Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.984
Filtrar
1.
Dis Markers ; 2022: 4627845, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308144

RESUMO

The importance of cell pyroptosis in immunity regulation is becoming increasingly obvious, especially in diseases of the cardiovascular system. Nevertheless, it is unknown whether the pyroptosis signalling pathway is involved in the immune microenvironment regulation of dilated cardiomyopathy (DCM). Therefore, the purpose of the study was to investigate the influence of pyroptosis on the immune environment in dilated cardiomyopathy. We found that expression of 19 pyrolysis-related genes (PRGs) in DCM samples was altered compared to healthy samples. Subsequently, based on these 12 hub pyrolysis-related genes, we developed a classifier that can distinguish between healthy samples and DCM samples. Among the hub pyrolysis-related genes, RT-PCR analyses demonstrated that five of them exhibited significant differential expression in DCM. Interestingly, we observed that immune characteristics are correlated with pyroptosis: higher expression of GSDMD is positively correlated with infiltrating activated pDCs; GSDMD is negatively correlated with Tregs; CASP1 is positively related to parainflammation; and CASP9 is negatively related to the type II IFN response. In addition, distinct pyroptosis-mediated patterns were identified, and immune characteristics under distinct patterns were revealed: pattern B mediates an active immune response, and pattern A leads to a relatively mild immune response to DCM. We also compared the biological functions between these patterns. Compared with pattern A, pattern B had more abundant pathways, such as the NOTCH signalling pathway and pentose phosphate pathway. In summary, this study proves the important influence of pyrolysis on the immune microenvironment of dilated cardiomyopathy and provides new clues for understanding the pathogenesis of dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada , Perfilação da Expressão Gênica , Fatores Imunológicos , Mapas de Interação de Proteínas , Piroptose/imunologia , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
2.
BMC Cardiovasc Disord ; 22(1): 41, 2022 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-35151254

RESUMO

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a rare, heritable myocardial disorder that is a leading cause of ventricular arrhythmia and sudden cardiac death (SCD) in young people. Desmoplakin (DSP) mutations account for 3-20% of AC cases. However, the number of patients with DSP mutations is extremely small in all published reports and genotype-phenotype correlations are scant and mostly non-gene-specific. CASE PRESENTATION: A 45-year-old man was admitted after an out-of-hospital cardiac arrest, with documented ventricular fibrillation. He had no previous history of heart disease or family history of SCD or cardiomyopathy. The cardiac magnetic resonance showed a mildly dilated left ventricle with an ejection fraction of 30% and a non-dilated right ventricle with mildly depressed systolic function, and extensive subepicardial late gadolinium enhancement. Genetic screening identified a heterozygote nonsense mutation in DSP (NM_004415.2: c.478 C > T; p.Arg160Ter). Cascade genetic screening of the relatives revealed a high prevalence of the genotype and cutaneous phenotype, but a very low penetrance of the cardiac phenotype. CONCLUSIONS: We report a case of SCD and an autosomal dominant mutation in DSP that causes arrhythmogenic dilated cardiomyopathy/AC. Like the recessive mutation in DSP known to cause Carvajal syndrome, Arg160Ter may be associated with cutaneous abnormalities.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Códon sem Sentido , Morte Súbita Cardíaca/etiologia , Desmoplaquinas/genética , Doenças do Cabelo/genética , Ceratodermia Palmar e Plantar/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Evolução Fatal , Predisposição Genética para Doença , Doenças do Cabelo/complicações , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/fisiopatologia , Heterozigoto , Humanos , Ceratodermia Palmar e Plantar/complicações , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo
3.
Clin Sci (Lond) ; 136(2): 181-196, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35048952

RESUMO

Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure (HF) reflected by morphometric parameters as well as increased fetal genes, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy (CM) and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II (Ang II)-induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of c-jun N-terminal kinase (JNK) MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the Ang II-induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload (PO)-induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy (DCM), interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.


Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Aorta , Cardiomegalia/fisiopatologia , Linhagem Celular , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética
4.
Circ Arrhythm Electrophysiol ; 15(2): e009979, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35089806

RESUMO

BACKGROUND: Spontaneous nonsustained ventricular tachycardia (NSVT) on Holter, VT inducibility during electrophysiology study, and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) have been associated with sustained ventricular arrhythmias (SVAs) in nonischemic dilated cardiomyopathy (DCM). This study aimed to analyze whether these parameters carry independent prognostic value for spontaneous SVA in DCM. METHODS: Between 2011 and 2018, patients with the DCM clinical spectrum and documented SVA, suspected SVA, or considered to be at intermediate or high risk for SVA were enrolled in the prospective Leiden Nonischemic Cardiomyopathy Study. Patients underwent a comprehensive evaluation including 24-hour Holter, LGE-CMR, and electrophysiology study. Holters were assessed for the presence of NSVT (≥3 beats; rate, ≥120 bpm; lasting <30 s) and NSVT characteristics (coupling interval, duration, cycle length, morphology, regularity). Patients were followed at 6 to 12 monthly intervals. RESULTS: Of all 115 patients (age, 59±12 years; 77% men; left ventricular ejection fraction, 33±13%; history of SVA, 36%; LGE in 63%; median LGE mass, 13 g; interquartile range, 8-23 g), 62 (54%) had NSVT on Holter, and sustained monomorphic VT was inducible in 34 of 114 patients (30%). NSVT was not associated with LGE on CMR or VT inducibility during electrophysiology study nor were its features (all P>0.05). During 4.0±1.8 years of follow-up, SVA occurred in 39 patients (34%). NSVT (HR, 4.47 [95% CI, 1.87-10.72]; P=0.001) and VT inducibility (HR, 3.08 [95% CI, 1.08-8.81]; P=0.036) were independently associated with SVA during follow-up. A bivariable model including only noninvasively acquired parameters also allowed identification of a high-risk subgroup (ie, those with both NSVT and LGE on CMR). The findings remained similar when only patients without prior SVA were included. CONCLUSIONS: In patients with DCM, NSVT on Holter and VT inducibility during electrophysiology study predict SVA during follow-up independent of LGE on CMR. NSVTs may serve as an initiator, and sustained VT inducibility indicates the presence of the substrate for SVA in DCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01940081.


Assuntos
Cardiomiopatia Dilatada/complicações , Frequência Cardíaca , Taquicardia Ventricular/etiologia , Idoso , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Eletrocardiografia Ambulatorial , Técnicas Eletrofisiológicas Cardíacas , Feminino , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia
5.
Biomark Med ; 16(1): 11-21, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34856814

RESUMO

Aim: We aimed to investigate the association of SIRT4 gene polymorphisms with the susceptibility and prognosis of dilated cardiomyopathy (DCM) in a Chinese population. Materials & methods: A total of 369 controls and 373 DCM patients were enrolled. Three tag single-nucleotide polymorphisms (rs2261612, rs2522138 and rs16950058) on SIRT4 were evaluated. Results: G carriers of rs2261612 were associated with the susceptibility of DCM in codominant, dominant and overdominant genetic models (all p < 0.01). Furthermore, the AG/GG and AG genotype of rs2261612 in dominant and overdominant models correlated with poor prognosis of DCM, independent of left ventricular ejection fraction and cardiac resynchronization therapy (p < 0.001). Conclusion: SIRT4 polymorphisms were associated with the susceptibility and prognosis of DCM in a Chinese population.


Assuntos
Cardiomiopatia Dilatada/genética , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único , Sirtuínas/genética , Adulto , Cardiomiopatia Dilatada/fisiopatologia , China , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/fisiologia , Função Ventricular Esquerda
6.
Cardiovasc Res ; 118(1): 241-253, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33135063

RESUMO

AIMS: Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants. METHODS AND RESULTS: We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants. CONCLUSION: Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Proteínas de Transporte/metabolismo , Conectina/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Troponina I/metabolismo , Adulto , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Conectina/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Mutação , Miofibrilas/patologia , Fenótipo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteínas Virais/metabolismo , Adulto Jovem
7.
J Thorac Cardiovasc Surg ; 163(3): 1058-1067, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32653287

RESUMO

OBJECTIVE: The study objective was to evaluate the short- and long-term outcomes of patients with ischemic cardiomyopathy after surgical ventricular restoration and to identify risk factors related to poor results. METHODS: Between August 2002 and April 2016, 62 patients affected by ischemic cardiomyopathy underwent surgical left ventricular restoration at our unit. Patients' mean age at operation was 63 years (39-79 years). Mean ejection fraction was 29.6%. The Surgical Treatment for Ischemic Heart Failure trial criteria have been used as indications for surgery. Fifty-seven patients (91%) received surgical myocardial revascularization. Mitral valve repair was performed in 39 patients (63%). The surgical technique consisted of the classic Dor operation or a different approach reducing the equatorial diameter of the left ventricle and avoiding the use of a patch. The data were analyzed retrospectively for perioperative results and short- and long-term clinical outcomes. RESULTS: One patient died of noncardiac causes within 30 days (1.6%). All-cause death occurred in 36 patients (58%) during follow-up (0.6-14.7 years; median follow-up time, 7.02 years), of whom 15 died of cardiac causes. Age, need for preoperative intra-aortic balloon pump, reduction less than 35% of postoperative left ventricular end-diastolic and end-systolic volumes, type of surgical technique, and ejection fraction less than 25% were identified as risk factors for late cardiac mortality. Perioperative levosimendan administration and presence of preoperative moderate to severe mitral regurgitation influenced early and intermediate-term outcomes, but no statistical relevance on long-term results was demonstrated. CONCLUSIONS: Patients with ischemic dilative cardiomyopathy have favorable short- and long-term outcomes after ventricular restoration. Age, preoperative ejection fraction less than 25%, inadequate left ventricular surgical reverse remodeling, and type of surgical technique negatively affect long-term survival.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cardiomiopatia Dilatada/cirurgia , Ventrículos do Coração/cirurgia , Isquemia Miocárdica/complicações , Função Ventricular Esquerda , Adulto , Fatores Etários , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/fisiopatologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/mortalidade , Isquemia Miocárdica/fisiopatologia , Qualidade de Vida , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento
8.
Radiology ; 302(1): 72-81, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34698565

RESUMO

Background There is increasing recognition that left atrial (LA) function is prognostically important in cardiovascular disease. LA strain is a sensitive parameter to describe complex LA phasic function. However, the prognostic value of LA strain in participants with idiopathic dilated cardiomyopathy (DCM) remains unclear. Purpose To evaluate the prognostic value of LA strain derived from cardiac MRI in study participants with idiopathic DCM. Materials and Methods Participants with idiopathic DCM who underwent cardiac MRI between June 2012 and November 2018 were prospectively enrolled. The fast long-axis strain MRI method was performed to assess LA strain. The primary end point was all-cause mortality and heart transplant, and the secondary end point was a combination of primary end point, heart failure readmission, and aborted sudden cardiac death. Cox regression analyses and Kaplan-Meier survival analysis were performed to identify the association between variables and outcomes. Results There were 497 participants (mean age, 47 years ± 14 [standard deviation]; 357 men) evaluated. During a median follow-up of 36 months (interquartile range, 26-54 months), 113 participants reached primary end points and 203 participants reached secondary end points. LA reservoir, conduit and booster strain, and strain rate were lower in participants with primary end points (P < .001). In multivariable Cox regression analysis, LA reservoir strain and conduit strain were independent predictors for primary end point (hazard ratio [HR] per 1% increase, 0.95 [95% CI: 0.91, 0.99; P = .008] and 0.92 [95% CI: 0.87, 0.98; P = .010], respectively) and secondary end points (HR per 1% increase, 0.95 [95% CI: 0.93, 0.97; P < .001] and 0.93 [95% CI: 0.89, 0.97; P < .001], respectively). In addition, LA reservoir strain and conduit strain added incremental prognostic value to clinical risk factors and late gadolinium enhancement presence (all, P < .05). Conclusion Left atrial reservoir and conduit strain, derived from cardiac MRI by using the fast long-axis method, were independent predictors of adverse clinical outcomes in idiopathic dilated cardiomyopathy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh in this issue.


