The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update.

BACKGROUND: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. AIM: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. METHODS: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. DISCUSSION: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.

Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.

BACKGROUND: Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death. METHODS: Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation. RESULTS: By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents' places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %). CONCLUSION: The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004-2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region.

Haplotype sharing test maps genes for familial cardiomyopathies.

Identifying a mutation in a heterogeneous disease such as inherited cardiomyopathy is a challenge because classical methods, like linkage analysis, can often not be applied as there are too few meioses between affected individuals. However, if affected individuals share the same causal mutation, they will also share a genomic region surrounding it. High-density genotyping arrays are able to identify such regions shared among affected individuals. We hypothesize that the longest shared haplotype is most likely to contain the disease-causing mutation. We applied this method to two pedigrees: one with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one with dilated cardiomyopathy (DCM), using high-density genome-wide SNP arrays. In the ARVC pedigree, the largest haplotype was on chromosome 12 and contained a causative PKP2 mutation. In the DCM pedigree, a causative MYH7 mutation was present on a large shared haplotype on chromosome 14. We calculated that a pedigree containing at least seven meioses has a high chance of correctly detecting the mutation-containing haplotype as the largest. Our data show that haplotype sharing analysis can assist in identifying causative genes in families with low penetrance Mendelian diseases, in which standard tools cannot be used due to lack of sufficient pedigree information.

Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population. METHODS: Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation. RESULTS: The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women. CONCLUSION: We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583-91.).

Arrhythmogenic right ventricular cardiomyopathy: asymptomatic to life threatening as illustrated by the cases of two sisters.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder of unknown cause that is characterised by fibrofatty replacement, primarily of the right ventricular myocardium, which can lead to life-threatening arrhythmias. It is a disease with a very diverse phenotype. In the present article we describe two sisters, each with a different manifestation of this disorder. The first patient died suddenly at the age of 18 during exercise. Her 17-year-old sister did not have any abnormalities at first cardiac consultation, but a few years later she met several diagnostic criteria for ARVC and an internal cardioverter defibrillator was implanted. Genetic analysis identified a mutation in the plakophilin- 2 (PKP2) gene. Cardiac evaluation of a third sister did not reveal any abnormalities and no mutation in the PKP2 gene was found. Thus, ARVC can vary in its clinical presentation, not only between siblings but also in time. This raises difficulties for the physician for diagnosis, treatment and followup. It is important for the physician involved to consider this disease in patients with palpitations and syncope, especially when there is a family history of ARVC or unexplained sudden death. (Neth Heart J 2007;15:348-53.).

Recommendations and cardiological evaluation of athletes with arrhythmias: Part 1.

Besides the consensus meeting in Amersfoort in 1988 and the Bethesda conference in 1994 recommendations are not available in the Netherlands for screening and evaluation of athletes with cardiac arrhythmias. Guidelines for competitive athletes with cardiac arrhythmias in the United States and Italy were published in 2000. In 1998 Estes et al. published the most important opinions on sudden cardiac death, screening and evaluation of athletes and arrhythmias. This study addresses the physiological and morphological consequences of athletic training, cardiac pathology and risk stratification for sudden cardiac death. Recommendations for competitive athletes with cardiovascular abnormalities, arrhythmias and proposals for specific protocols are given.

Recommendations and cardiological evaluation of athletes with arrhythmias: Part 2.

Confronted with a competitive or recreational athlete, the physician has to discriminate between benign, paraphysiological and pathological arrhythmias. Benign arrhythmias do not represent a risk for SCD, nor do they induce haemodynamic consequences during athletic activities. These arrhythmias are not markers for heart disease. Paraphysiological arrhythmias are related to athletic performance. Long periods of endurance training induce changes in rhythm, conduction and repolarisation. These changes are fully reversible and disappear when the sport is terminated. Pathological arrhythmias have haemodynamic consequences and express disease, such as sick sinus syndrome, cardiomyopathy or inverse consequences of physical training. Arrhythmias can be classified as bradyarrhythmias and tachyarrhythmias. Conduction disorders can be seen in fast as well as in slow arrhythmias.

Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA.

