Incidence and predictors of sudden death in patients with cardiac amyloidosis.

INTRODUCTION: Although sudden death (SD) is a recognized complication of cardiac amyloidosis, there is scarce data about its incidence, mechanisms, and predictors. The aim of this study was to describe incidence of SD and to analyze possible risk factors. METHODS: Consecutive patients with ATTR or AL cardiac amyloidosis evaluated at two European centers were identified. SD was defined as unexpected death in clinically stable patients. Cox proportional hazard regression was performed to assess risk factors in univariate analysis. Those statistically significant were then assessed through age-adjusted multivariate analysis. RESULTS: Analysis included 784 patients, 569 with ATTR amyloidosis (mean age 74.1 ± 12.1 years) and 215 with AL amyloidosis (mean age 64.5 ± 10.8 years). After a median follow-up of 1.9 years, SD rate at 2 years was 1.8% in ATTR. Previous pacemaker implantation (PPM) was associated with increased risk after age-adjusted analysis (HR 4.97; 95%CI: 1.39-17.7; p = 0.01). SD rate in AL amyloidosis patients at 2 years was 8.0% after a median follow-up of 1.2 years. Betablockers and NYHA III-IV were independently associated with an increased risk after age-adjusted multivariate analysis (HR 7.06 95%CI (2.31-21.5) p = 0.001) and (HR 4.56 95%CI (1.51-13.8) p = 0.007) respectively. CONCLUSIONS: SD is more frequent in AL than in ATTR cardiac amyloidosis. SD is associated with different risk factors in both entities.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium.

INTRODUCTION AND OBJECTIVES: Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. METHODS: We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. RESULTS: Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. CONCLUSIONS: FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling.

Las mutaciones missense en el dominio ROD2 de la filamina C muestran un fenotipo con miocardiopatía restrictiva/hipertrófica y miocardio en dientes de sierra / ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive/hypertrophic cardiomyopathy and saw-tooth myocardium

Introducción y objetivos Recientemente se han descrito mutaciones missense en la filamina C (FLNC) como causa de miocardiopatía. Los conocimientos sobre la patogenicidad y la correlación genotipo-fenotipo son escasos. Nuestro objetivo es describir un fenotipo cardiaco distintivo relacionado con mutaciones missense en el dominio ROD2 de FLNC (FLNC-mRod2). Métodos Incluimos 21 familias independientes con fenotipo de miocardiopatía hipertrófica (MCH)/miocardiopatía restrictiva (MCR) portadoras de variantes missense en FLNC-mRod2. Se estudió clínicamente a los portadores, además de hacer un cribado en cascada. Se analizó histológicamente el tejido miocárdico de tres corazones explantados y se comparó con un corazón portador de un truncamiento de FLNC y con un control sano. Se transfectaron plásmidos con mutaciones missense de FLNC y se analizaron mediante microscopía confocal. Resultados En 11 familias (52%) con 20 individuos evaluados (37 [23,7-52,7] años), 15 casos presentaron un fenotipo cardiaco consistente en una superposición de MCH-MCR e hipertrabeculación ventricular izquierda (apariencia de dientes de sierra). Durante una mediana de seguimiento de 6,49 años presentaron principalmente insuficiencia cardiaca avanzada (16 (80%) disfunción diastólica, 3 trasplantes cardiacos, 3 muertes por insuficiencia cardiaca) en ausencia de alteraciones de la conducción cardiaca o miopatía esquelética. Un total de 6 familias presentaban segregación genotipo-fenotipo leve, y las restantes eran mutaciones de novo. Se observó una remodelación de la matriz extracelular y distribución de la FLNC diferencial en los cardiomiocitos. Las células HT1080 y H9c2 no revelaron agregados citoplasmáticos de FLNC. Conclusiones Las variantes en FLNC-mRod2 exhiben una alta prevalencia de fenotipo solapado de MCR, MCH e hipertrabeculación en dientes de sierra, con una remodelación histopatológica cardiaca distintiva (AU)

Introduction and objectives Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. Methods We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. Results Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. Conclusions FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling (AU)