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Coronary microcirculation and peripheral endothelial function evaluation after acute ST elevation myocardial infarction treated with primary angioplasty

Baptista, Sérgio Bravo Cordeiro · 2017

Abstract

ABSTRACT: Introduction: Despite achieving normal epicardial coronary artery flow after primary percutaneous coronary intervention (P-PCI), a significant proportion of patients with acute ST elevation myocardial infarction has a poorer outcome because of microvascular coronary damage and/or dysfunction. Endothelial dysfunction may play a role in this microvascular coronary damage after STEMI, and its evaluation by peripheral arterial tonometry may be useful to predict the extent of microvascular coronary damage and the extent of myocardial infarction. Objectives: To evaluate the relation of early peripheral endothelial dysfunction, as measured by the reactive hyperemia index (RHI, obtained by peripheral arterial tonometry) and the index of microcirculatory resistance (IMR) immediately after P-PCI and to access the relation between RHI and IMR values and: 1) the extent of myocardial infarct evaluated by contrast enhanced cardiac magnetic resonance (ceCMR) and troponin release; 2) the extent of microvascular obstruction (MVO), evaluated by ceCMR and by other available indirect indicators; 3) late (3 months) left ventricular remodelling, measured by echocardiography. Methods: Observational, prospective cohort study. Patients with a first STEMI successfully treated with P-PCI, hemodynamically stable and without contra-indications for adenosine administration were included. After successful P-PCI, IMR was determined, using a pressure-wire. RHI was evaluated acutely and after 24 hours, using EndoPAT; endothelial dysfunction was defined as RHI<1.67, and RHI was also analysed by tertiles. Corrected TIMI frame count (cTFC) and TIMI myocardial perfusion grade (TMBG) were evaluated at the end of the procedure. Blood tests for cardiac biomarkers were collected on admission and on scheduled intervals during the first 48 hours. ECGs were recorded before and immediately after P-PCI and at 90 and 180 minutes, for ST resolution evaluation. Left ventricular global and regional function were evaluated by echocardiography at baseline and at 3 months. ceCMR was performed on the 7-8th day post-MI. Results: 60 patients were included (48 males, mean age 59.6±12.7 years). In the first acute RHI values were higher than expected (mean 2.15±0.58) suggesting important technical pitfalls; no relation was found between this acute RHI and any of the infarct extent or microvascular obstruction indicators. Mean RHI values measured at 24 hours were 1.87±0.60. Patients with an RHI<1.67 on this second evaluation tended to have higher IMR (median 40.5 IQR 54.4 vs. median 22.0 IQR 26.0, p=0.09), worse ST resolution, worse angiographic (cTFC and TMPG) results and had more MVO in the ceCMR (54.1% vs. 11.1%, p=0.03). They also had significantly larger infarcts as evaluated by peal TnI (p=0.024) and AUC TnI (p=0.012) and a tendency to have larger infarcts in the ceCMR. Left ventricular ejection fraction (LVEF) was lower and wall motion score index (WMSI) was higher in the first Echocardiogram in these patients. IMR median values were 24 (IQR 33). IMR strongly correlated with MVO on the ceCMR (r=0.91, p<0.0001; ROC curve 0.723, CI95% 0.500-0.896, p=0.018). Patients with IMR>24 had significantly worse ST resolution and angiographic indicators of microvascular dysfunction. IMR also correlated with infarct mass (r=0.70, p<0.001) and salvage mass (r=0.35, p=0.014) in the ceCMR. Patients with IMR>24 had significantly higher peak (p=0.013) and AUC (p=0.003) TnI. LVEF improved significantly only in patients with IMR<24 (p=0.01). IMR independent predictors were age, glucose and HbA1c. Conclusions: RHI measured in the acute phase of STEMI after P-PCI seems to be unfeasible. RHI measured 24h after the P-PCI is feasible and predicts infarct size and MVO, confirming endothelial dysfunction as an important mechanism in microvascular dysfunction in STEM patients. IMR is strongly correlated with MVO and predicts both infarct size and LV remodelling.

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Coronary microcirculation and peripheral endothelial function evaluation after acute ST elevation myocardial infarction treated with primary angioplasty

Author: Baptista, Sérgio Bravo Cordeiro
Year: 2017
Source: https://run.unl.pt/bitstream/10362/21526/1/Baptista%20Sergio%20TD%202016.pdf
CORONARY MICROCIRCULATION AND PERIPHERAL ENDOTHELIAL
FUNCTION EVALUATION AFTER ACUTE ST ELEVATION
MYOCARDIAL INFARCTION TREATED WITH PRIMARY
ANGIOPLASTY
SÉRGIO BRAVO CORDEIRO BAPTISTA
Thesis o he PhD deg ee in Medicine
Subspecial y o Clinical In es iga ion
NOVA Medical School, Lisbon
Sep embe 2016
CORONARY MICROCIRCULATION AND PERIPHERAL ENDOTHELIAL
FUNCTION EVALUATION AFTER ACUTE ST ELEVATION
MYOCARDIAL INFARCTION TREATED WITH PRIMARY
ANGIOPLASTY
SÉRGIO BRAVO CORDEIRO BAPTISTA
Supe iso : P o esso Dou o Vic o Gil
Co-supe iso : P o esso Dou o José F aga a
Thesis o ob aining he PhD deg ee in Medicine, Subspecial y Clinical In es iga ion
Sep embe 2016
MICROCIRCULAÇÃO CORONÁRIA E A AVALIAÇÃO DA FUNÇÃO
ENDOTELIAL PERIFÉRICA APÓS ENFARTE AGUDO DO MIOCÁRDIO
COM ELEVAÇÃO DO ST TRATADO POR INTERVENÇÃO
CORONÁRIA PERCUTÂNEA PRIMÁRIA
SÉRGIO BRAVO CORDEIRO BAPTISTA
Tese pa a a ob enção do g au de Dou o em Medicina
na especialidade de In es igação Clínica
na Faculdade de Ciências Médicas de Lisboa
Se emb o de 2016

MICROCIRCULAÇÃO CORONÁRIA E A AVALIAÇÃO DA FUNÇÃO
ENDOTELIAL PERIFÉRICA APÓS ENFARTE AGUDO DO MIOCÁRDIO
COM ELEVAÇÃO DO ST TRATADO POR INTERVENÇÃO
CORONÁRIA PERCUTÂNEA PRIMÁRIA
SÉRGIO BRAVO CORDEIRO BAPTISTA
O ien ado : P o esso Dou o Vic o Gil
Coo ien ado : P o esso Dou o José F aga a
Tese pa a a ob enção do G au de Dou o em Medicina na especialidade de In es igação
Clínica
Se emb o de 2016
Pa a a Te esa,
e pa a a Ma iana, a So ia e o Miguel
Con en s
16
1.4. Seconda y endpoin : Ex en o myoca dial in a c ion and mic o ascula
epe usion acco ding o RHI alues on he second EndoPAT ................................... 166
1.5. Seconda y endpoin : Ex en o myoca dial in a c ion and mic o ascula
epe usion acco ding o IMR alues ......................................................................... 167
DISCUSSION ....................................................................................................................... 169
1. Main indings o he s udy ................................................................................................. 171
2. Pa ien inclusion and alidi y o he sample ...................................................................... 172
3. Fi s EndoPAT esul s ......................................................................................................... 174
3.1. Implica ions o he RHI esul s in he i s EndoPAT e alua ion ................................ 174
3.2. IMR, mic o ascula obs uc ion and ex en o in a c ion acco ding o RHI on he
i s EndoPAT .............................................................................................................. 178
4. Second EndoPAT esul s .................................................................................................... 179
4.1. RHI esul s in he second EndoPAT e alua ion .......................................................... 179
4.2. IMR, mic o ascula obs uc ion and ex en o in a c ion acco ding o RHI on he
second EndoPAT ........................................................................................................ 180
5. IMR esul s ......................................................................................................................... 182
5.1. IMR and mic o ascula obs uc ion ........................................................................... 182
5.2. IMR and in a c ex ension .......................................................................................... 183
5.3. IMR and le en icula emodelling ......................................................................... 183
5.4. P edic o s o IMR ....................................................................................................... 184
STUDY LIMITATIONS AND STRENGTHS ................................................................................ 187
CONCLUSIONS AND FUTURE PERSPECTIVES ........................................................................ 191
BIBLIOGRAPHY ................................................................................................................... 195
ACKNOWLEDGMENTS ........................................................................................................ 213
APPENDIX – PAPERS ..................................................................... E o ! Bookma k no de ined.
1 – Endo helial dys unc ion e alua ed by pe iphe al a e ial onome y is ela ed
wi h peak TnI alues in pa ien s wi h ST ele a ion myoca dial in a c ion ea ed
wi h p ima y angioplas y ................................................. E o ! Bookma k no de ined.
2 – The Index o Mic oci cula o y Resis ance as a P edic o o Echoca diog aphic Le
Ven icula Pe o mance Reco e y in Pa ien s Wi h ST-Ele a ion Acu e
Myoca dial In a c ion Unde going Success ul P ima y Angioplas y ..... E o ! Bookma k
no de ined.
3 – Ea ly pe iphe al endo helial dys unc ion p edic s myoca dial in a c ex ension
and mic o ascula obs uc ion in pa ien s wi h ST ele a ion myoca dial
in a c ion .......................................................................... E o ! Bookma k no de ined.

S a emen o Responsibili y
17
Con ibu ions and esponsibili ies
The candida e was esponsible o he design, implemen a ion (including logis ics and inancial),
pa ien inclusion, da a egis y and s a is ical analysis o he s udy, as well as o he ull w i ing o
his hesis.
All pa ien s included we e admi ed o Hospi al P o . Dou o Fe nando da Fonseca´s Ca diology
Depa men (Di ec o un il 2013: P o . Dou o Vic o Gil; since 2013: D . Ca los Mo ais).
The acu e in asi e p ocedu e (IMR measu emen ) was pe o med ei he by he candida e, o by
one o he In e en ional Ca diologis s o he In e en ional Ca diology Uni o Hospi al P o .
Dou o Fe nando da Fonseca (Coo dina o : D . Ped o Fa o e Ab eu).
The EndoPAT e alua ions we e pe o med in he Endo helial Func ion Labo a o y o Hospi al P o .
Dou o Fe nando da Fonseca (Di ec o : P o . Dou o Vic o Gil), ei he by he candida e, D a.
Ma iana Faus ino o one o he ained echnicians.
The Echoca diog aphic e alua ions we e pe o med in he Echoca diog aphy Uni o Hospi al P o .
Dou o Fe nando da Fonseca (Coo dina o : D . An ónio F ei as), by adequa ely ained physicians.
Thei analysis was pe o med by D . An ónio F ei as and D a. Ma iana Faus ino.
The ECGs we e pe o med by ained ca diopulmona y echnicians.
All labo a o y e alua ions we e pe o med by he Clinical Pa hology Depa men o Hospi al P o .
Dou o Fe nando da Fonseca (Di ec o : D a. Luísa Sancho).
The ca diac magne ic esonance exams we e pe o med in Hospi al dos Lusíadas, Lisbon
(Ca dio ascula Depa men , coo dina ed by P o . Dou o Vic o Gil and Imaging Depa men ,
coo dina ed by D ª G aça Co eia), by D . João Abecasis, who was also esponsible o hei
in e p e a ion.
Publica ions
19
LIST OF PUBLICATIONS
Pape s in Pe iodicals wi h Re e ees
This hesis esul ed so a in he ollowing publica ions:
 Bap is a SB, Faus ino M, Simões J, Nédio M, Mon ei o C, Lou enço E, Leal P, Fa o e Ab eu P,
Gil V. Endo helial dys unc ion e alua ed by pe iphe al a e ial onome y is ela ed wi h peak
TnI alues in pa ien s wi h ST ele a ion myoca dial in a c ion ea ed wi h p ima y
angioplas y. Mic o asc Res. 2016 May;105:34-9. doi: 10.1016/j.m .2015.12.010. Epub 2015
Dec 22.
 Faus ino M, Bap is a SB, F ei as A, Mon ei o C, Leal P, Nédio M, An unes C, Ab eu PF, Gil V,
Mo ais C. The Index o Mic oci cula o y Resis ance as a P edic o o Echoca diog aphic Le
Ven icula Pe o mance Reco e y in Pa ien s Wi h ST-Ele a ion Acu e Myoca dial In a c ion
Unde going Success ul P ima y Angioplas y. J In e Ca diol. 2016 Ap ;29(2):137-45. doi:
10.1111/joic.12278. Epub 2016 Ma 1.
 Bap is a SB, Faus ino M, B izida L, Lou ei o J, Augus o J, Abecasis J, Mon ei o C, Leal P, Nédio
M, Fa o e Ab eu P, Gil V, Mo ais C. Ea ly pe iphe al endo helial dys unc ion p edic s
myoca dial in a c ex ension and mic o ascula obs uc ion in pa ien s wi h ST ele a ion
myoca dial in a c ion. Submi ed
A o h manusc ip is cu en ly being p epa ed:
 Bap is a SB, Faus ino M, Lou ei o J, B ízida L, F ei as A, Augus o A, Abecasis J, Mon ei o C, Leal
P, Nédio M, An unes C, Fa o e Ab eu P, Gil V, Mo ais C. The index o mic o ascula esis ance
as a su oga e o myoca dial in a c ex ension, mic o ascula obs uc ion and le
en icula emodelling in pa ien s wi h ST ele a ion myoca dial in a c ion ea ed by
p ima y angioplas y.
Pape s in Con e ence P oceedings
This hesis esul ed in he ollowing publica ions as abs ac s in con e ence p oceedings:
 Bap is a SB, Faus ino M, Gil V. Se e i y O Co ona y A e y Disease And Endo helial
Dys unc ion E alua ed By Pe iphe al A e ial Tonome y. Jou nal o he Ame ican College o
Ca diology 2013;62 (18_S1):B183-B183
Publica ions
20
 Bap is a SB, Faus ino M, Ab eu PF, Gil V. Impac o endo helial dys unc ion e alua ed by
pe iphe al a e ial onome y in he ex ension o ST ele a ion myoca dial in a c ion ea ed
wi h p ima y angioplas y. Jou nal o he Ame ican College o Ca diology 2013;62 (18_S1),
B183-B183
 Bap is a SB., Faus ino M., Lou ei o J., B izida L., Al es P., Nedio M., Mon ei o C., Lou enço E.,
Leal P., Fa o e Ab eu P., Gil V., Mo ais C. Index o mic oci cula o y esis ance in pa ien s wi h
STEMI ea ed wi h p ima y angioplas y: ela ion wi h o he indica o s o mic o ascula
epe usion, in a c size and egional sys olic unc ion. Eu oin e en ion 2015; Abs ac s
Eu oPCR 2015; Eu o15A-MA006.
 Bap is a SB., Faus ino M., Lou ei o J., B izida L., Al es P., Nedio M., Mon ei o C., Lou enço E.,
Leal P., Fa o E Ab eu P., Gil V., Mo ais C. P edic o s o mic oci cula o y dys unc ion in STEMI
pa ien s ea ed wi h p ima y angioplas y. Eu oin e en ion 2015; Abs ac s Eu oPCR 2015;
Eu o15A-MA009
 Faus ino M, Bap is a SB, F ei as A, Mon ei o C, Leal P, Nédio M, An unes C, Fa o e Ab eu P, Gil
V, Mo ais C. Co ona y index o mic oci cula o y esis ance and echoca diog aphic pa ame e s
e olu ion in pa ien s wi h ST-ele a ion acu e myoca dial in a c ion ea ed wi h p ima y
angioplas y. Eu opean Hea Jou nal 2015;36 (suppl 1):240
 Faus ino M, Bap is a SB, F ei as A, Augus o JA, Leal P, Nédio M, An unes C, Ab eu PF, Gil V,
Mo ais C. Global longi udinal s ain and co ona y mic oci cula ion s a us in p edic ion o le
en icle unc ional eco e y a e ST ele a ion myoca dium in a c ion. Eu Hea J Ca dio asc
Imaging 2015;16(suppl 2):S156-S182.
Lis o Abb e ia ions
21
LIST OF ABBREVIATIONS
∆P P essu e g adien
2D Two-dimensional
ACE Angio ensin-con e ing-enzyme
ACEi Angio ensin-con e ing-enzyme inhibi o s
ACS Acu e co ona y synd omes
ADMA Asymme ical dime hyla ginine
ARB Angio ensin II ecep o blocke s
AUC A ea unde he cu e
BMI Body mass index
BNP B- ype na iu e ic pep ide
CABG Co ona y a e y bypass g a
CAD Co ona y a e y disease
CAMs Cellula adhesion molecules
ceCMR Con as enhanced ca diac magne ic esonance
CFR Co ona y low ese e
CI Con idence in e al
CK C ea ine kinase
CKD Ch onic kidney disease
CK-Mb Mb ac ion o c ea ine kinase
CT Ca diac omog aphy
cTFC Co ec ed TIMI ame coun
CV Ca dio ascula
DBP Dias olic blood p essu e
DICOM Digi al Imaging and Communica ions in Medicine
ECG Elec oca diog am
Echo Echoca diog am
EDHF Endo helium-dependen hype pola izing ac o
EECP Enhanced ex e nal coun e pulsa ion
FMD Flow-media ed dila ion
FRS F amingham Risk Sco e
GLS Global longi udinal s ain
HbA1c Glycosyla ed haemoglobin
HF Hea ailu e
hMR Hype aemic mic o ascula esis ance index
HR Haza d a io
hs-CRP High sensi i e C- eac i e p o ein
IMR Index o mic oci cula o y esis ance
IMR ue Index o mic oci cula o y esis ance co ec ed o colla e al low
IQR In e qua ile ange
IS In a c size
ISR In-s en es enosis

Publica ions
22
IVUS In a ascula ul asound
L_RHI Loga i hmic ans o ma ion o eac i e hype aemia index
LA Le a ium
LAD Le an e io descending a e y
LCx Le ci cum lex a e y
LDF Lase Dopple lowme y
LDL-C Low-densi y lipop o ein choles e ol
L-FMC Low low media ed cons ic ion
Lp-PLA2 Lipop o ein-associa ed phospholipase A2
LV Le en icle
LVEdV Le en icula end dias olic olume
LVEF Le en icula ejec ion ac ion
LVEsV Le en icula end sys olic olume
MACE Majo ad e se ca diac e en s
MBG Myoca dial blush g ade
MCE Myoca dial con as echoca diog aphy
MI Myoca dial in a c ion
MVO Mic o ascula obs uc ion
NO Ni ic oxide
NST-ACS Non-ST ele a ion acu e co ona y synd ome
NSTEMI Non-ST ele a ion myoca dial in a c ion
NT-p o-BNP N- e minal p o b- ype na iu e ic pep ide
NYHA New Yo k Hea Associa ion classi ica ion o hea ailu es symp oms
OR Odds a io
OxLDL Oxidized low-densi y lipop o ein
Pa Ao ic p essu e
PAI-1 Plasminogen ac i a o inhibi o -1
PAT Pe iphe al a e ial onome y
PCI Pe cu aneous co ona y in e en ion
Pd Dis al p essu e
PET Posi on emission omog aphy
PGI2 P os aglandin I2 (P os acyclin)
P-PCI P ima y (u gen ) pe cu aneous co ona y in e en ion
PzF Ze o- low p essu e
Q Flow
R Resis ance
RCA Righ co ona y a e y
RHI Reac i e hype aemia index
ROC Recei e ope a ing cha ac e is ic
SBP Sys olic blood p essu e
SK S ep okinase
SMC Smoo h muscle cells
SPECT Single-pho on emission compu ed omog aphy
STEMI ST ele a ion myoca dial in a c ion
Lis o Abb e ia ions
23
SYNTAXsc Syne gy Be ween PCI Wi h Taxus and Ca diac Su ge y Sco e
Tmn Mean ansi ime
TMPG TIMI myoca dial pe usion g ade
TnI T oponin I
TnIAUC A ea unde he cu e o oponin
TnIpeak Peak alue o oponin
-PA Tissue plasminogen ac i a o
VOP Venous occlusion ple hysmog aphy
WMSI Wall mo ion sco e index
LIST OF STUDY ACRONYMS
APPROACH Albe a P o incial P ojec o Ou come Assessmen in Co ona y Hea Disease
ARTS A e ial Re ascula iza ion The apies S udy
BARI Bypass Angioplas y Re ascula iza ion In es iga ion Myoca dial Jeopa dy
PROSPECT P o iding Regional Obse a ions o S udy P edic o s o E en s in he Co ona y T ee
SYNTAX Syne gy Be ween PCI Wi h Taxus and Ca diac Su ge y
TIMI Th ombolysis In Myoca dial In a c ion
Lis o igu es
25
LIST OF FIGURES
Figu e 1 – Co ona y a e ial ci cula ion .......................................................................................... 38
Figu e 2 – Schema ic o physiological assessmen (FFR, CFR and IMR) using a co ona y
p essu e and empe a u e wi e ..................................................................................................... 53
Figu e 3 – Reac i e hype emia index acco ding o he se e i y o he co ona y a e y
disease (numbe o majo essels wi h lesions >70%) ................................................................... 73
Figu e 4 – Peak T oponin I alues acco ding o he p esence o endo helial dys unc ion
(RHI<1.67) in pa ien s wi h ST ele a ion myoca dial in a c ion ea ed wi h p ima y PCI ............ 75
Figu e 5 – Modi ied APPROACH sco e o e alua ing he a ea-a - isk ........................................... 87
Figu e 6 – A ea-a - isk calcula ion acco ding o he APPROACH and BARI sco es ......................... 88
Figu e 7 – The Ce us P essu e-wi e, wi h a p essu e and empe a u e senso , and he
RadiAnalyze Xp ess (S . Jude Medical®) ........................................................................................ 91
Figu e 8 – Example o baseline and hype aemic he modilu ion cu es ....................................... 92
Figu e 9 – The EndoPAT 2000 ......................................................................................................... 95
Figu e 10 – EndoPAT p ocedu e ..................................................................................................... 96
Figu e 11 - Flow diag am o he coho s udy .............................................................................. 101
Figu e 12 – Age dis ibu ion o pa ien s included ........................................................................ 102
Figu e 13 – P e alence o main isk ac o s ................................................................................. 102
Figu e 14 – Co ela ion be ween APPROACH and BARI sco es in iden i ying he a ea-a - isk
o each lesion loca ion ................................................................................................................ 103
Figu e 15 – Co ec ed TIMI ame coun , acco ding o TIMI myoca dial pe usion g ade .......... 104
Figu e 16 – Examples o IMR measu emen ................................................................................ 105
Figu e 17 – Reac i e hype aemia index (RHI) alues on he 1s EndoPAT (comple e coho ) ..... 107
Figu e 18 – Reac i e hype aemia index (RHI) alues on he 1s EndoPAT (excluding ou lie s) .... 107
Figu e 19 - Examples o pe iphe al endo helial unc ion measu ed by digi al pulse
ampli ude wi h endo helial pe iphe al a e ial onome y.......................................................... 109
Figu e 20 – Th ee examples o ceCMR ......................................................................................... 113
Figu e 21 – Boxplo o IMR alues acco ding o he p esence o endo helial dys unc ion
(RHI<1.67) on he i s EndoPAT e alua ion ................................................................................. 119
Figu e 22 – Boxplo o IMR alues acco ding o he p esence o endo helial dys unc ion
(RHI<1.67) on he second EndoPAT e alua ion ............................................................................ 129
Figu e 23 – ST ele a ion and de ia ion esolu ion (median alues) acco ding o he
p esence o endo helial dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion ...................... 140
Figu e 24 – ST esidual changes (median alues) acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion ............................................................. 141
Figu e 25 – ST ele a ion and de ia ion esolu ion (median alues) acco ding o he
p esence o endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion ................ 148
Figu e 26 – ST esidual changes (median alues) acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion ........................................................ 149
Figu e 27 – ST ele a ion and de ia ion esolu ion (median alues) acco ding o he
p esence o co ona y mic o ascula dys unc ion (IMR>24) ........................................................ 159
Resumo
32
RESUMO
In odução: Apesa da no malização do luxo co oná io epicá dico após in e enção co oná ia
pe cu ânea p imá ia (ICP-P), uma p opo ção signi ica i a dos doen es com en a e agudo do
miocá dio com ele ação do segmen o ST (EAMcST) êm pio es esul ados clínicos de ido ao
desen ol imen o de lesão ou dis unção mic o ascula co oná ia. A dis unção endo elial
p o a elmen e desempenha um papel nes a lesão mic o ascula co oná ia e a sua a aliação po
onome ia a e ial pe i é ica pode á se ú il pa a p e e a ex ensão da lesão mic o ascula e a
ex ensão do en a e.
Objec i os: A alia a elação da dis unção endo elial pe i é ica p ecoce, a aliada pelo índice de
hipe émia eac i a (IHR, ob ido po onome ia a e ial pe i é ica) com o índice de esis ência da
mic oci culação (IRM), medido imedia amen e após a ICP-P e es ima a elação en e o IHR e o
IRM e, 1) a ex ensão do en a e, a aliada po essonância magné ica ca díaca com con as e
(RMCc) e pela cu a de libe ação de T oponina I; 2) a ex ensão da obs ução mic o ascula
(OMV), a aliada po RMCc e po ou os indicado es indi ec os; 3) a emodelagem en icula
esque da a dia (aos 3 meses), a aliada po ecoca diog a ia.
Mé odos. Es udo obse acional, p ospec i o, de coo e. Fo am incluídos doen es com um
p imei o EAMcST, a ados com sucesso po ICP-P, hemodinamicamen e es á eis e sem con a-
indicações pa a adminis ação de adenosina. Depois da ICP-P, o IRM oi medido usando um io de
p essão. O IHR oi a aliado na ase aguda e no amen e 24 ho as depois da ICP-P. A dis unção
endo elial oi de inida como um IHR<1,67 e o IHR oi ambém analisado po e cis. Os indicado es
angiog á icos de epe usão (con agem co igida de ames e g au de pe usão miocá dica TIMI)
o am a aliados no inal da ICP-P. Fo am colhidas análises na admissão e em ho á ios de inidos
nas p imei as 48 ho as pa a a aliação da T oponina I. An es, imedia amen e após e 90 e 180
minu os depois da ICP-P o am egis ados elec oca diog amas, pa a a aliação da esolução das
al e ações do segmen o ST. A unção en icula esque da global e segmen a oi a aliada po
ecoca diog a ia após a ICP-P e aos 3 meses. A RCMc oi e ec uada ao 7-8º dia após o EAMcST.
Resul ados: Fo am incluídos 60 doen es (48 homens, idade media 59,6±12,7 anos). Na p imei a
a aliação, os alo es de IHR o am mui o supe io es ao espe ado (média 2,15±0,58),
p o a elmen e po e os écnicos incon o ná eis, não se elacionando com nenhum dos
indicado es de ex ensão do en a e ou de OMV. Na segunda a aliação, às 24h, os alo es médios
de IRH o am 1,87±0,60. Os doen es com IRH <1,67 i e am endencialmen e alo es mais
ele ados de IRM (mediana 40,5 IIQ 54,4 s. mediana 22,0 IIQ 26,0, p=0,09), pio esolução do
segmen o ST, pio es esul ados nos indicado es angiog á icos de OMV e maio p obabilidade de
e OMV na RMNc (54,1% s. 11,1%, p=0,03). Também i e am en a es de maio dimensão na
a aliação pela TnI I máxima (p=0,004) e pela á ea sob a cu a de TnI (p= 0,012). A acção de
ejecção do en ículo esque do (FEVE) oi meno e o sco e de mo ilidade segmen a (SMS) maio
nes es doen es. A mediana do IRM oi 24 (IIQ 33). O IRM co elacionou-se o emen e com a OMV
a aliada na RMNc ( =0.91, p<0.001; cu a ROC 0,723, IC95% 0,500-0,896, p=0,018). Nos doen es
com IRM >24, a esolução do ST oi signi ica i amen e meno e os indicado es angiog á icos de
epe usão o am signi ica i amen e pio es. O IRM ambém se co elacionou com a massa de
en a e ( =0,70, p<0,001) e a massa de miocá dio sal o ( =0,35, p=0,014) na RMCc. Os doen es
com IRM>24 i e am alo es signi ica i amen e mais ele ados de TnI máxima (p=0,013) e ASC de
TnI (p=0,003). A FEVE melho ou de o ma signi ica i a apenas nos doen es com IMR<24 (p=0,01).
Os p edi o es independen es do IRH o am a idade, a glicemia na admissão e a HbA1c na admissão.
Conclusões: Não pa ece se possí el a alia de o ma idedigna o IHR na ase aguda do EAMcST
após ICP-P. O IHR medido 24h após a ICP-P é mensu á el de o ma adequada e p e ê a dimensão
do en a e e da OMV, con i mando a dis unção endo elial como um mecanismo impo an e na
dis unção mic o ascula em doen es com EAMcST. O IRM co elaciona-se o emen e com a OMV
e pe mi e p e e a dimensão do en a e e o isco de emodelagem en icula esque da.

