combined) assessment) of) high1sensitive) troponin) …€¦ · · 2015-05-21combined)...
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! 1!
Combined) Assessment) of) High1Sensitive) Troponin) T) and) Non1invasive)
Coronary)Plaque)Composition)for)the)Prediction)of)Cardiac)Outcomes.)
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Text)word)count)(from)Introduction)to)Discussion):)2651)
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ClinicalTrials.gov)Identifier:)NCT02030704)
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Gitsios!Gitsioudis1,!Alena!Schüßler1,!Eszter!Nagy1,2,!Pál!Maurovich@Horvat2,!Sebastian!J.!
Buss1,! Andreas! Voss3,! Waldemar! Hosch4,! Nina! Hofmann1,! Hans@Ulrich! Kauczor4,!
Evangelos!Giannitsis1,!Hugo!A.!Katus1!&!Grigorios!Korosoglou1.!
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1.!!University!of!Heidelberg,!Department!of!Cardiology,!Heidelberg,!Germany.!
2.!MTA@SE!Lendület!Cardiovascular!Imaging!Research!Group,!Heart!and!Vascular!Center,!
Semmelweis!University,!Budapest,!Hungary.!
3.!University!of!Heidelberg,!Institute!of!Psychology,!Heidelberg,!Germany!!
4.! University! of! Heidelberg,! Department! of! Diagnostic! and! Interventional! Radiology,!
Heidelberg,!Germany.!
)Address!for!Correspondence:! Grigorios!Korosoglou,!MD!
University!of!Heidelberg!Department!of!Cardiology!!Im!Neuenheimer!Feld!410!Heidelberg,!69120,!Germany!
! ! ! ! ! !:[email protected]!! ! ! ! ! Tel:!++!49!6221!56!4130!! ! ! ! ! Fax:!++49!6221!56!5513!
No)support)from)any)organisation)for)the)submitted)work)
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Key) words:! atherosclerotic! plaque! composition,! quantification! analysis,! 256@slice!
cardiac!computed!tomography,!high!sensitive!troponin!T.!
! 2!
Advances)in)Knowledge.)
" Cardiac! computed! tomography! angiography! (CCTA)@based! quantitative! coronary!
plaque!volume!is!associated!with!serum!levels!of!high@sensitive!Troponin!T!(hsTnT)!
(r=0.27,!95%[email protected],!p<0.0001).!
" The! presence! of! none! or! purely! calcified! versus! non@calcified! plaques! (HR=26.08,!
95%[email protected],! p=0.005),! plaque! volume! by! tertiles! (HR=12.14,! 95%CI=1.87@
78.74,! p=0.009),! and! increased! hsTnT! (≥14pg/ml)! (HR=10.31,! 95%[email protected],!
p=0.0006)! are! independent! predictors! of! outcome,! surpassing! the! value! of!
conventional!atherogenic!risk!factors!and!calcium!scoring.!
" Cardiac!events!mainly!occur!in!patients!with!simultaneously!elevated!plaque!volume!
and!hsTnT!values,! and! in! those!with!non@calcified! lesions! and! increased!hsTnT.! In!
contrast! to! hsTnT,! hsCRP! does! not! provide! complementary! value! to! CCTA! for! the!
prediction!of!future!myocardial!infarction!and!cardiac!death.!
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Implications)for)Patient)Care.)
" The!presence!of!simultaneously!increased!plaque!burden!and!hsTnT!(>12pg/ml)!in!
patients!with! stable! CAD! indicates! a! potentially! unstable! cardiovascular! condition.!
Such!patients!may!be!future!candidates!for!more!aggressive!pharmacologic!therapy,!
with!hsTnT!serving!as!a!therapeutic!target.!
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! 3!
Abstract)
Purpose.) To! determine! the! ability! of! plaque! volume! and! composition! assessment! by!
cardiac! computed! tomography! angiography! (CCTA)! and! high! sensitive! troponin! T!
(hsTnT)! for! the! risk! stratification! of! patients! at! intermediate! risk! for! coronary! artery!
disease!(CAD).!
Materials) and) Methods.) Our! study! complied! with! the! Declaration! of! Helsinki,! was!
approved!by!our!local!ethic!committee!and!all!patients!gave!written!informed!consent.!
521! consecutive! patients! (62±10! years,! 49%! male! gender)! were! included! in! our!
prospective!observational! longitudinal! single@center! study.!Quantitative!CCTA!analysis!
was! performed! in! all! patients! (n=7,690! coronary! segments),! whereas! biomarkers!
(hsTnT! &! hsCRP)! were! available! in! 408! patients! (78%).! To! evaluate! the! incremental!
value!of!CCTA!and!hsTnT!for!the!prediction!of!cardiovascular!events,!multivariate!Cox@
regression!and!integrated!discrimination!improvement!(IDI)!analysis!were!applied.!
Results.)In!521!patients,)13!hard!cardiac!events!occurred!during!a!2.3±1.1!year!follow@
up! period! (median! 2.4,! range! [email protected]),! while! 23! patients! underwent! late! coronary!
revascularization.! The! Duke! clinical! score! was! 51±30%,! indicating! intermediate! risk.!
The!presence!of!none!or!purely!calcified!versus!non@calcified!plaques,!plaque!volume!by!
tertiles! and! increased! hsTnT! (≥14pg/ml)! were! independently! associated! with! hard!
cardiac! events! (HR=26.08,! 95%[email protected];! HR=12.14,! 95%[email protected]! and!
HR=10.31,! 95%[email protected],! respectively,! p<0.01! for! all).! Patients!with! both! elevated!
hsTnT!and!plaque!burden!(n=53)!showed!the!highest!incidence!for!hard!cardiac!events!
(annual! rate=12.7%),! followed!by! those!with! either! elevated! hsTnT!or! plaque! burden!
(n=145;! annual! rate=0.44%,! p<0.03),! while! those! with! both! lower! hsTnT! and! plaque!
burden!exhibited!excellent!outcomes!and!no!hard!event!during!the! follow@up!duration!
(n=210;!annual!rate=0%,!p<0.001).!!
! 4!
