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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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We report a case of successful combined heart liver transplant in a patient with a congenital solitary kidney. The patient had normal renal function before combined heart-liver transplantation and developed acute kidney injury requiring slow continuous dialysis and subsequent intermittent dialysis for almost 8 weeks post transplantation. Her renal function recovered and she remains off dialysis now 7 months post transplantation. She only currently has mild chronic renal insufficiency. We believe this is the first reported case of successful heart liver transplant in a patient with a congenital solitary kidney.
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Trasplante de Corazón/métodos , Trasplante de Hígado/métodos , Riñón Único/congénito , Lesión Renal Aguda/etiología , Adulto , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Femenino , Trasplante de Corazón/efectos adversos , Humanos , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/etiología , Diálisis Renal , Insuficiencia Renal Crónica/etiologíaRESUMEN
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
We report on time-resolved measurements of the first order spatial coherence in an exciton-polariton Bose-Einstein condensate. Long-range spatial coherence is found to set in right at the onset of stimulated scattering, on a picosecond time scale. The coherence reaches its maximum value after the population and decays slowly, staying up to a few hundred picoseconds. This behavior can be qualitatively reproduced, using a stochastic classical field model describing interaction between the polariton condensate and the exciton reservoir within a disordered potential.
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Homocysteine is a risk factor for the development of thromboembolic disorders and vascular diseases. Furthermore, complications during pregnancy have been ascribed to hyperhomocysteinemia. We report on a pregnant woman being substituted by high doses folic acid for hyperhomocysteinemia. Thereby, the underlying pernicious anemia was masked. After birth, the neonate was exclusively breastfed. At the age of 5 months, the infant had to be admitted to hospital due to severe vitamin B(12)-deficiency. Using parenteral vitamin B(12) substitution, homocystein levels of the mother normalized and the infant throve and prospered again.
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Aborto Habitual/etiología , Anemia Perniciosa/diagnóstico , Enfermedades Autoinmunes/diagnóstico , Insuficiencia de Crecimiento/etiología , Ácido Fólico/administración & dosificación , Gastritis Atrófica/diagnóstico , Tromboembolia/etiología , Deficiencia de Vitamina B 12/diagnóstico , Adulto , Lactancia Materna , Diagnóstico Diferencial , Femenino , Ácido Fólico/efectos adversos , Homocisteína/sangre , Humanos , Lactante , Factor Intrinseco/inmunología , Ácido Metilmalónico/orina , Células Parietales Gástricas/inmunología , EmbarazoRESUMEN
We report on a Bell experiment with spacelike separation assuming that the measurement time is related to gravity-induced state reduction. Two energy-time entangled photons are sent through optical fibers and directed into unbalanced interferometers at two receiving stations separated by 18 km. At each station, the detection of a photon triggers the displacement of a macroscopic mass. The timing ensures spacelike separation from the moment a photon enters its interferometer until the mass has moved. Two-photon interference fringes with a visibility of up to 90.5% are obtained, leading to a violation of the Bell inequality.
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Condensation of exciton polaritons in semiconductor microcavities takes place despite in-plane disorder. Below the critical density, the inhomogeneity of the disorder limits the spatial extension of the ground state. Above the critical density, in the presence of weak disorder, this limitation is spontaneously overcome by the nonlinear interaction, resulting in an extended synchronized phase. In the case of strong disorder, several non-phase-locked condensates can be evidenced. The transition from a synchronized phase to a desynchronized phase is addressed by sampling the cavity disorder.
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Second-order time correlations of polaritons have been measured across the condensation threshold in a CdTe microcavity. The onset of Bose-Einstein condensation is marked by the disappearance of photon bunching, demonstrating the transition from a thermal-like state to a coherent state. Coherence is, however, degraded with increasing polariton density, most probably as a result of self-interaction within the condensate and scatterings with noncondensed excitons and polaritons. Such behavior clearly differentiates polariton Bose condensation from photon lasing.
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Phase transitions to quantum condensed phases--such as Bose-Einstein condensation (BEC), superfluidity, and superconductivity--have long fascinated scientists, as they bring pure quantum effects to a macroscopic scale. BEC has, for example, famously been demonstrated in dilute atom gas of rubidium atoms at temperatures below 200 nanokelvin. Much effort has been devoted to finding a solid-state system in which BEC can take place. Promising candidate systems are semiconductor microcavities, in which photons are confined and strongly coupled to electronic excitations, leading to the creation of exciton polaritons. These bosonic quasi-particles are 10(9) times lighter than rubidium atoms, thus theoretically permitting BEC to occur at standard cryogenic temperatures. Here we detail a comprehensive set of experiments giving compelling evidence for BEC of polaritons. Above a critical density, we observe massive occupation of the ground state developing from a polariton gas at thermal equilibrium at 19 K, an increase of temporal coherence, and the build-up of long-range spatial coherence and linear polarization, all of which indicate the spontaneous onset of a macroscopic quantum phase.