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1.
Pediatr Rheumatol Online J ; 19(1): 29, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726806

RESUMO

BACKGROUND: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. METHODS: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. RESULTS: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. CONCLUSION: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.


Assuntos
/fisiopatologia , Doença da Artéria Coronariana/fisiopatologia , Hipotensão/fisiopatologia , Linfopenia/fisiopatologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Miocardite/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Distribuição por Idade , Antirreumáticos/uso terapêutico , Aspirina/uso terapêutico , Proteína C-Reativa/metabolismo , /metabolismo , Criança , Pré-Escolar , Tosse/fisiopatologia , Diarreia/fisiopatologia , Dispneia/fisiopatologia , Feminino , Glucocorticoides/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Humanos , /fisiopatologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Unidades de Terapia Intensiva Pediátrica , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Itália/epidemiologia , Masculino , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/metabolismo , Síndrome de Linfonodos Mucocutâneos/terapia , Inibidores da Agregação de Plaquetas/uso terapêutico , Choque/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/terapia , Taquipneia/fisiopatologia , Troponina T/metabolismo , Vômito/fisiopatologia
2.
Int Heart J ; 62(1): 142-147, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33390565

RESUMO

The aim of this study was to evaluate the clinical efficacy of N-acetylcysteine (NAC) in the treatment of ST segment elevation myocardial infarction (STEMI).PubMed, EMBASE, Cochrane Library, and Web of Science were searched systematically from the establishment of the database to June 2020. Two researchers independently completed literature screening and data extraction and conducted a meta-analysis.Nine articles including 1419 patients were enrolled. Meta-analysis showed that all-cause mortality [RR = 0.56, 95%CI (0.33, 0.93), P = 0.02], occurrence of major adverse cardiovascular events (MACE) [RR = 0.63, 95%CI (0.47, 0.85), P = 0.002], and myocardial enzyme hs-TnT level [SMD = -0.42, 95%CI (-0.71, -0.13), P = 0.005] were significantly lower in patients with STEMI treated with NAC than those in the control group. There was no significant difference between the NAC group and the control group in new congestive heart failure [RR = 0.94, 95%CI (0.48, 1.82), P = 0.84], ejection fraction [MD = 2.00, 95%CI (-0.59, 4.60), P = 0.13], and CK-MB [SMD = -0.18, 95%CI (-0.47, 0.11), P = 0.23]. There was no significant difference in the occurrence of adverse reactions between the NAC group and the control group [RR = 1.04, 95%CI (0.57-1.89), P = 0.90].NAC can reduce the all-cause mortality and MACE cases of STEMI.


Assuntos
Acetilcisteína/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Acetilcisteína/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Estudos de Casos e Controles , Creatina Quinase Forma MB/metabolismo , Feminino , Depuradores de Radicais Livres/administração & dosagem , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Volume Sistólico , Resultado do Tratamento , Troponina T/metabolismo
3.
Food Chem ; 340: 127914, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32889207

RESUMO

The objective of this study was to investigate the influence of oxidation on heat shock protein 27 (HSP27) and cytochrome c translocation, myofibrils degradation and endogenous enzymes activities, perfecting tenderization mechanism after slaughter. Bovine muscle (longissimus thoracis) was obtained at 30 min postmortem. Bovine muscle was cut and exposed to saline solution with or without H2O2 at 4 °C for 0.25, 1, 3 and 5 days, followed by detection of proteins degradation, location and enzymes activities. Results showed that oxidation promoted the translocation of HSP27 and cytochrome c from the cytoplasm to the cell membrane, which reduced µ-calpain activity, but increased caspase-3 activity through mediating the interaction with the two enzymes. Oxidation retarded troponin-T degradation, but accelerated desmin degradation, which is probably because oxidative modification of myofibrils induced different susceptibility to proteolysis. Therefore, oxidation leads to different regulatory mechanism on µ-calpain and caspase-3, as well as the degree of degradation of myofibrillar proteins, possibly through mediating HSP27 and cytochrome c.


