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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.
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Cardiomiopatía Hipertrófica , Humanos , Estudios Transversales , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/genética , Fenotipo , Biomarcadores , MutaciónRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts. RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations. CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.
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Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Proteínas Portadoras/genética , Metilación de ADN , Expresión Génica , Genes Homeobox , Histonas/genética , Humanos , Mutación , TranscriptomaRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. AIM: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. METHODS: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827Câ¯>â¯T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥â¯20â¯mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). RESULTS: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. CONCLUSION: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.
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In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.
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INTRODUCTION: Despite major advances in our understanding of genetic cardiomyopathies, they remain the leading cause of premature sudden cardiac death and end-stage heart failure in persons under the age of 60 years. Integrated research databases based on a large number of patients may provide a scaffold for future research. Using routine electronic health records and standardised biobanking, big data analysis on a larger number of patients and investigations are possible. In this article, we describe the UNRAVEL research data platform embedded in routine practice to facilitate research in genetic cardiomyopathies. DESIGN: Eligible participants with proven or suspected cardiac disease and their relatives are asked for permission to use their data and to draw blood for biobanking. Routinely collected clinical data are included in a research database by weekly extraction. A text-mining tool has been developed to enrich UNRAVEL with unstructured data in clinical notes. PRELIMINARY RESULTS: Thus far, 828 individuals with a median age of 57 years have been included, 58% of whom are male. All data are captured in a temporal sequence amounting to a total of 18,565 electrocardiograms, 3619 echocardiograms, data from over 20,000 radiological examinations and 650,000 individual laboratory measurements. CONCLUSION: Integration of routine electronic health care in a research data platform allows efficient data collection, including all investigations in chronological sequence. Trials embedded in the electronic health record are now possible, providing cost-effective ways to answer clinical questions. We explicitly welcome national and international collaboration and have provided our protocols and other materials on www.unravelrdp.nl .
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Chemotherapy-induced cardiomyopathy (CCMP) is a complication of chemotherapy treatment occurring in 9% of patients treated with the use of anthracyclines. Currently, risk stratification is based on clinical risk factors that do not adequately account for variable individual susceptibility. This suggests the presence of other determinants. In this case series, we describe 2 women with breast cancer who developed severe heart failure within months after chemotherapy. Genetic screening revealed truncating frameshift mutations in TTN, encoding the myofilament titin, in both women. To our knowledge, this is the 1st report of an association between truncating TTN variants and CCMP. Because truncations in TTN are the most common cause of familial and sporadic dilated cardiomyopathy, further research is needed to establish their prevalence in patients presenting with CCMP.
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Antineoplásicos/efectos adversos , Cardiomiopatías/inducido químicamente , Cardiomiopatías/genética , Conectina/genética , Variación Genética/genética , Adulto , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Carcinoma Ductal/diagnóstico por imagen , Carcinoma Ductal/tratamiento farmacológico , Carcinoma Ductal/genética , Cardiomiopatías/diagnóstico por imagen , Resultado Fatal , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Long-term survival is similar after open or endovascular repair of abdominal aortic aneurysm. Few data exist on the effect of either procedure on long-term health-related quality of life (HRQoL) and health status. METHODS: Patients enrolled in a multicentre randomized clinical trial (DREAM trial; 2000-2003) in Europe of open repair versus endovascular repair (EVAR) of abdominal aortic aneurysm were asked to complete questionnaires on health status and HRQoL. HRQoL scores were assessed at baseline and at 13 time points thereafter, using generic tools, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36®) and EuroQol 5D (EQ-5D™). Physical (PCS) and mental component summary scores were also calculated. Follow-up was 5 years. RESULTS: Some 332 of 351 patients enrolled in the trial returned questionnaires. More than 70 per cent of questionnaires were returned at each time point. Both surgical interventions had a short-term negative effect on HRQoL and health status. This was less severe in the EVAR group than in the open repair group. In the longer term the physical domains of SF-36® favoured open repair: mean difference in PCS score between open repair and EVAR -1·98 (95 per cent c.i. -3·56 to -0·41). EQ-5D™ descriptive and EQ-5D™ visual analogue scale scores for open repair were also superior to those for EVAR after the initial 6-week interval: mean difference -0·06 (-0·10 to -0·02) and -4·09 (-6·91 to -1·27) respectively. CONCLUSION: In this study EVAR appeared to be associated with less severe disruption to HRQoL and health status in the short term. However, during longer-term follow-up to 5 years, patients receiving open repair appeared to have improved quality of life and health status.
