• No results found

Hemodynamic folluw-up after heart failure surgery : systolic and diastolic function Brinke, E.A. ten

N/A
N/A
Protected

Academic year: 2021

Share "Hemodynamic folluw-up after heart failure surgery : systolic and diastolic function Brinke, E.A. ten"

Copied!
19
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Hele tekst

(1)

Hemodynamic folluw-up after heart failure surgery : 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).

(2)

&+$37(5

6LQJOHEHDWHVWLPDWLRQRIWKH

OHIWYHQWULFXODUHQGGLDVWROLF

SUHVVXUH²YROXPHUHODWLRQVKLS

LQSDWLHQWVZLWKKHDUWIDLOXUH

(OOHQ$WHQ%ULQNH 'DQLHO%XUNKRII 5REHUW-.ODXW]

&DUVWHQ7VFK|SH 0DUWLQ-6FKDOLM -HURHQ-%D[

(UQVW(YDQGHU:DOO 5REHUW$'LRQ 3DXO6WHHQGLMN

+HDUW)HE  

(3)

&KDSWHU



$%675$&7

%DFNJURXQG $ PHWKRG WR SUHGLFW WKH HQGGLDVWROLF SUHVVXUHYROXPH UHODWLRQVKLS

('395 IURPDVLQJOHEHDWZDVWHVWHGLQSDWLHQWVZLWKKHDUWIDLOXUH

0HWKRGV 3DWLHQWV 1HZ <RUN +HDUW $VVRFLDWLRQ FODVV ,,,,9  VFKHGXOHG IRU PLWUDO

DQQXORSODVW\ Q   RU YHQWULFXODU UHVWRUDWLRQ Q   DQG SDWLHQWV ZLWK QRUPDO OHIW

YHQWULFXODUIXQFWLRQXQGHUJRLQJFRURQDU\DUWHU\E\SDVVJUDIWLQJ Q  ZHUHLQVWUX

PHQWHG ZLWK SUHVVXUHFRQGXFWDQFH FDWKHWHUV WR PHDVXUH SUHVVXUHYROXPH ORRSV

SUHDQGSRVWVXUJHU\'DWDREWDLQHGGXULQJYHQDFDYDRFFOXVLRQSURYLGHGGLUHFWO\

PHDVXUHG('395V%DVHOLQHHQGGLDVWROLFSUHVVXUH 3P DQGYROXPH 9P ZHUHXVHG

IRUVLQJOHEHDWSUHGLFWLRQRI('395V

5HVXOWV 5RRWPHDQVTXDUHGHUURU 506(  EHWZHHQ PHDVXUHG DQG SUHGLFWHG ('

395V ZDV ” PP+J 0HDVXUHG YV SUHGLFWHG HQGGLDVWROLF YROXPHV ('9  DWSUHVVXUHOHYHOVDQGPP+JVKRZHGWLJKWFRUUHODWLRQV 5 

%ODQG$OWPDQDQDO\VHVLQGLFDWHGRYHUHVWLPDWLRQDWPP+J ELDVSUHVXUJHU\P/

&,WRP/ SRVWVXUJHU\P/ WRP/ DQGXQGHUHVWLPDWLRQDW

PP+J ELDVSUHVXUJHU\P/ WRP/ SRVWVXUJHU\P/ WR

P/ ('9VZHUHVLJQLÀFDQWO\GLIIHUHQWEHWZHHQJURXSVDQGEHWZHHQFRQGLWLRQVEXW

WKHVHGLIIHUHQFHVZHUHQRWGHSHQGHQWRQWKHPHWKRG LHPHDVXUHGYVSUHGLFWHG 

506(VZHUHQRWGLIIHUHQWEHWZHHQJURXSVRUFRQGLWLRQVQRUGHSHQGHQWRQ9PRU3P

LQGLFDWLQJWKDW('395SUHGLFWLRQZDVHTXDOO\DFFXUDWHRYHUDZLGHYROXPHUDQJH

&RQFOXVLRQ 6LQJOHEHDW ('395V REWDLQHG IURP KHDUWV VSDQQLQJ D ZLGH UDQJH RI

VL]HV DQG FRQGLWLRQV DFFXUDWHO\ SUHGLFWHG GLUHFWO\PHDVXUHG ('395V ZLWK ORZ

506(6LQJOHEHDW('395LQGLFHVFRUUHODWHGZHOOZLWKGLUHFWO\PHDVXUHGYDOXHVEXW

V\VWHPDWLFELDVHVZHUHSUHVHQWDWORZDQGKLJKSUHVVXUHV7KHVLQJOHEHDWPHWKRG

IDFLOLWDWHVOHVVLQYDVLYH('395HVWLPDWLRQSDUWLFXODUO\ZKHQFRXSOHGZLWKHPHUJLQJ

QRQLQYDVLYHWHFKQLTXHVWRPHDVXUHSUHVVXUHVDQGYROXPHV

(4)



&+$37(5

,1752'8&7,21

'LDVWROLF OHIW YHQWULFXODU /9  SURSHUWLHV DUH GLYLGHG LQWR DFWLYH DQG SDVVLYH FRPSR

QHQWV $YDLODELOLW\ RI D IDPLO\ RI HFKRFDUGLRJUDSKLF DQG 'RSSOHUGHULYHG SDUDPHWHUV

KDVIDFLOLWDWHGVLJQLÀFDQWDGYDQFHVLQEDVLFXQGHUVWDQGLQJRIPDQ\DVSHFWVRIWKHDFWLYH

FRPSRQHQWRIOHIWYHQWULFXODUUHOD[DWLRQ4XDQWLÀFDWLRQRISDVVLYHGLDVWROLF/9SURSHU

WLHVUHPDLQVDFKDOOHQJHHYHQZKHQLQYDVLYHWHFKQLTXHVDUHHPSOR\HGDQGLWUHPDLQV

GHEDWHG ZKHWKHU HFKRFDUGLRJUDSKLF HYDOXDWLRQ LV VXIÀFLHQW WR GLDJQRVH GLDVWROLF

IXQFWLRQ DQG JXLGH FOLQLFDO FDUH LQ SDWLHQWV ZLWK KHDUW IDLOXUH7KLV LVVXH KDV UHFHLYHG

UHQHZHGLQWHUHVWZLWKWKHGHVLUHWREHWWHUFKDUDFWHUL]HSDWKRSK\VLRORJLFHQWLWLHVZKLFK

DUHFXUUHQWO\DFNQRZOHGJHGWRKDYHKLJKFOLQLFDOUHOHYDQFHVXFKDVKHDUWIDLOXUHZLWK

QRUPDOHMHFWLRQIUDFWLRQDQGGLDVWROLFKHDUWIDLOXUHDQGWRXQGHUVWDQGWKHLPSDFW

RIWUHDWPHQWVVXFKDVVXUJLFDOYHQWULFXODUUHFRQVWUXFWLRQDVVLVWGHYLFHVDQGFHOO

WKHUDS\RQYHQWULFXODUIXQFWLRQ,WLVZLGHO\DFFHSWHGWKDWWKHRSWLPDOZD\WRFKDU

DFWHUL]HSDVVLYHYHQWULFXODUSURSHUWLHVLVYLDWKHUHODWLRQEHWZHHQHQGGLDVWROLFSUHVVXUH

DQG HQGGLDVWROLF YROXPH 7KLV HQGGLDVWROLF SUHVVXUHYROXPH UHODWLRQVKLS ('395  XQLTXHO\GHVFULEHVWKHDPRXQWRIYROXPHUHTXLUHGWRDFKLHYHDVSHFLÀFSUHVVXUHLQWKH

