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1.
Cell Biol Int ; 46(3): 475-487, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34939719

RESUMO

Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia-induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a-PSEN1-KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a-PSEN1-KO group compared with the percent of these measures in the WT group, indicating that PSEN1-KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1-KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1-KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging-related cardiomyopathy, which might had important implications for the treatment of aging-related heart diseases.


Assuntos
Cálcio , Cardiomiopatia Dilatada , Animais , Cardiomiopatia Dilatada/genética , Homeostase , Camundongos , Camundongos Knockout , Miócitos Cardíacos/fisiologia , Retículo Sarcoplasmático
2.
Science ; 377(6606): eabo1984, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35926050

RESUMO

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.


Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Cardiomiopatias/genética , Cardiomiopatia Dilatada/genética , Ventrículos do Coração , Humanos , Transcriptoma
4.
Sci Rep ; 12(1): 13752, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962153

RESUMO

Dilated cardiomyopathy (DCM), one of the most common types of cardiomyopathies has a heterogeneous nature and can be seen in Mendelian forms. Next Generation Sequencing is a powerful tool for identifying novel variants in monogenic disorders. We used whole-exome sequencing (WES) and Sanger sequencing techniques to identify the causative mutation of DCM in an Iranian pedigree. We found a novel variant in the GATA6 gene, leading to substituting Histidine by Tyrosine at position 329, observed in all affected family members in the pedigree, whereas it was not established in any of the unaffected ones. We hypothesized that the H329Y mutation may be causative for the familial pattern of DCM in this family. The predicted models of GATA6 and H329Y showed the high quality according to PROCHECK and ERRAT. Nonetheless, simulation results revealed that the protein stability decreased after mutation, while the flexibility may have been increased. Hence, the mutation led to the increased compactness of GATA6. Overall, these data indicated that the mutation could affect the protein structure, which may be related to the functional impairment of GATA6 upon H329Y mutation, likewise their involvement in pathologies. Further functional investigations would help elucidating the exact mechanism.


Assuntos
Cardiomiopatia Dilatada , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Fator de Transcrição GATA6/genética , Humanos , Irã (Geográfico) , Mutação , Linhagem
5.
Stem Cell Res Ther ; 13(1): 409, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962420

RESUMO

BACKGROUND AND AIMS: The therapeutic efficacy of single-dose mesenchymal stromal cell (MSC) therapy for heart failure (HF) remains inconsistent. This study aimed to investigate whether infusion with two-dose human umbilical cord MSC (hUCMSCs) could be therapeutically superior to single-dose therapy in a rat model of dilated cardiomyopathy (DCM) and explored the underlying mechanisms. METHODS: Male Sprague-Dawley rats were intraperitoneally injected with doxorubicin (DOX) to establish a DCM model and randomized to intravenously receive single-dose or two-dose hUCMSCs at an interval of 14 days. Their left ventricular (LV) systolic and diastolic functions were analyzed by echocardiography. The percentages of Th1, Th2, Th17, and Treg cells in the heart, spleen, lymph nodes, and peripheral blood and the levels of serum cytokines in individual rats were analyzed by flow cytometry and cytometric bead assay, respectively. The degrees of cardiac fibrosis and cardiomyocyte apoptosis were examined by histology. The importance of indoleamine 2,3-dioxygenase (IDO), an activator of Treg differentiation, in the therapeutic effect of hUCMSCs on inflammation and heart function of rats was determined after induction of IDO over-expression (IDO-OE) using IFN-γ (1 ng/ml) and TNF-α (10 ng/ml) stimulation or silencing (IDO-KD) using small interfering RNA (siRNA) technology. RESULTS: Compared with the single dose, two-dose hUCMSCs were more effective in improving LV performance, attenuating cardiac dilation, reducing cardiomyocyte apoptosis and cardiac fibrosis. Two-dose hUCMSC therapy significantly increased Treg number in the heart and peripheral blood, accompanied by increased cardiac IDO expression. Compared with the control hUCMSCs, IDO-OE hUCMSCs significantly enhanced Treg and Th2 cell responses and decreased systemic Th17 cell responses and Th1 cell numbers in the mediastinal lymph nodes. Treatment with IDO-OE hUCMSCs significantly improved LV remodeling and dysfunction. However, treatment with IDO-KD hUCMSCs had opposite effects in rats. CONCLUSIONS: Administration of two-dose hUCMSCs has better therapeutic effects than single-dose therapy for inhibiting myocardial inflammation to improve LV function in DCM rats. These effects are associated with upregulating IDO expression and its systemic anti-inflammatory activities.


Assuntos
Cardiomiopatia Dilatada , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/terapia , Fibrose , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Acta Myol ; 41(2): 59-75, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35832504

RESUMO

Bcl2-associated athanogene 3 (BAG3) is a multifunctional cochaperone responsible for protein quality control within cells. BAG3 interacts with chaperones HSPB8 and Hsp70 to transport misfolded proteins to the Microtubule Organizing Center (MTOC) and degrade them in autophagosomes in a process known as Chaperone Assisted Selective Autophagy (CASA). Mutations in the second conserved IPV motif of BAG3 are known to cause Dilated Cardiomyopathy (DCM) by inhibiting adequate removal of non-native proteins. The proline 209 to leucine (P209L) BAG3 mutant in particular causes the aggregation of BAG3 and misfolded proteins as well as the sequestration of essential chaperones. The exact mechanisms of protein aggregation in DCM are unknown. However, the similar presence of insoluble protein aggregates in Charcot-Marie-Tooth disease type 2 (CMT2) induced by the proline 182 to leucine (P182L) HSPB1 mutant points to a possible avenue for future research: IPV motif. In this review, we summarize the molecular mechanisms of CASA and the currently known pathological effects of mutated BAG3 in DCM. Additionally, we will provide insight on the importance of the IPV motif in protein aggregation by analyzing a potential association between DCM and CMT2.


Assuntos
Cardiomiopatia Dilatada , Doença de Charcot-Marie-Tooth , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatia Dilatada/genética , Doença de Charcot-Marie-Tooth/genética , Humanos , Leucina , Prolina , Agregados Proteicos
7.
BMC Cardiovasc Disord ; 22(1): 320, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35850644

RESUMO

BACKGROUND: The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM. METHODS: We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results. RESULTS: FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments. CONCLUSION: These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.


Assuntos
Cardiomiopatia Dilatada , Animais , Biomarcadores , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Camundongos , RNA-Seq
8.
Sci Rep ; 12(1): 12717, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882913

RESUMO

The left ventricular ejection fraction does not accurately predict exercise capacity or symptom severity and has a limited role in predicting prognosis in heart failure. A better method of assessing ventricular performance is needed to aid understanding of the pathophysiological mechanisms and guide management in conditions such as heart failure. In this study, we propose two novel measures to quantify myocardial performance, the global longitudinal active strain energy (GLASE) and its density (GLASED) and compare them to existing measures in normal and diseased left ventricles. GLASED calculates the work done per unit volume of muscle (energy density) by combining information from myocardial strain and wall stress (contractile force per unit cross sectional area). Magnetic resonance images were obtained from 183 individuals forming four cohorts (normal, hypertension, dilated cardiomyopathy, and cardiac amyloidosis). GLASE and GLASED were compared with the standard ejection fraction, the corrected ejection fraction, myocardial strains, stroke work and myocardial forces. Myocardial shortening was decreased in all disease cohorts. Longitudinal stress was normal in hypertension, increased in dilated cardiomyopathy and severely decreased in amyloid heart disease. GLASE was increased in hypertension. GLASED was mildly reduced in hypertension (1.39 ± 0.65 kJ/m3), moderately reduced in dilated cardiomyopathy (0.86 ± 0.45 kJ/m3) and severely reduced in amyloid heart disease (0.42 ± 0.28 kJ/m3) compared to the control cohort (1.94 ± 0.49 kJ/m3). GLASED progressively decreased in the hypertension, dilated cardiomyopathy and cardiac amyloid cohorts indicating that mechanical work done and systolic performance is severely reduced in cardiac amyloid despite the relatively preserved ejection fraction. GLASED provides a new technique for assessing left ventricular myocardial health and contractile function.


Assuntos
Amiloidose , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Hipertensão , Cardiomiopatia Dilatada/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia
9.
J Am Heart Assoc ; 11(14): e025473, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35861818

RESUMO

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life-threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P-wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter-defibrillator or anti-tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow-up, 4.4 years [2.1; 7.4]). The LTA-free survival distribution significantly differed between IAB or AF versus no IAB (both P<0.01), but not between IAB versus AF (P=0.999). This association remained statistically significant in the multivariable model (IAB: HR, 4.8 (1.4-16.1), P=0.013; AF: HR, 6.4 (1.7-24.0), P=0.007). In the external validation cohort, the survival distribution was also significantly worse for IAB or AF versus no IAB (P=0.037; P=0.005), but not for IAB versus AF (P=0.836). Conclusions IAB is an easy to assess, widely applicable marker associated with LTA in DCM. IAB and AF seem to confer similar risk of LTA. Further research on IAB in DCM, and on the management of IAB in DCM is warranted.


Assuntos
Fibrilação Atrial , Cardiomiopatia Dilatada , Fibrilação Atrial/epidemiologia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/terapia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Eletrocardiografia/métodos , Humanos , Bloqueio Interatrial/complicações , Bloqueio Interatrial/diagnóstico
10.
J Am Heart Assoc ; 11(14): e025935, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35861824

RESUMO

Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.


Assuntos
Sobreviventes de Câncer , Cardiomiopatias , Cardiomiopatia Dilatada , Neoplasias , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Biomarcadores , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Estudos de Casos e Controles , Criança , Humanos , Peptídeo Natriurético Encefálico , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos , Volume Sistólico , Função Ventricular Esquerda
11.
Medicine (Baltimore) ; 101(30): e29180, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35905204

RESUMO

RATIONALE: Cardiac rehabilitation (CR) after heart transplantation (HT) decreases the mortality rate and increases exercise capacity of patients. Dilated cardiomyopathy develops in most patients with muscular dystrophy (MD), leading to advanced heart failure, necessitating the use of left ventricular assist devices or HT. As the clinical outcomes of left ventricular assist devices and HT in patients with myopathy differ from those in patients without myopathy, CR adapted to patients with MD should be considered. PATIENT CONCERNS: A 39-year-old man with limb-girdle muscular dystrophy developed dilated cardiomyopathy and underwent HT. DIAGNOSIS: The patient was diagnosed as having limb-girdle muscular dystrophy in 1997. INTERVENTION: Early CR was performed based on the patient's physical condition and ability. OUTCOMES: With chest physiology, aerobic, and resistance exercises, the patient was able to walk using a walker 28 days after HT. This is important because his lower-extremity strength and walking ability were, to some extent, maintained after surgery. LESSONS: Since an increasing number of patients with MD are undergoing HT, specific CR programs for these patients should be discussed.


Assuntos
Reabilitação Cardíaca , Cardiomiopatia Dilatada , Transplante de Coração , Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Adulto , Transplante de Coração/efeitos adversos , Humanos , Masculino , Distrofia Muscular do Cíngulo dos Membros/diagnóstico
12.
Medicine (Baltimore) ; 101(27): e29330, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35801756

RESUMO

RATIONALE: The treatment of dilated cardiomyopathy (DCM) has recently been greatly improved, especially with the widespread use of sacubitril/valsartan (ARNI) combination therapy. We know that ARNI-like drugs can significantly improve the symptoms of heart failure with reducing ejection fraction. However, clinical studies evaluating the safety and efficacy of ARNI in DCM-associated arrhythmia are limited, and whether individuals with arrhythmia would benefit from ARNI remains controversial. In this case, we report a patient with complete left bundle branch block (CLBBB) associated with DCM whose CLBBB returned to normal after treatment with ARNI. PATIENT CONCERNS: A 38-year-old man was admitted to the hospital for 20 days for idiopathic paroxysmal dyspnea. He presented with exacerbated dyspnea symptoms at night, accompanied by cough and sputum. DIAGNOSIS: Physical examination revealed a grade 4/6 systolic murmur could be heard in the apical area of the heart and mild edema was present in both lower limbs. Laboratory examination found that the B-type natriuretic peptide was significantly increased. Echocardiography indicated left atrial internal diameter, right ventricular internal diameter, and left ventricular diastolic diameter were enlarged and ejection fraction was significantly decreased. Besides, the pulsation of the wall was diffusely attenuated. Electrocardiogram was suggestive of tachycardia and CLBBB. A diagnosis of DCM with CLBBB was considered based on a comprehensive evaluation of the physical examination, laboratory examination, echocardiography and electrocardiogram. INTERVENTIONS: The patient was treated with ARNI at a dose of 50 mg (twice a day) at first, gradually increasing to the target dose (200 mg, twice a day) in the following 9 months as shown in Table 1, along with metoprolol 25 mg (once a day [qd]), diuretics 20 mg (qd), and aldosterone 20 mg (qd). OUTCOMES: After treatment with ARNI during the 9-month follow-up, the patient's symptoms improved, and CLBBB returned to normal. LESSONS: Clinical studies evaluating the safety and efficacy of ARNI in DCM-associated arrhythmia are limited, and whether individuals with arrhythmia would benefit from ARNI remains controversial. This report will help to instruct the clinical treatment of DCM patients with CLBBB and the potential application of ARNI.


Assuntos
Cardiomiopatia Dilatada , Insuficiência Cardíaca , Adulto , Aminobutiratos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Bloqueio de Ramo/induzido quimicamente , Bloqueio de Ramo/complicações , Bloqueio de Ramo/tratamento farmacológico , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/tratamento farmacológico , Combinação de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Volume Sistólico , Tetrazóis/uso terapêutico , Resultado do Tratamento , Valsartana/uso terapêutico
13.
Sci Transl Med ; 14(652): eabl5654, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35857625

RESUMO

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3cKO mice, TYA-018 protected against sarcomere damage and reduced Nppb expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.


Assuntos
Cardiomiopatia Dilatada , Aprendizado Profundo , Insuficiência Cardíaca , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Miócitos Cardíacos/metabolismo , Volume Sistólico , Função Ventricular Esquerda
14.
Basic Res Cardiol ; 117(1): 33, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35776225

RESUMO

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.


Assuntos
Estenose da Valva Aórtica , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Cardiomiopatia Dilatada/genética , Mamíferos , Camundongos , Miócitos Cardíacos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Função Ventricular Esquerda
15.
J Cardiovasc Med (Hagerstown) ; 23(8): 505-512, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35904996

RESUMO

BACKGROUND: Chronic heart valve regurgitation induces left ventricular (LV) volume overload, leading to the development of hypertrophy and progressive dilatation of the ventricle to maintain physiological cardiac output. In order to prevent potential irreversible LV structural changes, the identification of the best timing for treatment is pivotal. OBJECTIVE: To assess the presence and extent of fibrosis in myocardial tissue in asymptomatic patients with valvular heart disease (VHD) and preserved LV dimensions and function undergoing cardiac surgery. METHODS: Thirty-nine patients were enrolled. Sixteen patients were affected by aortic or mitral regurgitation: they were all asymptomatic, undergoing valve surgery according to VHD European Society of Cardiology guidelines. Twenty-three patients with end-stage nonischemic dilated cardiomyopathy (DCM) and severe LV dysfunction undergoing cardiac surgery for implantation of a durable left ventricular assist device (LVAD) served as controls. During surgery, VHD patients underwent three myocardial biopsies at the level of the septum, the lateral wall and LV apex, while in LVAD patients the coring of the apex of the LV was used. For both groups, the tissue samples were analyzed on one section corresponding to the apical area. All slides were stained with hematoxylin and eosin and Masson's trichrome staining and further digitalized. The degree of fibrosis was then calculated as a percentage of the total area. RESULTS: Of 39 patients, 23 met the inclusion criteria: 12 had mitral or aortic insufficiency with a preserved ejection fraction and 11 had idiopathic dilated cardiomyopathy. Quantitative analysis of apical sections revealed a myocardial fibrosis amount of 10 ±â€Š6% in VHD patients, while in LVAD patients the mean apical myocardial fibrosis rate was 38 ±â€Š9%. In VHD patients, fibrosis was also present in the lateral wall (9 ±â€Š4%) and in the septum (9 ±â€Š6%). CONCLUSION: Our case series study highlights the presence of tissue remodeling with fibrosis in asymptomatic patients with VHD and preserved LV function. According to our results, myocardial fibrosis is present at an early stage of the disease, well before developing detectable LV dysfunction and symptoms. Since the relationship between the progressive magnitude of myocardial fibrosis and potential prognostic implications are not yet defined, further studies on this topic are warranted.


Assuntos
Insuficiência da Valva Aórtica , Cardiomiopatias , Cardiomiopatia Dilatada , Doenças das Valvas Cardíacas , Insuficiência da Valva Mitral , Disfunção Ventricular Esquerda , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/cirurgia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/cirurgia , Fibrose , Humanos , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia , Função Ventricular Esquerda
16.
Curr Cardiol Rep ; 24(9): 1077-1084, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35900642

RESUMO

PURPOSE OF REVIEW: The disease burden of inherited dilated cardiomyopathy (DCM) is large and likely underestimated. This population stands to benefit immensely from therapeutic approaches tailored to the underlying genetic causes. Here, we review recent advances in understanding novel genotype-phenotype relationships and how these can improve the care of patients with inherited DCM. RECENT FINDINGS: In the last several years, discovery of novel DCM-associated genes, gene-specific DCM outcomes, and nuanced information about variant-environment interactions have advanced our understanding of inherited DCM. Specifically, novel associations of genes with specific clinical phenotypes can help to assess sudden cardiac death risk and guide counseling around behavioral and environmental exposures that may worsen disease. Important expansions of the current genotype-phenotype profiling include the newly DCM-associated FLNC variant, prognostically significant LMNA, DSP inflammatory cardiomyopathy, and the highly penetrant features of RBM20 variants as well as the role of TTN variants in compounding the effects of environmental factors on toxin-mediated DCM. Future directions to improve diagnostic accuracy and prognostic improvement in DCM will center not just on identification of new genes, but also on understanding the interaction of known and novel variants in known DCM genes with patient genetic background and environment.


