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2. Slower Calcium Handling Balances Faster Crossbridge Cycling in Human MYBPC3 HCM

Author

Pioner, Josè Manuel, Vitale, Giulia, Steczina, Sonette, Langione, Marianna, Margara, Francesca, Santini, Lorenzo, Giardini, Francesco, Lazzeri, Erica, Piroddi, Nicoletta, Scellini, Beatrice, Palandri, Chiara, Schuldt, Maike, Spinelli, Valentina, Girolami, Francesca, Mazzarotto, Francesco, van der Velden, Jolanda, Cerbai, Elisabetta, Tesi, Chiara, Olivotto, Iacopo, Bueno-Orovio, Alfonso, Sacconi, Leonardo, Coppini, Raffaele, Ferrantini, Cecilia, Regnier, Michael, and Poggesi, Corrado

Published
2023
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4. Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes

Author

Buikema, Jan W., Lee, Soah, Goodyer, William R., Maas, Renee G., Chirikian, Orlando, Li, Guang, Miao, Yi, Paige, Sharon L., Lee, Daniel, Wu, Haodi, Paik, David T., Rhee, Siyeon, Tian, Lei, Galdos, Francisco X., Puluca, Nazan, Beyersdorf, Benjamin, Hu, James, Beck, Aimee, Venkamatran, Sneha, Swami, Srilatha, Wijnker, Paul, Schuldt, Maike, Dorsch, Larissa M., van Mil, Alain, Red-Horse, Kristy, Wu, Joy Y., Geisen, Caroline, Hesse, Michael, Serpooshan, Vahid, Jovinge, Stefan, Fleischmann, Bernd K., Doevendans, Pieter A., van der Velden, Jolanda, Garcia, K. Christopher, Wu, Joseph C., Sluijter, Joost P.G., and Wu, Sean M.

Published
2020
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5. Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

Author

Onderzoek Precision medicine, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., van der Velden, Jolanda, Onderzoek Precision medicine, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., and van der Velden, Jolanda

Published
2024

6. Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

Author

Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., van der Velden, Jolanda, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., and van der Velden, Jolanda

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups. METHODS: We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling. RESULTS:HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients. CONCLUSIONS: We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.

Published
2024

8. Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy

Author

Schuldt, Maike, Pei, Jiayi, Harakalova, Magdalena, Dorsch, Larissa M., Schlossarek, Saskia, Mokry, Michal, Knol, Jaco C., Pham, Thang V., Schelfhorst, Tim, Piersma, Sander R., dos Remedios, Cris, Dalinghaus, Michiel, Michels, Michelle, Asselbergs, Folkert W., Moutin, Marie-Jo, Carrier, Lucie, Jimenez, Connie R., van der Velden, Jolanda, and Kuster, Diederik W.D.

Published
2021
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9. EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy

Author

Algül, Sila, primary, Schuldt, Maike, additional, Manders, Emmy, additional, Jansen, Valentijn, additional, Schlossarek, Saskia, additional, de Goeij-de Haas, Richard, additional, Henneman, Alex A., additional, Piersma, Sander R., additional, Jimenez, Connie R., additional, Michels, Michelle, additional, Carrier, Lucie, additional, Helmes, Michiel, additional, van der Velden, Jolanda, additional, and Kuster, Diederik W.D., additional

Published
2023
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10. Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 c.2373InsG in the Netherlands

Author

Hilderink, Sarah, Schuldt, Maike, Goebel, Max, Jansen, Valentijn J, Manders, Emmy, Moorman, Stan, Dorsch, Larissa M, van Steenbeek, Frank G, van der Velden, Jolanda, Kuster, Diederik W D, Hilderink, Sarah, Schuldt, Maike, Goebel, Max, Jansen, Valentijn J, Manders, Emmy, Moorman, Stan, Dorsch, Larissa M, van Steenbeek, Frank G, van der Velden, Jolanda, and Kuster, Diederik W D

Published
2023

11. EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy

Author

Algül, Sila, Schuldt, Maike, Manders, Emmy, Jansen, Valentijn, Schlossarek, Saskia, de Goeij-de Haas, Richard, Henneman, Alex A., Piersma, Sander R., Jimenez, Connie R., Michels, Michelle, Carrier, Lucie, Helmes, Michiel, van der Velden, Jolanda, Kuster, Diederik W.D., Algül, Sila, Schuldt, Maike, Manders, Emmy, Jansen, Valentijn, Schlossarek, Saskia, de Goeij-de Haas, Richard, Henneman, Alex A., Piersma, Sander R., Jimenez, Connie R., Michels, Michelle, Carrier, Lucie, Helmes, Michiel, van der Velden, Jolanda, and Kuster, Diederik W.D.

Published
2023

12. Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

Author

Jansen, M.M.P.M., Schuldt, Maike, Driel, Beau O. van, Schmidt, Amand F., Christiaans, Imke, Crabben, Saskia N. van der, Hoedemaekers, Y.M., Asselbergs, Folkert W., Baas, Annette F., Jansen, M.M.P.M., Schuldt, Maike, Driel, Beau O. van, Schmidt, Amand F., Christiaans, Imke, Crabben, Saskia N. van der, Hoedemaekers, Y.M., Asselbergs, Folkert W., and Baas, Annette F.

Abstract

Item does not contain fulltext

Published
2023

13. Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

Author

Jansen, Mark, Schuldt, Maike, Driel, Beau O. van, Schmidt, Amand F., Christiaans, Imke, Crabben, Saskia N. van der, Hoedemaekers, Y.M., Asselbergs, Folkert W., Baas, Annette F., Jansen, Mark, Schuldt, Maike, Driel, Beau O. van, Schmidt, Amand F., Christiaans, Imke, Crabben, Saskia N. van der, Hoedemaekers, Y.M., Asselbergs, Folkert W., and Baas, Annette F.

Abstract

Contains fulltext : 290549.pdf (Publisher’s version ) (Open Access)

Published
2023

14. Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 c.2373InsG in the Netherlands

Author

CS_Genetics, Interne geneeskunde GD, Genetics, Hilderink, Sarah, Schuldt, Maike, Goebel, Max, Jansen, Valentijn J, Manders, Emmy, Moorman, Stan, Dorsch, Larissa M, van Steenbeek, Frank G, van der Velden, Jolanda, Kuster, Diederik W D, CS_Genetics, Interne geneeskunde GD, Genetics, Hilderink, Sarah, Schuldt, Maike, Goebel, Max, Jansen, Valentijn J, Manders, Emmy, Moorman, Stan, Dorsch, Larissa M, van Steenbeek, Frank G, van der Velden, Jolanda, and Kuster, Diederik W D

Published
2023

15. Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

Author

Onderzoek Precision medicine, Genetica, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Genetica Sectie Metabole Diagnostiek, Brain, Child Health, Cancer, Team Medisch, Genetica Klinische Genetica, Jansen, Mark, Schuldt, Maike, van Driel, Beau O, Schmidt, Amand F, Christiaans, Imke, van der Crabben, Saskia N, Hoedemaekers, Yvonne M, Dooijes, Dennis, Jongbloed, Jan D H, Boven, Ludolf G, Deprez, Ronald H Lekanne, Wilde, Arthur A M, Jans, Judith J M, van der Velden, Jolanda, de Boer, Rudolf A, van Tintelen, J Peter, Asselbergs, Folkert W, Baas, Annette F, Onderzoek Precision medicine, Genetica, Genetica Sectie Genoomdiagnostiek, Circulatory Health, Genetica Sectie Metabole Diagnostiek, Brain, Child Health, Cancer, Team Medisch, Genetica Klinische Genetica, Jansen, Mark, Schuldt, Maike, van Driel, Beau O, Schmidt, Amand F, Christiaans, Imke, van der Crabben, Saskia N, Hoedemaekers, Yvonne M, Dooijes, Dennis, Jongbloed, Jan D H, Boven, Ludolf G, Deprez, Ronald H Lekanne, Wilde, Arthur A M, Jans, Judith J M, van der Velden, Jolanda, de Boer, Rudolf A, van Tintelen, J Peter, Asselbergs, Folkert W, and Baas, Annette F

