Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.859
Filtrar
1.
PLoS One ; 15(9): e0239850, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986766

RESUMO

Massively parallel sequencing (MPS) has revolutionised clinical genetics and research within human genetics by enabling the detection of variants in multiple genes in several samples at the same time. Today, multiple approaches for MPS of DNA are available, including targeted gene sequencing (TGS) panels, whole exome sequencing (WES), and whole genome sequencing (WGS). As MPS is becoming an integrated part of the work in genetic laboratories, it is important to investigate the variant detection performance of the various MPS methods. We compared the results of single nucleotide variant (SNV) detection of three MPS methods: WGS, WES, and HaloPlex target enrichment sequencing (HES) using matched DNA of 10 individuals. The detection performance was investigated in 100 genes associated with cardiomyopathies and channelopathies. The results showed that WGS overall performed better than those of WES and HES. WGS had a more uniform and widespread coverage of the investigated regions compared to WES and HES, which both had a right-skewed coverage distribution and difficulties in covering regions and genes with high GC-content. WGS and WES showed roughly the same high sensitivities for detection of SNVs, whereas HES showed a lower sensitivity due to a higher number of false negative results.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma/métodos , Alelos , Cardiomiopatias/genética , Canalopatias/genética , Exoma , Genoma Humano , Genótipo , Humanos , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos
2.
Am J Physiol Heart Circ Physiol ; 319(3): H582-H603, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762558

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates postexercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac ß-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in patients with DMD.NEW & NOTEWORTHY Duchenne muscular dystrophy (DMD) carriers are at risk for cardiomyopathy. The nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is released from damaged muscle in DMD and impairs exercise performance. Transgenic expression of dimethylarginine dimethylaminohydrolase to degrade ADMA prevents cardiac hypertrophy, improves cardiac function, and improves exercise tolerance in DMD carrier mice. These findings highlight the relevance of ADMA to muscular dystrophy and have important implications for therapies targeting nitric oxide in patients with DMD and DMD carriers.


Assuntos
Arginina/análogos & derivados , Cardiomiopatias/metabolismo , Circulação Coronária , Tolerância ao Exercício , Heterozigoto , Distrofia Muscular de Duchenne/metabolismo , Miocárdio/metabolismo , Músculo Quadríceps/metabolismo , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Arginina/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Miocárdio/patologia , Necrose , Músculo Quadríceps/patologia , Músculo Quadríceps/fisiopatologia , Função Ventricular Esquerda
3.
Life Sci ; 259: 118199, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781064

RESUMO

Cellular senescence, a process whereby cells enter a state of permanent growth arrest, appears to regulate cardiac pathological remodeling and dysfunction in response to various stresses including myocardial infarction (MI). However, the precise role as well as the underlying regulatory mechanism of cardiac cellular senescence in the ischemic heart disease remain to be further determined. Herein we report an inhibitory role of Nrf2, a key transcription factor of cellular defense, in regulating cardiac senescence in infarcted hearts as well as a therapeutic potential of targeting Nrf2-mediated suppression of cardiac senescence in the treatment of MI-induced cardiac dysfunction. MI was induced by left coronary artery ligation for 28 days in mice. Heart tissues from the infarct border zone were used for the analyses. The MI-induced cardiac dysfunction was associated with increased myocardial cell senescence, oxidative stress and apoptosis in adult wild type (WT) mice. In addition, a downregulated Nrf2 activity was associated with upregulated Keap1 levels and increased phosphorylation of JAK and FYN in the infarcted border zone heart tissues. Nrf2 Knockout (Nrf2-/-) enhanced the MI-induced myocardial, cardiac dysfunction and senescence. Qiliqiangxin (QLQX), a herbal medicine which could reverse the MI-induced suppression of Nrf2 activity, significantly inhibited the MI-induced cardiac senescence, apoptosis, and cardiac dysfunction in WT mice but not in Nrf2-/- mice. These results indicate that MI downregulates Nrf2 activity thus promoting oxidative stress to accelerate cellular senescence in the infarcted heart towards cardiac dysfunction and Nrf2 may be a drug target for suppressing the cellular senescence-associated pathologies in infarcted hearts.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/patologia , Senescência Celular/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Animais , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/diagnóstico por imagem , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/farmacologia , Remodelação Ventricular/fisiologia
4.
BMC Med Genet ; 21(1): 152, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698886

