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.

Ética y laboratorio clínico: conceptos básicos / Ethics and the clinical laboratory: basic concepts / Ética e laboratório clínico: conceitos básicos / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen Los profesionales bioquímicos, y quienes desempeñan su trabajo en el laboratorio de análisis clínicos, en el ejercicio de su deber como individuos, como profesionales y proveedores del servicio de salud, deben desarrollar sus tareas en un marco de cumplimiento de los estándares éticos, tal como ocurre en otras áreas vinculadas con la atención de la salud. Para abordar con éxito los complejos problemas suscitados en el ámbito específico de la atención sanitaria y para estudiar los factores naturales (p. ej.: aparición del coronavirus SARS-CoV-2), tecnológicos [p. ej.: inteligencia artificial (IA)] y sociales (p. ej.: desplazamientos demográficos) que pueden tener repercusiones sobre la salud humana y la biósfera en su conjunto, es necesario que los profesionales de la salud y quienes desempeñan sus funciones en ese medio, tomen conocimiento de los conceptos básicos de ética aplicados a la salud. El objetivo de este artículo es considerar los dilemas éticos que deben afrontar en el trabajo diario los profesionales del laboratorio clínico. Para ello la propuesta consistió en abordar los principios, documentos y declaraciones nacionales e internacionales sobre ética aplicados a la salud, en particular al laboratorio de análisis clínicos y, en segundo término, brindar un marco teórico basado en los principios de la Bioética Principalista, para afrontar los problemas éticos que se generan en las diferentes fases del proceso bioquímico total (preanalítica, analítica y posanalítica).

Abstract Biochemical professionals, and those who carry out their work in the clinical analysis laboratory, in performing their duties as individuals, professionals and health service providers, must carry out their tasks within a framework of compliance with ethical standards, such as it occurs in other areas related to health care. To successfully address the complex problems raised in this specific field and to study the natural (i.e.: appearance of the SARSCoV- 2 coronavirus), technological [i.e.: artificial intelligence (AI)] and social (i.e.: demographic shifts) factors that may have repercussions on human health and the biosphere as a whole, it is necessary that health professionprofeals and those who perform their duties in this environment, become aware of basic concepts on ethics applied to health. The objective of this article is to consider the ethical dilemmas that clinical laboratory professionals must face in their daily work. To this aim, we set out to address the national and international principles, documents and declarations on ethics applied to health, in particular, to the clinical analysis laboratory and secondly, to provide a theoretical framework based on the principles of Principalist Bioethics, to face the ethical problems that are generated in the different phases of the complete biochemical process (pre-analytical, analytical and post-analytical).

Resumo Os profissionais bioquímicos, e aqueles que exercem o seu trabalho no laboratório de análises clínicas, no exercício das suas funções como indivíduos, como profissionais e prestadores do serviço de saúde, devem desempenhar as suas funções num quadro de observância dos padrões éticos, tal como ocorre em outras áreas relacionadas com o atendimento da saúde. Para abordar com sucesso os problemas complexos levantados no campo específico dos cuidados da saúde e estudar os fatores naturais (por exemplo: aparecimento do coronavírus SARS-CoV-2), tecnológicos [por exemplo: inteligência artificial (IA)] e sociais (por exemplo: deslocamentos demográficos) que podem têm repercussões na saúde humana e na biosfera como um todo, é necessário que os profissionais da saúde e aqueles que exercem suas funções neste ambiente, tomem conhecimento dos conceitos basicos da ética aplicados à saúde. O objetivo deste artigo é considerar os dilemas éticos que devem ser enfrentados no trabalho diário pelos profissionais de laboratórios clínicos. Para isso, nos propusemos abordar os princípios, documentos e declarações nacionais e internacionais sobre a ética aplicados à saúde, em particular, ao laboratório de análises clínicas e, em segundo lugar, fornecer um quadro teórico baseado nos princípios da Bioética Principalista, para enfrentar os problemas éticos que são gerados nas diferentes fases do processo bioquímico total (pré-analítica, analítica e pós-analítica).

Efectos inflamatorios, oxidativos y aterogénicos del receptor endotelial de la lipoproteína de baja densidad oxidada-1 / Inflammatory, oxidative and atherogenic effects of endothelial lectin-like receptor of oxidized low density lipoprotein-1 / Efeitos inflamatórios, oxidativos e aterogênicos do receptor endotelial da lipoproteína de baixa densidade oxidativa-1

LOX-1 es un receptor endotelial de la familia de las lectinas. Su actividad biológica tiene un fuerte impacto en los fenómenos inflamatorios, oxidativos y aterogénicos endoteliales. Cuando se conoció el receptor de la lipoproteína de baja densidad (RLDL) y su regulación, se afirmó el papel aterogénico del colesterol transportado en esta lipoproteína (C-LDL). Este papel de las lipoproteínas fue la base de la denominación de dislipoproteinemias en reemplazo de dislipemias. En condiciones post-prandiales, las lipoproteínas ricas en triglicéridos, como quilomicrones y lipoproteínas de muy baja densidad (VLDL), son degradadas por la lipoproteína lipasa (LPL) de la pared vascular, produciéndose remanentes de quilomicrones (RQ) y lipoproteínas de densidad intermedia (IDL), respectivamente, que en conjunto se denominan lipoproteínas remanentes (RLPs). Dependiendo del estrés oxidativo las RLPs son oxidables y pueden unirse al LOX-1. También se liberan ácidos grasos que injurian células endoteliales y contribuyen a abrir brechas en el endotelio, que en condiciones fisiológicas es una barrera de células con uniones estrechas. El dominio intracelular de LOX-1 regula el reconocimiento de lipoproteínas de baja densidad oxidadas (LDLOX) y de RLPs. Además, posee un efecto dependiente de los radicales reactivos de oxígeno (ROS). Su dominio transmembrana actúa en el pasaje de LDLOX y monocitos al subendotelio. La inhibición de LOX-1 con anticuerpos específicos impide su unión con LDLOX, restableciendo la barrera entre el lumen vascular y el subendotelio. En cambio, las LDLOX unidas al dominio transmembrana, producen apoptosis de las células endoteliales y suprimen uniones estrechas intercelulares en el endotelio, facilitando la actividad de las moléculas de adhesión leucocitarias que promueven el pasaje al subendotelio de los elementos del lumen, tales como monocitos, plaquetas, LDLOX, RLPs oxidables y lipoproteínas (a) (Lp(a)) semejantes al plasminógeno. Las LDLOX subendoteliales aumentan la movilidad de células musculares lisas. Los monocitos subendoteliales se establecen como residentes, e incorporan LDLOX, convirtiéndose sucesivamente en macrófagos, células espumosas y lesiones aterogénicas. Sin embargo, desde Assmann G y su estudio PROCAM no puede ignorarse el papel de los triglicéridos y colesterol de lipoproteínas de alta densidad (C-HDL) como componentes del cuadro de riesgo en ECV.

LOX-1 is an endothelial receptor belonging to the family of lectins. Its biological activity has a strong impact on inflammatory, oxidative and atherogenic phenomena in endothelium. When Low Density Lipoprotein receptor (RLDL) and its regulation were known, the atherogenic role of the cholesterol transported in LDL (LDL-C) was confirmed. This lipoprotein role in atherosclerosis was the base to use the term dyslipoproteinemia instead of dyslipidemia. In post-prandial conditions, triglyceride-rich lipoproteins like chylomicrons and very low-density lipoproteins (VLDL), are degraded by lipoprotein lipase (LPL) on the vascular wall, with the resultant formation of chylomicron remnants (CR) and intermediate density lipoproteins (IDL) respectively, which as a whole are called remnant lipoproteins (RLPs). Depending on oxidative stress, RLPs are oxidized and then they can bind the LOX-1. In this process, fatty acids are also released, injuring endothelial cells and contributing to open gaps in endothelium, which under physiological conditions, is a barrier of cells with tight junctions. The intracellular domain of LOX-1 regulates the recognition of oxidized LDL (oxLDL) and RLPs, and its effect depends on reactive oxygen species (ROS). LOX-1 transmembrane domain acts in the passage of oxLDL and monocytes to the sub-endothelium. Inhibition of LOX-1 by specific antibodies prevents its binding with OxLDL, restoring the barrier between the vascular lumen and sub-endothelium. By contrast, the oxLDL, attached to the transmembrane domain, produce apoptosis of endothelial cells and the suppression of narrow intercellular junctions in the endothelium. Thus, enabling the activity of leucocyte adhesion molecules that promote the transfer to subendothelial elements lumen of monocytes, platelets, oxLDL, oxidized RLPs and lipoprotein (a) (Lp (a)), similar to plasminogen such as. Sub-endothelial OxLDL increase the mobility of smooth muscle cells. Sub-endothelial monocytes establish as resident, up-take oxLDL and successively become into macrophages, foam cells and atherosclerotic lesions. However, since Assman’s PROCAM study, the role of triglycerides and High Density Lipoprotein-cholesterol (HDL-C), as components of cardiovascular risk, cannot be ignored.

LOX-1 é um receptor endotelial da família das lectinas. Sua atividade biológica tem um importante impacto nos fenômenos inflamatórios, oxidativos e aterogênicos endoteliais. Quando foi conhecido o receptor da lipoproteína de baixa densidade (RLDL) e sua regulação, afirmou-se o papel aterogênico do colesterol transportado nesta lipoproteína (C-LDL). Este papel das lipoproteínas foi a base da denominação de dislipoproteinemias em substituição de dislipidemias. Em condições pós-prandiais, as lipoproteínas ricas em triglicérides como quilomícrons e Lipoproteínas de muito baixa densidade (VLDL) são degradadas pela lipoproteína lipase (LPL) da parede vascular, produzindo remanescentes de quilomícrons (RQ) e lipoproteínas de densidade intermediária (IDL) respectivamente, que em conjunto são chamadas lipoproteínas remanescentes (RLPs). Dependendo do estresse oxidativo, as RLPs são oxidáveis e podem se ligar ao LOX-1. Também são liberados ácidos graxos que injuriam células endoteliais e contribuem na abertura de fendas no endotélio, que em condições fisiológicas é uma barreira de células com uniões estreitas. O domínio intracelular de LOX-1 regula o reconhecimento de lipoproteínas de baixa densidade oxidativa (LDLOX) e de RLPs. Também possui um efeito dependente dos radicais reativos de oxigênio (ROS). Seu domínio transmembrana atua na passagem de LDLOX e monócitos para o subendotélio. A inibição de LOX-1 com anticorpos específicos impede sua união com LDLOX restabelecendo a barreira entre o lúmem vascular e o subendotélio. Entretanto, as LDLOX ligadas ao domínio transmembrana produzem apoptose das células endoteliais e suprimem estreitas junções intercelulares no endotélio, facilitando a atividade das moléculas de adesão leucocitária que promovem a passagem para o subendotélio de elementos do lúmem, tais como monócitos, plaquetas, LDLOX, RLPs oxidáveis e lipoproteínas (a) [Lp(a)] semelhantes ao plasminogênio. As LDLOX subendoteliais aumentam a mobilidade das células musculares lisas. Os monócitos subendoteliais se estabelecem como residentes, e incorporam LDLOX, virando sucessivamente em macrófagos, células espumosas e lesões aterogênicas. No entanto, desde Assman G e seu estudo PROCAM, não pode se ignorar o papel dos triglicérides e do colesterol de lipoproteínas de alta densidade (C-HDL) como componentes do evento de risco em ECV.

Do insulin resistance conditions further impair the lipid and inflammatory profile in end-stage renal disease patients on hemodialysis?

BACKGROUND: Type 2 diabetes (T2DM) and chronic renal disease constitute important risk factors of atherosclerotic cardiovascular disease, associated with lipid abnormalities, and proinflammatory states. Advances in renal replacement therapy such as hemodialysis (HD) have not reduced morbi-mortality. It has not been elucidated if the concomitant presence of T2DM or metabolic syndrome with end-stage renal disease further impairs the atherogenic profiles. METHODS: We studied 122 HD patients, among which 44 presented with T2DM (HD-T2DM) and 30 with metabolic syndrome (HD-MS); 48 had neither T2DM nor metabolic syndrome (HD-C). Lipoprotein profile, including atherogenic remnant lipoproteins (RLP), and inflammation markers--high sensitivity C-reactive protein (hsCRP), adiponectin, and interleukin-6 (IL-6)--were measured. RESULTS: In all HD patients, triglycerides, free fatty acids, and RLP showed no differences between HD groups, whereas high-density lipoprotein cholesterol (HDL-C) was decreased, particularly in HD-T2DM and HD-MS, with respect to HD-C (P<0.01). Regarding inflammatory parameters, both IL-6 and hsCRP were found to be similar between HD groups. Adiponectin paradoxically shows higher values in relation to those expected for insulin resistance situations showing no differences between HD groups. CONCLUSIONS: The presence of T2DM or metabolic syndrome did not worsen atherogenic lipoprotein levels, but did reduce HDL-C. Neither was the proinflammatory profile further altered in HD patients in the presence of insulin resistance conditions.

