278 results on '"Van Tintelen JP"'
Search Results
2. P764Phospholamban p.Arg14del-mutation related cardiomyopathy is a biventricular arrhythmogenic cardiomyopathy and protein-aggregate associated disease
- Author
-
Te Rijdt, WP, Van Der Zwaag, PA, Van Tintelen, JP, Gho, JMI, De Boer, RA, Van Den Berg, MP, Van Der Wal, AC, Vink, A, and Suurmeijer, AS
- Published
- 2014
- Full Text
- View/download PDF
3. P573Added diagnostic value of multiplex ligation-dependent probe amplification of plakophilin-2 in arrhythmogenic cardiomyopathy
- Author
-
Lazzarini, E, Rigato, I, Jongbloed, JD, Celeghin, R, Cason, M, Carturan, E, Thiene, G, Basso, C, Pilichou, K, and Van Tintelen, JP
- Published
- 2014
- Full Text
- View/download PDF
4. Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5
- Author
-
Dominguez F, Zorio E, Jimenez-Jaimez J, Salguero-Bodes R, Zwart R, Gonzalez-Lopez E, Molina P, Bermúdez-Jiménez F, Delgado JF, Braza-Boïls A, Bornstein B, Toquero J, Segovia J, Van Tintelen JP, Lara-Pezzi E, and Garcia-Pavia P
- Subjects
Arrhythmia, Arrhythmogenic right ventricular cardiomyopathy, Exercise, Genetics, TMEM43 - Abstract
Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the nondesmosomal gene TMEM43-endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or whether the disease is influenced by genetic or environmental factors.
- Published
- 2020
5. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome
- Author
-
Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, Bezzina CR., Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, and Bezzina CR.
- Abstract
Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS c
- Published
- 2020
6. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes
- Author
-
Ingles, J, Goldstein, J, Thaxton, C, Caleshu, C, Corty, EW, Crowley, SB, Dougherty, K, Harrison, SM, McGlaughon, J, Milko, LV, Morales, A, Seifert, BA, Strande, N, Thomson, K, Van Tintelen, JP, Wallace, K, Walsh, R, Wells, Q, Whiffin, N, Witkowski, L, Semsarian, C, Ware, JS, Hershberger, RE, Funke, B, and Wellcome Trust
- Subjects
Science & Technology ,Cardiac & Cardiovascular Systems ,heart failure ,1103 Clinical Sciences ,macromolecular substances ,Original Articles ,syndrome ,1117 Public Health and Health Services ,Phenotype ,Peripheral Vascular Disease ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,cardiovascular system ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Cardiomyopathy, Hypertrophic, Familial ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Genetic Testing ,uncertainty ,Life Sciences & Biomedicine ,1102 Cardiorespiratory Medicine and Haematology - Abstract
Supplemental Digital Content is available in the text., Background: Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations. Methods: A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource. Results: Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence (CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association. Conclusions: The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families.
- Published
- 2019
7. Heritable Thoracic Aortic Disorders
- Author
-
Mulder, BJM, De Graaf - van de Laar, Ingrid, Backer, J, Baars, HF, Doevendans, PAFM, Houweling, AC, van Tintelen, JP, and Clinical Genetics
- Published
- 2016
8. The current role of Next generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions. A viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics
- Author
-
Mogensen, J, van Tintelen JP, Fokstuen, S, Elliott, P, van Langen IM, Meder, B, Richard, P, Syrris, P, Caforio, A, Adler, Y, Anastasakis, A, Gimeno, Jr, Klingel, K, Linhart, A, Imazio, M, Pinto, Y, Newbery, R, Schmidtke, J, and Charron, P.
- Published
- 2015
9. Gene-Panel Based Next Generation Sequencing (NGS) Greatly Improves Clinical Genetic Diagnostics in Inherited Cardiomyopathies
- Author
-
Jongbloed, JD, Posafalvi, A, Niessen, RC, Hoedemaekers, YM, van der Zwaag, PA, Barge-Schaapveld, DQ, Piers, SR, van der Smagt, JJ, Asselbergs, FW, de Boer, RA, van den Berg, MP, Almomani, R, Sinke, RJ, van Tintelen, JP, and Human Genetics
- Published
- 2014
10. BENIGN JOINT HYPOMOBILITY SYNDROME: A NEW CLINICAL ENTITY, POSSIBLY CAUSED BY A PROBLEM IN THE COLLAGEN SYNTHESIS?
- Author
-
Engelbert, RHH, Uiterwaal, CSPM, Van Tintelen, JP, Pruijs, JEH, Helders, PJM, TeKoppele, JM, and Bank, RA
- Subjects
Physical therapy -- Research - Abstract
PURPOSE: To describe the clinical features and problems in collagen synthesis of a new clinical entity, which we propose to call the "benign joint hypomobility syndrome." SUBJECTS: Eight children (six boys, two girls; age 5-15 years) with generalized hypomobility of the joints in the absence of signs of rheumatic, neurologic, skeletal or metabolic diseases are included. METHODS AND MATERIALS: Range of joint motion, anthropological measurements, muscle strength and motor performance were measured. Collagen degradation products (Hyp, LP, HP) were measured in urine and compared with urines of 91 healthy children. Collagen modifications were determined in skin, hypertrophic scar tissue and in joint capsule of one patient and compared with a reference group of 10 healthy persons. ANALYSIS: Urinary data were compared with urine samples from age-related healthy children (Mann-Whitney U test). RESULTS: No consistent pattern of dysmorphic features was noticed and no known syndromes could be traced. Most children were habitual toe-walkers and this was seen in male family members as well. Exercise-induced pain occurred in the calf muscles. Generalized hypomobility of the joints was present and muscle strength, age of independent walking, anthropometrical characteristics and motor development were normal. Increased levels of pyridinoline cross-links were seen in skin and hypertrophic scar, increased amounts of collagen levels in the skin. In urine, the median amounts of collagen degradation products were: 90 [micro]mol/mmol (range: 54 to 130) in patients and 143 [micro]mol/mmol (range: 20 to 1060) in healthy controls for Hyp (p=0.025) 192 [micro]mol/mmol (range: 154-248) in patients, 385 [micro]mol/mmol (range 26-2434) in controls for the combined amount of HP and LP (p=0.007). CONCLUSIONS: Otherwise healthy children with generalized hypomobility may be characterized by changes in collagen metabolism. We propose to call the described new clinical entity the "benign joint hypomobility syndrome.", Engelbert RHH, Uiterwaal CSPM, Van Tintelen JP, Pruijs JEH, Helders PJM, TeKoppele JM, Bank RA. Departments of Pediatric Physical Therapy, Epidemiology, Medical Genetics, Pediatric Orthopedics, Collagen and Vascular Research, University [...]
- Published
- 2001
11. Bohring syndrome
- Author
-
Brunner, HG, van Tintelen, JP, de Boer, RJ, Other departments, and Cardiovascular Centre (CVC)
- Subjects
Clinical description and delineation of genetic syndromes ,Klinische beschrijving en moleculaire definiëring van genetische syndromen ,Genetics (clinical) - Abstract
Item does not contain fulltext
- Published
- 2000
12. Detection of genomic deletions ofPKP2in arrhythmogenic right ventricular cardiomyopathy
- Author
-
Roberts, JD, primary, Herkert, JC, additional, Rutberg, J, additional, Nikkel, SM, additional, Wiesfeld, ACP, additional, Dooijes, D, additional, Gow, RM, additional, van Tintelen, JP, additional, and Gollob, MH, additional
- Published
- 2012
- Full Text
- View/download PDF
13. Haplotype sharing test maps genes for familial cardiomyopathies†
- Author
-
van der Zwaag, PA, primary, van Tintelen, JP, additional, Gerbens, F, additional, Jongbloed, JDH, additional, Boven, LG, additional, van der Smagt, JJ, additional, van der Roest, WP, additional, van Langen, IM, additional, Bikker, H, additional, Hauer, RNW, additional, van den Berg, MP, additional, Hofstra, RMW, additional, and te Meerman, GJ, additional
- Published
- 2011
- Full Text
- View/download PDF
14. Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome
- Author
-
Radonic, T, primary, de Witte, P, additional, Groenink, M, additional, de Bruin-Bon, RACM, additional, Timmermans, J, additional, Scholte, AJH, additional, van den Berg, MP, additional, Baars, MJH, additional, van Tintelen, JP, additional, Kempers, M, additional, Zwinderman, AH, additional, and Mulder, BJM, additional
- Published
- 2011
- Full Text
- View/download PDF
15. Desmin-related myopathy
- Author
-
van Spaendonck-Zwarts, KY, primary, van Hessem, L, additional, Jongbloed, JDH, additional, de Walle, HEK, additional, Capetanaki, Y, additional, van der Kooi, AJ, additional, van Langen, IM, additional, van den Berg, MP, additional, and van Tintelen, JP, additional
- Published
- 2010
- Full Text
- View/download PDF
16. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.
- Author
-
van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, Alings AM, Bosker HA, Bracke FA, van den Heuvel F, Waalewijn RA, Bikker H, van Tintelen JP, Bhuiyan ZA, van den Berg MP, and Wilde AA
- Published
- 2012
- Full Text
- View/download PDF
17. Desmin-related myopathy.
- Author
-
van Spaendonck-Zwarts, KY, van Hessem, L, Jongbloed, JDH, de Walle, HEK, Capetanaki, Y, van der Kooi, AJ, van Langen, IM, van den Berg, MP, and van Tintelen, JP
- Subjects
NEUROMUSCULAR diseases ,MOLECULAR genetics ,META-analysis ,CREATINE kinase ,CARDIOMYOPATHIES ,HEART conduction system ,CYTOARCHITECTONICS ,DISEASES - Abstract
van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JDH, de Walle HEK, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP. Desmin-related myopathy. Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene ( DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta-analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers ( n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
18. 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.
- Author
-
Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, Noorman M, Bhuiyan ZA, Wiesfeld AC, Volders PG, van Langen IM, Atsma DE, Dooijes D, van den Wijngaard A, Houweling AC, Jongbloed JD, Jordaens L, Cramer MJ, Doevendans PA, de Bakker JM, Wilde AA, and van Tintelen JP
- Published
- 2011
- Full Text
- View/download PDF
19. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy.
- Author
-
van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ, Dooijes D, and van den Berg MP
- Published
- 2010
- Full Text
- View/download PDF
20. Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene.
- Author
-
van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, van Berlo JH, Boven LG, Suurmeijer AJ, White SJ, den Dunnen JT, te Meerman GJ, Vos YJ, van der Hout AH, Osinga J, van den Berg MP, van Veldhuisen DJ, Buys CH, Hofstra RM, and Pinto YM
- Published
- 2007
- Full Text
- View/download PDF
21. Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?