UHOD[HGOHIWYHQWULFOHDQGYLFHYHUVDWKHGLDVWROLFÀOOLQJWKDWZLOORFFXUIRUDVSHFLÀHG

ÀOOLQJSUHVVXUH7KLVJOREDOUHODWLRQVKLSLQWHJUDWHVWKHQHWHIIHFWVRIFKDPEHUJHRPHWU\

P\RFDUGLDO ZDOO WKLFNQHVV DQG VWUXFWXUH DQG FRPSRVLWLRQ RI WKH P\RFDUGLXP ,Q SD

WLHQWVZLWKKHDUWIDLOXUHHDFKRIWKHVHIDFWRUVPD\EHDEQRUPDOHLWKHUGLUHFWO\FDXVHG

E\ WKH GLVHDVH RU DV D FRPSHQVDWRU\ UHVSRQVH W\SLFDOO\ UHVXOWLQJ LQ D FKDQJH LQ WKH

JOREDO('395

$Q HVVHQWLDO IHDWXUH RI WKH ('395 LV LWV QRQOLQHDULW\ UHÁHFWLQJ WKH IDFW WKDW GLDVWROLF

VWLIIQHVVG3G9JUDGXDOO\LQFUHDVHVZLWKORDGLQJ7KLVUHVXOWVLQDQ('395WKDWLVFRQYH[

WRZDUGV WKH YROXPH D[LV DQG LV W\SLFDOO\ ZHOO GHVFULEHG E\ DQ H[SRQHQWLDO RU SRZHU

IXQFWLRQ 7KLV SURSHUW\ GLFWDWHV WKDW ('395 TXDQWLÀFDWLRQ UHTXLUHV PHDVXUHPHQW RI

HQGGLDVWROLFSUHVVXUHDQGYROXPHIURPPXOWLSOHEHDWVRYHUDIDLUO\ZLGHUDQJHRIHQG

GLDVWROLF SUHVVXUHV 5HFHQWO\ .ORW] HW DO  SURSRVHG D PHWKRGRORJ\ WR HVWLPDWH WKH

('395IURPDVLQJOHEHDW7KLVPHWKRGZDVEDVHGRQWKHREVHUYDWLRQWKDW('395VIURP

SDWLHQWVZLWKZLGHO\GLIIHUHQWKHDUWVL]HVDQGHYHQ('395VIURPGLIIHUHQWVSHFLHVDOOKDYH

DIDLUO\FRPPRQVKDSHSURYLGHGWKDWYHQWULFXODUYROXPHLVQRUPDOL]HGZLWKDQDSSURSUL

DWHVFDOLQJPHWKRG7KHDXWKRUVWHVWHGWKHLUDSSURDFKSURVSHFWLYHO\RQDOLPLWHGQXPEHU

RIKXPDQVXEMHFWVDQGFRQFOXGHGWKDWWKHSURSRVHGVFKHPHDOORZHGDUHDVRQDEO\DF

FXUDWHSUHGLFWLRQRIWKH('395SDUWLFXODUO\ZKHQDQDO\]HGDWDJURXSOHYHO

$OWKRXJKWKLVDSSURDFKZDVYDOLGDWHGWRSUHGLFWWKH('395LQKXPDQGLODWHGFDUGLR

P\RSDWKLFKHDUWVH[YLYR IROORZLQJWKHLUUHPRYDOIRUKHDUWWUDQVSODQW WKHVLQJOHEHDW

PHWKRG KDV QRW \HW EHHQ YDOLGDWHGLQ YLYR LQ SDWLHQWV ZLWK GLODWHG FDUGLRP\RSDWK\

7KHUHIRUH WKH SXUSRVH RI RXU VWXG\ ZDV WR DVVHVV SURVSHFWLYHO\ WKH DFFXUDF\ RI WKH

(5)

&KDSWHU



DSSURDFK LQ SDWLHQWV ZLWK HQGVWDJH KHDUW IDLOXUH VFKHGXOHG IRU VXUJHU\ XVLQJ WKH

FRQYHQWLRQDOPXOWLEHDW('395REWDLQHGIURPSUHVVXUHYROXPHORRSVDFTXLUHGGXULQJ

JUDGXDOSUHORDGUHGXFWLRQE\YHQDFDYDRFFOXVLRQDVWKHJROGVWDQGDUG

,Q DGGLWLRQ WR SK\VLRORJLFDO VWXGLHV UHJDUGLQJ PHFKDQLVPV RI GLDVWROLF G\VIXQFWLRQ

WKHVLQJOHEHDWPHWKRGRORJ\KDVGLUHFWSUDFWLFDOFOLQLFDOXWLOLW\EHFDXVHLWDOORZVPRUH

VSHFLÀFLHOHVVORDGGHSHQGHQWTXDQWLÀFDWLRQRIGLDVWROLFIXQFWLRQ$VDQH[DPSOHLW

VKRXOGDOORZDPRUHGHWDLOHGHYDOXDWLRQRIVXUJLFDOLQWHUYHQWLRQVZKLFKSRWHQWLDOO\KDYH

RSSRVLQJHIIHFWVRQV\VWROLFDQGGLDVWROLFIXQFWLRQ$OVRWKLVPHWKRGPD\HQDEOHPRUH

VSHFLÀFWDUJHWLQJRISKDUPDFRORJLFDOVXSSRUWLQLQWHQVLYHFDUH

0(7+2'6 3DWLHQWV

7KHVWXG\JURXSVFRQVLVWHGRISDWLHQWVZLWKKHDUWIDLOXUH 1HZ<RUN+HDUW$VVRFLDWLRQ

FODVV ,,,,9 /9 HMHFWLRQ IUDFWLRQ   GHVSLWH RSWLPDO PHGLFDO WUHDWPHQW VFKHGXOHG

IRUUHVWULFWLYHPLWUDODQQXORSODVW\ 50$JURXSQ  RUVXUJLFDOYHQWULFXODUUHVWRUDWLRQ

695 ZLWKRUZLWKRXW50$ 695JURXSQ  $WKLUGJURXSFRQVLVWHGRISDWLHQWVZLWK

QRUPDO /9 IXQFWLRQ ()!  XQGHUJRLQJ HOHFWLYH FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ

&$%*  &$%*JURXSQ  7KHVDPSOHVL]HZDVEDVHGRQWKHDLPWRGHWHFWGLIIHUHQFHV

EHWZHHQ JURXSV DQG FRQGLWLRQV WKDW ZRXOG EH FRQVLGHUHG SK\VLRORJLFDOO\ UHOHYDQW

!  %DVHG RQ HDUOLHU VWXGLHV ZH DVVXPHG D  ZLWKLQJURXS YDULDELOLW\ IRU WKH

PDLQ SDUDPHWHUV 7KH DLP WR GHWHFW GLIIHUHQFHV ! ZLWK W\SH , HUURU  DQG D

SRZHURILQGLFDWHGWKDWDSSUR[LPDWHO\SDWLHQWVSHUJURXSVKRXOGEHHQUROOHG,Q

SULQFLSOHDOOSDWLHQWVVFKHGXOHGIRU&$%*50$DQGRU695ZHUHFRQVLGHUHGHOLJLEOHIRU

WKHVWXG\3RWHQWLDOHQUROPHQWLQWKHVWXG\ZDVOHIWWRWKHGLVFUHWLRQRIWKHVXUJHRQZKR

ZRXOGRSHUDWHRQWKHSDWLHQW7KUHHSDWLHQWVLQLWLDOO\HQUROOHGZHUHQRWLQFOXGHGLQWKH

DQDO\VLVEHFDXVHXOWLPDWHO\QRFRPSOHWHPHDVXUHPHQWVZHUHSHUIRUPHGRZLQJWRWLPH

OLPLWDWLRQVRUWHFKQLFDOGLIÀFXOWLHVGXULQJWKHSURFHGXUH

+HDUW IDLOXUH V\PSWRPV ZHUH TXDQWLÀHG E\ 1<+$ FODVVLÀFDWLRQ DQG EDVHOLQH DQ

JLRJUDSKLF/9HMHFWLRQIUDFWLRQVZHUHREWDLQHGGXULQJGLDJQRVWLFFDWKHWHUL]DWLRQ,QDOO

SDWLHQWV /9 SUHVVXUHYROXPH ORRSV VHH EHORZ  ZHUH DVVHVVHG LQ WKH RSHUDWLQJ URRP

EHIRUH SUH  DQG DIWHU SRVW  WKH VXUJLFDO LQWHUYHQWLRQ 7KXV DOO PHDVXUHPHQWV ZHUH

REWDLQHGLQDQHVWKHWL]HGFRQGLWLRQVZLWKRSHQFKHVWDQGRSHQSHULFDUGLXPDQGHLWKHU

MXVWEHIRUH SUH RUDIWHU SRVW FDUGLRSXOPRQDU\E\SDVV$OOSDWLHQWVXQGHUZHQWQRUPR

WKHUPLFKHDUWRSHUDWLRQVDVVFKHGXOHGZLWKLQWHUPLWWHQWDQWHJUDGHZDUPR[\JHQDWHG

EORRGFDUGLRSOHJLD7KHVWXG\SURWRFROZDVDSSURYHGE\RXUORFDO(WKLFV&RPPLWWHH

DQGDOOSDWLHQWVJDYHZULWWHQLQIRUPHGFRQVHQW

(6)



&+$37(5

$QHVWKHVLD

%HIRUHVXUJHU\WKHSDWLHQWVUHFHLYHGPJRIORUD]HSDPDVVXEOLQJXDOSUHPHGLFDWLRQ

6XEVHTXHQWO\DOOSDWLHQWVUHFHLYHGWRWDOLQWUDYHQRXVDQHVWKHVLDZLWKWDUJHWFRQWUROOHG

LQIXVLRQ RI SURSRIRO UHPLIHQWDQLO DQG VXIHQWDQLO DV GHVFULEHG SUHYLRXVO\  :H H[

SHFWHGWKDWVRPHSDWLHQWVZRXOGQHHGLQRWURSLFVXSSRUWDQGWKHUHIRUHWRDYRLGELDV

ZH SURYLGHG WKH VDPH ORZ GRVH  LQRWURSLF VXSSRUW LQ DOO SDWLHQWV ZLWK KHDUW IDLOXUH

,QRWURSLFVXSSRUWZDVVWDUWHGGLUHFWO\DIWHULQGXFWLRQRIDQHVWKHVLDZLWKDORZORDG

LQJGRVHRIPJNJHQR[LPRQHDGPLQLVWHUHGRYHUPLQXWHVDQGWKHUHDIWHUZH

SURYLGHG FRQWLQXRXV LQIXVLRQ DW D UDWH RI  ˜JïNJïPLQ ZKLFK ZDV PDLQWDLQHG

GXULQJWKHZKROHRSHUDWLRQ

,QVWUXPHQWDWLRQ

7RDFTXLUHSUHVVXUHYROXPHORRSVZHXVHGD)SUHVVXUHFRQGXFWDQFHFDWKHWHU &'

