Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype.

AIMS: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. METHODS AND RESULTS: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. CONCLUSION: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.

Increased Risk of Heart Failure in Elderly Patients Treated with Beta-Blockers After AV Node Ablation.

INTRODUCTION: Controversy exists regarding the indication of beta-blockers (BB) in different scenarios in patients with cardiovascular disease. We sought to evaluate the effect of BB on survival and heart failure (HF) hospitalizations in a sample of pacemaker-dependent patients after AV node ablation to control ventricular rate for atrial tachyarrhythmias. METHODS: A retrospective study including consecutive patients that underwent AV node ablation was conducted in a single center between 2011 and 2019. The study's primary endpoints were the incidence of all-cause mortality, first HF hospitalization and the cumulative incidence of subsequent hospitalizations for HF. Competing risk analyses were employed. RESULTS: A total of 111 patients with a mean age of 73.9 years were included in the study. After a median follow-up of 45.5 months, 43 patients had died (38.7%) and 31 had been hospitalized for HF (27.9%). The recurrent HF hospitalization rate was 74/1000 patients/year. Patients treated with BB had a non-significant trend to higher mortality rates and a higher risk of recurrent HF hospitalizations (incidence rate ratio 2.23, 95% confidence interval 1.12-4.44; p = 0.023). CONCLUSION: After an AV node ablation, the use of BB is associated with an increased risk of HF hospitalizations in a cohort of elderly patients.

Electrocardiographic Screening of Arrhythmogenic Cardiomyopathy in Genotype-Positive and Phenotype-Negative Relatives.

Background: Arrhythmogenic cardiomyopathy is a hereditary cause of ventricular arrhythmias and sudden death. Identifying the healthy genetic carriers who will develop the disease remains a challenge. A novel approach to the analysis of the digital electrocardiograms of mutation carriers through signal processing may identify early electrocardiographic abnormalities. Methods: A retrospective case-control study included a population of healthy genetics carriers and their wild-type relatives. Genotype-positive/phenotype-negative individuals bore mutations associated with the development of arrhythmogenic cardiomyopathy. The relatives included had a non-pathological 12-lead electrocardiogram, echocardiogram, and a cardiac magnetic resonance. Automatic digital electrocardiographic analyses comprised QRS and terminal activation delay duration, the number of QRS fragmentations, ST slope, and T-wave voltage. Results: Digital 12-lead electrocardiograms from 41 genotype-positive/ phenotype-negative (29 simple carriers and 12 double mutation carriers) and 73 wild-type relatives were analyzed. No differences in the QRS length, the number of QRS fragmentations, and the voltage of the T-wave were observed. After adjusting for potential confounders, double carriers showed an average ST-slope flatter than those of the simple carriers and wild type [5.18° (0.73-8.01), 7.15° (5.14-11.05), and 11.46° (3.94-17.49), respectively, p = 0.005]. There was a significant negative correlation between the ST slope and the age in genotype-positive/phenotype-negative relatives (r = 0.376, p = 0.021) not observed in their wild-type counterparts (r = 0.074, p = 0.570). Conclusions: A flattened ST segment may be an early sign of electrical remodeling that precedes T-wave inversion in healthy genetic carriers. A thorough analysis of the digital electrocardiographic signal may help identify and measure early electrical abnormalities.

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers.

INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. METHODS: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. RESULTS: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. CONCLUSIONS: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations.

Global longitudinal strain is associated with heart failure outcomes in hypertrophic cardiomyopathy.

OBJECTIVE: We hypothesised that abnormal global longitudinal strain (GLS) would predict outcome in hypertrophic cardiomyopathy (HCM) better than current echocardiographic measures. METHODS: Retrospective analysis of risk markers in relation to outcomes in 472 patients with HCM at a single tertiary institution (2006-2012). Exclusion criteria were left ventricular (LV) hypertrophy of other origin, patients in atrial fibrillation, lost to follow-up and insufficient image quality to perform strain analysis. Standardised echocardiogram recordings were reviewed and standard variables and LV GLS were measured. The primary end-point included all cardiac deaths, appropriate defibrillator shocks and heart failure (HF) admissions. The secondary end-point was death by HF and admissions related to HF. RESULTS: Mean age was 50.0±15.0 years; 322 (68%) were men. At a median of 4.3 years (IQR 0.1-7.8) follow-up, 21 (4.4%) patients experienced cardiovascular death: 6 (1.3%) died from HF, 13 (2.7%) had sudden cardiac death and 2 (0.4%) died secondary to stroke. Four (0.8%) patients experienced appropriate defibrillator shock, and 13 (2.7%) were admitted for HF. On multivariate Fine-Gray proportional hazard analyses, GLS was significantly associated with the primary end-point (HR=0.90, 95% CI 0.83 to 0.98, p=0.018) independently of age, maximal provoked LV outflow-tract gradient and LV end-systolic volume. Moreover, GLS was particularly associated with the secondary end-point (HR=0.82, 95% CI 0.75 to 0.90, p<0.0001) independently of age, previous atrial fibrillation, New York Heart Association (NYHA) class III-IV, LV end-systolic volume, E/E', and outflow-tract gradient. Survival curves confirmed that GLS was associated with HF events (GLS <15.6%, p=0.0035). CONCLUSIONS: In patients with HCM, reduced GLS is an independent factor associated with poor cardiac outcomes, and particularly HF outcomes.

