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To address concerns about cognitive decline with the use of PCSK9 inhibitors, automated neuropsychological testing was performed in patients who received evolocumab or placebo. Evolocumab was noninferior to placebo with respect to cognitive changes from baseline over 19 months.

In a 24-week, randomized, placebo-controlled trial, evolocumab, a fully human anti-PSCK9 monoclonal antibody, was studied in pediatric patients who had heterozygous familial hypercholesterolemia and were receiving stable lipid-lowering treatment. Evolocumab reduced the LDL cholesterol level and other lipid variables.

(1) Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced α-SMA, SM22α, Oct-4, and upregulation of KLF-4 and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1β secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1β in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis.

LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Amgen.

To assess the associations of exposure and modifications in exposure (i.e., discontinuation on admission, initiation during hospitalization) to eight common cardiovascular therapies with the risk of in-hospital death among inpatients with coronavirus disease 2019 (COVID-19). In this observational study including 838 hospitalized unvaccinated adult patients with confirmed COVID-19, the use of cardiovascular therapies was assessed using logistic regression models adjusted for potential confounders. No cardiovascular therapy used before hospitalization was associated with an increased risk of in-hospital death. During hospitalization, the use of diuretics (aOR 2.59 [1.68-3.98]) was associated with an increase, and the use of agents acting on the renin-angiotensin system (aOR 0.39 [0.23-0.64]) and lipid-lowering agents (aOR 0.41 [0.24-0.68]) was associated with a reduction in the odds of in-hospital death. Exposure modifications associated with decreased survival were the discontinuation of an agent acting on the renin-angiotensin system (aOR 4.42 [2.08-9.37]), a β-blocker (aOR 5.44 [1.16-25.46]), a lipid-modifying agent (aOR 3.26 [1.42-7.50]) or an anticoagulant (aOR 5.85 [1.25-27.27]), as well as the initiation of a diuretic (aOR 5.19 [2.98-9.03]) or an antiarrhythmic (aOR 6.62 [2.07-21.15]). Exposure modification associated with improved survival was the initiation of an agent acting on the renin-angiotensin system (aOR 0.17 [0.03-0.82]). In hospitalized and unvaccinated patients with COVID-19, there was no detrimental association of the prehospital use of any regular cardiovascular medication with in-hospital death, and these therapies should be continued as recommended.

Aims To assess the associations of exposure and modifications in exposure (i.e., discontinuation on admission, initiation during hospitalization) to eight common cardiovascular therapies with the risk of in-hospital death among inpatients with coronavirus disease 2019 (COVID-19). Methods In this observational study including 838 hospitalized unvaccinated adult patients with confirmed COVID-19, the use of cardiovascular therapies was assessed using logistic regression models adjusted for potential confounders. Results No cardiovascular therapy used before hospitalization was associated with an increased risk of in-hospital death. During hospitalization, the use of diuretics (aOR 2.59 [1.68–3.98]) was associated with an increase, and the use of agents acting on the renin-angiotensin system (aOR 0.39 [0.23–0.64]) and lipid-lowering agents (aOR 0.41 [0.24–0.68]) was associated with a reduction in the odds of in-hospital death. Exposure modifications associated with decreased survival were the discontinuation of an agent acting on the renin-angiotensin system (aOR 4.42 [2.08–9.37]), a β-blocker (aOR 5.44 [1.16–25.46]), a lipid-modifying agent (aOR 3.26 [1.42–7.50]) or an anticoagulant (aOR 5.85 [1.25–27.27]), as well as the initiation of a diuretic (aOR 5.19 [2.98–9.03]) or an antiarrhythmic (aOR 6.62 [2.07–21.15]). Exposure modification associated with improved survival was the initiation of an agent acting on the renin-angiotensin system (aOR 0.17 [0.03–0.82]). Conclusion In hospitalized and unvaccinated patients with COVID-19, there was no detrimental association of the prehospital use of any regular cardiovascular medication with in-hospital death, and these therapies should be continued as recommended.

Prompt and proficient basic life support (BLS) maneuvers are essential to increasing the odds of survival after out-of-hospital cardiac arrest. However, significant time can elapse before the arrival of professional rescuers. To decrease these delays, many countries have developed first responder networks. These networks are composed of BLS-certified lay or professional rescuers who can be dispatched by emergency medical communication centers to take care of those who experience out-of-hospital cardiac arrest. Many systems are, however, limited by a relatively low number of active first responders, and first-year medical and dental students may represent an almost untapped pool of potential rescuers. On top of providing an enhanced BLS coverage to the population, this could also help medical students be better prepared to their future role as certified health care providers and address societal expectations regarding health care students. Our objective was to describe the impact of a short motivational intervention followed by a blended BLS course (e-learning and practice session) designed to motivate first-year medical and dental students to enlist as first responders. A short, web-based, motivational intervention presenting this project took place, and first-year University of Geneva, Faculty of Medicine students were provided with a link to the study platform. Those who agreed to participate were redirected to a demographic questionnaire before registering on the platform. The participants were then asked to answer a second questionnaire designed to determine their baseline knowledge prior to following an interactive e-learning module. Upon completion, a web-based booking form enabling them to register for a 1-hour practice session was displayed. These sessions were held by senior medical students who had been trained and certified as BLS instructors. The participants who attended these practice sessions were asked to answer a postcourse questionnaire before receiving the certificate enabling them to register as first responders. Out of the 529 first-year students registered at University of Geneva, Faculty of Medicine on January 14, 2021, 190 (35.9%) initially agreed to participate. Moreover, 102 (19.3%) attended the practice sessions, and 48 (9.1%) had completed all training and enlisted as first responders on the dedicated platform, Save a Life, at 6 months (July 14, 2021). Postcourse confidence in resuscitation skills was associated with a higher likelihood of registering as first responder (P=.03). No association was found between prior BLS knowledge and the probability of registering to a practice session (P=.59), of obtaining a course completion certificate (P=.29), or of enlisting as first responder (P=.56). This study shows that a motivational intervention associated with a short BLS course can convince medical students to enlist as first responders. Further studies are needed to understand the rather low proportion of medical students finally registering as first responders. RR2-10.2196/24664.

In this clinical trial, rosuvastatin was compared with placebo in elderly patients with systolic, ischemic heart failure. Although rosuvastatin significantly lowered levels of both low-density lipoprotein cholesterol and high-sensitivity C-reactive protein, it did not significantly reduce cardiovascular outcomes. However, it did reduce the number of hospitalizations. On the basis of these data, the role of statin therapy in heart failure appears to be limited. Although rosuvastatin significantly lowered levels of both low-density lipoprotein cholesterol and high-sensitivity C-reactive protein, it did not significantly reduce cardiovascular outcomes. Although a high proportion of patients with heart failure caused by left ventricular systolic dysfunction have coronary artery disease, reported rates of myocardial infarction have been low in previous clinical trials. 1 – 4 Therefore, the potential value of statins has been questioned because their benefit is largely due to the prevention of myocardial infarction. In addition, in this population of patients, low levels of total cholesterol are common and are associated with worse outcomes. 1 – 6 Lipoproteins may remove endotoxins that enter the circulation through the intestinal wall, which may be edematous and leaky in patients with heart failure. 7 Statins could also . . .

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE -genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm ( p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm ( p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant ( p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, ( p ’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person’s lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20–50%. AKCEA-APO(a)- L RX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50–80%. A Phase III study with AKCEA-APO(a)- L RX will start in order to evaluate the effect on cardiovascular outcomes.