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  1. Article ; Online: Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors.

    Wijnker, Paul J M / Dinani, Rafeeh / van der Laan, Nico C / Algül, Sila / Knollmann, Bjorn C / Verkerk, Arie O / Remme, Carol Ann / Zuurbier, Coert J / Kuster, Diederik W D / van der Velden, Jolanda

    Cardiovascular research

    2024  Volume 120, Issue 3, Page(s) 301–317

    Abstract: Aims: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced ... ...

    Abstract Aims: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation.
    Methods and results: Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current.
    Conclusion: SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM.
    MeSH term(s) Humans ; Canagliflozin ; Calcium ; Induced Pluripotent Stem Cells ; Cardiomyopathy, Hypertrophic/drug therapy ; Cardiomyopathy, Hypertrophic/genetics ; Cardiomyopathy, Hypertrophic/pathology ; Myocytes, Cardiac/pathology ; Troponin T/genetics ; Sodium ; Glucose ; Benzhydryl Compounds ; Glucosides
    Chemical Substances empagliflozin (HDC1R2M35U) ; dapagliflozin (1ULL0QJ8UC) ; Canagliflozin (0SAC974Z85) ; Calcium (SY7Q814VUP) ; Troponin T ; Sodium (9NEZ333N27) ; Glucose (IY9XDZ35W2) ; Benzhydryl Compounds ; Glucosides
    Language English
    Publishing date 2024-01-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvae004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: The microtubule signature in cardiac disease: etiology, disease stage, and age dependency.

    Algül, Sıla / Dorsch, Larissa M / Sorop, Oana / Vink, Aryan / Michels, Michelle / Dos Remedios, Cristobal G / Dalinghaus, Michiel / Merkus, Daphne / Duncker, Dirk J / Kuster, Diederik W D / van der Velden, Jolanda

    Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology

    2023  Volume 193, Issue 5, Page(s) 581–595

    Abstract: Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common ... ...

    Abstract Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common experimental models has been incompletely defined. Here, we assessed the tubulin signature in a large set of human cardiac samples and myocardium of animal models with cardiac remodeling caused by pressure overload, myocardial infarction or a gene defect. We studied levels of total, acetylated, and detyrosinated α-tubulin and desmin in cardiac tissue from hypertrophic (HCM) and dilated cardiomyopathy (DCM) patients with an idiopathic (n = 7), ischemic (n = 7) or genetic origin (n = 59), and in a pressure-overload concentric hypertrophic pig model (n = 32), pigs with a myocardial infarction (n = 28), mature pigs (n = 6), and mice (n = 15) carrying the HCM-associated MYBPC3
    Language English
    Publishing date 2023-08-29
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 231245-1
    ISSN 1432-136X ; 0174-1578
    ISSN (online) 1432-136X
    ISSN 0174-1578
    DOI 10.1007/s00360-023-01509-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.171: Show issues Location:
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  3. Article ; Online: High heart rate associated early repolarization causes J-waves in both zebra finch and mouse.

    Offerhaus, Joost A / Snelderwaard, Peter C / Algül, Sila / Faber, Jaeike W / Riebel, Katharina / Jensen, Bjarke / Boukens, Bastiaan J

    Physiological reports

    2021  Volume 9, Issue 5, Page(s) e14775

    Abstract: High heart rates are a feature of small endothermic-or warm-blooded-mammals and birds. In small mammals, the QT interval is short, and local ventricular recordings reveal early repolarization that coincides with the J-wave on the ECG, a positive ... ...

    Abstract High heart rates are a feature of small endothermic-or warm-blooded-mammals and birds. In small mammals, the QT interval is short, and local ventricular recordings reveal early repolarization that coincides with the J-wave on the ECG, a positive deflection following the QRS complex. Early repolarization contributes to short QT-intervals thereby enabling brief cardiac cycles and high heart rates. We therefore hypothesized high hearts rates associate with early repolarization and J-waves on the ECG of endothermic birds. We tested this hypothesis by comparing isolated hearts of zebra finches and mice and recorded pseudo-ECGs and optical action potentials (zebra finch, n = 8; mouse, n = 8). In both species, heart rate exceeded 300 beats per min, and total ventricular activation was fast (QRS < 10 ms). Ventricular activation progressed from the left to the right ventricle in zebra finch, whereas it progressed from apex-to-base in mouse. In both species, the early repolarization front followed the activation front, causing a positive J-wave in the pseudo-ECG. Inhibition of early repolarization by 4-aminopyridine reduced J-wave amplitude in both species. Action potential duration was similar between ventricles in zebra finch, whereas in mouse the left ventricular action potential was longer. Accordingly, late repolarization had opposite directions in zebra finch (left-right) and mouse (right-left). This caused a similar direction for the zebra finch J-wave and T-wave, whereas in the mouse they were discordant. Our findings demonstrate that early repolarization and the associated J-wave may have evolved by convergence in association with high heart rates.
    MeSH term(s) Action Potentials/physiology ; Animals ; Arrhythmias, Cardiac/physiopathology ; Electrocardiography/methods ; Finches/physiology ; Heart/physiology ; Heart Conduction System/physiology ; Heart Rate/physiology ; Heart Ventricles/physiopathology ; Mice
    Language English
    Publishing date 2021-03-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2724325-4
    ISSN 2051-817X ; 2051-817X
    ISSN (online) 2051-817X
    ISSN 2051-817X
    DOI 10.14814/phy2.14775
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy.

    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

    Circulation research

    2023  Volume 133, Issue 5, Page(s) 387–399

    Abstract: Background: Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding ... ...

    Abstract Background: Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM.
    Methods: We optimized and increased the throughput of unloaded shortening measurements and screened a kinase inhibitor library in isolated adult cardiomyocytes from wild-type mice. One hundred fifty-seven kinase inhibitors were screened. To assess which kinases are dysregulated in patients with HCM and could contribute to impaired relaxation, we performed a tyrosine and global phosphoproteomics screen and integrative inferred kinase activity analysis using HCM patient myocardium. Identified hits from these 2 data sets were validated in cardiomyocytes from a homozygous
    Results: Screening of 157 kinase inhibitors in wild-type (N=33) cardiomyocytes (n=24 563) resulted in the identification of 17 positive inotropes and 21 positive lusitropes, almost all of them novel. The positive lusitropes formed 3 clusters: cell cycle, EGFR (epidermal growth factor receptor)/IGF1R (insulin-like growth factor 1 receptor), and a small Akt (α-serine/threonine protein kinase) signaling cluster. By performing phosphoproteomic profiling of HCM patient myocardium (N=24 HCM and N=8 donors), we demonstrated increased activation of 6 of 8 proteins from the EGFR/IGFR1 cluster in HCM. We validated compounds from this cluster in mouse HCM (N=12) cardiomyocytes (n=2023). Three compounds from this cluster were able to improve relaxation in HCM cardiomyocytes.
    Conclusions: We showed the feasibility of screening for functional modulators of cardiomyocyte relaxation and contraction, parameters that we observed to be modulated by kinases involved in EGFR/IGF1R, Akt, cell cycle signaling, and FoxO (forkhead box class O) signaling, respectively. Integrating the screening data with phosphoproteomics analysis in HCM patient tissue indicated that inhibition of EGFR/IGF1R signaling is a promising target for treating impaired relaxation in HCM.
    MeSH term(s) Mice ; Animals ; Proto-Oncogene Proteins c-akt/metabolism ; Myocardial Contraction ; Cardiomyopathy, Hypertrophic/metabolism ; Myocytes, Cardiac/metabolism ; ErbB Receptors/genetics ; ErbB Receptors/metabolism
    Chemical Substances Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2023-07-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.122.322133
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ui IV Zs.70: Show issues Location:
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    Ui IV Zs.60: Show issues Location:
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  5. Article ; Online: Blood-based biomarkers for the prediction of hypertrophic cardiomyopathy prognosis: a systematic review and meta-analysis.

    Jansen, Mark / Algül, Sila / Bosman, Laurens P / Michels, Michelle / van der Velden, Jolanda / de Boer, Rudolf A / van Tintelen, J Peter / Asselbergs, Folkert W / Baas, Annette F

    ESC heart failure

    2022  Volume 9, Issue 5, Page(s) 3418–3434

    Abstract: Aims: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease. HCM is an important cause of sudden cardiac death and may also lead to outflow tract obstruction and heart failure. Disease severity is highly variable and risk ... ...

    Abstract Aims: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease. HCM is an important cause of sudden cardiac death and may also lead to outflow tract obstruction and heart failure. Disease severity is highly variable and risk stratification remains limited. Therefore, we aimed to review current knowledge of prognostic blood-based biomarkers in HCM.
    Methods and results: A systematic literature search was performed on PubMed, Embase, and the Cochrane library to identify studies assessing plasma or serum biomarkers for outcomes involving malignant ventricular arrhythmia, outflow tract obstruction, and heart failure. Risk of bias was assessed using the QUIPS tool. Meta-analyses were performed using the random effects method. A total of 26 unique cohort studies assessing 42 biomarkers were identified. Overall risk of bias was moderate. Thirty-two biomarkers were significantly associated to an HCM outcome in at least one study (nine biomarkers in at least two studies). In pooled analyses, cardiovascular mortality was predicted by N-terminal prohormone of brain natriuretic peptide (hazard ratio [HR] 5.38 per log[pg/mL], 95% confidence interval [CI] 2.07-14.03, P < 0.001, I
    Conclusions: Several blood-based biomarkers were identified as predictors of HCM outcomes. Additional studies are required to validate their prognostic utility within current risk stratification models.
    MeSH term(s) Humans ; Cardiomyopathy, Hypertrophic/diagnosis ; Natriuretic Peptide, Brain ; Death, Sudden, Cardiac/etiology ; Biomarkers ; Heart Failure/complications
    Chemical Substances Natriuretic Peptide, Brain (114471-18-0) ; Biomarkers
    Language English
    Publishing date 2022-07-17
    Publishing country England
    Document type Meta-Analysis ; Systematic Review ; Journal Article
    ZDB-ID 2814355-3
    ISSN 2055-5822 ; 2055-5822
    ISSN (online) 2055-5822
    ISSN 2055-5822
    DOI 10.1002/ehf2.14073
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers.

    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

    International journal of molecular sciences

    2021  Volume 22, Issue 7

    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 ... ...

    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.
    MeSH term(s) Aged ; Aortic Valve Stenosis/diagnostic imaging ; Aortic Valve Stenosis/metabolism ; Aortic Valve Stenosis/surgery ; Biomarkers/blood ; Blood/metabolism ; Case-Control Studies ; Eicosanoids/blood ; Endothelial Cells ; Fatty Acids/blood ; Female ; Heart Valve Prosthesis Implantation ; Humans ; Male ; Metabolomics ; Middle Aged ; Nitric Oxide/blood ; Nitric Oxide/genetics ; Nitric Oxide/metabolism ; Positron-Emission Tomography ; Transcriptome
    Chemical Substances Biomarkers ; Eicosanoids ; Fatty Acids ; Nitric Oxide (31C4KY9ESH)
    Language English
    Publishing date 2021-03-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22073569
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy.

    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

    Cells

    2021  Volume 10, Issue 11

    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 ...

    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 (
    MeSH term(s) Adult ; Cardiomyopathy, Hypertrophic/metabolism ; Energy Metabolism ; Female ; Humans ; Male ; Metabolome ; Metabolomics ; Middle Aged ; Multivariate Analysis ; Mutation/genetics ; Sarcomeres/genetics
    Language English
    Publishing date 2021-10-29
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10112950
    Database MEDical Literature Analysis and Retrieval System OnLINE

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