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1.
Eur J Heart Fail ; 24(12): 2212-2225, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36161443

RESUMO

AIM: Chronic heart failure (CHF) can be classified as heart failure with preserved ejection fraction (HFpEF) or with reduced ejection fraction (HFrEF). Currently, there is an unmet need for a minimally invasive diagnostic tool for different forms of CHF. We aimed to investigate the diagnostic potential of circulating microRNAs (miRNAs) for the detection of different CHF forms via a systematic review and meta-analysis approach. METHODS AND RESULTS: Comprehensive search on Medline, Web of Science, Scopus, and EMBASE identified 45 relevant studies which were used for qualitative assessment. Out of these, 29 studies were used for qualitative and quantitative assessment and allowed to identify a miRNA panel able to detect HFrEF and HFpEF with areas under the curve (AUC) of 0.86 and 0.79, respectively. A panel of eight miRNAs (hsa-miR-18b-3p, hsa-miR-21-5p, hsa-miR-22-3p, hsa-miR-92b-3p, hsa-miR-129-5p, hsa-miR-320a-5p, hsa-miR-423-5p, and hsa-miR-675-5p) detected HFrEF cases with a sensitivity of 0.85, specificity of 0.88 and AUC of 0.91. A panel of seven miRNAs (hsa-miR-19b-3p, hsa-miR-30c-5p, hsa-miR-206, hsa-miR-221-3p, hsa-miR-328-5p, hsa-miR-375-3p, and hsa-miR-424-5p) identified HFpEF cases with a sensitivity of 0.82 and a specificity of 0.61. CONCLUSIONS: Although conventional biomarkers (N-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide) presented a better performance in detecting CHF patients, the results presented here pointed towards specific miRNA panels with potential additive values to circulating natriuretic peptides in the diagnosis of different classes of CHF. Equally important, miRNAs alone showed a reasonable capacity for 'ruling out' patients with HFrEF or HFpEF. Additional studies with large populations are required to confirm the diagnostic potential of miRNAs for sub-classes of CHF.


Assuntos
Insuficiência Cardíaca , MicroRNAs , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Peptídeo Natriurético Encefálico , Volume Sistólico , MicroRNAs/genética , Biomarcadores
2.
Sci Rep ; 12(1): 3440, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35236899

RESUMO

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is a matter of investigation and its diagnosis remains challenging. Although the mechanisms that are responsible for the development of HFpEF are not fully understood, it is well known that nearly 80% of patients with HFpEF have concomitant hypertension. We investigated whether early biochemical alterations were detectable during HFpEF progression in salt-induced hypertensive rats, using Fourier-transformed infrared (FTIR) and Raman spectroscopic techniques as a new diagnostic approach. Greater protein content and, specifically, greater collagen deposition were observed in the left atrium and right ventricle of hypertensive rats, together with altered metabolism of myocytes. Additionally, Raman spectra indicated a conformational change, or different degree of phosphorylation/methylation, in tyrosine-rich proteins. A correlation was found between tyrosine content and cardiac fibrosis of both right and left ventricles. Microcalcifications were detected in the left and right atria of control animals, with a progressive augmentation from six to 22 weeks. A further increase occurred in the left ventricle and right atrium of 22-week salt-fed animals, and a positive correlation was shown between the mineral deposits and the cardiac size of the left ventricle. Overall, FTIR and Raman techniques proved to be sensitive to early biochemical changes in HFpEF and preceded clinical humoral and imaging markers.


Assuntos
Insuficiência Cardíaca , Hipertensão , Animais , Insuficiência Cardíaca/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Volume Sistólico/fisiologia , Tirosina
3.
J Am Coll Cardiol ; 77(4): 405-419, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33509397

RESUMO

BACKGROUND: Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. OBJECTIVES: This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. METHODS: T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. RESULTS: HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. CONCLUSIONS: Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.


Assuntos
Cálcio/metabolismo , Insuficiência Cardíaca Diastólica/etiologia , Miócitos Cardíacos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Ecocardiografia , Feminino , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/patologia , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia
4.
Hypertension ; 75(5): 1195-1204, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32200677

RESUMO

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP31-67, on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt-Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.


Assuntos
Fator Natriurético Atrial/uso terapêutico , Cardiotônicos/uso terapêutico , Albuminúria/etiologia , Animais , Fator Natriurético Atrial/farmacologia , Remodelamento Atrial/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/etiologia , Cardiomegalia/prevenção & controle , Cardiomegalia/urina , Cardiotônicos/farmacologia , Dinoprostona/urina , Avaliação Pré-Clínica de Medicamentos , Fibrose , Taxa de Filtração Glomerular/efeitos dos fármacos , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Hipertensão/etiologia , Hipertensão/prevenção & controle , Hipertensão/urina , Rim/efeitos dos fármacos , Nefropatias/etiologia , Nefropatias/prevenção & controle , Nefropatias/urina , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Natriurese/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Potássio/urina , Ratos , Ratos Endogâmicos Dahl , Proteína Smad2/metabolismo , Cloreto de Sódio na Dieta/toxicidade , Remodelação Ventricular/efeitos dos fármacos
5.
Sci Rep ; 8(1): 17772, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538258

RESUMO

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.


Assuntos
Cisteína/metabolismo , Metabolismo Energético/fisiologia , Estresse Oxidativo/fisiologia , Animais , Respiração Celular , Tolerância ao Exercício/fisiologia , Malato Desidrogenase/metabolismo , Masculino , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Oxirredução , Condicionamento Físico Animal/fisiologia , Resistência Física/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Ratos , Corrida/fisiologia
6.
Prog Cardiovasc Dis ; 60(1): 130-151, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28666746

RESUMO

A significant body of evidence supports the protective role of exercise training (ET) in cardiovascular diseases, skeletal muscle dystrophies, several types of cancer, Alzheimer disease or even in the recovery of spinal cord injury. In spite of this, the molecular mechanisms underlying the beneficial effects of exercise training are not well understood and remain elusive. Several mechanisms have been proposed in the past, but more recently microRNAs (miRNAs), small non-coding RNA molecules involved in a variety of basic biological processes that negatively modulate gene expression, recognized as important regulatory molecules. In this review, we highlight recent advances on the miRNA involvement in the benefits of ET. Here, we assess the role of microRNAs expressed in the heart, in the skeletal muscle, detected in the circulation (serum and plasma), and in other conditions (e.g., spinal cord injury). Additionally, the long-term effects of diverse ET modalities (e.g., running, cycling, resistance training) in the cardiac miRNA profile are properly addressed.

7.
J Mol Cell Cardiol ; 97: 162-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27192016

RESUMO

Coronary heart disease is the most common cause of death, and the number of individuals at risk is increasing. To better manage this pandemic, improved tool for risk prediction, including more accurate biomarkers are needed. The objective of this study was to assess the utility of circulating microRNAs (miRs) to predict future fatal acute myocardial infarction (AMI) in healthy participants. We performed a prospective nested case-control study with 10-year observation period and fatal AMI as endpoint. In total, 179 miRs were quantified by real-time polymerase chain reaction in serum of 112 healthy participants (40-70years) that either (1) suffered from fatal AMI within 10years [n=56], or (2) remained healthy [n=56, risk factor-matched controls]. Candidate miRs were validated in a separate cohort of healthy individuals (n=100). Twelve miRs were differently expressed in cases and controls in the derivation cohort (p<0.05). Among these, 10 miRs differed significantly between cases and controls in the validation cohort (p<0.05). We identified gender dimorphisms, as miR-424-5p and miR-26a-5p were associated exclusively with risk in men and women, respectively. The best model for predicting future AMI consisted of miR-106a-5p, miR-424-5p, let-7g-5p, miR-144-3p and miR-660-5p, providing 77.6% correct classification for both genders, and 74.1% and 81.8% for men and women, respectively. Adding these 5 miRs to the Framingham Risk Score, increased the AUC from 0.72 to 0.91 (p<0.001). In conclusion, we identified several miRs associated with future AMI, revealed gender-specific associations, and proposed a panel of 5 miRs to enhance AMI risk prediction in healthy individuals.