/H\FRP=RHWHUPHHU7KH1HWKHUODQGV LQFRUSRUDWLQJDVROLGVWDWHSUHVVXUHVHQVRUDQG

 HOHFWURGHV  PP VSDFLQJ  ZKLFK ZDV FRQQHFWHG WR D /H\FRP &DUGLDF )XQFWLRQ

/DE VLJQDO SURFHVVRU &'/H\FRP  $ PXOWLSODQH WUDQVHVRSKDJHDO HFKRFDUGLRJUDSK\

7(( SUREHZDVLQVHUWHGWRPRQLWRUFDUGLDFIXQFWLRQDQGIDFLOLWDWHSRVLWLRQLQJRIWKH

FRQGXFWDQFHFDWKHWHULQWUDRSHUDWLYHO\7KHFRQGXFWDQFHFDWKHWHUZDVLQWURGXFHGYLDD

VKHDWKLQWKHDVFHQGLQJDRUWDDQGSRVLWLRQHGZLWKWKHSLJWDLOLQWKH/9DSH[DQGWKHWZR

PRVWSUR[LPDOHOHFWURGHVMXVWDERYHWKHDRUWLFYDOYHWRJHWDQRSWLPDOPDWFKZLWKWKH/9

ORQJD[LV7KHFRQGXFWDQFHVLJQDOVZHUHFDOLEUDWHGE\WKHUPRGLOXWLRQDQGK\SHUWRQLF

VDOLQHGLOXWLRQ7RWKLVHQGDWKHUPDOÀODPHQWFDWKHWHUZDVSODFHGZLWKLWVWLSLQWKH

SXOPRQDU\DUWHU\YLDWKHULJKWLQWHUQDOMXJXODUYHLQIRUVHPLFRQWLQXRXVWKHUPRGLOXWLRQ

FDUGLDFRXWSXWPHDVXUHPHQWV (GZDUGV/LIH6FLHQFHV8GHQ7KH1HWKHUODQGV DQGIRU

K\SHUWRQLFVDOLQHLQMHFWLRQV$FDYDOWRXUQLTXHWZDVDSSOLHGDURXQGWKHLQIHULRUFDYDWR

SHUIRUPWHPSRUDU\SUHORDGUHGXFWLRQVE\FDYDORFFOXVLRQ(SLFDUGLDOSDFLQJZLUHVZHUH

SODFHGRQWKHULJKWDWULXP

('395E\FDYDORFFOXVLRQDQGE\VLQJOHEHDWHVWLPDWLRQ

7KHVWXG\SURWRFROLQYROYHGSUHVVXUHYROXPHPHDVXUHPHQWVDWDÀ[HG SDFHG KHDUWUDWH

RIESPGXULQJVWHDG\VWDWHFRQGLWLRQVDQGGXULQJJUDGXDOSUHORDGUHGXFWLRQE\LQIH

ULRUYHQDFDYDORFFOXVLRQ 9&2 7RDYRLGLQWHUIHUHQFHZLWKUHVSLUDWLRQDOOPHDVXUHPHQWV

ZHUHDFTXLUHGDIWHUGLVFRQQHFWLQJWKHYHQWLODWRU7KHFRQYHQWLRQDO('395VZHUHGHULYHG

IURPWKHVHULDOSUHVVXUHYROXPHORRSVDFTXLUHGGXULQJSUHORDGUHGXFWLRQDVVKRZQLQ

)LJXUH)URPHDFKORRSWKHHQGGLDVWROLFSUHVVXUHYROXPHSRLQWZDVLGHQWLÀHGDQG

WKHVHWRISRLQWVZHUHÀWE\OHDVWVTXDUHGUHJUHVVLRQDQDO\VLVWRDVWDQGDUGFXUYHWR

(7)

&KDSWHU



FKDUDFWHUL]H WKH ('395 3  &('ÃH[S .('9 7KLV ('395 ZDV GHVLJQDWHG DV WKH 9&2

GHULYHG('395 ('3959&2 )URPWKHÀWZHGHWHUPLQHGWKHYROXPHVDWHQGGLDVWROLF

SUHVVXUHV ('3[ DQGPP+J('9('9('9DQG('9UHVSHFWLYHO\

,QDGGLWLRQWKH('395ZDVGHWHUPLQHGE\WKHVLQJOHEHDWPHWKRG7KHFRPSXWDWLRQDO

PHWKRGKDVEHHQH[SODLQHGLQGHWDLOHOVHZKHUH%ULHÁ\.ORW]HWDOSURSRVHGWKDWDIWHU

DSSURSULDWHQRUPDOL]DWLRQRIYROXPHVWRDFFRXQWIRUKHDUWVL]HWKH('395LVDSSUR[L

PDWHO\LQYDULDQWEHWZHHQVXEMHFWVDQGHYHQEHWZHHQVSHFLHV6SHFLÀFDOO\QRUPDOL]HG

YROXPH 9Q LVEDVHGRQHVWLPDWHVRIWKHYROXPHDWZKLFKSUHVVXUHLVaPP+J 9R DQG

WKHYROXPHDWZKLFKSUHVVXUHHTXDOVPP+J 9 VRWKDW9Q  99  99 7KH

('395EDVHGRQ9QLVGHVLJQDWHGDV('395Q%DVHGRQPHDVXUHPHQWVLQH[YLYRLVRODWHG

KXPDQKHDUWVWKLVYROXPHQRUPDOL]HGFXUYHZDVIRXQGWREHZHOOUHSUHVHQWHGE\WKH

HTXDWLRQ3 $Q9Q%QZLWK$Q PP+JDQG%Q 7KHDXWKRUVDOVRGHULYHG

DQ HPSLULFDO UHODWLRQVKLS WR HVWLPDWH 9 9  ('9    ('3  %DVHG RQ WKHVH

CHAPTER 3 Figures Figure 1

LV Volume (mL)

LV Pressure (mmHg)

Time (s)

EDV20

LV Pressure EDV15

(mmHg)

EDV10

EDV5

50 100 150 200

0 25 50 75 100

0 8

0 5 10 15 20 25

50 100 150 200

LV Volume (mL)

)LJXUH/HIWYHQWULFOH /9 SUHVVXUHDQGYROXPHVLJQDOVGXULQJJUDGXDOSUHORDGUHGXFWLRQREWDLQHG

E\YHQDFDYDRFFOXVLRQ(QGGLDVWROLFSUHVVXUHYROXPHSRLQWVZHUHÀWWHGZLWKDQH[SRQHQWLDOFXUYH

DQGWKHLQWHUFHSWVDWDQGPP+JDUHLQGLFDWHG ('9(9'('9DQG('9 

(8)



&+$37(5

UHODWLRQVWKH(3'95LQDQLQGLYLGXDOVXEMHFWFDQEHSUHGLFWHG LHVSHFLÀHGDQDO\WLFDOO\  IURP D VLQJOH PHDVXUHG HQGGLDVWROLF SUHVVXUHYROXPH SRLQW 9P 3P  E\ FDOFXODWLQJ

9DV9 9 9P9  3P$Q %Q DQGVXEVHTXHQWO\UHSUHVHQWHGDV3 α9βZLWKβ  ORJ 3P ORJ 9P9 DQGα 9β7KXVαDQGβDUHGLUHFWO\FDOFXODWHGIURPWKH

9P DQG 3P YDOXHV DQG GHÀQH WKH VLQJOHEHDW GHULYHG ('395 ('3956%  ,Q RXU VWXG\

ZHXVHGWKHÀUVWEHDWRIWKH9&2GDWDVHWWRGHWHUPLQHWKH('3956%DVLOOXVWUDWHGLQ

)LJXUH,QDQDORJ\ZLWKWKH('3959&2ZHDOVRFDOFXODWHGWKHYDOXHVRIYROXPHVRQWKH

('3956%DWWKHSUHVVXUHOHYHOVDQGPP+J&RPSDULVRQVEHWZHHQ('3959&2 DQG('3956%ZHUHSHUIRUPHGLQLQGLYLGXDOSDWLHQWVDQGDOVRDQDO\]HGDWWKHJURXSOHYHO

