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.

Treatment of mild-to-moderate hypertriglyceridemia. / Tratamiento de la hipertrigliceridemia leve-moderada.

The atherogenic role of triglycerides (TG) as an independent cardiovascular risk factor has been discussed for many years, largely because hypertriglyceridaemia (HTG) is a complex metabolic entity of multiple aetiology involving processes of diverse nature. In this chapter, a discussion will be presented on the current recommendations for the management of mild-moderate hypertriglyceridaemia (150-880mg/dL). The aim of the interventions used is to decrease the LDL-cholesterol (c-LDL) and control the HTG. This entails reducing apoprotein B (ApoB) levels, the number of remaining TG-rich lipoproteins (LRP), non-HDL-cholesterol (c-non-HDL), and increasing HDL-cholesterol (c-HDL). The management strategy includes healthy lifestyle recommendations, and subsequent use of lipid-lowering drugs, including statins, fibrates, n-3 fatty acids and PCSK9 inhibitors.

Evaluation and management of residual cardiovascular risk in patients with diabetes. / Evaluación y manejo del riesgo cardiovascular residual en el paciente con diabetes.

Presence of diabetes (types 1 and 2) increases the risk of atherosclerotic cardiovascular disease. Despite adequate metabolic control and treatment of vascular risk factors until the goals recommended by the clinical practice guidelines are achieved, residual cardiovascular risk may be very high in some patients with diabetes. Stratifying the vascular risk for each patient as precisely as possible is therefore necessary. Consolidated strategies to improve patient prognosis include aggressive reduction of LDL cholesterol, blood pressure control, achievement of the best HbA1c control possible without inducing hypoglycemia, use of hypoglycemic drugs shown to have cardiovascular benefits, and use of platelet aggregation inhibitors in patients with greater initial risk. Emerging strategies for patients with very high or extreme risk would include use of drugs intended to decrease triglyceride-rich lipoproteins and inflammation.

Control of the overall lipid profile. / Control del perfil lipídico global.

The importance of overall lipid control in cardiovascular prevention is reviewed. Several studies and meta-analyses show that the control of LDL cholesterol (LDL-C) still maintains a high cardiovascular risk, which is related to the presence of triglyceride-rich lipoproteins, and therefore with an increase in plasma triglycerides and the values of apolipoprotein B (apoB) containing these lipoproteins. The importance of this relationship is due to the change in the lipid profile of our population in recent years. This is related to the increase in obesity and insulin resistance, and is called atherogenic dyslipidaemia. Thus, hypertriglyceridaemia should be considered a cardiovascular risk factor, especially when the desirable objectives of LDL-C have been achieved. The indications for treatment with fibrates in primary and secondary prevention, using the medical evidence-based recommendations, are described, along with its importance in the reduction of cardiovascular risk. Finally, the established indications of the combined statin-fibrate treatment are presented, always after changes in lifestyle.

Residual cardiovascular risk of lipid origin. Components and pathophysiological aspects. / Riesgo cardiovascular residual de origen lipídico. Componentes y aspectos fisiopatológicos.

There is no doubt about the relationship between LDL-c and cardiovascular risk, as well as about the benefits of statin treatment. Once the objective of LDL-c has been achieved, the evidences that demonstrate the persistence of a high cardiovascular risk, a concept called residual risk, are notable. The residual risk of lipid origin is based on atherogenic dyslipidemia, characterized by an increase in triglycerides and triglyceride-rich lipoproteins, a decrease in HDL-c and qualitative alterations in LDL particles. The most commonly used measures to identify this dyslipidemia are based on the determination of total cholesterol, triglycerides, HDL, non-HDL cholesterol and remaining cholesterol, as well as apolipoprotein B100 and lipoprotein (a) in certain cases. The treatment of atherogenic dyslipidemia is based on weight loss and physical exercise. Regarding pharmacological treatment, we have no evidence of cardiovascular benefit with drugs aimed at lowering triglycerides and HDL-c, fenofibrate seems to be effective in situations of atherogenic dyslipidemia.

Lipoproteínas ricas en triglicéridos y riesgo cardiovascular residual / Triglyceride rich lipoproteins and residual cardiovascular risk / Lipoproteínas ricas em triglicerídeos e risco cardiovascular residual / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen Una vasta evidencia científica de resultados de ensayos clínicos, preclínicos, epidemiológicos y genéticos, mostraron una asociación causal entre el aumento de triglicéridos (TG), lipoproteínas ricas en TG (LRT) y sus remanentes para la enfermedad cardiovascular aterosclerótica (ECA). La acumulación de LRT circulantes puede explicar, en parte, el riesgo cardiovascular residual que se observa en pacientes eficazmente tratados para reducir sus niveles de LDL; sin embargo, persiste el riesgo de ECA. Es imprescindible que en el estudio del perfil lipídico se considere la determinación o estimación de estas lipoproteínas, sumada a la medida de TG plasmáticos. El objetivo de la presente revisión fue actualizar el conocimiento acerca de los niveles incrementados de TG, de LRT y sus remanentes, brindar alternativas para su determinación y comprender los mecanismos que involucran a las LRT en el desarrollo acelerado de la aterosclerosis. La actualización de los diferentes parámetros asociados al aumento de TG y sus valores de corte o límites de decisión clínica según la clasificación del riesgo de ECA para cada paciente, permitirá el rediseño de un informe de resultados que será de gran utilidad para el médico y el paciente con respecto a las conductas preventivas y terapéuticas de la ECA.

Abstract Vast scientific evidence from clinical, preclinical, epidemiological, and genetic trial results show a causal association between increased triglycerides (TG), TG-rich lipoproteins (TRL), and their remnants for atherosclerotic cardiovascular disease (ASCVD). The accumulation of circulating LRT may explain, in part, the residual cardiovascular risk observed in patients successfully treated to reduce their LDL levels, however, the risk of ASCVD still persists. It is essential that in the assessment of the lipid profile, the determination or estimation of these lipoproteins be considered, added to the measurement of plasmatic TG. The objective of this review is to update the knowledge about the increased levels of TG, LRT and their remnants, proprovide alternatives for their determination and understand the mechanisms that involve LRT in the accelerated development of atherosclerosis. Updating the different parameters associated with increased TG and their cut-off values or clinical decision limits according to the ASCVD risk classification for each patient will allow for the redesign of a results report that will be very useful for the physician and the patient regarding the preventive and therapeutic behaviours of the ASCVD.

Resumo Vastas evidências científicas de resultados de ensaios clínicos, pré-clínicos, epidemiológicos e genéticos mostraram uma associação causal entre o aumento de triglicerídeos (TG), lipoproteínas ricas em TG (LRT) e seus remanescentes para doença cardiovascular aterosclerótica (DCA). O acúmulo de LRT circulante pode explicar, em parte, o risco cardiovascular residual observado em pacientes tratados de maneira eficaz para reduzir seus níveis de LDL, no entanto, o risco de DCA persiste. É fundamental que no estudo do perfil lipídico seja considerada a determinação ou estimativa dessas lipoproteínas, somada à dosagem de TG plasmáticos. O objetivo desta revisão foi atualizar o conhecimento sobre os níveis aumentados de TG, LRT e seus remanescentes, fornecer alternativas para sua determinação e compreender os mecanismos que envolvem as LRT no desenvolvimento acelerado da aterosclerose. A atualização dos diferentes parâmetros associados ao aumento de TG, e seus valores de corte ou limites de decisão clínica de acordo com a classificação do risco de DCE para cada paciente, permitirá o redesenho de um relatório de resultados que será muito útil para o médico e o paciente quanto às condutas preventivas e terapêuticas da DCE.

[Atherogenic dyslipidemia and residual risk. State of the art in 2014]. / Dislipidemia aterogénica y riesgo residual. Estado de la cuestión en 2014.

Pandemics of metabolic síndrome, obesity, and type 2 diabetes is a major challenge for the next years and supported the grat burden of cardiovascular diseases. The R3i (Residual Risk Reduction initiative) has previously highlighted atherogenic dyslipidaemia as an important and modifiable contributor to the lipid related residual cardiovascular risk. Atherogenic dyslipidaemia is defined as an imbalance between proatherogenic triglycerides-rich apoB-containing lipoproteins and antiatherogenic AI containing lipoproteins. To improve clinical management of atherogenic dyslipidaemia a despite of lifestyle intervention includes pharmacological approach, and fibrates is the main option for combination with a statin to further reduce non-HDL cholesterol.

[Therapeutic targets in the treatment of dyslipidemia: HDL and non-HDL cholesterol]. / Dianas terapéuticas en el tratamiento de las dislipemias: colesterol no unido a lipoproteínas de alta densidad y colesterol unido a lipoproteínas de alta densidad.

Atherogenic dyslipidemia (AD) consists of the combination of an increase in very low density lipoproteins (VLDL), which results in increased plasma triglyceride (TG) levels, with a reduction of levels of high-density lipoprotein bound cholesterol (HDL-C), also accompanied by a high proportion of small and dense LDL particles. AD is considered the main cause of the residual risk of experiencing cardiovascular disease (CVD), which is still presented by any patient on treatment with statins despite maintaining low-density lipoprotein bound cholesterol (LDL-C) levels below the values considered to be the objective. Non-HDL cholesterol (non-HDL-c) reflects the number of atherogenic particles present in the plasma. This includes VLDL, intermediate density lipoproteins (IDL) and LDL. Non-HDL-c provides a better estimate of cardiovascular risk than LDL-c, especially in the presence of hypertriglyceridemia or AD. The European guidelines for managing dyslipidemia recommend that non-HDL-c values be less than 100 and 130 mg/dL for individuals with very high and high cardiovascular risk, respectively. However, these guidelines state that there is insufficient evidence to suggest that raising HDL-c levels incontrovertibly results in a reduction in CVD. Therefore, the guidelines do not set recommended HDL-c levels as a therapeutic objective. The guidelines, however, state that individuals with AD on treatment with statins could benefit from an additional reduction in their risk by using fibrates.

[The fixed combination of pravastatin and fenofibrate: what can it provide?]. / Combinación fija pravastatina/fenofibrato: ¿qué puede aportar?

The treatment of patients with high cardiovascular risk and mixed hyperlipidemia is difficult due to multiple quantitative and qualitative lipid abnormalities. The priority is to reduce LDL-c levels, for which statins are the drug of choice. Despite the benefits of statins, the residual cardiovascular risk is very high in patients with atherogenic dyslipidemia. To reduce this risk, we also need to control non-HDL cholesterol levels, decreasing triglyceride levels and increasing HDL-c levels. To achieve these objectives and lifestyle changes, the use of combined therapy is often required. Fibrates are drugs that can be used in combination with statins to reduce this residual risk. Fenofibrate is well tolerated in combination with statins. The fixed combination of pravastatin/ fenofibrate has been shown to have complementary benefits in the atherogenic lipid profile in general. The combination is well tolerated and is indicated in patients with high risk and mixed hyperlipidemia who have controlled or are close to their objectives for LDL-c levels, using 40-mg pravastatin in monotherapy. The beneficial eff ect of the combination on LDL-c levels is minimal and is primarily observed in non-HDL cholesterol, triglycerides and HDL-c. The combination of pravastatin 40 and fenofibrate 160 can provide a considerable clinical benefit to patients with high risk and mixed atherogenic dyslipidemia, to patients with LDL-c levels that are controlled or near the objectives for decreasing their residual risk of lipid origin and is especially useful for patients with type 2 diabetes, obesity and combined metabolic syndrome and familial hyperlipidemia.

[Atherogenic dyslipidemia: a multidisciplinary consensus panel]. / Consenso multidisciplinar sobre dislipidemia aterogénica.

The dyslipidaemias are conditions that are still under-diagnosed, under-treated, and poorly controlled. This condition is common to the rest of the risk factors considered fundamental. Within the dyslipidaemias, the data that we have available, generally refer to the hypercholesterolaemias or in particular to the dyslipidaemias not dependent on LDL in patients who are already being treated with statins. However, there is only limited data available on atherogenic dyslipidaemia, characterised by the elevation of triglycerides and/or a decrease in HDL-cholesterol. However, given its profile, to determine the particularities of this atherogenic dyslipidaemia could help to control this anomaly more effectively. The present study, conducted in accordance with the Delphi method, has as its purpose to demonstrate the level of agreement or disagreement of an expert group, made up from different scientific societies, on what atherogenic dyslipidaemia is and represents, as well as what is the most suitable diagnostic and therapeutic approach. It has been concluded that the level of knowledge of the epidemiological aspects, its association with cardiovascular risks, of clinical identification, and specific treatment, has reached a significant level of agreement between the experts consulted. However, some aspects have been detected that, even today, are still subject to controversy: the role of isolated hypertriglyceridaemia as a risk factor, and its consideration as a therapeutic objective both in primary and secondary prevention, the effects linked to HDL-cholesterol, and that are strictly associated with the capacity to produce cholesterol efflux, the appropriateness of the therapeutic objectives to individual particularities, as well as the need to employ - frequently - combined treatment to correctly approach the correction of the lipid profile as a whole.

Dislipidemias: Controversias del riesgo residual

Las estatinas son el principal tratamiento para la reducción del colesterol LDL habiendo demostrado un claro beneficio en la reducción de enfermedad cardiovascular (ECV). Sin embargo, a pesar de los pacientes alcanzar la meta de colesterol LDL, queda un remanente de riesgo relativo de ECV entre un 60% a 70%, el cual ha sido denominado Riesgo Residual. Por ello, el enfoque actual se inclina sobre objetivos adicionales al colesterol LDL, siendo el colesterol HDL bajo y/o triglicéridos elevados los objetivos terapéuticos para reducir el riesgo residual. Se han empleado diversas combinaciones de hipolipemiantes asociados a las estatinas para optimizar el perfil lipídico. La mayorías de estas drogas clásicas (fibratos, niacina y ácidos grasos omega-3), así como un nuevo grupo de moléculas inhibidoras de la Proteína Transportadora de Esteres de Colesterol, son capaces de mejorar las concentraciones de colesterol HDL y triglicéridos en asociación con estatinas, sin embargo, dichas combinaciones en la mayoría de los casos, no han demostrado beneficios en reducir la presencia de ECV, incluso, en el caso de la niacina, se observan efectos deletéreos en las combinaciones a pesar de la optimización del perfil lipídico. Estos hechos nos hacen replantear el conocimiento que tenemos sobre la dislipidemia y su tratamiento, por lo que se presenta la siguiente revisión.

Statins are the principal treatment for highest levels of LDL cholesterol, with clear benefits in reduction of cardiovascular disease (CVD). However, although patients reach LDL cholesterol goal, 60% to 70% have a relative risk remnant of CVD, named Residual Risk. By this, the discussion is focused in other objectives beside LDL cholesterol, being the low HDL cholesterol and/or elevated triglycerides a relevant therapeutic target to reduce the residual risk. Many combinations of drugs have been associated to statins to optimize lipid profile. Most of these classics drugs (fibratos, niacin, and fatty acids omega-3) and the new drugs of Cholesteryl Ester Transfer Proteins inhibitors, increase HDL cholesterol and reduce triglycerides combined with statins, however, in mostly of cases these combinations have not reduced CVD; in studies with niacin, the combination increase deleterious effects despite the optimization of lipid profile. These facts make us reconsider the knowledge we have on dyslipidemia and its treatment, so we present the following review.

Comportamiento de marcadores serológicos en donantes de sangre del territorio de Colón, 1998-2007 / Behavior of the serologic markers in blood donors in the territory of Colon, 1998-2007

En el laboratorio de Sistema Ultra-Micro-Analítico, del banco de sangre del Hospital Territorial Universitario Dr Mario Muñoz Monroy, del municipio Colón, provincia Matanzas, se realizó un estudio descriptivo prospectivo longitudinal, sobre el comportamiento de marcadores serológicos, donde se determinó la incidencia y prevalencia del antígeno de superficie del virus de la hepatitis B (VHB, HBsAg) y de los anticuerpos contra los virus de la hepatitis C (VHC, anti-VHC) y de la inmunodeficiencia humana 1 y 2 (VIH 1 y 2, anti-VIH 1+2), en donantes de sangre del territorio, y el estimado de infección potencial no detectada transmisible por sangre o riesgo residual (RR) en la sangre donada, en el tiempo comprendido del 1 de enero de 1998 al 31 de diciembre de 2007. La investigación se realizó con todo el universo de donantes útiles y sus respectivas donaciones de sangre, y quedó constituido por 49 749 donantes y 84 932 bolsas de sangre. Los índices de prevalencia (x 100 000 donantes), incidencia (x 100 000 donantes), y estimado de riesgo residual (x 1 000 000 de unidades de sangre donada) en el citado período de tiempo fueron: para el VHB 0,81; 0,17 y 0,20; para el VHC 0,55; 0,12 y 0,23; y para los VIH 1y2 0,005; 0,01x10-2 y 0,02 x10-3, respectivamente, índices bajos según la clasificación internacional; pero no para Cuba con respecto al HBsAg.

We carried out a prospective descriptive longitudinal study on the behavior of the serologic markers in the Ultra-Micro-Analytic System laboratory, of the blood bank of the territorial university hospital Dr Mario Muñoz Monroy, of the municipality of Colon, province of Matanzas. We determined the incidence and prevalence of the surface Hepatitis B virus antigen (HBV, HBsAg) and of the antibodies against the Hepatitis C (HCV, anti HCV) and the human immunodeficiency virus 1 and 2 (HIV 1 and 2, anti-HIV 1+2) in blood donors of the territory, and the estimate of non-detected potential infection transmissible by blood or residual risk (RR) in the donated blood, in the period from January 1st 1998 to December 31st 2007. The research was made with all the universe of utile donors and their respective blood donations, and was formed by 49 749 donors and 84 932 blood bags. The prevalence rates (x 100 000 donors), incidence (x 100 000 donors), and estimated residual risk (x 1 000 000 units of donated blood) in the quoted time period were: for the HBV 0,81; 0,17 and 0,20; for the HCV 0,55; 0,12 and 0,23, and for the HIV 1 and 2 0,005; 0,01x10-2 and 0,02x10-3 respectively, low rates according to the international classification, but not for Cuba with respect of the HBsAg.