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1.
J Thorac Cardiovasc Surg ; 159(2): 637-646, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31668539

RESUMO

OBJECTIVES: Endothelial-to-mesenchymal transition (EndMT) has been identified as the underlying mechanism of endocardial fibroelastosis (EFE) formation. The purpose of this study was to determine whether hemodynamic alterations due to valvar defects promote EndMT and whether age-specific structural changes affect ventricular diastolic compliance despite extensive surgical resection of EFE tissue. MATERIAL AND METHODS: We analyzed EFE tissue from 24 patients with hypoplastic left heart syndrome (HLHS) who underwent left ventricular (LV) rehabilitation surgery at Boston Children's Hospital between December 2011 and March 2018. Six patients with flow disturbances across the aortic valve and/or mitral valve but no HLHS diagnosis and macroscopic appearance of "EFE-like tissue" in the LV were included for comparison. All samples were examined for amount of collagen/elastin production and degradation, and presence of active EndMT by histologic analysis. RESULTS: EFE tissue from patients with and without HLHS consisted predominantly of elastin and collagen fibers. There was no alteration in degradation activity for collagen or elastin as shown by in situ zymography. Active EndMT was found in all patients with and without HLHS with flow disturbances ("EFE-like"). In patients with HLHS, EFE infiltrated into the underlying myocardium with increasing age. CONCLUSIONS: Patients with and without HLHS with flow disturbances due to stenotic or incompetent valves develop EndMT-derived fibrotic tissue covering the LV. When EFE recurs, it is directly associated with flow disturbances and switches to an infiltrative growth pattern with increasing age, leading to increased diastolic stiffness of the LV.


Assuntos
Fibroelastose Endocárdica , Síndrome do Coração Esquerdo Hipoplásico , Procedimentos Cirúrgicos Cardíacos , Criança , Pré-Escolar , Estudos de Coortes , Colágeno/metabolismo , Elastina/metabolismo , Fibroelastose Endocárdica/etiologia , Fibroelastose Endocárdica/patologia , Fibroelastose Endocárdica/fisiopatologia , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Hemodinâmica/fisiologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/complicações , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Lactente
2.
BMC Med Genomics ; 12(1): 141, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640709

RESUMO

BACKGROUND: Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries. METHODS: We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996-2000), and measures of target organ damage were assessed in a follow-up visit (2000-2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated. RESULTS: After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed. CONCLUSIONS: Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.


Assuntos
Negro ou Afro-Americano/genética , Epigênese Genética , Hipertensão/patologia , Fatores Etários , Idoso , Índice Tornozelo-Braço , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Creatinina/urina , Metilação de DNA , Feminino , Taxa de Filtração Glomerular , Ventrículos do Coração/química , Humanos , Hipertensão/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Albumina Sérica Humana/urina
3.
Peptides ; 121: 170139, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31472173

RESUMO

BACKGROUND: Apelin signalling pathways have important cardiovascular and metabolic functions. Recently, apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)], were reported to function independent of the apelin receptor in vivo to produce beneficial metabolic effects without modulating blood pressure. We aimed to show that these peptides bound to the apelin receptor and to further characterise their pharmacology in vitro at the human apelin receptor. METHODS: [Pyr1]apelin-13 saturation binding experiments and competition binding experiments were performed in rat and human heart homogenates using [125I]apelin-13 (0.1 nM), and/or increasing concentrations of apelin-36, apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)] (50pM-100µM). Apelin-36 and its analogues apelin-36-[F36A], apelin-36-[L28A], apelin-36-[L28C(30kDa-PEG)], apelin-36-[A28 A13] and [40kDa-PEG]-apelin-36 were tested in forskolin-induced cAMP inhibition and ß-arrestin assays in CHO-K1 cells heterologously expressing the human apelin receptor. Bias signaling was quantified using the operational model for bias. RESULTS: In both species, [Pyr1]apelin-13 had comparable subnanomolar affinity and the apelin receptor density was similar. Apelin-36, apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)] competed for binding of [125I]apelin-13 with nanomolar affinities. Apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)] inhibited forskolin-induced cAMP release, with nanomolar potencies but they were less potent compared to apelin-36 at recruiting ß-arrestin. Bias analysis suggested that these peptides were G protein biased. Additionally, [40kDa-PEG]-apelin-36 and apelin-36-[F36A] retained nanomolar potencies in both cAMP and ß-arrestin assays whilst apelin-36-[A13 A28] exhibited a similar profile to apelin-36-[L28C(30kDa-PEG)] in the ß-arrestin assay but was more potent in the cAMP assay. CONCLUSIONS: Apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)] are G protein biased ligands of the apelin receptor, suggesting that the apelin receptor is an important therapeutic target in metabolic diseases.


