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1.
Effectiveness, Adherence, and Safety of Evolocumab in a Swiss Multicenter Prospective Observational Study.
Nanchen, D, Carballo, D, Bilz, S, Rickli, H, Koskinas, KC, Mach, F, Mueller, C, Crljenica, C, Rossi, M, Reichert, N, et al
Advances in therapy. 2022;(1):504-517
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Abstract
INTRODUCTION The aims of this study were to describe patient characteristics, lipid parameters, lipid-lowering drug use, and safety of patients receiving evolocumab in a real-world clinical setting. METHODS We conducted a 1-year multicenter observational study of adults using evolocumab with confirmed atherosclerotic cardiovascular disease (CVD) or at high cardiovascular risk, and elevated LDL-C despite maximally tolerated statin doses. An e-health application optionally supported patient management. The primary outcome was change in lipid parameters over time. The secondary outcomes included evolocumab safety. RESULTS Of 100 participants, 81% had pre-existing CVD, 71% self-reported statin-related muscle symptoms, 44% received statins. All patients received evolocumab, 65% were PCSK9i pre-treated at baseline. PCSK9i-naïve patients achieved a mean LDL-C reduction of 60% within 3 months of evolocumab treatment, which was maintained thereafter; 74% achieved LDL-C < 1.8 mmol/L at least once during observation, 69% attained < 1.4 mmol/L. In PCSK9i pre-treated patients, LDL-C remained stable throughout; 79% and 74% attained < 1.8 mmol/L and < 1.4 mmol/L, respectively, at least once. Goal attainment was higher with any combination of evolocumab, statin, and/or ezetimibe. Overall, 89% self-reported full evolocumab adherence. Treatment-emergent adverse events (TEAE) were reported in 30% of patients, two serious TEAEs occurred in one patient; three patients discontinued evolocumab because of TEAEs. CONCLUSION In real-world clinical practice, evolocumab was mainly used in patients with statin intolerance and pre-existing CVD. In this population, adherence to evolocumab and low LDL-C levels were maintained over 1 year, with better LDL-C goal achievement in patients using evolocumab in combination with other lipid-lowering drugs. Safety of evolocumab was similar to that documented in randomized controlled trials.
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Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review.
Vuong, JT, Stein-Merlob, AF, Nayeri, A, Sallam, T, Neilan, TG, Yang, EH
Journal of the American College of Cardiology. 2022;(6):577-593
Abstract
Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.
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Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.
Gonzalez-Cantero, A, Teklu, M, Sorokin, AV, Prussick, R, González-Cantero, J, Martin-Rodriguez, JL, Patel, N, Parel, PM, Manyak, GA, Teague, HL, et al
The Journal of investigative dermatology. 2022;(1):88-96
Abstract
Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n = 76 psoriasis participants and 76 controls), nonalcoholic fatty liver disease, assessed by the sonographic hepatorenal index, was more prevalent in psoriasis than in controls (61% vs. 45%; P = 0.04). Participants with psoriasis with nonalcoholic fatty liver disease had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than participants with psoriasis without nonalcoholic fatty liver disease (61% vs. 23%; P = 0.006) and controls with nonalcoholic fatty liver disease (61% vs. 32%; P < 0.05). Sonographic hepatorenal index was a determinant of subclinical atherosclerosis in psoriasis (OR = 3.5; P = 0.01). In the United States cohort (n = 162 participants with psoriasis who underwent positron emission tomography and coronary computed tomography angiography), those with high hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake had higher noncalcified (1.3 [0.49 mm2] vs. 1.0 [0.40 mm2]), fibrofatty (0.23 [0.15 mm2] vs. 0.11 [0.087 mm2]), and lipid-rich necrotic core (4.3 [2.3 mm2] vs. 3.0 [1.7 mm2]) coronary burden (all P < 0.001). Hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake associated with noncalcified (β = 0.28; P < 0.001), fibrofatty (β = 0.49; P < 0.001), and lipid-rich necrotic core (β = 0.28; P = 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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Bempedoic Acid: A New Tool in the Battle Against Hyperlipidemia.
Powell, J, Piszczatoski, C
Clinical therapeutics. 2021;(2):410-420
Abstract
PURPOSE This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia. METHODS A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid. FINDINGS The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy. IMPLICATIONS Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.
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Comparison of the effectiveness of Martin's equation, Friedewald's equation, and a Novel equation in low-density lipoprotein cholesterol estimation.
Song, Y, Lee, HS, Baik, SJ, Jeon, S, Han, D, Choi, SY, Chun, EJ, Han, HW, Park, SH, Sung, J, et al
Scientific reports. 2021;(1):13545
Abstract
Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500-600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin's equation may be optimal for LDL-C and ASCVD risk estimation.
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Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis.
Yeo, KP, Lim, HY, Angeli, V
Cells. 2021;(6)
Abstract
In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.
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Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?
Zhou, R, Stouffer, GA, Smith, SC
Journal of cardiovascular pharmacology and therapeutics. 2021;(6):533-549
Abstract
Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.
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Rice bran oil could favorably ameliorate atherogenicity and insulin resistance indices among men with coronary artery disease: post hoc analysis of a randomized controlled trial.
Mahdavi-Roshan, M, Salari, A, Vakilpour, A, Savar Rakhsh, A, Ghorbani, Z
Lipids in health and disease. 2021;(1):153
Abstract
BACKGROUND Despite recent advances in recognizing more reliable indicators to estimate the coronary artery disease (CAD) patients' response to treatment and prognosis, less attention has been paid to evaluating them in clinical trials. Hence, the present research was conducted to study the impact of rice bran oil (RBO) versus sunflower oil (SFO) on various atherogenicity and insulin resistance markers. METHODS In the present 8-week randomized controlled trial, 40 CAD men with an average age of 56 years were allocated randomly into the intervention or control group to use RBO or SFO (30 g/day) plus a standardized dietary plan. As a further analysis, eight atherosclerosis-related indices were calculated before and after the study. RESULTS Analysis of covariance test in which potential confounders and baseline levels were considered, indicated that using RBO compared to SFO reduced Castelli's risk index I and II (adjusted means:3.29, 1.52 vs. 4.61, 2.20, respectively), atherogenic coefficient (2.29 vs. 3.61), lipoprotein combine index (6.54 vs. 17.53), and cholesterol index (0.46 vs. 1.20) after the trial (P-value ≤ 0.002). Also, the RBO group yielded significantly lower triglyceride glucose index (8.73 vs. 9.13) (P-value = 0.010). Further, marginally significant amelioration in triglyceride/HDL ratio and atherogenic index of plasma (1.48 and 0.13 vs. 1.86 and 0.24 respectively) were noted (P-value = 0.07). Spearman correlation analysis detected significant positive correlations between alterations in TNF-α serum levels (ng/L) and the majority of evaluated indices (P-value < 0.05). CONCLUSION Taken together, incorporating 30 g of RBO into the patient's usual diet appeared effective in ameliorating atherogenicity and insulin resistance indicators among men with CAD, probably in relation to its anti-inflammatory properties. TRIAL REGISTRATION The protocol of the current trial was retrospectively recorded in the Iranian clinical trial registration system (IRCT) with the registration number of IRCT20190313043045N1 (URL: https://en.irct.ir/trial/38346 ; Registration date: 2019-04-27).
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PCSK9 and atherosclerosis: Looking beyond LDL regulation.
Ragusa, R, Basta, G, Neglia, D, De Caterina, R, Del Turco, S, Caselli, C
European journal of clinical investigation. 2021;(4):e13459
Abstract
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels.
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The Beneficial Effects of Astaxanthin on Glucose Metabolism and Modified Low-Density Lipoprotein in Healthy Volunteers and Subjects with Prediabetes.
Urakaze, M, Kobashi, C, Satou, Y, Shigeta, K, Toshima, M, Takagi, M, Takahashi, J, Nishida, H
Nutrients. 2021;(12)
Abstract
UNLABELLED Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. METHODS We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. RESULTS After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. CONCLUSIONS our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.