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1.
BMC Med Genet ; 21(1): 19, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005173

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. METHODS: We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. RESULTS: We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. CONCLUSIONS: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Cardiomiopatia Dilatada/genética , Desmoplaquinas/genética , Predisposição Genética para Doença , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Gadolínio/administração & dosagem , Ventrículos do Coração/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Penetrância , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia
2.
High Blood Press Cardiovasc Prev ; 26(6): 501-508, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612431

RESUMO

INTRODUCTION: Early alterations in the cardiovascular system have been described in offspring of hypertensive parents, but with conflicting results. AIM: To evaluate the influence of genetic predisposition to hypertension on left ventricular (LV) geometry and function, 30 normotensive male offspring of hypertensive parents (EH+) and 30 matched offspring of normotensive families (EH-), were studied. METHODS: All subjects underwent office and 24-h ambulatory blood pressure monitoring (ABPM), conventional and Tissue Doppler Echocardiography (TDE), including assessment of myocardial performance index (MPI). RESULTS: EH+ showed an increase in office BP with statistical significance in diastolic BP (84 ± 7 vs 73 ± 6 mmHg; p < 0.05). Relative wall thickness (RWT) was greater in EH+ (0.37 ± 0.05 vs 0.31 ± 0.03; p < 0.05) and significantly related to the EH+ condition at the univariate analysis (p < 0.003), whilst the LV mass index was unchanged (84.3 ± 14 vs 80 ± 17 g/m2; p = NS), suggesting a trend towards concentric remodeling. Systolic and diastolic function, in both ventricles, were superimposable in the two groups. The MPI was higher in EH+ (0.49 ± 0.10 vs 0.45 ± 0.08; p = NS) and significantly correlated to RWT (r = 0.47, p < 0.01). However, at the stepwise multiple regression analysis, only the condition of EH + was independently associated with RWT (p <0.006). RWT, according to ROC curves analysis, predicted the condition of EH+ (cutoff 0.359, specificity 89%, sensitivity 82%). CONCLUSION: Current results provide information about LV myocardial performance in EH+ subjects, related to a LV concentric remodeling and to endothelial dysfunction.


Assuntos
Pressão Sanguínea , Filho de Pais Incapacitados , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Estudos de Casos e Controles , Ecocardiografia Doppler , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Medição de Risco , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
3.
Clin Interv Aging ; 14: 1719-1728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631991

RESUMO

Purpose: Left ventricular diastolic dysfunction with preserved ejection fraction (LVDD-PEF) is an early-stage manifestation but poorly understood in the process of heart failure. This study was designed to investigate risk factors and epigenetic markers for predicting LVDD-PEF. Patients and methods: A community-based study in 1568 residents over 65 years was conducted in Shanghai, People's Republic of China, from June 2014 to August 2015. Echocardiography was performed to diagnose LVDD-PEF. DNA methylation by whole-genome bisulfite sequencing was used to determine those potential epigenetic markers contributing to LVDD-PEF. Results: A total of 177 participants (11.3%) were diagnosed with LVDD-PEF, and higher prevalence in females than in males (15.0% vs 6.5%, P<0.001). Multivariate logistic regression analysis indicated that female sex (OR 2.46, 95% CI 1.47-4.13), body mass index (BMI) (OR 1.09, 95% CI 1.04-1.14), pulse pressure (PP) (OR 1.03, 95% CI 1.01-1.05) and carotid intima-media thickness (CIMT) (OR 4.20, 95% CI 1.40-12.55) showed a significant association with LVDD-PEF. Overall, 638 CpG sites were differentially methylated in LVDD-PEF group compared to non-LVDD-PEF group (P<0.001); 242 sites were significantly hypermethylated (covering 238 genes) and 396 sites were significantly hypomethylated (covering 265 genes). Conclusion: Our findings found female, BMI, PP, and CIMT were independent predictors for LVDD-PEF in the community-dwelling elderly population. Regulation of DNA methylation might play a crucial role for LVDD-PEF.