- Author
-
van Tintelen JP, Hofstra RMW, Wiesfeld ACP, van den Berg MP, Hauer RNW, and Jongbloed JD
- Published
- 2007
- Full Text
- View/download PDF
22. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.
- Author
-
van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, van der Smagt J, Boven LG, Mannens MM, van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, van Gelder IC, and Hauer RN
- Published
- 2006
23. Counsel the genotype, treat the phenotype.
- Author
-
van der Zwaag PA and van Tintelen JP
- Published
- 2011
24. P573 Added diagnostic value of multiplex ligation-dependent probe amplification of plakophilin-2 in arrhythmogenic cardiomyopathy.
- Author
-
Lazzarini, E, Rigato, I, Jongbloed, JD, Celeghin, R, Cason, M, Carturan, E, Thiene, G, Basso, C, Pilichou, K, and Van Tintelen, JP
- Subjects
GENE amplification ,CARDIOMYOPATHIES ,VENTRICULAR arrhythmia ,GENETIC code ,DNA copy number variations ,POLYMERASE chain reaction ,DISEASE risk factors - Abstract
Background: Arrhythmogenic Cardiomyopathy (ACM) is an inherited myocardial disease characterized by fibro-fatty replacement of myocardium. Patients are at risk of ventricular arrhythmias and sudden death. Screening of desmosomal genes currently results in a diagnostic yield of about 50%.Aim: The aim of this study is to investigate whether detection of large deletions/duplications of the plakophilin-2 gene (PKP2) increase the yield of genetic screening in ACM.Methods: 60 index cases with a clinical diagnosis of ACM consecutively enrolled at our referral center underwent bidirectional sequencing using ABI-PRISM 3730 (Life Technologies) for all desmosomal-encoding genes. Genotype-negative patients were additionally screened for copy number variations (CNVs) in PKP2 by Multiplex Ligation-dependant Probe Amplification (MLPA) using SALSA MLPA kit P168 ARVC-PKP2 (MRC-Holland) and by quantitative Real-Time PCR on a Roche Light Cycler 480 platform.Results: Conventional sequencing of the ACM patients identified disease-causing nucleotide variants in 36 of the 60 ACM-patients (60%); 8% (n=5) of the cohort presented mutation in Desmoglein-2 gene, 23% (n=14) in Desmoplakin, 12% (n=7) in PKP2, 3% (n=2) in Desmocollin-2, 3% in Plakoglobin (n=2) whereas 10% (n=6) were multiple mutations carriers. MLPA analysis successfully identified a heterozygous deletion of exon 4 in an otherwise genotype-negative case, which was further confirmed by qPCR analysis showing a reduction of PKP2 copy number when compared to control samples.Conclusions: This study highlights the potential of increasing the diagnostic genetic yield - in our population by nearly 2% for just one gene- by searching CNVs in ACM patients. This will be also achieved by extending the analysis to all ACM disease-causing genes as well as to genotype-positive patients. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
- Full Text
- View/download PDF
25. P764 Phospholamban p.Arg14del-mutation related cardiomyopathy is a biventricular arrhythmogenic cardiomyopathy and protein-aggregate associated disease.
- Author
-
Te Rijdt, WP, Van Der Zwaag, PA, Van Tintelen, JP, Gho, JMI, De Boer, RA, Van Den Berg, MP, Van Der Wal, AC, Vink, A, and Suurmeijer, AS
- Subjects
PHOSPHOLAMBAN ,GENETIC mutation ,CARDIOMYOPATHIES ,PROTEIN analysis ,AUTOPHAGY ,IMMUNOHISTOCHEMISTRY - Abstract
Purpose: To examine the gross and microscopic pathological features of complete heart specimens from patients carrying the phospholamban (PLN) p.Arg14del mutation and to test our hypothesis that this mutation leads to aggregation and autophagy of mutant PLN protein in cardiomyocytes.Methods: Sixteen hearts were studied, acquired from 8 male and 8 female patients with a median age of 51.5 years (range 29-74). Eleven were obtained from autopsies and five were explants. Six autopsy cases had died suddenly. The other 10 patients were clinically evaluated on the basis of widely accepted criteria for ARVC and DCM. Immunohistochemistry (IHC) for PLN was performed to visualize protein aggregation. IHC for sequestosome-1 (SQSTM-1/p62) was applied to visualize autophagy. Double IHC staining was performed to study co-localization of PLN and SQSTM-1/p62 in aggregates.Results: All hearts had an ARVC phenotype with gross or microscopic fibrofatty replacement of the RV wall. LV involvement was present in 15/16 hearts, characterized by interstitial fibrosis and myocyte hypertrophy. Microscopic LV fibrofatty replacement was seen in 8/16 hearts. Clinically, 8/10 patients were diagnosed with combined ARVC/DCM and 2/10 had ARVC. Large perinuclear PLN protein aggregates were found in cardiomyocytes in both ventricles in all examined hearts. The median number of PLN aggregates was 8 per 5mm2 (range 1-19) in RV myocardium and 12 per 5mm2 (range 2-39) in LV myocardium. Co-localization of SQSTM-1/p62 and PLN was observed in these aggregates.Conclusions: In this series of 16 hearts, it appeared that PLN p.Arg14del-mutation related cardiomyopathy is a biventricular arrhythmogenic cardiomyopathy and a protein-aggregate associated disease characterized by large perinuclear PLN aggregates that are degraded by autophagy.Typical example gross pathological feat. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
- Full Text
- View/download PDF
26. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
- Author
-
van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ, van Tintelen JP, van den Berg MP, Pilotto A, Pasotti M, Jenkins S, Rowland C, Aslam U, Wilde AA, Perrot A, Pankuweit S, Zwinderman AH, Charron P, and Pinto YM
- Published
- 2012
27. Mortality risk of untreated Myosin-binding protein C-related hypertrophic cardiomyopathy insight into the natural history.