Assuntos
Calpaína/metabolismo , Caspase 3/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Músculo Esquelético/metabolismo , Miofibrilas/metabolismo , Animais , Bovinos , Citocromos c/metabolismo , Peróxido de Hidrogênio/química , Masculino , Músculo Esquelético/química , Oxirredução , Mudanças Depois da Morte , Proteólise , Carne Vermelha , Troponina T/metabolismo
4.
Am J Physiol Heart Circ Physiol ; 319(2): H306-H319, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618513

RESUMO

Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin-filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. Contraction and Ca2+ reuptake times were slowed, which contrast with some findings in murine models of myofilament Ca2+ desensitization. We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in sodium-calcium exchanger activity. We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes expressing DCM mutations. These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM. Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes. However, we find several common pathways such as increased relaxation times and NFAT activation that are also hallmarks of HCM. This suggests more complex intracellular signaling underpinning DCM, driven by the primary mutation.NEW & NOTEWORTHY Dilated cardiomyopathy (DCM) is a frequently occurring cardiac disorder with a degree of genetic inheritance. We have found that DCM mutations in proteins that regulate the contractile machinery cause alterations to contraction, calcium-handling, and some new signaling pathways that provide stimuli for disease development. We have used guinea pig cells that recapitulate human calcium-handling and introduced the mutations using adenovirus gene transduction to look at the initial triggers of disease before remodeling.


Assuntos
Sinalização do Cálcio , Cardiomiopatia Dilatada/genética , Proteínas dos Microfilamentos/genética , Mutação , Contração Miocárdica , Miócitos Cardíacos/enzimologia , Fatores de Transcrição NFATC/metabolismo , Proteína Oncogênica v-akt/metabolismo , Função Ventricular Esquerda , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/fisiopatologia , Células Cultivadas , Predisposição Genética para Doença , Cobaias , Masculino , Proteínas dos Microfilamentos/metabolismo , Fenótipo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo
5.
Proc Natl Acad Sci U S A ; 117(31): 18822-18831, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690703

RESUMO

Muscle contraction is regulated by the movement of end-to-end-linked troponin-tropomyosin complexes over the thin filament surface, which uncovers or blocks myosin binding sites along F-actin. The N-terminal half of troponin T (TnT), TNT1, independently promotes tropomyosin-based, steric inhibition of acto-myosin associations, in vitro. Recent structural models additionally suggest TNT1 may restrain the uniform, regulatory translocation of tropomyosin. Therefore, TnT potentially contributes to striated muscle relaxation; however, the in vivo functional relevance and molecular basis of this noncanonical role remain unclear. Impaired relaxation is a hallmark of hypertrophic and restrictive cardiomyopathies (HCM and RCM). Investigating the effects of cardiomyopathy-causing mutations could help clarify TNT1's enigmatic inhibitory property. We tested the hypothesis that coupling of TNT1 with tropomyosin's end-to-end overlap region helps anchor tropomyosin to an inhibitory position on F-actin, where it deters myosin binding at rest, and that, correspondingly, cross-bridge cycling is defectively suppressed under diastolic/low Ca2+ conditions in the presence of HCM/RCM lesions. The impact of TNT1 mutations on Drosophila cardiac performance, rat myofibrillar and cardiomyocyte properties, and human TNT1's propensity to inhibit myosin-driven, F-actin-tropomyosin motility were evaluated. Our data collectively demonstrate that removing conserved, charged residues in TNT1's tropomyosin-binding domain impairs TnT's contribution to inhibitory tropomyosin positioning and relaxation. Thus, TNT1 may modulate acto-myosin activity by optimizing F-actin-tropomyosin interfacial contacts and by binding to actin, which restrict tropomyosin's movement to activating configurations. HCM/RCM mutations, therefore, highlight TNT1's essential role in contractile regulation by diminishing its tropomyosin-anchoring effects, potentially serving as the initial trigger of pathology in our animal models and humans.


Assuntos
Cardiomiopatias/metabolismo , Mutação/genética , Tropomiosina , Troponina T , Actinas/química , Actinas/metabolismo , Animais , Cálcio/metabolismo , Diástole/genética , Diástole/fisiologia , Proteínas de Drosophila , Humanos , Miócitos Cardíacos/química , Miócitos Cardíacos/metabolismo , Ligação Proteica , Ratos , Tropomiosina/química , Tropomiosina/metabolismo , Troponina T/química , Troponina T/genética , Troponina T/metabolismo
6.
PLoS One ; 15(6): e0234087, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511282

