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1.
Comparative effects of 2.5mg levamlodipine and 5mg amlodipine on vascular endothelial function and atherosclerosis.
Lu, Y, Yin, J, Wu, X, Fan, Y, Liu, F
Pakistan journal of pharmaceutical sciences. 2019;(5(Special)):2433-2436
Abstract
This study was designed to compare the efficacy of two different racemic antihypertensive drugs on elderly patients with hypertension and their effects on vascular endothelial function and atherosclerosis. A total of 84 elderly hypertensive patients were randomly divided into control and treatment group with 42 patients in each group. The control group was treated with 2.5mg levamlodipine while the treatment group was given 5mg amlodipine. Total effective rate of the treatment group was 90.5%, higher than the control group, that was 71.4% (P<0.05). The time for recovery of related indicators like blood pressure, the total duration of medication were significantly (P<0.05) shorter in the treatment group. Only 1 case of adverse drug reaction was found in the treatment group while 6 cases in control group. Compared to the control group, the treatment group had massive improvement in fingertip pulse volume, flow-mediated dilation of the brachial arteries and endothelin-1 level, carotid intima-media thickness, plaque length & thickness, and blood pressure after the administration. The rate of satisfaction with the in treatment group was 95.3%, higher than that the control group, which was 78.6%. The study concluded that in elderly patients with hypertension, the treatment with 5mg amlodipine enhanced curative effect, fully improved endothelial function & arteriosclerosis and reduced adverse reactions thereby shortening treatment time.
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2.
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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3.
[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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4.
Icosapent ethyl reduces atherogenic markers in high-risk statin-treated patients with stage 3 chronic kidney disease and high triglycerides.
Vijayaraghavan, K, Szerlip, HM, Ballantyne, CM, Bays, HE, Philip, S, Doyle, RT, Juliano, RA, Granowitz, C
Postgraduate medicine. 2019;(6):390-396
Abstract
Objective: Patients with chronic kidney disease (CKD) have increased cardiovascular disease (CVD) risk, likely driven by atherogenic and inflammatory markers beyond low-density lipoprotein cholesterol (LDL-C). The objective of this hypothesis-generating post hoc subgroup analysis was to explore the effects of icosapent ethyl at 2 or 4 g/day (prescription pure ethyl ester of the omega-3 fatty acid eicosapentaenoic acid [EPA]) on atherogenic lipid, apolipoprotein, inflammatory parameters (high-sensitivity C-reactive protein [hsCRP], lipoprotein-associated phospholipase A2 [Lp-PLA2]), and oxidative parameters (oxidized-LDL [ox-LDL]) in statin-treated patients from ANCHOR with stage 3 CKD.Methods: The 12-week ANCHOR study evaluated icosapent ethyl in 702 statin-treated patients at increased CVD risk with triglycerides (TG) 200-499 mg/dL despite controlled LDL-C (40-99 mg/dL). This post-hoc analysis included patients from ANCHOR with stage 3 CKD (estimated glomerular filtration rate [eGFR] ≤60 mL/min/1.73 m2 for ≥3 months) randomized to icosapent ethyl 4 g/day (n = 19), 2 g/day (n = 30), or placebo (n = 36).Results: At the prescription dose of 4 g/day, icosapent ethyl significantly reduced TG (-16.9%; P = 0.0074) and other potentially atherogenic lipids/lipoproteins, ox-LDL, hsCRP, and Lp-PLA2, and increased plasma and red blood cell EPA levels (+879% and +579%, respectively; both P < 0.0001) versus placebo. Icosapent ethyl did not significantly alter eGFR or serum creatinine. Safety and tolerability were similar to placebo.Conclusions: In patients with stage 3 CKD at high CVD risk with persistent high TG despite statins, icosapent ethyl 4 g/day reduced potentially atherogenic and other cardiovascular risk factors without raising LDL-C, with safety similar to placebo. These findings suggest prospective investigation may be warranted.
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5.
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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The Atherosclerosis Risk Variant rs2107595 Mediates Allele-Specific Transcriptional Regulation of HDAC9 via E2F3 and Rb1.
Prestel, M, Prell-Schicker, C, Webb, T, Malik, R, Lindner, B, Ziesch, N, Rex-Haffner, M, Röh, S, Viturawong, T, Lehm, M, et al
Stroke. 2019;(10):2651-2660
Abstract
Background and Purpose- Genome-wide association studies have identified the HDAC9 (histone deacetylase 9) gene region as a major risk locus for atherosclerotic stroke and coronary artery disease in humans. Previous results suggest a role of altered HDAC9 expression levels as the underlying disease mechanism. rs2107595, the lead single nucleotide polymorphism for stroke and coronary artery disease resides in noncoding DNA and colocalizes with histone modification marks suggestive of enhancer elements. Methods- To determine the mechanisms by which genetic variation at rs2107595 regulates HDAC9 expression and thus vascular risk we employed targeted resequencing, proteome-wide search for allele-specific nuclear binding partners, chromatin immunoprecipitation, genome-editing, reporter assays, circularized chromosome conformation capture, and gain- and loss-of-function experiments in cultured human cell lines and primary immune cells. Results- Targeted resequencing of the HDAC9 locus in patients with atherosclerotic stroke and controls supported candidacy of rs2107595 as the causative single nucleotide polymorphism. A proteomic search for nuclear binding partners revealed preferential binding of the E2F3/TFDP1/Rb1 complex (E2F transcription factor 3/transcription factor Dp-1/Retinoblastoma 1) to the rs2107595 common allele, consistent with the disruption of an E2F3 consensus site by the risk allele. Gain- and loss-of-function studies showed a regulatory effect of E2F/Rb proteins on HDAC9 expression. Compared with the common allele, the rs2107595 risk allele exhibited higher transcriptional capacity in luciferase assays and was associated with higher HDAC9 mRNA levels in primary macrophages and genome-edited Jurkat cells. Circularized chromosome conformation capture revealed a genomic interaction of the rs2107595 region with the HDAC9 promoter, which was stronger for the common allele as was the in vivo interaction with E2F3 and Rb1 determined by chromatin immunoprecipitation. Gain-of-function experiments in isogenic Jurkat cells demonstrated a key role of E2F3 in mediating rs2107595-dependent transcriptional regulation of HDAC9. Conclusions- Collectively, our findings imply allele-specific transcriptional regulation of HDAC9 via E2F3 and Rb1 as a major mechanism mediating vascular risk at rs2107595.
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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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10.
Applying contemporary antithrombotic therapy in the secondary prevention of chronic atherosclerotic cardiovascular disease.
Welsh, RC, Peterson, ED, De Caterina, R, Bode, C, Gersh, B, Eikelboom, JW
American heart journal. 2019;:100-109
Abstract
For 4 decades, antithrombotic therapy with aspirin has been a cornerstone of secondary prevention for patients with chronic atherosclerotic cardiovascular disease (ASCVD). Unfortunately, despite the use of evidence-based therapies, patients with ASCVD continue to have recurrent major adverse cardiovascular events including death, myocardial infarction, and stroke-at a rate of approximately 2%-4% per year. To combat this continuing risk, several recent trials have evaluated the efficacy and safety of more intensive antithrombotic strategies through prolonged dual antiplatelet therapy (DAPT), combining a P2Y12 receptor antagonists and low-dose aspirin, or alternatively applying a dual pathway inhibition approach, combining low-dose non-vitamin K antagonist anticoagulant and low-dose aspirin. Both combination strategies have been shown to reduce recurrent ischemic events but at the cost of increased bleeding events. The clinical application of these antithrombotic strategies requires clinicians to assess and balance the risk of recurrent ischemic and bleeding events in an individual patient. Furthermore, clinicians may also need to adapt their antithrombotic strategies to achieve best patient outcomes, as ASCVD is a progressive disease and the risks of cardiovascular ischemic and bleeding events may shift over time. This state-of-the-art article reviews evidence from the trials and provides a practical approach to the application of DAPT and dual pathway antithrombotic therapy in the long-term management of patients with chronic ASCVD.