Assuntos
Função do Átrio Esquerdo/fisiologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Feminino , Seguimentos , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Nat Commun ; 12(1): 7151, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887420

RESUMO

The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts as well as an increase in diastolic Ca2+ level, slower Ca2+ transient decay and longer Ca2+ transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cálcio/metabolismo , Cardiomiopatia Dilatada/genética , Etiocolanolona/análogos & derivados , Peixe-Zebra/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Etiocolanolona/administração & dosagem , Feminino , Técnicas de Introdução de Genes , Humanos , Masculino , Contração Miocárdica , Miocárdio/metabolismo , Deleção de Sequência , Peixe-Zebra/genética
10.
Sci Rep ; 11(1): 24000, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907272

RESUMO

The current stratification of arrhythmic risk in dilated cardiomyopathy (DCM) is sub-optimal. Cardiac fibrosis is involved in the pathology of arrhythmias; however, the relationship between cardiovascular magnetic resonance (CMR) derived extracellular volume (ECV) and arrhythmic burden (AB) in DCM is unknown. This study sought to evaluate the presence and extent of replacement and interstitial fibrosis in DCM and to compare the degree of fibrosis between DCM patients with and without AB. This is a prospective, single-center, observational study. Between May 2019 and September 2020, 102 DCM patients underwent CMR T1 mapping. 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) composed study population. AB was defined as the presence of VT or a high burden of PVCs. There were 41 (41.4%) patients with AB and 58 (58.6%) without AB. Replacement fibrosis was assessed with late gadolinium enhancement (LGE), whereas interstitial fibrosis with ECV. Overall, LGE was identified in 41% of patients. There was a similar distribution of LGE (without AB 50% vs. with AB 53.7%; p = 0.8) and LGE extent (without AB 4.36 ± 5.77% vs. with AB 4.68 ± 3.98%; p = 0.27) in both groups. ECV at nearly all myocardial segments and a global ECV were higher in patients with AB (global ECV: 27.9 ± 4.9 vs. 30.3 ± 4.2; p < 0.02). Only indexed left ventricular end-diastolic diameter (HR 1.1, 95%CI 1.0-1.2; p < 0.02) and global ECV (HR 1.12, 95%CI 1.0-1.25; p < 0.02) were independently associated with AB. The global ECV cut-off value of 31.05% differentiated both groups (AUC 0.713; 95%CI 0.598-0.827; p < 0.001). Neither qualitative nor quantitative LGE-based assessment of replacement fibrosis allowed for the stratification of DCM patients into low or high AB. Interstitial fibrosis, expressed as ECV, was an independent predictor of AB in DCM. Incorporation of CMR parametric indices into decision-making processes may improve arrhythmic risk stratification in DCM.


Assuntos
Arritmias Cardíacas/diagnóstico por imagem , Cardiomiopatia Dilatada/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio , Adulto , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
11.
Cells ; 10(11)2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34831402

