Mark Henein Thesis sep.20 page 1-50 - DiVA portal558953/...VI Abstract TheObjectivesofthisthesisare:...

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LEFTATRIALFUNCTIONINHEALTHAND DISEASE MARKHENEIN 2012 DepartmentofPublicHealthandClinicalMedicine Umeå2012

Transcript of Mark Henein Thesis sep.20 page 1-50 - DiVA portal558953/...VI Abstract TheObjectivesofthisthesisare:...

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LEFT�ATRIAL�FUNCTION�IN�HEALTH�AND��DISEASE�

MARK�HENEIN�

2012�

Department�of�Public�Health�and�Clinical�Medicine�Umeå�2012�

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Responsible�publisher�under�swedish�law:�the�Dean�of�the�Medical�Faculty�This�work�is�protected�by�the�Swedish�Copyright�Legislation�(Act�1960:729)�Copy�right�2012�by�Mark�Henein�New�Series�No�:�1523�ISBN�:978�91�7459�4829�ISSN:�0346�6612���������������������������������������������������

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����������

��������

This�Thesis�Is�Dedicated�To�

�My�Dearest�Brother�Michael�

And�To�The�Spirits�Of�My�Mom�And�Dad.�

�������������������������������������

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Table�of�Contents�Table�of�Contents�...........................................................................................�IV�Abstract�.........................................................................................................�VI�List�of�Papers�...................................................................................................�X�Abbreviations�.................................................................................................�XI�Permissions�..................................................................................................�XIII�Introduction�....................................................................................................�1�

Anatomy�of�the�Left�Atrium�..............................................................................�1�Gross�Anatomy�..............................................................................................�1�Histology�.......................................................................................................�4�����Fibre�Structures�and�Architectures�............................................................�4�

��������������Interatiral�Relationship�..............................................................................�4���������������Left�Atrial�–�Left�Ventraicular�Intimate�Relationship�.................................�5�

Physiology�.........................................................................................................�6�Left�Atrial�Function�........................................................................................�6�Pathophysiology�of�Left�Atrial�Mechanical�Function�.....................................�6�Atrial�Electrical�Function�...............................................................................�9�����P�wave�.......................................................................................................�9�����P�R�Interval�................................................................................................�9�Atrial�Electromechanical�Delay�...................................................................�10�Common�condition�affecting�Left�Atrial�function�.......................................�11�����Exercise�....................................................................................................�11�����Atrial�Fibrillation�......................................................................................�12�����Distension�of�Cardiac�Chambers�and�Cardiopulmonary�Baroreceptors�...�13�Intracardiac�Pressures�.................................................................................�13�����LA�Emotying�Function�(LV�Filling)�............................................................�13�����LA�Vol�Measurments�................................................................................�16�����

Pathology.........................................................................................................�18�Atrial�Stunning�.............................................................................................�18�Atrial�Paralysis�.............................................................................................�19�

Echocardiography�............................................................................................�19�Assessment�of�Left�Atrial�Structure�and�Function�.......................................�20�����Left�Atrial�Measurments�..........................................................................�20�����Left�Atrial�Myocardial�Function�...............................................................�22�

Aims�..............................................................................................................�23�Materials�and�Methods�.................................................................................�24�

Study�Populations�...........................................................................................�24�Study�I�.........................................................................................................�24�Study�II�........................................................................................................�24�Study�III�.......................................................................................................�25�

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Study�IV�.......................................................................................................�25�Methods�Used�.................................................................................................�25�

Study�I�.........................................................................................................�25�Study�II�........................................................................................................�26�Study�III�.......................................................................................................�27�Study�IV�.......................................................................................................�28�

Echocardiographic�Techniques�used�in�clinical�practice�................................�30�M�mode�Echocardiography�.........................................................................�30�Myocardial�Doppler�Imaging�.......................................................................�32�Limitation�of�TDI�..........................................................................................�34�

Assessment�of�Left�Atrium�and�Appendage�Function�by�TDI�........................�34�Application�in�this�thesis�.............................................................................�36�

Speckle�Tracking�Echocardiography�...............................................................�37�Speckle�Tracking�Measurements.................................................................�38�Strain�...........................................................................................................�38�����Advantage�of�STE�.....................................................................................�40�����Limitations�of�STE�....................................................................................�40�����Application�in�this�thesis�..........................................................................�41�Strain�Rate�...................................................................................................�42�����Speckle�Tracking�Images�in�Normals�.......................................................�43�

Other�Echocardiographic�Techniques�.............................................................�45�Color�flow�Doppler�Ultrasound�...................................................................�45�Continous�Wave�Doppler�Ultrasound�.........................................................�45�Spectral�Doppler�Ultrasound�.......................................................................�47�Contrast�Enhanced�Ultrasound�...................................................................�47�

MRI�for�Assessing�LA�Structure�and�Function�................................................�47�Statistics�.......................................................................................................�49�Main�findings�................................................................................................�51�Results�..........................................................................................................�53�Discussion�.....................................................................................................�78�Limitations�....................................................................................................�83�Conclusion�....................................................................................................�85�Acknowledgments�.........................................................................................�86�References�....................................................................................................�88�Full�Version�of�the�papers�............................................................................�104�

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Abstract��The�Objectives�of�this�thesis�are:�

1)�To� study�possible�atrial� interaction� in�patients�with� right�and� left�ventricular� outflow� tract� obstruction� due� to� significant� pulmonary�(PS)�and�aortic�valve�stenosis�(AS),�respectively.�

2)� To� assess� left� atrial� (LA)� intrinsic� myocardial� function� and� its�relationship� to� indirect� measures� of� left� ventricular� (LV)� filling�pressures�in�patients�with�paroxysmal�atrial�fibrillation�(PAF).�

3)�To�test�the�hypothesis�that�the�LA�function�is�affected�in�patients�with�pulmonary�arterial�hypertension�(PAH).�

4)� To� test� the� hypothesis� that� raised� LA� pressure� as� shown� by�pulmonary�capillary�wedge�pressure�(PCWP)�correlates�with�severity�of�LA�intrinsic�systolic�function.�

We�conducted�4�studies�to�achieve�the�objectives�above.�

Study�I��

Methods:�We� studied� 41� PS� patients� (age� 36±10� year)� and� 41� AS�patients�(age�35±12�year)�and�compared�them�with�27�controls�(age�30±7� year).� RV� and� LV� filling� were� recorded� by� conventional� PW�Doppler.�Biventricular�segmental�function�was�studied�using�the�PW�tissue�Doppler�imaging�(TDI)�and�M�mode�techniques.�

Results:� The� 2� patient� groups� had� similar� degree� of� ventricular�outflow� tract� obstruction.� In� the� pressure�overloaded� ventricle,�global� systolic� function� was� preserved� but� long� axis� function� was�impaired.�Patients�had�higher�peak� late�filling�(A�wave)�and�TDI� late�diastolic�(a’)�velocities�recorded�in�the�disease�free�ventricles�despite�having� similar� peak� early� filling� velocities� (E� wave),� E� wave�deceleration� time� and� E/e’� ratios� were� not� different� from� controls�(p>0.05� for� all).� The� accentuation� of� atrial� activity� (A� wave)� was�

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moderately� correlated�with� the� degree� of� contra� lateral� ventricular�outflow�tract�obstruction�(p<0.001�for�both).��

Conclusion:�In�the�pressure�overloaded�ventricle�long�axis�function�is�more� sensitive� than� global� function� in� revealing� myocardial�dysfunction.� The� increased� contra� lateral� atrial� systolic� activity�suggests�an�evidence�for�atrial�interaction�in�the�form�of�‘Cross�Talk’.�

Study�II�

Methods:� Twenty�five� PAF� patients� (age� 68±7� year,� 10� males)� with�Doppler� signs� of� raised� filling� pressures� were� studied� using� speckle�tracking� echocardiography� and� compared� with� 21� controls.� LA�segmental� longitudinal� strain� (S),� strain� rate� (SR)� and� myocardial�velocities�during�atrial�systole�were�measured�as�were�LA�longitudinal�and� transverse� diameters.� Markers� of� LV� filling� pressures� were� E/A�and�E/e’.��

Results:� LA� longitudinal� diameter�was� larger� in� patients� (5.5±0.6� vs.�4.8±0.6�cm,�p<0.01)�and�global�LA�S�and�SR�were�reduced�(p<0.05�for�both)� and� correlated�with�E/A� (r=0.52�and� r=0.43,�p<0.05� for�both).�LA� segmental� S� and� SR� were� uniformly� reduced� compared� with�controls�(p<0.05�for�all)�and�also�correlated�with�E/A�(p<0.05�for�all).�LA�myocardial� velocities� (TDI)�were�highest�at� the�annular� level�and�lowest�at�the�rear�in�both�patients�and�controls�(p<0.01�for�all),�with�the� absolute� values� at� each� level� not� different� between� groups.�Myocardial� velocities� negatively� correlated� with� E/A� at� the� annular�level� only� in� patients� (septal:� r=�0.52;� lateral:� r=�0.62,� p<0.01� for�both).�

Conclusion:� In�PAF�patients,�LA�systolic�function�is�suppressed�and�is�directly� related� to� the� raised� filling� pressures.�While� intrinsic� global�and� segmental� function� can� reproducibly� be� studied� by� S� and� SR,�myocardial� velocities� reflect� only� regional� motion.� These� findings�provide� a� sound� explanation� to� the� known� beneficial� effect� of�vasodilators�in�PAF�patients.��

��

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Study�III�

Methods:�We� studied� LA� size� and� reservoir� function� in� 35� patients��(age�63±15�years,�16�male)�with�idiopathic�PAH�using�speckle�tracking�echocardiography� who� also� underwent� right� heart� catheterization�simultaneously� to� assess� pulmonary� artery� systolic� pressure,� and�compared�them�with�27�age�and�gender�normal�controls.��

Results:� In�PAH�patients,�LA� longitudinal�diameter�was�not�different�from� controls� but� transverse� diameter� was� reduced� (3.0±0.6� vs.�3.7±0.5�cm,�p<0.001).�LA�lateral�wall�strain�rate�(SR)�during�LV�systole�(atrial�reservoir�function)�was�reduced�at�annular�(p<0.001)�and�mid��cavity� (p<0.01)� levels� as� were� septal� segments� (p<0.03,� for� both)�compared� to� controls.� Opposite� to� controls,� the� two� LA� walls�responded� differently� to� right� heart� pressures.� Lateral� SR� inversely�correlated�with� pulmonary� artery� systolic� pressure� (PASP)� (annular:�r=�0.45,�p<0.005�and�mid�cavity:� r=0.43,�p<0.01),�but�not�with� right�atrial�pressure�(RAP).�In�contrast,�septal�SR�inversely�correlated�with�RAP� (annular:� r=�0.39,� p=0.02� and� mid�cavity:� r=�0.38,� p=0.03)� but�not�with�PASP.�

Conclusion:�In�patients�with�PAH,�LA�reservoir�function�is�significantly�impaired� showing� reduced� myocardial� strain� rate� properties.� In�addition,�segmental� function�differs� in�their�response�to�raised�right�heart� pressures�with� the� septal�wall� related� to� right� atrial� pressure�and� lateral� wall� related� to� the� PASP.� These� findings� suggest� an�evidence� for� atrial� interaction� in� PAH,� which� is� likely� to� have�significant�impact�on�LV�performance.��

Study�IV��

Methods:�We�studied�46�patients,�mean�age�61�±13�years,�17�males,�of� various�etiologies�with�exertional�breathlessness�who�underwent�right� heart� catheterization� and� simultaneous� transthoracic� Doppler�echocardiography�using�spectral,�tissue�Doppler�and�speckle�tracking�echocardiography�techniques�for�assessing�LA�structure�and�function.��

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Results:�PCWP�correlated�with�direct�measurements�of�LA�structure�and� function:� LA� volume� (r=� 0.43,� p<0.01),� LA� global� systolic� strain�rate� (r=0.79,� p<0.001)� and� to� a� lesser� extent�with� LA� systolic� filling�fraction� (r=0.52,� p<0.001).� PCWP� also� correlated� with� indirect�measures� of� LA� pressure:� LV� E/A� (r=0.66,� p<0.001),� E� wave�deceleration� time� (r=0.54,� p<0.001),� lateral� E/e’� (r=0.49,� p<0.001)�and�LV�isovolumic�relaxation�time�(r=0.36,�p<0.01).�LA�strain�rate�was�78%�sensitive�and�84%�specific�in�identifying�patients�with�PCWP�>�15�mm�Hg,�having�accurately�predicted�PCWP�in�63�%�of�the�cases.���

Conclusion:�PCWP�correlates�with�LA�intrinsic�systolic�function�and�to�a� much� lesser� degree� with� indirect� Doppler� measures� of� raised� LV�filling� pressures.� These� findings� should� have� significant� clinical�implications� in� identifying� breathless� patients� with� raised� LA�pressure.�

�����������������

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List�of�papers�This�thesis�is�based�on�the�following�papers.�They�are�referred�to�by�their� Roman� numerical� and� the� papers� are� in� their� full� format�included�as�appendices�at�the�end�of�this�thesis.�

I.� Atrial� interaction� in� the� form� of� ‘cross� talk’� in� patients� with�ventricular� outflow� tract� obstruction� Mark� Henein� ,� Yat�Yin� Lam� ,�Anders�Waldenström� ,� Michael� Y.� Henein.� Int� J� Cardiol� 147� (2011)�388–392�

II.� Disturbed� Left� atrial� mechanical� function� in� paroxysmal� atrial�fibrillation:� A� speckle� tracking� study.� Mark� Henein,� Ying� Zhao,�Michael�Y.�Henein,�Per�Lindqvist.�Int�J�Cardiol�2012;�155:437�41�

�III.� Left� atrial� function� in� idiopathic� pulmonary� hypertension.� Mark�Henein,� Gani� Bajraktari,� Stefan� Söderberg� ,� PhD,�Michael� Y�Henein,��Per�Lindqvist.�Submitted.���IV.� Left� atrial� strain� rate� using� speckle� tracking� echocardiography�during� atrial� systole� in� estimation� of� Pulmonary� Capillary� Wedge�Pressure:� A� Simultaneous� Echocardiography� and� Cardiac�Catheterization� Study.� Mark� Henein,� Stefan� Söderberg,� Manuel�Gonzalez,� Erik� Tossavainen,� Michael� Y� Henein� and� Per� Lindqvist.�Submitted.���

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Abbreviations�AF��� Atrial�fibrillation�

PAF�� Paroxysmal�atrial�fibrillation�

STE� Speckle�tracking�echocardiography�

LA�� Left�atrium�

LV� Left�ventricle�

RV�� Right�ventricle�

RA�� Right�atrium�

TDI�� Tissue�Doppler�Imaging�

AS��� Aortic�stenosis��

MV� Mitral�valve�

EF�� Ejection�fraction�

SV� Stroke�volume�

CO� Cardiac�output�

ECG� Electrocardiogram�

HR� Heart�rate�

S�� Strain�

SR� Strain�rate�

s,�Sm’������������������ Peak�velocity�during�systole�

e’,�Em������������������ Peak�velocity�in�early�diastole�

a’,�Am����������������� Peak�velocity�during�atrial�systole�

E/A� Ratio�of�E�and�A�velocity�

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BNP� Brain�natriuretic�peptide��

ROI�� Region�of�interest�

MRI�� Magnetic�resonance�imaging�

FT� Filling�time�

LAESV�� Left�atrial�end�systolic�volume�

LAEDV� Left�atrial�end�diastolic�volume�

SA�node� Sino�atrial�node�

AV�node�� Atrio���ventricular�node�

MI�� Myocardial�infarction�

PAH�� Pulmonary�arterial�hypertension�

IPAH� Idiopathic�pulmonary�arterial�hypertension�

AVC��� Aortic�valve�closure�

AVO�� Aortic�valve�opening�

LAVmax� Maximum�left�atrial�volume�

LAVmin� Minimum�Left�atrial�volume�

LAVpreA� Pre�atrial�contraction�left�atrial�volume�

MVC� Mitral�valve�closure�

PS� Pulmonary�Stenosis�

PW� Pulse�Wave�����

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Permissions�

Figures� and� graphs� in� the� introduction� and� method� sections� were�reproduced�by�permission�from�the�following�publishers:��

�� BMJ�Group,�Ltd.��� Elsevier��� Oxford�University�Press��� Wiley�Liss�,�Inc.��� BioMed�Center�

�Figure� 1.� Ke� Wang.� Architecture� of� atrial� musculature� in�Humans.�Eur�Heart�J�supplements�2000;�Vol.2�(suppl�K):K4�K8.��Fig�5.�By�permission�of�Rights�Link�on�behalf�of�BMJ�Group�Ltd.�

Figure�2�and�3.�Ho�SY,�Sánchez�Quintana�D.�The�importance�of�atrial� structure� and� fibers.� Clin.� Anat.� 2009� Jan;� 22(1):52�63.�Fig�3�and�7.�By�permission�from�Rights�Link�on�behalf�of�Wiley�Liss,�Inc.�

Figure� 4.� Left� atrial� longitudinal� strain� by� speckle� tracking�echocardiography� correlates� well� with� left� ventricular� filling�pressures� in� patients� with� heart� failure.� Cardiovasc�Ultrasound.�2010�Apr�21;�8:14.�Fig�1.�By�permission�from�the�author.�

Figure�8.�Mori�M.�et�al.�Impact�of�reduced�left�atrial�function�on� diagnosis� of� paroxysmal� atrial� fibrillation:� result� from�analysis�of�time��left�atrial�volume�curve�determined�by�two�dimensional�speckle�tracking�J�Cardiol.�2011�Jan;�57(1):89�94.��Fig�2.�By�permission�from�Rights�Link�on�behalf�of�Elsevier.�

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Figure�14.�Mandillo�S.�et�al.�Early�Detection�of�left�atrial�strain�abnormalities�by�speckle�tracking�in�hypertensive�and�diabetic�patients�with�normal� Left�Atrial� Size.� J�Am�Soc�Echocardiogr.�2011� Aug;� 24(8):898�908.� Fig� 1.� By� permission� from� Rights�Link�on�behalf�of�Elsavier.�

Figure�15�and�17.�Shih�JY.�et�al.�Association�of�decreased�left�atrial� strain� and� strain� rate� with� stroke� in� chronic� atrial�fibrillation.� J� Am� Soc� Echocardiogr.� 2011� May;� 24(5):513�9.��Fig� 1� and� 2.� By� permission� from� Rights� Link� on� behalf� of�Elsevier.���

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Introduction�

Anatomy�of�the�Left�Atrium��Gross�Anatomy��For� decades� anatomy� text� books� tended� to� focus� on� the� ventricles�because�of�their�important�role�as�pumping�chambers.�The�two�atria�have� long� been� looked� at� as� collecting� chambers,� or� even� just�conduits�for�blood�to�get�through�to�the�ventricles,�hence�attracted�less� interest� for� studying� them.� Thanks� to� non�invasive� imaging�techniques,�detailed�assessment�of�the�right�and�left�atrium,�in�terms�of� structure,� anatomical� relations� as� well� as� function� has� been�allowed.����The�left�atrium�is�located�in�the�mid�line�of�the�body�plane�and�is�the�most�posterior�of�the�cardiac�chambers.�It�lies�directly�adjacent�to�the�esophagus�in�the�bifurcation�of�the�trachea�[1]�and�is�separated�from�the� two� by� fibrous� pericardium.� With� the� plane� of� the� interatrial�septum�oblique,� from�anterior� to�posteriorly� rightward,� it�makes�an�angle�of�approximately�65°�to�the�sagital�plane�[2].�This�angle�makes�part� of� the� right� atrium;� the� ascending� aorta� and� the� pulmonary�trunk�overlie�the�anterior�of�the�left�atrium.�The�left�atrial�appendage�is�anteriorly� seen�around� the�side�of� the�pulmonary� trunk,�with� the�coronary�sinus�passing�from�superior�to�inferior�closely�related�to�the�back.�

��Figure�1.��Atria�viewed�from�above�after�removal�of�epicardium�showing�the�circumferential�muscle�connecting�the�back.��

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The� left� atrium� links� the� pulmonary� venous� circulation� to� the� left�ventricle,� thus� allows� oxygenated� blood� coming� back� from� the�pulmonary� circulation� to� pass� through� to� the� left� ventricle� [2].� The�inlet�of�the�LA� is�made�of�the�four�pulmonary�veins�and� its�outlet� is�made� of� the� mitral� valve� apparatus.� The� lower� end� of� the� LA� is�connected� to� the� left� ventricular� myocardium� through� the� mitral�valve�apparatus�and�the�mitral�annulus.�It�is�also�related�outwardly�to�the�structures�passing�in�the�left�atrioventricular�groove,�namely�the�coronary� sinus� and� the� circumflex� coronary� artery.� However,� the�coronary�sinus�does�not�always�run�parallel�to�the�mitral�annulus�or�mitral�orifice.���The� left�atrium� is� separated� from�the� right�atrium�by� the� interatrial�septum�which�consists�mainly�of�the�flap�valve�of�the�oval�fossa.�It�is�only�the�immediate�circumference�of�the�fossa�and�its�floor�that�is�a�muscular� interatrial� structure.� The� fossa� has� a� well� marked� rim� of�muscle.� The� inferior� part� of� the� rim,� known� as� the� sinus� septum,�separates� the�orifice�of� the�coronary� sinus� from� that�of� the� inferior�caval�vein.�The�tendon�of�Todaro�courses�through�this�area�from�the�zone�of�fusion�between�the�fibromuscular�valve,�guarding�the�orifice�of�the�inferior�caval�vein�(the�Eustachian�valve)�and�the�orifice�of�the�coronary� sinus� (the� Besian� valve).� The� sinus� septum� is� continuous�anteriorly� with� the� atrioventricular� muscular� septum,� the� atrial�component�of�which� forms� the� surface�of� the� triangle�of�Koch.� The�wall�of�the�anterior�portion�of�the�septal�aspect,�known�as�the�aortic�mound,�lies�immediately�behind�the�aortic�root�[3].��The� left� atrium� is� described� as� having� three� components,� venous,�appendage�and�vestibule.�The�venous�component�of�the�left�atrium�is�larger�than�the�appendage.�The�pulmonary�veins�are�usually�arranged�two� to� each� side;� they� enter� this� pouch� superiorly,� with� the� left�venous� orifices� at� slightly� higher� level� than� those� of� the� right.� The�right� upper� pulmonary� vein� courses� posterior� to� the� superior� caval�vein� at� its� junction� with� the� right� atrium,� whereas� the� right� lower�pulmonary�vein�passes�behind� the� intercaval�area.�The� left� superior�caval� vein� courses� between� the� left� appendage� and� left� pulmonary�veins�to�enter�the�coronary�sinus�that�runs�along�the�inferior�wall�of�

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the�left�atrium�in�the�atrioventricular�groove;�this�is�the�oblique�vein�of�the�left�atrium�which�drains�to�the�coronary�sinus.��The� anterior� wall� of� the� left� atrium� lies� behind� the� transverse�pericardial�sinus�which�in�turn�is�immediately�behind�the�aortic�root.�The�postero�inferior�wall�of�the�LA�is�close�to�the�coronary�sinus,�with�its� continuation,� the� great� cardiac� vein� runs� along� the� epicedial�aspect�of�it.�Normally�there�are�no�clear�demarcations�between�atrial�and� venous� walls.� The� superior� wall� is� most� substantial� with�transmural�thickness�of�4�6�mm�significantly�thicker�than�the�anterior�wall.�Inwardly,�the�endocardial�surface�of�the�LA�is�smoother�than�the�right� atrium�and� it� lacks� the�prominent� ridges� that� characterize� the�right� atrium.� The� LA� lacks� the� terminal� crest� (crista� terminalis)� and�rough� surface� of� pectinate� muscles� that� characterizes� the� right�atrium.� In� contrast,� the� pectinate� muscles� are� exclusively� confined�within� the� atrial� appendage.� They� form� a� complicated� network� of�muscular�ridges�and�the�narrow�ostium�of�the�appendage�marks�the�division�between�the�rough�and�smooth�walls�[4].�

�Figure�2.�Anatomical�section�showing�nearly�parallel�arrangement�of�the�pectinate�muscles�and�shows�a�variation�with�fan�like�arrangement�and�many�criss�cross�branches.���

The�vestibular�component�of�the�LA�is�the�lower�circumferential�area�leading� to� the� orifice� of� the�mitral� valve,�which� is� characterized� by�smooth� and� thin� wall,� tapering� as� it� adjoins� the� mitral� valve.� The�posterior�aspect�of�the�vestibule�is�directly�adjacent�to�the�wall�of�the�coronary�sinus.�The�LA�myocardium�in�the�distal�part�of�the�vestibule�overlaps� the� atrial� part� of� the� tricuspid� and� mitral� valve� leaflets,�however�it�is�electrically�isolated�from�ventricular�myocardium�by�the�fibro�fatty�tissue�at�the�hing�line�of�the�mitral�valve�(mitral�annulus).�

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Histology���Fiber�structure�and�architecture��The� wall� of� the� left� atrium� is� composed� of� overlapping� layers� of�differently�aligned�myocardial�fibers.�Local�variations�in�arrangement�are�frequently� found�but�a�common�overall�pattern� is�seen� in�many�cases.� The� subepicedial� or� superficial� fibers� tend� to� run�circumferentially� and� parallel� to� the� atrioventricular� groove.�Bachmann’s� bundle� is� the� interatrial� bundle� that� can� be� traced�rightward�to�the�junction�between�the�right�atrium�and�the�superior�caval�vein.�It�reinforces�the�integral�with�the�circumferential�fibers�of�the� anterior� wall.� It� is� jointed� inferiorly� by� fibers� arising� from� the�anterior� rim� of� the� oval� fossa.� Superiorly,� it� blends�with� fibers� that�arise�from�the�antero�superior�part�of�the�septal�raphe�[1�&�2].��The�circumferential�fibers�pass�to�either�side�of�the�neck�of�the�atrial�appendage�and�reunite�on�the�lateral�wall�and�posterior�wall�to�enter�the�posterior�septal�raphe.�Frequently,�small�tongues�of�fibers�extend�over� the� wall� of� the� coronary� sinus.� The� superior� wall� is� usually�composed�of� longitudinal� fibers� that� arise� from� the�antero�superior�septal� raphe� beneath� the� circumferential� fibers.� At� the� insertion� of�the� pulmonary� veins,� these� fibers� tend� to� encircle� them� or� pass�obliquely�to�either�side.��Interatrial�relationship���The� longitudinal� atrial� fibers� pass� over� the� dome� to� the� posterior�wall,� and� they� bifurcate� to� become� two� oblique� bundles.� The�leftward�branch�blends�with�the�circumferential�fibers�of�the�anterior�and�lateral�walls�while�the�rightward�branch�turns�into�the�posterior�septal� raphe.� Some� fibers� from� the� rightward� branch� may� extend�across�to�the�right�atrium�[4].��The�arrangement�of� subenocardial�or�deep� fibers� shows�a� common�pattern.� The� fibers� of� the� anterior� wall� are� predominantly� oblique,�taking�origin�from�the�anterior� interatrial� raphe�and�combining�with�

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oblique�fibers�arising�from�the�vestibule.�Fibers�encircle�the�mouth�of�the�appendage�and�loop,�or�branch,�to�follow�the�arrangement�of�the�pectinate� muscles� inside� the� appendage.� And� at� the� orifice� of� the�pulmonary�veins�the�fibers�are�usually�seen�as� loop�–� like�extension�from�the�longitudinal�fibers.��

�Figure�3.�A�heart�dissection�showing�the�subepicardial�myoarchitecture�of�the�atria�viewed����������������������from�the�front.�Also�myofibers�of�bachmann’s�bundle�(BB)�and�the����������������������septopulmonary�������bundle�(SP).����

Left�Atrial�–�Left�Ventricle�Intimate�Relationship��

The� left�atrium� is�anatomically� related� to� the� left� ventricle�with� the�outlet�of�the�LA�(the�mitral�valve)�is�the�inlet�of�the�left�ventricle.�The�most� active� region� of� the� left� ventricle� (basal� component)� is� the�closest� to� the� most� active� compartment� of� the� left� atrium� (apical�part).� Furthermore,� the� mitral� annulus� serves� as� an� important�insertion� structure� for� longitudinal� left� ventricular� and� left� atrium�myocardial� fibers.� In� view� of� this� intimate� anatomical� relationship�between�the�two�chambers,�they�interact�functionally�with�systole�of�one�and�diastole�of�the�other,�i.e.�with�longitudinal�shortening�of�LV�long�axis,� the�mitral� annulus�moves� towards� the�apex�enlarging� the�cavity� of� the� LA,� reducing� its� pressure� and� allowing� a� significant�volume� of� blood� to� enter� from� the� pulmonary� veins.� The� two�chambers� are� also� electrically� related� with� atrial� depolarization� (P�wave)� preceding� ventricular� depolarization� (QRS)� with� the�intercavitary�conduction�time�(PR�interval)�optimally�adjusted.�In�fact,�loss� of� such� close� electrical� relationship� results� in� significant�functional�disturbances,�e.g.�complete�heart�block,�which�might�have�drastic�clinical�consequences.�

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PHYSIOLOGY��Left�Atrial�Function���Left�atrial� (LA)� function� is�normally� in�a�close� interdependence�with�left�ventricular�(LV)�function,�and�it�plays�a�key�role�in�maintaining�an�optimal�cardiac�performance.�The�LA�modulates�LV�filling�through�its�reservoir,� conduit� and� systolic� pump� function,�whereas� LV� function�influences�LA�function�throughout�the�cardiac�cycle.�The�LA�acts�as�a�reservoir�during�ventricular�systole,�as�a�conduit�(for�blood�from�the�pulmonary�veins�to�the�left�ventricle)�during�early�diastole,�and�as�an�active�pumping�chamber�that�augments�left�ventricular�filling�in�late�diastole.�The�LA�is�sucking�blood�to�fill�its�cavity�in�early�systole�of�the�succeeding�cycle�[5].��The� LA� pressure� abnormally� increases� in� significant� mitral� valve�diseases� and� reacts� to� increased� left� ventricular� diastolic� pressures�(e.g.� stiff� cavity)� in� patients� with� ventricular� diseases,� e.g.� long�standing�hypertension.� In�patients�with�remodelled�LV�and�impaired�overall� function,� the� left� atrium� dilates� and� also� remodels,� despite�that�it�augments�its�contractile�function�in�order�to�secure�LV�filling�in�patients� with� impaired� relaxation.� In� more� advanced� LV� disease�states,� the� left� atrium� secures� filling� of� the� left� ventricle� on� the�expense�of�raising�its�pressure�(LV�filling�pressure)�[6].���Pathophysiology�of�Left�Atrial�Mechanical�Function��Left�atrial� function�analysis� can�be�achieved�by�detailed�assessment�of� its�phasic�response�to�changes�in�the�overall�cardiac�performance�in�different�phases�of�the�cardiac�cycle,�including�various�components�of�systole�and�diastole.��

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.� �Figure�4.�Measurement�of�peak�atrial�longitudinal�strain�(PALS)�from�apical�two�chamber���������������������view.�The�dashed�curve�represents�the�average�atrial�longitudinal�strain�along����������������������the�cardiac�cycle.�(AVC,�aortic�valve�closure)���������������������A)� During� LV� systole� and� isovolumic� relaxation� phase,� the� LA�functions� as� a� reservoir,� receiving� blood� from� the� pulmonary� veins�and�storing�energy�in�the�form�of�pressure.�This�part�of�atrial�function�is�modulated�by�three� factors,�mainly�LV�systole�and�the�descent�of�the� LA� base� during� systole,� by�moving� the�mitral� valve� ring� toward�the� cardiac� apex,� increasing� LA� capacity� as� its� floor� moves�downwards.� The� LA� volume� increases,� the� LA� pressure� falls,� and�blood�is�drawn�into�the�LA�from�pulmonary�veins�[5�&�7].���This�phase�is�also�controlled�by�the�right�ventricular�systolic�pressure�transmitted�through� the� pulmonary� circulation� to� the� left� atrium,� and� by� LA�intrinsic�myocardial�properties�(relaxation�and�chamber�compliance).��B)� During� early� diastole� ’E’� wave� and� the� diastasis� phase� of� the�cardiac�cycle,�the�LA�again�functions�as�a�conduit�with�blood�passing�directly�from�the�pulmonary�veins�into�the�left�ventricle�through�the�opened�mitral� valve,� and�when� the�mitral� ring� returns� back� to� the�base� of� the� heart� resulting� in� blood� entering� the� LV� [5� &� 7]� via� the�small�pressure�gradient�during�early�diastole�between�the�LA�and�the�left�ventricle.��The�main�determinant�of�this�component�of�LA�conduit�function� is� the�diastolic� intrinsic� properties�of� the� left� ventricle� and�the�extent�of� its�relaxation�abnormalities.�Also,� in�patients�with�stiff�left� ventricle� and� raised� LA� pressure,� the� high� pressure� gradient�

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between� the� two� chambers� contributes� to� the� LV� filling� velocities,�blood�acceleration�and�deceleration�[6].��C)�In�late�ventricular�diastole�(atrial�systole)�‘A’�wave�following�the�P�wave� of� the� ECG,� the� LA� functions� as� a� pump,� contracting� and�ejecting� blood� into� the� left� ventricle� to� augment� its� overall� stroke�volume� by� approximately� 20�30%.� In� normal� young� subjects� and�substantially�more�than�that�percentage�in�healthy�older�subjects�and�in� the� presence� of� impaired� LV� relaxation,� LA� pump� function� is�controlled� by� the� LV� compliance� and� LV� end�diastolic� pressure;� the�lower�the�cavity�compliance,�the�more�compromised�is�the�volume�of�blood�pumped�by�the�LA�in�late�diastole�[5�&�7].��It�must� be�mentioned� that� the� Frank�Starling�mechanism� has� been�shown� to� apply� to� the� LA,� with� its� output� increasing� as� the� cavity�diameter� increases,� in� an� attempt� to� maintain� a� normal� stroke�volume.� In� contrast,� LA� contractile� function�usually�decreases�when�the� cavity� is� severely� dilated� and� when� the� optimal� Frank�Starling�relationship� is� exceeded� [5].� Atrial� systole� ‘A’�wave� is� dominated�by�the�contraction�of�the�pectinate�muscle�and�movement�of�the�mitral�valve� annulus� towards� the� rear� of� the� LA.�While� contraction� of� the�circumferential�muscle� bundles� result� in� a� backward�motion� of� the�aorta,�both�contribute�to�the�decrease�in�the�LA�volume.�At�the�same�time�the�associated�development�of�tension�in�the�LA�wall,�increases�pressure� within� the� cavity,� which� generates� an� atrioventricular�pressure�gradient�and�hence�the�‘A’�wave�flow.�In�general,�left�atrial�systolic�function�is�affected�by�the�following�factors:���1.�The�force�of�myocardial�fiber�length�according�to�the�Frank�Starling�mechanism�[8].�2.�The�afterload�which�becomes�the�major�determinant�of�LA�ejection�fraction.��3.�Autonomic�nervous�system,�which�exhibit�a�positive�intropic�effect�via� catecholamine� release,� activating� the� beta1� and� beta2�adrenoreceptors,� or� negative� intropic� effect� via� the� muscarinic�receptors�[9].�4.�The�renin�angiotesinogen�system,�via�angiotesin�I�and�angiotesin�II.�This�positive�intropic�effect�is�mediated�by�the�AT1�receptors�[10].�

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The� above� four� factors� also,� affect� the� LV� function� in� a� similar�fashion.��

�����������������������Figure�5.��Frank�Starling�curve�showing�the�change�in�LA�volume�with�change�in�pressure.������

�Atrial�Electrical�Function��P�Wave��

The� electrocardiogram� displays� P� wave� which� reflects� the� normal�atrial�depolarization.�The�main�electrical�vector� is�directed� from�the�senatorial� (SA)� node� towards� the� atrioventricular� (AV)� node,� and�spread� from� the� right� atrium� to� the� left� atrium.� An� absent� P�wave�may� indicate� non�sinus� node� activation� or� atrial� fibrillation� or� SA�block.� While� increased� P� wave� amplitude� may� indicate� right� atrial�hypertrophy�or�hypokalemia,�reduced�P�wave�amplitude�may�indicate�hyperkalemia.� Finally,� P� wave�morphology� may� also� guide� towards�clinical�diagnosis.�A�biffed�P�wave� indicates�LA�hypertrophy,�while�P�wave�saw�tooth�shape�may�indicate�atrial�flutter.��P�R�Interval�

The� P�R� is� the� electric� interval� between� the� onset� of� the� P� wave�(atrial� depolarization)� and� the� onset� of� the� R� wave� QRS� complex�(ventricular� depolarization)� on� an� electrocardiogram.� It� represents�the�atrioventricular�conduction�time,�which�is�normally�between�120�and�200�millisecond.�P�R� interval�may�be�prolonged�in�patients�with�first�degree�AV�block,�where�the�impulse�conducted�from�the�atria�to�the�ventricles�through�the�AV�node�is�delayed�and�travels�slower�than�

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normal.� The� commonest� causes� of� prolonged� P�R� interval� are�myocardial� infarction� (especially� acute� MI),� myocarditis,� acute�rheumatic� fever,� electrolyte� disturbance� and� medications� (calcium�channel�blockers,�beta�blockers,�and�others�that�increase�cholinergic�activity).� Also� digitalis� may� prolong� P�R� interval� [11,� 12� &� 13].� In�contrast,� P�R� interval� may� shorten� in� conditions� like� hypertension,�accessory� pathways,� e.g.� Wolf�Parkinson�White� syndrome� and�pheochromocytoma�[14].�

Atrial�Electromechanical�Delay��

Mechanical� activation� of� the� cardiac� chambers� usually� follow� the�electrical� excitation,� studies� show� in� normals� with� sinus� rhythm,�there� is� a� delay� between� the� end� of� P� wave� of� the� ECG� and� the�beginning�of�atrial�contraction�or�atrial�shortening�[15�&�16].�This�delay�is� explained� by� the� time� the� atrial� wall� becomes� fully� depolarized.�This� pattern� needs� more� investigation� to� figure� out� factors� which�influence�this� time� interval,�e.g.�age,�gender,�exercise,�capacity,�etc.��Age�is�a�known�cause�of�atrio�ventricular�conduction�delay�as�well�as�the� increased� incidence� of� atrial� fibrillation� [5],� however,� its� exact�effect� on� the� atrial� electromechanical� delay,� as� a� potential�association�with�such�rhythm�disturbance�is�not�known.�Likewise,�the�specific�effect�of�gender�and�exercise�on�such�atrial�function�has�not�been� clearly� understood.� These� and� other� atrial� arrhythmia� related�function�need�to�be�thoroughly�investigated�as�well�as��studies�proof�that�left�atrial�delay�can�happens�in�patient�with�DDD�pacemaker�[16].�

