Heart failure and cardiomyopathies Open Heart: first published as 10.1136/openhrt-2016-000474 on 9 January 2017. Downloaded from Clinical disease presentation and ECG characteristics of LMNA mutation carriers Laura Ollila,1 Kjell Nikus,2 Miia Holmström,3 Mikko Jalanko,1 Raija Jurkko,1 Maija Kaartinen,1 Juha Koskenvuo,4,5 Johanna Kuusisto,6 Satu Kärkkäinen,7 Eeva Palojoki,1 Eeva Reissell,8 Päivi Piirilä,9 Tiina Heliö1 To cite: Ollila L, Nikus K, ABSTRACT et al KEY QUESTIONS Holmström M, . Clinical Objective: Mutations in the LMNA gene encoding disease presentation lamins A and C of the nuclear lamina are a frequent and ECG characteristics of What is already known about this subject? cause of cardiomyopathy accounting for 5–8% of LMNA mutation carriers. ▸ Although ventricular dilation and dysfunction Open Heart 2017;4:e000474. familial dilated cardiomyopathy (DCM). Our aim was to may remain less severe than in other forms of doi:10.1136/openhrt-2016- study disease onset, presentation and progression dilated cardiomyopathy, the penetrance of cardi- 000474 among LMNA mutation carriers. olaminopathy mutations is almost complete Methods: Clinical follow-up data from 27 LMNA often resulting in serious arrhythmias or heart mutation carriers and 78 patients with idiopathic DCM failure. Cardiomyopathy-causing LMNA muta- Received 14 May 2016 without an LMNA mutation were collected. In addition, tions often present with typical ECG abnormal- Revised 3 September 2016 ECG data were collected and analysed systematically ities, such as atrioventricular block and atrial or Accepted 1 November 2016 from 20 healthy controls. ventricular arrhythmias. Results: Kaplan-Meier analysis revealed no difference in event-free survival (death, heart transplant, What does this study add? ▸ LMNA resuscitation and appropriate implantable cardioverter- We report that most mutation carriers defibrillator therapy included as events) between LMNA present with non-sustained ventricular tachycar- mutation carriers and DCM controls (p=0.5). LMNA dia (NSVT) in close follow-up. In addition, we LMNA mutation carriers presented with atrial fibrillation at a reaffirm that male mutation carriers have an earlier disease onset than females. We younger age than the DCM controls (47 vs 57 years, http://openheart.bmj.com/ LMNA p=0.003). Male LMNA mutation carriers presented with suggest that mutation carriers likely clinical manifestations roughly a decade earlier than benefit from close follow-up. We also present a females. In close follow-up non-sustained ventricular new ECG entity, septal remodelling, present in LMNA tachycardia was detected in 78% of LMNA mutation most mutation carriers and suggesting carriers. ECG signs of septal remodelling were present that the pathological process leading to cardiola- in 81% of the LMNA mutation carriers, 21% of the minopathy typically affects the myocardial DCM controls and none of the healthy controls giving septum. a high sensitivity and specificity for the standard ECG How might this impact on clinical practice? in distinguishing LMNA mutation carriers from patients ▸ The detection of septal remodelling in standard on September 28, 2021 by guest. Protected copyright. with DCM and healthy controls. ECG should lead to an echocardiogram and Conclusions: Male LMNA mutation carriers present thorough enquiry of cardiac family history. clinical manifestations at a younger age than females. ▸ Even asymptomatic LMNA mutation carriers ECG septal remodelling appears to distinguish LMNA need follow-up to detect atrial fibrillation and mutation carriers from healthy controls and patients NSVTs. with DCM without LMNA mutations. consequently implantable cardioverter- defibrillator (ICD) implantation has been INTRODUCTION suggested as primary prophylaxis for all LMNA mutations are prevalent in familial LMNA mutation carriers, or after further risk dilated cardiomyopathy (DCM), accounting assessment.45Cardiolaminopathy often for about 5–8% of the cases.1 The typical follows an age-dependent disease progression For numbered affiliations see LMNA end of article. early manifestations of mutations are in which the ECG and rhythm abnormalities ECG abnormalities including flat P wave, tend to precede structural heart disease and Correspondence to atrioventricular block, supraventricular and systolic impairment, which in turn often does 23 fi Dr Laura Ollila; ventricular arrhythmias. LMNA mutations not ful l the echocardiography criteria for [email protected] pose a risk for sudden cardiac death, and DCM due to milder dilation of the left Ollila L, Nikus K, Holmström M, et al. Open Heart 2017;4:e000474. doi:10.1136/openhrt-2016-000474 1 Open Heart Open Heart: first published as 10.1136/openhrt-2016-000474 on 9 January 2017. Downloaded from ventricle or dilation with preserved ejection fraction.36 hospital records. First incidences of atrial fibrillation, Lately LMNA mutations have also been linked to familial non-sustained ventricular tachycardia (NSVT), resuscita- forms of mainly right ventricular disease manifestations