33
INTRODUCTION
In oduc ion
35
1. The scope o he p oblem: mic oci cula o y dys unc ion in
pa ien s wi h acu e STEMI
The in e en ional ca diologis s ha pe o m p ima y pe cu aneous co ona y in e en ions ha e
a common insecu i y when hey ace a pa ien wi h an occluded co ona y a e y in he se ing o
an acu e ST ele a ion myoca dial in a c ion: wha i opening he a e y is no enough?
This anguish can ake se e al o ms: ei he mo e immedia e – like he no- e low phenomenon,
he inabili y o imp o e pa ien ’s pain o he unexpec ed absence o ST esolu ion – o la e – like
unexpec ed se e e le en icula emodelling o le en icula dys unc ion in he ollow-up,
e en a e a success ul and imely p ocedu e. All hese ques ions and ea s seem o ha e a
common g ound, one we need o unde s and be e in o de o u he imp o e STEMI pa ien s
ou comes: he co ona y mic oci cula ion.
The diagnosis and ea men o acu e ST ele a ion myoca dial in a c ion (STEMI) has undoub edly
been he subjec o in ense in es iga ion o e he las decades. As a esul , p omp
implemen a ion o bo h mechanical (p ima y pe cu aneous co ona y in e en ion) and
pha macological (adju an an i-pla ele s and an icoagulan s) app oaches o eopen he occluded
co ona y a e y is nowadays uni e sally accep ed as he ea men o choice o imp o e su i al
in STEMI pa ien s.1,2
No wi hs anding all he imp o emen s we ha e seen in p ima y PCI p og ams, wi h d ama ic
educ ions in he ime be ween symp om onse and he in e en ion, and despi e a no mal
epica dial co ona y a e y low is almos always achie ed in a imely ashion a e p ima y
pe cu aneous co ona y in e en ion (P-PCI), a signi ican p opo ion o pa ien s ( om 20% o 60%)
has a poo ou come because o mic o ascula co ona y damage.3,4 In ac , mic o ascula pe usion
is o en impai ed a e P-PCI, and epe usion o he epica dial co ona y a e y will no always
gua an ee epe usion a he myoca dial issue le el5.
The ex en o his mic o ascula co ona y dys unc ion has been shown o be an impo an and
independen con ibu o o subsequen changes in le en icula geome y and pe o mance.6,7
Pa ien s wi h impai ed mic o ascula pe usion ha e la ge in a c s, as e alua ed by CK and
oponin elease, less elec oca diog aphic ST ele a ion esolu ion, la ge long- e m le
en icula wall mo ion abno mali ies and lowe le en icula ejec ion ac ion, and la ge
nec o ic a eas as e alua ed by ca diac magne ic esonance. As a consequence o hese, co ona y
mic o ascula dys unc ion is associa ed wi h highe e en a es, isk o p og ession o hea ailu e
and mo ali y.
The p ecise mechanisms unde lying co ona y mic oci cula ion dys unc ion be o e and a e he
es o a ion o epica dial blood low a e la gely unknown and likely o be mul i ac o ial.
Unde s anding wha happens in he mic oci cula ion in he se ing o a ST ele a ion myoca dial
in a c ion is hus e y ele an . Mos esea ch done on his ma e , howe e , has ocused on he
changes occu ing on mic oci cula ion a e he STEMI and e y li le is known abou he e ec o
p e-exis en mic o ascula co ona y dys unc ion.
In oduc ion
36
The ecen de elopmen o in asi e echniques o he p ecise e alua ion o he co ona y
mic oci cula ion (such as he esis ance – IMR) and o non-in asi e me hods o he e alua ion o
endo helial dys unc ion (such as digi al pe iphe al a e ial onome y - PAT) opens a new window
o oppo uni y o he unde s anding o he pa hophysiological p ocesses occu ing in co ona y
mic o ascula u e in pa ien s wi h STEMI.
I ha e been deeply in ol ed in he a ea o unc ional e alua ion o co ona y disease in he pas
ew yea s, bo h locally8–13and a a na ional14 and in e na ional le els15–17 and I am cu en ly
in ol ed in se e al ials e alua ing new non-hype aemic echnologies o physiological
assessmen o in e media e lesions and/o new clinical indica ions. The e o e, bo h I and all he
In e en ional Ca diology Depa men in which I wo k a e e y amilia wi h he use o p essu e-
wi e echnology, bo h o clinical and in es iga ional pu poses.
On he o he hand, I am also qui e amilia wi h he PAT echnology, ollowing he c ea ion o an
Endo helial Func ion Labo a o y by P o . Vic o Gil. This labo a o y has conduc ed se e al s udies,
no only in co ona y a e y disease,18–21, bu also in o he clinical condi ions, like heuma ologic
diseases22, obesi y23–25 o e ec ile dys unc ion26, in which I had he oppo uni y o collabo a e.
The e o e, using hese new in asi e (IMR) and non-in asi e (EndoPAT®) echniques wi h he
in en ion o imp o e ou unde s anding o he co ona y mic oci cula ion dys unc ion in STEMI
pa ien s was a na u al s ep.
In he ollowing pages, he e idence ha suppo s his s udy will be p esen ed, o ganized in six
sec ions:
 Sec ion 2 is a sho desc ip ion o he no mal co ona y mic oci cula ion.
 Sec ion 3 p esen s he changes hough o occu in acu e STEMI and he p e ailing
heo ies on he ole o mic oci cula ion, wi h pa icula ocus on he endo helial unc ion
and on he gaps in knowledge ha led o he cu en s udy.
 Sec ion 4 ou lines he ools a ailable o e alua ing co ona y mic o ascula ci cula ion.
 Sec ion 5 ocus on he index o mic oci cula o y esis ance he clinical e idence cu en ly
a ailable.
 Sec ion 6 is dedica ed o desc ibing he ools a ailable o endo helial unc ion e alua ion.
 Sec ion 7 u he de ails non-in asi e pe iphe al a e ial onome y (EndoPAT).
Finally, a sho summa y o he undamen s o his hesis a e p esen ed in Sec ion 8.
In oduc ion
37
2. The no mal co ona y mic oci cula ion
2.1. Ana omy and unc ion o he co ona y a e ial sys em
The co ona y a e ial sys em can be subdi ided in o h ee unc ional compa men s: conduc i e
essels, p e-a e iola essels and a e ioles.27–29 The co ona y blood low is d i en by he p essu e
di e ence be ween he ao ic sinus and he co ona y sinus (o he igh a ium p essu e) ac oss
hese h ee compa men s:
 Conduc i e essels (co esponding o epica dial a e ies) a e he i s compa men and
in he absence o obs uc i e s enosis, hey o e e y li le esis ance o co ona y blood
low (e en a maximum hype emia), se ing mainly as conduc ance essels.
App oxima ely 60% o hei wall hickness consis s o he muscula media, which can
espond o changes in ao ic p essu e and modula es co ona y one in esponse o low-
media ed endo helium-dependen asodila o s, ci cula ing asoac i e subs ances and
neu al s imuli.
 The in e media e compa men is ep esen ed by p e-a e ioles, which a e esis i e
essels connec ing he conduc i e a e ies o he a e ioles. They a e epica dial (ex a-
myoca dial) essels and ha e a diame e in he ange o 200 o 500 μm. These essels
eac o changes in shea s ess and in a ascula p essu e o p ese e adequa e pe usion
p essu e in he dis al a e iola bed, being esponsible o app oxima ely 25% o he o al
co ona y ascula esis ance.
 The dis al compa men consis s o a e ioles. They a e smalle han 200 μm in diame e
and a e he main egula o y componen o he co ona y ci cula ion, ep esen ing
app oxima ely 55% o he o al co ona y ascula esis ance. A e ioles a e usually
subdi ided in wo ca ego ies, acco ding o hei diame e and he mechanism(s) ha
egula e hei one30: endo helium-dependen aso eac i i y p e ails in he la ge
a e ioles (100–200 μm) and ansla es low- ela ed s imuli in o asomo o esponses, i.e.
asodila ion wi h inc ease in low and ice e sa. Medium-sized mic o essels (40–100 μm
in diame e ) eac p edominan ly o in aluminal p essu e changes sensed by s e ch
ecep o s loca ed in ascula smoo h muscle cells (myogenic con ol), i.e. hey cons ic
when he in aluminal p essu e inc eases and, con e sely, dila e when he p essu e
dec eases. Finally, he one o he smalle a e ioles ( essels less han 40 mm in diame e )
is modula ed by he me abolic ac i i y o he myoca dium.
The a e ioles a e esponsible o he p ocess o co ona y au o egula ion31,32: co ona y low is
egula ed independen ly o he a e ial pe usion p essu e despi e la ge a ia ions in his
p essu e. Vasodila a ion o he smalle a e ioles is induced by inc eased me abolic ac i i y, which
leads o p essu e educ ion in he medium-sized mic o essels and myogenic dila ion, which, in
u n, inc eases low ups eam esul ing in endo helium-dependen asodila ion (Figu e 1).

In oduc ion
38
Figu e 1 – Co ona y a e ial
ci cula ion
Conduc i e essels and p oximal
p ea e ioles a e mos esponsi e o low-
dependen dila ion. Dis al p ea e ioles a e
mos esponsi e o changes in in a ascula
p essu e (and a e mainly esponsible o
au o egula ion o co ona y blood low),
whe eas a e ioles a e mos esponsi e o
changes in he myoca dial concen a ion o
me aboli es, and a e mainly esponsible o
he me abolic egula ion o co ona y blood
low (Adap ed om Camici e al33)
These mechanisms e ec i ely and e icien ly allow he mic oci cula ion o egula e myoca dial
pe usion bo h a es and a di e en le els o myoca dial me abolic demand.30 When p essu e
alls o he lowe limi o au o egula ion, co ona y esis ance a e ies a e maximally asodila ed
by in insic s imuli, and low becomes p essu e-dependen , esul ing in he onse o
subendoca dial ischemia. Res ing co ona y blood low unde no mal hemodynamic condi ions
a e ages 0.7 o 1.0 mL/min/g and can inc ease ou o i e old du ing asodila ion.34
2.2. Regula ion o co ona y ascula one
Co ona y blood low is adjus ed o he me abolic needs o he myoca dium by a leas h ee
essen ial egula o s o co ona y one:
 The me abolic asodila o y sys em, h ough he p oduc ion o adenosine and
simul aneous opening o he ATP-dependen K+ channels wi hin he myoca dial cells (bo h
po en asodila o s) in he p esence o an inc ease in he oxygen consump ion and
me abolic demand35;
 The neu ogenic con ol sys em, h ough ad ene gic ac i a ion o α- ecep o s, esul ing in
a e iola asocons ic ion. Vasocons ic ion media ed by α1- ecep o ac s mainly on he
la ge co ona y a e ies, whe eas bo h α1- and α2- ecep o ac i i y is in ol ed in
In oduc ion
39
egula ing he deg ee o asocons ic ion o he smalle esis ance essels.29 These
in luences a e opposed by he asodila o y e ec o ascula β- ecep o s imula ion and
me abolic mechanisms. Impo an ly, choline gic s imula ion, no mally asodila o y
because i eleases ni ic oxide, becomes asocons ic i e when he endo helium is
damaged (see below).
 The ascula endo helium, ha ac s bo h h ough asodila ion and asocons ic ion,
playing a cen al ole in he egula ion o ascula one, since i closely in e ac s wi h he
wo o he sys ems in ol ed:
o Endo helial-dependen asodila ion is media ed by ni ic oxide (which is a e y
sho -li ed asodila ing ac o ) and by he endo helium-dependen
hype pola izing ac o (EDHF), bo h sec e ed by heal hy endo helial cells in
esponse o i) ascula shea o ces associa ed wi h inc eased co ona y low36; ii)
adenosine (ac ing on endo helial ATP-dependen K+ channels37); iii) o o he
agonis s (e.g. eleased om pla ele s o ca diac ne es). P os acyclin, o
p os aglandin I2 (PGI2), is also p oduced in he co ona y endo helium o colla e al
essels and causes onic asodila ion.
o Endo helial-dependen asocons ic ion is media ed by endo helin-1 which
ac i a es p o ein kinase C in ascula smoo h muscle o p oduce co ona y
cons ic ion and compe es wi h endo helium-de i ed elaxing ac o s. This e ec
is enhanced in diseased a he oscle o ic a e ies wi h ex ensi ely damaged
endo helium.38
2.3. The ascula endo helium
The ascula endo helium is a monolaye o cells co e ing he in e nal lumen o all blood essels,
sepa a ing he blood om he ascula wall and o gan issues. The ascula endo helium has
di e en unc ions39:
 I plays a c ucial ole in ascula one and blood low egula ion (as desc ibed in he
p e ious sec ion);
 I is an an i-coagulan su ace, wi h an ac i e ole on pla ele adhesion and agg ega ion,
and on h ombosis.40 Unde physiological condi ions, he endo helium p e en s h ombus
o ma ion h ough a numbe o mechanisms: h ombomodulin, p o ein S, hepa in
sulpha e, and issue ac o pa hway inhibi o a e all endo helium-de i ed inhibi o s o
coagula ion, whe eas PGI2, NO, and su ace-bound CD39 inhibi pla ele agg ega ion.41
 I egula es ascula pe meabili y o plasma cons i uen s be ween blood and issues42;
 I con ibu es o ascula homeos asis and epai .43
Addi ionally, he endo helium also ac i ely p oduces p oin lamma o y and an i-in lamma o y
molecules, and is he ac ual a ge o ci cula ing in lamma o y media o s ha a e syn hesized
by o he cell ypes, including pla ele s, leukocy es, hepa ocy es, and adipocy es.41
In oduc ion
40
3. Co ona y mic oci cula ion dys unc ion
3.1. Classi ica ion and mechanisms o co ona y mic oci cula ion dys unc ion
Co ona y mic o ascula dys unc ion has been widely s udied in he las wo decades, pa icula ly
in pa ien s ches pain despi e ha ing no mal co ona y a e iog ams (i.e. mic o ascula angina).
In an a emp o summa ize he mechanisms in ol ed and i s clinical ansla ion, Camici and C ea
p oposed44 (and ecen ly e iewed45) a classi ica ion o he di e en clinical ypes o co ona y
mic o ascula dys unc ion (Table 1). O he ou ypes o mic o ascula dys unc ion p oposed,
Types 3 (obs uc i e co ona y a e y disease) and 4 (ia ogenic) a e he ones in ol ed in pa ien s
wi h acu e ST ele a ion myoca dial in a c ion.
The au ho s also pu o wa d he main pa hogenic mechanisms mo e likely o be in ol ed in hese
ypes o co ona y mic o ascula dys unc ion (luminal obs uc ion by h ombo ic deb is,
endo helial dys unc ion, smoo h muscula cell dys unc ion and au onomic dys unc ion).
Table 1 – Classi ica ion o co ona y mic o ascula dys unc ion
Clinical Se ing
Main pa hogenic mechanisms
Type 1: In he absence o
myoca dial diseases and obs uc i e
CAD
Risk ac o s
Mic o ascula angina
Endo helial dys unc ion
SMC dys unc ion
Vascula emodelling
Type 2: In myoca dial diseases
Hype ophic ca diomyopa hy
Dila ed ca diomyopa hy
Ande son-Fab y’s disease
Amyloidosis
Myoca di is
Ao ic s enosis
Vascula emodelling
SMC dys unc ion
Ex amu al comp ession
Luminal obs uc ion
Type 3: In obs uc i e CAD
S able angina
Acu e co ona y synd ome
Endo helial dys unc ion
SMC dys unc ion
Luminal obs uc ion
Type 4: Ia ogenic
PCI
Co ona y a e y g a ing
Luminal obs uc ion
Au onomic dys unc ion
Adap ed om Camici and C ea.45 CAD: co ona y a e y disease; SMC: smoo h muscle cells; PCI: pe cu aneous co ona y in e en ion
Howe e , he exac ole o each o he abo emen ioned mechanisms is di icul o iden i y,
pa icula ly in pa hogenic p ocesses. In ac , a subs an ial numbe o hypo heses o he
pa hophysiology o co ona y mic o ascula dys unc ion has been p oposed in he li e a u e44,46
including:
 S uc u al changes:
o Luminal obs uc ion, caused by mic oemboliza ion in acu e co ona y synd omes
o a e ecanaliza ion.
In oduc ion
41
o Vascula wall in il a ion (e.g. in in il a i e diseases, like Ande son-Fab y
ca diomyopa hy)
o Al e ed mic o ascula emodelling, h ough scle osis o small a e ies and
a e ioles wi h pe i ascula ib osis, swollen endo helial nuclei in capilla ies, and
i egula lumina o small a e ies.47
o Vascula a e ac ion and pe i ascula ib osis (e.g. in ao ic s enosis and a e ial
hype ension).
 Func ional changes:
o Endo helial dys unc ion, including he elease o subs ances wi h opposing e ec s
(such as endo helin, h omboxane A2, p os aglandin H2, and supe oxide) and
esul ing in a shi om a ne dila o esponse o a ne cons ic o esponse o a
a ie y o s imuli. Endo helial dys unc ion also in ol es a swi ch om a quiescen
o an ac i a ed s a e p omo ing in lamma o y esponses, chemokine and
adhesion molecule exp ession, and subsequen in e ac ion wi h pla ele s and
leukocy es.48
o Smoo h muscle dys unc ion, as showed by a educed co ona y blood low
esponse o endo helium-independen asodila o s (e.g. adenosine,
dipy idamole, papa e ine) in pa ien s wi h mic o ascula angina.49
o Mic o ascula spasm and sympa he ic dys unc ion, media ed ia bo h α1 and α2-
ad enocep o s in epica dial condui a e ies and mic o essels50,51, e.g. a e
co ona y e ascula iza ion.
 Ex a ascula ac o s
o Ex amu al comp ession (ao ic s enosis, hype ophic ca diomyopa hy, a e ial
hype ension)
o Reduc ion in dias olic pe usion ime (ao ic s enosis).
Howe e , hese mechanisms could no be c i ically es ed, es ablishing clea and accep ed
pa hophysiological concep s. In ac , he e is no adequa e in o ma ion on he ele ance o
indi idual mechanisms in gene al, le alone in indi idual pa ien s. As such, he s a i ica ion o
indi idual pa ien s and he a ional de elopmen o a ge ed s a egies is unde de eloped, as
ecen ly acknowledged in he 2015 William Ha ey Lec u e on Basic Science a he Eu opean
Socie y o Ca diology Cong ess in London46, dedica ed o co ona y mic o ascula dys unc ion.
3.2. Co ona y mic oci cula ion dys unc ion in STEMI
Despi e he ac ha p ima y PCI is highly success ul in es o ing epica dial co ona y blood low,
when pe o med in a imely ashion, epe usion a he myoca dial le el is no accomplished in a
signi ican p opo ion o pa ien s ( om 20 o 60%, depending on he echnique used o i s
e alua ion5). The nega i e p ognos ic implica ions (bo h on he isk o le en icle emodelling
and on he isk o ha d endpoin s, including dea h) associa ed wi h co ona y mic o ascula
damage ha e been epea edly con i med, wha e e non-in asi e o in asi e indica o o
mic o ascula dys unc ion/obs uc ion is used (Table 2).
In oduc ion
48
in humans in i o, i would s ill be an incomple e e alua ion. The e o e, mic oci cula o y unc ion
is indi ec ly assessed using se e al in asi e and nonin asi e echniques ha enable he
measu emen o pa ame e s ha (unde no mal ci cums ances) a e s ongly dependen on he
unc ional in eg i y o he co ona y mic oci cula ion.
Consis en wi h i s p ima y hemodynamic unc ion, unc ional echniques o he assessmen o
he co ona y mic o ascula u e ely on he measu emen o co ona y blood low, which changes
mainly as a esul o al e a ions in ascula one. Al hough he e a e se e al imaging echniques
ha allow es ima ing co ona y blood low, a p esen , he mos de ini e e alua ion o he co ona y
mic oci cula ion emains in asi e.
In he ollowing pages, he mos used in asi e and non-in asi e echniques o he e alua ion o
mic o ascula co ona y ci cula ion in pa ien s wi h acu e ST ele a ion myoca dial in a c ion a e
desc ibed in sho . The index o mic oci cula o y esis ance, used in his s udy, will be de ailed in
Sec ion 5.
4.1. Non-in asi e me hods
4.1.1. ECG ST esolu ion
ECG ST-segmen esolu ion is a simple, cheap and alida ed ool o e alua e acu ely
mic o ascula pe usion134 and has been used o se e al yea s in ib inolysis and p ima y
angioplas y ials.3,4
A e p ima y PCI, incomple e ST esolu ion has been ela ed o co ona y mic o ascula
obs uc ion and wo se clinical ou come.135 Di e en me hods ha e ocused on he
assessmen o mul iple leads o single leads showing maximum ST ele a ion a baseline and
a consensus is s ill lacking abou which leads o analyse, he op imal iming o
elec oca diog am analysis, and whe he s anda d ECG o con inuous ECG moni o ing is
p e e able.
Assessmen o single lead ST esolu ion showing maximum ST ele a ion a baseline seems o
be as accu a e as he sum o ST esolu ion measu emen s.136,137
Addi ionally, esidual ST-segmen ele a ion was ound o be an independen ma ke o
co ona y mic o ascula obs uc ion138 and a p edic o o e en s a e p ima y PCI.139

