Research ArticleEffect of Left Ventricular Outflow Tract Obstruction onLeft Atrial Mechanics in Hypertrophic Cardiomyopathy

Lynne K Williams12 Raymond H Chan1 Shemy Carasso3 Miranda Durand4

Jimmy Misurka1 Andrew M Crean14 Anthony Ralph-Edwards5 Christiane Gruner6

Anna Woo1 John R Lesser7 Barry J Maron7 Martin S Maron8 and Harry Rakowski1

1Division of Cardiology Toronto General Hospital Toronto ON Canada M5G 2C42Department of Cardiology Papworth Hospital NHS Foundation Trust Papworth Everard Cambridge CB23 3RE UK3Department of Cardiology Baruch Padeh Medical Center Poriya and Bar-Ilan University 15208 Tiberias Israel4Department of Medical Imaging Toronto General Hospital Toronto ON Canada M5G 2C45Department of Cardiac Surgery Toronto General Hospital Toronto ON Canada M5G 2C46Division of Cardiology University Hospital Zurich 8091 Zurich Switzerland7Hypertrophic Cardiomyopathy Center Minneapolis Heart Institute Foundation Minneapolis MN 55407 USA8Hypertrophic Cardiomyopathy Center Tufts Medical Center Boston MA 02111 USA

Correspondence should be addressed to Lynne K Williams lynnewilliams12gmailcom

Received 8 October 2015 Accepted 19 November 2015

Academic Editor Tomas Palecek

Copyright copy 2015 Lynne K Williams et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Left atrial (LA) volumes are known to be increased in hypertrophic cardiomyopathy (HCM) and are a predictor of adverseoutcome In addition LA function is impaired and is presumed to be due to left ventricular (LV) diastolic dysfunction as a resultof hypertrophy and myocardial fibrosis In the current study we assess the incremental effect of outflow tract obstruction (andconcomitant mitral regurgitation) on LA function as assessed by LA strain Patients with HCM (50 obstructive 50 nonobstructive)were compared to 50 normal controls A subset of obstructive patients who had undergone septal myectomy was also studiedUtilising feature-tracking software applied to cardiovascular magnetic resonance images LA volumes and functional parameterswere calculated LA volumes were significantly elevated and LA ejection fraction and strain were significantly reduced in patientswithHCMcomparedwith controls andwere significantlymore affected in patients with obstruction LA volumes and functionweresignificantly improved after septal myectomy LVOT obstruction and mitral regurgitation appear to further impair LA mechanicsSeptal myectomy results in a significant reduction in LA volumes paralleled by an improvement in function

1 Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited cardiacdisorder characterized by pathological left ventricular (LV)hypertrophy complex pathophysiology and diverse clinicaloutcomes Increased LV mass and diastolic dysfunction areassociated with progressive left atrial (LA) dilatation and dys-function often compounded by the presence of LV outflowtract (LVOT) obstruction and concomitant mitral regurgita-tion LA size and volume have been shown to be determinantsof both exercise capacity [1] and major adverse cardiacand cerebrovascular events in patients with HCM [2ndash4]

In addition LA dysfunction and in particular LA boosterpump function have been shown to correlate with heartfailure symptoms in HCM [5] as well as being a strong pre-dictor for the development of atrial fibrillation (AF) requiringhospitalization [6] A recent study of a large cohort of HCMpatients undergoing CMR has demonstrated LA ejectionfraction (LAEF) and minimum LA volumes as predictors ofthe development of AF [7]

The relationship between the LV and LA is highlydynamic and interdependent All phasic aspects of LA func-tion are to some degree affected not only by LV contractility

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 481245 10 pageshttpdxdoiorg1011552015481245

2 BioMed Research International

LA volume curve LA strain curve

LA strain curve

LA strain curve

LA volume curve

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LA volume curve

MV opening

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MV closure

MV opening

MV opening MV opening

MV opening

MV opening

MV closure

MV closure

MV closure

Reservoir filling(LV systole)

Conduit passive emptying

Booster active emptying

Figure 1 Diagrammatic representation of phasic LA function LA volume and strain curves An ECG curve is superimposed to highlighttiming of LV systole and diastole

relaxation compliance and filling pressures but in additionby intrinsic LA contractility relaxation and compliance [89]

LA strain and strain rate analysis by means of featuretracking provides a feasible noninvasive method of assess-ment of LA function [10ndash12] Three distinct phases ofatrial function assessed are (1) reservoir function whichrepresents the storage of pulmonary venous return duringventricular systole and isovolumic relaxation (2) conduitfunction which represents the period of passive emptying ofthe LA down a pressure gradient during early diastole and(3) booster or active contractile function which representsintrinsic atrial contractility during which the atria emptybefore the end of ventricular diastole (see Figure 1) A recentstudy has demonstrated the feasibility and reliability of quan-tification of LA strain and strain rate using CMR myocardialfeature tracking in both normal controls and patients withHCM [13]

The aim of this study was to evaluate alterations in LAvolumes and function in patients with HCM particularlybetween patients with and without LVOT obstruction and

to identify the determinants of LA myopathy in this diseasestate In addition we aimed to study the effects of relief ofLVOT obstruction on LA function in a subset of patientsundergoing septal myectomy

2 Methods and Materials

21 Study Population A retrospective cohort of one hundredadult patients from theHypertrophic Cardiomyopathy Clinicat the Toronto General Hospital with HCM (maximal septalthickness of ge15mm and a septal-to-posterior wall thicknessratio of ge13 in the absence of another cardiac or systemicdisease that could cause LV hypertrophy) was included inthe study All patients had preserved LV systolic function(defined as a CMR-derived LVEF ge55) Patients were insinus rhythm at the time of both the CMR study and echocar-diogram Studies were performed on active cardiac medica-tions Patients were subdivided into two groups as follows(1) a nonobstructive HCM subgroup with LVOT gradient oflt30mmHg both at rest and with provocation (with Valsalvaand amyl nitrate) and (2) an obstructive HCM subgroup with

BioMed Research International 3

resting LVOT gradient of ge30mmHg Patients with latentobstruction only were not included in the current study Acohort of fifty normal controlswhohad previously undergoneCMR at the Tufts Medical Center and the Minneapolis HeartInstitute were included for comparison In addition a subsetof twenty patients with obstructiveHCMwho had undergoneCMR studies before and after septal myectomy was studied

22 Clinical and 2D Echocardiographic Data A retrospectivechart review was performed in order to obtain demographicdata and symptomatic status Standard 2D echocardiographicdata was obtained from the study performed closest to theCMR with all echocardiographic measurements acquired asper ASE guidelines [14 15] Mitral regurgitation was qualita-tively assessed by a single observer and graded as none trivialmild moderate or severe The study was approved by theResearch Ethics Board of the Toronto General Hospital andthe Investigational Review Board of the participating centersin the United States of America

23 CMR Protocol At the Toronto General Hospital CMRimaging was performed on 15T or 3T whole body magnets(Magnetom Avanto Magnetom Verio Siemens HealthcareErlangen Germany) using a 32-element phased-array coilAt Tufts Medical Center CMR imaging was performed on aPhilips Gyroscan ACS-NT 15T scanner (Best Netherlands)and at the Minneapolis Heart Institute on a Siemens Avanto15T scanner (Erlangen Germany) Cine steady state free pre-cession (SSFP) images were acquired in short axis (sequential10mm slices from the atrioventricular ring to the apex) and2- 3- and 4-chamber long axes LV ejection fraction ventric-ular volumes ventricular mass and maximal wall thicknesswere measured by standard offline analysis using customizedsoftware (QMassMR Medis Leiden Netherlands)

24 MR Velocity Vector Imaging VVI is a feature-trackingmethod which incorporates feature and endocardial contourtracking VVI quantifies myocardial motion by automaticallytracking user-defined endocardial and epicardial contours todefine the inward and outward myocardial motion Based onmotion of the tracked points between the frames and knowl-edge of the time interval between frames 2D tissue velocityis computed Strain and strain rate are computed by the rangein the relative distance between localized tracked trace pointscombined with the difference in the relative displacement ofthe tissue motion between tracked points Strain was definedas the instantaneous local trace lengtheningshortening andstrain rate as the rate of lengtheningshortening

The feature-tracking program VVI Version 300 (Siem-ens Healthcare Mountain View CA) was applied to thecine SSFP images from archived studies allowing for strainparameter assessment Cine SSFP data derived from CMRimages were converted from Digital Imaging and Commu-nications in Medicine (DICOM) to Audio Video Interleave(AVI) format creating 30 cardiac phases Subsequently LAmotion was quantified by automatic tracking of user-definedpoints in both the subendocardial and subepicardial regions

Table 1 Phasic LA function parameters

Reservoir functionExpansion index () (119881max minus 119881min)119881mintimes 100Left atrialejectionemptying fraction()

(119881max minus 119881min)119881maxtimes 100

Conduit functionPassive emptyingindexfraction () (119881max minus 119881pre119860)119881maxtimes 100

Conduit volume (mLm2) LV stroke volume minus (119881max minus 119881min)Boosterpump functionActive emptyingindexfraction () (119881pre

119860minus 119881min)119881pre119860 times 100

119881max maximal left atrial volume 119881min minimum left atrial volume 119881pre119860

left atrial volume immediately prior to atrial contraction

25 Left Atrial Volumes LA volumes were determined byVVI software from the four-chamber view using Simpsonrsquosmethod of disks Pulmonary veins and the LA appendagewere excluded in the calculation of volumes The followingwere measured (indexed to body surface area) (1) maximumvolume at end-systole (119881max) (2) pre-119860 volume prior to theonset of atrial contraction (119881pre

119860) and (3) minimum vol-

ume at end-diastole (119881min) From these volumes LA phasicparameters were derived as shown in Table 1

26 Left Atrial Mechanics In the long-axis four-chamberviews endocardial and epicardial borders were manuallytraced in the end-systolic frame The software subsequentlytraced the borders in the other frames of the cardiac cycleautomatically Strain parameters were recorded after visualconfirmation of the best endocardial and epicardial motiontracking (by operator subjective visual assessment) Thestrain curves were gated in systole (119877wave) and longitudinalstrainstrain rate parameters were calculated A diagram-matic representation of the phases of LA function is shownin Figure 1

27 Intra- and Interobserver Variability Offline analysis of allcine SSFP data sets was performed by a single observer (LW)Ten randomly selected studies were reanalyzed by the sameobserver (LW) and a second observer (JM)

28 Statistical Analyses Continuous and categorical data areexpressed as mean (plusmnSD) or 119899 () respectively Comparisonbetween the HCM subgroups and normal controls was per-formed using anANOVA Intra- and interobserver variabilitywere assessed using Bland-Altman analysis Correlationsbetween variables were assessed using Pearsonrsquos correlationor Spearmanrsquos rank correlation coefficient test where appro-priate The independent effects of LVOT obstruction onLA strain parameters were tested using multivariable linearregression models All statistical analyses were performedusing SAS 93 (Cary North Carolina) and MedCalc version11600 (MedCalc Software Belgium) Statistical significancewas defined as a 2-sided 119901 value lt005

4 BioMed Research International

minus15

minus1

minus05

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1

15

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120

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152

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15

2

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

Figure 2 Representative volume strain and strain rate curves from a normal control and patients with nonobstructive and obstructiveHCM

3 Results

31 Patient Demographics and Clinical Data311 Clinical Demographic and 2D EchocardiographicParameters Baseline demographic and echocardiographicparameters for the normal control group and the HCMgroup as a whole are shown in Table 2 with the data forobstructive and nonobstructive HCM subgroups shown inTable 3

312 Cardiovascular Magnetic Resonance Imaging Conven-tional CMR parameters are shown in Tables 2 and 3 WhileLVEF and LVEDVi were not significantly different betweenHCM patients and normal controls LVMI was significantlyelevated in patientswithHCM(806plusmn26 versus 525plusmn11 gm2119901 lt 00001) There was no significant difference in LVEDVibetween HCM patients with and without obstruction How-ever patients with obstructive HCM had a higher LVMI(877 plusmn 24 versus 730 plusmn 26 gm2 119901 = 0006)

32 LA Volumes and Myocardial Mechanics All LA volumeswere significantly elevated in patients with HCM and LAEFsignificantly reduced (448 plusmn 9 versus 65 plusmn 11 119901 lt 00001)

Table 2 Baseline clinical and CMR parameters

Normal controls(119899 = 50)

HCM(119899 = 100) 119901 value

Clinical characteristicsAge at CMR (years) 426 plusmn 16 497 plusmn 15 0007Sex (male 119899 ) 28 (56) 70 (70) 009BSA 194 plusmn 03 194 plusmn 02 096NYHA IIIIIIIV () 100000 5619250 lt00001CMR parametersLVEF () 625 plusmn 6 631 plusmn 7 058LVEDVi (mLm2) 877 plusmn 16 868 plusmn 13 072LVMi (gm2) 525 plusmn 11 806 plusmn 26 lt00001CMR cardiac magnetic resonance BSA body surface area NYHA NewYork Heart Association functional class LVEF left ventricular ejectionfraction LVEDVi indexed left ventricular end-diastolic volume LVMiindexed left ventricular mass

with all phases of LA function (reservoir conduit andbooster) affected These findings remained even after adjust-ment for age LVMI and LVEDVi Representative LA volumestrain and strain rate curves are shown in Figure 2

BioMed Research International 5

r = minus082

r = minus054

0

10

20

30

40

50

60

70

80

90LA

EF (

)

0

10

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50

60

70

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90

LAEF

()

20 40 60 80 100 1200Vmax (mLm2)

20 40 60 800Vmin (mLm2)

(a)

r = minus053

r = minus086

0

100

200

300

400

500

600Ex

pans

ion

inde

x (

)

20 40 60 800Vmin (mLm2)

20 40 60 80 100 1200Vmax (mLm2)

0

100

200

300

400

500

600

Expa

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()

(b)

Figure 3 (a) Correlation between LA ejection fraction (LAEF ) and maximumminimum LA volumes (b) Correlation between LAexpansion index and maximumminimum LA volumes

33 Relationship between LVOT Obstruction and LAMechan-ics Patientswith obstructiveHCMhad a significantly greaterimpairment in LA function and larger LA volumes (Table 4)and LAEF was significantly lower (423 plusmn 8 versus 472 plusmn 9119901 = 0004) Although conduit function was not differentbetween the two HCM subgroups patients with obstructionhad significantly more impairment of LA reservoir functionwith lower reservoir strain (145 plusmn 4 versus 177 plusmn 5 119901 =0002) and strain rate (059 plusmn 02 versus 073 plusmn 02s 119901 =0001) In addition there was a significant reduction in bothbooster strain (61plusmn2 versus 75plusmn3119901 = 001) and strain rate(minus044plusmn01 versusminus058plusmn025s119901 = 0004)The reduction inLA function and increase in LA volumes remained significanteven after adjusting for age LVMI LVEDVi and degree ofmitral regurgitation

34 Correlation of LA Mechanics and Echocardiographic andCMR Parameters There were no significant correlationsbetween strain or strain rate parameters and 2D echocar-diographic parameters of diastolic function or between rest-ingprovocable LVOT gradients and either strain or strainrate parameters LVMI correlated inversely with reservoirstrain (119903 = minus061 119901 lt 00001) booster strain (119903 = minus052 119901 lt00001) and LAEF (minus056119901 lt 00001) Correlations betweenLA volumes and LA mechanics are shown in Figure 3 andTable 5

35 Effect of Septal Myectomy on Left Atrial Volumes andMechanics The mean time from surgery to repeat CMRwas 86 months (range 5 to 18 months) No patients under-went a concomitant surgical MAZE procedure Significant

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 BioMed Research International

LA volume curve LA strain curve

LA strain curve

LA strain curve

LA volume curve

10

30

50

70

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

10

30

50

70

10

30

50

70

0 50 100 0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 50 100

LA volume curve

MV opening

MV closure

MV closure

MV closure

MV opening

MV opening MV opening

MV opening

MV opening

MV closure

MV closure

MV closure

Reservoir filling(LV systole)

Conduit passive emptying

Booster active emptying

Figure 1 Diagrammatic representation of phasic LA function LA volume and strain curves An ECG curve is superimposed to highlighttiming of LV systole and diastole

relaxation compliance and filling pressures but in additionby intrinsic LA contractility relaxation and compliance [89]

LA strain and strain rate analysis by means of featuretracking provides a feasible noninvasive method of assess-ment of LA function [10ndash12] Three distinct phases ofatrial function assessed are (1) reservoir function whichrepresents the storage of pulmonary venous return duringventricular systole and isovolumic relaxation (2) conduitfunction which represents the period of passive emptying ofthe LA down a pressure gradient during early diastole and(3) booster or active contractile function which representsintrinsic atrial contractility during which the atria emptybefore the end of ventricular diastole (see Figure 1) A recentstudy has demonstrated the feasibility and reliability of quan-tification of LA strain and strain rate using CMR myocardialfeature tracking in both normal controls and patients withHCM [13]

The aim of this study was to evaluate alterations in LAvolumes and function in patients with HCM particularlybetween patients with and without LVOT obstruction and

to identify the determinants of LA myopathy in this diseasestate In addition we aimed to study the effects of relief ofLVOT obstruction on LA function in a subset of patientsundergoing septal myectomy

2 Methods and Materials

21 Study Population A retrospective cohort of one hundredadult patients from theHypertrophic Cardiomyopathy Clinicat the Toronto General Hospital with HCM (maximal septalthickness of ge15mm and a septal-to-posterior wall thicknessratio of ge13 in the absence of another cardiac or systemicdisease that could cause LV hypertrophy) was included inthe study All patients had preserved LV systolic function(defined as a CMR-derived LVEF ge55) Patients were insinus rhythm at the time of both the CMR study and echocar-diogram Studies were performed on active cardiac medica-tions Patients were subdivided into two groups as follows(1) a nonobstructive HCM subgroup with LVOT gradient oflt30mmHg both at rest and with provocation (with Valsalvaand amyl nitrate) and (2) an obstructive HCM subgroup with

BioMed Research International 3

resting LVOT gradient of ge30mmHg Patients with latentobstruction only were not included in the current study Acohort of fifty normal controlswhohad previously undergoneCMR at the Tufts Medical Center and the Minneapolis HeartInstitute were included for comparison In addition a subsetof twenty patients with obstructiveHCMwho had undergoneCMR studies before and after septal myectomy was studied

22 Clinical and 2D Echocardiographic Data A retrospectivechart review was performed in order to obtain demographicdata and symptomatic status Standard 2D echocardiographicdata was obtained from the study performed closest to theCMR with all echocardiographic measurements acquired asper ASE guidelines [14 15] Mitral regurgitation was qualita-tively assessed by a single observer and graded as none trivialmild moderate or severe The study was approved by theResearch Ethics Board of the Toronto General Hospital andthe Investigational Review Board of the participating centersin the United States of America

23 CMR Protocol At the Toronto General Hospital CMRimaging was performed on 15T or 3T whole body magnets(Magnetom Avanto Magnetom Verio Siemens HealthcareErlangen Germany) using a 32-element phased-array coilAt Tufts Medical Center CMR imaging was performed on aPhilips Gyroscan ACS-NT 15T scanner (Best Netherlands)and at the Minneapolis Heart Institute on a Siemens Avanto15T scanner (Erlangen Germany) Cine steady state free pre-cession (SSFP) images were acquired in short axis (sequential10mm slices from the atrioventricular ring to the apex) and2- 3- and 4-chamber long axes LV ejection fraction ventric-ular volumes ventricular mass and maximal wall thicknesswere measured by standard offline analysis using customizedsoftware (QMassMR Medis Leiden Netherlands)

24 MR Velocity Vector Imaging VVI is a feature-trackingmethod which incorporates feature and endocardial contourtracking VVI quantifies myocardial motion by automaticallytracking user-defined endocardial and epicardial contours todefine the inward and outward myocardial motion Based onmotion of the tracked points between the frames and knowl-edge of the time interval between frames 2D tissue velocityis computed Strain and strain rate are computed by the rangein the relative distance between localized tracked trace pointscombined with the difference in the relative displacement ofthe tissue motion between tracked points Strain was definedas the instantaneous local trace lengtheningshortening andstrain rate as the rate of lengtheningshortening

The feature-tracking program VVI Version 300 (Siem-ens Healthcare Mountain View CA) was applied to thecine SSFP images from archived studies allowing for strainparameter assessment Cine SSFP data derived from CMRimages were converted from Digital Imaging and Commu-nications in Medicine (DICOM) to Audio Video Interleave(AVI) format creating 30 cardiac phases Subsequently LAmotion was quantified by automatic tracking of user-definedpoints in both the subendocardial and subepicardial regions

Table 1 Phasic LA function parameters

Reservoir functionExpansion index () (119881max minus 119881min)119881mintimes 100Left atrialejectionemptying fraction()

(119881max minus 119881min)119881maxtimes 100

Conduit functionPassive emptyingindexfraction () (119881max minus 119881pre119860)119881maxtimes 100

Conduit volume (mLm2) LV stroke volume minus (119881max minus 119881min)Boosterpump functionActive emptyingindexfraction () (119881pre

119860minus 119881min)119881pre119860 times 100

119881max maximal left atrial volume 119881min minimum left atrial volume 119881pre119860

left atrial volume immediately prior to atrial contraction

25 Left Atrial Volumes LA volumes were determined byVVI software from the four-chamber view using Simpsonrsquosmethod of disks Pulmonary veins and the LA appendagewere excluded in the calculation of volumes The followingwere measured (indexed to body surface area) (1) maximumvolume at end-systole (119881max) (2) pre-119860 volume prior to theonset of atrial contraction (119881pre

119860) and (3) minimum vol-

ume at end-diastole (119881min) From these volumes LA phasicparameters were derived as shown in Table 1

26 Left Atrial Mechanics In the long-axis four-chamberviews endocardial and epicardial borders were manuallytraced in the end-systolic frame The software subsequentlytraced the borders in the other frames of the cardiac cycleautomatically Strain parameters were recorded after visualconfirmation of the best endocardial and epicardial motiontracking (by operator subjective visual assessment) Thestrain curves were gated in systole (119877wave) and longitudinalstrainstrain rate parameters were calculated A diagram-matic representation of the phases of LA function is shownin Figure 1

27 Intra- and Interobserver Variability Offline analysis of allcine SSFP data sets was performed by a single observer (LW)Ten randomly selected studies were reanalyzed by the sameobserver (LW) and a second observer (JM)

28 Statistical Analyses Continuous and categorical data areexpressed as mean (plusmnSD) or 119899 () respectively Comparisonbetween the HCM subgroups and normal controls was per-formed using anANOVA Intra- and interobserver variabilitywere assessed using Bland-Altman analysis Correlationsbetween variables were assessed using Pearsonrsquos correlationor Spearmanrsquos rank correlation coefficient test where appro-priate The independent effects of LVOT obstruction onLA strain parameters were tested using multivariable linearregression models All statistical analyses were performedusing SAS 93 (Cary North Carolina) and MedCalc version11600 (MedCalc Software Belgium) Statistical significancewas defined as a 2-sided 119901 value lt005

4 BioMed Research International

minus15

minus1

minus05

0

05

1

15

2

0

10

20

30

40

50

0

20

40

60

80

100

120

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

152

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

15

2

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

Figure 2 Representative volume strain and strain rate curves from a normal control and patients with nonobstructive and obstructiveHCM

3 Results

31 Patient Demographics and Clinical Data311 Clinical Demographic and 2D EchocardiographicParameters Baseline demographic and echocardiographicparameters for the normal control group and the HCMgroup as a whole are shown in Table 2 with the data forobstructive and nonobstructive HCM subgroups shown inTable 3

312 Cardiovascular Magnetic Resonance Imaging Conven-tional CMR parameters are shown in Tables 2 and 3 WhileLVEF and LVEDVi were not significantly different betweenHCM patients and normal controls LVMI was significantlyelevated in patientswithHCM(806plusmn26 versus 525plusmn11 gm2119901 lt 00001) There was no significant difference in LVEDVibetween HCM patients with and without obstruction How-ever patients with obstructive HCM had a higher LVMI(877 plusmn 24 versus 730 plusmn 26 gm2 119901 = 0006)

32 LA Volumes and Myocardial Mechanics All LA volumeswere significantly elevated in patients with HCM and LAEFsignificantly reduced (448 plusmn 9 versus 65 plusmn 11 119901 lt 00001)

Table 2 Baseline clinical and CMR parameters

Normal controls(119899 = 50)

HCM(119899 = 100) 119901 value

Clinical characteristicsAge at CMR (years) 426 plusmn 16 497 plusmn 15 0007Sex (male 119899 ) 28 (56) 70 (70) 009BSA 194 plusmn 03 194 plusmn 02 096NYHA IIIIIIIV () 100000 5619250 lt00001CMR parametersLVEF () 625 plusmn 6 631 plusmn 7 058LVEDVi (mLm2) 877 plusmn 16 868 plusmn 13 072LVMi (gm2) 525 plusmn 11 806 plusmn 26 lt00001CMR cardiac magnetic resonance BSA body surface area NYHA NewYork Heart Association functional class LVEF left ventricular ejectionfraction LVEDVi indexed left ventricular end-diastolic volume LVMiindexed left ventricular mass

with all phases of LA function (reservoir conduit andbooster) affected These findings remained even after adjust-ment for age LVMI and LVEDVi Representative LA volumestrain and strain rate curves are shown in Figure 2

BioMed Research International 5

r = minus082

r = minus054

0

10

20

30

40

50

60

70

80

90LA

EF (

)

0

10

20

30

40

50

60

70

80

90

LAEF

()

20 40 60 80 100 1200Vmax (mLm2)

20 40 60 800Vmin (mLm2)

(a)

r = minus053

r = minus086

0

100

200

300

400

500

600Ex

pans

ion

inde

x (

)

20 40 60 800Vmin (mLm2)

20 40 60 80 100 1200Vmax (mLm2)

0

100

200

300

400

500

600

Expa

nsio

n in

dex

()

(b)

Figure 3 (a) Correlation between LA ejection fraction (LAEF ) and maximumminimum LA volumes (b) Correlation between LAexpansion index and maximumminimum LA volumes

33 Relationship between LVOT Obstruction and LAMechan-ics Patientswith obstructiveHCMhad a significantly greaterimpairment in LA function and larger LA volumes (Table 4)and LAEF was significantly lower (423 plusmn 8 versus 472 plusmn 9119901 = 0004) Although conduit function was not differentbetween the two HCM subgroups patients with obstructionhad significantly more impairment of LA reservoir functionwith lower reservoir strain (145 plusmn 4 versus 177 plusmn 5 119901 =0002) and strain rate (059 plusmn 02 versus 073 plusmn 02s 119901 =0001) In addition there was a significant reduction in bothbooster strain (61plusmn2 versus 75plusmn3119901 = 001) and strain rate(minus044plusmn01 versusminus058plusmn025s119901 = 0004)The reduction inLA function and increase in LA volumes remained significanteven after adjusting for age LVMI LVEDVi and degree ofmitral regurgitation

34 Correlation of LA Mechanics and Echocardiographic andCMR Parameters There were no significant correlationsbetween strain or strain rate parameters and 2D echocar-diographic parameters of diastolic function or between rest-ingprovocable LVOT gradients and either strain or strainrate parameters LVMI correlated inversely with reservoirstrain (119903 = minus061 119901 lt 00001) booster strain (119903 = minus052 119901 lt00001) and LAEF (minus056119901 lt 00001) Correlations betweenLA volumes and LA mechanics are shown in Figure 3 andTable 5

35 Effect of Septal Myectomy on Left Atrial Volumes andMechanics The mean time from surgery to repeat CMRwas 86 months (range 5 to 18 months) No patients under-went a concomitant surgical MAZE procedure Significant

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

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Evidence-Based Complementary and Alternative Medicine

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BioMed Research International 3

resting LVOT gradient of ge30mmHg Patients with latentobstruction only were not included in the current study Acohort of fifty normal controlswhohad previously undergoneCMR at the Tufts Medical Center and the Minneapolis HeartInstitute were included for comparison In addition a subsetof twenty patients with obstructiveHCMwho had undergoneCMR studies before and after septal myectomy was studied

22 Clinical and 2D Echocardiographic Data A retrospectivechart review was performed in order to obtain demographicdata and symptomatic status Standard 2D echocardiographicdata was obtained from the study performed closest to theCMR with all echocardiographic measurements acquired asper ASE guidelines [14 15] Mitral regurgitation was qualita-tively assessed by a single observer and graded as none trivialmild moderate or severe The study was approved by theResearch Ethics Board of the Toronto General Hospital andthe Investigational Review Board of the participating centersin the United States of America

23 CMR Protocol At the Toronto General Hospital CMRimaging was performed on 15T or 3T whole body magnets(Magnetom Avanto Magnetom Verio Siemens HealthcareErlangen Germany) using a 32-element phased-array coilAt Tufts Medical Center CMR imaging was performed on aPhilips Gyroscan ACS-NT 15T scanner (Best Netherlands)and at the Minneapolis Heart Institute on a Siemens Avanto15T scanner (Erlangen Germany) Cine steady state free pre-cession (SSFP) images were acquired in short axis (sequential10mm slices from the atrioventricular ring to the apex) and2- 3- and 4-chamber long axes LV ejection fraction ventric-ular volumes ventricular mass and maximal wall thicknesswere measured by standard offline analysis using customizedsoftware (QMassMR Medis Leiden Netherlands)

24 MR Velocity Vector Imaging VVI is a feature-trackingmethod which incorporates feature and endocardial contourtracking VVI quantifies myocardial motion by automaticallytracking user-defined endocardial and epicardial contours todefine the inward and outward myocardial motion Based onmotion of the tracked points between the frames and knowl-edge of the time interval between frames 2D tissue velocityis computed Strain and strain rate are computed by the rangein the relative distance between localized tracked trace pointscombined with the difference in the relative displacement ofthe tissue motion between tracked points Strain was definedas the instantaneous local trace lengtheningshortening andstrain rate as the rate of lengtheningshortening

The feature-tracking program VVI Version 300 (Siem-ens Healthcare Mountain View CA) was applied to thecine SSFP images from archived studies allowing for strainparameter assessment Cine SSFP data derived from CMRimages were converted from Digital Imaging and Commu-nications in Medicine (DICOM) to Audio Video Interleave(AVI) format creating 30 cardiac phases Subsequently LAmotion was quantified by automatic tracking of user-definedpoints in both the subendocardial and subepicardial regions

Table 1 Phasic LA function parameters

Reservoir functionExpansion index () (119881max minus 119881min)119881mintimes 100Left atrialejectionemptying fraction()

(119881max minus 119881min)119881maxtimes 100

Conduit functionPassive emptyingindexfraction () (119881max minus 119881pre119860)119881maxtimes 100

Conduit volume (mLm2) LV stroke volume minus (119881max minus 119881min)Boosterpump functionActive emptyingindexfraction () (119881pre

119860minus 119881min)119881pre119860 times 100

119881max maximal left atrial volume 119881min minimum left atrial volume 119881pre119860

left atrial volume immediately prior to atrial contraction

25 Left Atrial Volumes LA volumes were determined byVVI software from the four-chamber view using Simpsonrsquosmethod of disks Pulmonary veins and the LA appendagewere excluded in the calculation of volumes The followingwere measured (indexed to body surface area) (1) maximumvolume at end-systole (119881max) (2) pre-119860 volume prior to theonset of atrial contraction (119881pre

119860) and (3) minimum vol-

ume at end-diastole (119881min) From these volumes LA phasicparameters were derived as shown in Table 1

26 Left Atrial Mechanics In the long-axis four-chamberviews endocardial and epicardial borders were manuallytraced in the end-systolic frame The software subsequentlytraced the borders in the other frames of the cardiac cycleautomatically Strain parameters were recorded after visualconfirmation of the best endocardial and epicardial motiontracking (by operator subjective visual assessment) Thestrain curves were gated in systole (119877wave) and longitudinalstrainstrain rate parameters were calculated A diagram-matic representation of the phases of LA function is shownin Figure 1

27 Intra- and Interobserver Variability Offline analysis of allcine SSFP data sets was performed by a single observer (LW)Ten randomly selected studies were reanalyzed by the sameobserver (LW) and a second observer (JM)

28 Statistical Analyses Continuous and categorical data areexpressed as mean (plusmnSD) or 119899 () respectively Comparisonbetween the HCM subgroups and normal controls was per-formed using anANOVA Intra- and interobserver variabilitywere assessed using Bland-Altman analysis Correlationsbetween variables were assessed using Pearsonrsquos correlationor Spearmanrsquos rank correlation coefficient test where appro-priate The independent effects of LVOT obstruction onLA strain parameters were tested using multivariable linearregression models All statistical analyses were performedusing SAS 93 (Cary North Carolina) and MedCalc version11600 (MedCalc Software Belgium) Statistical significancewas defined as a 2-sided 119901 value lt005

4 BioMed Research International

minus15

minus1

minus05

0

05

1

15

2

0

10

20

30

40

50

0

20

40

60

80

100

120

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

152

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

15

2

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

Figure 2 Representative volume strain and strain rate curves from a normal control and patients with nonobstructive and obstructiveHCM

3 Results

31 Patient Demographics and Clinical Data311 Clinical Demographic and 2D EchocardiographicParameters Baseline demographic and echocardiographicparameters for the normal control group and the HCMgroup as a whole are shown in Table 2 with the data forobstructive and nonobstructive HCM subgroups shown inTable 3

312 Cardiovascular Magnetic Resonance Imaging Conven-tional CMR parameters are shown in Tables 2 and 3 WhileLVEF and LVEDVi were not significantly different betweenHCM patients and normal controls LVMI was significantlyelevated in patientswithHCM(806plusmn26 versus 525plusmn11 gm2119901 lt 00001) There was no significant difference in LVEDVibetween HCM patients with and without obstruction How-ever patients with obstructive HCM had a higher LVMI(877 plusmn 24 versus 730 plusmn 26 gm2 119901 = 0006)

32 LA Volumes and Myocardial Mechanics All LA volumeswere significantly elevated in patients with HCM and LAEFsignificantly reduced (448 plusmn 9 versus 65 plusmn 11 119901 lt 00001)

Table 2 Baseline clinical and CMR parameters

Normal controls(119899 = 50)

HCM(119899 = 100) 119901 value

Clinical characteristicsAge at CMR (years) 426 plusmn 16 497 plusmn 15 0007Sex (male 119899 ) 28 (56) 70 (70) 009BSA 194 plusmn 03 194 plusmn 02 096NYHA IIIIIIIV () 100000 5619250 lt00001CMR parametersLVEF () 625 plusmn 6 631 plusmn 7 058LVEDVi (mLm2) 877 plusmn 16 868 plusmn 13 072LVMi (gm2) 525 plusmn 11 806 plusmn 26 lt00001CMR cardiac magnetic resonance BSA body surface area NYHA NewYork Heart Association functional class LVEF left ventricular ejectionfraction LVEDVi indexed left ventricular end-diastolic volume LVMiindexed left ventricular mass

with all phases of LA function (reservoir conduit andbooster) affected These findings remained even after adjust-ment for age LVMI and LVEDVi Representative LA volumestrain and strain rate curves are shown in Figure 2

BioMed Research International 5

r = minus082

r = minus054

0

10

20

30

40

50

60

70

80

90LA

EF (

)

0

10

20

30

40

50

60

70

80

90

LAEF

()

20 40 60 80 100 1200Vmax (mLm2)

20 40 60 800Vmin (mLm2)

(a)

r = minus053

r = minus086

0

100

200

300

400

500

600Ex

pans

ion

inde

x (

)

20 40 60 800Vmin (mLm2)

20 40 60 80 100 1200Vmax (mLm2)

0

100

200

300

400

500

600

Expa

nsio

n in

dex

()

(b)

Figure 3 (a) Correlation between LA ejection fraction (LAEF ) and maximumminimum LA volumes (b) Correlation between LAexpansion index and maximumminimum LA volumes

33 Relationship between LVOT Obstruction and LAMechan-ics Patientswith obstructiveHCMhad a significantly greaterimpairment in LA function and larger LA volumes (Table 4)and LAEF was significantly lower (423 plusmn 8 versus 472 plusmn 9119901 = 0004) Although conduit function was not differentbetween the two HCM subgroups patients with obstructionhad significantly more impairment of LA reservoir functionwith lower reservoir strain (145 plusmn 4 versus 177 plusmn 5 119901 =0002) and strain rate (059 plusmn 02 versus 073 plusmn 02s 119901 =0001) In addition there was a significant reduction in bothbooster strain (61plusmn2 versus 75plusmn3119901 = 001) and strain rate(minus044plusmn01 versusminus058plusmn025s119901 = 0004)The reduction inLA function and increase in LA volumes remained significanteven after adjusting for age LVMI LVEDVi and degree ofmitral regurgitation

34 Correlation of LA Mechanics and Echocardiographic andCMR Parameters There were no significant correlationsbetween strain or strain rate parameters and 2D echocar-diographic parameters of diastolic function or between rest-ingprovocable LVOT gradients and either strain or strainrate parameters LVMI correlated inversely with reservoirstrain (119903 = minus061 119901 lt 00001) booster strain (119903 = minus052 119901 lt00001) and LAEF (minus056119901 lt 00001) Correlations betweenLA volumes and LA mechanics are shown in Figure 3 andTable 5

35 Effect of Septal Myectomy on Left Atrial Volumes andMechanics The mean time from surgery to repeat CMRwas 86 months (range 5 to 18 months) No patients under-went a concomitant surgical MAZE procedure Significant

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

EndocrinologyInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 BioMed Research International

minus15

minus1

minus05

0

05

1

15

2

0

10

20

30

40

50

0

20

40

60

80

100

120

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

152

0

20

40

60

80

100

120

0

10

20

30

40

50

minus15

minus1

minus05

0

05

1

15

2

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

Volume curves (mL)

Strain curves ()

Strain rate curves (s)

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

20 40 60 80 1000Obstructive HCM

20 40 60 80 1000Nonobstructive HCM

20 40 60 80 1000Normal control

Figure 2 Representative volume strain and strain rate curves from a normal control and patients with nonobstructive and obstructiveHCM

3 Results

31 Patient Demographics and Clinical Data311 Clinical Demographic and 2D EchocardiographicParameters Baseline demographic and echocardiographicparameters for the normal control group and the HCMgroup as a whole are shown in Table 2 with the data forobstructive and nonobstructive HCM subgroups shown inTable 3

312 Cardiovascular Magnetic Resonance Imaging Conven-tional CMR parameters are shown in Tables 2 and 3 WhileLVEF and LVEDVi were not significantly different betweenHCM patients and normal controls LVMI was significantlyelevated in patientswithHCM(806plusmn26 versus 525plusmn11 gm2119901 lt 00001) There was no significant difference in LVEDVibetween HCM patients with and without obstruction How-ever patients with obstructive HCM had a higher LVMI(877 plusmn 24 versus 730 plusmn 26 gm2 119901 = 0006)

32 LA Volumes and Myocardial Mechanics All LA volumeswere significantly elevated in patients with HCM and LAEFsignificantly reduced (448 plusmn 9 versus 65 plusmn 11 119901 lt 00001)

Table 2 Baseline clinical and CMR parameters

Normal controls(119899 = 50)

HCM(119899 = 100) 119901 value

Clinical characteristicsAge at CMR (years) 426 plusmn 16 497 plusmn 15 0007Sex (male 119899 ) 28 (56) 70 (70) 009BSA 194 plusmn 03 194 plusmn 02 096NYHA IIIIIIIV () 100000 5619250 lt00001CMR parametersLVEF () 625 plusmn 6 631 plusmn 7 058LVEDVi (mLm2) 877 plusmn 16 868 plusmn 13 072LVMi (gm2) 525 plusmn 11 806 plusmn 26 lt00001CMR cardiac magnetic resonance BSA body surface area NYHA NewYork Heart Association functional class LVEF left ventricular ejectionfraction LVEDVi indexed left ventricular end-diastolic volume LVMiindexed left ventricular mass

with all phases of LA function (reservoir conduit andbooster) affected These findings remained even after adjust-ment for age LVMI and LVEDVi Representative LA volumestrain and strain rate curves are shown in Figure 2

BioMed Research International 5

r = minus082

r = minus054

0

10

20

30

40

50

60

70

80

90LA

EF (

)

0

10

20

30

40

50

60

70

80

90

LAEF

()

20 40 60 80 100 1200Vmax (mLm2)

20 40 60 800Vmin (mLm2)

(a)

r = minus053

r = minus086

0

100

200

300

400

500

600Ex

pans

ion

inde

x (

)

20 40 60 800Vmin (mLm2)

20 40 60 80 100 1200Vmax (mLm2)

0

100

200

300

400

500

600

Expa

nsio

n in

dex

()

(b)

Figure 3 (a) Correlation between LA ejection fraction (LAEF ) and maximumminimum LA volumes (b) Correlation between LAexpansion index and maximumminimum LA volumes

33 Relationship between LVOT Obstruction and LAMechan-ics Patientswith obstructiveHCMhad a significantly greaterimpairment in LA function and larger LA volumes (Table 4)and LAEF was significantly lower (423 plusmn 8 versus 472 plusmn 9119901 = 0004) Although conduit function was not differentbetween the two HCM subgroups patients with obstructionhad significantly more impairment of LA reservoir functionwith lower reservoir strain (145 plusmn 4 versus 177 plusmn 5 119901 =0002) and strain rate (059 plusmn 02 versus 073 plusmn 02s 119901 =0001) In addition there was a significant reduction in bothbooster strain (61plusmn2 versus 75plusmn3119901 = 001) and strain rate(minus044plusmn01 versusminus058plusmn025s119901 = 0004)The reduction inLA function and increase in LA volumes remained significanteven after adjusting for age LVMI LVEDVi and degree ofmitral regurgitation

34 Correlation of LA Mechanics and Echocardiographic andCMR Parameters There were no significant correlationsbetween strain or strain rate parameters and 2D echocar-diographic parameters of diastolic function or between rest-ingprovocable LVOT gradients and either strain or strainrate parameters LVMI correlated inversely with reservoirstrain (119903 = minus061 119901 lt 00001) booster strain (119903 = minus052 119901 lt00001) and LAEF (minus056119901 lt 00001) Correlations betweenLA volumes and LA mechanics are shown in Figure 3 andTable 5

35 Effect of Septal Myectomy on Left Atrial Volumes andMechanics The mean time from surgery to repeat CMRwas 86 months (range 5 to 18 months) No patients under-went a concomitant surgical MAZE procedure Significant

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 5

r = minus082

r = minus054

0

10

20

30

40

50

60

70

80

90LA

EF (

)

0

10

20

30

40

50

60

70

80

90

LAEF

()

20 40 60 80 100 1200Vmax (mLm2)

20 40 60 800Vmin (mLm2)

(a)

r = minus053

r = minus086

0

100

200

300

400

500

600Ex

pans

ion

inde

x (

)

20 40 60 800Vmin (mLm2)

20 40 60 80 100 1200Vmax (mLm2)

0

100

200

300

400

500

600

Expa

nsio

n in

dex

()

(b)

Figure 3 (a) Correlation between LA ejection fraction (LAEF ) and maximumminimum LA volumes (b) Correlation between LAexpansion index and maximumminimum LA volumes

33 Relationship between LVOT Obstruction and LAMechan-ics Patientswith obstructiveHCMhad a significantly greaterimpairment in LA function and larger LA volumes (Table 4)and LAEF was significantly lower (423 plusmn 8 versus 472 plusmn 9119901 = 0004) Although conduit function was not differentbetween the two HCM subgroups patients with obstructionhad significantly more impairment of LA reservoir functionwith lower reservoir strain (145 plusmn 4 versus 177 plusmn 5 119901 =0002) and strain rate (059 plusmn 02 versus 073 plusmn 02s 119901 =0001) In addition there was a significant reduction in bothbooster strain (61plusmn2 versus 75plusmn3119901 = 001) and strain rate(minus044plusmn01 versusminus058plusmn025s119901 = 0004)The reduction inLA function and increase in LA volumes remained significanteven after adjusting for age LVMI LVEDVi and degree ofmitral regurgitation

34 Correlation of LA Mechanics and Echocardiographic andCMR Parameters There were no significant correlationsbetween strain or strain rate parameters and 2D echocar-diographic parameters of diastolic function or between rest-ingprovocable LVOT gradients and either strain or strainrate parameters LVMI correlated inversely with reservoirstrain (119903 = minus061 119901 lt 00001) booster strain (119903 = minus052 119901 lt00001) and LAEF (minus056119901 lt 00001) Correlations betweenLA volumes and LA mechanics are shown in Figure 3 andTable 5

35 Effect of Septal Myectomy on Left Atrial Volumes andMechanics The mean time from surgery to repeat CMRwas 86 months (range 5 to 18 months) No patients under-went a concomitant surgical MAZE procedure Significant

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 BioMed Research International

Table 3 Baseline clinical CMR and 2D echocardiographic parameters in the nonobstructive and obstructive HCM subgroups

Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50) 119901 valueClinical characteristicsAge at CMR (years) 447 plusmn 15 546 plusmn 12 0001Sex (male 119899 ) 36 (72) 34 (68) 083BSA 192 plusmn 02 196 plusmn 02 035NYHA IIIIIIIV () 821440 3222460 lt00001Atrial fibrillation (119899 ) 3 (6) 4 (8) 069Beta-blockers (119899 ) 22 (44) 42 (84) 00001Calcium channel blockers (119899 ) 5 (10) 4 (8) 073Disopyramide (119899 ) 0 (0) 38 (76) lt00001ACE-iARB (119899 ) 7 (14) 6 (12) 077Amiodarone (119899 ) 2 (4) 1 (2) 056Coumadin (119899 ) 4 (8) 2 (4) 040CMR parametersLVEF () 617 plusmn 6 646 plusmn 7 003LVEDVi (mLm2) 861 plusmn 15 875 plusmn 12 062LVMi (gm2) 730 plusmn 26 877 plusmn 24 00062D echocardiographic parametersLVOT resting (mmHg) 66 plusmn 2 562 plusmn 28 lt00001LVOT provocable (mmHg) 121 plusmn 7 827 plusmn 30 lt00001Maximal wall thickness (mm) 191 plusmn 5 207 plusmn 4 0002MR trivialmildmoderatesevere () 742600 1846288 lt00001119864 wave (msec) 068 plusmn 02 086 plusmn 02 lt0001119860 wave (msec) 049 plusmn 02 073 plusmn 02 lt0001119864119860 ratio 154 plusmn 06 132 plusmn 06 007Deceleration time (ms) 217 plusmn 48 264 plusmn 62 lt0001Isovolumic relaxation time (ms) 89 plusmn 17 94 plusmn 23 0321198641198641015840 ratio 72 plusmn 3 112 plusmn 5 lt00001

CMR cardiac magnetic resonance BSA body surface area NYHA New York Heart Association functional class LVEF left ventricular ejection fractionLVEDVi indexed left ventricular end-diastolic volume LVMi indexed left ventricular mass LVOT left ventricular outflow tract gradient MR mitralregurgitation

reductions in NYHA class LVOT gradient and degree ofmitral regurgitation were seen after myectomy (Table 6) LAvolumes decreased and LAEF increased significantly (416 plusmn13 versus 484 plusmn 10 119901 = 0006) Although conduit functionremained unchanged an improvement in both reservoir(141plusmn6 versus 173plusmn7119901 = 001) and booster strain (68plusmn4versus 98 plusmn 5 00001) was seen

36 Intra- and Interobserver Variability Intra- and interob-server variability demonstrated good agreement for bothvolumetric and strain parameters and are shown in Table 7

4 Discussion

In the present study we demonstrate not only a significantincrease in LA volumes but also a marked impairment in allcomponents of LA function in patients with HCM comparedwith normal controls While previous studies have demon-strated abnormalities in LA function in patients with HCMfor the first timewehave demonstrated significantlyworse LAfunction in those with resting LVOT obstruction comparedto patients with nonobstructive HCM Septal myectomy via

relief of LVOT obstruction and reduction in degree of mitralregurgitation results in both a significant reduction in LAvolumes and improvement in LA function

The pathological hypertrophy characteristic of HCMmyocardial ischemia secondary to abnormalities of themicrovasculature and the presence of myocardial disarrayandfibrosis all serve to result in a reduction in LV complianceabnormal ventricular relaxation and diastolic dysfunctionThe resultant elevation in LV filling pressures is transmittedback to the LA necessitating an increase in LA pressuresin order to maintain adequate diastolic filling Subsequentincreases in LA wall tension serve to drive LA enlargementreflected in the significantly greater LA volumes seen inpatients with HCM compared with normal controls

In the present study patientswith LVOTobstructionwereolder andmore symptomatic and had significantly greater LAvolumes In addition they had evidence of a higher burdenof hypertrophy a greater degree of mitral regurgitationand more severe diastolic dysfunction LVMI was shownto correlate inversely with measures of LA strain but nocorrelations were noted between absolute LVOT gradient andparameters of strain and strain rate However even after

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 7

Table 4 LA volumes and myocardial mechanics

Normal controls (119899 = 50) Nonobstructive HCM (119899 = 50) Obstructive HCM (119899 = 50)LA volume indices119881max (mLm2) 383 plusmn 10 543 plusmn 15lowast 634 plusmn 17lowast

119881pre119860(mLm2) 223 plusmn 8 401 plusmn 13lowast 493 plusmn 14lowast

119881min (mLm2) 133 plusmn 5 289 plusmn 10lowast 369 plusmn 13lowast

Left atrial ejectionemptying fraction () 650 plusmn 11 472 plusmn 9lowast 423 plusmn 8lowast

Left ventricular stroke volume (mLm2) 545 plusmn 9 526 plusmn 11 555 plusmn 9Conduit volume 584 plusmn 26 523 plusmn 22 564 plusmn 23Reservoir functionExpansion index () 2190 plusmn 113 952 plusmn 36lowast 763 plusmn 23lowast

Longitudinal reservoir strain () 395 plusmn 13 177 plusmn 5lowast 145 plusmn 4lowast

SRs (sec) 137 plusmn 04 073 plusmn 02lowast 059 plusmn 02lowast

Conduit functionPassive emptying indexfraction () 416 plusmn 13 264 plusmn 9lowast 223 plusmn 7lowast

SRe (sec) minus099 plusmn 05 minus043 plusmn 02lowast minus035 plusmn 02lowast

Booster functionActive emptying indexfraction () 399 plusmn 14 280 plusmn 10lowast 257 plusmn 8lowast

Longitudinal booster strain () 153 plusmn 7 75 plusmn 3lowast 61 plusmn 2lowast

SRa (sec) minus105 plusmn 05 minus058 plusmn 02lowast minus044 plusmn 01lowast

SRs strain rate in systole SRe strain rate during passive emptying SRa strain rate during active emptying lowast119901 lt 005 compared with normal controls 119901 lt005 between obstructive and nonobstructive HCM

Table 5 Correlations between LA volumes and myocardial mechanics

119881max (mLm2) 119881min (mLm2)Correlation coefficient 119901 value Correlation coefficient 119901 value

Left atrial ejectionemptying fraction () minus054 lt00001 minus082 lt00001Expansion index () minus053 lt00001 minus086 lt00001Reservoir strain (ST

119878 ) minus049 lt00001 minus073 lt00001

Booster strain (ST119860 ) minus032 00001 minus052 lt00001

Active emptying indexfraction () minus035 lt00001 minus057 lt00001

multivariate analysis (adjusting for age gender LVMILVEDVi and degree of mitral regurgitation) there remaineda significant difference in both LA volumes and functionbetween patients with and without LVOT obstruction

LA reservoir function reflects both active left ventricularcontraction (and systolic descent of the mitral annulus) andpassive LA stretch and is largely determined both by LVsystolic function and by LA compliance Given that LVlongitudinal strain has been shown to be reduced in patientswith HCM despite a preserved LV ejection fraction with aneven greater degree of impairment in patients with LVOTobstruction [16] this may in part explain the differences inreservoir function seen in patients with obstructive versusnonobstructive HCM In addition the presence of a preexist-ing atrial myopathy or even fibrosis in the atrial wall may leadto an increase in LA stiffness and a concomitant reductionin compliance LA chamber stiffness (assessed by invasivelymeasured LA pressure-volume relations) has been demon-strated to be increased in patients with HCM compared withcontrols and to correlate with the degree of LV hypertrophy[17]

Conduit function appears to be governed mainly by LVrelaxation which is affected by increased LV mass myocar-dial ischemia and the presence ofmyocardial fibrosis No sig-nificant difference was noted between patients with obstruc-tive and nonobstructive HCM in conduit volume passiveempting index or SRe despite a higher LVMI and highergrade of diastolic dysfunction in patients with obstruction

LA booster function is dependent on preload (via theFrank-Starling mechanism) afterload and intrinsic LA con-tractility While there is initially a compensatory increase inLA contractility in response to an increase in LA volumeseventually further increases in LA volumes will result in adecline in atrial function as evidenced by the inverse corre-lation we have demonstrated between 119881max and LA ejectionfraction reservoir and booster strain Sanada et al havepreviously demonstrated the effect of LA afterload mismatchon LA booster pump function in HCM [18] The increase inLA afterload seen in patients with obstruction is likely tocontribute to the greater reduction in LA booster strainseen in these patients and may explain the improvement infunction seen after septal myectomy

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 BioMed Research International

Table 6 Effects of septal myectomy on LA volumes and mechanics

Premyectomy (119899 = 20) Postmyectomy (119899 = 20) 119901 valueNYHA IIIIIIIV () 001000 802000 lt00001lowast

LVOT resting (mmHg) 681 plusmn 40 110 plusmn 6 lt00001lowast

LVOT provocable (mmHg) 983 plusmn 27 212 plusmn 14 lt00001lowast

MR trivialmildmoderatesevere () 10404010 406000 00004lowast

LVEF () 659 plusmn 8 614 plusmn 9 008LA volume indices119881max (mLm2) 662 plusmn 23 498 plusmn 20 lt00001lowast

119881pre119860(mLm2) 532 plusmn 24 393 plusmn 18 lt00001lowast

119881min (mLm2) 405 plusmn 23 266 plusmn 16 lt00001lowast

Left atrial ejectionemptying fraction () 416 plusmn 13 484 plusmn 10 0006lowast

Left ventricular stroke volume (mLm2) 555 plusmn 11 480 plusmn 10 001lowast

Conduit volume 572 plusmn 21 473 plusmn 20 0066Reservoir functionExpansion index () 805 plusmn 44 1001 plusmn 36 001lowast

Longitudinal reservoir strain () 141 plusmn 6 173 plusmn 7 001lowast

SRs (sec) 051 plusmn 02 057 plusmn 02 015Conduit functionPassive emptying indexfraction () 214 plusmn 9 222 plusmn 9 066SRe (sec) minus027 plusmn 02 minus027 plusmn 02 098Booster functionActive emptying indexfraction () 264 plusmn 11 337 plusmn 8 0002lowast

Longitudinal booster strain () 68 plusmn 4 98 plusmn 5 00001lowast

SRa (sec) minus048 plusmn 02 minus068 plusmn 02 0001lowast

lowast denotes 119901 lt 005 between pre- and postmyectomy values

Table 7 Inter- and intraobserver variability

Diff means (plusmn196 SD)Interobserver Intraobserver

119881max (mLm2) 15 (plusmn77) 15 (plusmn26)119881pre119860(mLm2) 08 (plusmn84) 15 (plusmn30)

119881min (mLm2) 26 (plusmn98) 15 (plusmn58)Longitudinal reservoir strain () 13 (plusmn52) 02 (plusmn66)Longitudinal booster strain () 05 (plusmn31) 01 (plusmn37)SRs (sec) 007 (plusmn016) 001 (plusmn018)SRe (sec) 002 (plusmn018) 000 (plusmn037)SRa (sec) 009 (plusmn026) 002 (plusmn024)Difference of means plusmn196 SD bias and limits of agreement derived fromBland-Altman analysis

An intrinsic atrial myopathy may in addition affect activeLA contraction and booster strain Indirect evidence tosuggest the presence of an intrinsic myopathy in HCM isthe increase in the number of calcium antagonist receptorsdemonstrated in the atrial myocardium of patients withHCM suggesting an abnormality in calcium fluxes throughvoltage-sensitive calcium channels that may play a role inatrial dysfunction [19]

In the present study no correlations were noted between2D echocardiographic parameters of diastolic function andstrain or strain rate parameters Importantly no correlationwas seen between 119860 wave velocity on transmitral Doppler

filling profiles and any parameters of LA booster functionsuggesting that peak 119860 wave may not accurately reflect LAcontractile function but rather reflects the atrioventricularpressure gradient between the atrium and ventricle WhileLA volumes and transmitral 119860 wave are readily obtainedfrom standard transthoracic echocardiography our presentfindings highlight the need formore sophisticated techniquesfor the assessment of LA function if we are to use thisinformation to predict risk of adverse events

While strain analysis is not yet part of routine clinicalpractice the simple addition of measurement of 119881min to rou-tinelymeasured119881max appears to provide valuable informationregarding function 119881min demonstrates a stronger correlationwith not only measures of global LA function and compli-ance but also markers of LA contractility (active and boosterfunction) The present data suggest that measurement ofminimumvolumeprovides a valuable surrogatemarker of LAfunction

5 Study Limitations

Although measurements using VVI applied to CMR imageshave not been previously validated against VVI applied toechocardiographic images in the same patient group for theanalysis of LA function a recent study utilizing the feature-tracking software has demonstrated both the feasibility andreliability of this technique for assessing LA strain andstrain rate [13] Although differences in signal characteristics

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 9

between different scanners and scans performed at differentfield strengths might also impact feature tracking Kowallicket al have demonstrated good reproducibility of measure-ments of LA function irrespective of scanner type [13] Thethin-walled LA may result in technical difficulties with theapplication of feature tracking using VVI In addition the LAappendage and origin of the pulmonary veins pose additionalchallenges to tracking LA function has previously beendemonstrated to be abnormal in patients with primary severemitral regurgitation without HCM [20] and in the currentstudy patients with obstructive HCM had a significantlygreater degree ofmitral regurgitation than the nonobstructivegroup Some of the effects on left atrial volume and functionafter septal myectomy may be explained by the relief ofmitral regurgitation in addition to relief of outflow tractobstruction Left atrial fibrosis which may represent animportant intrinsic determinant of left atrial function wasnot assessed onCMR in the current study butmay account forsome of the demonstrated changes in function noted

6 Conclusions

Left atrial volumes and functional parameters are abnormalin patients with HCM and are significantly worse in thosewith obstructionThe associated effects of left ventricular out-flow tract obstruction and mitral regurgitation appear to fur-ther impair left atrialmechanics Surgicalmyectomy via reliefof obstruction appears to have a positive impact on both leftatrial volume and function and further studies are needed toassess whether aggressive management of LVOT obstructionwill result in a reduction in the occurrence of adverse eventsparticularly atrial fibrillation

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] V Sachdev Y Shizukuda C L Brenneman et al ldquoLeft atrialvolumetric remodeling is predictive of functional capacity innonobstructive hypertrophic cardiomyopathyrdquoAmericanHeartJournal vol 149 no 4 pp 730ndash736 2005

[2] S Nistri I Olivotto S Betocchi et al ldquoPrognostic significanceof left atrial size in patients with hypertrophic cardiomyopathy(from the Italian Registry for Hypertrophic Cardiomyopathy)rdquoThe American Journal of Cardiology vol 98 no 7 pp 960ndash9652006

[3] T Tani T Yagi T Kitai et al ldquoLeft atrial volumepredicts adversecardiac and cerebrovascular events in patients with hyper-trophic cardiomyopathyrdquo Cardiovascular Ultrasound vol 9 no1 article 34 2011

[4] W-I Yang C Y Shim Y J Kim et al ldquoLeft atrial volume indexa predictor of adverse outcome in patients with hypertrophiccardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 12 pp 1338ndash1343 2009

[5] M Roca B A Popescu C C Beladan et al ldquoLeft atrial dysfunc-tion as a correlate of heart failure symptoms in hypertrophic

cardiomyopathyrdquo Journal of the American Society of Echocardio-graphy vol 23 no 10 pp 1090ndash1098 2010

[6] I A Paraskevaidis D Farmakis C Papadopoulos et al ldquoTwo-dimensional strain analysis in patients with hypertrophic car-diomyopathy and normal systolic function a 12-month follow-up studyrdquo American Heart Journal vol 158 no 3 pp 444ndash4502009

[7] B JMaron T SHaasM SMaron et al ldquoLeft atrial remodelingin hypertrophic cardiomyopathy and susceptibility markersfor atrial fibrillation identified by cardiovascular magneticresonancerdquo The American Journal of Cardiology vol 113 no 8pp 1394ndash1400 2014

[8] P Barbier S B Solomon N B Schiller and S A Glantz ldquoLeftatrial relaxation and left ventricular systolic function determineleft atrial reservoir functionrdquo Circulation vol 100 no 4 pp427ndash436 1999

[9] Y Toma Y Matsuda K Moritani H Ogawa M Matsuzakiand R Kusukawa ldquoLeft atrial filling in normal human subjectsrelation between left atrial contraction and left atrial earlyfillingrdquoCardiovascular Research vol 21 no 4 pp 255ndash259 1987

[10] M Cameli M Caputo S Mondillo et al ldquoFeasibility andreference values of left atrial longitudinal strain imaging by two-dimensional speckle trackingrdquo Cardiovascular Ultrasound vol7 article 6 2009

[11] H Motoki A Dahiya M Bhargava et al ldquoAssessment of leftatrial mechanics in patients with atrial fibrillation comparisonbetween two-dimensional speckle-based strain and velocityvector imagingrdquo Journal of the American Society of Echocardio-graphy vol 25 no 4 pp 428ndash435 2012

[12] R M Saraiva S Demirkol A Buakhamsri et al ldquoLeft atrialstrain measured by two-dimensional speckle tracking repre-sents a new tool to evaluate left atrial functionrdquo Journal of theAmerican Society of Echocardiography vol 23 no 2 pp 172ndash1802010

[13] J T Kowallick S Kutty F Edelmann et al ldquoQuantification ofleft atrial strain and strain rate using Cardiovascular MagneticResonance myocardial feature tracking a feasibility studyrdquoJournal of Cardiovascular Magnetic Resonance vol 16 no 1article 60 2014

[14] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos Guidelines and Standards Committeeand the Chamber Quantification Writing Group developed inconjunction with the European Association of Echocardiogra-phy a branch of the European Society of Cardiologyrdquo Journalof the American Society of Echocardiography vol 18 no 12 pp1440ndash1463 2005

[15] S F Nagueh C P Appleton T C Gillebert et al ldquoRec-ommendations for the evaluation of left ventricular diastolicfunction by echocardiographyrdquo Journal of the American Societyof Echocardiography vol 22 no 2 pp 107ndash133 2009

[16] S CarassoH Yang AWoo et al ldquoSystolicmyocardialmechan-ics in hypertrophic cardiomyopathy novel concepts and impli-cations for clinical statusrdquo Journal of the American Society ofEchocardiography vol 21 no 6 pp 675ndash683 2008

[17] H Sanada M Shimizu N Sugihara K Shimizu H Ino and RTakeda ldquoIncreased left atrial chamber stiffness in hypertrophiccardiomyopathyrdquo British Heart Journal vol 69 no 1 pp 31ndash351993

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 BioMed Research International

[18] H Sanada M Shimizu K Shimizu Y Kita N Sugihara andR Takeda ldquoLeft atrial afterload mismatch in hypertrophic car-diomyopathyrdquo The American Journal of Cardiology vol 68 no10 pp 1049ndash1054 1991

[19] J AWagner F L SaxH FWeisman et al ldquoCalcium-antagonistreceptors in the atrial tissue of patients with hypertrophiccardiomyopathyrdquo The New England Journal of Medicine vol320 no 12 pp 755ndash761 1989

[20] L T Yang Y W Liu J Y Shih et al ldquoPredictive value of leftatrial deformation on prognosis in severe primarymitral regur-gitationrdquo Journal of the American Society of Echocardiographyvol 128 Article ID A11443 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom