Clinical disease presentation and ECG characteristics of LMNA mutation carriers

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 Hea ailu e and ca diomyopa hies g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 2Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 Open Hea g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 Hea ailu e and ca diomyopa hies g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 . 4Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 Open Hea g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 Hea ailu e and ca diomyopa hies g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 Open Hea g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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 g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 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/ REFERENCES 1. Jacoby D, McKenna WJ. Gene ics o inhe i ed ca diomyopa hy. Eu Hea J 2012;33:296–304. 2. B od C, Sieg ied JD, Ho meye M, e al. Tempo al ela ionship o conduc ion sys em disease and en icula dys unc ion in LMNA ca diomyopa hy. J Ca d Fail 2013;19:233–9. 3. an Be lo JH, de Voog WG, an de Kooi AJ, e al. Me a-analysis o clinical cha ac e is ics o 299 ca ie s o LMNA gene mu a ions: do lamin A/C mu a ions po end a high isk o sudden dea h? J Mol Med (Be l) 2005;83:79–83. 4. Meune C, Van Be lo JH, Anselme F, e al. P ima y p e en ion o sudden dea h in pa ien s wi h lamin A/C gene mu a ions. N Engl J Med 2006;354:209–10. 5. an Rijsingen IA, A bus ini E, Ellio PM, e al. Risk ac o s o malignan en icula a hy hmias in lamin a/c mu a ion ca ie s a Eu opean coho s udy. J Am Coll Ca diol 2012;59:493–500. 6. He shbe ge RE, Mo ales A, Sieg ied JD. Clinical and gene ic issues in dila ed ca diomyopa hy: a e iew o gene ics p o essionals. Gene Med 2010;12:655–67. 7. Ollila L, Kuusis o J, Peuhku inen K, e al. Lamin A/C mu a ion a ec ing p ima ily he igh side o he hea . Ca diogene ics 2013;3: e1. 8. Qua a G, Sy is P, Ashwo h M, e al. Mu a ions in he lamin A/C gene mimic a hy hmogenic igh en icula ca diomyopa hy. Eu Hea J 2012;33:1128–36. 9. Momiyama Y, Mi amu a H, Kimu a M. ECG cha ac e is ics o dila ed ca diomyopa hy. J Elec oca diol 1994;27:323–8. 10. Kasse I, Kennedy JW. The ela ionship o inc eased le a ial olume and p essu e o abno mal P wa es on he elec oca diog am. Ci cula ion 1969;39:339–43. 11. Cha on P, Dubou g O, Desnos M, e al. Diagnos ic alue o elec oca diog aphy and echoca diog aphy o amilial hype ophic ca diomyopa hy in a geno yped adul popula ion. Ci cula ion 1997;96:214–19. 12. McC ohon JA, Moon JC, P asad SK, e al. Di e en ia ion o hea ailu e ela ed o dila ed ca diomyopa hy and co ona y a e y disease using gadolinium-enhanced ca dio ascula magne ic esonance. Ci cula ion 2003;108:54–9. 13. Holms öm M, Ki is ö S, Heliö T, e al. La e gadolinium enhanced ca dio ascula magne ic esonance o lamin A/C gene mu a ion ela ed dila ed ca diomyopa hy. J Ca dio asc Magn Reson 2011;13:30. 14. Fo leo C, Ca mosino M, Res a N, e al. Clinical and unc ional cha ac e iza ion o a no el mu a ion in lamin a/c gene in a mul igene a ional amily wi h a hy hmogenic ca diac laminopa hy. PLoS ONE 2015;10:e0121723. 15. Kä kkäinen S, Heliö T, Mie inen R, e al.A no el mu a ion, Se 143P o, in he lamin A/C gene is common in Finnish pa ien s wi h amilial dila ed ca diomyopa hy. Eu Hea J 2004;25:885–93. 16. Kä kkäinen S, Reissell E, Heliö T, e al. No el mu a ions in he lamin A/C gene in hea ansplan ecipien s wi h end s age dila ed ca diomyopa hy. Hea 2006;92:524–6. 17. Akin inade O, Ollila L, Va ulainen S, e al. Gene ics and geno ype-pheno ype co ela ions in Finnish pa ien s wi h dila ed ca diomyopa hy. Eu Hea J 2015;36:2327–37. 18. Cheng S, Keyes MJ, La son MG, e al. Long- e m ou comes in indi iduals wi h p olonged PR in e al o i s -deg ee a io en icula block. JAMA 2009;301:2571–7. 19. A e alo AC, Spagnuolo M, Feins ein AR. A simple elec oca diog aphic indica ion o le a ial enla gemen . A s udy o young pa ien s wi h heuma ic hea disease. JAMA 1963;185:358–62. 20. Mac a lane P. Comp ehensi e elec oca diology. Ka ge Publishe , 2011. 21. Sokolow M, Lyon T. The en icula complex in le en icula hype ophy as ob ained by unipola p eco dial and limb leads. Am Hea J 1949;37:161–86. 22. Okin PM, Roman MJ, De e eux RB, e al. Elec oca diog aphic iden i ica ion o inc eased le en icula mass by simple ol age-du a ion p oduc s. J Am Coll Ca diol 1995;25:417–23. 23. Okin PM, De e eux RB, Nieminen MS, e al. Rela ionship o he elec oca diog aphic s ain pa e n o le en icula s uc u e and unc ion in hype ensi e pa ien s: he LIFE s udy. Losa an In e en ion Fo End poin . J Am Coll Ca diol 2001;38:514–20. 24. Lakdawala NK, Thune JJ, Ma on BJ, e al. Elec oca diog aphic ea u es o sa come e mu a ion ca ie s wi h and wi hou clinically o e hype ophic ca diomyopa hy. Am J Ca diol 2011;108:1606–13. 25. Konno T, Fujino N, Hayashi K, e al. Di e ences in he diagnos ic alue o a ious c i e ia o nega i e T wa es o hype ophic ca diomyopa hy based on a molecula gene ic diagnosis. Clin Sci (Lond) 2007;112:577–82. 26. Das MK, Khan B, Jacob S, e al. Signi icance o a agmen ed QRS complex e sus a Q wa e in pa ien s wi h co ona y a e y disease. Ci cula ion 2006;113:2495–501. 8Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 Open Hea g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om 27. Zema MJ, Klig ield P. Elec oca diog aphic poo R wa e p og ession. I: co ela ion wi h he F ank ec o ca diog am. J Elec oca diol 1979;12:3–10. 28. Dumon CA, Monse a L, Sole R, e al. In e p e a ion o elec oca diog aphic abno mali ies in hype ophic ca diomyopa hy wi h ca diac magne ic esonance. Eu Hea J 2006;27:1725–31. 29. an Rijsingen IA, Nannenbe g EA, A bus ini E, e al. Gende -speci ic di e ences in majo ca diac e en s and mo ali y in lamin A/C mu a ion ca ie s. Eu J Hea Fail 2013;15:376–84. 30. Hasselbe g NE, Ed a dsen T, Pe i H, e al. Risk p edic ion o en icula a hy hmias and myoca dial unc ion in lamin A/C mu a ion posi i e subjec s. Eu opace 2014;16:563–71. Ollila L, Nikus K, Holms öm M, e al.Open Hea 2017;4:e000474. doi:10.1136/openh -2016-000474 9 Hea ailu e and ca diomyopa hies g oup.bmj.com on Ma ch 28, 2017 - Published by h p://openhea .bmj.com/Downloaded om