Research Advance of Chinese Medicine in Treating Atherosclerosis: Focus on Lipoprotein-Associated Phospholipase A2 / 中国结合医学杂志

As a serious cardiovascular disease, atherosclerosis (AS) causes chronic inflammation and oxidative stress in the body and poses a threat to human health. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 (PLA2) family, and its elevated levels have been shown to contribute to AS. Lp-PLA2 is closely related to a variety of lipoproteins, and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine (oxPC) to produce lysophosphatidylcholine (lysoPC). Moreover, macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability. This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

Paeonol reduces microbial metabolite α-hydroxyisobutyric acid to alleviate the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in atherosclerosis mice / 中国天然药物

Gut microbiota dysbiosis is an avenue for the promotion of atherosclerosis (AS) and this effect is mediated partly via the circulating microbial metabolites. More microbial metabolites related to AS vascular inflammation, and the mechanisms involved need to be clarified urgently. Paeonol (Pae) is an active compound isolated from Paeonia suffruticoas Andr. with anti-AS inflammation effect. However, considering the low oral bioavailability of Pae, it is worth exploring the mechanism by which Pae reduces the harmful metabolites of the gut microbiota to alleviate AS. In this study, ApoE-/- mice were fed a high-fat diet (HFD) to establish an AS model. AS mice were administrated with Pae (200 or 400 mg·kg-1) by oral gavage and fecal microbiota transplantation (FMT) was conducted. 16S rDNA sequencing was performed to investigate the composition of the gut microbiota, while metabolomics analysis was used to identify the metabolites in serum and cecal contents. The results indicated that Pae significantly improved AS by regulating gut microbiota composition and microbiota metabolic profile in AS mice. We also identified α-hydroxyisobutyric acid (HIBA) as a harmful microbial metabolite reduced by Pae. HIBA supplementation in drinking water promoted AS inflammation in AS mice. Furthermore, vascular endothelial cells (VECs) were cultured and stimulated by HIBA. We verified that HIBA stimulation increased intracellular ROS levels, thereby inducing VEC inflammation via the TXNIP/NLRP3 pathway. In sum, Pae reduces the production of the microbial metabolite HIBA, thus alleviating the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in AS. Our study innovatively confirms the mechanism by which Pae reduces the harmful metabolites of gut microbiota to alleviate AS and proposes HIBA as a potential biomarker for AS clinical judgment.

Rosuvastatin acts on the lymphatic system to improve atherosclerosis / 中华心血管病杂志

Objective: To investigate whether rosuvastatin acts on lymphatic system and influences lymphatic system-mediated reverse cholesterol transport to play an anti-atherosclerosis role. Methods: Forty-eight apolipoprotein E-/- mice fed a high fat diet were used to construct the atherosclerosis model. They were randomly divided into 4 groups with 12 rats in each group. They were treated with rosuvastatin, vascular endothelial growth factor-C (VEGF-C) and rosuvastatin+VEGF-C inhibitors as experimental group, and no intervention measures were given in control group. After 8 weeks, aortic plaque area, high density lipoprotein cholesterol (HDL-C) content in lymph fluid, the function of popliteal lymphatic drainage of peripheral Evans blue, and the ability of lymphatic system to transport peripheral cell membrane red fluorescent probes to label high-density lipoprotein (HDL) were detected. Subsequently, the effects of rosuvastatin on proliferation, migration and tubular function of lymphoendothelial cells and the expression of scavenger receptor class B type 1 (SR-B1) on lymphoendothelial cells at different concentrations were detected. Results: Compared with the control group, Rosuvastatin and VEGF-C could reduce the area of aortic atherosclerotic plaque (P<0.05). In addition to rosuvastatin plus VEGF-C inhibitor, the intra-aortic plaque area increased (P<0.05). Compared with the control group, Rosuvastatin could increase the content of HDL-C in lymphatic fluid (P<0.05), enhance the drainage function of lymphatic vessels, and enhance the capacity of HDL in the transport tissue fluid of lymphatic system. Compared with the control group, VEGF-C increased the content of HDL-C in mouse lymph fluid (P<0.01), enhanced the drainage function of popliteal lymphatic canal, and enhanced the ability of lymphatic system to transport HDL. With the addition of VEGF-C inhibitor on the basis of rosuvastatin, the content of HDL-C in lymph fluid was reduced, the drainage of popliteal lymphatic canal was interrupted, and the ability of lymphatic system to transport HDL was reduced. Western blotting showed that rosuvastatin increased the protein expression of SR-B1. Conclusion: Rosuvastatin can promote the proliferation, migration and tube formation of lymphatic endothelial cells. At the same time, SR-B1 expression on lymphatic endothelial cells is promoted, thus enhancing the lymphatic system mediated cholesterol reversal transport and playing the role of anti-atherosclerosis.

Network Meta-analysis of Chinese patent medicine containing Hirudo in treatment of atherosclerosis / 中国中药杂志

This study aimed to evaluate the efficacy and safety of Chinese patent medicines containing Hirudo in the treatment of atherosclerosis(AS) by network Meta-analysis, and to provide evidence-based reference for clinical treatment of AS. The clinical randomized controlled trial(RCT) on the treatment of atherosclerosis with Chinese patent medicines containing Hirudo were searched in CNKI, Wanfang, VIP, SinoMed, PubMed and EMbase from the establishment of the databases to July 1, 2022. And data extraction and quality assessment of the included RCT was performed according to the Cochrane standards. Stata 17 and ADDIS 1.16.5 were then used for Bayesian model network Meta-analysis. Finally, 67 RCTs with a total sample size of 6 826 cases were included, 3 569 cases in the experimental group and 3 257 cases in the control group, involving three oral Chinese patent medicines. Network Meta-analysis showed that in terms of reducing intima-media thickness(IMT), the top three Chinese patent medicines were Tongxinluo Capsules+sta-tins>Maixuekang Capsules+statins>Maixuekang Capsules. In terms of reducing plaque area, the top one was Maixuekang Capsules+sta-tins, and the other Chinese patent medicines had similar efficacy. For lowering AS Crouse scores, the top three were Maixuekang Capsules>Tongxinluo Capsules+statins>Naoxintong Capsules. For decreasing plaque number, the top three were Naoxintong Capsules+sta-tins>Tongxinluo Capsules+statins>Tongxinluo Capsules. With regard to adverse reactions/events, Naoxintong Capsules+statins had the lo-west incidence. In conclusion, in Chinese patent medicines containing Hirudo for the treatment of AS, Tongxinluo Capsules+statins, Maixuekang Capsules, Maixuekang Capsules+statins, and Naoxintong Capsules+statins were the primary choices to reduce IMT, AS Crouse scores, plaque area, and plaque number, respectively. The efficacy of Chinese patent medicines containing Hirudo with or without statins was more significant than that of statins alone in the four outcome indexes. Additionally, the treatment of AS should be evaluated comprehensively, and attention should be paid to Chinese patent medicines or their combination with western medicine, to optimize the treatment effect and minimize adverse reactions as the benchmark.

Are statins a risk factor in patients with atherosclerosis? / ¿Son las estatinas un factor de riesgo en pacientes con aterosclerosis?

SUMMARY: Statins inhibit cholesterol synthesis, but also have other pleiotropic effects. There are indications that they affect macrophage survival trough the regulation of apoptosis. We analyzed 50 samples of aortic wall, selected based on statins in patients' therapy (n=25, Th-S group) or statin-free therapy (n=25, Th-nonS group). Each group had 5 samples of healthy aortic tissue, 10 samples of mild and 10 samples of severe atherosclerotic changes in aortic wall. Tissue was stained with hematoxylin-eosin and immunohistochemical methods (anti-Bcl-2 antibody). Presence of Bcl2-positive macrophages (Bcl-2+ MP) was determined semiquantitatively, and data were processed in Microsoft Excell and IMB SPSS 23 Statistics. 60 % of patients in the Th-S group had a mild increase of Bcl-2+ MP The use of statins leads to a significantly more frequent increase in Bcl2+ macrophages in the intima of the healthy aortic tissue. Analysis of all aortic samples with pathohistological diagnosis showed that statin therapy was statistically significantly more often leading to a markedly increased presence of Bcl-2+ MP. In the media, all samples of the Th-S group have a mild increase of Bcl-2+ MP, and in adventitia 40 % of patients. The use of statins more often leads to a markedly increased presence of Bcl-2+ MP in aortic tissue with diagnosed mild and severe atherosclerosis. In samples of severe atherosclerosis, statins lead to a markedly increased presence of Bcl-2+ MP in the parts of the plaque towards the intima and towards the media. Statins lead to an increased presence of Bcl-2+ macrophages, prolong their life, both in healthy and atherosclerotic altered aortic tissue. This indicates potentiation of inflammation and damage to the aortic wall, and calls into question the positive effect of statins on the aortic wall with atherosclerosis.

RESUMEN: Las estatinas inhiben la síntesis de colesterol, pero también tienen otros efectos pleiotrópicos. Hay indicios de que afectan la supervivencia de los macrófagos a través de la regulación de la apoptosis.Se analizaron 50 muestras de pared aórtica, seleccionadas en base a estatinas en tratamiento de pacientes (n=25, grupo Th-S) o en tratamiento libre de estatinas (n=25, grupo Th- nonS). Cada grupo tenía 5 muestras de tejido aórtico sano, 10 muestras de cambios ateroscleróticos leves y 10 muestras de cambios ateroscleróticos severos en la pared aórtica. El tejido se tiñó con hematoxilina-eosina y métodos inmunohistoquímicos (anticuerpo anti-Bcl-2). La presencia de macrófagos positivos para Bcl2 (Bcl- 2+ MP) se determinó semicuantitativamente y los datos se procesaron en Microsoft Excell e IMB SPSS 23 Statistics. El 60 % de los pacientes del grupo Th-S tuvo un aumento leve de Bcl-2+ MP. El uso de estatinas conduce a un aumento significativamente más frecuente de macrófagos Bcl2+ en la íntima del tejido aórtico sano. El análisis de todas las muestras aórticas con diagnóstico anatomopatológico mostró que la terapia con estatinas fue significativamente más frecuente desde el punto de vista estadístico, lo que condujo a una presencia marcadamente mayor de Bcl-2+ MP. En los medios, todas las muestras del grupo Th-S tienen un leve aumento de Bcl-2+ MP, y en adventicia en el 40 % de los pacientes. El uso de estatinas con mayor frecuencia conduce a una presencia marcadamente mayor de MP Bcl-2+ en el tejido aórtico con aterosclerosis leve y grave diagnosticada. En muestras de aterosclerosis severa, las estatinas conducen a una presencia aumentada de Bcl-2+ MP en las partes de la placa hacia la íntima y hacia la media. Las estatinas conducen a una mayor presencia de macrófagos Bcl-2+, prolongan su vida, tanto en tejido aórtico sano como aterosclerótico alterado. Esto indica la potenciación de la inflamación y el daño a la pared aórtica y pone en duda el efecto positivo de las estatinas en la pared aórtica con aterosclerosis.

Low-density lipoprotein cholesterol levels and lipid-lowering treatment status among young and middle-aged ultra-high-risk patients with acute coronary syndrome in China / 中华心血管病杂志

Objective: To assess low-density lipoprotein cholesterol (LDL-C) levels and use of lipid-lowering treatment among young and middle-aged ultra-high-risk patients with acute coronary syndrome (ACS) in China. Methods: The study was based on the"Improving Care for Cardiovascular Disease in China (CCC)-ACS"project, a collaborative registry by and Chinese Society of Cardiology (CSC) and the American Heart Association. Hospitalized-patients with ACS were consecutively enrolled from 159 tertiary and 82 secondary hospitals across China, related clinical information was collected. This study included young and middle-aged hospitalized patients (18-59 years) with ACS from November 2014 to December 2019 registered in CCC-ACS project. Ultra-high-risk was defined according to Chinese expert consensus on lipid management of ultra-high-risk atherosclerotic cardiovascular disease (ASCVD) patients of CSC. The mean LDL-C levels at admission, pre-hospital lipid-lowering therapy and proportion of patients with LDL-C target achieved were analyzed. Results: A total of 42 230 patients younger than 60 years with ACS were included in this study. The mean age was (50.4±6.9) years, and 86.8% (36 676/42 230) of the ACS patients were male. Among them, 86.9% (36 687/42 230) met the criteria of ultra-high-risk. The mean level of LDL-C at admission was (2.8±1.0)mmol/L, only 5.3 % (1 948/36 687) patients achieved the targeted goal of LDL-C<1.4 mmol/L. Among the ultra-high-risk ASCVD patients, 17.5% (6 430/36 687) received lipid-lowering drugs before hospitalization, 96.4% (6 198/6 430) of whom received statins monotherapy. Among patients receiving pre-hospital statins, only 9.9% (626/6 323) patients reached an LDL-C<1.4 mmol/L at admission. Conclusions: The majority of young and middle-aged hospitalized patients with ACS are ultra-high-risk patients for ASCVD in China. Pre-hospital lipid-lowering drugs use is lower in these ultra-high-risk ASCVD patients and most patients do not reach the new LDL-C target level at admission.

Naringenin promotes cell autophagy to improve high-fat-diet-induced atherosclerosis in ApoE-/- mice

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.

Regulatory T Cells: A New Target of Chinese Medicine in Treatment of Atherosclerosis / 中国结合医学杂志

Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis (AS). With the role of regulatory T cells (Tregs) in immune regulation attracting attention, it has been widely accepted that Treg decrease and dysfunction are involved in AS pathogenesis. Chinese medicine (CM) has the advantages of being dual-directional, multi-targeted, and having minimal side effects in immune regulation. The anti-atherosclerosis effects of CM via Treg modulation have been revealed in clinical and animal studies. Therefore, this article reviews existing research on Tregs, the relationship between Tregs and AS, and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating Tregs. Although the underlying mechanisms remain to be elucidated, CM treatment targeting Treg cells might provide a promising and novel future approach for prevention and treatment of AS.

Current studies of cytokines in the pathogenesis of atherosclerosis and its therapeutic measures / 生理学报

Atherosclerosis is a chronic inflammatory disease. Cytokine-related research provides an important direction for the prevention and treatment of atherosclerosis. Cytokines, produced by different types of cells and acting on a range of targets, play a key role in the pathogenesis and progression of atherosclerosis. This review summarizes the main pro-inflammatory and anti-inflammatory cytokines related to atherosclerosis and their underlying mechanism. We also outline current anti-atherosclerosis treatments targeting cytokines. The research and treatment prospects of cytokines in the prevention and treatment of atherosclerosis are discussed briefly as well.

Rol de los fitoestrógenos en la calcificación vascular e interacciones óseo-vasculares / Role of phytoestrogens in vascular calcification and bonevascular interactions

La osteoporosis y las enfermedades cardiovasculares son patologías prevalentes en mujeres posmenopáusicas. La calcificación vascular es un proceso en el que se produce una distorsión de la arquitectura natural del tejido arterial con una transformación símil osteogénica. La fisiología vascular y la osteogénesis (formación y remodelación ósea) comparten una complejidad metabólica y funcional crítica, que ha sido poco explorada en forma conjunta, lo que ha impulsado la concepción del Eje Óseo-Vascular como nueva área de investigación, con una visión de estudio integradora con la finalidad de identificar vínculos entre ambos sistemas. En virtud de la controversia planteada sobre los riesgos/beneficios de la terapia de reemplazo hormonal para prevenir enfermedades asociadas a la menopausia, se ha incentivado la búsqueda de nuevas opciones de tratamiento. Los fitoestrógenos, como compuestos nutracéuticos, surgen como una potencial alternativa terapéutica. En particular, las isoflavonas presentan gran analogía estructural con el estrógeno humano 17ß-estradiol, lo que les permite unirse al receptor de estrógenos e inducir acciones estrogénicas tanto en células animales como humanas. Basado en la experiencia propia como en lo reportado en la bibliografía, este artículo analiza la información disponible sobre las acciones vasculares y óseas de los fitoestrógenos (específicamente la isoflavona genisteína), con una visión de ciencia traslacional. Es de esperar que los avances en el conocimiento derivado de la ciencia básica, en un futuro cercano, pueda contribuir a decisiones clínicas a favor de promover terapias naturales de potencial acción dual, para la prevención de enfermedades de alta prevalencia y significativo costo social y económico para la población. (AU)

Osteoporosis and cardiovascular diseases are prevalent diseases in postmenopausal women. Vascular calcification is a cellmediated process that leads to the loss of the natural architecture of the arterial vessels due to osteogenic transdifferentiation of smooth muscle cells, and matrix mineralization. Vascular physiology and osteogenesis (bone formation and remodeling) share a critical metabolic and functional complexity. Given the emerging integrative nature of the bonevascular axis, links between both systems are a matter of ongoing interest. In view of the controversy stated about the risks/benefits of hormone replacement therapy to prevent diseases associated with menopause, phytoestrogens arise as a potential natural therapeutic alternative. In particular, isoflavones have a strong structural analogy with the human estrogen 17ß-estradiol, that allows them to bind to the estrogen receptor and induce estrogenic actions in animal and human cells. Based in on our own experience and the information available in the literature, in this paper we provide an overview of the role of phytoestrogens on vascular and bone tissues, with focus on Genistein actions. We wish that the basic knowledge acquired may contribute to guide clinical decisions for the promotion of natural therapies for the treatment of diseases that conspire against human health. (AU)

Regulatory effect of Di'ao Xinxuekang on TLR4/MyD88/NF-κB signaling pathway in atherosclerotic rats / 中国中药杂志

The aim of this paper was to observe the effect of Di'ao Xinxuekang(DXXK) on TLR4/MyD88/NF-κB signaling pathway in atherosclerotic rats, and to explore its anti-atherosclerotic mechanism. Sixty SD rats were randomly divided into normal group, model group, atorvastatin group(4.0 mg·kg~(-1)), and DXXK groups(100, 30, 10 mg·kg~(-1)), with 10 rats in each group. The atherosclerosis model was induced by high fat diet plus vitamin D_2. Experimental drugs were administered intragastrically once daily for 8 weeks starting from the 9 th week. Biochemical analyzers were used to detect levels of triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C) in blood lipid. The levels of serum tumor necrosis factor(TNF)-α, interleukin(IL)-6 and IL-1β were detected by ELISA. Pathological changes of aortic tissues were observed by using Sudan Ⅳ and HE staining. The mRNA and protein expressions of TLR4, MyD88 and NF-κB p65 in aortic tissues were detected by RT-PCR and Western blot, respectively. As compared with the model group, TC, TG, and LDL-C levels in serum were significantly decreased, HDL-C content was significantly increased, and levels of TNF-α, IL-6, and IL-1β in serum were significantly decreased in atorvastatin group and DXXK high and middle dose groups. Aortic lesions in atorvastatin group and DXXK group were significantly improved, and the mRNA and protein expressions of TLR4, MyD88, NF-κB p65 in the aorta were decreased. DXXK has a preventive and therapeutic effect on atherosclerosis in rats, and its mechanism may be related to inhibiting inflammatory reaction by regulating TLR4/MyD88/NF-κB signal transduction, thereby inhibiting the progression of atherosclerosis.

Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.

PCSK9 inhibitors in the current management of atherosclerosis / Los inhibidores de la PCSK9 en el manejo clínico actualizado de la aterosclerosis

Abstract: The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States)

Resumen: La historia de la proproteína convertasa subtilisin/kexin tipo 9 (PCSK9) es fascinante y la evolución del conocimiento de su función ha resultado en nuevos fármacos de gran importancia para el paciente cardiovascular. La PCSK9 funciona como un control negativo de receptores en la superficie de células para la lipoproteína de baja densidad con su componente de colesterol (LDL-C). El hallazgo inicial y clave fue que anormalidades diferentes de la PCSK9 resultan en un aumento o una disminución de la LDL-C, relacionados en una mayor o menor supresión de los receptores. Fueron estas observaciones las que proporcionaron evidencias indirectas a la idea de preparar anticuerpos monoclonales de la PCSK9 que pudieran disminuir su actividad y que esto se reflejara en receptores más activos para disminuir la LDL-C. El resto es una historia fascinante que ahora ofrece 2 inhibidores de la PCSK9, alirocumab y evolocumab, los cuales disminuyen la LDL-C en un 50%. Sin embargo, si no hay una contraindicación, las estatinas son el estándar de prevención para el paciente cardiovascular de alto riesgo e incluyen la prevención secundaria y primaria. Estos nuevos inhibidores están indicados en aquel paciente en el que no se obtiene el objetivo de tratamiento con la dosis máxima de una estatina o que no tolera ninguna de ellas. Debemos pensar en la aterosclerosis como una enfermedad metabólica y el clínico necesita darse cuenta de esta realidad y considerar las posibilidades disponibles para la prevención cardiovascular. Estos inhibidores pueden contribuir a la estabilización y regresión de placas ateroscleróticas y evitar episodios cardiovasculares mayores. (Estados Unidos)

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches

Atherosclerosis is a chronic progressive vascular disease. It starts early in life, has a long asymptomatic phase, and a progression accelerated by various cardiovascular risk factors. The endothelium is an active inner layer of the blood vessel. It generates many factors that regulate vascular tone, the adhesion of circulating blood cells, smooth muscle proliferation, and inflammation, which are the key mechanisms of atherosclerosis and can contribute to the development of cardiovascular events. There is growing evidence that functional impairment of the endothelium is one of the first recognizable signs of development of atherosclerosis and is present long before the occurrence of atherosclerotic cardiovascular disease. Therefore, understanding the endothelium's central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify cardiovascular risk, and assess response to treatments. In the present review, we will discuss the clinical implications of endothelial function as well as the therapeutic issues for endothelial dysfunction in cardiovascular disease as primary and secondary endothelial therapy.

Pycnogenol attenuates atherosclerosis by regulating lipid metabolism through the TLR4-NF-kappaB pathway

Atherosclerosis is a leading cause of death worldwide and is characterized by lipid-laden foam cell formation. Recently, pycnogenol (PYC) has drawn much attention because of its prominent effect on cardiovascular disease (CVD). However, its protective effect against atherosclerosis and the underlying mechanism remains undefined. Here PYC treatment reduced areas of plaque and lipid deposition in atherosclerotic mice, concomitant with decreases in total cholesterol and triglyceride levels and increases in HDL cholesterol levels, indicating a potential antiatherosclerotic effect of PYC through the regulation of lipid levels. Additionally, PYC preconditioning markedly decreased foam cell formation and lipid accumulation in lipopolysaccharide (LPS)-stimulated human THP-1 monocytes. A mechanistic analysis indicated that PYC decreased the lipid-related protein expression of adipose differentiation-related protein (ADRP) and adipocyte lipid-binding protein (ALBP/aP2) in a dose-dependent manner. Further analysis confirmed that PYC attenuated LPS-induced lipid droplet formation via ADRP and ALBP expression through the Toll-like receptor 4 (TLR4) and nuclear factor-kappaB (NF-kappaB) pathway, because pretreatment with anti-TLR4 antibody or a specific inhibitor of NF-kappaB (PDTC) strikingly mitigated the LPS-induced increase in ADRP and ALBP. Together, our results provide insight into the ability of PYC to attenuate bacterial infection-triggered pathological processes associated with atherosclerosis. Thus PYC may be a potential lead compound for the future development of antiatherosclerotic CVD therapy.

Effects of Emblica Officinalis (AMLA) on Serum Lipids and Atherogenesis in Albino Rats Fed with High Fat Diet.

Objective: To evaluate the effects of Emblica officinalis (Amla) extract on serum lipids and atherogenesis, in albino rats fed with high fat diet. Materials and Methods: Healthy albino rats of Wistar strain (150-200 gm each) were randomized into five groups of six animals each- Group A (received normal diet), Group B (received normal diet + Emblica officinalis extract 1 gm/kg BW) Group C (received high fat diet consisting of vanaspati ghee and coconut oil at a ratio of 3:2, at a dose of 10 ml/kg/day), Group D (received high fat diet + Emblica officinalis extract 1 gm/kg BW) and Group E (received high fat diet + simvastatin 1.8 mg/ kg BW). Treatment period was 8 weeks. At the end of 8 weeks, lipid profile was evaluated by estimating total cholesterol, serum triglyceride, serum LDL, serum HDL and atherogenic index. Results: Ethanolic extract of Emblica officinalis showed significant antihyperlipidaemic activity (P< 0.01) with significant improvement in atherogenic index (p<0.01). Conclusion: Present study suggests that Emblica officinalis extract at a dose of 1 gm/kg BW exerts antihyperlipidaemic effect comparable to that of simvastatin. It also possesses hypolipidaemic activity.

Aterosclerose: diagnóstico macroscópico nas autópsias / Atherosclerosis: macroscopic diagnosis at autopsy

O diagnóstico macroscópico da aterosclerose nas autópsias é essencial; por ser um processo inflamatório crônico do leito arterial, tem graves consequências para o aparelho circulatório, tendo como resultado o infarto cerebral isquêmico, hemorragias encefálicas, infarto agudo do miocárdio, arteropatias, aneurismas, cardiopatias isquêmicas e morte súbita. Fatores de risco genéticos e ambientais influenciam fortemente seu surgimento. Seu diagnóstico macroscópico durante as autópsias é condição sine qua non para entender a sequência de eventos fisiopatológicos que levaram ao óbito, permitindo a identificação da causa mortis.

Efectos de las estatinas en cáncer: ¿potencial rol en terapéutica y prevención? / Effects of statins in cancer

This review explores the evidence supporting a potential benefit of statins in cancer. In particular, the lipophilic forms (i.e. lovastatin, simvastatin, or similar) would have a therapeutic but not a preventive role. The pleiotropic effects that statins possess mainly explain this phenomenon, influencing the natural history of disease and the response to currently available therapies. By inhibiting the mevalonate pathway, statins would have a systemic effect, similar to that observed in atherosclerosis, reducing the inflammatory stimuli present in the tumor micro-environment and inhibiting the activation of intracellular signaling cascades critical for proliferation, migration/invasion and metastasis of the cancer cell. Despite all this evidence, randomized trials are needed to confirm the benefit of statins on cancer, before promoting their widespread use as a therapeutic or preventive strategy for this condition.