RESUMEN
BACKGROUND: The early diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains a significant challenge in neurology, with conventional methods often limited by subjectivity and variability in interpretation. Integrating deep learning with artificial intelligence (AI) in magnetic resonance imaging (MRI) analysis emerges as a transformative approach, offering the potential for unbiased, highly accurate diagnostic insights. OBJECTIVE: A meta-analysis was designed to analyze the diagnostic accuracy of deep learning of MRI images on AD and MCI models. METHODS: A meta-analysis was performed across PubMed, Embase, and Cochrane library databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on the diagnostic accuracy of deep learning. Subsequently, methodological quality was assessed using the QUADAS-2 checklist. Diagnostic measures, including sensitivity, specificity, likelihood ratios, diagnostic odds ratio, and area under the receiver operating characteristic curve (AUROC) were analyzed, alongside subgroup analyses for T1-weighted and non-T1-weighted MRI. RESULTS: A total of 18 eligible studies were identified. The Spearman correlation coefficient was -0.6506. Meta-analysis showed that the combined sensitivity and specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.84, 0.86, 6.0, 0.19, and 32, respectively. The AUROC was 0.92. The quiescent point of hierarchical summary of receiver operating characteristic (HSROC) was 3.463. Notably, the images of 12 studies were acquired by T1-weighted MRI alone, and those of the other 6 were gathered by non-T1-weighted MRI alone. CONCLUSION: Overall, deep learning of MRI for the diagnosis of AD and MCI showed good sensitivity and specificity and contributed to improving diagnostic accuracy.
ANTECEDENTES: O diagnóstico precoce da doença de Alzheimer (DA) e do comprometimento cognitivo leve (CCL) continua sendo um desafio significativo na neurologia, com métodos convencionais frequentemente limitados pela subjetividade e variabilidade na interpretação. A integração da aprendizagem profunda com a inteligência artificial (IA) na análise de imagens de ressonância magnética surge como uma abordagem transformadora, oferecendo o potencial para insights diagnósticos imparciais e altamente precisos. OBJETIVO: Uma metanálise foi projetada para analisar a precisão diagnóstica do aprendizado profundo de imagens de ressonância magnética em modelos de DA e CCL. MéTODOS: Uma metanálise foi realizada nos bancos de dados das bibliotecas PubMed, Embase e Cochrane seguindo as diretrizes Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), com foco na precisão diagnóstica do aprendizado profundo. Posteriormente, a qualidade metodológica foi avaliada por meio do checklist QUADAS-2. Medidas diagnósticas, incluindo sensibilidade, especificidade, razões de verossimilhança, razão de chances diagnósticas e área sob a curva característica de operação do receptor (area under the receiver operating characteristic curve [AUROC]) foram analisadas, juntamente com análises de subgrupo para ressonância magnética ponderada em T1 e não ponderada em T1. RESULTADOS: Um total de 18 estudos elegíveis foram identificados. O coeficiente de correlação de Spearman foi de -0,6506. A metanálise mostrou que a sensibilidade e a especificidade combinadas, a razão de verossimilhança positiva, a razão de verossimilhança negativa e a razão de chances de diagnóstico foram 0,84, 0,86, 6,0, 0,19 e 32, respectivamente. A AUROC foi de 0,92. O ponto quiescente do resumo hierárquico da característica de operação do receptor (hierarchical summary of receiver operating characteristic [HSROC]) foi 3,463. Notavelmente, as imagens de 12 estudos foram adquiridas apenas por ressonância magnética ponderada em T1, e as dos outros 6 foram obtidas apenas por ressonância magnética não ponderada em T1. CONCLUSãO: Em geral, a aprendizagem profunda da ressonância magnética para o diagnóstico de DA e CCL mostrou boa sensibilidade e especificidade e contribuiu para melhorar a precisão diagnóstica.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Aprendizaje Profundo , Imagen por Resonancia Magnética , Sensibilidad y Especificidad , Humanos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Imagen por Resonancia Magnética/métodos , Diagnóstico Precoz , Curva ROCRESUMEN
Abstract Background The early diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains a significant challenge in neurology, with conventional methods often limited by subjectivity and variability in interpretation. Integrating deep learning with artificial intelligence (AI) in magnetic resonance imaging (MRI) analysis emerges as a transformative approach, offering the potential for unbiased, highly accurate diagnostic insights. Objective A meta-analysis was designed to analyze the diagnostic accuracy of deep learning of MRI images on AD and MCI models. Methods A meta-analysis was performed across PubMed, Embase, and Cochrane library databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on the diagnostic accuracy of deep learning. Subsequently, methodological quality was assessed using the QUADAS-2 checklist. Diagnostic measures, including sensitivity, specificity, likelihood ratios, diagnostic odds ratio, and area under the receiver operating characteristic curve (AUROC) were analyzed, alongside subgroup analyses for T1-weighted and non-T1-weighted MRI. Results A total of 18 eligible studies were identified. The Spearman correlation coefficient was -0.6506. Meta-analysis showed that the combined sensitivity and specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.84, 0.86, 6.0, 0.19, and 32, respectively. The AUROC was 0.92. The quiescent point of hierarchical summary of receiver operating characteristic (HSROC) was 3.463. Notably, the images of 12 studies were acquired by T1-weighted MRI alone, and those of the other 6 were gathered by non-T1-weighted MRI alone. Conclusion Overall, deep learning of MRI for the diagnosis of AD and MCI showed good sensitivity and specificity and contributed to improving diagnostic accuracy.
Resumo Antecedentes O diagnóstico precoce da doença de Alzheimer (DA) e do comprometimento cognitivo leve (CCL) continua sendo um desafio significativo na neurologia, com métodos convencionais frequentemente limitados pela subjetividade e variabilidade na interpretação. A integração da aprendizagem profunda com a inteligência artificial (IA) na análise de imagens de ressonância magnética surge como uma abordagem transformadora, oferecendo o potencial para insights diagnósticos imparciais e altamente precisos. Objetivo Uma metanálise foi projetada para analisar a precisão diagnóstica do aprendizado profundo de imagens de ressonância magnética em modelos de DA e CCL. Métodos Uma metanálise foi realizada nos bancos de dados das bibliotecas PubMed, Embase e Cochrane seguindo as diretrizes Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), com foco na precisão diagnóstica do aprendizado profundo. Posteriormente, a qualidade metodológica foi avaliada por meio do checklist QUADAS-2. Medidas diagnósticas, incluindo sensibilidade, especificidade, razões de verossimilhança, razão de chances diagnósticas e área sob a curva característica de operação do receptor (area under the receiver operating characteristic curve [AUROC]) foram analisadas, juntamente com análises de subgrupo para ressonância magnética ponderada em T1 e não ponderada em T1. Resultados Um total de 18 estudos elegíveis foram identificados. O coeficiente de correlação de Spearman foi de -0,6506. A metanálise mostrou que a sensibilidade e a especificidade combinadas, a razão de verossimilhança positiva, a razão de verossimilhança negativa e a razão de chances de diagnóstico foram 0,84, 0,86, 6,0, 0,19 e 32, respectivamente. A AUROC foi de 0,92. O ponto quiescente do resumo hierárquico da característica de operação do receptor (hierarchical summary of receiver operating characteristic [HSROC]) foi 3,463. Notavelmente, as imagens de 12 estudos foram adquiridas apenas por ressonância magnética ponderada em T1, e as dos outros 6 foram obtidas apenas por ressonância magnética não ponderada em T1. Conclusão Em geral, a aprendizagem profunda da ressonância magnética para o diagnóstico de DA e CCL mostrou boa sensibilidade e especificidade e contribuiu para melhorar a precisão diagnóstica.
RESUMEN
Abstract Introduction: Allergic rhinitis is a chronic inflammatory disease which affects 1 out of 6 individuals. Perennial allergic rhinitis accounts for 40% of AR cases. Ciclesonide is one of the relatively new intranasal steroid for allergic rhinitis. Objective: The purpose of this study was to evaluate the efficacy and safety of ciclesonide in the treatment of perennial allergic rhinitis. Methods: We searched Pubmed, Scientific Citation Index, Embase, Clinical Trial Registries for randomized controlled trials and Cochrane Central Register of Controlled Trials to find out the randomized controlled Trial comparing ciclesonide with placebo for PAR. Results: Eight studies were included. In comparison with placebo groups, ciclesonide groups significantly decreased Reflective Total Nasal Symptom Score (MD = −0.56; 95% CI −0.72 to 0.39, p < 0.00001) with heterogeneity (p = 0.19, I2 = 24%), Instantaneous Total Nasal Symptom Score (MD = −0.57; 95% CI −0.75 to −0.39, p < 0.00001) with heterogeneity (p = 0.34, I2 = 11%). A significant effect for Reflective Nasal Symptom Score Subtotal (MD = −0.15; 95% CI −0.18 to −0.13, p < 0.00001) with heterogeneity (p = 0.12, I2 = 24%) was also demonstrated. Rhinoconjunctivitis quality of life questionnaire score (RQLQs) (MD = −0.27; 95% CI −0.39 to −0.15, p < 0.00001) with heterogeneity (p = 0.58, I 2 = 0%) in the treatment of ciclesonide was also significantly reduced. In addition, the difference in Treatment-Emergent Adverse Events between the two groups was not significant. Conclusion: Ciclesonide can improve perennial allergic rhinitis without increasing adverse events. Ciclesonide may be another valuable choice for perennial allergic rhinitis in the future.
Resumo Introdução: A rinite alérgica é uma doença inflamatória crônica que afeta um a cada seis indivíduos. A rinite alérgica perene é responsável por 40% dos casos de rinite alérgica. A ciclesonida é um dos corticosteroides intranasais mais novos para o tratamento dessa condição clínica. Objetivo: Avaliar a eficácia e segurança da ciclesonida no tratamento da rinite alérgica perene. Método: Uma busca foi feita nos bancos de dados Pubmed, Scientific Citation Index, Embase e Clinical Trial Registries por ensaios clínicos randomizados e Cochrane Central Register of Controlled Trials por estudos controlados randomizados que comparassem ciclesonida com placebo no tratamento da rinite alérgica perene. Resultados: Oito estudos foram incluídos. Em comparação com os grupos placebo, os grupos ciclesonida mostraram diminuição significante no escore do Reflective Total Nasal Symptom Score (DM = −0,56; IC 95%: −0,72 a −0,39, p < 0,00001) com heterogeneidade (p = 0,19, I2 = 24%), do Instantaneous Total Nasal Symptom Score (DM = −0,57; IC95%: −0,75 a −0,39, p < 0,00001) com heterogeneidade (p = 0,34, I2 = 11%). Um efeito significante no escore do Reflective Nasal Symptom Score Subtotal (DM = −0,15; IC 95%: −0,18 a −0,13, p < 0,00001) com heterogeneidade (p = 0,12, I2 = 24%) também foi demonstrado. O escore do Rhinoconjunctivitis Quality of Life Questionnaire score (RQLQs) (DM = −0,27; IC 95%: −0,39 a −0,15, p < 0,00001) com heterogeneidade (p = 0,58, I2 = 0%) também foi significantemente reduzido no tratamento com ciclesonida. Além disso, a diferença em relação aos eventos adversos emergentes do tratamento entre os dois grupos não foi significante. Conclusão: A ciclesonida pode melhorar a rinite alérgica perene sem aumentar os eventos adversos. Esse fármaco pode ser outra opção valiosa para a rinite alérgica perene no futuro.
Asunto(s)
Humanos , Pregnenodionas/uso terapéutico , Rinitis Alérgica Perenne/tratamiento farmacológico , Antialérgicos/uso terapéutico , Administración Intranasal , Ensayos Clínicos Controlados como AsuntoRESUMEN
INTRODUCTION: Allergic rhinitis is a chronic inflammatory disease which affects 1 out of 6 individuals. Perennial allergic rhinitis accounts for 40% of AR cases. Ciclesonide is one of the relatively new intranasal steroid for allergic rhinitis. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of ciclesonide in the treatment of perennial allergic rhinitis. METHODS: We searched Pubmed, Scientific Citation Index, Embase, Clinical Trial Registries for randomized controlled trials and Cochrane Central Register of Controlled Trials to find out the randomized controlled Trial comparing ciclesonide with placebo for PAR. RESULTS: Eight studies were included. In comparison with placebo groups, ciclesonide groups significantly decreased Reflective Total Nasal Symptom Score (MD=-0.56; 95% CI -0.72 to 0.39, p<0.00001) with heterogeneity (p=0.19, I2=24%), Instantaneous Total Nasal Symptom Score (MD=-0.57; 95% CI -0.75 to -0.39, p<0.00001) with heterogeneity (p=0.34, I2=11%). A significant effect for Reflective Nasal Symptom Score Subtotal (MD=-0.15; 95% CI -0.18 to -0.13, p<0.00001) with heterogeneity (p=0.12, I2=24%) was also demonstrated. Rhinoconjunctivitis quality of life questionnaire score (RQLQs) (MD=-0.27; 95% CI -0.39 to -0.15, p<0.00001) with heterogeneity (p=0.58, I2=0%) in the treatment of ciclesonide was also significantly reduced. In addition, the difference in Treatment-Emergent Adverse Events between the two groups was not significant. CONCLUSION: Ciclesonide can improve perennial allergic rhinitis without increasing adverse events. Ciclesonide may be another valuable choice for perennial allergic rhinitis in the future.
Asunto(s)
Antialérgicos/uso terapéutico , Pregnenodionas/uso terapéutico , Rinitis Alérgica Perenne/tratamiento farmacológico , Administración Intranasal , Ensayos Clínicos Controlados como Asunto , HumanosRESUMEN
FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Asunto(s)
Animales , Masculino , Ratas , Benzamidas/farmacología , Fibrosis Endomiocárdica/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Western Blotting , Benzamidas/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Desoxicorticosterona , Modelos Animales de Enfermedad , Fibrosis Endomiocárdica/patología , Fibronectinas/análisis , Fibronectinas/metabolismo , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Nefrectomía/métodos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Ratas Sprague-Dawley , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Resultado del Tratamiento , Tenascina/análisis , Tenascina/metabolismoRESUMEN
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRß) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were significantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Asunto(s)
Benzamidas/farmacología , Fibrosis Endomiocárdica/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Benzamidas/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Western Blotting , Desoxicorticosterona , Modelos Animales de Enfermedad , Fibrosis Endomiocárdica/patología , Fibronectinas/análisis , Fibronectinas/metabolismo , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Mesilato de Imatinib , Masculino , Nefrectomía/métodos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Tenascina/análisis , Tenascina/metabolismo , Resultado del TratamientoRESUMEN
Cardiovascular complications are a leading cause of mortality in patients with diabetes mellitus (DM). The present study was designed to investigate the effects of trimetazidine (TMZ), an anti-angina drug, on transient outward potassium current (Ito) remodeling in ventricular myocytes and the plasma contents of free fatty acid (FFA) and glucose in DM. Sprague-Dawley rats, 8 weeks old and weighing 200-250 g, were randomly divided into three groups of 20 animals each. The control group was injected with vehicle (1 mM citrate buffer), the DM group was injected with 65 mg/kg streptozotocin (STZ) for induction of type 1 DM, and the DM + TMZ group was injected with the same dose of STZ followed by a 4-week treatment with TMZ (60 mg·kg-1·day-1). All animals were then euthanized and their hearts excised and subjected to electrophysiological measurements or gene expression analyses. TMZ exposure significantly reversed the increased plasma FFA level in diabetic rats, but failed to change the plasma glucose level. The amplitude of Ito was significantly decreased in left ventricular myocytes from diabetic rats relative to control animals (6.25 ± 1.45 vs 20.72 ± 2.93 pA/pF at +40 mV). The DM-associated Ito reduction was attenuated by TMZ. Moreover, TMZ treatment reversed the increased expression of the channel-forming alpha subunit Kv1.4 and the decreased expression of Kv4.2 and Kv4.3 in diabetic rat hearts. These data demonstrate that TMZ can normalize, or partially normalize, the increased plasma FFA content, the reduced Ito of ventricular myocytes, and the altered expression Kv1.4, Kv4.2, and Kv4.3 in type 1 DM.
Asunto(s)
Animales , Ratas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Trimetazidina/farmacología , Vasodilatadores/farmacología , Ácidos Grasos/sangre , Glucosa/análisis , Miocitos Cardíacos/metabolismo , Canales de Potasio/metabolismo , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Cardiovascular complications are a leading cause of mortality in patients with diabetes mellitus (DM). The present study was designed to investigate the effects of trimetazidine (TMZ), an anti-angina drug, on transient outward potassium current (Ito) remodeling in ventricular myocytes and the plasma contents of free fatty acid (FFA) and glucose in DM. Sprague-Dawley rats, 8 weeks old and weighing 200-250 g, were randomly divided into three groups of 20 animals each. The control group was injected with vehicle (1 mM citrate buffer), the DM group was injected with 65 mg/kg streptozotocin (STZ) for induction of type 1 DM, and the DM + TMZ group was injected with the same dose of STZ followed by a 4-week treatment with TMZ (60 mg·kg-1·day-1). All animals were then euthanized and their hearts excised and subjected to electrophysiological measurements or gene expression analyses. TMZ exposure significantly reversed the increased plasma FFA level in diabetic rats, but failed to change the plasma glucose level. The amplitude of Ito was significantly decreased in left ventricular myocytes from diabetic rats relative to control animals (6.25 ± 1.45 vs 20.72 ± 2.93 pA/pF at +40 mV). The DM-associated Ito reduction was attenuated by TMZ. Moreover, TMZ treatment reversed the increased expression of the channel-forming alpha subunit Kv1.4 and the decreased expression of Kv4.2 and Kv4.3 in diabetic rat hearts. These data demonstrate that TMZ can normalize, or partially normalize, the increased plasma FFA content, the reduced Ito of ventricular myocytes, and the altered expression Kv1.4, Kv4.2, and Kv4.3 in type 1 DM.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Trimetazidina/farmacología , Vasodilatadores/farmacología , Animales , Ácidos Grasos/sangre , Glucosa/análisis , Miocitos Cardíacos/metabolismo , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin when bound to dermatan sulfate or heparin. HCII-deficient mice are viable and fertile but rapidly develop thrombosis of the carotid artery after endothelial injury. We now report the effects of HCII deficiency on atherogenesis and neointima formation. HCII-null or wild-type mice, both on an apolipoprotein E-null background, were fed an atherogenic diet for 12 weeks. HCII-null mice developed plaque areas in the aortic arch approximately 64% larger than wild-type mice despite having similar plasma lipid and glucose levels. Neointima formation was induced by mechanical dilation of the common carotid artery. Thrombin activity, determined by hirudin binding or chromogenic substrate hydrolysis within 1 hour after injury, was higher in the arterial walls of HCII-null mice than in wild-type mice. After 3 weeks, the median neointimal area was 2- to 3-fold greater in HCII-null than in wild-type mice. Dermatan sulfate administered intravenously within 48 hours after injury inhibited neointima formation in wild-type mice but had no effect in HCII-null mice. Heparin did not inhibit neointima formation. We conclude that HCII deficiency promotes atherogenesis and neointima formation and that treatment with dermatan sulfate reduces neointima formation in an HCII-dependent manner.