RESUMO

BACKGROUND: Ventricular septal perforation and left ventricular aneurysm are examples of potentially fatal complications of myocardial infarction. While various artificial materials are used in the repair of these issues, the possibility of associated infection and calcification is non-negligible. Cell-seeded biodegradable tissue-engineered patches may be a potential solution. This study evaluated the feasibility of a new left ventricular patch rat model to study neotissue formation in biodegradable cardiac patches. METHODS: Human induced pluripotent stem cell-derived cardiac progenitor cells (hiPS-CPCs) were cultured onto biodegradable patches composed of polyglycolic acid and a 50:50 poly (l-lactide-co-ε-caprolactone) copolymer for one week. After culturing, patches were implanted into left ventricular walls of male athymic rats. Unseeded controls were also used (n = 10/group). Heart conditions were followed by echocardiography and patches were subsequently explanted at 1, 2, 6, and 9 months post-implantation for histological evaluation. RESULT: Throughout the study, no patches ruptured demonstrating the ability to withstand the high pressure left ventricular system. One month after transplantation, the seeded patch did not stain positive for human nuclei. However, many new blood vessels formed within patches with significantly greater vessels in the seeded group at the 6 month time point. Echocardiography showed no significant difference in left ventricular contraction rate between the two groups. Calcification was found inside patches after 6 months, but there was no significant difference between groups. CONCLUSION: We have developed a surgical method to implant a bioabsorbable scaffold into the left ventricular environment of rats with a high survival rate. Seeded hiPS-CPCs did not differentiate into cardiomyocytes, but the greater number of new blood vessels in seeded patches suggests the presence of cell seeding early in the remodeling process might provide a prolonged effect on neotissue formation. This experiment will contribute to the development of a treatment model for left ventricular failure using iPS cells in the future.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Engenharia Tecidual , Implantes Absorvíveis , Animais , Modelos Animais de Doenças , Ecocardiografia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/transplante , Poliésteres/química , Ácido Poliglicólico/química , Ratos , Ratos Nus , Tecidos Suporte/química , Troponina T/metabolismo , Função Ventricular
7.
BMC Neurol ; 20(1): 227, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32498673

RESUMO

BACKGROUND: We present a case with a close temporal association of the first diagnosis of multiple sclerosis and stress cardiomyopathy. CASE PRESENTATION: A 19-year-old man experienced severe dyspnoea. The cardiac biomarkers troponin T and NT-proBNP were elevated, and transthoracic echocardiography showed basal hypokinesia. The man was diagnosed with stress cardiomyopathy after main differential diagnoses such as acute coronary syndrome, myocarditis, and pheochromocytoma were excluded. Furthermore, the patient reported vertigo and paraesthesia. Brain and spinal MRI revealed T2-hyperintense lesions with a prominent acute lesion in the pontomedullary area. Cerebrospinal fluid findings revealed a lymphocytic pleocytosis and intrathecal IgG synthesis. Serum neurofilaments were elevated. The patient was diagnosed with MS, and treatment with intravenous Methylprednisolone was initiated. The brainstem lesion due to multiple sclerosis was assumed to be the cause of stress cardiomyopathy. The patient fully recovered. CONCLUSION: Stress cardiomyopathy may be linked with the first manifestation of multiple sclerosis in the presented case since pontomedullary lesions could affect the sympathetic nervous system. This case highlights the importance of neurological history and examination in young patients with unexplained acute cardiac complaints.


Assuntos
Ecocardiografia , Esclerose Múltipla/complicações , Cardiomiopatia de Takotsubo/etiologia , Biomarcadores/metabolismo , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Troponina T/metabolismo , Adulto Jovem
8.
Travel Med Infect Dis ; 36: 101782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526372

RESUMO

INTRODUCTION: There are currently no satisfactory methods for predicting the outcome of Coronavirus Disease-2019 (COVID-19). The aim of this study is to establish a model for predicting the prognosis of the disease. METHODS: The laboratory results were collected from 54 deceased COVID-19 patients on admission and before death. Another 54 recovered COVID-19 patients were enrolled as control cases. RESULTS: Many laboratory indicators, such as neutrophils, AST, γ-GT, ALP, LDH, NT-proBNP, Hs-cTnT, PT, APTT, D-dimer, IL-2R, IL-6, IL-8, IL-10, TNF-α, CRP, ferritin and procalcitonin, were all significantly increased in deceased patients compared with recovered patients on admission. In contrast, other indicators such as lymphocytes, platelets, total protein and albumin were significantly decreased in deceased patients on admission. Some indicators such as neutrophils and procalcitonin, others such as lymphocytes and platelets, continuously increased or decreased from admission to death in deceased patients respectively. Using these indicators alone had moderate performance in differentiating between recovered and deceased COVID-19 patients. A model based on combination of four indicators (P = 1/[1 + e-(-2.658+0.587×neutrophils - 2.087×lymphocytes - 0.01×platelets+0.004×IL-2R)]) showed good performance in predicting the death of COVID-19 patients. When cutoff value of 0.572 was used, the sensitivity and specificity of the prediction model were 90.74% and 94.44%, respectively. CONCLUSIONS: Using the current indicators alone is of modest value in differentiating between recovered and deceased COVID-19 patients. A prediction model based on combination of neutrophils, lymphocytes, platelets and IL-2R shows good performance in predicting the outcome of COVID-19.


Assuntos
Infecções por Coronavirus/mortalidade , Pneumonia Viral/mortalidade , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/metabolismo , Aspartato Aminotransferases/metabolismo , Betacoronavirus , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/metabolismo , Feminino , Ferritinas/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Peptídeo Natriurético Encefálico/metabolismo , Neutrófilos , Pandemias , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/metabolismo , Pró-Calcitonina/metabolismo , Prognóstico , Tempo de Protrombina , Curva ROC , Receptores de Interleucina-2/metabolismo , Troponina T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , gama-Glutamiltransferase/metabolismo
9.
Food Chem ; 321: 126677, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247180

RESUMO

Myosin heavy chain (MHC) isoforms in goat muscles and their possible relationships with meat quality have not been fully elucidated. This study characterized the MHC isoforms in different caprine muscles using sodium dodecyl sulphate glycerol gel electrophoresis (SDS-GGE). The relationships between MHC isoforms, calpain systems and meat quality characteristics of different muscles in goats were examined. Four muscles, namely infraspinatus (IF), longissimus dorsi (LD), psoas major (PM) and supraspinatus (SS) were obtained from ten Boer crossbred bucks (7-10 months old; 26.5 ± 3.5 kg, BW). The percentages of MHC I, MHC IIa and MHC IIx in SS, IF, PM and LD were 47.2, 38.3, 32.1, 11.9; 28.0, 42.1, 33.0, 36.4; and 24.8, 19.6, 34.9 and 51.7, respectively. IF and SS had higher levels of calpastatin, total collagen and insoluble collagen contents than did PM and LD. PM had longer sarcomere length than did other muscles. LD had higher collagen solubility, troponin-T degradation products and glycogen content than did other muscles. These results infer that variable fiber-type composition could account partially for the differences in the physicochemical properties of goat muscles.


Assuntos
Calpaína/metabolismo , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Eletroforese , Eletroforese em Gel de Poliacrilamida , Cabras , Carne/análise , Músculo Esquelético/química , Isoformas de Proteínas/metabolismo , Troponina T/metabolismo
10.
Food Chem ; 319: 126571, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169769

RESUMO

This study aims to investigate the changes in mitochondrial apoptotic factors and proteolysis of two porcine muscles (psoas major - PM and longissimus dorsi - LD) during aging. Results found that during 2-168 h postmortem mitochondrial membrane permeability, mitochondrial lipid peroxidation, Ca2+ levels were increased, while the reduction level and abundance of cytochrome c were decreased (P < 0.05) in both muscle types. Furthermore, the activation of caspase-3 along with increases in troponin-T and desmin degradation, and µ-calpain autolysis were found (P < 0.05), regardless of muscle type. PM maintained higher mitochondrial apoptotic factors, but had more intact desmin, less troponin-T degradation and less extent of autolyzed products of µ-calpain compared to LD (P < 0.05). These results indicate that the rapid onset of mitochondrial apoptosis of PM would not lead to a subsequent impact on myofibrillar protein degradation, suggesting that the mitochondrial apoptosis mediated tenderization process could be muscle-specific.


Assuntos
Apoptose , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Carne Vermelha , Animais , Autólise/metabolismo , Calpaína/metabolismo , Desmina/metabolismo , Miofibrilas/metabolismo , Proteólise , Suínos , Fatores de Tempo , Troponina T/metabolismo
11.
Clin Chim Acta ; 505: 15-25, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32061575

RESUMO

The early concentration kinetic profiles of cardiac troponin in patients with non-ST-elevated myocardial infarction (NSTEMI) measured by high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays have not been described. In intermediate-to-high-risk of NSTEMI patients we measured serial cTn concentrations on ED arrival, at 1, 2, 3, 6-12, 24 and 48-hours with hs-cTnI and hs-cTnT assays. Log-normal curves were fitted to concentrations from time from symptom onset, and the time to rule-out decision thresholds estimated (hs-cTnI: 2 ng/L and 5 ng/L; hs-cTnT: 5 ng/L). Among 164 patients there were 58 NSTEMI. The hs-cTnI to hs-cTnT ratio increased linearly over the first 6-12 h following symptom onset. The estimated times from symptom onset to the 2 ng/L and 5 ng/L thresholds for hs-cTnI were 1.8 (0.1-3.1) and 1.9 (1.1-3.5) hours, and to the 5 ng/L threshold for hs-cTnT 1.9 (1.1-3.8) hours. The estimated time to exceed 5 ng/L was ≥3 hours in 32.6% (95%CI: 20.0% to 48.1%) cases for hs-cTnI and 33.3% (19.6% to 50.0%) for hs-cTnT. cTnI concentrations increased at a much more rapid rate than cTnT concentrations in patients with NSTEMI. Concentrations of a high proportion of patients took longer than 3 hours from symptom onset to exceed the 5 ng/L rule-out decision threshold.


Assuntos
Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Troponina I/análise , Troponina I/metabolismo , Troponina T/análise , Troponina T/metabolismo , Idoso , Biomarcadores , Tomada de Decisão Clínica , Feminino , Humanos , Cinética , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Estudos Prospectivos , Medição de Risco , Resultado do Tratamento
12.
Am J Physiol Heart Circ Physiol ; 318(3): H715-H722, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083971

RESUMO

Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor.NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.


Assuntos
Benzilaminas/farmacologia , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Sarcômeros/efeitos dos fármacos , Uracila/análogos & derivados , Animais , Cardiomiopatia Hipertrófica/genética , Camundongos , Mutação , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Sarcômeros/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo , Uracila/farmacologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-32033112

RESUMO

The objective of this study was to compare the release of cardiac troponin T (cTnT) after a football 7 match between two cohorts of children and adult players. Thirty-six male football players (children = 24, adult = 12) played a football 7 match, and cTnT was measured before, and 3 h after exercise. Concentrations of cTnT were compared between groups and time, and correlated with participants' characteristics, as well as internal and external exercise load. Cardiac troponin T was elevated in all participants (p < 0.001), and exceeded the upper reference limit for myocardial infarction in 25 (~70%) of them. Baseline concentrations were higher in adults (p < 0.001), but the elevation of cTnT was comparable between the groups (p = 0.37). Age (p < 0.001), body mass (p = 0.001) and height (p < 0.001), and training experience (p = 0.001) were associated to baseline cTnT values, while distance (p < 0.001), mean speed (p < 0.001), and peak (p = 0.013) and mean (p = 0.016) heart rate were associated to the elevation of cTnT. The present study suggests that a football 7 match evoked elevations of cTnT during the subsequent hours in healthy players regardless of their age. However, adults might present higher resting values of cTnT than children. In addition, results suggest that the exercise-induced elevations of cTnT might be mediated by exercise load but not participant characteristics.


Assuntos
Atletas , Miocárdio/metabolismo , Futebol , Troponina T/metabolismo , Adulto , Biomarcadores/metabolismo , Criança , Humanos , Masculino , Pessoa de Meia-Idade
14.
Clin Chem ; 66(2): 333-341, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040581

RESUMO

BACKGROUND: Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). METHODS: We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. RESULTS: Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. CONCLUSION: Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.


Assuntos
Infarto do Miocárdio/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Animais , Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Sarcômeros/metabolismo , Troponina I/sangue , Troponina T/sangue
15.
Am J Cardiol ; 125(8): 1194-1201, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32106929

RESUMO

The role of NT-proBNP and hs-cTnT levels in predicting heart failure (HF) and cardiovascular disease (CVD) events in persons with prediabetes (pre-DM) and diabetes mellitus (DM) is not well-established. We examined the individual and combined relations of N-terminal natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) levels among asymptomatic adults with pre-DM and DM with the development of incident HF and CVD events. 5,584 participants with biomarker measures aged 45 to 84 years were included from the Multi-Ethnic Study of Atherosclerosis, of which 4,090 were normoglycemic, 799 had pre-DM, and 695 had DM at baseline and were followed for 12.4 ± 3.8 years. In those with DM, HF incidence rates per 1,000 person-years ranged from 3.2 to 39.4 across quartiles of NT-proBNP and 0.6 to 18.2 for hs-cTnT, respectively. Corresponding values for CVD incidence per 1,000 person-years ranged from 13.7 to 39.4 for NT-proBNP and 13.2 to 35.4 for hs-cTnT. Multivariate adjusted HRs were highest when both NT-proBNP and hs-cTnT were above versus below the median in those with pre-DM/DM (16.7 for incident HF and 2.1 for CVD events, both p <0.01). In conclusion, the combination of both biomarkers to traditional risk factors in participants who were normoglycemic or with pre-DM or DM improved risk prediction for both incident HF and total CVD events in an ethnically diverse population.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insuficiência Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Estado Pré-Diabético/metabolismo , Acidente Vascular Cerebral/metabolismo , Troponina T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/epidemiologia , Angina Pectoris/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doença das Coronárias/metabolismo , Doença das Coronárias/mortalidade , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/mortalidade , Medição de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Estados Unidos/epidemiologia
16.
Ann Neurol ; 87(4): 568-583, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31970803

RESUMO

OBJECTIVE: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. METHODS: Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. RESULTS: Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. INTERPRETATION: This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.


Assuntos
Músculo Esquelético/patologia , Miopatias da Nemalina/fisiopatologia , RNA Mensageiro/metabolismo , Troponina T/genética , Animais , Criança , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Morfolinos , Músculo Esquelético/ultraestrutura , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Rabdomiólise/genética , Rabdomiólise/fisiopatologia , Troponina T/metabolismo , Peixe-Zebra
17.
Am Heart J ; 221: 84-94, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954328

RESUMO

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) assays enhance detection of lower circulating troponin concentrations, but the impact on outcomes in clinical practice is unclear. Our objective was to compare outcomes of chest pain patients discharged from emergency departments (EDs) using hs-cTn and conventional troponin (cTn) assays. METHODS: We conducted an observational study of chest pain patients aged 40-105 years who presented to an ED from April 1, 2013, to March 31, 2017, and were discharged home. We compared 30-day and 1-year outcomes of EDs that used hs-cTn versus cTn assays. The primary outcome was a composite of all-cause death, myocardial infarction or unstable angina. Comparisons were conducted with (1) no adjustment; (2) adjustment for demographic, socioeconomic, and hospital characteristics; and (3) full clinical adjustment. RESULTS: Among the 394,910 patients, 62,138 (15.7%) were evaluated at hs-cTn EDs and 332,772 (84.3%) were evaluated at cTn EDs. Patients discharged from hs-cTn EDs were less likely to have diabetes, hypertension, or prior heart disease. At 30 days, the unadjusted primary outcome rate was lower in hs-cTn EDs (0.9% vs 1.0%, P < .001). The 30-day hazard ratios for the primary outcome were 0.84 (95% CI 0.77-0.92) for no adjustment and 0.98 (95% CI 0.88-1.08) for full adjustment. Over 1 year, patients discharged from hs-cTn EDs had significantly fewer primary outcomes (3.7% vs 4.1%, P < .001) and lower hazard ratio (0.93; 95% CI 0.89-0.98) even after full adjustment. CONCLUSIONS: Hs-cTn testing was associated with a significantly lower adjusted hazard of myocardial infarction, angina, and all-cause hospitalization at 1 year but not 30 days.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Angina Instável/epidemiologia , Dor no Peito/etiologia , Técnicas de Laboratório Clínico/métodos , Mortalidade , Infarto do Miocárdio/epidemiologia , Troponina I/análise , Troponina T/análise , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Alta do Paciente , Modelos de Riscos Proporcionais , Troponina I/metabolismo , Troponina T/metabolismo
18.
FASEB J ; 34(2): 3224-3238, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31917470

RESUMO

Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12Rß2 and IL-27Rα receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12Rß2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.


Assuntos
Receptor gp130 de Citocina/metabolismo , Interleucinas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Troponina T/metabolismo
19.
Ann Thorac Cardiovasc Surg ; 26(5): 263-269, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31813921

RESUMO

PURPOSE: Sivelestat, a neutrophil elastase inhibitor, attenuates global ischemia-induced myocardial damage and coronary endothelial dysfunction. Here, we investigated whether sivelestat exerts the cardioprotective effects against cardioplegic arrest in rat hearts. METHODS: Isolated Langendorff-perfused rat hearts were randomly allocated to three groups and subjected to 2-min infusions with St. Thomas' Hospital cardioplegic solution No. 2 (STH2) and 30-min global ischemia followed by 60-min reperfusion as follows: (i) control (STH2 treatment only), (ii) sivelestat (19 µmol/L) infusion for the first 10 min of reperfusion, and (iii) sivelestat (19 µmol/L) infusion for 10 min before ischemia and for the first 10 min of reperfusion. Left ventricular developed pressure (LVDP) recovery and troponin T leakage were measured at the end of reperfusion. Coronary flow response to acetylcholine (ACh) was assessed. RESULTS: Single and multiple doses of sivelestat significantly improved LVDP recovery (69 ± 15 and 69 ± 14 vs 48 ± 15 [control]; p <0.05) and decreased troponin T leakage (0.4 ± 0.3 and 0.7 ± 0.5 vs 1.7 ± 0.6 [control]; p <0.05). Multiple doses of sivelestat significantly improved coronary flow response to ACh (121 ± 9 vs 105 ± 4; p <0.05). CONCLUSIONS: Addition of sivelestat to STH2 attenuates myocardial injury after cardioplegic arrest in rat hearts. This cardioprotective effect was achieved even when sivelestat was administered during early reperfusion.


Assuntos
Glicina/análogos & derivados , Parada Cardíaca Induzida/efeitos adversos , Elastase de Leucócito/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Serino Proteinase/farmacologia , Sulfonamidas/farmacologia , Animais , Modelos Animais de Doenças , Glicina/farmacologia , Preparação de Coração Isolado , Elastase de Leucócito/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Ratos Wistar , Troponina T/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos
20.
Exp Cell Res ; 387(1): 111736, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759053

RESUMO

Symptom of ventricular hypertrophy caused by cardiac troponin T (TNNT2) mutations is mild, while patients often showed high incidence of sudden cardiac death. The 92nd arginine to glutamine mutation (R92Q) of cTnT was one of the mutant hotspots in hypertrophic cardiomyopathy (HCM). However, there are no such human disease models yet. To solve this problem, we generated TNNT2 R92Q mutant hESC cell lines (heterozygote or homozygote) using TALEN mediated homologous recombination in this study. After directed cardiac differentiation, we found a relative larger cell size in both heterozygous and homozygous TNNT2 R92Q hESC-cardiomyocytes. Expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a) were downregulated, while myocyte specific enhancer factor 2c (MEF2c) and the ratio of beta myosin to alpha myosin heavy chain (MYH7/MYH6) were increased in heterozygous TNNT2 R92Q hESC-cardiomyocytes. TNNT2 R92Q mutant cardiomyocytes exhibited efficient responses to heart-related pharmaceutical agents. We also found TNNT2 R92Q heterozygous mutant cardiomyocytes showed increased calcium sensitivity and contractility. Further, engineered heart tissues (EHTs) prepared by combining rat decellularized heart extracellular matrices with heterozygous R92Q mutant cardiomyocytes showed similar drug responses as to HCM patients and increased sensitivity to caspofungin-induced cardiotoxicity. Using RNA-sequencing of TNNT2 R92Q heterozygous mutant cardiomyocytes, we found dysregulation of calcium might participated in the early development of hypertrophy. Our hESC-derived TNNT2 R92Q mutant cardiomyocytes and EHTs are good in vitro human disease models for future disease studies and drug screening.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Células-Tronco Embrionárias Humanas/citologia , Cardiomiopatia Hipertrófica/metabolismo , Linhagem Celular , Células HEK293 , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Hipertrofia/metabolismo , Hipertrofia/patologia , Mutação/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Fenótipo , Troponina T/metabolismo
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