RESUMEN
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation. METHODS: We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant. RESULTS: All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-ß1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice. CONCLUSIONS: Hyperactivation of the ATF4/TGF-ß1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-ß1 signaling may be a novel therapeutic target for managing ACM.
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Factor de Transcripción Activador 4 , Desmogleína 2 , Fibrosis , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Humanos , Ratones , Desmogleína 2/genética , Desmogleína 2/metabolismo , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Masculino , Femenino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Adulto , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/patología , Persona de Mediana Edad , LinajeRESUMEN
A wide variety of non-invasive and invasive techniques for SCD risk stratification in non ischemic cardiomyopathy (NICM) have been proposed, including left ventricular (LV) ejection fraction, QRS duration, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and invasive electrophysiologic study with or without three-dimensional electroanatomic mapping (3D-EAM), to identify and characterize the arrhythmogenic substrate. There is still no clear consensus on the risk stratification in this clinical setting. The aim of our study is to characterize the 3D-EAM substrate in patients with the same clinical presentation of unexplained complex VAs and NICM using CMR, three-dimensional electranatomic mapping (3D-EAM) in association with endomyocardial biopsy (EMB) and genetic screening, as a more precise and early diagnostic assessment may provide important subsequent prognostic impact. The study was designed as a prospective multi-center observational evaluation and the patient follow-up was scheduled at 6 months interval. We enrolled 125 patients distinct into four different group by complete diagnostic work-up: myocarditis, non-dilated left ventricular cardiomyopathy, arrhythmogenic cardiomyopathy and control group. The four groups were compared in terms of clinical, imaging and 3D-EAM data. At multivariate analysis sustained VT/VF on admission [HR: 3.64 (1.79-7.4), p < 0.001], total bipolar scar area of left and right ventricle detected by 3D-EAM [HR: 2.24 (1.13-4.49), p = 0.02], histological diagnosis of myocarditis by 3D-EAM guided endomyocardial biopsy (EBM) [HR: 2.79 (1.04-7.44), p = 0.01] were independent predictors of complex VAs or death at follow-up. 3D-EAM guided EMB represent not only a valid diagnostic tool to identify the arrhythmogenic substrate in patients with NICM and ventricular arrhythmic phenotype but also an important predictor of complex Vas at long term follow-up.
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Miocarditis , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Pronóstico , Miocarditis/patología , Miocarditis/diagnóstico por imagen , Miocarditis/diagnóstico , Estudios de Seguimiento , Miocardio/patología , Imagen por Resonancia Cinemagnética/métodos , Biopsia/métodos , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/patología , Cardiomiopatías/diagnóstico , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagenRESUMEN
Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac disorder characterized by the gradual replacement of cardiomyocytes with fibrous and adipose tissue, leading to ventricular wall thinning, chamber dilation, arrhythmias, and sudden cardiac death. Despite advances in treatment, disease management remains challenging. Animal models, particularly mice and zebrafish, have become invaluable tools for understanding AC's pathophysiology and testing potential therapies. Mice models, although useful for scientific research, cannot fully replicate the complexity of the human AC. However, they have provided valuable insights into gene involvement, signalling pathways, and disease progression. Zebrafish offer a promising alternative to mammalian models, despite the phylogenetic distance, due to their economic and genetic advantages. By combining animal models with in vitro studies, researchers can comprehensively understand AC, paving the way for more effective treatments and interventions for patients and improving their quality of life and prognosis.
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Modelos Animales de Enfermedad , Animales , Humanos , Pez Cebra , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/genética , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Ratones , Cardiomiopatías/patología , Cardiomiopatías/genéticaRESUMEN
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis. METHODS: The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives. RESULTS: WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD. CONCLUSION: The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.