Assuntos
Receptores de Apelina/metabolismo , Apelina/metabolismo , Ventrículos do Coração/metabolismo , Peptídeos/metabolismo , beta-Arrestinas/metabolismo , Adulto , Animais , Apelina/química , Apelina/farmacologia , Receptores de Apelina/química , Ligação Competitiva , Células CHO , Colforsina/farmacologia , Misturas Complexas/química , Misturas Complexas/metabolismo , Cricetulus , AMP Cíclico/metabolismo , Feminino , Ventrículos do Coração/química , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Peptídeos/síntese química , Peptídeos/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley
4.
J Proteomics ; 191: 107-113, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29572163

RESUMO

Right ventricle (RV) remodelling occurs in neonatal patients born with ventricular septal defect (VSD). The presence of a defect between the two ventricles allows for shunting of blood from the left to right side. The resulting RV hypertrophy leads to molecular remodelling which has thus far been largely investigated using right atrial (RA) tissue. In this study we used proteomic and phosphoproteomic analysis in order to determine any difference between the proteomes for RA and RV. Samples were therefore taken from the RA and RV of five infants (0.34 ±â€¯0.05 years, mean ±â€¯SEM) with VSD who were undergoing cardiac surgery to repair the defect. Significant differences in protein expression between RV and RA were seen. 150 protein accession numbers were identified which were significantly lower in the atria, whereas none were significantly higher in the atria compared to the ventricle. 19 phosphorylation sites (representing 19 phosphoproteins) were also lower in RA. This work has identified differences in the proteome between RA and RV which reflect differences in contractile activity and metabolism. As such, caution should be used when drawing conclusions based on analysis of the RA and extrapolating to the hypertrophied RV. SIGNIFICANCE: RV hypertrophy occurs in neonatal patients born with VSD. Very little is known about how the atria responds to RV hypertrophy, especially at the protein level. Access to tissue from age-matched groups of patients is very rare, and we are in the unique position of being able to get tissue from both the atria and ventricle during reparative surgery of these infants. Our findings will be beneficial to future research into heart chamber malformations in congenital heart defects.


Assuntos
Comunicação Interventricular/metabolismo , Miocárdio/química , Proteoma/análise , Átrios do Coração/química , Comunicação Interventricular/patologia , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Humanos , Hipertrofia , Lactente , Fosfoproteínas/análise , Proteômica/métodos
5.
Heart Vessels ; 34(3): 538-544, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30159657

RESUMO

Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5 mM as gold atoms, 200 µL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24 h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56 ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.


Assuntos
DNA/genética , Regulação da Expressão Gênica , Ouro/análise , Insuficiência Cardíaca/metabolismo , Nanopartículas Metálicas/análise , Miocárdio/química , Fator de Necrose Tumoral alfa/genética , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Reação em Cadeia da Polimerase , Fator de Necrose Tumoral alfa/biossíntese
6.
Eur J Cardiothorac Surg ; 51(6): 1063-1071, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28329269

RESUMO

OBJECTIVES: We investigated the impact of mechanical unloading with a left ventricular assist device (LVAD) on the myocardial proteome. METHODS: We collected 11 patient-matched samples of myocardial left ventricular tissue of patients with non-ischaemic dilate cardiomyopathy, harvested at time of LVAD implant ('pre-LVAD') and heart transplant ('post-LVAD'). Samples were studied by quantitative proteomics. Further we performed histological assessment of deposited collagens and immune infiltration in both pre- and post-LVAD samples. RESULTS: A core set of >1700 proteins was identified and quantified at a false discovery rate <1%. The previously established decrease post-LVAD of alpha-1-antichymotrypsin was corroborated. We noted a post-LVAD decrease of matricellular proteins and proteoglycans such as periostin and versican. Also, proteins of the complement system and precursors of cardiac peptide hormones were decreased post-LVAD. An increase post-LVAD was evident for individual proteins linked to the innate immune response, proteins involved in diverse metabolic pathways, and proteins involved in protein synthesis. Histological analysis did not reveal significant alterations post-LVAD of deposited collagens or immune infiltration. The proteomic data further highlighted a pronounced inter-patient heterogeneity with regards to the impact of LVAD therapy on the left ventricular myocardial proteome. Finally, the proteomic data showed differential proteolytic processing in response to LVAD therapy. CONCLUSIONS: Our findings underline a strong impact of LVAD therapy on the left ventricular myocardial proteome. Together with previous studies, protein markers of LVAD therapy such as alpha-1-antichymotrypsin are becoming apparent. Further, matricellular proteins are emerging as important components in response to LVAD therapy.


Assuntos
Matriz Extracelular/metabolismo , Ventrículos do Coração , Coração Auxiliar , Proteínas/análise , Proteômica/métodos , Adulto , Idoso , Análise por Conglomerados , Matriz Extracelular/química , Feminino , Ventrículos do Coração/química , Ventrículos do Coração/metabolismo , Ventrículos do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Proteínas/química , Proteínas/metabolismo
7.
Oxid Med Cell Longev ; 2017: 8156594, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29333212

RESUMO

Aronia melanocarpa has attracted scientific interest due to its dense contents of different polyphenols. We aimed to analyse effects of Aronia melanocarpa (AME) extract on blood pressure (BP), lipid peroxidation, cytokine level, total NOS activity in the left ventricle (LV), and aorta of L-NAME-induced hypertensive rats. 12-week-old male WKY rats were assigned to the control group and groups treated with AME extract (57.90 mg/kg/day), L-NAME (40 mg/kg/day), or combination of L-NAME (40 mg/kg/day) and AME (57.90 mg/kg/day) in tap water for 3 weeks. NOS activity, eNOS protein expression, and conjugated diene (CD) concentration were determined in the LV and aorta. After 3 weeks of L-NAME treatment, BP was increased by 28% and concomitant treatment with AME reduced it by 21%. NOS activity of the LV and aorta in the L-NAME group was decreased by about 40%, while AME increased it almost on the control level. AME-induced eNOS upregulation may contribute to increase NOS activity. Moreover, AME decreased CD concentration in the LV and aorta and TNF-α and IL-6 production in the plasma were increased by L-NAME treatment. In conclusion, our results showed that active substances of Aronia melanocarpa may have a positive effect on blood pressure, NOS activity, and proinflammatory processes in L-NAME-induced hypertension.


Assuntos
Aorta/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Photinia/química , Extratos Vegetais/farmacologia , Regulação para Cima/efeitos dos fármacos , Alcadienos/análise , Alcadienos/metabolismo , Animais , Aorta/química , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Ventrículos do Coração/química , Ventrículos do Coração/enzimologia , Hipertensão/etiologia , Hipertensão/prevenção & controle , Hipertensão/veterinária , Interleucina-6/sangue , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Photinia/metabolismo , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Ratos , Ratos Endogâmicos WKY , Fator de Necrose Tumoral alfa/metabolismo
8.
Europace ; 18(suppl 4): iv156-iv162, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28011843

RESUMO

AIMS: Chronic inflammation in the atrial myocardium was shown to play an important role in the development of atrial fibrosis in patients with atrial fibrillation (AF). However, it is not clear to what extent atrial inflammatory reaction associated with AF extends on the ventricular myocardium. Our aim was to assess the extent of fibrosis and lymphomononuclear infiltration in human ventricular myocardium and explore its association with AF. METHODS AND RESULTS: Medical records from consecutive autopsies were checked for presence of AF. Heart specimens from 30 patients died from cardiovascular causes (64 ± 12 years, 17 men) were collected in three equal groups: no AF, paroxysmal AF, and permanent AF. Tissue samples were taken from the Bachmann's bundle, crista terminalis, posterior left atrium, left ventricle and right ventricle free walls and stained with Masson's trichrome for analysis of fibrosis extent. Immunohistochemistry was performed using antibodies against CD3- and CD45-antigens and quantified as number of antigen-positive cells per 1 mm2. Fibrosis extent, CD3+ and CD45+ cell counts were elevated in AF patients at all sites (P < 0.001 for all). Fibrosis extent demonstrated correlation with both CD3+ and CD45+ cell counts in the right (r = 0.781, P < 0.001 for CD45+ and r = 0.720, P < 0.001 for CD3+) and the left (r = 0.515, P = 0.004 for CD45+ and r = 0.573, P = 0.001 for CD3+) ventricles. Neither fibrosis nor inflammatory cell count showed association with either age or comorbidities. CONCLUSION: Histological signs of chronic inflammation affecting ventricular myocardium are strongly associated with AF and demonstrate significant correlation with fibrosis extent that cannot be explained by cardiovascular comorbidities otherwise.


Assuntos
Fibrilação Atrial/patologia , Átrios do Coração/patologia , Ventrículos do Coração/patologia , Miocardite/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Autopsia , Biomarcadores/análise , Biópsia , Complexo CD3/análise , Estudos de Casos e Controles , Feminino , Fibrose , Átrios do Coração/química , Átrios do Coração/fisiopatologia , Ventrículos do Coração/química , Ventrículos do Coração/fisiopatologia , Humanos , Imuno-Histoquímica , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Miocardite/fisiopatologia , Prognóstico , Função Ventricular Esquerda , Função Ventricular Direita , Remodelação Ventricular
9.
J Cardiothorac Surg ; 11(1): 163, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27906085

RESUMO

BACKGROUND: Thousands of babies are born with congenital heart defects that require surgical repair involving a prosthetic implant. Lack of growth in prosthetic grafts is especially detrimental in pediatric surgery. Cell seeded biodegradable tissue engineered grafts are a novel solution to this problem. The purpose of the present study is to evaluate the feasibility of seeding human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) onto a biodegradable cardiac patch. METHODS: The hiPS-CMs were cultured on a biodegradable patch composed of a polyglycolic acid (PGA) and a 50:50 poly (l-lactic-co-ε-caprolactone) copolymer (PLCL) for 1 week. Male athymic rats were randomly divided into 2 groups of 10 animals each: 1. hiPS-CM seeded group, and 2. Unseeded group. After culture, the cardiac patch was implanted to repair a defect with a diameter of 2 mm created in the right ventricular outflow tract (RVOT) wall. Hearts were explanted at 4 (n = 2), 8 (n = 2), and 16 (n = 6) weeks after patch implantation. Explanted patches were assessed immunohistochemically. RESULTS: Seeded patch explants did not stain positive for α-actinin (marker of cardiomyocytes) at the 4 week time point, suggesting that the cultured hiPS-CMs evacuated the patch in the early phase of tissue remodeling. However, after 16 weeks implantation, the area fraction of positively stained α-actinin cells was significantly higher in the seeded group than in the unseeded group (Seeded group: 6.1 ± 2.8% vs. Unseeded group: 0.95 ± 0.50%, p = 0.004), suggesting cell seeding promoted regenerative proliferation of host cardiomyocytes. CONCLUSIONS: Seeded hiPS-CMs were not present in the patch after 4 weeks. However, we surmise that they influenced the regeneration of host cardiomyocytes via a paracrine mechanism. Tissue-engineered hiPS-CMs seeded cardiac patches warrant further investigation for use in the repair of congenital heart diseases.


Assuntos
Implantes Absorvíveis , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/cirurgia , Miócitos Cardíacos/fisiologia , Miócitos Cardíacos/transplante , Regeneração , Actinina/análise , Animais , Caproatos , Modelos Animais de Doenças , Estudos de Viabilidade , Ventrículos do Coração/química , Humanos , Células-Tronco Pluripotentes Induzidas , Lactonas , Masculino , Miocárdio/química , Ácido Poliglicólico , Distribuição Aleatória , Ratos , Ratos Nus , Engenharia Tecidual , Alicerces Teciduais
10.
Drug Des Devel Ther ; 10: 3483-3492, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27822012

RESUMO

OBJECTIVE: Exogenous administration of placental growth factor (PlGF) stimulates angiogenesis and improves ventricular remodeling after acute myocardial infarction (AMI), and supplementation with l-arginine ameliorates endothelial function. The objective of the present study was to compare the cardioprotective effects of combination therapy of PlGF and l-arginine with those of direct administration of PlGF alone in a rat model of AMI. MATERIALS AND METHODS: Fifty male Sprague Dawley rats were randomly divided into five groups: sham group, normal saline group, l-arginine group, PlGF group, and combination group (PlGF + l-arginine). An AMI rat model was established by ligation of the left anterior descending of coronary arteries. After 4 weeks of postligation treatment, cardiac function, scar area, angiogenesis and arteriogenesis, myocardial endothelial nitric oxide synthase (eNOS) and collagen I protein content, and plasma concentration of brain natriuretic peptide (BNP) were studied. Echocardiography, Masson's staining, immunohistochemical analyses, Western blot, and enzyme-linked immunosorbent assay were performed. RESULTS: Left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and capillary and arteriole densities were higher in the PlGF group than in the normal saline group (P<0.01). Scar area, collagen I protein content, and plasma concentration of BNP were decreased in the PlGF group (P<0.01). Myocardial eNOS protein level was elevated in the l-arginine group and PlGF + l-arginine group (P<0.01). Compared with the PlGF group, LVEF, LVFS, myocardial eNOS, and capillary and arteriole densities were higher in the combination group (P<0.01). Scar area, content of collagen I protein, and plasma concentration of BNP were reduced in the combination group (P<0.01). CONCLUSION: Exogenous administration of PlGF stimulates angiogenesis and improves cardiac function. l-arginine increases the expression of the eNOS protein. PlGF and l-arginine have a more pronounced, synergistic protective effect on myocardial protection compared with that of exogenous PlGF therapy alone.


Assuntos
Arginina/administração & dosagem , Ventrículos do Coração/química , Fator de Crescimento Placentário/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Arginina/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Ventrículos do Coração/metabolismo , Infarto do Miocárdio/fisiopatologia , Fator de Crescimento Placentário/química , Ratos , Ratos Sprague-Dawley
11.
Biophys J ; 111(6): 1192-1202, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27653478

RESUMO

The cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA) establishes the intracellular calcium gradient across the sarcoplasmic reticulum membrane. It has been proposed that SERCA forms homooligomers that increase the catalytic rate of calcium transport. We investigated SERCA dimerization in rabbit left ventricular myocytes using a photoactivatable cross-linker. Western blotting of cross-linked SERCA revealed higher-molecular-weight species consistent with SERCA oligomerization. Fluorescence resonance energy transfer measurements in cells transiently transfected with fluorescently labeled SERCA2a revealed that SERCA readily forms homodimers. These dimers formed in the absence or presence of the SERCA regulatory partner, phospholamban (PLB) and were unaltered by PLB phosphorylation or changes in calcium or ATP. Fluorescence lifetime data are compatible with a model in which PLB interacts with a SERCA homodimer in a stoichiometry of 1:2. Together, these results suggest that SERCA forms constitutive homodimers in live cells and that dimer formation is not modulated by SERCA conformational poise, PLB binding, or PLB phosphorylation.


Assuntos
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Cálcio/química , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/metabolismo , Cães , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Ventrículos do Coração/química , Ventrículos do Coração/enzimologia , Humanos , Imunoprecipitação , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Modelos Moleculares , Células Musculares/química , Células Musculares/enzimologia , Mutação , Fosforilação , Fotodegradação , Multimerização Proteica , Coelhos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
12.
Lipids Health Dis ; 14: 26, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25889944

RESUMO

BACKGROUND: Several studies show that the consumption of vegetable oils, such as soybean oil, rich in polyunsaturated fatty acids (PUFAs) has beneficial health effects by preventing or reducing the risk factors of cardiovascular diseases. While the demonstration of beneficial effects of the consumption of unsaturated fatty acids on the cardiovascular system has been proven in a macroscopic level, the molecular/cellular mechanisms responsible for this phenomenon are poorly understood. METHODS: In this work, a comparative proteomic approach, two-dimensional gel electrophoresis (2-DE) coupled to mass spectrometry (MALDI-TOF/TOF), was applied to investigate proteome differences in the left ventricle (LV) of rats that received 0.1 mL of soybean oil intramuscularly for 15 days (treated group-TR) and rats that had not (control group-CT). RESULTS: Soybean oil treatment improved left ventricular function, TR animals presented lower value of LVEDP and significantly changed LV proteome. The protein profile of VE revealed differences in the expression of 60 protein spots (p<0.05) between the experimental groups (CT and TR), 14 of those were identified by MS and MS/MS, and 12 of the 14 being non-redundant proteins. Robust changes were detected in proteins involved in cellular structure and antioxidant system and muscular contraction. CONCLUSIONS: The TR group presented an increase in the intensity of proteins involved in muscle contraction (myosin light chain-3 (3-MCL), creatine kinase M (CKM)) and thireodoxin, an antioxidant enzyme. Low intensity cytoskeletal protein, desmin, was also detected in TR animals. The results suggest that soybean oil induces changes in the levels of heart proteins which may partially account for the underlying mechanisms involved in the benefits provided by oils rich in polyunsaturated fatty acids.


Assuntos
Ventrículos do Coração/efeitos dos fármacos , Proteômica , Óleo de Soja/farmacologia , Animais , Eletroforese em Gel Bidimensional , Ventrículos do Coração/química , Injeções Intramusculares , Masculino , Proteínas/análise , Proteômica/métodos , Ratos , Ratos Wistar , Óleo de Soja/administração & dosagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Função Ventricular Esquerda/efeitos dos fármacos
13.
Clin Chim Acta ; 438: 246-7, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25195007

RESUMO

BACKGROUND: When dealing with rare samples of which only minute amounts are available, e.g. human heart tissue, simultaneous extraction of DNA, RNA, and proteins from the same sample is crucial for a comprehensive analysis on the physiological or pathological state of such precious tissue. In this study we provethe efficacy of a modified TRIzol protocol to extract proteins from samples of small size, such as endomyocardial biopsies (EMBs). METHOD: Initially, we compared TRIzol protein extraction efficacy to urea/thiourea extraction from total murine left ventricles and then small amounts of left and right murine ventricles. Finally, we applied the modified TRIzol protocol to the proteomic profiling of EMBs from human left and right ventricles. RESULTS: Analysis of the proteins extracted from mouse and human samples revealed sufficient protein amount for downstream applications. Thus, LC-tandem mass spectrometry permitted highly sensitive protein identifications and comparable protein patterns and coverage of cellular components as a standard extraction protocol. 2D gel-based analysis confirmed the high quality and reproducibility of the TRIzol derived protein extracts. CONCLUSION: Our results prove the utility of the modified TRIzol protocol for proteomics analyses involving minute amounts of precious samples.


Assuntos
Ventrículos do Coração/química , Microextração em Fase Líquida/métodos , Miocárdio/química , Proteoma/isolamento & purificação , Animais , Biópsia , Cromatografia Líquida , Guanidinas/química , Humanos , Camundongos , Anotação de Sequência Molecular , Fenóis/química , Proteoma/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Tioureia/química , Ureia/química
14.
Eur J Cardiothorac Surg ; 47(3): 464-72, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24948413

RESUMO

OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. CLINICALTRIALSGOV ID: NCT00845364.


Assuntos
Cardiotônicos/uso terapêutico , Ponte de Artéria Coronária/métodos , Vasos Coronários/cirurgia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Perexilina/uso terapêutico , Idoso , Débito Cardíaco/efeitos dos fármacos , Ponte de Artéria Coronária/efeitos adversos , Método Duplo-Cego , Feminino , Ventrículos do Coração/química , Ventrículos do Coração/metabolismo , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/metabolismo , Placebos , Complicações Pós-Operatórias , Estudos Prospectivos
15.
NMR Biomed ; 27(11): 1378-86, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25200106

RESUMO

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy (n = 14) and from normal donors (n = 5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1 ), secondary (D2 ) and tertiary (D3 ) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were -0.51, 0.59, 0.56 and 0.62 (P < 0.05), respectively. The correlation between D1 and collagen content was not significant (r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts.


Assuntos
Imagem de Tensor de Difusão/métodos , Insuficiência Cardíaca/patologia , Miocárdio/patologia , Adulto , Idoso , Anisotropia , Biópsia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/patologia , Colágeno/análise , Simulação por Computador , Feminino , Fibrose , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Método de Monte Carlo , Miocárdio/química , Adulto Jovem
16.
J Vet Intern Med ; 28(5): 1534-40, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25146933

RESUMO

HYPOTHESIS/OBJECTIVES: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV). ANIMALS: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9). METHODS: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]. RESULTS: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20-4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70-4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85-4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63-1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4-106.7) versus non-HD (3.6 ng/mg; range, 0-28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0-104.8) versus other-HD (0.9 ng/mg; range, 0-10.1; P = .011) and non-HD (2.5 ng/mg; range, 0-6.9; P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation.


Assuntos
Doenças do Cão/sangue , Doenças das Valvas Cardíacas/veterinária , Ventrículos do Coração/química , Valva Mitral/química , Serotonina/análise , Animais , Plaquetas/química , Doenças do Cão/metabolismo , Cães , Ecocardiografia/veterinária , Feminino , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/metabolismo , Masculino , Contagem de Plaquetas/veterinária , Serotonina/sangue
17.
Life Sci ; 111(1-2): 6-11, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-24953608

RESUMO

AIMS: The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. MAIN METHODS: Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. KEY FINDINGS: The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. SIGNIFICANCE: Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Coração/efeitos dos fármacos , Indanos/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Ecocardiografia , Coração/fisiopatologia , Ventrículos do Coração/química , Indanos/uso terapêutico , Insulina/sangue , Masculino , Óxido Nítrico Sintase Tipo III/análise , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sulfonamidas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos
18.
J Am Heart Assoc ; 3(3): e000716, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24895160

RESUMO

BACKGROUND: Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca(2+) sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH. METHODS AND RESULTS: RV samples from PAH patients undergoing heart-lung transplantation were compared to non-failing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western-blot analyses using antibodies to protein-kinase-A (PKA), Cα (PKCα) and Ca(2+)/calmoduling-dependent-kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (P<0.0001). To test the functional relevance of PKA-, PKCα-, and CamKIIδ-mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness while CamKIIδ had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca(2+) sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (P<0.05) and reduced PKA-mediated cTnI phosphorylation (Ser22/23) (P<0.001). Finally, alterations in Ca(2+)-handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca(2+) clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (P<0.05). CONCLUSIONS: Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca(2+) handling proteins contribute to RV diastolic dysfunction in PAH.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Miócitos Cardíacos/química , Disfunção Ventricular Direita/fisiopatologia , Adulto , Western Blotting , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/análise , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Estudos de Casos e Controles , Conectina/análise , Conectina/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/análise , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Feminino , Ventrículos do Coração/química , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Miócitos Cardíacos/fisiologia , Fosforilação , Proteína Quinase C-alfa/análise , Proteína Quinase C-alfa/fisiologia , Troponina I/fisiologia
19.
J Mol Cell Cardiol ; 72: 231-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24726887

