Deep Learning of Retinal Imaging: A Useful Tool for Coronary Artery Calcium Score Prediction in Diabetic Patients

Retina fundus imaging; Deep learning; Medical imagingImatge del fons de la retina; Aprenentatge profund; Imatges mèdiquesImagen del fondo de la retina; Aprendizaje profundo; Imágenes médicasCardiovascular diseases (CVD) are one of the leading causes of death in the developed countries. Previous studies suggest that retina blood vessels provide relevant information on cardiovascular risk. Retina fundus imaging (RFI) is a cheap medical imaging test that is already regularly performed in diabetic population as screening of diabetic retinopathy (DR). Since diabetes is a major cause of CVD, we wanted to explore the use Deep Learning architectures on RFI as a tool for predicting CV risk in this population. Particularly, we use the coronary artery calcium (CAC) score as a marker, and train a convolutional neural network (CNN) to predict whether it surpasses a certain threshold defined by experts. The preliminary experiments on a reduced set of clinically verified patients show promising accuracies. In addition, we observed that elementary clinical data is positively correlated with the risk of suffering from a CV disease. We found that the results from both informational cues are complementary, and we propose two applications that can benefit from the combination of image analysis and clinical data.This research was funded by “RTI2018-095232-B-C22” grant from the Spanish Ministry of Science, Innovation and Universities (FEDER funds)

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

Cardiovascular disease biomarkers; Diabetic complications; Type 2 diabetesBiomarcadores de enfermedades cardiovasculares; Complicaciones de la diabetes; Diabetes tipo 2Biomarcadors de malalties cardiovasculars; Complicacions de la diabetis; Diabetis tipus 2Risk 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.This research was funded by grants from the Spanish Institute of Health (ISCIII) in the setting of Integrative Excellence Projects (PIE 2013/27) and the European Foundation for the Study of Diabetes (EFSD Pilot Research Grant Programme for Innovative Measurement of Diabetes Outcomes 2017). The study funders were not involved in the design of the study

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

Type 2 diabetes; Diabetic retinopathy; Subclinical cardiovascular diseaseDiabetis tipus 2; Retinopatia diabètica; Malalties cardiovasculars subclíniquesDiabetes tipo 2; Retinopatía diabética; Enfermedades cardiovasculares subclínicasObjective 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 (p400 (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.This work was supported by an Integrative Excellence Project by the Spanish Institute of Health, Instituto de Salud Carlos III, grant PIE 2013/27, CIBER CV, CIBERDEM, and the European Regional Development Fund (ERDF-FEDER). The Neurovascular Research Laboratory is part of the Spanish Stroke Research Network INVICTUS+ (RD16/0019/0021)

New clinical strategies to detect cardiovascular disease in subjects with type 2 diabetes

Els pacients amb diabetis tipus 2 presenten un major risc de malaltia macrovascular. Malgrat que la diabetis tipus 2 és un factor de risc independent de malaltia cardiovascular (MCV), no tots els pacients amb diabetis semblen tenir el mateix risc. Per tant, la identificació precoç de pacients diabètics amb el risc de desenvolupar MCV continua sent un desafiament. La hiperglucemia crònica està relacionada amb les complicacions cardiovasculars de la diabetis. No obstant, el risc exagerat de MCV en aquesta població no s'explica completament pels factors de risc clàssics; de fet, una proporció substancial d'aquest risc roman sense explicació. Per tant, es creu que condicions específiques relacionades amb la diabetis haurien d'estar involucrades en l'excés de risc de MCV en aquesta població, i l'acumulació tissular de productes finals de glicación (AGEs) podria ser un d'ells. Els AGEs s'acumulen en el cos durant l'envelliment, i aquest procés s'accelera per la hiperglucemia crònica i l'estrès oxidatiu. La formació i acumulació de AGEs estan accelerades en la diabetis mellitus i podrien contribuir a la disfunció vascular i al desenvolupament accelerat del procés ateroescleròtic. S'ha validat un mètode simple i no invasiu per a l'avaluació de AGEs a través de l'autofluorescència de la pell (SAF) i s'ha relacionat amb la presència de micro i macroangiopatia en subjectes amb diabetis tipus 2. Múltiples estudis indiquen que la presència de complicacions microvasculars de la diabetis augmenta el risc de MCV. En particular, la retinopatia diabètica (RD) s'ha relacionat amb un augment en el risc de mortalitat cardiovascular i de mort per qualsevol causa en pacients amb diabetis. El principal objectiu d'aquesta tesi doctoral és desenvolupar noves estratègies clíniques per a identificar millor a aquells pacients amb DM2 amb alt risc de desenvolupar un esdeveniment CV. En la primera part d'aquesta tesi doctoral, es plantegen dos objectius específics. En primer lloc, examinar si la càrrega i el grau de microangiopatia és un factor de risc independent per a determinar la presència de MCV subclínica; en segon lloc, examinar la utilitat del mesurament no invasiu de AGEs en la pell i la seva relació amb les complicacions diabètiques i la MCV subclínica, en subjectes diabètics sense antecedents de ECV. Es va realitzar un estudi prospectiu de casos i controls que va incloure 200 subjectes diabètics tipus 2 sense antecedents de ECV i 60 subjectes no diabètics apariats per edat. En aquest estudi evidenciem que l'RD és un predictor independent de ECV subclínica i que SAF és un bon predictor de CAC> 400 AU (un marcador fiable d'aterosclerosi coronària). Per tant, l'avaluació de la RD i de SAF pot plantejar-se com una bona estratègia que ens ajudi a seleccionar una població diabètica d'alt risc CV. En la segona part, l'objectiu va ser avaluar si la presència de retinopatia diabètica i l'acumulació en el teixit subcutani de AGEs poden ajudar a identificar pacients amb diabetis tipus 2 amb alt risc de desenvolupar un esdeveniment CV. Després d'un seguiment de 4,35 anys, es van registrar un total de 24 esdeveniments CV, 23 esdeveniments CV en el grup de diabetis i 1 en el grup control de no diabètics. Evidenciem que l'RD i SAF (com a mesura de l'acumulació de AGEs en la pell) són eficaces predictors d'esdeveniments cardiovasculars en subjectes amb diabetis tipus 2. Concloem, que l'RD i valors alts de SAF són importants predictors d'esdeveniments CV en subjectes amb diabetis tipus 2 i, per tant, podrien incloure's com a variables significatives en l'estratificació del risc CV.Los pacientes con diabetes tipo 2 presentan un mayor riesgo de enfermedad macrovascular. A pesar que la diabetes tipo 2 es un factor de riesgo independiente de enfermedad cardiovascular (ECV), no todos los pacientes con diabetes parecen tener el mismo riesgo. Por lo tanto, la identificación precoz de pacientes diabéticos con riesgo de desarrollar ECV sigue siendo un desafío. La hiperglucemia crónica está relacionada con las complicaciones cardiovasculares de la diabetes. Sin embargo, el riesgo exagerado de ECV en esta población no se explica completamente por los factores de riesgo clásicos; de hecho, una proporción sustancial de este riesgo permanece sin explicación. Por lo tanto, se cree que condiciones específicas relacionadas con la diabetes deberían estar involucradas en el exceso de riesgo de ECV en esta población, y la acumulación tisular de productos finales de glicación (AGEs) podría ser uno de ellos. Los AGEs se acumulan en el cuerpo durante el envejecimiento, y este proceso se acelera por la hiperglucemia crónica y el estrés oxidativo. La formación y acumulación de AGEs están aceleradas en la diabetes mellitus y podrían contribuir a la disfunción vascular y al desarrollo acelerado del proceso aterosclerótico. Se ha validado un método simple y no invasivo para la evaluación de AGEs a través de la autofluorescencia de la piel (SAF) y se ha relacionado con la presencia de micro y macroangiopatía en sujetos con diabetes tipo 2. Múltiples estudios indican que la presencia de complicaciones microvasculares de la diabetes aumenta el riesgo de ECV. En particular, la retinopatía diabética (RD) se ha relacionado con un aumento en el riesgo de mortalidad cardiovascular y de muerte por cualquier causa en pacientes con diabetes. El principal objetivo de esta tesis doctoral es desarrollar nuevas estrategias clínicas para identificar mejor a aquellos pacientes con DM2 con alto riesgo de desarrollar un evento CV. En la primera parte de esta tesis doctoral, se plantean dos objetivos específicos. En primer lugar, examinar si la carga y el grado de microangiopatía es un factor de riesgo independiente para determinar la presencia de ECV subclínica; en segundo lugar, examinar la utilidad de la medición no invasiva de AGEs en la piel y su relación con las complicaciones diabéticas y la ECV subclínica, en sujetos diabéticos sin antecedentes de ECV. Se realizó un estudio prospectivo de casos y controles que incluyó 200 sujetos diabéticos tipo 2 sin antecedentes de ECV y 60 sujetos no diabéticos pareados por edad. En este estudio evidenciamos que la RD es un predictor independiente de ECV subclínica y que SAF es un buen predictor de CAC> 400 AU (un marcador fiable de aterosclerosis coronaria). Por lo tanto, la evaluación de la RD y de SAF puede plantearse como una buena estrategia que nos ayude a seleccionar una población diabética de alto riesgo CV. En la segunda parte, el objetivo fue evaluar si la presencia de retinopatía diabética y la acumulación en el tejido subcutáneo de AGEs pueden ayudar a identificar pacientes con diabetes tipo 2 con alto riesgo de desarrollar un evento CV. Tras un seguimiento de 4,35 años, se registraron un total de 24 eventos CV, 23 eventos CV en el grupo de diabetes y 1 en el grupo control de no diabéticos. Evidenciamos que la RD y SAF (como medida de la acumulación de AGEs en la piel) son eficaces predictores de eventos cardiovasculares en sujetos con diabetes tipo 2. Concluimos, que la RD y valores altos de SAF son importantes predictores de eventos CV en sujetos con diabetes tipo 2 y, por lo tanto, podrían incluirse como variables significativas en la estratificación del riesgo CV.Type 2 diabetes confers a substantial burden of macrovascular disease. Although type 2 diabetes is an independent risk factor for cardiovascular disease (CVD), not all patients with diabetes appear to be at equal risk. In fact, a high percentage of these patients will never experience vascular complications. Therefore, early identification of diabetic patients at risk of developing CVD remains a challenge to be met. It is well known that chronic hyperglycemia is related to cardiovascular (CV) complications of diabetes. However, the exaggerated risk for CVD in this population is not explained fully by conventional risk factors. Therefore, specific diabetes-related risk factors should be involved in the excess risk for CVD, and the tissue accumulation of advanced glycation end-products (AGEs) could be one of them. AGEs accumulate in the body during aging, and this process is accelerated by chronic hyperglycemia and oxidative stress. Therefore, the formation and accumulation of AGEs are accelerated by the diabetic milieu and contribute to vascular dysfunction and the accelerated development of atherosclerotic processes. In recent years, a simple and non-invasive method for AGEs assessment through skin autofluorescence (SAF) has been validated and related to the presence of micro- and macroangiopathy in individuals with type 2 diabetes. Emerging data indicate that the presence of diabetic microvascular complications increases the risk of CVD. In particular, diabetic retinopathy (DR) has been linked with an increase in risk for all-cause and cardiovascular mortality in patients with diabetes. On this basis, the main objective of this doctoral thesis is to develop new clinical strategies to better identify those patients with T2D at high risk of developing a CV event. In the first part of this thesis, there are two specific objectives. First, to examine whether the burden and degree of microangiopathy is an independent risk factor for subclinical CVD; second to examine the usefulness of non-invasive measurement to determine skin AGEs and their relationship to diabetic complications and subclinical CVD, in diabetic subjects with no history of clinical CVD. For this purpose, a prospective case-control study comprising 200 type 2 diabetic subjects without history of clinical CVD and 60 age-matched non-diabetic subjects. We provided evidence that DR is an independent predictor of subclinical CVD and that SAF is a good predictor of a CACs > 400 AU (a reliable marker of coronary atherosclerosis). Therefore, assessment of DR and SAF measurement can be envisaged as a method to help us to select a high CV risk diabetic population. In the second part of this doctoral thesis, the aim was to evaluate whether the presence of diabetic retinopathy and the accumulation of advanced glycation end-products (AGEs) in subcutaneous tissue can help to identify patients with type 2 diabetes at high risk of developing CV events. After a follow-up of 4.35 years, a total of 24 CV events were registered, 23 CV events in type 2 diabetes group, and 1 in the non-diabetic control group. We provide evidence that DR and SAF (as a measure of tissue AGE accumulation) are powerful predictors of CV events in subjects with type 2 diabetes. In conclusion, we reconfirmed that patients with type 2 diabetes have significantly more CV events than non-diabetic subjects. In addition, DR and higher values of SAF are powerful predictors of CV events in subjects with type 2 diabetes and, therefore, might be included as meaningful variables in CV-risk stratification.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin