Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: phenotypic insights from cardiovascular magnetic resonance imaging.

Aims: The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia (VA) and heart failure. It has been shown to lead to calcium overload, cardiomyocyte damage, and eventually to myocardial fibrosis.

Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.

Aims: Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM.

Methods And Results: We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60].

Atlas of the clinical genetics of human dilated cardiomyopathy.

Aim: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort.

Outcome in phospholamban R14del carriers: results of a large multicentre cohort study.

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.

Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.

Aims: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort.

Methods And Results: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM.

Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers.

Aims: Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality.

Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications.

Background: Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications.

Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.

Aims: To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).

Methods And Results: We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients.

Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.

Objectives: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers.

Background: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure.

[Ambiguities in the diagnosis of heart failure].

The diagnosis of heart failure has improved in the renewed heart failure practice guideline of the Dutch College of General Practitioners (NHG), of which the contents correspond to the multidisciplinary guideline 'Heart failure 2010'. This guideline recommend cut-off values for NT-proBNP for exclusion of heart failure and an echocardiogram for confirming diagnosis. In our opinion, however, the guideline will refer too many patients to hospital - partly due to the low cut-off values for NT-proBNP for excluding chronic heart failure - risking unnecessary diagnostic measures.