Background: Cardiolaminopathies, heterogeneous and complex manifestations of LMNA gene mutations, are characterized by the frequent occurrence of dilated cardiomyopathy (DCM), atrioventricular conduction disorders, and both atrial and ventricular tachyarrhythmias, leading to a high risk of sudden cardiac death and heart failure. They exhibit high penetrance, early onset, rapid and progressive course, and poor prognosis. Many aspects remain unclear, particularly genotype-phenotype correlations. Objectives: The study aims to: 1) clinically and instrumentally characterize patients with LMNA gene mutations and compare patients with pathogenic or likely pathogenic variants (P/LP, Class 4 and 5) to patients with variants of uncertain significance (VUS, Class 3) of the LMNA gene; 2) identify predictors of outcomes in the cohort of patients with LMNA variant; 3) compare the clinical and instrumental characteristics of patients with Class 4 and 5 mutations of the LMNA gene to those with Class 4 and 5 mutations of the Desmoplakin (DSP) gene. Materials and Methods: 54 patients with LMNA gene variants were analyzed based on phenotype (DCM, Arrhythmogenic Right Ventricular Cardiomyopathy-ARVC, Non-Dilated Left Ventricular Cardiomyopathy-NDLVC, and patients not meeting diagnostic criteria). They were then divided into two groups based on genotype: patients with Class 4/5 genetic variants and those with Class 3 variants (VUS), who were compared clinically and instrumentally. Additionally, patients with Class 4/5 LMNA mutations were compared to those with Class 4/5 DSP gene variants. Results: The population under study included 54 patients, 38 (70.37%) diagnosed with cardiomyopathy and 16 (29.63%) not meeting the cardiomyopathy diagnostic criteria. The former were further divided into three groups based on phenotype: 17 with DCM (44.74%), 17 with NDLVC (44.74%), and 4 with ARVC (10.52%). No significant clinical-instrumental differences were found between patients with Class 4/5 variants and those with VUS; however, heart failure outcomes (P+LP= 63%, VUS=0, p=0.004) and cardiac transplantation (P+LP= 33%, VUS=0, p=0.002) were more frequent in patients with Class 4/5 variants. In the total population with LMNA variant, predictors of outcomes included atrial fibrillation (p=0.006), right ventricular end-diastolic volume (p=0.016), left (p=0.002), and right (p=0.003) ejection fraction. Conversely, left bundle branch block and pacemaker-induced rhythm showed a trend towards statistical significance (p=0.06) and a high odds ratio (OR = 8.25). No significant differences in arrhythmic outcomes (p=0.25) were found between patients with DSP mutations and those with LMNA mutations. Patients with LMNA mutation had a higher incidence of heart failure (p=0.01) and greater need for cardiac transplantation (p<0.001) compared to those with DSP mutation. However, the latter group exhibited more fibrosis on cardiac magnetic resonance imaging (MRI) (p<0.001). Conclusions: Patients with LMNA gene variants may present with different phenotypic expressions, diagnosed as DCM, NDLVC, and ARVC with varying penetrance. Patients with VUS had characteristics overlapping those with P or LP mutations except for outcomes, which were more significant in the group with Class 4/5 mutations. Predictors of outcomes included atrial fibrillation, right end-diastolic volume, and both right and left ejection fractions. Finally, in the LMNA group, the incidence of heart failure and transplantation was higher compared to the DSP group, which showed a greater presence of fibrosis on cardiac MRI. However, the degree of electrical instability was similar between the two groups.
Background Le cardiolaminopatie, manifestazioni eterogenee e complesse delle mutazioni del gene LMNA, si caratterizzano per la frequente comparsa di cardiomiopatia dilatativa (dilated cardiomyopathy: DCM), disturbi di conduzione atrioventricolare e tachiaritmie sia atriali che ventricolari, con conseguenti alto rischio di morte cardiaca improvvisa e scompenso cardiaco. Presentano: elevata penetranza, esordio giovanile, decorso rapido e progressivo e prognosi infausta. Molti aspetti sono poco chiari, in particolare le correlazioni genotipo-fenotipo. Scopi: 1) la caratterizzazione clinico-strumentale di pazienti con mutazioni del gene LMNA ed il confronto di pazienti con varianti patogene o probabilmente patogene (P/LP, Classe 4/5) con pazienti con varianti di incerto significato (VUS, Classe 3) del gene LMNA; 2) la ricerca di predittori di outcome nella coorte di pazienti con variante LMNA; 3) il confronto delle caratteristiche clinico-strumentali di pazienti con mutazioni di Classe 4/5 del gene LMNA e pazienti con mutazioni del gene Desmoplachina (DSP) di Classe 4/5. Materiali e metodi 54 pazienti con varianti del gene LMNA sono stati analizzati in base al fenotipo (DCM, Cardiomiopatia Aritmogena del Ventricolo destro-ARVC, Cardiomiopatia con Ventricolo Sinistro Non Dilatato-NDLVC e pazienti che non rientrano nei criteri diagnostici). Indi sono stati suddivisi in 2 gruppi in base al genotipo: pazienti con varianti genetiche di Classe 4/5 e con varianti di Classe 3 (VUS), che sono stati confrontati dal punto di vista clinico-strumentale. Inoltre, i pazienti con mutazioni del gene LMNA di classe 4/5 sono stati confrontati con pazienti portatori di varianti del gene DSP di Classe 4/5. Risultati La popolazione oggetto di studio includeva 54 pazienti, di cui 38 (70.37%) con diagnosi di cardiomiopatia e 16 (29.63%) che non soddisfacevano i criteri diagnostici di cardiomiopatia. I primi sono stati ulteriormente suddivisi in 3 gruppi in base al fenotipo: 17 con DCM (44.74%), 17 con NDLVC (44.74%) e 4 con ARVC (10,52%). Dal confronto tra pazienti con varianti di Classe 4/5 e pazienti con VUS non sono emerse differenze significative di carattere clinico-strumentale, tuttavia gli outcome scompenso cardiaco (P+LP= 63%, VUS=0, p=0.004) e trapianto cardiaco (P+LP= 33%, VUS=0, p=0.002) sono risultati più frequenti nei pazienti con varianti di classe 4/5. Nella popolazione totale con variante LMNA sono risultati come predittori di outcome: la fibrillazione atriale (p=0.006), il volume telediastolico del ventricolo destro (p=0.016), la frazione d’eiezione sinistra (p=0.002) e destra (p=0.003). Al contrario, il blocco di branca sinistra ed il ritmo indotto da pacemaker hanno mostrato una tendenza verso la significatività statistica (p=0.06) e un elevato odds ratio (OR = 8.25). Dal confronto con pazienti con mutazione DSP, non sono emerse differenze significative tra i due gruppi riguardo l’outcome aritmico (p=0.25). I pazienti con mutazione LMNA presentavano maggiore incidenza di scompenso (p=0.01), con maggiore necessità di trapianto cardiaco (p<0.001) rispetto ai pazienti con mutazione DSP. Al contrario questi ultimi presentavano più fibrosi alla risonanza magnetica (RM) cardiaca (p<0.001). Conclusioni I pazienti con varianti del gene LMNA possono presentare diversa espressione fenotipica, con diagnosi di DCM, NDLVC e ARVC con diversa penetranza. I pazienti con VUS avevano caratteristiche sovrapponibili a quelli con mutazioni P o LP eccetto per gli outcome, che risultavano più significativi nel gruppo con mutazioni di classe 4/5. Sono risultati predittori di outcome: la fibrillazione atriale, il volume telediastolico destro, la frazione d’eiezione destra e sinistra. Infine, nel gruppo LMNA, l'incidenza di scompenso cardiaco e trapianto è risultata più alta rispetto al gruppo DSP, che invece mostrava una maggiore presenza di fibrosi alla RM cardiaca. Tuttavia, il grado di instabilità elettrica è risultato simile nei due gruppi.