RESUMO

BACKGROUND: Intermediate filament proteins that construct the nuclear lamina of a cell include the Lamin A/C proteins encoded by the LMNA gene, and are implicated in fundamental processes such as nuclear structure, gene expression, and signal transduction. LMNA mutations predominantly affect mesoderm-derived cell lineages in diseases collectively termed as laminopathies that include dilated cardiomyopathy with conduction defects, different forms of muscular dystrophies, and premature aging syndromes as Hutchinson-Gilford Progeria Syndrome. At present, our understanding of the molecular mechanisms regulating tissue-specific manifestations of laminopathies are still limited. METHODS: To gain deeper insight into the molecular mechanism of a novel LMNA splice-site mutation (c.357-2A > G) in an affected family with cardiac disease, we conducted deep RNA sequencing and pathway analysis for nine fibroblast samples obtained from three patients with cardiomyopathy, three unaffected family members, and three unrelated, unaffected individuals. We validated our findings by quantitative PCR and protein studies. RESULTS: We identified eight significantly differentially expressed genes between the mutant and non-mutant fibroblasts, that included downregulated insulin growth factor binding factor protein 5 (IGFBP5) in patient samples. Pathway analysis showed involvement of the ERK/MAPK signaling pathway consistent with previous studies. We found no significant differences in gene expression for Lamin A/C and B-type lamins between the groups. In mutant fibroblasts, RNA-seq confirmed that only the LMNA wild type allele predominately was expressed, and Western Blot showed normal Lamin A/C protein levels. CONCLUSIONS: IGFBP5 may contribute in maintaining signaling pathway homeostasis, which may lead to the absence of notable molecular and structural abnormalities in unaffected tissues such as fibroblasts. Compensatory mechanisms from other nuclear membrane proteins were not found. Our results also demonstrate that only one copy of the wild type allele is sufficient for normal levels of Lamin A/C protein to maintain physiological function in an unaffected cell type. This suggests that affected cell types such as cardiac tissues may be more sensitive to haploinsufficiency of Lamin A/C. These results provide insight into the molecular mechanism of disease with a possible explanation for the tissue specificity of LMNA-related dilated cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Lamina Tipo A/genética , Transdução de Sinais/genética , Sequência de Bases , Família , Regulação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/genética , Lâmina Nuclear/metabolismo
5.
Am J Cardiol ; 128: 140-146, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650908

RESUMO

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized infiltrative cardiomyopathy in which conduction system disease is common. The aim of our study was to define the incidence and prevalence of high-grade atrioventricular (AV) block requiring pacemaker implantation in our quaternary referral center. This was a single-center retrospective cohort study of 369 consecutive patients with ATTR-CA who underwent 12-lead electrocardiogram at the time of ATTR-CA diagnosis. During a mean follow-up of 28 months, serial ECGs and the electronic medical record were examined for the development of high-grade AV block and pacemaker implantation. Wild-type ATTR-CA (wtATTR-CA) was diagnosed in 261 patients and 108 had hereditary ATTR-CA (hATTR-CA). A total of 35 (9.5%) had high-grade AV block requiring pacemaker implantation at the time of diagnosis of ATTR-CA. The most common conduction abnormalities evident on the baseline ECG were a wide QRS complex, present in 51% with wtATTR-CA and 48% with hATTR-CA (p = 0.62), followed by first-degree AV block, which was present in 49% with wtATTR-CA and 43% with hATTR-CA (p = 0.31). During follow-up, high-grade AV block developed in 10% of those with hATTR-CA and 12% of patients with wtATTR-CA (p = 0.64). On multivariable models, high-grade AV block was not significantly associated with increased mortality. More advanced ATTR-CA stage and a history of obstructive coronary artery disease were associated with increased mortality on multivariable models. In conclusion, the incidence and prevalence of high-grade AV block is high in patients with ATTR-CA. Patients with ATTR-CA require close monitoring during follow-up for the development of conduction system disease.


Assuntos
Neuropatias Amiloides Familiares/fisiopatologia , Bloqueio Atrioventricular/epidemiologia , Cardiomiopatias/fisiopatologia , Mortalidade , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Amiloidose/complicações , Amiloidose/fisiopatologia , Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/terapia , Bloqueio de Ramo/epidemiologia , Bloqueio de Ramo/etiologia , Estimulação Cardíaca Artificial , Cardiomiopatias/complicações , Cardiomiopatias/genética , Estudos de Coortes , Eletrocardiografia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Marca-Passo Artificial , Pré-Albumina/genética , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndrome do Nó Sinusal/epidemiologia , Síndrome do Nó Sinusal/etiologia
6.
Am J Physiol Heart Circ Physiol ; 319(2): H443-H455, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618511

RESUMO

Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of erythroblastic leukemia viral oncogene homolog (ERBB)4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 wk. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (ANG II), or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis, and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 wk following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 wk. Similarly, 4 wk after ANG II treatment, myocardial fibrosis was less pronounced compared with control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.NEW & NOTEWORTHY The role of NRG1/ERBB signaling in endothelial cells is not completely understood. Our study contributes to the understanding of spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury and shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.


Assuntos
Comunicação Autócrina , Cardiomiopatias/metabolismo , Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Neuregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Neovascularização Fisiológica , Comunicação Parácrina , Receptor ErbB-4/deficiência , Receptor ErbB-4/genética , Transdução de Sinais
8.
J Card Surg ; 35(7): 1508-1513, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485041

RESUMO

BACKGROUND: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases (VHDs). The objective of the study is to identify microRNA (miRNA) molecules expressed in VHDs and the differential expression patterns of miRNA in AVs with either calcification or rheumatism etiologies. METHODS: Human AVs were collected during valve replacement surgery. RNA was extracted and miRNA containing libraries were prepared and sequenced using the next generation sequencing (NGS) approach. miRNAs identified as differentially expressed between the two etiologies were validated by quantitative real-time polymerase chain reaction (qPCR). The receiver operating characteristic (ROC) curve analysis was performed to examine the ability of relevant miRNA to differentiate between calcification and rheumatism etiologies. RESULTS: Rheumatic and calcified AV samples were prepared for the NGS and were successfully sequenced. The expression was validated by the qPCR approach in 46 AVs, 13 rheumatic, and 33 calcified AVs, confirming that miR-145-5p, miR-199a-5p, and miR-5701 were significantly higher in rheumatic AVs as compared with calcified AVs. ROC curve analysis revealed that miR-145-5p had a sensitivity of 76.92% and a specificity of 94.12%, area under the curve (AUC) = 0.88 (P = .0001), and miR-5701 had a sensitivity of 84.62% and a specificity of 76.47%, AUC = 0.78 (P = .0001), whereas miR-199a-5p had a sensitivity of 84.62%, and a specificity of 57.58%, AUC = 0.73 (P = .0083). CONCLUSION: We documented differential miRNA expression between AV disease etiologies. The miRNAs identified in this study advance our understanding of the mechanisms underlining AV disease.