- Author
-
Nannenberg EA, Michels M, Christiaans I, Majoor-Krakauer D, Hoedemaekers YM, van Tintelen JP, Lombardi MP, Ten Cate FJ, Schinkel AF, Tijssen JG, van Langen IM, Wilde AA, and Sijbrands EJ
- Published
- 2011
28. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.
- Author
-
Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MG, Bhuiyan Z, Bikker H, Wiesfeld AC, Hauer RN, van Tintelen JP, Jongbloed JD, Calkins H, Judge DP, Wilde AA, Ackerman MJ, Kapplinger, Jamie D, Landstrom, Andrew P, and Salisbury, Benjamin A
- Abstract
Objectives: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.Background: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.Methods: Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.Results: The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.Conclusions: This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
29. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.
- Author
-
Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, Mannens MM, Wilde AA, Ackerman MJ, Medeiros-Domingo, Argelia, Bhuiyan, Zahurul A, Tester, David J, Hofman, Nynke, Bikker, Hennie, van Tintelen, J Peter, Mannens, Marcel M A M, Wilde, Arthur A M, and Ackerman, Michael J
- Abstract
Objectives: This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc).Background: Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts.Methods: Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45).Results: Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons.Conclusions: Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
30. Developmental aspects of long QT syndrome type 3 Brugada syndrome on the basis of a single SCN5A mutation in childhood.
- Author
-
Beaufort-Krol GCM, van den Berg MP, Wilde AAM, van Tintelen JP, Viersma JW, Bezzina CR, and Bink-Boelkens ME
- Published
- 2005
- Full Text
- View/download PDF
31. Clinical features and outcomes in carriers of pathogenic desmoplakin variants.
- Author
-
Gasperetti A, Carrick RT, Protonotarios A, Murray B, Laredo M, van der Schaaf I, Lekanne RH, Syrris P, Cannie D, Tichnell C, Cappelletto C, Gigli M, Medo K, Saguner AM, Duru F, Gilotra NA, Zimmerman S, Hylind R, Abrams DJ, Lakdawala NK, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Casella M, Tondo C, Yazdani M, Ware JS, Prasad SK, Calò L, Smith ED, Helms AS, Hespe S, Ingles J, Tandri H, Ader F, Peretto G, Peters S, Horton A, Yao J, Dittmann S, Schulze-Bahr E, Qureshi M, Young K, Carruth ED, Haggerty C, Parikh VN, Taylor M, Mestroni L, Wilde A, Sinagra G, Merlo M, Gandjbakhch E, van Tintelen JP, Te Riele ASJM, Elliott PM, Calkins H, and James CA
- Abstract
Background and Aims: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown., Methods: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes., Results: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively)., Conclusions: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
32. Absence of an increased wall thickness does not rule out cardiac amyloidosis.
- Author
-
Muller SA, Achten A, van der Meer MG, Zwetsloot PP, Sanders-van Wijk S, van der Harst P, van Tintelen JP, Te Riele ASJM, van Empel V, Knackstedt C, and Oerlemans MIFJ
- Subjects
- Humans, Male, Female, Aged, Middle Aged, Echocardiography, Amyloidosis pathology, Amyloidosis diagnosis, Amyloidosis diagnostic imaging, Cardiomyopathies diagnostic imaging, Cardiomyopathies pathology, Cardiomyopathies diagnosis
- Published
- 2024
- Full Text
- View/download PDF
33. A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.
- Author
-
Carrick RT, Gasperetti A, Protonotarios A, Murray B, Laredo M, van der Schaaf I, Dooijes D, Syrris P, Cannie D, Tichnell C, Gilotra NA, Cappelletto C, Medo K, Saguner AM, Duru F, Hylind RJ, Abrams DJ, Lakdawala NK, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Compagnucci P, Casella M, Conte G, Tondo C, Yazdani M, Ware JS, Prasad SK, Calò L, Smith ED, Helms AS, Hespe S, Ingles J, Tandri H, Ader F, Peretto G, Peters S, Horton A, Yao J, Schulze-Bahr E, Dittman S, Carruth ED, Young K, Qureshi M, Haggerty C, Parikh VN, Taylor M, Mestroni L, Wilde A, Sinagra G, Merlo M, Gandjbakhch E, van Tintelen JP, Te Riele ASJM, Elliott P, Calkins H, Wu KC, and James CA
- Subjects
- Humans, Female, Male, Risk Assessment methods, Adult, Middle Aged, Arrhythmias, Cardiac genetics, Heterozygote, Tachycardia, Ventricular genetics, Desmoplakins genetics
- Abstract
Background and Aims: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population., Methods: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86)., Results: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%., Conclusions: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
34. Diagnostic value of late gadolinium enhancement at cardiovascular magnetic resonance to distinguish arrhythmogenic right ventricular cardiomyopathy from differentials.
- Author
-
Rekker LY, Muller SA, Gasperetti A, Bourfiss M, Oerlemans MIFJ, Cramer MJ, Zimmerman SL, Dooijes D, Schalkx H, van der Harst P, James CA, van Tintelen JP, Guglielmo M, Velthuis BK, and Te Riele ASJM
- Abstract
Background: While late gadolinium enhancement (LGE) is proposed as a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC), the potential of LGE to distinguish ARVC from differentials remains unknown. We aimed to assess the diagnostic value of LGE for ARVC diagnosis., Methods: We included 132 subjects (60% male, 47 ± 11 years) who had undergone cardiac magnetic resonance imaging with LGE assessment for ARVC or ARVC differentials. ARVC was diagnosed as per 2010 Task Force Criteria (n = 55). ARVC differentials consisted of familial/genetic dilated cardiomyopathy (n = 25), myocarditis (n = 13), sarcoidosis (n = 20), and amyloidosis (n = 19). The diagnosis of all differentials was based on the most current standard of reference. The presence of LGE was evaluated using a 7-segment right ventricle (RV) and 17-segment left ventricle (LV) model. Subsequently, we assessed LGE patterns for every patient individually for fulfilling LV- and/or RV-LGE per Padua criteria, independent of their clinical diagnosis (i.e. phenotype). Diagnostic values were analyzed using sensitivity and specificity for any RV-LGE, any LV-LGE, RV-LGE per Padua criteria, and prevalence graphs for LV-LGE per Padua criteria. The optimal integration of LGE for ARVC diagnosis was determined using classification and regression tree analysis., Results: One-third (38%) of ARVC patients had RV-LGE, while half (51%) had LV-LGE. RV-LGE was less frequently observed in ARVC vs non-ARVC patients (38% vs 58%, p = 0.034) leading to a poor discriminatory potential (any RV-LGE: sensitivity 38%, specificity 42%; RV-LGE per Padua criteria: sensitivity 36%, specificity 44%). Compared to ARVC patients, non-ARVC patients more often had LV-LGE (91% vs 51%, p < 0.001) which was also more globally distributed (median 9 [interquartile range (IQR): 3-13] vs 0 [IQR: 0-3] segments, p < 0.001). The absence of anteroseptal and absence of extensive (≥5 segments) mid-myocardial LV-LGE, and absence of moderate (≥2 segments) mid-myocardial LV-LGE predicted ARVC with good diagnostic performance (sensitivity 93%, specificity 78%)., Conclusion: LGE is often present in ARVC differentials and may lead to false positive diagnoses when used without knowledge of LGE patterns. Moderate RV-LGE without anteroseptal and mid-myocardial LV-LGE is typically observed in ARVC., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. A.G. has served as part of the advisory board of LEXEO Therapeutics for unrelated work. The remaining authors have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
35. Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.
- Author
-
Nicastro M, Vermeer AMC, Postema PG, Tadros R, Bowling FZ, Aegisdottir HM, Tragante V, Mach L, Postma AV, Lodder EM, van Duijvenboden K, Zwart R, Beekman L, Wu L, van der Zwaag PA, Alders M, Allouba M, Aguib Y, Santomel JL, de Una D, Monserrat L, Miranda AMA, Kanemaru K, Cranley J, van Zeggeren IE, Aronica EMA, Ripolone M, Zanotti S, Sveinbjornsson G, Ivarsdottir EV, Hólm H, Guðbjartsson DF, Skúladóttir ÁT, Stefánsson K, Nadauld L, Knowlton KU, Ostrowski SR, Sørensen E, Vesterager Pedersen OB, Ghouse J, Rand S, Bundgaard H, Ullum H, Erikstrup C, Aagaard B, Bruun MT, Christiansen M, Jensen HK, Carere DA, Cummings CT, Fishler K, Tøring PM, Brusgaard K, Juul TM, Saaby L, Winkel BG, Mogensen J, Fortunato F, Comi GP, Ronchi D, van Tintelen JP, Noseda M, Airola MV, Christiaans I, Wilde AAM, Wilders R, Clur SA, Verkerk AO, Bezzina CR, and Lahrouchi N
- Abstract
POPDC2 encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia and morpholino knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2, but not in POPDC1 related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for POPDC2 as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functional POPDC2 display sinus and AV node dysfunction.
- Published
- 2024
- Full Text
- View/download PDF
36. Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis.
- Author
-
Muller SA, Peiró-Aventin B, Biagioni G, Tini G, Saturi G, Kronberger C, Achten A, Dobner S, Te Rijdt WP, Gasperetti A, Te Riele ASJM, Varrà GG, Ponziani A, Hirsch A, Porcari A, van der Meer MG, Zampieri M, van der Harst P, Kammerlander A, Biagini E, van Tintelen JP, Barbato E, Asselbergs FW, Menale S, Gräni C, Merlo M, Michels M, Knackstedt C, Nitsche C, Longhi S, Musumeci B, Cappelli F, Garcia-Pavia P, and Oerlemans MIFJ
- Abstract
Aims: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement., Methods and Results: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%., Conclusions: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
37. Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.
- Author
-
van der Heide MYC, Verstraelen TE, van Lint FHM, Bosman LP, de Brouwer R, Proost VM, van Drie E, Taha K, Zwinderman AH, Dickhoff C, Schoonderwoerd BA, Germans T, Houweling AC, Gimeno-Blanes JR, van der Zwaag PA, de Boer RA, Cox MGPJ, van Tintelen JP, and Wilde AAM
- Subjects
- Female, Humans, Male, Calcium-Binding Proteins genetics, Death, Sudden, Cardiac etiology, Death, Sudden, Cardiac prevention & control, Reproducibility of Results, Risk Factors, Adult, Middle Aged, Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac therapy, Defibrillators, Implantable
- Abstract
Aims: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up., Methods and Results: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97., Conclusion: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up., Competing Interests: Conflict of interest: The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. R.A.deB. has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. T.G. has had speaker engagements with Bristol Myers Squibb. M.Y.C.vd.H. and A.A.M.W. report grants from PLN foundation, grants from CVON Netherlands Heart Foundation (PREDICT2) and ZonMw (PSIDER-Heart) during this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
38. Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.
- Author
-
Carrick RT, De Marco C, Gasperetti A, Bosman LP, Gourraud JB, Trancuccio A, Mazzanti A, Murray B, Pendleton C, Tichnell C, Tandri H, Zeppenfeld K, Wilde AAM, Davies B, Seifer C, Roberts JD, Healey JS, MacIntyre C, Alqarawi W, Tadros R, Cutler MJ, Targetti M, Calò L, Vitali F, Bertini M, Compagnucci P, Casella M, Dello Russo A, Cappelletto C, De Luca A, Stolfo D, Duru F, Jensen HK, Svensson A, Dahlberg P, Hasselberg NE, Di Marco A, Jordà P, Arbelo E, Moreno Weidmann Z, Borowiec K, Delinière A, Biernacka EK, van Tintelen JP, Platonov PG, Olivotto I, Saguner AM, Haugaa KH, Cox M, Tondo C, Merlo M, Krahn AD, Te Riele ASJM, Wu KC, Calkins H, James CA, and Cadrin-Tourigny J
- Subjects
- Humans, Retrospective Studies, Arrhythmias, Cardiac epidemiology, Arrhythmias, Cardiac therapy, Arrhythmias, Cardiac etiology, Death, Sudden, Cardiac epidemiology, Death, Sudden, Cardiac prevention & control, Death, Sudden, Cardiac etiology, Risk Factors, North America epidemiology, Europe epidemiology, Defibrillators, Implantable adverse effects, Arrhythmogenic Right Ventricular Dysplasia complications, Arrhythmogenic Right Ventricular Dysplasia epidemiology, Arrhythmogenic Right Ventricular Dysplasia therapy
- Abstract
Background and Aims: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC., Methods: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed., Results: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans., Conclusions: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
39. Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study.
- Author
-
Jansen M, de Brouwer R, Hassanzada F, Schoemaker AE, Schmidt AF, Kooijman-Reumerman MD, Bracun V, Slieker MG, Dooijes D, Vermeer AMC, Wilde AAM, Amin AS, Lekanne Deprez RH, Herkert JC, Christiaans I, de Boer RA, Jongbloed JDH, van Tintelen JP, Asselbergs FW, and Baas AF
- Subjects
- Humans, Male, Adult, Child, Preschool, Child, Female, Penetrance, Cohort Studies, Prognosis, Mutation, Myosin Heavy Chains genetics, Cardiac Myosins genetics, Heart Failure, Cardiomyopathies genetics, Cardiomyopathy, Hypertrophic, Cardiomyopathy, Dilated genetics
- Abstract
Background: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene., Objectives: This study sought to study the penetrance and prognosis of MYH7 variant-associated cardiomyopathies., Methods: In this multicenter cohort study, penetrance and major cardiomyopathy-related events (MCEs) were assessed in carriers of (likely) pathogenic MYH7 variants by using Kaplan-Meier curves and log-rank tests. Prognostic factors were evaluated using Cox regression with time-dependent coefficients., Results: In total, 581 subjects (30.1% index patients, 48.4% male, median age 37.0 years [IQR: 19.5-50.2 years]) were included. HCM was diagnosed in 226 subjects, NCCM in 70, and DCM in 55. Early penetrance and MCEs (age <12 years) were common among NCCM-associated variant carriers (21.2% and 12.0%, respectively) and DCM-associated variant carriers (15.3% and 10.0%, respectively), compared with HCM-associated variant carriers (2.9% and 2.1%, respectively). Penetrance was significantly increased in carriers of converter region variants (adjusted HR: 1.87; 95% CI: 1.15-3.04; P = 0.012) and at age ≤1 year in NCCM-associated or DCM-associated variant carriers (adjusted HR: 21.17; 95% CI: 4.81-93.20; P < 0.001) and subjects with a family history of early MCEs (adjusted HR: 2.45; 95% CI: 1.09-5.50; P = 0.030). The risk of MCE was increased in subjects with a family history of early MCEs (adjusted HR: 1.82; 95% CI: 1.15-2.87; P = 0.010) and at age ≤5 years in NCCM-associated or DCM-associated variant carriers (adjusted HR: 38.82; 95% CI: 5.16-291.88; P < 0.001)., Conclusions: MYH7 variants can cause cardiomyopathies and MCEs at a young age. Screening at younger ages may be warranted, particularly in carriers of NCCM- or DCM-associated variants and/or with a family history of MCEs at <12 years., Competing Interests: Funding Support and Author Disclosures This work was supported by the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation. Dr Jansen has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA [Dutch Cardiovascular Alliance] 2020B005 DoubleDose) and from the Dutch Heart Foundation (Dekker 2015T041). Dr Christiaans has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2015-12 e-Detect). Dr de Boer has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose). Dr van Tintelen has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect). Dr Asselbergs has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect) and from the UCL Hospitals NIHR Biomedical Research Centre. Dr Baas has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect) and from the Dutch Heart Foundation (Dekker 2015T041). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
