RI50$PD\EHFRQIRXQGHGE\DGGLWLRQDOVXUJHU\+RZHYHURXUSULPDU\JRDOZDVWR
HYDOXDWHKHPRG\QDPLFHIIHFWVLQKHDUWIDLOXUHSDWLHQWVLQZKRP50$ZDVSHUIRUPHG
DVWKHSULPDU\VXUJLFDOSURFHGXUH)XUWKHUPRUHDOWKRXJKWKHVDPSOHVL]HRIRXUVWXG\
ZDVUHODWLYHO\VPDOOE\XVLQJHDFKSDWLHQWDVLWVRZQFRQWUROVWDWLVWLFDOSRZHUZDVRSWL
PL]HG0RUHRYHUZHXVHGLQYDVLYHSUHVVXUHYROXPHPHDVXUHPHQWVZKLFKDUHJHQHUDOO\
UHJDUGHGDVKLJKO\DFFXUDWHDQGWKHJROGVWDQGDUGIRU/9IXQFWLRQDVVHVVPHQWV
&RQFOXVLRQV
,QYDVLYHPHDVXUHPHQWVLQKHDUWIDLOXUHSDWLHQWVWUHDWHGZLWK50$GHPRQVWUDWHGH[FHO
OHQWPLWUDOYDOYHUHSDLUE\50$ZLWKQRUHFXUUHQFHRI05DWPLGWHUPIROORZXS&OLQLFDO
GDWDUHYHDOHGJRRGFOLQLFDORXWFRPHHYLGHQFHGE\LPSURYHG1<+$FODVVPLQXWHKDOO
ZDONWHVWDQGTXDOLW\RIOLIHVFRUH+HPRG\QDPLFDQDO\VHVGHPRQVWUDWHGDQXQFKDQJHG
JOREDO/9IXQFWLRQZLWKLPSURYHGV\VWROLFIXQFWLRQEXWSDUWO\LPSDLUHGGLDVWROLFIXQF
WLRQ &RQVLGHULQJ WKH LPSURYHG FOLQLFDO SHUIRUPDQFH LPSURYHG V\VWROLF IXQFWLRQ DQG
VXEVWDQWLDOUHYHUVHUHPRGHOLQJZLWKQRLPSRUWDQWKHPRG\QDPLFDGYHUVHHIIHFWV50$
VHHPVWREHDQDSSURSULDWHWKHUDS\IRUSDWLHQWVZLWKKHDUWIDLOXUHDQG05
5()(5(1&(6
/HYLQH5$6FKZDPPHQWKDO(,VFKHPLFPLWUDOUHJXUJLWDWLRQRQWKHWKUHVKROGRIDVROXWLRQIURP
SDUDGR[HVWRXQLI\LQJFRQFHSWV&LUFXODWLRQ
*ULJLRQL)(QULTXH]6DUDQR0=HKU.-HWDO,VFKHPLFPLWUDOUHJXUJLWDWLRQORQJWHUPRXWFRPH
DQGSURJQRVWLFLPSOLFDWLRQVZLWKTXDQWLWDWLYH'RSSOHUDVVHVVPHQW&LUFXODWLRQ
7ULFKRQ%+)HONHU*06KDZ/.HWDO5HODWLRQRIIUHTXHQF\DQGVHYHULW\RIPLWUDOUHJXUJLWDWLRQWR
VXUYLYDODPRQJSDWLHQWVZLWKOHIWYHQWULFXODUV\VWROLFG\VIXQFWLRQDQGKHDUWIDLOXUH$P-&DUGLRO
.DXO66SRWQLW]:'*ODVKHHQ:3HWDO0HFKDQLVPRILVFKHPLFPLWUDOUHJXUJLWDWLRQ$QH[SHUL
PHQWDOHYDOXDWLRQ&LUFXODWLRQ
%ROWZRRG&07HL&:RQJ0HWDO4XDQWLWDWLYHHFKRFDUGLRJUDSK\RIWKHPLWUDOFRPSOH[LQGLODWHG
FDUGLRP\RSDWK\WKHPHFKDQLVPRIIXQFWLRQDOPLWUDOUHJXUJLWDWLRQ&LUFXODWLRQ
%XUNKRII'1HZKHDUWIDLOXUHWKHUDS\WKHVKDSHRIWKLQJVWRFRPH"-7KRUDF&DUGLRYDVF6XUJ
%ROOLQJ 6) 0LWUDO YDOYH UHFRQVWUXFWLRQ LQ WKH SDWLHQW ZLWK KHDUW IDLOXUH+HDUW )DLO 5HY
&DUDEHOOR%$7KHFXUUHQWWKHUDS\IRUPLWUDOUHJXUJLWDWLRQ-$P&ROO&DUGLRO
0DUZLFN7+5HVWULFWLYHDQQXORSODVW\IRULVFKHPLFPLWUDOUHJXUJLWDWLRQWRROLWWOHRUWRRPXFK"-
$P&ROO&DUGLRO
)DWWRXFK . *XFFLRQH ) 6DPSRJQDUR 5HW DO 32,17 (IÀFDF\ RI DGGLQJ PLWUDO YDOYH UHVWULFWLYH
DQQXORSODVW\WRFRURQDU\DUWHU\E\SDVVJUDIWLQJLQSDWLHQWVZLWKPRGHUDWHLVFKHPLFPLWUDOYDOYH
UHJXUJLWDWLRQDUDQGRPL]HGWULDO-7KRUDF&DUGLRYDVF6XUJ
0LKDOMHYLF 7 /DP %. 5DMHVZDUDQ -HW DO ,PSDFW RI PLWUDO YDOYH DQQXORSODVW\ FRPELQHG ZLWK
UHYDVFXODUL]DWLRQLQSDWLHQWVZLWKIXQFWLRQDOLVFKHPLFPLWUDOUHJXUJLWDWLRQ-$P&ROO&DUGLRO
0DJQH-6HQHFKDO00DWKLHX3HWDO5HVWULFWLYHDQQXORSODVW\IRULVFKHPLFPLWUDOUHJXUJLWDWLRQ
PD\LQGXFHIXQFWLRQDOPLWUDOVWHQRVLV-$P&ROO&DUGLRO
%D[--%UDXQ-6RPHU67HWDO5HVWULFWLYHDQQXORSODVW\DQGFRURQDU\UHYDVFXODUL]DWLRQLQLVFKHPLF
PLWUDOUHJXUJLWDWLRQUHVXOWVLQUHYHUVHOHIWYHQWULFXODUUHPRGHOLQJ&LUFXODWLRQ,,,,
%UDXQ-%D[--9HUVWHHJK0,HWDO3UHRSHUDWLYHOHIWYHQWULFXODUGLPHQVLRQVSUHGLFWUHYHUVHUHPRG
HOLQJIROORZLQJUHVWULFWLYHPLWUDODQQXORSODVW\LQLVFKHPLFPLWUDOUHJXUJLWDWLRQ(XU-&DUGLRWKRUDF
6XUJ
*HLGHO6/DVV06FKQHLGHU&HWDO'RZQVL]LQJRIWKHPLWUDOYDOYHDQGFRURQDU\UHYDVFXODUL]DWLRQ
LQVHYHUHLVFKHPLFPLWUDOUHJXUJLWDWLRQUHVXOWVLQUHYHUVHOHIWYHQWULFXODUDQGOHIWDWULDOUHPRGHOLQJ
(XU-&DUGLRWKRUDF6XUJ
:HVWHQEHUJ--%UDXQ-YDQGH9HLUH15HWDO0DJQHWLFUHVRQDQFHLPDJLQJDVVHVVPHQWRIUHYHUVH
OHIW YHQWULFXODU UHPRGHOLQJ ODWH DIWHU UHVWULFWLYH PLWUDO DQQXORSODVW\ LQ HDUO\ VWDJHV RI GLODWHG
FDUGLRP\RSDWK\-7KRUDF&DUGLRYDVF6XUJ
%UDXQ - YDQ GH 9HLUH 15 .ODXW] 5-HW DO 5HVWULFWLYH PLWUDO DQQXORSODVW\ FXUHV LVFKHPLF PLWUDO
UHJXUJLWDWLRQDQGKHDUWIDLOXUH$QQ7KRUDF6XUJ
*HOVRPLQR6/RUXVVR5'H&LFFR*HWDO)LYH\HDUHFKRFDUGLRJUDSKLFUHVXOWVRIFRPELQHGXQ
GHUVL]HGPLWUDOULQJDQQXORSODVW\DQGFRURQDU\DUWHU\E\SDVVJUDIWLQJIRUFKURQLFLVFKDHPLFPLWUDO
UHJXUJLWDWLRQ(XU+HDUW-
6WHHQGLMN 3 6WDDO ( -XNHPD -:HW DO +\SHUWRQLF VDOLQH PHWKRG DFFXUDWHO\ GHWHUPLQHV SDUDOOHO
FRQGXFWDQFHIRUGXDOÀHOGFRQGXFWDQFHFDWKHWHU$P-3K\VLRO+HDUW&LUF3K\VLRO+
+
'LRQ5,VFKHPLFPLWUDOUHJXUJLWDWLRQZKHQDQGKRZVKRXOGLWEHFRUUHFWHG"-+HDUW9DOYH'LV
&+$37(5
&DUSHQWLHU$)/HVVDQD$5HOODQG-<HWDO7KH´SK\VLRULQJµDQDGYDQFHGFRQFHSWLQPLWUDOYDOYH
DQQXORSODVW\$QQ7KRUDF6XUJ
WHQ%ULQNH($.ODXW]5-7XOQHU6$HWDO+DHPRG\QDPLFVDQGOHIWYHQWULFXODUIXQFWLRQLQKHDUW
IDLOXUHSDWLHQWVFRPSDULVRQRIDZDNHYHUVXVLQWUDRSHUDWLYHFRQGLWLRQV(XU-+HDUW)DLO
/HHXZHQEXUJK%36WHHQGLMN3+HOELQJ:$HWDO,QGH[HVRIGLDVWROLF59IXQFWLRQORDGGHSHQ