Assuntos
Valva Aórtica/metabolismo , Calcinose/complicações , Cardiomiopatias/complicações , Expressão Gênica , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/genética , MicroRNAs/análise , MicroRNAs/genética , Doenças Reumáticas/complicações , Idoso , Valva Aórtica/cirurgia , Calcinose/genética , Cardiomiopatias/genética , Feminino , Doenças das Valvas Cardíacas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Doenças Reumáticas/genética
9.
Orphanet J Rare Dis ; 15(1): 157, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571376

RESUMO

Inherited heart disease represent a very heterogenous group of cardiac disorders, characterized by inherited, acquired, and often rare disorders affecting the heart muscle (cardiomyopathies) or the cardiac electrical system (ion channel disease). They are often familial diseases, and are among the leading cause of juvenile sudden death and heart failure. The aim of this paper is to give a perspective on how to run a clinical service during an epidemic or pandemic emergency and to describe the potential COVID-19 associated risks for patients affected by inherited heart diseases.


Assuntos
Betacoronavirus , Cardiomiopatias/complicações , Cardiomiopatias/genética , Canalopatias/complicações , Canalopatias/genética , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Predisposição Genética para Doença , Humanos , Ambulatório Hospitalar/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Doenças Raras/complicações , Fatores de Risco , Telemedicina/organização & administração
10.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
11.
Zhonghua Er Ke Za Zhi ; 58(6): 476-481, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521959

RESUMO

Objective: To evaluate and improve the performance of the newborn screening program for primary carnitine deficiency (PCD) based on tandem mass spectrometry and to investigate the incidence of PCD and molecular characteristics of SLC22A5 gene in Guangzhou. Methods: A total of 200 180 neonates born in Guangzhou from 2015 to 2019 were enrolled into the newborn screening program for PCD by tandem mass spectrometry at Guangzhou Newborn Screening Center. The positive results of screening for PCD was defined as free carnitine (C0) less than 10 µmol/L with decreased acylcarnitine species in dried blood spots of three to seven days after birth. Screen-positive newborns and their mothers were recalled for another blood spot sample. The diagnosis was confirmed based on decreased levels of C0 and acylcarnitine species in recalled blood spots and genetic analysis in SLC22A5 gene sequencing. The utility of using the sum of propionylcarnitine and palmitoylcarnitine (C3+C16) as a biomarker for acylcarnitine species in newborn screening was retrospectively evaluated. The levels of C0 and (C3+C16) at first screening were compared between newborns with PCD and newborns born to mothers with PCD by independent t test. The variant spectrum and known pathogenic variants carrier rate of SLC22A5 in 2 395 healthy children in Guangzhou Women and Children's Medical Center through whole exon sequencing were analyzed. Results: Among 200 180 neonates, 239 (0.12%) cases were screen-positive for PCD. A total of 37 patients including 15 newborns and 22 mothers had confirmed PCD. The incidence of PCD was 1/13 345 in newborns and 1/9 099 in mothers, respectively. The positive predictive value of this program was 15.5%. Taking cutoff values of C0<8.5 µmol/L or C0 8.5~9.9 µmol/L with (C3+C16)<2 µmol/L, the number of screen-positive cases would be reduced from 810 to 224 without additional false negative case, when compared with cutoff value C0<10 µmol/L only. Both levels of C0 and (C3+C16) at first screening were not significant difference between newborns with PCD and newborns born to mothers with PCD ((6.2±2.4) vs. (5.0±1.8) µmol/L, (1.4±0.4) vs. (1.2±0.5) µmol/L, t=3.826, 0.326; P=0.058, 0.572). Seven PCD mothers experienced moderate fatigue and dizziness in the morning. One of them presented with cardiomyopathy in pregnancy. Genetic analysis of the SLC22A5 gene showed that p.S467C, p.F17L, p.R254X were the three most common variants in newborns with PCD. In PCD mothers and healthy children, the p.S467C, p.F17L and R399W were the three most common whereas the severe variant p.R254X was rare. The population carrier rate for pathogenic variants was 1 in 65 and the estimated incidence of PCD was about 1/16 500. Conclusions: Newborn screening can detect PCD both in newborns and mothers. Adding a quantitative biomarker (C3+C16) <2 µmol/L into the newborn screening program can improve the PCD screen performance. The severe variant p.R253X was common in PCD newborns but rare in PCD mothers and healthy children, indicating that the current screening program maybe failed to detect all PCD newborns and under-estimated the incidence rate of PCD in Guangzhou.