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Aneurisma de la Aorta Abdominal/cirugía , Procedimientos Endovasculares , Calidad de Vida , Anciano , Bélgica , Femenino , Estudios de Seguimiento , Estado de Salud , Humanos , Masculino , Países Bajos , Encuestas y Cuestionarios , Escala Visual AnalógicaRESUMEN
Genetics plays an important role in the pathophysiology of cardiovascular diseases, and is increasingly being integrated into clinical practice. Since 2008, both capacity and cost-efficiency of mutation screening of DNA have been increased magnificently due to the technological advancement obtained by next-generation sequencing. Hence, the discovery rate of genetic defects in cardiovascular genetics has grown rapidly and the financial threshold for gene diagnostics has been lowered, making large-scale DNA sequencing broadly accessible. In this review, the genetic variants, mutations and inheritance models are briefly introduced, after which an overview is provided of current clinical and technological applications in gene diagnostics and research for cardiovascular disease and in particular, dilated cardiomyopathy. Finally, a reflection on the future perspectives in cardiogenetics is given.
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BACKGROUND: Deterioration of renal function after major vascular surgery is an important complication, and may vary between patients undergoing endovascular (EVAR) or open surgical (OR) repair of an abdominal aortic aneurysm (AAA). The objective was to determine the impact of OR and EVAR on renal function after 5 years. METHODS: This was a post hoc analysis of data collected prospectively from the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial. Five years after surgery, creatinine levels were available for 189 patients (94 after OR and 95 after EVAR). The severity of renal disease was staged using the chronic kidney disease classification of the US National Kidney Foundation clinical guidelines. RESULTS: Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the estimated glomerular filtration rate (eGFR) for the entire group declined over time, with a mean(s.d.) preoperative value of 80·0(7·6) ml per min per 1·73 m(2) compared with 75·7(9·7) ml per min per 1·73 m(2) after 5 years (mean difference 4·2 (95 per cent confidence interval 3·2 to 5·3) ml per min per 1·73 m(2) ; P < 0·001). Five years after surgery, the mean eGFR (CKD-EPI equation) was not significantly different between the OR and EVAR groups: 76·3(9·3) versus 75·1(10·0) ml per min per 1·73 m(2) (mean difference 1·2 (-1·6 to 3·9) ml per min per 1·73 m(2) ; P = 0·410). CONCLUSION: Renal function 5 years after OR and EVAR for AAA was similar. Neither surgical procedure accelerated the loss of renal function.
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Aneurisma de la Aorta Abdominal/cirugía , Tasa de Filtración Glomerular/fisiología , Complicaciones Posoperatorias/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Anciano , Aneurisma de la Aorta Abdominal/fisiopatología , Procedimientos Endovasculares , Femenino , Estudios de Seguimiento , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Insuficiencia Renal Crónica/etiologíaRESUMEN
With data from four randomized trials on elective endovascular abdominal aortic aneurysm repair and many more additional post-hoc publications, the evidence can be somewhat overwhelming for the surgeon, let alone the patient. This chapter aims to present the most recent and relevant data for decision making in abdominal aortic aneurysm (AAA) repair in a comparative and concise format. After a comparison of the short- and long-term survival data of the randomized trials, the following post-hoc analyses of the four randomized trials will be presented: causes of death, reinterventions, renal function, prediction of complications, and quality of life. When both open and endovascular repair are a reasonable option for an individual patient, we need to objectively inform our patient about the available evidence from the trials. The three-fold reduction of operative mortality with endovascular repair as compared to open repair should be presented. Next, the convergence of the overall survival curves should be discussed as a key factor in the decision process. The counterintuitive observation may be considered that if endovascular repair is better for any specific subgroup it is for younger patients with low surgical risks. Finally, the patient needs to understand that the risks of reintervention and complications are higher after endovascular than after open repair and that this is even more relevant in older patients with larger aneurysms. The information that the quality of life advantage of endovascular repair is only short lived and for several domains surpassed by open repair is most likely not suitable for direct discussion with the individual patient, but it may put the procedures in the right perspective for the physician and health care managers.
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Aneurisma de la Aorta Abdominal/cirugía , Toma de Decisiones , Procedimientos Quirúrgicos Vasculares/métodos , Procedimientos Endovasculares/métodos , Humanos , Resultado del TratamientoRESUMEN
Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor beta (TGF-beta) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-beta pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case-control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a P<0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (P<0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11-1.56 P=0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12-1.54 P=0.001 and rs4522809 OR 1.28 95% CI 1.12-1.46 P=0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options.