Assuntos
Cardiomiopatia Dilatada , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Morte Súbita Cardíaca/etiologia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo , Prognóstico
17.
Med Biol Eng Comput ; 60(9): 2655-2663, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35809191

RESUMO

Diagnosis of etiology in early-stage ischemic heart disease (IHD) and dilated cardiomyopathy (DCM) patients may be challenging. We aimed at investigating, by means of classification and regression tree (CART) modeling, the predictive power of heart rate variability (HRV) features together with clinical parameters to support the diagnosis in the early stage of IHD and DCM. The study included 263 IHD and 181 DCM patients, as well as 689 healthy subjects. A 24 h Holter monitoring was used and linear and non-linear HRV parameters were extracted considering both normal and ectopic beats (heart rate total variability signal). We used a CART algorithm to produce classification models based on HRV together with relevant clinical (age, sex, and left ventricular ejection fraction, LVEF) features. Among HRV parameters, MeanRR, SDNN, pNN50, LF, LF/HF, LFn, FD, Beta exp were selected by the CART algorithm and included in the produced models. The model based on pNN50, FD, sex, age, and LVEF features presented the highest accuracy (73.3%). The proposed approach based on HRV parameters, age, sex, and LVEF features highlighted the possibility to produce clinically interpretable models capable to differentiate IHD, DCM, and healthy subjects with accuracy which is clinically relevant in first steps of the IHD and DCM diagnostic process.


Assuntos
Cardiomiopatia Dilatada , Isquemia Miocárdica , Cardiomiopatia Dilatada/diagnóstico , Frequência Cardíaca/fisiologia , Humanos , Isquemia Miocárdica/diagnóstico , Volume Sistólico , Função Ventricular Esquerda
18.
Nat Commun ; 13(1): 3947, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803927

RESUMO

Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.


Assuntos
Cardiomiopatia Dilatada , Animais , Cardiomiopatia Dilatada/metabolismo , Fumaratos/metabolismo , Camundongos , Dinâmica Mitocondrial/fisiologia , Mitofagia , Miócitos Cardíacos/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
19.
Am J Med Genet A ; 188(9): 2707-2711, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35785415

RESUMO

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D-2-hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D-2-HGA. Murine models have demonstrated how D-2-hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D-2-HGA type I, who was treated with an anthracycline-free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long-term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D-2-HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.


Assuntos
Encefalopatias Metabólicas Congênitas , Cardiomiopatias , Cardiomiopatia Dilatada , Leucemia Mieloide Aguda , Doenças Metabólicas , Anormalidades Urogenitais , Animais , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Cardiomiopatias/complicações , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Criança , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Camundongos , Doenças Raras
20.
Am J Cardiol ; 178: 119-123, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35787339

RESUMO

High-mobility group box protein 1 (HMGB1) is released during tissue damage and activates the innate immune system through toll-like receptor 4. Because mortality in dilated cardiomyopathy (DCM) is associated with activation of the innate immune system, we hypothesized that HMGB1 possesses a prognostic value in estimating mortality in patients with DCM. We determined HMGB1 and N-terminal B-type natriuretic peptide (NT-proBNP) levels in 67 patients with DCM (12 women, mean age 53.6 ± 1.5 years). Kaplan-Meier analyzes revealed that higher levels of HMGB1 and NT-proBNP are related to increased all-cause mortality. Multivariable Cox regression confirmed HMGB1 as a risk factor for mortality in patients with DCM, independent of NT-proBNP, age, and gender (hazard ratio per 1 SD 1.920, 95% confidence interval 1.401 to 2.631, p <0.001). HMGB1 is a promising candidate to estimate the prognosis of patients with DCM.


Assuntos
Cardiomiopatia Dilatada , Proteína HMGB1 , Biomarcadores , Cardiomiopatia Dilatada/complicações , Feminino , Humanos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Prognóstico , Modelos de Riscos Proporcionais
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