Assuntos
Cardiomiopatias/genética , Carnitina/sangue , Carnitina/deficiência , Hiperamonemia/diagnóstico , Doenças Musculares/diagnóstico , Triagem Neonatal/métodos , Membro 5 da Família 22 de Carreadores de Soluto/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Carnitina/genética , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hiperamonemia/genética , Recém-Nascido , Doenças Musculares/genética , Gravidez , Estudos Retrospectivos , Espectrometria de Massas em Tandem
13.
Cardiovasc Drugs Ther ; 34(5): 591-604, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32424654

RESUMO

PURPOSE: Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the  myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. METHODS: Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. RESULTS: CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-ß1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-ß1-induced Smad3 activation. CONCLUSION: CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.


Assuntos
Cardiomiopatias/prevenção & controle , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Comunicação Parácrina , Fator de Crescimento Transformador beta1/farmacologia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Miócitos Cardíacos/patologia , Transdução de Sinais
16.
J Hum Genet ; 65(8): 711-713, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32269295

RESUMO

Amyloidosis, caused by a mutation in the transthyretin (TTR) gene, is the most common hereditary type disease. More than 120 mutations have been described, with extensive phenotypic heterogeneity. Val30Met (p.Val50Met) is the most frequent mutation, and patients exhibit polyneuropathy, possibly including cardiac, renal, gastrointestinal, and/or ocular involvement. Val122Ile (p.Val142Ile) is the mutation associated with cardiomyopathy, and few cases have been reported in Brazil. Most individuals are heterozygous for one pathogenic mutation. Herein, we report a compound heterozygote with two pathogenic mutations (Val30Met/ Val122Ile), and a family history of a deceased brother with amyloidosis, who also carried the same TTR gene mutations. The patient presented with neuropathic, cardiac, and renal impairment and a faster disease progression. Cases of the double mutation have been linked to changes in disease presentation. The concomitance of two pathogenic mutations may have contributed to more exuberant manifestations and faster disease progression.


Assuntos
Amiloidose Familiar/genética , Cardiomiopatias/genética , Polineuropatias/genética , Pré-Albumina/genética , Amiloidose Familiar/fisiopatologia , Brasil , Cardiomiopatias/fisiopatologia , Progressão da Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polineuropatias/fisiopatologia
18.
Sci Rep ; 10(1): 4888, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184434

RESUMO

Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.


Assuntos
Antraquinonas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Adulto , Western Blotting , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 300-307, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128748

RESUMO

Cardiomyopathies are a group of heterogeneous diseases which can be caused by various factors (often genetic) and can lead to heart failure, arrhythmia and sudden death. Primary cardiomyopathies includes hereditary hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, mitochondrial cardiomyopathy, mixed (hereditary and acquired) dilated cardiomyopathy and restrictive cardiomyopathy, left ventricular densification insufficiency, and other unclassified cardiomyopathies. With the help of genomic technology, common mutations in the population have been identified. In vivo and in vitro study of such mutations has provided insight into the pathogenesis and treatment of these diseases. The compilation of this guideline is based on the consensus of basic and clinical research and guidelines from other countries, and has summarized the phenotype, diagnosis, treatment and consultation of various types of genetic cardiomyopathies with an aim to standardize the clinical management of patients.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatias/terapia , Guias de Prática Clínica como Assunto , Displasia Arritmogênica Ventricular Direita , Cardiomiopatia Dilatada , Cardiomiopatia Hipertrófica , Cardiomiopatia Restritiva , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA