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The effect of negative intrathoracic pressure on heart-lung interaction in the presence of elevated lung… Cheyne, William Spencer 2015

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THE EFFECT OF NEGATIVE INTRATHORACIC PRESSURE ON HEART-LUNG INTERACTION IN THE PRESENCE OF ELEVATED LUNG VOLUME AND INCREASED RIGHT VENTRICULAR PRELOAD AND AFTERLOAD.  by   William Spencer Cheyne  B.H.Kin The University of British Columbia – Okanagan, 2012    A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF   MASTER OF SCIENCE   in   The College of Graduate Studies  (Interdisciplinary Studies)   THE UNIVERSITY OF BRITISH COLUMBIA  (Okanagan)   October 2015   © William Spencer Cheyne, 2015 ! ii!Abstract(!While!the!hemodynamic!effects!of!spontaneous!respiration!are!normally!considered!minimal,! large! increases! in! negative! intrathoracic! pressure! (ITP)! are! known! to!impair! left! ventricular! (LV)! function.! Increased! negative! ITP! is! a! hallmark! of!obstructive! respiratory! disease,! and! is! often! accompanied! by! elevations! in! lung!volume! and! changes! to! the! pulmonary! vasculature,! both! of! which! have! adverse!effects!on!LV!function!through!both!series!and!direct!ventricular!interaction!(DVI).!While! the! hemodynamic! effects! of! these! stressors! in! isolation! are! generally! well!established,!the!interaction!of!these!mechanisms,!and!their!summative!effect!on!LV!function,!has!not!been!investigated.!!This! study!examined! the!hemodynamic!effects!of! increased!negative! ITP,!dynamic!lung! hyperinflation! (DH),! increased! pulmonary! vascular! resistance! (PVR)! and!increased! preload! (VL)! alone! and! in! combination! in! healthy,! spontaneously!breathing! humans! using! echocardiography! to! evaluate! LV! volumes! and! geometry.!!Reducing! ITP! on! inspiration! to! F20! cmH2O! significantly! decreased! LV! SV! by! 7%!(p<0.001),!due!to!a!reduced!LV!endFdiastolic!volume!(LVEDV).!DVI!was!implicated!in! this! reduction,! as! evidenced! by! a! significant! increase! in! the! radius! of! septal!curvature!(RSC)!(p=0.002),!indicating!leftward!septal!shift.!DH!alone!also!decreased!LV!SV!by!12%!(p=0.001)!and,!in!combination!with!increased!negative!ITP,!caused!a!greater! reduction! in! LVEDV! than! either! condition! in! isolation! (p=0.001).! This! LV!underFfilling!was!exacerbated!by!increased!PVR,!resulting!in!a!14%!decrease!in!LV!SV! (p=0.001),! which! appears! to! be! partially! mediated! by! DVI,! as! indicated! by!! iii!significant! increases! in!RSC! (p=0.001).!Under! these! conditions,!when!preload!was!increased!by!acute!VL,!we!observed!a!paradoxical!further!decrease!in!LVEDV!(F16%,!p<0.001)!and!thus!LV!SV!(F21%,!p<0.001).!Together!with!the!observed!increase!in!RSC! (p=0.001),! this! is! strong! evidence! for! the! role! of! DVI! in! impairing! LV! filling!under!these!conditions.!!In!conclusion,!large!increases!in!lung!volume!have!a!considerable!deleterious!effect!on!cardiac!function.!Moreover,!at!high!volumes,!DH!may!play!a!larger!role!than!the!associated! increases! in! negative! ITP! in! influencing! hemodynamics.! These! findings!have! important! implications! for! better! understanding! altered! cardiopulmonary!interaction!in!obstructive!respiratory!disease.!( (! iv!Preface(!This! thesis! is!based!on!work!conducted!at! the!Center! for!Heart!Lung!and!Vascular!Health!at!the!University!of!British!Columbia,!Okanagan.!The!study!was!conducted!by!Mr.!William!Cheyne!in!partial!fulfillment!of!the!requirements!for!Master!of!Science,!in! association! with! Dr.! Neil! Eves! as! the! Principal! Investigator! and!Ms.! Alexandra!Williams,! MSc.! Mr.! Cheyne! was! responsible! for! all! aspects! of! this! study,! from!developing! the! proposal! and! submitting! ethics! to! data! collection,! analysis! and!writing! of! this! thesis! as! well! as! preparing! the! manuscript(s)! for! publication.! Mr.!Cheyne!gratefully!acknowledges!the!contributions!of!Dr.!Eves,! for!his!considerable!assistance!with! study!design,! data! interpretation! and! revisions! to! both! this! thesis!and! study! manuscripts,! and! Ms.! Williams’! sonographic! expertise! during! data!collection.!!A!modified! version! of! chapter! 2! is! currently! being! revised! for! publication! by!Mr.!Cheyne,!with!assistance!from!Dr.!Eves.!This!study!received!ethical!approval!from!the!UBC!Clinical!Research!Ethics!Board,!under!the!project!title! ‘Investigating!the!effect!of! changes! in! intrathoracic! pressure! on! heartFlung! interaction! in! the! presence! of!increased!rightFventricular!afterload,!elevated!lung!volume!and!hypervolemia’,!UBC!CREB!number!H14F01163.!( (! v!Table(of(Contents((Abstract(......................................................................................................................................(ii(Preface(.......................................................................................................................................(iv(Table(of(Contents(......................................................................................................................(v(List(of(Tables(..............................................................................................................................(x(List(of(Figures(.........................................................................................................................(xii(List(of(Abbreviations(............................................................................................................(xv(Acknowledgements(............................................................................................................(xvii(Dedication(............................................................................................................................(xviii(Chapter(1:((Review(of(Literature(........................................................................................(1(1.1(Introduction(..................................................................................................................(1!1.2(Overview(of(pulmonary(function(............................................................................(1!1.2.1!Lung!mechanics!F!The!pressureFvolume!relationship!..........................................!1!1.2.2!Mechanics!of!ventilation!....................................................................................................!4!1.2.3!The!role!of!ventilation!in!cardiac!function!–!the!respiratory!pump!...............!6!1.3(Overview(of(cardiac(function(...................................................................................(7!1.3.1!Cardiac!mechanics:!determinants!of!diastolic!function!.......................................!7!1.3.2!Cardiac!mechanics:!determinants!of!systolic!function!.........................................!9!1.3.3!The!pulmonary!circulation!.............................................................................................!11!1.4(Mechanical(cardiopulmonary(interaction(.........................................................(12!1.4.1!Series!versus!direct!ventricular!interaction!...........................................................!12!1.4.2!Effects!of!spontaneous!respiration:!venous!return!and!preload!...................!15!1.4.3!Effects!of!spontaneous!respiration:!afterload!........................................................!18!1.4.4!The!effects!of!increased!negative!intrathoracic!pressure!on!cardiac!function!....................................................................................................................................!20!1.4.5!The!effects!of!increased!lung!volumes!on!cardiac!function!..............................!22!1.4.6!The!effects!of!increased!and!excessive!preload!on!cardiac!function!............!25!! vi!1.4.7!The!effects!of!hypoxicFmediated!increases!in!pulmonary!vascular!resistance!on!cardiac!function!.......................................................................................!27!1.5(Cardiopulmonary(interaction(in(obstructive(respiratory(disease(............(30!1.6(Study(aims(and(hypothesis(.....................................................................................(33!1.6.1!Investigating!the!effects!of!lung!hyperinflation!and!inspiratory!loading!on!cardiac!function!.............................................................................................................!33!1.6.2!Investigating!the!effects!of!increased!right!ventricular!preload!during!inspiratory!loading!.............................................................................................................!36!1.6.3!Investigating!the!interactive!effects!of!increased!pulmonary!vascular!resistance,!lung!volumes!and!negative!intrathoracic!pressure!.......................!37!Chapter(2:(The(effect(of(negative(intrathoracic(pressure(on(heartOlung(interaction(in(the(presence(of(elevated(lung(volume(and(increased(right(ventricular(preload(and(afterload(...................................................................................(41(2.1(Synopsis(of(Chapter(1(...............................................................................................(41!2.2(Methods:(.......................................................................................................................(45!2.2.1!Subjects!...................................................................................................................................!45!2.2.2!Study!design!..........................................................................................................................!45!2.2.2.1!Phase!1!and!2:!Baseline!and!inspiratory!resistance!....................................!46!2.2.2.2!Phase!3:!Dynamic!lung!hyperinflation!..............................................................!47!2.2.2.3!Phase!4:!HeadFdown!tilt!..........................................................................................!47!2.2.2.4!Phase!5:!Hypoxia!........................................................................................................!48!2.2.2.5!Phase!6:!All!interventions!simultaneously!......................................................!49!2.2.3!Specific!methodology!........................................................................................................!49!2.2.3.1!Ventilatory!parameters!...........................................................................................!49!2.2.3.2!Intrathoracic!pressure!measurement!...............................................................!50!2.2.3.3!Echocardiography!measurements!......................................................................!51!2.2.4!Specific!interventions!.......................................................................................................!56!2.2.4.1!Inspiratory!loading!....................................................................................................!56!2.2.4.2!Dynamic!lung!hyperinflation!................................................................................!57!2.2.4.3!Volume!loading!...........................................................................................................!58!! vii!2.2.4.4!Hypoxia!familiarization!trial!.................................................................................!59!2.2.4.5!Hypoxia!intervention!................................................................................................!60!2.2.5!Statistical!analysis!..............................................................................................................!61!2.3(Results(...........................................................................................................................(63!2.3.1!Repeated!baseline!measures!.........................................................................................!64!2.3.2!Effects!of!inspiratory!resistance!on!cardiopulmonary!function!!!!!!(Phase!2)!.................................................................................................................................!66!2.3.3!Effects!of!dynamic!hyperinflation!on!cardiopulmonary!function!!!(Phase!3a)!...............................................................................................................................!70!2.3.4!Effects!of!dynamic!hyperinflation!and!inspiratory!resistive!loading!on!cardiopulmonary!function!(Phase!3b)!.......................................................................!72!2.3.5!Effects!of!headFdown!tilt!on!cardiopulmonary!function!(Phase!4a)!............!74!2.3.6!Effects!of!headFdown!tilt!and!inspiratory!resistive!loading!on!cardiopulmonary!function!(Phase!4b)!.......................................................................!75!2.3.7!Effects!of!hypoxia!on!cardiopulmonary!function!(Phase!5a)!..........................!78!2.3.8!Effects!of!hypoxia!and!inspiratory!resistive!loading!on!cardiopulmonary!function!(Phase!5b)!.......................................................................!81!2.3.9!Effects!of!hypoxia,!dynamic!hyperinflation!and!inspiratory!resistive!loading!on!cardiopulmonary!function!(Phase!5c)!.................................................!83!2.3.10!Effects!of!hypoxia,!dynamic!hyperinflation,!inspiratory!resistive!loading!and!headFdown!tilt!on!cardiopulmonary!function!(Phase!6)!..........!87!2.4(Discussion(....................................................................................................................(91!2.4.1!Effects!of!increased!negative!ITP!on!cardiovascular!function!........................!92!2.4.2!Effects!of!increased!lung!volumes!on!cardiovascular!function!.......................!97!2.4.3!Effects!of!elevated!lung!volumes!and!increased!negative!ITP!on!cardiovascular!function!....................................................................................................!98!2.4.4!Effects!of!volume!loading!on!cardiovascular!function!.....................................!101!2.4.5!Effects!of!volume!loading!with!increased!negative!ITP!on!cardiovascular!function!.................................................................................................!102!2.4.6!Effects!of!increased!pulmonary!vascular!resistance!on!cardiovascular!function!.................................................................................................................................!103!! viii!2.4.7!Effects!of!increased!PVR!with!increased!negative!ITP!on!cardiovascular!function!.................................................................................................................................!104!2.4.8!Effects!of!elevated!lung!volume!and!increased!negative!ITP!on!cardiovascular!function!when!PVR!is!elevated.!..................................................!106!2.4.9!Effects!of!further!increases!in!preload!during!spontaneous!respiration!with!elevated!lung!volumes,!increased!negative!ITP!and!increased!PVR!107!2.5(Summary(of(discussion(.........................................................................................(110!Chapter(3(–(Extended(Discussion(and(Conclusions(.................................................(112(3.1(Extended(discussion(..............................................................................................(112!3.1.1!Negative!intrathoracic!pressure!F!how!much!is!too!much?!...........................!112!3.1.2!Utilizing!hypoxia!and!dynamic!hyperinflation!during!inspiratory!resistive!loading!as!a!novel!model!of!obstructive!respiratory!disease!.....!115!3.1.3!Sex!differences!in!cardiopulmonary!interaction!................................................!120!3.2(Study(limitations(.....................................................................................................(121!3.2.1!Limitations!of!transthoracic!echocardiography!.................................................!121!3.2.2!Acquisition!of!right!ventricular!echocardiographic!data!...............................!124!3.2.3!Limitations!to!analysis!and!interpretation!of!data!across!several!respiratory!and!cardiac!cycles!....................................................................................!125!3.3(Clinical(relevance(....................................................................................................(129!3.4(Future(directions(....................................................................................................(130!3.4.1!Investigating!a!graded!negative!ITP!“doseFresponse”!relationship!to!LV!function!.................................................................................................................................!130!3.4.2!Investigating!integrated!cardiopulmonary!and!cerebrovascular!hemodynamics!...................................................................................................................!130!3.4.3!Investigating!the!effects!of!dynamic!hyperinflation!on!LV!function!and!exercise!tolerance!in!patients!with!COPD!..............................................................!131!3.5(Conclusion(.................................................................................................................(133!References(............................................................................................................................(136((! ix!Appendices(...........................................................................................................................(151(Appendix(A:(Supplemental(Figures(..........................................................................(152!Appendix(B:(Study(Ethics(.............................................................................................(164!B.1!Subject!consent!form!.........................................................................................................!164!B.2!Certificate!of!Ethics!Approval!........................................................................................!172!!( (! x!List(of(Tables(!Chapter(2(Table!2.1!Subject!characteristics!......................................................................................................!63!Table!2.2!Baseline!measures!of!cardiopulmonary!function!(Phase!1)!.............................!65!Table!2.3!The!effect!of!inspiratory!resistive!loading!(Phase!2)!on!cardiopulmonary!function!and!LV!geometry.!.............................................................................................!69!Table!2.4!The!effect!of!dynamic!hyperinflation!(Phase!3a)!on!cardiopulmonary!function!and!LV!geometry.!.............................................................................................!71!Table!2.5!Difference!in!LV!function!between!DH!and!DH!with!IR!......................................!72!Table!2.6!The!effect!of!dynamic!hyperinflation!and!inspiratory!resistive!loading!(Phase!3b)!on!cardiopulmonary!function!and!LV!geometry.!..........................!73!Table!2.7!The!effect!of!headFdown!tilt!(Phase!4a)!on!cardiopulmonary!function!and!LV!geometry.!................................................................................................................!74!Table!2.8!Difference!between!HDT!and!HDT!with!IR!..............................................................!75!Table!2.9!The!Effect!of!headFdown!tilt!and!inspiratory!resistive!loading!(Phase!4b)!on!cardiopulmonary!function!and!LV!geometry.!..................................................!77!Table!2.10!The!effect!of!hypoxia!(Phase!5a)!on!cardiopulmonary!function!and!LV!geometry.!...............................................................................................................................!80!Table!2.11!The!effect!of!hypoxia!and!inspiratory!resistive!loading!(Phase!5b)!on!cardiopulmonary!function!and!LV!geometry.!........................................................!82!Table!2.12!Difference!in!LV!function!between!normoxic!and!hypoxic!DH!with!IR!.....!83!Table!2.13!The!effect!of!hypoxia,!dynamic!hyperinflation!and!inspiratory!resistive!loading!(Phase!5c)!on!cardiopulmonary!function!and!LV!geometry.!..........!86!Table!2.14!Difference!in!LV!function!between!Phase!5c!and!Phase!6!..............................!87!Table!2.15!The!effect!of!hypoxia,!dynamic!hyperinflation,!headFdown!tilt!and!inspiratory!resistive!loading!(Phase!6)!on!cardiopulmonary!function!and!LV!geometry.!................................................................................................................!89!Table!2.16!Interactive!effects!of!DH,!HDT!and!hypoxia!with!IR!on!cardiovascular!function!and!LV!geometry!..............................................................................................!89!(! xi!Chapter(3(Table!3.1!Changes!in!LV!function!and!geometry!during!DH!(Phase!3a)!relative!to!during!IR!(Phase!2).!........................................................................................................!116!Table!3.2!Summary!of!changes!to!LV!function!between!IR!alone!(phase!2)!and!DH!with!IR!(phase!3b),!and!subsequently!changes!between!normoxic!(phase!3b)!and!hypoxic!(phase!5c)!DH!with!IR.!.................................................!119!Table!3.3!Sex!differences!in!the!cardiovascular!response!to!IR!(Phase!2)!and!DH!(Phase!3a)!...........................................................................................................................!121!!( (! xii!List(of(Figures(!Chapter(1(Figure!1.1!Total!respiratory!system!compliance!as!a!function!of!lung!and!chest!wall!compliance!....................................................................................................................!3!Figure!1.2!The!pressure!volume!relationship!of!the!LV.!...........................................................!9!Figure!1.3!Illustration!of!direct!ventricular!interaction!(DVI)!from!a!parasternal!shortFaxis!view!at!endFdiastole!....................................................................................!14!Figure!1.4!The!normal!venous!return!curve!initially!proposed!by!Guyton!et#al!(1957)!......................................................................................................................................!17!Figure!1.5!Changes!to!total!pulmonary!vascular!resistance!(PVR),!as!a!function!of!alveolar!and!extraFalveolar!vessel!resistance,!in!response!to!changes!in!lung!volume!..........................................................................................................................!23!Figure!1.6!Acute!volume!loading!increases!cardiac!output!(point!B)!by!increasing!preload!(upward!shift!of!venous!return!curve),!relative!to!cardiac!output!achieved!under!normal!loading!conditions!(point!A),!assuming!no!change!to!the!cardiac!function!curve.!.................................................................!26!Figure!1.7!The!theorized!effects!of!DH!on!LV!function!...........................................................!34!Figure!1.8!The!theorized!effects!of!DH!during!inspiratory!loading!on!LV!function!....!35!Figure!1.9!The!theorized!effects!of!DH!during!IR!in!hypoxic!conditions!on!LV!function!...................................................................................................................................!38!Figure!1.10!The!theorized!effects!of!additional!preload!under!the!same!conditions!on!LV!function!......................................................................................................................!39!Chapter(2(Figure!2.1!Flowchart!of!Study!Protocol!.........................................................................................!46!Figure!2.2!Balloon!catheter!(a)!being!inserted!into!subject’s!nasal!passage!after!local!anaesthesia!(b)!.........................................................................................................!51!Figure!2.3!Example!of!IVC!measurement!......................................................................................!53!Figure!2.4!Example!of!tricuspid!regurgitation!velocity!jet!(a)!and!MFmode!velocity!tracing!in!normoxic!(b)!and!hypoxic!(c)!conditions.!...........................................!54!Figure!2.5!Method!for!Determining!Radius!of!Septal!Curvature!(RSC).!..........................!56!! xiii!Figure!2.6!Adapters!used!to!fit!inFline!resistance!to!inspiratory!or!expiratory!port!of!HansFRudolf!nonFrebreather!mouthpiece!(a),!and!interchangeable!resistances!(b)!marked!with!flow!bore!size!in!mm.!............................................!57!Figure!2.7!InFline!2mm!bore!breathing!resistances!mounted!to!both!the!inspiratory!(a)!and!expiratory!(b)!ports!of!the!HansFRudolph!nonFrebreather!mouthpiece!....................................................................................................!58!Figure!2.8!Subject!in!20°!HDT!leftFlateral!position!with!echocardiographic!measures!being!collected!................................................................................................!59!Figure!2.9!Subject!shown!in!HDT!leftFlateral!position!breathing!hypoxic!gas!from!Douglas!bag!reservoir!......................................................................................................!61!Figure!2.10!ITP!changes!across!all!phases!as!depicted!by!mean!expiratory!(light!blue!bars)!and!inspiratory!(dark!blue!bars)!esophageal!pressure!(Pes)!....!67!Figure!2.11!Respiratory!cycle!times!across!all!phases!............................................................!68!Figure!2.12!Inspiratory!capacity!(IC)!at!baseline!(P1)!and!across!all!phases!involving!DH!.........................................................................................................................................................!71!Figure!2.13!Difference!in!right!ventricular!systolic!pressure!from!normoxia!to!hypoxia!....................................................................................................................................!78!Figure!2.14!SubFxiphoid!view!of!the!IVC!from!the!same!subject!during!normoxia!at!maximal!diameter!(a)!and!during!sniff!test!(b),!and!in!hypoxia!at!maximal!diameter!(c)!and!during!sniff!test!(d).!....................................................!79!Figure!2.15!LV!volumes!and!ejection!fraction!(EF)!across!all!phases!..............................!85!Figure!2.16!Cardiac!output!(Q)!as!a!product!of!changes!to!stroke!volume!(SV)!and!heart!rate!(HR)!across!all!phases!................................................................................!90!Figure!2.17!Parasternal!shortFaxis!view!at!the!mitral!level!of!the!same!subject!at!baseline!(phase!1)!at!endFdiastole!(a)!and!end!systole!(c)!versus!during!phase!6!at!endFdiastole!(b)!and!endFsystole!(d)!................................................!109!Chapter(3(Figure!3.1!Theorized!relationship!between!inspiratory!pressure!sustained!across!multiple!cardiac!cycles!and!the!effect!on!LV!SV!.................................................!113(! xiv!Figure!3.2!Observed!differences!between!inspiratory!and!expiratory!left!ventricular!endFdiastolic!volume!(LVEDV)!and!left!ventricular!stroke!volume!(SV)!across!all!phases!....................................................................................!128!Appendix(A(Figure!A.1!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!IR!(Phase!2)!............................................................................................!152!Figure!A.2!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!DH!(Phase!3a)!........................................................................................!153!Figure!A.3!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!DH+IR!(Phase!3b)!................................................................................!154!Figure!A.4!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!HDT!(Phase!4a)!.....................................................................................!155!Figure!A.5!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!HDT+IR!(Phase!4b)!.............................................................................!156!Figure!A.6!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!Hypoxia!(Phase!5a)!.............................................................................!157!Figure!A.7!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!Hypoxia+IR!(Phase!5b)!......................................................................!158!Figure!A.8!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!Hypoxia+DH+IR!(Phase!5c)!.............................................................!159!Figure!A.9!Individual!(coloured!lines)!and!mean!(thick!black!line)!cardiovascular!responses!to!all!interventions!(Phase!6)!...............................................................!160!Figure!A.10!Changes!to!respiratory!rate!(RR),!tidal!volume!(VT)!and!minute!ventilation!(VE)!across!all!phases.!...........................................................................!161!Figure!A.11!Changes!to!mean!arterial!pressure!(MAP),!systemic!vascular!resistance!(SVR)!and!peripheral!capillary!oxygen!saturation!(SpO2)!across!all!phases!..............................................................................................................!162!Figure!A.12!Changes!in!radius!of!septal!curvature!(RSC)!and!radius!of!LV!free!wall!curvature!(RFWC)!at!endFdiastole!(ED)!and!endFsystole!(ES)!across!all!phases!...................................................................................................................................!163!! xv!List(of(Abbreviations ANOVA( Analysis!of!variance!AV( Atrioventricular!BMI( Body!mass!index!CBF( Cerebral!blood!flow!cmH2O( Centimeters!of!water!(a!unit!of!pressure)!COPD( Chronic!obstructive!pulmonary!disease!COV( Coefficient!of!variation!CVI( Caval!respiratory!index!DH( Dynamic!hyperinflation!(of!the!lung)!DVI( Direct!ventricular!interaction!ECG( Electrocardiogram!EELV( EndFexpiratory!lung!volume!EF( Ejection!fraction!EFL( Expiratory!flow!limitation!EILV( EndFinspiratory!lung!volume!EL( Expiratory!loading!FEV1( Forced!expiratory!volume!in!one!second!FiO2( Fraction!of!inspired!oxygen!FRC( Functional!residual!capacity!FVC( Forced!vital!capacity!HDT( HeadFdown!tilt!IC( Inspiratory!capacity!ICA( Internal!carotid!artery!IL( Inspiratory!loading!(aka.!Inspiratory!resistance)!iPEEP( Intrinsic!positive!endFexpiratory!pressure!(aka.!AutoFPeep)!IR( Inspiratory!resistance!(aka.!Inspiratory!loading)!ITP( Intrathoracic!pressure!IVC( Inferior!vena!cava!LV( Left!ventricle!LVEDV( Left!ventricular!endFdiastolic!volume!LVESV( Left!ventricular!endFsystolic!volume!MAP( Mean!arterial!pressure!MCA( Middle!cerebral!artery!MEP( Maximum!expiratory!pressure!MIP( Maximum!inspiratory!pressure!P1( Phase!1:!baseline!measurements!P2( Phase!2:!inspiratory!resistance!P3a( Phase!3,!part!a:!dynamic!lung!hyperinflation!P3b( Phase!3,!part!b:!dynamic!lung!hyperinflation!with!inspiratory!resistance!P4a( Phase!4,!part!a:!headFdown!tilt!P4b( Phase!4,!part!b:!headFdown!tilt!with!inspiratory!resistance!P5a( Phase!5,!part!a:!baseline!hypoxic!measurements!P5b( Phase!5,!part!b:!inspiratory!resistance!under!hypoxic!conditions!! xvi!P5c( Phase!5,!part!c:!dynamic!lung!hyperinflation!with!inspiratory!resistance!under!hypoxic!conditions!P6( Phase!6:!dynamic!lung!hyperinflation!with!inspiratory!resistance!and!headFdown!tilt!under!hypoxic!conditions!PAP( Pulmonary!artery!pressure!Pes! Esophageal!pressure!PFT( Pulmonary!function!test!PSA( Parasternal!shortFaxis!PVR( Pulmonary!vascular!resistance!Q( Cardiac!output!RAP( Right!atrial!pressure!RFWCOED( Radius!of!LV!freeFwall!curvature!at!endFdiastole!RFWCOES( Radius!of!LV!freeFwall!curvature!at!endFsystole!RR( Respiratory!rate!RSCOED( Radius!of!septal!curvature!at!endFdiastole!RSCOES( Radius!of!septal!curvature!at!endFsystole!RV( Right!ventricle!RVEDV( Right!ventricular!endFdiastolic!volume!RVESV( Right!ventricular!endFsystolic!volume!RVSP( Right!ventricular!systolic!pressure!SpO2( Peripheral!capillary!oxygen!saturation!SV( Stroke!volume!SVC( Superior!vena!cava!SVR( Systemic!vascular!resistance!TCD( Transcranial!Doppler!ultrasound!TDI( Tissue!Doppler!imaging!TE( Expiratory!time!TEE( Transesophageal!echocardiography!TI( Inspiratory!time!TI/TTOT( Inspiratory!time/total!respiratory!cycle!time!TLC( Total!lung!capacity!TRV( Tricuspid!valve!regurgitation!velocity!TTE( Transthoracic!echocardiography!VA/Q( Alveolar!ventilation/perfusion!ratio!VE( Minute!ventilation!VL( Volume!load!VR( Residual!volume!VT( Tidal!volume!WOB( Work!of!breathing!( (! xvii!Acknowledgements((I!offer!my!sincere!gratitude!to!the!University!of!British!Columbia!Okanagan,!and!the!Center!for!Heart!Lung!and!Vascular!Health!(CHLVH)!for!the!opportunity!to!pursue!my! graduate! education! at! a! worldFclass! facility! under! the! tutelage! of! remarkably!talented!and!inspiring!Professors.!I!would!like!to!thank!my!supervisory!committee!for! their! continual!encouragement!and! insight! into! this!project,! and!my! fellow! lab!mates! for! their!assistance!and!camaraderie!over! the! last! two!years.!Additionally,! I!would!like!to!thank!the!College!of!Graduate!Studies’!scholarship!programs!for!their!financial!assistance!throughout!my!program.!!I!owe!special!thanks!to!Dr.!Neil!Eves!for!his!unwavering!enthusiasm!and!countless!hours!of!assistance!and!sage!counsel!in!completing!this!thesis.!Dr.!Eves’!dedication!to!his!students!and!his!research!is!truly!inspirational,!and!I!will!be!forever!grateful!to! have! had! the! opportunity! to! study! under! his! supervision,! and! for! everything! I!have!learned!in!the!process.!!Finally,! I! would! like! to! thank!my! family! and! friends! for! their! continued! love! and!support! throughout!my! graduate! studies,!without!whom!none! of! this!would! have!been!possible.!( ( 	 !! +))*$+)*,   "!!%   #	 %" ( &'#! 1!Chapter(1:((Review(of(Literature(1.1(Introduction(The!heart!and!lungs!are!both!functionally!and!anatomically!coupled,!and!as!such!the!process! of! ventilation! significantly! impacts! cardiovascular! function.! The!mechanisms! governing! this! interaction! are! complex! and! often! have! conflicting!effects! on! hemodynamics.! Thus,! while! heartFlung! interaction! has! been! of!considerable! research! interest! for! over! 60! years1,2,! many! of! these! complex!mechanisms!and!their!role! in! influencing!hemodynamics! in!health!and!disease!are!not!well! understood.!HeartFlung! interaction! is! generally! discussed! in! terms!of! the!effects! of! changes! to! the! pressureFvolume! relationship! of! the! lung! on! cardiac!function.!These!effects!act!on!the!right!and!left!sides!of!the!heart!differently,!which!is!a! function! of! the! anatoFphysiological! coupling! of! the! heart! and! lungs! through! the!pulmonary!circulation,!as!well!as!their!coexistence!within!the!sealed!chest!cavity.!To!understand! these! complex! interactions,! a! brief! overview! of! both! pulmonary! and!cardiovascular!structure!and!function!is!necessary.!!1.2(Overview(of(pulmonary(function(1.2.1!Lung!mechanics!0!The!pressure0volume!relationship!At! the! level! of! the! lung,!mechanical! forces! implicit! to! pulmonary! function! can! be!divided!into!static!and!dynamic!forces.!Static!forces!are!considered!forces!acting!on!the! lung! primarily! through! changes! in! intrathoracic! pressure! (ITP),! which!manipulate!the!pressureFvolume!relationship3,!while!dynamic!forces!are!considered!! 2!the! dynamics! of! airflow! into! and! out! of! the! lung,! which! are! governed! by! flow!patterns! and! airway! resistance4.! The! most! fundamental! aspect! of! respiratory!mechanics,!which!also!has!the!largest!influence!on!hemodynamics,!is!the!transmural!pressureFvolume!relationship,!which!is!altered!during!any!respiratory!event.!!The!pressureFvolume!relationship!of!the!respiratory!system,!was!first!described!by!Fenn#et#al#in!19465,6.!Since!then,!considerable!work!in!this!area!has! led!to!a!better!understanding!of!the!physiological!importance!of!this!relationship,!and!how!it!may!change!in!disease.!Both!the!lung!and!the!chest!wall!have!their!respective!pressureFvolume! relationships,! generally! referred! to! as! compliance! curves.! Compliance!describes! the! slope! of! the! pressureFvolume! line,! and! is! defined! as! the! change! in!volume!for!a!given!change!in!pressure6.!The!lung!and!chest!wall!compliance!curves!are! integrated! to! define! total! respiratory! system! compliance! (Figure! 1.1),! which!ultimately! dictates! the! performance! of! mechanical! ventilation.! The! physiological!importance!of!total!respiratory!system!compliance!is!that,!during!resting!breathing!in!healthy!individuals,!the!system!is!optimized!such!that!minimal!changes!in!ITP!are!needed! to! generate! the! necessary! tidal! volumes! (VT)! above! functional! residual!capacity!(FRC)!to!maintain!adequate!alveolar!ventilation!(VA).!This! is!essential!not!only! to! minimize! the! energy! cost! of! breathing,! but! also! because! changes! to! ITP!generated!during!ventilation!inherently!affect!hemodynamics.!As!such,!spontaneous!breathing! at! rest! in! healthy! humans! has! minimal! influence! on! cardiovascular!function7.! However,! changes! to! respiratory! system! compliance! resultant! from!respiratory! disease,! and! concomitant! changes! to! lung! volume,! can! dramatically!! 3!change!where!on!the!compliance!curve!the!respiratory!system!is!operating.!In!this!scenario! the! ITP! swings! required! to! generate! adequate! VA! may! be! greatly!exaggerated8.! Thus,! increases! in! ITP! swings! in! respiratory! disease! can! have!significant!implications!for!cardiac!function9.!!!!!Figure!1.1!Total!respiratory!system!compliance!as!a!function!of!lung!and!chest!wall!compliance!(( (! 4!1.2.2!Mechanics!of!ventilation!Air! movement! in! and! out! of! the! lung! is! driven! by! changes! in! alveolar! pressure!relative! to!atmospheric!pressure,!which! is! governed!by! changes! in! ITP.! In!healthy!individuals!during!resting!breathing,!both!inspiration!and!expiration!are!performed!in!a!negative!pressure!environment.!During!inspiration,!ITP!becomes!more!negative!relative!to!atmospheric!pressure,!while!during!expiration!ITP!becomes!less!negative!as!the!respiratory!system!returns!to!functional!residual!capacity!(FRC)10.!The!forces!and! mechanisms! generating! these! pressure! differentials! during! inspiration! and!expiration! are,! however,! fundamentally! different.! At! the! start! of! a! normal! resting!inspiration,! lung! volume! is! at! FRC,! or! the! relaxation! volume! of! the! respiratory!system!(Figure!1.1).!At!FRC,!the!elastic!forces!acting!on!the!lung!and!chest!wall!are!equal!and!opposite10.!To!increase!lung!volume!above!FRC!these!elastic!forces!must!be!overcome,!thus!inspiration!is!an!active!process!driven!primarily!by!contraction!of!the!diaphragm!at!rest,!with!increasing!contribution!of!accessory!inspiratory!muscles!as!ventilatory!demands!increase!(i.e.!during!exercise)11.!The!movement!of!air!itself!generates! an! oppositional! force! to! movement! through! viscous! and! turbulent!resistance,! which! must! also! be! overcome,! and! therefore! the! classical! view! of!respiratory! mechanics! is! that! the! force! required! of! the! inspiratory! muscles! is!considered! the!sum!of! these!elastic!and!resistive! forces10,11.!However!more!recent!work!outlines!the!importance!of!the!abdominal!wall!during!the!inspiratory!process,!as! it! has! been! suggested! that! extrusion! of! the! abdominal! wall! at! endFexpiration!allows! for! subsequent! distal! movement! of! the! diaphragm! and! therefore! the!diaphragm! may! be! more! of! a! flowFgenerator! than! a! pressureFgenerator12,13.!! 5!AbdominoFthoracic! interaction! is! also! implicit! in! hemodynamics,! as! will! be!discussed!in!Section!1.4.2,!and!as!such!the!role!of!the!abdomen!need!be!considered!in!all!aspects!of!cardiopulmonary!interaction14.!!Expiration! is! a! passive! process! at! rest,! driven! by! the! stored! elastic! energy! from!distension! of! the! lung! and! chest! wall! during! inspiration10.! An! important!consideration! for! the!expiratory!process! is! that!only! the!energy!used! to!overcome!elastic! forces! is! stored! and! available! to! power! expiration,! therefore,! in! a! scenario!where! airway! resistance! has! largely! increased! through! increased! viscosity! or!turbulent! flow,!expiration!may!become!an!active!process.!This!most!notably! is! the!case! in!COPD,!where! floppy! airways,! airway! inflammation! and! airway! remodeling!dramatically!increase!airway!resistance!and!thus!the!required!work!of!breathing15.!The! increased!airway! resistance! results! in!expiratory! flow! limitation! (EFL),!which!increases! ITP! generation! and! operational! lung! volumes! to! meet! ventilatory!demands,! both! of! which! influence! cardiopulmonary! interaction! through!mechanisms!that!will!be!discussed!in!Section!1.4.!!While! the!healthy!human!has!the!ability! to! increase!ventilation!15F20!times!above!resting! levels,! the! required!work!of!breathing! (WOB)! to!do!so! is!nearly!500! times!that! of! the! resting!WOB11.! This! raises! two! important! considerations;! first,! resting!breathing! is! ideally! situated! near! FRC! such! that! the! requirements! to! overcome!elastic! forces! are! minimal,! and! second;! the! relationship! between! VE! and!WOB! is!exponential,! such! that! changes! to! respiratory! system! compliance! or! airway!! 6!resistance! have! a! large! impact! on! WOB.! Given! that! an! increase! in! WOB! will!inherently! increase! the! magnitude! of! ITP! swings! during! ventilation,! especially!during!inspiration,!this!has!important!implications!for!cardiopulmonary!interaction.!#1.2.3!The!role!of!ventilation!in!cardiac!function!–!the!respiratory!pump!During!spontaneous!respiration!in!healthy!humans,!inspiratory!pressure!generation!is!utilized!to!increase!blood!flow!back!to!the!heart!and,!in!turn,!blood!flow!out!of!the!heart! to! enhance!perfusion! of! vital! organs16.! This! process,! termed! the! respiratory!pump,! is! driven! by! the! change! in! intrathoracic! pressure! associated! with!inspiration16.! ITP! becomes! more! negative! during! inspiration,! which! increases!venous! return! to! the! heart,! and! consequently! right! ventricular! stroke! volume!increases.!Series!ventricular!interaction,!whereby!each!ventricle!ejects!all!the!blood!it! receives! from! the! other! ventricle! (a! consequence! of! the! FrankFStarling!mechanism)!dictates!that!cardiac!output!from!the!right!side!of!the!heart!must!match!the! left! side! of! the! heart,! therefore! increasing! rightFsided! output! will! ultimately!increase! leftFsided! output17.! Moreover,! small! increases! in! negative! inspiratory!pressure!beyond!normal! resting! ITP! swings!have!been! shown! to! further! augment!stroke! volume18,19,20.! This! has! led! to! the! theorized! role! for! harnessing! the!respiratory!pump!through!mild!inspiratory!loading!as!a!countermeasure!for!various!clinical!presentations!characterized!by!hypotension21.!It!is!generally!considered!that!the!process!of!inspiration!is!essential!to!maintaining!adequate!perfusion!to!the!brain!and! other! vital! organs16,21.! However,! it! is! equally! clear! that! large! increases! in!negative!ITP!are!detrimental!to!cardiac!function9.!The!mechanisms!whereby!normal!! 7!and! elevated! levels! of! negative! inspiratory! pressure! affect! cardiopulmonary!interaction!are!discussed!in!Sections!1.4.2!and!1.4.4,!respectively.!(1.3(Overview(of(cardiac(function(1.3.1!Cardiac!mechanics:!determinants!of!diastolic!function!Cardiac!mechanics!are!generally!discussed!in!terms!cardiac!cycle!phase:!1)!diastolic!relaxation!and! filling,!and!2)!systolic!emptying.!Cardiac!performance! through!both!diastole! and! systole! is! governed!by! three!key!mechanical! concepts:! 1)!preload,! 2)!afterload! and! 3)! contractility22.#There! are! four! discrete! phases! to! diastolic! filling,!however!the!hemodynamic!events!occurring!during!diastole!are!generally!referred!to!as!occurring!in!early!or!late!diastole,!the!former!being!a!passive!filling!process!of!the! ventricle,! with! the! latter! being! an! active! contribution! to! ventricular! filling!through!atrial! contraction22.!Given! that!early!phase! (passive)! filling!predominates,!the! passive! pressureFvolume! relationship! of! the! heart! is! essential! to! diastolic!function.! As! discussed! previously!with! respiratory! pressureFvolume! relationships,!the!slope!of!this!relationship!represents!the!compliance!of!the!system.!With!respect!to! compliance! of! the! left! ventricle,! this! relationship! is! influenced! by! the! size! and!shape!of!the!ventricle,!as!well!as!the!viscoelastic!properties!of!the!myocardium!and!pericardium22.! Flow! into! the! ventricle! during! diastole! is! governed! by! the! atrioFventricular! (AV)! pressure! gradient.! This! pressure! gradient! is! predominantly! a!function! of! preload! and! left! ventricular! (LV)!mechanics,! but! is! augmented! in! late!diastole! by! atrial! contraction,! and! opposed! by! the! elastic! forces! of! the! atria,!! 8!ventricle,! and! pericardium! (compliance! of! the! system).! Preload! constitutes! the!upstream! or! driving! pressure! for! ventricular! filling! in! early! diastole,! while! the!“twisting”!of!the!LV!during!systole!causes!rapid!“untwisting”!of!the!ventricle!during!isovolumic! relaxation! which! creates! a! very! low! (sometimes! negative)! pressure!environment! that! enhances! the! AV! pressure! gradient23.! Resistance! to! flow! is!considerably! impacted! by! the! AV! valve! structures,! and! thus! any! narrowing!(stenosis)! or! dysfunction! of! these! valves! may! drastically! impair! diastolic!function24,25.! At! endFdiastole,! the! pressureFvolume! relationship! (EDPVR)! directly!influences!systolic!performance!and!ultimately!the!stroke!volume!(SV)!ejected!from!the!ventricle!(Figure!1.2).!Thus,!in!the!healthy!heart,!preload!is!generally!considered!the!primary!factor!influencing!cardiac!performance26.!Preload!itself! is!governed!by!venous!return,!which!can!be!modulated!through!changes! in! ITP.!This! is!one!of! the!fundamental!cardiopulmonary!interactions!that!will!be!further!discussed.!! !! 9!!Figure! 1.2! The! pressure! volume! relationship! of! the! LV.! The! endFdiastolic! pressureFvolume!relationship!(EDPVR)!represents!the!theoretical!maximum!pressure!generation!of!the!ventricle!at! endFdiastole,! while! the! endFsystolic! pressureFvolume! relationship! (ESPVR)! represents! the!maximal!pressure!generation!of!the!ventricle!at!endFsystole,!both!of!which!are!governed!by!the!FrankFStarling! Law.! The! theoretical! work! done! by! the! ventricle! to! eject! a! stroke! volume! is!represented!by! the!pressureFvolume! area! (PVA),! or! the! kinetic! energy! of! the! system,! plus! the!potential!energy!generated!in!the!system,!as!defined!by!area!PE!(Work!=!PVA+PE).!!1.3.2!Cardiac!mechanics:!determinants!of!systolic!function!The! balance! of! forces! acting! on! the! ventricles! during! systole! determines! systolic!performance,! and! constitutes! the! endFsystolic! pressureFvolume! relationship!(ESPVR)! (Figure! 1.2).! Preload,! as! previously! discussed,! is! a! critical! component! of!this! relationship,! and! defines! the! operational! lengthFtension! relationship! of! the!myocardium!on!a!beatFbyFbeat!basis.!The! intrinsic! lengthFtension!relationship!that!defines!the!force!of!contraction!is!known!as!the!FrankFStarling!relationship,!and!it!is!universally! accepted! that! increasing! preload! stretches! the! myocardium! and!increases!force!of!contraction,!ultimately!improving!systolic!function17.!The!force!of!contraction! is! additionally! modulated! by! the! intrinsic! property! of! myocardial!! 10!contractility,!which! is! under! autonomic! control! and! can! respond! to! alterations! in!loading! conditions! (preload! and! afterload)! to! maintain! stroke! volume!appropriately22,27.!Variations!in!systolic!ventricular!performance!occur!on!a!beatFtoFbeat!basis,!as!an!interaction!between!preload!and!contractility,!most!notably!as!an!effect! of! the! respiratory! cycle28.! Chronically,! increasing! systolic! performance!through! volume! loading! (increasing! preload),! is! an! important! compensatory!mechanism! for!maintaining! systolic! function! in! the!event!of! impaired!contractility!(i.e.!heart!failure)26.!!Afterload!has!been!defined!in!several!ways!in!the!literature,!but!in!it’s!simplest!form!is! generally! considered! the! force! opposing! ventricular! ejection22.! Several!mechanisms!interact!to!generate!the!summative!force!which!is!afterload,!including!arterial!pressure!and!stress!acting!on!the!ventricular!wall!(transmural!pressure)29.!While!afterload!was!classically!considered!in!terms!of!arterial!pressure,!subsequent!work! has! shown! that! negating! the! effect! of! wall! stress! will! considerably!underestimate! the!afterload!seen!by! the!ventricle29.!This! is!particularly! true!when!considering! the! afterload! seen! by! the! LV! during! spontaneous! respiration,! as!discussed!in!Section!1.4.3.!It!is!well!established!that!there!is!an!inverse!relationship!between!afterload!and!ventricular!stroke!volume!and!contraction!velocity22.!Indeed,!it!is!generally!considered!that!endFsystolic!volume!(ESV)!is!directly!proportional!to!afterload,! and! furthermore! this! relationship! has! been! demonstrated! to! be!maintained! independent! of! preload22.! Fluctuations! in! ITP! directly! influence!afterload! through! changing! ventricular! and! intrathoracic! arterial! (i.e.! aortic! and!! 11!pulmonary)! transmural! pressures.! During! inspiration! increased! negative! ITP!increases!the!transmural!pressure!gradient,!which!increases!afterload,!while!during!expiration!the!opposite!occurs30,9.!Thus,!in!addition!to!influencing!venous!return,!the!effect! of! spontaneous! respiration! on! afterload! is! considered! the! second! key!cardiopulmonary!interaction.!While!the!healthy!heart!has!considerable!mechanical!reserve!to!increase!contractility!in!the!face!of!increasing!afterload26,!when!afterload!is! greatly! increased,! and/or! when! preload! and/or! contractility! is! reduced,! these!effects!may!be!profoundly!detrimental!to!cardiac!function.!!1.3.3!The!pulmonary!circulation!The!structure!and!function!of!the!pulmonary!circulation!has!important!implications!for! both! cardiovascular! and! respiratory! performance,! and! cardiopulmonary!interaction,!as!it!is!the!site!of!anatoFphysiological!coupling!of!the!two!systems7.!The!structure! of! the! pulmonary! circulation! has! evolved! as! a! result! of! its! unique!functional!requirements;!to!provide!a!very!large!surface!area!and!thin!vascular!walls!for! passive! diffusion! of! gasses! across! the! bloodFgas! barrier,! while! maintaining!sufficient! vessel! strength! to! withstand! large! elevations! in! pulmonary! capillary!pressures!when!cardiac!output!increases31.!!Additionally,!the!pulmonary!vasculature!plays!a!key!role!in!optimizing!ventilationFperfusion!(VA/Q)!matching!through!active!vasoconstriction! in! underFventilated! regions! of! the! lung32.! Importantly,! the!resistance!of! the!pulmonary!vascular!system!is!a! large!component!of! the!afterload!seen!by! the! right!ventricle! (RV)! (in!addition! to!RV!wall! stress).!Thus,! any!process!that!results!in!large!increases!in!pulmonary!vascular!resistance!(PVR),!namely!acute!! 12!hypoxic! exposure! or! respiratory! disease,! significantly! impacts! RV! systolic!performance33.!These!mechanisms,!and!their!subsequent! impact!on!cardiovascular!function!are!discussed!in!greater!detail!in!Section!1.4.7.!!1.4(Mechanical(cardiopulmonary(interaction(1.4.1!Series!versus!direct!ventricular!interaction!The! right! and! left! sides! of! the! heart! are! arranged! in! series! and! connected! via! the!pulmonary! and! systemic! circulation,! respectively.! As! a! result! of! this! anatomical!arrangement,! rightFsided! and! leftFsided! cardiac! output! are! roughly! equal! under!normal! physiological! conditions,! despite! the! profoundly! different! pump!characteristics! of! the! right! and! left! ventricles! that! result! from! differences! in!ventricular! geometry! and! myocardial! mass34.! As! previously! discussed,! in! series!interaction,! stroke! volume! is! governed! predominantly! by! the! FrankFStarling!mechanism,! and! a! linear! relationship! exists! between! preload! and! subsequent!ventricular! stroke! volume22.! Afterload! also! modulates! series! interaction! through!opposing!ventricular!ejection.!However,!the!healthy!heart!is!predominantly!preloadFdependent,! and! thus! it! is! generally! accepted! that! afterload! effects! are! minimal!unless! afterload! is! substantially! increased,! preload! is! substantially! decreased,! or!some!form!of!intrinsic!systolic!dysfunction!exists26.!!The! right! and! left! sides! of! the! heart! share! a! common! septum! and! pericardium,!therefore!not!only!do!they!function!in!series,!where!output!from!one!side!affects!the!! 13!other,! but! also! in! parallel! as! changes! to! volume,! pressure! or! compliance! of! one!ventricle! will! have! an! opposing! influence! on! compliance! of! the! other35.! This!relationship!is!termed!ventricular!interdependence,!or!direct!ventricular!interaction!(DVI).! Studies! using! intact! feline! and! canine! hearts! have! demonstrated! that! the!magnitude! and! direction! of! DVI! is! dependent! on! cardiac! phase,! in! that! during!diastole! the! RV! pressureFvolume! relationship! dictates! LV! filling,! while! during!systole,!contraction!of!the!RV!depends!on!systolic!performance!of!the!LV34.!Thus,!the!role! of! DVI! in! impairing! LV! SV! is! generally! considered! a! diastolic! phenomenon35.!Current!evidence!suggests!that!DVI!is!primarily!mediated!by!the!constraining!effect!of!the!pericardium,!though!the!septum!likely!also!plays!a!role.!!!The! pericardium! encloses! all! but! the! left! atrium! of! the! heart,! and! due! to! its!composition! of! predominantly! collagen! fibers,! it! is! relatively! nonFdistensible.!Pericardial! compliance! follows! a! ‘J’! shaped! curve,! such! that! at! unstressed! heart!volumes!it!is!relatively!complaint,!however!small!increases!in!volume!generate!large!increases! in! pericardial! pressure! and! thus! large! reductions! in! compliance36.! The!notion! that! the! pericardium! presents! a! constraint! to! ventricular! filling! was! first!proposed!by!Barnard!in!189837,!and!has!since!been!of!considerable!research!interest!to! understanding! the! mechanisms! of! DVI.! While! the! detrimental! effects! of! a!pericardial! constraint! to! ventricular! filling! are! generally! only! evident! during!pathophysiological! cardiopulmonary! interaction,! such! as! acute! pulmonary!embolism!or!congestive!heart!failure38,!it!is!generally!accepted!that!the!pericardium!exerts!a!restraining!force!against!ventricular!filling!in!the!healthy!heart!even!under!! 14!normal! loading!conditions39,40.!However,! the!magnitude!of! this!restraining! force!at!unstressed! ventricular! volumes! is! considered! almost! negligible,! such! that! the!pericardium!has!little!or!no!effect!on!cardiac!filling!at!rest22.!!Thus,!the!physiological!consequences!of!DVI!in!healthy!resting!humans!are!generally!small.! However! in! pathological! states! characterized! by! excessive! RV! pressure! or!volume!(Figure!1.3b),!or!in!the!presence!of!increased!pericardial!pressure!through!mediastinal! constraint,! DVI! can! have! a! considerable! detrimental! effect! on! cardiac!function35.!It!has!been!shown!that!even!small!increases!in!RV!endFdiastolic!pressure!(RVEDP)!are!associated!with!some!degree!of!leftward!septal!shift,!which!reduces!LV!cavity!size!and!thus!increases!LV!endFdiastolic!pressure!(LVEDP),!even!though!true!filling! pressure! (transmural! LVEDP)! hasn’t! changed41,42.! Therefore! the!hemodynamic!consequence!of!leftward!septal!shift!and!elevated!LV!filling!pressures!are! a! smaller! LV! filling! volume,! and! a! reduction! in! the!AV!pressure! gradient! such!that!LVEDV!and!ultimately!LV!SV!is!decreased42,35.!(Figure!1.3!Illustration!of!direct!ventricular!interaction!(DVI)!from!a!parasternal!shortFaxis!view!at! endFdiastole.! During! normal! loading! conditions! (a),! LV! pressures! exceed! RV! pressures! and!thus! the! septum! is! shifted! rightward.! During! severe! RV! pressure! or! volume! overload! (b),! RV!pressures! exceed!LV!pressures! and! the! septum!shifts! leftward,! increasing!LV! filling!pressures!and!constraining!LV!volume.!! 15!Mechanical! cardiopulmonary! interaction! is! inherently! complex,! and! can! be!discussed! in!terms!of!diastolic!versus!systolic!effects,!as!well!as!differential!effects!on!the!right!and! left!side!of! the!heart.! In!addition!to! this! interplay!of!mechanisms,!given! the! anatomy! of! the! heart! and! physiological! coupling! to! pulmonary! and!systemic! circulations,! both! series! and! DVI! have! been! shown! to! occur! during!spontaneous! respiration.! It! is! generally! accepted! that! during! spontaneous!respiration! in! the! healthy! individual,! series! interaction! drives! cardiopulmonary!interaction7,! however! the! role! of! DVI! is! not! completely! understood.! Additionally,!when! the! respiratory! system! is! stressed! by! pathological! changes! to! ventilatory!mechanics,!the!roles!of!series!versus!direct!ventricular!interaction!and!their!relative!contribution!to!cardiac!function!are!not!clear.((1.4.2!Effects!of!spontaneous!respiration:!venous!return!and!preload!Right! atrial! pressure! (RAP)! is! the! backFpressure! to! venous! return,! and! therefore!venous! flow! is! governed! by! the! pressure! differential! between! mean! systemic!pressure!and!RAP43.!Mean!systemic!pressure!is!considered!the!static!pressure!of!the!circulatory!system!and!is!influenced!by!intrinsic!elastic!properties!of!the!vasculature!and! is! also! highly! dependent! on! blood! volume43.! Given! the! thinFwalled! and!distensible!nature!of!the!RA,!fluctuations!in!ITP!are!easily!transmitted!to!the!RA!and!thus!RAP!is!seen!to!change!proportionally!to!ITP!during!the!respiratory!cycle44.!It!is!universally!accepted!that!the!normal!decrease!in!ITP!during!inspiration!results!in!an!increased!venous!return!by!manipulating! this!pressure!gradient45,7.!The!reverse! is!also!true,!in!that!increased!positive!ITP!during!expiration!increases!RAP!and!reduces!! 16!venous! return! and! subsequently! reduces! RV! preload.! However,! expiration! is!generally! considered! to! play! a! smaller! role! in! hemodynamic! regulation! during!spontaneous!respiration,!due!to!smaller!relative!changes!in!ITP11.!!The! classic!model! proposed! by! Guyton! et# al! of! the! relationship! between! ITP! and!venous! return! suggests! that! venous! return! does! not! increase! infinitely! as! RAP!decreases,! and! was! observed! to! become! flowFlimited! as! RAP! decreases! below!atmospheric!pressures!due!to!collapse!of!the!inferior!vena!cava!(IVC)!as!it!enters!the!thorax,! causing! attenuation! of! venous! return43! (Figure! 1.4).! ! Indeed,! venous! flow!limitation!due!to!IVC!collapse!during!inspiratory!resistive!loading!has!subsequently!been! demonstrated! in! human!models46.! However,!while! the! venous! return!model!proposed! by! Guyton! et# al! is! useful! for! understanding! the! direct! effects! of!fluctuations! in! ITP! on! venous! return,! it! neglects! several! other! important!considerations.!!Changes! in! abdominal! pressure! can! also! have! profound! implications! for! venous!return.! During! a! normal! inspiration,! abdominal! pressure! becomes! more! positive!which,! in! conjunction! with! an! increased! negative! ITP,! increases! the! abdominalFthoracic! pressure! gradient! for! IVC! flow! and! is! generally! shown! to! increase! IVC!flow47.!However,!even!this!may!be!an!oversimplification!of!the!venous!return!model,!as!the!direction!and!magnitude!of!this!relationship!has!been!shown!to!be!dependent!on! intravascular! blood! volume! in! addition! to! the! magnitude! of! diaphragmatic!contraction48.!Furthermore,!increased!flow!from!the!IVC!would!lead!to!an!increased!! 17!RAP! and! thus! a! reduced! pressure! gradient! and! flow! from! the! superior! vena! cava!(SVC)9.! Clearly,! the! interaction!of! ITP!and!abdominal!pressures!on!hemodynamics!during! normal! respiration! is! complex,! and! not! completely! understood.! During!obstructed!respiratory!patterns!characterized!by!large!ITP!swings!and!increases!in!operational!lung!volume,!the!role!of!abdominal!pressure!in!mediating!venous!return!is! unknown.! Thus,! while! the! effect! of! ITP! on! RAP! alone! may! neglect! other!contributing!mechanisms!to!venous!return,!in!the!absence!of!a!more!conclusive!role!for! abdominalFthoracic! interaction! during! respiratory! stressors,! the! rationale! for!this!study!is!based!on!the!effects!of!ITP!on!the!heart!itself.!!Figure!1.4!The!normal! venous! return! curve! initially! proposed!by!Guyton!et#al! (1957).! Venous!return! is!proportional!to!the!decrease! in!right!atrial!pressure!(RAP)!to!the!point!at!which!RAP!falls!below!atmospheric!pressure!!Through! the! mechanism! of! modulating! venous! return,! ITP! fluctuations! during!spontaneous!respiration!are!seen!to! transiently! increase!RV!SV!during! inspiration,!and!decrease!RV!SV!during!expiration49.!This!is!seen!to!be!an!earlyFphase!effect,!and!SV! normalizes! by! endFinspiration! and! endFexpiration,! with! the! overall! effect! of!! 18!spontaneous! respiration! being! increased! rightFsided! cardiac! output50.! Enhanced!pulmonary! flow! over! successive! cardiac! cycles! will! increase! pulmonary! venous!return! to! the! LA! and! thus! increase! LV! preload! and! LV! SV! via! series! interaction.!Indeed,!several!studies!have!documented!enhanced!cardiac!output!over!successive!respiratory! cycles! with! mildly! increased! negative! ITP! in! healthy! individuals49,51.!However,!paradoxically,!a!large!increase!in!negative!inspiratory!ITP,!as!seen!in!cases!of! obstructive! respiratory! disease,! has! been! shown! to! significantly! reduce! SV!through!potential!mechanisms!of!attenuated!venous!return,!increased!afterload!and!exacerbated!DVI,!which!are!discussed!in!detail!in!Section!1.4.4.!1.4.3!Effects!of!spontaneous!respiration:!afterload!While!negative! ITP!during!normal! inspiration!augments! the! flow!of!blood!back! to!the!heart!during!diastole,!this!same!pressure!impedes!outflow!from!the!heart!during!systole.! A! more! negative! pleural! pressure! increases! ventricular! transmural!pressure,! which! is! seen! by! the! ventricle! as! an! increase! in! wall! stress! and! thus!afterload.!!Assuming!a!fixed!preload!and!contractility,!there!is!commonly!an!inverse!relationship! between! afterload! and! systolic! ventricular! performance22.! Given! that!both! ventricles! see! the! same! relative! increase! in! transmural! pressure! it! is!reasonable!to!assume!that!the!afterload!effects!would!be!similar!on!both!the!RV!and!LV,!however!this!is!not!the!case.!Indeed,!it!is!well!established!that!inspiration!during!early!diastole!increases!RV!SV!while!LV!SV!is!decreased28,7,50.!!This! paradoxical! response! is! an! aspect! of! cardiopulmonary! interaction! that! has!historically!challenged!physiologists,!however! it! is!now!accepted!that!spontaneous!! 19!inspiration! causes! a! disproportionate! increase! in! LV! wall! stress! relative! to! the!change! in! ITP,! and! thus! LV! afterload! is! greater! than! RV! afterload! for! a! given!decrease!in!ITP!7.!Paramount!to!understanding!this!paradox!is!the!notion!that!the!LV!and! systemic! circulation! is! an! inherently! higher! pressure! system,! and! thus!transmural!pressure! for!any!given! ITP!change!will!be!greater! in! the!LV.!However,!equally!important!is!that!transmural!pressure!as!a!function!of!pleural!pressure!does!not! accurately!predict! true! afterload,! as! it! does!not! represent! the! true!wall! stress!seen! by! the! LV,! which! is! influenced! by!mechanical! interdependence! between! the!heart!and!the!surrounding!lung1,7.!This!interdependence!dictates!that!inflation!of!the!lung!during!a!normal!inspiration!increases!the!regional!surface!pressure!across!the!LV!such!that!the!fall! in!pleural!pressure!underFpredicts!the!actual!LV!wall!stress52.!Thus,! while! the! fall! in! pleural! pressure,! and! subsequent! increased! ventricular!transmural! pressure,! is! a! major! component! of! wall! stress,! heartFlung!interdependence! must! be! considered! in! defining! the! effects! of! inspiration! on! LV!systolic! function.! Regardless! of!mechanism,! the! observed! increase! in! LV! afterload!during! spontaneous! respiration! is! considered! to! have! minimal! effect! on! cardiac!function,! as! the!healthy!heart! is!predominantly!preload!dependent26,! and! thus! the!diastolic! effects!of! increased!venous! return!predominate! and!drive! cardiac!output!through! series! interaction16,7.! However! during! stressed! inspiration,! afterload!may!have!considerable!implication!for!hemodynamics,!though!the!contribution!of!pleural!pressure!and!heartFlung!interdependence!is!not!fully!understood.!!! 20!!The! impact!of!DVI!on! the!LV!during!spontaneous!breathing! is! less!clear,!however!there!is!some!evidence!that!it!contributes!to!the!observed!transient!decrease!in!LV!SV! during! early! inspiration.! It! has! been!well! documented! that! elevated! RV! filling!pressure!can! interfere!with!LV!filling42,53,!however!whether!DVI!affects!LV!systolic!performance! is! unknown.! It! is! generally! considered! that! DVI! during! spontaneous!respiration! is! a! diastolic! event! mediated! by! increased! RV! preload,! which! may!transiently! reduce! LV! diastolic! filling7.! The! extent! to! which! this! impacts!hemodynamics! in!healthy! individuals! is! thought! to! be!minimal,! however!DVI!may!have!profound!implications!for!LV!function!during!large!increases!in!negative!ITP,!as!is!seen!in!obstructive!respiratory!disease.!!1.4.4! The! effects! of! increased! negative! intrathoracic! pressure! on! cardiac!function!As!previously!discussed,!during!normal!breathing,! ITP! swings!are!generally! small,!and!have!minimal!impact!on!hemodynamics9.!However,!in!cases!of!acute!or!chronic!obstructive! breathing! patterns,! negative! inspiratory! pressures! are! seen! to! greatly!increase54,55.! These! large! increases! in!negative! ITP! are! seen! to! cause!proportional!decreases! in! LV! SV! and! arterial! blood! pressure,! a! phenomenon! known! as! pulsus!paradoxus9,56.!However,!while!the!detrimental!effects!of!large!increases!in!negative!ITP! on! LV! function! are! well! documented,! the! etiology! of! the! decrease! in! LV! SV!remains!controversial.!!The! effects! of! large! increases! in! negative! inspiratory! pressure! have! been! studied!extensively! in!humans!using!the!Mueller!maneuver,!which! is!a! forceful! inspiratory!! 21!effort! against! a! closed! glottis! that! generates! large! negative! ITP! at! a! static! lung!volume.! It! is! well! established! that! this! relatively! “pure”! mechanism! of! greatly!increased! and! sustained!negative! ITP! results! in! a! reduction! in! LV! SV53,57,9.! This! is!generally! considered! an! effect! of! the! large! associated! increases! in! ventricular!afterload,!as!has!been!demonstrated!by!an!increase!in!LVESV!with!minimal!change!to!LVEDV58,59.!However,! there! is!considerable!evidence!to!suggest! that!DVI!plays!a!role! in!reducing!LV!SV!during!the!Mueller!maneuver,!as!has!been!demonstrated!in!studies! reporting! an! increased! RVEDV,! reduced! LVEDV,! and! marked! change! to!septal!configuration53.!!While!the!hemodynamic!effects!of!the!Mueller!maneuver!are!relatively!clear,!there!is!some! disagreement! in! the! literature! as! to! the! mechanisms! of! decreased! stroke!volume!in!response!to!increased!negative!ITP!during!resistive!inspiratory!loading9.!Thus,! the!majority!of!work! in! this!area,!which!utilized!the!Mueller!maneuver,!may!not! adequately! explain! the! hemodynamic! effects! of! negative! ITP! as! they! occur! in!obstructive! respiratory! disease.! This! is! most! likely! attributed! to! the! absence! of!elevated! lung! volumes! during! the! Mueller! maneuver,! which! have! considerable!hemodynamic! effects,! though! the! absolute! increase! in! negative! ITP! during! the!Mueller! maneuver! is! larger! than! what! would! be! seen! with! inspiratory! resistive!loading,!or!even!in!severe!obstructive!disease9.!The!hemodynamic!effects!of!elevated!lung!volumes!are!generally!considered!to!be!an!increase! in!afterload!through!both!heartFlung! interdependence!and! compression!of! the!pulmonary!vasculature52,! and!! 22!exacerbation! of! DVI! through! mediastinal! constraint60,! mechanisms! which! are!discussed!in!greater!detail!in!Section!1.4.5.!!Contrary!to!findings!utilizing!the!Mueller!maneuver,!current!evidence!suggests!that!inspiratory! loading!during!spontaneous!respiration!may!result! in!a!reduced!LV!SV!that! is!a! function!of!a!reduced!LVEDV,!a! finding! in! line!with!diastolic!dysfunction9.!!This!has!been!documented!in!both!canine61,62!and!human!models63,64.!However,!this!finding! is! not! universal,! as! LVESV! has! also! been! shown! to! increase! during!inspiratory! loading65.! Thus,! the! relative! contribution!of! series! interaction! and!DVI!during! increased!negative! ITP!remains!unclear,!and!defining! these!roles!continues!to!challenge!researchers,!as!a!normal!respiratory!cycle!occurs!across!several!cardiac!cycles!and!thus!differentiating!diastolic!and!systolic!effects!of!increased!negative!ITP!in!a!spontaneously!breathing!model!is!exceedingly!difficult66,9.!!1.4.5!The!effects!of!increased!lung!volumes!on!cardiac!function!Lung! volume! influences! cardiopulmonary! interaction! through! changes! to! the!mechanical! forces! applied! to! the! pulmonary! vasculature.! Intrapulmonary! vessels!are! classified! as! either! alveolar! or! extraFalveolar7.! While! the! external! pressure!exerted! on! the! alveolar! vessels! is! determined! by! alveolar! pressure,! the! pressure!exerted!on!the!extraFalveolar!vessels! is! influenced!predominantly!by! lungFvascular!interdependence67.! LungFvascular! interdependence! causes! a! negative! differential!between!extraFalveolar!vessel!wall!pressure!and!pleural!pressure,!therefore!as!lung!volumes!increase!(ie.!pleural!pressure!decreases),!the!pressure!exerted!on!the!extraF! 23!alveolar! vessels! becomes! increasingly! negative67.! Thus,! as! lung! volumes! increase,!alveolar! pressure! increases! relative! to! pleural! pressure! and! the! overall! effect! is!compression!of!the!alveolar!vessels!and!distension!of!the!extraFalveolar!vessels68,7.!This! relationship! is! exponential,! such! that! large! increases! in! lung! volume!exponentially! increase! alveolar! vessel! compression! and! extraFalveolar! vessel!distension! (as! depicted! in! Figure! 1.5)! 68.! From! a! hemodynamic! perspective,! the!effect!of!alveolar!vessel!compression!considerably!outweighs!the!opposing!effects!of!extraFalveolar! vessel! distension.! ! Therefore,! the! key! response! to! increased! lung!volume! is! a!profound! increase! in!pulmonary!vascular! resistance,!which! is! seen!as!increased!afterload!by!the!RV59,7.!!!Figure!1.5!Changes! to! total!pulmonary!vascular!resistance!(PVR),!as!a! function!of!alveolar!and!extraFalveolar! vessel! resistance,! in! response! to! changes! in! lung! volume! (modified! from!Respiratory!Physiology:!the!Essentials!by!J.!B.!West68)!! 24!The! effects! of! increased!RV! afterload! can! be! reviewed! relative! to! its! influence! on!series!interaction!and!DVI.!As!previously!mentioned,!assuming!a!fixed!contractility!and! constant! venous! return,! any! increase! in! afterload! will! be! met! with! a!proportional! increase! in! both! endFdiastolic! and! endFsystolic! RV! volumes,! with! a!relatively! larger! increase! in! RVESV! leading! to! a! reduced! SV22.! Over! consecutive!cardiac!cycles!this!will!inherently!reduce!LV!SV!through!series!interaction.!Increased!RV!volumes!will! also! exacerbate!DVI,! as!RV!pressures!will! increase! relative! to! LV!pressures!mediating! a! leftward! septal! shift!which!will! reduce! LV! compliance! and!increase!filling!pressures!such!that!LVEDV!is!decreased69,9!(Figure!1.3b).!!!An!additional!consideration!of!increased!lung!volume!is!the!direct!mechanical!effect!of!the!inflated!lung!constraining!diastolic!filling!of!the!heart.!Studies!utilizing!intact!canine!models!have!demonstrated!mediastinal!constraint!of!the!heart!as!a!result!of!elevated! lung! volumes! during! inspiration! and! positiveFpressure! ventilation1,70.!Constraint! of! the! heart! by! the! lungs! is! analogous! to! a! reduction! in! pericardial!compliance!in!that! it! limits!diastolic! filling!and!amplifies!the!effects!of!DVI71.!Thus,!this! mediastinal! constraint,! in! conjunction! with! increased! PVR,! may! compound!reductions!in!LV!SV.!Additionally,!it!is!generally!accepted!that!mediastinal!constraint!increases! surface! pressure! on! the! heart,! which! would! increase! RAP! and! thus!decrease!venous!return9.!!!During! normal! breathing! in! healthy! individuals,! tidal! swings! in! lung! volume!generally! operate! close! to! FRC,! and! therefore! the! hemodynamic! effects! of! lung!! 25!volumes!are!minimal.!Within!these!operational!lung!volumes!mediastinal!constraint!is! negligible7,22,! and! thus! any! hemodynamic! effect! of! lung! volumes! would! be! a!function!of!changes!to!PVR.!Yet,!even!this!mechanism!is!debated!as!being!relevant!to!hemodynamics! during! spontaneous! respiration,! as! it! has! been! suggested! that!changes!to!pleural!pressure!(ITP)!outweigh!the!effects!of!changes!to!lung!volumes!in!mediating!cardiopulmonary! interactions,!even!at! lung!volumes!above!normal! tidal!breathing59,72.!However,!large!increases!in!lung!volumes,!seen!during!dynamic!lung!hyperinflation! (DH)! as! a! result! of! obstructive! respiratory! disease,! may! have!considerable!impact!on!cardiac!function.!At!substantially!elevated!levels!above!FRC,!increased! PVR! and! mediastinal! constraint! may! become! significant! hemodynamic!stressors.!Investigating!these!mechanisms!is!inherently!convoluted,!as!elevated!lung!volumes!do!not!occur!physiologically!in!isolation,!and!are!accompanied!generally!by!changes! in! lung! compliance! and! large! increases! in! ITP! swings,! therefore! isolating!the! effects! of! lung! volume! is! difficult.! Thus,! the! contribution! of! lung! volume! to!cardiopulmonary! interaction,!and!whether!series! interaction!or!DVI!predominates,!is!unknown.!!1.4.6!The!effects!of!increased!and!excessive!preload!on!cardiac!function!Preload!mediates!the!lengthFtension!relationship!of!the!myocardium,!defined!as!the!FrankFStarling!mechanism,! and! is! the! primary! determinant! of! cardiac! function! at!rest!in!healthy!individuals17,22.!This!relationship!is!the!fundamental!basis!for!volume!loading! therapy,!which! augments! LVEDV!by! increasing!RV!preload! and!ultimately!increases! LV! SV! through! series! interaction73.! Assuming! no! change! to! the! cardiac!! 26!function! curve! (namely! contractility! and! heart! rate),! volume! loading! increases!cardiac!output!(Q)!(shown!in!Figure!1.6).!As!such,!VL!has!been!used!extensively!as!a!therapeutic! intervention! in! any! clinical! scenario! characterized! by! hemodynamic!instability! or! cardiac! insufficiency74,75.! However,! the! traditional! model! of! volume!loading!as!a! tool! for!augmenting!SV!neglects! the!potential! for! increased!DVI!when!RV!preload!is!substantially!increased,!most!notably!in!scenarios!where!RV!afterload!may!also!be!increased76.!!Figure! 1.6! Acute! volume! loading! increases! cardiac! output! (point! B)! by! increasing! preload!(upward! shift! of! venous! return! curve),! relative! to! cardiac! output! achieved! under! normal!loading!conditions!(point!A),!assuming!no!change!to!the!cardiac!function!curve.!!!While!it!is!well!established!that!VL!in!response!to!inadequate!preload!is!beneficial!to!LV! function! and! indeed! a! critical! intervention! for! hypovolemia,! previous! studies!have!shown!that!volume!loading!in!conditions!characterized!by!cardiac!insufficiency!secondary!to!increased!RV!afterload!(i.e.!pulmonary!embolism),!may!actually!cause!further!hemodynamic!deterioration75,77.!This! is!attributed!primarily! to!an! increase!! 27!in!pericardial!pressure!and!leftward!shift!of!the!septum,!both!of!which!increase!LV!filling! pressure! and! constrain! filling! volume76,78.! In! light! of! this! evidence! it! is!suggested! that! excessive! preload! may! paradoxically! decrease! LV! function.! This!apparent! physiological! anomaly! has! previously! been! demonstrated! utilizing!incremental! volume! loading! in! patients! with! congestive! heart! failure78,! and! in! a!seminal!study!by!Jardin!et#al!in!patients!with!moderate!to!severe!COPD79.!Jardin!et#al!demonstrated!improved!LV!SV!in!response!to!volume!loading!up!to!a!critical!RAP!at!endFdiastole,!after!which!additional!volume! loading!caused!a!paradoxical!decrease!in! LV! SV.! They! attributed! these! results! to! DVI,! as! indicated! by! changes! in! septal!formation! and! LV! geometry80.! However,! the! presence! of! LV! hypertrophy,! and!variability! in! respiratory! function,! may! have! influenced! these! pressureFvolume!relationships,!and!thus!further!work!in!an!intact!healthy!human!model!is!needed!to!confirm! these! findings.! Therefore,! while! the! role! of! DVI! is! well! established! in!mediating!this!response38,76,78,79,! the!degree!to!which!this! is!may!be!detrimental! to!cardiac! function,! and! the! loading! conditions! under! which! this! occurs! in! healthy!humans!and!disease!models,!remain!unclear.!(1.4.7! The! effects! of! hypoxic0mediated! increases! in! pulmonary! vascular!resistance!on!cardiac!function!At!the!level!of!the!alveoli,!hypoxia!induces!regional!vasoconstriction!in!an!attempt!to!improve! matching! of! perfusion! to! alveolar! ventilation! (VA/Q).! This! phenomenon,!known! as! hypoxic! pulmonary! vasoconstriction! (HPV),! has! been! extensively!demonstrated! in! response! to! acute! hypoxia32,81.! However,! in! situations! of! global!! 28!hypoxia,!such!as!ascent!to!altitude!or!hypoxemic!respiratory!disease,!HPV!can!cause!a!significant!increase!in!pulmonary!vascular!resistance!(PVR),!ultimately!leading!to!increased! pulmonary! artery! pressures! (PAP)82,81.! The! pulmonary! circulation! has!evolved!to!be!a!highFflow,!lowFpressure!system!to!optimize!gas!exchange,!therefore!the! RV! is! pressureFpassive! and! even! small! increases! in! PVR! represent! large!increases!in!afterload!seen!by!the!RV31.!The!impact!of!acute!hypoxia!on!RV!function!is! proportional! to! the! PVR! increase,! and! it! is! generally! considered! that! hypoxia!induces! RV! diastolic! dysfunction! while! systolic! function! is! preserved83.! However,!severe!increases!in!PVR!have!been!shown!to!cause!RV!systolic!dysfunction!as!well84.!RV!dysfunction!secondary!to!RV!pressure!overload!has!been!shown!to!manifest! in!LV!diastolic!dysfunction!with!pathological! increases! in!PVR85,86,! and!has!also!been!demonstrated! to! a! lesser! extent! in! healthy! individuals! on! exposure! to! acute!hypoxia33,87.! The! etiology! for! LV! diastolic! dysfunction! secondary! to! increased!pulmonary! artery! pressures! is! not! fully! understood,! and! mechanisms! of! both!series84,88! and! direct! ventricular! interaction85,89,90! have! been! proposed! as!responsible!for!decreased!LV!SV.!!Increased! RV! afterload! should! decrease! LV! SV! through! series! interaction,! and!indeed!it! is!generally!seen!that!LVEDV!decreases!with!acute!hypoxic!exposure!to!a!degree!proportional!to!the!increase!in!pulmonary!pressures88,33.!However,!whether!this! translates! to! a! reduced! LV! SV! is! debated,! as! several! authors! have! reported! a!maintained!or!only!mildly!depressed!LV!SV,!presumably!due!to!the!healthy!heart’s!! 29!ability! to! overcome! increased! afterload! or! mild! under! filling! through! increasing!contractility91,92.!!!Despite! the!wellFdocumented!decrease! in!LVEDV! in!response! to!hypoxia,!evidence!for! DVI! in!mediating! this! response! is! limited! and! largely! speculative.! It! has! been!suggested!that!the!altered!diastolic!filling!pattern!of!the!LV!in!response!to!hypoxia!F!namely!reduced!early!filling!and!an!increased!atrial!contribution!to!late!filling,!may!indicate! reduced! compliance! and! impaired! diastolic! filling! secondary! to! DVI88.!However,!it!was!also!noted!that!the!decrease!in!LVEDV!was!not!accompanied!by!an!increase! in! LVEDP,! and! therefore! reduced! LV! preload! (series! interaction)!may! be!more! likely88.! Additionally,! TissueFDoppler! Imaging! (TDI)! to! evaluate! ventricular!performance!as!a!function!of!tissue!velocity!has!shown!altered!diastolic!function!of!both! ventricles,! with! preserved! RV! systolic! function! and! improved! LV! systolic!function!during!acute!hypoxic!exposure93.!Coupled!with! limited!echocardiographic!assessment! of! the! RV,!which! saw! no! increase! in! RVEDV,! these! authors! concluded!DVI!was!not! likely! the!cause!of! impaired!LV!diastolic! function93.!Thus,!while!acute!hypoxia! alone!may!not! constitute! a! significant!hemodynamic! stressor,! or! result! in!exacerbation!of!DVI!in!healthy!individuals,!increases!in!PVR!secondary!to!hypoxemic!pathology! may! have! a! considerably! more! detrimental! effect! on! cardiopulmonary!interaction.!(( (! 30!1.5(Cardiopulmonary(interaction(in(obstructive(respiratory(disease(Chronic!Obstructive!Respiratory!Disease! (COPD)! is!characterized!as!a!progressive,!irreversible! disease! resulting! in! parenchymal! and! vascular! destruction! and!obstruction!of!small!and!large!airways15.!While!the!disease!is!of!respiratory!origin,!the!systemic!effects!are!numerous!and!well!documented94,95,96.!Of!particular!interest!is!the!relationship!between!COPD!and!cardiac!dysfunction.!While!substantial!clinical!evidence!for!this!relationship!exists,!the!mechanisms!underlying!this!association!are!unclear95.! It! has! been! theorized! that! the! pathological! changes! to! pulmonary!structure!and!function!in!COPD!may!result!in!adverse!cardiopulmonary!interaction!and!ultimately!cardiac!dysfunction59,7,9,97.!While!there!has!been!limited!work!along!this! line! of! inquiry! in! both! clinical! populations98,99,100,80! and! mechanistic! studies!using! canine101,102! and! healthy! human! models59,72,! considerable! further! work! is!needed! to!define!cardiopulmonary! interaction! in!COPD,!and!which!mechanisms!of!respiratory! dysfunction! are! chiefly! responsible! for! impairing! cardiovascular!function.!#To!understand!changes!to!cardiopulmonary!interaction!in!COPD,!it!is!first!essential!to! understand! the! causal! changes! to! pulmonary! function.! These! changes! can! be!defined!as!changes!to!ventilatory!mechanics,!and!structural!changes!to!the!lungs!and!pulmonary! circulation.( Structurally,! the! change! that! is! most! likely! to! impact!cardiopulmonary! interaction! is! constriction! of! the! pulmonary! vasculature! due! to!alveolar!hypoxia!and!vascular!remodeling!leading!to!increased!PVR103,104,97,!as!was!previously!discussed!in!Section!1.4.7.!Indeed,!an!increase!in!RV!afterload!secondary!! 31!to! increased! PVR! is! generally! considered! the! primary! hemodynamic! effect! of!COPD97.!While!cardiac!function!is!generally!seen!to!be!maintained!despite!increased!PVR!in!healthy!individuals!in!response!to!acute!hypoxia88,33,!it!is!suggested!that!this!mechanism! may! be! considerably! more! detrimental! to! LV! function! in! disease!populations97.!!!The!fundamental!change!to!ventilatory!mechanics!as!a!result!of!COPD!is!expiratory!flow! limitation! (EFL)8,15,105.! EFL! occurs! as! a! result! of! increased! airway! resistance!through! airway! narrowing! and! remodeling,! and! degradation! of! parenchymal! lung!tissue,!which!reduces!lung!elastic!recoil8.!This!process!has!implications!for!both!ITP!generation! and! operational! lung! volumes,! and! thus! manipulates! the! respiratory!pressureFvolume!relationship.!While!positive!expiratory!ITP!is!seen!to!increase!(and!become! positive! during! exertion! or! symptom! exacerbation)! in! COPD! due! to!increased! airway! resistance! and! a! reduced! elastic! contribution! of! the! lung! to!expiration8,! negative! inspiratory! ITP! is! generally! seen! to! increase!more,! thus! the!overall! ITP! swing! is! considerably! larger,! and!mean! ITP! becomes!more! negative9.!Mechanistically,! this! increase! in! negative! ITP! is! due! to! having! to! overcome!decreased! lung! compliance! when! operating! at! higher! lung! volumes,! and! the!resultant!iPEEP!due!to!positive!alveolar!pressure!at!endFexpiration106.!!As!discussed!in!Section!1.4.4,! large!increases!in!negative!inspiratory!pressure!have!considerable! implication! for! cardiopulmonary! interaction.! Additionally,! when!ventilatory!demands!increase,!EFL!results!in!DH107,!which!also!has!the!potential!to!! 32!significantly! impair! cardiac! function,! as! discussed! in! Section! 1.4.5.!Whether! these!interactions!impact!hemodynamics! in! isolation!or!have!a!summative!effect!has!not!been!defined,!similarly!the!mechanism!of! interaction,!whether!series!or!DVI,! is!not!clear96.!!!While! there! have! been! limited! studies! investigating! these!mechanisms! in! a! COPD!population,! accurately!discerning!causal!mechanisms! is! inherently! convoluted!due!to!the!presence!of!multiFsystem!dysfunction!associated!with!the!disease96.!Clearly,!a!more! comprehensive! intact! human!model! is! required! to! better! understand! these!complex!interactions.!Changes!to!lung!volume!and!ITP!do!not!occur!in!isolation,!thus!while! it! is! important!to!understand!the!relative!contribution!of! these!mechanisms,!an! integrative! approach! is! needed! to! understand! the! summative! effect! of! these!respiratory!changes!on!cardiac!function.!Additionally,!while!increased!PVR!and!thus!RV! afterload! has! previously! been! defined! as! a! key! hemodynamic! challenge!associated!with!COPD,!it!has!been!neglected!in!previous!models!of!COPD!examining!cardiopulmonary! interaction72.! Therefore,! this! is! a! critical! consideration! for!developing!a!more! comprehensive!model.!The!aim!of! this! study!was! to!define! the!roles! of! these! changes! to! respiratory! function! in! mediating! changes! to! cardiac!function!alone!and!in!combination,!which!will!be!further!discussed!below.( (! 33!1.6(Study(aims(and(hypothesis(The!decrease! in! LV! SV! in! response! to! increased!negative! ITP! is!well! documented,!however! the!mechanisms! behind! this! decrease! remain! to! be! fully! elucidated,! and!furthermore!very!few!of!these!studies!have!investigated!these!mechanisms!utilizing!inspiratory! resistive! loading! in! a! spontaneously! breathing! human! model9.!Therefore,! the! overarching! aim! of! this! study! was! to! investigate! the! effects! of!negative!ITP!in!concert!with!additional!changes!to!ventilatory!mechanics!to!quantify!their!interactive!effect!on!hemodynamics,!with!the!goal!of!building!towards!a!more!comprehensive!model!of!obstructive! respiratory!disease! than!has!previously!been!reported!in!the!literature.!The!individual!aims!and!rationale!for!pursuing!this!line!of!inquiry!are!discussed!below.!!1.6.1!Investigating!the!effects!of!lung!hyperinflation!and!inspiratory!loading!on!cardiac!function!According! to! the!mechanisms!of! cardiopulmonary! interaction!discussed! in!Section!1.4.5,!elevations! in! lung!volumes!and!associated!positive!endFexpiratory!pressures!are!suggested!to!play!an!important!role!in!blood!flow!regulation.!These!mechanisms!have! been! previously! investigated! in! anaesthetized! canine! models101,102,! and! in!patients!with!COPD98,99,100.!However,!findings!from!these!studies!are!inconclusive!as!to! the! degree! to!which! dynamic! lung! hyperinflation! impairs! LV! function,!whether!this! is!a! function!of! lung!volume! itself!or!changing!pleural!pressures,!and!whether!these! changes! are! mediated! predominantly! by! series! or! direct! ventricular!! 34!interaction.! Thus,! considerable!work! is! required! to! elucidate! the! effects! of! DH! on!cardiovascular!function.!!!Figure!1.7!The!theorized!effects!of!DH!on!LV!function.!Increased!PVR!(a)!increases!RV!afterload!which,!in!conjunction!with!mediastinal!constraint!(b),!may!reduce!LV!SV!(c)!through!both!series!interaction!and!DVI.( !To! our! knowledge! very! few! studies! have! investigated! the! effects! of! elevated! lung!volumes! alone! and! in! combination! with! increased! negative! ITP! in! a! healthy,!spontaneously! breathing!human!model.!While! understanding! the! effects! of!DH!on!hemodynamics! is! in! itself! an! important! line! of! inquiry! to! better! understand! the!cardiovascular!effects!of!COPD,!physiologically,!DH!does!not!occur! in! isolation!and!inherently! results! in! increased! ITP! swings! with! large! increases! in! negative!inspiratory!pressure9.!Therefore,!a!primary!aim!of!this!study!was!to!investigate!the!effects! of! DH! on! LV! function! in! healthy! individuals.! Furthermore,! we! wanted! to!examine! how! DH! interacted! with! increased! negative! ITP,! as! a! more! integrative!! 35!model! of! obstructive! respiratory! patterns,! to! alter! hemodynamic! homeostasis.! As!depicted!in!Figure!1.7,!we!theorized!that!DH!would!reduce!LV!SV!through!increases!in! both!RV! afterload,!which! should! reduce! LVEDV! through! series! interaction,! and!mediastinal!constraint,!which!would!exacerbate!DVI.!Furthermore,!during!DH!with!concomitant!increased!negative!ITP,!the!diastolic!effects!of!increasing!venous!return!and! systolic! effects! of! increased! ventricular! afterload! would! further! increase! RV!volumes!while! the!hyperinflated! lungs!would!exert!a!mediastinal!constraint!which!would!presumably! increase!pericardial!pressure.!Thus,!DVI!would!be!amplified,!as!increased! pericardial! pressure! has! been! suggested! to! be! the! primary!mediator! of!ventricular!interdependence108!(Figure!1.8).!!!Figure! 1.8! The! theorized! effects! of! DH! during! inspiratory! loading! on! LV! function.! Increased!negative! ITP! should! increase! ventricular! afterload! during! systole! (a),! while! increasing! RV!preload!during!diastole!(b).! In!conjunction!with!elevated!PVR!and!mediastinal!constraint! from!DH! (Figure!1.7),! these!mechanisms!may! interact! to! further! exacerbate!DVI! and! thus! a! greater!reduction!in!LV!SV!would!be!observed!(c).!!!! 36!Accordingly,!it!was!hypothesized!that:!1. Dynamic#hyperinflation#would#reduce#LV#SV#due#to#reduced#filling#of#the#LV#2. Dynamic# hyperinflation# in# conjunction# with# increased# negative# ITP# would#result# in# larger# reductions# in# LV# SV# than# either# condition# alone,# through# an#interactive#effect#of#these#stressors#resulting#in#increased#DVI.#(1.6.2! Investigating! the! effects! of! increased! right! ventricular! preload! during!inspiratory!loading!In! the!absence!of! increased!afterload!or! systolic!dysfunction,! volume! loading! (VL)!increases!LV!SV! through!series! interaction73.!HeadFdown! tilt! (HDT)!has!been!used!extensively!as!a!nonFinvasive!method!of!acutely!volume! loading! the!heart! through!increasing!RV!preload!with!minimal!changes!to!afterload,!contractility!or!HR109.!As!discussed!in!Section!1.4.6,!VL!is!used!therapeutically!to!augment!SV!in!the!acute!care!setting! for! patients! presenting! with! hemodynamic! instability! and/or! arterial!desaturation!secondary!to!many!pathologies,! including!exacerbation!of!respiratory!disease74,75.!However,! there! is!some!evidence!that! in! this!setting! the! interaction!of!increased!negative!pleural!pressure!and!additional!preload!may!be!detrimental! to!hemodynamics!due!to!DVI80.!Thus,!a!better!understanding!of!how!these!mechanisms!interact! is! essential! for! optimizing! treatment! in! this! population.! Additionally,!systolic!dysfunction!is!often!seen!to!cause!a!compensatory!increase!in!blood!volume!(hypervolemia)!to!maintain!cardiac!output78,110.!Hypervolemia!is!common!in!COPD!with!comorbid!heart!failure111,95,!and!in!this!setting!may!again!be!detrimental!to!LV!function!via!the!same!mechanism!of!DVI.!However,! few!studies!have!examined!the!! 37!effects!of!an!acute!VL! in!healthy! individuals!during! large! increases! in!negative!ITP!and!thus!the!second!aim!of!this!study!was!to!evaluate!the!effects!of!negative!ITP!on!LV! function! when! RV! preload! is! further! increased! through! HDT.! It! has! been!suggested! that! the! diastolic! increase! in! RV! preload! and! systolic! increase! in!ventricular!afterload,!resultant!from!increased!negative!ITP,!may!interact!with!HDT!to!further!augment!RVEDV!during!diastole,!yet!in!the!face!of!increased!RV!afterload!during!systole!may!paradoxically!decrease!LVEDV!due!to!DVI!and!constraint!of!the!LV!by!the!pericardium76,112.!!Therefore,!it!was!hypothesized!that:!1. Increasing#preload#through#HDT#would#acutely#increase#LV#SV#2. HDT# in# conjunction# with# increased# negative# ITP# would# cause# a# paradoxical#decrease#in#LV#SV#due#to#increased#DVI.(!1.6.3! Investigating! the! interactive! effects! of! increased! pulmonary! vascular!resistance,!lung!volumes!and!negative!intrathoracic!pressure!Acute! hypoxic! exposure! in! healthy! humans! is! well! documented! to! impair! LV!diastolic! function! secondary! to! increasing! RV! afterload,! while! cardiac! output! is!conserved! through! increased! sympathetic! activation! leading! to! increased! HR! and!contractility33,93.!However,!the!hemodynamic!effects!of!hypoxia!in!combination!with!elevations! in! lung! volumes! and! increased! negative! ITP,! as! commonly! observed! in!obstructive!respiratory!disease,!are!not!well!understood.!Thus,!the!third!aim!of!this!! 38!study!was!to!investigate!the!hemodynamic!effects!of!hypoxicFmediated!increases!in!PVR! on! LV! function! in! conjunction!with! the! stressors! discussed! above;! increased!negative! ITP,! elevated! lung! volumes! and! volume! loading,! using! a! multiFphase!approach.!We! theorized! that! acute! hypoxic! exposure!would! result! in! a! decreased!LVEDV! secondary! to! an! increase! in! PVR.! In! the! absence! of! additional! changes! to!preload!or!afterload,!this!would!be!predominantly!a!series!interaction,!as!has!been!previously! documented33,93,87.! However,! we! also! postulated! that! inspiratory!resistive!loading!during!hypoxia!would!reduce!LV!SV!to!a!larger!degree!than!under!normoxic! conditions,! as! the!additive! influence!of! these! stressors!on! increasing!RV!afterload!would!further!restrict!diastolic!filling!of!the!LV.!Whether!this!is!mediated!by!series!interaction!or!DVI!is!unknown,!however!we!aimed!to!discern!the!presence!and!relative!contribution!of!DVI!through!analysis!of!LV!geometric!configuration.!!Figure!1.9!The!theorized!effects!of!DH!during!IR!in!hypoxic!conditions!on!LV!function.!Relative!to! normoxia,! RV! afterload! should! be! further! increased! due! to! hypoxic! pulmonary!vasoconstriction! (a),! while! venous! return! may! be! accentuated! through! attenuation! of! IVC!collapse! (b)! resulting! in! a! greater! degree! of! RV! pressure! overload! and! subsequent! leftward!septal!shift.!Thus,!the!LV!may!be!further!constrained!and!LV!SV!further!reduced!(c).!! 39!Integrating! DH! into! this! model! to! investigate! the! cumulative! effects! of! hypoxia,!elevated! lung! volumes! and! increased! negative! ITP! has! not! been! investigated! in!healthy!humans.!As!depicted! in!Figure!1.9,!we!postulated! that!when! lung!volumes!were! increased,! the! resultant! larger! increase! in!PVR!and!potential! for!mediastinal!constraint!of!the!ventricles!would!greatly!magnify!the!contribution!of!DVI!and!thus!LV! SV! would! decrease! to! a! greater! extent! than! was! seen! during! any! of! these!interventions! in! isolation.! As! a! final! investigation,! we! proposed! that! augmenting!preload! through! acute! VL! under! these! conditions! may! paradoxically! further!decrease! LV! SV,! if! the! above! interactions! were! mediated! predominantly! by! DVI!(Figure!1.10).!#Figure! 1.10! The! theorized! effects! of! additional! preload! under! the! same! conditions! on! LV!function.!Increasing!preload!through!acute!VL!(a)!may!paradoxically!further!decrease!LV!SV!(b)!through!exacerbation!of!DVI.!!!!! 40!As!such,!it!was!hypothesized!that:!1. Inspiratory#resistive#loading#under#hypoxic#conditions#would#result#in#a#greater#reduction#in#LV#SV#than#during#IR#in#normoxia#2. DH#during#IR#in#hypoxia#would#result#in#a#larger#decrease#in#LV#SV#than#during#these#conditions#in#normoxia#3. Acute# volume# loading# utilizing# HDT# would# lead# to# a# paradoxical# further#decrease#in#LV#SV#due#to#exacerbation#of#DVI.#( (! 41!Chapter(2:(The(effect(of(negative( intrathoracic(pressure(on(heartOlung( interaction( in( the( presence( of( elevated( lung( volume( and(increased(right(ventricular(preload(and(afterload( 2.1(Introduction(Negative! swings! in! ITP! that! occur! during! normal! inspiration! increase! right!ventricular! (RV)!endFdiastolic! volume! (RVEDV)49,58,113! and!ultimately! augment! left!ventricular!(LV)!stroke!volume!(SV)!through!series!interaction,!a!process!termed!the!respiratory! pump51.! In! contrast,! large! negative! ITP! swings! can! actually! attenuate!venous! return! through! collapse! of! the! inferior! vena! cava! (IVC)! at! the! point! of!entrance! to! the! thorax,!while! also! causing! a! large! increase! in! LV! afterload! during!systole,! resulting! in! a! reduced! LV! SV114.! Large! negative! swings! in! ITP! may! also!accentuate!direct!ventricular!interaction!(DVI),!whereby!increased!RV!endFdiastolic!volume! (RVEDV)! causes! a! leftward! displacement! of! the! intraventricular! septum!which! restricts! LV! dimensions! and! ultimately! reduces! LV! endFdiastolic! volume!(LVEDV)80,115.! Yet,! the! relative! contributions! of! series! interaction! and! DVI! to!impairing!LV!function!during!large!negative!inspiratory!pressures!remains!unclear.!Furthermore,!it!is!debated!whether!DVI!is!a!relevant!mechanism!of!reduced!LV!SV!in!the! absence! of! abnormally! elevated! RV! preload! or! mediastinal! constraint! of! the!heart38,116.! To! our! knowledge! few! studies! have! evaluated! the! effects! of! increased!negative! ITP! on! LV! function! in! the! face! of! additional! challenges! to! hemodynamic!homeostasis,! namely! increases! in! RV! preload! and! afterload,! and! mediastinal!constraint!of!the!heart!due!to!increased!lung!volume.!!!! 42!Lung!volume!has!a!profound!effect!on!the!resistance!of!the!pulmonary!vasculature,!which! has! downstream! implications! for! RV! hemodynamics.! Increased! endFexpiratory!lung!volumes!(EELV)!exponentially!increases!PVR!through!compression!of! the!alveolar!capillaries,!which!greatly! increases!RV!afterload!and!reduces!LV!SV!through! series! interaction99,117,118.! Large! lung! volumes! also! impose! an! external!(mediastinal)! constraint! on! the! heart,! which! is! akin! to! a! reduction! in! pericardial!compliance,!and!limits!excursion!of!the!LV!freeFwall!in!response!to!septal!shifts.!This!mediastinal! constraint! has! been! shown! to! amplify! DVI! and! thus! reduce!LVEDV119,60,120,121.! It! remains! unclear!whether! lung!hyperinflation! (either! static! or!dynamic)! impairs! LV! function! through! series! interaction! or! whether! DVI! also!contributes!to!the!attenuated!LV!SV.!!Furthermore,!what!role!elevated!lung!volumes!and!associated!iPEEP!might!play!in!conjunction!with!increased!negative!ITP!has!not!been!examined.!iPEEP!attenuates!IVC!collapse122,!which!would!further!increase!RV!preload! during! large! negative! ITP! swings,! and! thus! these!mechanisms! in! concert!may!profoundly!exacerbate!DVI.!!!Paradoxically,! increasing!RV!preload!through!acute!VL!during!the!abovementioned!conditions!may! cause! a! further! reduction! in! LVEDV! and! LV! SV.! In! the! absence! of!increased!afterload,!VL!increases!LV!SV73.!However,!when!RV!afterload!is!increased,!as!is!the!case!during!increased!negative!ITP!or!elevated!lung!volumes,!acute!VL!may!significantly! increase! RV! filling! pressure! to! the! point! of! exceeding! LV! pressures!during! diastole,! reversing! the! transFseptal! pressure! gradient! and! resulting! in! a!leftward!septal!shift!and!reduction!in!LV!SV53.!Thus,!DVI!is!likely!exacerbated!when!! 43!large!negative!ITP!swings!further!augment!RV!preload!and!ventricular!afterload,!or!when!collapse!of!the!IVC!is!attenuated!as!a!result!of!iPEEP.!!In!addition!to!the!impact!of!lung!volume!on!pulmonary!vascular!resistance,!hypoxia!at! the! level! of! the! alveoli! mediates! a! vasoconstriction! response! in! an! attempt! to!improve!VA/Q!matching81.!The!RV!and!pulmonary!circulation!are!pressureFpassive,!thus! any! increase! to! PVR! substantially! increase! RV! afterload83.! This! hypoxicFmediated! increase! in! PVR,! and! thus! increased! RV! afterload,! has! been! shown! to!reduce!LV!SV!through!series!interaction83.!However,!DVI!may!play!a!more!pertinent!role! when! RV! preload! is! also! increased! due! to! increased! negative! ITP! swings! or!volume!loading.!Thus,!while!the!individual!hemodynamic!effects!of!pleural!pressure,!lung! volume,! volume! loading! and! hypoxia! are! generally! established,! how! these!mechanisms! interact! is! unknown.! Given! that! these! stressors! do! not! occur! in!isolation,! and! indeed!many!pathologies! (most!notably!COPD)!are! characterized!by!all!of!the!above!stressors,!a!better!understanding!of!how!these!mechanisms!interact!is!essential!to!defining!cardiopulmonary!interaction!in!disease!states.!!The!aim!of!this!study!was!to!evaluate!and!quantify!the!interactive!effects!of!changes!to! RV! preload! and! afterload,! namely! increased! RV! preload! through! VL,! and!increased! RV! afterload! through! increased! PVR! (increased! lung! volume! and! acute!hypoxic!exposure),!on!LV!function!alone!and!in!combination!with!increased!negative!ITP! swings,! which! should! further! accentuate! both! RV! preload! and! ventricular!afterload.!Furthermore,!this!study!aimed!to!define!the!roles!of!series!versus!DVI!in!! 44!mediating! these! changes! to! LV! function.! It! was! hypothesized! that! lung!hyperinflation!would! reduce! LV! SV!due! to! a! reduction! in! LVEDV.! Furthermore,! in!conjunction! with! increased! negative! ITP,! increases! in! lung! volume! via! dynamic!hyperinflation! (DH)! would! further! reduce! LVEDV! due! to! increased! RV! afterload!(series! interaction)! and!mediastinal! constraint! of! the! LV! (amplification! of!DVI).! It!was!also!hypothesized!that! increasing!RV!preload!via!head!down!tilt!(HDT)!would!increase!LV!SV.! !However,!HDT! in! conjunction!with! increased!negative! ITP!would!paradoxically!decrease!LV!SV!due!to#exacerbation!of!DVI.!Our!final!hypotheses!were!that! negative! ITP! in! combination! with! increased! RV! afterload! through! hypoxicFmediated! increases! in! PVR! would! result! in! a! greater! reduction! in! LV! SV! than! in!normoxia!and!furthermore!the!reduction!in!LV!SV!would!be!greater!in!the!presence!of!DH.!!Finally,!acute!volume!loading!in!the!presence!of!negative!ITP!and!DH!would!lead!to!a!paradoxical!further!decrease!in!LV!SV#through!exacerbation!of!DVI.!( (! 45!2.2(Methods:(2.2.1!Subjects!Twenty! healthy! subjects! (23! ±! 2! yrs,! 10!male;! 10! female)! from! the!Kelowna! area!volunteered!for!the!study.!Subjects!were!excluded!if!they!were!current!smokers,!had!a! history! of! cardiovascular! or! respiratory! disease,! a! BMI>30kg/m2,! were!hypertensive!(blood!pressure!>140/90!mmHg)!or!had!a!poor!window!for!collecting!quality! echocardiographic! images.! Subjects!were! informed! of! any! risks! associated!with! their! participation! and! signed! an! institutionally! approved! informed! consent!form!before!participating!in!the!study.!!2.2.2!Study!design!Subjects!attended!the!integrative!clinical!cardiopulmonary!physiology!laboratory!at!UBC’s! Okanagan! campus! on! two! occasions.! The! first! visit! involved! familiarization!with!the!test!protocol!and!equipment,!as!well!as!baseline!pulmonary!function!testing!(PFT)! and! a! hypoxia! familiarization! trial! (see! Section! 2.2.4.4).! The! second! visit!included!the!experimental!protocol,!where!participants!performed!six!study!phases!as!described!below.! !Upon!arrival,! subjects!had!a! small!balloonFtipped!esophageal!catheter!inserted!through!the!nose!and!properly!positioned!in!the!lower!third!of!the!esophagus.!After!insertion!of!the!esophageal!catheter,!resting!data!were!collected!in!the! leftFlateral! supine! position,! including! echocardiographic! measurements! of! LV!function,! ventilatory! parameters! and! measurements! of! ITP! fluctuations! during!resting! breathing.! After! baseline! data! had! been! collected! and! it!was! ensured! that!! 46!good! ultrasound! images! could! be! obtained,! subjects! began! the! test! protocol.!Baseline! echocardiography! measures! were! repeated! prior! to! starting! each!intervention,! allowing! for! a! more! reliable! comparison! between! baseline! and!intervention!measures.! Each! intervention!was!measured! alone! and! in! conjunction!with! an! inspiratory! resistance! (IR)! generating! target! inspiratory! pressures! of! F20!cmH2O.!The!test!protocol!was!completed!as!follows:!!Figure! 2.1! Flowchart! of! Study! Protocol.! Abbreviations:! IR! =! inspiratory! resistance,! DH! =!dynamic!hyperinflation,!HDT!=!headFdown!tilt.!!2.2.2.1#Phase#1#and#2:#Baseline#and#inspiratory#resistance#Following! 5! minutes! of! supine! rest,! baseline! ventilatory! parameters! and! echo!measurements!were!performed! (Phase!1).! ! ! An! external! breathing! resistance! (see!Section!2.2.4.1)!was!then!fitted!to!the!inspiratory!side!of!the!twoFway!mouthpiece!to!generate!inspiratory!pressures!of!F20!cmH2O!during!normal!inspiration!(Figure!2.7).!Subjects!maintained!F20!cmH2O!inspiratory!pressures!over!consecutive!respiratory!cycles! while! echocardiographic! measures! were! taken.! Once! measurements! were!complete!the!IR!was!removed!and!subjects!were!given!a!5Fminute!rest!period.###! 47!2.2.2.2#Phase#3:#Dynamic#lung#hyperinflation#An!external!breathing! load/resistance!(EL)!was! fitted! to! the!expiratory!side!of! the!twoFway! mouthpiece! to! obstruct! expiratory! flow,! and! ventilatory! duty! cycle! was!paced! to! induce! lung! hyperinflation! (phase! 3a;! see! Section! 2.2.4.2).! Subjects!continued! to! breathe! through! the! EL! until! they! reached! a! constant!maximal! endFinspiratory! lung! volume! (EILV)! across! several! respiratory! cycles,! at! which! point!echocardiographic! measures! were! repeated.! IC! maneuvers! were! conducted!immediately!after!echocardiographic!images!were!acquired!to!document!the!change!in!EELV.!The!EL!was!then!removed!and!the!subject!was!given!a!5Fminute!rest!period.!After! the! rest!period! the!DH!challenge!was! repeated!with!both! IR!and!EL! in!place!(phase!3b).!Echocardiography!measures!were!repeated!once!the!subject!had!again!reached! constant! maximal! EILV! and! was! consistently! maintaining! F20! cmH2O!inspiratory! pressures.! IC!maneuvers!were! then! repeated! and! then! both! breathing!resistances!were!removed!and!the!subject!was!given!a!5Fminute!rest!period.!!2.2.2.3#Phase#4:#HeadCdown#tilt#Subjects!were!positioned! in! a! 20°!HDT!position! to! augment! central! blood! volume!and! increase!RV!preload! (phase! 4a,! see! Section! 2.2.4.3)123,124.! After! 30! seconds! of!HDT!echocardiographic!measures!were!taken!to!capture!peak!effect!on!RV!preload,!as!determined!from!pilot!work!from!this!study!and!previous! literature125.!Subjects!were! then! repositioned! supine! and! given! a! 5Fminute! rest! period.! The! HDT!intervention! was! then! repeated! with! the! IR! in! place! (phase! 4b)! and!echocardiographic!measures!were!repeated!at!30!seconds!of!HDT,!after!subjects!had!! 48!sustained! F20! cmH2O! over! several! consecutive! respiratory! cycles.! Subjects! were!then! returned! to! the! supine! position! and! given! a! 5Fminute! rest! period! before!initiation!of!the!hypoxia!intervention.!!#2.2.2.4#Phase#5:#Hypoxia#Subjects! were! connected! to! a! Douglas! bag! for! a! 45Fminute! hypoxic! washFin,!breathing!a!FiO2!individualized!to!achieve!an!SpO2!of!approximately!80%!at!the!end!of!the!exposure!(mean!FiO2!13.6!±!0.2%).!!After!45!minutes!of!hypoxic!exposure!and!stabilization! of! SpO2! (mean! SpO2! 81.3%! ±! 1.2%)! hypoxic! baseline!measures! were!conducted,!including!echocardiographic!measures!and!IC!maneuvers!(phase!5a,!see!Section! 2.2.4.5).! The! external! breathing! resistance! was! then! placed! into! the!inspiratory! port! of! the! low! resistance! valve! and! IR! was! repeated! under! hypoxic!conditions! (phase! 5b).! After! the! IR!was! removed,! subjects!were! given! a! 5Fminute!rest!while!continuing!to!breathe!the!hypoxic!gas.!To!examine!the!combined!effects!of!increased! lung! volumes! and! hypoxia! on! cardiac! function! during! exposure! to!increases!in!ITP,!both!the!inspiratory!and!expiratory!resistances!were!inserted!and!the! DH! during! IR! trial! was! repeated! under! hypoxic! conditions! (phase! 5c).! After!echocardiographic!measures!and!IC!maneuvers!were!completed!the!inspiratory!and!expiratory! resistances! were! removed! and! the! subject! was! given! a! 5Fminute! rest!period.!#! 49!2.2.2.5#Phase#6:#All#interventions#simultaneously#After! the!5Fminute! rest!period,! subjects!were! returned! to! the!20°!HDT!and! the! IL!and!EL!trial!under!hypoxic!conditions!from!the!previous!phase!was!repeated.!As!per!previous!EL! trials,!echocardiographic!data!was!collected!once!EILV!had!plateaued.!IC!maneuvers!were!performed!and!after!all!data!were!collected!the!subject!had!the!IL!and!EL! removed,!was! returned! to!breathing! room!air! and!moved! to! the! supine!position.!Subjects!were!then!monitored!for!>10!minutes!to!ensure!SpO2,!heart!rate!and! blood! pressure! had! returned! to! baseline! values! and! that! they! were! not!reporting!any!adverse!symptoms!before!leaving!the!laboratory.!!2.2.3!Specific!methodology!2.2.3.1#Ventilatory#parameters#Ventilatory!parameters!were!measured!continuously!via!a!twoFway!low!deadFspace,!lowFresistance! valve! (Hans! Rudolph,! Model! 2700,! Hans! Rudolf! Inc.,! Shawnee,! KS,!USA)! attached! to! inspiratory! and! expiratory! pneumotachometers! via! large! bore!tubing.!Signals!from!the!pneumotachometer!were!converted!to!a!digital!signal!using!a!data!acquisition!system!(Powerlab,!ADI! Instruments,!Colorado!Springs,!CO).! !The!flow! signal!was! integrated! over! time! to! obtain! volume.!! All! data!were! sampled! at!1Hz!and!stored!on!a!computer!for!analysis!at!a!later!date.!Baseline!PFT!maneuvers!were! performed,! including! forced! vital! capacity! (FVC),! forced! expiratory! volume!(FEV1),! inspiratory! capacity! (IC)! and! maximum! inspiratory! (MIP)! and! expiratory!pressures! (MEP).!Maneuvers!were! performed! in! the! seated! position! according! to!! 50!American! Thoracic! Society! standards126,! and! repeated! in! the! leftFlateral! supine!position.! Repeated! inspiratory! capacity! (IC)! maneuvers! were! used! during! all!expiratory!loading!(DH)!interventions!to!quantify!the!relative!change!in!operational!lung!volumes!at!each!phase.!Repeated!IC!maneuvers!assumes!a!constant!TLC,!which!has! been! shown! to! be! a! robust! assumption! in! both! healthy! individuals127,128! and!patients!with!COPD129.!TLC!was!not!measured!for!this!study,!thus!IC!was!used!as!a!relative!measure!where! the!percent! change! in! IC! indicates! a!proportional!percent!change!in!EELV128.!#2.2.3.2#Intrathoracic#pressure#measurement#ITP!was!measured!via!esophageal!balloon.!After!applying!a!topical!anaesthetic!to!the!patient’s! nares! and! nasal! conchae! (Xilocaine,! Lidocaine! Hydrochloride),! a!conventional!balloon!catheter!(Figure!2.2a)!(Ackrad!Laboratories!Inc.,!Cranford,!NJ)!was!passed!transFnasally!(Figure!2.2b)!and!advanced!into!the!stomach!by!sipping!a!small!amount!of!water!through!a!straw.!Subjects!were!then!asked!to!perform!a!brief!Valsalva!maneuver! while! the! catheter! was! open! to! the! atmosphere! to! empty! the!balloon.!For!all!measurements!the!balloon!was!inflated!with!0.5!ml!of!air!as!per!the!manufacturer’s!recommendation.!!The!balloon!was!then!withdrawn!gradually!until!a!negative!deflection!was!present!during!inspiration!before!being!withdrawn!another!5F10!cm!(~40!cm!from!the!nose!to!the!tip!of!the!balloon)!and!fixed!at!a!depth!where!cardiogenic! effects! were! minimized.! Following! confirmation! of! placement,! the!balloon! was! secured! by! taping! it! to! the! subject’s! nose! and! cheek.! The! balloon!catheter! was! connected! to! a! differential! pressure! transducer! (MP45,! Validyne,!! 51!Northridge,! CA),! which! was! calibrated! before! each! test! using! a! waterFfilled!manometer.!Signals!from!the!pressure!transducer!were!converted!to!a!digital!signal!using!a!data!acquisition!system!(Powerlab,!ADI!Instruments,!Colorado!Springs,!CO).!!!Figure! 2.2! Balloon! catheter! (a)! being! inserted! into! subject’s! nasal! passage! after! local!anaesthesia!(b)!!2.2.3.3#Echocardiography#measurements#Echocardiographic! images!were! acquired! by! a! trained! sonographer,! and! recorded!on! a! commercially! available! ultrasound! system! (VividFE9,! GE! Medical,! Horton,!Norway)!using!a!M5SFD!1.5F4.6!MHz!probe!for!2D!imaging,!and!a!4VFD!1.5F4.0!MHz!probe! for! 4D! (triFplane)! imaging.! Images! were! acquired! with! subjects! in! the! left!lateral! decubitus! position,! and! saved! for! offline! analysis! (EchoPAC! version! 7,! GE!Medical,!Horton,!Norway).!Images!were!acquired!for!the!assessment!of!LV!structure,!volumes! and! function,! in! accordance! with! current! guidelines130.! LV! parasternal!shortFaxis! images! just! below! the! level! of! the! mitral! valve! were! acquired! and!analyzed! for! determining! LV! geometry.! TriFplane! imaging! was! used! to! acquire!! 52!images! in! the! apical! fourF,! threeF! and! twoFchamber! views! simultaneously.! These!images! were! analyzed! for! LV! endFsystolic! volumes,! endFdiastolic! volumes! and!ejection! fraction! using! the! Simpson’s! triFplane! method131F133.! The! ECG! trace! was!used!to!accurately!time!the!beginning!and!end!of!systolic!ejection.!EndFdiastole!was!taken!as!the!frame!before!mitral!valve!closure,!and!endFsystole!as!the!frame!prior!to!mitral! valve! opening.! Endocardial! border! tracing! of! endFdiastolic! and! endFsystolic!images!were! then! performed! according! to! American! Society! of! Echocardiography!recommendations! to! measure! ejection! fraction! (EF,! calculated! as! LV!SV/LVEDV*100%! where! SV! =! LVEDVFLVESV)! from! the! corresponding! LV!volumes130.!!!!Fifteen! consecutive! cardiac! cycles! were! acquired! across! several! spontaneous,! or!paced,! respiratory! cycles,! depending! on! the! intervention.! A! respiratory! trace!was!applied!to!all! image!acquisitions! to! identify! the!phase!of! the!respiratory!cycle! that!corresponded!to!the!cardiac!cycles!acquired.!Every!effort!was!made!to!analyze!the!highest!quality! consecutive! cycles! across!different!phases!of! the! respiratory! cycle,!wherever! possible.!However,! this!was! not! always! possible! due! to! the! difficulty! in!obtaining!quality!parasternal!shortFaxis!(PSA)!and!apical!images!at!end!inspiration!with!increased!operational!lung!volumes.!!As!such,!we!report!mean!data!from!across!the!respiratory!cycle!and!did!not!differentiate!volumes!acquired!during!inspiration!and!expiration!(Please#see#Section#3.2.3#for#detailed#discussion).!!! ZX. '$) ( .0- .2 - + -!*-( //# ./-/*! #+#.  !*- 1*'0( /-$( .0- . 2 -  - + /  !*''*2$)"  3+*.0-  /*  # ./- ..*-E #$. 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WF$( ).$*)' .03$+#*$ 1$ 2B )(3$(0(  3+$-/*-4 ) ($)$(0( $).+$-/*-4 $( / -. 0-$)" /#  I.)$!!J / ./2 -  ( .0-  0.$)" /#  '$+ - !0)/$*) *! /#  #* .*!/2- E ''( .0- ( )/.*!$( / -2 - ( 2$/#$)W(*!/# *-$"$)*!/# M$"0-  WEXNE *)/$)0*0. 21  *++' - - *-$)". 2 -  + -!*-(  $) /#  +$'!*0-F#( -1$ 2!*-/# ( .0- ( )/*!/# /-$0.+$- "0-"$/)/% /B.#.  )$"0- WEX3(+' *! .0- ( )/E! 54!previously! described135.! Baseline! normoxic! and! hypoxic! right! ventricular! systolic!pressure! (RVSP)! was! calculated! using! the! aforementioned! IVC! diameter! and!collapsibility!index,!and!tricuspid!valve!regurgitation!(TRV)!jet!velocity!(Figure!2.4),!applying!the!modified!Bernoulli!equation,!and!was!used!as!a!surrogate! for!systolic!PAP136.! The! highest! quality! images! acquired! were! analyzed! for! all! structural,!volume,!and!DopplerFderived!data,!and!were!averaged!over!three!cardiac!cycles.!!!!Figure! 2.4! Example! of! tricuspid! regurgitation! velocity! jet! (a)! and!MFmode! velocity! tracing! in!normoxic!(b)!and!hypoxic!(c)!conditions!for!the!same!subject.!!A!research!assistant!independent!from!the!study!coded!all!data!such!that!the!single!trained! observer,!who! performed! all! the! analysis,! was! blinded! to! subject! identity!and! study! phase! during! analysis.! Once! all! analysis! was! complete,! and! prior! to!statistical!analysis,!the!data!code!was!broken!and!all!measurements!were!assigned!to! the! appropriate! subject! and! phase.!With! respect! to! reliability! of!measures,! the!sonographer’s! technical! error! of! measurement! for! measures! performed! on! two!different!occasions!on!the!same!day!were!2.5%!for!EF,!1.8!mL!for!LVEDV!and!4.5!mL!for!LVESV.!Additionally,!the!intraFobserver!coefficient!of!variation!for!image!analysis!! 55!was! 1.6%! for! LVEDV,! 4.1%! for! LVESV,! 2.3%! for! SV! and! 2.7%! for! EF! using! the!Simpson’s!triFplane!method.!!The!radius!of!septal!curvature!(RSC)!was!calculated!to!quantify!the!degree!of!septal!flattening,! and! thus! presence! of! DVI,! during! each! intervention.! The! radius! of! the!septal!segment!was!determined!using!a!modified!technique!developed!by!Brinker!et!al53,! and! calculated! from! the! PSA! view! at! both! endFdiastole! and! endFsystole! at!baseline! and! during! each! intervention.! As! demonstrated! in! Figure! 2.5,! RSC! was!obtained!by!defining!two!endocardial!arc!segments;!one!defining!the!septal!wall!and!the!other!defining!the!LV!free!wall.!Two!chords!were!constructed!to!span!separate!parts! of! the! arc! segment,! with! perpendicular! lines! bisecting! the! chords! and!extending!into!the!center!of!the!ventricle.!The!intersection!point!of!these!bisections!defined!the!center!of!the!circle!described!by!the!arc!segment53.!Thus,!a!straight!line!drawn!from!this!intersection!point!to!the!wall!of!the!arc!segment!gave!the!radius!of!curvature.! Three! such! lines!were! drawn! for! each! arc! segment! and! the! average! of!these! distances!was! calculated! to! determine! an! accurate! radius.! This! process!was!repeated!to!determine!the!radius!of!curvature!of!the!LV!freeFwall!(RFWC).!!! 56!!Figure! 2.5! Method! for! Determining! Radius! of! Septal! Curvature! (RSC).! Two! chords! (A! and! B)!span! the! septal! arc! segment,! and! are! bisected! by! perpendicular! lines! (A1! and! B1).! The!intersection!point!(C)!defines!the!center!of!the!circle!described!by!the!arc!segment,!from!which!three!radii!(R1,!R2!and!R3)!are!constructed,!the!average!length!of!which!is!calculated!to!provide!the!radius.!!2.2.4!Specific!interventions!2.2.4.1#Inspiratory#loading#Inspiratory! resistance! was! generated! by! a! custom! built! inFline! resistance! device!(Figure!2.6)!that!reduced!diameter!and!thus!increased!resistance!to!airflow,!fitted!to!the!inspiratory!side!of!a!twoFway!nonFrebreather!mouthpiece!(Hans!Rudolph,!Model!2700,!Hans!Rudolf! Inc,! Shawnee,!KS,!USA)! to! achieve!a! target!negative! ITP!of! –20!cmH2O!during!normal! inspiration! (Figure!2.7).!Resistance!was! initially! set!using!a!3mm!diameter!resistor,!and!subjects!were! instructed!to!breathe!normally! through!the! resistance.! If! subjects! were! unable! to! achieve! an! inspiratory! pressure! of! F20!cmH2O!without! considerably!altering! their!VE!or! inspiratory!effort,! resistance!was!increased!by!decreasing!the!resistor!diameter.!All!subjects!were!able!to!consistently!! 57!maintain!F20!cmH20!with!minimal!changes!to!VE!using!either!the!3mm!or!2mm!bore!resistor.! Echocardiographic! measurements! were! taken! once! the! subject! had!maintained!F20!cmH20!inspiratory!pressures!consistently!across!several!respiratory!cycles!(~30!seconds).!!Figure! 2.6! Adapters! used! to! fit! inFline! resistance! to! inspiratory! or! expiratory! port! of! HansFRudolf! nonFrebreather!mouthpiece! (a),! and! interchangeable! resistances! (b)!marked!with! flow!bore!size!in!mm.!!2.2.4.2#Dynamic#lung#hyperinflation#Lung! hyperinflation! (DH)! was! achieved! through! application! of! an! expiratory!resistance! (inFline! resistor! affixed! to! the! expiratory! side! of! the! twoFway! nonFrebreather!mouthpiece,!see!Figure!2.7).!Expiratory!resistance!was!chosen!to!match!inspiratory! resistance! from!phase!2,! thus!either!a!3mm!or!2mm!diameter! resistor!was! used.! Subjects! had! their! ventilation! paced! via! metronome! (Pro! Metronome!Application! for! Apple! devices,! EUM! Lab,! Berlin,! Germany)! such! that! their! RR!matched!their!resting!RR,!however!duty!cycle!was!manipulated!such!that!expiratory!time!(TE)!was!limited!to!50%!of!total!respiratory!cycle!time!(TI/TTOT!=!0.5).!During!the!DH!and! IR! intervention! (phase!3b),! duty! cycle!was!paced! at!TI/TTOT! =!0.67! to!allow!for!sustained!F20!cmH2O!inspiratory!pressures!while!limiting!expiratory!flow!! 58!such! that! DH! occurred.! Echocardiography! measurements! were! acquired! at! the!maximal!EELV!the!subject!was!able!to!maintain,!as!determined!by!realFtime!analysis!of! the! subject’s! expiratory! flow!and! volume,! and!was!quantified!by!performing! IC!maneuvers!after!echo!measurements!were!completed.!!!Figure! 2.7! InFline! 2mm! bore! breathing! resistances! mounted! to! both! the! inspiratory! (a)! and!expiratory!(b)!ports!of!the!HansFRudolph!nonFrebreather!mouthpiece!#2.2.4.3#Volume#loading#An!increase! in!RV!preload!was!achieved!by!positioning!subjects! in!a!20°!HDT!(left!lateral)! position! (Figure! 2.8)! using! a! bed! designed! for! 12°! Trendelenberg! and!reverse!Trendelenberg!positioning,!which!was!modified!by!elevating!and!supporting!the! foot! end! of! the! bed! to! achieve! 20°! HDT! (HillFRom! Century,! HillFRom! Canada,!Mississauga,!ON,!Canada).!Pilot!data!for!this!study,!and!previous!work137!has!shown!a! peak! effect! of! HDT! on! increased! LVEDV! within! 1! minute! of! initiating! HDT,!therefore!all!echocardiography!measurements!were!conducted!30!seconds!after!the!start!of!HDT!and!were!completed!within!2!minutes!of!HDT.!! 59!!Figure! 2.8! Subject! in! 20°! HDT! leftFlateral! position! with! echocardiographic! measures! being!collected!#2.2.4.4#Hypoxia#familiarization#trial#Subjects! breathed! 13.5%! FiO2! from! a! 200L! reservoir! bag! (Douglas! bag,! VacuMed,!Ventura,!CA,!USA)!connected!to!a!twoFway!nonFrebreather!mouthpiece!(Hans!Rudolf!Inc,!Shawnee,!KS,!USA)!for!30!minutes!to!determine!their!SpO2!response!to!hypoxia!and!target!FiO2!for!the!test!protocol.!After!30!minutes,!or!when!SpO2!had!stabilized,!FiO2! was! adjusted! such! that! steadyFstate! SpO2! of! ~80%! was! maintained! for! an!additional! 15! minutes! of! hypoxic! exposure.! The! required! FiO2! to! achieve! steadyFstate! 80%! SpO2! for! each! subject! was! recorded! for! the! subsequent! hypoxia!intervention.!!! 60!2.2.4.5#Hypoxia#intervention#A!normobaric!hypoxic!stressor!was!imposed!on!the!subject!through!breathing!12.5F14%! FiO2! titrated! room! air! (mean! FiO2! 13.6! ±! 0.2%),! as! determined! from! the!subjects! hypoxia! familiarization! trial,! run! through! a! hypoxic! generator! (HYP123,!Hypoxico!Inc,!New!York,!USA!)!and!collected!in!a!200L!reservoir!bag!(Douglas!bag,!VacuMed,!Ventura,!CA,!USA)!(Figure!2.9).!During!the!test!protocol,!subjects!breathed!the! hypoxic! gas! from! the! reservoir! bag! for! 45! minutes! through! a! twoFway! nonFrebreather! mouthpiece! (Hans! Rudolf! Inc,! Shawnee,! KS,! USA)! prior! to!echocardiography! measures! being! taken.! Previous! research! has! shown! that!significant!pulmonary!vasoconstriction!and!elevation!in!pulmonary!artery!pressures!(PAP)!occurs!within!45!minutes!of!acute!hypoxic!exposure,!while!peak!PAP!occurs!after!~90!min!of!exposure138,139.!Thus,!a!45Fminute!hypoxic!challenge!was!selected!to!ensure!significant!elevations!in!PAP!are!achieved,!while!not!unduly!increasing!the!duration! of! the! study! protocol.! PAP! was! estimated! via! tricuspid! regurgitation!velocity! measured! via! echocardiography! (see! Section! 2.2.3.3)140! and! oxygen!saturation!was!measured!continuously!via!nonFinvasive!pulse!oximetry.!!! 61!#Figure!2.9! Subject! shown! in!HDT! leftFlateral! position!breathing!hypoxic! gas! from!Douglas!bag!reservoir!(2.2.5!Statistical!analysis!!Descriptive! statistics!utilized!mean!±!SD.! !Before!applying! statistical!methods! that!assume! normalcy,! a! ShapiroFWilks! test! was! performed.! ! Dependent! tFtests! were!then! performed! on! normally! distributed! data! to! determine! whether! each!intervention!had!a!significant!effect!on!cardiopulmonary!parameters!relative!to!each!specifically!measured!baseline.!If!needed,!nonFparametric!data!was!analyzed!using!a!Wilcoxon!signedFrank!test.!Percent!change!scores!were!analyzed!using!a!oneFsample!tFtest! to! assess! whether! the! mean! percent! change! was! different! from! zero.! To!determine!differences! in!cardiopulmonary!parameters!across!all!phases,!repeatedF! 62!measures!oneFway!ANOVA!was!used!utilizing!a!HolmFSidak!postFhoc!comparison!to!allow!for!comparison!across!phases!with!different!sample!sizes,!relative!to!baseline!(phase!1)!parameters.!NonFparametric!data!was!analyzed!using!repeated!measures!ANOVA!on!ranks!with!a!Dunn’s!postFhoc!comparison!test.!!To! investigate! and! quantify! the! relative! contribution! of! specific! interventions! in!combination,! dependent! tFtests!were! used! between! IR! alone! (phase! 2),! and! IR! in!conjunction!with!each!independent!stressors!(e.g.!phase!3b:!DH!with!IR,!phase!4b:!HDT!with! IR,!phase!5b:!hypoxia!with! IR).!To!quantify! the!summative!effects!of! IR,!DH! and!Hypoxia,! oneFway! repeatedFmeasures!ANOVA!with! 3! dependent! variables!was!performed!between!IR!alone!(phase!2),!IR!with!DH!(phase!3b)!and!IR!with!DH!under! hypoxic! conditions! (phase! 5c).!When! a! significant! effect!was! found! for! the!ANOVA,! a!Tukey!postFhoc! test!was!used,! (when! sample! sizes!were!equal!between!phases).! For! nonFnormally! distributed! data,! repeated! measures! ANOVA! on! ranks!with! a! Dunn’s! postFhoc! comparison! was! used.! To! quantify! the! effect! of! volume!loading!in!addition!to!the!effects!of!IR,!DH!and!hypoxia,!a!repeatedFmeasures!ANOVA!(4! dependent! variable)!was! also! performed! including! phase! 6! (DH! and! IR! during!HDT!under!hypoxic!conditions).!LV!geometric!parameters!of!septal!and!LV!freeFwall!radius!were!analyzed!using!oneFway!repeatedFmeasures!ANOVA!and!a!HolmFSidak!!postFhoc!comparison!relative!to!control!(phase!1)!for!normally!distributed!data,!or!a!repeatedFmeasures! ANOVA! on! rank! with! Dunn’s! postFhoc! comparison! for! nonFnormally!distributed!data.!The!alpha!level!for!all!analysis!was!set!a#priori!at!p<0.05.!! !! 63!2.3(Results((Twenty!healthy! subjects! (10!Males:! 10!Females)!with!normal!pulmonary! function!and! no! history! of! cardiorespiratory! disease! volunteered! for! the! study,! and! all!completed!the!study!protocol.!Subject!characteristics!and!baseline!cardiorespiratory!parameters!are!reported!in!Tables!2.1!and!2.2,!respectively.!!Table!2.1!Subject!characteristics!!Parameter( Mean(±(SD(Age! 23!±!2!Ht!(m)! 1.71!±!0.10!Wt!(kg)! 69.0!±!12.8!BMI!(kg/m2)! 23.5!±!2.4!FVC!(l)! 4.53!±!1.09!FVC!!(%!Pred)! 100!±!11!FEV1!(l)! 3.52!±!0.81!FEV1!(%!Pred)! 90!±!12!FEV1/FVC!(%)! 78!±!7!IC!(L)! 2.65!±!0.71!MIP!(cmH2O)! F89!±!25!MIP!(%!Pred)! 87!±!21!MEP!(cmH2O)! 115!±!41!MEP!(%!Pred)! 86!±!25!!Data!presented!as!mean!±!SD,!n=20.!!Abbreviations:!!FVC!=!forced!vital!capacity,!FEV1!=!forced!expired!volume! in! 1! second,! %! Pred! =! percent! of! predicted,! IC! =! inspiratory! capacity,! MIP! =! maximal!inspiratory!pressure,!MEP!=!maximal!expiratory!pressure.!!!! !! 64!2.3.1!Repeated!baseline!measures!!No!significant!difference!in!baseline!measures!of!cardiovascular!(LVEDV,!LVESV,!EF,!SV,!Q!and!HR)!or!pulmonary!function!(VT,!VE,!TI/TTOT!and!ITP)!performed!at!the!start!of! each! of! phases! 1! through! 4! were! observed! (p>0.05).! However,! VE! was!significantly! different! between! phase! 1! baseline! and! phase! 3! (dynamic! lung!hyperinflation)!baseline!(p=0.037).!HR,!Q,!VE,!TI/TTOT!and!ITP!differed!significantly!between! normoxic! and! hypoxic! conditions! and! therefore! hypoxic! baseline! (phase!5a)! is! reported! relative! to! the! last! set! of! normoxic! baseline!measurements! taken!(see!Table!2.10).!! !! 65!!!!!Table!2.2!Baseline!measures!of!cardiopulmonary!function!(Phase!1)! !!!Parameter( Baseline(RR!(bpm)! 13.7!±!2.2!VT!(L)! 0.60!±!0.11!VE!(L/min)! 8.1!±!1.2!TI!(sec)! 1.7!±!0.3!TE!(sec)! 2.7!±!0.5!TI/TTOT! 0.39!±!0.05!Pes.ins!(cmH2O)! F4.5!±!2.3!Pes.exp!(cmH2O)! 1.1!±!1.8!IC!(l)! 2.65!±!0.71!LVEDV!(mL)! 117!±!23!LVESV!(mL)! 48!±!9!EF!(%)! 59!±!4!SV!(mL)! 77!±!39!Q!(L/min)! 4.0!±!0.8!HR!(bpm)! 60!±!12!MAP!(mmHg)! 76!±!8!RAP!(mmHg)! 3!±!1!CVI!(%)! 83!±!11!TRV!(m/s)! 2.0!±!0.2!RVSP!(mmHg)! 21!±!5!SpO2!(%)! 99!±!1!RSCFED!(cm)! 3.2!±!0.9!RSCFES!(cm)! 1.9!±!0.5!RFWCFED!(cm)! 2.5!±!0.2!RFWCFES!(cm)! 1.6!±!0.3!!Data!presented!as!mean!±!SD,!n=20.! !Abbreviations:! !RR!=! respiratory! rate,!VT!=! tidal! volume,!TI!=!inspiratory! time,!TE!=!expiratory! time,!TI/TTOT!!=! ratio!of! inspiratory! time! to! total! respiratory! cycle!time,! Pes!=! esophageal! pressure,! IC! =! inspiratory! capacity,! LVEDV! =! Left! ventricular! end! diastolic!volume,!LVESV!=!left!ventricular!end!systolic!volume,!EF!=!ejection!fraction,!SV!=!stroke!volume,!Q!=!cardiac! output,! HR! =! heart! rate,!MAP! =!mean! arterial! pressure,! RAP! =! right! atrial! pressure,! CVI! =!caval! respiratory! index,!TRV!=! tricuspid! regurgitation!velocity,! SVR!=! systemic!vascular! resistance,!RAP!=!right!atrial!pressure,!RVSP!=!right!ventricular!systolic!pressure,!CVI!=!caval!respiratory!index!of!IVC!collapse,!TRV!=!tricuspid!regurgitation!velocity,!SpO2!=!peripheral!capillary!oxygen!saturation,!RSCFED! =! radius! of! septal! curvature! at! end! diastole,! RSCFES! =! radius! of! septal! curvature! at! end!systole,!RFWCFED!=!radius!of!LV!freeFwall!curvature!at!end!diastole,! !RFWCFES!=!radius!of!LV!freeFwall!curvature!at!end!systole.!!! !! 66!2.3.2!Effects!of!inspiratory!resistance!on!cardiopulmonary!function!(Phase!2)!!!The!cardiopulmonary!responses! to! IR!are!summarized! in!Table!2.3!and! individual!subject! responses! are! shown! in! Appendix! A! Figure! A.1.! ! Inspiratory! resistance!resulted!in!a!mean!inspiratory!ITP!(Pes.ins)!of!F22!±!3!cmH2O,!which!was!a!significant!increase! from! baseline! inspiratory! pressures! (p<0.001).! Mean! expiratory! ITP!(Pes.exp),!or!peak!expiratory!pressures,!also!increased!significantly!(p=0.025)!(Figure!2.10).!IR!significantly!reduced!RR!by!33.0!±!27%!(p<0.001)!and!was!associated!with!an!82!±!74%!increase!in!VT!(P<0.001)!and!a!205!±!144%!increase!in!TI!(p<0.001).!Accordingly,!TI/TTOT!also!increased!significantly!(p<0.001)!(Figure!2.11)!but!VE!was!unchanged!from!baseline!(p=0.544).!!IR!caused!a!significant!4!±!5%!reduction!in!LVEDV!(p=0.002),!which,!in!conjunction!with!an!unchanged!LVESV!(p=0.992),!resulted!in!a!significant!reduction!in!EF!and!SV!(p=0.011,!<0.001,!respectively).!A!compensatory!13!±!17%!increase!in!HR!(p=0.004)!preserved!Q!such!that!it!was!not!significantly!different!from!baseline!(p=0.536).!IR!did! not! have! an! appreciable! effect! on! MAP! (p=0.649),! SVR! (p=0.318)! or! SpO2!(p=0.359).! ! Inspiratory! loading! caused! septal! flattening! and! incursion! into! the! LV!cavity!such!that!the!radius!of!septal!curvature!(RSC)!at!endFdiastole!increased!by!26!±!31%!(p=0.002)!(Appendix!A!Figure!A.12).!IR!did!not!alter!septal!geometry!at!endFsystole,!or!LV!freeFwall!geometry!(changes!in!LV!freeFwall!geometry!at!endFsystole!were!not!significant!across!all!interventions,!p=0.680).!!!!! 67!!!!!!!!!!!!!Figure!2.10!ITP!changes!across!all!phases!as!depicted!by!mean!expiratory!(light!blue!bars)!and!inspiratory! (dark!blue!bars)!esophageal!pressure! (Pes)! (n=20).!P1!=!baseline,!P2!=! Inspiratory!loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic! hyperinflation! with!inspiratory! loading! (DH+IR),! P4a! =! HeadFdown! tilt! (HDT),! P4b! =! HeadFdown! tilt! with!inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =! Hypoxia! with! inspiratory! loading!(Hypox+IR),! P5c! =! Hypoxia! with! IR! and! DH,! (Hypox+DH+IR),! P6! =! Hypoxia! with! IR! and! DH!during!HDT!(All!interventions).!Error!bars!represent!standard!deviation.!*!Denotes!a!significant!change!from!baseline!(P1)!(p<0.05).!! !!!!!!!! 68!!!!!!!!!!!Figure! 2.11! Respiratory! cycle! times! across! all! phases! (n=20).! TI! =! inspiratory! time,! TE! =!expiratory!time,!TI/TTOT!=!inspiratory!time!as!a!percentage!of!total!respiratory!cycle!time.!P1!=!baseline,! P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic!hyperinflation! with! inspiratory! loading! (DH+IR),! P4a! =! HeadFdown! tilt! (HDT),! P4b! =! HeadFdown! tilt! with! inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =! Hypoxia! with! inspiratory!loading!(Hypox+IR),!P5c!=!Hypoxia!with!IR!and!DH,!(Hypox+DH+IR),!P6!=!Hypoxia!with!IR!and!DH! during! HDT! (All! interventions).! Error! bars! represent! standard! deviations.! *! Denotes! a!significant!change!from!baseline!P1!(p<0.05).!!!!!!!!!! 69!!!!!!!!!!Table! 2.3! The! effect! of! inspiratory! resistive! loading! (Phase! 2)! on! cardiopulmonary!function!and!LV!geometry.!!(Parameter( Baseline( Condition( Δ(Abs.( p( Δ(%( p(RR!(bpm)! 13.5!±!2.6! 8.9!±!3.9! F4.6!±!4.2*! <0.001! F33!±!27*! <0.001!VT!(L)! 0.56!±!0.11! 1.00!±!0.47! 0.44!±!0.43*! <0.001! 82!±!74*! <0.001!VE!(L/min)! 7.3!±!1.0! 7.5!±!1.3! 0.2!±!1.7! 0.544! 5!±!23! 0.331!TI!(sec)! 1.7!±!0.3! 5.2!±!2.3! 3.4!±!2.3*! <0.001! 205!±!144*! <0.001!TE!(sec)! 2.8!±!0.7! 2.7!±!1.6! F0.1!±!1.6! 0.231! F20!±!45! 0.063!TI/TTOT!! 0.39!±!0.05! 0.65!±!0.06! 0.26!±!0.08*! <0.001! FF! FF!Pes.ins!(cmH2O)! F3.7!±!1.9! F22.4!±!2.8! F18.7!±!2.7! <0.001! 1262!±!259*! <0.001!Pes.exp!(cmH2O)! 1.6!±!1.5! 2.7!±!2.0! 1.1!±!1.9*! 0.025! 42!±!208! 0.372!LVEDV!(mL)! 112!±!22! 108!±!24! F4.5!±!5.2*! 0.001! F4!±!5*! 0.002!LVESV!(mL)! 47!±!10! 47!±!10! 0.0!±!3.7! 0.992! 0!±!9! 0.903!EF!(%)! 58!±!3! 56!±!4! F1.9!±!2.9*! 0.011! FF! FF!SV!(mL)! 65!±!13! 61!±!15! F4.3!±!4.1*! <0.001! F7!±!7*! <0.001!Q!(L/min)! 3.8!±!0.7! 3.9!±!0.7! 0.1!±!0.6! 0.536! 3!±!15! 0.331!HR!(bpm)! 59!±!12.0! 67!±!13.7! 7!±!9*! 0.004! 13!±!17*! 0.004!MAP!(mmHg)! 76!±!8! 77!±!7! 1!±!7! 0.649! 2!±!10! 0.513!SVR!(Δ!%)! FF! FF! FF! FF! 4!±!16! 0.318!SpO2!(%)! 99!±!1! 98!±!2! F0.4!±!1.5! 0.359! FF! FF!RSCFED!(cm)! 3.2!±!0.9! 3.9!±!1.1! 0.7!±!0.8! 0.299! 26!±!31*! 0.002!RSCFES!(cm)! 1.9!±!0.5! 2.2!±!0.7! 0.4!±!0.7! 0.880! 24!±!51! 0.056!RFWCFED!(cm)! 2.5!±!0.2! 2.5!±!0.2! 0.0!±!0.2! 0.937! 1!±!7! 0.564!RFWCFES!(cm)! 1.6!±!0.3! 1.6!±!0.2! 0.1!±!0.2! >0.05 5!±!16! >0.05!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=19! and! LV!geometry;!n=19.! !Abbreviations!RR!=!respiratory!rate,!VT!=! tidal!volume,!TI!=! inspiratory!time,!TE!=!expiratory! time,!TI/TTOT!!=! ratio!of! inspiratory! time! to! total! respiratory! cycle! time,!Pes!=! esophageal!pressure,! LVEDV! =! Left! ventricular! end! diastolic! volume,! LVESV! =! left! ventricular! end! systolic!volume,!EF!=!ejection!fraction,!SV!=!stroke!volume,!Q!=!cardiac!output,!HR!=!heart!rate,!MAP!=!mean!arterial!pressure,!SVR!=!systemic!vascular!resistance!SpO2!=!peripheral!capillary!oxygen!saturation,!RSCFED! =! radius! of! septal! curvature! at! end! diastole,! RSCFES! =! radius! of! septal! curvature! at! end!systole,!RFWCFED!=!radius!of!LV!freeFwall!curvature!at!end!diastole,! !RFWCFES!=!radius!of!LV!freeFwall! curvature! at! end! systole.! Δ!Abs!=! absolute! change! from!baseline,! Δ!%!=! relative! change! from!baseline.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!!!!!!! 70!2.3.3!Effects!of!dynamic!hyperinflation!on!cardiopulmonary!function!(Phase!3a)!The!cardiopulmonary!responses!to!DH!are!summarized!in!Table!2.4!while!individual!subject! responses! are! depicted! in! Appendix!A,! Figure!A.2.! DH! did! not! change! RR,!however!VT!increased!by!17!±!25%!(p=0.006)!and!thus!VE!by!24!±!23%!(p<0.001)!(see!Appendix!A!Figure!A.10).!TI!was!reduced!by!26!±!17%!(p<0.001)!and!similarly!TI/TTOT! was! reduced! by! 9! ±! 5%! (p<0.001)! (Figure! 2.11).! At! the! time! of!echocardiographic! image! acquisition,! EELV! was! increased! by! 1.70! ±! 0.81! L,! as!indicated!by!a!reduction!in!IC!of!57!±!18%!(p<0.001,!see!Figure!2.12).!!DH!reduced!LVEDV!by!9!±!10%!(p<0.001),!while!LVESV!did!not!change!significantly.!Thus,! EF! was! reduced! by! 2! ±! 5%,! (p=0.05),! while! SV! was! reduced! by! 12! ±! 13%!(p=0.001).!During!DH,!Q!was!maintained!by!an!8!±!10%!increase!in!HR!(p=0.003),!and!did!not!change!appreciably!(p=0.218)!(Figure!2.16).!SpO2!did!not!change!during!DH,!however!MAP!increased!by!5!±!10%!(p=0.052),!resulting!in!a!16!±!25%!increase!in! SVR! (p=0.020).! DH! caused! significant! flattening! of! the! septum,! reducing! the!radius!of! curvature!of! the! septal! segment! at! endFdiastole!by!44!±!58%! (p=0.017).!Septal!curvature!at!endFsystole!did!not!change!significantly,!nor!did!curvature!of!the!LV!freeFwall!at!endFdiastole!or!endFsystole!(Appendix!A!Figure!A.12).!!!!!!!! 71!Table! 2.4! The! effect! of! dynamic! hyperinflation! (Phase! 3a)! on! cardiopulmonary!function!and!LV!geometry.!!Parameter( Baseline( Condition( Δ(Abs.( p( Δ(%( p(RR!(bpm)! 13.4!±!2.5! 14.0!±!1.0! 0.5!±!2.2! 0.295! 7!±!19! 0.113!VT!(L)! 0.56!±!0.13! 0.66!±!0.15! 0.09!±!0.14*! 0.005! 17!±!25*! 0.006!VE!(L/min)! 7.3!±!1.0! 8.9!±!1.6! 1.6!±!1.6*! <0.001! 24!±!23*! <0.001!TI!(sec)! 1.8!±!0.5! 1.3!±!0.3! F0.5!±!0.4*! <0.001! F26!±!17*! <0.001!TE!(sec)! 2.6!±!0.4! 2.9!±!0.3! 0.3!±!0.5! 0.061! 7!±!17! 0.085!TI/TTOT! 0.40!±!0.05! 0.31!±!0.06! F0.09!±!0.05*! <0.001! FF! FF!Pes.ins!(cmH2O)! F3.2!±!1.5! F13.3!±!5.4! F10.1!±!5.1*! <0.001! F463!±!455*! <0.001!Pes.exp!(cmH2O)! 2.1!±!1.5! 3.8!±!3.4! 1.8!±!3.7*! 0.046! 205!±!482! 0.072!IC!(L)! 2.90!±!0.88! 1.20!±!0.54! F1.70!±!0.81*! <0.001! F57!±!18*! <0.001!LVEDV!(mL)! 113!±!22! 102!±!23! F10!±!11*! <0.001! F9!±!10*! <0.001!LVESV!(mL)! 47!±!9! 45!±!12! F2!±!5! 0.230! F5!±!11! 0.115!EF!(%)! 58!±!2! 56!±!4! F2!±!5! 0.050! FF! FF!SV!(mL)! 66!±!14! 57!±!12! F9!±!9*! <0.001! F12!±!13*! 0.001!Q!(L/min)! 3.8!±!0.6! 3.5!±!0.5! F0.2!±!0.6! 0.102! F5!±!17! 0.218!HR!(bpm)! 59!±!11! 63!±!12! 5!±!5*! 0.002! 8!±!10*! 0.003!MAP!(mmHg)! 76!±!8! 80!±!7! 3!±!8! 0.077! 5!±!10! 0.052!SVR!(Δ!%)! FF! FF! FF! FF! 16!±!25*! 0.020!SpO2!(%)! 99!±!1! 99!±!1! 0!±!1! 0.301! FF! FF!RSC!ED!(cm)! 3.0!±!0.5! 4.2!±!1.8! 1.3!±!1.8! 0.161! 44!±!58*! 0.017!RSC!ES!(cm)! 1.9!±!0.5! 2.3!±!0.9! 0.3!±!1.0! 0.827! 26!±!76! 0.246!RFWC!ED!(cm)! 2.5!±!0.2! 2.5!±!0.2! F0.1!±!0.2! 0.765! F2!±!7! 0.274!RFWC!ES!(cm)! 1.6!±!0.3! 1.6!±!0.2! 0.0!±!0.2! >0.05! 2!±!16! >0.05!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=18! and! LV!geometry;!n=15.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!!Figure! 2.12! Inspiratory! capacity! (IC)! at! baseline! (P1)! and! across! all! phases! involving! DH!(n=20).!P1!=!baseline,!P3a!=!Dynamic!Hyperinflation!(DH),!P3b!=!Dynamic!hyperinflation!with!inspiratory!loading!(DH+IR),!P5a!=!Hypoxia,!P5c!=!Hypoxia!with!IR!and!DH,!(Hypox+DH+IR),!P6!=!Hypoxia!with!IR!and!DH!during!HDT!(All!interventions).!*!Denotes!significant!difference!from!baseline!(p<0.05).!**!Denotes!significant!difference!between!phases!(p<0.05).! \W5,6,7 #"  ( (!#  "!#!( !""#%  !$!($#2"63)*)%0)/$*)2$/#B	"$)- .0'/ $).$")$!$)/#)" ./*M+cUEUUVNBM+cUEUUVN ) K M+cUEUUVN 2$/#*0/ #)" . /*  *- E  ) ) "/$1 $).+$-/*-4+- ..0- .2 -  $)- .  /* FWXE\aXEX (	W M+cUEUUVNB2#$'  + &+*.$/$1   3+$-/*-4 +- ..0- .2 -  '.* $)- .  /* \EZ a ZE[ (	WB M+cUEUUVNE "/$1   2. )*/ .$")$!$)/'4 $!! - )/ !-*( */# - +#. . $)1*'1$)" M+bUEW]WB.  $"0- WEVUNE2.$)- . 4WEV^aUE]X.$)$/ 4\Ya^_- 0/$*) $)  !-*(. '$) 1'0 . M+cUEUUVNB)2..$")$!$)/'4#$"# -/#)0-$)"	'*) M+cUEUUZB.  $"0- WEVWNE'  WEZ $!! - )  $)  !0)/$*)  /2  ) 	 )	2$/#).+$-/*-4'*$)"2$/#	- 0 4VWaVU_M+cUEUUVN)4\a^_M+bUEUUYNB2$/#) $)"- 0 4XaZ_)VUaVU_B- .+ /$1 '4M+bUEUX]B+cUEUUVNE#$.2.)*/.$")$!$)/'4 $!! - )/ !-*( /#   !! / *! 	 '*) M'  WEZNB #*2 1 - B  )  2 - .$")$!$)/'4- 0 !-*('*) M+bUEUUVBUEUWX) UEUV\B - .+ /$1 '4B .   '  WEV[NE 	$)- . 4VYaV\_M+bUEUUYNB /#0.2.)*/.$")$!$)/'4- 0 M+bUEZZ\NE	).$")$!$)/'4$)- . 4VUaVY_M+bUEUU[N)MXYaYV_B+bUEUUYNB 2#$'  +W  - .  .$")$!$)/'4 M+bUEUUVN M.   ++ )$3  $"0- ! - ( M(N FYa] UEU[[M(N FWaZ UEZWYM_N FVaZ UEZXWM(N FWa\ UEXUVMK($)N UEVaUE[ UE[VYM(N VEWaVEZQ UEUXUM(N UEYaVEV UEWYUM(N UEUaUEW UE[Y]M(N UEUaUEW UE\VV'  WEZ $!! - )  $)  !0)/$*) /2  )	)	2$/#/+- . )/ .( )aB)bV\!*- 1*'0( .B )bVW !*-  " *( /-4E Q )*/ ..$")$!$) M+cUEUZNE! 73!A.11).! Radius! of! septal! curvature! increased! significantly! from! baseline! at! endFdiastole,! suggesting! flattening! of! the! septum! (p<0.001).! RSC! at! endFdiastole! was!greater!during!DH!with! IR! than!during!either! IR! (p=0.031)!or!DH!(p=0.030)!alone!(Appendix! A! Figure! A.12).! The! cardiopulmonary! responses! to! DH! in! conjunction!with!IR!are!summarized!in!Table!2.6,!while!individual!subject!responses!are!shown!in!Appendix!A!Figure!A.3.!!!!!!!Table! 2.6! The! effect! of! dynamic! hyperinflation! and! inspiratory! resistive! loading!(Phase!3b)!on!cardiopulmonary!function!and!LV!geometry.!!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=17! and! LV!geometry;!n=12.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!!!For!abbreviations!please!see!Table!2.3.!!Parameter( Baseline( Condition( Δ(Abs.( p( Δ(%( p(RR!(bpm)! 13.4!±!2.5! 13.9!±!1.0! 0.5!±!2.2! 0.304! 7!±!19! 0.117!VT!(L)! 0.56!±!0.13! 0.55!±!0.14! F0.01!±!0.16! 0.690! 0!±!27! 0.957!VE!(L/min)! 7.30!±!1.05! 7.51!±!1.61! 0.21!±!1.63! 0.570! 4!±!24! 0.455!TI!(sec)! 1.8!±!0.5! 2.3!±!0.2! 0.5!±!0.5*! <0.001! 35!±!34*! <0.001!TE!(sec)! 2.6!±!0.4! 1.9!±!0.2! F0.7!±!0.4*! <0.001! F41!±!24*! <0.001!TI/TTOT!! 0.40!±!0.04! 0.55!±!0.04! 0.15!±!0.05*! <0.001! FF! FF!Pes.ins!(cmH2O)! F3.2!±!1.5! F23.7!±!3.3! F20.5!±!3.9*! <0.001! 1021!±!1071*! <0.001!Pes.exp!(cmH2O)! 2.1!±!1.5! 7.5!±!5.6! 5.4!±!5.4*! <0.001! 614!±!1353! 0.057!IC!(L)! 2.90!±!0.88! 0.71!±!0.19! F2.19!±!0.83*! <0.001! F74!±!9*! <0.001!LVEDV!(mL)! 111!±!21! 97!±!22! F14!±!11*! <0.001! F12!±!10*! <0.001!LVESV!(mL)! 46!±!8! 43!±!9! F3!±!4*! 0.003! F7!±!9*! 0.004!EF!(%)! 58!±!3! 55!±!5! F3!±!5*! 0.038! FF! FF!SV!(mL)! 65!±!14! 54!±!15! F10!±!10*! <0.001! F16!±!16*! <0.001!Q!(L/min)! 3.8!±!0.6! 3.6!±!0.9! F0.2!±!0.9! 0.382! F4!±!3! 0.557!HR!(bpm)! 60!±!11! 68!±!13! 8!±!9*! 0.009! 14!±!17*! 0.004!MAP!(mmHg)! 76!±!78! 85!±!11! 8!±!11*! 0.007! 10!±!14*! 0.006!SVR!(Δ!%)! FF! FF! FF! FF! 34!±!41*! 0.004!SpO2!(%)! 99!±!1! 97!±!3! F2!±!3*! 0.001! FF! FF!RSC!ED!(cm)! 3.3!±!1.1! 6.1!±!2.7! 2.7!±!2.2*! <0.001 85!±!70*! 0.001!RSC!ES!(cm)! 2.0!±!0.5! 3.0!±!1.4! 1.0!±!1.2! 0.488! 55!±!62*! 0.010!RFWC!ED!(cm)! 2.6!±!0.2! 2.5!±!0.2! 0.0!±!0.2! 0.865! F1!±!9! 0.793!RFWC!ES!(cm)! 1.6!±!0.3! 1.6!±!0.2! 0.0!±!0.3! >0.05! 4!±!20! >0.05!! 74!2.3.5!Effects!of!head0down!tilt!on!cardiopulmonary!function!(Phase!4a)!The! cardiopulmonary! responses! to! HDT! are! summarized! in! Table! 2.7,! while!individual!subject!responses!are!shown!in!Appendix!A,!Figure!A.4.!HDT!did!not!have!a!significant!effect!on!any!respiratory!parameters,!but!increased!LVEDV!by!8!±!6%!(p<0.001),!LVESV!by!5!±!9%!(p=0.018),!SV!by!10!±!10%!(p<0.001)!and!Q!by!11!±!15%!(p=0.005).!MAP,!SVR!and!SpO2!did!not!change!significantly.!HDT!increased!the!radius! of! septal! curvature! at! endFdiastole! by! 33! ±! 47%! (p=0.006),! while! also!increasing!LV!freeFwall!radius!of!curvature!at!endFdiastole!by!7!±!11%!(p=0.007).!At!endFsystole,!septal!and!LV!dimension!did!not!change!significantly!from!baseline.!Table!2.7!The!effect!of!headFdown!tilt ! (Phase!4a)!on!cardiopulmonary! function!and!LV!geometry.!!Parameter( Baseline( Condition( Δ(Abs.( p( Δ(%( p(RR!(bpm)! 14.5!±!1.8! 14.7!±!1.9! 0.2!±!2.1! 0.649! 2!±!14! 0.472!VT!(L)! 0.59!±!0.25! 0.55!±!0.08! F0.05!±!0.22! 0.571! F2!±!20! 0.630!VE!(l/min)! 8.5!±!3.7! 8.0!±!1.2! F0.6!±!3.3! 0.224! F1!±!16! 0.738!TI!(sec)! 1.6!±!0.4! 1.7!±!0.4! 0.1!±!0.3! 0.601! 7!±!30! 0.304!TE!(sec)! 2.4!±!0.4! 2.4!±!0.4! 0.0!±!0.4! 0.895! F2!±!16! 0.616!TI/TTOT!! 0.41!±!0.07! 0.42!±!0.05! 0.09!±!0.05! 0.443! FF! FF!Pes.ins!(cmH2O)! F3.5!±!1.7! F3.5!±!2.4! 0.0!±!1.5! 0.949! F3!±!48! 0.776!Pes.exp!(cmH2O)! 1.9!±!1.6! 2.1!±!1.8! 0.2!±!1.5! 0.487! 66!±!352! 0.413!LVEDV!(mL)! 115!±!21! 125!±!27! 10!±!8.0*! <0.001! 8!!±!6*! <0.001!LVESV!(mL)! 48!±!10! 50!±!10! 2!±!4*! 0.036! 5!!±!9*! 0.018!EF!(%)! 59!±!2! 60!±!3! 1!±!3! 0.202! FF! FF!SV!(mL)! 68!±!12! 75!±!17! 7!±!7*! <0.001! 10!±!10*! <0.001!Q!(L/min)! 3.9!±!0.5! 4.4!±!1.0! 0.5!±!0.6*! 0.007! 11!±!15*! 0.005!HR!(bpm)! 59!±!12! 60!±!12! 0!±!4! 0.665! 1!!±!8! 0.601!MAP!(mmHg)! 76!±!8! 76!±!8! 0!±!8! 0.928! 0!±!11! 0.895!SVR!(Δ!%)! FF! FF! FF! FF! F7!±!21! 0.173!SpO2!(%)! 99!±!1! 99!±!1! 0!±!1! 0.275! FF! FF!RSC!ED!(cm)! 3.2!±!0.9! 4.2!±!1.4! 0.9!±!1.3! 0.182! 33!±!47*! 0.006!RSC!ES!(cm)! 1.9!±!0.5! 2.2!±!1.0! 0.3!±!1.0! 0.717! 20!±!48! 0.085!RFWC!ED!(cm)! 2.5!±!0.2! 2.7!±!0.4! 0.2!±!0.3*! <0.001! 7!±!11*! 0.007!RFWC!ES!(cm)! 1.6!±!0.3! 1.6!±!0.3! 0.0!±!0.2! >0.05! 1!±!12! >0.05!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=18! and! LV!geometry;!n=20.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.! \Z5,6,8 #"  -& ##  "!#!( !""#%  !$!($#2"73# +0'(*)-4 !! /.*!	$)*)%0)/$*)2$/#2 - -$1 )4/# $).+$-/*-4'*$)" ) 2 -  )*/ .//$./$''4 $!! - )/ !-*(  '*)  M.   $"0- . WEVU )(,+NE  2. .$")$!$)/'4 - 0  4 XZ a V]_ M+cUEUUVNB #*2 1 - /#$. 2.*(+)$ 4\Va\]_$)- . $)M+cUEUUVNB.0#/#/2.0)#)" M+bUE\X]NE  2. $)- .  4 V^[ a W^_ M+cUEUUVNB ) /#0. K '.*$)- .  .$")$!$)/'4 M+cUEUUVNE -" / ) "/$1   2. #$ 1  0-$)" /#$.$)/ -1 )/$*)B2$/#*. -1 $).+$-/*-4+- ..0- .*!FWWE]aWEW(	WB2#$#2..$")$!$)/'4 $)- .  !-*(. '$)  M+cUEUUVNB 0/ $ )*/ $!! - !-*(+- ..0- .#$ 1 $)*/# -+#. .M+bUEW]WNE ) 3+$-/*-4+- ..0- .'.*$)- . 4W\W_B/*YEVaW(	WM+cUEUUVNE' WE]$!! - )  /2  )	)	2$/#  - .  4 [ a ^_ M+bUEUV[NB 2#$' $)*/#)" M+bUEW\YNE.- .0'/B*/# ) 2 -  .$")$!$)/'4 - 0 B 4 Y a Y_M+cUEUUVN ) ] a \_ M+cUEUUVNB - .+ /$1 '4E-$*0/+0/2.($)/$) 4*(+ )./*-4]aVW_$)- . $)	M+bUEUWVNB2#$' B) +W $ )*/ #)"  .$")$!$)/'4E  1*'0( .0-$)" /#$. +#.  2 -  )*/ .$")$!$)/'4 $!! - )/!-*('*) M+dUEUZNNB#*2 1 -2# )*(+- /*	B2#$#0"( )/ B	 2$/#  .$")$!$)/'4 - 0   M+cUEUUVNB  M+bUEUUVNB  M+cUEUUVN! - ( M(N FVZaVXQ cUEUUVM(N Va\ UEZ\XM_N FZaZQ UEUUVM(N FVYaVUQ cUEUUVMK($)N FUE[aUE[Q cUEUUVM(N WEWaWEXQ UEUUVM(N UE^aWE\Q UEUWVM(N UEVaUEX UEVY\M(N FUEVaUEZ UEUXZ'  WE] $!! - )   /2  ) 	)	2$/#/+- . )/ .( )aB)bV\!*-  1*'0( .B )bV] !*- " *( /-4E Q  )*/ . .$")$!$) M+cUEUZNE! 76!and!Q!(p<0.001)!(see!Table!2.8,!and!Figures!2.15,!2.16).!HDT!in!combination!with!IR!caused!greater!septal!flattening!than!either!condition!alone!with!RSC!ED!and!RFWC!ED!being!significantly! larger! than!Phase!2!(p=0.003!and!p<0.001,!respectively,!see!Appendix!A!Figure!A.12).!Relative!to!baseline,!HDT!with!IR! increased!the!radius!of!septal!curvature!at!endFdiastole!by!87!±!80%!(p<0.001),!and!at!endFsystole!by!73!±!112%! (p=0.013).! LV! freeFwall! curvature! also! changed,! with! an! 11%! increase! in!RFWC! at! endFdiastole! (p<0.001)! and! a! 6! ±! 10%! increase! in! RFWC! at! endFsystole!(p=0.020).! The! cardiorespiratory! responses! to! HDT! in! conjunction! with! IR! are!summarized!in!Table!2.9,!while!individual!subject!responses!are!shown!in!Appendix!A,!Figure!A.5.!! !! 77!!!!!!Table!2.9!The!Effect!of!headFdown! tilt ! and! inspiratory! resistive! loading! (Phase!4b)!on!cardiopulmonary!function!and!LV!geometry.!!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=17! and! LV!geometry;!n=18.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!! !Parameter( Baseline( Condition( Δ(Abs.( P( Δ(%( p(RR!(bpm)! 14.5!±!1.8! 9.3!±!2.6! F5.2!±!2.9*! <0.001! F35!±!18*! <0.001!VT!(L)! 0.59!±!0.25! 0.96!±!0.39! 0.35!±!0.46*! <0.001! 71!±!78*! <0.001!VE!(L/min)! 8.5!±!3.7! 7.9!±!1.4! F0.6!±!3.9! 0.674! 0!±!27! 0.951!TI!(sec)! 1.6!±!0.4! 4.7!±!1.8! 3.0!±!1.8*! <0.001! 196!±!29*! <0.001!TE!(sec)! 2.4!±!0.4! 2.4!±!1.0! 0.0!±!1.1! 0.165! F12!±!32! 0.102!TI/TTOT!! 0.41!±!0.07! 0.66!±!0.07! 0.25!±!0.09*! <0.001! FF! FF!Pes.ins!(cmH2O)! F3.5!±!1.7! F22.8!±!2.2! F19.3!±!2.4*! <0.001! F814!±!768*! <0.001!Pes.exp!(cmH2O)! 1.9!±!1.6! 4.1!±!2.0! 2.2!±!2.0*! <0.001! 273!±!860! 0.172!LVEDV!(mL)! 113!±!21! 107!±!20! F7!±!10*! 0.010! F6!±!9*! 0.016!LVESV!(mL)! 47!±!10! 47!±!9! 1!±!5! 0.274! 3!±!10! 0.279!EF!(%)! 59!±!2! 55!±!3! F4!±!4*! <0.001! FF! FF!SV!(mL)! 67!±!11! 59!±!12! F8!±!7*! <0.001! F11!±!12*! 0.001!Q!(L/min)! 3.9!±!0.5! 3.7!±!0.7! F0.2!!±!0.5! 0.102! F5!±!13! 0.113!HR!(bpm)! 59!±!12! 64!±!13! 4!±!7*! 0.025! 8!±!12*! 0.021!MAP!(mmHg)! 76!±!8! 76!±!9! 0!±!8! 0.860! 0!±!11! 0.990!SVR!(Δ!%)! FF! FF! FF! FF! 9!±!27! 0.211!SpO2!(%)! 99!±!1! 99!±!1! 0!±!1! 0.278! FF! FF!RSC!ED!(cm)! 3.3!±1.0! 6.1!!±!2.9! 2.8!±!2.5*! <0.001! 87!±!80*! <0.001!RSC!ES!(cm)! 1.9!±0.5! 3.4!!±!2.9! 1.5!±!2.7*! 0.007! 73!±!112*! 0.013!RFWC!ED!(cm)! 2.5!±0.2! 2.8!!±!0.3! 0.3!±!0.2*! 0.021! 11!±!10*! <0.001!RFWC!ES!(cm)! 1.6!±0.3! 1.7!!±!0.3! 0.1!±!0.1! 0.085! 6!±!10*! 0.020! \]5,6,9#"('!$!($#2"83#  -$*+0'(*)-4 - .+*). . /* #4+*3$ -  .0((-$5  $) '  WEVUB )$)$1$0'.0% /- .+*). .- .#*2)$)++ )$3$"0- (1E- /#$)"#4+*3$". - .0'/  $) '-" - ) "/$1  $).+$-/*-4 +- ..0- . /#) *. -1  $) )*-(*3$C!-*(  ( ) +- ..0-  *! FXEZ a VE\ (	W $) )*-(*3$ /* F[EY a YEU (	WM+bUEUU^NM$"0- WEVUNE$)- . (* -/ '4B- .0'/$)"$).$")$!$)/ - . $)KM+bUEUVYNE!/ -YZF($)0/ #4+*3$ 3+*.0- /# - 2.)*/.$")$!$)/#)" $)B*-!-*()*-(*3$. '$) M.  ++ )$3$"0- (,+NE$"0- WEVX$!! - ) $)-$"#/1 )/-$0'-.4./*'$+- ..0- !-*()*-(*3$/*#4+*3$-$ *0/+0/ 2. .$")$!$)/'4 $)- .  4 V[ aVV_ M+cUEUUVN !/ - #4+*3$  3+*.0- B .*' '4 . - .0'/ *! $)- . 	 M+cUEUUVNB .  1*'0( . $)*/ #)"  .$")$!$)/'4 !-*( )*-(*3$ *)$/$*).E	4+*3$ $ )*/ #1   .$")$!$)/  !! / *) B#*2 1 -  - . 4VWa V\_ M+bUEUU[N 0 /* ) $)- .  $) E  $)- .  4 YX a X\_M+cUEUUVN *(+-  /* )*-(*3$ . '$)  !/ - YZ($)0/ #4+*3$ 3+*.0- M$"0- WEVXNB. / -($) !-*($)$- /( .0- .*!M$"0- WEVYNB)M$"0- WEYNE )+W!/ -#4+*3$ 2. .$")$!$)/'4 - 0  /* ]V a W_ M+cUEUUVB .   ++ )$3  $"0- (,,NE	4+*3$$)*/#1 .$")$!$)/ !! /*)" *( /-4E$"0-  WEVX$!! - )  $) !-*( )*-(*3$ M-& '0 N /*#4+*3$ M'$"#/ '0 NB )bV]EQ )*/ ..$")$!$) M+cUEUZNE! 79!!!!!!!Figure! 2.14! SubFxiphoid! view! of! the! IVC! from! the! same! subject! during! normoxia! at! maximal!diameter!(a)!and!during!sniff! test!(b),!and!in!hypoxia!at!maximal!diameter!(c)!and!during!sniff!test!(d).!!! !! 80!!!!!!Table! 2.10! The! effect! of! hypoxia! (Phase! 5a)! on! cardiopulmonary! function! and! LV!geometry.!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20! cardiovascular;! n=19! and! LV!geometry;!n=19.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!Parameter( Baseline( Condition( Δ(Abs.( P( Δ(%( p(RR!(bpm)! 14.5!±!1.8! 14.4!±!2.2! F0.1!±!2.3! 0.894! 0!±!16! 0.923!VT!(L)! 0.59!±!0.25! 0.59!±!0.11! F0.01!±!0.19! 0.189! 4!±!17! 0.317!VE!(L/min)! 8.5!±!3.7! 8.3!±!1.1! F0.3!±!3.2! 0.133! F!4!±!18! 0.391!TI!(sec)! 1.6!±!0.4! 1.6!±!0.4! F0.1!±!0.42! 0.245! 2!±!41! 0.819!TE!(sec)! 2.4!±!0.4! 2.5!±!0.4! 0.2!±!0.6! 0.090! 2!±!35! 0.798!TI/TTOT!! 0.41!±!0.07! 0.39!±!0.06! F0.02!±!0.09*! 0.014! FF! FF!Pes.ins!(cmH2O)! F3.5!±!1.7! F6.4!±!4.0! F2.9!±!5.2*! <0.001! 136!±!210*! 0.009!Pes.exp!(cmH2O)! 1.9!±!1.6! F0.1!±!2.3! F2.0!±!2.5*! 0.002! F98!±!122*! 0.002!IC!(L)! 2.89!±!0.88! 2.54!±!0.93! F0.26!±!0.25*! <0.001! F11!±!10*! <0.001!LVEDV!(mL)! 115!±!21! 114!±!23! F1!±!5! 0.601! F1!±!4! 0.456!LVESV!(mL)! 47!±!10! 45!±!9! F2!±!4! 0.102! F3!±!9! 0.126!EF!(%)! 59!±!2! 60!±!3! 1!±!3! 0.067! FF! FF!SV!(mL)! 67!±!11! 68!±!15! 1!±!4! 0.265! 1!±!6! 0.430!Q!(L/min)! 3.9!±!0.5! 4.5!±!0.6! 0.6!±!0.4*! <0.001! 16!±!11*! <0.001!HR!(bpm)! 59!±!11! 68!±!13! 8!±!5*! <0.001! 14!±!9*! <0.001!MAP!(mmHg)! 76!±!8! 76!±!8! 0!±!9! 0.958! F1!±!11! 0.792!RAP!(mmHg)! 3!±!1! 6!±!3! 3!±!3! 0.004! 71!±!82! 0.001!CVI!(%)! 83!±!11! 56!±!19! F27!±!13! <0.001! FF! FF!TRV!(m/s)! 2.0!±!0.2! 2.4!±!0.2! 0.4!±!0.3! <0.001! 25!±!19! <0.001!SVR!(Δ!%)! FF! FF! FF! FF! F12!±!17*! 0.006!RVSP!(mmHg)! 21!±!5! 29!±!4! 8!±!5*! <0.001! 43!±!37*! <0.001!SpO2!(%)! 99!±!1! 81!±!2! F18!±!2*! <0.001! FF! FF!RSC!ED!(cm)! 3.2!±!1.0! 3.4!±!1.0! 0.2!±!1.1! 0.642! 10!±!35! 0.247!RSC!ES!(cm)! 1.9!±!0.5! 1.9!±!0.6! 0.0!±!0.6! 0.995! 2!±!25! 0.779!RFWC!ED!(cm)! 2.5!±!0.2! 2.5!±!0.3! 0.0!±!0.2! 0.905! F2!±!7! 0.318!RFWC!ES!(cm)! 1.6!±!0.3! 1.5!±!0.2! F0.1!±!0.2! >0.05! F5!±!12! >0.05!! 81!2.3.6! Effects! of! hypoxia! and! inspiratory! resistive! loading! on! cardiopulmonary!function!(Phase!5b)!The! respiratory! response! to! hypoxia! in! combination! with! IR! was! driven!predominantly! by! the! IR! intervention! and! was! not! statistically! different! from!previous!IR!phases!(see!Figures!2.11!and!A.10).!Relative!to!hypoxic!baseline,!RR,!VT!and!TI/TTOT!changed!significantly!(p<0.001).!VE!was!unchanged!(p=0.349),!as!the!69!±! 60%! increase! in! VT! (p<0.001)! was! countered! by! a! 36! ±! 19%! reduction! in! RR!(p<0.001).!Negative!ITP!was!significantly!increased!to!F23.1!±!3.0!cmH2O!(p<0.001),!while!positive!expiratory!pressure!did!not!change!significantly!(p=0.083).!Negative!inspiratory! pressures! were! not! significantly! different! during! this! phase! than!previous!IR!phases!(p=0.282,!see!Figure!2.10).!!LVEDV! and! LVESV! were! reduced! to! a! greater! degree! during! IR! under! hypoxic!conditions! than! during! normoxic! inspiratory! loading! (p=0.016! and! p<0.001,!respectively,! see!Table!2.16!and!Figure!2.15).!Relative! to!hypoxic!baseline,!LVEDV!was!significantly!reduced!by!9!±!7%!(p<0.001),!as!was!LVESV,!by!5!±!8%!(p=0.007).!This! resulted! in! a! significant! 2! ±! 3%! decrease! in! EF! (p=0.042)! and! a! 10! ±! 9%!decrease!in!SV!(p<0.001).!HR!increased!by!7!±!12%!(p=0.21)!to!maintain!Q,!which!was!not!significantly!reduced!(p=0.213).!MAP!and!SVR!did!not!change!significantly!from! hypoxic! baseline! (phase! 5a),! however! SpO2! increased! by! 3! ±! 5%! (p=0.011),!presumably! due! to! a! significantly! higher! VT! (p<0.001)! increasing! alveolar!ventilation.! RSC! increased! by! 45! ±! 42%! (p<0.001)! at! end! diastole,! and! 20! ±! 29%!(p=0.007)! at! endFsystole.! RFWC! did! not! change! significantly! during! this! phase.!! 82!Under! hypoxic! conditions,! IR! caused! a! greater! increase! in! RSCFED! than! under!normoxic! conditions! (p=0.032,! see! Appendix! A! Figure! A.12).! ! Pulmonary! and!cardiovascular! responses! to! hypoxia! and! IR! are! summarized! in! Table! 2.11,! and!individual!subject!responses!are!depicted!in!Appendix!A,!Figure!A.7.!!!!!!Table! 2.11! The! effect! of! hypoxia! and! inspiratory! resistive! loading! (Phase! 5b)! on!cardiopulmonary!function!and!LV!geometry.!!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=20! and! LV!geometry;!n=20.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!!!Parameter( Baseline( Condition( Δ(Abs.( P( Δ(%( P(RR!(bpm)! 14.4!±!2.2! 9.1!±!2.5! F5.3!±!3.1*! <0.001! F36!±!19*! <0.001!VT!(L)! 0.59!±!0.11! 0.99!±!0.39! 0.4!±!0.36*! <0.001! 69!±!60*! <0.001!VE!(L/min)! 8.3!±!1.1! 8.4!±!2.6! 0.1!±!2.6! 0.349! 4!±!18! 0.391!TI!(sec)! 1.6!±!0.4! 4.4!±!1.7! 2.8!±!1.7*! <0.001! 194!±!124*! <0.001!TE!(sec)! 2.5!±!0.4! 2.7!±!1.0! 0.2!±!1.1! 0.956! F2!±!31! 0.805!TI/TTOT!! 0.39!±!0.06! 0.61!±!0.09! 0.23!±!0.13*! <0.001! FF! FF!Pes.ins!(cmH2O)! F6.4!±!4.0! F23.1!±!3.0! F16.7!±!4.7*! <0.001! F396!±!348*! <0.001!Pes.exp!(cmH2O)! F0.1!±!2.3! 1.1!±!2.3! 1.4!±!3.0! 0.083! F405!±!840*! 0.040!LVEDV!(mL)! 112!±!23! 102!±!21! F10!±!9*! <0.001! F9!±!7*! <0.001!LVESV!(mL)! 45!±!9! 42!±!8! F3!±!4*! 0.006! F5!±!8*! 0.007!EF!(%)! 60!±!3! 58!±!4!  F2!±!3* 0.042! FF! FF!SV!(mL)! 67!±!15! 60!±!14! F7!±!7*! <0.001! F10!±!9*! <0.001!Q!(L/min)! 4.5!±!0.6! 4.2!±!0.8! F0.2!±!0.7! 0.208! F5!±!16! 0.213!HR!(bpm)! 68!±!12! 73!±!13! 4!±!7*! 0.021! 7!±!12*! 0.021!MAP!(mmHg)! 76!±!8! 77!±!8! 1!±!10! 0.782! 1!±!10! 0.851!SVR!(Δ!%)! FF! FF! FF! FF! 7!±!17! 0.090!SpO2!(%)! 81!±!2! 85!±!6! 3!±!5*! 0.011! FF! FF!RSC!ED!(cm)! 3.2!±!0.9! 4.6!±!1.6! 1.4!±!1.3*! 0.031! 45!±!42*! <0.001!RSC!ES!(cm)! 1.9!±!0.5! 2.3!±!0.7! 0.4!±!0.6! 0.885! 20!±!29*! 0.007!RFWC!ED!(cm)! 2.5!±!0.2! 2.5!±!0.3! 0.0!±!0.2! 0.992! 0!±!8*! 0.876!RFWC!ES!(cm)! 1.6!±!0.3! 1.6!±!0.3! 0.0!±!0.2! >0.05! F1!±!15! >0.05! ]X5,6,: #"  ('* ( (!#  "!#!( !""#%!$!($#2"83 .+$-/*-4+-( / -.0-$)"	)2 - )*/.$")$!$)/'4$!! - )/ /2  )#4+*3$))*-(*3$*)$/$*).M$"0- .WEVVB(,+NE - .+$-/$*).)0/44'  $ )*/ .$")$!$)/'4 #)"  B  *-  !-*( . '$)  #4+*3$ 1'0 .M+dUEUZNE	*2 1 -B2..$")$!$)/'4 $)- . 4\ZaVVW_M+bUEUU]N)2. - . 4X]aWZ_ M+cUEUUVN - '/$1  /*. '$) B .0# /#/K2.'.* .$")$!$)/'4 $)- .  M+cUEUUVNE  .2$)". 0-$)" - .+$-/$*) 2 -  '.*.$")$!$)/'4$)- . B2$/#( )) "/$1 $).+$-/*-4+- ..0- $)- .$)"/*FWYEWa YEU (	W M+cUEUUVN ) +*.$/$1   3+$-/*-4 +- ..0-  $)- .$)" /* [EY a ZEY(	W M+cUEUUVNE  "/$1  $).+$-/*-4 +- ..0- . 2 -  )*/ .$")$!$)/'4 $!! - )/!-*(*/# -+#. .M+bUEW]WB.  $"0- WEVUNE 2.- 0 4\[a]_!-*(#4+*3$ . '$)  M+cUEUUVNB #*2 1 - /#$.2. )*/ .$")$!$)/'4 $!! - )/ !-*(	)$))*-(*3$M$"0- WEVWNE'  W EVW $!! - )  $)   !0)/$*)  /2  ) )*-(*3$  )#4+*3$ 	2$/#  	 )  2$/# *)*($/)/ #4+*3$ .#*2  '-" - - 0/$*) $)  /#) 0) - )*-(*3$*)$/$*). M+bUEUU^NB 2#$'   2. $)- . M+bUEUVYB .   $"0-  WEVZNE  '/$1  /* #4+*3$. '$) *)$/$*).B2. - . 4VWa^_M+cUEUUVNB4\aVW_M+bUEUV[NB4 W a Y_ M+bUEUYWN )  4 VY a VX_ - ( M(N FWE\aVVE^ UEYXUM(N FYEVaYE\Q UEUU^M_N VE^a]E^ UEYY\M(N XEVaXE]Q UEUVYMK($)N UEV^aUE\Z UEX\\	M+(N VE]a]E] UEY\[FM(N UEZaWEZ UEZ]YFM(N UEXaVEW UEZW[FM(N UEWaUEX UEVU]FM(N UEUaUEX UE]]^'  WEVW $!! - )  $)  !0)/$*) /2  ) )*-(*3$ ) #4+*3$ 	2$/#/+- . )/ .( )aB)bVZ!*- 1*'0( .B )bVX !*-  " *( /-4E Q )*/ ..$")$!$) M+cUEUZNE! 84!(p=0.002).!A!compensatory!increase!in!HR!did!not!occur!in!this!phase!(p=0.931)!and!thus!Q!was!significantly!decreased!from!hypoxic!baseline!by!15!±!12%!(p<0.001,!see!Figure!2.16).!MAP!and!SVR!also!increased!significantly,!by!11!±!17%!(p=0.014)!and!37!±!19%!(p<0.001),!respectively.!SpO2!did!not!change!relative!to!hypoxic!baseline!conditions,! but! decreased! 18! ±! 2%! from! normoxic! baseline! (p<0.001).! DH! in!combination!with!IR!under!hypoxic!conditions!resulted! in!greater! flattening!of! the!septum! than! any! of! the! conditions! in! isolation! (see! Table! 2.16! and! Appendix! A!Figure!A.12).!RSC!increased!by!107!±!85%!(p=0.001)!at!endFdiastole,!and!increased!by!44%!(p=0.024)!at!endFsystole.!LV!freeFwall!geometry!also!changed!significantly,!with! the! RFWC! increasing! by! 7! ±! 9%! at! endFdiastole! (p=0.026).! Pulmonary! and!cardiovascular!responses!during!hypoxia!with!DH!and!IR!are!summarized!in!Table!2.13,!and!individual!subject!responses!are!reported!in!Appendix!A,!Figure!A.8.!! !!!!!!!!!!!!!!!!!!!!!!!!! 85!!!!!!!!!!!Figure! 2.15! LV! volumes! and! ejection! fraction! (EF)! across! all! phases,! n=15F20.! LVEDV! =! left!ventricular! endFdiastolic! volume,! LVESV! =! left! ventricular! endFsystolic! volume.! P1! =! baseline,!P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic!hyperinflation! with! inspiratory! loading! (DH+IR),! P4a! =! HeadFdown! tilt! (HDT),! P4b! =! HeadFdown! tilt! with! inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =! Hypoxia! with! inspiratory!loading!(Hypox+IR),!P5c!=!Hypoxia!with!IR!and!DH,!(Hypox+DH+IR),!P6!=!Hypoxia!with!IR!and!DH! during! HDT! (All! interventions).! Error! bars! represent! standard! deviation.! *! Denotes! a!significant!change!from!baseline!(P1)!(p<0.05).!!!!!!!! 86!!!!!!!!!Table! 2.13! The! effect! of! hypoxia,! dynamic! hyperinflation! and! inspiratory! resistive!loading!(Phase!5c)!on!cardiopulmonary!function!and!LV!geometry.!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=15! and! LV!geometry;!n=13.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!!!!!!! !Parameter( Baseline( Condition( Δ(Abs.( P( Δ(%( P(RR!(bpm)! 14.4!±!2.2! 14.1!±!0.9! 0.3!±!2.2! 0.448! 0!±!17! 0.933!VT!(L)! 0.59!±!0.11! 0.56!±!0.09! 0.03!±!0.14! 0.343! F2!±!23! 0.647!VE!(L/min)! 8.3!±!1.1! 7.8!±!1.0! 0.5!±!1.3! 0.073! F6!±!14! 0.105!TI!(sec)! 1.6!±!0.4! 2.6!±!1.2! 1.0!±!1.3*! <0.001! 75!±!112*! 0.008!TE!(sec)! 2.5!±!0.4! 1.8!±!0.2! 0.7!±!0.4*! <0.001! F38!±!25*! <0.001!TI/TTOT!! 0.39!±!0.06! 0.57!±!0.07! 0.18!±!0.1*! <0.001! FF! FF!Pes.ins!(cmH2O)! F6.4!±!4.0! F24.2!±!4.0! F17.7!±!5.8*! <0.001! F443!±!497*! <0.001!Pes.exp!(cmH2O)! F0.1!±!2.3! 6.4!±!5.4! 6.5!±!5.9*! <0.001! 2166!±!6972! 0.181!IC!(L)! 2.54!±!0.93! 0.62!±!0.20! 1.91!±!0.79*! <0.001! F76!±!8*! <0.001!LVEDV!(mL)! 113!±!21! 99!±!16! F15!±!11*! <0.001! F12!±!9*! <0.001!LVESV!(mL)! 45!±!9! 42!±!9! F3!±!5*! 0.022! F7!±!10*! 0.016!EF!(%)! 60!±!3! 58!±!5! F2!±!4*! 0.042! FF! FF!SV!(mL)! 68!±!14! 58!±!10! F10!±!10* 0.002! F14!±!13*! 0.001!Q!(L/min)! 4.4!±!0.5! 3.8!±!0.7! F0.7!±!0.5*! <0.001! F15!±!12*! <0.001!HR!(bpm)! 67!±!11! 66!±!10! 0!±!10! 0.931! 1!±!16! 0.791!MAP!(mmHg)! 76!±!8! 85!±!12! 8!±!12*! 0.015! 11!±!17*! 0.014!SVR!(Δ!%)! FF! FF! FF! FF! 37!±!19*! <0.001!SpO2!(%)! 81!±!2! 79!±!5! F2!±!6! 0.490! FF! FF!RSC!ED!(cm)! 3.1!±!0.6! 6.4!±!2.8! 3.3!±!2.7*! <0.001! 107!±!85*! 0.001!RSC!ES!(cm)! 1.9!±!0.5! 2.7!±!0.3! 0.8!±!1.2! 0.784! 44!±!59*! 0.024!RFWC!ED!(cm)! 2.6!±!0.2! 2.7!±!0.3! 0.2!±!0.2! 0.117! 7!±!9*! 0.026!RFWC!ES!(cm)! 1.6!±!0.3! 1.6!±!0.2! 0.0!±!0.2! >0.05! 4!±!11! >0.05! ]\5,6,; #"  ('* ( (!#* "!#!( !""#% -&##!$!($#2"93 + /$)" #4+*3$ 	 )  $) /#  	 +*.$/$*) $ )*/ .$")$!$)/'4 #)" - .+$-/*-4+-( / -.!-*(/# .0+$) +*.$/$*)M#. ZNE '/$1 /*. '$) B2. $)- .  2#$'    - .  ) /#0. K '.* $)- .  M+cUEUUVNE "/$1   2. .$")$!$)/'4 $)- .  !-*( #4+*3$ . '$) B /* FWYEU a XE[(	W M+cUEUUVN ) 2. )*/ .$")$!$)/'4 $!! - )/ !-*( +- 1$*0.  +#. .M+bUEW]WNE *.$/$1   3+$-/*-4 +- ..0-  '.* $)- .  .$")$!$)/'4B /* \EX a[EX(	WU M+cUEUUVNE 0-$)" /# .  $)/ -1 )/$*).B  2. - 0  4 \Z a VU_M+cUEUUVNB - .0'/$)" $)  VE^Z a UE]V  $)- .  $) B 2#$# 2. .$")$!$)/'4"- / -/#)	'*) M+cUEUUZNB#*2 1 -2.)*/$!! - )/!-*(+- 1$*0.	2$/#+#. .M$"0- WEVWNE' W EVY$!! - )  $) !0)/$*) /2  )#. Z)#. [  $/# #4+*3$B 	B  ) 	B  2.- 0  4 V[ a VU_ M+cUEUUVNB 2#$'  2. - 0  4 \ a V]_ M+bUEVVYNE  2..$")$!$)/'4- 0 4YaZ_M+bUEUU^N)4 WV a VU_ M+cUEUUVNE '/#*0"# /#  '-" ./*. -1  - 0/$*) $)  1*'0( .B /#$. 2. )*/ / -($)  /*  .$")$!$)/'4$!! - )/ !-*( /# #.  Z M+dUEUZB .   '  WEVYNE 	 $)- . 4 ] a WU_ M+bUEVV\N /* *(+ )./  !*- /#  - M(N FUEZaVUE\ UE]Z^M(N WEVa]EY UEX]XM_N FXEYa[EY UEU\^M(N FVE^aZEW UEV^[MK($)N UEUYaUE\\ UE]ZV	M+(N YEVa\EZ UEU\XFM(N VE\aZE[ UEYX[FM(N WEVaZEV UEY\]FM(N FUEVaUEY UEY]VFM(N UEVaUEY UEYZZ'  WEVY $!! - )  $)  !0)/$*) /2  )#. Z)#. [/+- . )/ .( )aB)bVZ!*- 1*'0( .B )bVV !*-  " *( /-4E Q )*/ ..$")$!$) M+cUEUZNE! 88!reduced! SV,! however! Q! was! still! significantly! reduced! by! 15! ±! 17%! (p=0.003).!Relative! to!hypoxic!baseline,!MAP!was! increased!by!12!±!10%!(p<0.001)!and!SVR!increased! by! 43! ±! 48%! (p=0.006).! SpO2! also! decreased! by! 2! ±! 6%,! from! hypoxic!baseline!(p=0.246),!which!was!a!21%!decrease! from!normoxic!baseline!(p<0.001).!LV! geometry! was! not! significantly! different! from! Phase! 5c,! however! relative! to!hypoxic!baseline,!RSC!increased!by!135!±!103%!at!end!diastole!(p=0.001),!and!120!±!130%!at!endFsystole!(p=0.012,!see!Appendix!A!Figure!A.12).!LV!freeFwall!curvature!did! not! change! significantly.! Respiratory! and! cardiovascular! responses! during!hypoxic!HDT!with!DH!and!IR!are!summarized!in!Table!2.15,!and!individual!subject!responses!are!depicted!in!Appendix!A!Figure!A.9.!!! !! 89!Table! 2.15! The! effect! of! hypoxia,! dynamic! hyperinflation,! headFdown! tilt ! and!inspiratory!resistive!loading!(Phase!6)!on!cardiopulmonary!function!and!LV!geometry.!!Data! presented! as! mean! ±! SD.! ! For! pulmonary! measures;! n=20,! cardiovascular;! n=16! and! LV!geometry;!n=11.!*!Denotes!a!significant!change!from!baseline!(p<0.05).!For!abbreviations!please!see!Table!2.3.!Table! 2.16! Interactive! effects! of! DH,! HDT! and! hypoxia! with! IR! on! cardiovascular!function!and!LV!geometry!!( Phase(3b:(IR+DH( Phase(4b:(IR+HDT( Phase(5b:(IR+Hypox(!  (Abs.( p(  (Abs.( p(  (Abs.( p(LVEDV!(mL)! F9.2!±!9.6*! 0.001! F2.6!±!11.6! 0.354! F6.4!±!10.5*! 0.016!LVESV!(mL)! F3.2!±!5.3*! 0.023! 0.15!±!4.5! 0.888! F5.3!±!5.5*! <0.001!EF!(%)! F5.9!±!9.2*! 0.017! F2.9!±!9.9! 0.245! 1.0!±!8.8! 0.622!SV!(mL)! F1.1!±!5.3! 0.406! F1.3!±!5.2! 0.323! 2.2!±!4.2*! 0.033!Q!(L/min)! F0.31!±!0.63! 0.061! F0.23!±!0.71! 0.208! 0.35!±!0.68*! 0.042!HR!(bpm)! 0.9!±!7.5! 0.642! F1.8!±!8.3! 0.375! 6.3!±!5.1*! <0.001!RSCFED!(cm)! 2.0!±!2.6*! 0.031! 1.9!±!2.2*! 0.003! 0.7!±!1.4*! 0.032!RSCFES!(cm)! 0.7!±!1.5! 0.188! 0.9!±!2.7! 0.329! 0.0!±!0.9! 0.465!RFWCFED!(cm)! 0.0!±!0.2! 0.781! 0.3!±!0.2*! <0.001! 0.0!±!0.3! 0.418!RFWCFES!(cm)! 0.0!±!0.2! 0.841! 0.0!±!0.1! 0.463! 0.1!±!0.2! 0.094!!Data!presented!as!mean!±!SD.! *!Denotes!a! significant!difference! from! IR!alone! (Phase!2)! (p<0.05).!!For!abbreviations!please!see!Table!2.3.! !Parameter( Baseline( Condition( Δ(Abs.( p( Δ(%( P(RR!(bpm)! 14.4!±!2.2! 14.1!±!0.9! F0.4!±!2.1! 0.460! 0!±!16! 0.894!VT!(L)! 0.59!±!0.11! 0.56!±!0.10! 0.03!±!0.15! 0.440! F2!±!25! 0.786!VE!(L/min)! 8.3!±!1.1! 7.8!±!1.4! F0.5!±!1.7! 0.252! F4!±!19! 0.353!TI!(sec)! 1.6!±!0.4! 2.3!±!0.2! 0.7!±!0.4*! <0.001! 54!±!37*! <0.001!TE!(sec)! 2.5!±!0.4! 1.8!±!0.1! F0.7!±!0.4*! <0.001! F41!±!24*! <0.001!TI/TTOT!! 0.39!±!0.06! 0.56!±!0.03! 0.18!±!0.18*! <0.001! FF! FF!Pes.ins!(cmH2O)! F6.4!±!4.0! F24.0!±!3.6! F17.6!±!5.8*! <0.001! 454!±!574*! 0.002!Pes.exp!(cmH2O)! F0.1!±!2.3! 7.3!±!6.3! 7.4!±!7.1*! <0.001! 1239!±!7421*! <0.001!IC!(L)! 2.54!±!0.93! 0.60!±!0.20! F1.95!±!0.81*! <0.001! F75!±!10*! <0.001!LVEDV!(mL)! 113!±!22! 96!±!22! F18!±!12*! <0.001! F16!!±!10*! <0.001!LVESV!(mL)! 45!±!9! 42!±!12! F3!!±!8! 0.182! F7!!±!18! 0.114!EF!(%)! 60!±!3! 57!±!5! F4!!±!5*! 0.009! FF! FF!SV!(mL)! 68!±!14! 54!±!12! F14!!±!8*! <0.001! F21!!±!10*! <0.001!Q!(L/min)! 4.4!±!0.5! 3.7!±!0.8! F0.7!±!0.8*! 0.005! F15!!±!17*! 0.003!HR!(bpm)! 66!±!12! 70!±!10! 4!±!10! 0.348! 8!!±!20! 0.117!MAP!(mmHg)! 76!±!8! 86!±!9! 10!±!7*! <0.001! 12!±!10*! <0.001!SVR!(Δ!%)! FF! FF! FF! FF! 43!±!48*! 0.006!SpO2!(%)! 81!±!2! 79!±!5! F2!±!6! 0.246! FF! FF!RSC!ED!(cm)! 3.5!±!1.1! 7.8!±!3.2! 4.3!±!3.2*! <0.001! 135!±!103*! 0.001!RSC!ES!(cm)! 2.1!±!0.5! 4.6!±!3.7! 2.5!±!3.5*! <0.001! 120!±!130*! 0.012!RFWC!ED!(cm)! 2.6!±!0.2! 2.7!±!0.4! 0.1!±!0.3! 0.601! 4!±!11! 0.274!RFWC!ES!(cm)! 1.7!±!0.3! 1.6!±!0.3! 0.0!±!0.4! >0.05! 0!±!23! >0.05!! 90!!!!Figure! 2.16! Cardiac! output! (Q)! as! a! product! of! changes! to! stroke! volume! (SV)! and! heart! rate!(HR)! across! all! phases,! n=15F20.! P1! =! baseline,! P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic!Hyperinflation! (DH),! P3b! =! Dynamic! hyperinflation! with! inspiratory! loading! (DH+IR),! P4a! =!HeadFdown!tilt!(HDT),!P4b!=!HeadFdown!tilt!with!inspiratory!loading!(HDT+IR),!P5a!=!Hypoxia,!P5b! =! Hypoxia! with! inspiratory! loading! (Hypox+IR),! P5c! =! Hypoxia! with! IR! and! DH,!(Hypox+DH+IR),! P6! =! Hypoxia! with! IR! and! DH! during! HDT! (All! interventions).! Error! bars!represent! standard! deviation.! *! Denotes! a! significant! change! from! baseline! (P1)! (p<0.05).! 91!2.4(Discussion(This!study!is!the!first!heartFlung!interaction!study!to!utilize!an!intact!human!model!to!evaluate!the!integrative!effects!of!increased!negative!ITP,!elevated!lung!volumes,!right! ventricular! volume! loading! and! increased! pulmonary! PVR! alone! and! in!combination!on!LV!function.!Additionally,!through!analysis!of!LV!wall!geometry!we!provide!novel!and!compelling!evidence!for!the!role!of!direct!ventricular!interaction!in!mediating! the!observed!changes! to!LV! function.!The!primary! findings! from! this!study! suggest! that! increasing! negative! ITP! through! inspiratory! loading! during!spontaneous! respiration! significantly! decreases! LV! SV! through! a! reduction! in!LVEDV.! This! decrease! is! exacerbated! at! high! lung! volumes,! as! DH! in! conjunction!with! inspiratory! loading!attenuated!LV!SV! to!a!greater!extent! than!either! stressor!alone,!a!result!largely!attributable!to!leftward!septal!shift!and!mediastinal!constraint!reducing!LV!filling!volumes.!!Another!key! finding!was! the!paradoxical!decrease! in!LV!SV!when!RV!preload!was!further! increased! through! volume! loading! during! IR.! This! finding! was! consistent!whether! pulmonary! vascular! pressures! were! normal! or! elevated! and! with! large!increases! in! lung! volume.! ! When! combined! with! the! observed! changes! to! septal!geometry,! this! finding! supports! that! the! preloadFmediated! effects! of! the!aforementioned! interventions!play! a! larger! role! in! impairing!LV!diastolic! function!through!the!mechanism!of!DVI!than!previously!thought.!Additionally,!findings!from!this! study! suggest! that! the! effect! of! lung! volume,!which!previous! studies59,72! have!! 92!suggested!plays!only!a!minimal!role!in!modulating!LV!function!relative!to!changes!in!ITP,!may!be!a!primary!determinant!of!LV!performance.!!!!Finally,! this! is! the! first! study! to! demonstrate! marked! LV! underFfilling! during!increased!intrathoracic!pressure!swings,!dynamic!lung!hyperinflation!and!increases!in!PVR!in!an!intact!human!model.!These!findings!provide!considerable! insight! into!the!mechanisms!governing!cardiopulmonary!interaction!in!respiratory!disease,!and!may! help! to! guide! future! research! into! the! causal! link! between! obstructive!respiratory!disease!and!rightFsided!heart!failure.!!!2.4.1!Effects!of!increased!negative!ITP!on!cardiovascular!function!It! is! generally! accepted! that! a!marked! increase! in! negative! intrathoracic! pressure!reduces!LV!SV,!however!despite!extensive!research!in!anaesthetized!canine!models,!the! etiology! of! this! decrease! is! unclear9.! Furthermore,! studies! utilizing! an! intact!human! model! during! spontaneous! respiration! are! limited! and! differ! widely! in!methodology! and! findings,! leading! to! divisive! conclusions! as! to! the! mechanisms!responsible.!Using!resistive!inspiratory!loading!to!generate!pressures!of!F20!cmH20,!we!demonstrate!that!LV!SV!is!markedly!decreased!in!a!healthy!human!model!during!spontaneous!respiration.!A!reduction!in!LV!SV!is!fundamentally!a!result!of!either!a!decreased! endFdiastolic! volume,! or! an! increased! endFsystolic! volume.! Decreased!LVEDV!may!be!mediated! by! series! and/or! direct! ventricular! interaction,!while! an!increase! in!LVESV!would!be!attributed! to!an! increase! in!LV!afterload! that!exceeds!the!heart’s!ability!to!compensate!through!increased!contractility9.!The!results!from!! 93!this!study!show!that!IR!caused!a!decrease!in!SV!predominantly!through!a!decrease!in! LVEDV,! while! LVESV! did! not! change! significantly.! The! healthy! LV! has!considerable! mechanical! reserve! for! maintaining! SV! in! the! face! of! increased!afterload,!which! is!mediated! through! increased!sympathetic!drive27.!The!observed!increase! in! HR! and! maintained! LVESV! during! inspiratory! loading! suggests!contractility! likely! increased! in! an! attempt! to! maintain! systolic! function! during!inspiratory!resistive!loading.!Thus,!an!increase!in!LV!afterload!does!not!adequately!explain!the!decrease!in!LV!SV!observed!in!this!study.!!!The!finding!that!LVESV!was!decreased!with!IR!conflicts!with!some!previous!human!studies! that! primarily! report! an! increase! in! LVESV! during! increased! negative! ITP!utilizing!radionuclide!ventriculogy58,59,65.!However,!it!should!be!noted!that!only!one!study65!utilized!a!similar!inspiratory!load!to!our!current!study!during!spontaneous!respiration,! while! others! who! report! an! increase! in! LVESV! used! the! Mueller!maneuver.! The!Mueller!maneuver! is! a! forceful! inspiratory! effort! against! a! closed!glottis,! which! is! fundamentally! different! from! inspiratory! loading! during!spontaneous!respiration,!as!negative! ITP! tends! to!be!greater!while! lung!volume! is!static9.! Additionally,! the! degree! of! negative! pressure! achieved!would! have! a! high!degree!of!individual!variability!and!depend!on!inspiratory!muscle!strength!and!the!lung! volume! at!which! the!Mueller!maneuver!was! performed.! Thus,! the! degree! of!negative! ITP! seen! during! this! maneuver! is! not! standardized.! Indeed,! the! general!consensus!is!that!the!Mueller!maneuver!globally!increases!both!RV!and!LV!volumes!through! profound! increases! in! afterload53,57,9.! Therefore,! it! is! very! difficult! to!! 94!extrapolate!the!findings!from!these!studies!to!a!spontaneously!breathing!model.!Our!findings!are!more!in!concert!with!the!body!of!literature!which!has!investigated!the!effects!of! increased!negative! ITP!during! spontaneous! respiration,! and!consistently!report!decreased!LVEDV!in!both!canine61,62!and!human!models63,64.!!Several!mechanisms!have!been!proposed! for! the!observed!LV!underFfilling!during!inspiratory! loading:! 1)! pooling! of! blood! in! the! pulmonary! vasculature! and! thus!reduced!venous!return!to!the!LV141!2)!attenuated!venous!return!due!to!collapse!of!the!IVC!during!increased!negative!inspiratory!pressure!swings46,!and!3)!a! leftward!septal!shift!caused!by!increased!RVEDV!mediating!an!increase!in!LV!filling!pressures!and! thus! impairing! LV! diastolic! filling63,50.! Current! opinion! favours! the! latter! two!mechanisms,! as! it! is! generally! accepted! that! pulmonary! flow! doesn’t! decrease!during! inspiration142,! however! evidence! for! series! interaction! versus!DVI! remains!divisive.!To!our!knowledge!this!study!is!the!first!to!utilize!changes!to!LV!geometry!as!a!marker!of!direct!ventricular! interaction!during! spontaneous! inspiratory! loading,!and!we!believe!our!findings!provide!strong!evidence!for!the!role!of!DVI!in!mediating!the!observed!decrease!in!LVEDV.!!!Evaluation! of! LV! geometry! provides! a! nonFinvasive! tool! for! investigating! the!potential! contribution! of! direct! ventricular! interaction! to! LV! hemodynamics.!Changes!to!LV!configuration!as!a!result!of!leftward!shift,!or!flattening,!of!the!septum!in! response! to! RV! loading! are! well! documented143,144,145.! Flattening! of! the!ventricular! septum! corresponds! to! an! increase! in! the! radius! of! septal! curvature!! 95!(RSC),! and! has! been! reported! as! evidence! for! the! role! of! ventricular!interdependence! during! RV! loading! using! the! Mueller! maneuver53,57.! Using! the!technique! for! assessing! septal! configuration! described! by! Brinker! et# al53,! during!inspiratory!loading!over!consecutive!cardiac!cycles!we!observed!an!increase!in!the!radius!of!septal!curvature!both!at!end!diastole!(RSCFED)!and!end!systole!(RSCFES).!In!the!absence!of!increases!in!LVESV,!these!changes!in!septal!curvature!support!the!role!of!DVI!in!mediating!the!observed!decrease!in!LVEDV.!!Despite!strong!evidence!for!leftward!septal!displacement!constraining!LV!filling,!in!the!absence!of!data!on!RV!volumes,!attenuated!venous!return!may!have!contributed!to! the!observed!reduction! in!LVEDV.! IVC!collapse!at! the!point!of!entrance! into!the!thorax!in!response!to!increased!negative!ITP!has!been!documented!in!canine146!and!intact! human! models46.! Determining! IVC! collapse! pressure! is! complex,! as! it! is!influenced!by!multiple!variables!that!constitute!the!surrounding!pressure!of!the!IVC.!No! study! has! defined! a!model! for! determining! exact! surrounding! pressure! of! the!great!veins9.!However,! it! is!reasonable!to!conclude!that!at! the! levels!of! inspiratory!loading! induced! in! this! study,! transFdiaphragmatic! pressures! would! be! such! that!this!mechanism!may!play!a!role!in!limiting!diastolic!filling!of!the!LV!through!series!interaction.!It!should!be!noted!that!there!was!considerable!subject!variability!in!the!degree! of! LVEDV! and! SV! reduction! (see! Appendix! A,! Figure! A.1),! indeed! several!subjects!displayed!an!increase!in!LVESV!while!others!showed!no!appreciable!change!to!LV!volumes!as! a! result!of! IR.!This! subject! variability! is!well!documented! in! the!! 96!literature! and! is! thought! to! be! a! result! of! individual! variability! in! the! degree! of!ventricular!interdependence!and!attenuation!of!venous!return!during!IR63,65.!!Inspirations!extending!over!multiple!cardiac!cycles!confound!the!ability! to!discern!the! exact! mechanism! for! the! observed! reduction! in! LVEDV,! as! the! systolic! and!diastolic!effects!of!increased!negative!ITP!are!likely!not!independent!and!may!have!additive!or!synergistic!effects!over!multiple!cardiac!cycles9.!We!further!discuss!these!complications!in!Chapter!3,!Section!3.1.1.!An!additional!consideration!is!the!effect!of!changes!in!autonomic!control!during!inspiratory!resistive!loading.!Results!from!this!study!showed!a!significant!increase!in!HR!during!all!IR!phases,!suggesting!a!change!in!autonomic!regulation!and!a!likely!increase!in!contractility,!though!MAP!remained!unchanged.!An!additional!explanation!for!this!observed!increase!may!be!activation!of! the! Bainbridge! reflex,! which! has! been! shown! to! increase! HR! in! response! to!stretch!of!the!right!atrium!when!venous!return!is!increased147.!This!aligns!with!our!observation! that! rightFsided! volumes! have! increased! during! IR,! as! indicated! by!leftward!septal!shift.!However,!whether!the!reflexive!increase!in!HR!is!a!result!of!the!Bainbridge!reflex,!or!an!arterial!baroreflex!response!to!decreased!LV!SV!is!unclear.!Previous!work!utilizing! the!Mueller!maneuver! to! increase!negative! ITP!has!shown!increases! in! LVEDV!during! the!maneuver!when!HR!was!maintained!or! decreased,!however! this! response!was! abolished!when! HR! increased148.! Thus,! an! interactive!effect!of!sympathetic!activation!on!LV!function!cannot!be!ruled!out.!While!we!cannot!quantify!the!exact!contribution!of!series!versus!DVI,!we!can!conclude!that!increasing!negative! inspiratory!pressures!to!F20!cmH2O!over!several!cardiac!cycles!decreases!! 97!LV!SV!through!a!reduction!in!LVEDV!in!spontaneous!breathing!humans,!and!that!this!decrease!is!mediated!at!least!in!part!by!DVI.!This!corroborates!previous!studies!that!identify!a!key!role!for!DVI!in!impairing!LV!function!during!increased!negative!ITP!in!spontaneously! breathing! canines63,149! and! provides! novel! evidence! for! this!mechanism!in!an!intact!human!model.!!2.4.2!Effects!of!increased!lung!volumes!on!cardiovascular!function!Mechanisms!of! cardiopulmonary! interaction!with! changes! in! expiratory!pressures!and!lung!volumes!have!been!investigated!in!anaesthetized!canines101,102,!and!COPD!patients144,98,99,100.! However,! defining! cardiopulmonary! mechanisms! of! LV!dysfunction! in! a! COPD! population! is! inherently! difficult,! as! findings! tend! to! be!confounded! by! the! presence! of! varying! degrees! of!multiFsystem! dysfunction.! Few!studies!have!evaluated!the!effects!of!DH!in!concert!with!increased!negative!ITP!on!LV!function,!and!to!our!knowledge!no!previous!study!has!examined!these!stressors!utilizing! a! dynamic! method! of! sustaining! maximal! lung! volumes! and! inspiratory!loading! over! several! cardiac! cycles.! Previous! studies! have! proposed! that! LV! SV!reduction! is! better! correlated! with! changes! to! pleural! pressure! than! lung!volume59,72.! However,! results! from! our! study,!which! induced! smaller! increases! in!ITP,! but! larger! increases! in! operational! lung! volumes! than! the! aforementioned!studies,!showed!a!greater!reduction!in!LV!SV,!which!suggests! lung!volume!is!a!key!mediator!of!LV!function!during!expiratory!flowFlimited!breathing.!Further!review!of!our!findings!in!relation!to!previous!work!is!presented!in!Chapter!3,!Section!3.1.2.!!! 98!The! contribution! of! DVI! to! reducing! LVEDV! has! previously! been! shown! to! be!amplified! by! mediastinal! constraint! from! the! lung,! which! increases! pericardial!pressure!and!thus!acts!in!a!similar!fashion!to!a!pericardial!constraint!by!restraining!ventricular! filling60,116.! Indeed,! previous! work! has! shown! that! the! pericardium!exerts!a! restraining! force!on! the!ventricles!even!under!normal! loading!conditions,!hence!some!degree!of!DVI!is! likely!always!present39,40.!Pericardial!pressure!cannot!be!accurately!measured!nonFinvasively150!and! therefore!was!not!attempted! in! this!study.!However,!the!extent!of!lung!hyperinflation!achieved!in!this!study!presumably!induced! considerable! mediastinal! constraint! resulting! in! increased! pericardial!pressure!and!reduced!LV!compliance,!restricting!LV!diastolic! filling.!Changes!to!LV!geometry,!namely!an!increase!in!the!radius!of!septal!curvature,!or!septal!flattening,!that! occurred! with! DH! supports! previous! reports! of! decreased! septalFlateral! LV!dimensions!with!increasing!lung!volume70.!We!observed!a!greater!septal!flattening!during!DH!than!during!IR,!despite!a!smaller!increase!in!pleural!pressure!swings!with!DH!alone!and!a!smaller!absolute!positive!and!negative!ITP.!We!therefore!conclude!that! increased! lung! volume! plays! a! key! role! in! impairing! LV! diastolic! function,!predominantly!through!the!mechanism!of!DVI.!!2.4.3! Effects! of! elevated! lung! volumes! and! increased! negative! ITP! on!cardiovascular!function!Most! types! of! airway! obstruction,! either! acute! (ie.! bronchospasm)! or! chronic! (ie.!airway!remodeling,!increased!airway!resistance!and!“floppy”!airways!in!COPD)!are!characterized!by!a!relatively!larger!increase!in!negative!inspiratory!pressures!than!! 99!positive!expiratory!pressures,! thus,!while! the! “swing”! in! ITP! increases,! the!overall!trend!is!towards!a!more!negative!ITP9.!It!has!been!suggested!that!increased!negative!ITP!in!conjunction!with!elevated!lung!volumes!may!be!more!detrimental!to!cardiac!function! than! either! condition! alone,! due! to! an! interaction! of! the! mechanisms!previously! discussed59.! The! results! of! this! study! show! that! LVEDV! decreased!significantly!more!during!DH!and! IR! than!during! IR!alone,!which! lead! to!a!greater!reduction!in!LV!SV!than!seen!in!previous!phases.!When!compared!to!DH!alone,!DH!with!IR!saw!a!trend!toward!further!reduction!in!LVEDV,!though!the!results!were!not!significant! (p=0.066).! There! are! two! important! considerations! for! discerning! the!potential! contribution! of!mechanisms! to! this! decrease! in! LV! SV.! First,! LVESV!was!also! observed! to! decrease! significantly! during! DH! with! concomitant! IR.! This!suggests! underFfilling! of! the! LV! and/or! a! large! increase! in! contractility,! as,! in! the!presence! of! increased! LV! afterload,! LVESV! would! be! expected! to! increase! or! be!maintained.!!Without!data!on!RV!hemodynamics,!we!cannot!determine!whether!underFfilling!of!the!LV!was!a!result!of! increased!RV!afterload,!or!whether! the!rightFsided!volumes!were!also!reduced.!However,!a!compelling!argument!against!RV!underFfilling!could!be!made! based! on! the! hemodynamic! effects! of! increased! intrinsic! endFexpiratory!pressures! (iPEEP),! a!phenomenon!which!occurs!with!dynamic! lung!hyperinflation!and! gas! trapping! when! the! alveoli! don’t! completely! empty! before! a! subsequent!inspiration! is! taken! and! thus! alveolar! pressure! is! increased8,15.! Fundamentally,!iPEEP!presents!a!scenario!where!the! first!part!of! inspiration! i.e.! the! initial!drop! in!! 100!pleural! pressure,! is! required! to! overcome! positive! alveolar! pressure! before! flow!generation!can!start.!This!negative!ITP!is!transmitted!to!the!RA,!which!enhances!the!gradient!for!venous!return!without!the!oppositional!effects!of!mechanical!heartFlung!interdependence! (which! increase! RA! pressure)! associated!with! elevations! in! lung!volume.!Mechanistically,!this!is!initially!similar!to!a!short!Mueller!maneuver!prior!to!inspiratory!airflow!starting,!thus!allowing!venous!return!to!continue!throughout!(or!for!longer!during)!inspiration122,151.!!Greater! venous! return! coupled! with! increased! RV! afterload! would! increase! RV!volumes!and,!in!the!presence!of!the!large!hyperinflated!lung!creating!a!mediastinal!constraint,!would!impair!LV!function!through!DVI.!!Our!data!on!LV!geometry!during!this!phase!appears!to!support!this!mechanism.!More!specifically,!utilizing!RSC!as!a!marker! of! the! intraventricular! pressure! gradient,! we! observed! a! significantly!greater!degree!of!septal!flattening!(increased!RSCFED)!and!corresponding!reduction!in! septalFlateral! LV! dimensions! during! DH! and! IR! as! compared! to! IR! alone.! This!suggests! that! the! hyperinflated! lung! reduces! LVEDV! through! amplifying! DVI,! a!finding!which!has!been!previously!reported!in!canine!models60.!Interestingly,!septal!flattening! was! sustained! through! systole,! which! suggests! that! RV! afterload! was!likely!greater!under!conditions!of!DH!and!IR!than!during!either!intervention!alone.!Therefore,! elevated! PVR! as! a! function! of! increased! lung! volumes! likely! also!contributed,! although! we! cannot! quantify! RV! afterload! versus! mediastinal!constraint!contributions!to!the!observed!septal!shift.!As!such,!data!from!the!present!study! supports! our! hypothesis! that! DH! with! concomitant! IR! would! impair! LV!! 101!function! to! a! greater! extent! than! IR! alone,! through! a! summative! effect! of! these!mechanisms! causing! exacerbation! of! DVI.! Furthermore,! we! conclude! that! lung!volume!alone!has!considerable!effect!on!hemodynamics,!and!may!be!more!pertinent!than!the!associated!increase!in!negative!ITP!in!reducing!LV!SV.!!2.4.4!Effects!of!volume!loading!on!cardiovascular!function!In! the! absence! of! increased! afterload! or! systolic! dysfunction,! volume! loading!increases!LV!SV! through!series! interaction73.!HeadFdown! tilt! (HDT)!has!been!used!extensively!as!a!nonFinvasive!method!of!acutely!volume! loading! the!heart! through!increasing! RV! preload!with!minimal! changes! to! afterload,! contractility! and!HR109.!However,! few! studies! have! examined! the! effects! of! an! acute! VL! in! healthy!individuals!during!large!increases!in!negative!ITP.!!As!expected,!we!observed!a!10%!increase!in!LV!SV!in!response!to!acute!20° HDT,!and!ultimately!a!similar!increase!in!Q,! as!HR!was!unchanged.!This! response! is! consistent!with!previous!work! that!has!shown! an! acute! effect! of! HDT! on! LV! SV! through! a! predominant! increase! in!LVEDV109,152.!Interestingly,!HDT!caused!acute!changes!in!LV!geometry!such!that!the!radius! of! septal! curvature! at! endFdiastole! increased! by! 33%,! suggesting! that! DVI!increased! in! response! to! increased! RVEDV! despite! no! increases! in! RV! afterload.!Previous!work!has!reported!increased!DVI!and!leftward!septal!shift! in!response!to!volume! loading! of! the! RV,! however! the! Mueller! maneuver! was! used! to! elicit!increases! in! RVEDV,! which! inherently! also! increases! systolic! afterload53.! It! has!previously!been!shown!that!the!pericardium!exerts!a!restraining!force!on!LV!filling!even! under! normal! loading! conditions39,40.! Thus,! it! is! feasible! that! in! response! to!! 102!increased!RV!preload,! the!pericardium!mediates!an! increase! in!DVI,! though! in! the!absence!of!increased!afterload,!series!interaction!predominates!and!LV!SV!increases.!This! mechanism! has! previously! been! reported,! and! it! is! thought! that! DVI! is! not!detrimental! to! LV! function! until! afterload! or! pericardial! pressure! also!increase85,76,38.!To!our!knowledge,!this! is!the!first!study!to!demonstrate!that!DVI! is!increased! in! healthy! individuals! in! response! to! acute! volume! loading! during!spontaneous!respiration.!!2.4.5! Effects! of! volume! loading!with! increased!negative! ITP! on! cardiovascular!function!During!HDT,!when!inspiratory!ITP!was!decreased!to!approximately!F20!cmH2O,!we!observed!an!11%!decrease! in!SV! from!baseline!(supine),!which! is!a!21%!decrease!from!the!volumeFloaded!state!(HDT!alone).!This!was!due!to!a!significant!decrease!in!LVEDV,!and!is!a! larger!decrease!in!LV!SV!than!was!seen!during!increased!negative!ITP! alone.! These! data! present! the! most! robust! evidence! for! the! role! of! DVI! in!impairing! LV! function! in! this! study;! that!when! RV! preload!was! further! increased!during! IR,! a! paradoxical! decrease! in! LV! SV! is! observed.! Evidence! for! DVI! is!substantiated! by! changes! to! septal! wall! geometry! during! this! intervention,! as!significant!septal! flattening!was!observed!to!occur!resulting!in!an!increased!radius!of!septal!curvature!at!both!endFdiastole!and!endFsystole,!while!LV!freeFwall!radius!of!curvature! increased! only! modestly! at! endFdiastole! and! did! not! change! at! endFsystole.!This!profound!septal!flattening!suggests!RV!volumes!are!elevated!relative!to!increased! negative! ITP! alone.! Therefore,! while! we! cannot! definitively! rule! out!! 103!attenuation!of!venous!return!during!increased!negative!ITP!without!RV!volume!data,!regression! analysis! shows! a! strong! relationship! between! the! preloadFmediated!augmentation! of! LVEDV! during! HDT,! and! paradoxical! decrease! in! LVEDV! during!HDT!and!IR.!Thus,!the!data!supports!our!hypothesis!that! increased!negative!ITP!is!more!detrimental!to!LV!function!in!the!hypervolemic!state,!an!interaction!which!we!postulate! is! primarily! governed! by! increased! leftward! septal! shift! and! thus!restricted!LV!diastolic!filling!in!response!to!elevated!RV!preload.!!2.4.6! Effects! of! increased! pulmonary! vascular! resistance! on! cardiovascular!function!!The!primary!hemodynamic!effect!of!hypoxia! is! an! increase! in!pulmonary!vascular!resistance! (PVR)! secondary! to! hypoxicFmediated! pulmonary! vasoconstriction!(HPV),! as! a! mechanism! of! improving! ventilationFperfusion! matching! (VA/Q)81.!Previous! studies! have! shown! a! decrease! in! LVEDV,! and! thus! LV! SV,! on! acute!exposure! to! hypoxia! in! healthy! individuals! that! is! proportional! to! the! degree! of!hypoxic!stimulus,!while!Q!is!maintained!by!a!compensatory!increase!in!HR88,33.!The!findings! from! this! study! differ! from! previous! work! in! that! we! did! not! observe! a!significant!change!in!LVEDV!or!LVESV,!though!there!was!a!significant!increase!in!Q!that!was!driven!solely!by!an!increase!in!HR.!We!therefore!reject!our!hypothesis!that!acute!hypoxic!exposure!would!reduce!LVEDV!and!suggest!this!may!be!attributed!to!the! severity! of! our! hypoxic! stimulus.!While!we! did! observe! a! similar! decrease! in!SpO2!to!previous!studies,!we!saw!a!smaller! increase! in!RVSP!than!was!reported!by!! 104!those!authors33,93,!though!we!acknowledge!a!smaller!sample!size.!We!attributed!this!to! the! time! course! of! our! hypoxic! intervention,! as! arterial! oxygen! desaturation!occurs! considerably! more! quickly! than! increases! in! PVR! during! acute! hypoxic!exposure.! Despite! evidence! that! PAP! plateaus! after! 45! minutes! of! hypoxic!exposure82,139,! the! longer!duration!hypoxic!exposure! in!previous!work!at!a!similar!FiO2! may! account! for! the! observed! difference! in! RVSP.! However,! individual!susceptibility! to! hypoxia! is! also! well! documented153,32! and! could! influence! the!observed! response.!We! observed! considerable! variability! in! the! RVSP! increase! in!response!to!hypoxia!(see!Table!2.10),!thus!the!relative!number!of!‘responders’!and!‘nonFresponders’! within! our! subject! group! relative! to! previous! studies! may! also!account! for! this! difference.! It! is! generally! accepted! that! the! healthy! heart! can!compensate! for! even! large! changes! to! afterload26.! Therefore,! it! is! possible! the!RV!was!able!to!maintain!normal!systolic!function!in!response!to!an!increase!in!PVR!in!this! study,! and! thus! LV! function!was! preserved,! as! has! been! previously! reported!with!acute!hypoxic!exposure!in!healthy!individuals83.!!2.4.7! Effects! of! increased! PVR! with! increased! negative! ITP! on! cardiovascular!function!!!To! our! knowledge! no! study! has! investigated! the! cumulative! effects! of! increased!negative! ITP,! in! addition! to!hypoxicFmediated! increases! in!PVR,! on!LV! function! in!healthy! humans.! According! to! the! established! hemodynamic! effects! of! increased!negative! ITP9! and! hypoxia83,! we! postulated! that! during! diastole,! venous! return!! 105!should! increase! as! a! result! of! negative! ITP! while,! during! systole,! larger! negative!inspiratory! pressures! in! addition! to! increased! PVR! would! compound! afterload!effects!on!the!RV.!Thus,! the!overall!effect!would!be!a! larger!degree!of!RV!pressure!overload,! which! would! accentuate! DVI! and! decrease! LV! SV.! However,! despite! a!significantly!lower!LVEDV!and!LVESV!relative!to!IR!in!normoxia!(phase!2),!LV!SV!did!not! change! appreciably,! as! EF! was! significantly! increased.! This! suggests! a! larger!degree!of!LV!diastolic!dysfunction!during!hypoxic! inspiratory! loading,!but!a! larger!compensatory!increase!in!contractility!to!augment!LV!SV.!Thus,!we!conclude!that!the!interactive! effects! of! hypoxia! and! IR! caused! a! greater! degree! of! LV! diastolic!dysfunction!than!under!normoxic!conditions!through!an!increase!in!DVI.!However,!in!a!healthy!population!this!did!not!transmit!to!a!larger!reduction!in!LV!SV!than!seen!during! inspiratory! loading! alone,! as! this!population! is! able! to!mobilize! contractile!reserve!to!compensate!for!increased!afterload83.!!There! is! no! evidence! in! the! literature! to! suggest! that! pulmonary! blood! flow!decreases! during! increased! negative! ITP142,! or! during! acute! hypoxic! exposure93.!Therefore,! the! observed! LV! underFfilling! was! unlikely! to! be! due! to! RV! systolic!dysfunction!or!a!reduction!in!pulmonary!blood!flow.!Our!findings!of!a!primary!role!of!DVI!in!impairing!LV!function!has!been!previously!demonstrated!in!canine!models!under! similar,! albeit! more! extreme,! conditions! of! increased! PVR! and! RV! preload!secondary! to! acute! pulmonary! embolism76,38.! These!models! showed! reductions! in!LV! SV!were! nearly! reversed! following! opening! of! the! pericardium,! suggesting! the!pericardium,! not! RV! afterload,! is! the! primary!modulator! of! DVI76,38.! ! It! should! be!! 106!noted! that! these! are! not! directly! comparable!models! to! our! current! study,! as! the!degree! of! RV! pressure! overload! achieved! in! the! aforementioned! studies! likely!greatly!exceeds! the! increase! in!RV!pressures! in! this! study!as!a! result!of! increased!negative!ITP!and!increased!PVR.!Nevertheless,!while!we!cannot!quantify!the!role!of!the! pericardium! in! this! study,!we! theorize! that,!were!RV! afterload!predominantly!responsible!for!DVI,!we!would!expect!to!see!an!increase!in!septal!flattening!through!systole!during! IR! and!hypoxia! relative! to!normoxic! conditions.!Given! that! this!did!not! occur,! we! suggest! our! findings! provide! novel! preliminary! evidence! that! the!pericardium!mediates! the!observed! increase! in!DVI!during! increased!negative! ITP!with!elevated!PVR.!!!2.4.8! Effects! of! elevated! lung! volume! and! increased! negative! ITP! on!cardiovascular!function!when!PVR!is!elevated.!When!DH!was!combined!with! inspiratory!resistive! loading!and! increased!PVR,!we!observed! a! significant! reduction! in! LV! SV! predominantly! through! a! reduction! in!LVEDV,! though!LVESV!also!decreased.!Relative! to! these! interventions! in!normoxia!(phase! 3b),! LVESV! was! significantly! lower,! while! EF! increased,! suggesting! an!increase!in!contractility!occurred!in!an!attempt!to!augment!LV!SV.!Contrary!to!our!hypothesis,!concomitant!hypoxia!did!not!result!in!greater!impairment!to!LV!function!than!was!seen!with!DH!and!IR!in!normoxia.!!This!finding!suggests!that,!at!the!levels!of! increased!PVR!achieved! in! this! study,! the! additional!RV!afterload!as! a! result! of!hypoxia!was!not!a!key!contributor!to!reduced!LV!SV.!Yet,!it!should!be!noted!that!the!healthy! heart! has! been! shown! to! be! able! to! compensate! for! increased! afterload!! 107!under!normal!loading!conditions!by!increasing!contractility!26!which,!in!conjunction!with!previous!work!showing!conserved!RV!function!in!response!to!acute!hypoxia!93,!supports! the! lack!of! an!observed!difference! in!LV! function!between!normoxic!and!hypoxic!conditions!in!this!study.!However,!the!chronically!stressed!and!failing!heart!has! been! shown! to! be! profoundly! afterloadFsensitive26,154,! therefore! these!mechanisms!may!be!considerably!more!detrimental! to!cardiac! function! in!disease,!such!as!COPD!with!comorbid!heart!failure.!Thus,!our!model!may!underestimate!the!interactive!effect!of!these!stressors!in!this!population.!!As! in! previous! phases,! we! suggest! the! observed! reduction! in! both! LVEDV! and!LVESV,!and!associated!increases!in!RSC!indicating!flattening!of!the!septum,!supports!a!primary!role!for!DVI!in!mediating!the!observed!reduction!in!LV!SV.!However,!given!the!relatively!small!amount!of!previous!work!investigating!the!interaction!of!these!mechanisms,!the!relative!importance!of!acute!hypoxia!with!additional!changes!to!RV!preload!and!afterload!remains!to!be!elucidated,!and!is!likely!influenced!by!individual!susceptibility!to!afterload!and!DVI63,65.!!2.4.9!Effects!of!further!increases!in!preload!during!spontaneous!respiration!with!elevated!lung!volumes,!increased!negative!ITP!and!increased!PVR!To! investigate! the! effects! of! increased! RV! preload! on! the! interaction! between!hypoxia,!DH!and! IR,! the!previous!phase!was! repeated! in! the!20°!HDT!position.!As!discussed! previously,! acute! volume! loading! through! HDT! allows! for! the! discrete!investigation! of! preloadFmediated! effects,! as! it! has! been! shown! not! to! influence!! 108!afterload,! contractility!or! adrenergic! stimulation109.!The! fundamental! finding! from!this!phase!was!that,!despite!an!increase!in!RV!preload,!LV!SV!did!not! increase!and!was! in! fact! further! reduced! from! the! previous! phase.! If! series! interaction!predominated,! we! would! expect! to! see! an! improvement! in! LV! SV! relative! to! the!previous!phase.!However,!we!observed!the!opposite;! increasing!preload!decreases!LV!SV,!which!suggests!an!increased!contribution!of!DVI.!!This! finding! has! previously! been! reported! in! COPD! patients! in! response! to!incremental!volume!loading,!whereby!LV!SV!was!increased!up!to!a!critical!RAP,!after!which!further!volume!loading!caused!a!paradoxical!decrease!in!LV!SV,!which!those!authors! attributed! to! DVI144.! While! the! degree! of! septal! flattening! was! not!significantly! increased! in! response! to! further! increasing! preload,! there! was!considerable!individual!variability!in!this!metric,!as!some!subjects!showed!profound!septal! flattening! (see! Figure!2.17),!while! others! showed! relatively! little.!However,!the! changes! in!LV!volumes!alone! supports! a!primary! role! for!DVI.!The!absence!of!changes! to! LV! geometry! with! volume! loading! may! be! explained! by! increased!myocardial! contractility! of! the! RV,! as! has! been! documented! in! previous! canine!models!investigating!acute!RV!afterload!and!volume!loading!effects38.!!It!has!been!shown!that!the!healthy!RV!has!considerable!contractile!reserve,!thus!in!the!present!scenario!contractility!may!have!increased!to!offset!the!increased!RVEDV!by!decreasing!RVESV!and! thereby!maintaining!RV!SV.!Thus,! septalFtoFRV! free!wall!diameter!would!not!increase!and!the!corresponding!septalFtoFLV!free!wall!diameter!! 109!would!not!change! from!the!nonFvolumeFloaded!state.!Again,!we!suggest! that! these!interactions! may! be! considerably! more! detrimental! to! LV! function! in! a! disease!population!if!RV!contractile!reserve!or!LV!diastolic!reserve!were!depleted.!!!!!Figure! 2.17! Parasternal! shortFaxis! view! at! the! mitral! level! of! the! same! subject! at! baseline!(phase!1)!at!endFdiastole!(a)!and!end!systole!(c)!versus!during!phase!6!at!endFdiastole!(b)!and!endFsystole! (d).! Approximations! of! the! septal! wall! segment! (blue)! and! LV! freeFwall! (red)! are!shown!for!ease!of!comparison.!( (! 110!2.5(Conclusions(To!our!knowledge!this!is!the!first!study!to!provide!quantitative!evidence!for!the!role!of! ventricular! interdependence! under! conditions! of! inspiratory! resistive! loading,!elevated!lung!volumes,!increased!PVR!and!excessive!RV!preload!in!an!intact!human!model,! and! to! assess! the! relative! contribution! of! these! stressors! to! reducing! LV!volumes.!We!discuss! these! findings! in! the! context!of! a!novel!model!of! obstructive!respiratory! disease! in! Chapter! 3,! Section! 3.1.2.! An! important! consideration! for!interpreting! these! findings! is! the! ability! of! the! healthy! versus! diseased! heart! to!tolerate!these!hemodynamic!stressors,!as!in!the!healthy!heart,!the!preloadFmediated!effects!of! these! interventions!were! likely!predominant,!while! the!diseased!heart! is!profoundly! afterload! sensitive! and! thus! these! interactions! would! likely! be!exacerbated!resulting!in!further!cardiac!impairment.!!Data!from!this!study!supports!that!dynamic!lung!hyperinflation!can!have!profound!hemodynamic!consequences!through!exacerbation!of!DVI!and!subsequent!LV!underFfilling,!a!finding!which!had!previously!been!attributed!to!changes!in!pleural!pressure!rather! than! lung! volume! itself59,72.! Additionally,! we! demonstrate! that! when! RV!afterload! is! increased! and/or! a!mediastinal! constraint! to! ventricular! filling! exists,!additional!preload!is!deleterious!to!cardiac!function!through!the!mechanism!of!DVI!and!leftward!shift!of!the!ventricular!septum.!The!degree!to!which!this!impairs!LV!SV!depends! to! some! extent! on! the! ability! of! the!myocardium! to!mobilize! contractile!reserves,! however! is! ultimately! governed! by! pericardial! constraint! to! ventricular!filling38.! We! suggest! these! findings! provide! considerable! insight! into! normal! and!! 111!adverse!cardiopulmonary!interaction!through!mechanisms!that!have!previously!not!been! investigated! in!a! spontaneously!breathing!human!model.!Furthermore,! these!conclusions! have! considerable! clinical! implication! into! better! understanding! the!pathogenesis! of! complete! circulatory! collapse! secondary! to! acute! respiratory!dysfunction,!a!process!which!continues!to!challenge!clinicians!and!researchers!alike.! !! 112!Chapter(3(–(Extended(Discussion(and(Conclusions(!3.1(Extended(discussion(3.1.1!Negative!intrathoracic!pressure!0!how!much!is!too!much?!Numerous! studies! have! shown! that,! in! the! absence! of! the! normally! generated!negative!inspiratory!pressure,!LV!SV!is!impaired!through!reduced!venous!return,!as!the!healthy!heart! is! inherently!preload!dependent26,154.!Similarly,! inspiratory! loads!generating! negative! ITP! beyond! physiological! norms! during! spontaneous!respiration! also! reduce! LV! SV,! as! has! been! shown! in! this! study,! and! in! previous!work65.!Thus,!there!must!exist!a!critical!negative!pressure!at!which!the!respiratory!pump! becomes! maladaptive! (Figure! 3.1).! However,! this! critical! pressure! has! not!been! identified! and! is! likely! influenced! by! a! complex! interplay! of! preload! and!afterload!effects!that!are!highly!individual.!!!As!discussed!previously,!increased!negative!ITP!generates!opposing!effects!through!diastole!and!systole,!and!has!implications!for!both!series!interaction!and!DVI.!During!diastole,!assuming!the!IVC!does!not!collapse,!preload!is!enhanced!as!RAP!follows!ITP!and! thus! the! gradient! for! venous! return! is! increased155.! However,! during! systole,!ventricular!transmural!wall!pressure!is!increased,!which!is!a!large!component!of!the!afterload!seen!by!the!ventricles,!and!thus!the!ventricle!must!overcome!this!increase!in!afterload!to!eject!a!normal!SV58.!The!relative!contribution!of!these!mechanisms!to!series! interaction! depends! on! the! degree! of! negative! ITP! generated! and! the!contractile!reserve!of!the!heart!to!overcome!the!increased!afterload.!With!respect!to!! 113!direct!ventricular!interaction,!increased!venous!return!augments!RVEDV,!which!has!been! shown! to! reduce! LVEDV! through! leftward! septal! shift,! mediated!predominantly! by! pericardial! constraint! to! ventricular! filling53,156.! Again,! whether!series!interaction!or!DVI!predominates!depends!on!a!multitude!of!factors!including!individual! susceptibility! to! IVC! collapse! and! ventricular! interdependence,! and!contractile!ability!of!the!heart!to!overcome!increased!afterload63,65.!!!Figure! 3.1! Theorized! relationship! between! inspiratory! pressure! sustained! across! multiple!cardiac! cycles! and! the! effect! on! LV! SV.! Normal! Range! defines! the! normal! physiological!inspiratory!pressures! (assuming!normal! inspiratory!pressure! range!of! F3! to! F9! cmH2O)!during!resting! spontaneous! breathing.! Note! that! the! slope! of! the! relationship,! and! whether! it! is!symmetrical! as! ITP! becomes! more! negative! or! more! positive,! is! unknown.! Additionally,! the!maximal! decrease! in! SV! is! unknown,! thus! the! SV! intercept! does! not! represent! 0.! PCritical!represents!the!negative!pressure!at!which!inspiration!becomes!detrimental!to!LV!function,! the!value!of!which!has!not!been!defined!to!date.!!! 114!Previous! studies! utilizing! inspiratory! loads! near! F10cm! H2O! have! reported!maintained! or! even! improved! cardiovascular! function! as! indicated! by!echocardiographic!assessment!of!LV!volumes154!and!ultrasonographic!assessment!of!femoral! blood! flow157.! Conversely,! when! inspiratory! loads! approach! F20! cmH2O!during! spontaneous! respiration,! previous!work! by!Karam! et#al,! and! the! results! of!this!study!show!a!reduction! in!LV!SV!by!10%!and!7%,!respectively,!albeit! through!different!proposed!mechanisms.!Karam!et#al!observed!a!relative!increase!in!LVESV!leading!to!a!reduced!LV!SV,!which!they!attributed!to!increased!LV!afterload!during!inspiratory! loading65.! Conversely,!we! observed! a! decrease! in! LVEDV!while! LVESV!was! relatively! unchanged.! Coupled! with! the! observed! septal! flattening,! we!concluded!the!decrease!in!LV!SV!was!predominantly!due!to!incursion!of!the!septum!into!the!LV,!which!constrained!LV!filling!volumes.!!As! previously! mentioned,! afterload! sensitivity! is! seen! to! have! high! individual!variability63,!which!may!explain! the!observed!difference! in!LV!volume!response! to!IR!between!this!study!and!previous!work!by!Karam!et#al65.!Additionally,!while!sex!differences!in!heartFlung!interaction!is!an!area!that!remains!largely!uninvestigated,!the! allFmale! subject! population! in! Karam! et# al’s! study! and! our! 50%! female!population! may! also! explain! observed! differences,! as! it! has! postulated! that! the!female!myocardium! exhibits! a! better! adaptive! response! to! increased! afterload158.!Thus,! while! the! LV! SV! response! to! changes! in! ITP! is! consistent! in! the! literature,!there!is!some!debate!as!to!the!mechanisms!responsible.!!!! 115!To!our!knowledge,!a!graded!or! “doseFresponse”!study! to!systematically! increasing!negative! ITP!has!not!been!conducted.!At!extreme! levels!of!negative! ITP! it! is! likely!that!effects!of!increased!afterload!predominate,!a!finding!that!has!been!consistently!demonstrated!using!the!Mueller!maneuver59,53,57.!However,!at!more!moderate!levels!of! inspiratory! loading!where! reduced! LV! SV! is! observed,! the!mechanisms! remain!unclear.! The! findings! from! the! present! study! suggest! that! diastolic! effects! of!increased!negative! ITP!play! a! larger! role! than!has!been!previously! reported,!with!compelling! evidence! for! the! role! of!DVI! in! contributing! to! the! reduction! in!LV!SV,!namely! significant! reductions! in! septalFtoFLV! free! wall! diameter! and! increased!radius!of!septal!curvature.!Furthermore,!at!inspiratory!loads!where!venous!return!is!not!attenuated!through!IVC!collapse,!the!effects!of!DVI!may!be!even!more!prevalent.!Discerning! the! response!of! the!LV! to! incremental! increases! in!negative! ITP!would!allow!for!a!quantitative!analysis!of!the!relative!contributions!of!series!versus!direct!ventricular! interaction,! and! the!point! at!which!afterload!effects!begin! to!outweigh!preload!in!the!healthy!heart.!!3.1.2!Utilizing!hypoxia!and!dynamic!hyperinflation!during!inspiratory!resistive!loading!as!a!novel!model!of!obstructive!respiratory!disease!The! mechanisms! of! altered! hemodynamic! function! in! chronic! obstructive!pulmonary! disease! (COPD)! are! multifaceted,! and! can! be! attributed! to! underlying!respiratory! dysfunction,! namely! altered! ventilatory! mechanics! and! physiological!changes! to! the! pulmonary! circulation.! The! primary! ventilatory! impairments! in!COPD! are! expiratory! flow! limitation! (EFL)! and! consequently! dynamic! lung!! 116!hyperinflation! (DH)15,! both! of! which! have! important! hemodynamic! consequences!which!have!been!previously!discussed! ,!and!are!proportional!to!the!severity!of!the!disease97.! Through! degradation! of! lung! tissue,! chronic! alveolar! hypoxia! and!chronically! elevated! lung! volumes,! pulmonary! vascular! resistance! is! seen! to! be!greatly! increased! in! this! population.! Additionally,! the! slope! of! pulmonary! artery!pressure!increase!when!cardiac!output!is!increased!is!much!steeper!in!moderate!to!severe!disease!than!in!healthy!populations159,97.!!While! considerable! work! has! been! done! in! investigating! hemodynamics! in! COPD!patients! during! exercise,! understanding! the! mechanisms! of! hemodynamic!compromise!in!a!disease!state!is!inherently!convoluted!due!to!the!integrative!nature!of! multiFsystem! dysfunction! associated! with! COPD160,96.! Surprisingly,! only! a! few!mechanistic! studies! using! healthy! humans! have! attempted! to! elucidate! the!mechanisms! whereby! the! ventilatory! limitations! associated! with! COPD! impair!cardiac!function.!To!our!knowledge,!only!two!previous!studies!have!investigated!the!effects! of! elevated! lung! volumes! with! concomitant! changes! to! intrathoracic!pressures59,72,! both! of! which! have! inherent! limitations! as! a! model! of! obstructive!respiratory!disease!which!limits!the!clinical!relevance!of!the!data.!!!!! !Table !3 .1 !Changes! in !LV!function!and!geometry!during!DH!(Phase!3a) !relat ive!to !during!IR!(Phase!2) . ! VV\#-!   $)1 ./$"/  /#   !! /. *! $)- . ) "/$1   /#-*0"# /#  0.  *! /#  0 '' -() 01 - '*)  ) $) *)%0)/$*) 2$/# 1*'0)/-4 .//$ $)- .  $) '0)" 1*'0( B )*)'0  /#/ $) *./-0/ - /#$)"+// -).B) "/$1   2. *! !- "- / - $(+*-/)  /*(*0'/$)"  !0)/$*) /#) '0)" 1*'0( .Z^E	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	+'4."- / --*'  /#)$)- . ) "/$1 $)- 0$)"M' XEVNE#0.B2 .0"" .//#/.//$'0)"1*'0( $)- . *1 * .)*/++-*3$(/ /# # (*4)($#'' )" ..  )0-$)"	$)*./-0/$1 - .+$-/*-4$. . B)/#/*)'0.$*).4#-!! - ( M(N F[aVVQ UEUYZM(N FVa[ UEXWUM_N FVaZ UEZ]YM(N FZaVU UEU[WMK($)N FUEYaUE[Q UEUWYM(N UE[aWEU UE[\\M(N UEUaUEZ UE\^UM(N FUEVaUEW UEWWYM(N UEUaUEW UE[^^'  XEV #)" . $)  !0)/$*))" *( /-40-$)"	M#. XN- '/$1 /*0-$)"M#. WNQ )*/ ..$")$!$)/#)" !-*('*) M+cUEUUZN! 118!al,! if! translated! to!a!disease!model,! likely!under!predicts! the!deleterious!effects!of!lung!volume!on!LV!function.!!!Subsequent! work! by! StarkFLeyva! et# al72# improved! upon! the! static! lung!hyperinflation! model! by! having! subjects! spontaneously! breathe! at! elevated! lung!volumes!alone!and!against!an!expiratory!resistance!to! increase!positive!expiratory!pressures.! While! these! researchers! demonstrate! a! significant! reduction! in! LV! SV!with!expiratory!loading,!this!was!reversed!during!expiratory!loading!with!elevated!lung!volumes72.! In!contrast,!we!demonstrated!a!marked!reduction! in!LV!SV!during!DH!and!inspiratory! loading,!with!similar!ITP!swings!reported!by!StarkFLeyva!et#al.!There!are!a!number!of!reasons!that!may!explain!the!differences!between!our!study!and!that!of!StarkFLeyva!et#al.##Firstly,!the!levels!of!dynamic!hyperinflation!induced!in!our! study! are! considerably! greater! than! those! observed! during! voluntary!hyperinflation.! Secondly,! the! use! of! openFcircuit! acetylene! to! measure! cardiac!output! during! dynamic! hyperinflation! is! inherently! flawed.! !More! specifically,! gas!trapping!would!serve!to!increase!the!concentration!of!acetylene!in!areas!of!alveolar!deadspace,!which!violates!the!required!assumption!that!alveolar!and!arterial!partial!pressures!of!acetylene!be!equal!for!valid!measurement!of!cardiac!output!using!this!technique161,162.! While! the! authors! acknowledge! this! limitation,! they! account! for!error!only!due!to!positive!expiratory!pressures!and!not!increased!lung!volume.!!As!such,! the! increased! LV! SV!with! hyperinflation! is! potentially! a! phenomenon! of! the!methodology!rather!than!the!actual!underlying!physiology.!!! 119!A!critical!feature!of!COPD,!which!has!also!been!neglected!in!previous!studies!using!healthy!humans!with!resistive!loading!as!a!model!of!COPD,!is!an!increase!in!PVR!as!a!result! of! chronic! alveolar! hypoxia! and! destruction! of! lung! parenchyma! in! certain!COPD!phenotypes163.!Such!alterations!to!the!vascular!bed!further!increase!afterload!on! the! already! stressed! RV! during! dynamic! lung! hyperinflation! and! increased!inspiratory!pressures.!Results!from!this!study!support!the!importance!of!increased!PVR,!as!significantly!larger!reductions!in!LVESV!and!an!increase!in!EF!was!observed!between! hypoxic! and! normoxic! dynamic! hyperinflation! with! inspiratory! loading.!While!we!acknowledge!that!LVEDV!and!SV!did!not!significantly!change!during!our!imposed!hypoxic!stressor!(Table!3.2),! these!results!suggest!a!greater!degree!of!LV!underFfilling!and!subsequent!systolic!compensation!by!the!LV.!Therefore,!we!believe!this!study!provides! the!most!comprehensive!model!of!COPD! in!healthy!humans! to!date!and!provides!insight!into!potential!mechanisms!of!cardiopulmonary!interaction!that!may!occur!in!this!population97.!Table!3.2!Summary!of!changes! to!LV! function!between! IR!alone!(phase!2)!and!DH!with!IR! (phase! 3b),! and! subsequently! changes! between! normoxic! (phase! 3b)! and! hypoxic!(phase!5c)!DH!with!IR.!( Change(from(IR((Phase(2)(to(IR(with(DH((Phase(3a)(Change(from(normoxic(to(hypoxic(DH(with(IR((Phase(3b(to(5c)(! Δ(Abs.( p( Δ(Abs.( p(LVEDV!(mL)! F9!±!10*! 0.001! F3!±!12! 0.430!LVESV!(mL)! F3!±!5*! 0.023! F4!±!5*! 0.009!SV!(mL)! F6!±!9*! 0.017! 2!±!9! 0.447!EF!(%)! F1!±!5! 0.406! 3!±!4*! 0.014!Q!(L/min)! F0.3!±!0.6! 0.061! 0.2!±!0.8! 0.377!RSCFED!(cm)! 2.0!±!2.6*! 0.031! 0.5!±!2.5! 0.584!RSCFES!(cm)! 0.7!±!1.5! 0.188! 0.3!±!1.2! 0.526!RFWCFED!(cm)! 0.0!±!0.2! 0.781! 0.2!±!0.3! 0.108!RFWCFES!(cm)! 0.0!±!0.2! 0.841! 0.0!±!0.3! 0.889!Data!reported!as!mean!±!SD.!*!Denotes!a!significant!difference!between!phases!(p<0.05).!!!! 120!3.1.3!Sex!differences!in!cardiopulmonary!interaction!While! sex! differences! in! respiratory164F166! and! cardiovascular167F169! physiology! are!well! documented! and! continue! to! be! of! considerable! research! interest,! to! our!knowledge!very!few!studies!have!investigated!how!these!differences!may!contribute!to!normal!and!adverse!cardiopulmonary!interaction.!Preliminary!subgroup!analysis!of! how! the! cardiopulmonary! effects! of! inspiratory! resistive! loading! and! dynamic!hyperinflation!differ!between!sexes!suggests!that!while!the!response!to!IR!is!similar,!DH! has! a! more! detrimental! effect! on! LV! function! in! males,! as! indicated! by!significantly! larger! reductions! in! LV! SV! (F14%,! p=0.005)! and! EF! (F6%,! p=0.000)!(Table! 3.3).! These! differences! were! observed! despite! a! similar! increase! in! EELV!between!males!and!females.!!It!has!been!shown!that!the!female!left!ventricle!in!both!rat170!and!human169!models!has!greater!compliance!and!systolic!functioning!than!the!male!ventricle.!From!this,!it!has!been!postulated!that!the!female!myocardium!should!be!better!able!to!cope!with!increased! afterload,! and! indeed! this! has! been! demonstrated! through! increased!contractility171,158!and!twist!mechanics172,!in!response!to!altered!loading!conditions.!We!theorized!this!may!account!for!the!more!preserved!LV!SV!observed!in!this!study!during! DH,! as! females! were! seen! to! reduce! LVESV! in! the! face! of! a! reduction! in!LVEDV! to! better! maintain! LV! SV.! However,! whether! males! and! females! are!differentially!susceptible!to!series!versus!direct!ventricular!interaction!is!unknown.!Further! investigation! into! the! differential! responses! in!males! and! females! is! now!! 121!warranted!to!define!sex!differences! in!cardiopulmonary! interaction!and!the!causal!mechanisms.!Table! 3.3! Sex! differences! in! the! cardiovascular! response! to! IR! (Phase! 2)! and! DH!(Phase!3a)!( IR((Phase(2)(change(from(baseline( DH((Phase(3a)(change(from(baseline(! Male!%! Female!%! Δ!%! p! Male!%! Female!%! Δ!%! p!LVEDV!(mL)( F3!±!5! F5!±!6! 2!±!7! 0.489! F12!±!10! F6!±!9! F5!±!14! 0.231!LVESV!(mL)( F1!±!7! 1!±!11! F1!±!11! 0.734! 0!±!12! F9!±!9! 8!±!15! 0.096!SV!(mL)( F5!±!7! F9!±!7! 4!±!12! 0.308! F20!±!11! F4!±!10! 14!±!16*! 0.005!EF!(%)( F1!±!2! F3!±!3! 1!±!5! 0.351! F6!±!3! 1!±!2! F6!±!3*! 0.000!Q!(L/min)( 5!±!13! 2!±!17! 4!±!21! 0.732! F13!±!13! 3!±!18! F13!±!26! 0.051!HR!(bpm)( 12!±!14! 15!±!21! F2!±!30! 0.722! 9!±!6! 7!±!13! 2!±!18! 0.0591!RSCFED!(cm)( 24!±!20! 27!±!40! F3!±!40! 0.864! 34!±!54! 68!±!68! F31!±!63! 0.347!RSCFES!(cm)( 27!±!70! 22!±!30! 12!±!68! 0.834! 30!±!89! 16!±!42! 48!±!144! 0.786!RFWCFED!(cm)( F1!±!7! 3!±!7! 4!±!7! 0.207! F4!±!8! 0!±!5! F2!±!8! 0.385!RFWCFES!(cm)( 2!±!16! 8!±!16! 5!±!19! 0.371! 5!±!17! F4!±!11! 14!±!23! 0.359!Data!reported!as!mean!±!SD.!*!Denotes!a!significant!difference!between!phases!(p<0.05).!(3.2(Study(limitations(!While! we! attempted! to! control! for! as!many! aspects! as! possible! within! our! study!design,! including! selection! of! a! homogenous! subject! population,! regulating!intervention! parameters! such! as! negative! inspiratory! pressure! generation! and!respiratory! duty! cycle,! and! repeating! baseline! measurements! within! each! phase,!there!are!a!number!of!potential!limitations!which!should!be!acknowledged.!!3.2.1!Limitations!of!transthoracic!echocardiography!There!are!several!limitations!inherent!to!the!use!of!transthoracic!echocardiography!that!challenges!clinicians!and!researchers!alike.!Most!notable! is! that! the!quality!of!data!and!subsequent!analysis!is!entirely!dependent!on!the!ability!of!the!sonographer!to!consistently!remain!on!axis!and!acquire!quality!images.!!The!quality!of!LV!image!! 122!acquisition! is! affected! by! the! angle! of! insonation,! and! the! risk! of! foreshortening,!malrotation,! or! angulation! in! the! apical! view! is! well! documented! and! can! render!volumetric! analysis! inaccurate131,130.! Additionally,! there! is! a! high! degree! of!individual! variability! in! the! clarity! of! a! subject! or! patient’s! echocardiographic!“window”,!which!is!influenced!by!the!anatomy!and!physiology!of!the!chest!wall!and!mediastinal!structures130.!!To! circumvent! these! potential! limitations,! it! is! suggested! researchers! screen!subjects!for!the!ability!to!acquire!good!quality!echocardiographic!images,!as!this!has!been!shown!to!reduce!variation!in!LV!volumetric!analysis173.!It!is!also!recommended!to!have!patients!exhale!and!hold!a!static!lung!volume!at!or!near!FRC!over!the!course!of! image! acquisition! to! mitigate! interference! of! the! lung! in! optimizing! image!clarity130.!While!we!addressed!the!issue!of!suboptimal!echocardiographic!windows!by! screening! subjects! to! ensure! quality! image! acquisition! prior! to! initiating! the!study!protocol,!a!static!breathe!hold!would!have!made! it! impossible! to! investigate!the! effects! of! dynamic! lung! volumes! and! intrathoracic! pressure! swings,! and!introduced! a! confounding! effect! on! LV! volumes.! We! therefore! acquired! images!during! spontaneous! respiration,! which! we! acknowledge! imposes! a! potential!limitation!for!optimizing!image!quality.!To!our!knowledge,!no!optimal!nonFinvasive!technique!for!analysis!of!LV!function!during!spontaneous!respiration!exists,!and!we!attempted! to! mitigate! this! limitation! by! acquiring! larger! data! sets,! repeating!baseline!measures,! and! being! highly! conservative!with! LV! volumetric! analysis,! as!reported!in!Section!2.2.3.3.!!! 123!!The! use! of! 3Fdimensional! (3D)! echocardiography! for! LV! function! analysis! is! now!recommended!over!the!use!of!2Fdimensional!(2D)!echocardiography!in!the!clinical!and!research!setting130.!3D!echocardiography!has!been!shown!to!resolve!several!of!the! limitations! inherent! to! 2D! echocardiography,! specifically! with! assumptions!made!about!LV!geometry!and!wall!movement130!and!thus!has!improved!accuracy!for!LV! volume! analysis132.! There! are! two! methods! of! volumetric! analysis! using! 3D!echocardiography;!the!first!uses!a!fullFvolume!data!set!to!render!a!3D!impression!of!the!LV!structure,!the!endocardial!border!of!which!is!then!traced!by!automated!edgeFdetection! software.! This! method! has! shown! significant! underestimation! of! LV!volumes!in!previous!validation!studies174,175,130,!and!is!heavily!dependent!on!optimal!image! quality.! Furthermore,! the! reliability! of! automated! edgeFdetection! for!volumetric! analysis! deteriorates! with! significant! or! abnormal! LV! wall! motion175,!such! as!was! observed! in! the! septal!wall! segment! during! the! stressors! imposed! in!this!study.!!!The!second!analysis!method,!and!the!one!used!in!this!study,!uses!simultaneous!2D!acquisition! across! three!orthogonal! planes! to! create! standard!2D! images!of! apical!fourFchamber,! twoFchamber! and! threeFchamber! views! that! are! automatically!optimized! to! ensure! an! “onFaxis”! image.! Endocardial! border! tracing! is! done!manually!by!the!observer,!and!has!been!shown!to!have!less!variability!in!calculating!LV!volumes! than!both!2D!and!3D!automated!edgeFdetection!methods130.!While!3D!echo!has!advantages!over!2D!echo,!these!benefits!come!at!the!cost!of!reduced!spatial!! 124!and! temporal! resolution.! Additionally,! utilizing! 2D! images! for! volumetric! analysis!suffers! from! some! of! the! same! geometric! assumptions! of! 2D! echocardiography.!However,! with! the! additional! data! provided! by! the! threeFchamber! view! and!optimized!onFaxis! imaging,!we! are! confident!we! collected! and! analyzed! images! to!the!highest!degree!of!accuracy!possible!within!the!confines!of!the!study!design!and!limitations!of!the!echocardiographic!technology!available!to!us.!!!3.2.2!Acquisition!of!right!ventricular!echocardiographic!data!Volumetric! analysis! of! the! RV! would! have! provided! considerable! insight! into!whether!series! interaction!or!DVI!primarily!contributed!to!the!observed!effects!on!LV!volumes!during!the!interventions!utilized!in!this!study.!In!the!absence!of!RV!endFdiastolic! volume! (RVEDV)!data,!we!were!unable! to!determine! the!extent! to!which!increased! negative! ITP! altered! RV! preload.! Additionally,! RV! endFsystolic! (RVESV)!and! stroke! volumes! (RV! SV)! would! have! quantified! RV! systolic! performance! in!response! to! increasing! afterload,! and! determined! how! much! series! interaction!contributed! to! LV!preload.! Thus,!while! septal! configuration! is! reported! as! a! fairly!robust! indicator! of! RV! relative! to! LV! volumes! and! pressures53,! RV! volumetric!analysis!would!have!greatly!increased!the!impact!of!this!study!and!strengthened!our!conclusion!for!a!primary!role!of!DVI!in!mediating!LV!function.!!Evaluation! of! RV! function! by! 2D! or! 3D! echocardiography! is! complicated! and! less!reliable!than!evaluation!of!LV!function,!due!to!the!complex!and!irregular!geometry!of! the!RV,! and! it’s!distensibility! and!nonFuniform!contraction!patterns176,177,93.! For!! 125!these!reasons,!we!did!not!attempt!to!image!the!RV!in!this!study,!as!these!limitations!would! have! likely! been! greatly! exacerbated! given! the! severity! of! the! stressors!imposed! in! this! study.! The! gold! standard! technique! for! measurement! of! RV!hemodynamics!remains! invasive!catheterization178,!which! is!rarely!used! in!studies!on!healthy!humans.!Given!the!absence!of!data!on!RV!function!in!this!study,!we!are!limited! in! the! assumptions! that! can! be! made! as! to! the! etiology! of! the! observed!changes!in!LV!function.!!While! using! LV! geometry! and! septal! wall! motion! as! a! surrogate! of! relative! RV!volume!and!pressure! is! fairly! robust53,89,! it! provides!no! insight! into!RV! filling! and!ejection!patterns.!Therefore,!we!could!not!quantify! the!effects!of! the! interventions!used!in!this!study!on!RV!venous!return!or!rightFsided!cardiac!output.!This!presents!a!limitation!to!discerning!the!mechanisms!responsible! for!the!observed!reduction! in!LV! SV! during! changes! to! inspiratory! pressures,! lung! volumes! and! RV! volume!overload.! Despite! this! limitation,! we! feel! the! data! from! this! study! provides! novel!preliminary! insight! into! cardiopulmonary! interaction! during! hemodynamic!stressors.!!3.2.3! Limitations! to! analysis! and! interpretation! of! data! across! several!respiratory!and!cardiac!cycles!During!spontaneous!respiration,!a!normal!respiratory!cycle!extends!across!several!cardiac! cycles,! making! it! difficult! to! differentiate! diastolic! and! systolic! effects! of!changes! to! intrathoracic! pressure9.! Further! complicating! this! issue! is! the! effect! of!respiratory!cycle! timing!on!the!observed! fall! in!LV!SV!during! inspiration.!Previous!! 126!studies!have!shown!that!during!spontaneous!respiration!with!normal!ITP!swings,!LV!SV! is! reduced! during! only! the! first! few! inspiratory! cardiac! cycles,! and! returns! to!baseline! during! a! prolonged! inspiration.! Similarly,! an! increase! in! LV! SV! during!expiration! is! seen! only! during! the! first! few! cardiac! cycles! of! expiration49.! Phasic!changes! to!venous!return!during!early!and! late!diastole!are!also! implicated! in! this!process,!as!the!timing!of!the!start!of!inspiration!relative!to!the!timing!of!the!cardiac!cycle! will! modulate! the! degree! to! which! LV! SV! is! changed.! Ventricular! filling! is!generally! greatest!during!early!diastole,! thus! initiating!an! inspiration!during!early!diastole!will! tend!to! increase!RV!volume!to!a!greater!degree!than! initiating!during!endFdiastole! for!a!given!cardiac!cycle50,9.!Therefore,!not!controlling! for!respiratory!phase! relative! to! cardiac! phase,! and! standardizing! assessment! of! LV! volumes! to!either! endFexpiration! or! endFinspiration! presents! a! limitation! to! this! study! with!regard!to!our!ability!to!differentiate!diastolic!and!systolic!mechanisms.!However,!we!feel! that! utilizing! an! intact! spontaneously! breathing! model,! while! not! as!mechanistically!clean,!provides!for!more!meaningful!extrapolation!of!results!to!the!interaction!of!these!mechanisms!in!humans!in!health!and!disease.!!!While! limited! studies! have! investigated! the!phasic! effects! of! respiration! on! LV! SV!during!normal!spontaneous!respiration! in!humans,!during! loaded! inspiration!with!changes! to! operational! lung! volumes! and! increases! to! RV! preload! and! afterload,!these! effects! remain! unclear! and! are! largely! uninvestigated.! It! is! reasonable! to!assume! that!with! increases! in! negative! inspiratory! pressures! a! larger! differential!between! inspiratory! and! expiratory! volumes! would! be! observed,! which! may! be!! 127!further! accentuated! by! changes! to! operational! lung! volumes,! and! changes! to! RV!preload! and! afterload.! As! depicted! in! Figure! 3.2,! we! observed! a! trend! towards! a!greater!decrease!in!LVEDV!and!LV!SV!during!inspiration!across!most!interventions;!with!significantly!lower!inspiratory!LV!SV!and!LVEDV!during!HDT!with!IR!(p=0.009,!p=0.041)!and!higher!inspiratory!LVEDV!during!hypoxia!(p=0.035).!As!we!reported!mean!data,!with!58%!of!images!analyzed!at!endFexpiration,!we!argue!that!our!data!is!likely! a! conservative! estimate! of! true! reductions! in! LV! volume,! and!we! are! likely!underFpredicting! the! generally! detrimental! effects! of! these! interventions! on! LV!function.!! 128!!!!Figure! 3.2! Observed! differences! between! inspiratory! and! expiratory! left! ventricular! endFdiastolic! volume! (LVEDV)! and! left! ventricular! stroke! volume! (SV)! across! all! phases.! P1! =!baseline,! P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic!hyperinflation! with! inspiratory! loading! (DH+IR),! P4a! =! HeadFdown! tilt! (HDT),! P4b! =! HeadFdown! tilt! with! inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =! Hypoxia! with! inspiratory!loading!(Hypox+IR),!P5c!=!Hypoxia!with!IR!and!DH,!(Hypox+DH+IR),!P6!=!Hypoxia!with!IR!and!DH!during!HDT!(All! interventions).! *!Denotes!a!significant!difference!between! inspiratory!and!expiratory!volumes!(p<0.05).!( (! 129!3.3(Clinical(relevance(Understanding!mechanical!heartFlung! interaction! is!at! the! foundation!of!managing!hemodynamics! in! patients! with! obstructive! respiratory! disease! in! both! the! acute!and!chronic!setting.!As!discussed!previously,!we!present!in!this!study!what!we!feel!is!a!novel!and!more! integrative!model!of!obstructive! lung!disease! in!healthy!humans!than!has!previously!been!reported.!Our!results!suggest!that!even!acute!ITP!and!lung!volume! challenges! can! negatively! impact! the! healthy! heart,! providing! insight! into!the!potential!mechanisms! in!COPD! that! likely! compound!chronically! to! cause!well!documented!adverse!structural!and!functional!changes!to!the!heart179,95,111,180.!!!Our! summative! approach! to! integrating! these! mechanisms! provides! quantitative!evidence! for! the! relative! contribution! of! these! stressors! on! mediating! LV!performance.!We!believe!these!findings!will!provide!a!foundation!for!future!studies!to! help! identify! the! mechanisms! whereby! multiple! systems! integrate! to! regulate!blood!flow!in!health!and!disease.!Further,!we!hope!this!study!will!provide!direction!for!identifying!which!facets!of!altered!respiratory!mechanics!are!chiefly!responsible!for!reducing!cardiac!output!in!COPD!patients,!allowing!clinicians!to!more!efficiently!target! these! respiratory! mechanisms! through! pharmaceutical! and! nonFpharmaceutical! interventions! to! increase! quality! of! life! and! improve! longFterm!prognosis!in!patients!with!comorbid!respiratory!and!cardiovascular!disease.!! 130!3.4(Future(directions(3.4.1! Investigating! a! graded! negative! ITP! “dose0response”! relationship! to! LV!function!As! discussed! previously,! few! studies! have! examined! the! effects! of! decreased!intrathoracic! pressure! during! spontaneous! respiration! in! healthy! humans.! To! our!knowledge,! only! one!previous! study!has! utilized! a! similar! inspiratory! load! to! this!study,! with! differing! results! from!what! we! report! here65.! Thus,! despite! extensive!mechanistic!studies!on!anaesthetized!canines,! the!mechanisms!of!decreased!LV!SV!during!inspiratory!resistive!loading!in!humans!remains!unclear.!An!important!next!step!would!be!to!determine!the!point!at!which!negative!ITP!becomes!detrimental!to!LV! SV! (as! depicted! in! Figure! 3.1),! which! would! help! to! elucidate! the! relative!contributions! of! series! interaction! versus!DVI! in!mediating! this! reduction.! To! our!knowledge!a!graded!inspiratory!load!test!to!determine!the!ITP!“tipping!point”!on!LV!function! has! not! been! conducted,! therefore! we! intend! to! pursue! this! line! of!inquisition,!utilizing!an!infinitely!variable!mechanical!inspiratory!load!which!allows!us!to!set!negative!pressures!independent!of!changes!to!ventilation,!while!acquiring!3D!transthoracic!echocardiographic!images!for!LV!volumetric!analysis.!!3.4.2! Investigating! integrated! cardiopulmonary! and! cerebrovascular!hemodynamics!Cardiopulmonary! interaction! during! changes! to! intrathoracic! pressure! has! been!studied!extensively!in!canine!models63,181,62,!and,!to!a!lesser!extent,!in!humans65,59,58.!However,!how!these!systems!interact!with!the!cerebrovascular!system!to!maintain!! 131!cerebral! blood! flow! (CBF)! during! changes! in! ITP! is! unknown.! Given! that! the!pulmonary! and! cerebral! circulation! operate! in! series,! changes! to! intrathoracic!pressure! should! alter!CBF! to! a! similar! extent! to!which! cardiac! function! is! altered,!unless! there! is! a! compensatory! increase! in! MAP.! Pilot! work! from! our! lab! has!demonstrated! an! increase! in! middle! cerebral! artery! blood! velocity! (MCAV)! and!internal! carotid! artery! (ICA)! diameter! in! response! to! decreased! LV! SV! during!inspiratory! loading.! These! findings! suggest! a! compensatory! increase! in! CBF! in!response! to! increased!negative! ITP.!However,! further!work! is! required! to! confirm!these!observations!in!a!larger!sample!size.!!!To!our!knowledge!the!relationship!of!CBF!to!increased!lung!volumes!with!changes!to!intrathoracic!pressure!has!not!been!investigated,!though!it!presents!considerable!clinical! relevance! to! understanding! cerebrovascular! function! in! COPD! patients.!Using! data! from! the! present! study,! we! intend! to! pursue! a! number! of! studies!investigating! alterations! to! CBF! and! cardiac! function! using! a! similar! model! of!obstructive!respiratory!disease!from!this!study!(phase!5c),! in!addition!to!how!ITP,!lung!volume!and!RV!volume!overload!interact!with!CBF!in!isolation.!#3.4.3! Investigating! the! effects! of! dynamic! hyperinflation! on! LV! function! and!exercise!tolerance!in!patients!with!COPD!Exercise!intolerance!in!COPD!is!well!documented,!and!has!generally!been!attributed!to! exacerbation! of! ventilatory! dysfunction,! namely! expiratory! flow! limitation!causing!dynamic!hyperinflation!and!severe!dyspnea15,94.!However,!additional!causes!! 132!of! exercise! limitation! have! been! proposed,! including!metabolic! and! gas! exchange!abnormalities,!peripheral!muscle!dysfunction,!and!impaired!cardiac!function15,97.! It!is!likely!that!exercise!intolerance!is!multifaceted,!and!cannot!be!attributed!solely!to!one! of! the! above!mechanisms.! However,! the! results! of! this! study! suggest! that! LV!dysfunction! in! response! to! altered! respiratory! status! may! be! significant,! and!therefore! suggest! that! adverse! cardiopulmonary! interaction! during! exercise! in!COPD!should!be!an!important!future!line!of!inquiry.!!While!it!is!generally!accepted!that!the!cardiac!output!response!to!exercise!in!COPD!is! adequate! and! follows! a! similar! slope! to! that! seen! in! healthy! individuals,! this!increase! is!accompanied!by!a!much!steeper! increase! in!HR!than! is!seen! in!healthy!humans159.!This!suggests!decreased!LV!SV,!which!is!consistent!with!the!findings!of!this!study!during!a!model!of!COPD!exacerbation.!Previous!work!has!attributed!this!impaired! SV! to! RV! systolic! dysfunction! through! increased! pulmonary! vascular!resistance.!Thus,!the!current!body!of!literature!supports!LV!impairment!in!COPD!is!a!function!of!series!interaction97,159.!To!our!knowledge!the!present!study!is!the!first!to!suggest! that! DVI! plays! a! considerable! role! in! reducing! LV! SV! in! an! intact,!spontaneously!breathing!human!model!of!COPD.!Additionally,!while!previous!work!has!attributed!LV!impairment!to!increased!ITP!swings!and!positive!endFexpiratory!pressure! seen! during! exercise! in! obstructive! respiratory! disease59,72,! our! study!suggests! the!hyperinflated! lung!plays!a!much! larger!role! in!mediating!LV! function.!Therefore,!we!are! investigating!cardiovascular!mechanisms!of!exercise! intolerance!during! exercise! in! COPD! focusing! on! the! impact! of! dynamic! hyperinflation! on! LV!! 133!function,!including!assessment!of!LV!geometry,!to!ascertain!the!contribution!of!DVI!to!impairing!LV!SV.!!3.5(Conclusion(!For! the! better! part! of! a! century! cardiopulmonary! interaction! has! been! of!considerable! research! interest.! Yet,! these! complex! interactions! are! not! well!understood,! and! relatively! few! studies! have! investigated! these! mechanisms! in!spontaneously! breathing! healthy! human!models7,9.! It! is! generally! considered! that!the!hemodynamic!effects!of!fluctuations!in!the!pressureFvolume!relationship!during!resting! spontaneous! respiration! are! minimal7.! What! is! equally! clear! is! that! large!increases!in!negative!inspiratory!pressure!is!detrimental!to!cardiac!function9.!This!is!seen! in! obstructive! respiratory! disease,! and! is! associated! with! large! increases! in!operational! lung! volumes! and! pathological! changes! to! the! pulmonary! circulation!that!increase!PVR97.!The!cumulative!influence!of!these!stressors!on!hemodynamics!in! COPD! is! not! well! understood,! however! given! the! strong! association! between!COPD!and!cardiac!dysfunction! it! is! theorized!adverse!cardiopulmonary! interaction!occurs97,95.!!This! thesis! presents! novel! evidence! for! the! role! of! DVI! in! causing! LV! diastolic!dysfunction! and! reduced! LV! SV! in! response! to! altered! ventricular! loading.!Specifically,!we!demonstrated!that! inspiratory! loading!causes!a!reduction! in!LV!SV!that!is!not!adequately!explained!by!an!increase!in!LV!afterload.!In!conjunction!with!evidence! of! leftward! septal! shift,! this! finding! suggests! DVI! due! to! elevated! RV!! 134!volume! plays! a! considerable! role.! Additionally,! we! report! that! large! increases! in!lung! volume! have! considerable! negative! effect! on! LV! diastolic! filling! through!exacerbation! of!DVI.! Previous! studies! have! suggested! changes! to! pleural! pressure!may!outweigh!the!effects!of!elevated!lung!volume!in!influencing!hemodynamics59,72.!However,! results! from! this! study! contrastingly! support! that,! at! a! substantial!elevation!above!FRC,!lung!volume!may!be!a!primary!determinant!of!LV!function.!We!attribute!this!to!both!increased!RV!afterload!and!mediastinal!constraint!of!the!heart!by!the!lung,!which!was!evidenced!through!substantial!leftward!septal!shift.!!While! increased! negative! ITP! and! DH! approximates! a! model! of! obstructive!respiratory! disease,! it! neglects! the! increase! in! PVR! due! to! HPV! and! vascular!remodeling103.!Thus,!we!investigated!this!interaction!in!response!to!acute!hypoxia!to!increase! PVR.! Though! LV! function! was! not! significantly! more! impaired! with!hypoxicFmediated! increases! in! PVR,! these! results! are! likely! a! reflection! of! the!considerable! ability! of! the! healthy! heart! to! overcome! increases! in! afterload! by!increasing! contractility91,92.! ! In! contrast,! in! diseases!where! cardiovascular! reserve!may!be!greatly! impaired!due!to!occult!CVD!such!as!COPD97,95,! this! increase! in!PVR!may!be!profoundly!detrimental.!!!Finally,! we! provide! compelling! evidence! for! the! role! of! 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Swan!HJ,!Ganz!W.!Measurement!of!right!atrial!and!pulmonary!arterial!pressures!and!cardiac!output:!clinical!application!of!hemodynamic!monitoring.!Adv!Intern!Med!1982;27:453–73.!!179.! Chen!W,!Thomas!J,!Sadatsafavi!M,!FitzGerald!JM.!Risk!of!cardiovascular!comorbidity!in!patients!with!chronic!obstructive!pulmonary!disease:!a!systematic!review!and!metaFanalysis.!Lancet!Respir!Med!2015;3(8):631–9.!!180.! Feary!JR,!Rodrigues!LC,!Smith!CJ,!Hubbard!RB,!Gibson!JE.!Prevalence!of!major!comorbidities!in!subjects!with!COPD!and!incidence!of!myocardial!infarction!and!stroke:!a!comprehensive!analysis!using!data!from!primary!care.!Thorax!2010;65(11):956–62.!!181.! Pinsky!MR,!Summer!WR,!Wise!RA,!Permutt!S,!BrombergerFBarnea!B.!Augmentation!of!cardiac!function!by!elevation!of!intrathoracic!pressure.!J!Appl!Physiol!Respir!Environ!Exerc!Physiol!1983;54(4):950–5.!!!! 151!((((((Appendices(( (! 152!Appendix(A:(Supplemental(Figures(!Figure!A.1! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!IR! (Phase! 2),! n=19.! Abbreviations:! Clockwise! from! top! left;! LVEDV! =! left! ventricular! endFdiastolic!volume,!SV!=!stroke!volume,!Q!=!cardiac!output,!HR!=!heart!rate,!EF!=!ejection!fraction,!LVESV! =! left! ventricular! endFsystolic! volume.! *! Denotes! a! significant! change! from! baseline!(p<0.05)!! 153!!!!!Figure!A.2! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!DH! (Phase! 3a),! n=18.! For! abbreviations! please! refer! to! Figure! A.1.! *! Denotes! a! significant!change!from!baseline!(p<0.05).!!!! 154!!!!!Figure!A.3! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!DH+IR! (Phase! 3b),! n=17.! For! abbreviations! please! refer! to! Figure!A.1.! *! Denotes! a! significant!change!from!baseline!(p<0.05).!! 155!!!!!!Figure!A.4! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!HDT! (Phase! 4a),! n=18.! For! abbreviations! please! refer! to! Figure! A.1.! *! Denotes! a! significant!change!from!baseline!(p<0.05).!! 156!!!!!!Figure!A.5! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!HDT+IR!(Phase!4b),!n=17.!For!abbreviations!please!refer! to!Figure!A.1.! *!Denotes!a!significant!change!from!baseline!(p<0.05).!! 157!!!!!!!Figure!A.6! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!Hypoxia!(Phase!5a),!n=19.!For!abbreviations!please!refer! to!Figure!A.1.! *!Denotes!a!significant!change!from!baseline!(p<0.05).!! 158!!!!!!!Figure!A.7! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!Hypoxia+IR! (Phase! 5b),! n=20.! For! abbreviations! please! refer! to! Figure! A.1.! *! Denotes! a!significant!change!from!baseline!(p<0.05).!! 159!!!!!!!Figure!A.8! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!Hypoxia+DH+IR! (Phase! 5c),! n=15.! For! abbreviations! please! refer! to! Figure! A.1.! *! Denotes! a!significant!change!from!baseline!(p<0.05).!! 160!!!!!!!Figure!A.9! Individual! (coloured! lines)!and!mean!(thick!black! line)!cardiovascular! responses! to!all! interventions! (Phase! 6),! n=16.! For! abbreviations! please! refer! to! Figure! A.1.! *! Denotes! a!significant!change!from!baseline!(p<0.05).!! 161!!!Figure! A.10! Changes! to! respiratory! rate! (RR),! tidal! volume! (VT)! and!minute! ventilation! (VE)!across! all! phases,! n=20.! P1! =! baseline,! P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic!Hyperinflation! (DH),! P3b! =! Dynamic! hyperinflation! with! inspiratory! loading! (DH+IR),! P4a! =!HeadFdown!tilt!(HDT),!P4b!=!HeadFdown!tilt!with!inspiratory!loading!(HDT+IR),!P5a!=!Hypoxia,!P5b! =! Hypoxia! with! inspiratory! loading! (Hypox+IR),! P5c! =! Hypoxia! with! IR! and! DH,!(Hypox+DH+IR),! P6! =! Hypoxia! with! IR! and! DH! during! HDT! (All! interventions).! Error! bars!represent!standard!deviation.!*!Denotes!a!significant!change!from!baseline!(P1)!(p<0.05).!! 162!!!Figure!A.11! Changes! to!mean!arterial! pressure! (MAP),! systemic! vascular! resistance! (SVR)! and!peripheral! capillary! oxygen! saturation! (SpO2)! across! all! phases,! n=20.! P1! =! baseline,! P2! =!Inspiratory! loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic! hyperinflation!with! inspiratory! loading! (DH+IR),! P4a! =! HeadFdown! tilt! (HDT),! P4b! =! HeadFdown! tilt! with!inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =! Hypoxia! with! inspiratory! loading!(Hypox+IR),! P5c! =! Hypoxia! with! IR! and! DH,! (Hypox+DH+IR),! P6! =! Hypoxia! with! IR! and! DH!during!HDT!(All!interventions).!Error!bars!represent!standard!deviation.!*!Denotes!a!significant!change!from!baseline!(P1)!(p<0.05).!! 163!Figure!A.12!Changes!in!radius!of!septal!curvature!(RSC)!and!radius!of!LV!free!wall!curvature!(RFWC)!at!end@diastole!(ED)!and!end@systole!(ES)!across! all! phases.! P1! =! baseline,! P2! =! Inspiratory! loading! (IR),! P3a! =! Dynamic! Hyperinflation! (DH),! P3b! =! Dynamic! hyperinflation! with!inspiratory! loading! (DH+IR),! P4a! =! Head@down! tilt! (HDT),! P4b! =! Head@down! tilt! with! inspiratory! loading! (HDT+IR),! P5a! =! Hypoxia,! P5b! =!Hypoxia!with! inspiratory! loading! (Hypox+IR),!P5c!=!Hypoxia!with! IR!and!DH,! (Hypox+DH+IR),!P6!=!Hypoxia!with! IR!and!DH!during!HDT!(All!interventions).!Error!bars!represent!standard!deviation.!*!Denotes!a!significant!change!from!baseline!(P1)!(p<0.05).!! 164!Appendix(B:(Study(Ethics(B.1$Subject$consent$form$(Subject(Information(and(Informed(Consent(!Title( of( Project:( Investigating! the! effect! of! changes! in! intrathoracic! pressure! on!heart5lung! interaction! in! the! presence! of! increased! right! ventricular! afterload,!elevated!lung!volume!and!hypervolemia.!!Principal(Investigator:( Dr.$Neil$Eves,$PhD$$ $ $ $ Associate!Professor!Centre!for!Heart,!Lung!and!Vascular!Health! !University!of!British!Columbia,!Okanagan!Campus!neil.eves@ubc.ca!! ! ! ! (250)!807!9676!!CoAInvestigators:! ! William$Spencer$Cheyne,$BHK!$ $ $ $ MSc!Student!Centre!for!Heart,!Lung!and!Vascular!Health! !University!of!British!Columbia,!Okanagan!Campus!scheyne@alumni.ubc.ca!(250)!212!3387!!!Institution:( ( ( Centre!for!Health,!Lung!and!Vascular!Health!School!of!Health!and!Exercise!Sciences(Faculty!of!Health!and!Social!Development!! ! ! ! University!of!British!Columbia,!Okanagan!Campus!!Contact(Person:( ( Spencer!Cheyne! !! ! ! ! E:!scheyne@alumni.ubc.ca!! ! ! T:!(250)!212!3387!!(((((((((! 165!INTRODUCTION(!You!are!being!invited!to!take!part!in!this!research!study!because!you!are!a!healthy!volunteer!between!the!ages!of!18!to!39!years.!This!study!is!designed!to!investigate!the!effect!of!changes!in!pressure!within!the!chest!cavity!on!how!the!heart!and!lungs!interact! to! regulate! blood! flow.! Additionally,! we! will! be! examining! the! effects! of!increasing!resistance!to!blood!flow!from!the!heart!and!increasing!blood!volume!back!to! the! heart,! and! how! these! factors! impact! the! ability! of! the! heart! to! effectively!pump! blood.! Understanding! these! mechanisms! will! help! us! to! better! understand!human! blood! flow! regulation! and! how! heart! function! changes! in! the! face! of!cardiovascular! disease.! Please! read! the! following! information! carefully! before!deciding!to!participate!in!the!study.!If!you!have!any!questions,!please!do!not!hesitate!to!ask.!!YOUR(PARTICIPATION(IS(VOLUNTARY((Your! participation! is! voluntary.! It! is! important! to! understand!what! is! involved! in!this!study!prior!to!making!a!decision.!Please!read!through!the!following!information!carefully,!and!discuss!it!with!your!family,!friends!and!doctor!before!you!decide.!This!consent! form! will! describe! the! study,! why! the! research! is! being! done,! what! will!happen!to!you!during!the!study,!the!possible!benefits,!risks!and!discomforts.!If!you!wish!to!participate,!you!will!be!asked!to!sign!this!form.!If!you!decide!to!take!part!in!the!study,!you!are!still!free!to!withdraw!at!any!time,!without!providing!any!reason!for!your!decision,!and!without!consequence.!!!WHO(IS(CONDUCTING(THE(STUDY?((This!study!is!primarily!run!by!Dr.!Neil!Eves!(principal!investigator)!in!collaboration!with!Mr.!Spencer!Cheyne.!All!investigators!are!from!the!Centre!for!Heart,!Lung!and!Vascular!Health,!within!the!School!of!Health!and!Exercise!Sciences,!Faculty!of!Health!and!Social!Development,!at!the!University!of!British!Columbia!5!Okanagan!campus.!The! study! will! be! conducted! by! Mr.! Spencer! Cheyne! as! a! requirement! for! his!Master’s!thesis.!!BACKGROUND(!Normal!breathing!results!in!pressure!changes!within!the!chest!cavity,!which!has!an!effect!on!blood!flow!into!and!out!of!the!heart.!Given!that!the!heart!and!lungs!work!together,! the!performance!of!one!system!significantly! impacts! the!other.!When!we!inspire,! the! pressure! being! generated! affects! the! right! and! left! sides! of! the! heart!differently,! resulting! in! a! complex! system!of!mechanisms! that! regulate!blood! flow!out! of! the! heart! and! to! other! organs.! This! interaction! is! further! complicated! by!factors!such!as!the!resistance!imposed!by!the!blood!vessels!on!the!heart’s!ability!to!pump!blood,! and! the!body’s! ability! to! return!adequate!blood!back! to! the!heart.! In!healthy! individuals,! the!breathing!cycle! is!essential! to!maintaining!blood! flow,!and!vessel!resistance!and!return!of!blood!is!optimized!to!ensure!efficient!pumping!of!the!! 166!heart.!The!interaction!of!these!mechanisms!and!how!they!adapt!to!stressors!such!as!low! oxygen! environments! and! increased! blood! volume! is! not! well! understood.!Therefore,! this! study! aims! to! better! understand! how! these! mechanisms! regulate!blood!flow!and!how!these!interactions!change!when!the!body!is!under!stress!or!in!disease!states.!!(WHAT(IS(THE(PURPOSE(OF(THE(STUDY?((The!purpose!of!the!proposed!research!is!to!better!understand!how!heart!function!is!altered! or!maintained! during! changes! to! the! body’s! natural! physiological! balance!(homeostasis).!This!will!be!accomplished!by!manipulating!the!pressures!needed!to!inspire! and! measuring! the! effect! on! blood! flow! into! and! out! of! the! heart.! These!measurements!will! be! repeated! after! imposing! a!physiological! stress! on! the!heart!and!lungs,!namely!artificially!increasing!blood!volume!(by!positioning!the!body!in!a!head5down!tilt),!and!increasing!outflow!from!the!heart!(by!breathing!a!low!level!of!oxygen).!The!results!from!this!study!will!help!to!tease!out!the!complex!mechanisms!governing!human!blood!flow!regulation,!and!provide!a!foundation!for!further!work!into! examining! the! impact! of! how!different! physiological! stressors! affect! how! the!heart!works.!(WHO(CAN(PARTICIPATE(IN(THE(STUDY?((You!are!being!invited!to!take!part!in!this!research!study!because!you!are!a!healthy!volunteer!between!the!ages!of!18!and!39!years.!!!You! should! not! participate! in! the! study! if! you! have! any! history! of! heart! or! lung!disease!(including!asthma,!any!other!respiratory!condition,!diabetes,!blood!pressure!greater! than! 140/90! or! lower! than! 100/90! at! rest,! or! any! heart! condition).!Additionally,! if! you!are!a! current! smoker! (or!have!quit!<!12!months),! if! you!are!a!pregnant! or! nursing! mother,! you! should! not! participate! in! the! study.! If! you! are!overweight! (i.e.! a! if! you! are! a! little! heavy! for! your! height! having! a! body! mass!index>30kg/m2),!you!may!not!be!eligible!for!this!study.!If!you!answer!“yes”!to!any!of!the!PAR5Q!questions,!you!should!not!participate!in!this!study.!It!is!required!that!we!are! able! to! obtain! quality! echocardiographic! images! of! your! heart! for! this! study,!therefore!if!we!are!unable!to!do!so!you!may!be!excluded!from!the!study.!In!the!event!you! volunteer! for! this! study! but! are! excluded! for! one! of! the! above! reasons,! the!rationale!for!our!exclusion!will!be!clearly!explained.!!WHAT(DOES(THE(STUDY(INVOLVE?(!You!will!be!asked!to!visit!the!laboratory!(ART!182)!on!one!occasion.!Your!total!time!commitment!will! be! approximately! 4! hours.!We! ask! that! no! caffeine! or! alcohol! is!consumed,!and!no!exercise! is!performed!within!24!hours!prior! to!each! laboratory!visit.! This! involves! refraining! from!moderate! to! high! intensity! structured! exercise!such!as!running,!cycling,!swimming,!circuit!training!etc.!! 167!Phase(1:(Inspiratory(loading(!Upon! attending! the! lab,! you!will! have! a! small! balloon! tipped! esophageal! catheter!inserted! through! the! nose! and! properly! positioned! in! the! lower! third! of! the!esophagus.! This! procedure! will! be! performed! by! Mr.! William! Cheyne! or! Dr.! Neil!Eves.!After!insertion!of!the!esophageal!catheter,!you!will!be!positioned!comfortably!lying!on!your!left!side.!You!will!be!fitted!with!a!two5way!non5rebreather!mouthpiece!and! asked! to!perform! several! breathing!maneuvers! that!will! be! fully! explained! to!you.!These!breathing!maneuvers!will!allow!us!to!determine!your!peak!lung!volumes!and! airflow.! After! completion! of! the! breathing!maneuvers,! a! trained! sonographer!will! perform! an! echocardiogram! on! you! to! ensure! we! are! able! to! collect! quality!images!of!your!heart.!!You!will!then!be!asked!to!breathe!through!a!resistance!which!makes!it!more!difficult!to!inspire,!forcing!you!to!generate!more!pressure!to!draw!air!in.!You!will!be!asked!to!breathe! through! this! resistance! for! one! minute,! after! which! time! the! trained!sonographer! will! repeat! the! echocardiogram.! After! this,! the! resistance! will! be!removed!and!you!will!be!given!a!55minute!rest!period.!!Phase(2:(Dynamic(Hyperinflation(!After! the!rest!period!a!second!resting!echocardiogram!will!be!performed.!You!will!then!be!asked!to!breathe!out!against!a!resistance!and!voluntarily!increase!your!lung!volume!so!that!you!are!breathing!at!what!you!feel!is!very!close!to!your!maximal!lung!volume!for!1!minute.!You!will!be!asked!to!perform!the!same!breathing!maneuvers!from!Phase!1!so!we!can!determine!your!operational! lung!volumes.!After!you!have!been!breathing!against!this!resistance!for!one!minute,!another!echocardiogram!will!be!performed.!The! resistance! from!phase!1!will! then!be! reapplied! so! that!you!are!breathing! both! in! and! out! against! resistance,! while! also! maintaining! high!operational!lung!volumes.!You!will!be!asked!to!maintain!this!breathing!for!1!minute,!at!which!time!an!echocardiogram!will!be!conducted.!The!breathing!resistances!will!then!be!removed!and!you!will!be!given!a!55minute!rest!period.!(Phase(3:(HeadAdown(Tilt(!A!third!resting!echocardiogram!will!be!conducted!while!you!are!quietly!resting.!You!will!then!be!positioned!in!a!20!degree!supine!head5down!tilt!to!increase!blood!flow!back! to! the! heart.! Immediately! after! being! tilted,! an! echocardiogram! will! be!performed..The!inspiratory!resistance!from!phase!1!will!then!be!reapplied!and!you!will! be! asked! to! breathe! normally! through! this! resistance! for! 1!minute,! at! which!point!another!echocardiogram!will!be!performed.!The!total!duration!of!head5down!tilt!will!be!no!more!than!5!minutes.!Once!all!measurements!have!been!taken!you!will!be!tilted!back!to!a!neutral!supine!position!and!given!a!55minute!rest!period.!!Once!rested,!your!mouthpiece!will!be!connected!to!a!large!reservoir!of!low5oxygen!(12%!O2)!gas,!and!you!will!be!asked!to!breathe!normally!for!30!minutes..!! 168!(Phase(4:(Hypoxia((Following! 30! minutes! of! hypoxic! gas! exposure,! an! echocardiogram! will! be!conducted.! The! inspiratory! resistance! from! the! previous! phases! will! then! be!reapplied!and!you!will!be!asked! to!breathe!normally! through! this! resistance! for!1!minute,! after! which! echocardiographic! measurements! will! be! repeated.! The!expiratory! load!will! then!by!applied!alongside! the! inspiratory!resistance! to!repeat!the! inspiratory5loaded! dynamic! hyperinflation! intervention! from! phase! 2.! An!additional! echocardiogram! will! then! be! performed.! The! resistance! will! then! be!removed,!however!you!will!continue!to!breathe!the!hypoxic!gas!and!will!be!given!a!55minute!rest!period.!(Phase(5:(All(Interventions((After! the! rest!period,! another! resting!echocardiogram!will! be!performed.!You!will!then!be!positioned!in!the!head5down!tilt!from!phase!3,!and!both!the!inspiratory!and!expiratory!resistances! (from!phase!2)!will!be!reapplied.!You!will! then!be!asked! to!breathe!at!as!high!a!lung!volume!as!possible!for!one!minute,!at!which!point!the!final!echocardiogram!will! be! performed.! You!will! then! be! returned! to! a! neutral! supine!position!and! the!mouthpiece!will!be!removed!so!you!may!resume!breathing!room!air!normally!(your!total!time!breathing!hypoxic!gas!will!be!1!hour!maximum).!You!will!then!be!given!a!final!rest!period!for!as!long!as!you!require.!(WHAT(ARE(THE(POSSIBLE(RISKS(AND(DISCOMFORTS?((You!are!asked!to!report!any!unusual!symptoms!during!the!tests.!You!may!stop!any!test!at!any!time!if!you!are!feeling!uncomfortable.!Every!effort!possible!will!be!made!to! minimize! discomfort! and! risk! during! the! tests.! However,! the! following! risks!should!be!considered:!$Ultrasound (Echocardiogram): Ultrasound is a non-invasive, painless technique used for measuring heart function in this study. It poses no risk.  Head-down tilt: Positioning the body in a head-down tilt causes a redistribution of blood from the legs toward the head. Some individuals may experience discomfort in this position, such as feeling a “head rush” or mild headache. Your heart rate and blood pressure will be monitored during the head-down tilt. Short-term head-down tilt does not pose any health risk to healthy individuals.  Hypoxia (breathing low-oxygen gas): The response to hypoxia is highly individual. With the degree of hypoxia being used in this study, you may develop mild symptoms of light-headedness or nausea. You may feel sensations of mild breathlessness or feel you are breathing rapidly. Your oxygen levels will be monitored continuously and the study will be terminated if you feel uncomfortable or your oxygen saturation levels drop below ! 169!75%. Any discomfort with this intervention will reverse within minutes of discontinuing the hypoxic gas.   Breathing against a resistance: Breathing in or out against a resistance and/or breathing at high lung volumes may cause some individuals to feel discomfort. The additional work required of the respiratory muscles may cause you to feel like you are having difficulty breathing, or feel you are not getting enough air. Additionally, breathing deeply or at high lung volumes may cause some individuals to feel mildly light-headed. There are no adverse effects of breathing against inspiratory or expiratory resistances. Your blood pressure, heart rate and oxygen saturation levels will be monitored throughout the protocol and the test will be discontinued if you feel uncomfortable. !!!This(study(should(not(leave(you(with(any(long(term(adverse(effects.(Qualified(technicians(will( be( present( for( all( the( testing( sessions( to( reduce( discomfort(and(monitor(your(condition.($In the unlikely occurrence of a serious adverse event 911 will be called via campus security and if needed cardiopulmonary resuscitation will be performed by a qualified resuscitator. An automated external defibrillator device is accessible through campus security and in an emergency can be at our laboratory within ~2 min. Participants needing emergency care will be taken via ambulance to the KGH which is approximately 15-20 minutes away.  !WHAT(ARE(THE(BENEFITS(OF(PARTICIPATING?(!If!you!agree!to!participate!in!this!study,!there!will!not!be!any!direct!benefit!to!you.!However,!you!will!gain!information!regarding!your!heart!and!lung!function.!!(WHAT(HAPPENS(IF(I(DECIDE(TO(WITHDRAW(MY(CONSENT(TO(PARTICIPATE?(!Your!participation! is!entirely!voluntary,!and!you!may!withdraw!from!this!study!at!any!time!without!providing!reason!for!your!withdrawal.!If!you!enter!the!study!and!decide! to!withdraw! in! the! course! of! the! study,! there!will! be!no!penalty! or! loss! of!benefits!to!which!you!are!otherwise!entitled,!and!your!future!medical!care!will!not!be! affected.! You! do! not! waive! any! rights! by! signing! this! consent! form.! If! you!withdraw!from!the!study,!we!will!use!all!of!your!data!or!information!collected!up!to!the!point!of!your!withdrawal.!By!law,!this!information!cannot!be!deleted.((WHAT(WILL(THE(STUDY(COST(ME?(!Any!parking!or!public!transit!expenses!that!you!incur!specifically!for!the!study!will!be!reimbursed!(upon!presentation!of!receipt)!while!participating!in!the!study.!Other!transportation!i.e.!taxi!will!not!be!covered.!!!! 170!CONFIDENTIALITY:!!Your! confidentiality! will! be! respected.! However,! research! records! and! health! or!other! source! records! identifying! you! may! be! inspected! in! the! presence! of! the!Investigator!or!his!or!her!designate!by!representatives!of! the!UBC!Research!Board!for!the!purpose!of!monitoring!the!research.!No!information!or!records!that!disclose!your! identity!will! be!published!without! your! consent,! nor!will! any! information!or!records! that! disclose! your! identity! be! removed! or! released!without! your! consent!unless!required!by!law.!!You! will! be! assigned! a! unique! study! number! as! a! participant! in! this! study.! This!number!will!not!include!any!personal!information!that!could!identify!you!(e.g.,!it!will!not! include! your! Personal! Health! Number,! SIN,! or! your! initials,! etc.).! Only! this!number! will! be! used! on! any! research5related! information! collected! about! you!during! the! course! of! this! study,! so! that! your! identity! will! be! kept! confidential.!Information! that! contains! your! identity! will! remain! only! with! the! Principal!Investigator!and/or!designate.!The!list!that!matches!your!name!to!the!unique!study!number! that! is!used!on!your! research5related! information!will!not!be! removed!or!released!without!your!consent!unless!required!by!law.!!Your! rights! to! privacy! are! legally! protected! by! federal! and! provincial! laws! that!require!safeguards!to!insure!that!your!privacy!is!respected.!You!also!have!the!legal!right!of!access!to!the!information!about!you!that!has!been!provided!to!the!sponsor!and,! if! need! be,! an! opportunity! to! correct! any! errors! in! this! information.! Further!details!about!these!laws!are!available!on!request!to!your!study!doctor.!(WHAT(IF(SOMETHING(GOES(WRONG?(!By! signing! this! form,! you! do! not! give! up! any! of! your! legal! rights! and! you! do! not!release! the!study!doctor,!participating! institutions,!or!anyone!else! from!their! legal!and! professional! duties.! If! you! become! ill! or! physically! injured! as! a! result! of!participation!in!this!study,!medical!treatment!will!be!provided!at!no!additional!cost!to!you.!The!costs!of!your!medical!treatment!will!be!paid!by!your!provincial!medical!plan!and/or!by!the!study!sponsor.!(WHO(DO(I(CONTACT(IF(I(HAVE(QUESTIONS(ABOUT(THE(STUDY(DURING(MY(PARTICIPATION?(!If!you!have!any!questions!or!require!further!information!about!the!study,!prior!to!or!during!participation,!you!may!contact!Dr.!Neil!Eves!via!email!(neil.eves@ubc.ca)!or!phone! (250! 807! 9676),! or! Spencer! Cheyne! via! email! (scheyne@alumni.ubc.ca)! or!phone!(250!212!3387).!!(((! 171!WHO( DO( I( CONTACT( IF( I( HAVE( ANY( QUESTIONS( OR( CONCERNS( ABOUT( MY( RIGHTS( AS( A(SUBJECT(DURING(THE(STUDY?(!If! you! have! any! concerns! or! complaints! about! your! rights! as! a! research! subject!and/or! your! experiences! while! participating! in! this! study,! contact! the! Research!Participant!Complaint!Line!in!the!University!of!British!Columbia!Office!of!Research!Services!by!e5mail!at!RSIL@ors.ubc.ca!or!by!phone!at!604582258598!(Toll!Free:!15877582258598)!TITLE:! Investigating! the! effect! of! changes! in! intrathoracic! pressure! on! heart5lung!interaction! in! the! presence! of! increased! right! ventricular! afterload,! elevated! lung!volume!and!hypervolemia.!(SUBJECT(CONSENT(TO(PARTICIPATE(!• I have read and understood the subject information and consent form.  • I have had sufficient time to consider the information provided and to ask for advice if necessary.  • I have had the opportunity to ask questions and have had satisfactory responses to my questions.  • I understand that all of the information collected will be kept confidential and that the results will only be used for scientific objectives.  • I understand that my participation in this study is voluntary and that I am completely free to refuse to participate or to withdraw from this study at any time without changing in any way the quality of care that I receive. • I understand that I am not waiving any of my legal rights as a result of signing this consent form. • I will receive a dated and signed copy of this consent form. • I have read this consent form and I freely consent to participate in this study. $SIGNATURES$ ! !  ! ! ! ! !!!Subject’s!Printed!Name! ! ! ! ! Signature!! ! Date!! ! !!!Principal!Investigator/! ! ! ! Signature! ! Date! !Designated!Representative’s!!Printed!Name! !!$ $! 172!B.2$Certificate$of$Ethics$Approval$!! 173!!!!!!

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