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Aneurisma de la Aorta Abdominal/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/cirugía , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Población Blanca/genéticaRESUMEN
BACKGROUND: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. METHODS: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. RESULTS: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. CONCLUSIONS: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Mutación , Adolescente , Adulto , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/genética , Niño , Preescolar , Atresia de las Coanas/diagnóstico , Atresia de las Coanas/genética , Coloboma/diagnóstico , Coloboma/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Edad Gestacional , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades de la Boca/diagnóstico , Enfermedades de la Boca/genética , Fenotipo , Enfermedades de la Columna Vertebral/diagnóstico , Enfermedades de la Columna Vertebral/genética , Síndrome , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genéticaRESUMEN
Germline mutations in LKB1 cause the rare cancer prone disorder Peutz-Jeghers syndrome (PJS). Gastrointestinal hamartomatous polyps constitute the major phenotypic trait in PJS. Hamartomatous polyps arising in PJS patients are generally considered to lack premalignant potential although rare neoplastic changes in these polyps and an increased gastrointestinal cancer risk in PJS are well documented. These conflicting observations are resolved in the current hypothesis by providing a unifying explanation for these contrasting features of PJS polyposis. We postulate that a genetic predisposition to epithelial prolapse underlies the formation of the polyps associated with PJS. Conventional sporadic adenomas arising in PJS patients will similarly show mucosal prolapse and carry the associated histological features.
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Mucosa Intestinal/patología , Síndrome de Peutz-Jeghers/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Prolapso , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND/AIMS: LKB1 is a tumour suppressor gene that is associated with Peutz-Jeghers syndrome (PJS), a rare autosomal dominant cancer predisposition syndrome. However, germline mutations in the LKB1 gene are found in only about 60% of patients with PJS, suggesting the existence of a second PJS gene. The STRAD gene, encoding an LKB1 interacting protein that activates LKB1, which subsequently leads to polarisation of cells, is an interesting candidate for a second PJS gene and a potential tumour suppressor gene in sporadic carcinomas. METHODS: The involvement of STRAD in 42 PJS associated tumours (sporadic lung, colon, gastric, and ovarian adenocarcinomas) was studied using loss of heterozygosity (LOH) analysis of eight microsatellite markers on chromosome 17, including TP53, BRCA1, and STRAD markers. RESULTS: Loss of the marker near the STRAD locus was seen in 13 of 29 informative cases, including all gastric adenocarcinomas. Specific LOH of the STRAD marker was found in four of 29 informative cases. For these patients all exons and exon-intron boundaries of the STRAD gene were sequenced, but no somatic mutations were identified. Furthermore, no germline STRAD mutations were found in 10 patients with PJS and family members without LKB1 germline mutation. CONCLUSIONS: Despite the frequent occurrence of LOH in the STRAD region, these results indicate that inactivation of the STRAD gene is not essential in the sporadic adenocarcinomas studied, although it is possible that STRAD may be inactivated in different ways. In addition, no evidence was found for the hypothesis that STRAD is a second PJS susceptibility gene.
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Proteínas Adaptadoras del Transporte Vesicular/genética , Adenocarcinoma/genética , Proteínas de Neoplasias/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Adenocarcinoma/metabolismo , Cromosomas Humanos Par 17/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Repeticiones de Microsatélite , Mutación , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Síndrome de Peutz-Jeghers/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
The LKB1 gene encodes a serine/threonine kinase mutated in Peutz-Jeghers cancer syndrome. Despite several proposed models for LKB1 function in development and in tumour suppression, the detailed molecular action of LKB1 remains undefined. Here, we report the identification and characterization of an LKB1-specific adaptor protein and substrate, STRAD (STe20 Related ADaptor). STRAD consists of a STE20- like kinase domain, but lacks several residues that are indispensable for intrinsic catalytic activity. Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners. STRAD determines the subcellular localization of wild-type, but not mutant LKB1, translocating it from nucleus to cytoplasm. One LKB1 mutation previously identified in a Peutz-Jeghers family that does not compromise its kinase activity is shown here to interfere with LKB1 binding to STRAD, and hence with STRAD-dependent regulation. Removal of endogenous STRAD by siRNA abrogates the LKB1-induced G(1) arrest. Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1.