40. Influence of stressful life events and personality traits on PLN cardiomyopathy severity: an exploratory study.
- Author
-
van Drie E, Taal SEL, Schmidt AF, Verstraelen TE, de Brouwer R, Schoormans D, Mommersteeg PMC, de Boer RA, Wilde AAM, Asselbergs FW, Baas AF, van Tintelen JP, and van den Heuvel LM
- Subjects
- Humans, Personality, Stress, Psychological complications, Cardiomyopathies complications
- Abstract
Competing Interests: Conflict of interest: none declared.
- Published
- 2023
- Full Text
- View/download PDF
41. Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.
- Author
-
Jansen M, Schmidt AF, Jans JJM, Christiaans I, van der Crabben SN, Hoedemaekers YM, Dooijes D, Jongbloed JDH, Boven LG, Lekanne Deprez RH, Wilde AAM, van der Velden J, de Boer RA, van Tintelen JP, Asselbergs FW, and Baas AF
- Subjects
- Humans, Cross-Sectional Studies, Phenotype, Biomarkers, Mutation, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic genetics
- Abstract
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
42. Predicting personal cardiovascular disease risk based on family health history: Development of expert-based family criteria for the general population.
- Author
-
Dijkstra T, van den Heuvel LM, van Tintelen JP, van der Werf C, van Langen IM, and Christiaans I
- Subjects
- Humans, Family Health, Risk Assessment, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases genetics, Aortic Aneurysm, Thoracic
- Abstract
In inherited and familial cardiovascular diseases (CVDs), relatives without current symptoms can still be at risk for early and preventable cardiovascular events. One way to help people evaluate their potential risk of CVD is through a risk-assessment tool based on family health history. However, family criteria including inherited CVD risk to be used by laypersons are non-existent. In this project, we employed a qualitative study design to develop expert-based family criteria for use in individual risk assessment. In the first phase of the project, we identified potential family criteria through an online focus group with physicians with expertise in monogenic and/or multifactorial CVDs. The family criteria from phase one were then used as input for a three-round Delphi procedure carried out in a larger group of expert physicians to reach consensus on appropriate criteria. This led to consensus on five family criteria that focus on cardiovascular events at young age (i.e., sudden death, any CVD, implantable cardioverter-defibrillator, aortic aneurysm) and/or an inherited CVD in one or more close relatives. We then applied these family criteria to a high-risk cohort from a clinical genetics department and demonstrated that they have substantial diagnostic accuracy. After further evaluation in a general population cohort, we decided to only use the family criteria for first-degree relatives. We plan to incorporate these family criteria into a digital tool for easy risk assessment by the public and, based on expert advice, will develop supporting information for general practitioners to act upon potential risks identified by the tool. Results from an expert focus group, a Delphi method in a larger group of experts, and evaluation in two cohorts were used to develop family criteria for assessing cardiovascular disease risk based on family health history for a digital risk-prediction tool for use by the general population. CVD Cardiovascular disease, ICD Implantable cardioverter defibrillator, TAA Thoracic aortic aneurysm, AAA Abdominal aortic aneurysm., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2023
- Full Text
- View/download PDF
43. A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.
- Author
-
Nagyova E, Hoorntje ET, Te Rijdt WP, Bosman LP, Syrris P, Protonotarios A, Elliott PM, Tsatsopoulou A, Mestroni L, Taylor MRG, Sinagra G, Merlo M, Wada Y, Horie M, Mogensen J, Christensen AH, Gerull B, Song L, Yao Y, Fan S, Saguner AM, Duru F, Koskenvuo JW, Cruz Marino T, Tichnell C, Judge DP, Dooijes D, Lekanne Deprez RH, Basso C, Pilichou K, Bauce B, Wilde AAM, Charron P, Fressart V, van der Heijden JF, van den Berg MP, Asselbergs FW, James CA, Jongbloed JDH, Harakalova M, and van Tintelen JP
- Subjects
- Humans, Plakophilins genetics, Phenotype, Arrhythmias, Cardiac, Mutation, Arrhythmogenic Right Ventricular Dysplasia diagnosis, Arrhythmogenic Right Ventricular Dysplasia genetics
- Abstract
The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
44. Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies.
- Author
-
van der Voorn SM, van Drie E, Proost V, Dimitrova K, Netherlands Acm/Pln Registry, Ernst RF, James CA, Tichnell C, Murray B, Calkins H, Saguner AM, Duru F, Ellinor PT, Bezzina CR, Jurgens SJ, van Tintelen JP, and van Veen TAB
- Subjects
- Humans, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism, Calcium metabolism, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Histidine genetics, Polymorphism, Genetic, Cardiomyopathies genetics, Cardiomyopathy, Dilated genetics
- Abstract
Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca
2+ ) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban ( PLN ) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.- Published
- 2023
- Full Text
- View/download PDF
45. [2023 ESC Guidelines for the management of cardiomyopathies].
- Author
-
Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, De Winter T, Elliott PM, Flather M, Garcia-Pavia P, Haugaa KH, Ingles J, Jurcut RO, Klaassen S, Limongelli G, Loeys B, Mogensen J, Olivotto I, Pantazis A, Sharma S, Van Tintelen JP, Ware JS, and Kaski JP
- Subjects
- Humans, Electrocardiography, Cardiomyopathies therapy
- Published
- 2023
- Full Text
- View/download PDF
46. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers.
- Author
-
de Brouwer R, Te Rijdt WP, Hoorntje ET, Amin A, Asselbergs FW, Cox MGPJ, van der Heijden JF, Hillege H, Karper JC, Mahmoud B, van der Meer P, Oomen A, Te Riele ASJM, Silljé HHW, Tan HL, van Tintelen JP, van Veldhuisen DJ, Westenbrink BD, Wiesfeld ACP, Willems TP, van der Zwaag PA, Wilde AAM, de Boer RA, and van den Berg MP
- Abstract
Competing Interests: Conflict of interest: R.A.d.B. is president-elect of the Dutch Cardiac Society (NVVC), member of the Executive Committee of the DELIVER-trial and has received grants from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche in the last 36 months. R.A.d.B. has received payment or honoraria from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche in the last 36 months. J.P.v.T. has received consulting fees from StrideBio in the last 36 months. A.A.M.W. has received grants from the Dutch Heart Foundation and consulting fees from LQT Therapeutics and ARMGO in the last 36 months. A.A.M.W. additionally is a member of the advisory board of the Leap Trial.
- Published
- 2023
- Full Text
- View/download PDF
47. Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.
- Author
-
Niskanen JE, Ohlsson Å, Ljungvall I, Drögemüller M, Ernst RF, Dooijes D, van Deutekom HWM, van Tintelen JP, Snijders Blok CJB, van Vugt M, van Setten J, Asselbergs FW, Petrič AD, Salonen M, Hundi S, Hörtenhuber M, Kere J, Pyle WG, Donner J, Postma AV, Leeb T, Andersson G, Hytönen MK, Häggström J, Wiberg M, Friederich J, Eberhard J, Harakalova M, van Steenbeek FG, Wess G, and Lohi H
- Subjects
- Humans, Animals, Dogs, Homeostasis, Models, Animal, Phenotype, Risk Factors, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated veterinary
- Abstract
Background: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis., Methods: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts., Results: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes., Conclusions: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
48. Exercise does not influence development of phenotype in PLN p.(Arg14del) cardiomyopathy.
- Author
-
van Lint FHM, Hassanzada F, Verstraelen TE, Wang W, Bosman LP, van der Zwaag PA, Oomen T, Calkins H, Murray B, Tichnell C, Beuren TMA, Asselbergs FW, Houweling A, van den Berg MP, Wilde AAM, James CA, and van Tintelen JP
- Abstract
Background: Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.(Arg14del) variant in the PLN gene are frequently diagnosed with ARVC or dilated cardiomyopathy (DCM). The aim of this study was to evaluate the effect of exercise in PLN p.(Arg14del) carriers., Methods: In total, 207 adult PLN p.(Arg14del) carriers (39.1% male; mean age 53 ± 15 years) were interviewed on their regular physical activity since the age of 10 years. The association of exercise with diagnosis of ARVC, DCM, sustained VA and hospitalisation for heart failure (HF) was studied., Results: Individuals participated in regular physical activities with a median of 1661 metabolic equivalent of task (MET) hours per year (31.9 MET-hours per week) until clinical presentation. The 50% most and least active individuals had a similar frequency of sustained VA (18.3% vs 18.4%; p = 0.974) and hospitalisation for HF (9.6% vs 8.7%; p = 0.827). There was no relationship between exercise and survival free from (incident) sustained VA (p = 0.65), hospitalisation for HF (p = 0.81), diagnosis of ARVC (p = 0.67) or DCM (p = 0.39) during follow-up. In multivariate analyses, exercise was not associated with sustained VA or HF hospitalisation during follow-up in this relatively not-active cohort., Conclusion: There was no association between the amount of exercise and the susceptibility to develop ARVC, DCM, VA or HF in PLN p.(Arg14del) carriers. This suggested unaffected PLN p.(Arg14del) carriers can safely perform mild-moderate exercise, in contrast to desmosomal variant carriers and ARVC patients., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
49. The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant.
- Author
-
Bos TA, Piers SRD, Wessels MW, Houweling AC, Bökenkamp R, Bootsma M, Bosman LP, Evertz R, Hellebrekers DMEI, Hoedemaekers YM, Knijnenburg J, Lekanne Deprez R, van Mil AM, Te Riele ASJM, van Slegtenhorst MA, Wilde AAM, Yap SC, Dooijes D, Koopmann TT, van Tintelen JP, and Barge-Schaapveld DQCM
- Abstract
Background: The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants., Methods: Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?))., Results: Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between 4 PKP2 founder variants, including c.1211dup., Conclusions: The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
50. MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset.
- Author
-
Marsili L, van Lint FHM, Russo F, van Spaendonck-Zwarts KY, Ader F, Bichon ML, Faivre L, Houweling AC, Isidor B, Lekanne Deprez RH, Cox MGPJ, Wilde AAM, Mazel B, Mercier S, Dooijes D, Millat G, Nguyen K, Post JG, Richard P, van de Beek I, Vermeer AMC, Boven L, Jongbloed JDH, and van Tintelen JP
- Abstract
Introduction: The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect., Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort., Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients., Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.