tion or appropriate ICD therapy, cardiogenic embolism resembling arrhythmogenic right ventricular and pacemaker/ICD implantations were recorded. cardiomyopathy.78 NSVT was defined as more than three consecutive ven- Structural heart disease can result in general, non- tricular beats in 24-hour Holter or clinical exercise test. localising ECG changes, such as left ventricular hyper- To avoid bias, NSVTs were not recorded in the DCM trophy (LVH), ST depression, widening of the QRS controls due to the less vigorous follow-up of the DCM complex, and P terminal force.910On the other hand, control group compared with the LMNA mutation ECG changes in leads overlying affected regions can carrier group. Owing to the small number of major clin- reflect regional disease processes. For instance, narrow ical events in the LMNA mutation carrier group, a com- and deep q waves are typical for localised wall thickening posite end point of resuscitation, appropriate ICD in hypertrophic cardiomyopathy.11 therapy, death and heart transplant was used. In LMNA Late gadolinium enhancement (LGE) in cardiac MRI mutation carriers with available CMR data, the presence (CMR) is considered an effective tool in showing myo- of the ECG parameter septal remodelling was compared cardial scarring.12 In LMNA mutation carriers LGE has with CMR findings from a previous article;13 the CMR been mainly seen in the basal or mid-ventricular septum methods were presented earlier. suggesting a possible localised disease process.13 14 The study patients gave written informed consent. The The aim of this study was to assess disease presenta- study was approved by the Ethics Committee of the tion, progression and clinical outcome in symptomatic Helsinki University Central Hospital (Decision number: and asymptomatic LMNA mutation carriers. Dnro 322/E5/03, Research permit number: T1010K0019). ECG analyses METHODS One standard 12-lead ECG recorded by 50 mm/s speed of Patients and controls each LMNA mutation carrier, DCM control and healthy fi This longitudinal retrospective study included all identi ed control was analysed in a systematic manner manually by LMNA adult mutation carriers from Helsinki and Kuopio one investigator (KN) blinded to the clinical data. The University Hospitals willing to participate in a follow-up ECG recording was from the time of study recruitment. LMNA study. Twenty-seven mutation carriers were recruited The age at the time of ECG recording was 42 years for all to the study between 1999 and 2010. The mutation car- LMNA mutation carriers; 49 years for those with DCM fi LMNA riers, each harbouring one of ve mutations (LMNA-DCM subgroup), and 37 years for those without. ((NM_170707.3 (LMNA), c427T>C, p.(Ser143Pro) in The following definitions were used in the ECG analyses: http://openheart.bmj.com/ exon 2; c.394G>C, p.(Ala132Pro) in exon 2; c.568C>T, first-degree atrioventricular block was defined as PR inter- p.(Arg190Trp) in exon 3; c. 1493delG, p.(Ala499Leufs*49) val >200 ms,18 P terminal force as negative portion of in exon 9; c. 1085delT, p.(Leu363Trpfs*117) in exon 6) the P wave in lead V1≥0.4 mm/s,19 flat P wave as P-wave were either probands or their family members from nine amplitude <1 mm in lead II, and broad P wave as ≥120 ms fi 15 16 families identi ed in two previous studies. Clinical in lead II20 LVH was defined according to the LMNA follow-up data from the mutation carriers and DCM Sokolow-Lyon criteria,21 or Cornell voltage duration controls were collected up to 31 December 2014. Control product (QRS-duration (ms)×(RaVL in mm+SV3 in mm patients (n=78) with idiopathic DCM were collected from a with 6 mm added for women) ≥2440),22 23 for ST segment patient database retrospectively. Probands with DCM, diag- depression we used ≥0.5 mm if the pattern was horizontal on September 28, 2021 by guest. Protected copyright. nosed and recruited before 2010 were included as DCM or descending, and ≥1mmifascendingin ≥2 adjacent controls; patients recruited after possible heart transplant- leads measured at the J point+60 ms,24 for T-wave inversion ation, were excluded to minimise possible collection bias. ≥1mmin≥2 adjacent leads, except for leads aVR and V1 Only probands who have been tested for cardiomyopathy- was used.25 For fragmented QRS in ≥2 adjacent leads we causing mutations using OsSeq, a next-generation- used the definitions by Das et al.26 Septal fragmentation sequencing method, as described before were included to was considered present if there was QRS fragmentation in LMNA ensure that there were no mutation carriers among ≥2 septal leads (V1–V3). Non-specific intraventricular con- 17 the DCM controls. duction defect was defined as QRS duration ≥120 ms not Concerning the ECG abnormalities, the study patients fulfilling criteria for right or left bundle branch block. were also compared with an available cohort of 20 (7 Owing to the high proportion of implanted pacemakers, men, 13 women) healthy controls. we used anamnestic data of AV block in addition to the findings in the ECG used for analysis.