Assuntos
Espessura Intima-Media Carotídea/estatística & dados numéricos , Metilação de DNA , Epigênese Genética , Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/diagnóstico , Idoso , China/epidemiologia , Ecocardiografia , Feminino , Humanos , Masculino , Prevalência , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Função Ventricular Esquerda
4.
PLoS One ; 14(4): e0215818, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31009519

RESUMO

This study aimed to analyze changes in the expression of autophagy- and phagocytosis-related genes in patients with dilated cardiomyopathy (DCM), especially in relation to left ventricular (LV) dysfunction. Furthermore, transmission electron microscopy of the diseased tissue was carried out to investigate if the gene expression changes are translated into ultrastructural alterations. LV tissue samples from patients with DCM (n = 13) and from controls (CNT; n = 10) were analyzed by RNA-sequencing, whereupon the altered expression (P < 0.05) of 13 autophagy- and 3 phagocytosis-related genes was observed. The expression changes of the autophagy-related genes NRBP2 and CALCOCO2 were associated with cardiac dysfunction and remodeling (P < 0.05). The affected patients had a higher activity of these degradation processes, as evidenced by the greater number of autophagic structures in the DCM tissue (P < 0.001). Differences in the ultrastructural distribution were also found between the DCM and CNT tissues. These results show that in patients with DCM, the altered expression of NRBP2 and CALCOCO2 is related to LV dysfunction and remodeling. Clarification of the molecular mechanisms of cardiac autophagy would help in the future development of therapies to improve LV performance.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Relacionadas à Autofagia/genética , Cardiomiopatia Dilatada/genética , Proteínas Nucleares/genética , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/genética , Disfunção Ventricular Esquerda/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Diuréticos/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Nucleares/metabolismo , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Análise de Sequência de RNA , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
5.
Gene ; 697: 1-10, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30790654

RESUMO

Left ventricular diastolic dysfunction (LVDD) is a central perturbation in heart failure with preserved ejection fraction, and there are currently no effective remedies to improve LVDD in clinical practice. The ß3-adrenergic receptor (ADRB3) was reported to play protective effects on inhibiting myocardial fibrosis in response to hemodynamic stress. However, the effects of ADRB3 on LVDD and its underlying mechanisms are still undefined. In the current study, the role of ADRB3 in LVDD was identified in ADRB3-knockout mice. Echocardiography parameters showed that depletion of ADRB3 had little effect on cardiac systolic function but obviously led to cardiac diastolic dysfunction in vivo. Proteomics (including the global proteome, phosphorylated and acetylated proteome) and bioinformatics analysis (including GO analysis, KEGG pathway analysis, GO-Tree network, Pathway-Act network, and protein-protein interaction network) were performed on cardiac specimens of ADRB3-KO mice and wild-type mice. The results showed that the cardiac energy metabolism (especially the citrate cycle), actin cytoskeleton organization, and cardiac muscle contraction (related to mitogen-activated protein kinase, toll-like receptor, and ErbB signalling pathway) were potential core mechanisms underlying ADRB3-KO-induced LVDD. In addition, the protein-protein interaction network indicated that the core proteins associated with ADRB3-KO-induced LVDD were FGG, ALDH1A1, FGA, APOC3, SLC4A1, SERPINF2, HP, CTNNB1, and TKT. In conclusion, the absence of ADRB3 leads to LVDD, which is potentially associated with the regulation of cardiac energy metabolism, actin cytoskeleton organization, and cardiac muscle contraction.


Assuntos
Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Cardiomiopatias , Diástole , Ecocardiografia , Metabolismo Energético/genética , Ontologia Genética , Insuficiência Cardíaca , Hemodinâmica , Masculino , Camundongos , Camundongos Knockout , Contração Miocárdica , Proteômica , Receptores Adrenérgicos , Transdução de Sinais , Volume Sistólico , Sístole , Disfunção Ventricular Esquerda/genética , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia
6.
Circulation ; 139(15): 1786-1797, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30700137

RESUMO

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. CONCLUSIONS: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.


Assuntos
Displasia Arritmogênica Ventricular Direita/mortalidade , Morte Súbita Cardíaca/etiologia , Ventrículos do Coração/patologia , Disfunção Ventricular Esquerda/mortalidade , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Causas de Morte , Morte Súbita Cardíaca/patologia , Feminino , Predisposição Genética para Doença , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Adulto Jovem
7.
Circulation ; 139(15): 1813-1827, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30700140

RESUMO

BACKGROUND: Titin is a giant elastic protein that spans the half-sarcomere from Z-disk to M-band. It acts as a molecular spring and mechanosensor and has been linked to striated muscle disease. The pathways that govern titin-dependent cardiac growth and contribute to disease are diverse and difficult to dissect. METHODS: To study titin deficiency versus dysfunction, the authors generated and compared striated muscle specific knockouts (KOs) with progressive postnatal loss of the complete titin protein by removing exon 2 (E2-KO) or an M-band truncation that eliminates proper sarcomeric integration, but retains all other functional domains (M-band exon 1/2 [M1/2]-KO). The authors evaluated cardiac function, cardiomyocyte mechanics, and the molecular basis of the phenotype. RESULTS: Skeletal muscle atrophy with reduced strength, severe sarcomere disassembly, and lethality from 2 weeks of age were shared between the models. Cardiac phenotypes differed considerably: loss of titin leads to dilated cardiomyopathy with combined systolic and diastolic dysfunction-the absence of M-band titin to cardiac atrophy and preserved function. The elastic properties of M1/2-KO cardiomyocytes are maintained, while passive stiffness is reduced in the E2-KO. In both KOs, we find an increased stress response and increased expression of proteins linked to titin-based mechanotransduction (CryAB, ANKRD1, muscle LIM protein, FHLs, p42, Camk2d, p62, and Nbr1). Among them, FHL2 and the M-band signaling proteins p62 and Nbr1 are exclusively upregulated in the E2-KO, suggesting a role in the differential pathology of titin truncation versus deficiency of the full-length protein. The differential stress response is consistent with truncated titin contributing to the mechanical properties in M1/2-KOs, while low titin levels in E2-KOs lead to reduced titin-based stiffness and increased strain on the remaining titin molecules. CONCLUSIONS: Progressive depletion of titin leads to sarcomere disassembly and atrophy in striated muscle. In the complete knockout, remaining titin molecules experience increased strain, resulting in mechanically induced trophic signaling and eventually dilated cardiomyopathy. The truncated titin in M1/2-KO helps maintain the passive properties and thus reduces mechanically induced signaling. Together, these findings contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications for genotype-phenotype relations that support a personalized medicine approach to the diverse titinopathies.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Mecanotransdução Celular , Miócitos Cardíacos/metabolismo , Proteínas Quinases/deficiência , Sarcômeros/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Direita/metabolismo , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Deleção de Genes , Masculino , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miócitos Cardíacos/patologia , Fenótipo , Proteínas Quinases/genética , Sarcômeros/patologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda , Função Ventricular Direita
9.
Eur Heart J Cardiovasc Imaging ; 20(1): 92-100, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635323

RESUMO

Aims: The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia (VA) and heart failure. It has been shown to lead to calcium overload, cardiomyocyte damage, and eventually to myocardial fibrosis. This study sought to investigate ventricular function, the extent and localization of myocardial fibrosis and the associations with ECG features and VA in PLN p.Arg14del mutation carriers. Methods and results: Cardiovascular magnetic resonance (CMR) data of 150 mutation carriers were analysed retrospectively. Left ventricular (LV) and right ventricular (RV) volumes, mass, and ejection fraction were measured. The extent of late gadolinium enhancement (LGE) was expressed as a percentage of myocardial mass. All standard ECG parameters were measured. Occurrence of VA was analysed on ambulatory 24-h and/or exercise electrocardiography, if available. Mean age was 40 ± 15 years, 42% males, and 7% were index patients while 93% were pre-symptomatic carriers identified after family cascade screening. Mean LV ejection fraction (LVEF) and RV ejection fraction were 58 ± 9% and 55 ± 9%, respectively. LV-LGE was present in 91% of mutation carriers with reduced LVEF (<45%) and in 30% of carriers with preserved LVEF. In carriers with positive LV-LGE, its median extent was 5.9% (interquartile range 3.2-12.7). LGE was mainly observed in the inferolateral wall. Carriers with inverted T-waves in the lateral ECG leads more often had LV-LGE (P < 0.01) than carriers without. Finally, the presence of LV-LGE, but not attenuated R-waves and inverted lateral T-waves, was independently associated with VA. Conclusion: LV myocardial fibrosis is present in many PLN p.Arg14del mutation carriers, and who still have a preserved LVEF. It is seen predominantly in the LV inferolateral wall and corresponds with electrocardiographic repolarization abnormalities. Although preliminary, myocardial fibrosis was found to be independently associated with VA. Our findings support the use of CMR with LGE early in the diagnostic work-up.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Adulto , Meios de Contraste , Eletrocardiografia , Feminino , Fibrose/patologia , Predisposição Genética para Doença , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Meglumina , Pessoa de Meia-Idade , Mutação , Países Baixos , Compostos Organometálicos , Fenótipo , Estudos Retrospectivos , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/genética
10.
Hematology ; 24(1): 20-25, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30095041

RESUMO

BACKGROUND: Cardiomyocytes are particularly susceptible to complications from iron loading. The blood transfusions in thalassaemia major create loading of iron that cannot be naturally excreted. Apolipoprotein E and Glutathione S-transferase act as the scavenger of free radicals, which are generated due to excess iron. The variants of Apolipoprotein E (ApoE) and Glutathione S-transferase (GST) may play a role in oxidative damage-induced cardiomyopathy, so we aimed to study the association of genetic variants of these genes on diastolic dysfunction in our patients. MATERIALS AND METHODS: One hundred and five ß-thalassaemia patients older than 10 years were enrolled for the study. Two-dimensional and M-mode echocardiography analysis was done in all patients. Genotyping of the genetic variants of aforementioned genes was done using the PCR-RFLP method. Serum Glutathione S-transferase levels were estimated by ELISA. RESULTS: Diastolic dysfunction was observed in 24 (22.8%) patients, whereas left ventricular hypertrophy was present in 37(35.2%) patients. There was a significant association of GSTM1 null allele with diastolic dysfunction only. Serum GST levels were also positively correlated with e/a and e/e' ratio. Positive association of ApoE E2 allele with the diastolic dysfunction was also seen. CONCLUSIONS: Patients having Glutathione S-transferase M1 allele and Apolipoprotein E E2 allele are predisposed to oxidative stress-induced cardiac injury.


Assuntos
Apolipoproteínas E/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Polimorfismo de Fragmento de Restrição , Disfunção Ventricular Esquerda/genética , Talassemia beta/genética , Adolescente , Adulto , Apolipoproteínas E/metabolismo , Criança , Feminino , Glutationa Transferase/metabolismo , Humanos , Masculino , Estresse Oxidativo/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Talassemia beta/metabolismo , Talassemia beta/patologia
11.
J Cell Physiol ; 234(2): 1491-1501, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30078191

RESUMO

Hyperoxia (>90% oxygen) is commonly implemented in mechanically ventilated patients. Reports suggest that hyperoxia is directly associated with in-hospital mortality in ventilated patients. Certain studies also show that mortality in women undergoing mechanical ventilation is significantly higher than that in men. Additionally, females are predisposed to certain cardiac electrophysiological risks, including QTc prolongation. In this study, we assessed the impact of hyperoxia in male and female mice (C57BL/6J) at age 8-10 weeks. On completion of either hyperoxia or normoxia exposures, physical, hemodynamic, biochemical, functional, electrophysiological, and molecular assessments were conducted. Hyperoxia-exposed mice lost a significant amount of body mass, compared with normoxia controls, in both sexes. However, while both genders developed brady-arrhythmia after hyperoxia exposure, female mice exhibited significantly reduced heart rates compared with males, with significantly elevated RR intervals. Additionally, 50% mortality was observed in females, whereas no mortality was reported in males. Furthermore, unlike in male mice, we observed no hypertrophy upon hyperoxia exposure in female mice. We reported that both hyperoxia-treated male and female mice exhibit significant hyperdynamic left ventricular ejection fraction, which is marked by % ejection fraction > 70 compared with the normoxia controls. We also noted significant reductions in stroke volume and cardiac output in both mice with hyperoxia. Surface ECG also demonstrated that hyperoxia exposure significantly augments RR, PR, QRS, QTc, and JT intervals in both sexes. Molecular analysis of left ventricular tissue demonstrated dysregulation of potassium ion channels in hyperoxia-treated males and females. In summary, we determined that sex differences are present with 72 hr hyperoxia exposure.


Assuntos
Bradicardia/etiologia , Hiperóxia/complicações , Disfunção Ventricular Esquerda/etiologia , Animais , Bradicardia/genética , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Frequência Cardíaca , Hiperóxia/genética , Hiperóxia/metabolismo , Hiperóxia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Canais de Potássio/genética , Canais de Potássio/metabolismo , Fatores de Risco , Fatores Sexuais , Volume Sistólico , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda
12.
Cardiol Clin ; 37(1): 11-26, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447711

RESUMO

Hypertrophic cardiomyopathy (HCM) is an inherited condition present in about 1/500 individuals with more than 1500 causative mutations identified in primarily 10 sarcomeric proteins. Although HCM is inherited in an autosomal dominant way, there is often incomplete penetrance and variable phenotype even with the same genotype. It is characterized by a degree of hypertrophy (usually asymmetric), that is, not due to another identifiable cause, as well as variable degrees of myocardial fibrosis and microvascular abnormalities.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ecocardiografia/métodos , Técnicas de Ablação/métodos , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/terapia , Diagnóstico Precoce , Humanos , Angiografia por Ressonância Magnética , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/genética , Insuficiência da Valva Mitral/terapia , Mutação/genética , Linhagem , Fenótipo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/terapia , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Obstrução do Fluxo Ventricular Externo/genética , Obstrução do Fluxo Ventricular Externo/terapia
13.
Circ Res ; 124(2): 292-305, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30582455

RESUMO

RATIONALE: The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. OBJECTIVE: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). METHODS AND RESULTS: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. CONCLUSIONS: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.


Assuntos
Proteínas de Ciclo Celular/deficiência , Desdiferenciação Celular , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Ciclo Celular , Proteínas de Ciclo Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Oncostatina M/metabolismo , Fosfoproteínas/metabolismo , Ratos Wistar , Transdução de Sinais , Fatores de Transcrição/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
14.
Cardiovasc Res ; 115(1): 71-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931050

RESUMO

Aims: Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results: Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions: Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Insuficiência Cardíaca/terapia , Hipertrofia Ventricular Esquerda/terapia , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/metabolismo , Terapêutica com RNAi , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/metabolismo , Neovascularização Fisiológica , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Transdução de Sinais , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
15.
Radiology ; 290(3): 640-648, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30561279

RESUMO

Purpose To evaluate myocardial strain and circumferential transmural strain difference (cTSD; the difference between epicardial and endocardial circumferential strain) in a genotyped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other anatomic and functional markers of disease status. Left ventricular (LV) dysfunction may indicate early disease in preclinical HCM (sarcomere mutation carriers without LV hypertrophy). Cardiac MRI feature tracking may be used to evaluate myocardial strain in carriers of HCM sarcomere mutation. Materials and Methods Participants with HCM and their family members participated in a prospective, multicenter, observational study (HCMNet). Genetic testing was performed in all participants. Study participants underwent cardiac MRI with temporal resolution at 40 msec or less. LV myocardial strain was analyzed by using feature-tracking software. Circumferential strain was measured at the epicardial and endocardial surfaces; their difference yielded the circumferential transmural strain difference (cTSD). Multivariable analysis to predict HCM status was performed by using multinomial logistic regression adjusting for age, sex, and LV parameters. Results Ninety-nine participants were evaluated (23 control participants, 34 participants with preclinical HCM [positive for sarcomere mutation and negative for LV hypertrophy], and 42 participants with overt HCM [positive for sarcomere mutation and negative for LV hypertrophy]). The average age was 25 years ± 11 and 44 participants (44%) were women. Maximal LV wall thickness was 9.5 mm ± 1.4, 9.8 mm ± 2.2, and 16.1 mm ± 5.3 in control participants, participants with preclinical HCM (P = .496 vs control participants), and participants with overt HCM (P < .001 vs control participants), respectively. cTSD for control participants, preclinical HCM, and overt HCM was 14% ± 4, 17% ± 4, and 22% ± 7, respectively (P < .01 for all comparisons). In multivariable models (controlling for septal thickness and log-transformed N-terminal brain-type natriuretic peptide), cTSD was predictive of preclinical and overt HCM disease status (P < .01). Conclusion Cardiac MRI feature tracking identifies myocardial dysfunction not only in participants with overt hypertrophic cardiomyopathy, but also in carriers of sarcomere mutation without left ventricular hypertrophy, suggesting that contractile abnormalities are present even when left ventricular wall thickness is normal. © RSNA, 2018 Online supplemental material is available for this article.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Imagem Cinética por Ressonância Magnética , Mutação/genética , Sarcômeros/genética , Disfunção Ventricular Esquerda/genética , Adulto , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
16.
J Am Heart Assoc ; 7(24): e010797, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561255

RESUMO

Background Particulate matter (particles < 2.5 µm [ PM 2.5]) exposure during the in utero and postnatal developmental periods causes cardiac dysfunction during adulthood. Here, we investigated the potential priming effects of preconception exposure of PM 2.5 on cardiac function in adult offspring. Methods and Results Male and female friend leukemia virus b (FVB) mice were exposed to either filtered air ( FA ) or PM 2.5 at an average concentration of 38.58 µg/m3 for 6 hours/day, 5 days/week for 3 months. Mice were then crossbred into 2 groups: (1)  FA male× FA female (both parents were exposed to FA preconception) and, (2) PM 2.5male× PM 2.5female (both parents were exposed to PM 2.5 preconception). Male offspring were divided: (1) preconception FA (offspring born to FA exposed parents) and, (2) preconception PM 2.5 (offspring born to PM 2.5 exposed parents) and analyzed at 3 months of age. Echocardiography identified increased left ventricular end systolic volume and reduced posterior wall thickness, reduced %fractional shortening and %ejection fraction in preconception PM 2.5 offspring. Cardiomyocytes isolated from preconception PM 2.5 offspring showed reduced %peak shortening, -dL/dT, TPS 90 and slower calcium reuptake (tau). Gene and protein expression revealed modifications in markers of inflammation ( IL -6, IL -15, TNF α, NF қB, CRP , CD 26E, CD 26P, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1) profibrosis (collagen type III alpha 1 chain), oxidative stress ( NOS 2), antioxidants (Nrf2, SOD , catalase), Ca2+ regulatory proteins ( SERCA 2a, p- PLN , NCX ), and epigenetic regulators (Dnmt1, Dnmt3a, Dnmt3b, Sirt1, and Sirt2) in preconception PM 2.5 offspring. Conclusions Preconception exposure to PM 2.5 results in global cardiac dysfunction in adult offspring, suggesting that abnormalities during development are not limited to the prenatal or postnatal periods but can also be determined before conception.


Assuntos
Exposição por Inalação/efeitos adversos , Exposição Materna/efeitos adversos , Material Particulado/toxicidade , Exposição Paterna/efeitos adversos , Lesões Pré-Concepcionais/induzido quimicamente , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Lesões Pré-Concepcionais/genética , Lesões Pré-Concepcionais/metabolismo , Lesões Pré-Concepcionais/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores Sexuais , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/genética
17.
J Transl Med ; 16(1): 241, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30165862

RESUMO

BACKGROUND: Cardiomyopathies are the most common clinical and genetic heterogeneity cardiac diseases, and genetic contribution in particular plays a major role in patients with primary cardiomyopathies. The aim of this study is to investigate cases of inherited cardiomyopathy (IC) for potential disease-causing mutations in 64 genes reported to be associated with IC. METHODS: A total of 110 independent cases or families diagnosed with various primary cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, and undefined cardiomyopathy, were collected after informed consent. A custom designed panel, including 64 genes, was screened using next generation sequencing on the Ion Torrent PGM platform. The best candidate disease-causing variants were verified by Sanger sequencing. RESULTS: A total of 78 variants in 73 patients were identified. After excluding the variants predicted to be benign and VUS, 26 pathogenic or likely pathogenic variants were verified in 26 probands (23.6%), including a homozygous variant in the SLC25A4 gene. Of these variants, 15 have been reported in the Human Gene Mutation Database or ClinVar database, while 11 are novel. The majority of variants were observed in the MYH7 (8/26) and MYBPC3 (6/26) gene. Titin (TTN) truncating mutations account for 13% in our dilated cardiomyopathy cases (3/23). CONCLUSIONS: This study provides an overview of the genetic aberrations in this cohort of Chinese IC patients and demonstrates the power of next generation sequencing in IC. Genetic results can provide precise clinical diagnosis and guidance regarding medical care for some individuals.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Translocador 1 do Nucleotídeo Adenina/genética , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Miosinas Cardíacas/genética , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Restritiva/genética , Proteínas de Transporte/genética , Conectina/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Cadeias Pesadas de Miosina/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Disfunção Ventricular Esquerda/genética , Adulto Jovem
18.
Cardiovasc Diabetol ; 17(1): 123, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180843

RESUMO

BACKGROUND: Diabetes is a leading cause of mortality and morbidity across the world. Over 50% of deaths among diabetic patients are caused by cardiovascular diseases. Cardiac diastolic dysfunction is one of the key early signs of diabetic cardiomyopathy, which often occurs before systolic dysfunction. However, no drug is currently licensed for its treatment. METHODS: Type 9 adeno-associated virus combined with cardiac Troponin T promoter were employed to manipulate miR-21 expression in the leptin receptor-deficient (db/db) mice. Cardiac structure and functions were measured by echocardiography and hemodynamic examinations. Primary cardiomyocytes and cardiomyocyte cell lines were used to perform gain/loss-of-function assays in vitro. RESULTS: We observed a significant reduction of miR-21 in the diastolic dysfunctional heart of db/db mice. Remarkably, delivery of miR-21 efficiently protected against the early impairment in cardiac diastolic dysfunction, represented by decreased ROS production, increased bioavailable NO and relieved diabetes-induced cardiomyocyte hypertrophy in db/db mice. Through bioinformatic analysis and Ago2 co-immunoprecipitation, we identified that miR-21 directly targeted gelsolin, a member of the actin-binding proteins, which acted as a transcriptional cofactor in signal transduction. Moreover, down-regulation of gelsolin by siRNA also attenuated the early phase of diabetic cardiomyopathy. CONCLUSION: Our findings reveal a new role of miR-21 in attenuating diabetic cardiomyopathy by targeting gelsolin, and provide a molecular basis for developing a miRNA-based therapy against diabetic cardiomyopathy.


Assuntos
Diabetes Mellitus/terapia , Cardiomiopatias Diabéticas/prevenção & controle , Gelsolina/metabolismo , Terapia Genética/métodos , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Dependovirus/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole , Modelos Animais de Doenças , Gelsolina/genética , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/patologia , Óxido Nítrico/metabolismo , Regiões Promotoras Genéticas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Volume Sistólico , Troponina T/genética , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda
19.
Stem Cell Res Ther ; 9(1): 235, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217223

RESUMO

BACKGROUND: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. METHODS: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. RESULTS: Patients were treated safely with a mean number of 6.57 ± 3.45 ×  106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = - 0.79, p = 0.01) and IL-6 (r = - 0.76, p = 0.02). CONCLUSION: Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02059681 . Registered 11 February 2014.


Assuntos
Angina Pectoris/terapia , Transplante de Medula Óssea/métodos , Cardiomiopatias/terapia , Isquemia Miocárdica/terapia , Intervenção Coronária Percutânea/métodos , Disfunção Ventricular Esquerda/terapia , Antígeno AC133/genética , Antígeno AC133/metabolismo , Idoso , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/genética , Angina Pectoris/patologia , Becaplermina/genética , Becaplermina/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatias/patologia , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Endocárdio , Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Segurança do Paciente , Estudos Prospectivos , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Autólogo , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia
20.
PLoS One ; 13(7): e0201498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30063764

RESUMO

Titin (TTN) Truncating variants (TTNtv) in the A-band of TTN predispose the mouse heart to systolic dysfunction when subjected to pressure-loading. However, the effects of TTNtv of the Z-disc are largely unexplored. A rat model of pressure-loaded heart is developed by trans-aortic constriction (TAC). Rats with TTNtv of the Z-disc were randomly assigned to TAC (Z-TAC) or sham-surgery (Z-Sham) and wildtype (WT) littermates served as controls (WT-TAC or WT-Sham). Left ventricular (LV) function was assessed by echocardiography. Pressure volume (PV) loops, histology and molecular profiling were performed eight months after surgery. Pressure-load by TAC increased LV mass in all cases when compared with Sham animals. Notably, systolic function was preserved in TAC animals throughout the study period, which was confirmed by terminal PV loops. Diastolic function was impaired in Z-disc TTNtv rats at baseline as compared to WT and became impaired further after TAC (dp/dtmin, mmHg/s): Z-TAC = -3435±763, WT-TAC = -6497±1299 (p<0.01). Z-TAC animals had greater cardiac fibrosis, with elevated collagen content and decreased vascular density as compared to WT-TAC animals associated with enhanced apoptosis of myocyte and non-myocyte populations. In the context of pressure overload, Z-disc TTNtv is associated with cardiac fibrosis, diastolic dysfunction, and capillary rarefaction in the absence of overt systolic dysfunction.


Assuntos
Conectina/química , Conectina/genética , Insuficiência Cardíaca/genética , Hipertensão/genética , Função Ventricular Esquerda , Animais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/fisiopatologia , Fibrose/genética , Fibrose/fisiopatologia , Predisposição Genética para Doença , Insuficiência Cardíaca/complicações , Hipertensão/complicações , Masculino , Fenótipo , Polimorfismo Genético , Domínios e Motivos de Interação entre Proteínas/genética , Isoformas de Proteínas/genética , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia
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