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1.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484128

RESUMO

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Assuntos
COVID-19/metabolismo , Cardiomiopatias/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/imunologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação , Gordura Intra-Abdominal/patologia , Obesidade/complicações , Obesidade/imunologia , Obesidade/patologia , Pericárdio , Prognóstico , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
2.
Obstet Gynecol Surv ; 76(8): 485-492, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34449851

RESUMO

Importance: Peripartum cardiomyopathy is a rare form of heart failure due to left ventricular systolic dysfunction that affects women late in pregnancy and the postpartum period. A diagnosis of exclusion, peripartum cardiomyopathy can be difficult to diagnose in the context of the normal physiologic changes of pregnancy and requires a high index of suspicion. Evidence Acquisition: Original research articles, review articles, and guidelines on peripartum cardiomyopathy were reviewed. Results: The etiology of peripartum cardiomyopathy remains poorly defined, but theories include genetic predisposition, as well as myocardial inflammation and angiogenic dysregulation. Risk factors for this condition include hypertensive disorders of pregnancy, Black race, and maternal age older than 30 years. Patients with peripartum cardiomyopathy are at increased risk of acute clinical decompensation, cardiac arrhythmias, thromboembolic complications, and death. Primary treatment modalities include initiation of a medication regimen aimed at the optimization of preload and reduction of afterload. Maternal clinical status is the primary determinant for timing of delivery. Conclusions: Prompt diagnosis and medical management by an interdisciplinary care team are vital for improving outcomes in patients with peripartum cardiomyopathy.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/patologia , Gerenciamento Clínico , Período Periparto , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/patologia , Cardiomiopatias/epidemiologia , Cardiomiopatias/etiologia , Feminino , Humanos , Gravidez , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/etiologia , Prognóstico , Fatores de Risco
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445659

RESUMO

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.


Assuntos
Cardiomiopatias/patologia , Biologia Computacional/métodos , Distrofina/deficiência , Genoma , Proteoma/análise , Transcriptoma , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Humanos
4.
Oxid Med Cell Longev ; 2021: 2989974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457111

RESUMO

In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.


Assuntos
Apoptose , Cardiomiopatias/patologia , Fibronectinas/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Sepse/patologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Fibronectinas/genética , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mitofagia , Miócitos Cardíacos/metabolismo , Ratos , Sepse/etiologia , Sepse/metabolismo
5.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299342

RESUMO

BACKGROUND: Cardiomyopathies are a heterogeneous group of pathologies characterized by structural and functional alterations of the heart. AIMS: The purpose of this narrative review is to focus on the most important cardiomyopathies and their epidemiology, diagnosis, and management. METHODS: Clinical trials were identified by Pubmed until 30 March 2021. The search keywords were "cardiomyopathies, sudden cardiac arrest, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy, arrhythmogenic cardiomyopathy (ARCV), takotsubo syndrome". RESULTS: Hypertrophic cardiomyopathy (HCM) is the most common primary cardiomyopathy, with a prevalence of 1:500 persons. Dilated cardiomyopathy (DCM) has a prevalence of 1:2500 and is the leading indication for heart transplantation. Restrictive cardiomyopathy (RCM) is the least common of the major cardiomyopathies, representing 2% to 5% of cases. Arrhythmogenic cardiomyopathy (ARCV) is a pathology characterized by the substitution of the myocardium by fibrofatty tissue. Takotsubo cardiomyopathy is defined as an abrupt onset of left ventricular dysfunction in response to severe emotional or physiologic stress. CONCLUSION: In particular, it has been reported that HCM is the most important cause of sudden death on the athletic field in the United States. It is needless to say how important it is to know which changes in the heart due to physical activity are normal, and when they are pathological.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/patologia , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Hipertrófica/patologia , Morte Súbita Cardíaca/patologia , Humanos , Miocárdio/patologia
6.
Cell Death Dis ; 12(7): 688, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244467

RESUMO

The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.


Assuntos
Actinas/metabolismo , Cardiomiopatias/prevenção & controle , Fibroblastos/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Angiotensina II , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Infusões Intravenosas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo
7.
Am J Physiol Cell Physiol ; 321(3): C519-C534, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34319827

RESUMO

Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased posttranslational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel cross talk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.


Assuntos
Cardiomiopatias/genética , Proteínas de Transporte de Cátions/genética , Isocitrato Desidrogenase/genética , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/genética , Miócitos Cardíacos/metabolismo , Proteínas de Transporte de Fosfato/genética , Processamento de Proteína Pós-Traducional , Proteínas Carreadoras de Solutos/genética , Acetilação , Animais , Transporte Biológico , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Proteínas de Transporte de Cátions/deficiência , Metabolismo Energético , Feminino , Redes Reguladoras de Genes , Isocitrato Desidrogenase/metabolismo , Masculino , Malonatos/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Proteínas Mitocondriais/deficiência , Modelos Moleculares , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Proteínas de Transporte de Fosfato/deficiência , Fosfatos , Conformação Proteica , Mapeamento de Interação de Proteínas , Transdução de Sinais , Sirtuínas/genética , Sirtuínas/metabolismo , Proteínas Carreadoras de Solutos/deficiência
8.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298968

RESUMO

Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.


Assuntos
Cardiomiopatias/genética , Coração/fisiopatologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Doenças Neuromusculares/genética , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Modelos Animais de Doenças , Metabolismo Energético , Humanos , Camundongos , Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Músculo Esquelético/ultraestrutura , Atrofia Muscular/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patologia , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/patologia , Fenótipo
9.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198873

RESUMO

Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains.


Assuntos
Aterosclerose/genética , Cardiomiopatias/genética , Miocárdio/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/genética , Fosforilação Oxidativa , Glândulas Suprarrenais/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Testículo/metabolismo
10.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207886

RESUMO

Interleukin-1ß (IL-1ß), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.


Assuntos
Infarto Miocárdico de Parede Anterior/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/farmacologia , Animais , Infarto Miocárdico de Parede Anterior/metabolismo , Infarto Miocárdico de Parede Anterior/patologia , Anti-Inflamatórios/farmacologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diástole , Modelos Animais de Doenças , Inflamassomos/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia
11.
FASEB J ; 35(8): e21761, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245616

RESUMO

Uremic cardiomyopathy is a common complication in chronic kidney disease (CKD) patients, accounting for a high mortality rate. Several mechanisms have been proposed to link CKD and cardiac alterations; however, the early cardiac modifications that occur in CKD that may trigger cardiac remodeling and dysfunction remain largely unexplored. Here, in a mouse model of CKD induced by 5/6 nephrectomy, we first analyzed the early transcriptional and inflammatory changes that occur in the heart. Five days after 5/6 nephrectomy, RNA-sequencing showed the upregulation of 54 genes in the cardiac tissue of CKD mice and the enrichment of biological processes related to immune system processes. Increased cardiac infiltration of T-CD4+ lymphocytes, myeloid cells, and macrophages during early CKD was observed. Next, since CC chemokine ligand-8 (CCL8) was one of the most upregulated genes in the heart of mice with early CKD, we investigated the effect of acute and transient CCL8 inhibition on uremic cardiomyopathy severity. An increase in CCL8 protein levels was confirmed in the heart of early CKD mice. CCL8 inhibition attenuated the early infiltration of T-CD4+ lymphocytes and macrophages to the cardiac tissue, leading to a protection against chronic cardiac fibrotic remodeling, inflammation and cardiac dysfunction induced by CKD. Altogether, our data show the occurrence of transcriptional and inflammatory changes in the heart during the early phases of CKD and identify CCL8 as a key contributor to the early cardiac inflammatory state that triggers further cardiac remodeling and dysfunction in uremic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Quimiocina CCL8/biossíntese , Miocárdio/metabolismo , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Uremia/metabolismo , Animais , Cardiomiopatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Miocárdio/patologia , Insuficiência Renal Crônica/patologia , Uremia/patologia
12.
J Pediatr Hematol Oncol ; 43(6): 226-227, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133375

RESUMO

Aspergillosis infection is a major complication of acquired immunosuppression, and is associated with poor prognosis in its invasive form. Cardiac dissemination of invasive aspergillosis is a rare and usually fatal consequence of systemic mycosis. We describe a pediatric case of myocardial aspergillosis abscess in a 12-year-old girl diagnosed with multimodality cardiac imaging approach. The patient underwent prolonged antimycotic treatment and bone marrow transplant, which improved her immunity, and, for the first time in the literature, resulted in a favorable outcome.