Epidemiología Inversa: baja concentración de LDL modificadas y morbimortalidad cardiovascular en pacientes en hemodiálisis / Reverse epidemiology: low concentration of modified LDL and cardiovascular morbidity and mortality in hemodialysis patients / Epidemiologia Reversa: baixa concentraþÒo de LDL modificadas e morbimortalidade cardiovascular em pacientes em hemodiálise

La disminución de colesterol-LDL (c-LDL) se considera meta principal del tratamiento de pacientes con riesgo cardiovascular. Sin embargo, pacientes con Enfermedad Renal Crónica (ERC) en hemodiálisis presentan c-LDL menor de 100 mg/dL, aumentos moderados de triglicéridos y baja frecuencia de colesterol-HDL por debajo de valores deseables. Esta condición se encuadra dentro del fenómeno conocido como "epidemiología inversa", en la cual la conocida asociación prevalente entre hipercolesterolemia, hipertensión arterial, obesidad y morbimortalidad por eventos cardiovasculares no se encuentra y, por el contrario se invierte la estrecha relación de estos parámetros con eventos cardiovasculares propia de los pacientes no hemodializados. Por un lado el 35% de los pacientes con ERC presentan diabetes mellitus tipo 2 y por otra parte, existen otros factores patogénicos menos conocidos como la Lipoproteína asociada a Fosfolipasa A2, la Proteína C Reactiva, los remanentes lipoproteicos, la Lp(a) y enzimas y proteínas asociadas a la HDL, como la Paraoxonasa y Apo A-I. El conjunto de factores descritos podrían reemplazar, en pacientes con ERC en hemodiálisis, al colesterol-LDL (c-LDL), típico analito que en otros pacientes actúa como factor de riesgo y/o patogénico de aterosclerosis y no sólo como marcador circulante. Una explicación plausible respecto al c-LDL disminuído es la modificación cualitativa de LDL por oxidación, glicación, carbamilación, la presencia de LDL pequeñas y densas, fenómenos inflamatorios y malnutrición.(AU)

The decrease in LDL cholesterol (LDL-C) is considered the main goal in the treatment of patients with atherosclerotic cardiovascular risk. However, patients with chronic kidney disease (CKD) on hemodialysis have LDL-C below 100 mg/dL, moderate increases in triglycerides and low frequency of HDL cholesterol values below desirable.This condition fits into the phenomenon known as "reverse epidemiology", in which the normal relationship between hypercholesterolemia, high blood pressure, obesity and cardiovascular morbidity and mortality is not found; contrarily, there is a reversal in the close relationship of these parameters with cardiovascular events typical of non-hemodialyzed patients. On the one hand, 35% of CKD patients have Type 2 diabetes mellitus and on the other hand, there are other lesser known pathogenic factors such as lipoprotein-associated phospholipase A2, C-reactive protein, remnant lipoproteins, Lp(a) and enzymes and proteins associated to HDL such as paraoxonase and Apo A-I. The set of factors described could replace, in CKD patients on hemodialysis, LDL cholesterol, a typical analyte that, in other patients, acts as a risk and/or pathogenesis factor of atherosclerosis and not only as a circulating marker. A likely explanation for decreased C-LDL cholesterol is qualitative modification of LDL as a result of oxidation, glycation, carbamylation, occurrence of small and dense LDL, inflammatory phenomena and malnutrition.(AU)

A diminuiþÒo de colesterol-LDL (c-LDL) considera-se objetivo principal do tratamento de pacientes com risco cardiovascular. Entretanto, pacientes com Doenþa Renal Cr¶nica (ERC) em hemodiálise apresentam c-LDL menor de 100 mg/dL, aumentos moderados de triglicerídeos e baixa frequÛncia de colesterol-HDL inferior aos valores desejáveis. Esta condiþÒo se enquadra dentro do fen¶meno conhecido como "epidemiologia reversa", na qual a conhecida associaþÒo prevalente entre hipercolesterolemia, hipertensÒo arterial, obesidade e morbimortalidade por eventos cardiovasculares nÒo se encontra e, pelo contrário se inverte a estreita relaþÒo destes parÔmetros com eventos cardiovasculares própria dos pacientes nÒo hemodialisados. De um lado, 35% dos pacientes com ERC apresentam Diabetes Melito tipo 2 e do outro, existem diferentes fatores patogÛnicos menos conhecidos como a Lipoproteína associada a Fosfolipase A2, a Proteína C Reativa, os remanescentes lipoproteicos, a Lp(a) e enzimas e proteínas associadas O HDL, como a Paraoxonase e Apo A-I. O conjunto de fatores descritos poderia substituir, em pacientes com ERC em hemodiálise, o colesterol-LDL (c-LDL), típico analito que em outros pacientes age como fator de risco e/ou patogÛnico de aterosclerose e nÒo só como marcador circulante. Uma explicaþÒo plausível a respeito do c-LDL diminuído é a modificaþÒo qualitativa de LDL por oxidaþÒo, glicaþÒo, carbamilaþÒo, a presenþa de LDL pequenas e densas, fen¶menos inflamatórios e malnutriþÒo.(AU)

Predominance of large VLDL particles in metabolic syndrome, detected by size exclusion liquid chromatography.

OBJECTIVE: To study size heterogeneity of triglyceride rich lipoproteins (TRL) in metabolic syndrome (MS). DESIGN AND METHODS: Thirty MS patients and 14 healthy subjects were included. In fasting serum we measured: lipid profile, free fatty acids (FFA) and adiponectin; TRL were isolated (d<1.006 g/mL) and analysis by size exclusion HPLC followed by UV detection was performed; each subfraction was expressed as percentage of total TRL. RESULTS: MS patients, even those with normal triglycerides, presented higher proportion of very large VLDL (90 nm diameter) and large VLDL (60 nm) and slightly lower of typical VLDL (37 nm) (p<0.04); increased FFA (p=0.04) and lower adiponectin (p=0.001). FFA correlated with large VLDL% (r=0.58; p=0.003), independently of insulin-resistance and waist. Furthermore, the lower the adiponectin, the greater the predominance of large VLDL (r=-0.40; p=0.04). CONCLUSION: MS was associated with large VLDL, described as more atherogenic beyond triglyceride levels. Size exclusion HPLC would represent a useful tool for assessing subfractions' lipoprotein profile.

Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome.