RESUMO

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting HSP70 expression in a model of nonischemic heart failure using protein phosphatase 2 catalytic subunit A (PP2CA)-expressing transgenic mice. These transgenic mice, with cardiac-specific overexpression of PP2CA, abruptly died after 12 weeks of postnatal life. Serial echocardiograms to assess cardiac function revealed that the ejection fraction (EF) was gradually decreased in transgenic PP2CA (TgPP2CA) mice. In addition, PP2CA expression exacerbated systolic dysfunction and LV dilatation, with free wall thinning, which are indicators of fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 in double transgenic mice (dTg) significantly improved the dilated cardiomyopathy phenotype of TgPP2CA mice. We observed better survival, preserved EF, reduced chamber enlargement, and suppression of free wall thinning. In the proposed molecular mechanism, HSP70 preferentially regulates the phosphorylation of AKT. Phosphorylation of AKT was significantly reduced in TgPP2CA mice but was not significantly lower in dTg mice. Signal crosstalk between AKT and its substrates, in association with HSP70, might be a useful intervention for patients with nonischemic heart failure to suppress cardiac remodeling and improve survival.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Proteína Fosfatase 2/metabolismo , Remodelação Ventricular , Animais , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Doença Crônica , Eletrocardiografia , Regulação da Expressão Gênica , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Camundongos Transgênicos , Fenótipo , Fosforilação , Processamento de Proteína Pós-Traducional , Análise de Sobrevida
12.
Cells ; 10(11)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34831118

RESUMO

Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal. We generated a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse to determine the effects of impaired VCP activity on the heart. Using echocardiography, we showed that cardiac-specific overexpression of DN-VCP induced a remarkable cardiac dilation and progressively declined cardiac function during the aging transition. Mechanistically, DN-VCP did not affect the endogenous VCP (EN-VCP) expression but significantly reduced cardiac ATPase activity in the DN-VCP TG mouse hearts, indicating a functional inhibition. DN-VCP significantly impaired the aging-related cytoplasmic/nuclear shuffling of EN-VCP and its co-factors in the heart tissues and interrupted the balance of the VCP-cofactors interaction between the activating co-factors, ubiquitin fusion degradation protein 1 (UFD-1)/nuclear protein localization protein 4 (NPL-4) complex, and its inhibiting co-factor P47, leading to the binding preference with the inhibitory co-factor, resulting in functional repression of VCP. This DN-VCP TG mouse provides a unique functional-inactivation model for investigating VCP in the heart in physiological and pathological conditions.


Assuntos
Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Proteína com Valosina/antagonistas & inibidores , Envelhecimento/patologia , Animais , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Miocárdio/patologia , Proteínas Repressoras/metabolismo , Proteína com Valosina/metabolismo
13.
Biomed Pharmacother ; 144: 112244, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601193

RESUMO

This study tested the hypothesis that Entresto (En) therapy protected the cardiomyocytes and heart function in cardiorenal syndrome (CRS) rats fed with high-protein diet (HPD) through regulating the oxidative-stress and Mfn2-mediated mitochondrial functional integrity. En (12.5 µM for the in-vitro study) protected the H9C2-cells against H2O2-induced cell apoptosis, whereas stepwise-increased H2O2 concentrations induced a significant increase in protein expressions of Mfn2/phosphorylated (p)-DRP1/mitochondrial-Bax in H9C2-cells. En downregulated H2O2-induced mitochondrial fission/upregulated mitochondrial fusion and deletion of Mfn2 gene (i.e., shMfn2) to significantly reduce H2O2-induced ROS production. En significantly suppressed and shMfn2 further significantly suppressed both H2O2-reduced mitochondrial-membrane potential and H2O2-induced ROS production/cell apoptosis/mitochondrial damage/mitochondrial-Bax released from mitochondria in H9C2 cells. En significantly reduced protein expressions of Mfn2 and p-DRP1. Additionally, En significantly suppressed and shMfn2 further significantly suppressed the protein expressions of mitochondrial-damaged (DRP1)/oxidative-stress (NOX-1/NOX-2)/apoptosis (mitochondrial-Bax/caspase-3/PARP)/autophagic (LC3B-II/LC3B-I) biomarkers (all p < 0.01). Rats were categorized into group 1 [sham-control + high-protein-diet (HPD)], group 2 (CRS + HPD) and group 3 (CRS+ HPD + En/100 mg/kg/day). By day 63 after CRS induction, the LVEF was significantly lower in group 3 and more significantly lower in group 2 than in group 1, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2/p22phox/oxidized protein)/apoptotic (mitochondrial-Bax/caspase-3/PARP), fibrotic (Smad-3/TGF-ß), autophagic (Beclin-1/Atg5/ratio of LC3B-II/LC3B-I) and mitochondrial-damaged (DRP1/cyclophilin-D/cytosolic-cytochrome-C) biomarkers exhibited an opposite pattern of LVEF among the groups. Downregulation of Mfn2 by En or shMfn2 in cardiomyocytes avoided H2O2 damage and En improved the cardiac function in HPD-feeding CRS rat via adjusting Mfn2-mediated mitochondrial functional integrity.


