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1.
Anticancer Res ; 41(11): 5355-5364, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732405

RESUMO

Cardiotoxicity is a common side effect induced by cancer therapies, which increases the risk of long-term morbidity and mortality in cancer survivors. To date, the mechanism leading to this toxicity is still unclear, thus complicating cardiac safety assessment and predictive factor identification. The advances in technology, particularly regarding radiation therapy and constant development of novel antineoplastic agents, require urgent development of efficient preclinical models to detect drug cardiotoxicity. A myriad of empirical preclinical models have been used to investigate cardiotoxicity, though with limited success. Recently, multicellular spheroid models have gained attention by mimicking the in vivo microenvironment. The aim of this review is to focus on the most relevant preclinical models used to assess antineoplastic drug- and radiotherapy-related cardiotoxicities, with an overview on their current use. It also aims to discuss the possible directions of translational research in the cardio-oncology field.


Assuntos
Antineoplásicos , Cardiopatias/induzido quimicamente , Lesões por Radiação/etiologia , Pesquisa Médica Translacional , Animais , Técnicas Biossensoriais , Cardiotoxicidade , Linhagem Celular , Técnicas de Cocultura , Modelos Animais de Doenças , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Lesões por Radiação/fisiopatologia , Radioterapia , Fatores de Risco , Especificidade da Espécie , Microambiente Tumoral
2.
Anticancer Res ; 41(10): 5241-5247, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593477

RESUMO

AIM: To clarify the clinical and radiological features of isolated tumor thrombi in the inferior vena cava (IVC)/right atrium in patients with hepatocellular carcinoma (HCC) without hepatic vein invasion. PATIENTS AND METHODS: In this retrospective study, from January 2007 to December 2019, a total of 35,163 chemoembolization sessions were performed in 7,704 patients with HCC. Among them, 10 (0.13%) patients had tumor thrombi in the IVC/right atrium without definitive hepatic vein invasion. Computed tomographic (CT) scans, digital subtraction angiograms, and cone-beam CT images were retrospectively reviewed and interpreted. RESULTS: The tumor thrombi were supplied by the right inferior phrenic artery (n=8) or the right internal mammary artery (n=2). Follow-up CT scans in eight patients showed linear accumulation of iodized oil along the diaphragm, which was presumed to be a thrombosis of the phrenic vein. Retrospective review of formal radiological reports of pre-procedural CT scans revealed that a correct diagnosis of tumor thrombi of the IVC/right atrium was made in only three cases. CONCLUSION: HCC invading the phrenic vein may have tumor thrombi in the IVC/right atrium without hepatic vein invasion.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/mortalidade , Átrios do Coração/patologia , Cardiopatias/terapia , Veias Hepáticas/patologia , Trombose/terapia , Veia Cava Inferior/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Feminino , Seguimentos , Cardiopatias/etiologia , Cardiopatias/patologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trombose/etiologia , Trombose/patologia
3.
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
4.
Int Heart J ; 62(5): 1096-1105, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34544982

RESUMO

While cardiac imaging has improved the diagnosis and risk assessment for cardiac sarcoidosis (CS), treatment regimens have consisted of generalized heart failure therapies and non-specific anti-inflammatory regimens. The overall goal of this study was to perform high-sensitivity plasma profiling of specific inflammatory pathways in patients with sarcoidosis and with CS.Specific inflammatory/proteolytic cascades were upregulated in sarcoidosis patients, and certain profiles emerged for CS patients.Plasma samples were collected from patients with biopsy-confirmed sarcoidosis undergoing F-18 fluorodeoxyglucose positron emission tomography (n = 47) and compared to those of referent control subjects (n = 6). Using a high-sensitivity, automated multiplex array, cytokines, soluble cytokine receptor profiles (an index of cytokine activation), as well as matrix metalloproteinase (MMP), and endogenous MMP inhibitors (TIMPs) were examined.The plasma tumor necrosis factor (TNF) and soluble TNF receptors sCD30 and sTNFRI were increased using sarcoidosis, and sTNFRII increased in CS patients (n = 18). The soluble interleukin sIL-2R and vascular endothelial growth factor receptors (sVEGFR2 and sVEGFR3) increased to the greatest degree in CS patients. When computed as a function of referent control values, the majority of soluble cytokine receptors increased in both sarcoidosis and CS groups. Plasma MMP-9 levels increased in sarcoidosis but not in the CS subset. Plasma TIMP levels declined in both groups.The findings from this study were the identification of increased activation of a cluster of soluble cytokine receptors, which augment not only inflammatory cell maturation but also transmigration in patients with sarcoidosis and patients with cardiac involvement.


Assuntos
Citocinas/metabolismo , Cardiopatias/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Sarcoidose/diagnóstico , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos de Avaliação como Assunto , Feminino , Fluordesoxiglucose F18/administração & dosagem , Cardiopatias/sangue , Cardiopatias/complicações , Cardiopatias/patologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Inflamação/metabolismo , Masculino , Inibidores de Metaloproteinases de Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de Interleucina-2/metabolismo , Receptores do Fator de Necrose Tumoral/sangue , Medição de Risco , Sarcoidose/sangue , Sarcoidose/complicações , Sarcoidose/patologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
BMC Genomics ; 22(1): 641, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34481466

RESUMO

BACKGROUND: Stroke can induce cardiac dysfunction in the absence of primary cardiac disease; however, the mechanisms underlying the interaction between the neurological deficits and the heart are poorly understood. The objective of this study was to investigate the effects of stroke on cardiac function and to identify the transcriptome characteristics of the heart. RESULTS: Stroke significantly decreased heart weight/tibia length ratio and cardiomyocyte cross-sectional areas and increased atrogin-1 and the E3 ubiquitin ligase MuRF-1, indicating myocardial atrophy in MCAO-induced mouse hearts. RNA sequencing of mRNA revealed 383 differentially expressed genes (DEGs) in MCAO myocardium, of which 221 were downregulated and 162 upregulated. Grouping of DEGs based on biological function and quantitative PCR validation indicated that suppressed immune response and collagen synthesis and altered activity of oxidoreductase, peptidase, and endopeptidase may be involved in MCAO-induced cardiomyopathy. The DEGs were mainly distributed in the membrane or extracellular region of cardiomyocytes and acted as potential mediators of stroke-induced cardiac dysregulation involved in cardiac atrophy. CONCLUSION: Stroke induced a unique transcriptome response in the myocardium and resulted in immediate cardiac atrophy and dysfunction.


Assuntos
Isquemia Encefálica , Cardiopatias , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/patologia , Cardiopatias/patologia , Camundongos , Atrofia Muscular , Miócitos Cardíacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Transcriptoma
6.
Anesth Analg ; 133(4): 1048-1059, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524989

RESUMO

BACKGROUND: Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cardiopatias/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Bupivacaína , Cardiotoxicidade , Linhagem Celular , Dano ao DNA , Modelos Animais de Doenças , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/patologia , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais
7.
Arterioscler Thromb Vasc Biol ; 41(11): 2648-2660, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34587760

RESUMO

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.


Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiopatias/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Cardiotoxicidade , Dano ao DNA , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Humanos , Terapia de Alvo Molecular/efeitos adversos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Medição de Risco , Fatores de Risco , Transdução de Sinais
8.
Infect Genet Evol ; 95: 105092, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34571275

RESUMO

OBJECTIVES: To compare the demographics, clinical characteristics and severity of patients infected with nine different SARS-CoV-2 variants, during three phases of the COVID-19 epidemic in Marseille. METHODS: A single centre retrospective cohort study was conducted in 1760 patients infected with SARS-CoV-2 of Nextstrain clades 20A, 20B, and 20C (first phase, February-May 2020), Pangolin lineages B.1.177 (we named Marseille-2) and B.1.160 (Marseille-4) variants (second phase, June-December 2020), and B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and A.27 (Marseille-501) variants (third phase, January 2021-today). Outcomes were the occurrence of clinical failures, including hospitalisation, transfer to the intensive-care unit, and death. RESULTS: During each phase, no major differences were observed with regards to age and gender distribution, the prevalence of chronic diseases, and clinical symptoms between variants circulating in a given phase. The B.1.177 and B.1.160 variants were associated with more severe outcomes. Infections occurring during the second phase were associated with a higher rate of death as compared to infections during the first and third phases. Patients in the second phase were more likely to be hospitalised than those in the third phase. Patients infected during the third phase were more frequently obese than others. CONCLUSION: A large cohort study is recommended to evaluate the transmissibility and to better characterise the clinical severity of emerging variants.


Assuntos
COVID-19/patologia , Diabetes Mellitus/patologia , Genoma Viral , Hipertensão/patologia , Obesidade/patologia , SARS-CoV-2/patogenicidade , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/mortalidade , COVID-19/virologia , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/mortalidade , Diabetes Mellitus/virologia , Feminino , França/epidemiologia , Genótipo , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Cardiopatias/patologia , Cardiopatias/virologia , Hospitalização/estatística & dados numéricos , Hospitais , Humanos , Hipertensão/epidemiologia , Hipertensão/mortalidade , Hipertensão/virologia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Neoplasias/patologia , Neoplasias/virologia , Obesidade/epidemiologia , Obesidade/mortalidade , Obesidade/virologia , Filogenia , Estudos Retrospectivos , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Análise de Sequência de RNA , Índice de Gravidade de Doença , Análise de Sobrevida
9.
PLoS One ; 16(9): e0257617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34551003

RESUMO

BACKGROUND: Hypertension and its consequent end-organ damage including Hypertensive Heart Disease (HHD) are a major concern that impact health, resulting into impairment and reduced quality of life (QOL). The purpose of this study was to describe the burden of HHD in Iran and comparing it with the World Bank upper middle-income countries (UMICs) in terms of disability-adjusted life years (DALY), mortality and prevalence. METHODS: Using data from the Global Burden of Disease study 2017, we compared the number of DALYs, deaths and prevalence trends for HHD from 1990 to 2017 in all age groups for both sex in Iran, and compared the epidemiology and trends with UMICs and globally. RESULTS: The age-standardized DALY rate for HHD increased by 51.6% for men (95% uncertainty interval [UI] 305.8 to 436.7 per 100,000) and 4.4% for women (95% UI 429.4 to 448.7 per 100,000) in Iran. The age-standardized prevalence of HHD in Iran was almost twice times higher than globally and 1.5-times more than the World Bank UMICs. The age-standardized death rate for HDD increased by 60.1% (95% UI 17.3 to 27.7% per 100,000) for men and by 21.7% (95% UI 25.85 to 31.48 per 100,000) for women from 1990 to 2017. Age-standardized death rate in Iran was 2.4 and 1.9 times higher than globally and UMICs, respectively. CONCLUSIONS: The higher prevalence and death rate in Iran in comparison with UMICs and globally should encourage health care provider to perform intensive screening activities in at risk population to prevent HHD and mitigate its mortality.


Assuntos
Carga Global da Doença , Cardiopatias/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Cardiopatias/patologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Análise de Sobrevida
10.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360531

RESUMO

Cardiac diseases such as myocardial infarction (MI) can lead to adverse remodeling and impaired contractility of the heart due to widespread cardiomyocyte death in the damaged area. Current therapies focus on improving heart contractility and minimizing fibrosis with modest cardiac regeneration, but MI patients can still progress to heart failure (HF). There is a dire need for clinical therapies that can replace the lost myocardium, specifically by the induction of new myocyte formation from pre-existing cardiomyocytes. Many studies have shown terminally differentiated myocytes can re-enter the cell cycle and divide through manipulations of the cardiomyocyte cell cycle, signaling pathways, endogenous genes, and environmental factors. However, these approaches result in minimal myocyte renewal or cardiomegaly due to hyperactivation of cardiomyocyte proliferation. Finding the optimal treatment that will replenish cardiomyocyte numbers without causing tumorigenesis is a major challenge in the field. Another controversy is the inability to clearly define cardiomyocyte division versus myocyte DNA synthesis due to limited methods. In this review, we discuss several studies that induced cardiomyocyte cell cycle re-entry after cardiac injury, highlight whether cardiomyocytes completed cytokinesis, and address both limitations and methodological advances made to identify new myocyte formation.


Assuntos
Proliferação de Células , Cardiopatias/patologia , Coração/fisiologia , Miócitos Cardíacos/citologia , Animais , Diferenciação Celular , Humanos
11.
Eur J Med Res ; 26(1): 90, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376255

RESUMO

BACKGROUND: The goal of this study was to investigate the diagnostic value of miR-29c-3p in sepsis and its role in sepsis-induced inflammatory response and cardiac dysfunction. METHODS: Serum level of miR-29c-3p was detected by qRT-PCR. The ROC curve was used to evaluate the diagnostic value of miR-29c-3p for Sepsis. The cecal ligation and puncture method (CLP) was used to establish a rat sepsis model. To assess cardiac function, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (± dp/dtmax) in different experimental groups were detected, and the serum cardiac troponin I (cTnI), creative kinase isoenzyme MB (CK-MB) were measured by ELISA. Meanwhile, TNF-α, IL-1ß, and IL-6 were detected by ELISA to assess the level of inflammatory response in animals. RESULTS: miR-29c-3p level was upregulated in sepsis patients. ROC curve revealed that miR-29c-3p had the ability to distinguish sepsis patients from healthy controls. Cardiac dysfunction and inflammation were observed in sepsis rat, which were characterized by the decrease of LVSP and + dp/dtmax, the increase of LVEDP, - dp/dtmax, cTnI, CK-MB, TNF-α, IL-1ß, IL-6. All effects were reversed by the injection of miR-29c-3p antagomir. Logistics regression analysis manifested miR-29c-3p is an independent factor in the occurrence of cardiac dysfunction in sepsis patients. CONCLUSIONS: miR-29c-3p has potential as a biomarker for the diagnosis of sepsis, and inhibition of miR-29c-3p expression in animal models reduced sepsis-induced cardiac dysfunction and inflammatory response.


Assuntos
Cardiopatias/sangue , MicroRNAs/sangue , Sepse/sangue , Idoso , Animais , Biomarcadores/sangue , Pressão Sanguínea , Citocinas/sangue , Feminino , Cardiopatias/etiologia , Cardiopatias/patologia , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/patologia , Troponina I/sangue
12.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445174

RESUMO

In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.


Assuntos
Trifosfato de Adenosina/metabolismo , Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Cardiopatias/metabolismo , Mitocôndrias Cardíacas/metabolismo , Peixe-Zebra , Animais , Carnitina/metabolismo , Modelos Animais de Doenças , Coração/fisiopatologia , Cardiopatias/patologia , Humanos , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia
13.
Cells ; 10(7)2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34359851

RESUMO

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.


Assuntos
Cardiopatias/imunologia , Leucócitos/imunologia , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Cardiomegalia/imunologia , Cardiomegalia/patologia , Cardiopatias/patologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Humanos
14.
Biochem Pharmacol ; 192: 114746, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461117

RESUMO

Long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are genetic diseases of the heart caused by mutations in specific cardiac ion channels and are characterized by paroxysmal arrhythmias, which can deteriorate into ventricular fibrillation. In LQTS3 and BrS different mutations in the SCN5A gene lead to a gain-or a loss-of-function of the voltage-gated sodium channel Nav1.5, respectively. Although sharing the same gene mutation, these syndromes are characterized by different clinical manifestations and functional perturbations and in some cases even present an overlapping clinical phenotype. Several studies have shown that Na+ current abnormalities in LQTS3 and BrS can also cause Ca2+-signaling aberrancies in cardiomyocytes (CMs). Abnormal Ca2+ homeostasis is also the main feature of CPVT which is mostly caused by heterozygous mutations in the RyR2 gene. Large numbers of disease-causing mutations were identified in RyR2 and SCN5A but it is not clear how different variants in the SCN5A gene produce different clinical syndromes and if in CPVT Ca2+ abnormalities and drug sensitivities vary depending on the mutation site in the RyR2. These questions can now be addressed by using patient-specific in vitro models of these diseases based on induced pluripotent stem cells (iPSCs). In this review, we summarize different insights gained from these models with a focus on electrophysiological perturbations caused by different ion channel mutations and discuss how will this knowledge help develop better stratification and more efficient personalized therapies for these patients.


Assuntos
Canalopatias/genética , Fenômenos Eletrofisiológicos/fisiologia , Cardiopatias/genética , Células-Tronco Pluripotentes Induzidas/fisiologia , Mutação/genética , Miócitos Cardíacos/fisiologia , Animais , Canalopatias/patologia , Canalopatias/fisiopatologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/patologia
15.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203974

RESUMO

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.


Assuntos
Cardiopatias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Modelos Animais de Doenças , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/genética , Regeneração
16.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328199

RESUMO

Myocardial fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix in myocardial interstitial spaces. Myocardial fibrosis is a fundamental process in ventricular remodeling and a primary contributor to the progression of heart failure. Liquiritigenin (LQ) is a flavanone compound with anti­oxidative, anti­carcinogenic, anti­inflammatory and estrogenic properties. The present study aimed to investigate the regulatory potential of LQ treatment in a mouse model of isoprenaline (ISO)­induced cardiac fibrosis and in cultured H9C2 cardiomyocytes stimulated with angiotensin II (Ang II). The treatment of ISO­induced mice with LQ significantly decreased the levels of cardiac injury­related proteins in the serum and ECM accumulation in mouse heart tissues. LQ treatment also effectively alleviated cardiac dysfunction in ISO­treated mice. Further analyses revealed that LQ inhibited ISO­induced collagen formation and activation of the transforming growth factor­ß1 (TGF­ß1)/Smad2 and protein kinase B (AKT)/extracellular signal­regulated kinase (ERK) signaling pathways. As a major pathological event in myocardial fibrosis, the apoptosis of cardiomyocytes has been considered a key mechanism contributing to impaired left ventricle performance. The pretreatment of rat cardiomyocytes with LQ significantly reduced the apoptosis of H9C2 cells, and inhibited Ang II­induced activation of the TGF­ß1/Smad2 and AKT/ERK pathways. In conclusion, the present study revealed that LQ ameliorated ISO­induced myocardial fibrosis in mice and inhibited the apoptosis of cardiomyocytes in vitro by inhibiting the TGF­ß1/Smad2 and AKT/ERK signaling pathways. These results suggested the anti­fibrotic and cardioprotective potential of LQ in fibrosis, thus supporting the use of LQ for the management of cardiomyocyte injury and myocardial fibrosis in patients with cardiac diseases.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/tratamento farmacológico , Flavanonas/farmacologia , Cardiopatias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Angiotensina II/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fibrose/induzido quimicamente , Flavanonas/uso terapêutico , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Testes de Função Cardíaca/efeitos dos fármacos , Isoproterenol/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores
17.
Int J Biochem Cell Biol ; 137: 106035, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34242685

RESUMO

The nucleus provides a physical and selective chemical boundary to segregate the genome from the cytoplasm. The contents of the nucleus are surrounded by the nuclear envelope, which acts as a hub of mechanosensation, transducing forces from the external cytoskeleton to the nucleus, thus impacting on nuclear morphology, genome organisation, gene transcription and signalling pathways. Muscle tissues such as the heart are unique in that they actively generate large contractile forces, resulting in a distinctive mechanical environment which impacts nuclear properties, function and mechanosensing. In light of this, mutations that affect the function of the nuclear envelope (collectively known as nuclear envelopathies and laminopathies) disproportionately result in striated muscle diseases, which include dilated and arrhythmogenic cardiomyopathies. Here we review the nucleus and its role in mechanotransduction, as well as associated defects that lead to cardiac dysfunction.


Assuntos
Núcleo Celular/metabolismo , Cardiopatias/patologia , Mecanotransdução Celular , Proteínas Nucleares/metabolismo , Animais , Núcleo Celular/genética , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Proteínas Nucleares/genética
18.
Cardiovasc Pathol ; 54: 107370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34273507

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is commonly associated with myocardial injury and heart failure. The pathophysiology behind this phenomenon remains unclear, with many diverse and multifaceted hypotheses. To contribute to this understanding, we describe the underlying cardiac findings in fifty patients who died with coronavirus disease 2019 (COVID-19). METHODS: Included were autopsies performed on patients with a positive SARS-CoV-2 reverse-transcriptase-polymerase-chain reaction test from the index hospitalization. In the case of out-of-hospital death, patients were included if post-mortem testing was positive. Complete autopsies were performed according to a COVID-19 safety protocol, and all patients underwent both macroscopic and microscopic examination. If available, laboratory findings and echocardiograms were reported. RESULTS: The median age of the decedents was 63.5 years. The most common comorbidities included hypertension (90.0%), diabetes (56.0%) and obesity (50.0%). Lymphocytic inflammatory infiltrates in the heart were present in eight (16.0%) patients, with focal myocarditis present in two (4.0%) patients. Acute myocardial ischemia was observed in eight (16.0%) patients. The most common findings were myocardial fibrosis (80.0%), hypertrophy (72.0%), and microthrombi (66.0%). The most common causes of death were COVID-19 pneumonia in 18 (36.0%), COVID-19 pneumonia with bacterial superinfection in 12 (24.0%), and COVID-19 pneumonia with pulmonary embolism in 10 (20.0%) patients. CONCLUSIONS: Cardiovascular comorbidities were prevalent, and pathologic changes associated with hypertensive and atherosclerotic cardiovascular disease were the most common findings. Despite markedly elevated inflammatory markers and cardiac enzymes, few patients exhibited inflammatory infiltrates or necrosis within cardiac myocytes. A unifying pathophysiologic mechanism behind myocardial injury in COVID-19 remains elusive, and additional autopsy studies are needed.


Assuntos
COVID-19/patologia , Cardiopatias/patologia , Miocárdio/patologia , SARS-CoV-2/patogenicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/mortalidade , Aterosclerose/patologia , Autopsia , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Comorbidade , Feminino , Cardiopatias/imunologia , Cardiopatias/mortalidade , Cardiopatias/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/mortalidade , Hipertensão/patologia , Mediadores da Inflamação/análise , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Necrose , SARS-CoV-2/imunologia , Regulação para Cima
19.
Biomed Pharmacother ; 138: 111524, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311527

RESUMO

BACKGROUND: Sepsis-associated cardiac dysfunction results in increased mortality. Hyperoside (Hyp) is a flavonoid, showing significant anti-inflammatory effects. However, its pharmacological effects on sepsis-induced cardiac dysfunction remain unknown. In this study, we attempted to explore whether Hyp could prevent cardiac dysfunction and its underlying mechanisms. METHODS: We established a mice mode of sepsis by cecal ligation and puncture (CLP) treatment, and constructed a cell model of myocardial injury by lipopolysaccharide (LPS) stimulation. The cardiac function indicators and the inflammatory cytokine levels were measured. Effect of Hyp on cardiomyocyte viability was evaluated using MTT assay. The expression and functional role of microRNA-21 (miR-21), a documented molecule that regulated by Hyp, was evaluated in the constructed models, and the potential targets of miR-21 were predicted. RESULTS: Hyp alleviated the impaired cardiac function and stimulated inflammation caused by CLP in the in vivo sepsis model, and alleviated the LPS-induced decrease in cell viability and increase in inflammation of cardiomyocytes. Additionally, Hyp significantly inhibited the expression of miR-21 in LPS-induced cardiomyocytes, and the increased cell viability and decreased inflammation caused by Hyp in the in vitro model could be reversed by miR-21 overexpression. In animal model of sepsis, the protective influence of Hyp against sepsis-induced cardiac dysfunction was attenuated by miR-21 upregulation. CONCLUSION: Our findings demonstrated that Hyp may serve as a promising natural drug for the treatment of sepsis-associated cardiac dysfunction, and its protective role may exerted through regulating cardiomyocyte viability and inflammation by suppressing miR-21.


Assuntos
Anti-Inflamatórios/farmacologia , Cardiopatias/prevenção & controle , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Quercetina/análogos & derivados , Sepse/tratamento farmacológico , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Quercetina/farmacologia , Sepse/metabolismo , Sepse/patologia , Sepse/fisiopatologia , Transdução de Sinais
20.
Biomed Pharmacother ; 138: 111531, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311530

RESUMO

Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Mediadores da Inflamação/metabolismo , Isoproterenol , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
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