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Muerte Súbita Cardíaca , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Linaje , Fenotipo , Humanos , Masculino , Muerte Súbita Cardíaca/etiología , Femenino , Irán , gamma Catenina/genética , Adulto , Mutación , Herencia , Desmoplaquinas/genética , Persona de Mediana Edad , Análisis Mutacional de ADN , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Factores de Riesgo , FilaminasRESUMEN
BACKGROUND: Electrocardiographic abnormalities are common in arrhythmogenic right ventricular cardiomyopathy and are included in the 2010 Task Force Criteria. Their time course, however, remains uncertain. In this retrospective observational study, we aimed to assess the long-term evolution of electrocardiographic characteristics and their relation to ventricular arrhythmias. METHODS AND RESULTS: Three hundred fifty-three patients with arrhythmogenic right ventricular cardiomyopathy as per the 2010 Task Force Criteria with 6871 automatically processed 12-lead digital ECGs were included. The relationship between the electrocardiographic parameters and the risk of ventricular arrhythmias was assessed at 10 years from the first ECG. Electrocardiographic parameters were compared between the first contact ECG, the ECG at diagnosis, and the most recent ECG. Median time between the first and the latest ECG was 6 [interquartile range, 1-14] years. Reductions of QRS voltage, R- and T-wave amplitudes between the first, diagnostic, and the latest ECGs were observed across precordial and extremity leads. Mean QRS duration increased from 96 to 102 ms (P<0.001), terminal activation duration (V1) from 47 to 52 ms (P<0.001), and QTc from 419 to 432 ms (P<0.001). T-wave inversions in leads V3 to V6 and aVF at first ECG were associated with ventricular arrhythmias (adjusted hazard ratio [HRadj][V3], 2.03 [95% CI, 1.23-3.34] and HRadj[aVF], 1.87 [95% CI, 1.13-3.08]). CONCLUSIONS: Depolarization and repolarization parameters evolved over time in patients with arrhythmogenic right ventricular cardiomyopathy, supporting the progressive nature of arrhythmogenic right ventricular cardiomyopathy. Electrocardiographic abnormalities may be detected before diagnosis and might, although not fulfilling the 2010 Task Force Criteria, be markers of early disease. T-wave inversion in leads V3 or aVF before diagnosis was associated with ventricular arrhythmias during follow-up.
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Displasia Ventricular Derecha Arritmogénica , Electrocardiografía , Humanos , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/complicaciones , Masculino , Estudios Retrospectivos , Femenino , Adulto , Persona de Mediana Edad , Factores de Tiempo , Factores de Riesgo , Progresión de la Enfermedad , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/etiología , Potenciales de Acción , Valor Predictivo de las PruebasRESUMEN
Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene and in the DSC2-gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion.
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Displasia Ventricular Derecha Arritmogénica , Cadherinas , Desmocolinas , Desmogleína 2 , Desmosomas , Unión Proteica , Desmosomas/metabolismo , Humanos , Cinética , Desmogleína 2/metabolismo , Desmogleína 2/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Desmocolinas/metabolismo , Desmocolinas/genética , Cadherinas/metabolismo , Cadherinas/genética , Mutación , Microscopía de Fuerza Atómica , TermodinámicaAsunto(s)
Displasia Ventricular Derecha Arritmogénica , Mitocondrias Cardíacas , Humanos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Animales , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaAsunto(s)
Displasia Ventricular Derecha Arritmogénica , Ablación por Catéter , Humanos , Displasia Ventricular Derecha Arritmogénica/cirugía , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Ablación por Catéter/métodos , Endocardio/cirugía , Endocardio/fisiopatología , Masculino , Electrocardiografía , Persona de Mediana Edad , Femenino , AdultoRESUMEN
