Evaluation of Left Ventricular Enlargement as a Marker of ...circgenetics.ahajournals.org/content/circcvg/early/2011/06/02/CIRC... · Evaluation of Left Ventricular Enlargement as

Evaluation of Left Ventricular Enlargement as a Marker of Early Disease

in Familial Dilated Cardiomyopathy

Running title: Fatkin et al.; Early Disease in Familial Dilated Cardiomyopathy

Diane Fatkin, MD1,3,4; Thomas Yeoh, MB BS, PhD1; Christopher S. Hayward, MD3,4;

Victoria Benson, MSc2; Angela Sheu, MB BS1; Zara Richmond, BSc, Grad Dip Gen Couns1;

Michael P. Feneley, MD2,3,4; Anne M. Keogh, MD2,3,4; Peter S. Macdonald, MB BS, PhD2,4

1Molecular Cardiology Division, 2Cardiac Physiology and Transplantation Division, Victor

Chang Cardiac Research Institute; 3Cardiology Department, St Vincent’s Hospital; and 4Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Corresponding author:

Diane Fatkin, MD

Victor Chang Cardiac Research Institute,

Lowy Packer Building, 405 Liverpool St,

PO Box 699, Darlinghurst NSW 2010

Australia

Phone: 61-2-9295 8618

Fax: 61-2-9295 8601

Email: [email protected]

Journal Subject Codes: [89] Genetics of cardiovascular disease

MMMMMMMMMMMMMMMMMMMMMMMacacacacaccacacacacacacaccacacacacacacaaaa dodododododododododododododododododododododddoddd nanananananananaanananananananaannannnnaldldldldldldldldldldldldldldldlddldldlldddldd, , ,,,,,,,,, MBMBMBMBMBMBMBMBMBMMBMBMBMBMBMBMBMBMBBMBM

i

R a

c e

ioooololololology Divivivivivisisisisisioioioon,n,n,n,n, 2CaCaCaCaCardrdrdrdrdiaiaiaiaac ccc PhPhPhysysysyy iolologyyyyy a aa aandnnndn TTTTTrarararaansnsnsnsnsplpp ananananantatatatatatititititionnonnon D DD DDivivivivivis

Reesesesesesearaaa ch IIIIInssnsnn tiituuteee; 3CaCaCaCaCardddddioioioiiolololoologygygygygy Depepararararartmtttmtmeeentt,t SSt ViVV ncncncncncent’t’tt ss sss HoHH spspspita

cine, Universrsrsrrsititititity y y yy ofofofofof N N NNNewewewewew S S S SSouououououttttth hh hh WaWaWaWaaleleleleles,sss SSSSSydydydydydneneneneney,y,y,y,y, N N NNNewewewewew S outh Walettt

by guest on July 5, 2018http://circgenetics.ahajournals.org/

Dow

nloaded from

http://circgenetics.ahajournals.org/

2

Abstract:

Background – Echocardiographic screening of families with dilated cardiomyopathy (DCM)

has identified a subgroup of asymptomatic relatives with left ventricular enlargement (LVE).

The prognostic significance of LVE in this setting is incompletely understood.

Methods and Results - We evaluated 457 asymptomatic relatives in 128 DCM families and

identified 110 individuals (24%) with LVE. Serial echocardiograms in 72 untreated LVE

relatives showed that 9 individuals (13%) developed DCM over 10 to 152 months (median

52). Thirty LVE relatives and 30 age- and sex-matched healthy control subjects were

evaluated using 2-dimensional and M-mode echocardiography, tissue Doppler imaging, non-

invasive pressure-volume assessment, exercise stress echocardiography, and brain natriuretic

peptide levels. LVE relatives showed mild defects of systolic and diastolic left ventricular

function with normal filling pressures and exercise-induced increments in systolic contraction

in most cases. Left ventricular dimensions and fractional shortening most effectively

differentiated LVE relatives from controls, with other functional indices lacking additive

discriminative value. In a receiver operating characteristics analysis, the area under the curve

for left ventricular end-diastolic diameter (LVEDD, %predicted) was 0.96 (P<0.001).

LVEDD (%predicted) >116%, or LVEDD (%predicted) 112-116% + fractional shortening

<29% had high sensitivity (100%) and specificity (93%) for LVE relatives and identified 8 of

9 progressors.

Conclusions –LVE is a common finding in asymptomatic relatives in DCM families and can

be a marker of pre-clinical cardiomyopathy. Assessment of left ventricular size and

contractile function is required for differentiating between pathological and physiological

causes of LVE and may help to identify those at risk of disease progression.

Key words: dilated cardiomyopathy, echocardiography, diagnosis, early disease.

ogogogogogogogogoggogogoogogogggogoggoggrararararaararrararararararararaarr phphphphphphphphphphphphphphphphphphphphhphphhpp y,y,y,y,y,y,y,y,y,y,y,y,y,yyy,y,yyyyyy,y a a aaaa aaa a aaa aaaaaandndndndndndndndndndnnndndndndnnnnd b bbbbbbbbbbbbbbbbbbrarararararararararrararararararararrrar iiiiiiiiiiiii

nd diiiasasasasasasasasasasasasasasasasasaasasstototototototototototototototototottot lilililiilililiililiiliiliilililiiiccccccccccccccccccccc leleleleleleleleleleleleleleleleleftftftftfftftftftftftftftfftftftftftfttftft vvvvvey

r i

eft ns v

V

y

rmmmmaaala fillingggg p preeeeessssssururururureseseseses aaa aandndndndnd eeexeeeeerccisee-indndndndnducucucucucededededed iiiincncncccrerererr memememementntntntnts s ss s ininininin s s sssysysysysystotototooli

eft veeeeentntntttririririricuulalalll rr diddidd mmem nsnssssioioioons aaaaandndnddnd ff ffrara ttctctioioioonanananan ll lll shshshshhororororortteteet niniiiinnngn mmmost tt efeffffefeffef tcttcttiv

VEVVEE rr relelatatativivvvveseses f f frororom m m cococontntntntrororolslsls, , , , , wiwiwiw thththtt o o othththererer f ffunununu ctctctc ioioioonananan l l ll inininndidididicececec s ss lalall ckckininggg


Dow

nloaded from


3

Dilated cardiomyopathy (DCM) is a common cause of heart failure and a significant health

and economic burden. There is increasing evidence of a substantial heritable component to

DCM and at least 20-35% individuals with “idiopathic” DCM have familial disease.1,2 Nearly

40 chromosomal loci and disease genes have been identified to date.3 Pre-symptomatic

diagnosis of early disease provides an opportunity for preventative intervention but reliable

methods for detection of individuals at risk are required. Ideally, family genotyping would

enable genotype-positive individuals to be identified before the onset of symptoms. Because

of the costs and time involved in screening large numbers of genes and the low yield (<30%)

of finding mutations, genotype results are not available for most families. Hence, assessment

of the clinical phenotype remains a cornerstone of family management.

Systematic echocardiographic screening of asymptomatic relatives in DCM families

has identified a subgroup of individuals who have abnormalities of left ventricular (LV) size

or function that do not fulfill criteria for DCM.4-8 Isolated LV enlargement (LVE) has been

observed most frequently with a lesser number of individuals having normal LV size and

depressed fractional shortening (dFS). It has been proposed that these echocardiographic

changes represent pre-clinical stages of disease. At least one third of cases do have latent

cardiomyopathy, indicated by myocardial histological changes, reduced maximal exercise

oxygen consumption, or cardiac autoantibodies.5,9-12 However, LVE may also result from

unrelated pathologies or physiological variation, particularly in young, fit individuals

engaged in competitive sporting activity. Differentiating family members with true early

DCM from those with “athlete’s heart” poses a major challenge with significant management

implications.

The major objective of this study was to evaluate the natural history of LVE and the

role of various indices for assessment of myocardial function. We used diagnostic techniques

that have been proposed to be more sensitive or specific indicators of LV functional defects

gegegegegegegegegeegegeggegegeeegeegegemememememememememememeemememememememeemementntntnntntntnntntntntnntnnntnntnn . ... ......

c relllllllllllllllllatataatatatatatatatatatattatatatataattiviiviiviviviviviviviiviviviviviviviviveseseseseeseseseseseseseseesessesseess iiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnn DCDDDDDDDDDDDDDDDDDDDDDDg p g y p

u a

d E

e

g p g y p

ubububbubggrgg oup ofofofoff i i ii dndndddivivivivividididididuauauauaualslslssls w ww wwhohohhoh hhhhhaavee aabnbnbnnnororororormammamam liiliititiitieseseseses of f f ff leleleleleftftftftft v v v v venenenentrtrtrtrtriciciciciculuuuu a

do nooooott t fufufufufullflll ililililill l crcrcrritiitii erererria fffffororororo DCMCMCMCMCM.4-84-84-84-84 IIIsososolalallalatetetetetedddd d LVLVLVLVLV eeeenllnlllaaara gegegemmmentntnt ( (((LVLVLVLVLVEEE

eqeeqequeueuentntntlylyyyy w w wititiith h h h a aa leleessssssserererer n n numumumummbebebeerrrr ooof f ff inininndididivivivvidududuualala s s s hahahaavivivv ngngnggg n n nnororormamamall LVLVVLV rrr


Dow

nloaded from


4

than standard assessment by 2-dimensional and M-mode echocardiography, including tissue

Doppler imaging,13 non-invasive determination of the preload recruitable stroke work

(PRSW) relationship,14-16 exercise stress echocardiography,17 and plasma levels of brain

natriuretic peptide (BNP).18 Our data confirm the prognostic significance of LVE as a marker

of early disease in familial DCM and suggest a practical approach to the investigation of

asymptomatic family members.

Materials and methods

Subjects

Probands from 128 kindreds with suspected familial DCM were identified from St Vincent’s

Hospital and by physician referral (Table 1). Family members aged >16 years were invited to

undergo clinical evaluation, 12-lead electrocardiography and transthoracic echocardiography.

M-mode echocardiographic dimensions were corrected for age and body surface area

according to Henry’s formula,19 with LV end-diastolic diameter (LVEDD) expressed as a

percentage of predicted diameter as follows: predicted LVEDD = (45.3 x body surface

area0.3) - (0.03 x age) - 7.2. DCM was defined as LVEDD (%predicted) >112% and LV

fractional shortening (LVFS) < 25%. Familial DCM was defined as DCM in 2 or more first-

degree relatives that was unexplained by other inherited cardiac or systemic disorders. In

asymptomatic relatives, LVE was defined as LVEDD (% predicted) >112%, and dFS was

defined as LVFS <25% .5,8,12 A group of 30 healthy volunteers who had no history of

cardiovascular disease comprised a control group. All subjects provided informed written

consent and protocols were approved by the institutional Human Research Ethics Committee.

Longitudinal observational study

identntntntnttntntntntntntntntntntntntttifififififififififififffififififififififffieieieieieieieieieieieieieieieeieiei ddddddddddddddddddddddd frfrfrfrfrfrfrfrfrfrfrfrfrfrffrfrfromomomomomomomomomomomomomomomomomomoom Sp

p ician . e

e c

d

p

phhhhhyysyy ician rererereefefff rrrrrrrrrralalalalal (((((TaTaTaTaTablblblblbleeee e 1)1)1)1)1 . FaFaFaFF miilly mmmmmemememmmbebebbb rsrsrs aaaaaggged ddd d >1>1>1>1>16 6 6 6 6 yeyeyeyeararararars ssss wwweww

evalululululuatatatatatioioiioion,n 1112-222 lleleadaa eeeeeleleeleectrooocacacacaarrrrrdidididd ogogograraphphphphphy yy y y aaanaa dddd d tttrrtrananstss hohohohh rararaciiicc ececchohhhhoc

didiogogograraraphphhhhicicici d ddimimimmenenensisisis onononons s s weweweweererere c c ccorororrererectctctedededd f f forororr a a a gegegegeg a a andndndnd b bbbododoody y y yy ssusurfrfacacace eee


Dow

nloaded from


5

Relatives were followed with serial echocardiograms. For relatives who had been screened

prior to study recruitment, the follow-up period was taken from the first available

echocardiogram. The duration of follow-up was determined as the time to disease

progression, or commencement of treatment for DCM prophylaxis, or the most recent

echocardiogram. Disease progression was defined by a new onset of contractile dysfunction

(LVFS <25%) or worsening of contractile dysfunction (if baseline LVFS <25%).

Phenotype assessment

Transthoracic echocardiography was performed according to American Society for

Echocardiography guidelines. In addition to LVEDD (%predicted) >112%, two alternative

methods for assessment of LV size were evaluated. LV dilatation was defined by LVEDD

greater than 2.7 cm / body surface area (expressed as m2) (NHLBI standard)20, or LVEDD

above height- and sex-adjusted 95th and 97.5th percentile limits (Framingham standard).21

Peak velocity of early (E) and late (A) diastolic filling, and isovolumic contraction and

relaxation times were measured from mitral inflow velocities, while ejection time was

measured from LV outflow velocity tracings. The myocardial performance index (MPI)

index was derived using the isovolumic contraction, isovolumic relaxation and ejection

times.22 Systolic (S), early (E') and late (A') diastolic myocardial tissue Doppler velocities

were recorded at the septal and lateral margins of the mitral annulus. The PRSW relationship

was determined from non-invasive peripheral arterial pressure waveforms and

echocardiographically-derived on-line LV volume23 using the linear regression equation:

stroke work=MW (end-diastolic volume -VW), where MW is the slope and VW is the volume

axis intercept.14-16 Data were obtained at rest and with variable preload induced by the

Valsalva manoeuvre. Exercise stress echocardiography was performed using the Bruce

protocol. LV end-diastolic and end-systolic areas were measured in the short-axis view at rest

eeeeeeeeeeeeeeeeed)d)d)d)d)d)d)d)d)dd)d)d)dddd)d)d)d)d)) >>>>> >>>>>>>>>>>>>>>>>1111111111111111111111111111111111111111 2%2%2%2%2%2%2%2%22%%2%2%2%2%2%%%2%%%%%, , ,,, , , ,,,,,,,,,,, twtwtwwwtwtwwtwtwwwtwwtwtwtwwwwooo o o o o ooooooo oooooo aaaaaaaaaaaaa

n waaaaaaaaaaaaaaaaasssssssssssssssss deddededededdedededdedededededededededddefififififififififififififififififififififiifinenneneneneneneneneenenenenennnennn dddddddddddddddddddddd bybbbbbbbbbbbby

c r

d n

e o

y

cmmm mm / body ssssururuuu fafafafafacececeee aa aaarererererea (e(e(e(e(expxpxpresssssss edd as mmmmm22222))) )) (N(N(N(N(NHLHLHLHLHLBIBBB ssssstatatattandndndndndarararard)d)d)d)d)202020202 , or

d sexxxxx-adadadadadjjjujj ststt dededed 99955555th andndndndnd 97.777 555ththththth ppperercecentntntnttilililille e lilililil mimimimimitttststs ( ( (FFrFrFFrammmininini ghhhhhamamm s sttattat n

eeeearararlyly ( (E)E)))) a a andndndn l l llatatateee (A(A(A(A(A) ) ) dididid asasasasstototolilililic c c fifififillllllinininng,g,g,, a a aandndndn i i sososoovovovolululuumimimmiic c c c cococontntntrararactctctioioo


Dow

nloaded from


6

and immediately following peak exercise. NT-pro BNP levels were measured in plasma

samples by electrochemiluminescence using the Elecsys II proBNP immunoassay (Roche

Diagnostics).

Statistical analysis

Differences between progressors and non-progressors, and between LVE cases and controls,

were evaluated using maximum likelihood repeated measures linear or logistic regression,

accounting for the clustering within families (Stata 10, StataCorp LP, Texas, TX). The

clustering within families was modeled using a random effect that was assumed to be

independent and identically normally distributed with mean zero and constant variance.

Receiver operating characteristic (ROC) analysis was performed using PASW Statistics 18

(IBM Corp., Somers, NY). A two-tail P value < 0.05 was considered statistically significant.

Data are reported as mean ± SD.

Results

Prevalence and outcome of asymptomatic echocardiographic changes

Four hundred fifty-seven asymptomatic relatives from 128 DCM families were evaluated

(Figure 1, Table 1). Eighteen relatives (4%) had unsuspected DCM and were commenced on

treatment. One hundred-fifteen relatives (25%) from 54 families had echocardiographic

changes, with LVE in 110 relatives and dFS in 5 relatives. One hundred-five relatives (100

LVE, 5 dFS) were followed prospectively over 10 to 202 months (median 55) with 16

individuals (15%; 15 LVE, 1 dFS) developing DCM. Seventy-four relatives (72 LVE, 2 dFS)

had serial echocardiograms available during periods in which they received no cardiovascular

medications. Thirty-seven individuals (LVE 34, dFS 3) were on treatment for some or all of

o o o oo oo o oo o o o oooo ananananananananananananananananananaand ddddddddd dddddddddddd cococococococococoococococoocococoocooconsnsnsnsnsnsnsnsnnsnsnsnsnsnsnnsssssstatatatatatatatatataatatatataatattat ntntttntntnttntntnttntnnnnt vv v vvvv vvv vvvvvvvvvvaaaaaaaaaaaaaaaa

d usiiiiiiiiingngngngngngngngngngngngngngngngngngngngg PPPPPPPPPPPPPPPPPPPPASASASASASASASASASASASASASASASASAASASASAASASASWWWWWWWWWWWWWWWWWWWWWWWW StSSSSSSg ( ) y p g

m , NY y

d

g ( ) y p g

meeeersrsrr , NY).))) AAAAA ttwowowowowo-t-t-t-t-taiaiaiaiail llll P P P PP vavavavavalululue << 0.005 wwwwwasasasasas c c cononnsisisisidedededd reeeeed d ddd stststststatatataatisiisisistititititicacacacacallllll y

d as mmmmmeaeaeaeaean ± ±±± SDSDSDSDD.


Dow

nloaded from


7

the follow-up period, including 6 LVE relatives who crossed over from the no-treatment

group.

Natural history of LVE

The natural history of LVE was further evaluated in the subgroup of 72 relatives who were

followed in the absence of treatment (“natural history” cohort, Figure 1). Nine relatives

(13%) showed disease progression over follow-up periods ranging from 10 to 152 months

(median 52), including one 17 year-old male who developed DCM requiring heart

transplantation. Baseline clinical and echocardiographic parameters were compared between

those who progressed and those who did not (Table 2). “Progressors” were relatively younger

than “non-progressors”, however the mean age at DCM diagnosis in family members of

progressors (42 ± 16 years, n=37) was similar to the study probands overall (Table 1). Our

findings are in keeping with recent data suggesting that screening of asymptomatic family

members can identify at-risk individuals at an earlier stage of disease. 24 There were no

differences in mean values for LVEDD, LVEDD (%predicted) or LVESD at study entry

between progressors and non-progressors.

Assessment of LV dilation

Previous studies of early disease have focussed on individuals with and without LVE within

families and the extent to which similar changes might be present in healthy control subjects

has not been considered. To better characterise the LVE phenotype, we studied 30

consecutive LVE relatives who agreed to undergo further more detailed echo evaluation and

30 age- and sex-matched control subjects. None of these LVE relatives was a progressor. By

design, all LVE subjects had LVEDD (%predicted) >112%, but unexpectedly, 11 of 30

healthy controls also fell within this range. A higher cut-off, >118%, proposed by Baig and

ssosososososososososososossosososososososorsrsrsrsrsrsrsrsrsrsrsrsrsrsrssrsrsrssr ” weweweweweweweweeweweweweweweeewwwwwwww rererererererererererererereerererrere rrrrr rr r r rrrelelelelelelelelelellelleleelelelatatatatatatatatatatatatatataatatataaata iiiiiiiiiiiiiiii

is innnnnnnnnnnnnnn fffffffffffffffffffffffamamamamamamamamamamamamamamamamamamaa ilililiilililililililililililililillilililyyyyyyyyyyyyyyyyyyyy mmememememmememememmmememememmemm m, g g y

± b

e t

n w

, g g y

± 1616666 years, n=n=nnn 3737373737) ) ) )) wawawawawassss s sisisisisimimimimm lalallar to tthhe ssssstututututudydydydydy pprororobababababandndnddds ss ss ovvvvverereereralallalall l l ll (T(T(T(T(Tabaaa

eepininininingg g wiwwww thhhhh r reececceenennt dadadadaatatataaa sugggggggegeg ssssstitittit ngngng tt thahahhahatttt t scscscscscreeeeenenenenenininini g g g g offfff aa asssympmpttototomamat

nnnntitifyfy aa at-t-t-ririririr sksksksk i i indndndndiviviividididi uauauaualslslsls a a aat t t t t ananan e e earararlililiererer s s statatatagegegegeg o o o f f f ff dididiseseseasasase.e.e.e 24 T T Thehererere w ww w


Dow

nloaded from


8

colleagues5 had greater stringency, identifying 23 LVE relatives and 2 controls. In a ROC

analysis, the area under the curve (AUC) for LVEDD (% predicted) was 0.96 (P<0.001,

Figure 2). LVEDD (% predicted) >116% gave the highest sensitivity (0.93) and specificity

(0.93) and was found in 28 relatives and 2 controls.

We compared LVEDD (% predicted) with two alternative methods for normalization

of LV size.20,21 The NHLBI standard identified 21 LVE relatives and 13 control subjects,

while the Framingham standard identified 24 LVE relatives and 2 controls at the 95th

percentile and 19 LVE relatives and 1 control at the 97.5th percentile. The AUC for the

NHLBI and Framingham 95th percentile standards were 0.75 (P=0.001) and 0.95 (P<0.001),

respectively (Figure 2). These data indicate that LVEDD (% predicted) and the Framingham

standards are superior to the NHBLI standard and have similar efficacy overall. Of the

criteria evaluated, LVEDD (% predicted) >116% most effectively differentiated family

members and controls.

Comparison of LV function in LVE relatives and control subjects

To determine whether pre-clinical defects of myocardial function are present in LVE

relatives, a range of parameters were evaluated and compared with control subjects (Table 3).

At rest, LVE relatives had increased end-diastolic and end-systolic LV dimensions and lower

LVFS, as well as lower peak E wave velocities, lower peak and longer time to peak S wave

velocities, and higher MPI index. Although there was a trend towards lower slope (Mw) and

higher intercept (Vw) of the PRSW relationship in LVE relatives, both of which are indices

of reduced contractility,14-16 there was a substantial scatter of data and the differences with

control subjects did not achieve statistical significance. With exercise stress, LVE relatives

achieved comparable peak heart rates but had lower systolic blood pressure and shorter

exercise duration. LV cross-sectional areas before and after exercise were increased in LVE

dididididididididididididdidididididididictctctccttctctctctctctcttctctctctccc ededededededededededededededededededededdededd) ))))) )))) ) ) ))))))))) ananananananananaananananananaannnnnnd dddddddd ddd dddddddd ththhhthththhhhthhthththhthe ee e ee ee e eee ee e eeeee FFFFFFFFFFFFFFFF

efficaaaaaaaaaaaaaaaaaacycycycycycycycycycycycycycycycycycycyccc ooooooooooooooooooovevevevevevevevevevevevevvevevveveevvev rararararararaarararaaaarrararaarallllllllllllllllllllllllllllllllllllll Op y

d d

n

p y

d, LLLVLL EDD DD (%(%(%(%( ppppprererereredididididictctctctctededededed) )))) > > >1111166%6% mmosososososttt t efefefefeffefffef ctcctivivivivvelee y y y y y dididdid fffffffffferererererenenenenntititititiatatatatatedeeee

ntrolslslslsls.


Dow

nloaded from


9

relatives but the relative increment in fractional area change at peak exercise was equivalent

to control subjects. Five LVE relatives and 2 control subjects had BNP levels that were

higher than those of an age- and sex-determined reference range, but there were no

differences in mean levels between the groups.

Predictive value of echocardiographic indices

The sensitivity and specificity of indices of systolic and diastolic LV function were assessed

by comparing the numbers of LVE relatives and control subjects who had values lying

outside a limit defined ± 2 SD of the mean values in control subjects. Individual parameters

had only weak to moderate sensitivity but generally high specificity (Table 4). The cut-off

value for LVEDD (%predicted) >122% defined by this method was less sensitive than

LVEDD (%predicted) >116%. The combined criteria of LVEDD (%predicted) >116%, or

LVEDD (%predicted) 112-116% + LVFS <29 identified all 30 LVE (100%) relatives and 2

control subjects (sensitivity 100%, specificity 93%). Addition of other parameters had no

incremental value for identifying LVE relatives. In the natural history cohort, 61 individuals

met these criteria, including 8 of the 9 progressors.

Discussion

Here we find that LVE is common in asymptomatic relatives and that 1 in 10 individuals with

LVE will progress to DCM within a 5-year period. LVE is also present in many normal

individuals, highlighting the need for criteria to distinguish between pathological and

physiological LV dilatation. Our natural history data indicate that LVE alone incompletely

identifies progressors and that assessment of LV size and contractile function is required for

risk stratification. While a variety of techniques for detecting pre-clinical cardiomyopathy

ciciciciciciciciciciciciccicicicicicicicitytytytytyytytytytytytytytytytytyytytyyyyy (((( ((( ( ( ((( ( ( (((( ( ((((TaTaTaTaTaTaTaTaTaaTaaTTTTaTaTTaaaaTT blblblblblblblblbblblblblblblbbllllle e e eee e e e eee e e ee eee e 4)4)4)4)4)4)4)4)4)4)4)4)4)44)44)4 . . . TThTThTTTTTTTThTThTThTTTT

was leleleleleleleleleleleleleleleleleeeeeesssssssssssssssssssssssssssssssssssss sssssssssssssssssseneneneneneneneneneneneeneneneneneneeenene sisisisisiisisisisisisisisiisiissiiititititittitititittititititittitititit vevvv( p ) y

>

( r

( p ) y

ccccteeeed) >11116%6%6%6%6%. ThThThThThee eee cococococombmbmbmbmbininini ededded ccriterriaaaaa ooo oof fff f LVLVLVLVLVEDEDEDDEDD DDDD (%(%(%(%(%prprrrrededededediciciicicteteteteted)d)d)d)d) >

cted)d)d)d)d) 11111121211 -111116161616% %%%% + +++ LVLVLVLVLVFFSFFF <<<<<2929292929 iii iddededd tntntifffffieeieeeddd dd aaalaa l llll 3030303030 LLLLLVEVEVEEVE (1(1(1(11000000%)%)%)%)) r rele

(sesesensnsnsititivivitititii y y y yy 1010100%0%0%, ,,,, spspspsppececece ififificicccititity y y yy 939393%)%)%)%)%). . AdAdAdA dididiitititionononn oo of f f f otototheheheheer r r r papapapp rararamememeteteterrrr


Dow

nloaded from


10

have been proposed, standard 2-dimensional and M-mode echocardiography is an effective

screening method for detection of early disease. These findings have implications for the

clinical screening and follow-up of asymptomatic relatives in DCM families.

The prevalence and natural history of LVE have been evaluated in several studies.4-

8,12 In the largest series to date, Mahon and colleagues8 screened 767 asymptomatic relatives

of 189 DCM probands and found 140 relatives (18%) with abnormal echocardiograms,

including 119 relatives with LVE and 21 relatives with dFS. Eight of the 107 LVE relatives

(8%) who were followed prospectively developed DCM over a median 53-month period. In

our cohort of 457 asymptomatic relatives in 128 DCM families, we found 115 of 457

asymptomatic relatives relatives (25%) with abnormal echocardiograms, most of whom

(n=110) had LVE. Nine of 72 untreated LVE individuals (13%) progressed to DCM over a

median 52-month period. Our data are concordant with those of Mahon et al. and show that a

clinically-significant number of asymptomatic relatives will deteriorate within 5 years after

LVE is detected.

Given its prognostic significance, the reliability of methods used to define LVE is

paramount. Diagnosis of LV dilatation based on a laboratory reference range for LVEDD (eg.

>56 mm) is relatively insensitive, particularly in women, and several different normalization

formulae have been proposed, that take into account factors such as age, sex, height, and

body surface area.19-21 Normalization of LVEDD to BSA using the Henry formula has been

recommended for clinical practice. 25 We selected LVEDD (%predicted) >112% since this is

a frequently-used criterion for LV dilatation and permits direct comparison with other early

disease studies, including that of Mahon et al. 5,8,12 Baig and colleagues5 suggested that

LVEDD (%predicted) >118% might be a better predictor of relatives at risk of developing

DCM, while Hershberger and colleagues26 concluded that the Framingham standard was

superior to LVEDD (%predicted) >112% or the NHLBI standard for detecting LVE. We

iiiiiiiiiiiiiiiogoogogogogogogogogogogogogogogogogogogogoggggrararaarararararararaararrararararaaaar msmsmsmsmsmsmsmsmsmsmsmsmmmmmsmmsmmmsmmmm ,, ,, , , ,,,, ,,,, momomomomomomomomomommmomomomomommmm sttstststststststststtstsststst o o o oo o o ooo oooo o oooooffffffffffffffff

progggggggggggggggggrerererererererererererererererererererressssssssssssssssssssssssssssssssededededededededededededededededdededededdeddd tttttttttttttttttoooooooooooooooooooo DCDDDDDDDDDDDDDDDD( ) p g

h riod. d

ca

( ) p g

h peeriod. OuOuOuuOurr dadadadadatatatatata aa aaarerererere ccccconononononcccordrdrdrddaantt wiwiiiiththththth ttttthohohohohosesee oo ooof f ff f MaMaMaaahohohohohon nnn n etetetetet a a aaal.llll aa aaandnnn

canttttt nnn numumumumumbeerr ofofofff a asysysysympmmpmpmptotototot maaaaatiiititic cc rerelallall tititit veveveveessss s wiwiwiwiwillllll d ddddetette ererioiiorararatetetet wwititi hihihihiinn 5 5555


Dow

nloaded from


11

concur with these findings but also show that LVEDD (%predicted) >116% gives even better

discrimination between family members and control subjects.

Our natural history data do not support a direct relationship between LV size and

disease progression in all cases, and some progressors had an only mild LVE together with

LV systolic dysfunction at the initial screening study. These differences in primary

manifestations of disease are likely to be explained at least in part, by the underlying family

gene mutation, and demonstrate that LV size and function need to be incorporated into risk

assessment. A number of non-invasive techniques for detection of early myocardial

dysfunction in familial DCM have been reported5,9-12 but a comprehensive comparative

analysis has not been performed. Our echocardiographic studies provide insights into

myocardial performance in LVE relatives as well as the sensitivity and specificity of various

functional parameters.

The majority of LVE relatives had LVFS values that were within a “normal”

reference range, however the mean LVFS was significantly lower than in control subjects.

LVE relatives had a lower mitral S wave velocity, prolonged time to peak S wave velocity

and higher MPI index, consistent with mild defects of LV systolic function. Indices of

diastolic function were similar in LVE relatives and control subjects, with no augmentation

of atrial contraction or rapid early filling that is characteristically seen in patients with

established DCM and elevated LV filling pressure. The low mitral inflow E wave velocity

suggests normal LV filling pressure, consistent with normal levels of BNP in the majority of

individuals. Despite the baseline impairment of systolic function, as well as higher chamber

volumes and heart rates, LVE relatives were able to partially compensate functionally to

maintain cardiac output with exercise and achieved similar increments in systolic contraction

and maximum heart rates to those in control subjects, explaining their lack of symptoms.

pppppppppppppppppppppprororororoorororororororororororoororovivivivivivivvivivivivvivivivivivivivivviviidededededededededededeededddddedddedd ii iiiiiiiiiiiiinsnsnsnsnsnsnsnsnsnsnnsnsnsnsnsnsnsnn igigigigigigigigiggggiggiggghthththththththththththththththththhthhth sssssssssssssssss

ity aaaaaaaaaaaaaaandndndndndndndndddndndndndndndndndndndndnnd sssssssssssssssspepepepepepepepepepepepepepepepeepeepepeeeeciciciciciciciciciciciciciciciiicic fifififfifififififififififfififififififificicccccccccccc ty p

e

ri ve d m

h l

y p

etetetete eeree s.

rity oooof fff LVLVLVLL E EEE rereelallall titittitives ssss hahahahh d LVLVLVLVLVFSFSFSFSFS v valallueuueueuesss thththththattttt www wwereree wiwiiiithththththiiniii aa “ “““nonon rmrm

hhhoowoweeveverererrr t t thehehehe m m meaeaean n n LVLVLVLVFSFSFSS w w wwwasasass s s siiigngngngg ififificiciccanananntltlttly y y yy loloooowewewer rr ththththanananan i iin n n cococontntntrororol


Dow

nloaded from


12

However, the peak pulse pressure, rate-pressure product, and exercise duration were

relatively reduced, consistent with blunting of peak myocardial work capacity.

While statistically significant differences between groups were found for many of the

functional parameters evaluated, there was a substantial scatter of data and overlap between

LVE relatives and control subjects. To derive some practical guidelines for the investigation

of individual family members, we determined the sensitivity and specificity of various

parameters using data dichotomized ± 2 SD from mean values in control subject. In this

analysis, individual factors had low-to-moderate sensitivity and sensitivity. Surprisingly, the

simple measures of LV dimensions and LVFS were more discriminative than the tissue

Doppler and exercise echo parameters. Most of the individuals with abnormal tissue Doppler

and exercise echo parameters were already identified by changes in LV dimensions and

LVFS, and there was no incremental value for including these factors. Selecting individuals

with more severe LV dilatation, (LVEDD (%predicted) >116%), or an intermediate extent of

LV dilatation together with LVFS less than 2SD from the control mean (LVEDD

(%predicted) 112-116% + LVFS <29%), gave a very high sensitivity (100.0%) and

specificity (93.3%) for differentiating LVE relatives from control subjects, and identified 8 of

the 9 progressors in the natural history study. These observations suggest that asymptomatic

relatives that meet these criteria have a high likelihood of having early disease and warrant

close-follow-up. In relatives with LVEDD (%predicted) 112-116% + LVFS >29%, some

may be genotype-positive and too young to show signs of disease, while others may in fact be

genotype-negative.

Identification of LVE relatives at greatest risk of progression remains a challenge.

Although useful for detecting early disease, LVEDD (%predicted) >116% or LVEDD

(%predicted) 112-116% + LVFS <29% had a positive predictive value of only 13% within a

5-year period. LVEDD and LVESD are independent predictors of congestive heart failure in

wiwiwwwiwiwwiwiwwiwiwwiwiwiwwwiwww thththththhthtthththththththththhth aa aa aaa a a aaaa aaaaaaaabnbnbnbnbnbnbnbnbnnbnbnbnbnbnbnbnbnbnbnnb orororororororoorororororororoororrrrmamamamamamamamamammamamamammammmm lllllllllllll l titititititititititititititititittitisssssssssssssssss

s in LLLLLLLLLLLLLLLLLLLLLLLVVVVVVVVVVVVVVVVVVVVVVV didididiidididididididididididididiididd memememememememememememememememmemmemmmmm nnsnsnsnsnnsnnsnnnsnsnsnsnsnnsnn iop y y g

s no i .

e i

g D

p y y g

wawawawwas no inccccrererrr memmemementntntntntalalalalal vv vvvalalalalalueueueueue f ff forrrrr ii inccluudididididingngngngng ttttthehehhh sesese fffffaaactooooorrrrsr . SeSeSSeS lelelelelectcctctc inininining

e LV VVVV dididiiilalalalalataatititt ononn, (L(L(L((LVEVEVEVEEDDDDDD (((((%p%p%p%p%predddddicicteteted))d)d)d) > >>>>1111111116%6%6%6%6%),),),), o oor ananan ii iiinttnttteerer ememem dddidd

geeeeththererer w witititti h h h h LVLVLVFSFSFS l lllesesesss ss s ththththananannn 2 2 2SDSDSDS f fffrororom mm thththe e e cocococ ntntntn rororol l ll mememeananana ( ( ( ((LVLVLVEDEDEDDDDD


Dow

nloaded from


13

a community-based population27 but we found no differences in the mean LVEDD or LVFS

between progressors and non-progressors at their baseline evaluation. Most of the diagnostic

indices evaluated in the case-control study were not included in the natural history study, and

hence we are unable to exclude the possibility that some of these may have a role in risk

stratification or serial patient monitoring. Continued evaluation of markers of early disease is

required and techniques such as cine magnetic resonance imaging may have a role in

detecting and monitoring preclinical LV dysfunction.28

A limitation of our study is the small number of genotyped individuals and we cannot

exclude the possible confounding effects of inclusion of some relatives with non-genetic

causes of LVE. Since mutations in known disease genes are present in a minority (<25%) of

DCM families,3 the practical reality is that most physicians are required to assess family

members who have unknown genotypes. Even if the genotype is known, there will be diverse

underlying molecular defects, unique individual profiles of background genetic and

environmental factors, and relatives are likely to be screened at varying temporal stages of

the disease process. Hence, a functional classification of early disease may be more

clinically-useful than genotype per se.

These observations highlight the importance of clinical screening of asymptomatic

relatives in DCM families and of ongoing follow-up for those with LVE. Accurate

identification of high-risk subgroups within LVE cohorts will not only have implications for

individual patient management, but will also help to define a target study group for clinical

trials. The ultimate goal of detection of early disease is preventative intervention but there are

currently no data to support either pharmacological treatment or wait-and-see approaches for

pre-symptomatic family members. Prospective studies are urgently required to determine the

most effective agents and optimal timing of prophylactic therapy.

seseseseeseseseseesesesseseseeeeeesentntnntntnttntntntnntntntntntntntnn iiiii iii iiiiiiiiinnnnnnnnnnnnnnnnnnnn aaaaaaaa aaaaaaaa mm m m m mmmmm m m mm mmmmmmmininininininininininiinninininiiinororororrorororrorororororororooorrrititititititititititititititititiitityyyyyyyyyyyyyyyyy

requiiiiiiiiiiiiiiiiirerererererererererererererererererreedddddddddddddddddddddd tototototototototototototoototototoottoo aaaaaaaaaaaaaaaasssssssssssssssssssssssssssssssssseeeeeseeeeeee sp y p y q

v nkno f e s w

cul a

c l

p y p y q

vvvevv unknownwnwnwwn g ggggenenenenenotototototypypypypypesesesss.. . EvEvEEvE ennnnn i f ththe gegggg nononononotyttytt pepepe iiiiis knnnnnowowowowown,n,n,n,n, ttttthehehehehererererere w

cularrrrr d ddddefefefefefecctststt , ,,,, ununu iiqiqiqi ue ii indndndndn ividididididuauauauaualllll prprpr fofofffilililii eeeese ooooofff bababababackckkckgrgrgrrg ouuundndnddd ggenenetetettticiiiic a

ctctctorororsss, aa andndndndn r r releleelatatativiviviveseses a a aarererer l l likikkikelelely y y yy tototo b bbbe ee scscscrererereenenenedede a a aat tt vavavaryryryyyininiinng g g gg tetetempmpmporororalaal


Dow

nloaded from


14

Acknowledgments: We thank M. Law for statistical advice and analysis; F. Ali, O.

Baddeley, H.Crotty, and J. Hansen for clinical investigations; and K. Alford, D. Amos, J.

Atherton, B. Bastian, F. Bates, M. Cooper, G. Carroll, T. Carruthers, G. Connor, G. Cranney,

R. Cranswick, L. Davis, B. Freedman, J. French, P. French, D. Guy, D. Hammill, D. Hayes,

P. Hayes, D. Kuchar, G. Lane, J. Leitch, S. May, D. Mumford, L. Pressley, D. Richmond, P.

Robinson, S. Roy, C. Semsarian, J. Silberberg, C. Thorburn, P. Thompson, E. Vogl, B.

Walker, for proband referrals.

Funding Sources: This work was supported by the National Health and Medical Research

Council of Australia, Canberra (grant numbers 354400, 404808), National Heart Foundation

(grant number G00S0736), St Vincent’s Clinic Foundation, Sylvia and Charles Viertel

Charitable Foundation, and a Pfizer Cardiovascular Lipid Research Grant (to TY).

Conflict of Interest Disclosures: None.

References:

1. Lee DS, Pencina MJ, Benjamin EJ, Wang TJ, Levy D, O’Donnell CJ, Nam BH, Larson

MG, D’Agostino RB, Vasan RS. Association of parental heart failure with risk of heart

failure in offspring. N Engl J Med. 2006;355:138-147.

2. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ,

Seidman CE, Young JB. Contemporary definitions and classification of the

cardiomyopathies. Circulation. 2006;113;1807-1816.

3. Fatkin D, Otway R, Richmond Z. Genetics of dilated cardiomyopathy. Heart Fail Clin.

2010;6:129-140.

4. Zachara E, Caforio AL, Carboni GP, Pellegrini A, Pompili A, del Porto G, Sciarra A,

Bosman C, Boldrini R, Prati PL, McKenna WJ. Familial aggregation of idiopathic

dilated cardiomyopathy: clinical features and pedigree analysis in 14 families. Br Heart

J. 1993;69:129-135.

encina MJ, l CJ, Nam

ostino RB Vasan RS Association of parental heart failure with

encina MJ, BeBeBeBeBenjnjnjnjnjamamammminininii EEEEEJ,J,J,J,J, W W W W Wananananang g g g g TJTJTJJJ, , , ,, LeLLLL vyvyvyvyvy D D D D D, , , O’O’O’O’O’DoDoDoDoDonnnnnnnnnneeelee l CJ, Nam

osoostitinono RRBB VVasasanan RRSS AAssssocociaiatitionon ooff paparerentntalal hheaeartrt ffaiailulurere wwitithhh


Dow

nloaded from


15

5. Baig MK, Goldman JH, Caforio AL, Coonar AS, Keeling PJ, McKenna WJ. Familial

dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives

and may represent early disease. J Am Coll Cardiol. 1998;31:195-201.

6. Crispell KA, Wray A, Ni H, Nauman DJ, Hershberger RE. Clinical profiles of four

large pedigrees with familial dilated cardiomyopathy. Preliminary recommendations for

clinical practice. J Am Coll Cardiol. 1999;34:837-847.

7. Michels VV, Olson TM, Miller FA, Ballman KV, Rosales AG, Driscoll DJ. Frequency

of development of idiopathic dilated cardiomyopathy among relatives of patients with

idiopathic dilated cardiomyopathy. Am J Cardiol. 2003;91:1389-1392.

8. Mahon NG, Murphy RT, MacRae CA, Caforio AL, Elliott PM, McKenna WJ.

Echocardiographic evaluation in asymptomatic relatives of patients with dilated

cardiomyopathy reveals preclinical disease. Ann Intern Med. 2005;143:108-115.

9. McKenna CJ, Sugrue DD, Kwon HM, Sangiorgi G, Carlson PJ, Mahon N, McCann

HA, Edwards WD, Holmes DR, Schwartz RS. Histopathologic changes in

asymptomatic relatives of patients with idiopathic dilated cardiomyopathy. Am J

Cardiol. 1999;83:281-283.

10. Mahon NG, Sharma S, Elliott PM, Baig MK, Norman MW, Barbeyto S, McKenna WJ.

Abnormal cardiopulmonary exercise variables in asymptomatic relatives of patients

with dilated cardiomyopathy who have left ventricular enlargement. Heart.

2000;83:511-517.

11. Mahon NG, Madden BP, Caforio AL, Elliott PM, Haven AJ, Keogh BE, Davies MJ,

McKenna WJ. Immunohistologic evidence of myocardial disease in apparently healthy

relatives of patients with dilated cardiomyopathy. J Am Coll Cardiol. 2002;39:455-462.

t ttt ttttt PMPMPMPMPMPMPMPMPMPMPMMPMPMPMPMPMPMPMPMMPMP , , ,, ,,, , ,,,,, ,,,, McMcMcMcMcMcMcMccMcMcMcMcMcMcMccMMMMMMMM KeKeKeKeKeKeKeKeKeKeKKKeKeKeKeKeKeKKK nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnna a aa aaaaaaaaaaaaaaa WWWWWWWWWW

f patitititititititititiitititiiittititiienenenenenenenenenenenenenenenenenennee tstststststststststststststststststsss wwwwwwwwwwwwwwwwwwwwwwwitiititititittitititititititiititttti hhhhhhhhhhhhhhhhhhhhhhh diddddddg p y p p

p 8

CJ, , ,

r

g p y p p

patatatatathhyhh reveaaaaalsllsl pppppreeeeeclclclclclinininininicicicicicalalalalal dddddisiii eaaaaasse. AnAnAnn nnn n InInInInInteteteteternrnn MM M MMedee . 202020202 0505050505;1;1;1;1;14343434343:1:1:1:1:108000

CJ, SuSuSuSS grgrgrgrg ueee DDDDD,D,D,DD KK KKKwooooonnnnn HMHMHMHMHM, SaSaSaSaSangngngioiorgrggrggii ii G,G,G,G,G, CC CCCarararararlslslsl onononn PPPPPJJ,JJJ MMMMMahhahhhonononn NNNNN,

rdddsss WDWDWD, HoHoHolmlmeseses D D DR,R,R,, S SSSchchhchwawawaww rtrtrtz zz RSRSS. HiHiHiH stststs opopopppatatathohohohh lolooogigiggg c c c chchcc ananangegegesss inin


Dow

nloaded from


16

12. Caforio AL, Mahon NG, Baig MK, Tona F, Murphy RT, Elliott PM, McKenna WJ.

Prospective familial assessment in dilated cardiomyopathy. Cardiac autoantibodies

predict disease development in asymptomatic relatives. Circulation. 2007;115:76-83.

13. Matsumura Y, Elliott PM, Mahon NG, Virdee MS, Doi Y, McKenna WJ. Familial

dilated cardiomyopathy: assessment of left ventricular systolic and diastolic function

using Doppler tissue imaging in asymptomatic relatives with left ventricular

enlargement. Heart. 2006;92:405-406.

14. Karunanithi MK, Feneley MP. Single beat determination of preload recruitable stroke

work relationship: derivation and evaluation in conscious dogs. J Am Coll Cardiol.

2000;35:502-513.

15. Hayward CS, Kalnins WV, Kelly RP. Gender-related differences in left ventricular

chamber function. Cardiovasc Res. 2001;49:340-350.

16. Mandarino WA, Pinsky MR, Gorcsan J 3rd. Assessment of left ventricular contractile

state by preload-adjusted maximal power using echocardiographic automated border

detection. J Am Coll Cardiol. 1998;31:861-868.

17. Sakata K, Ino H, Fujino N, Nagata M, Uchiyama K, Hayashi K, Konno T, Inoue M,

Kato H, Sakamoto Y, Tsubokawa T, Yamagishi M. Exercise-induced systolic

dysfunction in patients with non-obstructive hypertrophic cardiomyopathy and

mutations in the cardiac troponin genes. Heart. 2008;94:1282-1287.

18. McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I, Morrison CE, Tunstall-

Pedoe H, McMurray JJ, Dargie HJ. Biochemical detection of left ventricular systolic

dysfunction. Lancet. 1998;351:9-13.

19. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects

from infancy to old age. Circulation. 1980;62:1054-1061.

erenccccccccccccccccceseseseseseseseseseseseseseseseseseseseee iiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnn leleleleleleleleleleleleleleelelelelllll ftftftftftftfftftftftftftftftftftftft vvvvvvvvvvveny

u

e t

y

uncncncnncttittt on. CaCaCaaardrdrddrdiooooovavavaaascscscscsc RR R RReseseseses.. . 202020202 010101011;4; 99:34344440-0-00-0 35353535350.0.000

WAWAWAAA, PiPiPiPiPinssskykykykyky MMMMMRRR,RR GGGGGorororororcsannnnn J JJJJ 33 333rdrdrdrdrd. AAsAAA sesesesesesssssssssmemememem ntntntntnt oooff ff lelll ftftftftft vv veeentrtrtriciculullulararar

eeeloloadad aa-adjdjdjjdjusususteteted d dd mamamaxiximamamam l l popopopooweweweer r r usususining gg ecececechohooocacacac rdrdrdrr ioiooogrgrgrgg apapapapphihic c c auauautototomamaamattt


Dow

nloaded from


17

20. Manolio TA. Baughman KL, Rodeheffer R, Pearson TA, Bristow JD, Michels VV,

Abelmann WH, Harlan WR. Prevalence and etiology of idiopathic dilated

cardiomyopathy (summary of a National Heart, Lung and Blood Institute Workshop).

Am J Cardiol. 1992;69:1458-1466.

21. Vasan RS, Larson MG, Levy D, Evans JC, Benjamin EJ. Distribution and

categorization of echocardiographic measurements in relation to reference limits. The

Framingham Heart Study: formulation of a height- and sex-specific classification and

its prospective validation. Circulation. 1997;96:1863-1873.

22. Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, Seward AJ.

New index of combined systolic and diastolic myocardial performance: a simple and

reproducible measure of cardiac function – a study in normals and dilated

cardiomyopathy. J Cardiol. 1995;26:357-366.

23. Gorcsan J. Load-independent indices of left ventricular function using automated

border detection. Echocardiography.1999;16:63-76.

24. Moretti M, Merlo M, Barbati G, Di Lenarda A, Brun F, Pinamonti B, Gregori D,

Mestroni L, Sinagra G. Prognostic impact of familial screening in dilated

cardiomyopathy. Eur J Heart Fail. 2010;12:922-927.

25. Feigenbaum H. Appendix: Echocardiographic measurements and normal values. In:

Feigenbaum H, ed. Echocardiography. 5th ed. Philadelphia:Williams and Wilkins;

1994:658-683.

26. Hershberger RE, Ni H, Crispell KA. Familial dilated cardiomyopathy:

echocardiographic diagnostic criteria for classification of family members as affected. J

Card Fail. 1999;5:203-212.

pepepepepepepepepepepepeppepepeppepepepepep rfrfrfrfrfrfrfrfrfrfrfrfrfrfffffrffororororororoororororoorororororooorooro mamamamamamamamaamamamamamamamaammmmmmmmancncncncncncnccncncncncncncncncncnccnn e:e:e:e:e:e:e:e:e:eee:ee aaa aaaaaaa aaaaaaaaaaaa ssssssssssssssss

mals ananananananananananananananannanananannddddddddddddddddddddd didididididididididididididididididididdiididiilalalalalalalalalalalalalalalalalalal tetetettetetetetetetetetetetteteteteteedddddddddddddddddy

p

L t ce o

e

y

patatatatathhyhh . J CaCaCaaardrdrdr ioioioioiolllll.. 1919191919959595995;2;2;2;2;26:6:6:66 353535357-7-7-77 36666.

Loaaaddd-dd ininininindededdd pepependndndddenenennt ininininndididididices ofofoffof l lllleffeffft tttt veveventntntnntririririricucucucuculaaaaarrrrr fufufuf ncncncctiiiiiononon usiiingngng aaautututo

ecccctitiononon. EcEcEcchohohohocacacardrdddioioiogrgrgrgrg apapapapphyhyhyyy.1.1.19999999999;9;9;16166:6:6:63-3-3 7676766.


Dow

nloaded from


18

27. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and

the risk of congestive heart failure in people without myocardial infarction. N Engl J

Med. 1997;336:1350-1355.

28. Koikkalainen JR, Antial M, Lotjonen JMP, Heliö T, Lauerma K, Kivistö SM, Sipola P,

Kaartinen MA, Kärkkäinen ST, Reissell E, Kuusisto J, Laakso M, Oresic M, Nieminen

MS, Peuhkurinen KJ. Early familial dilated cardiomyopathy: identification with

determination of disease state parameter from cine MR image data. Radiology.

2008;249:88-96.

Table 1. Characteristics of 128 probands and their families

Clinical Feature No. individuals (%)

Proband demographics: - Males - Age at study entry (years) - Caucasian ethnicity

79 (62%) 42 ± 14

128 (100%) Family phenotype*:

- DCM only - DCM + conduction-system abnormalities - DCM + skeletal muscle involvement†

111 (87%) 16 (13%)

1DCM inheritance pattern‡:

- Autosomal dominant - Possible autosomal dominant or X-linked - X-linked - Autosomal recessive

94 (73%) 27 (21%) 7 (6%) 0 (0%)

Known genotype§ 4

DCM indicates dilated cardiomyopathy. * Classification based on predominant clinical manifestations of affected family members. † Calf tenderness during exercise and raised creatine kinase levels found in two affected individuals in one family. No individuals in any family had clinical signs of skeletal muscle weakness or wasting. Creatine kinase levels were not systematically assessed in all cases. ‡ Presumptive mode of inheritance based on distribution of affected individuals in family pedigrees. § Novel mutations (unpublished) were present in 4 families. Of 23 genotyped family members, 13 individuals were genotype-positive (DCM 3, LVE 5, obligate carrier 1) and 10 individuals were genotype-negative (all phenotypically normal).

a

un ethnicity

%4

128 (100%

a

aphihihiiicscscs:: :

uuuddy e ttntryryryryry ( ( ( (yeyeyeyey arararara s)s)ss) nnn etethnhnicicitityy

79 (62%424242 ±± ± 11 14444

121288 (1(100000%

No. individua


Dow

nloaded from


19

Table 2. Baseline characteristics of 72 untreated LVE relatives followed prospectively

Parameter No progression Progression P value

Individuals (no. families) 63 (35) 9 (9) -

Males (%) 38 (60.3%) 5 (55.6%) 0.83

Age at study entry (years) 34.4 ± 9.6 27.0 ±7.7 0.03

LVEDD (mm) 56.6 ± 3.3 55.7 ± 3.2 0.44

LVEDD (% predicted) 120.2 ± 5.0 119.3 ± 4.7 0.61

LVESD (mm) 38.1 ± 3.7 38.8 ± 3.3 0.58

LVFS (%) 32.4 ± 5.2 30.2 ± 3.8 0.22

Heart rate (bpm) 65 ± 12 66 ± 9 0.90

Follow-up duration (months) 55.2 ± 27.9 52.6 ± 32.0 0.47

LVEDD indicates left ventricular end-diastolic diameter; LVESD, left ventricular end-

systolic diameter; LVFS, left ventricular fractional shortening.

3333333333333333333330.0.000.00.0.0.000.0.00.00.0000 2 22222 222 2 222222222222 ± ±±±±±±±±± ±±±± ±±±±± ±±± 3.3.3.3.3.3.3.3.33.3.333.3.333 8 8 8 8888 8 8 8888 888 888 88

66666666666666666666 ±±±±±±±±±±±±±±±±±±±±± 9999999999999999999

o

a

oono (monthshshsshs)) ) 55.2.2.222 ± 2277.9 9 9 99 52525222.6.6.666 ±± ±±± 3 33 332.22.22 0 0 0 00

ss llleftftft vennnnntrtrtrtt iciciciculululululararar eeeeendndndndnd-d-d-diaiaiaai stststststoooolililic cc cc dididididiamamamammetetetererererr; ; ; ;; LVLVLVLVLVESESESESESD,D,D,D,D, l l lllefefefefeft t t tt veveveveventntnt iiriculalala


Dow

nloaded from


20

Table 3. Characteristics of LVE relatives and age- and gender-matched healthy controls

Parameter LVE relatives Control subjects P value

Individuals (no. families) Males (%) Age (years) LVEDD (mm)

30 (20)

17 (57)

39.0 ± 10.9

58.2 ± 3.9

30

17 (57)

39.0 ± 10.9

49.7 ± 3.6

-

-

-

<0.001LVEDD (% predicted) 122.9 ± 6.7 107.3 ± 7.4 <0.001LVESD (mm) 40.2 ± 3.5 30.9 ± 3.7 <0.001LVFS (%) 30.9 ± 4.8 37.8 ± 4.2 <0.001Mitral E (cm/s) 71.7 ± 14.0 84.9 ± 15.6 0.002 Mitral A (cm/s) 55.9 ± 9.6 58.1 ± 12.4 0.42 E/A ratio 1.32 ± 0.33 1.53 ± 0.38 0.07 Myocardial performance index 0.41 ± 0.11 0.28 ± 0.06 <0.001 Mitral S (cm/s) 8.2 ± 2.2 10.3 ± 2.3 <0.001 Time to peak S (cm/s) 0.22 ± 0.07 0.18 ± 0.04 0.01 Mitral E’ (cm/s) 13.4 ± 4.3 15.2 ± 2.9 0.06 Mitral A’ (cm/s) 7.3 ± 1.9 7.6 ± 2.3 0.64 E/E’ ratio 5.8 ± 2.0 5.7 ± 1.2 0.82 Mw (slope) 0.9 ± 0.3 1.0 ± 0.3 0.22 Vw (intercept) 30.3 ± 35.7 21.3 ± 35.6 0.38 End-diastolic area (rest, cm2) 22.7 ± 4.0 18.6 ± 2.9 <0.001 Fractional area change (rest, %) 49.4 ± 5.5 61.4 ± 8.6 <0.001

End-diastolic area (ex vs rest, cm2) -3.6 ± 2.9 -2.9 ± 1.9 0.27 Fractional area (ex vs rest,%) 10.5 ± 11.7 13.6 ± 9.5 0.25

Heart rate (rest, bpm) 67 ± 9 62 ± 10 0.04 Heart rate (maximum, bpm) 175 ± 19 177 ± 12 0.48 Systolic BP (rest, mmHg) 124 ± 12 121 ± 12 0.33 Systolic BP (max, mmHg) 168 ± 12 176 ± 14 0.05 Diastolic BP (rest, mmHg) 79 ± 7 78 ± 9 0.50 Diastolic BP (max, mmHg) 67 ± 6 63 ± 7 0.05 Rate-pressure product† 29326 ± 3601 31209 ± 3208 0.03 Peak pulse pressure (mmHg) 99 ± 10 113 ± 15 0.01 Exercise time (min) 11.6 ± 2.4 14.2 ± 2.9 <0.001 NT-pro BNP (ng/L) 88 ± 121 51 ± 54 0.12

BNP indicates brain natriuretic peptide; BP, blood pressure; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LVFS, left ventricular fractional shortening. * Lateral margin of mitral annulus; data for septal margin are similar (not shown). † maximum heart rate x maximum systolic BP.

1.1.1.1.11.1.11.111.11111.111 535353535353535353535335353535353353535335 ± ±±±±±±± ±±± ±± ± ± ±± ±±±± 00 0000 000 00000 000.3.3.3.3.3.3.3.33.3.3.3.3.3.333338 888888888888888880.2828882828282828282882888288882888 ±±± ±±±±±±±±±±±±±±±±±± 000000000000000000000000.000000000000000000006 666666666666666666666610 333333333333333333333 ±±±±±±±±±±±±±±±±±±±±±± 22222222222222222222 333333333333333333333333

c 0.22 .07 18 ± 0.04

0.3

a (rest cm ) 22 7 ± 4 0 18 6 ± 2 9

cmmmmm/s/s/s/s/s))))) 0.22 ±±±±± 00.07 0.18 ± 0.04 131313133.4 ±± 4.33.33.3 15.55.5.5.222 22 ± ±± ±± 2.2.2.22 9 9 9 9977.33 ±± 1.99999 7 7 777.6.6.6.66 ± 22222.33 55555 888.8 ±±± 2 222.00000 5.77777 ±±±± ± 1.22222 00000.9.9.9.9.9 ± ± ± ± 00000.3.3.33 11111.0.0.0.0.0 ± 0.3

3030303030.3.3.33 ± ± ± 3 3 3335.55.7 7 7 7 212121221.3.3.333 ± ± ±± 3 3 3335.5.5.666 aaa ((rerestst cmcm22222)) 2222 77 ±± 44 00 1188 66 ±± 22 99


Dow

nloaded from


21

Table 4. Discriminative value of echocardiographic variables in 30 LVE relatives and 30

control subjects

Parameter No. LVE

relatives

No.controlsubjects

Sensitivity* Specificity*

LVEDD >56.9 mm 17 0 56.7% 100%

LVEDD (%predicted) >122% 16 0 53.3% 100% LVESD >38.4 mm 20 1 66.7% 96.7% LVFS <29.4% 13 0 43.3% 100% Mitral E <53.6 cm/s 3 2 10.0% 93.3% E/A ratio <0.77 1 0 3.3% 100% Myocardial performance index >0.40 13 0 43.3% 100% Mitral S <5.7 cm/s 4 0 13.3% 100% Time to peak S >0.26cm/s 7 2 23.3% 93.3% Heart rate >82 bpm 3 1 10.0% 96.7% Systolic BP (max, ex)<148 mmHg 0 0 0% 100% Diastolic BP (max, ex) >77 mmHg 1 1 3.3% 96.7% Rate-pressure product <24793 3 1 10.0% 96.7% Peak pulse pressure <83 mmHg 2 0 6.7% 100% Exercise time <8.4 min 2 0 6.7% 100%

BP indicates blood pressure; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LVFS, left ventricular fractional shortening. * Sensitivity and specificity were determined using the numbers of individuals in each group with values outside the mean ± 2SD for the control group.

Figure Legends:

Figure 1. Results of baseline screening and follow-up of asymptomatic relatives of patients

with familial dilated cardiomyopathy.

DCM indicates dilated cardiomyopathy; dFS, depressed left ventricular fractional shortening;

LVE, left ventricular enlargement.

* The outcomes of relatives with LVE (n=72) who were not receiving any treatment during

the period between progress echocardiograms (“natural history” cohort) are indicated by the

13131313131331313131313131313131331313131 .3.3.3.3.3.33.3333.3.3.3.3333% % % % %% % % % %%%%% %% %%%%%2323232323232232323232323232323232332332232 33333.3333333333333333%%%%% %%%%%%%%%%%%%%%%%%%101010101010101010101010101010101010001001 0000000000000000000%%%%%%%%%%%%%%%%%%%%%%%%%p

x, 0 % a x) >ou

od pressure; LVEDD left ventricular end diastolic diameter; LV

px, exexexexex)<)<)<)<)<1414141414888 mmmmmm Hg 0 0 0% axxx,xx ex) >77777 m mmmmHmHmHmHmHgggg g 1 1111 111 11 3.3.3.3.3.3%3%3%3%3% oddddducucucucuct <2474444 93993 33 3 1 10000.0.0.00.0% %%ure <8<8<8<8<8333 33 mmHgHgHgHgHg 2 2222 0 6.6666 7%%%%% .4 min 2 2 2 2 2 0 0 0 0 0 6.7%

odd pressure; LLVEVEDDDD lleftft ventt iricullar endd didiasttolilic didiam teter; LVVLV


Dow

nloaded from


22

black lines. Six of these individuals subsequently crossed over to the treatment group and

underwent further follow-up.

† Cardiovascular medications, including -blockers, angiotensin converting enzyme

inhibitors, calcium antagonists, were administered for various indications (DCM prophylaxis,

hypertension, palpitations, atrial fibrillation) at some time during the follow-up period.

Figure 2. ROC analysis of different methods for assessment of left ventricular dilatation in

asymptomatic relatives and healthy control subjects.

AUC indicates area under the curve; Framingham, criteria based on data from the

Framingham Heart Study, LVEDD differences from 95th percentile values are shown;

NHLBI, criteria formulated by National Heart Lung and Blood Institute expert panel;

LVEDD (%predicted), ratio of actual left ventricular end-diastolic diameter to predicted

diameter, expressed as a percentage; ROC, receiver operating characteristic.

ttttttttttttttttttttilililililiiliililililililililililllilii e ee ee e e e e ee e ee e e eeeeeee vavavavavavavavavavavavavavavavavavavavavavavaavav lululululululululululuuulululluululul eseseseseeseseseseseseseseseesessesessses a a a a aa aaaaaaaaaaaaarerererererererereerererrrere sss ss ss ss sss sssssshhhhhhhhhhhhhhhhhhhh

Institttititttttttttttttuttttutututttututtututtututttuu eeee exeexexexexxxxppepeppepepeeerttttrttttrtrtrttrtrttrtrt py g p p

r

s

y g p p

cccteeed), ratio ofoffff aaaaaccccctututututualalalalal l lefefefefeft tttt veveventttttriicuular eeenee d-d-d-d-d-diddidd aaastototototoliiic dididididiammmmmetetetete ererererr tttttoo ooo pr

sed as a perceceeceentntntage;e;e;e;; RRRRROOOOOC, receivevev r opererrrratatata ing chahahahararr cttteristitic.


Dow

nloaded from


Asymptomatic relatives (n=457)

Probands (n=128)

DCM(n=18)

LVE(n=110)

dFS(n=5)

Normal echo(n=324)

No treatment* Nofollow-up

(n=10)

DCMLVE

Treatment† No treatment Treatment

DCMdFS

63

72 28

6

6

928 22 1

0

2 3

S5)

2828


Dow

nloaded from



Dow

nloaded from


Richmond, Michael P. Feneley, Anne M. Keogh and Peter S. MacdonaldDiane Fatkin, Thomas Yeoh, Christopher S. Hayward, Victoria Benson, Angela Sheu, Zara

CardiomyopathyEvaluation of Left Ventricular Enlargement as a Marker of Early Disease in Familial Dilated

Print ISSN: 1942-325X. Online ISSN: 1942-3268 Copyright © 2011 American Heart Association, Inc. All rights reserved.

TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Genetics

published online June 2, 2011;Circ Cardiovasc Genet.

http://circgenetics.ahajournals.org/content/early/2011/06/02/CIRCGENETICS.110.958918World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circgenetics.ahajournals.org//subscriptions/

is online at: Circulation: Cardiovascular Genetics Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. Further information aboutnot the Editorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center,Circulation: Cardiovascular Genetics Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:


Dow

nloaded from

http://circgenetics.ahajournals.org/content/early/2011/06/02/CIRCGENETICS.110.958918

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circgenetics.ahajournals.org//subscriptions/


Documents

Evaluation of Left Ventricular Enlargement as a Marker of ...circgenetics.ahajournals.org/content/circcvg/early/2011/06/02/CIRC... · Evaluation of Left Ventricular Enlargement as