Genetics of myocarditis in arrhythmogenic right ventricular dysplasia.

BACKGROUND: Myocarditis occasionally is related to arrhythmogenic right ventricular dysplasia (ARVD) and sometimes overlaps during the early stages, which may lead to misdiagnosis. Acute myocarditis may reflect an active phase of ARVD. OBJECTIVE: The purpose of this study was to evaluate the genetic basis of myocarditis in ARVD and to investigate the association with a poorer prognosis and a higher risk of ventricular arrhythmias. METHODS: Two groups were analyzed: group A, which consisted of 131 affected patients-84 with ARVD (62% male, age 45 years [range 33-55 years]) and 47 with left-sided forms (arrhythmogenic left ventricular dysplasia [ALVD]) (47% male, age 45 years [range 25-61 years]); and group B, which consisted of 64 nonaffected mutation-carrying relatives (36% male, age 42 years [range 22-56 years]; 23 from classic ARVD families and 41 from ALVD families). RESULTS: Seven patients (3.5%) presented with a clinical diagnosis of acute myocarditis over median follow-up of 34 months. Myocarditis was the first clinical presentation in 6 of 7 cases. In 2 patients, acute myocarditis preceded worsening of left ventricular systolic function. In 1 case, myocarditis was associated with an increased gadolinium pattern in cardiac magnetic resonance. Two patients presented with ECG changes weeks after myocarditis resolution. Myocarditis preceded the development of ventricular tachycardia in 2 other patients. Myocarditis clustered in families bearing DSP Q447* and LDB3 c.1051A>G. CONCLUSION: Acute myocarditis reflects an active phase of ARVD that leads to changes in phenotype and abrupt progression of the disease. An active phase should be suspected in a patient with myocarditis associated with a family history of ARVD. Certain mutations may increase the susceptibility to superimposed myocarditis in ARVD.

Factores que influyen en la expresión fenotípica de la miocardiopatía hipertrófica en portadores genéticos / Factors influencing the phenotypic expression of hypertrophic cardiomyopathy in genetic carriers

Introducción y objetivos: La miocardiopatía hipertrófica (MCH) es una enfermedad con expresión variable, causada principalmente por mutaciones en genes sarcoméricos, aunque otros factores podrían estar modulando el fenotipo. El objetivo es determinar si el sexo, la hipertensión arterial o la actividad física son moduladores de la gravedad de la enfermedad y establecer su papel en la penetrancia en relación con la edad al diagnóstico de la MCH. Métodos: Se evaluó a 272 individuos (media de edad, 49 ± 17 años; el 57% varones) procedentes de 72 familias con mutación causal y se estudió la relación del sexo, la hipertensión y la actividad física con la hipertrofia ventricular izquierda. Resultados: La proporción de afectados aumenta con la edad. Se diagnosticó a los varones una mediana ajustada de 12,5 años (IC95%, -17,52 a -6,48; p < 0,001) antes que a las mujeres. A los pacientes hipertensos, se les diagnosticó MCH una mediana ajustada de 10,8 años (IC95%, 6,28-17,09; p < 0,001) más tarde que a los normotensos. A los individuos que hacían ejercicio, se los diagnosticó significativamente antes (mediana ajustada, 7,3 años; IC95%, -14,49 a -1,51; p = 0,016). El sexo, la hipertensión y el ejercicio no resultaron significativamente asociados con la gravedad de la hipertrofia del ventrículo izquierdo. Los factores explorados no influyen en la supervivencia ajustada libre de muerte súbita y el evento combinado. Conclusiones: Se diagnostica a los varones y los deportistas portadores de mutaciones sarcoméricas antes que a las mujeres y los individuos sedentarios. Los portadores de mutaciones sarcoméricas hipertensos tienen un retraso en el diagnóstico. El sexo, la hipertensión y el ejercicio no se asocian con la gravedad de la enfermedad en portadores de mutaciones causales de MCH (AU)

Introduction and objectives: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. Methods: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. Results: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. Conclusions: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations (AU)

Mutación p. Arg14del en fosfolambán en una familia española con miocardiopatía arritmogénica: evidencia de una mutación europea fundadora / Phospholamban p.arg14del mutation in a spanish family with arrhythmogenic cardiomyopathy: evidence for a european founder mutation

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