Electrophysiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy
Authors: Cabrera-Borrego Eva , Bermúdez-Jiménez Francisco J. , Gasperetti Alessio , Tandri Harikrishna , Sánchez-Millán Pablo J. , Molina-Lerma Manuel , Roca-Luque Ivo , Vázquez-Calvo Sara , Compagnucci Paolo , Casella Michela , Tondo Claudio , Peichl Petr , Peretto Giovani , Paiotti Elena , Saguner Ardan M , Castro-Urda Víctor , Mora-Ayestarán Nerea , Larrañaga-Moreira José M , Fernández de-Aspe Pablo , Barriales-Villa Roberto , Muñoz-Esparza Carmen , Zorio Esther , Martínez-Solé Julia , Lopes Luis R. , Tonko Johanna B. , Lambiase Pier D. , Elliott Perry M. , Rodríguez-Mañero Moisés , Cañadas-Godoy Victoria , Giacoman Sebastian , Álvarez-López Miguel , Macías-Ruiz Rosa , McKenna William J. , Tercedor-Sánchez Luis , Jiménez-Jáimez Juan 
Published: November 2024

BACKGROUND:
Among inherited cardiomyopathies involving the left ventricle, whether dilated or not, certain genotypes carry a well-established arrhythmic risk, notably manifested as sustained monomorphic ventricular tachycardia (SMVT). Nonetheless, the precise localization and electrophysiological profile of this substrate remain undisclosed across different genotypes.

METHODS:
Patients diagnosed with cardiomyopathy and left ventricle involvement due to high-risk genetic variants and SMVT treated by electrophysiological study were recruited from 18 European/US centers. Electrophysiological study, imaging, and outcomes data after ablation were assessed in relation to genotype.

RESULTS:

Seventy-one patients were included (49.6 Q1–Q3 [40–60] years, 76% men). They were divided into 4 groups according to the affected protein: desmosomal (
DSP
,
PKP2
,
DSG2
, and
DSC2
), nuclear membrane (
LMNA
and
TMEM43
), cytoskeleton (
FLNC
and
DES
), and sarcoplasmic reticulum (
PLN
). Desmosomal genes,
TMEM43
, and
PLN
were associated with biventricular disease, while variants in
LMNA
and cytoskeleton genes had predominant left ventricle involvement (
P
=0.001). The location of the clinical-SMVT substrate was significantly different based on genotype (
P
=0.005).
DSP
and cytoskeleton genes presented SMVTs with right bundle branch block morphology, which origin was identified in the inferolateral segments of the left ventricle. The other desmosomal genes (
PKP2
and
DSG2
), along with
TMEM43
, showed SMVTs with left bundle branch block morphology and predominantly right ventricular substrate. In contrast,
LMNA
substrate was mainly observed in the interventricular septum. During a median of 26 Q1–Q3 (10.6–65) months, 27% of patients experienced recurrences of clinical SMVT with differences between genotypes (log-rank 0.016). Nuclear membrane genes demonstrated the highest recurrence rate compared with desmosomal genes (hazard ratio, 4.56 [95% CI, 1.5–13.8]).

CONCLUSIONS:
The anatomic substrate of SMVTs shows a strong correlation with the underlying genotype, electrocardiographic morphology, and recurrence rate. Particularly, patients with nuclear membrane gene variants have a significantly higher recurrence rate compared with those with desmosomal gene variants.