Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Epidemiology of atherosclerotic cardiovascular disease in polygenic hypercholesterolemia with or without high lipoprotein(a) levels.

Background and aims: Epidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL. Methods: Retrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement. Results: Medical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3-16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21-3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2-7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009). Conclusions: Patients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women.

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome.

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic.

SARS-CoV-2 infection is often associated with severe inflammation, oxidative stress, hypoxia and impaired physical activity. These factors all together contribute to muscle wasting and fatigue. In addition, there is evidence of a direct SARS-CoV-2 viral infiltration into skeletal muscle. Aging is often characterized by sarcopenia or sarcopenic obesity These conditions are risk factors for severe acute COVID-19 and long-COVID-19 syndrome. From these observations we may predict a strong association between COVID-19 and decreased muscle mass and functions. While the relationship between physical inactivity, chronic inflammation, oxidative stress and muscle dysfunction is well-known, the effects on muscle mass of COVID-19-related hypoxemia are inadequately investigated. The aim of this review is to highlight metabolic, immunity-related and redox biomarkers potentially affected by reduced oxygen availability and/or muscle fatigue in order to shed light on the negative impact of COVID-19 on muscle mass and function. Possible countermeasures are also reviewed.

Pediatric blinatumomab preparation: Risk assessment on SmPC for software compliance.

INTRODUCTION: Blinatumomab is an anticancer drug used in the treatment of Acute Lymphoblastic Leukaemia (ALL) in both adults and children. ALL is the most common form of cancer in children and patients who are refractory to standard treatments have poor prognosis. The preparation of blinatumomab is unique and extremely complex. It's important to carry out any information to identify all the critical issues related to the preparation of blinatumomab: sharing procedure between prescribers, staff of the Centralized Chemotherapy Preparation Unit [Unità Farmaci Antiblastici (UFA)] and administering nurses aimed at reducing the clinical risk related to the management of the drug blinatumomab and to obtain correct prescriptions on the real dose to be prepared, safe worksheets with computer processing of all variables (volumes to be added and corresponding dose of drug) and complete labels containing all the information necessary for the control of the preparation and its correct infusion. METHODS: A computerized process involves the use of specific software to which precise instructions must be given. This study is divided into two phases, the first one focused on the analysis of Summary of Product Characteristics (SmPC) and the extrapolation of any unclear part of SmPC. The second phase involved the manufacturer to answer a questionnaire. RESULTS: This comparison with the company allowed to perfect the blinatumomab preparation process leading to: 1. allow the patient to be discharged and return a few times for infusions and consequently reduce the number of medical prescriptions; 2. set up the drug for each patient every 4 days; 3. reduce costs related to devices, staff employed. CONCLUSION: Computerizing the preparation of anti-blastic drugs is a necessary path for the safety of the patient and all the operators involved, however it may be necessary to make changes in the preparation process to allow the software to work correctly. The comparison between pharmacist, clinician and, where necessary, the manufacturer of the drug, was effective in the preparation of this drug.

Correlation between antibiotic consumption and resistance of bloodstream bacteria in a University Hospital in North Eastern Italy, 2008-2014.

PURPOSE: The spread of multidrug-resistant bacteria is a worrisome problem worldwide. This study investigated the correlation between antibiotic consumption and antimicrobial resistance trends of the most important bacteria causing bacteremia at the University hospital of Trieste, Italy, from 2008 to 2014. METHODS: Antibiotic consumption (Defined Daily Dose-DDD-per 100 patient/days) and antibiotic resistance (percentage of antibiotic intermediate o resistant isolates) were analyzed independently with linear correlation by year. Potential correlations between antibiotic consumption and bacteria resistance rates were investigated through the Pearson's correlation. RESULTS: The overall consumption of antibiotic grew from 80 to 97 DDD 100 patient/days (p = 0.005) during the study period. The increased consumption of amoxicillin/clavulanate and piperacillin/tazobactam was associated with the reduction of MRSA rate from 48.5 to 25.9% (p = 0.007 and p = 0.04, respectively). The increased consumption of piperacillin/tazobactam was associated with the reduction of ESBL-positive Enterobacteriaceae rate from 28.9 to 20.9% (p = 0.01). The increased consumption of carbapenems was associated with the increased rate of carbapenem-resistant Acinetobacter baumannii from 0 to 96.4% (p = 0.03). No carbapenem-resistant Enterobacteriaceae isolates were reported. The consumption of vancomycin grew significantly (p = 0.005). A dramatic spread of vancomycin-resistant Enterococcus faecium occurred in 2014. The consumption of fluoroquinolones and extended-spectrum cephalosporins remained stable. CONCLUSIONS: An antibiotic stewardship program targeted to limit the consumption of extended-spectrum cephalosporins and fluoroquinolones in favor of amoxicillin/clavulanate and piperacillin/tazobactam correlates with a decreasing rate of MRSA and ESBL-positive Enterobacteriaceae. The analysis of correlations between antibiotic consumption and bacterial resistance rates is a useful tool to orient antimicrobial stewardship policies at local level.