Clinical disease p esen a ion
and ECG cha ac e is ics o LMNA
mu a ion ca ie s
Lau a Ollila,
1
Kjell Nikus,
2
Miia Holms öm,
3
Mikko Jalanko,
1
Raija Ju kko,
1
Maija Kaa inen,
1
Juha Kosken uo,
4,5
Johanna Kuusis o,
6
Sa u Kä kkäinen,
7
Ee a Palojoki,
1
Ee a Reissell,
8
Päi i Pii ilä,
9
Tiina Heliö
1
To ci e: Ollila L, Nikus K,
Holms öm M, e al. Clinical
disease p esen a ion
and ECG cha ac e is ics o
LMNA mu a ion ca ie s.
Open Hea 2017;4:e000474.
doi:10.1136/openh -2016-
000474
Recei ed 14 May 2016
Re ised 3 Sep embe 2016
Accep ed 1 No embe 2016
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
D Lau a Ollila;
lau [email p o ec ed]
ABSTRACT
Objec i e: Mu a ions in he LMNA gene encoding
lamins A and C o he nuclea lamina a e a equen
cause o ca diomyopa hy accoun ing o 5–8% o
amilial dila ed ca diomyopa hy (DCM). Ou aim was o
s udy disease onse , p esen a ion and p og ession
among LMNA mu a ion ca ie s.
Me hods: Clinical ollow-up da a om 27 LMNA
mu a ion ca ie s and 78 pa ien s wi h idiopa hic DCM
wi hou an LMNA mu a ion we e collec ed. In addi ion,
ECG da a we e collec ed and analysed sys ema ically
om 20 heal hy con ols.
Resul s: Kaplan-Meie analysis e ealed no di e ence
in e en - ee su i al (dea h, hea ansplan ,
esusci a ion and app op ia e implan able ca dio e e -
de ib illa o he apy included as e en s) be ween LMNA
mu a ion ca ie s and DCM con ols (p=0.5). LMNA
mu a ion ca ie s p esen ed wi h a ial ib illa ion a a
younge age han he DCM con ols (47 s 57 yea s,
p=0.003). Male LMNA mu a ion ca ie s p esen ed wi h
clinical mani es a ions oughly a decade ea lie han
emales. In close ollow-up non-sus ained en icula
achyca dia was de ec ed in 78% o LMNA mu a ion
ca ie s. ECG signs o sep al emodelling we e p esen
in 81% o he LMNA mu a ion ca ie s, 21% o he
DCM con ols and none o he heal hy con ols gi ing
a high sensi i i y and speci ici y o he s anda d ECG
in dis inguishing LMNA mu a ion ca ie s om pa ien s
wi h DCM and heal hy con ols.
Conclusions: Male LMNA mu a ion ca ie s p esen
clinical mani es a ions a a younge age han emales.
ECG sep al emodelling appea s o dis inguish LMNA
mu a ion ca ie s om heal hy con ols and pa ien s
wi h DCM wi hou LMNA mu a ions.
INTRODUCTION
LMNA mu a ions a e p e alen in amilial
dila ed ca diomyopa hy (DCM), accoun ing
o abou 5–8% o he cases.
1
The ypical
ea ly mani es a ions o LMNA mu a ions a e
ECG abno mali ies including fla P wa e,
a io en icula block, sup a en icula and
en icula a hy hmias.
23
LMNA mu a ions
pose a isk o sudden ca diac dea h, and
consequen ly implan able ca dio e e -
defib illa o (ICD) implan a ion has been
sugges ed as p ima y p ophylaxis o all
LMNA mu a ion ca ie s, o a e u he isk
assessmen .
45
Ca diolaminopa hy o en
ollows an age-dependen disease p og ession
in which he ECG and hy hm abno mali ies
end o p ecede s uc u al hea disease and
sys olic impai men , which in u n o en does
no ulfil he echoca diog aphy c i e ia o
DCM due o milde dila ion o he le
KEY QUESTIONS
Wha is al eady known abou his subjec ?
▸Al hough en icula dila ion and dys unc ion
may emain less se e e han in o he o ms o
dila ed ca diomyopa hy, he pene ance o ca di-
olaminopa hy mu a ions is almos comple e
o en esul ing in se ious a hy hmias o hea
ailu e. Ca diomyopa hy-causing LMNA mu a-
ions o en p esen wi h ypical ECG abno mal-
i ies, such as a io en icula block and a ial o
en icula a hy hmias.
Wha does his s udy add?
▸We epo ha mos LMNA mu a ion ca ie s
p esen wi h non-sus ained en icula achyca -
dia (NSVT) in close ollow-up. In addi ion, we
ea i m ha male LMNA mu a ion ca ie s ha e
an ea lie disease onse han emales. We
sugges ha LMNA mu a ion ca ie s likely
bene i om close ollow-up. We also p esen a
new ECG en i y, sep al emodelling, p esen in
mos LMNA mu a ion ca ie s and sugges ing
ha he pa hological p ocess leading o ca diola-
minopa hy ypically a ec s he myoca dial
sep um.
How migh his impac on clinical p ac ice?
▸The de ec ion o sep al emodelling in s anda d
ECG should lead o an echoca diog am and
ho ough enqui y o ca diac amily his o y.
▸E en asymp oma ic LMNA mu a ion ca ie s
need ollow-up o de ec a ial ib illa ion and
NSVTs.
Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 1
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en icle o dila ion wi h p ese ed ejec ion ac ion.
36
La ely LMNA mu a ions ha e also been linked o amilial
o ms o mainly igh en icula disease mani es a ions
esembling a hy hmogenic igh en icula
ca diomyopa hy.
78
S uc u al hea disease can esul in gene al, non-
localising ECG changes, such as le en icula hype -
ophy (LVH), ST dep ession, widening o he QRS
complex, and P e minal o ce.
910
On he o he hand,
ECG changes in leads o e lying a ec ed egions can
eflec egional disease p ocesses. Fo ins ance, na ow
and deep q wa es a e ypical o localised wall hickening
in hype ophic ca diomyopa hy.
11
La e gadolinium enhancemen (LGE) in ca diac MRI
(CMR) is conside ed an e ec i e ool in showing myo-
ca dial sca ing.
12
In LMNA mu a ion ca ie s LGE has
been mainly seen in he basal o mid- en icula sep um
sugges ing a possible localised disease p ocess.
13 14
The aim o his s udy was o assess disease p esen a-
ion, p og ession and clinical ou come in symp oma ic
and asymp oma ic LMNA mu a ion ca ie s.
METHODS
Pa ien s and con ols
This longi udinal e ospec i e s udy included all iden ified
adul LMNA mu a ion ca ie s om Helsinki and Kuopio
Uni e si y Hospi als willing o pa icipa e in a ollow-up
s udy. Twen y-se en LMNA mu a ion ca ie s we e ec ui ed
o he s udy be ween 1999 and 2010. The mu a ion ca -
ie s, each ha bou ing one o fi e LMNA mu a ions
((NM_170707.3 (LMNA), c427T>C, p.(Se 143P o) in
exon 2; c.394G>C, p.(Ala132P o) in exon 2; c.568C>T,
p.(A g190T p) in exon 3; c. 1493delG, p.(Ala499Leu s*49)
in exon 9; c. 1085delT, p.(Leu363T p s*117) in exon 6)
we e ei he p obands o hei amily membe s om nine
amilies iden ified in wo p e ious s udies.
15 16
Clinical
ollow-up da a om he LMNA mu a ion ca ie s and DCM
con ols we e collec ed up o 31 Decembe 2014. Con ol
pa ien s (n=78) wi h idiopa hic DCM we e collec ed om a
pa ien da abase e ospec i ely. P obands wi h DCM, diag-
nosed and ec ui ed be o e 2010 we e included as DCM
con ols; pa ien s ec ui ed a e possible hea ansplan -
a ion, we e excluded o minimise possible collec ion bias.
Only p obands who ha e been es ed o ca diomyopa hy-
causing mu a ions using OsSeq, a nex -gene a ion-
sequencing me hod, as desc ibed be o e we e included o
ensu e ha he e we e no LMNA mu a ion ca ie s among
he DCM con ols.
17
Conce ning he ECG abno mali ies, he s udy pa ien s
we e also compa ed wi h an a ailable coho o 20 (7
men, 13 women) heal hy con ols.
Gene al
The c i e ia used o he diagnosis o DCM we e Le
en icula end-dias olic diame e (LVEDD)>27 mm/m
2
and Le en icula ejec ion ac ion (LVEF)<45%.
15
Clinical end poin da a we e collec ed om all a ailable
hospi al eco ds. Fi s incidences o a ial fib illa ion,
non-sus ained en icula achyca dia (NSVT), esusci a-
ion o app op ia e ICD he apy, ca diogenic embolism
and pacemake /ICD implan a ions we e eco ded.
NSVT was defined as mo e han h ee consecu i e en-
icula bea s in 24-hou Hol e o clinical exe cise es .
To a oid bias, NSVTs we e no eco ded in he DCM
con ols due o he less igo ous ollow-up o he DCM
con ol g oup compa ed wi h he LMNA mu a ion
ca ie g oup. Owing o he small numbe o majo clin-
ical e en s in he LMNA mu a ion ca ie g oup, a com-
posi e end poin o esusci a ion, app op ia e ICD
he apy, dea h and hea ansplan was used. In LMNA
mu a ion ca ie s wi h a ailable CMR da a, he p esence
o he ECG pa ame e sep al emodelling was compa ed
wi h CMR findings om a p e ious a icle;
13
he CMR
me hods we e p esen ed ea lie .
The s udy pa ien s ga e w i en in o med consen . The
s udy was app o ed by he E hics Commi ee o he
Helsinki Uni e si y Cen al Hospi al (Decision numbe :
Dn o 322/E5/03, Resea ch pe mi numbe : T1010K0019).
ECG analyses
One s anda d 12-lead ECG eco ded by 50 mm/s speed o
each LMNA mu a ion ca ie , DCM con ol and heal hy
con ol was analysed in a sys ema ic manne manually by
one in es iga o (KN) blinded o he clinical da a. The
ECG eco ding was om he ime o s udy ec ui men .
The age a he ime o ECG eco ding was 42 yea s o all
LMNA mu a ion ca ie s; 49 yea s o hose wi h DCM
(LMNA-DCM subg oup), and 37 yea s o hose wi hou .
The ollowing defini ions we e used in he ECG analyses:
fi s -deg ee a io en icula block was defined as PR in e -
al >200 ms,
18
P e minal o ce as nega i e po ion o
he P wa e in lead V1≥0.4 mm/s,
19
fla P wa e as P-wa e
ampli ude <1 mm in lead II, and b oad P wa e as ≥120 ms
in lead II
20
LVH was defined acco ding o he
Sokolow-Lyon c i e ia,
21
o Co nell ol age du a ion
p oduc (QRS-du a ion (ms)×(RaVL in mm+SV3 in mm
wi h 6 mm added o women) ≥2440),
22 23
o ST segmen
dep ession we used ≥0.5 mm i he pa e n was ho izon al
o descending, and ≥1mm i ascending in ≥2 adjacen
leads measu ed a he J poin +60 ms,
24
o T-wa e in e sion
≥1mmin≥2 adjacen leads, excep o leads aVR and V1
was used.
25
Fo agmen ed QRS in ≥2 adjacen leads we
used he defini ions by Das e al.
26
Sep al agmen a ion
was conside ed p esen i he e was QRS agmen a ion in
≥2 sep al leads (V1–V3). Non-specific in a en icula con-
duc ion de ec was defined as QRS du a ion ≥120 ms no
ulfilling c i e ia o igh o le bundle b anch block.
Owing o he high p opo ion o implan ed pacemake s,
we used anamnes ic da a o AV block in addi ion o he
findings in he ECG used o analysis.
In addi ion o he es ablished ECG changes, we in o-
duced a no el ECG pa ame e , ‘sep al emodelling’,
which we define as one o he ollowing p esen in V1–
V3: (1) pa hological Q wa es in ≥2 pa allel leads, o (2)
sep al agmen a ion as defined abo e, (3) poo R-wa e
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p og ession (R wa e <3 mm) in leads V1–V3 accompan-
ied by QRS agmen a ion, o diso de ly dis ibu ed
R-wa e ampli udes, ei he RV2>RV3 o RV1>RV2. The
possibili y o lead swi ch was conside ed by assessing he
mo phology o he P and S wa es in he p eco dial
leads, and no suspicious cases we e obse ed.
27
Any Q
wa e ≥40 ms in du a ion, o ≥3 mm deep, o qR- a io
≥0.25, in ≥2 pa allel leads excep lead aVR was consid-
e ed pa hological.
28
S a is ical me hods
Con inuous a iables we e analysed using S uden ’s
- es . The no mali y o con inuous a iables was assessed
using he Shapi o-Wilk es o no mali y. In he ew
ins ances, whe e he a iables we e no no mally dis ib-
u ed Mann-Whi ney U es was used. Fo ca ego ical a i-
ables, he χ
2
es was used when he expec ed coun o
80% o mo e o he cells was ≥5. O he wise he Fishe ’s
exac es was used. All s a is ical es s we e wo-sided
wi h a 5% le el o significance, and no adjus men s we e
made o mul iplici y. Howe e , conce ning he ECG
analyses he numbe o pai ed-wise compa isons (LMNA
s DCM and LMNA s heal hy con ol) was accoun ed
o by mul iplying he p alues ob ained by 2. The
Kaplan-Meie analysis was used o su i al analysis. SPSS
V.22 was used o s a is ical analyses.
RESULTS
Gene al
The equencies and incidence ages o clinical mani es-
a ions a e epo ed in able 1. The mean age a
p e ious ollow-up o majo end poin was 48 yea s o
LMNA mu a ion ca ie s and 59 yea s o he DCM con-
ols (p<0.001). Twel e LMNA mu a ion ca ie s ul-
filled he c i e ia o DCM. Pacemake s we e mo e
common in he LMNA-DCM subg oup han in he
DCM con ol g oup (83% s 47%, p=0.047). NSVT was
e y common among he LMNA mu a ion ca ie s
(78%). Hea ansplan s we e mo e equen in he
LMNA-DCM subg oup han in he DCM con ol g oup
(25% s 11%), bu he di e ence was no s a is ically
significan . A ial fib illa ion was also mo e common
among LMNA mu a ion ca ie s han in he DCM con-
ols; p=0.007 when compa ing he LMNA-DCM sub-
g oup o he DCM con ol g oup. LMNA mu a ion
ca ie s had hei fi s episode o a ial fib illa ion a a
younge age han he DCM con ols (47 s 57 yea s,
p=0.003). All he cases o likely ca diogenic h ombo-
embolic e en s among he LMNA mu a ion ca ie s
occu ed among he LMNA-DCM subg oup. The e-
quency o h omboembolic e en s in he LMNA-DCM
subg oup was oughly wice as high as in he DCM
con ol g oup, bu he di e ence was no s a is ically
significan .
The e we e less majo end poin s in he en i e
LMNA ca ie g oup, and mo e in he LMNA-DCM
subg oup han in he DCM con ol g oup. Howe e ,
looking a majo end poin s including dea hs, hea
ansplan a ions and esusci a ions, Kaplan-Meie ana-
lysis (figu e 1A) e ealed no di e ence in e en - ee
su i al be ween LMNA mu a ion ca ie s and DCM
con ols. When pacemake s we e included in su i al
analysis, a s a is ically significan di e ence was seen;
Table 1 The equencies and incidence ages o clinical LMNA mu a ion o ca diomyopa hy mani es a ions
All LMNA mu a ion
ca ie s, n=27
LMNA mu a ion ca ie s
wi h DCM, ha is,
LMNA-DCM subg oup,
n=12 DCM con ols, n=78
N (%) p Value* N (%) p Value* N (%)
AF 15 (55.6) NS 11 (91.7) 0.007 39 (50.0)
NSVT 21 (77.8) 11 (91.7)
Pacemake (any, including ICDs) 16 (59.3) NS 10 (83.3) 0.020 37 (47.4)
ICD 9 (33.3) NS 6 (50.0) NS 26 (33.3)
Th ombosis 4 (14.8) NS 4 (33.3) NS 12 (15.4)
Majo end poin 7 (25.9) 0.039 7 (58.3) NS 38 (48.7)
Males 13 (48.1) 0.026 6 (50.0) NS 56 (71.8)
Mean (SD) Mean (SD) Mean (SD)
Age a DCM diagnosis 48.7 (10.7) NS 48.2 (10.4) NS 47.4 (12.2)
Age a AF 46.9 (10.9) 0.003 47.9 (10.7) 0.014 56.9 (10.1)
Age a NSVT 45.6 (11.8) 49.1 (10.1)
Age a PM 49.1 (10.6) NS 49.6 (11.1) NS 55.4 (13.0)
Age a ICD 48.5 (11.4) NS 52.0 (12.7) NS 53.0 (12.9)
Age a h ombosis 52.6 (10.0) NS 52.6 (10.0) NS 54.8 (12.5)
Age a majo end poin 51.0 (8.7) NS 51.0 (8.7) NS 59.0 (14.2)
Compa isons o all he LMNA mu a ion ca ie s and hose LMNA mu a ion ca ie s ul illing he c i e ia o DCM o he DCM con ols.
*Compa isons o all DCM con ols.
AF, a ial ib illa ion; DCM, dila ed ca diomyopa hy; ICD, implan able ca dio e e -de ib illa o ; NS, no signi ican ; NSVT, non-sus ained
en icula achyca dia; PM, pacemake .
Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 3
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Figu e 1 (A). Kaplan-Meie plo o e en - ee su i al in 27 LMNA mu a ion ca ie s and 78 DCM con ol pa ien s. Dea h, hea
ansplan a ion, esusci a ion o app op ia e ICD he apy included as e en s. Median age es ima e o LMNA mu a ion ca ie s o
i s e en was 63 yea s (CI 53 o 72) compa ed wi h 68 yea s (CI 64 o 72) o DCM con ols. No s a is ically signi ican di e ence
in e en - ee su i al be ween he wo g oups was obse ed (p=0.463, log- ank es ). (B). Kaplan-Meie plo o e en - ee su i al
in 27 LMNA mu a ion ca ie s and 78 DCM con ol pa ien s. Dea hs, hea ansplan s, esusci a ions, app op ia e ICD he apy o
pacemake implan a ions included as e en s. Median age es ima e o LMNA mu a ion ca ie s was 48 yea s (CI 42 o 53)
compa ed wi h 60 yea s (CI 55 o 64) o DCM con ols (p=0.005, log- ank es ). DCM, dila ed ca diomyopa hy; ICD, implan able
ca dio e e -de ib illa o .
Table 2 The equencies and incidence ages o clinical LMNA mu a ion o ca diomyopa hy mani es a ions
LMNA-males,
N=13
N (%)
p Value
LMNA
s DCM
Male DCM
con ols,
N=56
N (%)
LMNA- emales,
N=14
N (%)
p Value
LMNA
s DCM
Female DCM
con ols,
N=22
N (%)
p Value
LMNA-males s
LMNA- emales
AF 8 (61.5) NS 29 (51.8) 7 (50.0) NS 10 (45.5) NS
NSVT 10 (76.9) 11 (78.6) NS
Pacemake
(any, including
ICDs)
9 (69.2) NS 26 (46.4) 7 (50.0) NS 11 (50.0) NS
ICD 6 (46.2) NS 16 (28.6) 3 (21.4) NS 10 (45.5) NS
Th ombosis 2 (15.4) NS 8 (14.3) 2 (14.3) NS 4 (18.2) NS
Majo end
poin
5 (38.5) NS 27 (48.2) 2 (14.3) 0.03 11 (50.0) NS
Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Age a DCM
diagnosis
42.2 (7.0) NS 47.8 (11.4) 54.1 (10.3) NS 46.3 (14.2) 0.042
Age a AF 40.9 (9.3) <0.001 55.4 (8.7) 53.7 (8.6) NS 61.0 (13.1) 0.016
Age a NSVT 40.5 (9.7) 50.3 (11.9) NS
Age a PM 41.8 (4.1) <0.001 55.8 (12.7) 58.5 (8.6) NS 54.6 (14.5) 0.001
Age a ICD 41.5 (3.6) 0.007 51.2 (11.6) 62.7 (6.1) NS 55.8 (14.8) <0.001
Age a
h ombosis
48.5 (12.1) NS 56.7 (10.2) 56.8 (9.3) NS 51.1 (17.4) NS
Age a majo
end poin
47.7 (7.6) NS 60.1 (13.9) 59.5 (4.8) NS 56.3 (15.1) NS
Compa isons o male LMNA mu a ion ca ie s o male DCM con ols, emale LMNA mu a ion ca ie s o emale DCM con ols and male LMNA
mu a ion ca ie s o emale LMNA mu a ion ca ie s.
AF, a ial ib illa ion; DCM, dila ed ca diomyopa hy; ICD, implan able ca dio e e -de ib illa o ; NS, no signi ican ; NSVT, non-sus ained
en icula achyca dia; PM, pacemake .
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median age es ima e o LMNA mu a ion ca ie s o
fi s e en was 48 yea s (CI 42 o 53) compa ed wi h
60 yea s (CI 55 o 64, p=0.005) o DCM con ols
(figu e 1B).
The Finnish ounde mu a ion Se 143P o was he
mos common mu a ion among he LMNA mu a ion ca -
ie s, wi h 15 o he 27 mu a ion ca ie s ha bou ing
i .
15
The e we e no s a is ically significan di e ences
be ween he Se 143P o mu a ion ca ie s compa ed wi h
he o he LMNA mu a ion ca ie s (Ala132P o,
A g190T p, c. 1493delG, c. 1085delT) conce ning he
equencies o incidence ages o he clinical mani es a-
ions. O he DCM con ols 28% had a gene ic diagnosis.
The mos common ca diomyopa hy-causing mu a ions
Figu e 2 The incidence ages o
clinical LMNA mu a ion
mani es a ions. Squa es
ep esen males, ci cles emales.
DCM, dila ed ca diomyopa hy;
ICD, implan able
ca dio e e -de ib illa o .
Table 3 The ECG cha ac e is ics o he LMNA mu a ion ca ie s, DCM con ols and heal hy con ols
LMNA mu a ion
ca ie s, N=27%
DCM con ols,
N=78%
p Value
LMNA s
DCM
Heal hy
con ols,
N=20%
p Value
LMNA s
heal hy
con ol
Rhy hm
Sinus hy hm 70.4 75.6 NS 100 NS
AF 11.1 16.7 0
O he * 18.5 7.7 0
Fi s AV block 37.0 (55.6)†15.4 (20.7) 0.034 0 0.006
Cu en o p e ious AV block 59.3 24.4 0.002 0 <0.001
PTF 22.2 (30.0) 30.8 (40.0) NS 10.0 NS
Fla P wa e 33.3 (45.0) 6.4 (8.3) 0.002 0 0.012
B oad P wa e 7.4 (10.0) 5.1 (6.7) NS 0 NS
LVH 7.4 (11.8) 20.5 (34.0) NS 0 NS
ST dep ession 18.5 (29.4) 32.1 (53.2) NS 5.0 NS
T in e sion 7.4 (11.8) 32.1 (53.2) 0.012 5.0 NS
QRS agmen a ion 37.0 33.3 NS 5.0 0.028
Sep al agmen a ion 22.2 6.4 NS 0 0.062
Sep al emodelling 81.5 20.5 <0.001 0 <0.001
Sep al emodelling, la P wa e,
o cu en o p e ious AV block
96.3 41.0 <0.001 0 <0.001
LBBB 7.4 20.5 NS 0 NS
RBBB 0 2.6 NS 0 NS
NSIVCD 3.7 7.7 NS 0 NS
*Physiological pacemake o hi d AV block.
†The p e alence in b acke s o only hose applicable.
AF, a ial ib illa ion; AV block, a io en icula block; DCM, dila ed ca diomyopa hy; LBBB, le bundle b anch block; LVH, le en icula
hype ophy; NS, no signi ican ; NSIVCD, non-speci ic in a en icula conduc ion de ec ; PTF, P e minal o ce; RBBB, igh bundle b anch
block.
Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 5
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among he DCM con ols we e unca ing i in gene
mu a ions, which explained 18% o cases.
Di e ences be ween men and women
The equencies and incidence ages o clinical mani es-
a ions in male and emale LMNA mu a ion ca ie and
DCM con ol subg oups a e p esen ed in able 2. Male
LMNA mu a ion ca ie s p esen ed wi h clinical mani es-
a ions a an ea lie age han emale LMNA mu a ion
ca ie s. This di e ence is illus a ed in figu e 2. The e
was a end o a highe incidence o a ial fib illa ion
among he male LMNA mu a ion ca ie s compa ed
wi h he women. Men p esen ed wi h a ial fib illa ion a
an ea lie age han emale LMNA mu a ion ca ie s (41
s 54 yea s, p=0.016). They also ecei ed pacemake s
and ICDs a a younge age han emales (42 s 59 yea s
o any pacemake s, p=0.001, 42 s 63 o ICDs,
p<0.001). In addi ion, hey de eloped DCM a a younge
age han women (42 s 54 yea s, p=0.042). The as
majo i y o male and emale LMNA mu a ion ca ie s
had eco ded NSVT episodes. Al hough he e was no
gende di e ence in he equencies o NSVTs, men
appea ed o ha e he fi s eco ded episode oughly
10 yea s ea lie han women (41 s 50 yea s, NS).
ECG
The ECG cha ac e is ics o he LMNA mu a ion ca ie s,
DCM con ols and heal hy con ols a e p esen ed in
able 3. The no el ECG pa e n, sep al emodelling
p o ed o be e y equen (81%) in LMNA mu a ion
ca ie s, while his ECG pa e n was p esen in only 21%
o DCM con ols and in none o he heal hy con ols.
The di e ences we e e en mo e s iking when combin-
ing he ECG pa ame e s fla P wa e and AV block o
sep al emodelling in he analyses. The sensi i i ies, spe-
cifici ies, and posi i e and nega i e p edic i e alues o
sep al emodelling in classi ying LMNA mu a ion ca ie s
om he wo con ol g oups a e gi en in able 4.
Figu e 3 shows ECGs wi h a ying o ms o sep al emod-
elling oge he wi h CMR images o an LMNA mu a ion
ca ie p esen ing LGE in he sep um. We had a ailable
CMR da a om 17 o he 27 LMNA mu a ion ca ie s. In
76% o he cases (n=13), sep al emodelling in he ECG
and sep al LGE in CMR we e conco dan ly p esen . In
he emaining ou cases, ei he sep al emodelling in
ECG (n=2) o LGE in CMR (n=2) was p esen .
The e we e no mu a ion-specific ECG findings in
his s udy when compa ing all he fi e mu a ions, o he
Finnish ounde mu a ion Se 143P o (n=15) o he
o he ou mu a ions as one g oup (n=12).
DISCUSSION
Ou da a sugges a di e ence in he age o disease onse
in ca diolaminopa hy be ween men and women; men
p esen ed oughly a decade ea lie han women ega d-
ing all s udied clinical mani es a ions. Conce ning he
age o fi s incidence o a ial fib illa ion, age o
pacemake o ICD implan a ion, and age a DCM diag-
nosis, he di e ence was s a is ically significan . Also in a
p e ious s udy o LMNA mu a ion ca ie s, he equen-
cies o malignan en icula a hy hmias, end-s age
hea ailu e and mo ali y we e highe in men han in
women, bu he age o he fi s ca diac in ol emen was
simila in bo h gende s.
29
We sugges ha he disease
onse in LMNA mu a ion ca ie s in gene al akes place
ea lie in men han in women.
The incidence o en icula a hy hmias is known o
be high in LMNA mu a ion ca ie s wi h p e alence
numbe s o e 50% ci ed in se e al s udies.
14 30
The
p e alence o 78% ( o NSVT) in his s udy is e en
highe , which may be explained by epea ed documen a-
ions o Hol e ECGs and clinical exe cise es ing o he
same indi iduals o e se e al yea s. This finding sugges s
ha e en i en icula a hy hmias ha e no been
de ec ed in an indi idual LMNA mu a ion ca ie , hey
likely will be in egula ollow-up. Some yea s ago, i was
e en sugges ed ha ICDs should be implan ed p ophy-
lac ically o all LMNA mu a ion ca ie s.
4
Recen ly, a isk
assessmen scheme was sugges ed o iden i y hose
LMNA mu a ion ca ie s a g ea e isk o malignan
Table 4 The sensi i i ies, speci ici ies, and PPV and NPV
o (ECG) sep al emodelling in classi ying LMNA mu a ion
ca ie s om he DCM con ols, heal hy con ols o he
combined con ol g oup o DCM con ols and heal hy
con ols
Sep al
emodelling, N
(%)
Cu en o p e ious
AV block, la P wa e
o sep al emodelling,
N (%)
LMNA
mu a ion
ca ie s
22 (81.5) 26 (96.3)
Heal hy
con ols
00
DCM
con ols
16 (20.5) 32 (41.0)
LMNA s
DCM
con ols
Pe cen Pe cen
Sensi i i y 81.5 96.3
Speci ici y 79.5 59.0
PPV 57.9 44.8
NPV 92.5 97.9
LMNA s heal hy con ols
Sensi i i y 81.5 96.3
Speci ici y 100 100
PPV 100 100
NPV 80 95.2
LMNA s DCM o heal hy con ols
Sensi i i y 81.5 96.3
Speci ici y 83.7 67.3
PPV 57.9 44.8
NPV 94.3 98.5
DCM, dila ed ca diomyopa hy; NPV, nega i e p edic i e alue;
PPV, posi i e p edic i e alue.
6Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474
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en icula a hy hmias.
5
We ag ee wi h he p oposed
s a egy o indi idual isk s a ifica ion among LMNA
mu a ion ca ie s when conside ing he need o an
ICD. Howe e , he high p e alence o NSVT highligh s
he need o close ollow-up o hese pa ien s, as he clin-
ical p esen a ion is likely o p og ess. I can also be
specula ed ha close ollow-up and imely in e en ions
could educe he isk o e en s, o slow down disease
p og ession. Ou esul s sugges a simila o lowe inci-
dence o majo clinical end poin s, including hea
ansplan a ions, esusci a ions o dea hs, in LMNA
mu a ion ca ie s han in DCM con ols. The incidence
o majo end poin s was highe in he olde DCM
con ol g oup, bu Kaplan-Meie analysis showed a
simila e en - ee su i al a e in he LMNA mu a ion
ca ie and he DCM con ol g oups.
We in oduce a no el ECG concep , sep al emodel-
ling, as a eadily a ailable clinical ool o assess ca diac
in ol emen in LMNA mu a ion ca ie s. In ou s udy o
27 LMNA mu a ion ca ie s o a ying ages, 81% p e-
sen ed wi h his ECG finding compa ed wi h 21% o he
DCM con ols and none o he heal hy con ols. When
combining his abno mali y wi h he p e iously
desc ibed ECG signs associa ed wi h laminopa hy, fla P
wa es and AV block, all bu one o he LMNA mu a ion
ca ie s had a leas one o hese abno mali ies.
ST segmen dep ession, ma ke s o inc eased le en-
icula mass (LVH and b oad QRS), and ele a ed filling
p essu e (P e minal o ce) a e es ablished ECG signs o
s uc u al hea disease.
910
ECG changes associa ed wi h
egional disease p ocesses, mainly fib osis o nec osis, a e
less well es ablished. We sugges ha sep al emodelling
in he ECG leads V1–V3 ep esen s a localised disease
p ocess ypical o ca diolaminopa hy. Ou hypo hesis is
compa ible wi h he ac ha CMR s udies using LGE as a
ma ke o ca diac fib osis sugges disease localisa ion in
he basal and mid- en icula sep um and he basal le
en icula wall in LMNA mu a ions.
13 14
In his s udy in
76% (13/17) o he LMNA mu a ion ca ie s wi h a ail-
able CMR da a, sep al emodelling in he ECG and LGE
in he sep um we e conco dan . ECG sep al emodelling
was e y common in LMNA mu a ion ca ie s, qui e a e
in DCM con ols and absen in heal hy con ols.
Howe e , i seems logical ha any egional disease
p ocess, such as myoca dial in a c ion o myoca di is,
esul ing in nec osis o fib osis, would be eflec ed in a
simila way on he 12-lead ECG. The e o e, we p opose
u he clinical assessmen , including amily his o y and
ca diac imaging o ule ou s uc u al hea disease, in
indi iduals wi hou a his o y o ca diac disease, who
p esen wi h sep al emodelling in hei 12-lead ECG.
Gene ic es ing may also be app op ia e, aking in o
accoun he en i e clinical p esen a ion.
Owing o he explo a i e na u e o his s udy, mul ipli-
ci y co ec ion was no pe o med.
In conclusion, ou esul s sugges ha male LMNA
mu a ion ca ie s appea o p esen wi h ca diolamino-
pa hy mani es a ions oughly a decade ea lie han
Figu e 3 (A–E) Example ECGs p esen ing sep al emodelling. (A) Q wa es in V1–V2; (B) b oad QRS wi h agmen a ion in V2–
V3, and a Q wa e in V1; (C) RV1>RV2 wi h agmen ed QRS in V2; (D) poo R-wa e p og ession wi h QRS agmen a ion in V2;
(E) RV2>RV3 wi h agmen ed QRS in V1. 3. (F and G) CMR image o an LMNA mu a ion ca ie . A ows poin o he a eas
showing la e gadolinium enhancemen . CMR, ca diac MRI; LV, le en icle; RV, igh en icle.
Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 7
Hea ailu e and ca diomyopa hies
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women. The high incidence o a ial fib illa ion and en-
icula a hy hmias in LMNA mu a ion ca ie s suppo s
close ollow-up o enable imely ini ia ion o medical
and de ice-based an ia hy hmic he apy.
Finally, we in oduce a no el ECG pa ame e , sep al
emodelling, which was equen ly obse ed in LMNA
mu a ion ca ie s and seemed o di e en ia e hese indi-
iduals om pa ien s wi h o he o ms o DCM.
Limi a ions
The numbe o LMNA mu a ion ca ie s in his s udy
was a he small. I is possible ha some non-significan
s a is ical compa isons could ha e eached s a is ical sig-
nificance in a la ge pa ien ma e ial. Ou defini ion o
ECG sep al emodelling is no based on exac expe i-
men al o CMR-based co ela ions be ween egional
disease p ocesses and elec ophysiological changes.
Howe e , i ep esen s a collec ion o p e iously pub-
lished ECG pa ame e s o localised hea disease.
Au ho a ilia ions
1
Hea and Lung Cen e, Helsinki Uni e si y Hospi al, Helsinki, Finland
2
Hea Cen e, Tampe e Uni e si y Hospi al and School o Medicine, Uni e si y
o Tampe e, Tampe e, Finland
3
Depa men o Radiology, Uni e si y o Helsinki and HUS Radiology (Medical
Imaging Cen e), Helsinki, Finland
4
Bluep in Gene ics, Helsinki, Finland
5
Uni o Clinical Physiology and Nuclea Medicine, HUS Medical Imaging
Cen e , Helsinki Uni e si y Cen al Hospi al and Uni e si y o Helsinki,
Helsinki, Finland
6
Uni e si y o Eas e n Finland, Kuopio, Finland
7
Hea Cen e, Kuopio Uni e si y Hospi al, Kuopio, Finland
8
Na ional Ins i u e o Heal h and Wel a e, Helsinki, Finland
9
Uni o Clinical Physiology, HUS Medical Imaging Cen e , Uni e si y Cen al
Hospi al, Helsinki, Finland
Acknowledgemen s The au ho s hank Sini Wecks öm (RN) o in aluable
assis ance in da a collec ion, Te o Vahlbe g o excellen s a is ical
consul a ion and San u Ollila o expe image edi ing.
Con ibu o s LO, KN, MH, JuK, PP and TH pa icipa ed in da a collec ion, da a
analysis, d a ing and e ision o he manusc ip . MJ, RJ, MK, JoK, SK, EP
and ER pa icipa ed in da a collec ion, d a ing and e ision o he manusc ip .
Funding Aa ne Koskelo Founda ion, Finnish Founda ion o Ca dio ascula
Resea ch, Finnish Medical Founda ion, Go e nmen al subsidy (EVO-g an s:
TYH2014208, TYH2012120, TYH7106, TYH200921, TYH4241, TYH2205),
and Ida Mon in Founda ion.
Compe ing in e es s None decla ed.
E hics app o al E hics Commi ee o he Helsinki Uni e si y Cen al Hospi al.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Da a sha ing s a emen No addi ional da a a e a ailable.
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h
he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license,
which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-
comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided
he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p://
c ea i ecommons.o g/licenses/by-nc/4.0/
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