Background: Mutations in four desmosomal genes (PKP2, DSC2, DSG2, and DSP) are the primary cause of arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited disease characterized by fibrofatty replacement of the myocardium and an increased risk of life-threatening arrhythmic events that may provoke sudden cardiac death in young and otherwise healthy individuals. Recent insights showed that desmosomal mutations may be associated with a potentially overlapping spectrum of cardiomyopathies ranging from Dilated Cardiomyopathy (DCM) and the newly-defined Non-Dilated Left Ventricular Cardiomyopathy (NDLVC). Purpose: This study aims to elucidate the clinical impact, to establish genotype-specific signatures linked to arrhythmic outcomes and to assess the prognostic implications of the aforementioned desmosomal mutations in a large single center cohort. Methods: The study cohort included patients referred to our cardiomyopathy clinic who tested positive for mutations in the desmosomal genes PKP2, DSP, DSG2, and DSC2. Clinical data collected since the first visit were prospectively filed in our registry and included demographic information, personal and family medical history, arrhythmic events, electrocardiographic features, and therapies. Phenotypes of ARVC, DCM, and NDLVC were re-evaluated according to the 2023 ESC Guidelines for the Management of Patients with Cardiomyopathies. The primary endpoint was the occurrence of a life-threatening arrhythmic event (LAE: composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia). Follow-up for each patient was calculated from the age of diagnosis to the age at the occurrence of first LAE, death from non-arrhythmic cause, or age at last visit, whichever occurred first. Results: We enrolled 584 patients (57% males, median age 40 years, interquartile range [IQR] 22-55 years), who were followed-up for a median of 5 years (IQR 1-9 years). At odds with previously reported data, PKP2 (223/584, 38%) and DSP (181/584, 31%) mutations were similarly prevalent and accounted for majority of cases, followed by rarer mutations on DSG2 (105/584, 18%), and DSC2 (36/584, 6%). A small minority of patients (7%), with a notably more severe clinical phenotype, were found to be carriers of more than one desmosomal variant (double-mutation carriers). Our data show differential phenotypic signatures, depending on the genotype: PKP2 carriers were more likely to present with the classical right-dominant ARVC, while DSP carriers were more likely to show predominant left ventricular involvement. Importantly, the incidence of family history of sudden death was significantly higher in DSP carriers. Conclusions: Here, we showed that the presence of distinct, genotype-specific clinical presentations, phenotypic signatures and outcomes in carriers of desmosomal gene variants. Our study provides critical insights for the management of patients with cardiomyopathies linked to desmosomal gene mutations.
Background: Le mutazioni in quattro geni desmosomiali (PKP2, DSC2, DSG2 e DSP) sono la causa principale della cardiomiopatia aritmogena del ventricolo destro (ARVC), una malattia ereditaria caratterizzata da sostituzione fibroadiposa del miocardio e un aumento del rischio di eventi aritmici potenzialmente letali che possono provocare morte cardiaca improvvisa in giovani individui altrimenti sani. Recenti studi hanno dimostrato che le mutazioni desmosomiali possono essere associate a uno spettro potenzialmente sovrapposto di cardiomiopatie che vanno dalla cardiomiopatia dilatativa (DCM) alla cardiomiopatia ventricolare sinistra non dilatativa (NDLVC) recententemente introdotta. Scopo: Questo studio mira a chiarire l'impatto clinico, a stabilire manifestazioni genotipo-specifiche legate agli esiti aritmici e a valutare le implicazioni prognostiche delle suddette mutazioni desmosomiali in un'ampia coorte monocentrica. Metodi: La coorte di studio comprendeva pazienti riferiti alla nostra clinica per cardiomiopatie risultati positivi per mutazioni nei geni desmosomiali PKP2, DSP, DSG2 e DSC2. I dati clinici raccolti dalla prima visita sono stati registrati prospetticamente nel nostro registro e includevano informazioni demografiche, storia medica personale e familiare, eventi aritmici, caratteristiche elettrocardiografiche e terapie. I fenotipi di ARVC, DCM e NDLVC sono stati rivalutati secondo le Linee Guida ESC 2023 per la gestione dei pazienti con cardiomiopatie. L'endpoint primario era l'occorrenza di un evento aritmico potenzialmente letale (LAE: composito di morte cardiaca improvvisa, arresto cardiaco abortito o tachicardia ventricolare emodinamicamente non tollerata). Il follow-up per ciascun paziente è stato calcolato dall'età della diagnosi all'età dell'occorrenza del primo LAE, morte per causa non aritmica, o età dell'ultima visita, a seconda di quale evento si verificasse per primo. Risultati: Abbiamo arruolato 584 pazienti (57% maschi, età mediana 40 anni, intervallo interquartile [IQR] 22-55 anni), seguiti per un periodo mediano di 5 anni (IQR 1-9 anni). Contrariamente a dati precedentemente riportati, le mutazioni PKP2 (223/584, 38%) e DSP (181/584, 31%) erano similmente prevalenti e rappresentavano la maggior parte dei casi, seguite da mutazioni più rare su DSG2 (105/584, 18%) e DSC2 (36/584, 6%). Una piccola minoranza di pazienti (7%), con un fenotipo clinico notevolmente più severo, risultava portatrice di più di una variante desmosomiale (portatori di doppia mutazione). I nostri dati mostrano manifestazioni fenotipiche differenti a seconda del genotipo: i portatori di PKP2 erano più propensi a presentare la classica ARVC a dominanza destra, mentre i portatori di DSP mostravano una prevalente coinvolgimento del ventricolo sinistro. È importante notare che l'incidenza di storia familiare di morte improvvisa era significativamente più alta nei portatori di DSP. Conclusioni: Con il nostro studio abbiamo dimostrato la presenza di presentazioni cliniche, manifestazioni fenotipiche e esiti distinti e specifici per genotipo nei portatori di varianti dei geni desmosomiali. Il nostro studio fornisce intuizioni critiche per la gestione dei pazienti con cardiomiopatie legate a mutazioni dei geni desmosomiali.
Correlazioni Genotipo - Fenotipo in Portatori di Mutazioni sui Geni Desmosomiali
SUGAMIELE, ANDREA
2023/2024
Abstract
Background: Mutations in four desmosomal genes (PKP2, DSC2, DSG2, and DSP) are the primary cause of arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited disease characterized by fibrofatty replacement of the myocardium and an increased risk of life-threatening arrhythmic events that may provoke sudden cardiac death in young and otherwise healthy individuals. Recent insights showed that desmosomal mutations may be associated with a potentially overlapping spectrum of cardiomyopathies ranging from Dilated Cardiomyopathy (DCM) and the newly-defined Non-Dilated Left Ventricular Cardiomyopathy (NDLVC). Purpose: This study aims to elucidate the clinical impact, to establish genotype-specific signatures linked to arrhythmic outcomes and to assess the prognostic implications of the aforementioned desmosomal mutations in a large single center cohort. Methods: The study cohort included patients referred to our cardiomyopathy clinic who tested positive for mutations in the desmosomal genes PKP2, DSP, DSG2, and DSC2. Clinical data collected since the first visit were prospectively filed in our registry and included demographic information, personal and family medical history, arrhythmic events, electrocardiographic features, and therapies. Phenotypes of ARVC, DCM, and NDLVC were re-evaluated according to the 2023 ESC Guidelines for the Management of Patients with Cardiomyopathies. The primary endpoint was the occurrence of a life-threatening arrhythmic event (LAE: composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia). Follow-up for each patient was calculated from the age of diagnosis to the age at the occurrence of first LAE, death from non-arrhythmic cause, or age at last visit, whichever occurred first. Results: We enrolled 584 patients (57% males, median age 40 years, interquartile range [IQR] 22-55 years), who were followed-up for a median of 5 years (IQR 1-9 years). At odds with previously reported data, PKP2 (223/584, 38%) and DSP (181/584, 31%) mutations were similarly prevalent and accounted for majority of cases, followed by rarer mutations on DSG2 (105/584, 18%), and DSC2 (36/584, 6%). A small minority of patients (7%), with a notably more severe clinical phenotype, were found to be carriers of more than one desmosomal variant (double-mutation carriers). Our data show differential phenotypic signatures, depending on the genotype: PKP2 carriers were more likely to present with the classical right-dominant ARVC, while DSP carriers were more likely to show predominant left ventricular involvement. Importantly, the incidence of family history of sudden death was significantly higher in DSP carriers. Conclusions: Here, we showed that the presence of distinct, genotype-specific clinical presentations, phenotypic signatures and outcomes in carriers of desmosomal gene variants. Our study provides critical insights for the management of patients with cardiomyopathies linked to desmosomal gene mutations.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/17535