RESUMO

Cardiac and skeletal muscle myosins have the central role in contraction transducing ATP free energy into the mechanical work of moving actin. Myosin has a motor domain containing ATP and actin binding sites and a lever-arm that undergoes rotation impelling bound actin. The lever-arm converts torque generated in the motor into the linear displacement known as step-size. The myosin lever-arm is stabilized by bound essential and regulatory light chains (ELC and RLC). RLC phosphorylation at S15 is linked to modified lever-arm mechanical characteristics contributing to myosin filament based contraction regulation and to the response of the muscle to disease. Myosin step-size was measured using a novel quantum dot (Qdot) assay that previously confirmed a 5nm step-size for fast skeletal myosin and multiple unitary steps, most frequently 5 and 8nm, and a rare 3nm displacement for ß cardiac myosin (ßMys). S15 phosphorylation in ßMys is now shown to change step-size distribution by advancing the 8nm step frequency. After phosphorylation, the 8nm step is the dominant myosin step-size resulting in significant gain in the average step-size. An increase in myosin step-size will increase the amount of work produced per ATPase cycle. The results indicate that RLC phosphorylation modulates work production per ATPase cycle suggesting the mechanism for contraction regulation by the myosin filament.


Assuntos
Actinas/metabolismo , Trifosfato de Adenosina/metabolismo , Ventrículos do Coração/metabolismo , Contração Miocárdica/fisiologia , Cadeias Leves de Miosina/metabolismo , Miosinas Ventriculares/metabolismo , Animais , Fenômenos Biomecânicos , Movimento Celular , Ventrículos do Coração/química , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Fosforilação , Pontos Quânticos , Coelhos , Suínos
20.
Ann Hematol ; 93(3): 375-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23949317

RESUMO

Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine ß-thalassemia patients receiving chelation therapy (mean age of 20.8 ± 6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean ± standard deviation (range) of cardiac T2* was 28.5 ± 11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7 ± 4.7 % (55 to 78 %), and the liver iron concentration (LIC) was 26.1 ± 13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510 ± 2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 %, the serum ferritin was >2,500 ng/ml. The prevalence of myocardial siderosis (T2* of <20 ms) was 24.7 % (mean age 20.9 ± 7.5 years), with mean T2* of 12.7 ± 4.4 ms, mean LVEF of 68.6 ±5.8 %, mean LIC of 30.9 ± 13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P = 0.65, P = 0.085, P = 0.99, and P = 0.63, respectively). Severe cardiac siderosis (T2* of <10 ms) was present in 7.9 %, with a mean age of 18.4 ± 4.4 years. Although these patients had a mean T2* of 7.8 ± 1.7 ms, the LVEF was 65.1 ± 6.2 %, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 %). LIC and serum ferritin results were 29.8 ± 17.0 mg/g and 7,200 ± 6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P = 0.5), LVEF (P = 0.14), LIC (P = 0.97), or serum ferritin (P = 0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.


Assuntos
Cardiomiopatias/etiologia , Terapia por Quelação , Hemossiderose/etiologia , Reação Transfusional , Talassemia beta/terapia , Adolescente , Adulto , Cardiomiopatias/epidemiologia , Cardiomiopatias/prevenção & controle , Criança , Estudos de Coortes , Egito/epidemiologia , Ferritinas/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/química , Ventrículos do Coração/fisiopatologia , Hemossiderose/epidemiologia , Hemossiderose/prevenção & controle , Hospitais Pediátricos , Humanos , Ferro/análise , Fígado/química , Imageamento por Ressonância Magnética , Prevalência , Volume Sistólico , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/fisiopatologia
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