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Myocardial Perfusion and Metabolic Imaging in Hypertrophic Cardiomyopathy

Timmer, S.A.J.

2012

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citation for published version (APA)Timmer, S. A. J. (2012). Myocardial Perfusion and Metabolic Imaging in Hypertrophic Cardiomyopathy:Unraveling the Pathophysiology.

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Chapter!5!!

Effects!of!Alcohol!Septal!Ablation!on!Coronary!Microvascular!Function!and!Myocardial!Energetics!in!

Hypertrophic!Obstructive!Cardiomyopathy!!

S.A.J.!Timmer,!P.!Knaapen,!T.!Germans,!P.A.!Dijkmans,!!!!!!!!!!!!!!!!!M.!Lubberink,!J.M.!ten!Berg,!F.J.!ten!Cate,!I.K.!Russel,!!!!!!!!!!!!!!M.J.W.!Gotte,!A.A.!Lammertsma,!A.C.!van!Rossum!

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Am"J"Physiol"Heart"Circ"Physiol"2011;"301:H129O37.!

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PART!II!

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Abstract!

Background:! To! investigate! the! effects! of! alcohol! septal! ablation! (ASA)! on!microcirculatory! function! and! myocardial! energetics! in! patients! with!

hypertrophic! cardiomyopathy! (HCM)! and! left! ventricular! outflow! tract! (LVOT)!

obstruction.!

Methods:! In! fifteen!HCM!patients!who!underwent!ASA,! echocardiography!was!performed! prior! to! and! 6! months! after! the! procedure! to! assess! LVOTG.!

Additionally,![15O]water!PET!was!performed!to!obtain!resting!myocardial!blood!

flow!(MBF)!and!coronary!vasodilator!reserve!(CVR).!Changes!in!LV!mass!(LVM)!

and! volumes! were! assessed! by! CMR.! Myocardial! oxygen! consumption! (MVO2)!

was! evaluated! by! [11C]acetate! PET! in! a! subset! of! 7! patients! to! calculate!

myocardial!external!efficiency!(MEE).!!

Results:!After!ASA,!peak!LVOTG!decreased!from!41±32!to!23±19!mmHg,!p=0.04,!as! well! as! LVM! (215±74! to! 169±63! g,! p<0.001).! MBF! remained! unchanged!(0.94±0.23! to! 0.98±0.15! mL•minH1•gH1,! p=0.45),! whereas! CVR! increased!(2.55±1.23! to! 3.05±1.24,! p=0.05).! Preoperatively,! the! endoHtoHepicardial! MBF!ratio!was! lower! during! hyperemia! compared! to! rest! (0.80±0.18! vs.! 1.18±0.15,!

p<0.001).!After!ASA,!the!endoHtoHepi!hMBF!ratio!increased!to!1.03±0.26!(p=0.02)."Delta!CVR!was!correlated!to!delta!LVOTG!(r=!H0.82,!p<0.001)!and!delta!LVM!(r=!H0.54,!p=0.04).!MEE!increased!from!15±6!to!20±9%!(p=0.04).!Conclusion:!Coronary!microvascular!dysfunction!in!obstructive!HCM!is!at! least!in! part! reversible! by! relief! of! LVOT! obstruction.! After! ASA,! hMBF! and! CVR!

increased!predominantly!in!the!subendocardium.!The!improvement!in!CVR!was!

closely! correlated! to! the! absolute! reduction! in! peak! LVOTG,! suggesting! a!

pronounced! effect! of! LV! loading! conditions! on! microvascular! function! of! the!

subendocardium.! Furthermore,! ASA! has! favourable! effects! on! myocardial!

energetics.!!!

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Introduction!

In!approximately!one!quarter!patients!affected!by!hypertrophic!cardiomyopathy!(HCM),! the! disease!process! of! asymmetrical! septal! hypertrophy! is! complicated!by!dynamic! left! ventricular! outflow! tract! (LVOT)!obstruction!due! to!bulging!of!the!thickened!septum!into!the!outflow!tract!and!abnormal!anterior!motion!of!the!of! the!mitral! valve! during! systole.(26)! Recent! studies! have! demonstrated! that!the! increased! LV! loading! condition! accompanied! with! LVOT! obstruction! is!associated! with! coronary! microvascular! dysfunction.(20,42)! The! poorer!prognosis!of!outflow!tract!obstruction!in!HCM!is,!at! least!in!part,!believed!to!be!mediated! by! the! induction! of! myocardial! ischaemia.(6,9,26,27)! Furthermore,!myocardial!energetics!and!efficiency!are! impaired!in!HCM.(15,39,46)!The! latter!may,! in! analogy! with! dilated! cardiomyopathy,! hold! prognostic!relevance.(22,31,32)! Treatment! strategies! to! alter! the! clinical! course! of! HCM!may!therefore!be!targeted!at!enhancing!coronary!microvascular!function!and/or!restoring!myocardial!energetics.!

Alcohol! septal! ablation! (ASA)! reduces! LVOT! obstruction! and! alleviates!symptoms! in! patients! with! HCM.(40)! Although! randomized! trials! are! lacking,!relief! of!LVOT!obstruction! is! associated!with!a!more! favourable!prognosis.(33)!The!reduction!in!LV!loading!conditions!and!regression!of!LV!hypertrophy!(LVH),!due! to! reversed! remodeling,! could! restore! perfusion! and! improve! myocardial!energetics.(48)!Indeed,!previous!investigations!suggest!that!perfusion!reserve!is!improved! after! LVOT! obstruction! relief.(3,4,16,34,41,51)! These! studies,!however,! have! been! conducted! with! semiHquantitative! perfusion! indices.!Furthermore,! data! regarding! the! effects! of! ASA! on! myocardial! energetics! and!efficiency! are! currently! lacking.! The! present! study!was! therefore! conducted! to!study!the!effects!of!ASA!on!coronary!microvascular!dysfunction!and!energetics!in!patients! with! HCM,! using! positron! emission! tomography! (PET),!echocardiography,! and! cardiovascular! magnetic! resonance! imaging!(CMR).(19,21)!!

Methods!

Fifteen!patients!with!obstructive!HCM!undergoing!ASA! (10!men!and!5!women,!mean!age!55!±!9!years)!were!enrolled! in!the!study.!HCM!was!diagnosed!by!the!presence! of! a! nondilated! and! hypertrophied! LV,! in! the! absence! of! any! other!systemic! or! cardiac! causes! of! LV! hypertrophy,! on! 2Hdimensional! (2D)!echocardiography! (maximal! wall! thickness! >! 15! mm! in! adult! patients).! All!patients! exhibited! an! asymmetrical! pattern! of! septal! hypertrophy.! Coronary!angiography!was!only!performed!prior!to!inclusion,!in!order!to!exclude!coronary!

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artery!disease!(CAD)!and!myocardial!bridging.!The!indication!for!ASA!was!based!

on! a! significant! peak! LVOT! gradient! (LVOTG! ≥! 50! mmHg! at! rest! or! during!Valsalva! maneuver! measured! with! Doppler! echocardiography)! and! symptoms!

(New!York!Heart!Assocation!(NYHA)!Class!II!or!III,!despite!medical!therapy).!The!

ASA! procedure! was! performed! as! described! previously.(49)! The! imaging!

protocol!consisted!of!echocardiography,!PET!and!CMR!within!one!week!prior!to!and! 6! months! after! ASA.! Medication! was! kept! constant! during! the! study.! The!

study!was!approved!by!the!medical!ethics!committees!of!all!participating!centers!

and!all!patients!gave!written!informed!consent.!

Imaging!protocol!

PET!

All!scans!were!performed!in!2D!mode,!using!an!ECAT!EXACT!HR+!(Siemens/CTI,!

Knoxville,! Tennessee,! USA).! The! protocol! was! performed! as! previously!

described.(18,21)!In!short,!after!overnight!fasting,!myocardial!blood!flow!(MBF)!was! measured! using! 1100! MBq! of! oxygenH15Hlabeled! water! under! resting!

conditions! and! during! pharmacologically! induced! hyperemia! with! adenosine!

(140! μg•kgH1•minH1),! and! oxidative! metabolism! was! assessed! using! 550! MBq![11C]acetate.!!

