ABSTRACT
Background: The deadly outbreak of COVID-19 disease caused by novel SARS CoV2 has created an unprecedented global health crisis affecting every sectors of human life and enor-mous damage to world's economy. With >16.1 million infections and >650,000 deaths worldwide as of July 27, 2020, there is no treatment for this disease neither is there any available vaccine. Seri-ous research efforts are ongoing on all fronts including treatment, prevention and diagnosis to combat the spread of this infection. A number of targets that include both viral and host proteins have been identified and became part of intense investigation. In this respect the viral surface spike (S) glycoprotein caught the attention most. It is cleaved by multiple host proteases to allow recognition by host receptor human Angiotensin Converting Enzyme2 (hACE2) leading to fusion and viral re-plication. Natural products, small compounds, antioxidants, peptides, proteins, oligonucleotides, antibodies and other compounds are under investigation for development of antiviral agents against COVID-19. Objective(s): Recently cholesterol lowering phytocompounds Quercetin, Swertiamarin and Berberine which promote human Low Density Lipoprotein Receptor (hLDLR) via inhibition of human Pro-protein Convertase Subtilisin Kexin9 (hPCSK9) have been shown to block viral infections caused by ebola, influenza, Respiratory Syncytial Virus (RSV), Hepatitis C virus (HCV) and other RNA type viruses. Since SARS CoV2 is a RNA virus with similar genetic structure and infection machin-ery, it is hypothesised that these phytocompounds may also exhibit antiviral property against COVID-19. Method(s): Our above concept is based on recently published studies as well as our herein presented in silico modeling and computational data which suggested strong interactions of hPCSK9 with above phytocompounds and most importantly with hACE2 following its complexation with receptor binding domain (RBD) of SARS CoV2 S protein. Result(s): These results and a proposed schematic model showing association of hPCSK9 with SARS CoV2 infection are presented in this manuscript. It is proposed that hPCSK9 plays the role of a co-receptor in binding with hACE2:RBD complex and thereby facilitates viral fusion. Conclusion(s): Our studies suggest that PCSK9 inhibitors may provide beneficial effect against COVID-19 infection by retarding viral fusion through displacement of bound hPCSK9 from its complex with ACE2:RBD of SARS CoV2 S protein.Copyright © 2021 Bentham Science Publishers.
ABSTRACT
Background: Low-density lipoprotein-cholesterol (LDL-C) is a well-accepted causal risk factor for atherothrombotic cardiovascular disease. Several randomized controlled trials and meta-analyses have shown that lipid-lowering therapies reduce cardiovascular events and have a positive effect in reducing vulnerable plaques. In particular, the recommended target for LDL-C has become more and more stringent, moving to 1.4 mmol/l (55 mg/dl) for very high-risk patients. According to the 2019 ESC/EAS Guidelines, the current paradigm for lipid management favors a stepwise approach consisting of early initiation of high-intensity statin, followed by subsequent addition of ezetimibe, and ultimately a consideration of PCSK9 inhibitor treatment if LDL-C levels remain elevated. Methods: We recruited 307 patients admitted for acute coronary syndrome (ACS) during the COVID-19 pandemic from March 2020 to December 2020. Baseline LDL-C concentration and prescribed hypolipemiant treatment at hospital admission and discharge were registered. Therefore, we included all consecutive patients identified as very-high cardiovascular risk, according to 2019 ESC guidelines. We stratified our population through variables independently associated with non-attainment of LDL-cholesterol such as hypertension, diabetes, peripheral arterial disease, clinical manifestations of ACS, number of main vessels treated, and complexity of the atherosclerotic disease. Results: 274 patients were included. Mean age was 69,9 years (SD 11,4), 20,8%were women, 23,7%had diabetes, 16,4%had PAD and 32,1 % suffered from valvular disease, mainly with mitral regurgitation or aortic stenosis no more than mild or moderate. Of 25.1% with a previous history of acute myocardial infarction, the 33,3% of whom didn't have statin therapy pre-ACS index (p =0,001). At admission, medium cholesterol levels of patients that underwent previous coronary revascularization (25,5% of the total population) were 84,21 ± 31,2 mg/dL, not in range according to both 2016 and 2019 ESC guidelines. At discharge, 77,37 % of all the patients included received only statin therapy VS 22,63% with statin plus ezetimibe. In the subpopulation of patients with recurring ACS events with LDL pre-admission > 100 mg/dL,despite high dose statin, only 25% of this population were discharged adding ezetimibe (VS 75% who kept on the treatment of high dose statin without up-titration). Conclusions: Management of dyslipidemia is frequently suboptimal and the gap between guidelines and clinical practice for lipid management across Europe has been exacerbated by the 2019 guidelines. A greater utilization of non-statin lipid-lowering therapies is likely needed to reach the LDL-C optimal target. A correct stratification of the risk class would help to identify, in a personalized perspective of treatment, patients at very high risk that would take advantage of more aggressive therapy to reach the lowest target of LDL-C ('the lower is better'). (Figure Presented).
ABSTRACT
Background: Injection site reactions (ISRs) are known side effects of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab. Transient ISR to alirocumab after a long phase of good tolerability have not been reported previously. Case summary: A 55-year-old woman (Patient 1) and a 77-year-old man (Patient 2) were treated with alirocumab for the management of dyslipidaemia. Both patients tolerated the treatment without side effects for 7 and 2 months, respectively. After an upper respiratory tract infection in Patient 1 and a first COVID-19 vaccination in Patient 2, both patients suddenly developed ISR with erythema, calor, and itching upon 2 (Patient 1) and 1 (Patient 2) subsequent injection(s), respectively. Symptoms resolved with local steroids, oral antihistamines, and cooling. After termination of the presumed immune system activated state, alirocumab was well tolerated again in both patients without recurrence of any ISR upon repeated applications. Discussion: These are the first cases to report transient ISR to a PCSK9 inhibitor, possibly triggered by activation of the immune system, after prolonged good tolerability. Based on the transient and benign nature of the reaction, such patients should be encouraged to continue supervised treatment, as tolerability may return after resolution of the pro-inflammatory state.
ABSTRACT
A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with acute myocardial injury had more than fourfold higher mortality than those without such injury. Since the COVID-19 pandemic exacerbates already existing health inequalities, there is an urgent need to create measures to protect the most vulnerable patient groups, including those with a pre-existing increased risk of atherosclerotic cardiovascular disease (ASCVD). A typical example is familial hypercholesterolemia (FH), a common genetic disease affecting over 30 million individuals worldwide. If left untreated or undertreated, FH patients suffer from complications of premature ASCVD, such as acute coronary syndromes, resulting in acute myocardial injury/infarction. A recent population-based analysis provided strong evidence suggesting that COVID-19 poses an even higher risk for myocardial injury in FH patients. From the long-term preventive point of view, it is important to note that, in addition to the acutely elevated risk of myocardial injury, an elevated risk of ASCVD and its complications will persist after COVID-19. The decline in outpatient preventive care during the pandemic is likely to influence ASCVD risk and outcomes, particularly in high-risk patients, such as those with FH. This commentary aims to raise global awareness of the challenges that clinicians treating FH patients continue to face during the COVID-19 pandemic, with two low- to middle-income countries, South Africa and Brazil, serving as examples.
ABSTRACT
SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.