The athero-contour: A novel tool for global and rapid assessment of atherogenic parameters. A use case in saroglitazar treatment of MAFLD patients.

BACKGROUND AND AIMS: Comprehensive assessment of pharmacotherapy effects on atherogenic parameters (AP) that influence the risk of cardiovascular disease (CVD) is challenging due to interactions among a large number of parameters that modulate CVD risk. METHODS: We developed an illustrative tool, athero-contour (AC), which incorporates weighted key lipid, lipo- and glycoprotein parameters, to readily illustrate their overall changes following pharmacotherapy. We demonstrate the applicability of AC to assess changes in AP in response to saroglitazar treatment in patients with metabolic associated fatty liver disease (MAFLD) in the EVIDENCES IV study. RESULTS: The baseline AC of saroglitazar and placebo groups was worse than the mean of the general population. After 16-week treatment, AC improved significantly in the saroglitazar group due to alterations in very low-density lipoprotein, triglyceride, and glycoproteins. CONCLUSION: Using AC, we could readily and globally evaluate and visualize changes in AP. AC improved in patients with MAFLD following saroglitazar therapy.

Clinical characterization and detection of subclinical atherosclerosis in subjects with extreme hyperalphalipoproteinemia. / Caracterización clínica y detección de arteriosclerosis subclínica en sujetos con hiperalfalipoproteinemia extrema.

INTRODUCTION AND OBJECTIVES: The association between HDL cholesterol (HDL-C) levels and death from cardiovascular disease follows a U-shaped pattern, increasing at the extremes. The objective of the study was to characterize a sample of subjects with extreme hyperalphalipoproteinemia (HAE). MATERIAL AND METHODS: 53 cases with HAE were recruited, 24 women (HDL-C>135mg/ dL) and 29 men (HDL-C>116mg/ dL). A detailed medical history was taken and questionnaires on adherence to the Mediterranean diet and physical activity were collected. Carotid ultrasounds were performed to detect the presence of suclinical atherosclerosis. RESULTS: The most prevalent cardiovascular risk factor (CVRF) was dyslipidemia (64%) with no significant differences between men and women, unlike hypertension (21% in women, versus 55% in men, p=0.01) and others CVRF, for example, diabetes. 7% of the series had previous cardiovascular disease, women had higher LDL cholesterol (p=0.002) and HDL-C than men (without significant differences). Plaque was detected in 53% of cases, being more prevalent in men. Patients with plaque were older, drank more alcohol and smoked more (p<0.05). CONCLUSIONS: Men had a higher prevalence of CVRF than women, except for dyslipidemia. Subclinical atherosclerosis occurred in more than half of the series. Age, alcohol consumption and smoking were independently associated with the presence of plaque, however, our data do not show a significant influence of HDL-C levels.

Nuevo índice aterogénico para la predicción de aterosclerosis carotídea basado en la ratio proteína C reactiva no ultrasensible/HDL / New atherogenic index for the prediction of carotid atherosclerosis based on the non-ultrasensitive c-reactive protein/HDL ratio

Introducción La valoración del riesgo cardiovascular aparece en las guías clínicas como medida de prevención de enfermedades cardiovasculares, cuya etiología fundamental es la arteriosclerosis. Una de las herramientas que se utiliza para estimar el riesgo en práctica clínica son los índices aterogénicos (IA), cocientes entre fracciones lipídicas con rangos de referencia bien establecidos. A pesar de su uso extendido, existe todavía información limitada sobre su utilidad clínica. En los últimos años, algunas investigaciones han reforzado el papel de la inflamación en la etiología y cronicidad del proceso aterosclerótico. La inclusión de parámetros inflamatorios en el cálculo de IA podría mejorar su rendimiento diagnóstico en la detección de arteriosclerosis. Nos propusimos evaluar un nuevo IA en forma de ratio entre los valores de proteína C reactiva (PCR) no ultrasensible y las cifras de colesterol unido a lipoproteínas de alta densidad (HDL). Métodos Se incluyeron en el estudio 282 pacientes, asintomáticos, y sin historia de enfermedad cardiovascular. Se realizó en todos ellos analítica con perfil lipídico y PCR, y en el plazo inferior a un mes, ecografía carotídea para evaluar la presencia de ateromatosis. El nuevo IA se estableció como el cociente entre el valor de PCR no ultrasensible en mg/dL (multiplicado por 100) y el valor de HDL en mg/dL. Se comparó con los índices de Castelli I y II, y el índice aterogénico del plasma. La curva ROC determinó que el punto de corte óptimo del nuevo IA fue valor=1, con un área bajo la curva de 0,678 (IC 95% 0,60-0,75; p<0,001). ResultadosLa edad media de la muestra fue 60,4±14,5 años. Un total de 118 pacientes (41,8% del total) tenían arteriosclerosis carotídea. Al evaluar el rendimiento diagnóstico de los IA, encontramos que la ratio PCR·100/HDL mostró los valores más elevados de sensibilidad y valor predictivo positivo (0,73 y 0,68, respectivamente) ... Conclusiones... (AU)

Introduction Current guidelines recommend cardiovascular risk assessment as a preventive measure for cardiovascular diseases, whose fundamental etiology is arteriosclerosis. One of the tools used to estimate risk in clinical practice are atherogenic indices (AI), ratios between lipid fractions with well-established reference ranges. Despite its widespread use, there is still limited information on its clinical utility. In recent years, some research has reinforced the role of inflammation in the etiology and chronicity of the atherosclerotic process. The inclusion of inflammatory parameters in the AI calculation could improve its diagnostic performance in the detection of arteriosclerosis. We sought to evaluate a new AI as a ratio between C-reactive protein (CRP) values and high-density lipoprotein cholesterol (HDL) values. Methods A total of 282 asymptomatic patients with no history of cardiovascular disease were included in the study. Laboratory tests with lipid profile and CRP, and carotid ultrasound to assess the presence of atheromatosis were performed in all of them. The new AI is established as the ratio between non-ultrasensitive CRP value in mg/dL (multiplied by 100) and HDL value in mg/dL. It was compared with the Castelli I and II indices, and the plasma atherogenic index. The optimal cut-off point of the new AI was value=1 as determined by ROC curve, with an area under the curve of 0.678 (95% CI 0.60-0.75; p<0.001).Results Mean age of patients was 60.4±14.5 years. A total of 118 patients (41.8% of total) had carotid arteriosclerosis. When evaluating the diagnostic performance of different AIs, we found that CRP·100/HDL ratio showed the highest values of sensitivity and positive predictive value (0.73 and 0.68, respectively) compared to the Castelli I and II indices, and the plasma atherogenic index. ... Conclusions ... (AU)

New atherogenic index for the prediction of carotid atherosclerosis based on the non-ultrasensitive c-reactive protein/HDL ratio. / Nuevo índice aterogénico para la predicción de aterosclerosis carotídea basado en la ratio proteína C reactiva no ultrasensible/HDL.

INTRODUCTION: Current guidelines recommend cardiovascular risk assessment as a preventive measure for cardiovascular diseases, whose fundamental etiology is arteriosclerosis. One of the tools used to estimate risk in clinical practice are atherogenic indices (AI), ratios between lipid fractions with well-established reference ranges. Despite its widespread use, there is still limited information on its clinical utility. In recent years, some research has reinforced the role of inflammation in the etiology and chronicity of the atherosclerotic process. The inclusion of inflammatory parameters in the AI calculation could improve its diagnostic performance in the detection of arteriosclerosis. We sought to evaluate a new AI as a ratio between C-reactive protein (CRP) values and high-density lipoprotein cholesterol (HDL) values. METHODS: A total of 282 asymptomatic patients with no history of cardiovascular disease were included in the study. Laboratory tests with lipid profile and CRP, and carotid ultrasound to assess the presence of atheromatosis were performed in all of them. The new AI is established as the ratio between non-ultrasensitive CRP value in mg/dL (multiplied by 100) and HDL value in mg/dL. It was compared with the Castelli I and II indices, and the plasma atherogenic index. The optimal cut-off point of the new AI was value=1 as determined by ROC curve, with an area under the curve of 0.678 (95% CI 0.60-0.75; p<0.001). RESULTS: Mean age of patients was 60.4±14.5 years. A total of 118 patients (41.8% of total) had carotid arteriosclerosis. When evaluating the diagnostic performance of different AIs, we found that CRP·100/HDL ratio showed the highest values of sensitivity and positive predictive value (0.73 and 0.68, respectively) compared to the Castelli I and II indices, and the plasma atherogenic index. It was also the only predictor of carotid atheromatosis both when considering its values quantitatively (with OR 1.4 [95% CI 1.1-1.7]; p=0.005), and qualitatively (with OR 2.9 [95% CI 1.5-5.5]; p<0.001) in patients with a CRP·100/HDL ratio>1. CONCLUSIONS: The new PCR·100/HDL index showed the best diagnostic performance in the detection of carotid atheromatosis compared to other classic AIs in this Spanish population of asymptomatic patients.

Uso de Índices Aterogênicos como Métodos de Avaliação das Doenças Ateroscleróticas Clínicas / Use of Atherogenic Indices as Assessment Methods of Clinical Atherosclerotic Diseases

Resumo Fundamento A busca por métodos clinicamente úteis de avaliação de doenças ateroscleróticas, com boa acurácia, de baixo custo, sem invasividade e de fácil manejo, há anos vem sendo estimulada. Dessa forma, os índices aterogênicos avaliados deste estudo podem se encaixar nesta demanda crescente. Objetivos Avaliar o potencial dos índices aterogênicos como métodos de avaliação de pacientes portadores de aterosclerose clínica. Métodos Estudo transversal de centro único, por meio do qual foram avaliados os índices de Castelli I e II, índice aterogênico plasmático (IAP), índice de combinação de lipoproteínas e a variação do índice de perfusão periférica entre 90 e 120 segundos após um estímulo vasodilatador endotélio-dependente (ΔIPP90-120) na predição de aterosclerose. A significância estatística foi estabelecida em p < 0,05. Resultados A amostra foi composta por 298 indivíduos com idade média de 63,0 ± 16,1 anos, dos quais 57,4% eram mulheres. Comparações pareadas da análise curva ROC dos índices que alcançaram área sob a curva (ASC) > 0,6 mostram que ΔIPP90-120 e IAP foram superiores aos demais índices, sem diferenças observadas entre si (diferença entre ASC = 0,056; IC95% -0,003-0,115). Ademais, tanto a ΔIPP90-120 [odds ratio (OR) 9,58; IC95% 4,71-19,46] quanto o IAP (OR 5,35; IC95% 2,30-12,45) foram preditores independentes de aterosclerose clínica. Conclusões O IAP e ΔIPP90-120 apresentaram melhor acurácia para discriminar aterosclerose clínica. Além disso, foram preditores independentes de aterosclerose clínica, evidenciando uma possibilidade promissora para o desenvolvimento de estratégias preventivas e de controle para doenças cardiovasculares. Tratam-se, portanto, de marcadores adequados para estudos multicêntricos do ponto de vista de praticidade, custo e validade externa.

Abstract Background The search for clinically useful methods to assess atherosclerotic diseases (ASCVD) with good accuracy, low cost, non-invasiveness, and easy handling has been stimulated for years. Thus, the atherogenic indices evaluated in this study may fit this growing demand. Objectives To assess the potential of atherogenic indices to evaluate patients with clinical atherosclerosis. Methods Single-center cross-sectional study, through which the Castelli I and II indices, the atherogenic index of plasma (AIP), the lipoprotein combine index, and the variation in the peripheral perfusion index between 90 and 120 seconds after an endothelium-dependent (ΔPI90-120) vasodilator stimulus were evaluated in the prediction of atherosclerosis. Statistical significance was set at p < 0.05. Results The sample consisted of 298 individuals with an average age of 63.0±16.1 years, of which 57.4% were women. Paired comparisons of the ROC curve analysis of the indices that reached the area under the curve (AUC) > 0.6 show that ΔPI90-120 and AIP were superior to other indices, and no differences were observed between them (difference between AUC = 0.056; 95%CI -0.003-0.115). Furthermore, both the ΔPI90-120 [odds ratio (OR) 9.58; 95%CI 4.71-19.46)] and AIP (OR 5.35; 95%CI 2.30-12.45) were independent predictors of clinical atherosclerosis. Conclusions The AIP and ΔPI90-120 represented better accuracy in discriminating clinical ASCVD. Moreover, they were independent predictors of clinical ASCVD, evidencing a promising possibility for developing preventive and control strategies for cardiovascular diseases. Therefore, they are markers for multicenter studies from the point of view of practicality, low cost, and external validity.

lipoproteínas y colesterol total en adultos con colesterolemia normal y elevada en un policlínico de Lima-Perú 2022: Un estudio correlacional / Lipoproteins and total cholesterol in adults with normal and elevated cholesterolemia in a clinic in Lima-Peru 2022: A correlational study

RESUMEN Objetivo: Evaluar el grado de correlación entre las lipoproteínas de alta densidad, baja densidad, muy baja densidad y el colesterol total en pacientes con colesterolemia normal y alta. Metodología: Estudio observacional, analítico y transversal realizado desde enero a setiembre de 2022 con 207 pacientes mayores de 18 años, divididos en un grupo de colesterol normal y otro con hipercolesterolemia. Se realizó la prueba de correlación de Spearman. Resultados: En normocolesterolémicos, hubo una correlación baja y negativa entre lipoproteínas de alta densidad y las lipoproteínas de baja densidad (-0.263) así como entre lipoproteínas de alta densidad y las de muy baja densidad (-0.220). En hipercolesterolémicos, hubo una correlación baja y positiva entre lipoproteínas de alta densidad con colesterol total (0.344). En ambos grupos, hubo una correlación alta entre colesterol y lipoproteínas de baja densidad y baja y positiva entre colesterol y lipoproteínas de muy baja densidad. Conclusiones: Las lipoproteínas se correlacionan en normocolesterolémicos y las lipoproteínas de alta densidad se correlacionan en hipercolesterolémicos.

ABSTRACT Objective: To evaluate the degree of correlation between high-density, low-density, and very low-density lipoproteins and total cholesterol in patients with normal and high cholesterolemia. Methodology: Observational, analytical and cross-sectional study carried out from January to September 2022 with 207 patients over 18 years of age divided into a group with normal cholesterol and another with hypercholesterolemia. The Spearman correlation test was performed. Results: In normocholesterolemic subjects there was a low and negative correlation between high-density lipoproteins and low-density lipoproteins (-0.263) as well as between high-density lipoproteins and very low-density lipoproteins (-0.220). In hypercholesterolemic patients there was a low and positive correlation between high-density lipoproteins and total cholesterol (0.344). In both groups there was a high correlation between cholesterol and low-density lipoproteins and a low and positive correlation between cholesterol and very low-density lipoproteins. Conclusions: Lipoproteins are correlated in normocholesterolemics and high-density lipoproteins are correlated in hypercholesterolemics.

Interferencia generada por la lipemia en la medición de constituyentes bioquímicos

Introducción. La turbidez por lipemia en las muestras para diagnóstico es una de las principales causas de la aparición de sesgos clínicamente significativos en la medición de magnitudes bioquímicas. Objetivo. Valorar la interferencia por lipemia en la medición de 25 constituyentes bioquímicos en dos analizadores con tecnología de química seca (Vitros 7600®) y química liquida (Atellica® Solution). Métodos. Estudio pre-experimental con pre y posprueba. Se añadieron cantidades crecientes de una emulsión lipídica de nutrición parenteral a siete alícuotas de una mezcla de sueros y se determinó por duplicado la influencia del interferente en 25 constituyentes. Se calculó el porcentaje relativo de desviación de la concentración del constituyente por influencia de la turbidez con respecto a una muestra sin interferente. Se establecieron límites de tolerancia para la interferencia utilizando tres criterios: del distribuidor de reactivos, del error sistemático deseable y del error máximo admisible. Resultados. Los constituyentes que presentaron los mayores sesgos para el analizador de química liquida fueron: fósforo (-84,72%), ALT (+81,25%) y AST (-75,76%), mientras que para la plataforma de química seca los constituyentes: ALT (-79,41%), CK (-28,92%) y lipasa (+24,85%). Se detectó interferencia significativa en diferente número de los constituyentes de acuerdo con el criterio de límite tolerable utilizado. Conclusiones. Los distintos resultados encontrados según la metodología y el analizador utilizado, además de la falta de replicabilidad de los ensayos para la valoración de interferencia por lipemia, origina la necesidad de armonizar los procesos e instaurar límites idénticos de interferencia tolerables entre los laboratorios y proveedores de insumos.

Introduction. Turbidity due to lipemia in diagnostic samples is one of the main causes of the appearance of clinically significant biases in the measurement of biochemical magnitudes. Objective. To assess the interference by lipemia in the measurement of 25 biochemical constituents in two analyzers with dry chemistry technology (Vitros 7600®) and liquid chemistry (Atellica® Solution). Methods. Pre-experimental study with pre and post test. Increasing amounts of a parenteral nutrition lipid emulsion were added to seven aliquots of pooled sera and the influence of the interferent on 25 constituents was determined in duplicate. The relative percentage deviation of the concentration of the constituent due to the influence of turbidity with respect to a sample without interference, was calculated. Tolerance limits for interference were established using three criteria: reagent distributor, desirable systematic error, and maximum permissible error. Results. The constituents that presented the greatest biases for the liquid chemistry analyzer were: Phosphorus (-84.72%), ALT (+81.25%) and AST (-75.76%), while for the dry chemistry platform the constituents, ALT (-79.41%), CK (-28.92%) and lipase (+24.85%). Significant interference was detected in a different number of constituents according to the tolerable limit criteria used. Conclusions. The different results found according to the methodology and the analyzer used, in addition to the lack of replicability of the tests for the evaluation of interference by lipemia, originates the need to harmonize the processes and establish identical limits of tolerable interference between the laboratories and suppliers of inputs.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis / Los beneficios de medir el tamaño y el número de partículas de lipoproteínas para la predicción del riesgo cardiovascular: una revisión sistemática y un metaanálisis

Objective: Cardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. Material and methods: A literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case–control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). Results: This review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. Conclusion: Larger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.(AU)

Objetivo: El riesgo cardiovascular (RCV) se calcula convencionalmente midiendo el contenido de colesterol total de las lipoproteínas de alta densidad (HDL) y las lipoproteínas de baja densidad (LDL). El propósito de esta revisión sistemática fue evaluar el RCV asociado con el tamaño y el número de partículas de LDL y HDL, según lo determinado por espectroscopia de resonancia magnética nuclear (RMN). Material y métodos: Se realizó una búsqueda bibliográfica utilizando las bases de datos electrónicas Medline y Scopus. Se incluyeron todos los estudios de cohortes y de casos y controles publicados antes del 1 de enero de 2019, que cumplieron con los siguientes criterios de inclusión: HDL-P, LDL-P, HDL-Z y/o LDL-Z medidos por espectroscopia de RMN; evento cardiovascular como variable de resultado; riesgo de eventos cardiovasculares expresado como cociente de posibilidades o cociente de riesgos instantáneos; solo pacientes adultos. Se realizó un metaanálisis para cada variable de exposición (cuatro para LDL y cinco para HDL) y para cada medida de exposición (cuartil más alto vs. más bajo e incremento de 1 desviación estándar [DE]). Resultados: Esta revisión incluyó 24 estudios. El número de partículas LDL se asoció directamente con el RCV: el riesgo aumentó 28% con cada incremento de la DE. El tamaño de las partículas de LDL se asoció inversa y significativamente con el RCV: cada incremento de la DE correspondió a una reducción del riesgo de 8%. El RCV aumentó 12% con cada aumento de la DE en el número de partículas pequeñas de LDL. HDL, número y tamaño de partículas se asociaron inversamente con CVR. Conclusión: El tamaño de partícula más grande proporcionó una mayor protección, aunque esta relación fue inconsistente entre los estudios. Un mayor número de partículas de LDL y un tamaño de partícula de LDL más pequeño se asocian con un aumento de la RCV. El riesgo disminuye con el aumento del número y tamaño de las partículas de HDL.(AU)

Colesterol remanente, riesgo vascular y prevención de la arteriosclerosis / Remnant cholesterol, vascular risk, and prevention of atherosclerosis

En los pacientes que han alcanzado un control óptimo del c-LDL persiste un riesgo residual de enfermedad cardiovascular aterotrombótica (ECVA) relacionado con alteraciones del metabolismo lipídico, entre las que las alteraciones de las lipoproteínas ricas en triglicéridos y del colesterol que contienen, denominado colesterol remanente, juegan un papel principal. El colesterol remanente tiene una relación con el riesgo residual de ECVA que es independiente del c-LDL y ha sido demostrada en los estudios epidemiológicos y de aleatorización mendeliana, y en los análisis de los ensayos clínicos con fármacos hipolipidemiantes. Las partículas remanentes de las lipoproteínas ricas en triglicéridos son altamente aterogénicas, por su capacidad de entrar y ser retenidas en la pared arterial, su alto contenido en colesterol y su capacidad de generar células espumosas y una respuesta inflamatoria. La valoración del colesterol remanente puede aportar información sobre el riesgo residual de ECVA más allá de la información aportada por el c-LDL, el c-no HDL y la apoB, en particular en los individuos con hipertrigliceridemia, diabetes tipo 2 o síndrome metabólico. En el estudio REDUCE-IT se demostró que el icosapento de etilo tiene un efecto preventivo frente a la ECVA en los pacientes de muy alto riesgo cardiovascular con hipertrigliceridemia tratados con estatinas y con un c-LDL en objetivos. Los nuevos fármacos hipolipidemiantes contribuirán a definir la eficacia y los criterios en el tratamiento del exceso de colesterol remanente y de la hipertrigliceridemia en la prevención de la ECVA.(AU)

In patients who have achieved optimal LDL-C control, there remains a residual risk of atherothrombotic cardiovascular disease (ACVD) related to alterations in lipid metabolism, where alterations in triglyceride-rich lipoproteins and the cholesterol they contain, called remnant cholesterol, play a major role. Remnant cholesterol has an association with residual risk of ACVD that is independent of LDL-C and has been demonstrated in epidemiological and Mendelian randomisation studies, and in analyses of clinical trials of lipid-lowering drugs. Remnant triglyceride-rich lipoproteins particles are highly atherogenic, due to their ability to enter and be retained in the arterial wall, their high cholesterol content, and their ability to generate “foam cells” and an inflammatory response. Assessment of remnant cholesterol may provide information on residual risk of ACVD beyond the information provided by LDL-C, Non-HDL-C, and apoB, particularly in individuals with hypertriglyceridaemia, type 2 diabetes, or metabolic syndrome. In the REDUCE-IT study, icosapent ethyl was shown to have a preventive effect against ACVD in very high cardiovascular risk patients with hypertriglyceridaemia treated with statins and target LDL-C. New lipid-lowering drugs will help to define efficacy and criteria in the treatment of excess remnant cholesterol and hypertriglyceridaemia in the prevention of ACVD.(AU)

Remnant cholesterol, vascular risk, and prevention of atherosclerosis. / Colesterol remanente, riesgo vascular y prevención de la arteriosclerosis.

In patients who have achieved optimal LDL-C control, there remains a residual risk of atherothrombotic cardiovascular disease (ACVD) related to alterations in lipid metabolism, where alterations in triglyceride-rich lipoproteins and the cholesterol they contain, called remnant cholesterol, play a major role. Remnant cholesterol has an association with residual risk of ACVD that is independent of LDL-C and has been demonstrated in epidemiological and Mendelian randomisation studies, and in analyses of clinical trials of lipid-lowering drugs. Remnant triglyceride-rich lipoproteins particles are highly atherogenic, due to their ability to enter and be retained in the arterial wall, their high cholesterol content, and their ability to generate "foam cells" and an inflammatory response. Assessment of remnant cholesterol may provide information on residual risk of ACVD beyond the information provided by LDL-C, Non-HDL-C, and apoB, particularly in individuals with hypertriglyceridaemia, type 2 diabetes, or metabolic syndrome. In the REDUCE-IT study, icosapent ethyl was shown to have a preventive effect against ACVD in very high cardiovascular risk patients with hypertriglyceridaemia treated with statins and target LDL-C. New lipid-lowering drugs will help to define efficacy and criteria in the treatment of excess remnant cholesterol and hypertriglyceridaemia in the prevention of ACVD.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis.

OBJECTIVE: Cardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. MATERIAL AND METHODS: A literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case-control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). RESULTS: This review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. CONCLUSION: Larger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.

Os Ácidos Graxos Poli-insaturados Ômega-6 e Ômega-3 Presentes nas Hemácias Exercem uma Influência Distinta sobre o Tamanho das Partículas de LDL e suas Alterações Estruturais / Red Blood Cells' Omega-6 and Omega-3 Polyunsaturated Fatty Acids Have a Distinct Influence on LDL Particle Size and its Structural Modifications

Resumo Fundamento Embora os ácidos graxos poli-insaturados ômega-3 e ômega-6 (AGPIs n-3 e n-6) tenham efeitos bem conhecidos sobre os fatores de risco de doenças cardiovasculares (DCV), ainda existe um conhecimento limitado sobre como eles afetam os indicadores de qualidade da LDL. Objetivo Avaliar as associações dos AGPIs n-3 e n-6 de hemácias com o tamanho da partícula da LDL, LDL-c pequena e densa (sdLDL-c) e com LDL eletronegativa [LDL(-)] em adultos com fatores de risco para DCV. Métodos Estudo transversal com 335 homens e mulheres de 30 a 74 anos com, pelo menos, um fator de risco cardiovascular. Foram realizadas análises de parâmetros bioquímicos, como glicose, insulina, HbA1c, proteína C reativa (PCR), perfil lipídico, subfrações de lipoproteínas, partícula eletronegativa de LDL [LDL(-)] e seu autoanticorpo, e os AGPIs n-3 e n- 6 de hemácias. Os testes t independente/teste de Mann-Whitney, ANOVA unidirecional/teste de Kruskal-Wallis e regressões lineares múltiplas foram aplicados. Todos os testes foram bilaterais e um valor de p inferior a 0,05 foi considerado estatisticamente significativo. Resultados A relação n-6/n-3 de hemácias foi associada ao aumento dos níveis de LDL(-) (β = 4,064; IC de 95% = 1,381 - 6,748) e sdLDL-c (β = 1,905; IC de 95% = 0,863 - 2,947), e redução do tamanho das partículas de LDL (β = -1,032; IC de 95% = -1,585 − -0,478). Individualmente, os AGPIs n-6 e n-3 apresentaram associações opostas com esses parâmetros, realçando os efeitos protetores do n-3 e evidenciando os possíveis efeitos adversos do n-6 na qualidade das partículas de LDL. Conclusão O AGPI n-6, presente nas hemácias, foi associado ao aumento do risco cardiometabólico e à aterogenicidade das partículas de LDL, enquanto o AGPI n-3 foi associado a melhores parâmetros cardiometabólicos e à qualidade das partículas de LDL.

Abstract Background While Omega-3 and omega-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs) have established effects on cardiovascular disease (CVD) risk factors, little is known about their impacts on LDL quality markers. Objective To assess the associations of n-3 and n-6 PUFA within red blood cells (RBC) with LDL particle size, small dense LDL-c (sdLDL-c), and electronegative LDL [LDL(-)] in adults with CVD risk factors. Methods Cross-sectional study involving 335 men and women aged 30 to 74 with at least one cardiovascular risk factor. Analyses were conducted on biochemical parameters, such as glucose, insulin, HbA1c, C-reactive protein (CRP), lipid profile, lipoprotein subfractions, electronegative LDL particle [LDL(-)] and its autoantibody, and RBC n-3 and n-6 PUFAs. Independent t-test/Mann-Whitney test, one-way ANOVA/Kruskal-Wallis test, and multiple linear regressions were applied. All tests were two-sided, and a p-value of less than 0.05 was considered statistically significant. Results The RBC n-6/n-3 ratio was associated with increased LDL(-) (β = 4.064; 95% CI = 1.381 - 6.748) and sdLDL-c (β = 1.905; 95% CI = 0.863 - 2.947) levels, and reduced LDL particle size (β = -1.032; 95% CI = -1.585 − -0.478). Separately, n-6 and n-3 PUFAs had opposing associations with those parameters, reinforcing the protective effects of n-3 and showing the potential negative effects of n-6 on LDL particle quality. Conclusion RBC n-6 PUFA was associated with increased cardiometabolic risk and atherogenicity of LDL particles, while n-3 PUFA was associated with better cardiometabolic parameters and LDL particle quality.

Investigação da Relação entre Índice de Triglicerídeos-Glicose e Fluxo Lento Coronariano: Um Estudo Retrospectivo de Caso-Controle / Investigation of the Relationship Between Triglycerides-Glucose İndex and Coronary Slow Flow: A Retrospective Case-Control Study

Resumo Fundamento O fluxo lento coronariano (FLC) refere-se à opacificação retardada dos vasos distais na ausência de estenose da artéria coronária epicárdica. O mecanismo etiopatogênico do FLC ainda não está claro. Objetivos Este estudo investiga a relação entre o FLC e o índice de triglicerídeos-glicose (TyG). Métodos A amostra do estudo consistiu de 118 pacientes com FLC e 105 pacientes com fluxo coronariano normal (FCN). A taxa de fluxo coronariano foi medida por medio do método de contagem de quadros (TFC) Thrombolysis in Myocardial Infarction (TIMI) em todos os pacientes. O índice TyG foi calculado como o logaritmo do valor [triglicerídeos em jejum (mg/dL)×glicose em jejum (mg/dL)]/2. Adotou-se como estatisticamente significativo o nível de significância < 0,05. Resultados O índice TyG, lipoproteína de baixa densidade (LDL), índice de massa corporal (IMC), relação neutrófilo-linfócito (RNL) e valores de TFC, proporção masculina e proporção de fumantes foram maiores, enquanto os níveis de lipoproteína de alta densidade (HDL) foram significativamente menores no grupo FLC em comparação com o grupo FNC (p<0,05). A análise de correlação revelou que o FLC estava significativamente correlacionado com os valores do índice TyG, IMC, RNL e HDL. A mais forte dessas correlações foi entre o FLC e o índice TyG (r= 0,57, p<0,001). Além disso, a análise multivariada revelou que o índice TyG, IMC, razão RNL e sexo masculino foram preditores independentes para FLC (p<0,05). A análise da curva ROC (Receiver Operating Characteristic) indicou que um valor de corte ≥ 9,28 para o índice TyG previu FLC com sensibilidade de 78% e especificidade de 78,1% [Área sob a curva (AUC): 0,868 e 95% intervalo de confiança (IC): 0,823-0,914]. Conclusão Os achados deste estudo revelaram uma relação muito forte entre o FLC e o índice TyG.

Abstract Background Coronary slow flow (CSF) refers to delayed distal vessel opacification in the absence of epicardial coronary artery stenosis. The etiopathogenic mechanism of CSF is still unclear. Objectives This study investigates the relationship between CSF and the triglyceride-glucose (TyG) index. Methods The study sample consisted of 118 CSF patients and 105 patients with normal coronary flow (NCF). The coronary flow rate was measured via the Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) method in all patients. The TyG index was calculated as the logarithm of the [fasting triglyceride (mg/dL)×fasting glucose (mg/dL)]/2 value. A significance level of < 0.05 was adopted as statistically significant. Results The TyG index, low-density lipoprotein (LDL), body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR) and TFC values, male ratio, and the ratio of smokers were higher, whereas high-density lipoprotein (HDL) levels were significantly lower in the CSF group compared to the NCF group (p<0,05). The correlation analysis revealed that CSF was significantly correlated with TyG index, BMI, NLR, and HDL values. The strongest of these correlations was between CSF and TyG index (r= 0.57, p<0.001). Additionally, the multivariate analysis revealed that TyG index, BMI, NLR ratio, and male gender were independent predictors for CSF (p<0.05). Receiver operating characteristic (ROC) curve analysis indicated that a cut-off value of ≥ 9.28 for the TyG index predicted CSF with a sensitivity of 78% and a specificity of 78.1% [Area under the curve (AUC): 0.868 and 95% Confidence Interval (CI): 0.823-0.914]. Conclusion The findings of this study revealed a very strong relationship between CSF and TyG index.

Associação Positiva entre Autoanticorpos contra LDL Oxidada e HDL-C: Um Novo Mecanismo para Cardioproteção de HDL? / Positive Association between Autoantibodies Against Oxidized LDL and HDL-C: A Novel Mechanism for HDL Cardioprotection?

Resumo Fundamento No microambiente da placa aterosclerótica, os fosfolipídios oxidados expressos na superfície de lipoproteína de baixa densidade oxidada (oxLDL) se ligam a receptores scavenger em macrófagos provocando a formação de células espumosas e a progressão da placa. Autoanticorpos contra oxLDL (oxLDL-Ab) interagem com epítopos oxidativos levando à formação de imunocomplexos que são incapazes de interagir com receptores de macrófagos, assim suprimindo a aterogênese. A liberação de oxLDL-Ab pelas células B envolve a resposta da interleucina 5 e Th2, que por sua vez são potencializadas pela HDL. Assim, levantamos a hipótese de que indivíduos com níveis mais altos de HDL-C podem apresentar níveis elevados de oxLDL-Ab. Objetivo Avaliar a relação entre os níveis de HDL-C e oxLDL-Ab. Métodos Indivíduos assintomáticos (n = 193) foram agrupados de acordo com sua concentração de HDL-C para uma das três categorias seguintes: baixa (< 68 mg/dL), intermediária (de 68 a 80 mg/dL) ou alta (> 80 mg/dL). Os valores p < 0,05 foram considerados estatisticamente significativos. Resultados Nossa análise incluiu 193 indivíduos (média etária: 47 anos; masculino: 26,3%). Em comparação com os indivíduos no menor tercil de HDL-C, os mais elevados foram mais velhos (36 versus 53 anos; p = 0,001) e, menos frequentemente, masculinos (42,6% versus 20,9%; p = 0,001). Os valores médios de oxLDL-Ab aumentaram à medida que o grupo HDL-C aumentou (0,31, 0,33 e 0,43 unidades, respectivamente; p = 0,001 para tendência). A regressão linear simples encontrou uma relação significativa e positiva entre a variável independente, HDL-C, e a variável dependente, oxLDL-Ab (R = 0,293; p = 0,009). Essa relação manteve-se significativa (R = 0,30; p = 0,044), após ajuste por covariáveis. Os níveis de apolipoproteína AI também estiveram relacionados a oxLDL-Ab nos modelos de regressão linear simples e ajustada. Conclusões HDL-C e oxLDL-Ab estão independentemente relacionados.

Abstract Background In the atherosclerotic plaque microenvironment, oxidized phospholipids expressed in the oxidized low-density lipoprotein (oxLDL) surface bind to scavenger receptors of macrophages eliciting foam cell formation and plaque progression. Auto-antibodies against oxLDL (oxLDL-Ab) interact with oxidative epitopes leading to the formation of immune complexes that are unable to interact with macrophage receptors, thus abrogating atherogenesis. Release of oxLDL-Ab by B cells involves interleukin 5 and Th2 response, which in turn are potentiated by HDL. Thereby, we hypothesized that individuals with higher levels of HDL-C may plausibly display elevated titers of oxLDL-Ab. Objective To evaluate the relationship between HDL-C and oxLDL-Ab levels. Methods Asymptomatic individuals (n = 193) were grouped according to their HDL-C concentration to one of three categories: low (< 68 mg/dL), intermediate (68 to 80 mg/dL) or high (> 80 mg/dL). P values < 0.05 were considered statistically significant. Results Our analysis included 193 individuals (mean age: 47 years; male: 26.3%). Compared to individuals in the lowest HDL-C tertile, those in the highest tertile were older (36 versus 53 years; p = 0.001) and less frequently male (42.6% versus 20.9%; p = 0.001). Mean values of oxLDL-Ab increased as the HDL-C group escalated (0.31, 0.33 and 0.43 units, respectively; p = 0.001 for trend). Simple linear regression found a significant, positive relationship between the independent variable, HDL-C, and the dependent variable, oxLDL-Ab (R = 0.293; p = 0.009). This relation remained significant (R = 0.30; p = 0.044), after adjustment by covariates. Apolipoprotein AI levels were also related to oxLDL-Ab in both simple and adjusted linear regression models. Conclusion HDL-C and oxLDL-Ab are independently related.

Perfil lipoproteico por espectroscopia nuclear magnética en pacientes con insuficiencia cardiaca crónica comparado con controles emparejados / 1H-magnetic resonance spectroscopy lipoprotein profile in patients with chronic heart failure versus matched controls

Introducción y objetivos El fenotipado avanzado de lipoproteínas es mejor predictor del riesgo aterosclerótico que el colesterol. El perfil de lipoproteínas en la insuficiencia cardiaca (IC) no está completamente caracterizado. Nuestro objetivo fue describir el perfil de lipoproteínas en IC crónica en comparación con una población de control emparejada. Métodos Estudio transversal entre mayo 2006 y abril 2014, que incluyó pacientes ambulatorios con IC crónica. Las concentraciones de lípidos y el tamaño de las principales fracciones de lipoproteínas (lipoproteínas de alta densidad [HDL], lipoproteínas de baja densidad [LDL] y lipoproteínas de muy alta densidad) y concentración de sus subfracciones (grandes, medianas y pequeñas) se evaluaron mediante espectroscopia de resonancia magnética. Resultados 429 pacientes con IC crónica se compararon con 428 controles. Los pacientes con IC crónica presentaron menor colesterol total y menor concentración de partículas de LDL (1.115 frente a 1.352 nmol/L; p <0,001) y HDL (25,7 frente a 27,9μmol/L; p <0,001), esta última mediada principalmente por la reducción de la subfracción pequeña de HDL (15,2 frente a 18,6μmol/L; p <0,001). El tamaño medio de las partículas lipoproteínas de muy alta densidad, LDL y HDL fue significativamente mayor en los pacientes con IC. Todas las diferencias relacionadas con la partícula HDL persistieron después del ajuste por clase funcional o índice de masa corporal. Encontramos fuertes correlaciones negativas entre biomarcadores cardiacos (fracción aminoterminal del propéptido natriurético cerebral y interleucina-1 tipo de receptor 1) con concentraciones de LDL y HDL, sus subfracciones pequeñas y el tamaño de la partícula HDL. Conclusione Los pacientes con IC crónica difieren significativamente en su perfil de lipoproteínas en comparación con controles emparejados. Se necesitan más investigaciones para comprender mejor la relevancia patogénica de esta diferencia (AU)

Introduction and objectives Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. Methods This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. Results The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9μmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6μmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. Conclusions Patients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference (AU)

¿Por qué los osos pardos están protegidos contra la aterosclerosis a pesar de que sus niveles de colesterol plasmático doblan al de los humanos? / Why are brown bears protected against atherosclerosis even though their plasma cholesterol levels are twice that of humans?

Los niveles plasmáticos de colesterol y triglicéridos son 2 veces más altos en los osos pardos (Ursus arctos) durante el periodo de hibernación que en los humanos sanos. Sin embargo, los osos no muestran signos de desarrollo de aterosclerosis. Para explorar esta aparente paradoja, analizamos lipoproteínas del plasmas de 10 osos recolectados durante el invierno (hibernación: febrero) y verano (activo: junio) en el mismo año. El plasma de 14 humanos sanos se analizó como comparador. Se utilizaron métodos estándar para el aislamiento de lipoproteínas, la composición y la investigación funcional. Los resultados muestran que en los osos pardos la ausencia de aterosclerosis a pesar del colesterol elevado probablemente se asocie con 2 propiedades ateroprotectoras principales de las lipoproteínas circulantes. En primer lugar, una afinidad significativamente, 10 veces menor, de las partículas de lipoproteínas de baja densidad (LDL) por los proteoglicanos arteriales y, en segundo lugar, una capacidad elevada de eflujo de colesterol en plasma comparado con humanos. ¿Qué nos dicen los datos del oso pardo? Ese colesterol total elevado y las lipoproteínas que contienen ApoB no siempre se asocian con la enfermedad de aterosclerosis. Necesitamos observar también las características bioquímicas y la funcionalidad de las lipoproteínas, ya que son relevantes para la fisiopatología arterial. ¿Cuál es la traducibilidad al humano de estos resultados? Los humanos necesitamos controlar nuestros niveles de colesterol total y LDL. ¡No somos osos pardos!.(AU)

Plasma cholesterol and triglyceride levels are twice as high in hibernating brown bears (Ursus arctos) than in healthy humans. Yet, bears display no sign of atherosclerosis development. To explore this apparent paradox, we analyzed lipoproteins from same ten individual bears plasma collected during winter (hibernation; February) and summer (active; June) in the same year. Plasma from fourteen healthy humans were analyzed as comparator. We used standard methods for lipoprotein isolation, composition and functional investigation. The results shows that in brown bears the absence of atherosclerosis despite elevated cholesterol is likely associated with two main athero-protective properties of circulating lipoproteins. First, a significant ten times lower affinity of low-density-lipoprotein (LDL) particles for arterial proteoglycans and secondly, an elevated plasma cholesterol efflux capacity. What does the brown bear data tell us? That elevated total cholesterol and ApoB-containing lipoproteins not always associates with atherosclerosis disease. We need to look also at the lipoprotein biochemical features and functionality as they are relevant for arterial pathophysiology. What is the translatability into human of these results? We humans need to control our total and LDL-cholesterol levels. We are not brown bears!.(AU)

Alteration in serum oxidative stress balance in patients with different circulating high-density lipoprotein cholesterol levels.

INTRODUCTION AND OBJECTIVES: High-density lipoprotein cholesterol (HDL-C) is known to be a key player in reverse cholesterol transport and this function is associated with its atheroprotective role. Low HDL-C is a strong independent risk factor for cardiovascular disease, premature atherosclerosis and increased oxidative stress. However, the clinical benefit of high HDL-C through diet or drug therapy is still controversial. METHODS: This study included 50 patients with isolated low HDL-C (≤35 mg/dl), 52 patients with isolated high HDL-C (≥70 mg/dl), and 33 age- and gender-matched controls with normal HDL-C. 'Isolated' was defined as excluding all clinical conditions associated with increased oxidative stress and inflammation, which may affect the structural state of HDL-C. In addition to arylesterase (ARES) activity and plasma thiol levels, laboratory parameters associated with oxidative stress were also assessed. RESULTS: Levels of ARES (758 [169-1150] vs. 945 [480-1215] and 821 U/l [266-1220]; p<0.01) and total thiols (233±41 vs. 259±46 µmol/l; p=0.02) were markedly higher in patients with high HDL-C. More importantly, total antioxidant capacity, oxidative stress index, creatine and serum ARES levels were associated with changes in serum HDL-C levels. CONCLUSION: In patients with isolated high HDL-C, we determined that while serum ARES activity and plasma thiol concentrations were significantly higher, the other markers associated with oxidative stress decreased markedly. Additionally, the present study demonstrated that serum oxidative stress status is very important to maintain the positive effects of HDL-C.