Conclusion.! Using! hsTnT,! as! a! marker! of! myocardial! micro@injury,! and! CCTA,! as! a!
marker!of!the!total!atherosclerotic!burden,!improves!the!prediction!of!cardiac!outcome!
in! presumably! stable! CAD! patients,! and! may! aid! personalized! risk@stratification! in!
patients!at!intermediate!risk.!
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! 5!
Introduction!
Rupture! of! ‘vulnerable’! atherosclerotic! lesions! with! subsequent! coronary! artery!
thrombosis!is!the!most!common!cause!of!myocardial!infarction!(MI)!and!sudden!cardiac!
death! (1).! Plaque! composition,! such! as! a! large! necrotic! core,! thin! fibrous! cap! and!
positive! artery! vessel! remodeling! are! indicators! of! plaque! vulnerability! and! cardiac!
events!in!patients!with!ischemic!heart!disease!(2,!3).!
Cardiac!computed!tomography!angiography!(CCTA)! is!a!well@established!technique!for!
visualization! of! both! coronary! lumen! narrowing! and! plaque! composition! (4,! 5).! Thus,!
several! CCTA! outcome! studies! have! assessed! plaque! burden! and! composition! in! both!
symptomatic!and!asymptomatic!patients!(6@8).!Cardiac!troponins!on!the!other!hand,!are!
sensitive!biomarkers!of!myocardial!injury!associated!with!death,!MI!and!heart!failure!in!
patients! with! chronic! ischemic! heart! disease! and! preserved! systolic! LV@function! (9).!
Although!elevations!of!cardiac!troponins!are!predictive!for!outcome!in!non@ACS!patients!
with!presumably!stable!CAD,!the!role!of!plaque!volume!and!composition!by!CCTA!on!the!
predictive!power!of!high!sensitive!troponin!T!(hsTnT)!has!not!been!investigated!so!far.!!
We! therefore! sought! to! determine! the! ability! of! plaque! volume! and! composition!
assessment! by! cardiac! computed! tomography! angiography! (CCTA)! and! high! sensitive!
troponin! T! (hsTnT)! for! the! risk! stratification! of! patients! at! intermediate! risk! for!
coronary!artery!disease!(CAD).!
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! 6!
Materials)and)Methods)
Study) Population.) Our! observational! longitudinal! single@center! study! included!
prospectively!564!consecutive!patients!scheduled!for!CCTA!due!to!suspected!or!known!
coronary! artery! disease! (CAD)! between! February! 2008! and! April! 2012!
(www.clinicaltrials.gov,!HDCCTA01).!A! flow!chart!of!our!study! is!provided! in!Figure!1.!
Inclusion!and!exclusion!criteria!as!well!as!the!demographic!and!clinical!characteristics,!
which!were! recorded! in! our! patient! cohort,! are! provided! in! the! online! Appendix! and!
Suppl.!Table!1.!Our! study!complied!with! the!Declaration!of!Helsinki,!was!approved!by!
our!local!ethic!committee!and!all!patients!gave!written!informed!consent.!
Cardiac)CT)Imaging)and)Analysis.!All!imaging!was!performed!with!a!256@detector!row!
CT! scanner! (iCT,! Philips! Medical! Systems,! Best,! The! Netherlands)! with! a!
2x128x0.625mm!detector!configuration,!as!previously!described!(10).!Details! in! terms!
of! patient! preparation! and! CCTA! protocols! are! provided! in! the! online! Appendix.!
Coronary!CT!angiograms!were!analyzed!independently!by!two!experienced!readers!(G.G.!
&! S.B.)! both! with! >5! years! of! experience! in! coronary! CTA! equivalent! to! the! clinical!
competence! statement! training! level! 3! of! the! American! College! of! Cardiology!
Foundation/American!Heart!Association! (AHA)! (11).!The!methods!used! for!evaluation!
of! diagnostic! image! quality,! visual! plaque! evaluation! and! quantitative! assessment! of!
Agatston!score,!luminal!narrowing!and!coronary!plaque!volume!and!composition!using!
the! dedicated! software! (Extended! Brilliance!Workspace! 4.0,! Philips!Medical! Systems)!
have!been!described!previously!(details!provided!in!the!online!Appendix)!(5,!12).!!
Biomarkers.) Blood! samples!were! taken! before! the! CCTA! examination! for! hsCRP! and!
hsTnT!measurements.! A! detailed! description! of! biomarker! analysis! is! available! in! the!
online!Appendix.!
Follow1up) and) Study) Endpoints.! Personnel! unaware! of! the! CCTA! results! contacted!
each!subject!or!an! immediate! family!member.!Follow@up!evaluation!was!performed!by!
! 7!
A.S.!&!G.G..!The!most!important!portions!of!this!study!were!performed!and!reviewed!by!
G.G.!and!G.K.,!who!both!have!>5!years!experience! in!coronary!CTA!and!cardiovascular!
imaging.!
The!date!of! this!contact!was!used! for! the!calculation!of! the! follow@up!time!duration.!A!
standardized!questionnaire!was!used!to!collect!outcome!data!determined!from!patient!
interviews!at!the!outpatient!clinic!or!by!telephone!interviews.!Reported!clinical!events!
were! confirmed! by! review! of! the! corresponding! medical! records! in! our! electronic!
Hospital! Information! System,! and! contact! with! the! general! practitioner,! referring!
cardiologist,!or!the!treating!hospital.!!
The! primary! endpoints! were! cardiac! death! (sudden! death! due! to! arrhythmia,! fatal!
myocardial! infarction! or! intractable! heart! failure)! and! non@fatal! MI! (13).! Secondary!
endpoints! were! the! occurrence! of! clinically! indicated! revascularization! procedures! 3!
months!of!CCTA!by!percutaneous!coronary!intervention!(PCI)!or!coronary!artery!bypass!
graft!surgery!(CABG).!Early!revascularizations!with!less!than!3!months!of!CCTA!were!not!
considered,!because!CCTA!results!may!have!triggered!revascularization!procedures,!and!
these!patients!were!censored!at!the!time!of!early!revascularization!(n=23).!!!
Statistical)Analysis.)Categorical!variables!are!presented!as!number!(%)!and!continuous!
variables!as!mean!±!standard!deviation!(SD)!or!median!and!interquartile!range!(IQR),!as!
appropriate.! The! chi@square! test! was! used! for! comparison! of! categorical! variables.!
Comparisons!between!groups!were!made!using!either!the!independent@samples!t@test!or!
the!Mann@Whitney!U! test,! as! appropriate.! For!all! continuous!parameters!derived! from!
CCTA! analysis! and! biomarkers,! receiver! operating! characteristics! (ROC)! curves! were!
plotted! and! cut! off! values! were! determined! to! derive! the! optimal! trade@off! between!
sensitivity!and!specificity!for!each!parameter.!For!survival!analysis,!Kaplan@Meier!curves!
were!generated!to!estimate!the!distribution!of!cardiac!events!and!the!annual!event!rate!
as! a! function! of! the! follow@up! duration! using! categorical! or! ROC! optimized! values! for!
! 8!
quantitative! variables.! To! identify! predictors! of! cardiac! endpoints! we! performed! a!
successive! Cox! proportional@hazards! univariate! and! multivariate! analysis! with!
Bonferroni! adjustment! for! multiple! comparisons.! Integrated! Discrimination!
Improvement! (IDI)! values! were! calculated! using! the! ‘survIDINRI’! software! package.!
Power! of! Cox! regression! was! analyzed! using! the! ‘powerSurvEpi’! library! for! the! R!
software.! !Power! is!presented! for!a!Hazard!ratio!of!HR=2! for!a!variable!with!standard!
deviation! 1! (i.e.,! an! increase! of! 1! SD! is! assumed).! Intraobserver! and! interobserver!
variability! for! quantification! of! plaques! and! lumen! narrowing! were! calculated! by!
repeated!analysis!of!40!randomly!selected!CCTA!cases.!The!readings!were!separated!by!
8! weeks! to! minimize! recall! bias.! P<0.05! was! indicative! of! significant! difference.!
Statistical! analyses! were! performed! with! use! of! MedCalc! software! (MedCalc®! 13.2.0,!
Ostend,!Belgium)!by!G.K.!&!G.G..!A.V.!performed!IDI!analysis!and!power!calculation.!
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Results!
Clinical) Characteristics) and) Outcomes.) Diagnostic! image! quality! was! achieved! in!
7,690! of! 7,815! (98.4%)! coronary! segments.! During! the! follow@up! period! (median! 2.4!
years,[email protected]!years),!13!hard!cardiac!events!occurred,!including!3!cardiac!deaths!
and!10!nonfatal! infarctions,!while!23!patients!underwent! late!revascularization!(17!by!
PCI! and! 6! by! CABG).! The! Duke! clinical! score! was! 51±30%! indicating! intermediate!
likelihood!for!CAD.!Significant!differences!were!observed!between!patients!with!(n=36)!
and!without!cardiac!events!(n=485)!in!terms!of!atherogenic!risk,!history!of!CAD,!serum!
creatinine,!hsTnT,!calcium!score!and!plaque!burden!and!stenosis!(Suppl.!Table!1).!
Association) of) Plaque) Volume) and) Stenosis) with) hsTnT.) Increasing! hsTnT! was!
observed!with! increasing!plaque!burden.!Patients!with!stenosis!<25%!exhibited! lower!
hsTnT!compared! to! those!with! stenosis!≥25%,!whereas!no!differences!were!observed!
with!further!lumen!narrowing!increase!(Suppl.!Figure!1a,!c).!Patients!within!the!highest!
! 9!
tertile! for! plaque! burden! and! intermediate! stenosis! (50@75%)! exhibited! the! highest!
rates!for!cardiac!events!of!83%!and!58%,!respectively!(Suppl.!Figure!1b,!d).!!
Uni1)and)Multivariable)Analysis.!For!the!prediction!of!the!combined!endpoint,!power!
was! 0.96! for! univariate! analyses! and! 0.90! for! multivariate! analyses! (assuming! a!
common! variance! of! R²=0.25! for! each! covariate! with! all! other! covariates).! For! the!
primary! endpoint,! power! is! reduced! to! 0.60! for! univariate! analyses! and! 0.48! for!
multivariate! analyses.! By! univariate! analysis! clinical! parameters,! hsTnT,! calcium!
scoring,! plaque! composition! and! volume! were! predictive! for! cardiac! events! (Suppl.!
Table!2).! By! multivariable! analysis! plaque! volume! and! stenosis! severity! both!
exhibited! independent! predictive! value! for! hard! cardiac! events.! Adding! hsTnT! to! this!
model,!the!latter!together!with!total!plaque!volume!provided!the!most!robust!prediction!
of!cardiac!events,!while!hsCRP!was!not!predictive!(Table!1).!!!
Subsection)Visual)Plaque)Characteristics.!Patients!with!no!or!purely!(n=334)!calcified!
plaque!exhibited!lower!event!rates!compared!to!those!with!non@calcified!plaque!(n=187)!
(Figure! 2A).! Especially! in! patients! with! hsTnT<14pg/ng,! patients! with! no! or! purely!
calcified!plaque!(n=227)!showed!excellent!outcome!without!any!hard!event!(Figure!2B),!
compared! to! those! with! non@calcified! plaques! (n=118).! A! representative! case! of! a!
patient!with! non@calcified! plaque! and! increased! hsTnT>14.0pg/ml! is! presented! in! the!
Suppl.!Figure!2.!
ROC)and)IDI)Analysis.)Accuracy!for!the!prediction!of!cardiac!events!by!AUC!was!higher!
for! hsTnT,! plaque! volume! and! calcium! score! compared! with! the! Duke! clinical! score!
(Duke! score@AUC=0.55,! 95%[email protected];! calcium! score@AUC=0.80,! 95%[email protected];!
hsTnT@AUC=0.80,! 95%[email protected]! and! plaque! volume@ACU=0.87,! 95%[email protected],!
p<0.05!for!all,!Figure!3A).!!!
Using!a!series!of!Cox!models,!each!variable! including!calcium!score,! lumen!narrowing,!
total!plaque!volume!and!hsTnT!offered! incremental! information! for! the!assessment!of!
! 10!
hard!cardiac!events.!Both!by!χ²!and!by!IDI,!hsTnT!offered!incremental!value!to!clinical!
and!CCTA!findings!(Figure!3B).)
Survival)Analysis.!Patients!with!non@calcified!plaque!composition!showed!significantly!
poorer!outcomes!than!those!without!or!with!purely!calcified!plaque!(Figure!2A),!even!in!
the! subgroup! with! hsTnT<14pg/ml! (Figure! 2B).! In! addition! hsTnT! and! total! plaque!
volume! clearly! discriminated! between! patients!with! and!without! hard! cardiac! events!
(Figure!2C@D),!exhibiting! independent!and!additive!value! (Figure!2E@F).!Thus,!patients!
with!both!high!hsTnT!and!plaque!volume!(n=53)!showed!the!highest!annual!event!rates!
(12.7%! for!hard!and!15.6%! for!all! cardiac!events),! followed!by! those!with!either!high!
hsTnT!or!plaque!volume!(n=145,!0.4%!for!hard!and!2.9%!for!all!cardiac!events),!while!
those!with!both!low!hsTnT!and!plaque!volume!exhibited!excellent!outcomes!(n=210,!0%!
for!hard!and!0.3%!for!all!cardiac!events).!!
Analysis) by) Tertiles.) Analysis! by! tertiles! is! provided! in! Suppl.! Figure! 3.! Significant!
differences!were!observed!between!patients!within! the! lower!versus! those!within! the!
upper! tertile! of! hsTnT! (Suppl.! Figure! 3A@B).! The! clinically! established! cut@off! value! of!
hsTnT=14.0! pg/ml! was! also! strongly! predictive! (Suppl.! Figure! 3C@D).! Similar! results!
were!obtained!for!plaque!volume!(Suppl.!Figure!3E@F).!Patients!within!the!lower!tertiles!
for!hsTnT!and!plaque!volume!exhibited!no!cardiac!events.!92%!of!hard!and!81%!of!all!
cardiac!events!on!the!other!hand!occurred!in!patients!within!the!mid!or!upper!tertile!for!
hsTnT!and!plaque!volume!(Table!2).!!!
Observer) Agreement) and) Variabilities) and) Time1spent.) Inter@! and! intra@observer!
variabilites! for! the!assessment!of!plaque!volume!and!stenosis!were!13%!and!7%,!and!
11%! and! 9%,! respectively.! Agreement! between! observers! for! the! differentiation! of!
calcified! (i.e.! calcified! and! partially! calcified)! and! non@calcified! plaques! was! 93%!
(κ=0.85).! Quantitative! assessment! required! a! mean! time! spent! of! 3.9±3.1! min! per!
patient.!
! 11!
Discussion)
The!present!study!demonstrates! the! incremental!value!of! the!combined!assessment!of!
hsTnT! and! CCTA! for! the! prediction! of! cardiac! outcome! in! patients!with! intermediate!
likelihood! for! CAD.! In! our! cohort,! plaque! volume! and! composition! as! well! as!
quantification!of! luminal!narrowing!assessed!by!CCTA!were! independent!predictors!of!
outcome.! In! addition,! hsTnT! increased! with! increasing! plaque! burden! but! not! with!
increasing! lumen! narrowing.! Cardiac! events! primarily! occurred! in! patients! with! high!
plaque! burden! (by! quantitative! analysis),! and! hsTnT! values! and! in! those! with! non@
calcified! lesions! (by! visual! analysis)! and! moderate! lumen! narrowing! (50@75%,! by!
stenosis!quantification).!In!contrast!to!hsCRP,!hsTnT!provided!complementary!value!to!
CCTA!for!the!prediction!of!future!myocardial!infarction!and!cardiac!death.!!
A!critical!coronary!obstruction! is!usually!associated!with!the!presence!of!symptomatic!
disease! (14).! Increasing! evidence! on! the! other! hand,! shows! that! plaque! morphology!
assessed!by!CCTA!adds!value!to!lumen!narrowing!for!the!prediction!of!cardiac!events!(6,!
8,! 15,! 16).! Quantitative! analysis! of! plaque! burden!was! also! recently! shown! to! predict!
future!acute!coronary!syndrome!in!patients!with!stable!CAD!(5).!Our!CCTA@based!plaque!
analysis! in!7,690! coronary! segments! confirmed! the!predictive! value!of! plaque!burden!
and!lumen!narrowing,!which!in!our!cohort!both!surpassed!the!value!of!conventional!risk!
factors!and!calcium!score.!Using!multivariate!analysis,!both!variables!were!independent!
predictors!for!cardiac!events.!Plaque!volume!was!linearly!related!to!increasing!rates!of!
cardiac! events,! which! is! in! agreement! with! previous! CCTA! studies! (5).!With! stenosis!
severity,!on!the!other!hand!rather!intermediate!(50@75%)!lesions,!which!may!have!been!
partially! judged! as! functionally! non@significant! by! FFR! subsequently! caused! hard!
endpoints!(3,!14,!17).!This!weaker!association!of!increasing!lumen!narrowing!with!hard!
events! is! in! line! with! the! results! of! the! FAME! 2! trial,! where! targeting! functional!
significant! lesions! reduced! the! subsequent! revascularization! rates! but! not! the! rate! of!
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‘hard!cardiac!events’,!such!as!infarction!and!cardiac!death!(18).!Calcium!scoring!on!the!
other!hand,!exhibited!significant!HR!for!the!prediction!of!hard!and!all!cardiac!events!by!
univariate!analysis,!which!is! in!agreement!with!previous!large!scale!clinical!trials!(19).!
However,!when!plaque!volume!was!also!considered!in!the!multivariable!model,!calcium!
scoring! was! no! longer! significant,! which! is! also! in! agreement! with! previous! studies,!
showing!that!CCTA!is!superior!to!calcium!scoring!for!the!estimation!of!cardiac!outcomes!
(20,!21).!
The! role! of! cardiac! troponins! for! the! assessment! of! cardiac! risk! both! in! stable! CAD!
patients! and! in! apparently! healthy! subjects!was! demonstrated! in! several! studies! (22,!
23).! This! association! could! be! confirmed! in! the! PEACE! study,! showing! that! cardiac!
troponins! measured! by! high! sensitivity! assays! are! independent! markers! of! cardiac!
outcomes! in! a! large! patient! cohort! (9).! In! our! study,! we! confirmed! this! association!
between!hsTnT!blood! levels!and!cardiac!outcomes.! In! line!with!previous!CCTA!studies!
we!also!demonstrated!a!correlation!between!hsTnT!and!CCTA@based!plaque!burden!(24,!
25).!Interestingly,!we!found!an!increase!of!hsTnT!with!increasing!plaque!burden!but!not!
with!increasing!lumen!narrowing.!In!this!regard,!increased!hsTnT!levels!in!the!absence!
of!flow!limiting!stenosis!but!in!the!presence!of!increased!plaque!burden,!indicates!severe!
myocardial! injury! or! irreversible! myocyte! death,! possibly! caused! by! silent! plaque!
rupture,! micro@embolization! and! microvascular! obstruction,! which! may! precede! the!
clinical!manifestation!of!MI!(26).!In!the!same!line,!a!recent!prospective!clinical!trial!could!
demonstrate!that!patients!with!presumably!stable!CAD!but!vulnerable!coronary!plaques!
by! 18F@fluoride! positron! emission! tomography,! had! higher! plasma! concentration! of!
cardiac! troponins,! compared! to! patients! without! such! unstable! plaques! (27).! These!
observations!are!in!agreement!with!earlier!angioscopy!studies,!identifying!silent!plaque!
rupture! in!~20%!of!patients!with!clinically!stable!CAD!(28).!As!plaque!burden!reflects!
the!anatomic!surrogate!of!potentially!critical!lesions!and!hsTnT!the!functional!surrogate!
! 13!
of! silent!plaque!rupture!causing!micronecrosis,! the!markedly! increased!cardiac!events!
rate! in! patients! with! increased! plaque! burden! and! hsTnT,! i.e.! in! those! who! combine!
these!2!potential!hazards!is!not!surprising.!Since!clinical!and!experimental!data!suggest!
that! systemic! response! to! ischemic! injury! or! micro@injury! may! aggravate! chronic!
atherosclerosis!(29),!hsTnT!may!represent!a!novel!therapeutic!target!for!the!primary!or!
secondary!prevention!of!CAD.!
CRP!was!initially!supposed!to!be!a!causal!player!for!atherosclerotic!plaque!development!
and!inflammation!(30).!However,!further!basic!science!research!has!questioned!a!direct!
atherogenic!mechanism!(31,!32).!Others!and!we!showed!previously!that!serum!levels!of!
hsCRP! are! only! weakly! correlated! with! plaque! composition! and! coronary! artery!
calcification!and!largely!determined!by!the!presence!of!risk!factors!(25,!33).!In!this!line,!
we! demonstrated! that! hsTnT! but! not! hsCRP! provide! complementary! value! to! CCTA@
based!plaque!volume!and!composition!for!the!prediction!of!future!myocardial!infarction!
and!cardiac!death.!)
Limitations.!The!number!of!cardiac!events!such!as!cardiac!death!and!MI!was!relatively!
small.! In! addition,!both! retrospective! and!prospective!ECG!gated!acquisition!protocols!
were!used!in!our!study,!so!that!we!cannot!surely!exclude!some!impact!of!the!scanning!
protocols! on! plaque! quantification! by! our! computer! assisted! algorithm.! No! perfusion!
analysis! was! performed.! HsTnT! and! hsCRP! data! were! available! in! only! ~80%! of! our!
patients,!while!HbA1c!was!available!in!the!minority!of!our!patients,!which!is!a!limitation.!
Despite,!the!high!isotropic!resolution!of!0.65mm!we!cannot!exclude!that!some!portion!of!
very!“flat”!coronary!plaques,!which!were!missed!by!quantitative!plaque!analysis.!Finally,!
multiple! other! conditions! for! elevated! hsTnT! serum! levels,! which! may! be! related! to!
other! non@coronary! reasons,! such! as! cardiomyopathy,! left! ventricular! hypertrophy,!
myocarditis!or!excessive!endurance!exercise!(34,!35),!cannot!be!completely!excluded!in!
our!patient!cohort.)
! 14!
Conclusion!
Our!study!demonstrates!the!complementary!value!of!hsTnT!and!quantitatively!assessed!
coronary! plaque! burden! for! the! prediction! of! cardiac! outcome! in! patients! with!
intermediate!likelihood!for!CAD.!This!approach!may!aid!personalized!risk@stratification!
in! patients! with! presumably! stable! CAD.! Since! all! techniques! used! herein! are! readily!
available! in! the! clinical! routine! and! are! associated!with! an! acceptable! time! spent! the!
translation!of!our!findings!to!the!clinical!realm!appears!promising.!
!
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! 17!
Table) 1.) Multivariate! value! of! clinical,! laboratory! and! CCTA! data! for! the! prediction! of! hard!cardiac!events!and!revascularization!procedures.!
) Prediction) of) hard) cardiac)events) Prediction)of)all)cardiac)events!
Parameters) p1value) Hazard)ratios)
95%)Confidence)interval)
p1value) Hazard)ratios)
95%)Confidence)interval)
! Model)A:)Clinical)and)CCTA)data)
Total! number! of! risk! factors!(range!0@7)! NS! 0.50! 0.31 - 1.05! NS! 0.94! 0.67 - 1.32!
MDRD!(ml/min/1.73m2)! NS! 1.03! 0.99 - 1.06! NS! 0.99! 0.98 - 1.01!
Calcium!score!(Agatston!Units)! NS! 1.00! 0.99 - 1.00! NS! 1.00! 0.99 – 1.00!
Plaque)volume)by)tertiles)) 0.006) 17.95! 2.36 - 134.5! 0.003) 2.98! 1.44 – 6.18!
Lumen)narrowing)>)70%) 0.01) 5.50! 1.53 - 19.8! 0.0001) 4.32! 2.06 - 9.07!
! Model)B:)Clinical)data,)biomarkers)and)plaque)volume)by)CCTA)
Total!risk!factors!(range!0@7)! 0.008) 0.43! 0.23 - 0.80! NS! 0.92! 0.66!–!1.29!
MDRD!(ml/min/1.73m2)! NS! 1.00! 0.97!–!1.03! NS! 1.00! 0.98!–!1.02!
HsCRP!(mg/l)! NS! 0.98! 0.86!–!1.12! NS! 0.95! 0.87!–!1.05!
Normal) versus) increased)hsTnT)(<)vs.)≥14)pg/ml)) 0.0008) 10.26! 2.64!–!39.94! 0.036) 2.25! 1.06!–!4.78!
Plaque)volume)by)tertiles) 0.009) 12.14! 1.87!–!78.74! <0.0001) 4.78! 2.27!–!10.04!
! Model)C:)Clinical)data,)biomarkers)and)plaque)composition)
Total!risk!factors!(range!0@7)! 0.016) 0.44! 0.23!–!0.85! NS! 1.00! 0.72!–!1.39!
MDRD!(ml/min/1.73m2)! NS! 1.00! 0.97!–!1.03! NS! 1.00! 0.98!–!1.01!
HsCRP!(mg/l)! NS! 0.99! 0.88!–!1.12! NS! 0.96! 0.87!–!1.05!
Normal) versus) increased)hsTnT)(<)vs.)≥14)pg/ml)) 0.0006) 10.31! 2.72!–!39.00! 0.022) 1.05! 1.01!–!1.09!
None)or)purely)calcified)versus)non1calcified)plaques) 0.0045) 26.08! 2.78–244.99! 0.0002) 6.17! 2.41!–!15.77!
Data!are!presented!as!mean±SD!or!as!number!of!patients!and!corresponding!percentages.!HsTnT!and! hsCRP! indicate! high! sensitive! troponin! T! and! C@reactive! protein,! respectively,! and!MDRD!Modification! of! Diet! in! Renal! Disease.! Atherogenic! risk! factors! include! arterial! hypertension,!hyperlipidemia,!diabetes!mellitus,! advanced!age! (>65yrs.),! cigarette@smoking,! family!history!of!CAD,!overweight.!!!!!!!!!!!!!!!
! 18!
!Table)2.)Hard!and!all!cardiac!events!as!a!function!of!hsTnT!and!total!plaque!volume!tertiles.!!
! Hard% cardiac%events%
All% cardiac%events%
% HsTnT)tertiles)
HsTnT%lower%tertile%(3.063.5pg/ml)% 1!(8%)! 6!(17%)!
HsTnT%mid%tertile%(3.668.9pg/ml)% 2!(15%)! 11!(30%)!
HsTnT%upper%tertile%(9.0641.0pg/ml)% 10!(77%)! 19!(53%)!
% Plaque)volume)tertiles)
Plaque%volume%lower%tertile%(0.7632.9%mm3)% 0!(0%)! 1!(3%)!
Plaque%volume%mid%tertile%(33.0686.9%mm3)% 1!(8%)! 5!(14%)!
Plaque%volume%upper%tertile%(87.06331.2%mm3)% 12!(92%)! 30!(83%)!
% Lower) and) upper) tertiles) for)plaque)volume)&)HsTnT)
HsTnT%&%Plaque%volume%lower%tertiles;%N=70%(17%)% 0)(0%)) 0)(0%))
HsTnT% low% tertile%&Plaque%vol.%mid%&%upper% tertiles%or%vice%versa%N=142%(35%)% 1!(8%)! 7!(19%)!
HsTnT%&%Plaque%vol.%mid%&%upper%tertiles;%N=196%(48%)% 12)(92%)) 29)(81%))
!
!
!
!
! 19!
Figure)Captions.)Figure)1.)Flowchart.)521!patients!with!complete!CCTA!and!follow@up!data,!who!consisted!our!study!population.!Figure) 2.) Survival) analysis.) Patients!with! no! or! purely! calcified! plaque! exhibited! preferable!
outcome!compared!to!those!with!non@calcified!plaque!(A).!Especially!patients!with!no!or!purely!calcified! plaque! and! hsTnT<14! pg/ml! showed! no! hard! cardiac! events! (B).! Increased! hsTnT!plasma!concentration!or!plaque!burden!were!both!associated!with!a!higher!rate!of!hard!cardiac!events!(C@D).!Patients!with!both!increased!hsTnT!and!plaque!burden!exhibited!the!highest!rates!
for!hard!and!all!cardiac!events,!followed!by!those!with!either!increased!hsTnT!or!plaque!burden,!whereas!those!with!both!low!hsTnT!and!plaque!burden!demonstrated!excellent!outcome!(E@F).!Cumulative!event!rates!are!also!provided.!(#):!ROC!optimized!values).!Figure)3.)A:)ROC!analysis!for!Calcium!score,!hsTnT!(high@sensitive!Troponin!T),!plaque!volume!and!Duke! clinical! score! to! evaluate! the! accuracy! for! the! prediction! of! hard! cardiac! events.!B:!
Total) χ²) and) IDI) values.) In! a! series! of! Cox! models! and! starting! with! conventional! clinical!
markers! (atherogenic! risk! score! and! Modified! Diet! in! Renal! Disease! (MDRD)),! coronary!
calcification,! lumen! narrowing! and! quantitatively! assessed! plaque! burden! all! provided!
incremental!value! for! the!prediction!of!hard!cardiac!events.!Both!by!χ²!and!by! IDI! (Integrated!
Discrimination!Improvement),!hsTnT!offered!incremental!value!to!clinical!and!CCTA!findings!for!the!prediction!of!outcomes.!!!Supplementary) Figure) 1.) Association) of) hsTnT) with) plaque) burden) and) stenosis.)
Increasing!hsTnT!was!observed!with!increasing!plaque!burden.!Patients!with!stenosis<25%!on!
the! other! hand,! exhibited! lower! hsTnT! compared! to! those! with! stenosis≥25%,! whereas! no!
differences!were!observed!with! further! increasing! lumen!narrowing! (a,! c).!Patients!within! the!
highest! tertile! for! plaque! burden! and! intermediate! stenosis! (50%@75%)! exhibited! the! highest!
rates! for! cardiac! events! of! 83%! and! 58%,! respectively! (b,! d).! Values! are! shown! as!
mean±standard!deviation.)!
Supplementary) Figure) 2.) Patient) case.)This! example! shows! a! case! of! a!male!patient!with! a!
partially! calcified! and! a! non@calcified! lesion! in! the! first! diagonal! branch! and! circumflex! artery!
(red! and! blue! arrows! in! A),! respectively! both! resulting! to! moderate! lumen! narrowing.! His!
baseline! hsTnT!was! 18! pg/ml.! Stress@echocardiography!was! initially! performed!with! negative!
results.!10!months!later!this!patient!presented!in!with!non@ST!elevation!MI!(B),!presumably!due!
to!plaque!rupture!at!both!sites.!!He!then!received!PCI!and!stent!placement!in!both!lesions!(red!&!
blue! arrows)! (C).! CCTA! =! Coronary! CT@Angiography,! NSTEMI! =! non@ST! elevation! myocardial!
infarction,!LCX!=!left!circumflex!artery.!
Supplementary) Figure) 3.) Survival) analysis) by) tertiles.) Rates! for! hard! and! for! all! cardiac!
events!were!markedly!different!between!patients!with!hsTnT!(A@B)!and!plaque!volume!values!
(E@F)! within! the! lower! (hsTnT<3! to! 3.6! pg/ml)! versus! the! upper! tertiles! (hsTnT! 9.0! to! 41.0!
! 20!
pg/ml)! for! both! variables;! markedly! different! rates! for! cardiac! events! with! high! HR! and! χ²!
values!were!also!observed!using!the!predefined!upper!reference!limit!of!14.0pg/ml!(C@D).!
!
Supplementary,Tables.,Supplementary,Table,1.,Demographic,-laboratory-and-cardiac-CT-findings-in-patients-with-and-without-cardiac-events.-
Parameters, All,Patients,,,(n=521),
Patients,w/o,cardiac,events,(n=485),
Patients,with,hard,events,,,(n=13),
Patients,with,late,revasc.,,,(n=23)!
P#values!
- Clinical!data! -Age- 62±10- 62±10- 63±13- 62±10- NS-1.-Advanced-age->-65yrs.- 215-(42%)- 199-(41%)- 6-(46%)- 10-(43%)- NS-2.-Male-gender;-n-(%)- 256-(49%)- 230-(47%)- 10-(77%)- 16-(70%)- 0.02-3.-Arterial-hypertension! 398-(78%)- 364-(75%)- 12-(92%)- 22-(96%)- 0.03-4.-Hyperlipidemia! 330-(64%)- 303-(62%)- 6-(46%)- 21-(91%)- 0.008-5.-Smoking! 139-(27%)- 130-(27%)- 4-(31%)- 5-(22%)- NS-6.-Diabetes-mellitus! 59-(12%)- 51-(11%)- 0-(0%)- 8-(35%)- 0.001-7.-Family-history-of-CAD- 173-(34%)- 160-(33%)- 3-(23%)- 10-(43%)- NS-Sum-of-risk-factors-(0S7)- 3.0-±-1.3- 3.0-±-1.3- 3.2-±-0.8- 4.0-±-1.1- 0.001-Body-mass-index-(kg/m²)- 27.3-±-4.7- 27.2-±-4.7- 28.2-±-6.0- 28.5-±-4.7- NS-Typical-angina- 26-(5%)- 20-(4%)- 2-(15%)- 4-(17%)- 0.004-Atypical-angina- 104-(20%)- 100-(21%)- 1-(8%)- 3-(13%)- NS-Duke-clinical-score-(%)- 51-±-30- 51-±-31*- 49-±-26- 64-±-24- NS-History-of-CAD- 98-(19%)- 79-(16%)- 7-(54%)- 12-(52%)- <0.001-
! Laboratory!data!&!biomarkers! -Serum-creatinine-(mg/dl)- 0.90-±-0.22- 0.89-±-0.22- 0.94-±-0.29- 1.02-±-0.27- 0.01-Serum-urea-(mg/dl)- 35.0-±-10.6- 34.7-±-10.2- 40.8-±-18.9- 38.2-±-9.2- 0.05-MDRD-(ml/min/1.73m2)- 83.5-±-20.6- 83.7-±-20.4- 87.7-±-27.5- 77.1-±-19.9- NS-HsSCRP-(mg/l)- 4.2-±-4.5- 4.2-±-4.7- 4.9-±-2.7- 2.8-±-1.4- NS-HsSTnT-(pg/ml)- 8.6-±-7.1- 8.1-±-6.6- 18.6-±-11.2- 9.9-±-8.4- <0.001-
- Cardiac!computed!tomography!data! -Calcium-score-(Agatston-Units)-
115-±-207- 99-±-184- 267-±-170- 363-±-406- <0.001-
CAD-(any-plaque-or-stenosis)- 250-(49%)- 215-(44%)- 13-(100%)- 22-(97%)- <0.001-Max.-lumen-narrowing-(%)- 28-±-29- 25-±-28- 64-±-15- 65-±-17- <0.001-Lumen-narrowing->-50%- 162-(32%)- 130-(27%)- 12-(92%)- 20-(87%)- <0.001-Lumen-narrowing->-70%- 45-(9%)- 27-(6%)- 5-(38%)- 13-(57%)- <0.001-Plaques-per-patient- 1.2-±-1.8- 1.1-±-1.7- 3.1-±-1.7- 2.8-±-1.9- <0.001-Quantitative-plaque-volume-(mm³)-
39-±-65- 34-±-61- 141-±-79- 90-±-74- <0.001-
- Cardiac!medications! -ßSblockers! 264-(51%)- 235-(48%)- 10-(77%)- 19-(83%)- 0.001-ACE-inhibitors/AT-II-blockers!
274-(53%)- 250-(52%)- 6-(46%)- 18-(78%)- 0.04-Aspirin-or-Clopidogrel! 236-(45%)- 209-(43%)- 6-(46%)- 21-(91%)- <0.001-Coumadin! 42-(8%)- 44-(9%)- 2-(15%)- 3-(13%)- NS-Diuretics! 138-(26%)- 126-(26%)- 5-(38%)- 7-(30%)- NS-Statins- 232-(45%)- 204-(42%)- 6-(46%)- 22-(96%)- <0.001-Calcium-antagonists- 89-(7%)- 77-(16%)- 3-(23%)- 9-(39%)- 0.01-Data-are-presented-as-mean±standard-deviation-or-as-proportions.-hsSTnT-and-hsSCRP-indicate,-high- sensitive- troponin- T- and- CSreactive- protein,- respectively;- ACE- indicates- angiotensinSconverting- enzyme;-max.,-maximal;- AT,- angiotensin;- and-MDRD,-Modification- of- Diet- in- Renal-Disease.-(*,-p=0.04-versus-patients-without-events-for-the-Duke-Clinical-score).-
Supplementary, Table, 2., Univariate- value- of- clinical- laboratory- and- CCTA- data- for- the-prediction-of-hard-cardiac-events-and-revascularization-procedures.-, Prediction,of,hard,cardiac,
events, Prediction,of,all,cardiac,events!
Parameters, pEvalue, Hazard,ratios,
95%,Confidence,intervals,
pEvalue, Hazard,ratios,
95%,Confidence,intervals,
- Clinical,variables,Age- NS- 1.00- 0.95 - 1.06- NS- 1.00- 0.97 - 1.04-Male-gender;-n-(%)- 0.07- 3.20- 0.88 - 11.6- 0.004- 2.88- 1.39 - 5.95-Arterial-hypertension! NS- 3.31- 0.43 - 25.3- 0.02- 5.32- 1.28 - 21.9-Hyperlipidemia! 0.08- 0.37- 0.12 - 1.14- NS- 1.66- 0.78 - 3.52-Smoking! NS- 1.22- 0.37 - 3.95- NS- 0.99- 0.46 - 2.09-Diabetes-mellitus! NS- 0.00- 0.0 - 330222- 0.03- 2.41- 1.10 - 5.27-Family-history- NS- 0.51- 0.14 - 1.87- NS- 1.06- 0.53 - 2.08-Total-risk-factors-(range-0S7)- NS- 1.17- 0.72 - 1.90- 0.001- 1.54- 1.18 - 2.00-
History-of-coronary-artery-disease- 0.02- 3.69- 1.20 - 11.4- <0.0001- 4.54- 2.35-–-8.74-
- Biomarkers,&,Calcium,score,Serum-creatinine-(mg/dl)- NS- 1.65- 0.25 - 10.7- 0.003- 5.25- 1.74 - 15.8-Serum-urea-(mg/dl)- 0.06- 1.04- 0.99 - 1.09- 0.01- 1.03- 1.01 - 1.06-MDRD-(ml/min/1.73m2)- NS- 1.00- 0.98 - 1.03- NS- 0.99- 0.97 - 1.00-HsSCRP-(mg/l)- NS- 1.03- 0.93 - 1.15- NS- 0.98- 0.90 - 1.06-HsSTnT-(pg/ml)- <0.0001- 1.12- 1.07 - 1.17- <0.0001- 1.07- 1.04 - 1.10-HsSTnT-by-tertiles- 0.0086- 3.43- 1.37-–-8.57- 0.0076- 1.76- 1.17-–-2.67-Calcium-score-(Agatston-Units)- 0.005- 1.00- 1.00 - 1.00- <0.0001- 1.00- 1.00 - 1.01-
- CCTA:,Number,of,plaques,&plaque,composition,Total-number-of-plaques-- 0.0003- 1.45- 1.18 - 1.77- <0.0001- 1.41- 1.26 - 1.59-Presence-of-nonScalcified-plaques- <0.003- 22.2- 2.90 - 169.2- <0.0001- 23.5- 3.39 - 17.6-
Number-of-nonScalcified-plaques-(calcium-content<20%)-
<0.02- 1.97- 1.22 - 3.52- 0.05- 1.6- 1.00 - 2.41-
Number-of-partially-calcified-plaques-(calcium-content-20S80%)-
<0.001- 2.27- 1.53-S-3.37- <0.001- 1.92- 1.48-S-2.48-
Number-of-calcified-plaques-(calcium-content->80%)-
0.03- 1.38- 1.04-S-1.85- <0.001- 1.43- 1.20-S-1.68-
- CCTA:,Plaque,volume,&,lumen,narrowing-Plaque-volume-(mm³)- <0.0001- 1.01- 1.00 - 1.01- <0.0001- 1.01- 1.00-- 1.01-Plaque-volume-by-increments-of-10mm³- <0.0001- 1.19- 1.11-S-1.28- <0.0001- 1.14- 1.09-S-1.19-
Plaque-volume-by-tertiles- 0.009- 11.9- 1.87-S-75.70- <0.0001- 5.21- 2.67-S-10.1-Maximal-lumen-narrowing-(0S100%)- 0.0004- 1.05- 1.02 - 1.09- <0.0001- 1.07- 1.05 - 1.09-
Lumen-narrowing->-50%- 0.0006- 7.30- 2.37 - 22.4- <0.0001- 17.3- 8.9 - 33.7-Lumen-narrowing->-70%- 0.002- 24.50- 3.20 - 187.4- <0.0001- 20.4- 7.2 - 57.4-Single-versus-multiSvessel-CAD- 0.0002- 17.57- 3.9-S-78.9- <0.0001- 6.54- 3.28-S-13.1-
Data-are-presented-as-mean±standard-deviation-or-as-number-of-patients-and-corresponding-percentages.-HsTnT-and-hsCRP-indicate-high-sensitive-troponin-T-and-CSreactive-protein,-respectively,-and-MDRD-Modification-of-Diet-in-Renal-Disease.
Figure'1.'
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