Irene M van Langen

Publications (34)222.34 Total impact

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

  Karin Y van Spaendonck-Zwarts, Ingrid A W van Rijsingen, Maarten P van den Berg, Ronald H Lekanne Deprez, Jan G Post, Anneke M van Mil, Folkert W Asselbergs, Imke Christiaans, Irene M van Langen, Arthur A M Wilde, Rudolf A de Boer, Jan D H Jongbloed, Yigal M Pinto, J Peter van Tintelen
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  ABSTRACT: 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. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. CONCLUSION: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.
  European Journal of Heart Failure 01/2013; · 4.90 Impact Factor
• Source

  Available from: Dennis Dooijes

  Article: Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation.

  Jasper J van der Smagt, Paul A van der Zwaag, J Peter van Tintelen, Moniek G P J Cox, Arthur A M Wilde, Irene M van Langen, Amber Ummels, F A M Hennekam, Dennis Dooijes, Frans Gerbens, Hennie Bikker, Richard N W Hauer, Pieter A Doevendans
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  ABSTRACT: Objectives: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. Methods: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. Results: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. Conclusions: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.
  Cardiology 11/2012; 123(3):181-189. · 1.71 Impact Factor
• Article: Diagnostic yield in adults screened at the Marfan outpatient clinic using the 1996 and 2010 Ghent nosologies.

  Jan J J Aalberts, Chris H L Thio, Agnes G Schuurman, Irene M van Langen, Bert A E van der Pol, J Peter van Tintelen, Maarten P van den Berg
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  ABSTRACT: Marfan syndrome (MFS) is diagnosed according to the Ghent nosology, which has recently been revised. In the Netherlands, evaluation for possible MFS is performed in specialized Marfan outpatient clinics. We investigated the diagnostic yield in our clinic and the impact of the 2010 nosology. All adult patients (n = 343) who visited our clinic between 1998 and 2008 were included. We analyzed their reasons for referral, characteristics, and established diagnoses. In addition, we applied the 2010 nosology to all patients and compared the outcomes to those obtained with the 1996 nosology. Diagnoses that were made using the 1996 and the 2010 Ghent nosology included MFS (44/343 vs. 47/343), familial thoracic aortic aneurysm and/or dissection (22/343 vs. 22/343 patients), Loeys-Dietz syndrome (4/343 vs. 4/343 patients), and (familial) mitral valve prolapse (MVPS; 5/343 vs. 28/343 patients). In both nosologies, 77% of MFS patients had an FBN1 mutation. The 2010 nosology led to an increase in the number of diagnoses made: 4 additional cases of MFS were identified (one patient was "lost" who no longer fulfilled the criteria) and 23 additional cases of MVPS were diagnosed. The diagnostic yield of patients with aortic root dilatation was 65% using the 1996 nosology and 70% using the 2010 nosology. The change in diagnoses did not lead to a difference in clinical follow-up. We conclude that the diagnostic yield of our specialized clinic was high, in particular in patients with aortic root dilatation. Further more the 2010 Ghent nosology led to a significant increase in the number of diagnoses made, mainly due to lowering of the diagnostic threshold for MVPS.
  American Journal of Medical Genetics Part A 03/2012; 158A(5):982-8. · 2.39 Impact Factor
• Article: Mortality of inherited arrhythmia syndromes: insight into their natural history.

  Eline A Nannenberg, Eric J G Sijbrands, Lea M Dijksman, Marielle Alders, J Peter van Tintelen, Martijn Birnie, Irene M van Langen, Arthur A M Wilde
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  ABSTRACT: For most arrhythmia syndromes, the risk of sudden cardiac death for asymptomatic mutation carriers is ill defined. Data on the natural history of these diseases, therefore, are essential. The family tree mortality ratio method offers the unique possibility to study the natural history at a time when the disease was not known and patients received no treatment. In 6 inherited arrhythmia syndromes caused by specific mutations, we analyzed all-cause mortality with the family tree mortality ratio method (main outcome measure, standardized mortality ratio [SMR]). In long-QT syndrome (LQTS) type 1, severely increased mortality risk during all years of childhood was observed (1-19 years), in particular during the first 10 years of life (SMR, 2.9; 95% CI, 1.5-5.1). In LQTS type 2, we observed increasing SMRs starting from age 15 years, which just reached significance between age 30 and 39 (SMR, 4.0; 95% CI, 1.1-10.0). In LQTS type 3, the SMR was increased between age 15 and 19 years (SMR, 5.8; 95% CI, 1.2-16.9). In the SCN5A overlap syndrome, excess mortality was observed between age 10 and 59 years, with a peak between 20 and 39 years (SMR, 3.8; 95% CI, 2.5-5.7). In catecholaminergic polymorphic ventricular tachycardia, excess mortality was restricted to ages 20 to 39 years (SMR, 3.0; 95% CI, 1.3-6.0). In Brugada syndrome, excess mortality was observed between age 40 and 59 (SMR, 1.79; 95% CI, 1.2-2.4), particularly in men. We identified age ranges during which the mortality risk manifests in an unselected and untreated population, which can guide screening in these families.
  Circulation Cardiovascular Genetics 02/2012; 5(2):183-9. · 6.11 Impact Factor
• Article: Mortality risk of untreated myosin-binding protein C-related hypertrophic cardiomyopathy: insight into the natural history.

  Eline A Nannenberg, Michelle Michels, Imke Christiaans, Danielle Majoor-Krakauer, Yvonne M Hoedemaekers, J Peter van Tintelen, M Paola Lombardi, Folkert J ten Cate, Arend F L Schinkel, Jan G P Tijssen, Irene M van Langen, Arthur A M Wilde, Eric J G Sijbrands
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  ABSTRACT: The goal of this study was to assess the mortality of hypertrophic cardiomyopathy (HCM), partly in times when the disease was not elucidated and patients were untreated. HCM is feared for the risk of sudden cardiac death (SCD). Insight in the natural history of the disorder is needed to design proper screening strategies for families with HCM. In 6 large, 200-year multigenerational pedigrees (identified by using genealogical searches) and in 140 small (contemporary) pedigrees (first-degree relatives of the proband) with HCM caused by a truncating mutation in the myosin-binding protein C gene (n = 1,118), we determined all-cause mortality using the family tree mortality ratio method. The study's main outcome measure was the standardized mortality ratio (SMR). In the large pedigrees, overall mortality was not increased (SMR 0.86 [95% confidence interval (CI): 0.72 to 1.03]), but significant excess mortality occurred between 10 and 19 years (SMR 2.7 [95% CI: 1.2 to 5.2]). In the small families, the SMR was increased (SMR 1.5 [95% CI: 1.3 to 1.6]) [corrected] and excess mortality was observed between 10 and 39 years (SMR 3.2 [95% CI: 2.3 to 4.3]) and 50 and 59 years (SMR 1.9 [95% CI: 1.4 to 2.5]). We identified specific age categories with increased mortality risks in HCM families. The small, referred pedigrees had higher mortality risks than the large 200-year multigenerational pedigrees. Our findings support the strategy of starting cardiological and genetic screening in the first-degree relatives of a proband from 10 years onward and including persons in the screening at least until the age of 60 years. Screening of more distant relatives is probably most efficient between 10 and 19 years.
  Journal of the American College of Cardiology 11/2011; 58(23):2406-14. · 14.16 Impact Factor
• Source

  Available from: Dennis Dooijes

  Article: Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.

  Moniek G P J Cox, Paul A van der Zwaag, Christian van der Werf, Jasper J van der Smagt, Maartje Noorman, Zahir A Bhuiyan, Ans C P Wiesfeld, Paul G A Volders, Irene M van Langen, Douwe E Atsma, [......], Arthur van den Wijngaard, Arjan C Houweling, Jan D H Jongbloed, Luc Jordaens, Maarten J Cramer, Pieter A Doevendans, Jacques M T de Bakker, Arthur A M Wilde, J Peter van Tintelen, Richard N W Hauer
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  ABSTRACT: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.
  Circulation 06/2011; 123(23):2690-700. · 14.74 Impact Factor
• Article: Incidence, causes, and outcomes of out-of-hospital cardiac arrest in children. A comprehensive, prospective, population-based study in the Netherlands.

  Abdennasser Bardai, Jocelyn Berdowski, Christian van der Werf, Marieke T Blom, Manon Ceelen, Irene M van Langen, Jan G P Tijssen, Arthur A M Wilde, Rudolph W Koster, Hanno L Tan
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  ABSTRACT: This study sought to determine comprehensively the incidence of pediatric out-of-hospital cardiac arrest (OHCA) and its contribution to total pediatric mortality, the causes of pediatric OHCA, and the outcome of resuscitation of pediatric OHCA patients. There is a paucity of complete studies on incidence, causes, and outcomes of pediatric OHCA. In this prospective, population-based study, OHCA victims younger than age 21 years in 1 province of the Netherlands were registered through both emergency medical services and coroners over a period of 4.3 years. Death certificate data on total pediatric mortality, survival status, and neurological outcome at hospital discharge also were obtained. With a total mortality of 923 during the study period and 233 victims of OHCA (including 221 who died and 12 who survived), OHCA caused 24% (221 of 923) of total pediatric mortality. Natural causes of OHCA amounted to 115 (49%) cases, with cardiac causes being most prevalent (n = 90, 39%). The incidence of pediatric OHCA was 9.0 per 100,000 pediatric person-years (95% confidence interval: 7.8 to 10.3), whereas the incidence of pediatric OHCA from cardiac causes was 3.2 (95% confidence interval: 2.5 to 3.9). Of 51 resuscitated patients, 12 (24%) survived; among survivors, 10 (83%) had a neurologically intact outcome. Out-of-hospital cardiac arrest accounts for a significant proportion of pediatric mortality, and cardiac causes are the most prevalent causes of OHCA. The vast majority of OHCA survivors have a neurologically intact outcome.
  Journal of the American College of Cardiology 05/2011; 57(18):1822-8. · 14.16 Impact Factor
• Source

  Available from: Dennis Dooijes

  Article: Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers: determining the best cardiological screening strategy.

  Imke Christiaans, Erwin Birnie, Gouke J Bonsel, Marcel M A M Mannens, Michelle Michels, Daniëlle Majoor-Krakauer, Dennis Dooijes, J Peter van Tintelen, Maarten P van den Berg, Paul G A Volders, [......], Douwe E Atsma, Apollonia T J M Helderman-van den Enden, Arjan C Houweling, Karin de Boer, Jasper J van der Smagt, Richard N W Hauer, Carlo L M Marcelis, Janneke Timmermans, Irene M van Langen, Arthur A M Wilde
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  ABSTRACT: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for sudden cardiac death (SCD), and cardiac events during follow-up in predictively tested-not known to have a clinical diagnosis of HCM before the DNA test-carriers of a sarcomeric gene mutation and associations with age and gender to determine the best cardiological screening strategy. One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed manifest HCM was <10% per person-year under the age of 40 years and >10% in older carriers, although numbers were small in carriers <15 years. Twenty-three percent of carriers, with and without manifest disease, had established risk factor(s) for SCD (no significant difference). During an average follow-up of 3.5 ± 1.7 years two carriers, both with manifest disease, died suddenly (0.13% per person-year). A high-risk status for SCD (≥2 risk factors and manifest HCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associated with a high-risk status for SCD. Thirty percent of carriers had or developed manifest HCM after predictive DNA testing and risk factors for SCD were frequently present. Our data suggest that the SCD risk is low and risk stratification for SCD can be omitted in carriers without manifest disease and that frequency of cardiological evaluations can possibly be decreased in carriers between 15 and 40 years as long as hypertrophy is absent.
  European Heart Journal 04/2011; 32(9):1161-70. · 10.48 Impact Factor
• Article: Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young: a population-based approach.

  Anneke Hendrix, C Jan Willem Borleffs, Aryan Vink, Pieter A F M Doevendans, Arthur A Wilde, Irene M van Langen, Jasper J van der Smagt, Michiel L Bots, Arend Mosterd
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  ABSTRACT: To investigate the yield of cardiogenetic screening of relatives of young sudden cardiac death (SCD) and sudden unexplained death (SUD) victims in a population-based setting. A population-based study was carried out between 2000 and 2006. Records of the hospital, death declaration certificates, and resuscitation records were reviewed for SCD and SUD cases (1-40 years). Information on autopsy results and cardiogenetic screening of the victims' first-degree relatives was collected. Relatives were invited for additional cardiogenetic screening when this had not yet been performed. The search led to 16 cases of SCD/SUD and 4 cases of aborted SCD/SUD. Causes of SCD/SUD were myocardial infarction (n = 3), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 2), long-QT syndrome (n = 1), hypertrophic cardiomyopathy (n = 2), left ventricular hypertrophy due to aortic stenosis (n = 1), and unknown cause of death (n = 7). Causes of aborted SCD/SUD were myocardial infarction (n = 2), idiopatic ventricular fibrillation (n = 1), and the Brugada syndrome (n = 1). The cardiogenetic screening of 37 relatives of 12 victims led to a diagnosis of Brugada syndrome in 3 relatives and the suspicion of ARVC in 2 relatives. The yield of screening of these relatives was 14% (95% confidence interval: 3-25%). In the usual care, relatives of (aborted) SCD and SUD victims are often not referred for cardiogenetic screening. Screening is often not performed according to a systematic approach, and the detection rate of inherited diseases in relatives of (aborted) SCD and SUD victims in a population-based setting, although substantial, is lower than expected based on previous studies.
  Europace 01/2011; 13(5):716-22. · 1.98 Impact Factor
• Article: Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands.

  Christian van der Werf, Nynke Hofman, Hanno L Tan, Pascal F van Dessel, Marielle Alders, Allard C van der Wal, Irene M van Langen, Arthur A M Wilde
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  ABSTRACT: In sudden unexplained death (SUD) in the young (age 1-50 years), cardiologic and genetic examination in surviving relatives may unmask the cause of death in a significant proportion. The causes of aborted cardiac arrest (ACA) in this age group likely are similar to those in sudden cardiac death. However, there is a paucity of recent data on this topic. The purpose of this study was to gain insight into the yield of current diagnostic strategies used in relatives of SUD victims and in ACA victims aged 1-50 years in our dedicated tertiary referral center. We studied (1) all consecutive families who presented to the cardiology department for examination because of ≥1 first-degree related SUD victim aged 1-50 years and (2) all consecutive ACA victims aged 1-50 years who presented to the cardiology department from 1996 to 2009. Comprehensive cardiologic and genetic examination was performed in both populations. A certain or probable diagnosis was made in 47 (33%) of 140 SUD families, including 45 (96%) cases of inherited cardiac diseases. Long QT syndrome (19%) was the most prevalent diagnosis. In 42 (61%) of 69 ACA victims, the cause of the event was determined (inherited in 31 [74%]). Hypertrophic cardiomyopathy was most prevalent (17%). The yield of the current diagnostic workup in relatives of young SUD victims is 33% and is almost twice as high in young ACA victims. Inherited cardiac diseases are predominantly causative in both groups.
  Heart rhythm: the official journal of the Heart Rhythm Society 10/2010; 7(10):1383-9. · 4.56 Impact Factor
• Article: Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks.

  Ellen Otten, Angeliki Asimaki, Alexander Maass, Irene M van Langen, Allard van der Wal, Nicolaas de Jonge, Maarten P van den Berg, Jeffrey E Saffitz, Arthur A M Wilde, Jan D H Jongbloed, J Peter van Tintelen
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  ABSTRACT: Mutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients. To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes. We evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients. Except for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers. We confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.
  Heart rhythm: the official journal of the Heart Rhythm Society 08/2010; 7(8):1058-64. · 4.56 Impact Factor
• Article: Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment?

  Nynke Hofman, Hanno L Tan, Marielle Alders, Irene M van Langen, Arthur A M Wilde
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  ABSTRACT: The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 +/- 31 months (LQTS), 60 +/- 19 months (CPVT), and 56 +/- 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases.
  Journal of the American College of Cardiology 06/2010; 55(23):2570-6. · 14.16 Impact Factor
• Article: Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers.

  Imke Christiaans, Klaartje van Engelen, Irene M van Langen, Erwin Birnie, Gouke J Bonsel, Perry M Elliott, Arthur A M Wilde
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  ABSTRACT: We performed a systematic literature review of recommended 'major' and 'possible' clinical risk markers for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). We searched the Medline, Embase and Cochrane databases for articles published between 1971 and 2007. We included English language reports on HCM patients containing follow-up data on the endpoint (sudden) cardiac death using survival analysis. Analysis was undertaken using the quality of reporting of meta-analyses (QUORUM) statement checklist. The quality was checked using a quality assessment form from the Cochrane Collaboration. Thirty studies met inclusion criteria and passed quality assessment. The use of the six major risk factors (previous cardiac arrest or sustained ventricular tachycardia, non-sustained ventricular tachycardia, extreme left ventricular hypertrophy, unexplained syncope, abnormal blood pressure response, and family history of sudden death) in risk stratification for SCD as recommended by international guidelines was supported by the literature. In addition, left ventricular outflow tract obstruction seems associated with a higher risk of SCD. Our systematic review provides sound evidence for the use of the six major risk factors for SCD in the risk stratification of HCM patients. Left ventricular outflow tract obstruction could be included in the overall risk profile of patients with a marked left ventricular outflow gradient under basal conditions.
  Europace 03/2010; 12(3):313-21. · 1.98 Impact Factor
• Article: Sudden death in the young: what do we know about it and how to prevent?

  Christian van der Werf, Irene M van Langen, Arthur A M Wilde
  Circulation Arrhythmia and Electrophysiology 02/2010; 3(1):96-104. · 6.46 Impact Factor
• Article: [Hypertrophic cardiomyopathy: DNA diagnosis, genetic counselling and the risk of sudden cardiac death].

  Hubert F Baars, Imke Christiaans, Pim T A M de Nijs, Maarten J Cramer, Irene M van Langen, Pieter A F M Doevendans
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  ABSTRACT: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease with a clinical prevalence of 1 in 500. HCM is a monogenetic disease and is inherited autosomal dominantly. The disease can manifest itself at any age. Clinical presentation varies from symptom-free to severe dyspnoea and sudden cardiac death from ventricular arrhythmia. Diagnosis is mainly based on echocardiography and on MRI if necessary. In 50-60% of patients, molecular genetic investigation reveals a pathogenic mutation in one of the sarcomeric protein genes. The treatment of HCM depends on the symptoms and the potential presence of an obstruction in the left ventricular outflow tract. The risk of sudden cardiac death must be evaluated in order to determine if a prophylactic intracardiac defibrillator is necessary. In view of its mendelian form of inheritance, in the Netherlands practice guidelines have been issued recently regarding genetic counselling of the patient and his or her family and to initiate and coordinate research within the family.
  Nederlands tijdschrift voor geneeskunde 01/2010; 154:A698.
• Article: The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening.

  Imke Christiaans, Erwin Birnie, Irene M van Langen, Karin Y van Spaendonck-Zwarts, J Peter van Tintelen, Maarten P van den Berg, Douwe E Atsma, Apollonia T J M Helderman-van den Enden, Yigal M Pinto, J F Hermans-van Ast, Gouke J Bonsel, Arthur A M Wilde
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  ABSTRACT: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM) and of risk factors for sudden cardiac death (SCD) at the first cardiological evaluation after predictive genetic testing in asymptomatic carriers of an MYBPC3 gene mutation. Two hundred and thirty-five mutation carriers were cardiologically evaluated on the presence of HCM and risk factors. A clinical diagnosis of HCM was made in 53 carriers (22.6%). Disease penetrance at 65 years was incomplete for all types of MYBPC3 gene mutations. Women were affected less often than men (15 and 32% respectively, P = 0.003) and disease penetrance was lower in females than in males (13 and 30% at 50 years, respectively, P = 0.024). One risk factor was present in 87 carriers and 9 had two or more risk factors. Twenty-five carriers (11%) with one or more risk factors and manifest HCM could be at risk for SCD. At first cardiological evaluation almost one-quarter of asymptomatic carriers was diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers could be at risk for SCD. Predictive genetic testing in HCM families and frequent cardiological evaluation on the presence of HCM and risk factors for SCD are justified until advanced age.
  European Heart Journal 12/2009; 31(7):842-8. · 10.48 Impact Factor
• Article: Obtaining insurance after DNA diagnostics: a survey among hypertrophic cardiomyopathy mutation carriers.

  Imke Christiaans, Tjitske M Kok, Irene M van Langen, Erwin Birnie, Gouke J Bonsel, Arthur A M Wilde, Ellen M A Smets
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  ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with increased mortality. Disclosure of DNA test results may have social implications such as low access to insurance. In The Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act. A cross-sectional survey was used to assess the frequency and type of problems encountered by HCM mutation carriers applying for insurance, and associations with carriers' characteristics. The response rate was 86% (228/264). A total of 66 carriers (29%) applied for insurance of whom 39 reported problems (59%) during an average follow-up of 3 years since the DNA test result. More problems were encountered by carriers with manifest disease (P<0.001) and carriers with symptoms of HCM (P=0.049). Carriers identified after predictive DNA testing less frequently experienced problems (P=0.002). Three carriers without manifest HCM reported problems (5% of applicants). Frequently reported problems were higher premium (72%), grant access to medical records (62%), and complete rejection (33%). In conclusion, HCM mutation carriers frequently encounter problems when applying for insurances, often in the case of manifest disease, but the risk assessment of insurance companies is largely justified. Still, 5% of carriers encounter potentially unjustified problems, indicating the necessity to monitor the application of the existing laws and regulations by insurance companies and to educate counselees on the implications of these laws and regulations.
  European journal of human genetics: EJHG 09/2009; 18(2):251-3. · 3.56 Impact Factor
• Source

  Available from: amc.nl

  Article: Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy mutation carriers: the patients' perspective.

  Imke Christiaans, Irene M van Langen, Erwin Birnie, Gouke J Bonsel, Arthur A M Wilde, Ellen M A Smets
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  ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with sudden cardiac death. Predictive genetic counseling and testing are performed using adapted Huntington guidelines, that is, psychosocial care and time for reflection are not obligatory and the test result can be disclosed by telephone or mail. Proven mutation carriers detected by predictive DNA testing are advised to undergo regular cardiac follow-up according to international guidelines. We evaluated the opinion of 143 predictively tested HCM mutation carriers on received cardiogenetic care using questionnaires (response rate 86%). Predictive genetic counseling and DNA testing were evaluated on four domains: information provision, satisfaction with counseling, social pressure in DNA testing and regret of DNA testing. Opinions on cardiac follow-up were assessed pertaining to communication, nervous anticipation, reassurance, and general disadvantages. Genetic counseling was valued positively and only four carriers would rather not have known that they were a mutation carrier. A majority received their DNA test result by mail or telephone, and almost all were satisfied. Only 76% of carriers received regular cardiac follow-up. Those who did, had a positive attitude regarding the cardiac visits. General disadvantages of the visits were valued as low, especially by older carriers, men and carriers with manifest HCM. We conclude that our adapted Huntington guidelines are well accepted and that cardiogenetic care is generally appreciated by predictively tested HCM mutation carriers. To better understand the cause of the substantial portion of mutation carriers not receiving regular cardiac follow-up, although recommended in international guidelines, further research is needed.
  American Journal of Medical Genetics Part A 08/2009; 149A(7):1444-51. · 2.39 Impact Factor
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  Available from: onlinejacc.org

  Article: The relationship between pre-participation screening of young competitive athletes and family screening.

  Christian van der Werf, Irene M van Langen, Arthur A M Wilde
  Journal of the American College of Cardiology 07/2009; 53(24):2309; author reply 2309-10. · 14.16 Impact Factor
• Article: Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy.

  Imke Christiaans, Ronald H Lekanne dit Deprez, Irene M van Langen, Arthur A M Wilde
  Heart rhythm: the official journal of the Heart Rhythm Society 06/2009; 6(9):1366-9. · 4.56 Impact Factor