OBJECTIVES: Arrhythmogenic cardiomyopathy (ACM) is a complex cardiac disorder associated with ventricular arrhythmias. Understanding the relationship between mechanical uncoupling and cardiac structural changes in ACM patients is crucial for improved risk stratification and management. METHODS: In this study, we enrolled 25 ACM patients (median age 34 years, 72% men) based on the 2019 Modified Task Force and Padua criteria. Patients were categorized by the presence or absence of clinically relevant ventricular tachycardia (crVT), necessitating emergency interventions. Right ventricular-arterial coupling (VAC) was assessed using echocardiography. Low-rank regression splines were employed to model left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) in relation to VAC. RESULTS: Positive associations were observed between VAC and LVEF (ρ = 0.472, p = 0.023), RVEF (ρ = 0.522, p = 0.038), and right ventricular (RV) indexed stroke volume (ρ = 0.79, p < 0.001). Patients with crVT exhibited correlations with RV shortening, reduced RVEF (39.6 vs. 32.2%, p = 0.025), increased left ventricular (LV) mass (38.99 vs. 45.55, p = 0.045), and LV end-diastolic volume (LVEDV) (56.99 vs. 68.15 mL/m2, p = 0.045). Positive associations for VAC were noted with LVEDV (p = 0.039) and LV mass (p = 0.039), while negative correlations were observed with RVEF by CMR (p = 0.023) and RV shortening by echocardiography (p = 0.026). CONCLUSIONS: Our findings underscore the significance of right VAC in ACM, demonstrating correlations with RV and LVEF, RV stroke volume, and clinically relevant arrhythmias. Insights into RVEF, LV mass, and end-diastolic volume provide valuable contributions to the understanding of ACM pathophysiology and may inform risk assessment strategies.
OBJETIVOS: La miocardiopatía arritmogénica (MCA) es un trastorno cardíaco complejo asociado con arritmias ventriculares (AV). Comprender la relación entre el desacoplamiento mecánico y los cambios estructurales cardíacos en pacientes con MCA es crucial para una estratificación de riesgos y una gestión mejorada. MÉTODOS: En este estudio, reclutamos a 25 pacientes con MCA (edad media 34 años, 72% hombres) basándonos en los criterios del Task Force 2019 y los criterios de Padua. Los pacientes se clasificaron según la presencia o ausencia de taquicardia ventricular clínicamente relevante (crVT), que requería intervenciones de emergencia. Se evaluó el acoplamiento ventricular derecho-arterial (VAC) mediante ecocardiografía. Se utilizaron low-rank regression splines para modelar la fracción de eyección del ventrículo izquierdo (FEVI) y la fracción de eyección del ventrículo derecho (FEVD) en relación con el VAC. RESULTADOS: Se observaron asociaciones positivas entre el VAC y la FEVI (ρ = 0.472, p = 0.023), la FEVD (ρ = 0.522, p = 0.038) y el volumen de eyección indexado del ventrículo derecho (ρ = 0.79, p < 0.001). Los pacientes con crVT mostraron correlaciones con acortamiento del ventrículo derecho, disminución de la FEVD (39.6 vs. 32.2%, p = 0.025), aumento de la masa ventricular izquierda (38.99 vs. 45.55, p = 0.045) y volumen diastólico final del ventrículo izquierdo (VDVI) (56.99 vs. 68.15 mL/m2, p = 0.045). Se observaron asociaciones positivas para el VAC con el VDVI (p = 0.039) y la masa ventricular izquierda (p = 0.039), mientras que se observaron correlaciones negativas con la FEVD por RMC (p = 0.023) y el acortamiento del ventrículo derecho por ecocardiografía (p = 0.026). CONCLUSIONES: Nuestros hallazgos subrayan la importancia del VAC derecho en la MCA, demostrando correlaciones con la FEVD y FEVI, el volumen de eyección del ventrículo derecho y arritmias clínicamente relevantes. Las percepciones sobre la FEVD, la masa ventricular izquierda y el volumen diastólico final proporcionan contribuciones valiosas para comprender la fisiopatología de la MCA y pueden informar estrategias de evaluación de riesgos.
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Displasia Ventricular Derecha Arritmogénica , Volumen Sistólico , Humanos , Masculino , Femenino , Adulto , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Volumen Sistólico/fisiología , Persona de Mediana Edad , Ecocardiografía/métodos , Imagen por Resonancia Magnética/métodos , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/diagnóstico por imagen , Taquicardia Ventricular/etiología , Prueba de Estudio Conceptual , Adulto Joven , Función Ventricular Derecha/fisiología , Función Ventricular Izquierda/fisiologíaRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.