BACKGROUND: Evidence from earlier studies indicates that intake of very long-chain n-3 polyunsaturated fatty acids (n-3 PUFA, also named omega-3 fatty acids) as present in fish oil reduces the risk of sudden death. Sudden death forms a major part of mortality from cardiovascular disease and is in most cases a direct consequence of cardiac arrhythmia. n-3 PUFA may exert their protective effect through reducing the susceptibility for cardiac arrhythmia. OBJECTIVE: To investigate the effect of n-3 PUFA on the incidence of recurrent ventricular arrhythmia. This paper presents the rationale, design and methods of the Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) and discusses problems encountered in conducting a multicentre clinical trial on food. DESIGN: A randomised, parallel, placebo-controlled, double blind intervention study, which obeys the guidelines for Good Clinical Practice. SETTING: Multiple cardiology centres in Europe. SUBJECTS: A total of 500 patients with an implantable cardioverter defibrillator (ICD). An ICD detects, treats and stores cardiac arrhythmic events in its memory chip. INTERVENTIONS: Patients receive either 2 g/day of fish oil, containing approximately 450 mg eicosapentaenoic acid and 350 mg docosahexaenoic acid, or placebo for 12 months. PRIMARY OUTCOME: Spontaneous ventricular tachyarrhythmias as recorded by the ICD or all-cause mortality. CONCLUSION: SOFA is designed to answer the question whether intake of n-3 PUFA from fish-a regular food ingredient-can reduce the incidence of life-threatening cardiac arrhythmia. If this proves to be true, increasing the intake of n-3 PUFA could be an easy, effective and safe measure to prevent fatal arrhythmia in the general population.

Implantable cardioverter defibrillator recipients: quality of life in recipients with and without ICD shock delivery: a prospective study.

AIMS: The experiences of patients who received shocks from their implantable cardioverter defibrillator (ICD) and how these events affect their overall adjustment are poorly understood. Our goal was to evaluate quality of life and psychological well-being, and the prevalence of, and changes in, depression and anxiety of patients who did or did not experience defibrillatory shocks in the first 12 months after ICD implantation. In total 167 patients were monitored after discharge. Four self-administered questionnaires were used. The first assessment took place before ICD implantation, the remaining three at 1, 6 and 12 months after discharge. RESULTS: We classified patients into three shock groups and one no shock group. A small group of ICD recipients (26%) received ICD shock delivery, usually during the last 6 months of the study. Borderline significant differences were found within the groups over time regarding physical role limitations (P < 0.051). Those who experienced shocks throughout the year (group 1) felt more limited in their daily activities due to physical or mental problems. All groups health (P < 0.001). Overall quality of life did not change significantly after 6 months. Anxiety and depression did not change significantly over time. In total 22-66% of patients reported clinically significant depressive symptoms throughout the first year, and 31-83% clinically significant symptoms of anxiety. ICD recipients who had experienced a shock were significantly more anxious one-year postdischarge than those who had not received a shock. CONCLUSIONS: Overall quality of life and psychological well-being did not change in ICD recipients, irrespective of whether they experienced defibrillatory shocks. The high prevalence of depression and anxiety can be interpreted as a response to the perceived physical and mental problems regarding daily activities. Our data indicate that patients who have experienced an ICD shock do not adapt well to living with an ICD, they are more anxious than ICD recipients who received no shocks. However, the anticipation of having another shock after experiencing one is less stressful than that of the first shock. We conclude that the lasting psychological distress will not dissipate spontaneously or naturally and that psychosocial interventions may be warranted.

Ablación del sustrato de arritmias cardíacas con catéter de radiofrecuencia / Radiofrequency catheter ablation of the substrate of cardiac arrhythmias

Este trabajo presenta los resultados de siete años de experiencia de ablación con catéter de radiofrecuencia en el Hospital de la Universidad de Utrecht, Holanda. 448 pacientes fueron tratados por una variedad de taquiarritmias supraventriculares y ventriculares. Los porcentajes de éxito fueron excelentes en pacientes con vías accesorias aurículoventriculares y taquicardia aurículoventricular por reentrada nodal, con un 95 por ciento y 93 por ciento respectivamente. La incidencia de bloqueo aurículoventricular completo accidental en el último grupo fue bajo: 5,4 por ciento para la aproximación anteriory 1,5 por ciento para la posterior. La ablación del haz de His se efectuó predominantemente en pacientes con fibrilación auricular refractaria a las drogas, con 100 por ciento de éxito. En pacientes con taquiarritmia ventricular idiopática, 5 de 6 pacientes están libres de recurrencia. La ablación por radiofrecuencia es una modalidad segura y potencialmente curativa de tratamiento. Los hallazgos subrayan la enorme importancia de una cuidadosa localización del blanco y de la localización del catéter para el éxito y el uso racional de la ablación por radiofrecuencia