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  • 1
    Online Resource
    Online Resource
    Data_Sheet_1.PDF
    Frontiers Media SA ; 2019
    In:  Frontiers in Cardiovascular Medicine Vol. 6 ( 2019-10-22)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 6 ( 2019-10-22)
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    URL: Article
    DOI: 10.3389/fcvm.2019.00151
    DOI: 10.3389/fcvm.2019.00151.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2781496-8
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  • 2
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    Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
    Frontiers Media SA ; 2022
    In:  Frontiers in Cardiovascular Medicine Vol. 9 ( 2022-9-23)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 9 ( 2022-9-23)
    Abstract: Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    DOI: 10.3389/fcvm.2022.997352
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2781496-8
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  • 3
    Online Resource
    Online Resource
    Table1.xlsx
    Frontiers Media SA ; 2023
    In:  Frontiers in Cardiovascular Medicine Vol. 10 ( 2023-4-21)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 10 ( 2023-4-21)
    Abstract: Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC. Methods and results As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca 2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (β-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca 2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca 2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine. Conclusions The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fcvm.2023.1129349
    DOI: 10.3389/fcvm.2023.1129349.s001
    DOI: 10.3389/fcvm.2023.1129349.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2781496-8
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  • 4
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    Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy
    Frontiers Media SA ; 2022
    In:  Frontiers in Cardiovascular Medicine Vol. 9 ( 2022-5-19)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 9 ( 2022-5-19)
    Abstract: Metabolites derived from N −3 and N −6 polyunsaturated fatty acids (PUFAs) have both beneficial and detrimental effects on the heart. However, contribution of these lipid mediators to dilated cardiomyopathy (DCM)-associated mitochondrial dysfunction remains unknown. This study aimed to characterize DCM-specific alterations in the PUFA metabolome in conjunction with cardiac mitochondrial quality in human explanted heart tissues. Methods Left ventricular tissues obtained from non-failing control (NFC) or DCM explanted hearts, were assessed for N −3 and N −6 PUFA metabolite levels using LC-MS/MS. mRNA and protein expression of CYP2J2, CYP2C8 and epoxide hydrolase enzymes involved in N −3 and N −6 PUFA metabolism were quantified. Cardiac mitochondrial quality was assessed by transmission electron microscopy, measurement of respiratory chain complex activities and oxygen consumption (respiratory control ratio, RCR) during ADP-stimulated ATP production. Results Formation of cardioprotective CYP-derived lipid mediators, epoxy fatty acids (EpFAs), and their corresponding diols were enhanced in DCM hearts. These findings were corroborated by increased expression of CYP2J2 and CYP2C8 enzymes, as well as microsomal and soluble epoxide hydrolase enzymes, suggesting enhanced metabolic flux and EpFA substrate turnover. DCM hearts demonstrated marked damage to mitochondrial ultrastructure and attenuated mitochondrial function. Incubation of fresh DCM cardiac fibers with the protective EpFA, 19,20-EDP, significantly improved mitochondrial function. Conclusions The current study demonstrates that increased expressions of CYP-epoxygenase enzymes and epoxide hydrolases in the DCM heart correspond with enhanced PUFA-derived EpFA turnover. This is accompanied by severe mitochondrial functional impairment which can be rescued by the administration of exogenous EpFAs.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    DOI: 10.3389/fcvm.2022.879209
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2781496-8
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  • 5
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    Online Resource
    Table1.DOCX
    Frontiers Media SA ; 2022
    In:  Frontiers in Physiology Vol. 13 ( 2022-6-8)
    Details
    In: Frontiers in Physiology, Frontiers Media SA, Vol. 13 ( 2022-6-8)
    Abstract: Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant K D of 6–24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (K D 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa 50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa 50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders.
    Type of Medium: Online Resource
    ISSN: 1664-042X
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fphys.2022.892979
    DOI: 10.3389/fphys.2022.892979.s001
    DOI: 10.3389/fphys.2022.892979.s002
    DOI: 10.3389/fphys.2022.892979.s003
    DOI: 10.3389/fphys.2022.892979.s004
    DOI: 10.3389/fphys.2022.892979.s005
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2564217-0
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  • 6
    Online Resource
    Online Resource
    Data_Sheet_1.DOCX
    Frontiers Media SA ; 2022
    In:  Frontiers in Public Health Vol. 10 ( 2022-5-19)
    Details
    In: Frontiers in Public Health, Frontiers Media SA, Vol. 10 ( 2022-5-19)
    Abstract: The COVID-19 pandemic has seen a large surge in case numbers over several waves, and has critically strained the health care system, with a significant number of cases requiring hospitalization and ICU admission. This study used a decision tree modeling approach to identify the most important predictors of severe outcomes among COVID-19 patients. Methods We identified a retrospective population-based cohort ( n = 140,182) of adults who tested positive for COVID-19 between 5 th March 2020 and 31 st May 2021. Demographic information, symptoms and co-morbidities were extracted from a communicable disease and outbreak management information system and electronic medical records. Decision tree modeling involving conditional inference tree and random forest models were used to analyze and identify the key factors(s) associated with severe outcomes (hospitalization, ICU admission and death) following COVID-19 infection. Results In the study cohort, nearly 6.37% were hospitalized, 1.39% were admitted to ICU and 1.57% died due to COVID-19. Older age ( & gt;71Y) and breathing difficulties were the top two factors associated with a poor prognosis, predicting about 50% of severe outcomes in both models. Neurological conditions, diabetes, cardiovascular disease, hypertension, and renal disease were the top five pre-existing conditions that altogether predicted 29% of outcomes. 79% of the cases with poor prognosis were predicted based on the combination of variables. Age stratified models revealed that among younger adults (18–40 Y), obesity was among the top risk factors associated with adverse outcomes. Conclusion Decision tree modeling has identified key factors associated with a significant proportion of severe outcomes in COVID-19. Knowledge about these variables will aid in identifying high-risk groups and allocating health care resources.
    Type of Medium: Online Resource
    ISSN: 2296-2565
    URL: Article
    URL: Article
    DOI: 10.3389/fpubh.2022.838514
    DOI: 10.3389/fpubh.2022.838514.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2711781-9
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