Caratterizzazione clinica di pazienti portatori di varianti patogene del gene LMNA
PALESCANDOLO, ALBA
2023/2024
Abstract
Background: Cardiolaminopathies, heterogeneous and complex manifestations of LMNA gene mutations, are characterized by the frequent occurrence of dilated cardiomyopathy (DCM), atrioventricular conduction disorders, and both atrial and ventricular tachyarrhythmias, leading to a high risk of sudden cardiac death and heart failure. They exhibit high penetrance, early onset, rapid and progressive course, and poor prognosis. Many aspects remain unclear, particularly genotype-phenotype correlations. Objectives: The study aims to: 1) clinically and instrumentally characterize patients with LMNA gene mutations and compare patients with pathogenic or likely pathogenic variants (P/LP, Class 4 and 5) to patients with variants of uncertain significance (VUS, Class 3) of the LMNA gene; 2) identify predictors of outcomes in the cohort of patients with LMNA variant; 3) compare the clinical and instrumental characteristics of patients with Class 4 and 5 mutations of the LMNA gene to those with Class 4 and 5 mutations of the Desmoplakin (DSP) gene. Materials and Methods: 54 patients with LMNA gene variants were analyzed based on phenotype (DCM, Arrhythmogenic Right Ventricular Cardiomyopathy-ARVC, Non-Dilated Left Ventricular Cardiomyopathy-NDLVC, and patients not meeting diagnostic criteria). They were then divided into two groups based on genotype: patients with Class 4/5 genetic variants and those with Class 3 variants (VUS), who were compared clinically and instrumentally. Additionally, patients with Class 4/5 LMNA mutations were compared to those with Class 4/5 DSP gene variants. Results: The population under study included 54 patients, 38 (70.37%) diagnosed with cardiomyopathy and 16 (29.63%) not meeting the cardiomyopathy diagnostic criteria. The former were further divided into three groups based on phenotype: 17 with DCM (44.74%), 17 with NDLVC (44.74%), and 4 with ARVC (10.52%). No significant clinical-instrumental differences were found between patients with Class 4/5 variants and those with VUS; however, heart failure outcomes (P+LP= 63%, VUS=0, p=0.004) and cardiac transplantation (P+LP= 33%, VUS=0, p=0.002) were more frequent in patients with Class 4/5 variants. In the total population with LMNA variant, predictors of outcomes included atrial fibrillation (p=0.006), right ventricular end-diastolic volume (p=0.016), left (p=0.002), and right (p=0.003) ejection fraction. Conversely, left bundle branch block and pacemaker-induced rhythm showed a trend towards statistical significance (p=0.06) and a high odds ratio (OR = 8.25). No significant differences in arrhythmic outcomes (p=0.25) were found between patients with DSP mutations and those with LMNA mutations. Patients with LMNA mutation had a higher incidence of heart failure (p=0.01) and greater need for cardiac transplantation (p<0.001) compared to those with DSP mutation. However, the latter group exhibited more fibrosis on cardiac magnetic resonance imaging (MRI) (p<0.001). Conclusions: Patients with LMNA gene variants may present with different phenotypic expressions, diagnosed as DCM, NDLVC, and ARVC with varying penetrance. Patients with VUS had characteristics overlapping those with P or LP mutations except for outcomes, which were more significant in the group with Class 4/5 mutations. Predictors of outcomes included atrial fibrillation, right end-diastolic volume, and both right and left ejection fractions. Finally, in the LMNA group, the incidence of heart failure and transplantation was higher compared to the DSP group, which showed a greater presence of fibrosis on cardiac MRI. However, the degree of electrical instability was similar between the two groups.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/65845