Postprandial lipid metabolism and its relationship with metabolic syndrome in patients with coronary disease

INTRODUCTION Postprandial lipemia (PPL) influences the development of atherosclerosis. However, there are still significant gaps to fully understanding of postprandial metabolism and its regulating factors. OBJECTIVES Main objective: To determine whether metabolic syndrome (MetS) traits influence the PPL of coronary patients, and whether this influence depends on the number of MetS criteria. Secondary objectives: 1) To investigate whether the number of criteria of metabolic syndrome may predict the degree of postprandial response in patients with normal fasting triglycerides (TGs); 2) To determine the exact contribution of the presence of MetS to age-associated enlarged PPL; 3) To explore the phenotypic flexibility of high risk patients, measured with an oral fat tolerance test (OFTT), according to different cardio-metabolic abnormalities and body mass index (BMI). METHODS We developed two independent studies: A first one where we compared the PPL response to a rich fatty meal of 88 healthy young men (<30 years old) and 97 older participants (77 MetS patients aged > 40; and 20 healthy people > 65) (all ApoE3/E3), at fasting state and at 2nd and 4th postprandial hours; and a second one where 1002 coronary artery disease patients from the CORDIOPREV study were submitted at the beginning of the study to an OFTT with 0.7 g fat/kg body weight and serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Patients were classified according to the presence of MetS and the number of its traits. We also explored in that cohort the dynamic response according to six body size phenotypes: (i) normal weight, metabolically healthy; (ii) normal weight, metabolically abnormal; (iii) overweight, metabolically healthy; (iv) overweight, metabolically abnormal; (v) obese, metabolically healthy; and (vi) obese, metabolically abnormal. RESULTS In the first study, we didn’t find differences between the healthy young men and the healthy elderly. MetS patients displayed a higher postprandial TG area below the curve than the other two cohorts p < 0.001. In the CORDIOPREV study, PPL response was directly related to the presence of MetS. We found a positive association between the number of MetS criteria and the response of postprandial plasma TGs (p= 0.001), area under the curve (AUC) of TGs (p= 0.001) and incremental AUC of TGs (p= 0.001). However, the influence of them on postprandial TGs remained statistically significant only in those patients without basal hypertriglyceridemia. Only fasting TGs, fasting glucose and waist circumference appeared as significant independent contributors (p < 0.05). Metabolically healthy patients displayed lower PPL compared with those metabolically abnormal, independently whether or not they were obese (p < 0.001 and p < 0.01, respectively). CONCLUSIONS MetS may account for the differences in PPL that have been attributed to age. Fasting TGs are the major contributors to the postprandial TGs levels. MetS influences the PPL in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients. Finally, our findings showed that certain types of the metabolic phenotypes of obesity are more favorable modulating their response to a fat load test. To identify these phenotypes may be the best strategy for personalized treatment of obesity.INTRODUCCIÓN La lipemia postprandial (LPP) influye en el desarrollo de arteriosclerosis. Sin embargo, existen importantes áreas de incertidumbre para comprender completamente el metabolismo energético postprandial y sus factores reguladores. OBJETIVOS Objetivo principal: Determinar si los rasgos de síndrome metabólico (SMet) influyen en la LPP en pacientes coronarios, y si esta influencia depende del número de criterios presentes de SMet. Objetivos secundarios: 1) investigar si el número de criterios de SMet puede predecir el grado de respuesta postprandial en pacientes con triglicéridos (TGs) plasmáticos en ayunas normales; 2) determinar la contribución exacta de la presencia de SMet en la respuesta anormal de LPP asociada a la edad; y 3) explorar la flexibilidad fenotípica de pacientes de alto riesgo, medida a través de un test de sobrecarga oral de grasa (TSOG), de acuerdo a diferentes anormalidades cardiometabólicas y al índice de masa corporal (IMC). MÉTODOS Se han desarrollado dos estudios independientes: un primer estudio comparando la respuesta en la LPP a una comida rica en grasa en 88 hombres jóvenes sanos (<30 años) y 97 participantes mayores (77 pacientes con SMet >40 años, y 20 sanos >65 años) (todos ApoE3/E3), en ayunas y a las 2 y 4 horas tras la sobrecarga; y un segundo estudio donde 1002 pacientes con enfermedad coronaria pertenecientes al estudio CORDIOPREV completaron al inicio del mismo un TSOG con 0.7 g de grasa/kg, con extracciones sanguíneas a las 0, 1, 2, 3 y 4 horas durante el estado postprandial. Los pacientes fueron clasificados según la presencia de SMet y el número de sus criterios. También se exploró en esta cohorte de pacientes coronarios su respuesta dinámica de acuerdo a seis fenotipos diferentes corporales: (i) normopeso, metabólicamente sano; (ii) normopeso, metabólicamente enfermo; (iii) sobrepeso, metabólicamente sano; (iv) sobrepeso, metabólicamente enfermo; (v) obeso, metabólicamente sano; y (vi) obeso, metabólicamente enfermo. RESULTADOS En nuestro primer estudio, no encontramos diferencias entre los varones sanos jóvenes y los mayores sanos. Los pacientes con SMet mostraron mayor magnitud en la respuesta de TGs postprandiales que los otros dos grupos (p < 0.001). En el estudio CORDIOPREV, la magnitud en la respuesta de la LPP se relacionó directamente con la presencia de SMet. Encontramos una asociación positiva entre el número de criterios de SMet y la respuesta de TGs plasmáticos postprandiales (p= 0.0001), ABC de TGs (p= 0.0001) y el incremento del area bajo la curva (AUC) de TGs plasmáticos (p= 0.001). La influencia de estos criterios sobre los TGs postprandiales sólo se mantuvo significativa en aquellos pacientes sin hipertrigliceridemia basal. Tan sólo la cifras de TGs y glucosa en ayunas, así como el perímetro de cintura se mantuvieron como predictores independientes significativos de LPP (p < 0.05). Los pacientes metabólicamente sanos mostraron menor LPP comparados con aquellos metabólicamente enfermos, independientemente de si eran obesos o no (p< 0.001). CONCLUSIONES La presencia de SMet puede modular las diferencias en LPP que han sido atribuidas a la edad. Las cifras de TG en ayunas son el factor que más influye en el grado de respuesta de TGs plasmáticos postprandiales. El SMet influye en la magnitud de la LPP de pacientes coronarios, especialmente en aquellos sin hipertrigliceridemia basal. Finalmente, nuestros hallazgos muestran que ciertos fenotipos metabólicos de obesidad son más favorables modulando su respuesta a un TSOG. Identificar estos fenotipos podría constituir la mejor estrategia para un tratamiento personalizado de la obesidad

Mediterranean Diet and Endothelial Function: A Review of Its Effects at Different Vascular Bed Levels

The Mediterranean diet has recently been the focus of considerable attention as a palatable model of a healthy diet. Its influence on many cardiovascular risk factors, combined with its proven effect in reducing the risk of cardiovascular events in primary prevention, has boosted scientific interest in this age-old nutritional model. Many of the underlying mechanisms behind its health-giving effects have been revealed, from the modulation of the microbiota to the function of high-density lipoproteins (HDL), and it seems to deliver its health benefits mainly by regulating several key mechanisms of atherosclerosis. In this review, we will review the evidence for its regulation of endothelial function, a key element in the early and late stages of atherosclerosis. In addition, we will assess studies which evaluate its effects on the functioning of different arterial territory vessels (mainly the microvascular, peripheral and central vascular beds), focusing mainly on the capillary, brachial and carotid arteries. Finally, we will evaluate the molecular mechanisms which may be involved

Ceruloplasmin and Coronary Heart Disease-A Systematic Review

Several studies indicate that oxidative stress might play a central role in the initiation and maintenance of cardiovascular diseases. It remains unclear whether ceruloplasmin acts as a passive marker of inflammation or as a causal mediator. To better understand the impact of ceruloplasmin blood levels on the risk of cardiovascular disease, and paying special attention to coronary heart disease, we conducted a search on the two most commonly used electronic databases (Medline via PubMed and EMBASE) to analyze current assessment using observational studies in the general adult population. Each study was quality rated using criteria developed by the US Preventive Services Task Force. Most of 18 eligible studies reviewed support a direct relationship between ceruloplasmin elevated levels and incidence of coronary heart disease. Our results highlight the importance of promoting clinical trials that determine the functions of ceruloplasmin as a mediator in the development of coronary heart disease and evaluate whether the treatment of elevated ceruloplasmin levels has a role in the prognosis or prevention of this condition

Evolution of Metabolic Phenotypes of Obesity in Coronary Patients after 5 Years of Dietary Intervention: From the CORDIOPREV Study

Background: Obesity phenotypes with different metabolic status have been described previously. We analyzed metabolic phenotypes in obese coronary patients during a 5-year follow-up, and examined the factors influencing this evolution. Methods: The CORDIOPREV study is a randomized, long-term secondary prevention study with two healthy diets: Mediterranean and low-fat. All obese patients were classified as either metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO). We evaluated the changes in the metabolic phenotypes and related variables after 5 years of dietary intervention. Results: Initially, 562 out of the 1002 CORDIOPREV patients were obese. After 5 years, 476 obese patients maintained their clinical and dietary visits; 71.8% of MHO patients changed to unhealthy phenotypes (MHO-Progressors), whereas the MHO patients who maintained healthy phenotypes (MHO-Non-Progressors) lost more in terms of their body mass index (BMI) and had a lower fatty liver index (FLI-score) (p < 0.05). Most of the MUO (92%) patients maintained unhealthy phenotypes (MUO-Non-Responders), but 8% became metabolically healthy (MUO-Responders) after a significant decrease in their BMI and FLI-score, with improvement in all metabolic criteria. No differences were found among dietary groups. Conclusions: A greater loss of weight and liver fat is associated with a lower progression of the MHO phenotype to unhealthy phenotypes. Likewise, a marked improvement in these parameters is associated with regression from MUO to healthy phenotypes

Circulating miRNAs as predictive biomarkers of type 2 diabetes mellitus development in coronary heart disease patients fromt he CORDIOPREV study

Circulating microRNAs (miRNAs) have been proposed as type 2 diabetes biomarkers, and they may be a more sensitive way to predict development of the disease than the currently used tools. Our aim was to identify whether circulating miRNAs, added to clinical and biochemical markers, yielded better potential for predicting type 2 diabetes. The study included 462 non-diabetic patients at baseline in the CORDIOPREV study. After a median follow-up of 60 months, 107 of them developed type 2 diabetes. Plasma levels of 24 miRNAs were measured at baseline by qRT-PCR, and other strong biomarkers to predict diabetes were determined. The ROC analysis identified 9 miRNAs, which, added to HbA1c, have a greater predictive value in early diagnosis of type 2 diabetes (AUC = 0.8342) than HbA1c alone (AUC = 0.6950). The miRNA and HbA1cbased model did not improve when the FINDRISC was included (AUC = 0.8293). Cox regression analyses showed that patients with low miR-103, miR-28-3p, miR-29a, and miR-9 and high miR-30a-5p and miR-150 circulating levels have a higher risk of disease (HR = 11.27; 95% CI = 2.61–48.65). Our results suggest that circulating miRNAs could potentially be used as a new tool for predicting the development of type 2 diabetes in clinical practice

Hypertriglyceridemia Influences the Degree of Postprandial Lipemic Response in Patients with Metabolic Syndrome and Coronary Artery Disease: From the Cordioprev Study

Objective To determine whether metabolic syndrome traits influence the postprandial lipemia response of coronary patients, and whether this influence depends on the number of MetS criteria. Materials and Methods 1002 coronary artery disease patients from the CORDIOPREV study were submitted to an oral fat load test meal with 0.7 g fat/kg body weight (12% saturated fatty acids, 10% polyunsaturated fatty acids, 43% monounsaturated fatty acids), 10% protein and 25% carbohydrates. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Total and incremental area under the curves of the different postprandial parameters were calculated following the trapezoid rule to assess the magnitude of change during the postprandial state Results Postprandial lipemia response was directly related to the presence of metabolic syndrome. We found a positive association between the number of metabolic syndrome criteria and the response of postprandial plasma triglycerides (p<0.001), area under the curve of triglycerides (p<0.001) and incremental area under the curve of triglycerides (p<0.001). However, the influence of them on postprandial triglycerides remained statistically significant only in those patients without basal hypertriglyceridemia. Interestingly, in stepwise multiple linear regression analysis with the AUC of triglycerides as the dependent variable, only fasting triglycerides, fasting glucose and waist circumference appeared as significant independent (P<0.05) contributors. The multiple lineal regression (R) was 0.77, and fasting triglycerides showed the greatest effect on AUC of triglycerides with a standardized coefficient of 0.75. Conclusions Fasting triglycerides are the major contributors to the postprandial triglycerides levels. MetS influences the postprandial response of lipids in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients

Diet and SIRT1 Genotype Interact to Modulate Aging-Related Processes in Patients with Coronary Heart Disease: From the CORDIOPREV Study

We investigated whether long-term consumption of two healthy diets (low-fat (LF) or Mediterranean (Med)) interacts with SIRT1 genotypes to modulate aging-related processes such as leucocyte telomere length (LTL), oxidative stress (OxS) and inflammation in patients with coronary heart disease (CHD). LTL, inflammation, OxS markers (at baseline and after 4 years of follow-up) and SIRT1-Single Nucleotide Polymorphisms (SNPs) (rs7069102 and rs1885472) were determined in patients from the CORDIOPREV study. We analyzed the genotype-marker interactions and the effect of diet on these interactions. Regardless of the diet, we observed LTL maintenance in GG-carriers for the rs7069102, in contrast to carriers of the minor C allele, where it decreased after follow-up (p = 0.001). The GG-carriers showed an increase in reduced/oxidized glutathione (GSH/GSSG) ratio (p = 0.003), lower lipid peroxidation products (LPO) levels (p < 0.001) and a greater decrease in tumor necrosis factor-alpha (TNF-α) levels (p < 0.001) after follow-up. After the LF diet intervention, the GG-carriers showed stabilization in LTL which was significant compared to the C allele subjects (p = 0.037), although the protective effects found for inflammation and OxS markers remained significant after follow-up with the two diets. Patients who are homozygous for the SIRT1-SNP rs7069102 (the most common genotype) may benefit from healthy diets, as suggested by improvements in OxS and inflammation in patients with CHD, which may indicate the slowing-down of the aging process and its related diseases

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study

Background/aims: Previous evidences have shown the presence of a prolonged and exaggerated postprandial response in type 2 diabetes mellitus (T2DM) and its relation with an increase of cardiovascular risk. However, the response in prediabetes population has not been established. The objective was to analyze the degree of postprandial lipemia response in the CORDIOPREV clinical trial (NCT00924937) according to the diabetic status. Methods: 1002 patients were submitted to an oral fat load test meal (OFTT) with 0.7 g fat/kg body weight [12 % saturated fatty acids (SFA), 10 % polyunsaturated fatty acids (PUFA), 43 % monounsaturated fatty acids (MUFA), 10 % protein and 25 % carbohydrates]. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 h during postprandial state. Postprandial triglycerides (TG) concentration at any point >2.5 mmol/L (220 mg/dL) has been established as undesirable response. We explored the dynamic response in 57 non-diabetic, 364 prediabetic and 581 type 2 diabetic patients. Additionally, the postprandial response was evaluated according to basal insulin resistance subgroups in patients non-diabetic and diabetic without pharmacological treatment (N = 642). Results: Prevalence of undesirable postprandial TG was 35 % in non-diabetic, 48 % in prediabetic and 59 % in diabetic subgroup, respectively (p < 0.001). Interestingly, prediabetic patients displayed higher plasma TG and large triacylglycerol- rich lipoproteins (TRLs-TG) postprandial response compared with those non-diabetic patients (p < 0.001 and p = 0.003 respectively). Moreover, the area under the curve (AUC) of TG and AUC of TRLs-TG was greater in the prediabetic group compared with non-diabetic patients (p < 0.001 and p < 0.005 respectively). Patients with liver insulin resistance (liver-IR) showed higher postprandial response of TG compared with those patients with muscle-IR or without any insulin-resistance respectively (p < 0.001). Conclusions: Our findings demonstrate that prediabetic patients show a lower phenotypic flexibility after external aggression, such as OFTT compared with nondiabetic patients. The postprandial response increases progressively according to non-diabetic, prediabetic and type 2 diabetic state and it is higher in patients with liver insulin-resistance. To identify this subgroup of patients is important to treat more intensively in order to avoid future cardiometabolic complications

Beta cell functionality and hepatic insulin resistance are major contributors to type 2 diabetes remission and starting pharmacological therapy: from CORDIOPREV randomized controlled trial

In order to assess whether previous hepatic IR (Hepatic-IR fasting) and beta-cell functionality could modulate type 2 diabetes remission and the need for starting glucose- lowering treatment, newly-diagnosed type 2 diabetes participants who had never received glucose-lowering treatment (190 out of 1002) from the CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (a prospective, randomized and controlled clinical trial), were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was defined according to the American Diabetes Association recommendation for levels of HbA1c, fasting plasma glucose and 2h plasma glucose after oral glucose tolerance test, and having maintained them for at least 2 consecutive years. Patients were classified according to the median of Hepatic-IR fasting and beta-cell functionality, measured as the disposition index (DI) at baseline. Cox proportional hazards regression determined the potential for Hepatic-IR fasting and DI indexes as predictors of diabetes remission and the probability of starting pharmacological treatment after a 5-year follow-up. Low-Hepatic-IR fasting or high-DI patients had a higher probability of diabetes remission than high-Hepatic-IR fasting or low-DI subjects (HR:1.79; 95% CI 1.06_3.05; and HR:2.66; 95% CI 1.60_4.43, respectively) after a dietary intervention with no pharmacological treatment and no weight loss. The combination of low- Hepatic-IR fasting and high-DI presented the highest probability of remission (HR:4.63; 95% CI 2.00_10.70). Among patients maintaining diabetes, those with high- Hepatic-IR fasting and low-DI showed the highest risk of starting glucose-lowerin

A plasma fatty acid profile associated to type 2 diabetes development: from the CORDIOPREV study

Purpose: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. For this reason, it is essential to identify biomarkers for the early detection of T2DM risk and/or for a better prognosis of T2DM. We aimed to identify a plasma fatty acid (FA) profile associated with T2DM development. Methods: We included 462 coronary heart disease patients from the CORDIOPREV study without T2DM at baseline. Of these, 107 patients developed T2DM according to the American Diabetes Association (ADA) diagnosis criteria after a median follow-up of 60 months. We performed a random classification of patients in a training set, used to build a FA Score, and a Validation set, in which we tested the FA Score. Results: FA selection with the highest prediction power was performed by random survival forest in the Training set, which yielded 4 out of the 24 FA: myristic, petroselinic, α-linolenic and arachidonic acids. We built a FA Score with the selected FA and observed that patients with a higher score presented a greater risk of T2DM development, with an HR of 3.15 (95% CI 2.04–3.37) in the Training set, and an HR of 2.14 (95% CI 1.50–2.84) in the Validation set, per standard deviation (SD) increase. Moreover, patients with a higher FA Score presented lower insulin sensitivity and higher hepatic insulin resistance (p < 0.05). Conclusión: Our results suggest that a detrimental FA plasma profile precedes the development of T2DM in patients with coronary heart disease, and that this FA profile can, therefore, be used as a predictive biomarker