Transaxial!parametric!MBF! images!were!generated!as!described!previously,(2)!!

as!well! as!maximum! intensity! [11C]acetate! uptake! images.! Subsequently,! these!

images!were! reoriented! according! to! the! anatomic! axis! of! the! heart! and! slices!were!displayed!as!shortHaxis!slices.!The!same!reslicing!parameters!were!applied!

to! the! dynamic! [15O]water! and! [11C]acetate! images.! Regions! of! interest! (ROIs)!

were! defined! on! these! images! corresponding! to! septal,! anterior,! lateral,! and!

inferior!walls!of! the! left!ventricle! in! the!basal,!mid,! and!apical!planes.(18)!ROIs!that! did! not! display! water! /! acetate! uptake! after! ASA! (i.e.! indicative! of! scar!

tissue)! were! excluded! from! analysis.! Additional! ROIs! were! defined! in! the! left!

atrial!and!right!ventricular!chamber.!This! latter!set!of!ROIs!was!projected!onto!

the!dynamic! [15O]water! images! in!order! to!generate! tissue! time!activity! curves!(TAC).! These! TACs!were! used! as! imageHderived! input! functions! and! for! use! in!

spillHover!correction!of!myocardial!tissue!TACs.!Using!the!standard!single!tissue!

compartment!model! together!with! these! input! functions,!MBF! (mL•minH1•gH1!of!perfusable!tissue)!was!determined!for!all!myocardial!tissue!time!activity!curves.!

Corrections!were!made! for! left! and! right! ventricular! spillover! effects! by!use! of!

the!method!described!by!Hermansen!et!al.(13)!Kmono!was!fitted!from!the!washout!phase! of! the! [11C]acetate! scan! as! an! index! of! oxidative! metabolism.21! For! the![15O]water! images,! additional! subendocardial! and! subepicardial! layers! were!

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identified!by!dividing!myocardial!ROIs!with!a!central!line.!Coronary!vasodilator!reserve!(CVR)!was!calculated!as!the!ratio!of!hyperemic!MBF!to!resting!MBF.!As!resting!MBF!is!related!to!the!LV!rateHpressureHproduct!(LV!RPP!=!(systolic!blood!pressure! +! peak! LVOTG)! •! heart! rate! (HR)),! corrected! resting!MBF! (MBF! •! LV!RPPH1! •! 10.000)! was! also! determined.! Additionally,! LV! RPP! during! hyperemia!was! calculated.! Resting! coronary! microvascular! resistance! (CMVR)! was!calculated!by!dividing!mean!arterial!pressure! (MAP)!with!MBF,!whilst!minimal!CMVR!was!derived!in!a!similar!fashion,!only!during!infusion!of!adenosine.(19)!!

CMR"

CMR! studies! were! performed! on! a! 1.5HTesla! whole! body! scanner! (Magnetom!Sonata,! Siemens,! Erlangen,! Germany),! using! a! sixHchannel! phasedHarray! body!coil.!After!survey!scans,!a!retroHtriggered,!balanced!steadyHstate!free!precession!gradientHecho!sequence!was!used!for!cine!imaging.!Image!parameters!were:!slice!thickness!5!mm,!slice!gap!5!mm,!temporal!resolution!<!50!ms,!repetition!time!3.2!ms,! echo! time!1.54!ms,! flip! angle! 60!degrees! and! a! typical! image! resolution!of!1.3*1.6!mm.!The!number!of!phases!within!the!cardiac!cycle!was!set!at!twenty.!

After! the! 4H,! 3H,! and! 2Hchamber! view! cines! were! obtained,! a! stack! of! 6H10!transversely! oriented! slices! was! planned! on! an! endHdiastolic! (ED)! 2Hchamber!view!at! the! level!of! the! lower! leading!edge!of! the!mitral!valve!annulus!to!cover!the! left! atrium! (LA).(10)! Subsequently,! a! stack! of! 10H12! short! axis! slices!were!acquired!for!full!coverage!of!the!LV.(25)!Cine!images!were!acquired!during!one!breathHhold! in!mild!expiration.!Left!ventricular!volume!analysis!was!performed!by! manually! drawing! epicardial! and! endocardial! contours!on! all! ED! and! endHsystolic! (ES)!LV!shortHaxis!images.!Global!LV! function!parameters,! including!ED!volume! (LVEDV),!ES! volume! (LVESV),! and! LV!mass! (LVM),! were! then! derived!from!the!cine!images!with!use!of!the!MASS!software!package!(MEDIS,!Leiden,!The!Netherlands).!The! forward!stroke!volume!(SV)!was!obtained! from!the!velocityHencoded!phaseHcontrast!aortic!flow!maps!by!dividing!the!forward!cardiac!output!by!HR.!

Delayed! contrast! enhanced! (DCE)! images! were! acquired! 10H15! minutes! after!intravenous! administration! of! 0.2! mmol•kgH1! gadolinium,! by! using! a! 2D!segmented! inversionHrecovery! prepared! gradientHecho! sequence.! InversionHrecovery! time!was! 250H300!ms.! Hyperenhancement!was! defined! as! an! area! of!signal!enhancement!greater!than!5!SD!of!the!signal!of!nonenhanced!myocardium.!!

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Echocardiography""

Transthoracic! echocardiography! was! performed! using! a! Vivid! 7! (General!ElectricsHVingmed,!Milwaukee,!Wisconsin,!USA),!according!to!the!ACC/AHA/ASE!guidelines.(7)! PulsedHwave!Doppler!was! used! to! derive! the! peak! outflow! tract!pressure! gradient! (peak!LVOTG)!across! the! subvalvular!obstruction,! as!well! as!the!mean!LVOTG.!Mitral!regurgitation!(MR)!and!systolic!anterior!motion!of! the!mitral! valve! (SAM)! were! graded! qualitatively.! LV! ejection! time! (LVET)! was!measured!on!the!continuous!wave!Doppler!trace!from!the!opening!to!the!closure!of!the!aortic!valve.!!

Diastolic"perfusion"time"calculation"

The! RHR! interval! was! measured! at! rest! and! during! hyperemia! on! the! ECG!obtained!during!the!PET!scan.!Diastolic!perfusion!time!(DPT)!(seconds!•!minH1)!=!(RHR! interval! H!LVET)!•!heart! rate!was!subsequently!calculated!during!rest!and!hyperemia.!

Myocardial!external!efficiency!

MEE!was! calculated!according! to! the!equation!depicted!below.(21,46)!External!work!(EW)!was!defined!as! the!product!of!SV!derived!by!MRI!and!mean!LVOTG!plus! mean! arterial! pressure! (MAP).! The! caloric! equivalent! of! 1! mmHg•mL! is!1.33•10H4!J,!whereas!1!mL!O2!is!≈!20!J.!

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Statistics!

Data!were!expressed!as!mean!±!SD.!For!comparison!of!two!data!sets,!a!paired!or!unpaired!Student’s!t!test!was!performed!where!appropriate.!For!the!comparison!of!multiple! data! sets,! oneHway! analysis! of! variance! (ANOVA)!was! applied!with!post! hoc! Bonferroni! adjustment! for! inequality.! Linear! regression! was! used! to!analyze! the! relationship!between!variables.!All! analyses!were!performed!using!SPSS! 14! (SPSS! Inc.,! Chicago,! Illinois,! USA).! A! p! value! <! 0.05! was! considered!statistically!significant.!

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Results!

Study!population!characteristics!

Baseline!and!follow!up!characteristics!are!depicted! in!table!1.!All!HCM!patients!except!three,!in!whom!side!effects!were!considered!intolerable,!used!βHreceptor!blockers!and/or!Ca2+!channelHblockers.!Baseline!peak!LVOTG!during!the!imaging!protocol! averaged! 41! ±! 32! mmHg.! After! ASA,! peak! LVOTG! was! significantly!reduced! to! 23! ±! 19! mmHg! (p" =" 0.04).! Thirteen! patients! exhibited! a! certain!degree!of!MR!at!baseline!(grade!1,!n"=!4;!grade!2,!n"=!6;!grade!3,!n"=!3;!grade!4,!n"=!0).!NYHA!class!at!baseline!was!2.7!±!0.61,!and!was!significantly!reduced!to!1.9!±!0.42!after!ASA!(p"=!0.01).!