GHQFHDQGFKDQJHVDIWHUFKURQLF59SUHVVXUHRYHUORDGLQODPEV$P-3K\VLRO+HDUW&LUF3K\VLRO
++
:HVWHUPDQQ'.DVQHU06WHHQGLMN3HWDO5ROHRIOHIWYHQWULFXODUVWLIIQHVVLQKHDUWIDLOXUHZLWK
QRUPDOHMHFWLRQIUDFWLRQ&LUFXODWLRQ
6WHHQGLMN 3 7XOQHU 6$ 6FKUHXGHU --HW DO 4XDQWLÀFDWLRQ RI OHIW YHQWULFXODU PHFKDQLFDO G\VV\Q
FKURQ\E\FRQGXFWDQFHFDWKHWHULQKHDUWIDLOXUHSDWLHQWV$P-3K\VLRO+HDUW&LUF3K\VLRO
++
'LEDUGLQR'-(OEDUGLVVL$:0F&OXUH56HWDO)RXUGHFDGHVRIH[SHULHQFHZLWKPLWUDOYDOYHUHSDLU
$QDO\VLVRIGLIIHUHQWLDOLQGLFDWLRQVWHFKQLFDOHYROXWLRQDQGORQJWHUPRXWFRPH-7KRUDF&DUGLR
YDVF6XUJ
'LRGDWR0'0RRQ053DVTXH0.HWDO5HSDLURILVFKHPLFPLWUDOUHJXUJLWDWLRQGRHVQRWLQFUHDVH
PRUWDOLW\RULPSURYHORQJWHUPVXUYLYDOLQSDWLHQWVXQGHUJRLQJFRURQDU\DUWHU\UHYDVFXODUL]DWLRQ
DSURSHQVLW\DQDO\VLV$QQ7KRUDF6XUJ
7XOQHU6$6WHHQGLMN3.ODXW]5-HWDO$FXWHKHPRG\QDPLFHIIHFWVRIUHVWULFWLYHPLWUDODQQXOR
SODVW\ LQ SDWLHQWV ZLWK HQGVWDJH KHDUW IDLOXUH DQDO\VLV E\ SUHVVXUHYROXPH UHODWLRQV- 7KRUDF
&DUGLRYDVF6XUJ
2QRUDWL)6DQWDUSLQR*0DUWXUDQR'HWDO6XFFHVVIXOVXUJLFDOWUHDWPHQWRIFKURQLFLVFKHPLFPL
WUDOUHJXUJLWDWLRQDFKLHYHVOHIWYHQWULFXODUUHYHUVHUHPRGHOLQJEXWGRHVQRWDIIHFWULJKWYHQWULFXODU
IXQFWLRQ-7KRUDF&DUGLRYDVF6XUJ
,VKLKDUD+<RNRWD06REXH7HWDO5HODWLRQEHWZHHQYHQWULFXORDUWHULDOFRXSOLQJDQGP\RFDUGLDO
HQHUJHWLFVLQSDWLHQWVZLWKLGLRSDWKLFGLODWHGFDUGLRP\RSDWK\-$P&ROO&DUGLRO
1DMMDU666FKXOPDQ63*HUVWHQEOLWK*HWDO$JHDQGJHQGHUDIIHFWYHQWULFXODUYDVFXODUFRXSOLQJ
GXULQJDHURELFH[HUFLVH-$P&ROO&DUGLRO
*DDVFK:+0H\HU7(/HIWYHQWULFXODUUHVSRQVHWRPLWUDOUHJXUJLWDWLRQLPSOLFDWLRQVIRUPDQDJH
PHQW&LUFXODWLRQ
5RVV--U$IWHUORDGPLVPDWFKLQDRUWLFDQGPLWUDOYDOYHGLVHDVHLPSOLFDWLRQVIRUVXUJLFDOWKHUDS\
-$P&ROO&DUGLRO
=LOH05*DDVFK:+/HYLQH+-/HIWYHQWULFXODUVWUHVVGLPHQVLRQVKRUWHQLQJUHODWLRQVEHIRUHDQG
DIWHUFRUUHFWLRQRIFKURQLFDRUWLFDQGPLWUDOUHJXUJLWDWLRQ$P-&DUGLRO
.DQJ'+.LP0-.DQJ6-HWDO0LWUDOYDOYHUHSDLUYHUVXVUHYDVFXODUL]DWLRQDORQHLQWKHWUHDWPHQW
RILVFKHPLFPLWUDOUHJXUJLWDWLRQ&LUFXODWLRQ,,
7XOQHU6$6WHHQGLMN3.ODXW]5-HWDO6XUJLFDOYHQWULFXODUUHVWRUDWLRQLQSDWLHQWVZLWKLVFKHPLF
GLODWHGFDUGLRP\RSDWK\HYDOXDWLRQRIV\VWROLFDQGGLDVWROLFYHQWULFXODUIXQFWLRQZDOOVWUHVVG\V
V\QFKURQ\DQGPHFKDQLFDOHIÀFLHQF\E\SUHVVXUHYROXPHORRSV-7KRUDF&DUGLRYDVF6XUJ