J

Hvam

KTT

D

RA

0d

ournal of Cardiology (2008) 51, 95—105

ypertrophic cardiomyopathy with mild leftentricular remodeling: Echocardiographicssessment using left ventricular wallotion score

ayo Hayato, Makoto Okawa, Yoshihisa Matsumura, Hiroaki Kitaoka,oru Kubo, Nobuhiko Hitomi, Naohito Yamasaki, Toshikazu Yabe,akashi Furuno, Jun Takata, Masanori Nishinaga, Yoshinori L. Doi ∗

epartment of Medicine and Geriatrics, Kochi Medical School, Oko-cho, Nankoku, Kochi 783-8505, Japan

eceived 5 October 2007; received in revised form 24 December 2007; accepted 10 January 2008vailable online 14 March 2008

KEYWORDSEchocardiography(transthoracic);Hypertrophiccardiomyopathy;Ventricular remodeling;Wall motion score

SummaryObjectives: The present study sought to investigate the echocardiographic featuresof hypertrophic cardiomyopathy (HCM) with mild left ventricular (LV) remodeling,particularly in relation to wall motion abnormalities.Methods: Among the 137 consecutive patients with HCM, 13 patients (mean age52 ± 13 years) who progressed to mild LV systolic dysfunction (LV ejection fraction(LVEF) of 35—50%) were studied. By reviewing the echocardiograms of these patients,wall motion score index (WMSI) was scored using 16 segments model.Results: HCM patients with mild LV systolic dysfunction exhibited mild LV dilata-tion, mild left atrial dilatation, septal hypertrophy, and LV wall motion impairmentlocalized in the septal and apical regions (septal WMSI 1.94 ± 0.33 vs. total WMSI1.51 ± 0.25 and posterior WMSI 1.02 ± 0.07; p < 0.001). During follow-up, furtherdeterioration of LV systolic function (LVEF < 35%) was noted in five patients, whohad less severe hypertrophy at the initial echocardiograms. These patients devel-oped progressive LV cavity enlargement and more severe and extensive wall motionabnormalities, accompanied by septal akinesis and wall thinning, although postero-lateral wall motion impairment was relatively mild (posterior WMSI 1.80 ± 0.27 vs.septal WMSI 2.95 ± 0.11; p < 0.001).

Conclusions: Septal and apical wall motions are reduced in HCM with mild LV remod-eling. As LV dysfunction prLV cavity enlargement becoimpairment is relatively mi© 2008 Japanese College oreserved.

∗ Corresponding author. Tel.: +81 88 880 2352; fax: +81 88 880 2349E-mail address: ydoi@kochi-u.ac.jp (Y.L. Doi).

914-5087/$ — see front matter © 2008 Japanese College of Cardiolooi:10.1016/j.jjcc.2008.01.003

ogresses, septal akinesis and wall thinning develop and

mes more prominent, though posterolateral wall motionld.f Cardiology. Published by Elsevier Ireland Ltd. All rights

.

gy. Published by Elsevier Ireland Ltd. All rights reserved.

htcp[pwtofe

E

Fdwruwt2wAeEfiwdetptcst

A

TLwtwtW(4cis

96

Introduction

Although hypertrophic cardiomyopathy (HCM) ischaracterized by a hypertrophied nondilated leftventricle with normal systolic function, a smallsubset of HCM patients evolve into so-called ‘end-stage’ phase with left ventricular (LV) systolicdysfunction, usually associated with wall thinningand cavity enlargement [1—4]. These morpho-logic features of end-stage HCM were previouslyreported to be similar to those of dilated cardiomy-opathy (DCM) [5,6]. However, pathologic studiessuggest characteristic features of end-stage HCMwith extensive transmural scarring in the ventric-ular septum, distinct from those of DCM [7—10].Moreover, DCM-like features may be manifest onlyafter LV remodeling is severe enough to be accom-panied by diffuse wall thinning. On the contrary,echocardiographic characteristics of HCM with ear-lier stage of LV remodeling, that is, mild LV systolicdysfunction in the course of transition from typi-cal HCM to DCM-like morphology, are incompletelyunderstood.

We therefore investigated the echocardiographicfeatures of HCM with mild LV systolic dysfunction,with particular focus on the earlier stage of LVremodeling, and also aimed to elucidate its rela-tionship to LV wall motion abnormalities.

Methods

Patient selection

Among the 137 consecutive patients with HCMdiagnosed at Kochi Medical School between Jan-uary 1983 and June 2001 (95 males, 42 females;mean age 52 ± 13 years; age range 9—79 years),15 patients evolved into LV systolic dysfunction.Four of the 15 patients already had LV systolic dys-function at diagnosis, and 11 patients developedLV systolic dysfunction during follow-up. Thirteenof these 15 patients who had mild LV systolicdysfunction, that is, LV ejection fraction (EF) of35—50% at rest by two-dimensional echocardiog-raphy, consisted of the present study. In order tofocus on the echocardiographic features of ear-lier stage LV remodeling, one patient with severeLV systolic dysfunction at initial diagnosis wasexcluded from the present study. Another patientwith inadequate echocardiographic image qualitywas also excluded. Precise clinical and echocar-

diographic features of the whole HCM cohorthave been already reported [11]. The diagno-sis of HCM was based on the two-dimensionalechocardiographic demonstration of unexplained LV

msai

K. Hayato et al.

ypertrophy (maximal wall thickness ≥ 15 mm) inhe absence of other cardiac or systemic diseasesapable of producing the magnitude of hypertro-hy evident (e.g. hypertension or aortic stenosis)1]. The echocardiograms of 13 patients were com-ared with those of 50 consecutive patients whoere recently diagnosed as HCM without LV sys-

olic dysfunction in our institution. Normal valuesf echocardiographic measurements were obtainedrom 10 normal subjects without cardiovascular dis-ases.

chocardiographic studies

or the analysis of this study, we used the echocar-iograms at the time when LV systolic dysfunctionas first documented. Transthoracic echocardiog-

aphy was performed using commercially availableltrasound machines. Echocardiographic imagesere taken with patients in the left lateral decubi-

us position and were stored in the VHS video tape.D and M-mode echocardiographic measurementsere carried out according to the guidelines of themerican Society of Echocardiography [12,13]. LVnd-diastolic and end-systolic volumes (EDV andSV, respectively) and LVEF was measured by modi-ed Simpson’s formula [13]. Left atrial (LA) volumeas calculated using the three orthogonal LAimensions at ventricular end-systole, as describedlsewhere [14]. The distribution of hypertrophy andhe wall thickness were assessed at end-diastole byarasternal short-axis views obtained at the tip ofhe mitral valve, at the papillary muscle and api-al levels [15]. The greatest wall thickness at anyite in the LV wall was regarded as the maximal wallhickness.

nalysis of LV wall motion

he echocardiograms of HCM patients with mildV systolic dysfunction were reviewed and LVall motion abnormalities were assessed using

he 16 segments model for assessment of LVall motion according to the recommendations of

he American Society of Echocardiography [12].all motion score (WMS) was scored as follows

Fig. 1): 1 = normal; 2 = hypokinetic; 3 = akinetic;= dyskinetic. The average value of WMS was cal-ulated in the total 16 segments as total WMSI,n the four septal and anteroseptal segments aseptal WMSI, in the four posterior and lateral seg-

ents as posterior WMSI, and in the four apical

egments as apical WMSI. Judgment of wall motionbnormalities was based on the agreement of twondependent observers.

HCM with mild LV remodeling 97

mme

F

AddmwwdTcnd

S

DCcFvSvtvo

R

Cfi

Td

sphcliermsddvbwlvtfiw

W

PiWsw(om

Figure 1 The 16 segments model according to the reco

ollow-up studies

ll the patients were followed at our outpatientepartment. The most recent echocardiographicata were reviewed and the wall motion abnor-alities were also analyzed using WMS. Patientshose systolic function progressively deteriorated,ith LVEF less than 35% in the follow-up echocar-iograms, were considered as progression group.he initial and the follow-up echocardiograms wereompared between the progression group and theo progression group. Collection of the follow-upata was ended at the end of 2006.

tatistical analysis

ata are expressed as the mean value ± S.D.omparison of categorical variables, expressed asounts and percentages, was performed using theisher’s exact test. Comparisons for continuousariables were made using the unpaired or pairedtudent’s t-tests when appropriate. A probabilityalue of <0.05 was considered significant. All statis-ical calculations were conducted using Stat-View,ersion 5.0 (SAS Institute Inc., Cary, North Car-lina).

esults

linical profile and echocardiographicndings

able 1 shows the clinical profiles and echocar-iographic data of HCM patients with mild LV

WmEl

ndations of the American Society of Echocardiography.

ystolic dysfunction, in comparison with those withreserved LV systolic function. Five patients hadeart failure symptoms of New York Heart Asso-iation class III or IV. LV size and volumes werearger in patients with LV systolic dysfunction thann those with preserved systolic function. How-ver, the degree of LV dilatation was modest witheference to normal values. Seven patients withild LV systolic dysfunction showed normal LV

ize or only minimal LV dilatation (LV end-diastolicimension < 55 mm). None of the patients had LVimension greater than 60 mm. LA diameter andolume were not different between the two groups,ut increased beyond the normal range. LA sizeas still dilated when patients with atrial fibril-

ation were excluded (LA diameter 45 ± 5 mm, LAolume 58 ± 16 ml). All of the 13 patients had sep-al hypertrophy of some degree (14—25 mm), andve patients (38%) showed severe LV hypertrophyith maximal wall thickness ≥20 mm.

all motion analyses

atients with mild LV systolic dysfunction exhib-ted significant higher values of total WMSI, septal

MSI, and apical WMSI than those with pre-erved systolic dysfunction, suggesting reducedall motions, especially in septal and apical regions

Table 1). Fig. 2A shows the spatial distributionf LV wall motion abnormalities in HCM withild LV systolic dysfunction (the average value of

MSI in each segment) using the 16 segments ofodel recommended by the American Society of

chocardiography. LV wall motion impairment wasocalized in the septal and apical regions (average

98 K. Hayato et al.

Table 1 Clinical characteristics and echocardiographic findings of HCM patients with mild LV systolic dysfunction

LV systolicdysfunction(n = 13)

Preserved LV systolicfunction (n = 50)

p Value* Normal values(n = 10)

Age at echocardiography 62 ± 13 61 ± 16 ns 56 ± 18Rhythm (Sinus rhythm/Af) 10/3 43/7 ns 10/0NYHA class III or IV 5 (38%) 4(8%) <0.001 0 (0%)LV end-diastolic dimension (mm) 54 ± 4 44 ± 5 <0.001 46 ± 4LV end-systolic dimension (mm) 40 ± 4 26 ± 5 <0.001 27 ± 4LA diameter (mm) 46 ± 5 44 ± 7 ns 34 ± 5IVS thickness (mm) 16 ± 3 18 ± 3 0.049 9 ± 1LV posterior wall thickness (mm) 11 ± 2 11 ± 2 ns 9 ± 1Maximal wall thickness (mm) 18 ± 4 21 ± 3 0.003 9 ± 1LV end-diastolic volume (ml) 105 ± 18 73 ± 21 <0.001 84 ± 24LV end-systolic volume (ml) 58 ± 11 22 ± 9 <0.001 29 ± 10Ejection fraction (%) 45 ± 2 71 ± 8 <0.001 66 ± 5LA volume (ml) 62 ± 17 60 ± 25 ns 33 ± 12MR (moderate or severe) 1 (8%) 7 (14%) ns 0 (0%)WMSI 1.51 ± 0.25 1.01 ± 0.03 <0.001Sep WMSI 1.94 ± 0.33 1.04 ± 0.10 <0.001Ap WMSI 1.83 ± 0.56 1.01 ± 0.04 <0.001Post WMSI 1.02 ± 0.07 1.01 ± 0.04 ns

Continuous values are mean ± S.D. HCM, hypertrophic cardiomyopathy; LV, left ventricular; Af, atrial fibrillation; NYHA, New York; MR

ll moth mi

tamsTn

Heart Association; LA, left atrial; IVS, interventricular septumSep WMSI, septal wall motion score index; Ap WMSI, apical waindex. *p Values for the comparisons between HCM patients wiLV systolic function (n = 50).

WMS ≥ 2.0). Septal WMSI was higher than total WMSIand posterior WMSI (1.94 ± 0.33 vs. 1.51 ± 0.25and 1.02 ± 0.07; p < 0.001, respectively), suggest-ing localized septal wall motion impairment inthese patients (Fig. 2B).

Progression of LV remodeling

During the follow-up period, five patientsshowed further deterioration of systolic func-

spoa

Figure 2 (A) The spatial distribution of LV wall motion abnonumbers on the figure show the mean values of wall motionmotion score ≥2.0 are shown as gray. See Fig. 1. (B) Average(seg. 1—16), septal segments (seg. 1, 6, 7 and 12: Sep WMSIsegments (seg. 3, 4, 9 and 10: Post WMSI).

, mitral regurgitation; WMSI, total wall motion score index;tion score index; Post WMSI, posterolateral wall motion scoreld LV systolic dysfunction (n = 13) and patients with preserved

ion (LVEF < 35%) (Fig. 3: progression group). Withinyear of echocardiographic documentation of

ild LV systolic dysfunction, one patient dieduddenly and another patient died from sepsis.herefore, their follow-up echocardiograms wereot available. The other six patients did not show

ignificant progression and were considered as norogression group. Table 2 shows the comparisonf clinical variables between the progression groupnd the no progression group. Age and medications

rmalities in HCM with mild LV systolic dysfunction. Thescore of each segment. Segments with the average wallvalues of wall motion score index (WMSI) in all segments), apical segments (seg. 13—16: Ap WMSI) and posterior

HCM with mild LV remodeling 99

Figure 3 Clinical course of HCM patients with mild LV systolic dysfunction. Thirteen HCM patients were diagnosedas mild LV systolic dysfunction (EF 35—50%). Among these 13 patients, two patients died within one year, six patientsd pat( entri

wpvTdtiidssg

oLe

afiinmgaimpmm

id not show significant progression, and the other fiveEF < 35%). HCM, hypertrophic cardiomyopathy; LV, left v

ere not significantly different. Patients in therogression group were followed with longer inter-als, which did not reach statistical significance.able 3 shows the comparison of echocardiographicata and their longitudinal changes between thewo groups. LV dimensions and EF were not signif-cantly different between the two groups at thenitial echocardiograms, in which mild LV systolicysfunction was first documented. Specifically,eptal thickness and maximal wall thickness weremaller and WMSI was greater in the progressionroup.

In the progression group, longitudinal changesf echocardiographic data showed progressiveV remodeling. LV cavity became progressivelynlarged, accompanied by septal wall thinning,

rp

p

Table 2 Comparison of clinical variables between the prog

No progression (n

Age at echocardiography 66 ± 15Intervals (years) 5.3 ± 2.4Rhythm (Sinus rhythm/Af) 5/1NYHA class III or IV 1 (17%)Family history of HCM 4 (67%)Family history of sudden death 1 (17%)

MedicationACEI/ARB 3 (50%)Beta-blocker 3 (50%)Diuretics 4 (67%)Digitalis 2 (33%)

Continuous values are mean ± S.D. Af, atrial fibrillation; NYHA, NewACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin re

ients showed further deterioration of systolic functioncular; EF, ejection fraction; F/U, follow-up.

s systolic function deteriorated. LV hypertrophynally disappeared at any site of the LV wall

n four of the five patients (maximal wall thick-ess ≤ 11 mm). Wall motion abnormalities becameore severe and extensive in the progression

roup (total WMSI 2.48 ± 0.10), with anterior,nteroseptal, inferoseptal, inferior and apicalnvolvement (Fig. 4A). Septal and apical wallotions were markedly reduced, often accom-anied by wall thinning resembling old anterioryocardial infarction. However, posterolateral wallotion impairment was relatively mild (poste-

ior WMSI 1.80 ± 0.27 vs. septal WMSI 2.95 ± 0.11;< 0.001) (Fig. 4B).Fig. 5 shows a representative case that showed

rogressive LV remodeling. This patient initially

ression and the no progression groups

= 6) Progression (n = 5) p Value

58 ± 10 ns8.2 ± 2.5 ns4/1 ns2 (40%) ns4 (80%) ns3 (60%) ns

3 (60%) ns2 (40%) ns2 (40%) ns1 (20%) ns

York Heart Association; HCM, hypertrophic cardiomyopathy;ceptor antagonist.

100K.

Hayato

etal.

Table 3 Echocardiographic variables and their longitudinal changes: comparison between the progression and the no progression groups

No progression (n = 6) Progression (n = 5) p Valueb between thetwo groups

Initial Follow-up p Valuea Initial Follow-up p Valuea Initial Follow-up

Age at echocardiography 66 ± 15 70 ± 14 0.009 58 ± 10 66 ± 11 0.002 ns nsLV end-diastolic dimension (mm) 54 ± 5 58 ± 5 ns 53 ± 2 62 ± 6 0.012 ns nsLV end-systolic dimension (mm) 40 ± 3 43 ± 5 ns 39 ± 3 50 ± 5 0.002 ns 0.044LA diameter (mm) 47 ± 1 53 ± 9 ns 45 ± 4 50 ± 10 0.030 ns nsIVS thickness (mm) 17 ± 3 15 ± 1 ns 14 ± 2 9 ± 3 0.030 0.001 0.001LV posterior wall thickness (mm) 11 ± 2 10 ± 1 ns 12 ± 1 11 ± 1 ns ns nsMaximal wall thickness (mm) 19 ± 2 17 ± 2 ns 15 ± 1 11 ± 1 0.003 0.002 <0.001LV end-diastolic volume (ml) 96 ± 18 113 ± 36 ns 109 ± 15 125 ± 12 0.029 ns nsLV end-systolic volume (ml) 52 ± 11 66 ± 21 ns 59 ± 6 88 ± 12 0.002 ns nsEjection fraction (%) 45 ± 2 42 ± 4 ns 45 ± 2 30 ± 4 0.002 ns 0.001LA volume (ml) 63 ± 19 95 ± 78 ns 64 ± 16 96 ± 30 0.035 ns nsWMSI 1.35 ± 0.15 1.66 ± 0.15 <0.001 1.70 ± 0.28 2.48 ± 0.10 0.007 0.031 <0.001Sep WMSI 1.75 ± 0.35 2.08 ± 0.34 0.025 2.15 ± 0.22 2.95 ± 0.11 0.003 ns <0.001Ap WMSI 1.54 ± 0.29 2.00 ± 0.32 0.048 2.15 ± 0.76 2.70 ± 0.33 ns ns 0.006Post WMSI 1.00 ± 0.00 1.00 ± 0.00 ns 1.05 ± 0.11 1.80 ± 0.27 0.009 ns <0.001

Values are mean ± S.D.a p Values for the comparisons between the initial and the follow-up echocardiograms, using paired t-tests.b p Values for the comparisons between the no progression and the progression groups, using unpaired t-tests. Abbreviations are the same as Table 1.

HCM with mild LV remodeling 101

Figure 4 (A) The spatial distribution of LV wall motion abnormalities and (B) the average values of LV wall motion scoreindex in the progression group (n = 5). Although septal and apical wall motions were severely reduced, posterolateralwall motion was relatively maintained. Abbreviations and gray segments are defined in the same way as in Fig. 2.

Figure 5 M-mode echocardiography of a patient who showed progressive LV remodeling. Left: asymmetric septalh diags allL

pwmLstf

D

Ig

baeLwhHrd

ypertrophy with normal LV wall motion at the initialystolic dysfunction at the age of 44 years. Right: septal wV remodeling. Abbreviations as in Fig. 3.

resented as typical asymmetric septal hypertrophyith preserved systolic function, later developedild LV remodeling, and finally evolved into severe

V systolic dysfunction with cavity enlargement andeptal akinesis. Fig. 6 demonstrates septal wallhinning in another patient with ‘end-stage’ heartailure, resembling old myocardial infarction.

iscussion

n the present study, we first demonstrated the pro-ressive LV remodeling process at its earliest stage

rwbn

nosis of hypertrophic cardiomyopathy. Middle: mild LVthinning and LV dilatation in the more advanced stage of

y assessing longitudinal changes of wall motionbnormalities. In particular, we presented herechocardiographic characteristics of HCM with mildV remodeling, that is, mild LV systolic dysfunctionith no or mild LV dilatation and preserved septalypertrophy, before DCM-like features of end-stageCM are manifested. HCM patients with mild LVemodeling showed wall motion abnormalities pre-ominantly involving septal and apical walls. As LV

emodeling progressed to the more advanced stageith severe LV systolic dysfunction, LV dilatationecame more prominent and akinesis and thin-ing of septal or apical walls developed, sometimes

102 K. Hayato et al.

t instern

is

Em

IpiitWtoasawTrw

oddssanetwwt

Figure 6 Two-dimensional echocardiography of a patienresembling old anterior myocardial infarction. Left: para

resembling anterior myocardial infarction, thoughposterolateral wall motion impairment was rela-tively mild.

Significance of LV remodeling in the HCMspectrum

Although LVEF is supernormal or preserved in mostcases of HCM, progression to systolic dysfunction(LVEF < 50%) occurs in 3—15% of patients whenthey are followed long enough [3,16—18]. Thissubtype of HCM was initially reported in casereports in the literature and referred as vari-ous terms such as ‘dilated phase,’ ‘burned-outphase’, or ‘end-stage’ [4]. We recently reportedthat heart-failure death related to ‘end-stage’ isan important mode of death in the community-based cohort of HCM patients in Japan [11].Patients with systolic dysfunction often exhibitsymptomatic deterioration with progressive con-gestive heart failure, which is often refractory tomedical treatment, and generally convey a poorprognosis [16—18]. This is in contrast with theimproved prognosis of DCM in the era of advance-ment of heart failure management [19]. Therefore,early recognition of LV remodeling and aggres-sive treatment strategies to prevent progressivedeterioration have substantial clinical relevance inthe management of HCM. In addition, consideringthe progressive and malignant nature of end-stage HCM, implantable cardioverter-defibrillatorimplantation or heart transplantation might be con-sidered in this subset of patients even when systolicdysfunction and LV dilatation are modest compared

with those of DCM. Although many case reports ofend-stage HCM have been published, clinical inves-tigations regarding echocardiographic features ofearlier stage of LV remodeling, particularly local-

tole

‘end-stage’ heart failure. It shows septal wall thinningal long axis view. Right: apical 4-chamber view.

zation of wall motion abnormalities, have beencarce.

chocardiographic features of HCM withild LV remodeling

n the present study, transthoracic echocardiogra-hy demonstrated regional wall motion abnormal-ties in HCM with mild LV remodeling, especiallyn the septal and apical regions, when LV dilata-ion is mild and septal hypertrophy is maintained.hen systolic function is severely reduced, sep-

al and apical wall motions become akinetic,ften accompanied by wall thinning and scarring,nd anterior and inferior wall motions are alsoeverely impaired. However, even in this moredvanced stage of LV remodeling, posterolateralall motion impairment may be relatively mild.hus, wall motion abnormalities of HCM with LVemodeling are not equally distributed in the LVall.Our results are consistent with the pathologic

bservations and the previous studies using otheriagnostic modalities. HCM hearts obtained aftereath or transplantation in congestive heart failurehowed grossly visible scars and myocardial fibro-is in the ventricular septum or LV free wall in thebsence of significant narrowing of epicardial coro-ary arteries [8,9]. Waller et al. investigated thexplanted hearts at the time of cardiac transplan-ation and reported that nine of the 10 patientsith dilated HCM had ventricular wall scarring,hich was more extensive in the ventricular sep-

um than in the free wall [10]. On the contrary,

hey only found grossly visible small scars in 23%f their patients with idiopathic DCM. These patho-ogic studies suggest distinct anatomic features ofnd-stage HCM, extensive myocardial scars pre-

H

df

rduFcrowvrMwawais

P

PHddfs(raaspnimtpitbgoetmptho

rde

(ofasea

dssmcetsfla[dpo

C

OmtfttiitDsrgapcl

tpestbesw

CM with mild LV remodeling

ominantly involving ventricular septum, differentrom those of DCM.

Previous investigations using cardiac magneticesonance tissue tagging reported regional myocar-ial systolic dysfunction especially in the ventric-lar septum and anterior wall in HCM [20,21].urthermore, gadolinium hyperenhancement in theardiac magnetic resonance study, assumed toepresent myocardial fibrosis and scarring, wasbserved predominantly in the septum, anteriorall, and the junctions of the IVS and the rightentricular free wall in HCM and associated withegional and global contractile dysfunction [22,23].oon et al. reported that this hyperenhancementas associated with progressive ventricular dilationnd reduction of wall thickness [24]. Therefore,all motion abnormalities may well appear initiallynd predominantly in the septal and anterior wallsn HCM with mild LV remodeling, leading to progres-ive LV dysfunction and myocardial fibrosis.

rogressive LV remodeling

rogressive LV remodeling is another aspect ofCM with LV dysfunction [25]. Though LV cavityilatation was mild and wall thinning was not yeteveloped in patients with mild LV systolic dys-unction, in the long-term observation five patientshowed further deterioration of LV systolic functionthe progression group). As systolic function dete-iorated, LV cavity became progressively enlarged,ssociated with septal wall thinning. Wall motionbnormalities became more severe and exten-ive in these patients. On the contrary, otheratients showed rather gradual LV remodeling (theo progression group). More severe wall motionmpairment and relatively smaller septal and maxi-al wall thickness at the initial echocardiograms in

he progression group may be associated with morerogressive and rapid LV remodeling. However, its not clear whether the apparent differences inhe longitudinal changes of LV systolic function,etween the progression group and the no pro-ression group, were due to the different durationf follow-up periods, or the results of the differ-nt pathologic process of LV remodeling betweenhe two groups. As gradual deterioration of LV wallotion was also observed even in those in the norogression group, further deterioration of LV sys-olic function could have been documented if theyad been followed with much longer follow-up peri-ds.

A recent multi-center observation including aelatively large number of HCM patients haveemonstrated heterogeneous pattern of LV remod-ling in end-stage HCM [16]. LV cavity dilatation

wsmd

103

end-diastolic dimension ≥ 55 mm) was observed innly 52% of their patients with LV systolic dys-unction (EF < 50%) at the most recent evaluation,nd 23% of the end-stage HCM patients showedeptal wall thickness ≥20 mm, although serialchocardiographic observations revealed consider-ble enlargement of the LV chamber over time.

Although several mechanisms leading to myocar-ial fibrosis and progressive LV remodeling areuggested in HCM, such as apoptosis or the geneticusceptibility to end-stage [16,26], one of theost important factors is myocardial ischemia

aused either by small-vessel coronary artery dis-ase or abnormal coronary vasodilator reserve inhe hypertrophied region. Previous studies havehown abnormal perfusion and decreased coronaryow reserve in the hearts of patients with HCM,nd particularly HCM with LV systolic dysfunction27—29]. These perfusion abnormalities are pre-ominantly observed in the septal region, and mayrecede the progression to congestive heart failurer evolution of LV systolic dysfunction [29].

linical implications

ur echocardiographic observations of HCM withild LV remodeling have several clinical implica-

ions. First, the characteristic echocardiographiceatures of LV remodeling in HCM demonstrated inhe present study may be useful in the differentia-ion from idiopathic DCM, in which LV wall motionmpairment is diffuse or predominantly involvedn posterolateral wall [10,30]. In fact, it happenshat patients who have been initially considered asCM prove to have relatives with typical HCM whenystematic family screening is carried out. Recenteports suggest that some mutations in the sameene encoding the cardiac sarcomere proteins, suchs �-myosin heavy chain, cardiac myosin-bindingrotein C, cardiac actin, and cardiac troponin T orardiac troponin I, can cause either HCM or DCM-ike phenotype [31—33].

Second, early identification of HCM patients inransition to end-stage might enable specific thera-ies targeted at delaying the progressive LV remod-ling or prevent cardiovascular deaths. Whetherpecific agents which inhibit renin—angiotensin sys-em or �-blockers will have any benefit remains toe clarified, augmentation of progressive LV remod-ling should be one of the targets of managementtrategies in this subset of HCM patients. Therefore,hen an impairment of septal, anterior, or apical

all motion is observed in HCM, special attention

hould be paid to the longitudinal changes of LVorphology and systolic function in the context ofevelopment of ‘end-stage’ phase.

R

[

[

[

[

[

104

Third, it is clinically important to identify thosewho will show rapid and progressive LV remodel-ing, among HCM patients with mild LV remodeling,in order to select candidates for heart transplan-tation. Assessment of wall motion abnormalitiesand wall thinning would be helpful in this respect,although prospective studies including larger num-ber of patients are required in order to clarify thisissue.

Study limitations

The present study has several limitations. First,the number of patients with mild LV remodeling israther small. Nevertheless, we believe that septaland anterior asynergy is the most common patternof wall motion impairment in ‘end-stage’ HCM, asseptal-dominant hypertrophy is most characteristicof HCM. Second, our study is in itself retrospec-tive. Hence, follow-up echocardiograms were notperformed annually in all of the patients. Third,although some HCM-causing mutations were foundand already reported in some patients includedin the present study [25], comprehensive geneticdata regarding major sarcomere proteins are notyet available. Finally, although WMS is a well-established method for assessing LV wall motion,it is rather subjective and therefore has limita-tions in the detection of subtle wall abnormalitiesin the hypertrophied regions, which may have ledto the nearly normal values of WMSI in those withpreserved systolic function. More objective meth-ods, such as strain imaging or tissue tracking, wouldpossibly enable us to detect wall motion abnor-malities in HCM before LV systolic dysfunction ismanifest.

Conclusion

In HCM with mild LV remodeling, septal and apicalwall motions are reduced, when septal hypertro-phy is fairly preserved and LV dilatation is mild.Identification of this LV remodeling at its earlystage may enable specific therapies targeted atpossibly delaying the progressive LV remodelingor prevent HCM-related cardiovascular events. AsLV remodeling progresses, wall motion abnormal-ities become more severe and extensive, oftenaccompanied by akinesis and thinning of septal orapical walls, and LV cavity enlargement becomesmore prominent, though posterolateral wall motion

is relatively maintained. These echocardiographicfeatures of mild and progressive LV remodeling arespecific for the process of ‘end-stage’ HCM and dis-tinct from those observed in DCM.

[

K. Hayato et al.

eferences

[1] Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ,Kuhn HJ, Seidman CE, et al. ACC/ESC clinical expert con-sensus document on hypertrophic cardiomyopathy: a reportof the American College of Cardiology Task Force on ClinicalExpert Consensus Documents and the European Society ofCardiology Committee for Practice Guidelines (Committeeto Develop an Expert Consensus Document on HypertrophicCardiomyopathy). J Am Coll Cardiol 2003;42:1687—713.

[2] Wigle ED, Rakowski H, Kimball BP, Williams WG. Hyper-trophic cardiomyopathy: clinical spectrum and treatment.Circulation 1995;92:1680—92.

[3] Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence andsignificance of progressive left ventricular wall thinning andrelative cavity dilatation in hypertrophic cardiomyopathy.Am J Cardiol 1987;59:123—9.

[4] Maron BJ, Spirito P. Implications of left ventricularremodeling in hypertrophic cardiomyopathy. Am J Cardiol1998;81:1339—44.

[5] Ten Cate FJ, Roelandt J. Progression to left ventriculardilatation in patients with hypertrophic obstructive car-diomyopathy. Am Heart J 1979;97:762—5.

[6] Fujiwara H, Onodera T, Tanaka M, Shirane H, Kato H,Yoshikawa J, et al. Progression from hypertrophic obstruc-tive cardiomyopathy to typical dilated cardiomyopathy-likefeatures in the end stage. Jpn Circ J 1984;48:1210—4.

[7] Maron BJ, Epstein SE, Roberts WC. Hypertrophic car-diomyopathy and transmural myocardial infarction withoutsignificant atherosclerosis of the extramural coronary arter-ies. Am J Cardiol 1979;43:1086—102.

[8] Shirani J, Maron BJ, Cannon III RO, Shahin S, RobertsWC. Clinicopathologic features of hypertrophic cardiomy-opathy managed by cardiac transplantation. Am J Cardiol1993;72:434—40.

[9] Varnava AM, Elliott PM, Mahon N, Davies MJ, McKenna WJ.Relation between myocyte disarray and outcome in hyper-trophic cardiomyopathy. Am J Cardiol 2001;88:275—9.

10] Waller TA, Hiser WL, Capehart JE, Roberts WC. Comparisonof clinical and morphologic cardiac findings in patients hav-ing cardiac transplantation for ischemic cardiomyopathy,idiopathic dilated cardiomyopathy, and dilated hyper-trophic cardiomyopathy. Am J Cardiol 1998;81:884—94.

11] Kitaoka H, Kubo T, Okawa M, Hitomi N, Furuno T, Doi YL.Left ventricular remodeling of hypertrophic cardiomyopa-thy: longitudinal observation in rural community. Circ J2006;70:1543—9.

12] Sahn DJ, DeMaria A, Kisslo J, Weyman A. The Com-mittee on M-Mode Standardization of the AmericanSociety of Echocardiography. Recommendations regard-ing quantitation in M-mode echocardiography: results ofa survey of echocardiographic measurements. Circulation1978;58:1072—83.

13] Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R,Feigenbaum H, et al. Recommendations for quantificationof the left ventricle by two-dimensional echocardiography.J Am Soc Echocardiogr 1989;2:358—67.

14] Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ,Bailey KR, Redfield MM. Left atrial volume as an index ofleft atrial size: a population based study. J Am Coll Cardiol2003;41:1036—43.

15] Maron BJ, Gottdiener JS, Epstein SE. Patterns and sig-nificance of distribution of left ventricular hypertrophyin hypertrophic cardiomyopathy: a wide-angle, two-dimensional echocardiographic study of 125 patients. AmJ Cardiol 1981;48:418—28.

H

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

CM with mild LV remodeling

16] Harris KM, Spirito P, Maron MS, Zenovich AG, FormisanoF, Lesser JR, et al. Prevalence, clinical profile, andsignificance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation2006;114:216—25.

17] Biagini E, Coccolo F, Ferlito M, Perugini E, Rocchi G,Bacchi-Reggiani L, et al. Dilated-hypokinetic evolution ofhypertrophic cardiomyopathy: prevalence, incidence, riskfactors and prognostic implications in pediatric and adultpatients. J Am Coll Cardiol 2005;46:1543—50.

18] Thaman R, Gimeno JR, Murphy RT, Kubo T, Sachdev B,Mogensen J, et al. Prevalence and clinical significance ofsystolic impairment in hypertrophic cardiomyopathy. Heart2005;91:920—5.

19] Matsumura Y, Takata J, Kitaoka H, Kubo T, Baba Y, HoshikawaE, et al. Long-term prognosis of dilated cardiomyopathyrevisited: an improvement in survival over the past 20years. Circ J 2006;70:376—83.

20] Kramer CM, Reichek N, Ferrari VA, Theobald T, Dawson J,Axel L. Regional heterogeneity of function in hypertrophiccardiomyopathy. Circulation 1994;90:186—94.

21] Mishiro Y, Oki T, Iuchi A, Tabata T, Yamada H, Abe M,et al. Regional left ventricular myocardial contractionabnormalities and asynchrony in patients with hypertrophiccardiomyopathy evaluated by magnetic resonance spatialmodulation of magnetization myocardial tagging. Jpn CircJ 1999;63:442—6.

22] Teraoka K, Hirano M, Ookubo H, Sasaki K, KatsuyamaH, Amino M, et al. Delayed contrast enhancement ofMRI in hypertrophic cardiomyopathy. Magn Reson Imaging2004;22:155—61.

23] Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD,Klocke FJ, et al. Myocardial scarring in asymptomatic ormildly symptomatic patients with hypertrophic cardiomy-

opathy. J Am Coll Cardiol 2002;40:2156—64.

24] Moon JC, McKenna WJ, McCrohon JA, Eliott PM, SmithGC, Pennel DJ. Toward clinical assessment in hypertrophiccardiomyopathy with gadolinium cardiovascular magneticresonance. J Am Coll Cardiol 2003;41:1561—7.

[

Available online at www.

105

25] Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N,Yamasaki N, et al. Lifelong left ventricular remodel-ing of hypertrophic cardiomyopathy caused by a founderframeshift deletion mutation in the cardiac myosin-bindingprotein C gene among Japanese. J Am Coll Cardiol2005;46:1737—43.

26] Ino T, Nishimoto K, Okubo M, Akimoto K, Yabuta K, KawaiS, et al. Apoptosis as a possible cause of wall thinningin end-stage hypertrophic cardiomyopathy. Am J Cardiol1997;79:1137—41.

27] Lorenzoni R, Gistri R, Cecchi F, Olivotto I, Chiriatti G, ElliottP, et al. Coronary vasodilator reserve is impaired in patientswith hypertrophic cardiomyopathy and left ventricular dys-function. Am Heart J 1998;136:972—81.

28] Yamada M, Elliott PM, Kaski JC, Prasad K, Gane JN, LoweCM, et al. Dipiridamole stress thallium-201 perfusion abnor-malities in patients with hypertrophic cardiomyopathy. EurHeart J 1998;19:500—7.

29] Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Giro-lami F, et al. Relevance of coronary microvascular flowimpairment to long-term remodeling and systolic dysfunc-tion in hypertrophic cardiomyopathy. J Am Coll Cardiol2006;47:1043—8.

30] Isomura T, Suma H, Horii T, Sato T, Kikuchi N. Partialleft ventriculectomy, ventriculoplasty or valvular surgeryfor idiopathic dilated cardiomyopathy — the role ofintra-operative echocardiography. Eur J Cardiothorac Surg2000;17:239—45.

31] Kokado H, Shimizu M, Yoshio H, Ino H, Okeie K, Emoto Y, etal. Clinical features of hypertrophic cardiomyopathy causedby a Lys183 deletion mutation in the cardiac troponin I gene.Circulation 2000;102:663—9.

32] Villard E, Duboscq-Bidot L, Charron P, Benaiche A, ConraadsV, Sylvius N, et al. Mutation screening in dilated cardiomy-

opathy: prominent role of the beta myosin heavy chaingene. Eur Heart J 2005;26:794—803.

33] Chien KR. Genotype, phenotype: upstairs, downstairs inthe family of cardiomyopathies. J Clin Invest 2003;111:175—8.

sciencedirect.com