BACKGROUND: It is not elucidated if liver fat deposits associated to metabolic syndrome (MS) aggravate the atherogenic state. We evaluated, in MS patients, if the presence of non-alcoholic hepatic steatosis (HS) determines differences in inflammatory markers and VLDL characteristics. METHODS: Seventy-five patients with MS were divided into 2 groups depending on the presence or absence of HS, assessed by ultrasound. Lipid profile, free fatty acids (FFA), VLDL composition, adiponectin, tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP), and soluble adhesion molecules (sVCAM-1 and sICAM-1) were measured. RESULTS: HS patients presented increased triglycerides levels, HOMA-IR and FFA. Patients with HS showed a reduction in adiponectin (p = 0.04) and increase in hs-CRP (p = 0.02), independently of insulin-resistance (IR). FFA correlated positively with TNF-α (p = 0.04) and inversely with adiponectin (p = 0.01). hs-CRP correlated with all inflammatory markers, independently of IR: TNF-α (r = 0.34, p = 0.02), sVCAM-1 (r = 0.29 p = 0.03), sICAM-1 (r = 0.56, p = 0.01), adiponectin (r = -0.34, p = 0.04). HS patients presented higher VLDL mass and number of particles. Adiponectin correlated with VLDL cholesterol content (r = -0.47, p = 0.04), independently of IR. VLDL, once secreted, would suffer from changes, becoming more atherogenic. CONCLUSIONS: Simple HS would play an important role increasing cardiovascular risk, independently of IR. hs-CRP may represent a useful biomarker of this condition.

Does non-alcoholic fatty liver impair alterations of plasma lipoproteins and associated factors in metabolic syndrome?

BACKGROUND: Hepatic steatosis (HS) is closely associated to metabolic syndrome (MS). Both, VLDL-triglyceride oversecretion and intrahepatic deposits, can take place. We evaluated VLDL characteristics, CETP, hepatic lipase (HL), IDL and small dense LDL (sdLDL), in patients with HS associated to MS. METHODS: We studied 3 groups matched by age and sex: 25 MS patients with HS (diagnosed by ultrasonography), 25 MS patients without HS and 25 healthy controls. Main measurements were: lipid profile, free fatty acids, VLDL composition, VLDL size by HPLC, CETP and HL activities, IDL-cholesterol and sdLDL-cholesterol. RESULTS: Patients with HS presented higher triglyceride levels, HOMA-IR and free fatty acids, VLDL mass and VLDL-apoB (p<0.05). No differences in VLDL composition were observed. MS groups presented higher proportion of large VLDL than controls (p<0.05). HS group showed higher CETP than controls (p=0.01) and almost higher than MS without HS (p=0.06). CETP correlated with VLDL-cholesterol content, r=0.48, p<0.005. The increase in sdLDL-cholesterol correlated with CETP (r=0.47) and HL (r=0.56), independent of insulin resistance (p<0.003). CONCLUSION: Despite intrahepatic fat, patients with HS secreted higher number of VLDL particles. CETP would have a remodeling action on VLDL in circulation, enriching it in cholesterol and also favoring, together with HL, the formation of sdLDL.

[Relation between paraoxonase activity, other HDL components and inflammatory state in hemodialyzed patients]. / Relación entre paraoxonasa, otros componentes de HDL y estado inflamatorio en hemodiálisis.

Advanced Chronic Renal Disease (CKD) is closely associated with a pro-inflammatory condition, with an increase in triglyceride-rich lipoproteins and decrease in HDL level. HDL contains antioxidant enzymes such as paraoxonase (PON), whose activity is diminished in CKD. The aim of our study was to evaluate the relationship between PON activity with HDL cholesterol, apo A1 and hs-CRP levels, which are known to be inflammatory markers in hemodialyzed patients. Forty-two patients were studied; age, median (range) = 50 (25-67) years old, gender M/F = 22/20, duration of hemodialysis = 4.4 ± 0.5 years, BMI: 23 ± 0.5 kg/m2. After a 12 h fast, a blood sample was obtained and classic components of lipid profile were determined, as well as apoproteins A1 and B, PON by means of its arylsterase activity and hs-CRP levels. On the basis of the latter, patients were divided into two groups: hs-CRP ≤ 1 (low risk, range: 0.1 to 1.0 mg/l) and > 1 mg/l (moderate and high risk, 1.1 to 10.7 mg/l). No difference was found in triglycerides, LDL cholesterol and apo B in the groups. Patients with hs-CRP > 1 showed lower HDL cholesterol (40 ± 2 mg/dl) and apo A1 (118 ± 4 mg/dl) than patients with hs-CRP ≤ 1 (50 ± 4 and 133 ± 5, respectively); p < 0.05. PON was lower in hs-CRP > 1 = 90.5 ± 24.0 µmol/ml.min than in hs-CRP ≤ 1 = 105.2 ± 18.0. Consequently, inverse correlations were obtained between apo A1 and hs-CRP, r = -0.381, p = 0.013 and between PON and hs-CRP, r = -0.32, p = 0.042. Furthermore, increase in hs-CRP correlated positively with BMI r = 0.318, p = 0.042. Since apo A1 has an anti-inflammatory role and PON an antioxidant activity, the decrease in HDL and its components, cholesterol, apo A1 and PON, in subjects with higher chronic inflammatory condition might explain, in part, the increased cardiovascular risk in these patients.

Relación entre paraoxonasa, otros componentes de HDL y estado inflamatorio en hemodiálisis / Relation between paraoxonase activity, other HDL components and inflammatory conditions in hemodialyzed patients

La enfermedad renal crónica (ERC) se asocia estrechamente con un estado pro-inflamatorio, aumento de lipoproteínas ricas en triglicéridos y disminución de HDL. La HDL contiene enzimas antioxidantes asociadas como la paraoxonasa (PON), cuya actividad en ERC se encuentra disminuida. Nuestro objetivo fue evaluar la relación entre la actividad de PON, apoA1, colesterol(col)-HDL y Proteína C reactiva-altamente sensible (PCR-as) como marcador de inflamación en pacientes en hemodiálisis. Se estudiaron n = 42 pacientes; edad, mediana (rango) = 50 (25-67) años; sexo M/F = 22/20; antigüedad de hemodiálisis = 4.4 ± 0.5 años; índice de masa corporal (IMC) = 23 ± 0.5 kg/m². Se obtuvo una muestra de sangre después de 12 h de ayuno y se determinaron los parámetros clásicos del perfil lipídico, se midieron los valores de apoproteínas A1 y B, PON a través de su actividad arilesterasa y PCR-as, la cual permitió dividir a los pacientes con PCR-as ≤ 1 (bajo riesgo, rango: 0.1 a 1.0 mg/l) y > 1 mg/l (moderado y alto riesgo, 1.1 a 10.7 mg/l). Los niveles de triglicéridos, col-LDL y apoB no fueron diferentes entre los grupos. Los pacientes con PCR-as > 1 presentaron menor col-HDL (40 ± 2 mg/dl) y apoA1 (118 ± 4 mg/dl) que los pacientes con PCR-as ≤ 1 (50 ± 4 y 133 ± 5, respectivamente); p < 0.05. La PON fue menor en PCR-as > 1: 90.5 ± 24.0 μmol/ml.min que en PCR-as ≤ 1: 105.2 ± 18.0. Consecuentemente, se obtuvieron correlaciones inversas entre apoA1 y PCR-as, r = -0.381 p = 0.013 y entre PON y PCR-as, r = -0.32, p = 0.042. Además, el aumento de PCR-as correlacionó positivamente con el IMC, r = 0.318, p = 0.042. La disminución de col-HDL, apoA1 y PON en los individuos con mayor estado inflamatorio explicaría, en parte, el aumento de riesgo cardiovascular de estos pacientes, dado los efectos antiinflamatorios de la apoA1 y antioxidantes de la PON.

Advanced Chronic Renal Disease (CKD) is closely associated with a pro-inflammatory condition, with an increase in triglyceride-rich lipoproteins and decrease in HDL level. HDL contains antioxidant enzymes such as paraoxonase (PON), whose activity is diminished in CKD. The aim of our study was to evaluate the relationship between PON activity with HDL cholesterol, apo A1 and hs-CRP levels, which are known to be inflammatory markers in hemodialyzed patients. Forty-two patients were studied; age, median (range) = 50 (25-67) years old, gender M/F = 22/20, duration of hemodialysis = 4.4 ± 0.5 years, BMI: 23 ± 0.5 kg/m². After a 12 h fast, a blood sample was obtained and classic components of lipid profile were determined, as well as apoproteins A1 and B, PON by means of its arylsterase activity and hs-CRP levels. On the basis of the latter, patients were divided into two groups: hs-CRP ≤ 1 (low risk, range: 0.1 to 1.0 mg/l) and >1 mg/l (moderate and high risk, 1.1 to 10.7 mg/l). No difference was found in triglycerides, LDL cholesterol and apo B in the groups. Patients with hs-CRP > 1 showed lower HDL cholesterol (40 ± 2 mg/dl) and apo A1 (118 ± 4 mg/dl) than patients with hs-CRP ≤ 1 (50 ± 4 and 133 ± 5, respectively); p < 0.05. PON was lower in hs-CRP > 1 = 90.5 ± 24.0 μmol/ml.min than in hs-CRP ≤ 1 = 105.2 ± 18.0. Consequently, inverse correlations were obtained between apo A1 and hs-CRP, r = -0.381, p = 0.013 and between PON and hs-CRP, r = -0.32, p = 0.042. Furthermore, increase in hs-CRP correlated positively with BMI r = 0.318, p = 0.042. Since apo A1 has an anti-inflammatory role and PON an antioxidant activity, the decrease in HDL and its components, cholesterol, apo A1 and PON, in subjects with higher chronic inflammatory condition might explain, in part, the increased cardiovascular risk in these patients.

[Atherogenic lipoprotein remnants in humans]. / Lipoproteínas remanentes aterogénicas en humanos.

Remnant lipoproteins (RLPs) are the lipolytic product of triglycerides transported by very low density lipoproteins (VLDL) of hepatic and intestinal origin and intestinal chylomicrons. Lipoprotein lipase activity hydrolyse triglycerides in several steps, producing heterogeneous particles. Fasting plasma concentration in normolipidemic subjects is low, but it increases in post-prandial states. Genetic alterations in Apo-E subtypes increases RLPs plasma concentration and produce dyslipoproteinemia phenotype. RLPs atherogenicity depends on their role as endothelial injuring factors, their impaired recognition by lipoprotein receptors, and their susceptibility to oxidative stress. They also promote the circulation of molecular adhesion molecules, the internalization in subendothelial macrophages via scavenger receptors and the accumulation in foam cells, all of them early mechanisms of atheromatosis. RLPs metabolism has been a subject of controversial studies. Their origin from different lipoproteins may explain their structural heterogeneity, therefore increasing the methodological difficulties to include RLPs in the atherogenic lipoprotein profile in the epidemiological studies of the field. Last advances on metabolism of RLPs and their emergent clinical role justifies an up dated revision of RLPs.

Lipoproteínas remanentes aterogénicas en humanos / Atherogenic lipoprotein remnants in humans

La lipoproteínas remanentes (RLPs) son el producto de la lipólisis de los triglicéridos transportados por las lipoproteínas de baja densidad (VLDL) de origen hepático e intestinal y de los quilomicrones intestinales. Dicha lipólisis es catalizada por la lipoproteína lipasa y se produce en pasos sucesivos, de manera que los productos son heterogéneos. Su concentración plasmática en ayunas es pequeña en pacientes normolipémicos y aumenta en el estado post-prandial. Las alteraciones genéticas en subtipos de su componente Apo-E aumentan notablemente su concentración plasmática y producen el fenotipo de disbetalipoproteinemia. Se las considera aterogénicas porque injurian el endotelio, sufren estrés oxidativo, son captadas por los macrófagos en el subendotelio vascular y generan las células espumosas que son precursoras de ateromas. Su origen metabólico, como productos de varios tipos de lipoproteínas, explican su estructura heterogénea, sus concentraciones plasmáticas variables y las dificultades metodológicas que dificultan su inclusión en el perfil lipoproteico como parte de los estudios epidemiológicos. Los últimos avances en los estudios metabólicos y la actualización de su papel clínico, justifican una revisión de los conocimientos actuales.

Remnant lipoproteins (RLPs) are the lipolytic product of triglycerides transported by very low density lipoproteins (VLDL) of hepatic and intestinal origin and intestinal chylomicrons. Lipoprotein lipase activity hydrolyse triglycerides in several steps, producing heterogeneous particles. Fasting plasma concentration in normolipidemic subjects is low, but it increases in post-prandial states. Genetic alterations in Apo-E subtypes increases RLPs plasma concentration and produce dyslipoproteinemia phenotype. RLPs atherogenicity depends on their role as endothelial injuring factors, their impaired recognition by lipoprotein receptors, and their susceptibility to oxidative stress. They also promote the circulation of molecular adhesion molecules, the internalization in subendothelial macrophages via scavenger receptors and the accumulation in foam cells, all of them early mechanisms of atheromatosis. RLPs metabolism has been a subject of controversial studies. Their origin from different lipoproteins may explain their structural heterogeneity, therefore increasing the methodological difficulties to include RLPs in the atherogenic lipoprotein profile in the epidemiological studies of the field. Last advances on metabolism of RLPs and their emergent clinical role justifies an up dated revision of RLPs.

Role of matrix metalloproteinase-2 in the cardioprotective effect of ischaemic postconditioning.

The activation of matrix metalloproteinases (MMPs) contributes to myocardial injury at the onset of reperfusion; however, their role in ischaemic postconditioning is unknown. The aim of the present study was to examine the effects of ischaemic postconditioning on MMP activity in isolated rabbit hearts. The isolated rabbit hearts were subjected to 30 min of global ischaemia followed by 180 min of reperfusion (I/R group; n = 8). In the ischaemic postconditioning group (n = 8), a postconditioning protocol was performed (2 cycles of 30 s reperfusion-ischaemia). In other experiments, we added doxycycline, an MMP inhibitor, at 25 (n = 7) or 50 micromol l(1) (n = 8) during the first 2 min of reperfusion. Coronary effluent and left ventricular tissue were collected during pre-ischaemic conditions and at different times during the reperfusion period to measure MMP-2 activity and cardiac protein nitration. We evaluated ventricular function and infarct size. In the I/R group, infarct size was 32.1 +/- 5.2%; Postcon reduced infarct size to 9.5 +/- 3.8% (P < 0.05) and inhibited MMP-2 activity during reperfusion. The administration of doxycycline at 50 micromol l(1) inhibited MMP-2 activity and cardiac protein nitration and reduced the infarct size to 9.7 +/- 2.8% (P < 0.05). A lower dose of doxycycline (25 micromol l(1)) failed to inhibit MMP-2 activity and did not modify the infarct size. Our results strongly suggest that ischaemic postconditioning may exert part of its cardioprotective effects through the inhibition of MMP-2 activity.

Rosuvastatin given during reperfusion decreases infarct size and inhibits matrix metalloproteinase-2 activity in normocholesterolemic and hypercholesterolemic rabbits.

There is evidence that statin treatment before ischemia protects myocardium from ischemia/reperfusion injury. The objective is to determine whether rosuvastatin administered during reperfusion modifies infarct size and the recovery of postischemic ventricular dysfunction in normocholesterolemic and hypercholesterolemic rabbits. In addition, we also evaluated the role of matrix metalloproteinase type 2 (MMP)-2 activation. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In group 2, we added rosuvastatin after 30 minutes of ischemia and from the beginning of reperfusion. In group 3, an MMP inhibitor (doxycycline) was administered during the first 2 minutes of reperfusion. Finally, we repeated these groups but in hypercholesterolemic rabbits (groups 4, 5, and 6). The infarct size was 16.6% +/- 3.9% in group 1 and 25.6% +/- 2.7% in group 4. Rosuvastatin reduced infarct size to 4.5% +/- 1.1% and 6.1% +/- 1.5% in groups 2 and 5, respectively (P < 0.05). Rosuvastatin significantly decreased MMP-2 activity during reperfusion, and doxycycline induced an inhibition of MMP-2 activity and a reduction of infarct size in normocholesterolemic (4.9% +/- 0.9%) and hypercholesterolemic animals (8.3% +/- 1.6%) (P < 0.05). Rosuvastatin reduces infarct size and attenuates MMP-2 activity. These data and the correlation between MMP-2 and infarct size suggest that MMP-2 plays an important role in the mechanisms of cardioprotection afforded by rosuvastatin.

Metalloproteases 2 and 9, Lp-PLA(2) and lipoprotein profile in coronary patients.

BACKGROUND AND AIMS: Many studies suggest that the different steps of the atherosclerotic process may be mediated by metalloproteases (MMPs). MMP-9 and MMP-2, which are highly expressed in the vulnerable regions of the atherosclerotic plaques, have been suggested to be causally involved in plaque rupture. In another manner linked with LDL, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) hydrolyzes phospholipids generating proinflammatory and proatherogenic products. Our aim was to evaluate plasma activity of MMP-2 and 9, as well as Lp-PLA(2), in subjects with coronary artery stenosis in comparison with controls and to correlate these activities with lipoprotein profile and general biomarkers of inflammation. METHODS: Forty two subjects who had undergone coronary angiography were divided into two groups: patients with coronary vessels with at least 45% stenosis (CAD [coronary artery disease], n = 24) and patients without angiographically detectable coronary artery disease (controls, n = 18). Plasma activity of MMP-2 and MMP-9 was measured and correlated with markers of systemic inflammation (hs-CRP), subendothelial inflammation (Lp-PLA(2)) and lipoprotein profile. RESULTS: Plasma activity of both MMPs was consistently higher in patients than in controls (p <0.01). Pro-MMP-2 (r = 0.34, p <0.01) and MMP-9 (r = 0.51, p <0.02) activities correlated with apoprotein B. Pro-MMP-2 correlated with hs-CRP (r = 0.47, p <0.01) and inversely with HDL cholesterol (r = -0.35, p <0.02). No differences were observed in Lp-PLA(2) between patients and controls (15.2 +/- 4.0 vs. 15.4 +/- 4.5 micromol/mL/h, p = NS, respectively), and no correlation was observed with MMPs. CONCLUSIONS: MMP activity was higher in CAD than in controls. The correlation observed between pro-MMP-2 and high-sensitive C-reactive protein (hs-CRP) may be due to specific systemic inflammatory processes. No correlation was observed between Lp-PLA(2) and MMPs.

Increased plasma activity of metalloproteinase 2 in women with metabolic syndrome.

Metalloproteinases (MMPs) play a significant role in vascular remodeling, and they have been suspected to be partly responsible for the pathogenesis of cardiovascular disease. Metalloproteinases have been reported to be increased in atherosclerosis and type 2 diabetes mellitus; however, so far they have not been evaluated in metabolic syndrome (MetS). Plasma activity of MMP-2 and MMP-9, high-sensitivity C-reactive protein concentration, dense low-density lipoprotein, and insulin-resistance markers were measured in 38 nondiabetic women with (n = 19) and without (n = 19) MetS. Women with MetS had significantly higher plasma activity of MMP-2 than controls (median [range], 1.3 [0.4-3.1] vs 0.7 [0.1-1.9]; P = .001). MMP-2 activity positively correlated with waist, homeostasis model assessment, and high-sensitivity C-reactive protein (P < .02) as well as with apolipoprotein B, dense low-density lipoprotein, triglycerides/high-density lipoprotein cholesterol index (P < .001) and negatively with high-density lipoprotein cholesterol (P < .002). Our finding of increased plasma activity of MMP-2 in women with MetS is important because they fit in with an early stage of cardiovascular disease; and measurement of soluble molecules may improve the risk assessment, early diagnosis, and prognosis of cardiovascular disease.

Efecto de la rosuvastatina sobre el infarto experimental en conejos normales e hipercolesterolémicos / Effects of Rosuvastatin on Experimental Infarction on Normal and in Hypercholesterolemic Rabbits

Es conocido que el pretratamiento con rosuvastatina disminuye el tamaño del infarto y mejora la disfunción ventricular. Sin embargo, no existe evidencia experimental que demuestre su efecto cuando se administra durante la reperfusión. El objetivo del presente estudio fue evaluar si la rosuvastatina administrada durante la reperfusión modifica el tamaño del infarto y la recuperación de la función ventricular posisquémica en corazones de conejos normocolesterolémicos e hipercolesterolémicos. Corazones aislados e isovolúmicos de conejo fueron perfundidos según la técnica de Langendorff. En el grupo 1 (G1) se realizó una isquemia global de 30 minutos seguidos por 120 minutos de reperfusión. En el grupo 2 (G2) se administró rosuvastatina (50 µM) durante toda la reperfusión. En los grupos 3 y 4 (G3 y G4) se repitieron los protocolos de G1 y G2, respectivamente, pero en conejos alimentados durante un mes con una dieta rica en colesterol al 1%. El colesterol total antes de iniciar la dieta fue de 59,6 ± 9,3 mg/dl y luego de la alimentación durante 4 semanas con una dieta rica en colesterol se incrementó hasta un valor de 185,4 ± 21,4 (p < 0,05). No hubo diferencias en la recuperación de la presión desarrollada (PDVI) ni en la presión diastólica final del ventrículo izquierdo (PDFVI) en los animales normocolesterolémicos. Sin embargo, en G3 y G4 la administración de rosuvastatina atenuó la disfunción ventricular posisquémica sistólica y diastólica. El tamaño del infarto de G1 y G3 fue de 16,6 ± 2,6 y 25,6 ± 2,7, respectivamente (p < 0,05). La administración de rosuvastatina redujo el tamaño del infarto en G2 y G4 a un valor de 4,5 ± 1,1 y 5,5 ± 1,6 (p < 0,05), respectivamente. La rosuvastatina administrada desde el inicio de la reperfusión disminuye el tamaño del infarto en conejos normales e hipercolesterolémicos y mejora la recuperación de la función ventricular sólo en los animales hipercolesterolémicos.

It is well accepted that previous treatment with rosuvastatin may reduce infarct size and improve ventricular dysfunction. Nevertheless, there is no experimental evidence of this action when administered during reperfusion. The objective of the present study was to assess if the administration of rosuvastatin during reperfusion might modify not only the infarct size but also ventricular function recovery after an ischemic episode in normocholesterolemic and hypercholesterolemic rabbits. Isolated and isovolumetric rabbit hearts were perfused according to Langendorff technique. Rabbits in group 1 (G1) underwent a 30-minute global ischemia followed by a reperfusion lasting for 120 minutes. Rosuvastatin (50 µM) was administered to rabbits in group 2 (G2) throughout the whole reperfusion. Protocols G1 and G2 were repeated in groups 3 and 4 (G3 and G4), respectively, but in rabbits previously fed for a month with a 1% cholesterol-rich diet. Total cholesterol levels were 59.6±9.3 mf/dl before treatment with the diet, and after a cholesterol-rich diet for 4 weeks, cholesterol levels increased to 185.4±21.4 (p<0.05). No differences among recovery in left ventricle developed pressure (LVDP) or in end-diastolic left ventricle pressure (EDLVP) were reported in normocholesterolemic animals. Nevertheless, the administration of rosuvastatin mitigated systolic and diastolic post-ischemic left ventricular dysfunction. Infarct size in G1 and G3 was 16.6±2.6 and 25.6 ± 2.7, respectively (p < 0.05). Administration of rosuvastatin reduced the infarct size in G2 and G4 to 4.5±1.1 y 5.5±1.6 (p<0.05), respectively. The administration of rosuvastatin since the beginning of reperfusion reduces the infarct size in normocholesterolemic and hypercholesterolemic rabbits, and improves ventricular function only in hypercholesterolemic animals.

Alterations in cell adhesion molecules and other biomarkers of cardiovascular disease in patients with metabolic syndrome.

Metabolic syndrome is considered a hyperinsulinemic and inflammatory state closely associated to endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. The main objective of the present study was to determine whether leukocitary and soluble cell adhesion molecules were altered in patients with metabolic syndrome in comparison with control subjects. Cell adhesion molecules, mainly of leukocitary location, have been not previously evaluated in specifically designed cross-sectional studies involving male patients with metabolic syndrome. Moreover, other circulating markers of different candidate atherogenic risk parameters were also studied and the potential existence of a progressive relation between the number of metabolic syndrome components and the above mentioned biomarkers was analyzed. Thirty one male patients with metabolic syndrome (ATPIII definition) and 56 male control subjects were studied. We evaluated different markers of insulin resistance, inflammation and atherosclerosis, as well as protective factors. Patients with metabolic syndrome showed (a) hypoadiponectinemia (4551 +/- 2302 ng/ml vs. 5865 +/- 2548 ng/ml, respectively; p<0.05), (b) an atherogenic lipid and lipoprotein profile, (c) altered HDL chemical composition accompanied by higher cholesteryl ester-triglyceride interchange carried out by CETP, (d) diminished Lp-PLA(2) activity (6.5 +/- 1.9 vs. 7.3 +/- 2.2, p<0.05, respectively), antioxidant enzyme related with LDL oxidation, which was positively associated with QUICKI and negatively with VCAM-1 and lymphocyte CD18, and (e) high soluble (VCAM-1: 17 +/-5 vs. 13 +/- 4 ng/ml, respectively; p<0.0005) and leukocyte adhesion molecule expression (monocyte CD54: 52 +/- 15 vs. 45 +/-12 arbitrary units, respectively; p<0.0005; and lymphocyte CD49d: 312 +/- 56 vs. 284 +/- 64 arbitrary units, respectively; p < 0.05). The increment in leukocyte and soluble cell adhesion molecules, crucial for leukocyte interaction with the endothelium and migration into the artery wall, in combination with the other disorders described above reinforce the presence of a clinical status with high propensity to type 2 diabetes and atherosclerotic cardiovascular disease.

Endothelial and leukocyte adhesion molecules in primary hypertriglyceridemia.

Hypertriglyceridemia is known to be associated to functional impairment of the endothelium and, consequently, to higher risk of atherosclerosis. Nevertheless, some crucial steps in the development of the atherosclerotic plaque are still unknown in primary hypertriglyceridemia. The aim of the present study was to explore the expression of soluble and leukocyte-associated cell adhesion molecules in a group of patients with primary hypertriglyceridemia, both including (n=50) and excluding (n=24) subjects with metabolic syndrome, in comparison with control normotriglyceridemic individuals (n=30). Lipid profile, CETP activity, HDL and VLDL chemical composition were evaluated. Soluble (VCAM-1, ICAM-1 and E-selectin) and leukocyte cell adhesion molecules (CD18, CD49d and CD54) were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. Patients with primary hypertriglyceridemia as compared with control subjects showed significantly higher VCAM-1 (15.6+/-4.5 ng/ml versus 13.9+/-3.8 ng/ml, respectively; p<0.05) and ICAM-1 (16.9+/-3.1 ng/ml versus 15.2+/-3.2 ng/ml, respectively; p<0.05). Regarding leukocyte cell adhesion molecules, significant increases were also detected in monocyte CD18 (398+/-180 versus 332+/-136 arbitrary units, respectively; p<0.05) and CD54 (49+/-14 versus 42+/-12 arbitrary units, respectively; p<0.05), and lymphocyte CD18 (122+/-53 versus 101+/-33 arbitrary units, respectively; p<0.05). ICAM-1 plasma levels, as well as monocyte CD18 and CD54, and lymphocyte CD18 persisted elevated even if patients with metabolic syndrome were discarded among those with hypertriglyceridemia. The increase in circulating and leukocyte cell adhesion molecules in primary hypertriglyceridemic patients would highlight the inflammatory process which is a key event in atherogenesis.

Factores circulantes de injuria endotelial y procesos subendoteliales en mujeres postmenopáusicas sanas / Endothelial injuring factors and subendothelial events in healthy postmenopausal women

La concentración elevada de lipoproteínas aterogénicas con apo B en mujeres posmenopáusicas (MPM), es un componente importante del mecanismo multifactorial causante de la enfermedad coronaria. En MPM sanas (n=30) en comparación con premenopáusicas (MpreM) (n=28), se evaluó el perfil lipoproteico incluyendo apoproteínas A-I y B, LDL pequeña y densa, composición y oxidabilidad de LDL, proteína transportadora de colesterol esterificado y lipasa hepática. Se determinaron los siguientes factores emergentes: homocisteína, fosfolipasa A2, ferritina, PCR-hs (alta sensibilidad) y fibronectina proveniente de la matriz extracelular. La insulino-resistencia fue evaluada por la circunferencia de cintura, el índice HOMA y el índice triglicéridos/colesterol-HDL. El índice de riesgo apo B/apoA-I fue significativamente mayor en MPM (p<0,0001). MPM presentaron mayor proporción de LDL pequeña y densa, la cual correlacionó con el aumento de actividad de lipasa hepática (p<0,005), y con marcadores de insulino-resistencia (p<0,05). Fosfolipasa A2 (p<0,05), homocisteína (p<0,005), ferritina (p<0,0001), PCR-hs (p<0,005) y fibronectina (p<0,05)) fueron mayores en MPM. La oxidabilidad de LDL no mostró diferencias significativas pero correlacionó positivamente con LDL pequeña y densa (p<0,01), fosfolipasa A2 (p<0,05), homocisteína (p<0,05), PCR-hs (p<0,04), fibronectina (p<0,05) y cintura (p<0,02). Luego de ajustar por la condición menopáusica, edad y cintura, la oxidabilidad de LDL permaneció asociada con LDL pequeña y densa (b:0,36, p=0,027), homocisteína (b:0,36, p<0,038), fibronectina (b:0,41 p=0,05) y cintura (b:0,35, p=0,047). En este estudio, la interacción de factores de riesgo aterogénico clásicos y no tradicionales sugiere una secuencia de eventos que comienzan con la injuria endotelial causada por homocisteína y LDL pequeña y densa, que penetra en subendotelio donde su oxidación es favorecida por la homocisteína. Se produciría un proceso inflamatorio, que cursa con aumento de PCR y ferritina. La fosfolipasa A2, proveniente de macrófagos, atravesaría el endotelio unida a la LDL modificada, y promueve la liberación de fibronectina desde la matriz extracelular. La estrecha interacción entre la injuria endotelial, inflamación e insulino-resistencia se observaría desde estadíos subclínicos de aterosclerosis en MPM sanas.

In postmenopausal women (PMW), high concentrations of atherogenic apoB lipoproteins is an important component of the multifactorial mechanism underlying a higher risk of coronary artery disease, as compared with premenopausal women (PreMW). Lipoprotein pattern, including apopoproteins A-I and B, LDL chemical composition and small dense LDL (sdLDL), hepatic lipase activity, circulating cholesterol transfer protein and LDL oxidability were assessed in PMW (n=30) in comparison to PreMW (n=28). The following endothelial injuring factors were measured: homocysteine, lipoprotein binding phospholipase A2 (LpPLA2), ferritin, hs-CRP and fibronectin coming from extracellular vascular matrix. Insulin-resistance was evaluated by waist circumference, HOMA and triglyceride/HDL-cholesterol. PMW showed higher apoB/apoA-I (p<0.0001) and a higher proportion of sdLDL which showed significant correlations with the increase in hepatic lipase activity (p<0.005) and insulin-resistance markers (p<0.05). LpPLA2 (p<0.05), homocysteine (p<0.005), hs-CRP (p<0.005), fibronectin (p<0.05) and ferritin (p<0.0001) were elevated in PMW. LDL oxidability showed no differences between groups, but was positively correlated with waist (p<0.02), homocysteine (p<0.05), fibronectin (p<0.05), hs-CRP (p<0.04), LpPLA2 (p<0.05) and sdLDL (p<0.01). After adjusting by age, menopausal condition and waist, LDL oxidability remained associated with homocysteine (b: 0,36) p<0,038), sdLDL (b: 0.36, p=0.027), waist (b: 0.35, p=0.047) and fibronectin (b: 0,41 p=0.05). In this study, the interaction of classic and emerging atherogenic risk factors would suggest a sequence of events starting with endothelial damage caused by homocysteine and sdLDL, promoting its passage into the subendothelial space where it is oxidatively modified, enhanced by homocysteine. The above mentioned inflammatory process takes place with an increase in circulating hs-CRP and ferritin. LpPLA2, coming from macrophages, passes through the endothelium bound to modified LDL, promoting a release of fibronectin from the subendothelial extracellular matrix. Results suggest that the close interaction among endothelial injury, inflammation and insulin resistance can be observed since subclinical atherosclerosis states in healthy PMW.