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4.1.2. Imaging echniques
Posi on emission omog aphy (PET) is a well-es ablished non-in asi e echnique o he
assessmen o co ona y blood low140,141, as i allows he de e mina ion o absolu e egional
myoca dial blood low a es and in esponse o a ious s imuli. Myoca dial blood low
measu emen using PET is achie ed by con inuous moni o ing o he adioac i i y emi ed by
an in a enously adminis e ed ace , in he ci cula ion and he myoca dium. The kine ics o
adio ace up ake in he myoca dium a e de i ed om ime-ac i i y cu es in he le
en icula ca i y and he myoca dium; i ing hese ime-ac i i y cu es wi h an ope a ional
equa ion p o ides accu a e es ima es o myoca dial blood low. Impo an ly, howe e , i may
lack sensi i i y and speci ici y o he diagnosis o co ona y asomo o dys unc ion and, in
gene al, is unable o di e en ia e be ween epica dial and mic o ascula abno mali ies.142
Myoca dial con as echoca diog aphy (MCE) uses ul asound o isualize con as
mic obubbles wi h a heology simila o ha o ed blood cells ha eely low wi hin pa en
mic oci cula ion while lack o in a-myoca dial con as opaci ica ion is due o mic o ascula
obs uc ion ha p edic s unc ional eco e y a e STEMI.54 I has p o en o be a use ul ool
o iden i ying pa ien s wi h he no- e low phenomenon a e in e en ional o h omboly ic
ea men o STEMI.54,143–145 Howe e , i has se e al limi a ions: mode a e spa ial esolu ion,
ope a o dependency, and incomple e le en icula co e age wi h subop imal isualiza ion
o he la e al wall, and semi-quan i a i e assessmen o co ona y mic o ascula obs uc ion.
Con as enhanced ca diac magne ic esonance (ceCMR) allows mul islice imaging wi h high
issue con as and high spa ial esolu ion, enabling accu a e quan i ica ion o co ona y
mic o ascula dys unc ion and obs uc ion, and in a c size. Co ona y mic o ascula
dys unc ion and obs uc ion appea as an absence o gadolinium enhancemen du ing i s
pass and lack o gadolinium enhancemen wi hin a nec o ic egion (la e gadolinium hype -
enhancemen ). Co ona y mic o ascula obs uc ion e alua ed by ceCMR co ela es wi h
MCE, and o he angiog aphic and in asi e indexes146 and is an independen p edic o o
ad e se clinical ou come, alone o adjus ed by o he ac o s, such as in a c size and le
en icula ejec ion ac ion.62,147–150
O he imaging modali ies, including CT-de i ed co ona y low ese e and hyb id posi on
emission omog aphy-compu ed omog aphy a e s ill mainly in es iga ional and ha e no
been widely used in STEMI pa ien s.
Finally, pe iungueal capilla oscopy is a simple and eliable non-in asi e echnique allowing
e alua ion o cu aneous mic oci cula ion. Howe e , i has been used mainly in pa ien s wi h
Raynaud’s phenomenon and in pa ien s wi h connec i e issue diseases, and he e is no
expe ience wi h his echnique in pa ien s wi h co ona y a e y disease. 151
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50
4.2. In asi e me hods
4.2.1. Angiog aphic indexes
In asi e TIMI low, TIMI ame coun and TIMI myoca dial pe usion g ade ha e all been
p oposed in he e alua ion o mic oci cula ion a e acu e ST ele a ion myoca dial in a c ion.
 The h ombolysis in myoca dial in a c ion (TIMI) sco e g ading sys em desc ibes he
a e o blood low in he epica dial essels, anging be ween no low a all (G ade 0)
o a no mal low a e (G ade 3)152,153 ( o mo e de ails, see Popula ion and Me hods,
Sec ion 3.4.1 - TIMI low g ade, page 89). TIMI low <3 is a ma ke o bo h co ona y
mic o ascula obs uc ion and o la ge in a c size and has been shown o a ec
p ognosis bo h a sho and long- e m ollow-up.58 Howe e , he alue o his index
is limi ed, since co ona y mic o ascula obs uc ion may occu in nea ly 35% o
pa ien s wi h TIMI 3 low.146
 The co ec ed TIMI ame coun (cTFC) index co esponds o he numbe o ames
equi ed o con as medium o each a s anda dized dis al landma k (see
Popula ion and Me hods, Sec ion 3.4.2 - Co ec ed TIMI ame coun , page 89). I
u he s a i ies he p ognosis o pa ien s wi h TIMI low 3 and co ela es wi h
in asi e assessmen o co ona y low ese e.154
 The TIMI myoca dial pe usion g ade (TMPG) and he myoca dial blush g ade
(MBG), assess he in ensi y o he adio-opaci y o myoca dial issue a e an
epica dial co ona y injec ion o con as medium (MBG), as well as i s wash-ou a e
(TMPG). An in ense myoca dial blush and as wash-ou o con as medium indica e
op imal mic o ascula epe usion.60,155 Bo h a e sco ed on a scale o 0–3, he la e
indica ing op imal pe usion (see Popula ion and Me hods, Sec ion 3.4.3 - TIMI
myoca dial pe usion g ade (TMPG), page 90). A MPG g ade 0–1 can be obse ed in
up o 50% o pa ien s wi h TIMI low g ade 3.57
Using bo h TIMI low and TIMI myoca dial pe usion g ade156, co ona y mic o ascula
obs uc ion can be de ined as a TIMI low g ade <3 o a TIMI low g ade 3 wi h a TMPG/MPG
0 o 1.
4.2.2. Dopple wi e-de i ed co ona y blood low ese e
Co ona y low ese e (CFR) ep esen s he ex en o which he co ona y ci cula ion can
inc ease myoca dial blood low in esponse o exe cise o a hype aemic s imulus. I is
calcula ed by di iding hype aemic low by es ing low. Acco dingly, he calcula ion o CFR
In oduc ion
51
assumes ha maximal asodila a ion is achie ed by abolishing co ona y asomo o one, by
in a enous adminis a ion o endo helium-independen asodila o s (mos ly adenosine).
CFR e alua es simul aneously he epica dial and mic oci cula o y compa men s o he
co ona y ee, al hough, heo e ically, in he absence o epica dial essel disease CFR e lec s
mic o ascula unc ion.157
In asi e e alua ion o CFR was i s pe o med wi h a Dopple guidewi e, posi ioned in o he
dis al pa o he co ona y a e y. Wi h he senso a he ip o his wi e, co ona y low
eloci y a es and du ing hype aemia can be measu ed, and he a io o maximum o
baseline co ona y low eloci y can be calcula ed.158
Howe e , his echnique has se e al p oblems, including equen guidewi e posi ional
changes (mo ion o he pa ien , o b ea hing), which dis u bs he Dopple signal and limi he
easibili y o he p ocedu e o less han 70% o all a e ies.159 O he echnical pi alls ha can
hampe signal acquisi ion include obs uc ion o he guiding ca he e , inaccu a e calib a ion,
u bulen low, and signal loss.160
S ill, in pa ien s wi h ST ele a ion myoca dial in a c ion, CRF e alua ed wi h a Dopple wi e
was shown as a good p ognos ic ma ke o LV unc ion eco e y a e an e io myoca dial
in a c ion ea ed wi h p ima y PCI.52,161 Mo e ecen ly, he p ognos ic alue o mic o ascula
unc ion as de e mined using Dopple wi e o p edic ing long- e m ca diac mo ali y was
assessed in bo h in a c - ela ed and e e ence co ona y a e ies in pa ien s immedia ely a e
p ima y PCI o ST-segmen ele a ion myoca dial in a c ion. Du ing ollow-up (median 11
yea s), a CFR <2.1 in a e e ence essel was associa ed wi h a ou old inc eased isk o long-
e m ca diac mo ali y, whe eas a a ge - essel CFR <1.5 was associa ed wi h an inc ease in
sho - e m (bu no long- e m) isk o ca diac mo ali y.63
4.2.3. P essu e wi e-de i ed co ona y blood low ese e
In an a emp o o e come he limi a ions o he Dopple wi e, he modilu ion-de i ed CFR
was in oduced. Fo his echnique, a p essu e wi e is used o measu e empe a u es, and
CFR is calcula ed using he p inciple o he modilu ion: by gi ing sho manual injec ions o 3
cc saline a oom empe a u e in o he co ona y a e y, he modilu ion cu es a e gene a ed
and mean ansi imes a hype emia and baseline can be calcula ed. Because co ona y low
is in e sely p opo ional o he mean ansi ime o a bolus o cold saline needed o a el
down he co ona y a e y, CFR can be easily calcula ed using he a io o mean ansi imes.
Wi h his echnique, success ul measu emen o CFR can be pe o med in 95% o pa ien s.159
CRF measu emen s pe o med his way co ela ed well wi h s anda d CFR, bo h in
expe imen al model and in humans.158,162
Howe e , CFR (measu ed bo h by Dopple -wi e o p essu e-wi e) a ies wi h age and sex in
heal hy humans163,164, making i impossible o de ine a clea cu -o alue below which
mic o ascula unc ion could be deemed abno mal. Addi ionally, since co ona y blood low
In oduc ion
52
unde es ing condi ions is dependen on de e minan s o myoca dial oxygen demand
(namely hea a e, con ac ili y and en icula load) and CFR being he a io o peak
hype aemic- o- es ing low, i is he e o e a ec ed by hese same de e minan s, a ac ha
can also a ec he ep oducibili y o he a io.165
CFR i is also signi ican ly in luenced by epica dial essel disease and hus does no dis inguish
epica dial om mic oci cula o y disease.158 Fo all hese easons, CFR alone is no a good ool
o e alua ing he mic oci cula ion in ST ele a ion myoca dial in a c ion pa ien s.
4.2.4. Index o mic oci cula o y esis ance
To o e come he limi a ions o CFR and allow o he isola ed e alua ion o he
mic oci cula o y co ona y compa men , a new index, he index o mic oci cula o y
esis ance (IMR) was de eloped.166 The IMR is based on he assump ion ha mic o ascula
esis ance ( ha p o ides an independen assessmen o mic oci cula o y unc ion) can be
calcula ed by di iding he dis al co ona y p essu e by absolu e co ona y low. Acco ding o
he me hodology p e iously desc ibed o CFR, IMR can be calcula ed as he dis al co ona y
p essu e di ided by he in e se o he hype aemic mean ansi ime (a co ela e o absolu e
low), measu ed simul aneously wi h he co ona y p essu e wi e.
The undamen s, me hodology and clinical e idence o his echnique will be u he
de eloped in Sec ion 5.
4.2.5. Dopple and P essu e combined indexes – hype aemic mic o ascula
esis ance index (hMR) and ze o- low p essu e (Pz )
Recen ly, a single dual senso wi e (Dopple and p essu e) was made a ailable (Combo Wi e,
Volcano The apeu ics), allowing o he simul aneous measu emen o phasic dis al p essu e
and low eloci y. Wi h his wi e and dedica ed so wa e, and using measu emen s
pe o med a baseline and a hype aemia induced by adenosine, bo h hMR (de ined as he
a io o a e age co ona y dis al p essu e and a e age ins an aneous peak eloci y du ing
hype aemia) and Pz (which is he dis al co ona y p essu e when heo e ically he low in a
co ona y a e y would cease; since i is no possible o measu e his di ec ly, as in i o
co ona y low does no cease unde no mal ci cums ances, Pz is ex apola ed om p essu e-
eloci y loops167) can be measu ed.
The ep oducibili y o epea ed hype aemic esis ance pa ame e s de i ed om dis al
p essu e and eloci y measu emen s was con i med in pa ien s wi h s able angina.168 In
pa ien s wi h acu e STEMI, a ew s udies we e pe o med, wi h p omising esul s: In 2003,
Shimada and colleagues169 s udied Pz using a Dopple wi e and assessing a e ial p essu e
om he guiding ca he e in pa ien s unde going p ima y PCI o an e io STEMI, and showed
In oduc ion
53
ha Pz co ela ed wi h iabili y e alua ed by PET. In 2007, i was con i med ha Pz alues
a e inc eased a e myoca dial in a c ion.170 Mo e ecen ly hMR, Pz , and Dopple co ona y
low ese e we e measu ed wi h he combo Dopple -p essu e wi e in pa ien s a e an e io
STEMI. All measu es co ela ed wi h peak c ea inine kinase-myoca dial and CMR measu es
o in a c size, and Pz was ound o be highe in hose wi h >75% in a c ansmu ali y.171 In
2015, hMR and Pz we e ound o be ela ed o mic o ascula inju y (assessed by ceCMR) and
myoca dial pe usion (e alua ed wi h PET).172 In he same yea , ano he s udy compa ed Pz ,
hMR and IMR, and sugges ed ha he o me was a be e p edic o o he ex en o
myoca dial in a c ion (assessed wi h ceCMR) han he la e wo.173 The e is only one s udy
epo ing clinical ou comes in STEMI pa ien s ea ed wi h p ima y PCI, and i also con i med
hMR as a s ong p edic o o a combined endpoin o dea h and hospi al admission o hea
ailu e.174 Howe e , unlike o he wi e-based echniques, hMR and Pz ha e no been
alida ed in animal o human models. Fu he mo e, he e a e conce ns ha hMR
measu emen may no be accu a e in pa ien s wi h se e e epica dial s enosis, since i does
no accoun o colla e al low (and hence may lead o an o e es ima ion o ue
mic o ascula esis ance in he p esence o a se e e s enosis).
5. The index o mic oci cula o y esis ance (IMR)
5.1. De ini ion and e alua ion o IMR
The IMR is a measu emen o he minimum achie able mic oci cula o y esis ance in a a ge
co ona y a e y e i o y and hus i p o ides a quan i a i e assessmen o he mic o ascula
in eg i y. Unlike CFR, which p o ides a combined assessmen o bo h he epica dial and he
mic o ascula beds, IMR enables a speci ic quan i a i e assessmen o he s a us o he
mic o ascula co ona y ci cula ion (Figu e 2).
Figu e 2 – Schema ic o physiological assessmen (FFR, CFR and IMR) using a co ona y p essu e
and empe a u e wi e
Epica dial co ona y
a e y
Mic oci cula io
n
P essu e
Wi e
Pd
Pa
FF
R
IM
R
CF
R

In oduc ion
54
IMR measu emen was made possible by he de elopmen o a wi e wi h bo h p essu e and
empe a u e senso s on i s ip.158,175 The dis al senso o he wi e measu es p essu e and
empe a u e and he sha o he wi e can be used as a second he mis o .
By injec ing oom- empe a u e saline down a co ona y a e y, an indica o -dilu ion cu e is
ob ained (acco ding o he dec ease in empe a u e) and he mean ansi ime (𝑻𝒎𝒏) can be
de e mined. 𝑻𝒎𝒏 has been shown o s ongly co ela e in e sely wi h absolu e low and
he e o e p o ides an easily measu able su oga e, bo h in i o, in animal models158 and in
humans.162
Acco ding o Ohm’s law, he esis ance (𝑹) in a gi en ci cui is ela ed o he p essu e g adien
(∆𝑷) and absolu e low (𝑸), acco ding o he o mula:
𝑹 = ∆𝑷
𝑸
In he co ona y mic oci cula ion, he p essu e g adien (∆𝑷) is de e mined by dis al p essu e
(dis ally in he epica dial essel) minus enous p essu e; a maximal hype aemia, howe e , enous
p essu e can be assumed o be ze o, implying ha ∆𝑷 app oxima es dis al p essu e (Pd),
measu ed wi h he p essu e-wi e.
Simila ly, a maximal hype emia, absolu e low (𝑸) has been shown o ha e a linea ela ionship
wi h he in e se o low eloci y (𝟏𝑻𝒎𝒏
⁄). The e o e, he mic oci cula ion esis ance can be
de i ed om he simpli ied o mula176:
𝑰𝑴𝑹 = 𝑷𝒅
(𝟏𝑻𝒎𝒏
⁄ )
O , o make i e en simple ,
𝑰𝑴𝑹 = 𝑷𝒅 ∗ 𝑻𝒎𝒏
Impo an ly, IMR is de i ed om he assump ion ha , a peak hype aemia, he a iabili y o
es ing ascula one and hemodynamic will be elimina ed, and he minimum mic o ascula
esis ance will be achie ed.
In he p esence o a se e e epica dial s enosis, myoca dial low is he composi e o bo h he
co ona y and colla e al lows. Acco dingly, dis al co ona y p essu e dec eases o a lesse deg ee,
gi en he con ibu ion o colla e als – his in u n will p oduce an o e es ima ion o IMR i no
co ec ed o colla e al low. The e o e, o calcula e he ue IMR (IMR ue) in his se ing, a mo e
complex o mula has been de eloped, which includes measu emen o he co ona y wedge
p essu e as a measu e o colla e al p essu e.177 Howe e , in he absence o signi ican colla e al
low, i is easonable o use IMR as a su oga e o IMR ue, a oiding he measu emen o co ona y
wedge p essu e.
IMR e alua ion was alida ed in animals and showed a s ong co ela ion wi h ue mic o ascula
esis ance, being independen on epica dial s enosis p esence and se e i y (since bo h dis al
In oduc ion
55
p essu e and low d op in he p esence o an epica dial s enosis).166 This was also alida ed in
humans.177,178
Despi e he ela i ely complex heo e ical backg ound, IMR is easy o e alua e and a e y
ep oducible measu emen .179 A dedica ed console, equipped wi h dedica ed so wa e o IMR
e alua ion makes he p ocedu e simple and easy o lea n. The comple e desc ip ion o he
p ocedu e is gi en in de ail in Popula ion and Me hods, Sec ion 3.5 – Index o mic oci cula o y
esis ance (IMR), page 90.
I is a sa e echnique o pe o m in STEMI pa ien s180 and has been used in se e al s udies
(desc ibed in he nex sec ion).
5.2. Clinical e idence on he use o IMR in STEMI pa ien s
The e alua ion o co ona y mic oci cula ion in ol emen and i s consequences in pa ien s wi h
acu e STEMI ea ed wi h p ima y angioplas y is a logical applica ion o IMR. Indeed, se e al
s udies we e pe o med in ST ele a ion acu e myoca dial in a c ion pa ien s, immedia ely a e
he p ima y PCI. These s udies, summa ized in Tables 3-6, showed ha IMR is ela ed wi h:
 Le en icula emodelling (ei he e alua ed by wall mo ion sco e index, imp o emen
in le en icula olumes o imp o emen in le en icle ejec ion ac ion) be ween he
acu e phase and ollow-up, using ei he echoca diog aphy o con as enhanced ca diac
magne ic esonance (ceCMR),
 In a c size, measu ed ei he by he amoun o ca diac bioma ke s eleased, by single-
pho on emission compu ed omog aphy (SPECT) o by ceCMR,
 The p esence o mic o ascula obs uc ion, e alua ed by ceCMR, and
 Myoca dial iabili y, assessed by posi on emission omog aphy (PET).
Addi ionally, ecen e idence sugges s ha IMR measu ed immedia ely a e he p ima y PCI in
STEMI pa ien s is a s ong and independen p edic o o majo e en s, including dea h (Table 5).
Al hough almos all o hese s udies we e unicen e and small ( he majo i y included less han 50-
60 pa ien s), hei esul s, coming om di e en g oups o in es iga o s, a e ema kably
consis en . The e o e, in he las yea s, IMR has also been used as a ool o e alua e bo h
pha macological s a egies (like IIb/IIIa inhibi o s, nico andil o ni op usside) and de ices (like
h ombus aspi a o s o dis al p o ec ion de ices) in he ea men o STEMI pa ien s (Table 6).
Finally, IMR has been widely used in s able pa ien s, o se e al indica ions176,181: as an adju an
o FFR in pa ien s wi h equi ocal clinical p esen a ion and in e media e co ona y s enosis182, in
pa ien s wi h p obable mic o ascula angina183, o e alua e d ugs184–186 o de ices187, o assess he
impac on mic oci cula ion o pe cu aneous e ascula iza ion188,189, and in o he speci ic clinical
condi ions (apical ballooning synd ome190, assessmen o s eam cell he apy191,192, ansplan
a e iopa hy193 e c.). Howe e , o he da e, he e a e no s udies ela ing IMR o endo helial-
dependen es s in pa ien s wi h acu e myoca dial in a c ion.
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56
Table 3 – S udies using IMR o e alua e LV emodelling in pa ien s wi h ST ele a ion myoca dial in a c ion
Au ho (Yea )
No. o
pa ien s
Compa a o
Ou come
Resul s
LV emodelling
Fea on (2008)238
28
Echoca diog aphy
WMS a 3 mon hs
Signi ican co ela ion ( = 0.59, p = 0.002)
IMR>32 associa ed wi h signi ican ly wo se WMS
IMR was he only independen p edic o o WMS
Lim (2009)249
40
Echoca diog aphy
Change in an e io wall mo ion
sco e a 6 mon h
Signi ican co ela ion ( = -0.464, p = 0.003)
Cu -o 33U IMR: AU ROC o p edic ing LV eco e y: 0.89 (CI 95% 0.888-0.894)
Seze (2010)250
35
Echoca diog aphy
LV olumes and LVEF a 5 mon hs
(IMR measu ed acu ely and a 5 mon hs); signi ican supe io imp o emen s in
LV olumes and LVEF in pa ien s ha inc eased mo e IMR be ween he 2
e alua ions
McGeoch (2010)251
47
Con as enhanced CMR
LV olumes and LVEF
(2 days and 3 mon hs)
IMR was an independen p edic o o LVEF a 2 days and 3 mon hs
Yoo (2012)252
34
Echoca diog aphy
Change in WMSI a 6 mon hs
Change in LVEF a 6 mon hs
Signi ican co ela ion ( = -0.61, P < 0.01) wi h change in WMSI
Signi ican co ela ion ( = -0.52, P < 0.01) wi h change in LVEF
Faus ino (2016)56
40
Echoca diog aphy
Change in WMSI, LVEF and E/e’
be ween acu e and 3 mon hs
All pa ame e s signi ican ly imp o ed mo e in pa ien s wi h lowe IMR
Lowe IMR was associa ed wi h lowe acu e global longi udinal s ain alues
Ca ick (2016)290
259
Con as enhanced CMR
Change in LV end-dias olic olume
and in LVEF a 6 mon hs
IMR was an independen p edic o o LV end-dias olic and LVEF imp o emen
be ween ceCMR pe o med a 2 days and 6 mon h, bu CFR was no
Pa k (2016)257
89
Echoca diog aphy
WMSI a 3 mon hs
Imp o emen in pa ien s wi h lowe IMR and highe FFR g oups, bu no on
pa ien s wi h bo h highe IMR and lowe CFR
Palme (2016)258
31
Echoca diog aphy
Change in WMSI and LVEF a 3
mon hs ( ea men = h ombolysis)
IMR co ela ed wi h LVEF (R = 0.652, p=0.005) and WMSI (R = 0.452, p=0.011)
Only pa ien s wi h lowe IMR showed LV eco e y a 3 mon hs
In oduc ion
57
Table 4 – S udies using IMR o e alua e he size o he in a c ion, mic o ascula obs uc ion and myoca dial iabili y in
pa ien s wi h ST ele a ion myoca dial in a c ion
Au ho (Yea )
No. o
pa ien s
Compa a o
Ou come
Resul s
Ex ension o he in a c ion
Fea on (2008)238
32
Ca diac bioma ke s
CK peak alues
Signi ican co ela ion wi h peak CK (R = 0.61, p = 0.0005)
IMR>32 associa ed wi h signi ican ly highe peak CK alues
IMR was he s onges independen p edic o o peak CK
Seze (2010)250
35
Tec-99m ses amibi SPECT
In a c size (IS)
(a 2 days and 5 mon hs)
IMR was a p edic o o IS a 5 mon hs (β = 0.280, P = 0.013)
IMR was a p edic o o change in IS be ween 1s and 2nd SPECT ( =0.55, P=0.001)
In pa ien s wi h an imp o emen in IMR >33%, IS dec eased signi ican ly
McGeoch (2010)251
47
Con as enhanced CMR
In a c olume
(2 days and 3 mon hs)
IMR was an independen p edic o o in a c olume a 2 days and 3 mon hs
Payne (2012)253
96
Con as enhanced CMR
In a c olume and sal age index
(2 days and 3 mon hs)
IMR was an independen p edic o o in a c olume and sal age index ( he
di e ence be ween in a c size and a ea a isk) a 2 days, bu no a 3 mon h
Ca ick (2016)290
281
Con as enhanced CMR
In a c size, % LV mass
Highe IMR alues we e associa ed wi h la ge in a c size
Mic o ascula obs uc ion
McGeoch (2010)251
53
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
IMR signi ican ly highe in pa ien s wi h MVO
Yoo (2012)252
34
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
MVO co ela ed wi h IMR ( = 0.754; P < 0.001)
Payne (2012)253
96
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
IMR was an independen p edic o o MVO (a 2 days)
Fukunaga (2014)254
88
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
Pa ien s wi h bimodal shape IMR cu e had signi ican ly highe MVO
Ahn (2016)248
40
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
IMR and CFR bo h good p edic o s o MVO, bu he combina ion o bo h was
e en be e o p edic ing MVO (AUC 0.941)
Ca ick (2016)290
219
Con as enhanced CMR
Mic o ascula obs uc ion (MVO)
IMR was an independen p edic o o MVO (a 2 days)
Myoca dial Viabili y
Lim (2009)249
38
PET (18F luo odeoxyglucose)
Regional myoca dial FDG up ake a
6 mon hs
Signi ican co ela ion (R = -0.738, p < 0.001)
In oduc ion
64
wi hin he onome e .213 The pulse-wa e o m shape ob ained p o ides in o ma ion abou
a e ial compliance (including he augmen a ion index, a a io be ween he pulse p essu e a
he second sys olic peak and he pulse p essu e a he i s sys olic peak, which is commonly
used as a measu e o a e ial s i ness) and abou endo helial unc ion (by measu ing he
changes in he pe iphe al p essu e wa e o m in esponse o β-2 ad ene gic s imula ion).214,215
Howe e , his echnique has a ely been used o in es iga e endo helial dys unc ion in clinical
se ings.
6.2.4. Pe iphe al (pulse) a e ial onome y
In addi ion o applana ion onome y, pulse wa e ampli ude o he pe iphe al
mic o ascula u e can be assessed by measu ing changes in digi al pulse olume using a inge
pho ople ysmog aph (pulse con ou analysis).216
Reac i e hype emia pe iphe al a e y onome y is a ecen de elopmen o his echnique,
which uses ple hysmog aphy o eco d digi al olume changes accompanying pulse wa es.217
I s undamen s and clinical e idence will be u he de ailed in he nex sec ion.
6.2.5. Lase Dopple lowme y o he skin
Lase Dopple lowme y (LDF) is a echnique ha enables he moni o ing o skin
mic o ascula blood low.218 The assump ion is ha he esponse obse ed in he cu aneous
ci cula ion is a window owa ds he esponses ha would be obse ed in o he ascula
beds.219 Du ing LDF, he o iginal beam o cohe en ligh changes in con ac wi h mo ing
issues ( ed blood cells) and a pho odiode measu es he eme ged beam. The ac ion o
shi ed ligh depends on he concen a ion o mo ing ed blood cells, whe eas he magni ude
o he equency b oadening depends on hei a e age eloci y.220
LDF has been used o e alua e endo helial unc ion o he skin mic o ascula u e using
pos occlusi e hype emia, local he mal hype emia, and ace ylcholine ion opho esis. Despi e
being nonin asi e and, he e o e, a ac i e o ou ine clinical and esea ch use, hese
echniques ha e ce ain limi a ions. Fi s ly, because he skin is a c i ical he mo egula o y
o gan, he e a e ex eme a ia ions in basal blood lux, which, in u n, dic a e he need o use
maximal asodila a ion (by ei he local wa ming o he skin o local sodium ni op usside
in usion) o no malize submaximal lux alues. Secondly, poo in e assay and in a-assay
ep oducibili y and lack o s anda diza ion (e.g., si e o he skin measu emen ) limi wi hin-
pa ien and ac oss-s udies compa isons. Thi dly, and mos impo an ly, ecen insigh s in o
he mechanisms o he pos occlusi e hype emia and ace ylcholine-media ed dila a ion
indica e ha hese phenomena a e no p ima ily NO media ed, sugges ing ha hey migh
ep esen a summa ion o complex, mic o ascula esponses in ol ing senso y ne es and