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Dieta Alta en Grasa , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Modelos Animales de Enfermedad , Miocardio/patología , Miocardio/metabolismo , Fibrosis , Masculino , Remodelación Ventricular , Desmogleína 2/genética , Miocarditis/etiología , Miocarditis/fisiopatología , Ratones Endogámicos C57BL , Displasia Ventricular Derecha Arritmogénica/etiología , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Adiponectina/sangre , Inflamación , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatologíaAsunto(s)
Modelos Animales de Enfermedad , Macrófagos , FN-kappa B , Receptores CCR2 , Transducción de Señal , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/patología , Receptores CCR2/metabolismo , Receptores CCR2/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Miocardio/metabolismo , Miocardio/patología , Humanos , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/patología , Ratones NoqueadosRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.
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Displasia Ventricular Derecha Arritmogénica , Células Madre Pluripotentes Inducidas , Proteínas de la Membrana , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Displasia Ventricular Derecha Arritmogénica/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Línea Celular , Adulto , Sitios de Empalme de ARN/genética , Diferenciación CelularRESUMEN
Purpose To demonstrate the myocardial strain characteristics of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), based on revised Task Force Criteria (rTFC), and to explore the prognostic value of strain analysis in ARVC. Materials and Methods This retrospective study included 247 patients (median age, 38 years [IQR, 28-48 years]; 167 male, 80 female) diagnosed with ARVC, based on rTFC, between 2014 and 2018. Patients were divided into "possible" (n =25), "borderline" (n = 40), and "definite" (n = 182) ARVC groups following rTFC. Biventricular global strain parameters were calculated using cardiac MRI feature tracking (FT). The primary outcome was defined as a composite of cardiovascular events, including cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator discharge. Univariable and multivariable cumulative logistic regression and Cox proportional hazards regression analysis were used to evaluate the diagnostic and prognostic value of right ventricle (RV) strain parameters. Results Patients with definite ARVC had significantly reduced RV global strain in all three directions compared with possible or borderline groups (all P < .001). RV global longitudinal strain (GLS) was an independent predictor for disease (odds ratio, 1.09 [95% CI: 1.02, 1.16]; P = .009). During a median follow-up of 3.4 years (IQR, 2.0-4.9 years), 55 patients developed primary end point events. Multivariable analysis showed that RV GLS was independently associated with the occurrence of cardiovascular events (hazard ratio, 1.15 [95% CI: 1.07, 1.24]; P < .001). Kaplan-Meier analysis showed that patients with RV GLS worse than median had a higher risk of combined cardiovascular events (log-rank P < .001). Conclusion RV GLS derived from cardiac MRI FT demonstrated good diagnostic and prognostic value in ARVC. Keywords: MR Imaging, Image Postprocessing, Cardiac, Right Ventricle, Cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy, Revised Task Force Criteria, Cardiovascular MR, Feature Tracking, Cardiovascular Events Supplemental material is available for this article. © RSNA, 2024.
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Displasia Ventricular Derecha Arritmogénica , Ventrículos Cardíacos , Humanos , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Pronóstico , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/patología , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Magnética , Función Ventricular Derecha/fisiologíaRESUMEN
Special Operations Servicemembers presenting with palpitations, pre-syncope, or exertional syncope during rigorous physical training are often experiencing a benign condition; however, life-threatening etiologies should be considered. We describe a 43-year-old Special Operator who presented to his medics during selection physical assessment testing with palpitations and lightheadedness, with a subsequent workup revealing arrhythmogenic right ventricular cardiomyopathy (ARVC). His initial electrocardiogram was unremarkable without characteristic ARVC changes. Outpatient evaluation with ambulatory cardiac monitoring recorded numerous episodes of non-sustained ventricular tachycardia. Transthoracic echocardiography demonstrated findings concerning for ARVC, with subsequent cardiac MRI confirming the diagnosis via the 2020 Padua criteria. Management includes activity modification, class III anti-arrhythmic medications, and possible placement of an implantable cardioverter defibrillator to prevent sudden cardiac death. This case demonstrates the importance of maintaining high clinical suspicion for rare diagnoses that present with exertional palpitations, such as arrhythmogenic right ventricular cardiomyopathy, in even our fittest Special Operators.
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Displasia Ventricular Derecha Arritmogénica , Electrocardiografía , Personal Militar , Humanos , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/terapia , Displasia Ventricular Derecha Arritmogénica/complicaciones , Adulto , Masculino , Ecocardiografía , Antiarrítmicos/uso terapéutico , Imagen por Resonancia Magnética , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia , Taquicardia Ventricular/etiología , Desfibriladores ImplantablesRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/ß-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.
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Displasia Ventricular Derecha Arritmogénica , Modelos Animales de Enfermedad , Animales , Humanos , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/patología , Placofilinas/genética , Placofilinas/metabolismo , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Vía de Señalización Wnt/genética , Desmogleína 2/genética , Desmogleína 2/metabolismo , Desmosomas/metabolismo , Desmosomas/genética , RatonesRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica , Humanos , Displasia Ventricular Derecha Arritmogénica/genética , Femenino , Masculino , Adulto , Persona de Mediana Edad , Proteínas de la Membrana/genética , Cadherinas/genética , Desmosomas/genética , Desmosomas/metabolismo , Predisposición Genética a la Enfermedad , Variación Genética , Filaminas/genética , Estudios Retrospectivos , Italia , Proteínas de Unión al Calcio/genética , Antígenos CD/genéticaRESUMEN
BACKGROUND: Epicardial approach in ventricular tachycardia (VT) ablation is still regarded as a second-step strategy, due to the risk of complications. We evaluated the frequency that epicardial ablation targets were identified and ablation performed following pericardial access compared with unnecessary pericardial access for different VT causes and potential markers of epicardial VT. METHODS: All VT ablation procedures including epicardial approach over a 10-year period were included. First-line epicardial approach was indicated in arrhythmogenic right ventricular cardiomyopathy (ARVC) and postmyocarditis VT; in patients with idiopathic dilated cardiomyopathy (IDCM) and postmyocardial infarction, indications resulted from available imaging techniques or 12-lead VT morphology. The epicardial approach was considered useful if epicardial ablation was performed after epicardial mapping. Feasibility, complications, and long-term outcome were reported. RESULTS: Four hundred and eighty-eight subjects with a median age of 60 years (interquartile range, 47-65) and of left ventricle ejection fraction 41% (interquartile range, 30-55) underwent 626 epicardial VT ablations. Percutaneous access had a success rate of 92.2% and a complication rate of 3.6%. Overall, epicardial approach was, respectively, indicated to 11.8% of postmyocardial infarction patients, 49.5% in IDCM, 94% in myocarditis, and 90.7% in ARVC. Epicardial ablation at the first ablation attempt was performed in 9.3% of postmyocardial infarction patients, 28.8% in IDCM, 86.5% in myocarditis, and 81.3% in patients with ARVC. In first-line epicardial group, ARVC and myocarditis showed the highest odds for epicardial ablation (OR, 4.057 [95% CI, 1.299-8.937]; P=0.007; OR, 3.971 [95% CI, 1.376-11.465]; P=0.005, respectively). IDCM independently predicted unnecessary epicardial approach (OR, 2.7 [95% CI, 1.7-4.3]; P<0.001). After a follow-up of 41 months (interquartile range, 19-64), patients with IDCM experienced higher rate of recurrences and mortality compared with other causes. CONCLUSIONS: Epicardial approach is integral part of ablation armamentarium regardless of the VT cause, with high feasibility and low complication rate in experienced centers. Our data support its use at first ablation attempt in VTs related to ARVC and myocarditis.