E\FRQVLGHULQJVL[JURXSVWKHSDWLHQWVZLWK&$%*EHIRUHDQGDIWHUVXUJHU\ &$%*SUH

&$%*SRVW WKHSDWLHQWVZLWK50$EHIRUHDQGDIWHUVXUJHU\ 50$SUH50$SRVW DQG

WKHSDWLHQWVZLWK695EHIRUHDQGDIWHUVXUJHU\ 695SUH695SRVW  'DWDDQDO\VLVDQGVWDWLVWLFDOPHWKRGV

7RGHWHUPLQHWKHSUHGLFWLYHDFFXUDF\RIWKH('3956%LQLQGLYLGXDOSDWLHQWVZHFDOFXODWHG

WKHURRWPHDQVTXDUHGHUURU 506( EHWZHHQDFWXDODQGHVWLPDWHGSUHVVXUH LHEDVHG

RQ('3956% DWWKHVDPHHQGGLDVWROLFYROXPH506(TXDQWLÀHVWKHDYHUDJHGLIIHUHQFH

EHWZHHQWKHHVWLPDWHGDQGWKHDFWXDOYDOXHVLQFOXGLQJERWKELDVDQGYDULDQFHRIWKH

HVWLPDWRU$OOGDWDSRLQWV LHEHDWV DFTXLUHGGXULQJD9&2ZHUHLQFOXGHGLQWKHFDOFX

ODWLRQ7KXV506( ¦> Q š 3PL3SL @LQZKLFKQHTXDOVWKHQXPEHURIGDWDSRLQWVš

LQGLFDWHVWKHVXPPDWLRQRYHUDOOQGDWDSRLQWV L WRQ 3PLUHSUHVHQWVWKHPHDVXUHG

SUHVVXUHVIRUDQLQGLYLGXDOGDWDSRLQWDQG3SLWKHFRUUHVSRQGLQJSUHGLFWHGSUHVVXUH

7RGHWHFWSRVVLEOHGLIIHUHQFHVLQ506(YDOXHVEHWZHHQJURXSV &$%*50$DQG695 RU

EHWZHHQFRQGLWLRQV SUHVXUJHU\SRVWVXUJHU\ ZHSHUIRUPHGDXQLYDULDWHDQDO\VLVRI

YDULDQFHXVLQJDJHQHUDOOLQHDUPRGHOZLWKSDWLHQWVDVUDQGRPIDFWRUDQGJURXSVDQG

FRQGLWLRQVDVÀ[HGIDFWRUVLQFOXGLQJDOOLQWHUDFWLYHHIIHFWV6LPLODUDQDO\VHVZHUHSHU

IRUPHGIRU9PDQG3P:HDOVRGHWHUPLQHG9&2GHULYHGDQGVLQJOHEHDWGHULYHG('9

('9('9DQG('97RFRPSDUHWKHVHYDOXHVEHWZHHQWKHWZRPHWKRGV VLQJOHEHDW

YV9&2 9&2GHULYHGDQGVLQJOHEHDWGHULYHG('9('9('9DQG('9YDOXHVZHUH

FRUUHODWHGZLWKOLQHDUUHJUHVVLRQDQGELDVHVDQGOLPLWVRIDJUHHPHQWZHUHGHWHUPLQHG

ZLWK %ODQG$OWPDQ DQDO\VHV 3UH DQG SRVWVXUJHU\ GDWD ZHUH DQDO\]HG VHSDUDWHO\ WR

REWDLQDFURVVVHFWLRQDO LHRQHGDWDSRLQWSHUSDWLHQW GHVLJQ3UHFLVLRQVRIELDVHVDQG

OLPLWVRIDJUHHPHQWZHUHTXDQWLÀHGE\FRQÀGHQFHLQWHUYDOV

7RDVVHVVSRVVLEOHGLIIHUHQFHVEHWZHHQJURXSVFRQGLWLRQVDQGPHWKRGVWKHGDWDZHUH

VXEMHFWHGWRDXQLYDULDWHDQDO\VLVRIYDULDQFHXVLQJDJHQHUDOOLQHDUPRGHOZLWKSDWLHQWV

DV UDQGRP IDFWRU DQG JURXSV FRQGLWLRQV DQG PHWKRGV DV À[HG IDFWRUV $OO LQWHUDF

WLYH HIIHFWV EHWZHHQ À[HG IDFWRUV ZHUH LQFOXGHG LQ WKH PRGHO LQ SDUWLFXODU WR DVVHVV

ZKHWKHUWKHGHWHFWHGGLIIHUHQFHVZHUHGHSHQGHQWRQWKHPHWKRG7KLVDSSURDFKWDNHV

(9)

&KDSWHU



LQWRDFFRXQWWKDWHDFKJURXSFRQVLVWHGRIDGLIIHUHQWVHWRISDWLHQWVEXWZLWKLQHDFK

JURXSHDFKSDWLHQWZDVPHDVXUHGLQWZRFRQGLWLRQV LHDUHSHDWHGPHDVXUHVGHVLJQ 

6WDWLVWLFDO DQDO\VHV ZHUH SHUIRUPHG ZLWK FRPPHUFLDOO\ DYDLODEOH VRIWZDUH 6366 

6366,QF&KLFDJR,/ 5HVXOWVDUHH[SUHVVHGDVPHDQV”VWDQGDUGGHYLDWLRQDOOWHVWV

ZHUHWZRVLGHGDQGDSUREDELOLW\YDOXHZDVFRQVLGHUHGVWDWLVWLFDOO\VLJQLÀFDQW

5(68/76

%DVHOLQHFKDUDFWHULVWLFVRIWKHSDWLHQWVDUHVXPPDUL]HGLQ7DEOH5HSUHVHQWDWLYH('

395VIURPSDWLHQWVVSDQQLQJDZLGHUDQJHRIYROXPHVDUHVKRZQLQ)LJXUH2QDYHU

DJH('9GHFUHDVHGE\”P/DQG('3GHFUHDVHGE\”PP+JGXULQJD9&2

7KHVH ORDGLQJ FKDQJHV FRUUHVSRQGHG WR ” RI EDVHOLQH ('9 9P  DQG ”

RIEDVHOLQH('3 3P ZKLFKDOORZHGDQDFFXUDWHGHWHUPLQDWLRQRI9&2GHULYHG('395

5HODWLYHFKDQJHVZHUHVLPLODULQDOOJURXSV &$%*JURXS”DQG”50$

JURXS”DQG”695JURXS”DQG”UHVSHFWLYHO\IRU('9

DQG('3 7KH506(VIRUWKHVHH[DPSOHVDUHLQGLFDWHGLQWKH)LJXUH7KHRYHUDOOPHDQ

506(REWDLQHGE\SRROLQJGDWDIURPDOOSDWLHQWVZDV”PP+J7DEOHSURYLGHV

WKHPHDQ506(VIRUHDFKRIWKHJURXSVLQERWKFRQGLWLRQV6WDWLVWLFDODQDO\VLV $129$  VKRZHGWKDWWKH506(ZDVQRWVLJQLÀFDQWO\GLIIHUHQWEHWZHHQJURXSVRUEHWZHHQFRQ

GLWLRQVLQGLFDWLQJWKDWWKHSUHGLFWLYHDFFXUDF\RIWKHVLQJOHEHDWPHWKRGZDVVLPLODU

LQDOOFDVHV

7DEOH  DOVR VKRZV PHDQ ('9 ('9 ('9 DQG ('9 REWDLQHG E\ WKH VLQJOHEHDW

PHWKRGDQGE\9&2IRUDOOJURXSVDQGFRQGLWLRQV'LIIHUHQFHVEHWZHHQJURXSVFRQGL

WLRQVDQGPHWKRGVDQGWKHLULQWHUDFWLRQVZHUHWHVWHGE\$129$7KHUHVXOWVLQGLFDWHG

WKHSUHVHQFHRIVLJQLÀFDQWGLIIHUHQFHVLQ('9VEHWZHHQJURXSVDWHDFKSUHVVXUHDQG

7DEOH%DVHOLQHSDWLHQWFKDUDFWHULVWLFV

&$%*JURXS 50$JURXS 695JURXS

1RRISDWLHQWV Q   

0DOHIHPDOH Q   

$JH \ ” ” ”

1<+$FODVV ” ”

/9()  ” ” ”

05JUDGH ” ”

1<+$ 1HZ <RUN +HDUW $VVRFLDWLRQ /9() DQJLRJUDSKLF OHIW YHQWULFXODU HMHFWLRQ IUDFWLRQ 05 PL

WUDOUHJXUJLWDWLRQ&$%*FRURQDU\DUWHU\E\SDVVJUDIWLQJ50$UHVWULFWLYHPLWUDODQQXORSODVW\695

VXUJLFDOYHQWULFXODUUHVWRUDWLRQ'DWDDUHSUHVHQWHGDVQXPEHURISDWLHQWVRUDVPHDQ”VWDQGDUG

GHYLDWLRQ

(10)



&+$37(5

0 5 10 15 20 25 30

0 50 100 150 200 250 300

0 5 10 15 20 25 30

0 50 100 150 200 250 300

0 5 10 15 20 25 30

0 50 100 150 200 250 300

EDP (mmHg)

0 5 10 15 20 25 30

0 50 100 150 200 250 300

0 5 10 15 20 25 30

0 50 100 150 200 250 300

EDV (mL) RMSE=2.56

RMSE=2.30

RMSE=2.76 RMSE=0.90 RMSE=0.29

)LJXUH,OOXVWUDWLRQRIWKHZLGHUDQJHRI

HQGGLDVWROLFYROXPHVFRYHUHGLQWKHYDUL

RXV SDWLHQWV JURXSV 5HSUHVHQWDWLYH H[

DPSOHV RI HQGGLDVWROLF SUHVVXUHYROXPH

SRLQWV GXULQJ SUHORDG UHGXFWLRQ YHQD

FDYD RFFOXVLRQ 9&2  DQG FRUUHVSRQGLQJ

VLQJOHEHDW GHULYHG ('395V DUH VKRZQ

7KH PHDVXUHG GDWD ZHUH ÀWWHG ZLWK DQ

H[SRQHQWLDO FXUYH EODFN OLQHV LQGLFDWH

('3959&2 3 &('ÃH[S .('9  7KH SUHGLFWHG

VLQJOHEHDWGHULYHG('395 VKRZQLQJUH\  ZDV EDVHG RQ WKH HQGGLDVWROLF SUHVVXUH

YROXPH SRLQWV RI WKH EDVHOLQH SUHVVXUH

YROXPH SRLQW PDUNHG LQ JUH\  3P 9P

5RRWPHDQVTXDUHG HUURUV 506(V  ZHUH

FDOFXODWHG LQFOXGLQJ DOO GDWD SRLQWV RE

WDLQHGGXULQJSUHORDGUHGXFWLRQ

(11)

&KDSWHU



7DEOH(QGGLDVWROLFSUHVVXUHYROXPHUHODWLRQ ('395 LQGLFHVLQDOOJURXSVDQGFRQGLWLRQVREWDLQHGE\WKHVLQJOHEHDW 6% DQGWKHYHQDFDYDRFFOXVLRQ 9&2 PHWKRGV &$%*50$6950DLQHIIHFWV,QWHUDFWLRQHIIHFWV 3UH3RVW3UH3RVW3UH3RVW*URXS&RQGLWLRQ0HWKRG*URXS &RQGLWLRQ*URXS 0HWKRG&RQGLWLRQ 0HWKRG 506( PP+J ””””””QDQDQD 9P P/ ””””””QDQDQD 3P PP+J ””””””QDQDQD ('9 P/ 6%”””””” 9&2”””””” ('9 P/ 6%”””””” 9&2”””””” ('9 P/ 6%”””””” 9&2”””””” ('9 P/ 6%”””””” 9&2”””””” 50$UHVWULFWLYHPLWUDODQQXORSODVW\&$%*FRURQDU\DUWHU\E\SDVVJUDIWLQJ695VXUJLFDOYHQWULFXODUUHVWRUDWLRQ('9HQGGLDVWROLFYROXPH506(URRW PHDQVTXDUHGHUURUQDQRWDSSOLFDEOH9DOXHVDUHPHDQ”VWDQGDUGGHYLDWLRQ,QGLFHVZHUHDQDO\]HGE\XQLYDULDWHDQDO\VLVRIYDULDQFHWRDVVHVVWKHHIIHFWV RIJURXSFRQGLWLRQDQGPHWKRG LIDSSOLFDEOH DQGDOOLQWHUDFWLYHHIIHFWV WKHJURXSFRQGLWLRQPHWKRGLQWHUDFWLRQZDVWHVWHGDQGQRQVLJQLÀFDQWDWS! LQDOOFDVHV 

(12)



&+$37(5

DOVREHWZHHQFRQGLWLRQVH[FHSWDWPP+J6LJQLÀFDQWGLIIHUHQFHVEHWZHHQPHWKRGV

IRU('9DQG('9ZHUHDOVRQRWHGLQGLFDWLQJWKDWWKHVLQJOHEHDWPHWKRGRYHUHVWL

PDWHG('9DQGXQGHUHVWLPDWHG('9,QWHUHVWLQJO\$129$GLGQRWVKRZDQ\VLJQLÀ

FDQWLQWHUDFWLRQHIIHFWVLQGLFDWLQJWKDWWKHREVHUYHGGLIIHUHQFHVEHWZHHQJURXSVDQG

EHWZHHQFRQGLWLRQV PDLQHIIHFWV ZHUHQRWGHSHQGHQWRQWKHPHWKRG RUYLFHYHUVD

WKDWWKHREVHUYHGGLIIHUHQFHVEHWZHHQPHWKRGVZHUHQRWGHSHQGHQWRQWKHJURXSRU

RQWKHFRQGLWLRQ 

7KH UHODWLRQV EHWZHHQ VLQJOHEHDW GHULYHG DQG 9&2GHULYHG ('9 ('9 ('9 DQG

('9ZHUHDOVRDQDO\]HGE\OLQHDUUHJUHVVLRQDQGE\%ODQG$OWPDQDQDO\VHV )LJXUH 

7KHVHSORWVVKRZDJRRGFRUUHODWLRQEHWZHHQWKHWZRPHWKRGV 5WR DQG

Figure 3

Linear Regression Bland-Altman

PRE POST PRE POST

y=0.76x+72.7 (R2=0.69) y=0.81x+57.8 (R2=0.69) Bias: 44 (95%CI: 29 to 58) Bias: 35 (95%CI: 23 to 47) Upper LoA: 122 (97 to 147) Upper LoA: 97 (77 to 117)

EDV5 (mL)

Lower LoA: -35 (-59 to -10) Lower LoA: -27 (-47 to -6.9)

y=0.83x+25.9 (R2=0.87) y=0.98x+12.9 (R2=0.95) Bias: -8.3 (95%CI: -19 to 2.7) Bias: 9.8 (95%CI: 5.0 to 15) Upper LoA: 52 (33 to 70) Upper LoA: 35 (27 to 43)

EDV10 (mL)

Lower LoA: -68 (-87 to -49) Lower LoA: -15 (-23 to -7.2)

y=0.69x+35.7 (R2=0.78) y=0.94x+6.77 (R2=0.97) Bias: -37 (95%CI: -54 to -20) Bias: -4.1 (95%CI: -8.4 to 0.2) Upper LoA: 57 (28 to 87) Upper LoA: 18 (11 to 26)

EDV15 (mL)

Lower LoA: -132 (-161 to -102) Lower LoA: -27 (-19 to -34)

y=0.60x+49.2 (R2=0.70) y=0.88x+10.0 (R2=0.94) Bias: -57 (95%CI: -80 to -34) Bias: -13 (95%CI: -20 to -7.0) Upper LoA: 69 (29 to 108) Upper LoA: 21 (9.9 to 32)

EDV20 (mL)

Lower LoA: -183 (-222 to -143) Lower LoA: -48 (-59 to -37)

VCO Method Mean

0 300 600

0 300 600

-300 0 300

-300 0 300

0 300 600

SB method

-300 0 300

Difference

0 300 600

0 300 600

-300 0 300

0 300 600

0 300 600 0 300 600

)LJXUH7KHUHODWLRQVEHWZHHQVLQJOHEHDWGHULYHGDQGYHQDFDYDRFFOXVLRQ 9&2 GHULYHG('9

('9('9DQG('9ZHUHDQDO\]HGIRUSUHVXUJHU\ 35( DQGSRVWVXUJHU\ 3267 GDWDE\OLQHDU

UHJUHVVLRQ OHIWSDQHOV DQGE\%ODQG$OWPDQDQDO\VHV ULJKWSDQHOV ,QWKHUHJUHVVLRQSORWVWKHIXOO

OLQHVJLYHWKHOLQHDUÀWVWKHGRWWHGOLQHVUHSUHVHQWWKHOLQHVRILGHQWLW\,QWKH%ODQG$OWPDQSORWV

WKHELDVHVDQGWKHOLPLWVRIDJUHHPHQW /R$ ELDV”6'V DUHLQGLFDWHGE\KRUL]RQWDOGRWWHG

OLQHV&RQÀGHQFHLQWHUYDOV  IRUELDVHVDQGOLPLWVRIDJUHHPHQWDUHJLYHQLQWKHÀJXUHV YDOXHV

EHWZHHQEUDFNHWV 

(13)

&KDSWHU



FRQÀUPWKHRYHUHVWLPDWLRQRI('9DQGXQGHUHVWLPDWLRQRI('9DVTXDQWLÀHGE\WKH

ELDVHVLQWKH%ODQG$OWPDQSORWV

7RLQYHVWLJDWHDSRVVLEOHGHSHQGHQFHRIWKHJRRGQHVVRIWKHÀWRQEDVHOLQHHQGGLDVWROLF

SUHVVXUH RU YROXPH ZH SHUIRUPHG OLQHDU UHJUHVVLRQV EHWZHHQ 506( DQG 3P DQG 9P

UHVSHFWLYHO\IRUDOOSRROHGGDWD7KHUHVXOWVLQGLFDWHGQRVLJQLÀFDQWFRUUHODWLRQV506(

Ã3P 5 S  DQG506( Ã9P 5 S  7R

IXUWKHU LOOXVWUDWH WKLV )LJXUH  VKRZV 506( LQ UHODWLRQ WR 3P DQG 9P IRU DOO JURXSV

)LJXUH  VKRZV PHDQ 9P3P  DQG WKH PHDQ ('3956% EDVHG RQ WKHVH YDOXHV IRU HDFK

JURXS7KHÀJXUHVKRZVWKHODUJHUYROXPHVDQGKLJKHUHQGGLDVWROLFSUHVVXUHVLQWKH

KHDUWIDLOXUHSDWLHQWV 50$DQG695JURXSV FRPSDUHGZLWKWKHSDWLHQWVZLWKUHODWLYHO\

QRUPDO/9IXQFWLRQ &$%*JURXSV ,QDOOSDWLHQWV('3LQFUHDVHGDQG('9GHFUHDVHGRU

DWOHDVWWHQGHGWRGRVRSRVWVXUJHU\$VH[SHFWHGWKLVHIIHFWZDVSDUWLFXODUO\HYLGHQW

LQ WKH SDWLHQWV XQGHUJRLQJ YHQWULFXODU UHVKDSLQJ 695 JURXS  1RWH WKDW WKH FKDQJH

FRPSDULQJSUHYVSRVWVXUJHU\ LQ('3956%ZDVDOVRPRVWSURQRXQFHGLQWKLVJURXS

',6&866,21

7KHSUHVHQWVWXG\DVVHVVHGWKHDFFXUDF\RIDPHWKRGWRHVWLPDWHWKH('395IURP('3

DQG('9PHDVXUHGRQDVLQJOHVWHDG\VWDWHEHDW6HYHUDOUHFHQWVWXGLHVKDYHDS

SOLHGWKLVFRQFHSWEXWLQYLYRYDOLGDWLRQLQGLODWHGFDUGLRP\RSDWK\SDWLHQWVZDVVWLOO

ODFNLQJ7KH('395LVWKHPRVWFRPSUHKHQVLYHDQGVSHFLÀFPHDQVRIFKDUDFWHUL]LQJ

SDVVLYHGLDVWROLFSURSHUWLHVRIWKH/9DQGWKXVSURYLGHVHVVHQWLDOLQIRUPDWLRQRQYHQ

Figure 4

0.0 2.0 4.0 6.0

0 5 10 15 20 25

Pm (mmHg)

RMSE (mmHg)

0.0 2.0 4.0 6.0

0 100 200 300 400

Vm (mL)

CABG-pre CABG-post RMA-pre RMA-post SVR-pre SVR-post

)LJXUH5RRWPHDQVTXDUHGHUURU 506( EHWZHHQPHDVXUHG LHXVLQJWKHYHQDFDYDRFFOXVLRQ

9&2 PHWKRG DQGSUHGLFWHG VLQJOHEHDW 6% PHWKRG SUHVVXUHDVDIXQFWLRQRIEDVHOLQHSUHVVXUH

3P DQGYROXPH 9P IRUDOOJURXSV7KHKRUL]RQWDOHUURUEDUVUHSUHVHQWWKH6'IRU3P OHIWSDQHO  DQG 9P ULJKW SDQHO  DQG WKH YHUWLFDO HUURU EDUV UHSUHVHQW WKH 6' IRU 506( 1R FRUUHODWLRQV ZHUH

SUHVHQW VHHWH[WIRUGHWDLOV 7KHRYHUDOO506( ”PP+J LVLQGLFDWHGE\WKHGRWWHGOLQHV

&$%*FRURQDU\DUWHU\E\SDVVJUDIWLQJ50$UHVWULFWLYHPLWUDODQQXORSODVW\695VXUJLFDOYHQWULFXODU

UHVWRUDWLRQ

(14)



6LQJOHEHDWHVWLPDWLRQRIWKHOHIWYHQWULFXODUHQGGLDVWROLFSUHVVXUH²YROXPHUHODWLRQVKLS

&+$37(5

WULFXODUUHPRGHOOLQJLQKHDUWIDLOXUH7KLVUHODWLRQHQDEOHVDFFXUDWHGHWHUPLQDWLRQRIWKH

HIIHFWVRIGLVHDVHDQGRIWKHUDSLHVRQYHQWULFXODUUHPRGHOOLQJDQGUHYHUVHUHPRGHOOLQJ

8QIRUWXQDWHO\ DVVHVVPHQW RI WKH ('395 LV FRPSOLFDWHG EHFDXVH LW UHTXLUHV FRQWLQX

RXV /9 SUHVVXUH DQG YROXPH PHDVXUHPHQWV REWDLQHG GXULQJ D FKDQJH LQ ORDGLQJ WR

DFKLHYHWKHUHTXLUHGYDULDWLRQLQSUHVVXUHVDQGYROXPHV7KLVW\SLFDOO\LQYROYHVWKHXVH

RIDFRQGXFWDQFHFDWKHWHUFRPELQHGZLWKHJDYHQDFDYDEDOORRQFDWKHWHUWRLQGXFH

D SUHORDG UHGXFWLRQ 7KH UHTXLUHG LQYDVLYH LQVWUXPHQWDWLRQ KDV OLPLWHG WKH HPSOR\

PHQWRIWKH('395FRQFHSWVLQURXWLQHFOLQLFDOSUDFWLFH7KHSURSRVHGFRPSXWDWLRQDO

PHWKRGDYRLGVWKHQHHGIRUDORDGLQWHUYHQWLRQDQGSDUWLFXODUO\ZKHQFRPELQHGZLWK

HYROYLQJQRQLQYDVLYHWHFKQLTXHVWRHVWLPDWHYHQWULFXODUSUHVVXUHDQGYROXPHZRXOG

SURYLGH DQ DWWUDFWLYH DOWHUQDWLYH IRU DVVHVVLQJ WKH ('395 1RQLQYDVLYH PHWKRGV IRU

PHDVXUHPHQWVRI/9YROXPHLQFOXGH05,HFKRFDUGLRJUDSK\DQGUDGLRQXFOLGHYHQWULFX

ORJUDSK\ ZKHUHDV ('3 PD\ EH HVWLPDWHG IURP SXOPRQDU\ YHLQ YHORFLW\ E\ 'RSSOHU

HFKRFDUGLRJUDSKLF WHFKQLTXHV RU E\ FRPELQLQJ WUDQVPLWUDO HDUO\ GLDVWROLF YHORFLW\ (  ZLWK HLWKHU WLVVXH'RSSOHU PLWUDO YHORFLW\ (·  RU WZRGLPHQVLRQDO HFKRFDUGLRJUDSKLF

JOREDOGLDVWROLFVWUDLQRUVWUDLQUDWHPHDVXUHPHQWV

'HYHORSPHQW DQG SULRU YDOLGDWLRQ RI WKH VLQJOHEHDW PHWKRG ZDV PDLQO\ EDVHG RQ

SUHVVXUHYROXPHPHDVXUHPHQWVLQH[YLYRKHDUWV:KLOHWKHVHPHDVXUHPHQWVDUHKLJKO\

0 5 10 15 20

0 50 100 150 200 250 300

EDV (mL)

EDP (mmHg)

CABG-pre CABG-post RMA-pre RMA-post SVR-pre SVR-post

)LJXUH 0HDQ HQGGLDVWROLF SUHVVXUHYROXPH SRLQWV 3P 9P  IRU DOO JURXSV DQG FRUUHVSRQGLQJ

VLQJOHEHDWGHULYHG HQGGLDVWROLF SUHVVXUHYROXPH UHODWLRQV ('9 HQGGLDVWROLF YROXPH ('3 HQG

GLDVWROLFSUHVVXUH&$%*FRURQDU\DUWHU\E\SDVVJUDIWLQJ50$UHVWULFWLYHPLWUDODQQXORSODVW\695

VXUJLFDOYHQWULFXODUUHVWRUDWLRQ

(15)

&KDSWHU



DFFXUDWHWKH\PD\QRWUHÁHFWLQYLYRFRQGLWLRQVLQSDUWEHFDXVHRIWKHLQÁXHQFHVRI

WKHSHULFDUGLXPDWULDDQGWKHULJKWYHQWULFOHVRQWKH/9('395,QWKHSUHVHQWVWXG\

ZH WHVWHG WKLV VLQJOHEHDW DSSURDFK YHUVXV WKH ('395 REWDLQHG E\ 9&2 LQ SDWLHQWV

ZLWK YHQWULFXODU YROXPHV VSDQQLQJ IURP QRUPDO WR VHYHUHO\ GLODWHG :H LQFOXGHG WKH

WKUHHVXUJLFDOJURXSVDWWZRFRQGLWLRQVWRREWDLQDZLGHUDQJHRI('395V$VH[SHFWHG

GLIIHUHQFHVLQGLDVWROLFSUHVVXUHVDQGYROXPHVZHUHKLJKO\VLJQLÀFDQWEHWZHHQJURXSV

DQGEHWZHHQFRQGLWLRQV7KHORZRYHUDOO506(YDOXHVWKDWFKDUDFWHUL]HVWKHGLIIHUHQFH

EHWZHHQPHDVXUHG 9&2GHULYHG DQGSUHGLFWHG VLQJOHEHDWGHULYHG ('395VLQGLFDWHG

JRRGSUHGLFWLYHDFFXUDF\RIWKHVLQJOHEHDWPHWKRG$OWKRXJKKHDUWVL]H ('9 DQG('3

ZHUHVXEVWDQWLDOO\GLIIHUHQWEHWZHHQJURXSVWKHPHDQ506(ZDVVLPLODU aPP+J LQ

HDFKJURXSDQGHVVHQWLDOO\WKHVDPHDVGHWHUPLQHGIRUWKHLQYLYRKHDUWVLQWKHRULJLQDO

YDOLGDWLRQVWXG\'DWDIURPWKHH[YLYRKXPDQKHDUWVVWXGLHGLQWKDWRULJLQDOVWXG\

VXJJHVWHGWKDWSUHGLFWHG('395VEDVHGRQPHDVXUHGSUHVVXUHYROXPHSRLQWVDWORZHU

SUHVVXUHV a PP+J  ZRXOG EH OHVV DFFXUDWH WKDQ WKRVH DW KLJKHU SUHVVXUHV a

PP+J 7KLVOLPLWDWLRQZDVQRWHQFRXQWHUHGLQWKHSUHVHQWVWXG\ZKLFKGLGQRWVKRZD

FRUUHODWLRQEHWZHHQHLWKHUPHDVXUHG('3RU('9DQGWKHDFFXUDF\LQWHUPVRI506(RI

WKHSUHGLFWHG('395

7KHFXUUHQWDQDO\VLVIRFXVHGRQWHVWLQJWKHDFFXUDF\RIWKHVLQJOHEHDWPHWKRGWRSUH

GLFW('9RYHUDUDQJHRI('3IURPWRPP+J7KHDQDO\VLVRISRROHGGDWDVKRZHG

D WLJKW FRUUHODWLRQ EHWZHHQ PHDVXUHG DQG SUHGLFWHG ('9 DW HDFK SUHVVXUH OHYHO 7KH

EHVWFRUUHVSRQGHQFHEHWZHHQWKHVLQJOHEHDWDQG9&2PHWKRGVZDVREWDLQHGDWWKH

PP+JOHYHOZKLFKZDVSDUWO\SUHGLFWDEOHEHFDXVHWKHHVWLPDWHG('395LVDQFKRUHG

WRWKHEDVHOLQHHQGGLDVWROLFSUHVVXUHYROXPHSRLQWDQGWKHRYHUDOOPHDQHQGGLDVWROLF

SUHVVXUHZDV”PP+J:HREVHUYHGDVWDWLVWLFDOO\VLJQLÀFDQWRYHUHVWLPDWLRQRI('9

DWWKHPP+JSUHVVXUHOHYHODQGDQXQGHUHVWLPDWLRQDWPP+J7KHUHDUHDWOHDVW

WZRSRVVLEOHH[SODQDWLRQVIRUWKHVHV\VWHPDWLFHUURUV)LUVWWKHYDOXHVRI$QDQG%QRQ

ZKLFK WKH SUHGLFDWLRQ LV EDVHG ZHUH GHWHUPLQHG IURP GLUHFW KLJKO\ UHOLDEOH YROXPH

PHDVXUHPHQWV PDGH ZLWK LQWUDYHQWULFXODU EDOORRQV LQ H[SODQWHG KHDUWV $ V\VWHPDWLF

GLIIHUHQFHLQYROXPHGHWHUPLQDWLRQE\FRQGXFWDQFHFDWKHWHUFRPSDUHGZLWKWKHEDO

ORRQ PHWKRG ZRXOG LPSDFW RQ WKH RSWLPDO YDOXHV RI $Q DQG %Q 6HFRQG DV LPSOLHG

DERYHRSWLPDOYDOXHVRI$QDQG%QPD\EHLQÁXHQFHGE\WKHHIIHFWVRIWKHSHULFDUGLXP

WKHDWULDDQGWKHULJKWYHQWULFOHRQWKH/9('395+RZHYHUWKHKLJKO\OLQHDUFRUUHODWLRQ

EHWZHHQPHDVXUHGDQGSUHGLFWHGYROXPHVDWHDFKSUHVVXUHOHYHODQGWKHIDFWWKDWWKHVH

UHODWLRQVDUHLQGHSHQGHQWRIKHDUWVL]HDQGXQGHUO\LQJFOLQLFDOFRQGLWLRQVXJJHVWWKDW

LWLVSRVVLEOHWRFRUUHFWWKHSUHGLFWLRQPHWKRGZLWKDOLQHDUWUDQVIRUPDWLRQXVLQJWKH

HTXDWLRQVVKRZQLQ)LJXUHIRUWKHGLIIHUHQWSUHVVXUHOHYHOV,QDGGLWLRQWRHVWLPDWLQJ

WKHYROXPHVRQWKH('395DWVSHFLÀFSUHVVXUHVZKLFKFDQEHXVHGWRLQGH[FKDQJHV

LQ YHQWULFXODU FDSDFLWDQFH LQ LQGLYLGXDO SDWLHQWV RU GLIIHUHQFHV EHWZHHQ JURXSV LQ D

UHODWLYHO\ORDGLQGHSHQGHQWIDVKLRQRWKHULPSRUWDQWSDUDPHWHUVXVHGWRFKDUDFWHUL]H

(16)