Published
2023

16. Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human MYBPC3 HCM

Author

Pioner, Josè Manuel, primary, Vitale, Giulia, additional, Steczina, Sonette, additional, Langione, Marianna, additional, Margara, Francesca, additional, Santini, Lorenzo, additional, Giardini, Francesco, additional, Lazzeri, Erica, additional, Piroddi, Nicoletta, additional, Scellini, Beatrice, additional, Palandri, Chiara, additional, Schuldt, Maike, additional, Spinelli, Valentina, additional, Girolami, Francesca, additional, Mazzarotto, Francesco, additional, van der Velden, Jolanda, additional, Cerbai, Elisabetta, additional, Tesi, Chiara, additional, Olivotto, Iacopo, additional, Bueno-Orovio, Alfonso, additional, Sacconi, Leonardo, additional, Coppini, Raffaele, additional, Ferrantini, Cecilia, additional, Regnier, Michael, additional, and Poggesi, Corrado, additional

Published
2023
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17. Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

Author

Jansen, Mark, primary, Schuldt, Maike, additional, van Driel, Beau O., additional, Schmidt, Amand F., additional, Christiaans, Imke, additional, van der Crabben, Saskia N., additional, Hoedemaekers, Yvonne M., additional, Dooijes, Dennis, additional, Jongbloed, Jan D. H., additional, Boven, Ludolf G., additional, Deprez, Ronald H. Lekanne, additional, Wilde, Arthur A. M., additional, Jans, Judith J. M., additional, van der Velden, Jolanda, additional, de Boer, Rudolf A., additional, van Tintelen, J. Peter, additional, Asselbergs, Folkert W., additional, and Baas, Annette F., additional

Published
2023
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19. miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly

Author

Wildung, Merit, primary, Herr, Christian, additional, Riedel, Dietmar, additional, Wiedwald, Cornelia, additional, Moiseenko, Alena, additional, Ramírez, Fidel, additional, Tasena, Hataitip, additional, Heimerl, Maren, additional, Alevra, Mihai, additional, Movsisyan, Naira, additional, Schuldt, Maike, additional, Volceanov-Hahn, Larisa, additional, Provoost, Sharen, additional, Nöthe-Menchen, Tabea, additional, Urrego, Diana, additional, Freytag, Bernard, additional, Wallmeier, Julia, additional, Beisswenger, Christoph, additional, Bals, Robert, additional, van den Berge, Maarten, additional, Timens, Wim, additional, Hiemstra, Pieter S., additional, Brandsma, Corry-Anke, additional, Maes, Tania, additional, Andreas, Stefan, additional, Heijink, Irene H., additional, Pardo, Luis A., additional, and Lizé, Muriel, additional

Published
2022
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21. Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy

Author

Schuldt, Maike, primary, van Driel, Beau, additional, Algül, Sila, additional, Parbhudayal, Rahana Y., additional, Barge-Schaapveld, Daniela Q. C. M., additional, Güçlü, Ahmet, additional, Jansen, Mark, additional, Michels, Michelle, additional, Baas, Annette F., additional, van de Wiel, Mark A., additional, Nieuwdorp, Max, additional, Levin, Evgeni, additional, Germans, Tjeerd, additional, Jans, Judith J. M., additional, and van der Velden, Jolanda, additional

Published
2021
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22. Identification of disease modifiers and novel treatment targets in hypertrophic cardiomyopathy

Author

Schuldt, Maike, van der Velden, J., Kuster, D.W.D., van der Velden, Jolanda, Kuster, Diederik, ACS - Heart failure & arrhythmias, and Physiology

Subjects
proteomics, transcriptomics, transcriptomics, proteomics, tubulin, SDG 3 - Good Health and Well-being, disease modifiers, mutant protein dose, mutation location, protein quality control, hypertrophic cardiomyopathy, metabolomics
Abstract

Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease with large differences in disease penetrance and severity between patients. Therefore, we hypothesize that a variety of disease modifiers can contribute and influence the clinical disease course in patients. In this thesis we explored the mutant protein dose and mutation location and the cellular protein quality control (PQC) as potential disease modifiers. We further used -omics techniques to identify differences at the RNA and protein level between different genetic groups to identify novel disease modifiers and potential novel treatment targets. In Chapter 2 we investigated the mutant protein dose and location effect of different TNNT2 mutations on cardiomyocyte function. We observed for two of the mutations, I79N and R94C, that a low dose of mutant protein (

Published
2021

23. Distinct metabolomic signatures in preclinical and obstructive hypertrophic cardiomyopathy

Author

Schuldt, Maike, van Driel, Beau, Algül, Sila, Parbhudayal, Rahana Y., Barge-Schaapveld, Daniela Q.C.M., Güçlü, Ahmet, Jansen, Mark, Michels, Michelle, Baas, Annette F., van de Wiel, Mark A., Nieuwdorp, Max, Levin, Evgeni, Germans, Tjeerd, Jans, Judith J.M., van der Velden, Jolanda, Schuldt, Maike, van Driel, Beau, Algül, Sila, Parbhudayal, Rahana Y., Barge-Schaapveld, Daniela Q.C.M., Güçlü, Ahmet, Jansen, Mark, Michels, Michelle, Baas, Annette F., van de Wiel, Mark A., Nieuwdorp, Max, Levin, Evgeni, Germans, Tjeerd, Jans, Judith J.M., and van der Velden, Jolanda

Abstract

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype–phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM). We performed non-quantitative direct-infusion high-resolution mass spectrometry-based untargeted metabolomics on serum from fasted asymptomatic gene variant carriers, symptomatic HOCM patients and healthy controls (n = 31, 14 and 9, respectively). Biomarker panels that discriminated the groups were identified by performing multivariate modeling with gradient-boosting classifiers. For all three group-wise comparisons we identified a panel of 30 serum metabolites that best discriminated the groups. These metabolite panels performed equally well as advanced cardiac imaging modalities in distinguishing the groups. Seven metabolites were found to be predictive in two different comparisons and may play an important role in defining the disease stage. This study reveals unique metabolic signatures in serum of preclinical carriers and HOCM patients that may potentially be used for HCM risk stratification and precision therapeutics.

Published
2021

24. Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy

Author

Genetica Klinische Genetica, Circulatory Health, Genetica Sectie Metabole Diagnostiek, Child Health, Schuldt, Maike, van Driel, Beau, Algül, Sila, Parbhudayal, Rahana Y, Barge-Schaapveld, Daniela Q C M, Güçlü, Ahmet, Jansen, Mark, Michels, Michelle, Baas, Annette F, van de Wiel, Mark A, Nieuwdorp, Max, Levin, Evgeni, Germans, Tjeerd, Jans, Judith J M, van der Velden, Jolanda, Genetica Klinische Genetica, Circulatory Health, Genetica Sectie Metabole Diagnostiek, Child Health, Schuldt, Maike, van Driel, Beau, Algül, Sila, Parbhudayal, Rahana Y, Barge-Schaapveld, Daniela Q C M, Güçlü, Ahmet, Jansen, Mark, Michels, Michelle, Baas, Annette F, van de Wiel, Mark A, Nieuwdorp, Max, Levin, Evgeni, Germans, Tjeerd, Jans, Judith J M, and van der Velden, Jolanda