Assuntos
MicroRNAs/genética , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Idoso , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Razão de Chances , Prognóstico , Curva ROC , Medição de Risco
8.
Annu Int Conf IEEE Eng Med Biol Soc ; 2016: 1397-1400, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28268587

RESUMO

There are a variety of medical imaging modalities available, although each modality focus into different aspects, for example: anatomical, physiological or geometrical information. This paper presents a new imaging modality (3D THERMO-SCAN) that combines anatomical computer tomography (CT) imaging slices, together with 2D infrared thermography images and 3D scanned shaped models of the area under study. Therefore, it is presented the 3D reconstructions involving a case study of a volunteer with bruxism. Some characteristics of bruxism are the hyperactivity of the chewing muscles, which changes the dynamics of microcirculation, also changing the correspondent skin's temperature. The emphasis is to show the corresponding structures, such as jaw/mandibular region that will produce either decrease or increase in temperature, which are related to bruxism and the associated use of an occlusal splint, respectively.


Assuntos
Bruxismo/diagnóstico por imagem , Odontologia/métodos , Imageamento Tridimensional , Mandíbula/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Feminino , Cabeça/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Mastigação , Microcirculação , Modelos Anatômicos , Modelos Teóricos , Músculo Esquelético/diagnóstico por imagem , Placas Oclusais , Temperatura Cutânea , Temperatura
9.
EMBO Mol Med ; 7(9): 1229-43, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26160456

RESUMO

Pathological cardiac hypertrophy is characterized by a shift in metabolic substrate utilization from fatty acids to glucose, but the molecular events underlying the metabolic remodeling remain poorly understood. Here, we investigated the role of liver X receptors (LXRs), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXRα acts to protect the heart against hypertrophy, fibrosis, and dysfunction. Gene expression profiling studies revealed that genes regulating metabolic pathways were differentially expressed in hearts with elevated LXRα. Functionally, LXRα overexpression in isolated cardiomyocytes and murine hearts markedly enhanced the capacity for myocardial glucose uptake following hypertrophic stress. Conversely, this adaptive response was diminished in LXRα-deficient mice. Transcriptional changes induced by LXRα overexpression promoted energy-independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O-GlcNAc modification of GATA4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXRα as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXRα may provide a unique opportunity for intervening in myocyte metabolism.


Assuntos
Cardiomegalia/prevenção & controle , Glucose/metabolismo , Receptores Nucleares Órfãos/metabolismo , Animais , Perfilação da Expressão Gênica , Metabolismo dos Lipídeos , Receptores X do Fígado , Camundongos Transgênicos , Miocárdio/patologia , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/genética
10.
Eur J Heart Fail ; 17(3): 263-72, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25655080

RESUMO

AIMS: Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training. METHODS AND RESULTS: Female Dahl salt-sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low-salt rats, high-salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast-to-slow twitch; fibre atrophy; a decreased pro-oxidative but increased anti-oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti-oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05). CONCLUSION: Our findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.


Assuntos
Diafragma/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/fisiopatologia , Volume Sistólico/fisiologia , Animais , Catalase/metabolismo , Diafragma/metabolismo , Tolerância ao Exercício/fisiologia , Feminino , Insuficiência Cardíaca/metabolismo , Modelos Animais , Músculo Esquelético/metabolismo , Cadeias Leves de Miosina/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos Dahl , Superóxido Dismutase/metabolismo , Troponina C/metabolismo
11.
Virology ; 476: 106-114, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25543961

RESUMO

Here we present the application of our adeno-associated virus (AAV2) vector where transgene expression is driven by a synthetic, p53-responsive promoter, termed PG, used to supply human vascular endothelial growth factor-A165 (VEGF-A). Thus, p53 is harnessed to promote the beneficial expression of VEGF-A encoded by the AAVPG vector, bypassing the negative effect of p53 on HIF-1α which occurs during cardiac hypertrophy. Wistar rats were submitted to pressure overload induced by thoracic aorta coarctation (TAC) with or without concomitant gene therapy (intramuscular delivery in the left ventricle). After 12 weeks, rats receiving AAVPG-VEGF gene therapy were compared to those that did not, revealing significantly improved cardiac function under hemodynamic stress, lack of fibrosis and reversal of capillary rarefaction. With these functional assays, we have demonstrated that application of the AAVPG-VEGF vector under physiologic conditions known to stimulate p53 resulted in the preservation of cardiac performance.


Assuntos
Cardiomegalia/genética , Cardiomegalia/terapia , Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética , Ventrículos do Coração/fisiopatologia , Proteína Supressora de Tumor p53/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Dependovirus/metabolismo , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Ventrículos do Coração/metabolismo , Humanos , Masculino , Ratos , Ratos Wistar , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Basic Res Cardiol ; 109(6): 447, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25344084

RESUMO

UCP3's exact physiological function in lipid handling in skeletal and cardiac muscle remains unknown. Interestingly, etomoxir, a fat oxidation inhibitor and strong inducer of UCP3, is proposed for treating both diabetes and heart failure. We hypothesize that the upregulation of UCP3 upon etomoxir serves to protect mitochondria against lipotoxicity. To evaluate UCP3's role in skeletal muscle (skm) and heart under lipid-challenged conditions, the effect of UCP3 ablation was examined in a state of dysbalance between fat availability and oxidative capacity. Wild type (WT) and UCP3(-/-) mice were subjected to high-fat feeding for 14 days. From day 6 onwards, they were given either saline or etomoxir. Etomoxir treatment induced an increase in markers of lipotoxicity in skm compared to saline. This increase upon etomoxir was similar for both, WT and UCP3(-/-) mice, suggesting that UCP3 does not play a role in protection against lipotoxicity. Interestingly, we observed 25 % mortality in UCP3(-/-)s upon etomoxir administration vs. 11 % in WTs. This increased mortality in UCP3(-/-) compared to WT mice could not be explained by differences in cardiac lipotoxicity, apoptosis, fibrosis (histology, immunohistochemistry), oxidative capacity (respirometry) or function (echocardiography). Electrophysiology demonstrated, however, prolonged QRS and QTc intervals and greater susceptibility to ventricular tachycardia upon programmed electrical stimulation in etomoxir-treated UCP3(-/-)s versus WTs. Isoproterenol administration after pacing resulted in 75 % mortality in UCP3(-/-)s vs. 14 % in WTs. Our results argue against a protective role for UCP3 on skm metabolism under lipid overload, but suggest UCP3 to be crucial in prevention of arrhythmias upon lipid-challenged conditions.


Assuntos
Morte Súbita Cardíaca/etiologia , Canais Iônicos/fisiologia , Mitocôndrias Musculares/fisiologia , Proteínas Mitocondriais/fisiologia , Animais , Canais Iônicos/deficiência , Lipídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Proteínas Mitocondriais/deficiência , Músculo Esquelético/ultraestrutura , Oxirredução , Proteína Desacopladora 3
13.
Nat Cell Biol ; 15(11): 1282-93, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24161931

RESUMO

Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2-dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Insuficiência Cardíaca/metabolismo , MicroRNAs/fisiologia , Fatores de Transcrição NFATC/fisiologia , Animais , Sequência de Bases , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição NFATC/metabolismo , Processamento Pós-Transcricional do RNA , Homologia de Sequência do Ácido Nucleico , Transcrição Gênica
14.
PLoS One ; 8(2): e57800, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23460909

RESUMO

MicroRNAs (miRNAs) are a class of non-coding RNAs of ∼22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3'UTR of protein encoding messenger RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/genética , Miocárdio/metabolismo , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Humanos , MicroRNAs/metabolismo , Miocárdio/patologia
15.
Ann Thorac Surg ; 95(4): 1422-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23434258

RESUMO

BACKGROUND: Traditional pulmonary artery banding (PAB) is not always suitable for mature subpulmonary ventricle retraining. We sought to assess in detail the myocardial morphologic adaptations of two different protocols for inducing right ventricular (RV) hypertrophy in an adult animal model. METHODS: Eighteen adult goats were distributed into three groups: sham (no systolic overload), traditional (continuous systolic overload), and intermittent (daily 12-hour systolic overload). Systolic overload was adjusted to achieve a 0.7 RV-to-aortic pressure ratio. All animals underwent weekly echocardiographic studies, and hemodynamic evaluations were performed 3 times a week. After 4 weeks, the animals were humanely killed for morphologic assessment. RESULTS: A 37.2% increase was observed in the RV wall thickness of the intermittent group (p<0.05), but no significant echocardiographic changes were observed in the other two groups. The intermittent and traditional groups had a 55.7% and 36.7% increase in RV mass, respectively, compared with the sham group (p<0.05). No differences were observed in myocardial water content of the three groups (p=0.27). RV myocardial fiber and nuclei diameters were increased in the intermittent group compared with the sham group (p<0.05). The area of collagen deposition in the RV interstitium was increased 98% in traditional group compared with the sham group (p<0.05). No significant cellular proliferation occurred in any group. CONCLUSIONS: This study suggests that a more effective and harmless hypertrophy can be achieved in adult animals using intermittent PAB compared with the traditional approach.


Assuntos
Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/terapia , Artéria Pulmonar/cirurgia , Função Ventricular Direita/fisiologia , Pressão Ventricular , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Ecocardiografia , Cabras , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Ligadura , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Resultado do Tratamento
16.
J Thorac Cardiovasc Surg ; 145(5): 1345-1351.e4, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22925567

RESUMO

BACKGROUND: Ventricle retraining with abrupt systolic overload can cause myocardial edema and necrosis, followed by late ventricular failure. Intermittent systolic overload could minimize the inadequacy of conventional pulmonary artery banding. The present study compared ventricle function under dobutamine stress in 2 protocols of systolic overload in young goats. METHODS: Nineteen young goats were divided into 3 groups: sham (n = 7; no systolic pressure overload), continuous (n = 6; systolic overload maintained for 96 hours), and intermittent (n = 6; 4 periods of 12-hour systolic overload, paired with a 12-hour resting period). Echocardiographic and hemodynamic evaluations were performed daily. The myocardial performance index and ejection fraction were evaluated at rest and during dobutamine stress. The goats were then killed for morphologic evaluation. RESULTS: The intermittent group underwent less systolic overload than the continuous group (P < .05). Nevertheless, both groups had increased right ventricular and septal masses compared with the sham group (P < .0002). Echocardiography revealed a major increase in right ventricular wall thickness in the intermittent group (+64.8% ± 23.37%) compared with the continuous group (+43.9% ± 19.26%; P = .015). Only the continuous group remained with significant right ventricular dilation throughout the protocol (P < .001). The intermittent group had a significantly better myocardial performance index at the end of the protocol, under resting and dobutamine infusion, compared with the continuous group (P < .012). CONCLUSIONS: Both systolic overload protocols have induced rapid right ventricular hypertrophy. However, only the intermittent group had better preservation of right ventricular function at the end of the protocol, both at rest and during dobutamine infusion.


Assuntos
Ecocardiografia sob Estresse , Hipertrofia Ventricular Direita/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Animais , Constrição , Modelos Animais de Doenças , Edema Cardíaco/diagnóstico por imagem , Edema Cardíaco/etiologia , Cabras , Hemodinâmica , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Contração Miocárdica , Artéria Pulmonar/fisiopatologia , Fatores de Tempo , Função Ventricular Direita , Pressão Ventricular
17.
J Thorac Cardiovasc Surg ; 142(5): 1108-13, 1113.e1, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21907360

RESUMO

OBJECTIVE: Increased myocardial glucose-6-phosphate dehydrogenase (G6PD) activity occurs in heart failure. This study compared G6PD activity in 2 protocols of right ventricle (RV) systolic overload in young goats. METHODS: Twenty-seven goats were separated into 3 groups: sham (no overload), continuous (continuous systolic overload), and intermittent (four 12-hour periods of systolic overload paired with a 12-hour resting period). During a 96-hour protocol, systolic overload was adjusted to achieve a 0.7 RV/aortic pressure ratio. Echocardiographic and hemodynamic evaluations were performed before and after systolic overload every day postoperatively. After the study period, the animals were humanely killed for morphologic and G6PD tissue activity assessment. RESULTS: A 92.1% and 46.5% increase occurred in RV and septal mass, respectively, in the intermittent group compared with the sham group; continuous systolic overload resulted in a 37.2% increase in septal mass. A worsening RV myocardial performance index occurred in the continuous group at 72 hours and 96 hours, compared with the sham (P < .039) and intermittent groups at the end of the protocol (P < .001). Compared with the sham group, RV G6PD activity was elevated 130.1% in the continuous group (P = .012) and 39.8% in the intermittent group (P = .764). CONCLUSIONS: Continuous systolic overload for ventricle retraining causes RV dysfunction and upregulation of myocardial G6PD activity, which can elevate levels of free radicals by NADPH oxidase, an important mechanism in the pathophysiology of heart failure. Intermittent systolic overload promotes a more efficient RV hypertrophy, with better preservation of myocardial performance and and less exposure to hypertrophic triggers.


Assuntos
Glucosefosfato Desidrogenase/metabolismo , Hipertrofia Ventricular Direita/enzimologia , Miocárdio/enzimologia , Artéria Pulmonar/cirurgia , Disfunção Ventricular Direita/enzimologia , Fatores Etários , Animais , Aorta/fisiopatologia , Pressão Sanguínea , Modelos Animais de Doenças , Metabolismo Energético , Cabras , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Ligadura , Miocárdio/patologia , Fatores de Tempo , Ultrassonografia , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Pressão Ventricular , Remodelação Ventricular
18.
Arq. bras. cardiol ; 95(3): 364-372, set. 2010. ilus, graf, tab
Artigo em Português | LILACS | ID: lil-560559

RESUMO

FUNDAMENTO: A transposição corrigida das grandes artérias frequentemente evolui com disfunção ventricular direita. O preparo ventricular para a correção anatômica em pacientes adultos apresenta resultados desapontadores. OBJETIVO: Analisar a hipertrofia do ventrículo direito (VD) induzida por dois tipos de bandagem pulmonar (BP), convencional e intermitente em animais adultos. MÉTODOS: Dezenove cabras adultas foram divididas em três grupos: Convencional (seis animais), Intermitente (seis animais) e Controle (sete animais). O grupo Convencional foi submetido à BP fixa com fita cardíaca, enquanto no grupo Intermitente foi usado dispositivo de BP ajustável, que gerava sobrecarga sistólica por 12 horas, alternada com 12 horas de descanso do VD. As pressões de VD, tronco pulmonar e aorta foram medidas durante todo o estudo. Ecocardiograma foi realizado semanalmente. Após quatro semanas, os animais foram eutanasiados para avaliação morfológica dos ventrículos. O grupo Controle foi submetido a eutanásia para análise em condições basais. RESULTADOS: A sobrecarga pressórica foi menor no grupo Intermitente (p=0,001), comparada ao grupo Convencional. Houve aumento na espessura do VD do grupo Intermitente, medida pelo ecocardiograma, comparado ao seu momento basal (p<0,05). O índice de performance miocárdica do VD foi melhor no grupo Intermitente (p=0,024), comparado ao Convencional. Os grupos estimulados apresentaram aumento da massa muscular em comparação ao grupo Controle (p=0,001). Não houve diferença no conteúdo de água miocárdica. CONCLUSÃO: A BP intermitente desenvolveu hipertrofia de melhor desempenho funcional, sugerindo este protocolo como método preferencial de preparo ventricular.