&+$37(5

GLDVWROLFSURSHUWLHVDUHP\RFDUGLDOVWLIIQHVVDQGYHQWULFXODUFKDPEHUVWLIIQHVVZKLFKDUH

ERWKUHODWHGWRWKHORFDOVORSHRIWKH('395DWGLIIHUHQWSUHVVXUHV,QWKHSULRUVWXG\LW

ZDVGHWHUPLQHGWKDWWKHSUHGLFWLRQRIWKH('395SURYLGHGE\WKHVLQJOHEHDWPHWKRG

ZDVQRWVXIÀFLHQWO\DFFXUDWHWRDOORZTXDQWLÀFDWLRQRIWKH('395VORSHWKHUHIRUHWKLV

PHWKRG ZDV QRW UHFRPPHQGHG IRU DVVHVVPHQW RI GLDVWROLF VWLIIQHVV 7R WHVW ZKHWKHU

WKLVOLPLWDWLRQZDVDOVRIRXQGLQRXUGDWDVHWZHGHWHUPLQHGFRQYHQWLRQDO9&2GHULYHG

VWLIIQHVV 69&2  DQG VLQJOHEHDW GHULYHG VWLIIQHVV 66%  DV WKH ORFDO VORSHV RI WKH FRU

UHVSRQGLQJ('395VDWWKHPHDVXUHGEDVHOLQH('3 3P /LQHDUUHJUHVVLRQLQGLFDWHGD

VLJQLÀFDQWEXWOLPLWHGFRUUHODWLRQDQGWKHUHODWLRQVKRZHGDVXEVWDQWLDORIIVHWLQGLFDWLQJ

RYHUHVWLPDWLRQE\WKHVLQJOHEHDWPHWKRG 69&2 66%5 S 

7KHUHIRUHWKHVDPHFRQFOXVLRQPD\EHGUDZQIURPWKHSUHVHQWVWXG\DQGIXUWKHUZRUN

LVQHHGHGWRLQYHVWLJDWHLIDVLQJOHEHDWPRGHOFDQEHGHYHORSHGWKDWPRUHDFFXUDWHO\

SUHGLFWVWKLVVSHFLÀFDVSHFWRIGLDVWROLFIXQFWLRQ,QJHQHUDODOWKRXJK('395GHULYHG

LQGLFHVDUHZLGHO\XVHGLQH[SHULPHQWDOSK\VLRORJLFDOVWXGLHVWKHLUFOLQLFDOXWLOLW\DQG

UHTXLUHGDFFXUDF\QHHGVWREHIXUWKHULQYHVWLJDWHG

,WVKRXOGEHQRWHGWKDWWKLVVWXG\WHVWHGWKHVLQJOHEHDWPHWKRGLQDQHVWKHWL]HGRSHQ

FKHVWRSHQSHULFDUGLXPVXUJLFDOSDWLHQWV7KHLQWUDRSHUDWLYHFRQGLWLRQVPD\KDYHDI

IHFWHGWKHGLDVWROLFSUHVVXUHYROXPHUHODWLRQVLQDGGLWLRQWRWKHHIIHFWVRIDQHVWKHVLDLQ

SDWLHQWVZLWKGLODWHGKHDUWIDLOXUHWKHUHODWLYHO\QRQGLVWHQVLEOHSHULFDUGLXPPD\LQFUHDVH

VWLIIQHVV DQG KDPSHU ÀOOLQJ HYHQ LQ UHVWLQJ FRQGLWLRQV DQG WKXV SHULFDUGHFWRP\ PD\

DFXWHO\LPSURYHGLDVWROLFIXQFWLRQ$OWKRXJKRXUDQDO\VLVLQGLFDWHGWKDWWKHVLQJOHEHDW

PHWKRGZDVHTXDOO\DFFXUDWHRYHUDZLGHUDQJHRIYROXPHVDQGFRQGLWLRQVVWULFWO\VSHDN

LQJIXUWKHUUHVHDUFKLVQHHGHGWRLQYHVWLJDWHZKHWKHUWKHÀQGLQJVFDQEHH[WUDSRODWHGWR

FRQGLWLRQVVXFKDVHQFRXQWHUHGLQDZDNHSDWLHQWVLQWKHFDWKHWHUL]DWLRQODERUDWRU\

&RQFOXVLRQ

,Q VXPPDU\ GLUHFW PHDVXUHPHQWV RI WKH ('395V IURP  SDWLHQWV ZLWK KHDUW IDLOXUH

EHIRUH DQG DIWHU VXUJLFDO LQWHUYHQWLRQV XVLQJ LQYDVLYH PHWKRGV FRUUHODWHG ZHOO ZLWK

WKRVHSUHGLFWHGE\DSUHYLRXVO\SURSRVHGVLQJOHEHDWPHWKRGLQGLFDWHGE\ORZ506(V

6LQJOHEHDWGHULYHGLQGLFHVVKRZHGWLJKWFRUUHODWLRQVZLWKFRUUHVSRQGLQJ9&2GHULYHG

LQGLFHVEXWV\VWHPDWLFELDVHVZHUHSUHVHQWDWORZDQGKLJKSUHVVXUHV7KHÀQGLQJVZHUH

TXDQWLWDWLYHO\ VLPLODU WR WKRVH REWDLQHG LQ SULRU LVRODWHG KHDUW VWXGLHV DQG LQLQ YLYR

VWXGLHVLQDVPDOOQXPEHURISDWLHQWVZLWKUHODWLYHO\QRUPDOKHDUWVL]HV7KHSUHVHQW

UHVXOWVREWDLQHGLQSDWLHQWVZLWKKHDUWIDLOXUHSURYLGHDFULWLFDOLQGHSHQGHQWYDOLGDWLRQ

RIWKHVLQJOHEHDWHVWLPDWLRQRIWKH('395$V QRQLQYDVLYH WHFKQLTXHVWRHVWLPDWH

HQGGLDVWROLF SUHVVXUHV DQG YROXPHV LPSURYH WKLV PHWKRG PD\ ÀQG DQ LQFUHDVLQJ

QXPEHU RI DSSOLFDWLRQV LQ TXDQWLI\LQJ WKH HIIHFW RI WUHDWPHQWV RQ UHPRGHOLQJ RI WKH

IDLOLQJKHDUWDQGLQKHOSLQJWRXQGHUVWDQGWKHSDWKRSK\VLRORJ\RIGLDVWROLFKHDUWIDLOXUH

(17)