Table!1.!Echocardiographic!and!cardiovascular!magnetic!resonance!data!at!baseline!and!during! follow! up.! LVOTG," left" ventricular" outflow" tract" gradient;" LVM," left" ventricular"mass;" LVEDV," left" ventricular" endOdiastolic" volume;" LVESV," left" ventricular" endOsystolic"volume;"SV,"stroke"volume;"LAOsize,"left"atrial"size.!

!Baseline!

(n!=!15)!

Follow!up!

(n!=!15)!P!

Echocardiography! ! ! !

peak!LVOTG!(mmHg)! 41!±!32! 23!±!19! 0.04!

MI!(grade)! 1.8!±!0.9! 1.5!±!0.7! 0.04!

CMR! ! ! !

LVM!(g)! 215!±!74! 169!±!63! <!0.001!

LVEDV!(mL)! 192!±!30! 184!±!28! 0.23!

LVESV!(mL)! 72!±!6! 71!±!22! 0.85!

SV!(mL)! 86!±!27! 92!±!18! 0.02!

LAHsize!(mL)! 161!±!71! 138!±!56! 0.02!

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Hemodynamic!data!

Heart! rates!were! comparable! between! baseline! and! followHup! studies,! both! at!rest!and!during!hyperemia!(Table!2).!Systolic!blood!pressure!(SBP)!at!rest!was!significantly! increased! (p"=! 0.04).! To! the! contrary,! there! was! no! difference! in!resting!diastolic!blood!pressure!(DBP),!resting!LV!mean!arterial!pressure!(MAP),!or!hyperemic!blood!pressures.!Resting!LV!RPP!was!not!significantly!altered!after!ASA! (10292" ±! 3884! to! 8979! ±! 1949! mmHg•bpm•minH1,! p" =! 0.34),! nor! was!hyperemic!LV!RPP!(13137!±!4338!to!11795!±!2884!mmHg•bpm•minH1,!p"=!0.29).!

Table! 2.!Hemodynamics! during! the!PET! studies! at! baseline! and!during! follow!up.!HR,"heart" rate;" SBP," systolic" blood" pressure;" DBP," diastolic" blood" pressure;" LV" MAP," left"ventricular"+"mean"arterial"pressure;"LV"RPP,"left"ventricular"rateOpressure"product."

LVM,!LV!dimensions!and!DCE!

As! listed! in! Table! 1,! LVM! decreased! significantly,! LVEDV! and! LVESV!were! not!significantly!altered,!whereas!SV!increased!and!LA!size!decreased.!

On!average,!infarct!size!was!16!±!6!g!at!6!months!after!ASA,!and!covered!9!±!4%!of! total! LVM.! In! all! patients,! the! infarct! extended! transmurally! throughout! the!interventricular! septum,! predominantly! involving! the! anteroH! and! inferobasal!

! Rest! Hyperemia!

! Baseline! Follow!up!

p! Baseline! Follow!up!

p!

HR!(bpm)! 60!±!11! 62!±!9! 0.70! 85!±!14! 87!±!10! 0.47!

SBP!(mmHg)! 127!±!26! 139!±!22! 0.04! 114!±!17! 120!±!23! 0.38!

DBP!(mmHg)! 74!±!9! 77!±!7! 0.18! 66!±!9! 65!±!7!0.81!

LV!MAP!(mmHg)! 105!±!16! 105!±!13! 0.91! 98!±!14! 92!±!15! 0.31!

LV!RPP!(mmHg!•bpm•minH1)!!

10292!±!3884!

8979!±!1949! 0.34! 13137!±!

4338!11795!±!2884! 0.29!

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segments.! There! was! no! evidence! for! infarctHrelated! hyperenhancement! in!

remote!myocardial!segments.!

Transmural!MBF!

ASA! did! not! significantly! affect! global! resting! transmural!MBF! (0.94! ±! 0.23! to!

0.98!±! 0.15!mL•minH1•gH1,!p"="0.45)! (Fig.! 1A),! or!MBFcorr! (1.00!±! 0.37! to! 1.12!±!0.34!mL•minH1•gH1,!p"=!0.10).! Preoperatively,! the!distribution!pattern!of! resting!MBF! was! somewhat! heterogeneous,! with! lower! MBF! in! the! septum! than! the!

lateral! wall,! although! not! reaching! statistical! significance! (p" =" 0.15,! Table! 3).!After! ASA,! a! similar! heterogeneous! distribution! pattern! of! transmural! resting!

MBF!was!observed!(p"="0.10).!!

Global! transmural! hMBF!did! increase! significantly! postoperatively! from!2.25!±!

0.91!to!2.94!±!1.18!mL•minH1•gH1!(p"=!0.013,!Fig.!1A),!as!well!as!CVR!(2.55!±!1.23!to! 3.05! ±! 1.24,! p" =" 0.05)! and! CVRcorr! (2.38! ±! 0.99! to! 2.88! ±! 1.14,! p" =! 0.03).!Preoperatively,! regional! perfusion! differences! at! rest! became! homogeneous!during!adenosine!infusion,!with!hMBF!not!being!significantly!different!between!

the! septum! and! lateral! wall! (p" =! 0.61,! Table! 3).! After! ASA,! the! distribution!pattern!of!hMBF!remained!homogeneous!(p"=!0.38).!!

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!Figure! 1A.! Baseline! and! follow! up! data! for! global! transmural!MBF! at! rest! and! during!hyperemia,!and!(B)!the!endoHtoHepicardial!MBF!ratio!at!rest!and!during!hyperemia.!

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EndoQtoQepicardial!MBF!

As!listed!in!Table!3,!endocardial!MBF!at!baseline!was!higher!than!epicardial!MBF,!

although! not! reaching! statistical! significance.! During! hyperemia,! endocardial!

MBF! increased! to!a! lesser!extent! than!epicardial!MBF,! resulting! in!a!decreased!

endoHtoHepicardial!hMBF!ratio,!compared!to!rest!(0.80!±!0.18!vs.!1.18!±!0.15,!p"<!0.001,! Fig.! 1B).! After! ASA,! the! endoHtoHepicardial! MBF! ratio! at! rest! was! not!

significantly! altered.! The! endoHtoHepicardial! hMBF! ratio,! however,! did! increase!

(p"=!0.02,!Fig.!1B),!mainly!due!to!a!significant!increase!in!endocardial!hMBF!(p"=!0.004,!Table!3).!As!a!result,!CVR!was!increased!in!the!subendocardium!after!ASA!(p"=!0.03),!but!not!in!the!subepicardium!(p"=!0.90,!Table!3).!!

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Figure! 1B.! Baseline! and! follow! up! data! the! endoHtoHepicardial! MBF! ratio! at! rest! and!during!hyperemia.!

Coronary!microvascular!resistance!and!diastolic!perfusion!time!

CMVR!at!rest!was!comparable!between!baseline!and!followHup!(102!±!26!to!101!

±! 14! mmHg•mlH1•min•gH1,! p! =! 0.88),! whereas! minimal! CMVR! was! slightly!decreased!after!ASA,!although!not!reaching!statistical!significance!(42!±!18!to!34!

±!16!mmHg•mlH1•min•gH1,!p!=!0.07).!ASA!did!not!affect!DPT!at!rest!(40.6!±!4.0!vs.!40.6!±!2.3!s•minH1,!p"=!0.97),!or!during!hyperemia!(32.8!±!4.9!vs!32.8!±!4.1!s•minH1,!p"=!0.98).!

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Table&3.!Subendocardial,!subepicardial!and!regional!MBF,!hMBF!and!CVR!at!baseline!and!during!follow!up.!Endo%and%Epi,%subendocardial%and%subepicardial%blood%flow%(expressed%in%mL•min81•g81);%CVR,%coronary%vasodilator%reserve.!*p%<!0.01!vs.!rest.

! Rest& Hyperemia& CVR&

Global& Endo& Epi& p" Endo/Epi& Endo& Epi& p" Endo/Epi& Endo& Epi& p"

Baseline! 1.03!±!0.24!

0.89!±!0.26! 0.14! 1.18!±!0.15! 1.89!±!

0.84*!2.43!±!0.94*! 0.11! 0.80!±!

0.18*!1.99!±!1.11!

2.94!±!1.38! 0.05!

Follow!up! 1.10!±!0.15!

0.94!±!0.18! 0.01% 1.18!±!0.16! 2.82!±!

1.30*!2.71!±!0.97*! 0.80! 1.03!±!0.26! 2.63!±!

1.34!2.98!±!1.21! 0.45!

p% 0.32! 0.44! % 0.88! 0.004! 0.26! % 0.02! 0.03! 0.90! %

Transmural& Septum& Lateral& p" & Septum& Lateral& p" & Septum& Lateral& p"

Baseline! 0.90!±!0.26!

1.01!±!0.25!

0.15! ! 2.20!±!0.95*!

2.38!±!0.99*!

0.61! ! 2.69!±!1.53!

2.48!±!1.09!

0.66!

Follow!up! 0.92!±!0.29!

1.03!±!0.13!

0.10! ! 2.59!±!1.31*!

3.00!±!1.24*!

0.38! ! 2.92!±!0.12!

2.97!±!0.83!

0.93!

p% 0.76! 0.68! ! ! 0.25! 0.04! ! ! 0.46! 0.12! !

PART%II%%

%86%

Myocardial*oxygen*consumption*and*myocardial*efficiency*

Table%4% lists% the%estimated%MVO2%and%MEE%values%of%7%HCM%patients%at%baseline%and%after%ASA.%MVO2%was%comparable%between%studies%(p"="0.25),%whereas%MEE%increased%significantly%from%15%±%6%%to%20%±%9%%(Fig.%2).%%

%*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

Figure*2.%Baseline%and%follow%up%data%for%myocardial%efficiency.%

Univariate*relationships*between*variables*

Univariate% regression% analysis% revealed% a% significant% relationship% between% the%absolute%change%in%workload%(as%defined%by%the%LV%RPP)%and%the%absolute%change%

in%resting%MBF%(r%=%0.71,%p"=%0.004),%hMBF%(r%=%X0.50,%p%=%0.05)%and%CVR%(r%=%X0.79,%p"<% 0.001).% Additionally,% the% absolute% change% in% resting% LV% RPP% after% ASA%was%directly%correlated%to%the%absolute%change%in%MVO2%(r%=%0.74,%p"=%0.05).%%

% % % % Chapter%5% % % % %

% % % % %

% % % 87%

There%was%no%relationship%between%the%absolute%change%in%LVOTG%and%change%in%resting%MBF%after%ASA.%The%absolute% change% in%LVOTG%was,%however,% inversely%related%to%the%absolute%change%in%CVR%(Fig.%3).%%

Figure* 3.% Linear% relationship% between% the% absolute% change% in% CVR% and% the% absolute%change% in% peak% LVOTG% at% six% months% after% ASA.% The% dotted% lines% represent% the% 95%%confidence%interval%of%the%regression%line.%

There%was% also% no% relationship% between% regression% of% LVH% (as% defined% by% the%absolute%change%in%LVM)%and%the%absolute%change%in%transmural%resting%MBF,%but%a%significant%inverse%relationship%with%the%absolute%change%in%LVM%and%CVR%(Fig.%4).%%%

There%was%a%significant%relationship%between%the%absolute%change%in%hyperemic%DPT%and%CVR%(Fig.%5).%%

*

*

PART%II%%

%88%

*

*

*

*

*

*

*

*

*

*

*

*

Figure* 4.% Linear% relationship% between% the% absolute% change% in% CVR% and% the% absolute%change%in%LVM%at%six%months%after%ASA.%The%dotted%lines%represent%the%95%%confidence%interval%of%the%regression%line.%

*

*

*

*

*

*%

%

Figure* 5.% Linear% relationship% between% the% absolute% change% in% CVR% and% the% absolute%change% in%hyperemic%DPT%at%six%months%after%ASA.%The%dotted% lines%represent% the%95%%confidence%interval%of%the%regression%line.%

! ! ! ! ! ! ! ! !! ! ! ! !

! ! !

Table&4.!Cardiovascular!magnetic!resonance,!oxidative!metabolism!and!myocardial!efficiency!data!of!the!subset!of!HCM!patients.*p#<!0.05!vs.!baseline.!EW,#external#work;#HR,#heart#rate;#LVM,#left#ventricular#mass;#MVO2,#myocardial#oxygen#consumption;#MEE,#myocardial#external#efficiency

& Baseline& Follow&up&

Patient&no.&

EW&(mmHg•mL)&

HR&(bpm)& LVM&(g)&

MVO2&&

(mL•mi&nB1•gB1)&

MEE&(%)&

EW&(mmHg•mL)&

HR&(bpm)& LVM&(g)&

MVO2&(mL•minB

1•gB1)&

MEE&(%)&

1! 12567! 64! 203! 0.12! 21! 10936! 62! 161! 0.11! 27!

2! 10631! 67! 421! 0.08! 14! 7208! 93! 326! 0.14! 11!

3! 7500! 69! 307! 0.12! 9! 7813! 52! 250! 0.09! 13!

4! 6486! 49! 136! 0.07! 21! 7840! 65! 104! 0.12! 28!

5! 8260! 59! 149! 0.12! 18! 8573! 70! 131! 0.12! 28!

6! 5980! 62! 187! 0.16! 8! 5412! 71! 212! 0.14! 9!

7! 7201! 70! 215! 0.13! 12! 10946! 64! 136! 0.17! 24!

Mean!±!SD!

8375!±!2385! 63!±!7! 231!±!

100!0.12!±!0.03! 15!±!6! 8390!±!

1998! 68!±!13! 188!±!79*!

0.13!±!0.03! 20!±!9*!

PART%II%

%90%

Discussion(

In% the% present% study,% transmural% hMBF% and% CVR% were% significantly% increased%

after%ASA,%indicating%that%impairment%of%microcirculatory%function%in%obstructive%

HCM% is,% at% least% in% part,% reversible% by% relief% of% LVOT% obstruction.% The%

improvement% in% CVR% was% attributable% to% increased% hMBF,% especially% in% the%

subendocardial% layers,% and%was% closely% correlated% to% the% absolute% reduction% in%

peak%LVOTG,%as%well%as%to%regression%of%LVM%albeit%to%lesser%extent.%As%a%result,%

the%endoLtoLepicardial%hMBF%ratio%increased%after%ASA,%suggesting%a%pronounced%

effect%of%LV%loading%conditions%on%microvascular%function%of%the%subendocardium.%

These%results%expand%on%previous%semiLquantitative%investigations%regarding%the%

effects% of% relief% of% LVOT% obstruction% on% perfusion% in% HCM% patients,% by% using%

[15O]water% PET% to% study% absolute% changes% in% regional%MBF.% In% addition,% it%was%

demonstrated%for%the%first%time%that%myocardial%efficiency%improves%after%ASA%in%

patients%with%LVOT%obstruction%due%to%HCM,%by%use%of%[11C]acetate%PET.%

Effects(of(ASA(on(transmural(MBF(

The%blunted%CVR%that%characterizes%HCM,% in% the%absence%of%epicardial%coronary%

stenosis,% is% indicative%of%microvascular%dysfunction.(6)%In%these%patients,%CVR%is%

predominantly% limited% by% an% inadequate% increase% in% MBF% in% response% to%

adenosine,(24,35,43)% compared% to% ageLmatched% healthy% subjects.(47)%

Microcirculatory% function% is% impaired% for% several% reasons% in% HCM.% Histological%

examination%has%revealed%remodeling%of%intramural%coronary%arterioles%resulting%

in% a% decreased% crossLsectional% arteriolar% lumen% area,(28,45)% and% concomitant%

increase% in% coronary% vascular% resistance.(23)% Additionally,% pathological% LVH% is%

accompanied% by% a% decreased% capillaryLtoLmyocyte% ratio,(23,45)% i.e.% a% relative%

reduction% in% capillary% density,% the% extent% of% which% has% been% shown% to%

independently% predict% the% reduction% in% hMBF% in%HCM,(20)%when% calculated% on%

the%basis%of%milliliters%per%gram%of%myocardial%tissue.%%

The% absolute% increase% in% CVR% after% ASA% was% correlated% to% regression% of% LVM.%

