Outcome in Phospholamban R14del Carriers

Abstract

Since the discovery of the first causative mutations for cardiomyopathies in the early 1990s, the importance of inherited genetic variants has been increasingly recognized. 1,2 These discoveries have led to a better understanding of disease pathogenesis and introduced genetic evaluation into clinical practice for affected individuals and their relatives. 2,3 Editorial see p 405 Clinical Perspective on p 465Early identification of asymptomatic mutation carriers via genetic cascade screening is potentially of major prognostic importance because cardiomyopathies can lead to sudden cardiac death (SCD) as a result of malignant ventricular arrhythmias even before the onset of any symptoms.2 Although our knowledge of the genetics of cardiomyopathies has expanded greatly, mutation carriers are mostly advised, among other as to lifestyle adjustments (ie, sports activity), and treated based on general guidelines based on their cardiac morphological and functional characteristics; there is little known about specific genotype-phenotype relationships. 2,4 Phospholamban (encoded by the PLN gene) is a transmembrane sarcoplasmic reticulum phosphoprotein and is a key Background-The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. Methods and Results-Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. Conclusions-Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and endstage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. regulator of calcium homeostasis. 5 Pathogenic mutations in PLN, mostly leading to inhibition of the calcium uptake into the sarcoplasmic reticulum, may cause inherited cardiomyopathy. 5 The pathogenic PLN R14del ...

Sudden Cardiac Arrest and Rare Genetic Variants in the Community

“…It is likely that the PLN-R14del mutation contributed importantly to the occurrence of VF in these patients, given that this mutation is known to be associated with a high incidence of malignant cardiac arrhythmias and sudden death. 31 Multiple mechanisms may cause arrhythmia in PLN-R14del mutation carriers. Primary disruptions in electric properties, specific to this mutation, may contribute (delayed afterdepolarizations caused by disrupted cellular Ca 2+ homeostasis).…”

Is the Phenotype–Genotype Relationship Necessary to Understand Cardiomyopathies?

“…The most striking ECG change is the reduced QRS amplitude especially in those with LV dilatations. 9,12,21 Reduced QRS amplitude is common in patients with heart failure of all causes, ARVD, 19 presence of peripheral edema, and in other conditions. 22 Patients with all types of cardiomyopathies, including congenital and acquired forms, are prone to ventricular arrhythmias and sudden cardiac death.…”

“…12 Challenge remains as how to not miss the high-risk individuals while eliminate the overuse in those in whom implantable cardioverter defibrillators are not necessary.…”

“…PLN R14del, a founder gene mutation responsible for dilated cardiomyopathy (DCM), 8,9 can produce ARVD-like phenotype as well. 10,11 By conducting a multicenter study, van Rijsingen et al 12 reported the clinical course of 403 mutation carriers from 83 families in this issue of the journal. Among 295 individuals with clinical information available, DCM phenotype is predominant, where 1% shows both DCM and ARVD and 6% with ARVD only.…”

Acute Inotropic and Lusitropic Effects of Cardiomyopathic R9C Mutation of Phospholamban

“…Disordered Ca 2ϩ transport or regulation may cause and result from cardiac diseases such as heart failure. In particular, mutations (8 -12) or deletions (13)(14)(15)(16) of PLB give rise to human disease, underscoring the importance of this peptide and providing some insight into the molecular mechanisms of SERCA regulation by PLB. Of particular interest is the human heart failure mutant R9C-PLB that causes dilated cardiomyopathy (DCM) (8).…”