&KDSWHU



5()(5(1&(6

  0DXUHU066SHYDFN'%XUNKRII'HWDO'LDVWROLFG\VIXQFWLRQFDQLWEHGLDJQRVHGE\'RSSOHU

HFKRFDUGLRJUDSK\"-$P&ROO&DUGLRO

  /HVWHU6-7DMLN$-1LVKLPXUD5$HWDO8QORFNLQJWKHP\VWHULHVRIGLDVWROLFIXQFWLRQGHFLSKHULQJ

WKH5RVHWWD6WRQH\HDUVODWHU-$P&ROO&DUGLRO

  3DXOXV:-7VFK|SH&6DQGHUVRQ-(HWDO+RZWRGLDJQRVHGLDVWROLFKHDUWIDLOXUHDFRQVHQVXV

VWDWHPHQWRQWKHGLDJQRVLVRIKHDUWIDLOXUHZLWKQRUPDOOHIWYHQWULFXODUHMHFWLRQIUDFWLRQE\WKH

+HDUW)DLOXUHDQG(FKRFDUGLRJUDSK\$VVRFLDWLRQVRIWKH(XURSHDQ6RFLHW\RI&DUGLRORJ\(XU+HDUW

-

  7VFK|SH&3DXOXV:-,VHFKRFDUGLRJUDSKLFHYDOXDWLRQRIGLDVWROLFIXQFWLRQXVHIXOLQGHWHUPLQLQJ

FOLQLFDOFDUH"'RSSOHUHFKRFDUGLRJUDSK\\LHOGVGXELRXVHVWLPDWHVRIOHIWYHQWULFXODUGLDVWROLFSUHV

VXUHV&LUFXODWLRQ

  %XUNKRII'0DXUHU063DFNHU0+HDUWIDLOXUHZLWKDQRUPDOHMHFWLRQIUDFWLRQLVLWUHDOO\DGLVRUGHU

RIGLDVWROLFIXQFWLRQ"&LUFXODWLRQ

  5HGÀHOG008QGHUVWDQGLQJ´GLDVWROLFµKHDUWIDLOXUH1(QJO-0HG

  'RU9'L'RQDWR06DEDWLHU0HWDO/HIWYHQWULFXODUUHFRQVWUXFWLRQE\HQGRYHQWULFXODUFLUFXODU

SDWFKSODVW\UHSDLUD\HDUH[SHULHQFH6HPLQ7KRUDF&DUGLRYDVF6XUJ

  7XOQHU6$6WHHQGLMN3.ODXW]5-HWDO6XUJLFDOYHQWULFXODUUHVWRUDWLRQLQSDWLHQWVZLWKLVFKHPLF

GLODWHGFDUGLRP\RSDWK\HYDOXDWLRQRIV\VWROLFDQGGLDVWROLFYHQWULFXODUIXQFWLRQZDOOVWUHVVG\V

V\QFKURQ\DQGPHFKDQLFDOHIÀFLHQF\E\SUHVVXUHYROXPHORRSV-7KRUDF&DUGLRYDVF6XUJ



  %XUNKRII':HFKVOHU$66XUJLFDOYHQWULFXODUUHPRGHOLQJDEDODQFLQJDFWRQV\VWROLFDQGGLDVWROLF

SURSHUWLHV-7KRUDF&DUGLRYDVF6XUJ

  6WDUOLQJ5&-HVVXS0:RUOGZLGHFOLQLFDOH[SHULHQFHZLWKWKH&RU&DS&DUGLDF6XSSRUW'HYLFH-

&DUG)DLO66

  .ORW] 6 'DQVHU $+ )RURQM\ 5)HW DO 7KH LPSDFW RI DQJLRWHQVLQFRQYHUWLQJ HQ]\PH LQKLELWRU

WKHUDS\RQWKHH[WUDFHOOXODUFROODJHQPDWUL[GXULQJOHIWYHQWULFXODUDVVLVWGHYLFHVXSSRUWLQSD

WLHQWVZLWKHQGVWDJHKHDUWIDLOXUH-$P&ROO&DUGLRO

  0HQDVFKH3&HOOXODUWUDQVSODQWDWLRQKXUGOHVUHPDLQLQJEHIRUHZLGHVSUHDGFOLQLFDOXVH&XUU2SLQ

&DUGLRO

  3HULQ(&*HQJ<-:LOOHUVRQ-7$GXOWVWHPFHOOWKHUDS\LQSHUVSHFWLYH&LUFXODWLRQ



  %XUNKRII ' 0LUVN\ , 6XJD + $VVHVVPHQW RI V\VWROLF DQG GLDVWROLF YHQWULFXODU SURSHUWLHV YLD

SUHVVXUHYROXPHDQDO\VLVDJXLGHIRUFOLQLFDOWUDQVODWLRQDODQGEDVLFUHVHDUFKHUV$P-3K\VLRO

+HDUW&LUF3K\VLRO++

  .ORW] 6 +D\ , 'LFNVWHLQ 0/HW DO 6LQJOHEHDW HVWLPDWLRQ RI HQGGLDVWROLF SUHVVXUHYROXPH UH

ODWLRQVKLS D QRYHO PHWKRG ZLWK SRWHQWLDO IRU QRQLQYDVLYH DSSOLFDWLRQ$P - 3K\VLRO +HDUW &LUF

3K\VLRO++

  .ORW] 6 'LFNVWHLQ 0/ %XUNKRII ' $ FRPSXWDWLRQDO PHWKRG RI SUHGLFWLRQ RI WKH HQGGLDVWROLF

SUHVVXUHYROXPHUHODWLRQVKLSE\VLQJOHEHDW1DW3URWRF

  -RQHV5+9HOD]TXH](-0LFKOHU5(HWDO&RURQDU\E\SDVVVXUJHU\ZLWKRUZLWKRXWVXUJLFDOYHQ

WULFXODUUHFRQVWUXFWLRQ1(QJO-0HG

  GH:DDO((5H[6.UXLWZDJHQ&/HWDO'\QDPLFSUHORDGLQGLFDWRUVIDLOWRSUHGLFWÁXLGUHVSRQVLYH

QHVVLQRSHQFKHVWFRQGLWLRQV&ULW&DUH0HG

  &DODÀRUH$07HRGRUL*0H]]HWWL$HWDO,QWHUPLWWHQWDQWHJUDGHZDUPEORRGFDUGLRSOHJLD$QQ

7KRUDF6XUJ

  7XOQHU6$.ODXW]5-(QJEHUV)+HWDO/HIWYHQWULFXODUIXQFWLRQDQGFKURQRWURSLFUHVSRQVHVDIWHU

QRUPRWKHUPLFFDUGLRSXOPRQDU\E\SDVVZLWKLQWHUPLWWHQWDQWHJUDGHZDUPEORRGFDUGLRSOHJLDLQ

SDWLHQWVXQGHUJRLQJFRURQDU\DUWHU\E\SDVVJUDIWLQJ(XU-&DUGLRWKRUDF6XUJ

(18)



&+$37(5

  7XOQHU6$.ODXW]5-5LMN=ZLNNHU*/HWDO3HULRSHUDWLYHDVVHVVPHQWRIOHIWYHQWULFXODUIXQFWLRQE\

SUHVVXUHYROXPHORRSVXVLQJWKHFRQGXFWDQFHFDWKHWHUPHWKRG$QHVWK$QDOJ

  %DDQ-9DQGHU9HOGH(7'H%UXLQ+HWDO&RQWLQXRXVPHDVXUHPHQWRIOHIWYHQWULFXODUYROXPHLQ

DQLPDOVDQGKXPDQVE\FRQGXFWDQFHFDWKHWHU&LUFXODWLRQ

  6WHHQGLMN 3 6WDDO ( -XNHPD -:HW DO +\SHUWRQLF VDOLQH PHWKRG DFFXUDWHO\ GHWHUPLQHV SDUDOOHO

FRQGXFWDQFHIRUGXDOÀHOGFRQGXFWDQFHFDWKHWHU$P-3K\VLRO+HDUW&LUF3K\VLRO+

+

  %ODQG-0$OWPDQ'*0HDVXULQJDJUHHPHQWLQPHWKRGFRPSDULVRQVWXGLHV6WDW0HWKRGV0HG

5HV

  /DP &6 5RJHU 9/ 5RGHKHIIHU 5-HW DO &DUGLDF VWUXFWXUH DQG YHQWULFXODUYDVFXODU IXQFWLRQ LQ

SHUVRQV ZLWK KHDUW IDLOXUH DQG SUHVHUYHG HMHFWLRQ IUDFWLRQ IURP 2OPVWHG &RXQW\ 0LQQHVRWD

&LUFXODWLRQ

  0HOLJD(6WHHQGLMN39DOJLPLJOL0HWDO(IIHFWVRISHUFXWDQHRXVWUDQVOXPLQDOVHSWDOP\RFDUGLDO

DEODWLRQ IRU REVWUXFWLYH K\SHUWURSKLF FDUGLRP\RSDWK\ RQ V\VWROLF DQG GLDVWROLF OHIW YHQWULFXODU

IXQFWLRQDVVHVVHGE\SUHVVXUHYROXPHORRSV$P-&DUGLRO

  )HUUD]]L36HQQL0,DVFRQH05HWDO,PSODQWDWLRQRIDQHODVWLFULQJDWHTXDWRURIWKHOHIWYHQWULFOH

LQÁXHQFHV FDUGLDF PHFKDQLFV LQ H[SHULPHQWDO DFXWH YHQWULFXODU G\VIXQFWLRQ- $P &ROO &DUGLRO



  'RNDLQLVK+6HQJXSWD53LOODL0HWDO8VHIXOQHVVRIQHZGLDVWROLFVWUDLQDQGVWUDLQUDWHLQGH[HV

IRUWKHHVWLPDWLRQRIOHIWYHQWULFXODUÀOOLQJSUHVVXUH$P-&DUGLRO

  2ODULX $ :HOOQKRIHU ( *UDIH 0HW DO 1RQLQYDVLYH HVWLPDWLRQ RI OHIW YHQWULFXODU HQGGLDVWROLF

SUHVVXUHE\SXOPRQDU\YHQRXVÁRZGHFHOHUDWLRQWLPH(XU-(FKRFDUGLRJU

  7HQ%ULQNH($.ODXW]5-7XOQHU6$HWDO+DHPRG\QDPLFVDQGOHIWYHQWULFXODUIXQFWLRQLQKHDUW

IDLOXUHSDWLHQWVFRPSDULVRQRIDZDNHYHUVXVLQWUDRSHUDWLYHFRQGLWLRQV(XU-+HDUW)DLO



  %ROWZRRG &0 -U 6NXOVN\ $ 'ULQNZDWHU '& -UHW DO ,QWUDRSHUDWLYH PHDVXUHPHQW RI SHULFDUGLDO

FRQVWUDLQWUROHLQYHQWULFXODUGLDVWROLFPHFKDQLFV-$P&ROO&DUGLRO

(19)

Referenties

GERELATEERDE DOCUMENTEN

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded

ZHUH GHPRQVWUDWHG ZLWK UHJDUG WR UHYHUVH /9 DQG DWULDO UHPRGHOLQJ DIWHU 50$     DQG SURPLVLQJ  DQG  \HDU VXUYLYDO UDWHV RI  DQG

7(( SUREH ZDV LQVHUWHG WR PRQLWRU FDUGLDF IXQFWLRQ DQG IDFLOLWDWH SRVLWLRQLQJ RI

VWLIIQHVV ZDV VLJQLÀFDQWO\ LQFUHDVHG 7KH IDFW WKDW G3GW 0,1  DQG 7DX GLG QRW

WDUJHW YROXPH UDQJH ZDV QRW H[SOLFLWO\ PHQWLRQHG 7R SXW WKH YDOXHV LQ SHUVSHFWLYH. UHFHQW05,VWXGLHVLQGLFDWHDQRUPDO('9,RI”P/P  LQPHQDQG”P/P

DIWHU P\RFDUGLDO LQIDUFWLRQ DQG LQ  RI WKH SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH 

HQGGLDVWROLF ('9  DQG HQGV\VWROLF (69  YROXPHV ZHUH PHDVXUHG DFFRUGLQJ WR WKH. 6LPSVRQ·VELSODQHPHWKRGDQG/9HMHFWLRQIUDFWLRQ () ZDVFDOFXODWHGDV&gt; ('9(69

SURFHGXUH DQG DW  \HDUV· IROORZXS WKH DOOFDXVH PRUWDOLW\ DQG KRVSLWDOL]DWLRQV IRU. +) ZHUH UHFRUGHG )LQDOO\ EDVHOLQH DQG  PRQWKV· IROORZXS FKDQJHV