Albeit%a%moderately%strong%relationship,%the%results%are%in%accordance%to%a%recent%

study% conducted% by% Soliman% et% al.(41)% Similar% results% have% been% found% in%

patients%with%pressureLoverload% cardiomyopathy%due% to% aortic% stenosis,(14,36)%

or% hypertension,(1)% indicating% that% restoration% of% the% capillary% density% by%

regression% of% afterload% dependent% LVH% or% reversed% remodeling% of% arteriolar%

walls%has%favourable%microcirculatory%effects.%

In%addition%to%the%aforementioned%morphological%features,%LV%loading%conditions%

and%wall% stress,% i.e.% extravascular% compressive% forces,% can% further% compromise%

microcirculatory%function.(42)%In%HCM,%CVR%is%more%severely%blunted%in%patients%

% % % % Chapter%5% % % % %% % % % %

% % % %

% % % 91%

with% LVOT% obstruction% compared% to% patients% without,(5,17)% and% the% absolute%reduction%in%CVR%has%been%shown%to%parallel%the%severity%of%LVOT%obstruction.(4)%Whilst% patients% with% LVOT% obstruction% due% to% aortic% stenosis% show% similar%blunting% of% CVR,(37)% coronary% arteriole% remodeling% is% absent% in% these%patients,(44)% providing% additional% evidence% that% augmented% extravascular%resistance% substantially% impedes% perfusion.% During% maximal% vasodilatation,%these% extravascular% forces% in% addition% to% intravascular% resistance,% rather% than%autoregulatory%mechanisms%itself,%become%the%main%determinant%of%MBF.(19)%In%line% with% this% hypothesis,% the% improvement% in% CVR% after% ASA% was% directly%correlated% to% the% absolute% reduction% in% peak% LVOTG.% Contrary% to% these% results,%JörgLCiopor%et%al.% showed% that% improvement%of%CVR% following%septal%myectomy%was% mainly% caused% by% a% reduction% of% resting% MBF.(17)% However,% since% preLinterventional%MBF%was% not% studied,% the% results%were% compared% to% a% group% of%medically% treated%HOCM%patients,% thereby% impeding% valid% interpretation% of% the%effects%of%treatment%on%myocardial%perfusion%in%the%myectomy%group.%In%addition,%the%RPP%in%the%medically%treated%group%was%higher%as%compared%to%the%myectomy%group,% and% inasmuch% as% resting% MBF% is% autoregulated% according% to% oxygen%demand,%this%may%explain%the%differences%in%resting%MBF%between%groups.%

Effects(of(ASA(on(endo7to7epicardial(MBF(

According% to% Laplace's% law,% wall% tension% increases% from% the% subepiLtoLsubendocardial% layer,% hence% creating% an% opposite% transmural% hyperemic%perfusion% pattern,% especially% in% the% presence% of% augmented% LV% loading%conditions.(8)%Indeed,%relief%of% the%LVOT%obstruction%significantly% improved%the%endoLtoLepicardial%MBF% ratio%during%hyperemia.% Interestingly,% endocardial% CVR%was%increased%by%nearly%30%,%whereas%epicardial%CVR%was%not%at%all%affected%by%ASA.%%

Diastolic% filling% of% the% epicardial% arterioles% and% accompanied% subepicardium%precedes%perfusion%of% the%subendocardial% layers,%due%to% the%epicardial%origin%of%the% coronary% vasculature.% The% physiological% implication% is% that% during% systole,%perfusion% at% the% subendocardium% is% compromised,% requiring% compensatory%recovery% from% diastolic% perfusion.% A% shortened% DPT% as% a% result% of% LVOT%obstruction% may% theoretically% hamper% perfusion.% Accordingly,% a% moderately%strong%positive%correlation%was% found%between%the%absolute%change% in%CVR%and%hyperemic% DPT% after% relief% of% LVOT% obstruction,% the% strength% of% which% was%increased% when% only% subendocardial% CVR% was% included% (r% =% 0.68,% p" =% 0.01).%Although% absolute% myocardial% perfusion% is% related% to% DPT,% as% previously%documented%in%patients%with%aortic%valve%stenosis%as%well,(38)%mean%DPT%did%not%significantly% change% between% baseline% and% follow% up.% Hence,% the% observed%changes%in%CVR%after%ASA%cannot%be%attributed%to%changes%in%diastolic%perfusion.%%

PART%II%

%92%

Effects(of(ASA(on(LVM(and(LV(dimensions(

Relief%of%LVOT%obstruction%by%ASA%or%surgical%myectomy%of%the%septum%has%been%associated% with% reversed% remodeling% of% the% LV% in% previous% HCM%investigations.(29,51)%This%can%be%ascribed%to%a%combination%of%alcohol% induced%scarring%and% thinning%of% the%hypertrophied% septum%and% regression%of% afterload%dependent% LVH,% the% latter% presumably% contributing% most% to% LV% mass%reduction.(48)%

In%our%study,%LVEDV%and%LVESV%were%not%significantly%changed%postoperatively,%contrary%to%other%investigations%who%generally%report%significant%increases%in%LV%volumes.(29,30,48,50)% LA% dimensions,% however,% were% significantly% decreased%postoperatively,% likely% reflecting% favourable%effects%of%ASA%on%diastolic% function%and%reduction%of%mitral%regurgitation.(11)%

Effects(of(ASA(on(myocardial(oxygen(consumption(and(efficiency(

Only%limited%data%is%available%on%the%effect%of%ASA%on%MVO2.%In%the%current%study,%both% MVO2%and% LV% RPP% as% an% indirect% marker% of% MVO2% were% not% significantly%affected% by%ASA.% Individual% changes% in%MVO2,% however,% could% be% related% to% the%changes% in% LV% RPP,% suggesting% that% decrements% in% oxidative% metabolism% after%ASA% can% mainly% be% ascribed% to% reduced% workload% due% to% relief% of% LVOT%obstruction,%as%described%earlier%by%Cannon%et%al.(4)%%%

Previously,% it% was% demonstrated% that% mechanical% external% efficiency% (MEE)% is%decreased%compared%to%healthy%subjects,%and%could% independently%be%predicted%by% SV% and% LVM.(46)% Although% peak% LVOTG% was% significantly% reduced%postoperatively,% the% total%amount%of%work%delivered%by% the%LV%was%not%altered,%and%was%mainly% attributable% to% a% significant% increase% in% forward% SV.% However,%due% to% a% substantial% reduction% in% LVM,% the% amount% of% work% per% gram% of%myocardial% tissue% was% significantly% increased.% The% absence% of% a% concomitant%increase%in%MVO2%per%gram%of%myocardial%tissue%resulted%in%an%increased%MEE.%%

Technical(considerations(

Rimoldi% and% coworkers% have%previously% validated% [15O]water%measurements% of%subendoLtoLsubepicardial% MBF% in% pigs,% by% comparison% with% radioactive%microspheres,%using%a%PET%scanner%with%a%similar%resolution%(~6.5%mm)%as%in%this%study.(38)% It%was%demonstrated% that%PET%subendoL%and%subepicardial%perfusion%are% in% fairly%good%agreement%with%the%microsphere%values,%over%a%wide%range%of%MBF%(0.30%–%4.46%mL/min/g).%Since%the%pigs%had%a%small%LV%wall%thickness%(~10%mm),% flow% measurements% were% affected% by% partialLvolume% effects,% due% to% the%limited%scanner%resolution.%Hence,%this%could%have%influenced%our%results%as%well.%

% % % % Chapter%5% % % % %% % % % %

% % % %

% % % 93%

In%human%hearts,% however,% [15O]water%PET%measurements% are% less% confounded%by% partialLvolume% effects% due% to% a% larger% LV% wall% thickness,% especially% in% the%currently% studied%hypertrophied%hearts.% Furthermore,%Rimoldi% et% al.% found% that%transmural% flow% differences% were% actually% underestimated,% i.e.% subendocardial%perfusion%was%overestimated%and% subepicardial%perfusion%was%underestimated,%because% of% the% large% spillover% component% between% both% myocardial% layers.%Thinning% of% the%myocardial%wall% after% ASA%will% increase% partialLvolume% effects,%due% to% treatment% induced% scarring% of% the% septum% and% regression% of% afterloadLdependent% LVH.% As% a% result,% the% actual% border% between% the% endocardial% and%epicardial% layer% may% also% be% changed.% The% effect% on% measurements% of% global%endoLtoLepicardial% flow%ratios% is%expected%to%be%minimal,%however,% inasmuch%as%significant% postoperative% reduction% of% LV% wall% thickness% occurs% only% in% the%septum% (~16%),% and% is% small% throughout% remote% myocardium% (~10%).(48)%Furthermore,% postoperative% hMBF%was% comparable% between% the% subendoL% and%subepicardial% layers.% Hence,% flow% measurements% in% both% layers% do% not% suffer%from% spillover% from%one% another,% as% they% are% similar% in% tracer% activity,% thereby%leaving% the% subendoLtoLsubepicardial% hMBF% ratio% unaffected% by% partialLvolume%effects.%Altogether,%this%suggests%that%the%actual%treatmentLinduced%improvement%in% the% subendoLtoLsubepicardial% hMBF% ratio% may% be% greater% than% currently%measured,%due%to%overestimation%of%the%baseline%endoLtoLepicardial%hMBF%ratio.%In% this% matter,% however,% future% PET% studies% incorporating% improved% spatial%resolution%seem%warranted.%

Limitations(

Despite%the%fact%that%all%patients%had%a%significant%LVOTG%at%the%time%of%inclusion%either% at% rest% or% during% Valsalva% maneuver,% the% degree% of% LVOT% obstruction%during% preoperative% imaging% varied% considerably% intraLindividually,% and% a%significant% LVOT% obstruction% at% rest% (i.e.% ≥% 50%mmHg% at% rest)%was% observed% in%only% 60%% of% patients% (i.e.% 9% had% significant% LVOT% obstruction% at% rest,% 6% only%during% provocation).% The% pressure% gradient% across% the% LVOT% in%HCM%has% been%shown%to%be%dependent%upon%ventricular%filling%and%myocardial%inotropy,%and%the%results% therefore% underline% the% dynamic% aspect% of% LVOT% obstruction% in% these%patients.(12)%Consequently,% however,% the% absolute% reduction% of% LVOTG% by% ASA%was%limited%in%a%number%of%patients,%especially%with%provocable%obstruction%only,%and%even%resulted%in%a%substantial%increase%in%one%subject.%Although%unsuccessful%reduction% of% LVOT% obstruction% in% these% subjects% is% not% uncommon,(48,49)% and%presumably% explains% the% substantial% variations% in%MBF% improvement% following%ASA,%the%data%require%validation%in%a%cohort%of%HCM%patients%with%severe%resting%obstruction.%Nevertheless,%the%results%clearly%indicate%a%significant%overall%benefit%in%coronary%vasodilatory%capacity%after%ASA%in%the%currently%studied%cohort,% the%

PART%II%

%94%

largest% improvement% of% which% was% observed% in% subjects% with% the% greatest%absolute%LVOTG%reduction.%

LVOTG% was% determined% during% resting% conditions% and% related% to% hyperemic%perfusion% induced% by% adenosine% infusion.% During% vasodilating% stress,% however,%preL% and% afterload% values%may% indeed% be% altered.% Although% data% are% lacking,% in%HCM%patients%adenosine%likely%augments%LVOTG.%In%addition,%hyperemic%diastolic%perfusion%time%was%calculated%under%the%presumption%that%ejection%time%between%rest%and%stress%conditions%was%the%same.%This%may%have%introduced%bias%into%the%relationship%between%diastolic%perfusion%time,%LVOTG%and%MBF.%Only%a% limited%number%of%HCM%patients%was%studied%with% [11C]acetate%PET,%and%therefore%the%results%regarding%the%effects%of%ASA%on%myocardial%efficiency%should%be% interpreted%with% care.% Additionally,% due% to% [11C]acetate% kinetics,%myocardial%scar% tissue% is% not% included% in% estimates% of% oxidative% metabolism.% To% prevent%underestimation%of%myocardial%efficiency%after%ASA,% the%septally% located%alcohol%induced%infarct%zone%was%subtracted%from%total%LVM%when%calculating%MEE.%The%noninvasive%estimation%of%EW%in%HCM%is%hampered%by%the%presence%of%mitral%regurgitation,%because%part%of%the%blood%volume%is%ejected%into%the%lowLpressured%LA%during%systole,%as%indicated%by%the%discrepancy%between%LV%enddiastolic%and%Lsystolic%volumes%and%SV.%We%largely%circumvented%this%issue%by%using%forward%SV%only,%acquired%by%MRI%flow%measurements%in%the%ascending%aorta.%%The% continued% use% of% medication% during% the% study% protocol% could% have%introduced%bias% in% the% results.%On% the%other%hand,% inasmuch%as%medication%was%kept% constant,% intraLindividual%variability%was%expected% to%be%minimal%between%studies.% Additionally,% myocardial% haemodynamics% and% [15O]water% PET% studies%were%obtained%simultaneously%to%further%minimize%intraLindividual%changes.(

Conclusion%Coronary% microvascular% dysfunction% in% obstructive% HCM% is% at% least% in% part%reversible% by% relief% of% LVOT% obstruction.% After% ASA,% hMBF% and% CVR% were%predominantly% increased% in% the% subendocardial% layers% of% the%myocardium.%The%improvement% in% CVR% was% closely% related% to% the% absolute% reduction% in% peak%LVOTG,% and% to% a% lesser% degree% to% regression% of% LVM.% These% results% suggest% a%pronounced% effect% of% LV% loading% conditions% on% microvascular% function% of% the%subendocardium,% in% addition% to% LV% hypertrophy.% Furthermore,% ASA% has%favourable%effects%on%myocardial%energetics%in%HCM.%

(

(

% % % % Chapter%5% % % % %% % % % %

% % % %

% % % 95%

References(1.% Antony%I,%Nitenberg%A,%Foult%JM,%Aptecar%E.%Coronary%vasodilator%reserve%in%untreated%and%

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5.% %Cannon% RO% 3rd,% Rosing% DR,% Maron% BJ,% Leon% MB,% Bonow% RO,% Watson% RM,% Epstein% SE.%Myocardial% ischemia% in% patients% with% hypertrophic% cardiomyopathy:% contribution% of%inadequate%vasodilator%reserve%and%elevated%left%ventricular%filling%pressures.%Circulation.%1985;%71:234L43.%

6.% %Cecchi%F,%Olivotto%I,%Gistri%R,%Lorenzoni%R,%Chiriatti%G,%Camici%PG.%Coronary%microvascular%dysfunction% and% prognosis% in% hypertrophic% cardiomyopathy.% N% Engl% J% Med.% 2003;%349:1027L35.%

7.% %Cheitlin%MD,%Armstrong%WF,%Aurigemma%GP,%Beller%GA,%Bierman%FZ,%Davis%JL,%Douglas%PS,%Faxon%DP,%Gillam%LD,%Kimball%TR,%Kussmaul%WG,%Pearlman%AS,%Philbrick%JT,%Rakowski%H,%Thys% DM,% Antman% EM,% Smith% SC,% Jr.,% Alpert% JS,% Gregoratos% G,% Anderson% JL,% Hiratzka% LF,%Hunt% SA,% Fuster% V,% Jacobs% AK,% Gibbons% RJ,% Russell% RO.% ACC/AHA/ASE% 2003% guideline%update%for%the%clinical%application%of%echocardiography:%summary%article:%a%report%of%the%American% College% of% Cardiology/American% Heart% Association% Task% Force% on% Practice%Guidelines% (ACC/AHA/ASE% Committee% to% Update% the% 1997% Guidelines% for% the% Clinical%Application%of%Echocardiography).%Circulation.%2003;%108:1146L62.%

8.% %Dunn%RB,%Griggs%DM%Jr.%Ventricular% filling%pressure%as%a%determinant%of%coronary%blood%flow%during%ischemia.%Am%J%Physiol.%1983;%244:429L436.%

9.% %Elliott%PM,%Gimeno% JR,%Tome%MT,%Shah% J,%Ward%D,%Thaman%R,%Mogensen% J,%McKenna%WJ.%Left% ventricular% outflow% tract% obstruction% and% sudden% death% risk% in% patients% with%hypertrophic%cardiomyopathy.%Eur%Heart%J.%2006;%27:1933L41.%

10.% %Germans%T,%Götte%MJ,%Nijveldt%R,%Spreeuwenberg%MD,%Beek%AM,%Bronzwaer%JG,%Visser%CA,%Paulus% WJ,% van% Rossum% AC.% Effects% of% aging% on% left% atrioventricular% coupling% and% left%ventricular%filling%assessed%using%cardiac%magnetic%resonance%imaging%in%healthy%subjects.%Am%J%Cardiol.%2007;%100:122L7.%

11.% Geske%JB,%Sorajja%P,%Nishimura%RA,%Ommen%SR.%The%relationship%of%left%atrial%volume%and%left%atrial%pressure%in%patients%with%hypertrophic%cardiomyopathy:%an%echocardiographic%and%cardiac%catheterization%study.%J%Am%Soc%Echocardiogr.%2009;%22:961L6.%

12.% Geske% JB,% Sorajja% P,% Ommen% SR,% Nishimura% RA.% Left% ventricular% outflow% tract% gradient%variability%in%hypertrophic%cardiomyopathy.%Clin%Cardiol.%2009;%32:397L402.%

13.% Hermansen%F,%Rosen%SD,%FathLOrdoubadi%F,%Kooner%JS,%Clark%JC,%Camici%PG,%Lammertsma%AA.%Measurement%of%myocardial%blood%flow%with%oxygenL15%labelled%water:%comparison%of%different%administration%protocols.%Eur"J"Nucl"Med%1998;25:751L759.""

PART%II%

%96%

14.% HildickLSmith% DJ,% Shapiro% LM.% Coronary% flow% reserve% improves% after% aortic% valve%replacement% for% aortic% stenosis:% an% adenosine% transthoracic% echocardiography% study.% J%Am%Coll%Cardiol.%2000;%36:1889L96.%

15.% %Ishiwata%S,%Maruno%H,%Senda%M,%Toyama%H,%Nishiyama%S,%Seki%A.%Mechanical%efficiency%in%hypertrophic% cardiomyopathy% assessed% by% positron% emission% tomography% with% carbon%[11]acetate.%Am%Heart%J.%1997;%133:497L503.%

16.% %Jaber%WA,%Yang%EH,%Nishimura%RA,%Sorajja%P,%Rihal%CS,%Elesber%A,%Eeckhout%E,%Lerman%A.%Immediate%improvement%in%coronary%flow%reserve%after%alcohol%septal%ablation%in%patients%with%hypertrophic%obstructive%cardiomyopathy.%Heart.%2009;%95:564L9.%

17.% %JörgLCiopor%M,%Namdar%M,%Turina% J,% Jenni%R,%Schwitter% J,%Turina%M,%Hess%OM,%Kaufmann%PA.%Regional%myocardial%ischemia%in%hypertrophic%cardiomyopathy:%impact%of%myectomy.%J%Thorac%Cardiovasc%Surg.%2004;%128:163L9.%

18.% Knaapen%P,%Boellaard%R,%Gotte%MJ,%Dijkmans%PA,%van%Campen%LM,%de%Cock%CC,%Luurtsema%G,%Visser%CA,% Lammertsma%AA,%Visser%FC.%Perfusable% tissue% index%as% a%potential%marker%of%fibrosis% in%patients%with% idiopathic%dilated%cardiomyopathy.% J%Nucl%Med.%2004;%45:1299L304.%

19.% %Knaapen%P,%Camici%PG,%Marques%KM,%Nijveldt%R,%Bax% JJ,%Westerhof%N,%Gotte%MJ,% JeroschLHerold% M,% Schelbert% HR,% Lammertsma% AA,% van% Rossum% AC.% Coronary% microvascular%resistance:% methods% for% its% quantification% in% humans.% Basic" Res" Cardiol% 2009%September;104(5):485L98.%

20.% %Knaapen%P,% Germans%T,% Camici% PG,% Rimoldi%OE,% ten% Cate% FJ,% ten%Berg% JM,%Dijkmans% PA,%Boellaard% R,% van% Dockum%WG,% Gotte% MJ,% Twisk% JW,% van% Rossum% AC,% Lammertsma% AA,%Visser% FC.% Determinants% of% coronary% microvascular% dysfunction% in% symptomatic%hypertrophic%cardiomyopathy.%Am%J%Physiol%Heart%Circ%Physiol.%2008;%294:H986LH993.%

21.% %Knaapen%P,%Germans%T,%Knuuti% J,%Paulus%WJ,%Dijkmans%PA,%Allaart%CP,%Lammertsma%AA,%Visser% FC.% Myocardial% energetics% and% efficiency:% current% status% of% the% noninvasive%approach.%Circulation.%2007;%115:918L27.%

22.% Km%IS,%Izawa%H,%Sobue%T,%Ishihara%H,%Somura%F,%Nishizawa%T,%Nagata%K,%Iwase%M,%Yokota%M.%Prognostic%value%of%mechanical%efficiency%in%ambulatory%patients%with%idiopathic%dilated%cardiomyopathy%in%sinus%rhythm.%J%Am%Coll%Cardiol.%2002;%39:1264L8.%

23.% %Krams%R,%Kofflard%MJ,%Duncker%DJ,%Von%Birgelen%C,%Carlier%S,%Kliffen%M,%ten%Cate%FJ,%Serruys%PW.% Decreased% coronary% flow% reserve% in% hypertrophic% cardiomyopathy% is% related% to%remodeling%of%the%coronary%microcirculation.%Circulation.%1998;%97:230L3.%

24.%% Lorenzoni%R,%Gistri%R,%Cecchi%F,%Olivotto% I,%Chiriatti%G,%Elliott%P,%McKenna%WJ,%Camici%PG.%Coronary%vasodilator%reserve%is%impaired%in%patients%with%hypertrophic%cardiomyopathy%and%left%ventricular%dysfunction.%Am%Heart%J.%1998;%136:972L81.%

25.% Marcus%JT,%Götte%MJ,%DeWaal%LK,%Stam%MR,%Van%der%Geest%RJ,%Heethaar%RM,%Van%Rossum%AC.% The% influence% of% throughLplane% motion% on% left% ventricular% volumes% measured% by%magnetic% resonance% imaging:% implications% for% image% acquisition% and% analysis.% J%Cardiovasc%Magn%Reson.%1999;%1:1L6.%

26.% Maron%MS,%Olivotto%I,%Betocchi%S,%Casey%SA,%Lesser%JR,%Losi%MA,%Cecchi%F,%Maron%BJ.%Effect%of% left% ventricular% outflow% tract% obstruction% on% clinical% outcome% in% hypertrophic%cardiomyopathy.%N%Engl%J%Med.%2003;%348:295L303.%

27.% %Maron%MS,%Olivotto%I,%Maron%BJ,%Prasad%SK,%Cecchi%F,%Udelson%JE,%Camici%PG.%The%case%for%myocardial%ischemia%in%hypertrophic%cardiomyopathy.%J%Am%Coll%Cardiol.%2009;%54:866L75.%

28.% %Maron% BJ,% Wolfson% JK,% Epstein% SE,% Roberts% WC.% Intramural% ("small% vessel")% coronary%artery%disease%in%hypertrophic%cardiomyopathy.%J%Am%Coll%Cardiol.%1986;%8:545L57.%

29.% %Mazur%W,% Nagueh% SF,% Lakkis% NM,% Middleton% KJ,% Killip% D,% Roberts% R,% Spencer%WH% 3rd.%Regression%of%left%ventricular%hypertrophy%after%nonsurgical%septal%reduction%therapy%for%hypertrophic%obstructive%cardiomyopathy.%Circulation.%2001;%103:1492L6.%

% % % % Chapter%5

% % % % %

% % % % %

% % % %

% % % 97%

30.% %Meliga% E,% Steendijk% P,% Valgimigli% M,% ten% Cate% FJ,% Serruys% PW.% Effects% of% percutaneous%

transluminal%septal%myocardial%ablation%for%obstructive%hypertrophic%cardiomyopathy%on%

systolic% and%diastolic% left% ventricular% function%assessed%by%pressureLvolume% loops.%Am% J%

Cardiol.%2008;%101:1179L84.%

31.% Neubauer%S.%The%failing%heartLLan%engine%out%of%fuel.%N%Engl%J%Med.%2007;%356:1140L51.%

32.% Neubauer% S,%Horn%M,%Cramer%M,%Harre%K,%Newell% JB,% Peters%W,%Pabst%T,% Ertl%G,%Hahn%D,%

Ingwall% JS,% Kochsiek% K.% Myocardial% phosphocreatineLtoLATP% ratio% is% a% predictor% of%

mortality%in%patients%with%dilated%cardiomyopathy.%Circulation.%1997;%96:2190L6.%

33.% %Ommen%SR,%Maron%BJ,%Olivotto%I,%Maron%MS,%Cecchi%F,%Betocchi%S,%Gersh%BJ,%Ackerman%MJ,%

McCully% RB,% Dearani% JA,% Schaff% HV,% Danielson% GK,% Tajik% AJ,% Nishimura% RA.% LongLterm%

effects%of%surgical%septal%myectomy%on%survival%in%patients%with%obstructive%hypertrophic%

cardiomyopathy.%J%Am%Coll%Cardiol.%2005;%46:470L6.%

34.%% Pedone% C,% Biagini% E,% Galema% TW,% Vletter% WB,% ten% Cate% FJ.% Myocardial% perfusion% after%

percutaneous% transluminal% septal% myocardial% ablation% as% assessed% by% myocardial%

contrast% echocardiography% in%patients%with%hypertrophic%obstructive% cardiomyopathy.% J%

Am%Soc%Echocardiogr.%2006;%19:982L6.%

35.% %Petersen% SE,% JeroschLHerold% M,% Hudsmith% LE,% Robson% MD,% Francis% JM,% Doll% HA,%

Selvanayagam% JB,% Neubauer% S,% Watkins% H.% Evidence% for% microvascular% dysfunction% in%

hypertrophic% cardiomyopathy:% new% insights% from%multiparametric% magnetic% resonance%

imaging.%Circulation.%2007;%115:2418L25.%

36.% Rajappan% K,% Rimoldi% OE,% Camici% PG,% Bellenger% NG,% Pennell% DJ,% Sheridan% DJ.% Functional%

changes% in% coronary% microcirculation% after% valve% replacement% in% patients% with% aortic%

stenosis.%Circulation.%2003;%107:3170L5.%

37.% Rajappan% K,% Rimoldi% OE,% Dutka% DP,% Ariff% B,% Pennell% DJ,% Sheridan% DJ,% Camici% PG.%

Mechanisms% of% coronary% microcirculatory% dysfunction% in% patients% with% aortic% stenosis%

and%angiographically%normal%coronary%arteries.%Circulation.%2002;%105:470L6.%

38.% Rimoldi%O,%Schäfers%KP,%Boellaard%R,%Turkheimer%F,%Stegger%L,%Law%MP,%Lammerstma%AA,%

Camici% PG.% Quantification% of% Subendocardial% and% Subepicardial% Blood% Flow% Using% 15OL

Labeled%Water%and%PET:%Experimental%Validation.%J%Nucl%Med.%2006;%47:163L172.%

39.% Sieverding% L,% Jung% WI,% Breuer% J,% Widmaier% S,% Staubert% A,% van% Erckelens% F,% Schmidt% O,%

Bunse% M,% Hoess% T,% Lutz% O,% Dietze% GJ,% Apitz% J.% % ProtonLdecoupled% myocardial% 31P% NMR%

spectroscopy% reveals% decreased% PCr/Pi% in% patients% with% severe% hypertrophic%

cardiomyopathy.%Am%J%Cardiol.%1997;%80:34AL40A.%

40.% %Sigwart% U.% NonLsurgical% myocardial% reduction% for% hypertrophic% obstructive%

cardiomyopathy.%Lancet.%1995;%346:211L4.%

41.% Soliman%OI,%Geleijnse%ML,%Michels%M,%Dijkmans%PA,%Nemes%A,%van%Dalen%BM,%Vletter%WB,%

Serruys% PW,% ten% Cate% FJ.% Effect% of% successful% alcohol% septal% ablation% on% microvascular%

function% in%patients%with%obstructive%hypertrophic%cardiomyopathy.%Am%J%Cardiol.%2008;%

101:1321L7.%

42.% Soliman% OI,% Knaapen% P,% Geleijnse% ML,% Dijkmans% PA,% Anwar% AM,% Nemes% A,% Michels% M,%

Vletter%WB,%Lammertsma%AA,%ten%Cate%FJ.%Assessment%of%intravascular%and%extravascular%

mechanisms% of% myocardial% perfusion% abnormalities% in% obstructive% hypertrophic%

cardiomyopathy%by%myocardial%contrast%echocardiography.%Heart.%2007;%93:1204L12.%

43.% Sotgia%B,%Sciagrà%R,%Olivotto%I,%Casolo%G,%Rega%L,%Betti%I,%Pupi%A,%Camici%PG,%Cecchi%F.%Spatial%

relationship% between% coronary% microvascular% dysfunction% and% delayed% contrast%

enhancement%in%patients%with%hypertrophic%cardiomyopathy.%J%Nucl%Med.%2008;%49:1090L

6.%

44.% Swartzkopff%B,%Frenzel%H,%Dieckerhoff%J,%Betz%P,%Flasshove%M,%Schulte%HD,%Mundhenke%M,%

Motz% W,% Strauer% BE.% Morphometric% investigation% of% human% myocardium% in% arterial%

hypertension%and%valvular%aortic%stenosis.%Eur%Heart%J.%1992;%13:17L23.%

PART%II%

%98%

45.% Swartzkopff% B,% Mundhenke% M,% Strauer% BE.% Alterations% of% the% architecture% of%subendocardial% arterioles% in% patients% with% hypertrophic% cardiomyopathy% and% impaired%coronary%vasodilator%reserve:%a%possible%cause%for%myocardial%ischemia.%J%Am%Coll%Cardiol.%1998;%31:1089L96.%

46.% Timmer%SA,%Germans%T,%Götte%MJ,%Rüssel%IK,%Dijkmans%PA,%Lubberink%M,%ten%Berg%JM,%ten%Cate% FJ,% Lammertsma% AA,% Knaapen% P,% van% Rossum% AC.% Determinants% of% myocardial%energetics%and%efficiency% in%symptomatic%hypertrophic%cardiomyopathy.%Eur% J%Nucl%Med%Mol%Imaging.%2010;%37:779L88.%

47.% Uren% NG,% Camici% PG,% Melin% JA,% Bol% A,% de% Bruyne% B,% Radvan% J,% Olivotto% I,% Rosen% SD,%Impallomeni%M,%Wijns%W.% Effect% of% aging% on%myocardial% perfusion% reserve.% J% Nucl%Med.%1995;%36:2032L6.%

48.%% Van%Dockum%WG,%Beek%AM,%ten%Cate%FJ,%ten%Berg%JM,%Bondarenko%O,%Gotte%MJ,%Twisk%JW,%Hofman%MB,%Visser%CA,% van%Rossum%AC.% Early% onset% and%progression%of% left% ventricular%remodeling% after% alcohol% septal% ablation% in% hypertrophic% obstructive% cardiomyopathy.%Circulation.%2005;%111:2503L8.%

49.% van%Dockum%WG,%ten%Cate%FJ,%ten%Berg%JM,%Beek%AM,%Twisk%JW,%Vos%J,%Hofman%MB,%Visser%CA,% van% Rossum% AC.% Myocardial% infarction% after% percutaneous% transluminal% septal%myocardial%ablation%in%hypertrophic%obstructive%cardiomyopathy:%evaluation%by%contrastLenhanced%magnetic%resonance%imaging.%J%Am%Coll%Cardiol.%2004;%43:27L34.%

50.%% van%Dockum%WG,%Knaapen%P,%Hofman%MB,%Kuijer%JP,%Ten%Cate%FJ,%Ten%Berg%JM,%Beek%AM,%Twisk%JW,%van%Rossum%AC.% Impact%of%alcohol%septal%ablation%on%left%anterior%descending%coronary%artery%blood%flow%in%hypertrophic%obstructive%cardiomyopathy.%Int%J%Cardiovasc%Imaging.%2009;%25:511L8.%

51.%% van% Dockum% WG,% Kuijer% JP,% Götte% MJ,% Ten% Cate% FJ,% Ten% Berg% JM,% Beek% AM,% Twisk% JW,%Marcus% JT,% Visser% CA,% van% Rossum% AC.% Septal% ablation% in% hypertrophic% obstructive%cardiomyopathy%improves%systolic%myocardial%function%in%the%lateral%(free)%wall:%a%follow%up%study%using%CMR%tissue%tagging%and%3D%strain%analysis.%Eur%Heart%J.%2006;%27:2833L9.%

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