In oduc ion
65
me abolic and endo helial asodila o s (independen om NO). The e o e, a he han
ep esen ing speci ic ma ke s o endo helial unc ion, hese es s p o ide a mo e global o m
o assessing mic o ascula unc ion.41
6.2.6. Biochemical bioma ke s
Ma ke s o coagula ion/ h ombosis
The plasma le els o se e al p ocoagulan media o s ha e been shown o inc ease wi h
endo helial damage, sugges ing ha hey could ep esen eliable ma ke s o endo helial
dys unc ion. Fu he mo e, a change in he p oduc ion o hese molecules by he endo helium
could di ec ly con ibu e o a he o ombo ic disease. These ma ke s include, among o he s,
on Willeb and ac o , issue plasminogen ac i a o ( -PA) and PAI-1. Howe e , p ospec i e
epidemiological s udies aiming o e alua e he associa ion be ween plasma le els o di e en
hemos a ic ma ke s and he isk o ca dio ascula disease a e ela i ely spa se and o en
ha e inconclusi e esul s.41
Ma ke s o in lamma ion
S ong e idence sugges s ha a he oscle o ic isk ac o s a e o en associa ed wi h sys emic
in lamma ion, which is a key playe in he de elopmen and p og ession o a he oscle osis.106
C- eac i e p o ein, in pa icula , has eme ged as a po en ial ma ke o ca dio ascula isk. I
can be measu ed wi h se e al s anda dized, alida ed, and inexpensi e high-sensi i i y
assays and is he only bioma ke eady o clinical use, adding p edic i e alue abo e he
cu en ly es ablished isk ac o s, bo h in s able and uns able pa ien s.41 Howe e , i is
a ec ed by se e al mechanisms and ac o s, which limi s i s use as a ma ke o endo helial
unc ion.
O he ma ke s o endo helial dys unc ion
Asymme ical dime hyla ginine (ADMA) and oxidized low-densi y lipop o ein (oxLDL) a e wo
o he ma ke s which ha e been in es iga ed as indica o s o endo helial unc ion. Howe e ,
despi e ini ial p omising esul s, sugges ing an associa ion wi h ca dio ascula disease and
isk, bo h had mo e ecen con lic ing esul s and he e a e doub s i hey ep esen eliable
subs i u es o di ec endo helial unc ion measu emen .211
Endo helial mic opa icles and bone-ma ow de i ed endo helial p ogeni o cells ha e also
been widely in es iga ed as ma ke s o endo helial dys unc ion, wi h p omising esul s, bu
hey emain mos ly in es iga ional es s.211
Finally, baseline plasma le els o se e al cellula adhesion molecules (CAMs), including
in e cellula adhesion molecule-1 and E-selec in, ha e been shown o be associa ed wi h
inc eased ca dio ascula isk in gene ally heal hy popula ion. In pa ien s wi h co ona y a e y
In oduc ion
66
disease, ele a ed ci cula ing ascula cell adhesion molecule-1 and in e cellula adhesion
molecule-1 alues we e also p edic o s o ad e se ou come. Howe e , he esul s om o he
la ge s udies indica ed ha , a e adjus men s o o he ca dio ascula isk ac o s, he
associa ion o CAMs wi h co ona y hea disease is no s a is ically signi ican .41
7. Pe iphe al (pulse) a e ial onome y (EndoPAT)
7.1. P inciple and me hodology
Reac i e hype emia pe iphe al a e y onome y uses ple hysmog aphy o eco d digi al olume
changes accompanying pulse wa es.217 On he basis o his p inciple, a inge pneuma ic
ple hysmog aphic cu , p o iding a ‘‘bea o bea ’’ blood low olume assessmen by eco ding
inge (pe iphe al) a e ial pulsa ile (PAT) olume changes, was de eloped by I ama Medical, and
made comme cially a ailable unde he name EndoPAT 2000® (Figu e 9, page 95).
I consis s o a inge ip ple hysmog aph capable o sensing olume changes in he digi wi h each
a e ial pulsa ion. The inge ip p obe has a igid ex e nal casing con aining in la able chambe s
and he uni o mly applied p essu e ield ac oss he inge p e en s enous pooling and pa ially
unloads a e ial wall ension (Figu e 10, Page 96). Volume changes in he inge ip a e eco ded
digi ally as pulse ampli ude ha can be acked o e ime.
Endo helial unc ion es ing wi h PAT is based on he same physiological mechanisms as he FMD
echnique, inducing ansien ischemia in he uppe limb as a s imulus o eac i e asodila a ion:
 A p essu e cu is placed a ound he a m and in la ed abo e sys olic p essu e a e a
baseline eco ding
 The cu is hen de la ed a e 5 minu es o induce eac i e hype emia in one a m (a main
ad an age o he sys em is ha he con ala e al a m se es as an in e nal con ol).
 The a io be ween hype aemic and baseline pulse olume analysis (PAT a io) is
no malized o he same a io in he con ala e al a m, hus ob aining he eac i e
hype emia index (RHI), o i s na u al loga i hm (L_RHI).221
This index is a alida ed ma ke o endo helial unc ion – a alue below 1.67 (o ≤0.51 o L_RHI)
is conside ed sugges i e o endo helial dys unc ion. The ep oducibili y o he p ocedu e was also
clea ly es ablished.222–224
The echnical de ails o he EndoPAT p ocedu e a e u he de ailed in Sec ion 3.9 o he Me hods
Chap e (Page 95).
Unlike low-media ed dila ion e alua ion, he PAT echnique is ope a o -independen , and he
pulse ampli ude eco dings a e digi ized and analysed by an au oma ed, p op ie a y algo i hm.
In oduc ion
67
7.2. Clinical e idence on he use o EndoPAT in co ona y a e y disease
The ole o EndoPAT in he e alua ion o pa ien s wi h co ona y a e y disease is suppo ed by he
s udy pe o med by Bone i and colleagues, in which hey showed ha a lowe PAT hype aemic
esponse is signi ican ly co ela ed wi h he p esence o co ona y endo helial dys unc ion
measu ed by ace ylcholine esponse207 in pa ien s unde going co ona y angiog aphy. This s udy
con i ms p e ious e idence endo sing he concep o a gene alized na u e o endo helial
dys unc ion206,208 and suppo s he use o endo helial dys unc ion e alua ed by EndoPAT as a
su oga e o co ona y endo helial dys unc ion.
Addi ionally, EndoPAT has been e alua ed in di e en s ages o co ona y a e y disease:
 In pa ien s wi hou known/suspec ed co ona y a e y disease, PAT hype aemic a io is
p og essi ely lowe wi h inc easing bu den o ca dio ascula isk ac o s225–227 and se e al
s udies con i med ha endo helial dys unc ion e alua ed wi h EndoPAT is ela ed bo h o
he isk o de eloping co ona y disease and he isk o ca diac e en s. In ac , as desc ibed
in Sec ion 3.3 abo e and also con i med wi h his echnique, he p esence o endo helial
dys unc ion appea s o ha e an inc emen al p ognos ic alue, a e con ol o hese
classical isk ac o s, which may be explained by he ac ha i e lec s he o e all bu den
o isk and signi ican ly p edic s he isk o ca dio ascula e en s.
The main p ognos ic s udies pe o med wi h EndoPAT o e alua e he isk o e en s in
pa ien s wi hou co ona y a e y disease a e p esen ed in Table 7.
 In pa ien s wi h known s able co ona y a e y disease, endo helial dys unc ion e alua ed
by EndoPAT was ela ed wi h he isk and se e i y o he disease and o he cha ac e is ics
o co ona y plaques (Table 8).
EndoPAT was also used o e alua e he e ec o enhanced ex e nal coun e pulsa ion in
pa ien s wi h s able angina and e ac o y complain s.
Addi ionally, h ee long- e m s udies pe o med wi h EndoPAT con i med i s addi ional
and independen alue in p edic ing e en s in pa ien s wi h co ona y a e y disease (Table
9).
 Finally, in pa ien s wi h acu e co ona y synd omes and ST ele a ion myoca dial
in a c ion, e idence wi h EndoPAT includes s udies p edic ing he isk o in-s en
es enosis, ini ial pa ency o he culp i a e y, angiog aphic se e i y o he co ona y
a e y disease and he ex ension o in a c ion in STEMI pa ien s (Table 10). These wo las
s udies we e pe o med in ou cen e, and hey will be u he desc ibed below, since hey
we e essen ial o he design o his hesis p o ocol.
In oduc ion
68
Table 7 – P ospec i e s udies in es iga ing he p edic i e ole o pe iphe al a e ial onome y in pa ien s wi h suspec ed
co ona y a e y disease o o he clinical se ings
Au ho , Yea
No. o
pa ien s
Clinical Con ex
FUP
du a ion
Clinical endpoin s
Resul s
Rubins ein (2010)129
270
Suspec ed CAD
5.8 yea s
CV dea h, non a al MI, co ona y
e ascula iza ion o CV
hospi aliza ion
Low L_RHI(<0.4) associa ed wi h highe a e o e en s (48% s. 28%, p=0.03)
L_HRI was an independen p edic o o ad e se e en s (HR 1.79 CI95 1.16-
2.76, P=0.008)
Akiyama (2012)275
321
Hea ailu e wi h
p ese ed ejec ion
ac ion
20 mon hs
CV dea h, non a al MI, uns able
angina pec o is, non a al ischemic
s oke, co ona y e ascula iza ion,
hospi aliza ion o HF
RHI (HR 0.80, 95% CI 0.67-0.94, P=0.007, o an inc ease in RHI o 0.1) was an
independen p edic o o e en s.
RHI imp o ed he p edic ion o e en s (C-s a is ics om 0.671 o 0.712)
when added o 5 o he isk ac o s (age, diabe es, NYHA classi ica ion, hea
ailu e hospi aliza ion his o y, and LVEF)
Ma sue (2013)276
159
Hea ailu e wi h
p ese ed ejec ion
ac ion
300 days
HF- ela ed dea h, hospi aliza ion
o HF
L_RHI (HR 0.56, 95% CI: 0.39-0.80 o an inc ease o 0.1) was an independen
p edic o o HF- ela ed e en s.
AUC o ROC cu e o L_RHI was 0.73 (95% CI: 0.62–0.83)
L_RHI 0.49 was sugges ed as he op imal cu -o alue o p edic ion o
ad e se e en s in his popula ion.
Ma suzawa (2013)277
528
Suspec ed CAD
2.8 yea s
CV dea h, non a al MI, uns able
angina, non a al ischemic s oke,
co ona y e ascula iza ion,
hospi aliza ion o HF, non a al
ao ic disease, and pe iphe al
a e ial disease
RHI (HR 0.761 95%CI 0.673-0.859; P<0.0001, o an inc ease o 0.1) was an
independen p edic o o e en s
RHI imp o ed he p edic ion o e en s (C-s a is ics om 0.728 o 0.766) when
added o 3 o he isk ac o s (FRS, SYNTAXsc and BNP)
Hi a a (2014)278
383
Ch onic kidney
disease
30 mon hs
CV dea h, non- a al MI, uns able
angina, non a al ischemic s oke,
co ona y e ascula iza ion,
hospi aliza ion o HF
Low L_RHI (HR 2.70, 95% CI: 1.62-4.51, p<0.001) was an independen
p edic o o e en s
RHI imp o ed he p edic ion o e en s (C-s a is ics om 0.49 o 0.62) when
added o FRS.
In oduc ion
69
Table 8 – P ospec i e s udies in es iga ing pe iphe al a e ial onome y in pa ien s wi h s able co ona y a e y disease
Au ho , Yea
No. o
pa ien s
Clinical Con ex
Objec i es
Resul s
Bone i (2003)222
23
S able CAD,
e ac o y angina
E ec o enhanced ex e nal
coun e pulsa ion (EECP)
RHI signi ican ly inc eased only in pa ien s ha clinically imp o ed (less symp oms) wi h
EECP
Bone i (2010)323
140
S able CAD
P edic ion o obs uc i e and
non-obs uc i e CAD
RHI signi ican ly a enua ed in bo h obs uc i e (median 1.57, IQR 1.42-1.76) and non-
obs uc i e CAD (median 1.58, IQR 1.41-1.78), as compa ed o non-IHD (2.15, IQR 1.85-
2.48, p < 0.001).
RHI (HR 0.51 95%CI 0.38-0.68; P<0.001) was an independen p edic o o CAD
AUC ROC cu e o p edic ion o CAD: 0.86, p<0.001
He e nan (2010)324
42
S able CAD
Iden i ica ion o pa ien s wi h
high isk CAD (ele a ed hs-
CRP and Lp-PLA2)
RHI signi ican ly lowe in he high- isk g oup (1.3 ± 0.04) compa ed o he mode a e- isk
(1.6± 0.07, P < 0.05) and low- isk (2.0± 0.1, P < 0.05).
RHI was a signi ican independen p edic o o high isk CAD
Schonenbe ge
(2012)267
362
S able CAD
IVUS-assessed co ona y
plaque s uc u e.
Pa ien s wi h RHI<1.67 had g ea e plaque bu den (41% s 39%, p = 0.047)
RHI signi ican ly associa ed wi h ib ous and ib o a y plaques and wi h nec o ic co e and
dense calcium olumes

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70
Table 9 – P ospec i e s udies in es iga ing he p edic i e ole o pe iphe al a e ial onome y in pa ien s wi h es ablished
co ona y a e y disease
Au ho , Yea
No. o
pa ien s
Clinical Con ex
FUP
du a ion
Clinical endpoin s
Resul s
Suessenbache (2014)325
96
S able CAD
44 mon hs
Re ascula iza ion, acu e co ona y
synd ome, ischemic s oke,
ca dio ascula dea h, epea
co ona y angiog aphy due o ches
pain
Risk simila in pa ien s below median RHI. Howe e , he combined endpoin
occu ed ea lie in he pa ien s wi h an RHI wi hin he 1s e ile (11.3±11.0
s. 27.5±18.6 mon hs o pa ien s in he 2nd/3 d e ile, p=0.03)
Ma sue (2014)326
213
S able CAD, unde
s a in ea men ,
LDL-C< 100 mg/dl
2.7 yea s
Angina pec o is equi ing co ona y
e ascula iza ion, ecu en angina
pec o is wi h p o en myoca dial
ischemia, non- a al MI, and dea h
om CAD
L_RHI (HR 0.79, 95% CI: 0.66-0.95, p=0.012) was an independen p edic o o
e en s
RHI imp o ed he p edic ion o e en s (C-s a is ics om 0.60 o 0.77) when
added o isk ac o s and es ima ed glome ula il a ion a e.
Taba a (2015)327
435
PCI pa ien s wi h
ch onic kidney
disease (CKD)
2.5 yea s
Ca dio ascula dea h, non a al
myoca dial in a c ion, ischemic
s oke, hospi aliza ion due o
uns able angina pec o is, and
co ona y e ascula iza ion
L_RHI lowe in pa ien s wi h e en s in he non-CKD g oup (0.46 ± 0.18
e sus 0.60 ± 0.25; P = 0.002)
L_RHI (HR: 0.096; 95 % CI 0.02–0.47; P = 0.004) was an independen
p edic o o ca dio ascula e en s in he non-CKD g oup
In oduc ion
71
Table 10 – P ospec i e s udies in es iga ing pe iphe al a e ial onome y which include pa ien s wi h acu e co ona y
synd omes o ST ele a ion myoca dial in a c ion
Au ho , Yea
No. o
pa ien s
Clinical Con ex
Objec i es
Resul s
Bap is a (2013)19
231
S able angina and
ACS pa ien s
Se e i y o CAD
RHI was p og essi ely lowe as CAD se e i y inc eased ( om no disease o 3 essel
disease: 1.98±0.46 -> 1.86±0.46 in 1 essel -> 1.85±0.43 in 2V -> 1.60±0.39 in 3V, p=0.003)
RHI (HR=0.16 o each uni o RHI educ ion , 95%CI 0.04-0.68, p=0.013) was independen
p edic o o se e i y o CAD
Yamamo o (2014)268
86
STEMI pa ien s
Risk o in-s en es enosis
(ISR)
RHI a 8 mon hs signi ican ly lowe in he pa ien s wi h ISR (1.75 s. 2.12; p=0.03).
RHI (OR: 4.23, 95% CI 1.25-14.28, p=0.02) was a signi ican isk ac o o ISR
Kandhai-Raguna h
(2014)269
71
STEMI pa ien s
Ini ial pa ency o culp i
a e y
RHI signi ican ly highe i culp i essel pa en be o e P-PCI (2.08±0.34 s. 1.75±0.35;
p<0.007).
RHI (OR 7.1, 95% CI 2.1-23.6) was an independen p edic o o culp i essel pa ency
Bap is a (2016)18
58
STEMI pa ien s
Ex ension o in a c ion
(peak TnI)
Pa ien s wi h an RHI<1.67 had signi ican la ge in a c s (TnI 73.5 [IQR 114.42] s. 33.2
[IQR 65.2 ng/mL]; p =0.028)
RHI was an independen p edic o o peak TnI alues
Komu a (2016)328
249
S able angina and
ACS pa ien s
Risk o in-s en es enosis
RHI_L a ollow-up lowe in pa ien s wi h ISR (0.52±0.23 e sus 0.65±0.27, P<0.01)
RHI_L (OR 0.13; 95% CI: 0.04-0.48; P=0.002) was a signi ican independen p edic o o ISR
In oduc ion
72
7.2.1. Se e i y o co ona y a e y disease and endo helial dys unc ion e alua ed by
pe iphe al a e ial onome y19
Wi h he pu pose o e alua ing he p e alence o endo helial dys unc ion by se e i y o
co ona y a e y disease, 231 pa ien s e e ed o diagnos ic angiog aphy and 39 con ol
subjec s, we e e alua ed by pe iphe al a e ial onome y (EndoPAT) in ou depa men . The
se e i y o co ona y a e y disease was de ined as he numbe o essels wi h disease (lesions
>70%).
O he 231 pa ien s, 92 (39.8%) had no ele an disease (“no mal” co ona ies), 78 (33.8%)
had 1 essel disease, 37 (16.0%) had 2 essel disease and 24 (10.4%) had 3 essel disease.
Mean RHI alues in he con ol g oup we e 2.10±0.63. In ca he e ised pa ien s, RHI was
p og essi ely lowe as CAD se e i y inc eased: 1.98±0.46, 1.86±0.46, 1.85±0.43 and
1.60±0.39, espec i ely in pa ien s wi h “no mal” co ona ies, 1, 2 and 3 essels disease
(p=0,003). Since pa ien s wi h 1 and 2 essels had simila RHI esul s, hey we e me ged in
one g oup o he analysis pe o med (Figu e 3, Table 11).
Table 11 – Pa ien cha ac e is ics acco ding o he se e i y o co ona y a e y disease
a p esen ed as N (%); b P esen ed as mean±s anda d de ia ion: c p- alue o he compa ison no mal co ona ies s. 1-2 essel
disease s. 3 essel disease: One-Way ANOVA o con inuous a iables and Chi-Squa e o ca ego ical a iables. d p=0.002 (One-
Way ANOVA; Con ols s. no mal co ona ies s. CAD)
Th ee essel disease was mo e p e alen in male pa ien s (in he unadjus ed analysis).
Pa ien s wi h mul i essel disease also ended o be olde and mo e o en diabe ics. The o he
cha ac e is ics we e simila be ween g oups.
Con ols
“No mal“
co ona ies
1-2 essel
disease
3 essel
disease
P alue c
Pa ien s a
39
92 (39.8%)
115 (49.8%)
24 (10.4%)
-
Reac i e hype emia index b
2.08 ± 0.63
1.98 ± 0.46 d
1.85 ± 0.45
1.60 ± 0.39
0.001
Physical cha ac e is ics
Age (yea s) b
39.5± 12.8
59.5 ± 13.7 †
60.3 ± 13.7
64.2 ± 13.1
ns
Male gende a
17 (40.5%)
44 (47.8%) ††
87 (75.7%)
20 (83.3%)
<0.001
Body mass index b
25.4 ± 5.6
27.2 ± 4.1 †
27.2 ± 4.4
28.3 ± 3.9
ns
Hea a e b
66.2 ± 9.2
65.0 ± 11.7 †
65.6 ± 11.2
69.1 ± 14.4
ns
Sys olic blood p essu e b
114.1 ± 14.4
121.7 ± 17.3 †
116.7 ± 20.8
118.4 ± 22.6
ns
Risk Fac o s a
Diabe es
0 (0.0%)
13 (14.2%)
28 (24.3%)
8 (33.3%)
ns
Hype ension
6 (14.3%)
66 (72.5%)
77 (67.0%)
18 (75.0%)
ns
Dyslipidaemia
12 (28.6%)
48 (52.2%)
54 (47.0%)
14 (58.3%)
ns
Smoking
9 (21.4%)
20 (22.2%) ‡
47 (40.9%)
9 (21.4%)
0.018
In oduc ion
73
Figu e 3 – Reac i e hype emia index acco ding o he se e i y o he
co ona y a e y disease (numbe o majo essels wi h lesions >70%)
In he uni a ia e analysis, compa ing 3- essel disease wi h 1 o 2- essel disease, RHI and non-
ST acu e co ona y synd ome as indica ion o he angiog aphy ( s. ST ele a ion myoca dial
in a c ion) we e he s onges p edic o s o he se e i y o disease (Table 12).
Howe e , when his analyses was adjus ed ( o age, gende , p e ious diabe es melli us o
dyslipidaemia, BMI and wais ci cum e ence), only RHI was independen ly associa ed wi h
he diagnosis o 3 essel disease (Table 13).
Table 12 – Uni a ia e analysis o p edic o s o 3 essel disease in he popula ion wi h
documen ed co ona y a e y disease
nST-ACS: non-ST acu e co ona y synd ome; STEMI: ST ele a ion myoca dial in a c ion
Uni a ia e analysis
1-2 Vessels
3 Vessels
RR
95% CI
P alue
Reac i e hype emia index
1,85±0,45
1,60±0,39
0,014
nST-ACS ( s STEMI)
44,3%
70,8%
2,54
1,12-5,73
0,016
Gende (male)
75,7%
83,3%
1,61
0,51-5,11
0,301
Dyslipidaemia
47,0%
58,3%
1,58
0,65-3,85
0,215
Diabe es melli us
24,3%
33,3%
1,55
0,60-4,02
0,251
Hype ension
67,0%
75,0%
1,48
0,54-4,03
0,304
Age (pe yea )
60,3±13,6
64,2±13,1
0,193
Wais ci cum e ence (cm)
98,5±13,0
104,6±16,3
0,051

S udy Objec i es
81
S udy Hypo hesis
The s udy´s main hypo hesis is: In pa ien s wi h acu e ST ele a ion myoca dial in a c ion ea ed
wi h p ima y PCI, endo helial dys unc ion (e alua ed by pe iphe al a e ial onome y) is ela ed
o he ex en o mic o ascula damage and, consequen ly, o he ex en o myoca dial nec osis.
Based on his hypo hesis, he s udy p ima y aim is o e alua e he ela ion be ween endo helial
dys unc ion (e alua ed wi h EndoPAT) and co ona y mic o ascula dys unc ion (e alua ed by IMR
immedia ely a e p ima y e ascula iza ion).
Seconda y aims include bo h con i ming IMR and e alua ing endo helial dys unc ion (as
measu ed by pe iphe al a e ial onome y) as p edic o s o mic o ascula dys unc ion and
ex ension o he myoca dial in a c ion.
S udy Ou come Measu es
The p ima y ou come measu e is he IMR alue. Since he e a e no clea ly de ined alues o
abno mal endo helial unc ion in co ona y a e y disease pa ien s, wo p e-speci ied e alua ions
o his p ima y ou come measu e we e de ined:
1. IMR alue in pa ien s wi h endo helial dys unc ion acco ding o he p e ailing h eshold
de ined o EndoPAT (RHI <1.67 e sus ≥1.67)
2. IMR alue in pa ien s acco ding o he e ile o RHI
Seconda y ou comes o he s udy a e:
1. The ela ion be ween RHI alues and
a) The ex en o myoca dial nec osis, e alua ed by oponin elease (in he i s 48
hou s), echoca diog aphic pa ame e s (bo h measu ed acu ely and a 3 mon hs) and
ceCMR;
b) The ex en o mic o ascula epe usion indica o s, including angiog aphic indica o s
(cTFC and TMPG), ECG (ST esolu ion), and ceCMR (mic o ascula obs uc ion).
2. The ela ion be ween IMR alues and
a) The ex en o myoca dial nec osis, e alua ed by oponin elease (in he i s 48
hou s), echoca diog aphic pa ame e s (bo h measu ed acu ely and a 3 mon hs) and
ceCMR;
b) The ex en o mic o ascula epe usion indica o s, including angiog aphic indica o s
(cTFC and TMPG), ECG (ST esolu ion), and ceCMR (mic o ascula obs uc ion)
83
POPULATION AND METHODS
Me hods
84
1. Type and Loca ion o he S udy
Obse a ional, p ospec i e, single cen e, coho s udy, pe o med in he Ca diology Depa men
o Hospi al P o . Dou o Fe nando da Fonseca (Amado a, Po ugal).
2. Popula ion
All pa ien s admi ed o Hospi al P o . Dou o Fe nando da Fonseca wi h a i s acu e ST ele a ion
myoca dial in a c ion, ea ed wi h p ima y angioplas y, we e conside ed o inclusion in he
s udy, acco ding o he inclusion and exclusion c i e ia de ined below.
2.1. Inclusion C i e ia
 Age > 18 yea s.
 Fi s ST ele a ion acu e myoca dial in a c ion, de ined by:
- Ches pain las ing a leas 20min and /o
- ST segmen ele a ion o a leas 1 mm in wo o mo e con iguous leads
 Pain o balloon ime < 6 hou s (o be ween 6 and 12 hou s i clea ly wi h ongoing pain)
 P ima y PCI pe o med wi h success on he culp i lesion (wi h no signi ican esidual
s enosis, independen ly o he inal TIMI low) in a na i e co ona y a e y.
 In o med consen ob ained
2.2. Exclusion C i e ia
 Pa ien s p esen ing wi h le bundle-b anch block and pa ien s wi h implan ed pacemake
– excluded since ST esolu ion could no be e alua ed.
 His o y o p e ious o myoca dial in a c ion (ei he ST ele a ion o non ST ele a ion MI) –
excluded in o de o educe he bias in he ceCMR and in he mic o ascula es s.
 Pa ien s wi h clea e og ade ci cula ion o he in a c ela ed a e y (Ren op ≥2).
 Killip class IV (ca diogenic shock) on p esen a ion o du ing he p ima y PCI p ocedu e
 Pa ien s wi h known myoca dial diseases (such as hype ophic ca diomyopa hy o
es ic i e ca diomyopa hies) and pa ien s wi h se e e le en icula hype ophy (wall
hickness > 15 mm) – we e excluded in o de o educe he bias in he ceCMR and in he
mic o ascula es s.
 P e ious co ona y a e y bypass su ge y.
 Pe cu aneous e ascula iza ion in he las 3 mon hs.
Me hods
85
 Long QT synd ome, 2nd o 3 d deg ee hea block and sick sinus synd ome (due o he isk
o se e e b adyca dia/a hy hmias induced by adenosine)
 Pa ien s in a ial ib illa ion (i ceCMR was o be pe o med) o wi h o he a hy hmias
conside ed by he in es iga o as se ious enough o con a-indica e he use o adenosine
immedia ely a e he p ima y angioplas y.
 Se e e as hma o ch onic pulmona y obs uc i e disease (due o he isk o b onchospasm
induced by adenosine)
 P e ious se e e eac ion o adenosine o any o he con aindica ion o adenosine, including
sys olic blood p essu e < 90 mmHg o b adyca dia deemed o be signi ican by he ope a o .
 P esence o any se ious non-ca diac disease associa ed wi h a li e expec ancy o less han
12 mon hs
 Inclusion in o he ials/s udies
2.3. Sample
Since he e we e no clea ly de ined “no mal” alues bo h o RHI and IMR in pa ien s wi h acu e
myoca dial in a c ion, sample calcula ion was a di icul ask o accomplish. Ou p e ious wo k
wi h EndoPAT in pa ien s wi h ST ele a ion myoca dial in a c ion18, showed ha RHI alues lowe
han 1.67 a e associa ed wi h la ge in a c s (measu ed by peak oponin I elease). Values lowe
han 1.67 we e p esen in app oxima ely 30% o pa ien s (unpublished da a), which ansla es in o
an “exposed/non-exposed” a io o 2.3. In pa ien s wi h RHI lowe han 1.67, app oxima ely 70%
had la ge in a c s (peak oponin I > 50 ng/dL).
Using he OpenEpi sample size calcula o (Kelsey me hod) 228, o a wo-sided signi icance le el (α)
o 0,05, a powe (1-β, % chance o de ec ing) o 80 and assuming a p opo ion wi h disease (la ge
in a c s) in pa ien s wi h RHI > 1.67 (“non-exposed”) o 30%, he sample size would be 58 pa ien s
(18 “exposed” + 40 “non-exposed”).
3. METHODS
3.1. Clinical in o ma ion
Da a conce ning pa ien physical cha ac e is ics (age, gende , weigh , heigh , body mass index,
wais ci cum e ence), majo isk ac o s (high blood p essu e, diabe es, dyslipidaemia, smoking
habi s) and p e ious co ona y/non-co ona y a he oscle o ic his o y (p e ious angina, p e ious
pe cu aneous e ascula iza ion we e collec ed in all pa ien s included. Da a on p e ious d ug
ea men was also egis e ed.

Me hods
86
3.2. P ima y Pe cu aneous Co ona y In e en ion
P ima y pe cu aneous co ona y angioplas y was pe o med acco ding o he ecommended
s anda ds. The ime o symp oms onse , ime o hospi al admission and ime o i s co ona y
in e en ion ( h ombus aspi a ion, balloon dila ion o s en ing, whiche e was i s ) was eco ded,
in o de o allow he de e mina ion o ischemic imes:
 “pain- o-hospi al”: ime be ween he onse o symp oms and he i s medical con ac ;
 “hospi al- o-balloon”: ime be ween he i s medical con ac and he i s co ona y
in e en ion; and,
 “pain- o-balloon”: ime be ween symp om onse and he i s co ona y in e en ion.
The ea men s a egy ( h ombus aspi a ion, di ec s en ing e sus balloon p e-dila a ion,
balloon pos -dila a ion, ype and numbe o s en s, dose o non- ac iona ed hepa in, use o GP
IIb/IIIa inhibi o s, dose and iming o clopidog el, e c.) was le o he disc e ion o he p ima y
ope a o . All hese echnical pa ame e s we e collec ed.
A e he p ima y PCI, pa ien s we e admi ed o he In ensi e Ca diac Uni and o e ed s anda d
ca e o pa ien s wi h acu e STEMI, including ecommended pha macological he apy (aspi in,
clopidog el/ icag elo , be a-blocke s, ACE inhibi o s and s a ins), acco ding o Po uguese229 and
Eu opean1 guidelines.
3.3. Co ona y angiog aphy and a ea-a - isk sco es
Angiog aphy was pe o med acco ding o usual p ocedu es, by one o he 4 senio ope a o s o
he In e en ional Ca diology Uni o Hospi al P o . Dou o Fe nando da Fonseca. All ope a o s
we e la gely expe ienced in ea ing pa ien s wi h acu e ST ele a ion myoca dial in a c ion.
The se e i y o co ona y a e y disease was e alua ed by he Syn ax Sco e.230 Lesion segmen s
we e classi ied (as in he Syn ax Sco e) based on he 16 segmen de ini ion p oposed by he
Ame ican Hea Associa ion and modi ied o he ARTS I and II ials.230
The p esence o colla e al low o he culp i a e y was e alua ed, using he Ren op colla e al
low classi ica ion231:
 G ade 0: None
 G ade 1: Filling o side b anches o he a e y o be dila ed ia colla e al channels wi hou
isualiza ion o he epica dial segmen ;
 G ade 2: Pa ial illing o he epica dial segmen ia colla e al channels;
 G ade 3: Comple e illing o he epica dial segmen o he a e y being dila ed ia
colla e al channels
Me hods
87
Pa ien s wi h a Ren op low 3 o 4 in he in a c ela ed a e y we e no included, in o de o
educe he bias in IMR measu emen in his e i o y.
Fo each lesion, he a ea-a - isk was calcula ed, acco ding o he segmen in ol ed and using wo
di e en sco es: he APPROACH sco e and he BARI sco e. These 2 sco es ha e been widely
alida ed in clinical p ac ice.232–235
3.3.1. Modi ied APPROACH Sco e
The Albe a P o incial P ojec o Ou come Assessmen in Co ona y Hea Disease
(APPROACH) sco e236 is an angiog aphic sco e in which he le en icle is di ided in o
egions acco ding o he pe cen age o myoca dium supplied by a essel o i s b anches. The
a ea-a - isk o a gi en lesions is calcula ed aking in o accoun he loca ion o he culp i
lesion, dominance and size o he seconda y b anches. The modi ied APPROACH sco e232
simpli ies his e alua ion, using a able wi h alues de ined o each lesion loca ion (Figu e 5).
Figu e 5 – Modi ied APPROACH sco e o e alua ing he a ea-a - isk
(adap ed om O iz-Pe ez e al233)
Me hods
88
3.3.2. BARI Sco e
The Bypass Angioplas y Re ascula iza ion In es iga ion Myoca dial Jeopa dy Index (BARI)
sco e was de eloped based on angiog aphic da a om he BARI ial.237 I assigns a sco e o
all e minal a e ies ( e minal po ion o he le an e io descending, le ci cum lex, and
igh co ona y a e y, as well as he amus, diagonals, ob use ma ginals, pos e io descending
and pos e ola e al b anches) based on hei leng h and calib e acco ding o speci ic c i e ia.
A alue o 0 ep esen s an almos insigni ican essel size, whe eas a alue o 3 de ines a
la ge-size a e y wi h a leng h o wo hi ds he dis ance be ween he base and ca diac apex.
Righ en icula ma ginals and pos e io descending a e y sep al b anches a e no aken
in o accoun . The inal sco e is ob ained by di iding he esul ing alue om he in a c -
ela ed a e y by he o e all sco e o all a e ies supplying he LV, which inally pe mi s
es ima ion o he pe cen age o myoca dial muscle a isk.
An example o he calcula ion o bo h he APPROACH and BARI sco es o a gi en pa ien is
p esen ed in Figu e 6. The pa ien had a STEMI due o a p oximal le an e io descending a e y
(LAD) occlusion. Since he e was a epe used diagonal b anch o medium impo ance, he a ea-
a - isk acco ding o he APPROACH sco e (Figu e 5) was 44.5%. Fo he BARI sco e, all le and
co ona y a e y b anches we e classi ied om 1 o 3, acco ding o hei impo ance. The o al
alue o b anches dis al o he occluded p oximal LAD ( o al 11 poin s, co esponding o: dis al
LAD = 3 poin s, majo diagonal b anch = 3 poin s, 2 mino diagonal b anches = 1 poin each, 3
sep al b anches = 1 poin each) was di ided by he o al poin s o he pa ien (26), esul ing in an
a ea-a - isk o 42.3%.
Figu e 6 – A ea-a - isk calcula ion acco ding o he APPROACH and BARI sco es
(adap ed om Mo al e al234)
Me hods
89
3.4. TIMI Flow, co ec ed TFC and TIMI myoca dial pe usion g ade
A he end o he p ima y PCI p ocedu e, a inal un o images o he culp i a e y was egis e ed,
a 30 ames pe second, in o de o measu e TIMI low, TIMI ame coun and TIMI pe usion
g ade. I necessa y, he iew was adjus ed, so ha he culp i essel e i o y was no
supe imposed. The du a ion o cine ilming was p olonged a leas 3 ca diac cycles, o make su e
ha he en i e washou phase was included. These h ee measu es o low we e analysed o line
by an ope a o blinded o o he e alua ions o he pa ien .
3.4.1. TIMI low g ade
TIMI low g ade was classi ied acco ding o he s anda d de ini ion152:
 TIMI 3 (comple e epe usion): An e og ade low in o he e minal co ona y a e y
segmen h ough a s enosis is as p omp as an e og ade low in o a compa able segmen
p oximal o he s enosis. Con as ma e ial clea s as apidly om he dis al segmen as
om an unin ol ed, mo e p oximal segmen . I he e a e di icul ies in ep oducibly
assessing myoca dial low ela i e o o he essels, he modi ied de ini ion o TIMI g ade
3 low153 can be used (opaci ica ion o he dis al co ona y a e y wi hin h ee ca diac
cycles)
 TIMI 2 (pa ial epe usion): Con as ma e ial lows h ough he s enosis o opaci y he
e minal a e y segmen . Howe e , con as en e s he e minal segmen pe cep ibly
mo e slowly han mo e p oximal segmen s. Al e na i ely, con as ma e ial clea s om
a segmen dis al o a s enosis no iceably mo e slowly han om a compa able segmen
no p eceded by a signi ican s enosis.
 TIMI 1 (pene a ion wi h minimal pe usion): A small amoun o con as lows h ough
he s enosis bu ails o ully opaci y he a e y beyond.
 TIMI 0 (no pe usion): No con as low h ough he s enosis.
3.4.2. Co ec ed TIMI ame coun
The co ec ed TIMI ame coun (cTFC) was measu ed as he numbe o ames equi ed o
epica dial con as o each s anda dized dis al landma ks, as p e iously desc ibed.154 The
i s ame used o TIMI ame coun ing was de ined as he ame in which a column o dye
ouched bo h bo de s o he co ona y a e y and mo ed o wa d, and he las ame was
de ined as he ame in which dye begins o en e (bu does no necessa ily ill) a s anda d
dis al landma k in he a e y.
Me hods
96
 A e cu elease, pulse ampli ude inc eases in he hype aemic inge . The pulse
ampli ude eco dings a e digi ized and analysed by an au oma ed, p op ie a y algo i hm.
A e age pulse ampli ude is calcula ed o each 30-second in e als a e cu occlusion o
up o 5 minu es.
 As a measu e o eac i e hype emia, he pulse ampli ude onome y is hen calcula ed as
he a io o he a e age ampli ude o he PAT signal o e a 1-min ime in e al s a ing 1
min a e cu de la ion di ided by he a e age ampli ude o he PAT signal o a 3.5-min
ime pe iod be o e cu in la ion (baseline).
 Subsequen ly, PAT index alues om he s udy a m a e no malized o he con ol a m. All
hese da a a e analysed by a compu e in an ope a o -independen manne , o ge he
eac i e hype emia index (RHI) and i s loga i hmic ans o ma ion (L_RHI).
In pa ien s wi h wo exams, he same s udy a m (le o igh ) was used in bo h es s.
Figu e 10 – EndoPAT p ocedu e
3.10. Con as Enhanced Ca diac Magne ic Resonance
Ca diac magne ic esonance was pe o med in a subse o pa ien s on he 7-8 h day pos -MI.243,
using a 1.5-T magne ic esonance imaging sys em (A an o, Siemens Medical Sys em, E langen,
Ge many) equipped wi h a dedica ed ca diac so wa e package and 8 a ailable independen
adio equency ecei e channels, ca diac coil, and ec o ca diog am.

Me hods
97
A e he acquisi ion o localizing images, long- and sho -axis cine images we e ob ained, using
e ospec i ely ECG-ga ed b ea h-hold segmen ed K-space balanced s eady-s a e ee p ecession
pulse sequence ( ueFISP) echnique. The sho -axis cine scans o 6-mm slices we e used o
de e mine he le en icula mass, olume, and unc ion (in-plane esolu ion 1.6x1.6mm; gap
2mm). STIR echnique, a iple-IR black-blood u bo spin echo pulse sequence was used o
oedema quan i ica ion (a ea a isk).
A bolus o con as medium (gadopen e a e dimeglumine - Magne is , Sche ing AG, Be lin,
Ge many) was injec ed a a dose o 0.2 mmol/kg. Ea ly enhancemen images o mic o ascula
obs uc ion assessmen we e ob ained by acqui ing an in e sion- eco e y segmen ed g adien
echo T1-weigh ed sequence wi h a high in e sion ime (app oxima ely 500 ms), 2-4 min a e
gadolinium injec ion. Delayed enhancemen images we e hen ob ained by acqui ing an in e sion-
eco e y segmen ed g adien echo T1-weigh ed sequence, 10 o 15 min a e he bolus.
All pos -p ocessing and analyses o he le en icula mass, olume, unc ion, a ea a isk,
myoca dial in a c size, and p esence o mic o ascula obs uc ion we e pe o med using CVI 42
Ve sion 5 So wa e (Ci cle Ca dio ascula Imaging Inc, Calga y, Canada) by a ca diologis
expe ienced in CMR and blinded o all clinical and in asi e physiological da a.
A ea-a - isk was manually quan i ied on sho -axis STIR sequences slices, delinea ing highe
in ensi y a eas (no h eshold de ini ion) a each slice, wi h subsequen compu a ion o mass
es ima ion. In a c size was also assessed manually by planime y on each sho -axis slice,
delinea ing he hype enhanced a ea, including a eas o hypoenhancemen su ounded by he
hype enhanced a ea, he la e being conside ed mic o ascula obs uc ion. In a c size, as a
pe cen age o le en icula mass, was compu ed om he sum o hype enhanced pixels om
each o he 10 sho -axis images di ided by he o al numbe o pixels wi hin he le en icula
myoca dium mul iplied by 100% (21)244. Mic o ascula obs uc ion mass was also manually
quan i ied as he sum o hypoenhanced pixels a delayed enhancemen sequences as be e
spa ial esolu ion was ound when compa ed o ea ly enhancemen sequences245.
4. STATISTICAL ANALYSIS
Con inuous a iables a e p esen ed as mean ± s anda d de ia ion (no mal dis ibu ion) o as
median and in e qua ile ange (non-no mal dis ibu ion); ca ego ical a iables a e p esen ed as
equencies.
All analysis o ca ego ical dependen a iables (i.e., RHI<1.67 s. >1.67, IMR<24 s >24, e c.) we e
pe o med using independen sample T-Tes o con inuous a iables wi h a no mal dis ibu ion,
Mann-Whi ney Tes , o con inuous a iables wi h a non-no mal dis ibu ion and Chi-squa e o
ca ego ical a iables (wi h Fishe co ec ion when applicable).
Me hods
98
Analysis acco ding o RHI e iles was pe o med using one-way ANOVA o con inuous a iables
wi h a no mal dis ibu ion and K uskal-Wallis o con inuous a iables wi h non-no mal
dis ibu ion.
Analysis o IMR o RHI as con inuous a iables we e pe o med using Pea son’s co ela ion o
con inuous a iables wi h a no mal dis ibu ion and Spea mans’s ho co ela ion o con inuous
a iables wi h a non-no mal dis ibu ion
The analysis o IMR p edic o s was adjus ed o con ounding a iables by linea eg ession
analyses, including he a iables iden i ied as ele an on uni a ia e analysis and also all a iables
conside ed clinically ele an .
Fo pai ed compa isons, pai ed sample T es , Wilcoxon o signs es was used, as indica ed.
S a is ical es s and co esponding p- alues we e wo-sided and a p alue <0.05 was conside ed
as s a is ically signi ican . IBM SPSS e sion 21.0 was used o all s a is ical analyses.
5. ETHICAL ASPECTS
The s udy complied wi h all e hical in e na ional s anda ds, including he Wo ld Medical
Associa ion’s Decla a ion o Helsinki – E hical P inciples o Medical Resea ch In ol ing Human
Subjec s.
I was submi ed o and app o ed by Hospi al P o . Dou o Fe nando da Fonseca´s E hics
Commi ee, Reseae ch Commi ee and Hospi al Adminis a ion and o No a Medical School E hics
Commi ee.
A de ailed, w i en in o med consen was ob ained om each pa ien . Inclusion in he s udy did
no a ec pa ien ’s ca e and all pa ien s we e ea ed wi h he bes a ailable esou ces and
knowledge, as usual.
6. FINANTIAL ASPECTS
The s udy was unded by he ollowing companies/ ounda ions:
 As a-Zeneca (un es ic ed g an )
 Me ck Founda ion (un es ic ed g an )
 S. Jude Medical Po ugal (p essu e-wi e o e )
 Med onic (un es ic ed g an )
 Co dis, Ca dinal Heal h (un es ic ed g an )
 Baye (un es ic ed g an )
99
RESULTS
Resul s
101
1. Popula ion included
Be ween June 2012 and June 2015, a o al o 543 ST ele a ion myoca dial in a c ion pa ien s
ea ed by p ima y pe cu aneous co ona y in e en ion we e admi ed o Hospi al P o . Dou o
Fe nando da Fonseca. O hese, 60 pa ien s ul illed all he inclusion c i e ia, accep ed o
pa icipa e in he s udy and we e conside ed eligible o he p ocedu e, acco ding o he ope a o .
The lowcha o pa ien inclusion is p esen ed in Figu e 11E o ! Re e ence sou ce no ound..
Figu e 11 - Flow diag am o he coho s udy

Me hods
102
1.1. Main epidemiological cha ac e is ics
O he 60 pa ien s included, 48 (80.0%) we e male. Mean age was 59.6±12.7 yea s (58.5±12.0 o
male and 63.9±14.7 o emale pa ien s). The his og am o age is p esen ed in Figu e 12. Hal o
he pa ien s had a p e ious his o y o dyslipidaemia and one ou h we e diabe ics. The main isk
ac o s in he popula ion included a e p esen ed in Figu e 13. Mean body mass index (BMI) was
27.5±4.0 kg/m2 (28.0±3.8 kg/m2 o males and 25.4±4.2 kg/m2 o emales). Mean wais
ci cum e ence was 99.2±12.2 cm (100.2±12.0 o male and 92.5±12.6 cm o emale pa ien s).
Figu e 12 – Age dis ibu ion o pa ien s
included
Figu e 13 – P e alence o main isk ac o s
Mos pa ien s had no his o y o co ona y a e y disease: only 9 pa ien s (15.0%) had p e ious
angina complain s and 2 (3.3%) had p e iously unde gone co ona y angiog aphy and
pe cu aneous co ona y in e en ion. Acco dingly, only 6 pa ien s (10.0%) we e on an i-pla ele
(aspi in o clopidog el) he apy. S a ins we e used by 9 pa ien s (15.0%). ACE
inhibi o s/angio ensin an agonis s, be a-blocke s and calcium channel an agonis s we e being
used, espec i ely, by 23 (38.3%), 4 (6.7%) and 4 (6.7%) pa ien s p io o hospi al admission.
1.2. Angiog aphic and angioplas y- ela ed cha ac e is ics
1.2.1 Ou -o -hospi al and in-hospi al ime delays
The median ime be ween he onse o symp oms and he i s medical con ac (“pain- o-doo ”
ime) was 130 minu es (IQR 126 minu es). The median ime be ween he i s medical con ac
and he i s balloon dila ion (“doo - o-balloon” ime) was 78 minu es (IQR 45 minu es). The
71,7%
25,0%
43,3%
50,0%
Hype ension Diabe es Ac i e
smoking
habi s
Dyslipidemia
Resul s
103
median o al ischemic ime ( ime be ween he onse o symp oms and i s balloon dila ion, o
“pain- o-balloon” ime) was 209 minu es (IQR 148 minu es).
1.2.2 Angiog aphic da a
The culp i a e y was he le an e io descending a e y (LAD) in 28 pa ien s (46.7%), he le
ci cum lex a e y (LCx) in 13 pa ien s (21.7%) and he igh co ona y a e y in 19 pa ien s
(31.7%). Mul i essel disease (classi ied as lesions >70% in majo co ona y a e ies) was p esen
in 25 pa ien s (41.7%). The median Syn ax sco e was 15.5 (IQR 10.0).
TIMI low on he i s injec ion was 0 (no low beyond he poin o occlusion) o 1 ( ain
co ona y low beyond he occlusion wi h incomple e illing o he dis al co ona y bed) in 50
pa ien s (83.8%).
1.2.3 A ea-a - isk sco es
Mean APPROACH and BARI sco es we e simila : 28.5%±6.6% and 28.0%±6.3%, espec i ely,
wi h a sligh endency o highe a eas wi h he APPROACH sco e. Co ela ion be ween he 2
sco es was e y high (R=0.90, p<0.001), sugges ing ha bo h sco es pe o m simila ly well in
iden i ying he a ea a isk o each lesion loca ion (Figu e 14).
Figu e 14 – Co ela ion be ween APPROACH and BARI sco es in iden i ying he a ea-a - isk
o each lesion loca ion
Resul s
104
1.2.4 Angioplas y p ocedu e
All pa ien s ecei ed in a enous non- ac iona ed hepa in and bo h aspi in (in a enous) and
clopidog el/ icag elo (o al). In aco ona y ni a es we e also adminis a ed in all pa ien s,
since i is manda o y o he IMR measu emen . Fou een pa ien s (23.3%) ecei ed
in a enous abciximab du ing angioplas y.
Mechanical h ombec omy (aspi a ion) was pe o med in 26 cases (43.3%). S en s we e
implan ed in 57 (95.0%) and a di ec s en ing echnique was used in 25 (41.7%), wi h balloon
pos -dila ion in 28 (38.3%).
1.2.5 Angiog aphic indica o s o mic o ascula pe usion
A no mal (TIMI 3) low was ob ained in all pa ien s. Co ec ed TIMI ame coun (cTFC) and
TIMI myoca dial pe usion g ade (TMPG) we e measu ed in all pa ien s immedia ely a e he
P-PCI. cTFC median alue was 17.0 (IQR 7.0). A no mal 3 TMPG was ob ained in 37 pa ien s
(61.7%). Pa ien s wi h lowe TMPG had, as expec ed, highe cTFC alues (Figu e 15).
Figu e 15 – Co ec ed TIMI ame coun , acco ding o TIMI myoca dial pe usion g ade
( alues exp essed as median and in e qua ile ange, p alue o K uskal-Wallis es )
Resul s
105
1.3. Index o mic oci cula o y esis ance (IMR)
IMR was measu ed in all pa ien s. Median IMR alue was 23.9 (IQR 32.9). An IMR alue highe
han 40 was measu ed in 21 pa ien s (35.0%).
Two examples o IMR measu emen s a e p esen ed in Figu e 16.
 Example 1 co esponds o a young 28 yea s old male pa ien wi h an in e io
myoca dial in a c ion, due o a p oximal RCA occlusion, e ascula ized (pain- o-balloon
ime) 155 minu es a e symp oms onse . His IMR was 17.
 Example 2 co esponds o a 75 yea s old emale pa ien , wi h an in e io myoca dial
in a c ion e ascula ized 192 minu es a e symp oms onse ; she had a p oximal LCx
occlusion success ully e ascula ized and he IMR a e he p ocedu e was 76.
Figu e 16 – Examples o IMR measu emen
Resul s
112
Table 21 – 2D measu emen s in i s (acu e) and second (3 mon hs) echoca diog aphic exams
Fi s (acu e) echo
Second (3 mon h) echo
p
aluec
All pa ien s
(n=47)
Pa ien s w/2 echos
(n=45)
All pa ien s
(n=54)
Pa ien s w/ 2 echos
(n=45)
LVEdV (ml) a
105.8±24.2
105.4±24.8
109.7±26.4
109.8±27.8
0.18
LVEsV (ml) a
54.7±12.7
54.1±12.5
52.9±18.8
53.0±19.6
0.60
LVEF (%) a
47.9±6.7
48.3±6.0
52.6±7.1
52.6±6.7
0.001
WMSI b
1.41 (0.35)
1.41 (0.35)
1.24 (0.35)
1.24 (0.35)
<0.001
LA Volume (ml/m2) a
34.8±12.2
34.3±11.8
39.1±15.4
39.8±16.6
0.005
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); C p- alue o he compa ison be ween he i s
and he second echo only in pa ien s wi h 2 e alua ions; pai ed samples T-Tes o a iables wi h no mal dis ibu ion and Wilcoxon
es o a iables wi h non-no mal dis ibu ion. LVEdV – le en icula end dias olic olume; LVEsV – le en icula end sys olic
olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion sco e index. LA – le a ia
Table 22 – Dopple and 2D speckle acking measu emen s in i s (acu e) and second (3
mon hs) echoca diog aphic exams
Fi s (acu e) echo
Second (3 mon h) echo
p
alueb
All pa ien s
(n=40)
Pa ien s w/2 echos
(n=35)
All pa ien s
(n=51)
Pa ien s w/ 2 echos
(n=35)
Dopple measu emen s
E/A a io a
1.00±0.34
0.99±0.34
1.20±0.56
1.14±0.51
0.022
E/e’ a io a
9.00±2.71
9.00±2.84
8.83±3.29
8.89±3.58
0.82
2D speckle acking imaging
GLS a
-13.54±2.28
-13.88±2.09
-15.77±3.11
-15.67±3.10
<0.001
a P esen ed as mean±s anda d de ia ion; b p- alue o he compa ison be ween he i s and he second echo only in pa ien s wi h 2
e alua ions; pai ed samples T-Tes o a iables. GLS – global longi udinal s ain
1.8. Con as enhanced ca diac magne ic esonance (ceCMR)
O he 60 pa ien s included in he s udy:
 4 e used o pe o m he ceCMR, mainly because o claus ophobia;
 3 did no pe o m he exam due o logis ic limi a ions;
 2 did he exam, bu images we e los ;
 2 did he exam, bu he quali y o he images was conside ed inadequa e o e alua ion;
 49 ha e he exam a ailable o e alua ion o he endpoin s de ined.

Resul s
113
The exam was pe o med 8.8 days (6-13) a e he p ima y PCI. Oedema was p esen in all bu 1
pa ien . Mic o ascula obs uc ion was iden i ied in 13 pa ien s (26.5%) and comple e ansmu al
nec osis was ound in 23 (46.9%).
Figu e 20 depic s h ee examples o ceCMR exams, wi h one case o ex ensi e no- e low, one case
o ansmu al in a c ion and one o subendoca dial in a c ion.
Figu e 20 – Th ee examples o ceCMR
Le column images depic myoca dial oedema (a ea a isk) as assessed by 2-weigh ed s i (sho au in e sion
eco e y) sequences; he column in he cen e shows ea ly enhancemen acquisi ion wi h a long ime o in e sion o
mic o ascula obs uc ion de ec ion; igh column shows delayed enhancemen sequences o in a c mass es ima ion.
Pa ien A: la ge a ea a isk (be ween a ows) wi h ex ensi e no- e low (yellow a ow), clea ly depic ed ac oss a
ansmu al an e o-sep al in a c ion (sho yellow a ow); Pa ien B: la e al oedema (be ween a ows) wi h absence o
no- e low despi e he p esence o a ansmu al in a c ion (*); Pa ien C: an e o-sep al oedema (be ween a ows),
nega i e o he p esence o no- e low and subendoca dial myoca dial in a c ion (sho yellow a ow)
Resul s
114
2. Ou come measu es - summa y
The p ima y ou come measu es we e, as s a ed abo e, he IMR alues acco ding o he p esence
o endo helial dys unc ion (RHI<1.67) and o RHI e iles. Since a second EndoPAT measu emen
was pe o med, hese 2 ou comes will be p esen ed o each EndoPAT exam. Addi ionally, analysis
o RHI as a con inuous a iable will also be p esen ed o each EndoPAT e alua ion. So, in
summa y, p ima y ou comes measu es will be p esen ed as ollows:
Fi s EndoPAT
1. IMR alues in pa ien s wi h and wi hou endo helial dys unc ion (RHI<1.67) in he i s
EndoPAT (Sec ion 3.1).
2. IMR alues acco ding o RHI e iles in he i s EndoPAT (Sec ion 3.2).
3. Rela ion o RHI as a con inuous a iable in he i s EndoPAT o IMR alues (Sec ion 3.3).
Second EndoPAT
4. IMR alues in pa ien s wi h and wi hou endo helial dys unc ion (RHI<1.67) in he second
EndoPAT (Sec ion 4.1).
5. IMR alues acco ding o RHI e iles in he second EndoPAT (Sec ion 4.2).
6. Rela ion o RHI as a con inuous a iable in he second EndoPAT o IMR alues (Sec ion
4.3).
Seconda y ou come measu emen s included he impac o ela ion be ween RHI and IMR and he
ex en o myoca dial nec osis and mic o ascula epe usion, e alua ed by se e al di e en
me hods. These esul s will be p esen ed as ollows:
Fi s EndoPAT
1. Impac o he p esence o endo helial dys unc ion (RHI<1.67) in he i s EndoPAT on he
ex en o myoca dial in a c ion, e alua ed by oponin elease, echoca diog aphic
pa ame e s and ceCMR (Sec ion 5.1).
2. Impac o he p esence o endo helial dys unc ion (RHI<1.67) in he i s EndoPAT on
mic o ascula epe usion indica o s, including angiog aphic indica o s (cTFC and TMPG),
ECG (ST esolu ion), and ceCMR (mic o ascula obs uc ion) (Sec ion 5.2).
Second EndoPAT
3. Impac o he p esence o endo helial dys unc ion (RHI<1.67) in he second EndoPAT on
he ex en o myoca dial in a c ion, e alua ed by oponin elease, echoca diog aphic
pa ame e s and ceCMR (Sec ion 6.1).
4. Impac o he p esence o endo helial dys unc ion (RHI<1.67) in he second EndoPAT on
mic o ascula epe usion indica o s, including angiog aphic indica o s (cTFC and TMPG),
ECG (ST esolu ion) and ceCMR (mic o ascula obs uc ion) (Sec ion 6.2).
Resul s
115
Index o mic oci cula o y esis ance (IMR)
5. Rela ion be ween IMR and pa ien baseline cha ac e is ics (Sec ion 7.1)
6. Impac o he p esence o co ona y mic o ascula damage as e alua ed by an IMR>24
(median alue) on he ex en o myoca dial in a c ion, e alua ed by oponin elease,
echoca diog aphic pa ame e s and ceCMR (Sec ion 7.2).
7. Rela ion be ween he p esence o co ona y mic o ascula damage as e alua ed by an
IMR>24 (median alue) on mic o ascula epe usion indica o s, including angiog aphic
indica o s (cTFC and TMPG), ECG (ST esolu ion) and ceCMR (mic o ascula obs uc ion)
(Sec ion 7.3).
Resul s
116
3. P ima y ou come – IMR and RHI alues on he i s EndoPAT
3.1. IMR alues in pa ien s wi h and wi hou endo helial dys unc ion (RHI<1.67) on
he i s EndoPAT
Endo helial dys unc ion, as e alua ed by an RHI<1.67, was p esen in 11/60 pa ien s (18.3%) in
he i s EndoPAT e alua ion. In he ollowing pages, he main pa ien s cha ac e is ics acco ding
o he p esence o endo helial dys unc ion will be sho ly desc ibed, ollowed by he IMR analysis.
3.1.1. Main cha ac e is ics o pa ien s acco ding o he p esence o endo helial
dys unc ion (RHI<1.67)
Table 23 summa izes he main cha ac e is ics o pa ien s wi h and wi hou endo helial
dys unc ion (RHI<1.67) in he i s EndoPAT e alua ion.
Table 23 – Main cha ac e is ics o pa ien s acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) in he i s EndoPAT e alua ion
Va iable
To al popula ion
(n=60)
Endo helial dys unc ion (RHI<1.67)
p alue c
No (n=49)
Yes (n=11)
Physical cha ac e is ics
Age (yea s) a
59.6±12.7
59.7±13.4
59.1±9.5
0.89 _
Male gende b
48 (80.0)
39 (79.6)
9 (81.8)
0.80 d
BMI a
27.5±4.0
27.5±4.0
27.4±4.2
0.94 _
Wais ci cum e ence a
99.2±12.2
98.9±12.0
100.8±14.0
0.68 _
Risk Fac o s and p e ious co ona y disease b
Hype ension
43 (71.7)
34 (69.4)
9 (81.8)
0.21 d
Diabe es
15 (25.0)
10 (20.4)
5 (45.5)
0.18 d
Dyslipidaemia
30 (50.0)
25 (51.0)
5 (45.5)
0.74 _
Ac i e smoking
26 (43.3)
17 (34.7)
9 (81.8)
0.01 d
P e ious angina
9 (15.0)
7 (14.3)
2 (18.2)
0.89 d
P e ious e ascula iza ion
2 (3.3)
1 (2.0)
1 (9.1)
0.80 d
P e ious medica ion b
Aspi in
5 (8.3)
3 (6.2)
2 (18.2)
0.50 d
Clopidog el
1 (1.7)
1 (2.1)
0 (0.0)
0.42 d
ACEi/ARBs
23 (38.3)
17 (35.4)
6 (54.5)
0.41 d
Be a-blocke s
4 (6.7)
1 (2.1)
3 (27.3)
0.04 d
Ni a es
1 (1.7)
0 (0.0)
0 (0.0)
-
S a ins
9 (15.0)
6 (12.5)
3 (27.3)
0.44 d
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c Independen - es o con inuous a iables, Chi-Squa e o
ca ego ical a iables; d Ya es co ec ion
Resul s
117
Pa ien s whi endo helial dys unc ion we e mo e equen ly ac i e smoke s (81.8% s. 34.7%,
p=0.01), bu he e we e no o he signi ican di e ences in physical cha ac e is ics o in o he
isk ac o s be ween he wo g oups. Pa ien s wi h endo helial dys unc ion we e mo e likely o
be on be a-blocke ea men , bu he numbe s we e oo small (1 s. 3 pa ien s) o allow o
any alid conclusion. The e we e no o he signi ican di e ences in p e ious ea men ,
including an i-pla ele s and s a ins.
Blood es s on admission, including c ea inine, NT-p o-BNP, hsCRP, glucose and HbA1c, we e
also simila be ween bo h popula ions (Table 24).
Table 24 – Labo a o y esul s on admission acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion
Va iable
To al popula ion
(n=60)
Endo helial dys unc ion (RHI<1.67)
p alue c
No (n=49)
Yes (n=11)
C ea inine (mg/dL) b
0.90 (0.31)
0.90 (0.35)
0.89 (0.16)
0.51
NT-p o-BNP (pg/mL) b
137.5 (255.5)
137.5 (256.3)
191.3 (265.8)
0.99
hsCRP (mg(dL) b
0.44 (0.59)
0.40 (0.58)
0.50 (1.11)
0.46
Glucose (mg/dL) b
133.5 (61.0)
131.0 (60.0)
139.0 (64.0)
0.77
HbA1c (%)b
5.7 (1.1)
5.7 (0.7)
5.7 (1.4)
0.91
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion.
3.1.2. Angiog aphy and angioplas y a iables acco ding o he p esence o
endo helial dys unc ion (RHI<1.67)
The e we e no signi ican di e ences in ischemic (pain- o-balloon) o hospi al- o-balloon imes
be ween pa ien s wi h and wi hou endo helial dys unc ion. Main angiog aphic cha ac e is ics,
including culp i a e y, p esence o mul i essel disease, Syn ax sco e and ini ial TIMI low we e
also simila in bo h g oups (Table 25).
The a ea-a - isk, measu ed bo h by he APPROACH and BARI sco es, was also simila .
Finally, ea men op ions (use o mechanical aspi a ion, s en implan a ion echnique and use
o abciximab) we e simila in pa ien s wi h and wi hou RHI<1.67 (Table 26).

Resul s
118
Table 25 – Ischemic imes and angiog aphic cha ac e is ics acco ding o he p esence o
endo helial dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion
Va iable
To al popula ion
(n=60)
Endo helial dys unc ion (RHI<1.67)
p alue d
No (n=49)
Yes (n=11)
Pain- o-balloon ime (min)c
209 (148)
210 (156)
174 (128)
0.52 x
Doo - o-balloon ime (min) c
78 (45)
76 (49)
80 (59)
0.37 x
Culp i a e y b
Le an e io descending
28 (46.7)
24 (49.0)
4 (36.4)
0.95 e
Le ci cum lex
13 (21.7)
10 (20.4)
3 (27.3)
Righ co ona y a e y
19 (31.7)
15 (30.6)
4 (36.4)
Mul i essel disease b
25 (41.7)
22 (44.9)
3 (27.3)
0.54 e
Syn ax sco e c
15.5 (10.0)
15.5 (11.0)
16.5 (9.0)
0.72 x
A ea a isk sco es a
APPROACH sco e
28.5±6.6
28.1±6.9
30.2±5.5
0.33 x
BARI sco e
27.7±6.3
27.4±6.4
30.6±5.4
0.13 x
Ini ial TIMI low 0-1 b
50 (83.3)
41 (83.7)
9 (81.8)
0.77 e
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; e Ya es co ec ion
Table 26 – Angioplas y ea men op ions acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion
Va iable a
To al popula ion
(n=60)
Endo helial dys unc ion (RHI<1.67)
p alue b
No (n=49)
Yes (n=11)
Mechanical aspi a ion
26 (43.3)
21 (42.9)
5 (45.5)
0.86
Balloon p e-dila a ion
35 (58.3)
29 (59.2)
6 (54.5)
0.96
S en implan a ion
57 (95)
46 (93.9)
11 (100.0)
0.94
Balloon pos -dila a ion
23 (38.3)
20 (40.5)
3 (27.3)
0.62
Abciximab ea men
14 (23.3)
9 (18.4)
5 (45.5)
0.13
a P esen ed as numbe (%); b Chi-Squa e es , wi h Ya es co ec ion
3.1.3. IMR acco ding o he p esence o endo helial dys unc ion (RHI<1.67)
IMR median alues did no di e (and ac ually ended o be lowe ) be ween pa ien s wi h and
wi hou endo helial dys unc ion on he i s EndoPAT e alua ion (Figu e 21, Table 27).
The e was also no di e ence in he p e alence o mic o ascula co ona y damage, whe he
his was de ined as an IMR >24 (median alue) o an IMR >40 ( alue published in he li e a u e
as p ognos ic ma ke in STEMI pa ien s). Finally, co ona y low ese e (CFR) alues we e also
simila in bo h g oups (Table 27)
Resul s
119
Table 27 – In asi e hemodynamic measu emen s acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he i s EndoPAT e alua ion
Va iable a
To al Popula ion
(n=60)
Endo helial Dys unc ion (RHI<1.67)
p alue d
No (n=49)
Yes (n=11)
IMR c
23.9 (32.9)
24.0 (31.2)
16.0 (37.3)
0.17
IMR < 24 (median) b
30 (50)
23 (46.9)
7 (63.6)
0.32
IMR < 40 b
21 (35)
31 (63.9)
8 (72.7)
0.55
Co ona y low ese e c
1.1 (0.8)
1.1 (0.8)
1.2 (2.0)
0.45
Basal SBP a
111.4±28.3
108.7±28.1
122.5±27.6
0.15
Basal DBP a
61.5±13.8
60.3±14.3
66.2±10.3
0.21
Hype aemic SBP a
91.6±22.5
91.0±23.6
94.2±18.2
0.68
Hype aemic DBP a
51.3±13.2
50.1±13.2
56.2±12.3
0.63
Ao ic p essu e a
65.3±15.7
64.1±16.0
69.8±14.2
0.13
Dis al p essu e a
71.8±23.1
69.5±22.8
81.1±22.8
0.29
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion. Chi-Squa e o ca ego ical a iables
Figu e 21 – Boxplo o IMR alues acco ding o he p esence o endo helial dys unc ion
(RHI<1.67) on he i s EndoPAT e alua ion
In summa y, he e we e no signi ican di e ences in IMR alues in pa ien s wi h and wi hou
RHI<1.67 on he i s EndoPAT e alua ion. Wi h he excep ion o ac i e smoking and p e ious
be a-blocke he apy, endo helial dys unc ion also did no ela e o any pa ien baseline
cha ac e is ics, including age, isk ac o s, blood es s on admission, co ona y ana omy o
p ocedu al aspec s o he P-PCI.
Resul s
120
3.2. IMR alues acco ding o RHI e iles on he i s EndoPAT
Acco ding o he de ined p o ocol, RHI was di ided in e iles:
 Te ile 1 (n=20): RHI< 1.92
 Te ile 2 (n=20): RHI 1.92 – 2.30
 Te ile 3 (n=20): RHI> 2.30.
In he ollowing pages, he main pa ien cha ac e is ics acco ding o RHI e iles will be sho ly
desc ibed, ollowed by he IMR analysis in hese g oups.
3.2.1. Main cha ac e is ics o pa ien s acco ding o e iles o RHI
Table 28 summa izes he main cha ac e is ics o pa ien s acco ding o RHI e iles on he i s
EndoPAT e alua ion. The e we e no signi ican di e ences in any o he analysed a iables,
including physical cha ac e is ics, isk ac o s and p e ious pha macological ea men . Blood
es s esul s on admission we e also simila (Table 29).
Table 28 – Main cha ac e is ics o pa ien s acco ding o RHI e iles on he i s EndoPAT
e alua ion
Va iable
To al popula ion
(n=60)
RHI
p
aluec
Te ile 1
(n=20)
Te ile 2
(n=20)
Te ile 3
(n=20)
Physical cha ac e is ics
Age (yea s) a
59.6±12.7
58.9±11.6
58.8±15.1
61.0±11.4
0.83 x
Male gende b
48 (80.0)
16 (80.0)
15 (75.0)
17 (85.0)
0.89 d
BMI a
27.5±4.0
27.6±3.93
28.4±4.02
26.5±3.99
0.33 x
Wais ci cum e ence a
99.2±12.2
100.4±14.1
102.4±13.4
99.2±12.2
0.25 x
Risk ac o s and p e ious co ona y disease b
Hype ension
43 (71.7)
16 (80.0)
13 (65.0)
14 (70.0)
0.56 x
Diabe es
15 (25.0)
6 (30.0)
5 (25.0)
4 (20.0)
0.77 x
Dyslipidaemia
30 (50.0)
9 (45.0)
10 (50.0)
11 (55.0)
0.82 x
Ac i e smoking
26 (43.3)
12 (60.0)
7 (35.0)
7 (35.0)
0.18 x
P e ious angina
9 (15.0)
4 (20.0)
2 (10.0)
3 (15.0)
0.86 d
P e ious
e ascula iza ion
2 (3.3)
1 (5.0)
1 (5.0)
0 (0.0)
0.94 d
P e ious medica ion b
Aspi in
5 (8.3)
2 (10.0)
1 (5.0)
2 (10.0)
0.97 d
ACEi/ARBs
23 (38.3)
9 (45.0)
7 (35.0)
7 (35.0)
0.79 x
Be a-blocke s
4 (6.7)
3 (15.0)
1 (5.0)
0 (0.0)
0.44 d
S a ins
9 (15.0)
4 (20.0)
3 (15.0)
2 (10.0)
0.88 d
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c One-way ANOVA o con inuous a iables, Chi-Squa e
o ca ego ical a iables; d Ya es co ec ion
Resul s
121
Table 29 – Labo a o y esul s on admission acco ding o RHI e iles on he i s EndoPAT
e alua ion
Va iable
To al Popula ion
(n=60)
RHI
p
aluec
Te ile 1
(n=20)
Te ile 2
(n=20)
Te ile 3
(n=20)
C ea inine (mg/dL) b
0.90 (0.31)
0.90 (0.17)
0.90 (0.40)
0.96 (0.36)
0.62
NT-p o-BNP (pg/mL) b
137.5 (255.5)
162.0 (269.0)
113.0 (170.5)
131.5 (298.0)
0.64
hs-CRP (mg(dL) b
0.44 (0.59)
0.64 (0.71)
0.29 (0.35)
0.44 (0.95)
0.10
Glucose (mg/dL) b
133.5 (61.0)
122.0 (54.0)
141.5 (60.0)
131.0 (61.0)
0.63
HbA1c (%)b
5.7 (1.1)
5.5 (0.9)
5.8 (1.9)
5.7 (2.3)
0.44
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c One-way ANOVA o con inuous a iables
wi h a no mal dis ibu ion, K uskal-Wallis es o con inuous a iables wi h a non-no mal dis ibu ion.
3.2.2. Angiog aphy and angioplas y a iables acco ding o RHI e iles
The e we e no signi ican di e ences in pain- o-balloon o hospi al- o-balloon imes in RHI
e iles g oups. Main angiog aphic cha ac e is ics, including culp i a e y, p esence o
mul i essel disease, Syn ax sco e and ini ial TIMI low we e also simila (Table 30).
Table 30 – Ischemic imes and angiog aphic cha ac e is ics acco ding RHI e iles on he i s
EndoPAT e alua ion
Va iable
To al Popula ion
(n=60)
RHI
p
alued
Te ile 1
(n=20)
Te ile 2
(n=20)
Te ile 3
(n=20)
Pain- o-balloon ime (min)c
209 (148)
223 (149)
201 (179)
200 (102)
0.85 x
Doo - o-balloon ime (min)c
78 (45)
82 (45)
67 (55)
76 (43)
0.43 x
Culp i a e y b
Le an e io descending
28 (46.7)
10 (50.0)
8 (40.0)
10 (50.0)
0.99 e
Le ci cum lex
13 (21.7)
4 (20.0)
5 (25.0)
4 (20.0)
Righ co ona y a e y
19 (31.7)
6 (30.0)
7 (35.0)
6 (30.0)
Mul i essel disease b
25 (41.7)
11 (55.0)
8 (40.0)
6 (30.0)
0.28 x
Syn ax sco e c
15.5 (10.0)
16.0 (9.0)
11.8 (12.0)
15.8 (7.0)
0.95 x
A ea a isk sco es
APPROACH sco e a
27.8 (2.0)
27.8 (4.0)
27.8 (4.0)
27.8 (2.0)
0.63 x
BARI sco e a
27.7±6.3
29.3±7.3
28.0±5.7
26.7±6.0
0.46 x
Ini ial TIMI low 0-1 b
50 (83.3)
17 (85.0)
19 (95.0)
14 (70.0)
0.23 e
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d One-way
ANOVA o con inuous a iables wi h a no mal dis ibu ion, K uskal-Wallis es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; e Ya es co ec ion
The a ea-a - isk, measu ed bo h by he APPROACH and BARI sco es, was also simila in he
h ee e iles. Finally, ea men op ions (use o mechanical aspi a ion, s en implan a ion
echnique and use o abciximab) was again, simila (Table 31).
Resul s
128
Table 41 – Ischemic imes and angiog aphic cha ac e is ics acco ding o he p esence o
endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Va iable
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue d
No (n=22)
Yes (n=16)
Pain- o-balloon ime (min)c
209 (173)
209 (186)
211 (167)
0.94
Doo - o-balloon ime (min) c
75 (52)
79 (46)
57 (44)
0.06
Culp i a e y b
Le an e io descending
21 (53.3)
11 (50.0)
10 (62.5)
0.89
Le ci cum lex
7 (18.4)
5 (22.7)
2 (12.5)
Righ co ona y a e y
10 (26.3)
6 (27.3)
4 (25.0)
Mul i essel disease b
19 (50.0)
8 (36.4)
11 (68.8)
0.10
SYNTAX sco e c
17.8±6.2
16.8±6.2
19.0±6.0
0.29
A ea a isk sco es a
APPROACH sco e
27.8 (3.0)
28.1 (5.0)
29.7 (10.0)
0.08
BARI sco e
28.5 (6.0)
26.7 (7.0)
30.2 (10.0)
0.07
Ini ial TIMI low 0-1 b
31 (81.6)
16 (72.7)
15 (93.8)
0.22
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; E Ya es co ec ion
Table 42 – Angioplas y ea men op ions acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Va iable a
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue b
No (n=22)
Yes (n=16)
Mechanical aspi a ion
16 (42.1)
9 (40.9)
7 (43.8)
0.86
Balloon p e-dila a ion
21 (55.3)
13 (59.1)
8 (50.0)
0.58
S en implan a ion
36 (94.7)
20 (90.9)
16 (100.0)
0.61
Balloon pos -dila a ion
24 (63.2)
14 (63.6)
10 (62.5)
0.94
Abciximab ea men
9 (23.7)
4 (18.2)
5 (31.5)
0.58
Mechanical aspi a ion
16 (42.1)
9 (40.9)
7 (43.8)
0.86
a P esen ed as numbe (%); b Chi-Squa e es , wi h Ya es co ec ion
4.1.3. IMR acco ding o he p esence o endo helial dys unc ion (RHI<1.67)
The e was a clea end owa ds highe alues o IMR in pa ien s wi h endo helial dys unc ion
on he second EndoPAT e alua ion: median alues (IQR) 40.5 (54.4) s. 22.0 (26.0) in pa ien s
wi hou endo helial dys unc ion (p=0.09) (Figu e 22, Table 43). The p e alence o
mic o ascula co ona y damage, ei he de ined as an IMR >24 (median alue) o an IMR >40
( alue published in he li e a u e as p ognos ic ma ke in STEMI pa ien s), was almos 2 imes
highe in pa ien s wi h endo helial dys unc ion, al hough di e ences did no each s a is ical
signi icance (Table 43). O he in asi e a iables, including co ona y low ese e (CFR) alues,
we e simila in bo h g oups.

Resul s
129
Table 43 – In asi e hemodynamic measu emen s acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Va iable a
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue d
No (n=22)
Yes (n=16)
IMR c
23.4 (35.2)
22.0 (26.0)
40.5 (54.4)
0.09
IMR < 24 (median) b
18 (47.4)
8 (36.4)
10 (62.5)
0.11
IMR < 40 b
14 (36.8)
6 (27.3)
8 (50.0)
0.15
Co ona y low ese e c
1.00 (0.70)
1.10 (0.60)
1.00 (0.90)
0.92
Basal SBP a
112.0±31.3
113.0±26.3
110.4±38.8
0.81
Basal DBP a
61.3±14.0
59.0±14.0
65.0±13.7
0.22
Hype aemic SBP a
92.8±22.0
96.1±19.3
87.8±25.4
0.28
Hype aemic DBP a
51.7±12.1
52.7±11.1
50.1±13.8
0.56
Ao ic p essu e a
75.7±25.1
74.7±20.3
77.2±31.7
0.72
Dis al p essu e a
64.6±14.9
67.1±14.3
60.9±15.5
0.24
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion. Chi-Squa e o ca ego ical a iables.
Figu e 22 – Boxplo o IMR alues acco ding o he p esence o endo helial dys unc ion
(RHI<1.67) on he second EndoPAT e alua ion
In summa y, he p esence o endo helial dys unc ion (de ined as an RHI<1.67) on he second
EndoPAT was associa ed wi h a end o highe IMR alues measu ed immedia ely a e P-PCI.
These pa ien s also ended o ha e mo e se e e co ona y a e y disease, highe a eas-a - isk and
wo se ini ial TIMI low.
Resul s
130
4.2. IMR alues acco ding o RHI e iles on he second EndoPAT
Acco ding o he de ined p o ocol, RHI in he second endo helial dys unc ion was di ided in
e iles:
 Te ile 1 (n=13): RHI< 1.62
 Te ile 2 (n=13): RHI 1.62 – 1.96
 Te ile 3 (n=12): RHI> 1.96 .
In he ollowing pages, main pa ien cha ac e is ics acco ding o RHI e iles will be sho ly
desc ibed, ollowed by he IMR analysis in hese g oups.
4.2.1. Main cha ac e is ics o pa ien s acco ding o e iles o RHI
Table 44 summa izes he main cha ac e is ics o pa ien s acco ding o RHI e iles on he
second EndoPAT e alua ion. The e was a end owa ds mo e male pa ien s and mo e
p e ious use o ACEi/ARBs o highe e iles o RHI. The e we e no signi ican di e ences in
any o he o he a iables, including physical cha ac e is ics, isk ac o s and o he p e ious
pha macological ea men . Blood es s on admission (Table 45) we e also simila .
Table 44 – Main cha ac e is ics o pa ien s acco ding o RHI e iles on he second EndoPAT
e alua ion
Va iable
To al popula ion
(n=38)
RHI
p
aluec
Te ile 1
(n=13)
Te ile 2
(n=13)
Te ile 3
(n=12)
Physical cha ac e is ics
Age (yea s) a
60.0±13.7
62.8±14.4
54.8±13.6
62.6±12.3
0.25 x
Male gende b
29 (76.3)
8 (61.5)
10 (76.9)
11 (91.7)
0.41 d
BMI a
27.2±4.0
26.3±3.2
28.9±3.9
26.4±4.5
0.17 x
Wais ci cum e ence a
100.0±11.5
96.8±10.6
102.8±12.9
100.0±10.8
0.50 x
Risk Fac o s and p e ious co ona y disease b
Hype ension
26 (68.4)
8 (61.5)
9 (69.2)
9 (75.0)
0.93 d
Diabe es
12 (31.6)
3 (23.1)
7 (53.8)
2 (16.7)
0.24 d
Dyslipidaemia
19 (50.0)
7 (53.8)
5 (38.5)
7 (58.3)
0.58 x
Ac i e smoking
13 (34.2)
3 (23.1)
6 (46.2)
4 (33.3)
0.69 d
P e ious angina
7 (18.4)
1 (7.7)
2 (15.4)
4 (33.0)
0.51 d
P e ious e ascula iza ion
2 (5.3)
1 (7.7)
0 (0.0)
1 (8.3)
0.94 d
P e ious medica ion b
Aspi in
3 (8.1)
1 (7.7)
0 (0.0)
2 (16.7)
0.64 d
ACEi/ARBs
13 (35.1)
2 (15.4)
5 (38.5)
6 (50.0)
0.43 d
Be a-blocke s
1 (2.7)
0 (0.0)
0 (0.0)
1 (8.3)
0.88 d
S a ins
4 (10.8)
1 (7.7)
3 (23.1)
0 (0.0)
0.46 d
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c One-way ANOVA o con inuous a iables, Chi-Squa e
o ca ego ical a iables; d Ya es co ec ion
Resul s
131
Table 45 –Labo a o y esul s on admission acco ding o RHI e iles on he second EndoPAT
e alua ion
Va iable
To al popula ion
(n=38)
RHI
p
aluec
Te ile 1
(n=13)
Te ile 2
(n=13)
Te ile 3
(n=12)
C ea inine (mg/dL) b
0.91±0.28
0.87±0.16
0.95±0.32
0.90±0.34
0.72
NT-p o-BNP (pg/mL) b
158.5 (305)
163.0 (204.0)
299.0 (290.0)
103.0 (434.8)
0.94
hs-CRP (mg(dL) b
0.57 (0.71)
0.60 (0.99)
0.95 (0.72)
0.29 (0.14)
0.12
Glucose (mg/dL) b
136.0 (63.0)
136.0 (108.5)
169.0 (132.5)
122.0 (43.8)
0.29
HbA1c (%)b
6.6 (1.3)
5.8 (0.9)
6.3 (4.3)
5.7 (0.6)
0.37
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c One-way ANOVA o con inuous a iables
wi h a no mal dis ibu ion, K uskal-Wallis es o con inuous a iables wi h a non-no mal dis ibu ion.
4.2.2. Angiog aphy and angioplas y a iables acco ding o RHI e iles
The e we e no signi ican di e ences in pain- o-balloon o hospi al- o-balloon imes in RHI
e iles g oups. The e was a clea end owa ds mo e complex co ona y disease in lowe
e iles o RHI: mul i essel disease was p esen in 75.0% o pa ien s in he lowe e ile, as
compa ed o 30.8% in pa ien s in he uppe e ile. Syn ax sco e also ended o be highe in
lowe e iles o RHI (Table 46).
Table 46 – Ischemic imes and angiog aphic cha ac e is ics acco ding RHI e iles on he
second EndoPAT e alua ion
Va iable
To al popula ion
(n=38)
RHI
p
alued
Te ile 1
(n=13)
Te ile 2
(n=13)
Te ile 3
(n=12)
Pain- o-balloon ime (min)c
209 (173)
257 (173)
235 (185)
247 (155)
0.69
Doo - o-balloon ime (min)c
75 (52)
55 (44)
63 (51)
82 (45)
0.52
Culp i a e y b
Le an e io descending
21 (55.5)
9 (69.2)
8 (61.5)
4 (33.3)
0.61 e
Le ci cum lex
7 (18.4)
1 (7.7)
3 (23.1)
3 (25.0)
Righ co ona y
10 (26.3)
3 (23.1)
2 (15.4)
5 (41.7)
Mul i essel disease b
19 (50.0)
9 (75.0)
6 (46.2)
4 (30.8)
0.08
Syn ax sco e c
17.8±6.1
20.4±5.7
17.0±6.0
15.8±6.4
0.15
A ea a isk sco es
APPROACH sco e c
27.8 (3.0)
29.7 (10.0)
29.7 (10.0)
27.7 (8.0)
0.07
BARI sco e a
29.1±6.7
31.1±7.4
31.4±5.3
24.5±5.1
0.011
Ini ial TIMI low 0-1 b
31 (81.6)
12 (92.3)
10 (76.9)
9 (75.0)
0.79 e
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d One-way
ANOVA o con inuous a iables wi h a no mal dis ibu ion, K uskal-Wallis es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; e Ya es co ec ion
Resul s
132
The a ea-a -a isk e alua ed by he BARI sco e was signi ican ly lowe in pa ien s in he hi d
e ile (highe alues) o RHI and a simila end was ound when he APPROACH sco e was
used (p=0.07). Ini ial un a ou able TIMI low (0-1) was also mo e p e alen in he lowes RHI
e ile, al hough he di e ence was no s a is ically signi ican (Table 46). Finally, ea men
op ions (use o mechanical aspi a ion, s en implan a ion echnique o use o abciximab) was
simila be ween he 3 g oups (Table 47).
Table 47 – Angioplas y ea men op ions acco ding o RHI e iles on he second EndoPAT
e alua ion
Va iable a
To al popula ion
(n=38)
RHI
p alue b
Te ile 1
(n=13)
Te ile 2
(n=13)
Te ile 3
(n=12)
Mechanical aspi a ion
16 (42.1)
5 (38.5)
5 (38.5)
6 (50.0)
0.80 x
Balloon p e-dila a ion
21 (55.3)
7 (53.8)
6 (46.2)
8 (66.7)
0.58 x
S en implan a ion
36 (94.7)
13 (100.0)
12 (92.3)
11 (91.7)
0.94 c
Balloon pos -dila a ion
14 (36.8)
4 (30.8)
7 (53.8)
3 (25.0)
0.52 c
Abciximab
9 (23.7)
5 (38.5)
2 (15.4)
2 (16.7)
0.59 c
a P esen ed as numbe (%); b Chi-Squa e es ; c Ya es co ec ion
4.2.3. IMR acco ding o RHI e iles
IMR median alues we e lowe in he hi d e ile o RHI, al hough his di e ence was no
s a is ically signi ican . The numbe o pa ien s wi h co ona y mic o ascula dys unc ion
(IMR>24 o IMR>40) also dec eased om he i s o he hi d e ile o RHI. CRF we e simila
be ween g oups (Table 48).
Table 48 – In asi e hemodynamic measu emen s acco ding o RHI e iles on he second
EndoPAT e alua ion
Va iable
To al popula ion
(n=38)
RHI
p alue c
Te ile 1
(n=13)
Te ile 2
(n=13)
Te ile 3
(n=12)
IMR a
23.4 (35.2)
39.0 (43.4)
23.8 (42.5)
19.5 (30.6)
0.64 x
IMR < 24 (median) b
18 (47.4)
8 (61.5)
6 (46.2)
4 (33.3)
0.37 x
IMR < 40 b
14 (36.8)
6 (46.2)
5 (38.5)
3 (25.0)
0.78 c
Co ona y low ese e a
1.1 (0.8)
1.3 (0.84)
1.0 (0.50)
1.1 (0.9)
0.36 x
a P esen ed as median (in e qua ile ange); b P esen ed as numbe (%); c Mann-Whi ney es o con inuous a iables wi h a non-
no mal dis ibu ion. Chi-Squa e o ca ego ical a iables
In summa y, he e was a end o lowe IMR alues in hi d e ile o RHI measu ed on he
second EndoPAT. These pa ien s also had lowe a eas-a - isk and a end o less complex
co ona y a e y disease (lowe Syn ax and lowe p e alence o mul i essel disease)
Resul s
133
4.3. Rela ion be ween RHI as a con inuous a iable on he second EndoPAT and
IMR alues
4.3.1. RHI as a con inuous a iable and main baseline pa ien cha ac e is ics
Male pa ien s had signi ican ly highe RHI alues on he second EndoPAT e alua ion (Table 49).
Table 49 – Co ela ions be ween RHI on he second EndoPAT and baseline con inuous
a iables
Va iable
Co ela ion (R)
p alue a
Physical cha ac e is ics
Age
-0.006
0.970
BMI
0.033
0.970
Wais ci cum e ence
0.132
0.470
Admission labo a o y pa ame e s
C ea inine (mg/dl)
0.030
0.258
NT-p o-BNP (pg/mL)
-0.193
0.259
hs-CRP (mg/dL)
0.249
0.131
Glucose (mg/dL)
-0.107
0.528
HbA1c (%)
0.008
0.965
a Spea mans’s ho
Table 50 – RHI alues on he second EndoPAT acco ding o baseline ca ego ical a iables
Va iable
Va iable p esen ? a
p alue b
No
Yes
Physical cha ac e is ics
Male gende (29/38)
1.43±0.53
2.00±0.56
0.024
Risk ac o s and p e ious co ona y disease
Hype ension (26/38)
1.84±0.46
1.88±0.67
0.87
Diabe es (12/38)
1.92±0.68
1.76±0.38
0.46
Dyslipidaemia (19/38)
1.84±0.65
1.89±0.56
0.78
Ac i e smoking (13/38)
1.86±0.70
1.87±0.37
0.99
P e ious angina (7/38)
1.84±0.64
1.98±0.41
0.58
P e ious e ascula iza ion (2/38)
1.89±0.59
1.50±0.99
0.38
P e ious medica ion
Aspi in (3/38)
1.85±0.53
2.16±1.35
0.40
ACEi/ARBs (13/38)
1.72±0.49
2.16±0.71
0.042
S a ins (9/38)
1.71±0.10
1.89±0.64
0.57
a RHI p esen ed as mean±s anda d de ia ion; b Independen - es o con inuous a iables wi h a no mal dis ibu ion. Mann-
Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion

Resul s
134
No signi ican associa ions we e ound be ween RHI and any o he baseline pa ien
cha ac e is ics, including age, physical cha ac e is ics, isk ac o s and blood es s on admission
(Table 49, Table 50). Howe e , diabe ic pa ien s and pa ien s wi h p e ious co ona y
e ascula iza ion ended o ha e lowe RHI alues.
Pa ien s ea ed p e iously wi h ACEi/ARBs had signi ican ly highe RHI alues, and hose
ea ed p e iously wi h s a ins and aspi in also showed a end o highe RHI alues (Table 50).
4.3.2. RHI as a con inuous a iable and angiog aphy/angioplas y a iables
The e we e no signi ican associa ions be ween RHI measu ed on he second EndoPAT and
ischemic imes. RHI ended o be lowe in pa ien s wi h mul i essel disease, lowe ini ial TIMI
low and LAD as he culp i a e y (Table 51, Table 52).
Table 51 – Co ela ions be ween RHI on he second EndoPAT and angiog aphy and P-PCI
ela ed con inuous a iables
Va iable
Co ela ion (R)
p alue a
Pain- o-balloon ime (min)
-0.107
0.523
Doo - o-balloon ime (min)
0.263
0.111
Syn ax sco e
-0.241
0.144
A ea a isk sco es
APPROACH sco e
-0.426
0.008
BARI sco e
-0.361
0.026
a Pea son’s Co ela ion o con inuous a iables wi h a no mal dis ibu ion; Spea mans’s
ho o con inuous a iables wi hou a no mal dis ibu ion
Table 52 – RHI alues on he second EndoPAT acco ding o angiog aphy and P-PCI
ca ego ical a iables
Va iable
Va iable p esen ? a
p alue b
No
Yes
Angiog aphy
Culp i a e y = LAD (21/38)
2.02±0.51
1.74±0.65
0.15
Mul i essel disease (20/38)
2.00±0.61
1.71±0.58
0.13
Ini ial TIMI low 0-1 (29/38)
2.05±0.43
1.81±0.64
0.30
P ima y PCI
Mechanical aspi a ion (16/38)
1.79±0.61
1.96±0.60
0.40
Balloon p e-dila a ion (21/38)
1.84±0.52
1.89±0.68
0.79
S en implan a ion (36/38)
2.71±1.24
1.82±0.54
0.21
Balloon pos -dila a ion (14/38)
1.80±0.58
1.98±0.65
0.39
Abciximab use (9/38)
1.90±0.68
1.76±0.25
0.57
a RHI p esen ed as mean±s anda d de ia ion; b Independen - es o con inuous a iables wi h a no mal dis ibu ion. Mann-
Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion
Resul s
135
The e was a signi ican nega i e co ela ion be ween bo h a ea-a - isk-sco es and RHI,
sugges ing ha pa ien s wi h highe a eas a isk had lowe RHI alues on he second EndoPAT
e alua ion (Table 51).
4.3.3. RHI as a con inuous a iable and IMR
The e was no ela ion be ween RHI measu ed on he second EndoPAT and IMR o any o he
in asi e measu emen s pe o med (Table 53). Howe e , he e was a end o lowe RHI alues
in pa ien s wi h co ona y mic o ascula dys unc ion, acco ding o he IMR cu -o s o 24 and
40 (Table 54).
Table 53 – RHI on he second EndoPAT and in asi e hemodynamic con inuous a iables
Va iable
Co ela ion (R)
p alue a
IMR
-0.090
0.593
Co ona y low ese e
0.018
0.917
Basal SBP
0.016
0.925
Basal DBP
-0.227
0.184
Hype aemic SBP
0.200
0.250
Hype aemic DBP
0.037
0.833
Ao ic p essu e
0.181
0.298
Dis al p essu e
-0.030
0.862
a Pea son’s Co ela ion o con inuous a iables wi h a no mal dis ibu ion; Spea mans’s
ho o con inuous a iables wi hou a no mal dis ibu ion
Table 54 – RHI alues on he second EndoPAT acco ding o IMR h esholds
Va iable
Va iable p esen ?
p alue b
No
Yes
IMR < 24 (median) (18/38)
1.92±0.59
1.81±0.62
0.56
IMR < 40 (14/38)
1.92±0.68
1.77±0.45
0.48
a P esen ed as mean±s anda d de ia ion; b Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion
In summa y, he e was a end o lowe RHI alues in pa ien s wi h co ona y mic o ascula
dys unc ion (inc eased IMR). RHI alues co ela ed wi h male gende and p e ious ea men wi h
ACEi/ARBs and ended o be lowe in diabe ic and p e iously e ascula ized pa ien s. Addi ionally,
RHI alues on he second EndoPAT co ela ed wi h he a ea-a - isk and ended o be lowe in
pa ien s wi h mo e complex co ona y a e y disease)
Resul s
136
5. Seconda y ou come – Ex en o myoca dial in a c ion and
mic o ascula epe usion acco ding o RHI on he i s EndoPAT
5.1. Impac o he p esence o endo helial dys unc ion (RHI<1.67) on he i s
EndoPAT on he ex en o myoca dial in a c ion
The ex en o in a c ion was e alua ed by:
 The a ea unde he cu e and he peak alues o 7 e alua ions o oponin I in he i s 48
hou s a e he P-PCI,
 The a ea o in a c ion in he con as enhanced ca diac magne ic esonance,
 And, indi ec ly, by echoca diog aphy pa ame e s, including le en icula olumes and
ejec ion ac ion, wall mo ion sco e index and global longi udinal s ain, bo h on he ini ial
and ollow-up (3 mon h) echoca diog ams.
5.1.1. Endo helial dys unc ion and oponin elease
The peak alues and he a ea unde he cu e o he 7 alues o oponin I in he i s 48 hou s,
a e p esen ed in Table 55. Bo h o al alues and alues indexed o he a ea-a - isk sco es
(APPROACH and BARI) a e shown, in pa ien s wi h and wi hou endo helial dys unc ion
(RHI<1.67) on he i s EndoPAT e alua ion. The e we e no signi ican di e ences in hese
popula ions.
Table 55 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on i s EndoPAT) on
T oponin I elease
Va iable a, b
To al Popula ion
(n=60)
Endo helial Dys unc ion (RHI<1.67)
p alue c
No (n=49)
Yes (n=11)
TnIpeak
117±82
117±87
115±55
0.96
TnIpeak (APPROACH)
34±27
33±29
35±19
0.82
TnIpeak (BARI)
33±25
32±26
36±20
0.62
TnIpeak (2 sco es)
33±26
33±27
36±19
0.72
TnIAUC
1938±1283
1951±1376
1883±787
0.88
TnIAUC (APPROACH)
565±441
564±472
574±275
0.94
TnIAUC (BARI)
548±405
541±43
584±282
0.75
TnIAUC (2 sco es)
557±421
552±449
579±278
0.85
a P esen ed as mean±s anda d de ia ion; b Peak alue and a ea unde he cu e (AUC) o 7 oponin I (TnI, in mg/dL)
measu emen s pe o med in he i s 48 hou s a e he p ima y angioplas y; o al alues and alues indexed o he
APPROACH, BARI o bo h a e p esen ed; c Independen - es .
Resul s
137
5.1.2. Endo helial dys unc ion and echoca diog aphy pa ame e s
The e we e no signi ican di e ences in 2D, Dopple o 2D speckle acking imaging
measu emen s in he i s echoca diog am be ween pa ien s wi h and wi hou endo helial
dys unc ion on he i s EndoPAT (Table 56). Likewise, all measu emen s we e simila in he
second echoca diog am in pa ien s wi h and wi hou RHI<1.67 (Table 57).
Table 56 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on i s EndoPAT) on he
i s echoca diog am pa ame e s
Va iable a, b
To al popula ion
Endo helial dys unc ion (RHI<1.67)
p alue c
No
Yes
2D measu emen s
(n=60)
(n=49)
(n=11)
LVEdV (ml) a
105.8±24.2
107.5±24.0
95.7±24.4
0.27
LVEsV (ml) a
54.7±12.7
55.6±12.9
49.5±11.1
0.28
LVEF (%)a
47.9±6.7
47.9±6.8
47.8±5.9
0.96
Wall mo ion sco e index b
1.41 (0.35)
1.41 (0.35)
1.53 (0.18)
0.78
Le a ia olume (ml/m2) a
34.8±12.2
35.7±12.9
30.6±7.2
0.32
Dopple measu emen s
(n=40)
(n=34)
(n=7)
E/A a io a
1.00±0.34
0.99±0.34
1.06±0.36
0.68
E/e’ a io a
9.00±2.71
8.91±2.85
9.58±1.55
0.61
2D speckle acking imaging
(n=40)
(n=34)
(n=7)
Global longi udinal s ain a
-13.54±2.28
-13.38±2.30
-14.7±1.96
0.23
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion. LVEdV – le en icula
end dias olic olume; LVEsV – le en icula end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion
sco e index.
Table 57 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on i s EndoPAT) on he 3
mon h echoca diog am pa ame e s
Va iable a, b
To al popula ion
Endo helial dys unc ion (RHI<1.67)
p alue c
No
Yes
2D measu emen s
(n=54)
(n=43)
(n=11)
LVEdV (ml) a
109.7±26.4
111.1±28.5
103.8±13.9
0.44
LVEsV (ml) a
52.9±18.8
54.2±20.4
47.6±8.8
0.32
LVEF (%)a
52.6±7.1
52.2±7.4
54.2±5.2
0.43
Wall mo ion sco e index b
1.24 (0.35)
1.24 (0.35)
1.29 (0.24)
0.93
Le a ia olume (ml/m2) a
39.1±15.4
40.4±16.7
34.3±7.2
0.25
Dopple measu emen s
(n=51)
(n=40)
(n=11)
E/A a io a
1.20±0.56
1.21±0.54
1.15±0.66
0.75
E/e’ a io a
8.92±3.29
8.83±3.51
9.29±2.30
0.69
2D speckle acking imaging
(n=40)
(n=40)
(n=11)
Global longi udinal s ain a
-15.77±3.11
-15.80±3.36
-15.68±2.11
0.91
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion. LVEdV – le en icula
end dias olic olume; LVEsV – le en icula end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion
sco e index.
Resul s
144
6. Seconda y ou come – Ex en o myoca dial in a c ion and
mic o ascula epe usion acco ding o RHI on he second
EndoPAT
6.1. Impac o he p esence o endo helial dys unc ion (RHI<1.67) on he second
EndoPAT on he ex en o myoca dial in a c ion
6.1.1. Endo helial dys unc ion and T oponin elease
The peak alues and he a ea unde he cu e o oponin I, acco ding o he p esence o
endo helial dys unc ion on he second EndoPAT e alua ion a e p esen ed in Table 63. Bo h
o al alues and alues indexed o he a ea-a - isk sco es (APPROACH and BARI) a e p esen ed,
in pa ien s wi h and wi hou endo helial dys unc ion (RHI<1.67) on he second EndoPAT
e alua ion. Pa ien s wi h endo helial dys unc ion had signi ican ly highe alues o bo h peak
TnI and AUC o TnI, bo h o al and indexed o he a ea-a - isk sco es.
Table 63 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on second EndoPAT) on
T oponin I elease
Va iable a, b
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue c
No (n=22)
Yes (n=16)
TnIpeak
95 (96)
67 (81)
118 (186)
0.024
TnIpeak (APPROACH)
25 (32)
17 (20)
34 (56)
0.009
TnIpeak (BARI)
24 (31)
17 (22)
33 (47)
0.008
TnIpeak (2 sco es)
24 (31)
17 (21)
33 (55)
0.009
TnIAUC
1293 (1580)
1076 (1042)
2305 (2486)
0.012
TnIAUC (APPROACH)
403 (522)
315 (303)
664 (1080)
0.008
TnIAUC (BARI)
383 (448)
314 (326)
618 (799)
0.007
TnIAUC (2 sco es)
393 (482)
314 (300)
641 (984)
0.007
a P esen ed as median (IQR); b Peak alue and a ea unde he cu e (AUC) o 7 oponin I (TnI, in mg/dL)
measu emen s pe o med in he i s 48 hou s a e he p ima y angioplas y; o al alues and alues indexed o he
APPROACH, BARI o bo h a e p esen ed; c Mann-Whi ney Tes .
6.1.2. Endo helial dys unc ion and echoca diog aphy pa ame e s
Pa ien s wi h endo helial dys unc ion had signi ican ly highe end-sys olic olumes, lowe LVEF
and wo se wall mo ion sco e index in he i s echoca diog am. Acco dingly wi h he di e ence

Resul s
145
in WSMI, hey also had highe alues o global longi udinal s ain (Table 64). These di e ences
we e no longe isible in he echoca diog am pe o med a 3 mon h (Table 65).
Table 64 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on second EndoPAT) on
he i s echoca diog am pa ame e s
Va iable
To al popula ion
Endo helial dys unc ion (RHI<1.67)
p alue c
No
Yes
2D measu emen s
(n=26)
(n=15)
(n=11)
LVEdV (ml) a
109.8±23.4
106.5±30.2
113.8±11.4
0.48
LVEsV (ml) a
55.9±12.6
51.1±12.3
61.7±10.9
0.047
LVEF (%)a
48.6±7.1
51.4±4.7
45.3±8.3
0.045
Wall mo ion sco e index b
1.44 (0.41)
1.35 (0.47)
1.77 (0.47)
0.006
Le a ia olume (ml/m2) a
36.1±11.0
36.7±12.1
35.3±10.0
0.78
Dopple measu emen s
(n=21)
(n=11)
(n=10)
E/A a io a
1.10±0.40
1.17±0.40
0.97±0.0.39
0.30
E/e’ a io a
8.91±3.30
8.83±3.91
9.05±2.18
0.89
2D speckle acking imaging
(n=21)
(n=11)
(n=10)
Global longi udinal s ain a
-13.16±2.35
-14.32±1.72
-11.89±2.35
0.014
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion. LVEdV – le en icula
end dias olic olume; LVEsV – le en icula end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion
sco e index.
Table 65 – Impac o endo helial dys unc ion (RHI<1.67, measu ed on second EndoPAT) on
he 3 mon h Echoca diog am pa ame e s
Va iable
To al Popula ion
Endo helial Dys unc ion (RHI<1.67)
p alue c
No
Yes
2D measu emen s
(n=30)
(n=19)
(n=11)
LVEdV (ml) a
109.7±28.1
103.9±29.8
119.7±22.4
0.14
LVEsV (ml) a
53.8±21.4
49.8±21.0
60.7±21.2
0.18
LVEF (%)a
52.2±7.9
53.2±7.6
50.5±8.3
0.37
Wall mo ion sco e index b
1.24 (0.40)
1.21 (0.35)
1.29 (0.66)
0.33
Le a ia olume (ml/m2) a
40.6±15.4
42.2±16.9
38.0±12.7
0.46
Dopple measu emen s
(n=29)
(n=19)
(n=10)
E/A a io a
1.31±0.68
1.30±0.62
1.34±0.82
0.87
E/e’ a io a
8.96±3.93
9.13±4.19
8.59±3.51
0.74
2D speckle acking imaging
(n=29)
(n=19)
(n=10)
Global longi udinal s ain a
-15.43±3.55
-15.95±3.01
-14.4±4.39
0.28
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion. LVEdV – le en icula
end dias olic olume; LVEsV – le en icula end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion
sco e index.
When he 2 echoca diog ams we e compa ed, signi ican imp o emen s in he wall mo ion
sco e index we e ound in bo h pa ien s wi h and wi hou endo helial dys unc ion. The e was
also a end o an imp o emen in he global longi udinal s ain in he g oup wi hou
Resul s
146
endo helial dys unc ion. The e we e no o he signi ican di e ences, independen ly o he
p esence o endo helial dys unc ion.
Table 66 – Baseline and 3 mon hs echoca diog aphic pa ame e s acco ding o he p esence o
endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
RHI > 1.67
RHI < 1.67
Echo pa ame e s
Echo1
Echo2
P aluec
Echo1
Echo2
P aluec
2D measu emen s
n=15
n=11
LVEdV (ml) a
106.5±3..2
101.0±33.0
0.33
113.8±11.8
119.7±22.4
0.61
LVEsV (ml) a
51.1±12.3
48.3±22.3
0.24
61.7±10.9
60.7±21.1
1.00
LVEF (%)a
51.4±4.8
53.2±5.1
0.24
45.3±8.3
50.5±8.3
0.24
WMSI b
1.35 (0.47)
1.18 (0.35)
0.012
1.65 (0.47)
1.24 (0.74)
0.049
Le a ia (ml/m2) a
36.7±12.1
43.8±18.8
0.16
35.3±10.0
38.0±12.7
0.16
Dopple measu emen s
n=12
n=11
E/A' a io a
1.14±0.40
1.24±0.43
0.61
0.97±0.39
1.34±0.82
0.08
E/e’ a io a
9.0±4.1
8.2±4.7
0.37
9.1±2.2
8.6±3.5
0.72
2D speckle acking imaging
n=10
n=10
Global longi udinal s ain a
-14.3±1.8
-16.1±2.6
0.07
-11.9±2.3
-14.4±4.4
0.53
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); C p- alue o he compa ison be ween he
i s and he second Echo only in pa ien s wi h 2 e alua ions; pai ed samples T-Tes o a iables wi h no mal dis ibu ion and
Wilcoxon es o a iables wi h non-no mal dis ibu ion. LVEdV – le en icula end dias olic olume; LVEsV – le en icula
end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion sco e index.
6.1.3. Endo helial dys unc ion and con as enhanced ca diac magne ic esonance
Con as enhanced CMR was pe o med in 29 o he 38 pa ien s wi h a second EndoPAT
e alua ion. O hese, 11 (37.9%) had endo helial dys unc ion (RHI<1.67) (Table 67).
Pa ien s wi h endo helial dys unc ion (RHI<1.67) had signi ican ly lowe le en icula
ejec ion ac ion and highe wall mo ion sco e index, as compa ed o pa ien s wi h RHI>1.67.
The e was a end o mo e ansmu al nec osis (22.2% s. 63.6%, p=0.06) and highe in a c
mass (median alue 10.1 s. 17.5, p=0.08) in pa ien s wi h RHI<1.67. The pe cen mass o
in a c indexed o a ea-a - isk sco es (APPROACH and BARI) also ended o be highe in pa ien s
wi h endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion.
Resul s
147
Table 67 – Impac o endo helial dys unc ion (RHI<1.67) measu ed on second EndoPAT on he
con as enhanced ca diac magne ic esonance pa ame e s
To al popula ion
(n=29)
Endo helial dys unc ion (RHI<1.67)
p alue d
No (n=18)
Yes (n=11)
LVEdV (ml) a
138.6±26.9
139.2±26.5
137.5±28.9
0.87
LVEsV (ml) a
63.5±21.0
59.3±19.4
70.4±22.6
0.17
LVEF (%)a
53.9±8.4
56.6±8.1
49.5±7.2
0.025
Wall mo ion sco e index a
1.37±0.33
1.28±0.31
1.53±0.32
0.05
Oedema mass b
19.1 (19.0)
17.2 (14.1)
21.2 (28.6)
0.28
T ansmu al nec osis c
12 (38.7)
4 (22.2)
7 (63.6)
0.06 e
In a c mass
To al b
11.6 (9.3)
10.1 (10.3)
17.5 (15.4)
0.08
Pe cen b
11.5 (13.7)
10.2 (7.6)
17.5 (21.8)
0.10
Indexed o APPROACH
3.2 (7.0)
2.7 (2.6)
4.9 (11.5)
0.10
Indexed o BARI
3.4 (5.8)
2.3 (2.7)
5.1 (11.5)
0.09
Sal age mass b
5.0 (14.0)
5.0 (8.8)
4.7 (27.6)
0.87
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c P esen ed as numbe (%); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; e Ya es co ec ion
In summa y, he p esence o endo helial dys unc ion (RHI<1.67) on he second EndoPAT was
ela ed wi h la ge in a c s, as assessed by oponin I elease and ceCMR. These pa ien s also had
lowe LVEF and wo se wall mo ion sco e index and GLS in he acu e echoca diog am and in he
ceCMR, al hough hese di e ences we e no p esen in he ollow-up exam echo.
Resul s
148
6.2. Impac o he p esence o endo helial dys unc ion (RHI<1.67) on he second
EndoPAT on mic o ascula epe usion
6.2.1. Endo helial dys unc ion and ST esolu ion on he ECG
The esidual o al ST ele a ion and de ia ion and he pe cen age o esolu ion o hese ST
changes a e p esen ed in Table 68 , in Figu e 25 and in Figu e 26, acco ding o he p esence o
endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion.
Figu e 25 – ST ele a ion and de ia ion esolu ion (median alues) acco ding o he p esence
o endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Al hough he e was a endency o highe esolu ion o ST ele a ion and de ia ion (pa icula ly
in pos -PCI and 90 minu es ECGs) in pa ien s wi hou endo helial dys unc ion, his di e ence
was no s a is ically signi ican .
Residual o al ST ele a ion immedia ely a e PCI and a 90 minu es was highe in pa ien s wi h
endo helial dys unc ion and he e was a end o simila ly wo se esul s in esidual ST
de ia ion and esidual ST ele a ion in hese pa ien s.
The p esence o Q wa es was simila in bo h g oups.
0
10
20
30
40
50
60
70
80
90
Pos PCI 90 min 180 min Pos PCI 90 min 180 min Pos PCI 90 min 180 min
Resolu ion o To al ST Ele a ion Resolu ion o To al ST De ia ion Resolu ion o ST de i a ion wi h
max ele a ion
RHI > 1.67 RHI < 1.67
Resul s
149
Figu e 26 – ST esidual changes (median alues) acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Table 68 – ECG ST esolu ion and esidual changes acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Va iable
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue d
No (n=49)
Yes (n=11)
Immedia ely pos -Angioplas y ECG a
To al ST ele a ion b
3.0 (6.0)
2.5 (5.0)
5.0 (12.0)
0.048
% Resolu ion
74.5 (39.0)
76.5 (41.0)
60.5 (72.0)
0.23
To al ST de ia ion b
4.8 (6.0)
4.5 (5.0)
5.8 (14.0)
0.22
% Resolu ion
67.8 (39.0)
70.5 (39.0)
59.0 (78.0)
0.39
ST a de i a ion wi h max ele a ion) b
1.0 (2.0)
0.8 (2.0)
1.3 (3.0)
0.06
% Resolu ion
67.0 (33.0)
70.0 (40.0)
67.0 (52.0)
0.15
90 minu es pos -Angioplas y ECG a
To al ST ele a ion b
1.8 (4.0)
1.3 (4.0)
3.0 (7.0)
0.036
% Resolu ion
77.0 (29.0)
78.5 (28.0)
69.0 (53.0)
0.07
To al ST de ia ion b
2.0 (5.0)
1.8 (5.0)
3.0 (7.0)
0.191
% Resolu ion
78.0 (30.0)
81.0 (31.0)
71.0 (59.0)
0.181
ST a de i a ion wi h max ele a ion b
1.0 (2.0)
0.5 (1.0)
1.3 (2.0)
0.07
% Resolu ion
69.0 (31.0)
73.0 (37.0)
67.0 (44.0)
0.19
180 minu es pos -Angioplas y ECG a
To al ST ele a ion b
1.3 (4.0)
1.0 (3.0)
2.8 (5.0)
0.30
% Resolu ion
85.5 (26.0)
81.5 (22.0)
83.5 (52.0)
0.67
To al ST de ia ion b
1.5 (5.0)
1.3 (4.0)
2.8 (5.0)
0.74
% Resolu ion
84.5 (32.0)
83.0 (32.0)
85.5 (54.0)
0.80
ST a de i a ion wi h max ele a ion b
0.5 (1.0)
0.5 (1.0)
1.3 (2.0)
0.20
% Resolu ion
81.0 (30.0)
80.5 (29.0)
81.0 (40.0)
0.65
QS wa es p esen
24 (63.2)
13 (59.1)
11 (68.8)
0.54
a Values exp essed as median (in e qua ile ange); b Values exp essed in mV; c alues exp essed as n(%); d Mann-Whi ney es o
con inuous a iables wi h a non-no mal dis ibu ion; e Chi-Squa e es
0
1
2
3
4
5
6
7
Pos PCI 90 min 180 min Pos PCI 90 min 180 min Pos PCI 90 min 180 min
Residual o al ST ele a ion Residual o al ST de ia ion Residual ST ele a ion max ST
de i a ion
RHI > 1.67 RHI < 1.67
p=0.048
p=0.036

Resul s
150
6.2.2. Endo helial dys unc ion and angiog aphic indica o s o mic o ascula
epe usion
Co ec ed TIMI ame coun and TIMI myoca dial pe usion g ade esul s acco ding o he
p esence o endo helial dys unc ion on he second EndoPAT e alua ion a e p esen ed in Table
69. The e was a end owa d highe alues o cTFC and wo se TMPG in pa ien s wi h
endo helial dys unc ion, al hough i did no each s a is ical signi icance.
Table 69 – Angiog aphic indica o s o mic o ascula epe usion acco ding o he p esence o
endo helial dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
Va iable
To al popula ion
(n=38)
Endo helial dys unc ion (RHI<1.67)
p alue c
No (n=22)
Yes (n=16)
Co ec ed TIMI ame coun a
17.0 (7.0)
16.4 (7.0)
19.5 (12.0)
0.07 x
TMPG 2-3 b
28 (73.7)
19 (86.4)
9 (56.3)
0.09 d
a da a p esen ed as median (in e qua ile ange); b da a p esen ed as n(%); c Mann-Whi ney es ; d Chi-Squa e es , wi h
Ya es co ec ion.
6.2.3. Endo helial dys unc ion and mic o ascula obs uc ion on he ceCMR
Only 8 pa ien s wi h he second EndoPAT e alua ion had mic o ascula obs uc ion on he
ceCMR: 2 (11.1%) in he g oup wi h RHI<1.67 and 6 (54.5%) in he g oup wi h RHI>1.67
(p=0.03). Likewise, he mic o ascula obs uc ion mass was highe in he g oup wi h RHI<1.67
(median alue 5.3 s. 6.8), al hough he di e ence was no signi ican (Table 70).
Table 70 - Mic o ascula obs uc ion on he ceCMR acco ding o he p esence o endo helial
dys unc ion (RHI<1.67) on he second EndoPAT e alua ion
To al Popula ion
(n=29)
Endo helial Dys unc ion (RHI<1.67)
p alue c
No (n=18)
Yes (n=11)
Mic o ascula obs uc ion
MVO p esen a
8 (27.6)
2 (11.1)
6 (54.5)
0.03 d
MVO mass b
6.1 (15.5)
5.3 (-)
6.8 (20.8)
0.29
a P esen ed as numbe (%); b P esen ed as median (in e qua ile ange); c Mann-Whi ney es o con inuous a iables wi h a non-
no mal dis ibu ion, Chi-Squa e o ca ego ical a iables; d Ya es co ec ion
In summa y, he e was a clea end o wo se angiog aphic and elec oca diog aphic indic o s
o mic o ascula epe usion in pa ien s wi h endo helial dys unc ion on he second EndoPAT.
The p opo ion o pa ien s wi h MVO on he ceCMR was highe in pa ien s wi h RHI<1.67 and
he e was a end o highe MVO mass in hese pa ien s.
Resul s
151
7. Seconda y ou come – Ex en o myoca dial in a c ion and
mic o ascula epe usion acco ding o IMR alues
In o de o e alua e he impac o IMR on he ex en o myoca dial nec osis and i s ela ion o
in asi e and non-in asi e indica o s o co ona y mic o ascula epe usion, pa ien s we e di ided
in o wo g oups, acco ding o he median alue o IMR measu ed (24). To simpli y he p esen a ion
o esul s and i s discussion, pa ien s wi h an IMR abo e he median 24 alue will be classi ied as
ha ing co ona y mic o ascula damage, as opposed o hose wi h IMR alues below 24. Whe e
indica ed, IMR as a con inuous a iable was also e alua ed. In he ollowing pages, he main
pa ien cha ac e is ics acco ding o IMR alues will be sho ly desc ibed, ollowed by he analysis
o he impac o co ona y mic o ascula damage.
7.1. IMR and baseline cha ac e is ics
7.1.1. IMR and pa ien ’s main cha ac e is ics
Pa ien s wi h co ona y mic o ascula dys unc ion (IMR>24) we e olde (Table 71). In ac , he e
was a weak, bu signi ican co ela ion be ween IMR and age ( =0.28, p=0.03).
Table 71 – Main cha ac e is ics o pa ien s acco ding o median IMR
Va iable
To al popula ion
(n=60)
Co ona y mic o ascula damage (IMR>24)
p alue c
No (n=30)
Yes (n=30)
Physical cha ac e is ics
Age (yea s) a
59.6±12.7
54.7±11.3
64.4±12.2
0.002 x
Male gende b
48 (80.0)
26 (86.7)
22 (73.3)
0.20 x
BMI a
27.5 ±4.0
27.4±4.4
27.6±3.7
0.79 x
Wais ci cum e ence a
99.2±12.2
96.5±12.0
102.3±12.0
0.11 x
Risk Fac o s and p e ious co ona y disease b
Hype ension
43 (71.7)
19 (63.3)
24 (80.0)
0.15 x
Diabe es
15 (25.0)
7 (23.3)
8 (26.7)
0.77 x
Dyslipidaemia
30 (50.0)
16 (53.3)
14 (46.7)
0.61 x
Ac i e smoking
26 (43.3)
16 (53.3)
10 (33.3)
0.12 x
P e ious angina
9 (15.0)
4 (13.3)
5 (16.7)
1.00 d
P e ious e ascula iza ion
2 (3.3)
1 (3.3)
1 (3.3)
0.49 d
P e ious medica ion b
Aspi in
5 (8.3)
3 (10.0)
2 (6.7)
0.96 x
ACEi/ARBs
23 (38.3)
12 (40.0)
11 (36.7)
0.87 x
Be a-blocke s
4 (6.7)
3 (10.0)
1 (3.33)
0.63 d
S a ins
9 (15.0)
3 (10.0)
6 (20.0)
0.44 d
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c Independen - es o con inuous a iables, Chi-Squa e o
ca ego ical a iables; d Ya es co ec ion
Resul s
152
The e we e no signi ican di e ences in gende , o he physical cha ac e is ics o isk ac o s.
NT-p o-BNP le els ended o be highe in pa ien s wi h an IMR>24 and he e was a weak bu
signi ican co ela ion be ween hese 2 a iables ( =0.33, p=0.015). Likewise, glucose and
HbA1c le els on admission we e highe in pa ien s wi h IMR>24, and signi ican co ela ions
we e ound be ween hese labo a o y es s and IMR ( =0.34, p=0.009 and =0.67, p<0.001,
espec i ely). Finally, he e was a end o highe alues o hs-CRP in pa ien s wi h co ona y
mic o ascula damage (Table 72).
Table 72 – Labo a o y esul on admission acco ding o median IMR
Va iable
To al popula ion
(n=60)
Co ona y mic o ascula damage (IMR>24)
p alue c
No (n=30)
Yes (n=30)
C ea inine (mg/dL) b
0.90 (0.31)
0.89 (0.17)
0.94 (0.44)
0.14
NT-p o-BNP (pg/mL) b
137.5 (255.5)
93 (165.5)
167.5 (222.8)
0.055
hs-CRP (mg(dL) b
0.44 (0.59)
0.33 (0.36)
0.49 (0.84)
0.09
Glucose (mg/dL) b
133.5 (61.0)
122.0 (48.8)
141.5 (60.0)
0.046
HbA1c (%)b
5.7 (1.1)
5.5 (0.6)
5.9 (3.5)
0.047
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion.
7.1.2. IMR and angiog aphy/angioplas y a iables
The e we e no signi ican di e ences in ischemic (pain- o-balloon) o hospi al- o-balloon imes
be ween pa ien s wi h and wi hou mic o ascula co ona y damage (IMR>24). Main
angiog aphic cha ac e is ics, including culp i a e y, p esence o mul i essel disease and
Syn ax sco e we e also simila in bo h g oups (Table 73).
Likewise, he a ea-a - isk, measu ed bo h by APPROACH and BARI sco es, was simila .
Howe e , pa ien s wi h an IMR>24 had a signi ican ly highe p e alence o ini ial TIMI low 0-
1 (93.3% s. 73.3%, p=0.038).
T ea men op ions, including he use o mechanical aspi a ion and s en implan a ion
echnique we e simila in pa ien s wi h and wi hou IMR>24 (Table 74). Howe e , pa ien s wi h
lowe IMR alues we e mo e likely o ha e ecei ed abciximab du ing he P-PCI p ocedu e
(36.7% s 10.0%, p=0.015).
Resul s
153
Table 73 – Ischemic imes and angiog aphic cha ac e is ics acco ding o median IMR
Va iable
To al Popula ion
(n=60)
Co ona y mic o ascula damage (IMR>24)
p alued
No (n=30)
Yes (n=30)
Pain- o-balloon ime (min)c
209 (148)
206 (107)
225 (163)
0.19
Doo - o-balloon ime (min) c
78 (45)
78 (34)
79 (59)
0.89
Culp i a e y b
Le an e io descending
28 (46.7)
14 (46.7)
14 (46.7)
0.94
Le ci cum lex
13 (21.7)
6 (20.6)
7 (23.3)
Righ co ona y a e y
19 (31.7)
10 (33.3)
9 (30.0)
Mul i essel disease b
25 (41.7)
15 (50.0)
20 (66.7)
0.19
Syn ax sco e c
15.5 (10.0)
16.9 (10.0)
14.8 (8.0)
0.21
A ea a isk sco es a
APPROACH sco e
27.8 (2.0)
27.8 (3.0)
27.8 (3.0)
0.48
BARI sco e
28.0±6.3
27.2±6.5
28.0±6.3
0.95
Ini ial TIMI low 0-1 b
50 (83.3)
22 (73.3)
28 (93.3)
0.038
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen
- es o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal
dis ibu ion, Chi-Squa e o ca ego ical a iables; E Ya es co ec ion
Table 74 – Angioplas y ea men op ions acco ding o median IMR alue
Va iable a
To al Popula ion
(n=60)
Co ona y mic o ascula damage (IMR>24)
p alueb
No (n=30)
Yes (n=30)
Mechanical aspi a ion
26 (43.3)
14 (46.7)
12 (40.0)
0.60
Balloon p e-dila a ion
35 (58.3)
15 (50.0)
20 (66.7)
0.19
S en implan a ion
57 (95.0)
28 (93.3)
29 (96.7)
1.00
Balloon pos -dila a ion
23 (38.3)
12 (40.0)
11 (36.7)
0.79
Abciximab ea men
14 (23.3)
11 (36.7)
3 (10.0)
0.015
a P esen ed as numbe (%); b Chi-Squa e es
7.1.3. Mul i a iable analysis o IMR p edic o s
Since he e we e se e al ele an di e ences in he popula ions wi h and wi hou
mic o ascula co ona y damage and in o de o cla i y he independen p edic o s o IMR,
mul i a iable analysis was pe o med, using IMR as a con inuous a iable. Va iables s a is ically
signi ican on he uni a ia e analysis we e included in he eg ession model: age, ini ial TIMI
low, admission glucose, admission HbA1c and abciximab ea men . Since glucose le els and
HbA1c a e in e dependen a iables, 2 di e en models we e used, wi h hese 2 blood es s.
Resul s a e shown in Table 75.
Appendix – Pape s
256
43. Bone i PO, Pumpe GM, Higano ST, Holmes DR, Ku in JT, Le man A. Nonin asi e iden i ica ion o pa ien s wi h
ea ly co ona y a he oscle osis by assessmen o digi al eac i e hype emia. J Am Coll Ca diol
2004;44(11):2137–41.
44. Flamme AJ, Ande son T, Cele maje DS, e al. The assessmen o endo helial unc ion: om esea ch in o
clinical p ac ice. Ci cula ion 2012;126(6):753–67.
45. Damy T, Ra ajczak P, Shah AM, e al. Inc eased neu onal ni ic oxide syn hase-de i ed NO p oduc ion in he
ailing human hea . Lance (London, England) 2004;363(9418):1365–7.
46. Ma i CN, Gheo ghiade M, Kaloge opoulos AP, Geo giopoulou V V, Quyyumi AA, Bu le J. Endo helial
dys unc ion, a e ial s i ness, and hea ailu e. J Am Coll Ca diol 2012;60(16):1455–69.
47. Winlaw DS, Keogh AM, Schy ens CG, Sp a PM, Macdonald PS, Smy he GA. Inc eased ni ic oxide p oduc ion
in hea ailu e. Lance 1994;344(8919):373–4.
48. Baue sachs J, Widde JD. Endo helial dys unc ion in hea ailu e. Pha macol Rep 60(1):119–26.
49. Dupuis J, Ta di J-C, Ce nacek P, Thé oux P. Choles e ol Reduc ion Rapidly Imp o es Endo helial Func ion A e
Acu e Co ona y Synd omes. Ci cula ion 1999;99(25):3227 LP – 3233.
50. Gómez-Doblas JJ, Jiménez-Na a o MF, Ga cía-Pinilla JM, e al. [E ec o s a in ea men begun ea ly a e
acu e myoca dial in a c ion on endo helial unc ion in pa ien s wi h no mal le els o choles e ol. VAATOPE
S udy (VAlue o ATO as a in in Pos in a c ion Endo helium)]. Med clinica 2006;126(9):325–8.
51. Aka JG, Al-Chekakie MO, Fuga e T, e al. Endo helial dys unc ion in hea ailu e iden i ies esponde s o
ca diac esynch oniza ion he apy. Hea Rhy hm 2008;5(9):1229–35.
52. Enomo o K, Yamabe H, Toyama K, e al. Imp o emen e ec on endo helial unc ion in pa ien s wi h conges i e
hea ailu e ea ed wi h ca diac esynch oniza ion he apy. J Ca diol 2011;58(1):69–73.
53. Tesselaa E, Schi e A, Widde sho en J, e al. E ec o ca diac esynch oniza ion he apy on endo helium-
dependen asodila a ion in he cu aneous mic o ascula u e. Pacing Clin Elec ophysiol 2012;35(4):377–84.

Appendix – Pape s
257
FIGURE LEGENDS
Figu e 1. S udy low cha
Figu e 2. A ea unde he cu e o and peak alues o oponin I (de e mined om 7 scheduled
blood es s in he i s 48 hou s a e P-PCI), acco ding o he p esence o endo helial dys unc ion
(RHI<1.67)
Figu e 3. Le en icula ejec ion ac ion (mean ± s anda d de ia ion) and wall mo ion sco e
index (median and in e qua ile ange) e alua ed by Echo, acco ding o he p esence o
endo helial dys unc ion de ined as an RHI<1.67 (*Independen T- es , **Mann-Whi ney es )
Appendix – Pape s
258
TABLES
Table 1. Baseline cha ac e is ics acco ding o he p esence o endo helial dys unc ion (RHI<1.67).
Va iable
To al Popula ion
(n=38)
Endo helial Dys unc ion (RHI<1.67)
p alue d
No (n=22)
Yes (n=16)
Physical cha ac e is ics
Age (yea s) a
60.0±13.7
60.1±12.4
59.8±15.7
0.94 x
Male gende b
29 (76.3)
18 (81.8)
11 (68.8)
0.58 e
BMI a
27.2±4.0
27.4±4.5
27.1±3.3
0.82 x
Wais ci cum e ence a
100.0±11.5
101.1±12.6
98.5±9.9
0.55 x
Risk Fac o s and p e ious co ona y disease b
Hype ension
26 (68.4)
16 (72.7)
10 (62.5)
0.50 x
Diabe es
12 (31.6)
8 (36.4)
4 (25.0)
0.46 x
Dyslipidemia
19 (50.0)
11 (50.0)
8 (50.0)
1.00 x
Ac i e smoking
13 (34.2)
9 (40.9)
4 (25.0)
0.31 x
P e ious angina
7 (18.4)
6 (27.3)
1 (6.3)
0.22 e
P e ious e ascula iza ion
2 (5.3)
1 (4.5)
1 (6.3)
0.61 e
P e ious medica ion b
Aspi in / Clopidog el
3 (7.9)
2 (9.1)
1 (6.3)
0.73 e
ACEi/ARBs
13 (34.2)
10 (45.5)
3 (18.8)
0.11 x
Be a-blocke s
1 (2.6)
1 (4.5)
0 (0.0)
0.85 e
S a ins
4 (10.5)
2 (9.1)
2 (12.5)
0.89 e
Admission labo a o y alues
C ea inine (mg/dL) c
0.88 (0.32)
0.87 (0.54)
0.90 (0.19)
0.67
NT-p o-BNP (pg/mL)c
158.5 (305.0)
154 (365)
163 (250)
0.95
hs-CRP (mg(dL) c
0.57 (0.71)
0.29 (0.45)
0.81 (0.98)
0.06
Glucose (mg/dL) c
136.0 (63.0)
131.0 (60.0)
145.5 (81.8)
0.51
HbA1c (%)c
5.8 (1.3)
5.7 (1.4)
5.9 (2.1)
0.69
Ischemic imes
Pain- o-balloon ime (min) c
209 (173)
209 (186)
211 (167)
0.94
Doo - o-balloon ime (min) c
75 (52)
79 (46)
57 (44)
0.06
Angiog aphic cha ac e is ics
Culp i a e y b
Le an e io descending
21 (53.3)
11 (50.0)
10 (62.5)
0.89 e
Le ci cum lex
7 (18.4)
5 (22.7)
2 (12.5)
Righ co ona y a e y
10 (26.3)
6 (27.3)
4 (25.0)
Mul i essel disease b
19 (50.0)
8 (36.4)
11 (68.8)
0.10 e
SYNTAX sco e c
17.8±6.2
16.8±6.2
19.0±6.0
0.29
Ini ial TIMI low 0-1 b
31 (81.6)
16 (72.7)
15 (93.8)
0.22
A ea a isk sco es c
APPROACH sco e
27.8 (3.0)
28.1 (5.0)
29.7 (10.0)
0.08
BARI sco e
28.5 (6.0)
26.7 (7.0)
30.2 (10.0)
0.07
Angioplas y a iables b
Mechanical aspi a ion
16 (42.1)
9 (40.9)
7 (43.8)
0.86
Balloon p e-dila a ion
21 (55.3)
13 (59.1)
8 (50.0)
0.58
S en implan a ion
36 (94.7)
20 (90.9)
16 (100.0)
0.61
Balloon pos -dila a ion
24 (63.2)
14 (63.6)
10 (62.5)
0.94
Abciximab ea men
9 (23.7)
4 (18.2)
5 (31.5)
0.58
Mechanical aspi a ion
16 (42.1)
9 (40.9)
7 (43.8)
0.86
a P esen ed as mean±s anda d de ia ion; b P esen ed as numbe (%); c P esen ed as median (in e qua ile ange); d Independen - es
o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion, Chi-
Squa e o ca ego ical a iables; e Ya e’s co ec ion
Appendix – Pape s
259
Table 2. T oponin I elease acco ding o he p esence o endo helial dys unc ion (RHI<1.67)
Va iable a, b
To al Popula ion
(n=38)
Endo helial Dys unc ion (RHI<1.67)
p alue c
No (n=22)
Yes (n=16)
Peak TnI alues
TnIpeak
95 (96)
67 (81)
118 (186)
0.024
TnIpeak (APPROACH)
25 (32)
17 (20)
34 (56)
0.009
TnIpeak (BARI)
24 (31)
17 (22)
33 (47)
0.008
TnIpeak (2 sco es)
24 (31)
17 (21)
33 (55)
0.009
A ea unde he cu e o TnI
TnIAUC
1293 (1580)
1076 (1042)
2305 (2486)
0.012
TnIAUC (APPROACH)
403 (522)
315 (303)
664 (1080)
0.008
TnIAUC (BARI)
383 (448)
314 (326)
618 (799)
0.007
TnIAUC (2 sco es)
393 (482)
314 (300)
641 (984)
0.007
a P esen ed as median (IQR); b Peak alue and a ea unde he cu e (AUC) o 7 oponin I (TnI, in mg/dL) measu emen s
pe o med in he i s 48 hou s a e he p ima y angioplas y; o al alues and alues indexed o he APPROACH, BARI
o bo h a e p esen ed; c Mann-Whi ney Tes
Appendix – Pape s
260
Table 3. Echoca diog aphic esul s acco ding o he p esence o endo helial dys unc ion
(RHI<1.67)
Va iable
To al Popula ion
Endo helial Dys unc ion (RHI<1.67)
p alue c
No
Yes
2D measu emen s
(n=26)
(n=15)
(n=11)
LVTdV (ml) a
109.8±23.4
106.5±30.2
113.8±11.4
0.48
LVTsV (ml) a
55.9±12.6
51.1±12.3
61.7±10.9
0.047
LVEF (%)a
48.6±7.1
51.4±4.7
45.3±8.3
0.045
Wall mo ion sco e index b
1.44 (0.41)
1.35 (0.47)
1.77 (0.47)
0.006
Le a ia olume (ml/m2) a
36.1±11.0
36.7±12.1
35.3±10.0
0.78
Dopple measu emen s
(n=21)
(n=11)
(n=10)
E/A a io a
1.10±0.40
1.17±0.40
0.97±0.0.39
0.30
E/e’ a io a
8.91±3.30
8.83±3.91
9.05±2.18
0.89
2D speckle acking imaging
(n=21)
(n=11)
(n=10)
Global longi udinal s ain a
-13.16±2.35
-14.32±1.72
-11.89±2.35
0.014
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c Independen - es o con inuous a iables
wi h a no mal dis ibu ion. Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion. LVEdV – le en icula end
dias olic olume; LVEsV – le en icula end sys olic olume; LVEF – le en icula ejec ion ac ion; WMSI – wall mo ion sco e index.
Appendix – Pape s
261
Table 4. ceCMR esul s acco ding o he p esence o endo helial dys unc ion (RHI<1.67)
Va iable
To al Popula ion
(n=29)
Endo helial Dys unc ion (RHI<1.67)
p alue d
No (n=18)
Yes (n=11)
LVTdV (ml) a
138.6±26.9
139.2±26.5
137.5±28.9
0.87
LVTsV (ml) a
63.5±21.0
59.3±19.4
70.4±22.6
0.17
LVEF (%)a
53.9±8.4
56.6±8.1
49.5±7.2
0.025
Wall mo ion sco e index a
1.37±0.33
1.28±0.31
1.53±0.32
0.05
Edema mass b
19.1 (19.0)
17.2 (14.1)
21.2 (28.6)
0.28
T ansmu al nec osis c
12 (38.7)
4 (22.2)
7 (63.6)
0.06 e
In a c mass
To al b
11.6 (9.3)
10.1 (10.3)
17.5 (15.4)
0.08
Pe cen b
11.5 (13.7)
10.2 (7.6)
17.5 (21.8)
0.10
Indexed o APPROACH
3.2 (7.0)
2.7 (2.6)
4.9 (11.5)
0.10
Indexed o BARI
3.4 (5.8)
2.3 (2.7)
5.1 (11.5)
0.09
Sal age mass b
5.0 (14.0)
5.0 (8.8)
4.7 (27.6)
0.87
Mic o ascula obs uc ion
MVO p esen c
8 (27.6)
2 (11.1)
6 (54.5)
0.03 e
MVO mass b
6.1 (15.5)
5.3 (-)
6.8 (20.8)
0.29
a P esen ed as mean±s anda d de ia ion; b P esen ed as median (in e qua ile ange); c P esen ed as numbe (%); d Independen - es
o con inuous a iables wi h a no mal dis ibu ion, Mann-Whi ney es o con inuous a iables wi h a non-no mal dis ibu ion, Chi-
Squa e o ca ego ical a iables; e Ya e’s co ec ion

Appendix – Pape s
262
FIGURES
Figu e 1
Appendix – Pape s
263
Figu e 2
Figu e 3