�Although�the�left�atrium�has�generally�been�considered�as�a�conduit�it�is� clear� that� its� myocardial� fibers� architecture,� electric� activation,�changes�in�size�during�various�phases�of�the�cardiac�cycle�confirm�its�essential� pump� function� in� optimizing� LV� filling� and� consequently�cardiac� output,� with� the� atrial� ‘Kick’� considerably� augmenting� left�ventricular�filling� [17].�Conversely,�the�absence�of�synchronized�atrial�contraction�can� result� in� symptomatic�deterioration�as� is� commonly�seen� in� atrial� fibrillation.�On� the� other� hand,� LV� disease� and� raised�end�diastolic� pressure� is� bound� to� compromise� its� filling� pattern,�making�it�mostly�during�early�diastole�and�on�the�expense�of�having�

��

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raised� LA� pressure,� cavity� enlargement� (remodelling)� and� potential�atrial�arrhythmias.���Similar�to�the�left�ventricle,�the�left�atrium�has�an�endocrine�function.�When� its� walls� stretch� it� responds� by� secreting� atrial� nautretic�peptides� (ANP)� [18� &� 19].� The� counter� balance�of� vasodilatation� and�inhibitors�of�the�sympathetic�and�rennin�–�angiotensin���aldosterone�system�allows�partial�restoration�of�fluid�and�hemodynamic�balance.��������������������������������Common�Conditions�Affecting�LA�Function���

A)� Exercise�

With� exercise� LA� reservoir� and� booster� function� are�augmented,� whereas� conduit� function� is� not� (because� of�shortening� of� ventricular� diastole).� Increased� reservoir�function�may�play�an�important�role� in�accelerating�LV�filling�by�helping�to�maintain�an�enhanced�atrioventricular�pressure�gradient� during� diastole� and� also� by� increasing� LA� booster�function�through�an�increase�in�preload.�An�isolated�decrease�in�LA�compliance�is�associated�with�a�relative�increase�in�the�conduit�function�[20,�21,�22�&�23].��

���Figure�6.��End�systolic�(Maximum)�LA�volume�from�an�elite�athlete�with�volume�index�of�33�ml/m2.��

��

��

��

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B)� Atrial�Fibrillation�

The� LA� systolic� function� ‘in� late�diastole’�plays�an� important�role,�particularly�in�patients�with�ventricular�dysfunction,�the�commonest� causes� for� this� are� long� standing� hypertension,�cardiomyopathy� and� aortic� stenosis.� Such� enhanced� LA�function� augments� LV� filling� component� and� hence� secures�adequate�stroke�volume.��Atrial�fibrillation�is�the�commonest�arrhythmia� in� clinical� cardiology� practice.� Also,� the�commonest� groups� of� patients� which� are� affected� by� atrial�fibrillation�are�those�with�long�standing�hypertension.�Studies�have� shown� that� such�patients�might� develop�diastolic� then�systolic� left� ventricular� dysfunction� as� well� as� LA� dilatation.�While� in�early�stages�of�hypertensive� left�ventricular�disease�patients� retain�their�sinus�rhythm�and�atrial� function,� in� late�stages,�they�may�develop�stiff�ventricular�cavity�and�raised�LA�pressure� [8],� further� cavity� enlargement� and� eventually�paroxysmal� then� chronic� atrial� fibrillation� would� develop.�Some� might� maintain� their� sinus� rhythm� with� conventional�medications� including� beta� blockers,� calcium� blockers� and�renin�angiotensin� system� blockers� [10,� 24� &� 25]� while� others�might� need� electric� cardioversion� in� order� to� regain� sinus�rhythm�[26�&�27].�While�it�is�always�desirable�to�maintain�sinus�rhythm,� in�patients�with�chronic�atrial� fibrillation,�trials�have�confirmed� that� the� clinical� outcome� of� rhythm� control� is�equal� to� that� of� rate� control.� � The� rationale� behind� better�cardiac� function�with� sinus� rhythm� is�based�on� the�need� for�the�atrial� systolic�pump�function� in�order� to�compensate� for�the� already� existing� LV� relaxation� abnormalities� and�compromised� early� diastolic� filling� commonly� seen� in� such�patients.� Loss� of� LA� systolic� component� in� atrial� fibrillation�results� in� significant� compromise� of� the� stroke� volume�entering�the�left�ventricle�and�ejected�to�the�body.�The�loss�of�stroke�volume�may�amount�for�a�reduction�in�cardiac�output�by�approximately�15�20%.�

��

��

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C)� Distension� of� Cardiac� Chambers� and� Cardiopulmonary�Baroreceptors�

Baroreceptors� are� located� in� the� atria� and� pulmonary� veins�contribute� to� the� regulation� of� the� right� ventricular� and� LV�output�to�compensate�for�changes�in�systemic�venous�return,�with�optimum�level�of�pulmonary�circulatory�parameter�such�as�pulmonary� arterial� pressure,� pulmonary� venous�pressure,�and�pulmonary�capillary�blood�flow�[9].�Activation� of� the� baroreceptors� by� distension� of� the� heart�chambers� or� vascular� lumen� has� been� shown� to� cause� a�sympathetically�mediated� increase� in� heart� rate,� a� decrease�in�sympathetic�activity�to�the�kidney,�renal�vasodilatation,�an�increase� in� urine� output,� and� loss� of� sodium� [28].� Atrial�baroreceptors� also� contribute� to� the� control� of� vasopressin�(oantidiuretic�hormone),�a�vasoconstrictive�hormone�that�act�on� the� kidneys� to� stimulate� the� conservation� of� solute�free�water�[29�&�29].��

Intracardiac�Pressures�

In�view�of�the�above�physiology�the�heart�maintains�normal�pressures�in� the� absence� of� disease.� Right� atrial� pressure� is� 2�6� mmHg,� left�atrial� pressure� is� 4�12� mmHg,� systolic� right� ventricular� pressure� is���15�25� mmHg,� diastolic� right� ventricular� pressure� is� 0�8� mmHg,� left�ventricular�systolic�pressure�100�140�mmHg�and�diastolic�pressure�is�0�5�mmHg.�

Left� atrial� pressures� increase� as� a� result� of� mitral� valve� disease,�stenosis� or� regurgitation� or� left� ventricular� disease� and� raised�diastolic� pressures,� e.g.� hypertension� [30]� and� long� standing� left�ventricular�hypertrophy,�as�is�in�aortic�stenosis�[31,�32�&�33].�

LA�Emptying�Function�(LV�Filling)��

Early� studies� used� radio� nucleotide� techniques� to� assess� left�ventricular�diastolic� function� from� its� filling� velocities.�Now� this� can�easily� be� studied� using�Doppler� techniques� in� a� highly� reproducible�fashion.�While� the� LA� emptying� pattern� is�well� defined,� it� does� not�

��

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only� reflect� LA� pressure� status� but� also� LV� myocardial� and� overall�cavity�function,�particularly� in�diastole.�LA�emptying�function�can�be�studied�by�assessing�transmitral�flow�patterns�[8].�

Normal� transmitral� blood� flow� is� laminar� and� of� relatively� low�velocity�(usually�<�1m/s).�It�consists�of��early�diastolic�velocity�caused�by� continued� LV� myocardial� relaxation� resulting� in� a� drop� of� LV�pressure� below� LA� pressure,�which� causes� the�mitral� valve� to� open�and� rapid� filling� to� occur� (E� wave).� E�wave� acceleration� is� directly�determined� by� LA� pressure� and� is� inversely� related� to� myocardial�relaxation� velocity.� The� latter� can� easily� be� studied� by� myocardial�Doppler� velocities� (TDI)� technique�which�demonstrates� a� respective�e’�wave�relaxation�velocity�for�any�myocardial�segment.�Studies�have�shown� that� in� individuals� with� normal� LA� pressure� the� E�wave�velocity� correlates� closely� with� that� of� the� myocardium� (e’)� which�already�starts�few�milliseconds�before�the�empting�velocity.�This�may�suggest� that� LV�myocardial� relaxation� properties� determine� the� LA�emptying�pattern�[34].�Age�is�another�important�natural�effect�on�the�E�wave�and�LA�emptying�velocities.�Age�has�been�shown�to�inversely�correlate�with� the� E�wave� velocity� in� normal� individuals.� Therefore,�absolute� values� of� E�wave� should� be� considered� in� the� light� of� the�above�determinants�[35�&�36].�

As�the�E�wave�becomes�compromised�with�any�of�the�above�or�other�factors�[37,�38,�&�39]�the�late�diastolic�‘atrial�systolic’�emptying�velocity�‘A�wave’�increases.�In�fact,�studies�have�shown�that�the�two�inversely�correlate�with�each�other�[40].�The�increase�in�the�‘A�wave’�velocities�is� not� determined� directly� by� LV� myocardial� relaxation� but� the�augmented�LA�systolic�function,�in�an�attempt�to�compensate�for�the�reduced�stroke�volume�entering�the�LV�in�early�diastole.�It�seems�that�the� latter� results� in�modest� rise�of� LA�pressure�which� increases� the�wall� stress,� and� according� to� Frank�Starling� augments� the� power� of�LA�myocardial�contraction,�and�hence�the�exaggerated�pumping�force�and�the�raised�‘A�wave’.�Although�this�pattern�may�be�referred�to�as�abnormal� relaxation,� it� has� been� shown� as� a� completely� normal�development�with�age,�therefore�should�always�be�considered�in�this�context.�����

��

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With�progressive� deterioration�of� intrinsic� LV�myocardial� properties�and� reduction� in� its� elastic� properties� and� compliance,� diastolic�pressures� rise,� particularly� in� late�diastole.� This� disturbs� the�normal�pattern�of�the�volume�of�blood�pumped�by�the�LA�in�late�diastole�‘A�wave’,� the�higher� the�LV�end�diastolic�pressure,� the� lower�becomes�the�‘A�wave’�velocity�[41].�As�a�result�further�rise�of�LA�pressure�occurs�forcing� the� mitral� valve� to� open� earlier� and� the� early� emptying�component� to� dominate,� again� as� a� result� of� significant� increase� in�early� diastolic� acceleration.� In� extreme� cases� the� E/A�may� become������>� 2.0,� then� the� ‘A�wave’� is� very� small� or� completely� absent.� These�findings� are� referred� to� as� ‘restrictive� LV� filling� pattern’,� which� is�known� for� its� undesirable� clinical� outcome� if� remains� resistant� to�medical� therapy.� Such� patients� usually� present� with� exertional�breathlessness� with� or� without� paroxysmal� atrial� fibrillation.�Eventually� they�develop�chronic�atrial� fibrillation�due� to�progressive�enlargement� of� the� LA.� Another� important� measure� of� raised� LA�pressure� is� the�short� isovolumic�relaxation�time� [42]�and�the�short�E�wave� deceleration� time.� Indeed,� an� inverse� relationship� has� been�found�between�mean�LA�pressure�and�E�wave�deceleration�time��

��

�Figure�7.�PW�Doppler�recording�of�LV�filling�showing�easurements�of�E�wave�deceleration�time.�

���

�E/A�ratio�has�been�proposed�as�a�marker�of�diastolic�LV�dysfunction,�with� values� <� 1.0� consistent� with� abnormal� relaxation� and� values��������>�2.0�in�a�patient�over�50�years�of�age�as�a�sign�of�raised�LA�pressure�and�restrictive�filling�pattern.�E/e’,�which�is�an�index�for�early�diastolic�

��

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velocities�from�blood�and�the�myocardium,�is�another�ratio�which�has�been� proposed� as� a�marker� of� raised� LA� pressure�with� values� >� 12�consistent� with� LA� pressure� >� 15� mmHg.� Although� such� measures�proved� reproducible� in� patients� with� end�stage� heart� failure� they�have�their�limitation�in�mildly�symptomatic�patients�as�well�as�those�falling� in� the�grey�area�between�8� �12.�Furthermore,� the�use�of� this�ratio�seems�less�useful�in�heart�failure�with�normal�LVEF�compared�to�heart�failure�with�reduced�LVEF.�Therefore,�the�use�of�such�measures�should�be�employed�with�caution�[43].��LA�Volume�Measurements���The�most�common�methods�used�for�the�assessment�of�LA�function�are�based�on�the�measurement�of�LA�phasic�volumes�[5,�7,�15,�44�&�45].��Measurement� of� LA� volume� is� highly� feasible� and� reliable� in� most�echocardiographic�studies�[46],�with�the�most�accurate�ones�obtained�using�the�apical�4�chamber�and�2�chamber�views.�This�assessment�is�clinically�important�because�there�is�a�significant�relation�between�LA�remodeling� and� echocardiographic� indices� of� diastolic� function.�However,�Doppler�velocities�and�time�intervals�reflect�filling�pressure�at� the� time�of�measurement,�whereas� LA�volume�often� reflects� the�cumulative�effects�of�filling�pressure�over�time�[47�&�48].��Mean� value� for� LA� indexed� volume� in� population� studies� is������������23±6�ml/m2.�LA�volume�is�obtained�by�biplane�Simpson’s�method�and�biplane�area� length�method�giving�normal� values�of�20±6�and�21±7�ml/m2,�respectively.��Phasic�LA�volumes�have�also�been�reported.�

�a)� Maximum� LA� Vol� (LAVmax)� is� measured� just� before� the�

opening�of�the�mitral�valve�at�the�end�of�T�wave�on�the�ECG.��It�is�also�known�as�left�atrial�end�systolic�volume�(LAESV)���

b)� Minimum� LA� Vol� (LAVmin)� is� measured� immediately� at� the�mitral�valve�closure,�at�the�beginning�of�QRS.�It�is�also�known�as�left�atrial�end�diastolic�volume�(LAEDV).�

��

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c)� LA�Vol�before�atrial�contraction�is�measured�at�the�onset�of�P�wave�on�the�ECG.���

d)� LA�Vol�before�atrial�systole�measured�at�the�end�of�P�wave�on�the�ECG�(LAV�pre�A)�[7].�������������

From� these� measures� the� following� dynamic� volumes� can� be�calculated:��

�a)� LA�reservoir�volume�=�(stroke�volume�“LASV”):�LAESV�LAEDV�b)� LA�passive�emptying��volume�=�LAESV�–�Vol�p�c)� LA�conduit�volume�=�LVSV�–�(LAESV_LAEDV)�d)� LA�active�emptying�Volume�=�Vol�p�–�LAEDV�e)� LA�contraction�volume�=�Vol�p���LAEDV�f)� LA�ejection�Fraction�(LAEF)�=�(LASV/�LAESV�)�X�100�

[5,�15,�45,�46,�47�&�49].�

Figure�8.��Schematic�representation�of�time�left�atrial�volume�and�its�measurement�of��LA�volume.���AVC�=�aortic�valve�closure;�AVO�=�aortic�valve�opening;��MVC�=�mitral�valve�closure;��MVO�=�mitral�valve�opening.���

As� is� the� case�with� LA� emptying� velocities,� it� should� be�mentioned�that� these�phasic�LA�volumes�differ�between�normal�aging,�athelets�and� disease� states.� Also,� the� extent� of� active,� passive� and� conduit�filling�by� the�LA� is� strongly� influenced�by� the�compliance�of� the� left�ventricle.� Studies� of� healthy� normal� cohorts� have� already�demonstrated�a�decrease�in�passive�atrial�filling�as�well�as�in�conduit�

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volume� in� the� elderly,� together� with� a� compensatory� increase� in�active�atrial�contraction�to�overcome�the�normal�age�related�increase�in�ventricular�diastolic�stiffness�[5,�50,�51,�52�&�53].�

Pathology�

Atrial�Stunning�

Atrial� stunning� is� defined� as� subnormal� LA� mechanical� function�despite�maintained� electrical� depolarization� as� shown�by� a� P�wave.�The�commonest�presentation�of�LA�stunning�is�after�DC�cardioversion�for� atrial� fibrillation.� LA� systolic� velocities� usually� normalize� within�one�week�in�patients�with�prolonged�AF�duration.�Others�who�remain�with� poor� systolic� function� are� considered� as� having� stunned� atrial�myocardium,�which�recover�over�a�period�of�3�4�weeks� [8�&�54].�The�same� scenario� occurs� in� patients� with� atrial� flutter� after� DC�cardioversion.� Atrial� stunning� is� at� its� maximum� immediately� after�cardioversion�and�improves�progressively�with�a�complete�resolution�within�a�few�minutes�to�4�6�weeks�depending�on�the�duration�of�the�preceding�atrial�fibrillation,�atrial�size,�and�structural�heart�disease.�It�may�be�complicated�by�postcardioversion�thromboembolism�despite�restoration� of� sinus� rhythm.� Therefore,� the� duration� of�anticoagulation�therapy�after�successful�cardioversion�should�depend�on� the� duration� of� atrial� stunning.� Lack� of� improvement� in� cardiac�output� and� functional� recovery� of� patients� immediately� after�cardioversion�is�usually�attributed�to�the�atrial�stunning.��

Atrial� stunning� is� a� function� of� the� underlying� arrhythmia� which�becomes� apparent� at� the� restoration� of� sinus� rhythm.� It� is� not� the�function�of�the�mode�of�conversion,�and�does�not�develop�after�the�unsuccessful� attempts� of� cardioversion� or� the� delivery� of� electric�current� to� the� heart� during� rhythms� other� than� atrial� fibrillation� or�flutter.�Tachycardia�induced�atrial�cardiomyopathy,�cytosolic�calcium�accumulation,� and� atrial� hibernation� have� been� suggested�mechanisms�of�atrial�stunning.��

Verapamil,� acetylstrophenathidine,� isoproterenol,� and� dofetilide�have� been� reported� to� protect� from� atrial� stunning� in� animal� and�

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small� human� studies.� Right� atrium� stunning� is� less� marked� and�improves� earlier� than� that� of� left� atrium,� resulting� in� a� differential�atrial� stunning� explaining� the� rare� occurrence� of� pulmonary� edema�after�cardioversion�[8,�26�&�27].�

�Atrial�Paralysis��

Evidence� exists� suggesting� that� in� patients� with� left� ventricular�disease� some� might� develop� clear� manifestation� of� left� atrial�mechanical�failure�as�shown�by�the�presence�of�normal�sinus�rhythm�but� complete� absence� of� mechanical� activity.� The� normal� atrial�activation� on� 12� lead� electrocardiograms� suggests� it� is� primarily�mechanical� in� origin.� The� possibility� of� left� atrial�mechanical� failure�must� be� considered�when�Doppler� patterns� of� Transmitral� flow�are�used� to� assess� left� ventricular� diastolic� function,� when� they�demonstrate�complete�absence�of�‘A�wave’�[55].�

Echocardiography�

The� echocardiogram�uses� standard� ultrasound� techniques� to� image�two�dimensional� slices� of� the� heart.� The� latest� ultrasound� systems�now� employ� 3D� real�time� imaging� [7,� 56� &� 57].� It� provides� accurate�assessment� of� cardiac� chamber� dimensions� and� volumes� as�well� as�wall� thickness.� Over� the� last� two� decades� echocardiography� has�uniquely� assisted� in� studying� ventricular� long� axis� function� which�represents�the�subendocardial�function.� �This�approach�transformed�our� understanding� of� normal� cardiac� physiology� as� well� as� the�pathophysiology�of�several�diseases�[58,�59�&�60].�

Early� echocardiographic� techniques� (M�mode)� focused� on�measurements� of� left� ventricular� dimensions,� size� and� function� but�recently� interest� has� been� extended� to� involve� detailed� studies� of�other�chambers,�e.g.�the�right�ventricle�and�the� left�atrium� [61].�The�left� atrium� can� be� easily� imaged� in� a� number� of� views� by�transthoracic�or�transesophageal�echo�techniques� [62�&�63].�Recently�developed� echocardiographic� techniques� i.e.� speckle� tracking�imaging,�which�is�a�non�Doppler�based�method�of�wall�motion,�have�allowed� direct� assessment� of� segmental� and� global� 2� dimensional�

��

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strain�and�strain� rate� function�and�also�being�an�angle� independent�method� [64].� They� characterize� the� mechanics� of� myocardial�contraction� and� relaxation� pattern� (deformation� imaging),� and���especially� useful� for� assessing� longitudinal� myocardial� deformation�analysis,�which�is�otherwise�difficult�to�assess�using�standard�Doppler�methods�or�echocardiographic�visual�inspection�[34,�65�&�66].�

In�addition�to�creating�two�dimensional�pictures�of�the�cardiovascular�system,�an�echocardiogram�can�also�produce�accurate�assessment�of�the�velocity�of�blood�flow�using�pulsed�or�continuous�wave�Doppler�ultrasound.�This�allows�assessment�of�cardiac�valve�flow�and�function�e.g.� regurgitation,� any� shunt� between� the� left� and� right� side�of� the�heart�and�calculation�of�the�cardiac�output�.��

Assessment�of�Left�Atrial�Structure�and�Function�

Left�Atrial�Measurements��The� left� atrial� wall� is� significantly� thin.� Therefore� is� bound� to� be�affected�by�various�pathologies�much�earlier�than�their�effect�on�the�left� ventricle.� It� dilates� with� age� [5,� 36,� 52� &� 53]� as� well� as� other�common�pathological�conditions�including:�hypertension,�[5,�30,�37,�38,�39�&�66]�coronary�artery�disease�[42],�mitral�valve�disease,�aortic�valve�disease�[32,�33�&�41],�intracardiac�shunt�and�even�intracavitary�tumors�e.g.�atrial�myxoma.�On�the�other�hand,�the�left�atrial�size�can�become�small� when� compressed� by� outside� structures� e.g.� intrathoracic�neoplasm,� descending� aortic� aneurysms,� hiatus� hernia,� or� fluid�collection.� Also,� it� can� be� compressed� in� patients� with� severe�enlargement� of� the� right� atrium� due� to� either� volume� overload�(severe� tricuspid� regurgitation)� or� pressure� overload� (pulmonary�hypertension)�[37].�

From� the� apical� cross� sectional� 4�chamber� view� the� left� atrium� is�clearly�displayed�and�its�relationship�to�surrounding�structures�(mitral�valve,� left� ventricle� and� the� right� atrium)� is� delineated.� From� this�view,�the�longitudinal�and�transverse�diameters�of�the�left�atrium�can�easily�be�measured�[7�&�41].�Likewise,�the�transverse�diameter�can�be�measured� from�the� long�axis�parasternal�view�using�either�M�mode�recordings�or�2�D�images�of�the�left�atrium�and�aortic�root.�

��

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���

Figure�9.�2D�picture�of�the�left�atrium�in�an�apical�4�chamber�view.�

LA�dimensions�

�Figure�10.�2D�of�left�atrium�and��measurments�of�its�diameters.�

���

��

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Left�atrial�myocardial�function��

The� change� of� the� LA� function� in� different� phases� can� be� assessed�non�invasively� by� echocardiography,� using� not� only� conventional�methods� such� as� changes� in� LA� area� and� volume,� but� also� novel�techniques�such�as�tissue�Doppler�imaging�(TDI)�and�strain�imaging�by�speckle� tracking.� Tissue� Doppler� imaging� quantifies� regional�myocardial�motion�velocity�whereas�strain�and�strain�rate�represent�the� extent� of� local� tissue� deformation� and� its� rate,� respectively.�These�novel�technologies�have�been�validated�for�the�assessment�of�both�global�and�regional�LV�function�and�have�recently�been�applied�to�the�evaluation�of�regional�LA�function.�From�an�electromechanical�perspective,� echocardiographic� parameters� that� assess� LA�mechanical� function� may� provide� a� greater� understanding� of� atrial�performance�and�its�relationship�with�ventricular�function�[5,�6�&�17].�

�������

��

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Aims�

The�general�aim�of�this�thesis�is�to�characterize�left�atrial�function�in�normal�and�disease�by�using�various�echocardiographic�techniques.��Study�I�

To� study� possible� atrial� interaction� in� patients� with� right� and� left�ventricular� outflow� tract� obstruction� due� to� significant� pulmonary�(PS)�and�aortic�valvular�stenosis�(AS),�respectively.��Study�II�

To� assess� left� atrial� (LA)� intrinsic� myocardial� function� and� its�relationship� to� left� ventricular� (LV)� filling� pattern� in� patients� with�paroxysmal�atrial�fibrillation�(PAF).��Study�III�

To�test�the�hypothesis�that�LA�function�is�disturbed,�as�a�sign�of�atrial�interaction,�in�patients�with�pulmonary�arterial�hypertension�(PAH).��

Study�IV��

To� test� the� hypothesis� that� raised� LA� pressure� as� shown� by�pulmonary�capillary�wedge�pressure�(PCWP)�correlates�with�severity�of�LA�intrinsic�systolic�function.��

�������

��

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Materials�&�Methods��Study�Populations��Study�I�

We�studied�41�moderate� to� severe�PS�and�41�AS�patients�and� their�results� were� compared�with� those� of� 27� age�� and� gender�matched�healthy�subjects�with�a�structurally�normal�heart�and�without�history�of� cardiovascular� diseases.� Significant� PS� and� AS� were� defined� as�continuous� wave� (CW)� Doppler�derived� mean� pulmonary� valvular�gradient� or� aortic� valvular� gradient� of� 40�mm�Hg.� Exclusion� criteria�were� patients� with� significant� left� or� right� ventricular� dysfunction�(ejection�fraction�<�50%),�other�significant�valvular�lesions�(e.g.�more�than�mild� pulmonary� or� aortic� regurgitation),� pacemakers,� atrial�arrhythmias�or�suboptimal�echo�window.���Study�II�

Twenty�three�hypertensive�PAF�patients� (age�68±7�years,�10�males)�were� studied�at� the�Heart�Centre�of� the�University�Hospital,�Umea,�Sweden,� and� using� transthoracic� Doppler� echocardiography.� They�were� referred� to� the� cardiology� department� for� the� assessment� of�cardiac� structure� and� function� because� of� a� history� or� documented�evidence� of� PAF� (>� 30� days� before� the� echocardiographic�examination),� as�well� as� exertional�breathlessness.� Patients�were� in�sinus�rhythm�at� the�time�of�examination�and�none�had� impaired�LV�systolic�function�(EF�<�50%)�or�prior�cardiac�surgery.�No�patient�had�more� than� mild� additional� valve� disease.� Twenty� one� healthy�individual,� of� mean� age� 64±11� years,� 7� males,� randomly� selected�from� the� Umeå� county� register,� constituted� a� control� group,� who�were� also� examined� using� the� same�protocol.� None� of� the� controls�had�any�cardiovascular�or�systemic�disease�or�other�risk�factors.�����

��

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Study�III�

Thirty� five� patients� (age� 60±8� years,� 16�males)�with� idiopathic� PAH,�underwent� right� heart� catheterization� (RHC)� to� assess� pulmonary�artery� systolic� pressure� (PASP).� None� of� the� patients� had� other�cardiac�pathology,�valve�disease�or�other�pulmonary�disease.�Patients�were� studied� at� the�Heart� Centre� of� the�University� Hospital,� Umeå,�Sweden,�having�been� referred� to� the� cardiology�department� for� the�assessment�of�cardiac�structure�and�function�because�of�a�history�of�breathlessness.� Patients’� results� were� compared� with� 27� healthy�individuals,�of�mean�age�60±14�years,�8�males.��Study�IV�

We�consecutively�investigated�46�patients�(mean�age�61±13�years,�17�males)� with� different� diagnoses:� 20� with� pulmonary� arterial�hypertension� (PAH)� including� 7� with� idiopathic� and� 13� with�associated� PAH,� 6� with� chronic� thromboembolism,� one� with�interstitial� lung� disease,� 13� with� left� heart� failure� due� to� diastolic�dysfunction�(7)�and�dilated�cardiomyopathy�(n�=�6),�2�with�pericardial�constriction,�1�with�SLE�(n�=�1)�and�3�with�clinical�signs�of�heart�failure�who�all�proved�to�be�normal�at�RHC.�All�patients�were�in�sinus�rhythm�and�none�of�them�had�more�than�mild�valve�regurgitation.�

Methods�Used��

Study�I�Echocardiograms� were� obtained� using� a� Philips� sonos� 5500� system�(Phillips,�Andover,�Massachusetts,�USA)�at� least�3�consecutive�beats�in�sinus�rhythm�were�recorded,�and�the�average�values�were�taken.�Peak� and� mean� pulmonary� valvular� gradient� were� measured� from�CW� Doppler� recordings� from� parasternal� short� axis� view� at� aortic�valve� level� by�modified� Bernoulli� equation.� Likewise,� the� degree� of�aortic� stenosis� (AS)� was� calculated� from� CW� Doppler� recording�obtained�at�apical�4�chamber�view.��

��

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The� left� (LV)� and� right� ventricular� (RV)� dimensions� were�measured�from� M�mode� recordings� from� parasternal� long� axis� view.� The� LV�mass�was� calculated� using� the�Devereux� formula� and� corrected� for�body� surface� area.� Right� and� left� atrial� transverse� diameter� was�measured� from�a� frozen�apical�4�chamber�view.� LV�and�RV�ejection�fraction� were� measured� using� Simpsons� volume� estimates.�Segmental� myocardial� function� assessed� by� recording� long� axis�motions� at� lateral� tricuspid� .septal� and� lateral� mitral� annular� sites�with�M�mode�and�PW�tissue�Doppler�imaging�TDI�technique�.�Long�axis�systolic�amplitude,�peak�systolic�(Sa),�early�diastolic�(Ea)�and�late� diastolic� (Aa)� velocities� were� all� measured.� LV� and� RV� filling�indices�were�obtained�by�placing�a�2�mm�PW�Doppler�sample�volume�at� the� tip� of�mitral� valve� and� tricuspid� valve� leaflets� from� apical� 4��chamber�view�respectively.�E�and�A�wave�velocities,�E/A�ratio,�E�wave�deceleration�time�and�isovolumic�time�were�then�measured.�All�recordings�were�made�using�a�sweep�speed�of�100�mm/s�and�all�a�phonocardiogram�superimposed.����

Study�II�

A� Vivid� 7� ultrasound� system� (GE� Vingmed� Ultrasound,� Horten,�Norway)� equipped�with� a� phased� array� transducer� (1.5�4�MHz)�was�used�for�the�transthoracic�echocardiographic�examination.�All�images�and�measurements�were�acquired�from�the�standard�views�according�to� the� guidelines� of� the� American� Society� of� Echocardiography� and�were� digitally� stored� for� offline� analysis.� � LA�maximum� longitudinal�and� transverse� diameters� at� end�systole� were� measured,� from�����������4�chamber� apical� view,� using� conventional� methods.� Transmitral�Doppler� blood� flow� velocities�were� recorded�with� the� pulsed�wave�sample� volume� placed� at� the� level� of� the� mitral� valve� leaflet� tips,�from�which�peak�velocities�in�early�and�late�diastole�were�measured�and�E/A�was�calculated.��

��

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We� used� STE� technique� to� study� global� and� segmental� lateral� and�septal� LA�myocardial� function� in� detail.� From� the� apical� 4�chamber�view,�also�global� and� segmental� longitudinal� LA� strain� (S)� and� strain�rate� (SR)� were� analyzed� using� the� commercially� available� off�line�software� (GE,� Echo� Pac� version� 5.0.1,� Waukesha,� Wisconsin,� US),�which� has� previously� been� used� and� shown� high� feasibility� and�reproducibility� .The� onset� of� the� P� wave� of� the� superimposed� ECG�was� used� as� the� reference� point� because� it� represents� diastolic� LA�cavity� status,� just� before� atrial� systole.� This� approach�allows� critical�observation� and� documentation� of� global� and� segmental� function�changes� during� LA� systole� with� respect� to� diastole.� The� LA�endocardial� surface� was� manually� traced� by� the� point�and�click�technique.� The� smallest� region� of� interest� (ROI)� was� adjusted�manually� to� cover� the� whole� of� the� LA� cavity� wall.� The� software�divided� the� LA� cavity� into� 6� segments,� lateral� and� septal� annular,�lateral� and� septal� mid�cavity� and� lateral� and� septal� rear� segments.�Poorly� displayed� segments� were� automatically� rejected� by� the�software�and�excluded�from�the�analysis.� Individual�LA�segmental�S,�SR�measurements�were�obtained�as�well�as�the�average�values�of�the�accepted�segments.�Raised�left�atrial�pressure�was�estimated�by�E/A�and� E/Em,� as� previously� recommended,� with� Em� the� peak� early�diastolic�lateral�wall�myocardial�velocity�recorded�from�pulsed�tissue�Doppler�imaging.�

Study�III�

LV�dimensions�were�measured�from�M�mode�recordings�of�the�basal�region� using� conventional� methods.� LV� ejection� fraction� was�measured�using� single�plane�Simpson� technique�and� cardiac�output�was�calculated�using�the�methods�proposed�by�the�European�Society�of� Cardiology� and� ASE.LV� mass� was� measured� using� the� M�mode�recording�of�basal�LV�dimensions,�from�which�posterior�wall�thickness�and�septal�thickness�were�measured�using�conventional�methods.�LV�myocardial� velocities� of� the� lateral� wall� were� studied� using� pulsed�wave� tissue� Doppler� imaging� technique� with� the� sample� volume�

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placed�approximately�1�cm�proximal�to�the�mitral�annulus�level.�From�the� tissue� Doppler� recordings� we� measured� peak� annulus� systolic�velocity� (s’)� and� early� diastolic� velocity� (e’).� LV� filling� pattern� was�obtained� from� the� Transmitral� Doppler� velocities� with� the� pulsed�wave�Doppler� sample� volume�placed� at� the� tips� of� the�mitral� valve�leaflets� from� the� apical� 4�chamber� view.� From� LV� filling� velocities�recording� we� measured� peak� early� (E)� diastolic� velocity,� E� wave�deceleration� time� and� E/A� ratio� was� calculated.� LV� isovolumic�relaxation�time�(IVRT)�was�measured�as�the�time�interval�between�LV�end�ejection�(from�the�pulsed�Doppler�recording�of�the�outflow�tract�velocity� and� the� onset� of� E� wave� velocity.� The� E/e’� ratio� was� also�calculated�and�taken�as�an�index�of�raised�LV�filling�pressures.��

Study�IV�

The� echocardiographic� examination� was� performed� with� the� same�machine�have�mentioned�in�study�II.�Conventional�right�and�left�heart�M�mode,�2D�and�spectral�Doppler�examinations�and�measurements�were� made� according� to� the� current� recommendations� of� the�American� Society� of� Echocardiography� and� European�Association�of�Echocardiography�and�were�digitally�stored�for�offline�analysis.��

Left� atrial� longitudinal� and� transverse� dimensions� at� end�� systole�were� measured� from� the� apical� 4�� and� 2�chamber� views� using�conventional�protocols�and�average�measurements�were�calculated.�LA� intrinsic�myocardial� function�was�assessed�using�speckle� tracking�echocardiography�technique�and�recordings�were�obtained�from�the�apical� 4�� and� 2�chamber� grey� scale� images� using� a� frame� rate� of������50�70�frame/second.��Effort�was�made�to�exclude�LA�appendage�from�the� images�to�avoid�affecting�the�global�LA�strain�(S)�and�strain�rate�(SR)�measurements.�Also�we�used�the�same�software�(Echo�PAC,�GE,�USA)� for�all� analyses�of� the�acquired� images.�One�cardiac�cycle�was�selected,� from� which� end�diastolic� frame� was� determined� in� the�apical�4�chamber�view� (mean� frame�rate�63�±�11/sec.).� LA�wall�was�tracked�on�a�frame�frame�basis.�LA�endocardial�border�was�traced�in�the�4�chamber�view�in�order�to�delineate�the�region�of�interest�(ROI).�Patients�with�less�than�5�accepted�segments�were�excluded�from�the�analysis.�LA�segmental�myocardial�velocities�were�also�obtained�using�

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tissue� Doppler� technique� with� the� sample� volume� placed� at� the�annular� end� of� the� lateral� and� septal� walls,� from� the� apical�����������������4�chamber�view.�Gain�was�optimally�adjusted�to�secure�the�clearest�possible� LA� systolic� velocity,� occurring� after� the� P� wave� of� the�superimposed�ECG.����

Transmitral� Doppler� flow� velocities� were� recorded� with� the� pulsed�wave�sample�volume�positioned�at�the�level�of�the�mitral�valve�leaflet�tips,�from�which�peak�velocities�in�early�diastole�(E�wave)�and�during�atrial�systole�(A�wave)�were�measured�and�E/A�was�calculated.�

Venous�access�was�obtained�by�inserting�a�cannula�in�a�medial�cubital�vein� or� in� the� femoral� vein.� A� Swan�Ganz� standard� catheterization�technique�with�thermodilution�catheters�(Edwards�Life�sciences)�was�used.�Mean�right�atrial�pressure�(RAP),�systolic�and�end�diastolic�right�ventricular� pressures,� pulmonary� artery�mean� systolic� and� diastolic�pressures� (PASP,� PAMP� and� PADP,� respectively)� and� pulmonary�capillary�wedge�pressure�(PCWP)�were�measured.�Blood�samples�for�estimation�of�oxygen� saturation�were�also�drawn� from� the� superior�and� inferior� caval� veins,� right� atrium,� and� from� the� pulmonary� and�femoral�arteries�for�calculation�of�cardiac�output�(CO)�and�to�exclude�intra�cardiac� shunts.� CO� was� determined� by� theremodulation.� PVR�was�calculated�using�the�equation:��

PVR�=�PAMP�–�PCWP�(trans�pulmonary�gradient)�/�CO.�

Where,�PAMP�calculated�(peak�systolic�pressure�X�0.61+2).���

Peak� � systolic� PA� pressure� was� calculated� from� peak� retrograde�tricuspid� pressure� drop� using� the� modified� Bernoulli� equation� and�applying� peak� tricuspid� regurgitation� continuous� wave� velocity�measurement�(PASP=�4�x�TR�velocity2�+�estimated�RAP�(10�mmHg).���

�������

��

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Echocardiographic�Techniques�Used�In�Clinical�Practice�

M��mode�Echocardiography���

������Figure�11.�M�Mode�Echocardiography�image�showing�LV�and�inteventricular�septum��

�M�Mode�echocardiography�(Time�motion�mode)�is�one�of�the�earliest�echocardiographic� techniques� used� in� clinical� practice.� It� was� first�experimentally� used� by� Edler� and� subsequently� developed� on�commercial� systems.� M�mode� recording� is� constructed� by�transmitting�and�receiving�at�only�one�scan�line,�giving�the�technique�substantially� unique� sensitivity� for� wall� motion� studies.� � M�mode�displays� on� the� vertical� axis� the� distance� of� each� point� from� the�transducer�and�on� the�horizontal� axis� the� time�period.� It� gives� very�high�resolution�in�the�time�axis�(>�500�frames/sec)�so�that�it�is�easy�to�time� various� events� of� the� cardiac� cycle,� especially� when� a�synchronized�ECG�tracing� is�displayed�along�with� it.�The�commonest�site�of�scanning� is� the�parasternal�region.�As� the�transducer�sweeps�from�base�to�apex,�the�initial�section�images�the�aorta�anteriorly�and�left�atrium�posteriorly.�This�is�the�conventional�section�clinically�used�for� measuring� left� atrial� transverse� diameter.� Such� principle� of�ultrasound� physics� makes� M�mode� measurements� unique� for�assessing� detailed�wall�motion� function� as�well� as� cardiac� chamber�dimensions,� particularly� when� studied� in� different� phases� of� the�cardiac�cycle�[50].�

��

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The� commonest� measurements� made� from� M�mode� echo�cardiographic�examination�are:�

A)� Left� atrial� transverse� dimension� from� the� parasternal� long�axis� images� between� the� posterior� wall� of� the� aortic� root�and�that�of�the�left�atrium,�in�systole.��

B)� Left� ventricular� dimensions� in� systole� and� diastole,� from�which� fractional� shortening� is� calculated� as� the� relative�difference� between� end�diastolic� dimension� and� end�systolic�dimension�with�respect�to�end�diastolic�dimension.�Also�ejection�fraction�can�be�estimated�using�cubed�values�of� the� same� measurements� and� same� equation.� This�method� of� estimating� ejection� fraction� has� now� been�replaced� by� Simpson’s� role� which� assumes� a� cylindrical�shape�to�the�left�ventricle.�The�same�principle�can�be�used�for�left�atrial�volume�measurements.�

�In� this� thesis,� we� used� M�mode� technique� for� measuring� the�following:���

�� LV� dimensions� at� the� basal� region� using� conventional�methods.�

�� LV�mass�using�basal�dimensions�and�posterior�and�septal�wall�thickness�and�applying�Penn�equation.�

�� LA�transverse�and�longitudinal�diameters�[7�&�41].��������

��

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Myocardial�Doppler�Imaging��

�Figure�12.Tissue�Doppler�based�strain�rate�measurements�of�LA�

Doppler� echocardiography� relies� on� detection� of� the� shift� in�frequency�of�ultrasound�signals�reflected�from�moving�objects.�With�this�principle,�conventional�Doppler�techniques�assess�the�velocity�of�blood�flow�by�measuring�high�frequency,�low�amplitude�signals�from�small,�fast�moving�blood�cells.�In�TDI,�the�same�Doppler�principles�are�used� to� quantify� the� higher�amplitude,� lower�velocity� signals� of�myocardial� tissue�motion.� TDI� technique� detects� ultrasound� signals�generated� by� the� myocardial� tissue� while� moving� during� different�phases� of� the� cardiac� cycle.� TDI� can� be� used� as� pulsed� TDI� (peak�velocities� and� high� frame� rate,� >� 500� f/s)� and� color� TDI� (mean�velocities�and�frame�rate�of�approx�100�f/s�in�a�full�sector�scan).�The�commonest� application� of� TDI� is� for� studying� long� axis� ventricular�function�which�is�reflected�on�the�motion�of�the�mitral�and�tricuspid�annuli.� This� is� referred� to� as� MAPSE� (mitral� annulus� peak� systolic�excursion)� and� TAPSE� (tricuspid� annulus� peak� systolic� excursion).�Such�sensitivity�of�TDI�in�assessing�long�axis�function�is�based�on�the�

��

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fact� that� longitudinally� oriented� subendocardial� fibers� are� most�parallel�to�the�ultrasound�beam�in�the�apical�views.�Because�the�apex�remains� relatively� stationary� throughout� the� cardiac� cycle,� mitral�annular�motion�is�a�good�alternative�measure�of�overall� longitudinal�LV�contraction�and�relaxation.����

The� TDI� sample� volume� is� placed� at� the� proximal� segment� of� the�different� sites� of� the�mitral� annulus�which� displays� the� longitudinal�motion� velocities.� TDI� recordings� consist� mainly� of� 3� velocities,�systolic� (s’),� early� diastolic� (e’)� and� atrial� (a’)� velocities.� The� systolic�velocity� reflects� systolic� function�and�early�diastolic�velocity� reflects�early� lengthening� function� of� that� segment.� The� atrial� velocity� (a’)�reflects�left�atrial�systolic�function,�which�is�expected�to�be�absent�in�patients� with� atrial� fibrillation.� Likewise,� those� with� prolonged� left�atrial� electromechanical� delay� are� expected� to� have� prolonged� P�a’�interval.�This�pattern�of�time�relations�copies�that�of�the�left�ventricle�when�the�time�relations�of�the�s’�and�e’�with�respect�to�the�onset�of�ventricular�depolarization�(the�q�wave�of�the�superimposed�ECG)�and�the�end�of�systole�(aortic�closure�sound�or�pulmonary�closure�sound�on� the� superimposed� phonocardiogram)� respectively,� is� measured.�This� has� been� shown� to� have� great� significance� in� assessing�segmental�incoordination�and�dyssynchrony�[47�&�67].��The� ratio�of� Transmitral� E�wave�velocity� to� that�of� the�myocardium�(e’)� has� been� used� to� reflect� left� atrial� pressure,� particularly� in�patients� with� end� stage� heart� failure.� Similar� applications� in� other�conditions�have�been�less�satisfactory.�The�frequency�of�acceleration�of�pre�systolic�velocity,�occurring�during�isovolumic�contraction�time�has� been� shown� to� be� a� good� index� for� systolic� performance� and�state�of�contractility�and�their�reduction�is�evident�in�several�cardiac�pathologies.� TDI� derived� systolic� and� diastolic� velocities� have� a�recognized� prognostic� value� in� heart� failure� and� after� acute�myocardial� infarction.� In� these� conditions� they� are� able� to� predict�both�left�ventricular�remodeling�and�mortality�[43].�

��

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Limitation�of�TDI�

TDI� is� known� for� important� limitations� as� it� is� an� angel� dependent�technique,�with�aligning�of� the�atrial�wall�parallel� to�Doppler�beam,�thus� it� measures� only� the� vector� of� motion� that� is� parallel� to� the�direction�of�the�ultrasound�beam.�TDI�has�suboptimal�reproducibility�being� angle� dependent� and� unable� to� reflect� specific� segmental�function,� compared� to� strain� and� strain� rate� measurements.�Furthermore,� in� the� setting� of�myocardial� tethering� and� translation�TDI� has� significant� limitations,� since� it� measures� absolute� tissue�velocity� and� is� unable� to� differentiate� between� passive� contractile�motion� (related� to� translation� or� tethering)� from� active� contractile�motion� of� myocardium� i.e.� fiber� shortening� or� lengthening� e.g.�healthy� vs.� tethered� myocardium.� Finally,� the� tissue� Doppler�technique� derived� strain� and� strain� rate� has� been� developed� as� a�means� for� assessing� intrinsic� myocardial� function.� It� however� has�major�limitation�in�its�dependence�on�the�angle�of�incidence�between�the�ultrasound�beam�and�myocardial�motion.�At�angels�greater�than�20�degrees�measurements�are�significantly�affected.�Also�high�frame�rate�imaging,�ideally�>�130�frame�per�second�is�required�for�this�type�of�imaging�[50].�

Assessment�of�Left�Atrium�and�Appendage�Function�by�TDI��

Both� spectral� and� pulsed� TDI� or� two�dimensional� color�coded� TDI�have� been� used� to� assess� regional� LA� function,� by� placing� a� small�sample�volume�at�basal�left�atrial�segment�of�interest,�usually�about�2�mm�for�measuring�velocity�and�preferably�not�more�than�12�mm�of�length�for�strain�and�strain�rate�(will�be�discussed�below),�because�of�its�thin�walled�structure.�Unlike�the�spectral�Doppler,�TDI�has�better�temporal� resolution� but� can�measure� only� one� segment� at� a� time.�Color�coded� TDI� images� can� be� post�� processed� off�line� and� offer�simultaneous� multi�segment� analysis� of� velocities� and� other� TDI�derived�parameters,�such�as�strain�and�strain�rate.�Thus,�different�LA�walls,� septal� and� lateral� from� the� apical� 4�chamber� view� and� the�anterior� and� posterior� segments� from� the� apical� 2�chamber� view,�with� their� corresponding� levels� from� the� mitral� annulus� can� be�assessed�and�compared�[8,�15�&�68].��

��

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Figure�12�Normal�Pulsed�wave�TDI�

Analysis� of� TDI� based� myocardial� strain� and� strain� rate� provides�similar� time� landmark� measurements,� with� three� components� in�strain� and� strain�rate� signals,� reflecting� respective� systolic,� early�diastolic� and� late� diastolic� myocardial� function.� Like� TDI,� the� strain�and�strain�rate�a’�component�has�been�regarded�as�a�direct�measure�of� regional� active� atrial� contraction� on� the� longitudinal� axis,� which�might� be� less� load�dependent� than� TDI.� The� s’� and� e’� waves� may�represent�the�PA�passive�expansion�and�emptying�components�of�the�LA� function.� The� feasibility� and� reproducibility� of� TDI� based�parameters,� in�particular� the�peak�velocity� (a’)� and�peak� strain� rate�(SRa)� of� the� active� atrial� contraction,� have� been� shown� in� previous�studies,� in� which� both� the� inter�� and� intra�observer� variability� for�measuring�the�a’�were�reported�to�be�in�the�order�of�10%.��Although�the� velocity� data� could� be� easily� obtained� in� nearly� all� patients,�strain�rate� measurements� were� only� feasible� in� about� 95%� of�patients�due�to�the�relatively�higher�noise�to�signal�ratio.�

��

��

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Application�In�this�thesis��

Standard�TDI� technique�was�performed�using�Vivid�7,�GE�Ving�med,�and� Horten,� Norway� echocardiograph� with� a� 3.5� MHz� multiphase�array�probe�in�subjects�lying�in�a�left�lateral�decubitus�position.�Two�dimensional� grey� scale� images� were� acquired� from� the� apical� four�chamber� view� for� three� cardiac� cycles� and� digitally� stored� with� a�frame�rate�of�approximately�50–90� frames�per�second.� �The� images�were� analyzed� off�line� and� stored� by� the� software� (Echo� PAC).� LA�segmental� myocardial� velocities� were� also� obtained� using� pulsed�tissue� Doppler� technique� with� the� sample� volume� placed� at� the�annular� end� of� the� lateral� and� septal� walls,� from� the� same� apical�������4�chamber�view.��������������������������

��

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Speckle�Tracking�Echocardiography���

�Figure�14.�Pattern�of�LA�strain�(top)�and�strain�rate�(bottom)�in�a�normal�

��Subject,�TPLS,�Time�to�Peal�atrial�longitudinal�strain���������������

Speckle�tracking�echocardiography�(STE)�is�a�digital�process�by�which�the�software�using�the�standard�B�mode�images�is�tracking�the�movements�of�natural�myocardial�marker�(speckles)�or��(acoustic�backscatter)�present�in�the�standard�grey�scale�images�generated�by�the�reflected�ultrasound�beam�by�following�the�speckles�from�frame�to�frame�in�different�directions�and�amplitude�of�motion.�This�displacement�of�the�speckles�is�described�as�myocardial�movement�or�myocardial�deformation�(2D�strain).�The�software�is�originally�designed�to�study�the�relatively�thick�walled�left�ventricle�but�has�now�been�tested�studying�both�the�right�ventricle�and�the�left�atrium.�

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Recent� studies� confirmed� that� 2D� STE� is�much�more� accurate� than�TDI� when� both� techniques� were� used� to� detect� atrial� deformation��[69,� 70,� 71� &� 72]� and� the� deference� between� contractile� and� non��contractile�atrial�segments�[34,�73,�74�&�75].�Another�study�showed�that�speckle� tracking� for� assessment� of� atrial� function� is� more� accurate�and� useful� than� the� old� method� which� depends� on� atrial� size� and�volume� having� shown� that� STE� can� detect� early� LA� remodeling�therefore�likely�to�predict�atrial�fibrillation�[76,�77,�78,�79�&�80].�

Also� studies� confirmed� the� accuracy� of� LA� speckle� tracking� using�strain�and� strain� rate� to�predict� the� recurrence�of�paroxysmal�atrial�fibrillation�and�reverse�remodeling�after�successful�catheter�ablation�[81]�and�other�factors�that�may�have�a�great�impact�on�the�outcome�of� catheter� ablation� [82].� Speckle� tracking� technology� accurately�detected� LA� abnormalities� in� patients� with� hypertension,� diabetes�[69]� and� also� LA� deformation� in� ageing� [52]� and� various� degrees� of�mitral�regurgitation�[83].�

Speckle�Tracking�Measurements��

Speckle� tracking� measures� the� optimum� longitudinal� LA� strain� and�strain� rate� of� segmental� myocardial� function� during� systole� and�diastole� [84�&�85].�Global�peak� longitudinal�strain�has�been�shown�to�demonstrate�the�highest�diagnostic�accuracy�and�excellent�specificity�and�sensitivity�in�predicting�elevation�of�filling�pressure�[86,�87,�88�&�89]�

Strain�

LA�strain�essentially�represents�the�stretch�or�shortening,�or�regional�deformation� of� the� myocardium.� It� was� first� described� in� clinical�studies� of� isolated� heart� muscle� and� intact� hearts� in� 1973� as�deformation�that�was�noted�to�occur�after�application�of�stress�[90].��

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Strain�is�a�dimensionless�index,�and�reflects�the�total�deformation�of�the�myocardium�during�cardiac�cycle�relative�to,�or�as�percent�of,�it’s�initial� length.� For� example,� if� the� velocities� measured� at� all� points�within�a�moving�object�are�the�same,�and�then�the�object�would�be�described� as� having� displacement.� If,� on� the� other� hand,� different�points�within�a�moving�object�are�moving�at�different�velocities,�then�the� object� will� exhibit� deformation� and� alter� its� shape� during�different�phases�of�the�cycle�[91].��Strain� allows� for� the�differentiation�of� active� vs.� passive�movement�within� a� myocardial� segment,� in� which� longitudinal� and�circumferential�strain�represents�the�shortening�of�the�myocardium,�are� shown� as� negative� curves,� while� reflecting� myocardial�lengthening�relative�to�the� initial�dimension�of�the�myocardium�and�has�a�positive�curves�[92].�Strain�could�be�described�as�differences�(%)�in�amplitudes�between�two�points�within�a�ROI.��

��

��Figure�15.��The�strain�curve�from�speckle�tracking�chocardiography�of�the�LA�in�AF����������������������obtained�from�both�apical�four�chamber�and�two�chamber�views.������������������������White�arrows�indicate�LASp.�����

��

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Advantages�of�STE:��A)� It� allows� angle� independent,� comprehensive� and� accurate�

assessment�of�myocardial�motion.�B)� It�is�shown�to�overcome�the�limitation�of�TDI�in�registering�the�

motion� of� tethered� myocardium� and� other� intracardiac�structure.��

C)� It�provides�accurate�and�reproducible�measurements�not�only�for� the� thick�walled� left� ventricle�but�also� the� right�ventricle�and� the� left� atrium,� thus� allowing� thorough� assessment� of�intrinsic�myocardial�function�[93].�

D)� The� accuracy� of� STE� technique� has� been� validated� in�experimental�and�clinical�studies.��

E)� Although�absolute�values�derived�from�a�2D�strain�and�a�TDI�derived�strain�are�not� identical,�they�do�correlate�reasonably�well�[85].�

�Limitations�of�STE:�

A)� Its�validation�as�a�gold�standard�for�left�atrial�study�[94].�B)� The� potential� difficulty� of� obtaining� the� region� of� interest�

(ROI)�C)� The�optimal�frame�rate�for�speckle�tracking�is�between�50�and�

70� f/s�but� the�clinical�applicability�of� its�use� in�all�patients� is�limited�by�the�necessity�for�high�image�quality,�as�inadequate�temporal�resolution�can�lead�to�under�sampling.�

D)� There�is�no�way�to�compensate�for�translational�motion�of�the�heart� in�which� specific� speckle� that�was� being� tracked� is� no�longer�in�the�2D�imaging�field.�

E)� Low�image�quality�and�its�vulnerability�for�noise�can�make�the�interpretation�difficult.��

F)� The� uncertainty� about� measurements� taken� from� 4�� and��������2�chamber� (i.e.� there� is� no� proof� about� the� deference� in�measurements� if� taken� from� 4� chamber� or� two� chamber�view).�

��

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Application�in�this�thesis���We� studied� LA� STE� from� the� 2D� echocardiography� 4� chamber� view�and� the� LA�endocardial� border�manually� defined�using� a�point�and�click�technique,�was�composed�of�6�segments�in�a�horseshoe�shape�at�the�inner�side�of�the�septal�and�lateral�walls�and�the�rear�of�the�LA.��An� epicedial� surface� tracing� was� automatically� generated� by� the�system,� creating� a� region� of� interest� (ROI),� which� was� manually�adjusted� to� cover� the� full� thickness� of� the� LA� myocardium� in� the�systolic� frame.� The� width� of� the� smallest� ROI� was� 8� mm.� Before�processing,� a� cine� loop�preview�was�used� to� confirm� if� the� internal�line� of� the� ROI� followed� the� LA� endocardial� border� throughout� the�cardiac� cycle.� Only� clearly� displayed� segments� which� provided�detailed� segmental� analysis� throughout� the� cardiac� cycle� were�accepted� by� the� software.� Patients� with� less� than� 5� accepted�segments� were� excluded� from� the� analysis.� Time�strain� and� time�strain� rate�plots�were� automatically� produced�by� the� software.� The�image� below� shows� the� 6� LA� segments� after� they� automatically�generated�by�the�soft�ware,�confirming�the�accuracy�of�the�curve�of�the�left�atrial�wall.��

���Figure�16.��Speckle�Tracking�Echocardiography�showing�the�Accepted�6�segments�of��the�ROI.�

��

��

��

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Strain�Rate�Is� the� rate� of� deformation� or� stretch� of� the� strain?� A� regression�calculation�is�performed�on�the�velocity�data�from�adjacent�sites�with�the�region�of�interest�(ROI)�parallel�to�the�ultrasound�beam�creating�SR� curve.� Strain� rate� has� been� shown� accurate� enough� to� detect�infarction� of� the� myocardial� muscle� predisposing� to� future�arrhythmias.� This� has� important� impact� in� the� clinical� practice,� for�example� by� strain� rate� we� can� predict� if� atrial� fibrillation� patients�needing� ablation� without� EST.� Strain� rate� can� be� explained� as�difference�of�velocities�(1/s)�between�two�segments�within�a�ROI�[92].��

������Figure�17.�The�strain�rate�curve�from�speckle�tracking�chocardiography�of�the�LA�in�AF�can�be�obtained�from�both�apical�four�and�two�–chamber�views�white�arrows�indicate�LASRc�of�the�LA.�

�����

���

��

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Speckle�Tracking�Images�in�Normals��

�Figure�18.�Left�Atrial�Strain�

�Figure�19.�Left�Atrial�Strain�Rate�

�Figure�20.�Left�Atrial�Velocity�

��

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�Figure�21.�Left�Atrial�Segmental�Strain�

�Figure�22.�Left�Atrial�Segment�Strain�Rate�

�Figure�23.�Left�Atrial�Segmental�Velocity�

��

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Other�Echocardiographic�Techniques�

Color�flow�Doppler���

It� is� a� form� of� pulse� wave� Doppler� in� which� the� energy� of� the�returning� echoes� is� displayed� as� an� assigned� color;� by� convention�echoes�representing�flow�towards�the�transducer�are�seen�as�shades�of� red,� and� those� representing� flow� away� from� the� transducer� are�seen�as�shades�of�blue.�The�color�display�is�usually�superimposed�on�the� B�mode� image,� thus� allowing� simultaneous� visualization� of�anatomy�and�flow�dynamics.��

Figure�24.�Color�flow�Doppler�of�the�mitral�valve�

�Continuous�Wave�Doppler��

A� technique� in� which� the� transducer� emits� and� receives� the�ultrasound� beam� continuously,� enabling� the� measurement� of� high�velocity�blood�flow,�such�as�that�occurs�through�heart�valve�stenosis.�

��

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�Figure�25.�Continuous�wave�Doppler�recording�from�a�patient�with�sever����������������������aortic�stenosis.��

��������

This� is� a� technique� in�which� the� transducer�emits� the�ultrasound� in�pulsed� waves.� Blood� flow� velocities� so� measured� are� limited� to�around�the�physiologic� range�(up�to�approximately�1.5�m/s)�but�the�depth� from�which� the� returning� echoes�originate� can�be� accurately�determined.�

In� this� thesis� mitral� inflow� velocity� was� obtained� by� pulsed� wave�Doppler� examination� from� the� apical� four�chamber� view�by� placing�the�sample�volume�at�the�tips�of�the�mitral� leaflets.�Peak�velocity�in�early� diastole� (E�wave)� and� late� diastole� (A�wave)� were� measured�and�the�E/A�ratio�calculated.�The�velocity�time�integral�of�the�A�wave�was� measured� and� the� atrial� emptying� fraction� estimated� as� the�������A�wave� velocity� time� integral� divided� by� the� total� mitral� inflow�velocity�time�integral.��

Pulmonary� vein� velocities� can� be� obtained� by�pulsed�wave�Doppler�examination� from� the� apical� four�chamber� view� by� placing� the�sample�within�the�proximal�2�cm�of�the�right�upper�pulmonary�vein.�Peak� velocity� in� systole,� diastole� and� atrial� reversal� was� measured�and�the�systolic/diastolic�ratio�calculated.�

��

��

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Spectral�Doppler��

Spectral�Doppler� refers� to� the� combination�of� either� continuous�wave� Doppler� or� pulsed� Doppler� with� a� spectral� display.� It�provides� a� quantitative� analysis� of� the� velocity� and� direction� of�blood� flow.�The�amplitudes�of� the� resulting�spectra�are�encoded�as� brightness.� In� the� 2D� spectral� display� the� range� of� blood�velocities� in� the� volume� produces� a� corresponding� range� of�frequency� abnormality.� Spectral� Doppler� is� used� to� display� the�normal�and�abnormal� signature�waveforms� that�are�unique� to�each�vessel.���

Contrast�Enhanced�Echocardiography�

Echocardiography� is� the� first� application� of� intravenous� cavity� to�assess�its�pump�function�and�wall�motion�function.�Echo�contrast�has�also�been�recently�applied�to�assess�myocardial�perfusion�in�patients�with�suspected�coronary�artery�disease.��Imaging�of�the�right�and�left�atria� and� their� appendages� can� provide� important� clinical�information.� Left� atrial� imaging� is� especially� important� in� patients�with�atrial� fibrillation�who�are�at� increased�risk� for� thromboembolic�events�resulting�from�left�atrial�or�atrial�appendage�thrombus.���

MRI�for�Assessing�LA�Structure�and�Function��

MRI� is�considered�the�most�accurate�technique�for�the�non�invasive�assessment� of� atrial� volumes,� because� of� its� high� spatial� resolution�and� its� excellent� myocardial� border� detection� [8].� Anderson� et� al�recently� reported� findings� on� LA� dimensions� and� LA� area� assessed�with�MRI�in�20�healthy�and�20�patients�with�cardiomyopathy�in�which�it� was� noted� that� LA� systolic� area� <� 24� cm2� was� the� upper� 95th�percentile�of�the�normal�range,�and�best�differentiated�normal�from�abnormal� heart� [95].� LA� volume� assessment� with� MRI� is� not�performed� in� a� daily� practice� because� of� the� long� acquisition� time�and�time�needed�for�data�analysis� [88].�Studies�compared�the�values�

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obtained� by� different� imaging� techniques� for� the� assessment� of� LA�size�and�volume�[96�&�97]�and�it�showed�that:��

A)� 2D�transthoracic�echocardiography�using�the�biplane�method�is�conventional�to�assess�LA�size�and�volume�[44].�

B)� MRI�and�CT�have�more�accurate�assessment�of�LA�size�and�volume�[98].�

C)� 3D�Techniques�are�not�preferred�for�LA�size�assessment�in��daily�clinic.���

] � ���������������������������������������Figure�26.�Views�of�the�4�Chambers�MRI�

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Statistics��

All� statistics� in� study� I� &� II� were� performed� using� the� standard�software�package�SPSS�13,� and� study� III� and�VI� using� SPSS�18,� SPSS�Inc.�Chicago,�IL,�USA.�

Study�I��

Categorical� variables� were� expressed� as� number� (n)� or� percentage�(%)� and� comparisons� were�made� using� Chi�square� test.� Parametric�data� were� expressed� as� mean� ±� standard� deviation� and� were�compared�using�2�tailed�unpaired�Student�t�test.�A�p�value�<0.05�and�<p<0.01� were� considered� statistically� significant.� Correlations� were�tested�with�Pearson�coefficients.�

Study�II��

Continuous� variables� are� presented� as� mean� ±� standard� deviation�(SD)�and�non�parametric�Mann–Whitney�U�test�was�used�to�compare�the� difference� between� groups.� A� Chi�� square� test� was� used� to�compare� categorical� values� between� the� two� groups.� Pearson's�correlation�and�linear�regression�analyses�were�performed�to�display�the�correlation�between�different�parameters.�A�p�value�<�0.05�was�considered�statistically�significant.������

Study�III�

Distributed� continuous� data� were� expressed� as� mean� ±� standard�deviation�(SD),�as�well�as�values�within�the�patient�groups�which�were�compared�using�Analysis�of�variance�(ANOVA)�and�unpaired�Student�t�test� for� significance� differences� between� groups.� Statistical�significances� were� taken� with� a� p� value� <� 0.05.� Linear� regression�analysis� was� performed� to� determine� relationships� between� atrial�function�and�invasively�measured�intra�cardiac�pressures.��

��

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Study�IV�

Distributed� continuous� data� were� expressed� as� mean� ±� standard�deviation�(SD),�as�well�as�values�within�the�patient�groups�which�were�compared�using�analysis�of�variance� (ANOVA)�and�unpaired�Student�t�test� for� significance� differences� between� groups.� Statistical�significances� were� taken� with� a� p� value� <� 0.05.� Linear� regression�analysis� was� performed� to� determine� relationships� between� LA�function�and�invasively�measured�intra�cardiac�pressures.��

�����������

�����

��

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Main�Findings��

Study�I�

Our� study� confirmed� the� superior� sensitivity� of� long� axis� function�than� global� systolic� function� in� revealing�myocardial� dysfunction� in�patients� with� hypertrophied� ventricles.� More� importantly,� an�accentuation�of� atrial� systolic� activity�was� found� in� the�disease�free�ventricles� in� both� AS� and� PS� patients.� Such� exaggeration� of� atrial�activity� was� related� to� the� severity� of� contra�lateral� ventricular�outflow� tract� obstruction,� suggesting� the� presence� of� atrial�interaction.� Thus,� in� patients� with� ventricular� outflow� tract�obstruction�and�myocardial�hypertrophy�there�is�a�clear�evidence�for�atrial� ‘cross�talk’�manifested� as� exaggerated�mechanical� function� of�the�contra�lateral�atrium.�

Study�II�

This�study�shows�significant�differences� in�LA�structure�and�function�between�controls�and�patients�with�PAF�while�in�sinus�rhythm�at�the�time� of� the� study.� In� patients,� the� LA�was� slightly� enlarged� and� its�global� as� well� as� segmental� strain� (S)� and� strain� rate� (SR)� were�significantly� reduced� in� a� uniform� fashion.� In� contrast,� myocardial�velocities�both�at�the�septal�and�lateral�walls�were�not�different�from�controls.�Global�S�and�SR�also�correlated�with�the�extent�of�LA�cavity�enlargement� as� well� as� with� E/A� ratio.� The� segmental� septal� S�correlated�with� E/A� but� both� septal� and� lateral� SR�were� correlated�with� E/A.� Atrial� myocardial� velocities� were� maintained� in� patients�and�only�modestly�correlated�with�E/A�ratio�as� they�did� in�controls.�Neither� LA� S,� SR� nor� myocardial� velocities� correlated� with� E/Em.�Moreover,�myocardial� velocities� had� a� specific� distribution� pattern,�

��

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being� highest� at� the� annular� level� of� the� LA� walls� and� reduced�exponentially�towards�the�rear,�equally�in�both�patients�and�controls.��

Study�III��

This� study� shows� that� in� PAH� left� atrial� structure� and� functions� are�significantly�abnormal.�LA�transverse�diameter�is�reduced�and�overall�reservoir� function�and� lateral�and�septal� segmental� function�was�all�compromised.� In� addition,� LA� segmental� function� differed� in� its�relationship�with� right� heart� pressures;�with� the� lateral�wall� SR� the�main� correlate� with� PASP� and� the� septal� wall� velocities� correlating�with�right�atrial�pressures.�

Study�IV��

This� study� shows� that� PCWP� correlates� with� measurements� of� LA�structure� and� function� with� the� strongest� relationship� with�myocardial�intrinsic�function�in�the�form�of�SR�and�to�a�lesser�extent�cavity� volume� and� systolic� filling� fraction.� A� LA� systolic� SR� cut� off�value�of�<1/s�accurately�discriminated�between�patients�with�PCWP�>�15�mmHg.�PCWP�also�correlated�with�indirect�measures�of�raised�LV�filling�pressures� as� shown�by�early�diastolic� filling� time�and� velocity�relations,�but�to�a�much�lesser�extent�than�LA�SR�measures.��

��������������

��

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Results��

Study�I���

Purpose�of�the�study�

To� assess� possible� relationship� between� the� contra�lateral� atrium�function�and�that�supporting�ventricular�outflow�tract�obstruction�i.e.�right�atrium� in�aortic�stenosis�and� left�atrium�in�pulmonary�stenosis�which�might�confirm�an�evidence�for�atrial�interaction.��

Results�

Measurements�reproducibility��

Intraobserver�and� interobserver�variability� for�conventional�Doppler�and�TDI�derived�variables� (LV�and�RV�E�wave�deceleration� time,�Sa,�Ea)�ranged�from�1%�to�7%.�Reproducibility�of�long�axis�measurements�has� previously� been� published.� � Table� 1� lists� patients'� clinical� data.�The�patients�had�similar�age�gender�prevalence,�heart�rate,�systemic�blood� pressures� as� the� controls.� All� subjects� had� similar� global�ventricular�systolic�function�(Table�2).�Seventy�six�percent�AS�patients�had�bicuspid�aortic�valves.�The�two�patient�groups�had�similar�degree�of�outflow�tract�obstruction�(Table�1).���

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Table�1.�Patient�Characteristics�

PS:�pulmonary�valvular�stenosis,�AS:�aortic�valvular�stenosis.�Peak�gradient�refers�to�pressure�drop�across�pulmonary�valve�and�aortic�valve�respectively.�

LV� septal� and� lateral�walls� and� RV� free�wall�were� hypertrophied� in�patients� with� aortic� stenosis� (AS)� and� pulmonary� stenosis� (PS)�respectively.�Pressure�overloaded�atria�were�also�dilated� in�patients�(p<0.01� for� all,� Table� 2).� Patients� had� significantly� higher� peak� late�filling�velocities�(A�wave)�recorded�in�the�disease�free�ventricles�(LV�A�wave� in�PS�patients�and�RV�A�wave� in�AS�patients)�but�similar�peak�early� filling� velocities� (E� wave),� E� wave� deceleration� time� and�isovolumic�relaxation�time,�compared�to�controls�(Table�2).�

� Group�1�

PS���������

�(n=41)�

Group�2�

AS�

�(n=41)�

Group�3�

Control�

�(n=27)�

p�value�

(1�vs�2)�

p�value�����

(1�vs�3)�

p�value����

(2�vs�3)�

Age�(yr)� 36�10� 35�12� 30�7� NS� NS� NS�

Sex�(M/F)� 19/22� 24/17� 13/14� NS� NS� NS�

HR�(beat/min)� 70�7� 70�13� 71�7� NS� NS� NS�

Co�morbidities� None� None� None� NS� NS� NS�

Bicuspid�aortic�valve� 0/41�(0%)� 31/41�(76%)� 0/27�(0%)� <0.01� NS� <0.01�

SBP�(mmHg)� 121�11� 125�10� 121�13� NS� NS� NS�

DBP�(mmHg)� 68�9� 72�10� 70�14� NS� NS� NS�

Peak�gradient�(mmHg)� 62�13� 66�18� ��� 0.27� ��� ���

��

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Table�2.�Global�cardiac�structure�and�function�� Group�1

PS���������(n=41)�

Group�2�AS�

�(n=41)�

Group�3Control�(n=27)�

p�value���(1�vs�2)�

p�value����(1�vs�3)�

p�value����(2�vs�3)�

Atrial�and�ventricular�geometry�LV� end�diastolic� diameter�index,�mm/m2�

31.8�4.7 33.4�4.1 32.5�4.2 NS� NS� NS�

RV� end�diastolic� diameter�index,�mm/m2�

22.3�5.2 19.5�4.9 19.9�4.5 <0.05� <0.05� NS�

Interventricular� septal�thickness,�mm�

11.3�2.8 12.0�2.6 8.8�1.6� NS� <0.01� <0.01�

LV�posterior�wall�thickness,�mm�

8.9�1.8� 11.6�2.4 8.6�1.6� <0.05� NS� <0.05�

RV�free�wall�thickness,�mm 9.5�2.3� 6.1�1.7� 5.9�1.6� <0.01� <0.01� NS�

Left�atrial�dimension,�mm� 34.1�3.3 38.4±4.2 32.1�3.5 <0.05� NS� <0.01�

Right�atrial�dimension,�mm 39.4±4.2 32.1�3.5 33.4�3.9 <0.01� <0.05� NS�

LV�mass�index,�gram/m2� 92�25� 135�26� 87�15� <0.05� NS� <0.05�

Global�ventricular�systolic�function� �

LV�ejection�fraction�(%)� 69.2�6.2 71.2�8.2 68.2�6.1 NS� NS� NS�

RV�ejection�fraction�(%)� 54.2�13.754.3�11.853.0�13.4 NS� NS� NS�

Global�ventricular�diastolic�function�

LV�filling�

E�(cm/s)

A�(cm/s)

DT�(ms)

IVRT�(ms)

70�18�

60�17�

194�40

69�11�

89�26�

67�14�

216�38�

67�10�

72�15�

51�10�

210�22

66�15�

<0.01�

<0.05�

<0.01�

NS�

0.71�

<0.01�

0.10�

NS�

<0.01�

<0.01�

0.47�

NS�

RV�filling�

E�(cm/s)

A�(cm/s)

DT�(ms)

IVRT�(ms)

56�13�

48�18�

177�32

67�13�

50�13�

52�17�

180�22�

61�18�

53�13�

37�15�

184�25

62�17�

NS�

0.30�

NS�

NS�

NS�

<0.01�

NS�

NS�

NS�

<0.01�

NS�

NS�

��

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Segmental�long�axis�function�(M�mode�systolic�amplitude,�TDI�Sa�and�Ea� velocities)� was� impaired� in� the� pressure�overloaded� ventricles�(Table� 3).� Septal� long� axis� function� was� impaired� in� both� patient�groups� as� compared� to� controls� (p<0.01� for� all).� Patients� had�increased� TDI� late� diastolic� velocities� (Aa)� in� disease�free� ventricles�(lateral� site� Aa� in� PS� patients� and� tricuspid� site� Aa� in� AS� patients)�despite�similar�E/Ea�ratios�as�compared�to�controls�(pb�0.05�for�all).��

� ���

��

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Table�3.�Segmental�ventricular�long�axis�function��

Group�1

PS��������

�(n=41)�

Group�2

AS�

�(n=41)�

Group�3

Control�

�(n=27)�

p�value����(1�vs�2)�

p�value���(1�vs�3)�

p�value�����(2�vs�3)�

LV�lateral�site�long�axis�

Lateral� Systolic�Amplitude,�LSA�(cm)� 1.5�0.3� 1.4�0.3� 1.6�0.3� 0.19� 0.05� 0.03�

Lateral�TDI��Sm�(cm/s) 9.1�2.0� 6.8�1.6� 9.9�1.9� <0.01� 0.10� <0.01�

��������������������Em�(cm/s) 9.8�3.1� 9.1�2.6� 10.8�2.0 0.24� 0.15� <0.01�

�������������������Am�(cm/s) 8.6�2.4� 8.0�1.9� 7.4�2.1� 0.20� 0.03� 0.30�

E/Em� 9.1�2.8� 8.9�3.4� 8.7�8.5� NS� NS� NS�

LV�Septal�site�

Septal� Systolic�Amplitude,�SSA�(cm)� 1.1�0.3� 1.2�0.2� 1.4�0.2� 0.30� <0.01� <0.01�

Septal�TDI���Sm�(cm/s) 6.3�1.5� 5.8�1.4� 9.1�2.0� 0.13� <0.01� <0.01�

��������������������Em�(cm/s) 7.2�2.2� 6.6�2.0� 9.9�3.0� 0.24� <0.01� <0.01�

��������������������Am�(cm/s) 7.3�1.5� 7.4�1.5� 6.1�1.1� 0.76� <0.01� <0.01�

��������������������E/Em� 8.7�3.5� 9.8�5.0� 9.3�4.7� NS� NS� NS�

RV�long�axis�

RV� Systolic�Amplitude,�SSA�(cm)� 1.4�0.3� 2.4�0.4� 2.4�0.4� <0.01� <0.01� 0.95�

RV�TDI������Sm�(cm/s)� 8.6�2.7� 11.1�1.9 11.1�2.0 <0.01� <0.01� 0.92�

�������������������Em�(cm/s)� 7.6�2.3� 10.4�2.6 13.0�2.8 <0.01� <0.01� <0.01�

�������������������Am�(cm/s) 8.5�2.4� 9.1�2.0� 7.9�2.2� 0.19� 0.24� 0.02�

�������������������E/Em� 9.7�4.2� 10.4�6.0 10.9�6.7 NS� NS� NS�

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Correlation� analysis� identified� a� positive� moderate� relationship�between�the�attenuation�of�atrial�systolic�activity�and�the�degree�of�contra�lateral�ventricular�outflow�obstruction�(LV�A�wave�velocity�and�peak� pulmonary� valve� gradient� in� PS� patients:� r=0.62;� RV� A� wave�velocity�and�peak�aortic�valve�gradient�in�AS�patients:�r=0.61,�p<0.001�for�both,�Figs.�1�and�2).��

LV late filling velocity (cm/s)

Peak pulmonary valve gradient (mmHg)

r=0.62, p<0.001

�Figure�1.�Correlation�between�PS�gradient�and�LV�late�filling�velocity�

RV late filling velocity (cm/s)

Peak aortic valve gradient (mmHg)

r=0.62, p<0.001

�Figure�2.�Correlation�between�AS�gradient�and�RV�late�filling�velocity�

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Study�II�

Purpose�of�the�study�

To�test�the�hypothesis�that�patients�with�long�standing�hypertension�and� paroxysmal� atrial� fibrillation� have� impaired� left� atrial� intrinsic�myocardial�function�and�determine�the�level�of�its�distribution.��

Results�

Measurements�reproducibility��

The� total� number� of� accepted� left� atrial� (LA)� segments� for� analysis�was� 258/276� (93.5%).� The� same� trace�measurements� intra�observer�reproducibility� of� global� LA� strain� was� �1.9%� and� global� strain� rate�was��2.0%.�Respective�values�for�inter�observer�reproducibility�were��3.2%�and��2.2%.�The�different�trace,�intra�observer�reproducibility�of�global� LA� strain� was� �2.9%� and� strain� rate� was� �3.6%.� Respective�values�for�inter�observer�reproducibility�were��7.1%�and��9.3�%.�

Demographic�and�echocardiographic�characteristics�(Table�1)�

Patients� were� older� than� controls� (p<0.01)� but� with� similar� gender�distribution.�LA�longitudinal�diameter�was�larger�in�patients�(p<0.01),�but� transverse� diameter� was� not� different� from� controls.� LV� filling�pattern� showed� higher� E� wave� velocity� (p<0.001)� and� hence� raised�E/A�(p<0.05)�in�patients�compared�to�controls.��

���������

��

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Table�1.�The�conventional�data�in�controls�and�AF�patients�

� Controls�(n=21) AF�(n=25)� p�

Age,�year� 60±14� 70±8� 0.006�

Female/Male� 13/8� 15/10� 0.89�

LA�longitudinal�diameter,�cm� 4.8±0.6� 5.6±0.7� 0.002�

LA�transverse�diameter,�cm� 3.7±0.5� 3.9±0.7� 0.31�

E,�cm/s� 63±15.� 89±25� 0.001�

A,�cm/s� 54±14� 58±27� 0.62�

E/A� 1.3±0.4� 1.8±0.8� 0.04�

Em,�cm/s� 10.6±3.3� 10.2±2.7� 0.52�

E/Em� 6.8±3.9� 9.7±5.1� 0.18�Values� are� presented� as� mean� ±� SD.� LA,� left� atrium.� E:� early� diastolic� velocity;����������A:�late�diastolic�velocity;�Em:�early�diastolic�myocardial�velocity�of�lateral�wall.��Normal�LA�Function�(Table�2)�

LA�myocardial�strain�(S)�values�were�invariably�not�different�between�the� 6� measured� segments.� Likewise,� myocardial� strain� rate� (SR)�measurements� were� equally� distributed� in� 5/6� segments� except� the�lateral�rear�segment�where�it�was�reduced�with�respect�to�the�lateral�annular� segment� (p=0.05).� In� contrast,� myocardial� velocities� took� a�different� pattern.� They�were� equally� highest� at� the� annular� level� of�the� lateral� and� septal� segments� and� exponentially� fell� at� the�respective�mid�cavity� and� rear� segments� (p<0.01� for� all)� except� the�lateral� rear� segment,�which�was� not� different� from� the� lateral�mid�cavity�segment�(p=ns).�

��

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PAF�vs.�Controls�(Table�2)�

LA�global�(the�sum�up�of�the�accepted�segments)�myocardial�S�and�SR�were� significantly� reduced� in� patients� compared� to� controls� (p<0.05�and�p<0.01,� respectively).� Individual�myocardial� segmental� S�and�SR�were� also� reduced� in� patients� at� the� three� levels� of� the� lateral� and�septal�walls� (p<0.01�and�p<0.05,�respectively)�compared�to�controls.�In� patients,� the� lateral� and� septal� S� of� the� rear� segments� was� the�lowest�compared�with�their�respective�annular�segments�(p<0.05�for�both).�Likewise,�SR�was�reduced�at�all�segments�compared�to�controls�(p<0.01)� with� the� rear� lateral� segment� lower� than� the� annular�segment� (p<0.05).� LA�myocardial� velocities�were� not� different� from�controls� at� any� level,� annular,� mid�cavity� or� rear� segments� and�followed�the�same�pattern�of�velocity�distribution�as�controls.��

��

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Table�2.�Comparison�of�Strain,�strain�Rate�and�Velocity�during�atrial�contraction� by� Speckle� Tracking� Echocardiography� in� PAF� patients�and�controls�� Controls�(n=21)� PAF�(n=25)� P�

Mean�Strain,�%� �13.1±4.3� �8.8±4.5� 0.03�

Mean�Strain�Rate,�1/s� �1.7±0.7� �1.1±0.5� 0.006�

Segmental�Strain�,�%�

����Septal�annular� �14.7±3.8� �9.1±5.6� 0.01�

����Septal�mid� �14.7±4.4� �8.8±5.3� 0.01�

����Septal�rear� �13.5±5.9� �6.9±5.4� 0.01�

����Lateral�annular� �13.8±5.5� �8.3±4.8� 0.006�

����Lateral�mid� �13.1±4.4� �6.4±5.0� 0.002�

����Lateral�rear� �12.1±6.3� �5.4±4.2� 0.002�

Segmental�Strain�Rate,�1/s�

����Septal�annular� �2.1±0.7� �1.4±0.8� 0.05�

����Septal�mid� �2.2±0.8� �1.3±0.7� 0.004�

����Septal�rear� �2.0±1.0� �1.3±0.6� 0.04�

����Lateral�annular� �2.4±0.9� �1.6±0.8� 0.03�

����Lateral�mid� �2.2±0.7� �1.3±0.7� 0.006�

����Lateral�rear� �1.9±0.8� �1.2±0.4� 0.001�

Segmental�Velocity,�cm/s�

����Septal�annular� 5.6±1.9� 4.3±2.6� 0.17�

����Septal�mid� 3.7±1.9� 3.2±1.4� 0.22�

����Septal�rear� 1.7±1.0� 1.8±1.1� 0.77�

����Lateral�annular� 5.5±1.8� 4.6±2.5� 0.24�

����Lateral�mid� 3.0±1.1� 2.9±1.7� 0.78�

����Lateral�rear� 2.4±1.1� 2.1±1.1� 0.62�

Values�are�presented�as�mean�±�SD.�

��

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LA�Function�vs.�E/A�and�E/Em�(Figure�2�and�3)�

There�was�no�relationship�between�S�or�SR�and�E/A�in�controls.�Both�global�S�(r=0.60,�p<0.01)�and�SR�(r=0.51,�p<0.01)�correlated�with�E/A,�in�the�patient’s�group.�All�segmental�S�and�SR�correlated�with�E/A,�the�highest�value� for�S�was�at� the�mid�septal�segment� (r=0.67,�p<0.001)�and�for�SR�at�the�mid�lateral�segment�(r=0.70,�p<0.001).�Only�a�weak�negative� relationship� was� found� between� LA� myocardial� velocities�and�E/A�at�the�septal�annular�(r=�0.49,�p<0.05)�and�septal�mid�cavity�segment�r=�0.51,�p<0.05)�in�controls.�Likewise,�a�negative�relationship�between� LA� velocities� and� E/A� was� found� in� patients� at� septal�(annular:�r=�0.52,�p<0.01)�and�at�lateral�(annular�r=�0.62,�p<0.01�and�mid�cavity� r=�0.47,� p<0.05)� segments.� E/Em� did� not� correlate� with�any�of�LA�global�or�segmental�S�or�SR�measurements.�There�was�no�relationship� between� S� or� SR� and� LA� dimensions� in� controls.� In�patients,�LA�longitudinal�dimension�correlated�with�lateral�mid�cavity�(r=0.56,� p=0.007)� and� lateral� annular� S� (r=0.48,� p=0.02)� as� well� as�lateral� mid�cavity� SR� (r=0.41,� p=0.05).� There� was� no� relationship�between�myocardial�velocities�and�LA�dimensions.���

��

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Table� 3.� Correlation� between� E/A� and� segmental� S� and� SR� in� AF�patients,� both� segmental� S� and� SR� are� no� correlation� with� E/A� in�controls.�

Correlation�E/A� and�Strain�

Mean�S�

Septal� Lateral�

� Annular Mid� Rear Annular Mid� Rear�

r� 0.60� 0.50� 0.67� 0.47� 0.45� 0.45� 0.36�

p� 0.002� 0.02� 0.000 0.03� 0.03� 0.04� 0.11�

Correlation�E/A�and�SR�

Mean�SR�

Septal� Lateral�

� Annular Mid� Rear Annular Mid� Rear�

r� 0.51� 0.40� 0.53� 0.50� 0.67� 0.70� 0.25�

P� 0.01� 0.05� 0.008 0.02� 0.000� 0.000� 0.27�

��

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�������������������Figure�1.�The�strain�(a)�and�strain�rate�(b)�during�atrial�����������������������������������������contraction�by�speckle�tracking�echocardiography.�

��

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�Figure�2.�Correlation�between�mean�S�with�E/A�in�patients�and�controls.�

�Figure�3.�Correlation�between�mean�SR�and�E/A�in�patients�and�controls.�

��

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Figure�4.�Correlation�between�segmental�septal�Strain�and�E/A�in�patients�

.Figure�5.�Correlation�between�segmental�lateral�Strain�and�E/A�in�patients�

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Study�III�

Purpose�of�the�study�

To� assess� left� atrial� intrinsic� function� in� patients� with� raised� right�

ventricular�after�load�in�the�form�of�pulmonary�hypertension.�

Results�

Table� 1� summarizes� significant� echocardiographic� measurements�

comparison� between� patients� and� controls.� In� patients,� LA�

longitudinal�diameter�was�not�different�from�controls�but�transverse�

diameter� was� reduced� (p<0.001).� LA� systolic� strain� during� the�

reservoir� phase� was� reduced� at� mid�cavity� and� annular� septal� wall�

(p<0.02� &� p<0.03,� respectively).� Lateral� wall� strain� (p<0.02� and�

p<0.05)� and� strain� rate� (p<0.001� and� p<0.01)� were� reduced� at�

annular�and�mid�cavity� levels.�Septal�strain�(p<0.04�and�p<0.01)�and�

strain� rate� (p<0.02� and� p<0.01)� at� mid�cavity� and� rear� levels� were�

also�reduced.�Transmitral�A�wave�was�increased�in�patients�(p<0.001)�

making�E/A�ratio�significantly�lower�than�controls�(p<0.001).��

�����������

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Table�1.�Echocardiographic�measurements�in�patients�&�control�group�� �

Variable� Patients��� Controls��� P�value�

�� (n=35)� (n=21)� ��

Longitudinal�diameter�(cm)� 4.7�±0.9� �4.8�±0.6� 0.61�

Transverse�diameter�(cm)�� 3.04�±�06� �3.7��±�0.4� <0.001�

Mean�strain�(reservoir)� 9.3�±�8.8� 13.7�±�4.7� 0.02�

Septal�mid�cavity�strain� 10.2�±�8.7� 14.8�±�7.4� 0.04�

Septal�rear�strain� 10.8�±�10.4� 16.7�±�5.6� 0.01�

Septal�mid�cavity�Strain�Rate� 1.2�±�0.6� 1.5�±�0.4� 0.02�

Septal�rear�Strain�Rate��� 1.2�±�0.6� 1.6�±�0.3� 0.01�

Lateral�rear�Strain�Rate�� 1.2�±�0.6� 1.5�±�0.4� 0.08�Lateral�mid�cavity�Strain�Rate�� 1.3�±�0.6� 1.8�±�0.5� 0.01�

Lateral�annular�Strain�Rate�� 1.4�±�0.7� 2.3�±�0.8� <0.001�

A� 0.8�±�0.1� 0.5�±�0.1� <0.001�

E/A� 0.8�±�0.2� 1.2�±�0.4� <0.001�A:�Late�diastolic�LV�filling�velocities.�E/A:�Early/late�diastolic�LV�velocity�ratio�

Pulmonary�artery�pressure�and�its�influence�on�LA�function���

Table� 2� shows� the� correlations� between� pulmonary� artery� systolic�pressure�(PASP)�and�LA�structure�and�function�measurements.�PASP�did� not� correlate� with� LA� dimensions,� but� only� with� myocardial�intrinsic� function� as� shown� by� mean� strain� during� reservoir� phase.�This� relationship�was�much�stronger�at� the� lateral�wall� three� levels;�annular� (r=0.45,� p<0.01),� mid�cavity� (r=� 0.43,� p<0.01)� and� rear�segment� (r=� 0.40,� p<0.02)� and� to� a� lesser� extent� the� septal� wall,�particularly�the�mid�cavity�and�rear�levels�(r=0.35,�p<0.04�and�r=0.39,�p<0.02�respectively).�PASP�did�not�correlate�with�LV�E/A.��

��

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Table�2.�Correlations�between�PASP�and�LA�parameters��

Variable� R� P�� �

Longitudinal�diameter�(cm)� �0.06 0.72� �Transversal�diameter�(cm)� �0.18� 0.31�

�LA�mean�systolic�strain�� 0.07 0.67� �LA�mean�strain�(reservoir)� �0.42� 0.01�

�Septal�annular�strain�(reservoir) �0.30 0.08� �Septal�mid�cavity�strain�(reservoir) �0.35 0.04� �Septal�rear�strain�(reservoir)�� �0.39� 0.02�

�Lateral�annular�strain�(reservoir) �0.45 0.01� �Lateral�mid�cavity�strain�(reservoir) �0.43 0.01� �Lateral�rear�strain�(reservoir)�� �0.40� 0.02�

�Septal�annular�strain�rate� 0.18 0.30� �Septal�mid�cavity�strain�rate 0.14 0.44� �Septal�rear�strain�rate�� 0.05� 0.79�

�Lateral�annular�strain�rate� 0.25 0.15� �Lateral�mid�cavity�strain�rate 0.06 0.75� �Lateral�rear�strain�rate�� �0.08� 0.65�

�Septal�annular�velocity�A �0.37 0.03� �Septal�mid�cavity�velocity�A 0.18 0.32� �Septal�back�velocity�A� 0.03� 0.83�

�Lateral�annular�velocity�A 0.09 0.62� �Lateral�mid�cavity�velocity�A 0.21 0.22� �Lateral�back�velocity�A� 0.22 0.21� �� � �� � � �

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Right�atrial�pressure�and�its�influence�on�LA�function��

Table� 3� shows� the� correlation� between� right� atrial� pressure�measurements� and� LA� structure� and� function.� Mean� right� atrial�pressure�was�8�mmHg.�It�did�not�correlate�with�LA�diameters,�neither�with�any�of�the�LA�global�or�segmental� intrinsic�myocardial� function�measurements� i.e.� strain� or� strain� rate.� It� did� however,� correlate�modestly� with� septal� annular� and� mid�cavity� velocities� (r=0.48,�p<0.00�and�r=0.44,�p<0.00�respectively).�Right�atrial�pressure�did�not�correlate�with�Transmitral�‘A’�velocity�neither�with�E/A�ratio.�

� � � �

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Table�3.�Correlation�between�RA�pressure�and�LA�parameters��

Variable�� r P� �

Longitudinal�diameter� �0.01� 0.97� �

Transversal�diameter� 0.05� 0.75� �

�� � � �

Mean�LA�systolic�strain� 0.15� 0.33� �

Mean�LA�strain�during�reservoir� �0.19� 0.23� �

�� � � �

Septal�annular�strain�(reservoir)� �0.17� 0.28� �

Septal�mid�cavity�strain�(reservoir)� �0.18� 0.25� �

Septal�rear�strain�(reservoir)� �0.18� 0.24� �

�� � � �Lateral�annular�strain�(reservoir)� �0.16� 0.30� �Lateral�mid�cavity�strain�(reservoir)�Lateral�rear�strain�(reservoir)����������������

�0.13��0.16�

0.39�0.29�

Septal�annular�strain�rate�� 0.27� 0.08� �

Septal�mid�cavity�strain�rate� 0.29� 0.06� �

Septal�rear�strain�rate�� 0.24� 0.11� �

�� � � �

Lateral�annular�strain�rate�� 0.27� 0.08� �

Lateral�mid�cavity�strain�rate� 0.22� 0.16� �

Lateral�rear�strain�rate�� 0.22� 0.15� �

�� � � �

Septal�annular�velocity�A� �0.48� 0.00� �

Septal�mid�cavity��velocity�A� �0.44� 0.00� �

Septal�back�velocity�A� �0.25� 0.11� �

�� � � �

Lateral�annular�velocity�A� �0.19� 0.22� �

Lateral�mid�cavity�velocity��A� �0.03� 0.85� �

Lateral�back�velocity�A� 0.02� 0.91� �

�� � � �

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Study�IV�

Purpose�of�the�study�

To� assess� the� relationship� between� intrinsic� left� atrial� myocardial�function� and� the� severity� of� intracavitary� pressure,� invasively�assessed�as�pulmonary�capillary�wedge�pressure.��

Results�

Reproducibility�of�LA�strain�rate�measurements�

The� intraobserver� and� interobserver� variability� for� LA� strain� rate�measurements� were� 7.1%� and� 9.3%.� This� has� been� previously�published.��

Table�1�shows�the�basic�cardiac�function�and�hemodynamic� invasive�measurements�obtained�from�the�right�heart�catheterisation.�Table�2�displays� patients� echocardiographic� measurments� of� LA� and� LV�structure� and� function.� Table� 3� shows� correlation� results� between�pulmonary�capillary�wedge�pressure�measurements,�LA�structure�and�function� and� indirect� Doppler�measures� of� LV� filling� pressures.� The�mean� values� for� LV� ejection� fraction�were�within� normal� range� but�PCWP� values� ranged� between� 5� mmHg� and� 35� mmHg.� This�combination� in� breathless� patients� is� conventionally� taken� as� a�manifestation� of� heart� failure� with� preservesd� systolic� function�(HFpEF).��

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Table�1.��Patient�demographics�and�hemodynamic�data�(RHC)�Variables� Means�

Age,�year 61±13�

Heart�rate,�bpm� 73±16�

Sex,�f/m�(%)� 29/17�(63/37)�Hemodynamics� �

PASP,�mmHg� 53±22�

PVR,�WU 4.8±3.8�

RAP,�mmHg� 9.3±6.4�

PCWP,�mmHg� 13.1±7.4�

CO,�l/min 5.0±1.5��

PASP:�pulmonary�artery�systolic�pressure;�PVR:�pulmonary�vascular�resistance;�RAP:�right� atrial� pressure;� PCWP:� pulmonary� capillary� wedge� pressures;� CO:� cardiac�output.���PCWP� strongly� correlated� with� global� LASRa� (p<0.001)� but� only�modestly� with� LA� volume� (p<0.01)� and� LA� systolic� filling� fraction�(p<0.001).�PCWP�also�correlated�with� indirect�measures�of�LV� filling�pressures,�with�E/A�(p<0.001)�the�highest�and�to�a�lesser�extent�with�E� wave� deceleration� time� (p<0.001),� E/e’� of� the� LV� lateral� wall�(p<0.001)� and� IVRT� (p<0.01).� The� highest� predictive� value� of� PCWP�for� LA�measurements�was� the� strain� rate,� being� able� to� accurately�predict� PCWP� in�63%�of�patients,� compared� to�18�%� for� LA� volume�and� 27�%� for� systolic� filling� fraction.� The� difference� between� these�accuracies� was� significant� (p<0.001).� The� strongest� predictor� of�indirect�measures� of� PCWP� (LV� filling� pressures)�was� the� E/A� ratio,�being�able� to� identify�44%�of� the�PCWP�results�compared�with�29%�for�E�wave�deceleration�time,�24%�for�E/e’�and�13%�for�IVRT.�Again,�the�difference�between�E/A�accuracy�and�those�of�the�other�variables�was� significant� (p<0.01).�A� LA� strain� rate� cut�off� value� � of� �� 1.0�1/s�predicted�PCWP�>�15�mmHg�with�a� �sensitivity�of�78%,�specificity�of�84%,�PPV�of�69%��and�NPV�of�90%.��

��

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Table�2.�LV�and�LA�size�and�function�(echocardiography)�Variables� Mean±SD�

Posterior�wall,�mm� 7.2±1.9Septum,�mm� 9.9±2.4LV�diastole,�mm� 50±10LV�systole,�mm� 32±11LVEF,�%� 58±14CO,�l/min 4.8±1.2E�wave�deceleration�time,�ms 167±67LV�IVRT,�ms� 79±29LV�E/A� 1.3±0.8LV�lateral�wall�E/e’� 9.3±4.6LA��volume,�ml� 53±29LASRa,�1/s� 1.2±0.6LV:� left� ventricular;� EF:� ejection� fraction;� CO:� cardiac� output;� IVRT:� isovolumic�relaxation�time;�LA:�left�atrial;�E:�early�diastolic�LV�filling�velocity;�A:�LV�late�diastolic�filling�velocity;�e’:�LV�lateral�wall�early�diastolic�velocity;�LASRa:�left�atrial�strain�rate�during�atrial�contraction.�

Table�3.�Correlations�between�PCWP�and�LA�structure�and�function�Variables� R�value�(r2)� P�value�

LA�volume�

LA�strain�rate�

LA�systolic�filling�fraction�

LV�E/A�

LV�E�wave�deceleration�

E/e’�lateral�wall�

LV�IVRT�

0.43�(0.18)�

0.79�(0.63)�

0.52�(0.27)�

0.66�(0.44)�

0.54�(0.29)�

0.49�(0.24)�

0.36�(0.13)�

<0.01�

<0.001�

<0.001�

<0.001�

<0.001�

<0.001�

<0.01�

LA:�left�atrial;�E:�early�diastolic�LV�filling�velocity;�A:�LV�late�diastolic�filling�velocity;�e’:�LV�lateral�wall�early�diastolic�velocity�

��

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��

�������������������Scatter�plot�between�LASRa�and�PCWP�

������������

�LASRa�in�patients�with�normal�PCWP�

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LASRa�in�patients�with�elevated�PCWP�

ROC� curve� analysis� testing� the� sensitivity� and� specificity� of� different� Doppler�Echocardiography�measurements�to�identify�patients�with�PCWP�>�15�mmHg.�

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Discussion�

The� findings� of� this� thesis� showed� that� in� patients� with� ventricular�outflow�tract�obstruction�the�contra�lateral�atrial�systolic�activity�was�exaggerated� and� related� to� the� severity� of� the� outflow� tract�obstruction,� suggesting� an� evidence� for� atrial� interaction.� A� similar�pattern� was� found� in� PAH,� with� left� atrial� free� wall� function�correlating� with� the� severity� of� pulmonary� hypertension.� In�paroxysmal� atrial� fibrillation� the� LA� was� slightly� enlarged� and� its�global� as� well� as� segmental� strain� (S)� and� strain� rate� (SR)� were�significantly� reduced� in� a� uniform� fashion� and� correlated� with� the�extent� of� LA� cavity� enlargement� as� well� as� with� E/A� ratio.�Furthermore,� LA� SR� inversely� correlated� with� the� severity� of� LA�pressure�rise�as�shown�by�PCWP.��

As�mentioned�before� in� the�anatomy�section,�the� left�atrium�shares�the� outer� circumferential�muscle� fibers� layer�with� the� right� atrium.�This�anatomical�fact�is�bound�to�have�physiological�application�as�part�of� the� integrated� function�of�all� cardiac�components.�Under�normal�physiological� conditions� and� normal� intracardiac� pressures,�traditional� text� books� do� not� tell� us� enough� about� any� possible�functional� interaction� between� the� two� atria.� Prior� documented��however,� has� already� demonstrated� clear� evidence� for� atrial�interaction� ‘cross� talk’� in� patients� with� left� ventricular� hypertrophy�irrespective� of� its� etiology,� which� explained� the� underlying�mechanism� behind� the� Bernheim� ‘a’� wave,� long� described� as� a�reflection� of� right� ventricular� inflow� tract� obstruction.� In� our� first�study�we�revisited�the�same�concept�and�tested�the�same�hypothesis�in� two�middle�age�groups�of�patients�with� right� and� left� ventricular�outflow� tract� obstruction� due� to� pulmonary� stenosis� and� aortic�stenosis,�respectively�[99,100].�In�the�two�groups�of�patients�we�found�significant�differences�in�ventricular�and�atrial�function.�By�inclusion,�all� patients� had� normal� right� and� left� ventricular� size� and� systolic�

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function� as� shown� by� the� conventional� criterion� ‘ejection� fraction’,�which� is� routinely� used� in� clinics.� However,� detailed� assessment� of�ventricular� function� showed� that� the� long� axis� component� is�significantly� abnormal� in� the� ventricle� facing� the� obstruction,� LV� in�aortic� stenosis� and� RV� in� pulmonary� stenosis.� Ventricular� free� wall�long� axis� amplitude� was� reduced� as� were� its� systolic� and� diastolic�velocities.�Septal�long�axis�function�followed�the�same�pattern�in�the�two� patient� groups� without� a� specific� bias.� Although� atrial�mechanical�function�was�exaggerated�as�expected�in�such�conditions�it�behaved�strikingly�independent�of�early�diastolic�filling�velocities�of�their� ventricles,� in� contrast� to� what� normal’s� do� [101].� The� most�important� finding� was� that� the� exaggerated� atrial� function� was�related� to� the� extent� of� outflow� tract� obstruction� of� the� contra�lateral�ventricle,� the� left�atrium� in�pulmonary�stenosis�and�the�right�atrium�in�aortic�stenosis.��The�left�atrium�was�slightly�enlarged�in�AS�patients� and� the� right� atrium� in� the� PS� patients.� Right� and� left�ventricular�isovolumic�relaxation�time�was�normal�in�the�two�patient�groups� as� was� E� wave� deceleration� time,� suggesting� normal� atrial�pressures,� at� rest.� Finally,� E/E’,� again� another� marker� of� atrial�pressures�did�not�differ�significantly�between�patients�and�controls�in�the� two� groups.� � These� findings� suggest� that� despite� normal�pressures� of� the� atrium� serving� the� ventricle� facing� outflow� tract�obstruction,�the�systolic�atrial�function�of�the�contra�lateral�atrium�is�exaggerated�as�a�result�of�a�cross�talk�mechanism�between�the�two.�The� exact� clinical� application� of� such� finding� has� not� been�investigated� yet� but� might� conceptually� indicate� a� degree� of�ventricular�function�disturbances�(other�than�ejection�fraction’�which�reflect� the�effect�of� the� long� term�obstruction�and�which� if� ignored�might�result� in� irreversible�ventricular�dysfunction.�We�have�already�demonstrated� that� those� ventricles� suffer� diastolic� and� systolic�disturbances� at� the� subendocardial� level� (long� axis� function),� in�addition� to� the� consequences� of� the� myocardial� hypertrophy� they�have.�The� implications�of� these�disturbances�was�clearly�manifested�

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in� the� form�of� a� compromised�early�diastolic� filling� component� and�accentuated�late�diastolic�one�and�lost�normal�relationship�between�the� two� ventricular� filling� components.� This� and� other� potential�explanations� of� this� phenomenon� need� to� be� thoroughly�investigated.��

We� again� tested� this� concept� in� another� group� of� patients� with�pulmonary� hypertension,� normal� left� ventricular� structure� and�function� as� well� as� normal� left� atrial� pressure,� as� shown� by�pulmonary� capillary� wedge� pressure.� In� them,� the� left� atrium� was�rather� smaller� in� size,� however� it� showed,� in� a� segmental� fashion,�clear�relationships�with�right�sided�heart�pressures.�Left�atrial�lateral�wall� intrinsic� function� shown� by� myocardial� strain� rate� correlated�with� right� ventricular� peak� systolic� pressure� but� septal� strain� rate�correlated�with�right�atrial�pressure.�These�findings�support�our�first�observation� in� patients� with� right� ventricular� outflow� tract�obstruction,� in�showing�evidence�for�atrial� interaction� in�such�group�of�patients�with�right�ventricular�pressure�overload.�Again,�the�exact�clinical� application�of� such�phenomenon�has� not� been� investigated,�but� it� may� suggest� a� potential� marker� of� worsening� right� atrial�function,� in�such�patients,�and�hence� the�need� for�potential�benefit�from� electrical� boosting� of� right� atrial� function� in� order� to� secure�optimum� right� atrial� emptying� and� consequently� cardiac� output.��Retesting� the� same� findings� in� a� larger� cohort� of� patients� may�determine� a� cut� off� value� of� atrial� dysfunction� and� a� need� for�optimizing�medical�management,�electrically�if�the�medical�treatment�fails.��

The�second�half�of�the�thesis�deals�with�the�effect�of�raised�left�atrial�pressure�on�its�intrinsic�myocardial�function�as�shown�by�its�velocities�and�strain�and�strain�rate�measurements�i.e.�myocardial�deformation.�In� a� study� that� looked� at� patients� with� long� standing� systemic�hypertension�and�paroxysmal�atrial�fibrillation,�whose�left�ventricular�

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systolic� function� was� normal� but� diastolic� function� demonstrated�signs�of�modestly�raised�left�atrial�pressure,�we�found�that�left�atrial�myocardial� velocities,� measured� by� tissue� Doppler� technique� were�not�different�from�normal�in�showing�progressive�fall� in�velocities�as�the� sample� volume�moved�back� to� the� rear� of� the� left� atrium.� This�pattern� mirrored� that� of� the� left� ventricle.� Such� finding� suggested�that�myocardial� tissue�Doppler� velocities� represent� regional�motion�rather� than� intrinsic� segmental� function� as� such.� In� contrast,� LA�myocardial� strain� and� strain� rate� were� significantly� reduced� in� the�patients� in� a� homogenous� and� uniform� fashion� compared� to� age�matched� controls.� These� findings� are� of� specific� importance� in�showing� that� what� could� be� seen� clinically� as� a� normal� left� atrial�function� in� a� patient� in� paroxysmal� atrial� fibrillation� reflects�dysfunctioning�myocardium�as�a�result�of�no�more�than�modest�rise�in� its� cavity� pressure.� Such� patients� represent� the� majority� of�participants�in�HFpEF�studies�and�trials�in�which�clinical�management�has� failed,� so� far,� to� identify� specific� treatment� but� rhythm� studies�have� shown� significant� benefit� from� renin�angiotensin� blocking�agents.�Early� identification�of� left�atrial�dysfunction� in�such�patients�should� guide� towards� stringent� left� atrial� pressure� lowering�treatment� in� order� to� save� them� potential� development� of� chronic�atrial�fibrillation�and�progressive�irreversible�left�atrial�dysfunction.�

The�Final�study�in�this�thesis�further�supported�the�above�findings.�In�a� group� of� patients� who� received� right� heart� catheterization� for�assessment� of� exertional� breathlessness� we� found� that� PCWP�correlates�with�measurements�of�LA�structure�and�function�with�the�strongest� relationship�with�myocardial� intrinsic� function� in� the� form�of�strain�rate�and�to�a�lesser�extent�cavity�volume�and�systolic�filling�fraction.� A� systolic� LA� SR� cut� off� value� of� =<� 1� 1/s� accurately�discriminated�between�patients�with�PCWP�of�>�or�<�than�15�mmHg�with�an�area�under�the�ROC�curve�of�87%.�PCWP�also�correlated�with�indirect� measures� of� raised� LV� filling� pressures� as� shown� by� early�

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diastolic� filling� time� and� velocity� relations,� but� to� a� much� lesser�extent� than� LA� strain� rate� measures.� None� of� these� measured�achieved�a�ROC�AUC�nearly�equal�to�that�of�the�LA�SR.�These�findings�confirm� Frank�Starling� law� in� the� left� atrium� with� the� direct�relationship�between�myocardial�function,�cavity�size�and�pressures.�It� supports� the� suggestion� above,� we� proposed� for� the� paroxysmal�atrial�fibrillation�patients,�that�early�identification�of�raised�left�atrial�pressure� and� impairment� of� myocardial� function� should� guide�towards�optimum�optimization�of�pressure�lowering�management,�in�order�to�save�the�left�atrium�irreversible�function�deterioration.���

�����������������������������

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Limitations�

Study�I�

We�studied�a�cohort�of�patients�with�aortic�and�pulmonary�stenosis�who�were�followed�up�in�the�cardiology�clinics�and�none�of�them�had�significant�documented�arrhythmia�of�mention�that�required�further�investigations.� This� should� not� exclude� possible� subclinical�arrhythmia.� We� did� not� have� invasive� measurements� of� atrial�pressure,� however� we� relied� on� right� and� left� ventricular� normal�isovolumic� relaxation� time,� deceleration� time� and� E/e’� in� the� two�patient�groups�to�exclude�significantly�raised�atrial�pressures.�An�MRI�scan�with�late�enhancement�may�have�shed�more�light�on�the�extent�of�ventricular�myocardial�dysfunction�in�these�patients.��

Study�II�

We� did� not� have� direct� invasive� measurements� of� LA� pressure� but�relied� on� the� conventional� non�invasive� Doppler� measurements,�which� have� previously� been� repeatedly� revalidated.� However,� from�study� 4� Tissue� Doppler� is� known� for� its� angle� dependency� thus�presents�an�important�limitation�due�to�poor�alignment�between�the�Doppler�beam�and�the�LA�myocardial�wall,�therefore�in�this�study�we�used� a� 2D� based� approach� to� quantify� regional� myocardial�deformation�which�is�independent�of�the�ultrasound�angle�as�it�tracks�speckle� patterns� within� serial� B�mode� scans.� We� adapted� the�software� which� was� originally� designed� to� study� the� left� ventricle.�However,� we� believe� that� the� acceptable� reproducibility� and�consistency� of� our� measurements� support� its� potential� use� in�assessing� LA� segmental� function,� despite� its� thin� wall.� There� was� a�clear�age�difference�between�patients�and�controls�but�we�corrected�all�our�measurements�for�that.�

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Study�III�

We�did�not�record�right�atrial�intrinsic�myocardial�function�because�of�its�thin�wall�in�combination�of�being�limited�to�trace�by�its�low�lateral�resolution,� which� together� might� have� raised� doubt� about� the�accuracy� of� the� measurements.� We� therefore,� deduced� that� right�atrial� myocardial� strain� and� strain� rate� function� is� expected� to� be�compromised�with�cavity�dilatation�as�we�have�previously� shown� in�the� left� atrium.� We� relied� on� LA� function� measurements� obtained�from� the� apical� 4�chamber� view� in� order� to� reduce� any� potential�measurement�error�if�they�were�taken�from�the�apical�2�chamber.������

Study�IV�

The� group� of� patients� we� studied� was� heterogeneous� with� various�right� and� left� cardiac� pathologies,� but� they� reflect� real� cohort� of�patients� commonly� presenting� to� cardiology� clinics.� The� apical�measurements,� we� acquired,� were� obtained� with� the� patient� lying�flat�on�the�catheter�lab�table,�which�might�have�affected�the�accuracy�of� the� LV� filling� velocities� and� hence� the� modest� relationship� with�PCWP.� Systolic� LA� SR�was�only�measured� from�one�apical� view�and�should,� in� optimal� approach,� have� been� measured� also� from� the�apical� two�chamber�view.� Isovolumic� relaxation� time�was�measured�from�Doppler� recordings�of� LV� filling�which�does�not� literally� reflect�the� accurate� definition� of� the� phase,� in� view� of� the� known� time�difference�between�mitral�valve�opening�and�the�onset�of�LV� filling.�Pulmonary� venous� flow�was� not�measured�mainly� due� to� technical�limitations� (i.e.� supine� position� of� the� patient).� Bi�plane� volume�measurements� of� both� left� atrium� and� ventricle� should� have� been�optimal� but� this� was� also� not� measured� mainly� due� to� technical�limitations.�

���

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Conclusion��

This� thesis� highlights� four� important� features� of� left� atrial� function�suggesting�close�relationship�between�the�two�atria�as�well�as�the�left�atrium�and�right�ventricular�function.��

A)� In� patients� with� right� ventricular� outflow� tract� obstruction�due� to� pulmonary� stenosis� the� left� atrial� function� is�accentuated,�as�is�the�right�atrial�function�in�patients�with�left�ventricular�outflow�tract�obstruction�by�aortic�stenosis.�These�findings�suggest�an�evidence�for�atrial�interaction�in�the�form�of�‘cross�talk’.��

B)� In� paroxysmal� atrial� fibrillation,� left� atrial� systolic� function� is�suppressed� and� is� directly� related� to� the� indirect� signs� of�raised� filling� pressures.� Also,� detailed� assessment� of�myocardial� function� shows� significantly� impaired� strain� and�strain� rate�measurements� in� contrast� to� TDI� velocities�which�reflect�only�regional�motion.��

C)� In�patients�with�right�ventricular�increased�pressure�afterload�due� to�pulmonary�hypertension,� left�atrial� reservoir� function�is� significantly� impaired� showing� reduced� myocardial� strain�rate�properties.�In�addition,�segmental�function�differ�in�their�response� to� raised�right�heart�pressures�with� the�septal�wall�related�to�right�atrial�pressure�and�lateral�wall�related�to�the�peak� systolic� pulmonary� artery� pressure.� These� findings�represent�a�further�evidence�for�atrial� interaction� in�patients�with�raised�right�ventricular�pressure�afterload.��

D)� Finally,� left� atrial� intrinsic� myocardial� function� correlate�inversely�with� the�extent�of� rise�of� intra�cavitary�pressure�as�shown�by�pulmonary�capillary�wedge�pressure.�These�findings�should� have� significant� clinical� implications� in� identifying�patients�as�a�cause�for�signs�of�heart�failure�and�thus�optimal�treatment�regimen.�

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Acknowledgements�

To�all�of�you�who�have�helped�me�during�the�time�of�my�study,�each�and� everyone� from� co�authors� to� people� who� supported� and�encouraged�me,�thank�you�all.�

First� of� all,� I� would� like� to� express� my� deepest� gratitude� to� my�supervisor�and� friend�Per� Lindqvist.� � Your�encouragement,� support,�and�trust�in�me�and�your�great�knowledge�in�cardiology�have�helped�me�through�these�years.�

Owe� Johnson� and� Ulf� Naslund,� I� am� grateful� for� you� trust,�acceptance� and� encouragement� that� allowed� me� to� join� the�department�and�accomplish�my�degree.��

Stellan� Mörner,� my� co�� supervisor,� I� appreciate� your� effort� for�keeping� me� on� track,� helping,� encouraging� and� providing� me� with�great�ideas.�

Michael� Henein,� words� cannot� express� my� gratitude� and�thankfulness� for� your� great� support� and� the� true�brotherhood.� You�were�always�there�for�me�when�I�needed�your�help�and�advise.�Your�great�knowledge� in�cardiology�and�academic�mentoring�kept�me�on�track�during�these�years.�

Anna�Engstrom�Laurent,�your�advices�and�guidance�gave�me�a�great�courage�during�these�years.��

Kerstin�Rosenqvist�and�Eva�Karlsson,�both�of�you�have�been�such�a�great� help� to� me� in� answering� all� my� questions.� Your� efforts� to�arrange� everything� for� me� in� Sweden� during� my� short� trips� has�helped�me�to�complete�my�objective�with�minimal�difficulties.��

Sandra� Gustafsson,� your� keenness� to� help�me� in� data� analysis� and�measurements�of�echocardiography�made�me�familiar�with�new�echo�technologies.��

��

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Rolf�Hornsten,�my� friend,�your�sincerety� in�welcoming�and�allowing�me� to� share�your� room�during� the�period�of�data�analysis�and�your�helpful�personality�always�encouraged�me�to�keep�me�going�back�and�forth�to�Umea.��

Maria,�Mary�and�Marie,� your� support,�help�and�application�of�your�talent� in� design� and� personal� effort� over� the� course� of� these� years�kept�me��on�track.�

Uncle�Michael�and�Uncle�Nazeih�Younan,��your�support,�frequent�calls�and�encouragement��inspired�me�along�these�years�of�work�and�study�to�complete�my�Ph.D.�Mina�Younan�your�weekly�calls�and�coming�across�the�Atlantic�to�visit�me�and�show�support�something�I�will�never�forget.��

All�my�friends�and�collegues�in�USA,�your�help�had�a�great�influence�on�me�to�achieve�my�goal.�You�all�wonderfully�competed�on�who�will�cover� me� during� my� absence� to� give� me� the� apportunity� to� travel�more� frequent� and� stay� focused� during�my� trips� between�USA� and�Sweden.�

��������������

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��

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��

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��

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��

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