Common and specific proteins and pathways in heart and cerebral ischemia.

OBJECTIVE: To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies. METHODS: Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler. RESULTS: Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3. CONCLUSIONS: The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes / Predicción de eventos clínicos por elasticidad hepática y enfermedad renal crónica por EHMet en pacientes con diabetes tipo 2

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. Methods: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d’Hebron Hospital and related primary care centers. Results: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5–7.3] vs 4.8 [4.2–5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. Conclusions: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care. (AU)

Antecedentes y objetivos: La esteatosis hepática metabólica (EHMet) se asocia con un peor control glucémico y un mayor riesgo de complicaciones de la diabetes tipo 2 (DM2), enfermedad extrahepática y cardiovascular (CV). El objetivo fue evaluar la asociación entre EHMet, complicaciones microvasculares y el desarrollo de eventos clínicos globales (ECG) (CV, hepáticos y mortalidad) en diabéticos. Métodos: Estudio unicéntrico prospectivo que incluye diabéticos sin historia de CV y controles sin DM2. Se seleccionaron pacientes de la consulta de Diabetes del Hospital Vall d’Hebron y centros de atención primaria asociados. Resultados: Se incluyeron 186 diabéticos y 57 controles. Entre los diabéticos, 124/186 presentaron EHMet (66,6%). Los pacientes DM2 con EHMet presentaron mayor carga metabólica y una elasticidad hepática superior (5,6kPa [4,5-7,3] vs. 4,8 [4,2-5,8]; p=0,004) a los diabéticos sin EHMet. Durante una mediana de seguimiento de 5,6 años, 33 (17,7%) diabéticos desarrollaron ECG vs. 4 (7,0%) controles (p=0,049). No hubo diferencias en ECG entre diabéticos con y sin EHMet (16,9% vs. 19,4%; p=0,68). El evento más reportado fue CV y solamente se produjo un evento hepático. La enfermedad renal crónica (ERC) fue más frecuente en diabéticos con EHMet, mientras que los ratios de complicaciones microvasculares y enfermedad CV silente fueron similares. El género masculino, una mayor edad y elasticidad hepática se asociaron de forma independiente a ECG para el total de diabéticos y para aquellos con EHMet. Conclusiones: La EHMet y la elasticidad hepática se asociaron a ERC y eventos clínicos en diabéticos. Se recomienda una evaluación hepática para identificar pacientes diabéticos de riesgo que se beneficiarían de una derivación precoz al especialista. (AU)

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. METHODS: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d'Hebron Hospital and related primary care centers. RESULTS: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5-7.3] vs 4.8 [4.2-5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. CONCLUSIONS: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

Advanced Glycations End Products in the Skin as Biomarkers of Cardiovascular Risk in Type 2 Diabetes.

The incidence and prevalence of diabetes are increasing worldwide, and cardiovascular disease (CVD) is the leading cause of death among subjects with type 2 diabetes (T2D). The assessment and stratification of cardiovascular risk in subjects with T2D is a challenge. Advanced glycation end products are heterogeneous molecules produced by non-enzymatic glycation of proteins, lipids, or nucleic acids. Accumulation of advanced glycation end products is increased in subjects with T2D and is considered to be one of the major pathogenic mechanism in developing complications in diabetes. Skin AGEs could be assessed by skin autofluorescence. This method has been validated and related to the presence of micro and macroangiopathy in individuals with type 2 diabetes. In this context, the aim of this review is to critically summarize current knowledge and scientific evidence on the relationship between skin AGEs and CVD in subjects with type 2 diabetes, with a brief reference to other diabetes-related complications.

Diabetic Retinopathy and Skin Tissue Advanced Glycation End Products Are Biomarkers of Cardiovascular Events in Type 2 Diabetic Patients.

Risk of cardiovascular events is not homogeneous in subjects with type 2 diabetes; therefore, its early identification remains a challenge to be met. The aim of this study is to evaluate whether the presence of diabetic retinopathy and accumulation of advanced glycation end-products in subcutaneous tissue can help identify patients at high risk of cardiovascular events. For this purpose, we conducted a prospective study (mean follow-up: 4.35 years) comprising 200 subjects with type 2 diabetes with no history of clinical cardiovascular disease and 60 non-diabetic controls matched by age and sex. The primary outcome was defined as the composite of myocardial infarction, coronary revascularization, stroke, lower limb amputation or cardiovascular death. The Cox proportional hazard multiple regression analysis was used to determine the independent predictors of cardiovascular events. The patients with type 2 diabetes had significantly more cardiovascular events than the non-diabetic subjects. Apart from the classic factors such as age, sex and coronary artery calcium score, we observed that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue were independent predictors of cardiovascular events. We conclude that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue could be useful biomarkers for selecting type 2 diabetic patients in whom the screening for cardiovascular disease should be prioritized, thereby creating more personalized and cost-effective medicine.

Usefulness of skin advanced glycation end products to predict coronary artery calcium score in patients with type 2 diabetes.

AIM: The early identification of type 2 diabetic (T2D) patients at risk of developing coronary artery disease (CAD) remains a challenge. The coronary artery calcium score (CACs) is considered the most sensitive tool for assessing CAD risk in diabetic population, and the identification of a more targeted population in which the CACs would be more cost-efficient seems warranted. The accumulation of advanced glycation end products plays an important role in the pathogenesis of cardiovascular disease (CVD) in patients with diabetes. The aim of this study was to evaluate whether the assessment of skin autofluorescence (SAF) could be useful tool to identify those diabetic patients in whom CACs assessment should be prioritized. METHODS: Prospective case-control study, comprising 156 subjects with T2D with no history of clinical CVD and 52 non-diabetic subjects matched by age. A value of CACs ≥ 400 Agatston Units (AU) was considered as "high CVD risk." Logistic regression analysis to predict a CACs ≥ 400 AU was performed. Sensibility and specificity were calculated using the optimal cutoff point based on ROC curve. RESULTS: T2D patients had higher value of SAF compared to controls (p = 0.011). Among subjects with diabetes, 122 presented CACs < 400 AU and 35 CACs ≥ 400 AU. SAF values were significantly higher among the group with CACs ≥ 400AU compared to patients with CACs < 400 (2.96 ± 0.86 vs. 2.59 ± 0.57; p = 0.0035). The logistic regression analysis showed that age, HDL-cholesterol and SAF values were independently related to CACs ≥ 400UA. CONCLUSION: Our finding suggests that SAF could be useful in selecting T2D patients in whom the screening for CAD by means of CACs assessment would be more cost-effective.

Diabetic retinopathy as an independent predictor of subclinical cardiovascular disease: baseline results of the PRECISED study.

Objective: Detection of subclinical cardiovascular disease (CVD) has significant impact on the management of type 2 diabetes. We examined whether the assessment of diabetic retinopathy (DR) is useful for identifying patients at a higher risk of having silent CVD. Research design and methods: Prospective case-control study comprising 200 type 2 diabetic subjects without history of clinical CVD and 60 age-matched non-diabetic subjects. The presence of subclinical CVD was examined using two parameters: (1) calcium coronary score (CACs); (2) composite of CACs >400 UA, carotid plaque ≥3 mm, carotid intima-media thickness ratio >1, or the presence of ECG changes suggestive of previous asymptomatic myocardial infarction. In addition, coronary angio-CT was performed. DR was assessed by slit-lamp biomicroscopy and retinography. Results: Type 2 diabetic subjects presented higher CACs than non-diabetic control subjects (p<0.01). Age, male gender, and the presence of DR were independently related to CACs >400 (area under the receiver operating characteristic curve (AUROC) 0.76). In addition, an inverse relationship was observed between the degree of DR and CACs <10 AU. The variables independently associated with the composite measurement of subclinical CVD were age, diabetes duration, the glomerular filtration rate, microalbuminuria, and the presence of DR (AUROC 0.71). In addition, a relationship (p<0.01) was observed between the presence and degree of DR and coronary stenosis. Conclusions: The presence and degree of DR is independently associated with subclinical CVD in type 2 diabetic patients. Our results lead us to propose a rationalized screening for coronary artery disease in type 2 diabetes based on prioritizing patients with DR, particularly those with moderate-severe degree.

Assessment of advanced glycation end-products as a biomarker of diabetic outcomes / Evaluación de forma no invasiva de los productos avanzados de la glicación como biomarcador de las complicaciones de la diabetes

There are substantial differences in the onset and severity of diabetes complications that are not fully explained by HbA1c levels and other risk factors. HbA1c is the gold standard for assessing metabolic control, but has limited value to identify patients at risk of developing diabetic complications. The main disadvantage of HbA1c is that it does not provide information about glycemic variability and does not reflect long-term exposure to hyperglycemia. One of the main pathogenetic mechanisms of diabetic complications is the generation and accumulation of advanced glycation end-products (AGEs). Based on its fluorescence properties, AGEs may be measured in tissues such as the skin or lens. These non-invasive measurements of AGE accumulation may be considered as promising biomarkers of late diabetic complications, and our objective is to summarize the available evidence supporting this statement. However, further translational research and prospective clinical trials are needed before these new biomarkers may be incorporated into clinical practice

La determinación de HbA1c es el «estándar de oro» para evaluar el control metabólico de los pacientes con diabetes, pero tiene limitaciones en identificar los pacientes riesgo de desarrollar complicaciones. Los inconvenientes de la HbA1c son que no proporciona información acerca de la variabilidad glucémica y no refleja la exposición a largo plazo a la hiperglucemia. Uno de los mecanismos patogénicos de las complicaciones de la diabetes es la acumulación de productos avanzados de la glicación (AGE). Basándose en sus propiedades fluorescentes, los AGE pueden determinarse en tejidos como la piel o el cristalino. Estas determinaciones no invasivas podrían contemplarse como biomarcadores de las complicaciones de la diabetes, y nuestro objetivo es resumir la evidencia disponible en referencia a ello. Sin embargo, es necesaria una mayor investigación traslacional en este campo, así como estudios prospectivos antes de que estos métodos puedan ser incorporados a la práctica clínica

Assessment of advanced glycation end-products as a biomarker of diabetic outcomes.

There are substantial differences in the onset and severity of diabetes complications that are not fully explained by HbA1c levels and other risk factors. HbA1c is the gold standard for assessing metabolic control, but has limited value to identify patients at risk of developing diabetic complications. The main disadvantage of HbA1c is that it does not provide information about glycemic variability and does not reflect long-term exposure to hyperglycemia. One of the main pathogenetic mechanisms of diabetic complications is the generation and accumulation of advanced glycation end-products (AGEs). Based on its fluorescence properties, AGEs may be measured in tissues such as the skin or lens. These non-invasive measurements of AGE accumulation may be considered as promising biomarkers of late diabetic complications, and our objective is to summarize the available evidence supporting this statement. However, further translational research and prospective clinical trials are needed before these new biomarkers may be incorporated into clinical practice.