Published
2021

25. Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers

Author

Onderzoek Precision medicine, Other research (not in main researchprogram), Circulatory Health, Genetica Klinische Genetica, Genetica Sectie Metabole Diagnostiek, Child Health, van Driel, Beau Olivier, Schuldt, Maike, Algül, Sila, Levin, Evgeni, Güclü, Ahmet, Germans, Tjeerd, Rossum, Albert C van, Pei, Jiayi, Harakalova, Magdalena, Baas, Annette, Jans, Judith J M, van der Velden, Jolanda, Onderzoek Precision medicine, Other research (not in main researchprogram), Circulatory Health, Genetica Klinische Genetica, Genetica Sectie Metabole Diagnostiek, Child Health, van Driel, Beau Olivier, Schuldt, Maike, Algül, Sila, Levin, Evgeni, Güclü, Ahmet, Germans, Tjeerd, Rossum, Albert C van, Pei, Jiayi, Harakalova, Magdalena, Baas, Annette, Jans, Judith J M, and van der Velden, Jolanda

Published
2021

26. Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy

Author

Onderzoek Precision medicine, Other research (not in main researchprogram), Circulatory Health, Team Medisch, Schuldt, Maike, Pei, Jiayi, Harakalova, Magdalena, Dorsch, Larissa M, Schlossarek, Saskia, Mokry, Michal, Knol, Jaco C, Pham, Thang V, Schelfhorst, Tim, Piersma, Sander R, Dos Remedios, Cris, Dalinghaus, Michiel, Michels, Michelle, Asselbergs, Folkert W, Moutin, Marie-Jo, Carrier, Lucie, Jimenez, Connie R, van der Velden, Jolanda, Kuster, Diederik W D, Onderzoek Precision medicine, Other research (not in main researchprogram), Circulatory Health, Team Medisch, Schuldt, Maike, Pei, Jiayi, Harakalova, Magdalena, Dorsch, Larissa M, Schlossarek, Saskia, Mokry, Michal, Knol, Jaco C, Pham, Thang V, Schelfhorst, Tim, Piersma, Sander R, Dos Remedios, Cris, Dalinghaus, Michiel, Michels, Michelle, Asselbergs, Folkert W, Moutin, Marie-Jo, Carrier, Lucie, Jimenez, Connie R, van der Velden, Jolanda, and Kuster, Diederik W D

Published
2021

27. Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers

Author

van Driel, Beau Olivier van, primary, Schuldt, Maike, additional, Algül, Sila, additional, Levin, Evgeni, additional, Güclü, Ahmet, additional, Germans, Tjeerd, additional, Rossum, Albert C. van, additional, Pei, Jiayi, additional, Harakalova, Magdalena, additional, Baas, Annette, additional, Jans, Judith J. M., additional, and van der Velden, Jolanda, additional

Published
2021
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28. Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy

Author

Schuldt, Maike, primary, Dorsch, Larissa M., additional, Knol, Jaco C., additional, Pham, Thang V., additional, Schelfhorst, Tim, additional, Piersma, Sander R., additional, dos Remedios, Cris, additional, Michels, Michelle, additional, Jimenez, Connie R., additional, Kuster, Diederik W. D., additional, and van der Velden, Jolanda, additional

Published
2021
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29. Proteomic profiling of a large cohort of HCM patients: Genotype-specific protein changes

Author

Schuldt, Maike, primary, Pei, Jiayi, additional, Harakalova, Magdalena, additional, Mokry, Michal, additional, Knol, Jaco C., additional, Pham, Thang V., additional, Schelfhorst, Tim, additional, Piersma, Sander R., additional, dos Remedios, Cris, additional, Dalinghaus, Michiel, additional, Michels, Michelle, additional, Asselbergs, Folkert W., additional, Jimenez, Connie R., additional, Kuster, Diederik W.D., additional, and van der Velden, Jolanda, additional

Published
2020
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30. Genotype‐specific pathogenic effects in human dilated cardiomyopathy

Author

Bollen, Ilse A. E., Schuldt, Maike, Harakalova, Magdalena, Vink, Aryan, Asselbergs, Folkert W., Pinto, Jose R., Krüger, Martina, Kuster, Diederik W. D., and van der Velden, Jolanda

Subjects
Adult, Cardiomyopathy, Dilated, Male, Genotype, troponin, Heart Ventricles, Troponin I, heart failure, Middle Aged, musculoskeletal system, Cardiovascular, Lamin Type A, protein phosphorylation, dilated cardiomyopathy, Young Adult, Mutation, Humans, Connectin, Female, Myocytes, Cardiac, Phosphorylation, Research Paper
Abstract

Key points Mutations in genes encoding cardiac troponin I (TNNI3) and cardiac troponin T (TNNT2) caused altered troponin protein stoichiometry in patients with dilated cardiomyopathy. TNNI3p.98trunc resulted in haploinsufficiency, increased Ca2+‐sensitivity and reduced length‐dependent activation. TNNT2p.K217del caused increased passive tension.A mutation in the gene encoding Lamin A/C (LMNA p.R331Q) led to reduced maximal force development through secondary disease remodelling in patients suffering from dilated cardiomyopathy.Our study shows that different gene mutations induce dilated cardiomyopathy via diverse cellular pathways. Abstract Dilated cardiomyopathy (DCM) can be caused by mutations in sarcomeric and non‐sarcomeric genes. In this study we defined the pathogenic effects of three DCM‐causing mutations: the sarcomeric mutations in genes encoding cardiac troponin I (TNNI3p.98truncation) and cardiac troponin T (TNNT2p.K217deletion; also known as the p.K210del) and the non‐sarcomeric gene mutation encoding lamin A/C (LMNAp.R331Q). We assessed sarcomeric protein expression and phosphorylation and contractile behaviour in single membrane‐permeabilized cardiomyocytes in human left ventricular heart tissue. Exchange with recombinant troponin complex was used to establish the direct pathogenic effects of the mutations in TNNI3 and TNNT2. The TNNI3p.98trunc and TNNT2p.K217del mutation showed reduced expression of troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73% and 97% of controls, respectively, and altered stoichiometry between the three cardiac troponin subunits. The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity and impaired length‐dependent activation. The TNNT2p.K217del mutation showed a significant increase in passive tension that was not due to changes in titin isoform composition or phosphorylation. Exchange with wild‐type troponin complex corrected troponin protein levels to 83% of controls in the TNNI3p.98trunc sample. Moreover, upon exchange all functional deficits in the TNNI3p.98trunc and TNNT2p.K217del samples were normalized to control values confirming the pathogenic effects of the troponin mutations. The LMNAp.R331Q mutation resulted in reduced maximal force development due to disease remodelling. Our study shows that different gene mutations induce DCM via diverse cellular pathways., Key points Mutations in genes encoding cardiac troponin I (TNNI3) and cardiac troponin T (TNNT2) caused altered troponin protein stoichiometry in patients with dilated cardiomyopathy. TNNI3p.98trunc resulted in haploinsufficiency, increased Ca2+‐sensitivity and reduced length‐dependent activation. TNNT2p.K217del caused increased passive tension.A mutation in the gene encoding Lamin A/C (LMNA p.R331Q) led to reduced maximal force development through secondary disease remodelling in patients suffering from dilated cardiomyopathy.Our study shows that different gene mutations induce dilated cardiomyopathy via diverse cellular pathways.

Published
2017

31. Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes

Author

Arts Assistenten Cardiologie, Circulatory Health, Regenerative Medicine and Stem Cells, Experimentele Afd. Cardiologie 2, Team Medisch, Onderzoek Cardiovasculair Reg. Med., Buikema, Jan W, Lee, Soah, Goodyer, William R, Maas, Renee G, Chirikian, Orlando, Li, Guang, Miao, Yi, Paige, Sharon L, Lee, Daniel, Wu, Haodi, Paik, David T, Rhee, Siyeon, Tian, Lei, Galdos, Francisco X, Puluca, Nazan, Beyersdorf, Benjamin, Hu, James, Beck, Aimee, Venkamatran, Sneha, Swami, Srilatha, Wijnker, Paul, Schuldt, Maike, Dorsch, Larissa M, van Mil, Alain, Red-Horse, Kristy, Wu, Joy Y, Geisen, Caroline, Hesse, Michael, Serpooshan, Vahid, Jovinge, Stefan, Fleischmann, Bernd K, Doevendans, Pieter A, van der Velden, Jolanda, Garcia, K Christopher, Wu, Joseph C, Sluijter, Joost P G, Wu, Sean M, Arts Assistenten Cardiologie, Circulatory Health, Regenerative Medicine and Stem Cells, Experimentele Afd. Cardiologie 2, Team Medisch, Onderzoek Cardiovasculair Reg. Med., Buikema, Jan W, Lee, Soah, Goodyer, William R, Maas, Renee G, Chirikian, Orlando, Li, Guang, Miao, Yi, Paige, Sharon L, Lee, Daniel, Wu, Haodi, Paik, David T, Rhee, Siyeon, Tian, Lei, Galdos, Francisco X, Puluca, Nazan, Beyersdorf, Benjamin, Hu, James, Beck, Aimee, Venkamatran, Sneha, Swami, Srilatha, Wijnker, Paul, Schuldt, Maike, Dorsch, Larissa M, van Mil, Alain, Red-Horse, Kristy, Wu, Joy Y, Geisen, Caroline, Hesse, Michael, Serpooshan, Vahid, Jovinge, Stefan, Fleischmann, Bernd K, Doevendans, Pieter A, van der Velden, Jolanda, Garcia, K Christopher, Wu, Joseph C, Sluijter, Joost P G, and Wu, Sean M

Published
2020

32. End‐diastolic force pre‐activates cardiomyocytes and determines contractile force: role of titin and calcium

Author

Najafi, Aref, primary, de Locht, Martijn, additional, Schuldt, Maike, additional, Schönleitner, Patrick, additional, Willigenburg, Menne, additional, Bollen, Ilse, additional, Goebel, Max, additional, Ottenheijm, Coen A. C., additional, der Velden, Jolanda, additional, Helmes, Michiel, additional, and Kuster, Diederik W. D., additional

Published
2019
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36. Genotype-specific pathogenic effects in human dilated cardiomyopathy

Author

Bollen, Ilse A.E., Schuldt, Maike, Harakalova, Magdalena, Vink, Aryan, Asselbergs, Folkert W., Pinto, Jose R., Krüger, Martina, Kuster, Diederik W.D., van der Velden, Jolanda, Bollen, Ilse A.E., Schuldt, Maike, Harakalova, Magdalena, Vink, Aryan, Asselbergs, Folkert W., Pinto, Jose R., Krüger, Martina, Kuster, Diederik W.D., and van der Velden, Jolanda

Published
2017

37. Genotype-specific pathogenic effects in human dilated cardiomyopathy

Author

Researchbureau DHL, Onderzoek Precision medicine, Pathologie Stafondersteuning, Pathologie Pathologen staf, Circulatory Health, Team Medisch, Bollen, Ilse A.E., Schuldt, Maike, Harakalova, Magdalena, Vink, Aryan, Asselbergs, Folkert W., Pinto, Jose R., Krüger, Martina, Kuster, Diederik W.D., van der Velden, Jolanda, Researchbureau DHL, Onderzoek Precision medicine, Pathologie Stafondersteuning, Pathologie Pathologen staf, Circulatory Health, Team Medisch, Bollen, Ilse A.E., Schuldt, Maike, Harakalova, Magdalena, Vink, Aryan, Asselbergs, Folkert W., Pinto, Jose R., Krüger, Martina, Kuster, Diederik W.D., and van der Velden, Jolanda

Published
2017

40. Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers.

Author

Driel, Beau Olivier van, Schuldt, Maike, Algül, Sila, Levin, Evgeni, Güclü, Ahmet, Germans, Tjeerd, Rossum, Albert C. van, Pei, Jiayi, Harakalova, Magdalena, Baas, Annette, Jans, Judith J. M., van der Velden, Jolanda, and Das, Anindita

Subjects
*AORTIC stenosis, *AORTIC valve diseases, *NITRIC oxide, *WESTERN immunoblotting, *AORTIC valve transplantation, *METABOLOMICS
Abstract

Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. Methods: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. Results: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. Conclusion: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy.

Author

Dorsch, Larissa M., Schuldt, Maike, dos Remedios, Cristobal G., Schinkel, Arend F. L., de Jong, Peter L., Michels, Michelle, Kuster, Diederik W. D., Brundel, Bianca J. J. M., and van der Velden, Jolanda

Subjects
*TUBULINS, *QUALITY control, *HYPERTROPHIC cardiomyopathy, *HEAT shock proteins, *PROTEINS
Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were (1) several key PQC players were more abundant in HCM compared to controls, (2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, (3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, (4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and (5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM. [ABSTRACT FROM AUTHOR]

Published
2019
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42. Abstract 14284: Detyrosinated Tubulin as Treatment Target in Genetic Heart Disease: Proteomic and Functional Studies in Hypertrophic Cardiomyopathy

Author

Schuldt, Maike, Pei, Jiayi, Harakalova, Magdalena, Dorsch, Larissa M, Mokry, Michal, Knol, Jaco C, Pham, Tang V, Schelfhorst, Tim, Piersma, Sander R, Dos Remedios, Cris G, Dalinghaus, Michiel, Michels, Michelle, Asselbergs, Folkert W, Jimenez, Connie R, van der Velden, Jolanda, and Kuster, Diederik W

Abstract

Introduction:Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. Mutations in genes encoding sarcomere proteins are the most common cause (sarcomere mutation positive: SMP), although in a group of patients no mutation is found (sarcomere mutation negative: SMN). We have still only limited knowledge about the pathomechanism leading to disease outcome.Hypothesis:Here, we applied an unbiased proteomics approach in cardiac samples from a clinically well-characterized HCM patient cohort to understand HCM pathophysiology as well as gain a better understanding of the genotype-phenotype relationship.Methods:We analyzed the proteome of 51 HCM samples (40 SMP, 11 SMN) obtained during septal myectomy by unlabeled LC-MS/MS mass spectrometry and compared it to 8 non-failing controls. Protein expression was quantified by peptide counts and protein-protein interaction networks of differentially expressed proteins were obtained from String database. Gene ontology analysis was performed with ClusterOne and Bingo. A new HCM mouse model was used to validate microtubule remodeling as a HCM disease modulator.Results:Next to a general downregulation of metabolic pathways and an upregulation of extracellular matrix proteins that have been found in all patient samples, we found an increase of tubulin and an altered posttranslational modification pattern in SMP patients. In an HCM mouse model we showed that inhibition of tubulin detyrosination normalizes contraction and relaxation of isolated cardiomyocytes.Conclusions:Mechanistically, these findings indicate that the tubulin network plays a role in the pathomechanism of individuals carrying a sarcomere mutation and that it might represent a potential treatment target to improve cardiac function.

Published
2019
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43. Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy.

Author

Nollet EE, Schuldt M, Sequeira V, Binek A, Pham TV, Schoonvelde SAC, Jansen M, Schomakers BV, van Weeghel M, Vaz FM, Houtkooper RH, Van Eyk JE, Jimenez CR, Michels M, Bedi KC Jr, Margulies KB, Dos Remedios CG, Kuster DWD, and van der Velden J

Subjects
Humans, Male, Female, Middle Aged, Adult, Myocardium metabolism, Myocardium pathology, Metabolomics, Proteomics, Lipidomics, Lipid Metabolism genetics, Sarcomeres metabolism, Sarcomeres genetics, Energy Metabolism genetics, Aged, Multiomics, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic metabolism, Cardiomyopathy, Hypertrophic pathology, Genotype, Phenotype
Abstract

Background: Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups., Methods: We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling., Results: HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients., Conclusions: We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM., Competing Interests: Disclosures Dr Margulies is a consultant for Bristol Myers Squibb and receives research support from Amgen.

Published
2024
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