BACKGROUND: Corrected transposition of great arteries often evolves with right ventricular dysfunction. The ventricular preparation for anatomic correction in adult patients has produced disappointing results. OBJECTIVE: To assess right ventricular hypertrophy (RV) induced by conventional and intermittent pulmonary banding (PB) in adult animals. METHODS: Nineteen adult goats were divided into three groups: conventional (six animals), intermittent (six animals) and control (seven animals). The Conventional group underwent fixed PB with cardiac tape, while the intermittent group received PB adjustable device, which generated systolic overload for 12 hours, alternated with 12 hours of rest of RV. The pressures of the RV, pulmonary artery and aorta were measured throughout the study. Echocardiography was performed weekly. After four weeks, the animals were euthanized for morphological evaluation of the ventricles. The Control group was put to euthanasia for analysis at baseline. RESULTS: Pressure overload was lower in the intermittent group (p = 0.001), compared to the conventional group. There was an increase in the thickness of the RV of the Intermittent group measured by echocardiography compared to their baseline values (p < 0.05). The myocardial performance index in the RV group was better in the Intermittent group (p = 0.024), compared to the Conventional group. The groups stimulated showed increased muscle mass compared to the Control group (p = 0.001). There was no difference in myocardial water content. CONCLUSION: The intermittent BP developed hypertrophy of better performance, suggesting this protocol as the preferred method of ventricular preparation.


FUNDAMENTO: La transposición corregida de las grandes arterias frecuentemente evoluciona con disfunción ventricular derecha. La preparación ventricular para la corrección anatómica en pacientes adultos presenta resultados desalentadores. OBJETIVO: Analizar la hipertrofia del ventrículo derecho (VD) inducida por dos tipos de vendaje pulmonar (VP), convencional e intermitente en animales adultos. MÉTODOS: Diecinueve cabras adultas fueron divididas en tres grupos: Convencional (seis animales), Intermitente (seis animales) y Control (siete animales). El grupo Convencional fue sometido al VP fijo con cinta cardíaca, mientras que en el grupo Intermitente fue usado dispositivo de VP ajustable, que generaba sobrecarga sistólica por 12 horas, alternada con 12 horas de descanso del VD. Las presiones de VD, tronco pulmonar y aorta fueron medidas durante todo el estudio. Ecocardiograma fue realizado semanalmente. Después de cuatro semanas, los animales fueron eutanasiados para evaluación morfológica de los ventrículos. El grupo Control fue sometido a eutanasia para análisis en condiciones basales. RESULTADOS: La sobrecarga presórica fue menor en el grupo Intermitente (p=0,001), comparada al grupo Convencional. Hubo aumento en el espesor del VD del grupo Intermitente, medida por el ecocardiograma, comparado a su momento basal (p<0,05). El índice de performance miocárdica del VD fue mejor en el grupo Intermitente (p=0,024), comparado al Convencional. Los grupos estimulados presentaron aumento de la masa muscular en comparación al grupo Control (p=0,001). No hubo diferencia en el contenido de agua miocárdica. CONCLUSIÓN: EL VP intermitente desarrolló hipertrofia de mejor desempeño funcional, sugiriendo este protocolo como método preferencial de preparación ventricular.


Assuntos
Animais , Feminino , Hemodinâmica/fisiologia , Hipertrofia Ventricular Direita/patologia , Artéria Pulmonar/fisiopatologia , Constrição , Cabras , Hipertrofia Ventricular Direita/fisiopatologia , Modelos Animais , Cuidados Pré-Operatórios/métodos , Distribuição Aleatória , Sístole/fisiologia , Transposição dos Grandes Vasos/cirurgia
19.
Arq Bras Cardiol ; 95(3): 364-72, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20721519

RESUMO

BACKGROUND: Corrected transposition of great arteries often evolves with right ventricular dysfunction. The ventricular preparation for anatomic correction in adult patients has produced disappointing results. OBJECTIVE: To assess right ventricular hypertrophy (RV) induced by conventional and intermittent pulmonary banding (PB) in adult animals. METHODS: Nineteen adult goats were divided into three groups: conventional (six animals), intermittent (six animals) and control (seven animals). The Conventional group underwent fixed PB with cardiac tape, while the intermittent group received PB adjustable device, which generated systolic overload for 12 hours, alternated with 12 hours of rest of RV. The pressures of the RV, pulmonary artery and aorta were measured throughout the study. Echocardiography was performed weekly. After four weeks, the animals were euthanized for morphological evaluation of the ventricles. The Control group was put to euthanasia for analysis at baseline. RESULTS: Pressure overload was lower in the intermittent group (p = 0.001), compared to the conventional group. There was an increase in the thickness of the RV of the Intermittent group measured by echocardiography compared to their baseline values (p < 0.05). The myocardial performance index in the RV group was better in the Intermittent group (p = 0.024), compared to the Conventional group. The groups stimulated showed increased muscle mass compared to the Control group (p = 0.001). There was no difference in myocardial water content. CONCLUSION: The intermittent BP developed hypertrophy of better performance, suggesting this protocol as the preferred method of ventricular preparation.


Assuntos
Hemodinâmica/fisiologia , Hipertrofia Ventricular Direita/patologia , Artéria Pulmonar/fisiopatologia , Animais , Constrição , Feminino , Cabras , Hipertrofia Ventricular Direita/fisiopatologia , Modelos Animais , Cuidados Pré-Operatórios/métodos , Distribuição Aleatória , Sístole/fisiologia , Transposição dos Grandes Vasos/cirurgia
20.
Clin Exp Pharmacol Physiol ; 37(4): 490-5, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19930431

RESUMO

1. Clinical and experimental evidence highlights the importance of the renin-angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin-converting enzyme (ACE) could influence the development of renovascular hypertension. 2. To test the effect of small gene perturbations on the development of renovascular hypertension, mice harbouring two or three copies of the Ace gene were submitted to 4 weeks of two-kidney, one-clip (2K1C) hypertension. Blood pressure (BP), cardiac hypertrophy, baroreflex sensitivity and blood pressure and heart rate variability were assessed and compared between the different groups. 3. The increase in BP induced by 2K1C was higher in mice with three copies of the Ace gene compared with mice with only two copies (46 vs 23 mmHg, respectively). Moreover, there was a 3.8-fold increase in the slope of the left ventricle mass/BP relationship in mice with three copies of the Ace gene. Micewith three copies of the Ace gene exhibited greater increases in cardiac and serum ACE activity than mice with only two copies of the gene. Both baroreflex bradycardia and tachycardia were significantly depressed in mice with three copies of the Ace gene after induction of 2K1C hypertension. The variance in basal systolic BP was greater in mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two copies of the gene (106 vs 54%, respectively). In addition, the low-frequency component of the pulse interval was higher mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two (168 vs 86%, respectively). Finally, in mice with three copies of the Ace gene, renovascular hypertension induced a 6.1-fold increase in the sympathovagal balance compared with a 3.2-fold increase in mice with only two copies of the gene. 4. Collectively, these data provide direct evidence that small genetic disturbances in ACE levels per se have an influence on haemodynamic, cardiac mass and autonomic nervous system responses in mice under pathological perturbation.


Assuntos
Dosagem de Genes , Predisposição Genética para Doença , Hipertensão Renovascular/genética , Peptidil Dipeptidase A/genética , Animais , Animais Geneticamente Modificados , Arritmias Cardíacas/genética , Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/genética , Pressão Sanguínea/genética , Estudos de Associação Genética , Coração/fisiopatologia , Hemodinâmica/genética , Hipertensão Renovascular/sangue , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Pulmão/enzimologia , Masculino , Camundongos , Miocárdio/enzimologia , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/metabolismo , Índice de Gravidade de Doença , Sistema Nervoso Simpático/fisiopatologia , Nervo Vago/fisiopatologia
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