Assuntos
Aminobutiratos/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Síndrome Cardiorrenal/tratamento farmacológico , Cardiomiopatia Dilatada/tratamento farmacológico , GTP Fosfo-Hidrolases/metabolismo , Rim/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Valsartana/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/patologia , Síndrome Cardiorrenal/fisiopatologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Dieta Rica em Proteínas , Modelos Animais de Doenças , Combinação de Medicamentos , Dinaminas/metabolismo , Fibrose , Rim/metabolismo , Rim/patologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Ratos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Cells ; 10(10)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34685747

RESUMO

Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted.


Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Fenômenos Eletrofisiológicos , Remodelação Ventricular , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Epigênese Genética , Humanos
15.
Elife ; 102021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34558411

RESUMO

Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic, and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.


Assuntos
Cardiomiopatia Dilatada/genética , Proteínas Musculares/genética , Pressão/efeitos adversos , Animais , Cálcio/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Conectina/metabolismo , Masculino , Camundongos Knockout , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Miocárdio , Miócitos Cardíacos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sarcômeros , Técnicas do Sistema de Duplo-Híbrido
16.
Ann Biomed Eng ; 49(12): 3524-3539, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34585335

RESUMO

Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Expressão Gênica , Células-Tronco Pluripotentes Induzidas/citologia , Lamina Tipo A/genética , Contração Miocárdica , Miócitos Cardíacos/fisiologia , Adulto , Idoso , Linhagem Celular , Humanos , Pessoa de Meia-Idade
17.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575848

RESUMO

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.


Assuntos
Apolipoproteína E4/genética , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Suscetibilidade a Doenças , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Alelos , Animais , Apolipoproteína E4/metabolismo , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Dieta Hiperlipídica , Ecocardiografia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Testes de Função Cardíaca , Humanos , Imuno-Histoquímica , Masculino , Mutação , Ratos , Disfunção Ventricular Direita/diagnóstico
18.
Nat Commun ; 12(1): 4722, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354059

RESUMO

Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3-4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1's function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.


Assuntos
Cardiomiopatia Dilatada/genética , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Dependovirus/genética , Feminino , Humanos , Lamina Tipo A/deficiência , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução Genética
19.
Genes (Basel) ; 12(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356086

RESUMO

Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disease that affects the musculoskeletal system, including the heart, causing rhythm disorders and cardiomyopathy, sometimes requiring an implantable cardioverter-defibrillator (ICD) or heart transplantation due to severe heart damage. The case described herein concerns a 16-year-old girl, with grade II obesity, without other known pathological antecedents or cardiac pathology diagnosis given an annual history of cardiological investigations. She was admitted to the Infectious Diseases Department with SARS-CoV-2 virus infection. The anamnesis showed that the cardiological investigations performed in the past were completed due to the medical history antecedents of her sister, who had been diagnosed with dilated cardiomyopathy, having undergone the placement of an ICD and a heart transplant. Numerous investigations were performed during hospitalization, which revealed high levels of high-sensitive cardiac troponin I (hs-cTnI), creatine kinase (CK) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Dynamic electrocardiographic evaluations showed ventricular extrasystoles, without clinical manifestations. The patient presented stage 2 arterial hypertension (AHT) during hospitalization. A cardiac ultrasound was also performed, which revealed suspected mild subacute viral myocarditis with cardiomyopathy, and antihypertensive medication was initiated. A heart MRI was performed, and the patient was diagnosed with dilated cardiomyopathy, refuting the suspicion of viral subacute myocarditis. After discharge, as the patient developed gait disorders with an impossible heel strike upon walking and limitation of the extension of the arms and ankles, was hospitalized in the Neurology Department. Electrocardiograms (ECGs) were dynamically performed, and because the rhythm disorders persisted, the patient was transferred to the Cardiology Department. On Holter monitoring, non-sustained ventricular tachycardia (NSVT) was detected, so antiarrhythmic treatment was initiated, and placement of an ICD was subsequently decided and was diagnosed with EDMD. Genetic tests were also performed, and a mutation of the lamin A/C gene was detected (LMNA gene exon 2, variant c448A > C (p.Thr150pro), heterozygous form, AD).


Assuntos
COVID-19 , Cardiomiopatia Dilatada , Distrofia Muscular de Emery-Dreifuss , SARS-CoV-2/metabolismo , Adolescente , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/fisiopatologia , COVID-19/terapia , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Feminino , Humanos , Distrofia Muscular de Emery-Dreifuss/sangue , Distrofia Muscular de Emery-Dreifuss/diagnóstico por imagem , Distrofia Muscular de Emery-Dreifuss/fisiopatologia , Distrofia Muscular de Emery-Dreifuss/terapia
20.
Biomed Pharmacother ; 141: 111886, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34426177

RESUMO

BACKGROUND: This study tested the hypothesis that early administration of SS31 and entresto (En) was superior to either one alone on preserving the heart function in setting of dilated cardiomyopathy (DCM) induced by doxorubicin (Dox) [accumulated dosage of 12.5 mg/kg/administered by intraperitoneal (IP) at 4 separated time points within 20 days] in rat. METHODS AND RESULTS: Adult-male SD rats (n = 40) were equally categorized into groups 1 (sham-control), 2 (DCM), 3 (DCM + SS31/0.7 mg/kg/day/IP, since day-14 after DCM induction to day-60), 4 [DCM + En (30 mg/kg/day/orally since day-14 after DCM induction to day-60)] and 5 (DCM + combined SS31-En), and animals were euthanized by day 60. By day 60, left-ventricular ejection-fraction (LVEF) was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3 and 4 (all p < 0.0001), but it showed no difference between groups 3/4. The microscopic study showed that the fibrosis area/cardiomyocyte size and DNA-damaged (γ-H2AX+)/inflammatory (CD14+//CD68+) markers, and flow analysis of inflammatory (Ly6G+/MPO+/CD11b/c+) and early/late apoptosis (AN-V+/PI-//AN-V+/PI+) cells exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). The protein expressions of inflammatory upstream (TLR2/TLR4/MyD88/Mal/ TRAF6/IKK-α/IKK-ß) and downstream (p-NF-κb/TNF-α/IL-1ß/MMP-9), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/cytosolic cytochrome-C/cyclophilin-D/DRP1) and autophagic/apoptotic (ratio of LC3B-II/LC3B-I and mitochondrial-Bax/caspase3/9) signaling pathways also exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). CONCLUSION: Combined SS31-En therapy was superior to either one alone on protecting the heart structural and functional integrities against Dox-induced DCM damage.


Assuntos
Aminobutiratos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Cardiomiopatia Dilatada/tratamento farmacológico , Doxorrubicina/toxicidade , Oligopeptídeos/administração & dosagem , Tempo para o Tratamento , Valsartana/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/administração & dosagem , Animais , Cardiomiopatia Dilatada/induzido quimicamente , Cardiomiopatia Dilatada/fisiopatologia , Combinação de Medicamentos , Quimioterapia Combinada , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...