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1.
The Role of Colchicine in Acute Coronary Syndromes.
Vaidya, K, Martínez, G, Patel, S
Clinical therapeutics. 2019;(1):11-20
Abstract
PURPOSE Because inflammation is a key process implicated in the pathogenesis of atherosclerosis at all stages, including plaque formation, progression, instability, and rupture, and because colchicine has unique anti-inflammatory properties, this review article summarizes the pathophysiologic mechanisms underpinning inflammation in atherosclerosis and acute coronary syndrome (ACS), outlines anti-inflammatory therapeutic approaches that have been tested thus far, and evaluates the evidence supporting the potential role of colchicine in improving outcomes and reducing cardiovascular morbidity and mortality in patients after ACS. METHODS PubMed was searched for publications on colchicine and ACSs and atherosclerosis, and www.clinicaltrials.org was searched for completed and ongoing trials of colchicine use in ACSs. FINDINGS Despite contemporary optimal medical therapy, patients remain at a high risk of future events after an ACS because of residual inflammation at culprit and nonculprit sites. Several attempts have been made to address this with targeted anti-inflammatory therapies, but until the recent promising results of canakinumab (an anti-interleukin-1β monoclonal antibody), most have failed to find any prognostic benefit in large clinical trials with hard end points. The pathogenic role of neutrophils and monocytes in atheroinflammation is well established, and a fundamental component in this process is the activation of the NOD-like receptor protein 3 inflammasome, a cytosolic multiprotein complex that, when activated by a stress signal such as cholesterol crystals, drives caspase-1-dependent release of 2 key proinflammatory cytokines, which are predictive of future adverse cardiovascular events: interleukin-1β and interleukin-18. Colchicine is a widely available, inexpensive, and well-tolerated medication that, among several anti-inflammatory mechanisms of action, inhibits activation of the NOD-like receptor protein 3 inflammasome complex. A seminal trial has found the beneficial properties of colchicine in reducing adverse cardiovascular events in the stable coronary artery disease population. IMPLICATIONS Despite promising results in small prospective observational and randomized trials, there is a need for more evidence evaluating the role of colchicine as a secondary preventive agent after ACSs.
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2.
[Prevention of cardiovascular disease and fermented alcoholic beverages. Reality or fiction?].
Sacanella Anglés, I, Casas Rodríguez, R, Viñas Esmel, E, Castro Barquero, S, Sacanella Meseguer, E
Nutricion hospitalaria. 2019;(Spec No3):58-62
Abstract
A large evidence-based reports a J-shaped association among moderate alcohol consumption and cardiovascular health. Low-moderate alcohol intake has been related to lower all-cause mortality (20%) and ischemic heart events (40%) compared to abstainers. The dose that is allegedly beneficial varies between 10-20 gr/day for women and men respectively. Moreover, the drinking pattern seems to be significant in order to get healthy effects. Moderate alcohol consumption hinders atherogenesis by several mechanisms mainly improving lipid profile and reducing thrombogenesis. Nevertheless, it is still unclear whether high-polyphenol alcoholic beverages, such as wine and beer, confer a greater cardiovascular protection than spirits, which have much less polyphenol content.
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3.
Familial Hypercholesterolemia and Lipoprotein Apheresis.
Makino, H, Koezuka, R, Tamanaha, T, Ogura, M, Matsuki, K, Hosoda, K, Harada-Shiba, M
Journal of atherosclerosis and thrombosis. 2019;(8):679-687
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Abstract
Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.
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Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis.
Lu, X
Current drug targets. 2019;(10):1029-1040
Abstract
BACKGROUND One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy. METHODS We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis. RESULTS New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis. CONCLUSION PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.
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Humoral Immunity Against HDL Particle: A New Perspective in Cardiovascular Diseases?
Satta, N, Frias, MA, Vuilleumier, N, Pagano, S
Current pharmaceutical design. 2019;(29):3128-3146
Abstract
BACKGROUND Autoimmune diseases are closely associated with cardiovascular diseases (CVD). Over the last decades, the comprehension of atherosclerosis, the principal initiator of CVD, evolved from a lipidcentered disease to a predominant inflammatory and immune response-driven disease displaying features of autoimmunity against a broad range of auto-antigens, including lipoproteins. Among them, high density lipoproteins (HDL) are important actors of cholesterol transport and bear several anti-atherogenic properties, raising a growing interest as therapeutic targets to decrease atherosclerosis and CVD burden, with nevertheless rather disappointing results so far. Reflecting HDL composition complexity, autoimmune responses and autoantibodies against various HDL components have been reported. RESULTS In this review, we addressed the important complexity of humoral autoimmunity towards HDL and particularly how this autoimmune response could help improving our understanding of HDL biological implication in atherosclerosis and CVD. We also discussed several issues related to specific HDL autoantibody subclasses characteristics, including etiology, prognosis and pathological mechanisms according to Rose criteria. CONCLUSION Finally, we addressed the possible clinical value of using these antibodies not only as potential biomarkers of atherogenesis and CVD, but also as a factor potentially mitigating the benefit of HDL-raising therapies.
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Potential Therapeutic Value of Interleukin 1b-targeted Strategies in Atherosclerotic Cardiovascular Disease.
Viana-Huete, V, Fuster, JJ
Revista espanola de cardiologia (English ed.). 2019;(9):760-766
Abstract
Clinical trials have unequivocally shown that cholesterol-lowering drugs decrease the risk of atherosclerotic cardiovascular disease in an exceptionally wide range of individuals. Yet, even when treated optimally according to current standards, many individuals still experience life-threatening ischemic events. Emerging experimental and clinical evidence strongly suggests that persistent inflammation is a major driver of this residual risk, which has opened the door to the application of anti-inflammatory drugs for cardiovascular disease prevention. Here, we review our current knowledge of the biology of interleukin-1β, a key regulator of inflammation in atherosclerotic plaque and the target of the first clinical trial to demonstrate that an anti-inflammatory drug can effectively reduce cardiovascular risk. We discuss the challenges faced by interleukin-1β inhibitors and other anti-inflammatory compounds in their translation to the clinical scenario, and identify other potential targets within this signaling pathway that hold promise in the cardiovascular setting.
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From Subclinical Atherosclerosis to Plaque Progression and Acute Coronary Events: JACC State-of-the-Art Review.
Ahmadi, A, Argulian, E, Leipsic, J, Newby, DE, Narula, J
Journal of the American College of Cardiology. 2019;(12):1608-1617
Abstract
It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies in which angiographic information was available from many months to years before the event. However, serial studies in which angiographic data were available from the past as also within 1 to 3 months of myocardial infarction have clarified that nonobstructive lesions progressively enlarged relatively rapidly before the acute event occurred. Noninvasive computed tomography angiography imaging data have confirmed that lesions that did not progress voluminously over time rarely led to events, regardless of the extent of luminal stenosis or baseline high-risk plaque morphology. Therefore, plaque progression could be proposed as a necessary step between early, uncomplicated atherosclerosis and plaque rupture. On the other hand, it has been convincingly demonstrated that intensive lipid-lowering therapy (to a low-density lipoprotein cholesterol level of <70 mg/dl) halts plaque progression. Given the current ability to noninvasively detect the presence of early atherosclerosis, the importance of plaque progression in the pathogenesis of myocardial infarction, and the efficacy of maximum lipid-lowering therapy, it has been suggested that plaque progression is a modifiable step in the evolution of atherosclerotic plaque. A personalized approach based on the detection of early atherosclerosis can trigger the necessary treatment to prevent plaque progression and hence plaque instability. Therefore, this approach can redefine the traditional paradigm of primary and secondary prevention based on population-derived risk estimates and can potentially improve long-term outcomes.
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Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation.
Marchio, P, Guerra-Ojeda, S, Vila, JM, Aldasoro, M, Victor, VM, Mauricio, MD
Oxidative medicine and cellular longevity. 2019;:8563845
Abstract
Atherosclerosis is a chronic vascular inflammatory disease associated to oxidative stress and endothelial dysfunction. Oxidation of low-density lipoprotein (LDL) cholesterol is one of the key factors for the development of atherosclerosis. Nonoxidized LDL have a low affinity for macrophages, so they are not themselves a risk factor. However, lowering LDL levels is a common clinical practice to reduce oxidation and the risk of major events in patients with cardiovascular diseases (CVD). Atherosclerosis starts with dysfunctional changes in the endothelium induced by disturbed shear stress which can lead to endothelial and platelet activation, adhesion of monocytes on the activated endothelium, and differentiation into proinflammatory macrophages, which increase the uptake of oxidized LDL (oxLDL) and turn into foam cells, exacerbating the inflammatory signalling. The atherosclerotic process is accelerated by a myriad of factors, such as the release of inflammatory chemokines and cytokines, the generation of reactive oxygen species (ROS), growth factors, and the proliferation of vascular smooth muscle cells. Inflammation and immunity are key factors for the development and complications of atherosclerosis, and therefore, the whole atherosclerotic process is a target for diagnosis and treatment. In this review, we focus on early stages of the disease and we address both biomarkers and therapeutic approaches currently available and under research.
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Remnant lipoproteins and atherosclerotic cardiovascular disease.
Tada, H, Nohara, A, Inazu, A, Mabuchi, H, Kawashiri, MA
Clinica chimica acta; international journal of clinical chemistry. 2019;:1-5
Abstract
Lipoproteins are one of the major risk factors for atherosclerotic cardiovascular disease (ASCVD), among which, low-density lipoprotein (LDL) particles have been definitively shown to be causally associated with the development of ASCVD. Additionally, the concept of remnant lipoproteins has emerged as lipoprotein metabolism has been fully investigated. The principal concept of this lipoprotein category is triglyceride-rich lipoproteins significantly increase at the postprandial state. Although there is no clear definition of remnant lipoproteins, they typically include chylomicron remnants, which are lipolyzed particles from chylomicron, as well as very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) remnants that are lipolyzed particles from VLDL and IDL particles. However, the most important factor of these lipoproteins is such remnant lipoproteins seem to be causally associated with ASCVD, independent of LDL particles or LDL cholesterol. It has been challenging to assert a causal association of remnant lipoproteins and ASCVD; however, accumulated evidence from epidemiological studies, as well as recent Mendelian randomization studies from common and rare genetic variations strongly support this association. In this article, a basic explanation of lipoprotein metabolism is presented, including remnant lipoproteins and the important causal associations with ASCVD from a clinical point of view.
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10.
Anatomical References to Evaluate Thoracic Aorta Calcium by Computed Tomography.
Pedrosa, JF, Barreto, SM, Bittencourt, MS, Ribeiro, ALP
Current atherosclerosis reports. 2019;(12):51
Abstract
PURPOSE OF REVIEW Thoracic aortic calcium (TAC) has received some interest in recent studies as an important subclinical marker of atherosclerosis. Besides that, using computed tomography (CT) scans performed with cardiac or chest protocols, ECG-gated, or non-gated, TAC can be easily evaluated with no addition in radiation dose. This review discusses the particularities of the aortic wall calcium formation, as well as the differences between the aortic segments and summarizes the current status of TAC evaluation, mainly concerning the anatomical references used in the studies. RECENT FINDINGS The studies have evaluated TAC considering different anatomical references. It was identified two different study groups. In the first one, researchers have analyzed the aorta as the sum of calcium in the ascending aorta (ATAC), aortic arch (AAC), and descending thoracic aorta (DTAC). The second group has used cardiac CT scans to assess TAC; therefore, they did not include AAC; however, the aortic root calcium (ARC) was added in the analysis. So, caution is advisable when interpreting and comparing studies that used different TAC anatomical references. The broad methodological variability, in addition to the variations in the population characteristics of the studies on TAC, may be in part contributing to the differences between results of different studies. Currently TAC does not have a role in clinical decisions, so it is necessary to create a standard protocol for the aortic calcium research as well as exists for the coronary artery calcium evaluation.