Assuntos
Abscesso/etiologia , Aspergilose/complicações , Cardiomiopatias/etiologia , Síndromes de Imunodeficiência/complicações , Miocárdio/patologia , Abscesso/patologia , Aspergilose/patologia , Cardiomiopatias/patologia , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/patologia
13.
Cell Mol Life Sci ; 78(14): 5447-5468, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34091693

RESUMO

Dystrophin is a large protein serving as local scaffolding repetitively bridging cytoskeleton and the outside of striated muscle cell. As such dystrophin is a critical brick primarily in dystrophin-associated protein complex (DAGC) and in a larger submembranous unit, costamere. Accordingly, the lack of functional dystrophin laying at the root of Duchenne muscular dystrophy (DMD) drives sarcolemma instability. From this point on, the cascade inevitably leading to the death of myocyte begins. In cardiomyocytes, intracellular calcium overload and related mitochondrial-mediated cell death mainly contribute to myocardial dysfunction and dilation while other protein dysregulation and/or mislocalization may affect electrical conduction system and favor arrhythmogenesis. Although clinically DMD manifests as progressive muscle weakness and skeletal muscle symptoms define characteristic of DMD, it is the heart problem the biggest challenge that most often develop in the form of dilated cardiomyopathy (DCM). Current standards of treatment and recent progress in respiratory care, introduced in most settings in the 1990s, have improved quality of life and median life expectancy to 4th decade of patient's age. At the same time, cardiac causes of death related to DMD increases. Despite preventive and palliative cardiac treatments available, the prognoses remain poor. Direct therapeutic targeting of dystrophin deficiency is critical, however, hindered by the large size of the dystrophin cDNA and/or stochastic, often extensive genetic changes in DMD gene. The correlation between cardiac involvement and mutations affecting specific dystrophin isoforms, may provide a mutation-specific cardiac management and novel therapeutic approaches for patients with CM. Nonetheless, the successful cardiac treatment poses a big challenge and may require combined therapy to combat dystrophin deficiency and its after-effects (critical in DMD pathogenesis). This review locates the multifaceted heart problem in the course of DMD, balancing the insights into basic science, translational efforts and clinical manifestation of dystrophic heart disease.


Assuntos
Arritmias Cardíacas/patologia , Cardiomiopatias/patologia , Distrofina/metabolismo , Distrofia Muscular de Duchenne/complicações , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Humanos
14.
Curr Hematol Malig Rep ; 16(4): 357-366, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34106429

RESUMO

PURPOSE OF REVIEW: Amyloidosis is a protein deposition disease whereby a variety of precursor proteins form insoluble fibrils that deposit in tissues, causing organ dysfunction and, many times, death. Accurate characterization of the disease based on the nature of the precursor protein, organ involvement, and extent of disease is paramount to guide management. Cardiac amyloidosis is critical to understand because of its impact on prognosis and new treatment options available. RECENT FINDINGS: New imaging methods have proven to be considerably valuable in the identification of cardiac amyloid infiltration. For treating clinicians, a diagnostic algorithm for patients with suspected amyloidosis with or without cardiomyopathy is shown to help classify disease and to direct appropriate genetic testing and management. For patients with light chain disease, recently introduced treatments adopted from multiple myeloma therapies have significantly extended progression-free and overall survival as well as organ response. In addition, new medical interventions are now available for those with transthyretin amyloidosis. Although cardiac amyloidosis contributes significantly to the morbidity and mortality associated with systemic disease, new tools are available to assist with diagnosis, prognosis, and management.


Assuntos
Amiloidose/complicações , Cardiomiopatias/etiologia , Amiloidose/patologia , Cardiomiopatias/patologia , Humanos
15.
Am J Physiol Cell Physiol ; 321(3): C489-C503, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34191626

RESUMO

Mitochondrial transplantation is emerging as a novel cellular biotherapy to alleviate mitochondrial damage and dysfunction. Mitochondria play a crucial role in establishing cellular homeostasis and providing cell with the energy necessary to accomplish its function. Owing to its endosymbiotic origin, mitochondria share many features with their bacterial ancestors. Unlike the nuclear DNA, which is packaged into nucleosomes and protected from adverse environmental effects, mitochondrial DNA are more prone to harsh environmental effects, in particular that of the reactive oxygen species. Mitochondrial damage and dysfunction are implicated in many diseases ranging from metabolic diseases to cardiovascular and neurodegenerative diseases, among others. While it was once thought that transplantation of mitochondria would not be possible due to their semiautonomous nature and reliance on the nucleus, recent advances have shown that it is possible to transplant viable functional intact mitochondria from autologous, allogenic, and xenogeneic sources into different cell types. Moreover, current research suggests that the transplantation could positively modulate bioenergetics and improve disease outcome. Mitochondrial transplantation techniques and consequences of transplantation in cardiomyocytes are the theme of this review. We outline the different mitochondrial isolation and transfer techniques. Finally, we detail the consequences of mitochondrial transplantation in the cardiovascular system, more specifically in the context of cardiomyopathies and ischemia.


Assuntos
Cardiomiopatias/terapia , Diabetes Mellitus Experimental/terapia , Mitocôndrias Cardíacas/transplante , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/terapia , Miócitos Cardíacos/metabolismo , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Fracionamento Celular/métodos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Humanos , Injeções Intralesionais , Mitocôndrias Cardíacas/fisiologia , Mitocôndrias Cardíacas/ultraestrutura , Dinâmica Mitocondrial/fisiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Fosforilação Oxidativa , Coelhos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Suínos
16.
J Physiol Biochem ; 77(3): 365-376, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047925

RESUMO

Myocardial fibrosis (MF) is an inevitable pathological process in the terminal stage of many cardiovascular diseases, often leading to serious cardiac dysfunction and even death. Currently, microRNA-29 (miR-29) is thought to be a novel diagnostic and therapeutic target of MF. Understanding the underlying mechanisms of miR-29 that regulate MF will provide a new direction for MF therapy. In the present review, we concentrate on the underlying signaling pathway of miR-29 affecting MF and the crosstalk regulatory relationship among these pathways to illustrate the complex regulatory network of miR-29 in MF. Additionally, based on our mechanistic understanding, we summarize opportunities and challenges of miR-29-based MF diagnosis and therapy.


Assuntos
Cardiomiopatias , MicroRNAs/fisiologia , Miocárdio , Animais , Biomarcadores/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Fibrose , Humanos , Miocárdio/metabolismo , Miocárdio/patologia
17.
Physiol Rev ; 101(4): 1745-1807, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949876

RESUMO

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.


Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Obesidade/complicações , COVID-19/complicações , COVID-19/mortalidade , Cardiomiopatias/mortalidade , Humanos , Obesidade/etiologia , Obesidade/genética , SARS-CoV-2
18.
Mol Genet Metab ; 133(2): 182-184, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34020866

RESUMO

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Transplante de Coração/métodos , Coração/fisiopatologia , Erros Inatos do Metabolismo/terapia , Adolescente , Adulto , Idade de Início , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/terapia , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos/metabolismo , Humanos , Hiperamonemia/genética , Hiperamonemia/patologia , Hiperamonemia/terapia , Hipoglicemia/genética , Hipoglicemia/patologia , Hipoglicemia/terapia , Recém-Nascido , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Triagem Neonatal , Rabdomiólise/genética , Rabdomiólise/patologia , Rabdomiólise/terapia , Adulto Jovem
19.
Nat Commun ; 12(1): 3142, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035264

RESUMO

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Cardiomiopatias/tratamento farmacológico , Macrófagos/imunologia , Pré-Albumina/antagonistas & inibidores , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Cardiomiopatias/patologia , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Mutação , Miocárdio/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/imunologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Heterólogo
20.
Can J Vet Res ; 85(2): 119-126, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33883819

RESUMO

While heart failure is a primary cause of death for many in-transit-loss (ITL) pigs, the underlying cause of these deaths is not known. Cardiomyopathies are considered a common cause of heart failure in humans and often have a genetic component. The objective of this study was to determine if genes associated with cardiomyopathies could be identified in ITL pigs. Samples from the hearts of pigs that died during transport to an abattoir in Ontario, Canada were collected and genotyped along with samples from pigs that did not die during transport (ILT hearts: n = 149; non-ITL/control hearts: n = 387). Genome-wide analyses were carried out on each of the determined phenotypes (gross cardiac lesions) using a medium density single nucleotide polymorphism (SNP) chip and 500 kb windows/regions for analysis, with 250 kb regions of overlap. The distribution derived by a multidimensional scaling (MDS) analysis of all phenotypes demonstrated a lack of complete separation between phenotypes of affected and unaffected animals, which made diagnosis difficult. Although genetic differences were small, a few genes associated with dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVM) were identified. In addition, multiple genes associated with cardiac arrhythmias and ventricular hypertrophy were identified that can possibly result in heart failure. The results of this preliminary study did not provide convincing evidence that a single, heritable cardiomyopathy is the cause of heart failure in ITL pigs.


Assuntos
Cardiomiopatias/veterinária , Predisposição Genética para Doença , Insuficiência Cardíaca/patologia , Doenças dos Suínos/genética , Transportes , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/genética , Estresse Fisiológico , Suínos , Doenças dos Suínos/patologia
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