RESUMEN
Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype-phenotype correlation, personalized management and cardiogenetic counselling.
Asunto(s)
Aneurisma de la Aorta Torácica/genética , Arritmias Cardíacas/genética , Cardiomiopatías/genética , Enfermedad de la Arteria Coronaria/genética , Muerte Súbita Cardíaca/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , HumanosAsunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Proteínas de Unión al Calcio/genética , Quinasa de Cadena Ligera de Miosina/genética , Anciano , Disección Aórtica/fisiopatología , Aneurisma de la Aorta Torácica/fisiopatología , Codón sin Sentido/genética , Femenino , Haploinsuficiencia/genética , Humanos , Masculino , Anamnesis , Persona de Mediana Edad , LinajeRESUMEN
Objective: The present study aims to identify the long-term effects of atrial fibrillation (AF) on atrial remodelling and on the progression of mitral/tricuspid valve regurgitation (MR/TR).Methods: The severity of MR/TR was assessed by the colour jet area and by multi-integrative approach at baseline and after a period of 65 ± 10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with sinus rhythm.Results: At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05 ± 1.3 cm2 in the control group, 0.73 ± 2.1 cm2 in the non-permanent AF group and 1.95 ± 3.6 cm2 in the permanent AF group (p = .001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. There was a significant positive correlation between progression of MR and increase of left atrium volume (r = 0.31, p < .001). After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. Although rhythm control was better with AF ablation than with medical treatment only, the MR evolution was similar. Comparable findings, albeit less pronounced, were observed for the association between of AF and TR progression.Conclusions: The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.
RESUMEN
The Long QT Syndrome (LQTS) is a complex and multi-factorial disorder that predisposes to life-threatening ventricular arrhythmias. Both hereditary and acquired subforms have been identified over the years. Recently, it has become clear that the interaction of multiple acquired and genetic aetiologic factors (e.g. disease modifiers) play an important role in differentiating genotype into a continuous spectrum of clinical or subclinical phenotypes. The genotype-phenotype correlation thereby remains very unpredictable in asymptomatic patients, raising important concerns for clinical practice and also for drug development. Therefore, this review aims at providing a comprehensive overview on LQTS highlighting the molecular mechanisms of arrhythmogenesis involved in both the hereditary and the acquired subtypes of the disorder. From this perspective this manuscript then focuses on how the genotype translates into phenotype. A logical overview is provided with the multitude of hereditary and acquired factors that are involved and of the complexity of the interactions that ultimately result in the heterogeneous expressivity and the unpredictability of the phenotype. Based on recent basic and clinical data this review further aims at providing an update on the clinical properties and management of LQT patients including diagnostic work-up and therapy.
Asunto(s)
Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/patología , Genotipo , Humanos , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , FenotipoRESUMEN
The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c.1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/genética , Enfermedades Genéticas Congénitas , Síndrome de QT Prolongado/genética , Anciano , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Secuencia de Bases , Canadá , Línea Celular , Femenino , Humanos , Países Bajos , Linaje , Fenotipo , Mutación Puntual , Población BlancaRESUMEN
Human ether-a-go-go-related gene (HERG) potassium channels contribute to the repolarization of the cardiac action potential and display unique gating properties with slow activation and fast inactivation kinetics. Deletions in the N-terminal 'proximal' domain (residues 135-366) have been shown to induce hyperpolarizing shifts in the voltage dependence of activation, suggesting that it modulates activation. However, we did not observe a hyperpolarizing shift with a subtotal deletion designed to preserve the local charge distribution, and other deletions narrowed the region to the KIKER containing sequence 362-372. Replacing the positively charged residues of this sequence by negative ones (EIEEE) resulted in a -45 mV shift of the voltage dependence of activation. The shifts were intermediate for individual charge reversals, whereas E365R resulted in a positive shift. Furthermore, the shifts in the voltage dependence were strongly correlated with the net charge of the KIKER region. The apparent speeding of the activation was attributable to the shifted voltage dependence of activation. Additionally, the introduction of negative charges accelerated the intermediate voltage-independent forward rate constant. We propose that the modulatory effects of the proximal domain on HERG gating are largely electrostatic, localized to the charged KIKER sequence.