Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset

Raffaello Ditaranto, Giuseppe Boriani, Mauro Biffi, Massimiliano Lorenzini, Maddalena Graziosi, Matteo Ziacchi, Ferdinando Pasquale, Giovanni Vitale, Alessandra Berardini, Rita Rinaldi, Giovanna Lattanzi, Luciano Potena, Sofia Martin Suarez, Maria Letizia Bacchi Reggiani, Claudio Rapezzi, Elena Biagini, Raffaello Ditaranto, Giuseppe Boriani, Mauro Biffi, Massimiliano Lorenzini, Maddalena Graziosi, Matteo Ziacchi, Ferdinando Pasquale, Giovanni Vitale, Alessandra Berardini, Rita Rinaldi, Giovanna Lattanzi, Luciano Potena, Sofia Martin Suarez, Maria Letizia Bacchi Reggiani, Claudio Rapezzi, Elena Biagini

Abstract

Objective: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation.

Methods: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated.

Results: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p < 0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively).

Conclusions: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy.

Keywords: Atrial fibrillation; Bradyarrhythmias; Emerin; Familial cardiomyopathies; Lamin; Neuromuscular disorders; Ventricular tachycardias.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a Cardiac phenotype spectrum at first clinical evaluation at our centre of patients with LMNA mutations and neurological onset (N = 14). SSS: sick sinus syndrome; AVB: atrio-ventricular block; CMP: cardiomyopathy; AF atrial fibrillation/flutter. b Cardiac phenotype spectrum at first clinical evaluation at our centre of patients with LMNA mutations without neurological onset (N = 26). SSS: sick sinus syndrome; AVB: atrio-ventricular block; CMP: cardiomyopathy; AF atrial fibrillation/flutter
Fig. 2
Fig. 2
Second degree sino-atrial block with 2:1 conduction ratio in a 22-year old female, with Emery Dreifuss muscular dystrophy due to p.Ile63Asn missense LMNA mutation
Fig. 3
Fig. 3
43-year old male with a LMNA frameshift mutation without neuromuscular presentation. a V1 lead ECG showing first degree atrio-ventricular block, b-c cardiac magnetic resonance showing midwall late gadolinium enhancement in the basal interventricular septum. Suggestive for myocardial fibrosis
Fig. 4
Fig. 4
CMR of a 54-year male, carrier of p.Arg401His missense LMNA mutation, affected by DCM. (a-b) Four chamber and RV long axis SSFP images show biventricular dilation, bulging of the RV free wall (white arrow, panel a-b) and diaphragmatic wall (white arrow, panel b). (c) Two chamber T1-weighted and (d) fat suppressed T1-weighted slices showing LV fatty replacement of mid lateral wall (white arrow). (e) IR LGE slice showing fibrosis in the infero-lateral wall (with focal transmural pattern) and in the interventricular septum (image quality was due to respiratory artifacts and to the presence of pacemaker [*]). CMR: cardiac magnetic resonance. DCM: dilated cardiomyopathy. SSFP: steady-state free precession. LV-RV: left-right ventricle. IR LGE: inversion recovery late gadolinium enhancement
Fig. 5
Fig. 5
Box and whiskers plot showing age distribution of different clinical events in LMNA patients with (white) and without (gray) neuromuscular onset. Middle horizontal line inside box indicates median. Bottom and top of the box are 25th and 75th percentiles, the whiskers indicate the lowest and highest value. PM: pacemaker. ICD: implantable cardioverter defibrillator
Fig. 6
Fig. 6
Different overall prevalence at the end of follow-up of clinical events in LMNA patients with (white) and without (gray) neuromuscular presentation. AF: atrial fibrillation; PM: pacemaker; CMP: cardiomyopathy; SVT: sustained ventricular tachycardias
Fig. 7
Fig. 7
Timeline of clinical events in the lifetime of patients with LMNA mutations and neuromuscular onset

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