Lipid-lowering approaches to manage statin-intolerant patients.

Statins have improved the potential to prevent cardiovascular disease events and to prolong the lives of patients. Statins, among the most widely used drugs worldwide, reduce the levels of low-density lipoprotein cholesterol (LDL-C) by an average of 30-50%. However, non-adherence to statin therapy, due to statin intolerance, might be as high as 60% after 24 months of treatment and is associated with a 70% increase in the risk of cardiovascular disease events. Statin intolerance can be classified as a complete inability to tolerate any dose of a statin or a partial intolerance with the inability to tolerate the dose necessary to achieve the patient-specific therapeutic objective. Reasons for discontinuation are many, with statin-associated muscle symptoms being cited as the most frequent reason for stopping therapy and the incidence of muscle symptoms increasing with treatment intensity. Considering the causal effect of LDL-C in the atherosclerotic process, clinicians should consider that regardless of the lipid-lowering drugs patients are willing to take, any reduction in LDL-C they achieve will afford them some benefit in reducing cardiovascular risk. Besides statins, the current therapeutic armamentarium offers different strategies to reach LDL-C targets in statin-intolerant patients (i.e. a fixed combination between a lower dose of statin plus ezetimibe, bempedoic acid, or proprotein convertase subtilisin/kexin type 9 inhibition).

Pollution from fine particulate matter and atherosclerosis: A narrative review.

According to the WHO, the entire global population is exposed to air pollution levels higher than recommended for health preservation. Air pollution is a complex mixture of nano- to micro-sized particles and gaseous components that poses a major global threat to public health. Among the most important air pollutants, causal associations have been established between particulate matter (PM), mainly < 2.5 µm, and cardiovascular diseases (CVD), i.e., hypertension, coronary artery disease, ischemic stroke, congestive heart failure, arrhythmias as well as total cardiovascular mortality. Aim of this narrative review is to describe and critically discuss the proatherogenic effects of PM2.5 that have been attributed to many direct or indirect effects comprising endothelial dysfunction, a chronic low-grade inflammatory state, increased production of reactive oxygen species, mitochondrial dysfunction and activation of metalloproteases, all leading to unstable arterial plaques. Higher concentrations of air pollutants are associated with the presence of vulnerable plaques and plaque ruptures witnessing coronary artery instability. Air pollution is often disregarded as a CVD risk factor, in spite of the fact that it is one of the main modifiable factors relevant for prevention and management of CVD. Thus, not only structural actions should be taken in order to mitigate emissions, but health professionals should also take care to counsel patients on the risks of air pollution.

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study.

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930.

Side effects of statins: from pathophysiology and epidemiology to diagnostic and therapeutic implications.

Treatment with statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, has proven beneficial preventive effects on cardiovascular events. However, discontinuation due to intolerance and non-adherence remain two of the major gaps in both primary and secondary prevention. This leads many patients with high-risk of atherosclerotic cardiovascular disease (ASCVD) to be inadequately treated or not to achieve target lipid level goals, and as consequence they undergo an increased risk of cardiovascular events. The aim of this review is thus to give an overview of the reasons for discontinuation and on the possible mechanisms behind them. Although statins, as a class, are generally safe, they are associated with an increased risk of diabetes mellitus and hepatic transaminase elevations. Incidence of cataracts or cognitive dysfunction and others presented in the literature (e.g. proteinuria and haematuria) have been never confirmed to have a causal link. Conversely, debated remains the effect on myalgia. Muscle side effects are the most commonly reported, although myalgia is still believed by some to be the result of a nocebo/drucebo effect. Concerning mechanisms behind muscular side effects, no clear conclusions have been reached. Thus, if on one side it is important to identify individuals either at higher risk to develop a side effect, or with confirmed risk factors and conditions of statin intolerance, on the other side alternative strategies should be identified to avoid an increased ASCVD risk.

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

PURPOSE OF REVIEW: Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). RECENT FINDINGS: While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9.

Immediate and aggressive lipid lowering therapies after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are supported by the ESC/EAS dyslipidemia guidelines, recommending the initiation of high-intensity statin therapy within the first 1-4 days of hospitalization. However, whether non statin lipid-lowering agents, added to statin treatment, could produce a further reduction in the risk of major adverse cardiovascular events (MACE) is still unknown. Thus, the efficacy of early treatment post-ACS with monoclonal antibodies (mAbs) anti PCSK9, evolocumab and alirocumab, is under investigation. The rationale to explore the rapid and aggressive pharmacological intervention with PCSK9 mAbs is supported by at least five confirmatory data in ACS: 1) circulating PCSK9 levels are raised during ACS 2) PCSK9 may stimulate platelet reactivity, this last being pivotal in the recurrence of ischemic events; 3) PCSK9 is associated with intraplaque inflammation, macrophage activation and endothelial dysfunction; 4) PCSK9 concentrations are associated with inflammation in the acute phase of ACS; and 5) statins raise PCSK9 levels promptly and, at times, dramatically. In this scenario, appropriate pharmacodynamic characteristics of anti PCSK9 therapies are a prerequisite for an effective response. Monoclonal antibodies act on circulating PCSK9 with a direct and rapid binding by blocking the interaction with the low-density lipoprotein receptor (LDLR). Evolocumab and alirocumab show a very rapid (within 4 h) and effective suppression of circulating unbound PCSK9 (- 95 % ÷ - 97 %). This inhibition results in a significant reduction of LDL-cholesterol (LDL-C) after 48 h (- 35 %) post injection with a full effect after 7-10 days (55-75 %). The complete and swift inhibitory action by evolocumab and alirocumab could have a potential clinical impact in ACS patients, also considering their potential inhibition of PCSK9 within the atherosclerotic plaque. Thus, administration of evolocumab or alirocumab is effective in lowering LDL-C levels in ACS, although the efficacy to prevent further cardiovascular (CV) events is still undetermined. The answer to this question will be provided by the ongoing clinical trials with evolocumab and alirocumab in ACS. In the present review we will discuss the pharmacological and biological rationale supporting the potential use of PCSK9 mAbs in ACS patients and the emerging evidence of evolocumab and alirocumab treatment in this clinical setting.

Brain-Derived Neurotrophic Factor and Extracellular Vesicle-Derived miRNAs in an Italian Cohort of Individuals With Obesity: A Key to Explain the Link Between Depression and Atherothrombosis.

Background: Obesity and depression are intertwined diseases often associated with an increased risk of cardiovascular (CV) complications. Brain-Derived Neurotrophic Factor (BDNF), altered in the brain both of subjects with depression and obesity, provides a potential link between depression and thrombosis. Since the relationship among peripheral BDNF, depression and obesity is not well-defined, the aim of the present report has been to address this issue taking advantage of the contribution played by extracellular vesicle (EV)-derived miRNAs. Research Process: Associations among circulating BDNF, depression and EV-derived miRNAs related to atherothrombosis have been evaluated in a large Italian cohort of obese individuals (n = 743), characterized by the Beck Depression Inventory (BDI-II) score. Results: BDI-II was negatively associated with BDNF levels without a significant impact of the rs6265 BDNF polymorphism; this association was modified by raised levels of IFN-γ. BDNF levels were linked to an increase of 80 EV-derived miRNAs and a decrease of 59 miRNAs related to atherosclerosis and thrombosis. Network analysis identified at least 18 genes targeted by these miRNAs, 7 of which involved in depression and CV risk. The observation of a possible link among BDNF, depression, and miRNAs related to atherothrombosis and depression in obesity is novel and may lead to a wider use of BDNF as a CV risk biomarker in this specific subject group.

Omega-3 and cardiovascular prevention - Is this still a choice?

There is currently growing attention being paid to the role of elevated triglycerides (TGs) as important mediators of residual atherosclerotic cardiovascular disease (ASCVD) risk. This role is supported by genetic studies and by the persistent residual risk of ASCVD, even after intensive statin therapy. Although TG lowering drugs have shown conflicting results when tested in cardiovascular outcome trials, data from the REDUCE-IT study with the ethyl ester of ω-3 eicosapentaenoic acid (EPA) have revived hope in this area of research. The aim of the present review is to critically discuss the most recent large trials with ω-3 fatty acids (FAs) trying to elucidate mechanistic and trial-related differences, as in the case of REDUCE-IT and STRENGTH studies. The ω-3 FAs may lower cardiovascular risk through a number of pleiotropic mechanisms, e.g., by lowering blood pressure, by mediating antithrombotic effects, by providing precursors for the synthesis of specialized proresolving mediators that can inhibit inflammation or by modulating the lipid rafts enriched in cholesterol and sphingolipids. In conclusion, in a field fraught with uncertainties, the ω-3 FAs and especially high dose icosapent ethyl (the ethyl ester of EPA) are at present a most valuable therapeutic option to reduce the ASCVD risk.

Bempedoic Acid: for Whom and When.

PURPOSE OF REVIEW: The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed. RECENT FINDINGS: Bempedoic acid with a single daily dose (180 mg) reduces LDL-C by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38-40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins.

Impact of Atorvastatin on Skeletal Muscle Mitochondrial Activity, Locomotion and Axonal Excitability-Evidence from ApoE-/- Mice.

The cardiovascular benefit of statins is well established. However, only 20% of high-risk patients remain adequately adherent after 5 years of treatment. Among reasons for discontinuation, statin associated-muscle pain symptoms are the most prevalent. Aim of the present study was to evaluate the impact of high dose atorvastatin on skeletal muscle mitochondrial activity, aerobic and anaerobic exercise, and axonal excitability in a murine model of atherosclerosis. ApoE-/- mice were fed 12 weeks a high-fat high-cholesterol diet alone or containing atorvastatin (40 mg/Kg/day). Outcomes were the evaluation of muscle mitochondrial functionality, locomotion, grip test, and axonal excitability (compound action potential recording analysis of Aα motor propioceptive, Aß mechanoceptive and C nociceptive fibres). Atorvastatin led to a reduction in muscle mitochondrial biogenesis and mitochondrial ATP production. It did not affect muscular strength but led to a time-dependent motor impairment. Atorvastatin altered the responsiveness of mechanoceptive and nociceptive fibres, respectively, the Aß and C fibres. These findings point out to a mild sensitization on mechanical, tactile and pain sensitivity. In conclusion, although the prevalence of muscular side effects from statins may be overestimated, understanding of the underlying mechanisms can help improve the therapeutic approach and reassure adherence in patients needing-to-be-treated.

The Role of High-Density Lipoprotein Cholesterol in 2022.

PURPOSE OF THE REVIEW: High-density lipoproteins (HDL) are responsible for the transport in plasma of a large fraction of circulating lipids, in part from tissue mobilization. The evaluation of HDL-associated cholesterol (HDL-C) has provided a standard method for assessing cardiovascular (CV) risk, as supported by many contributions on the mechanism of this arterial benefit. The present review article will attempt to investigate novel findings on the role and mechanism of HDL in CV risk determination. RECENT FINDINGS: The most recent research has been aimed to the understanding of how a raised functional capacity of HDL, rather than elevated levels per se, may be responsible for the postulated CV protection. Markedly elevated HDL-C levels appear instead to be associated to a raised coronary risk, indicative of a U-shaped relationship. While HDL-C reduction is definitely related to a raised CV risk, HDL-C elevations may be linked to non-vascular diseases, such as age-related macular disease. The description of anti-inflammatory, anti-oxidative and anti-infectious properties has indicated potential newer areas for diagnostic and therapeutic approaches. In the last two decades inconclusive data have arisen from clinical trials attempting to increase HDL-C pharmacologically or by way of recombinant protein infusions (most frequently with the mutant A-I Milano); prevention of stent occlusion or heart failure treatment have shown instead significant promise. Targeted clinical studies are still ongoing.

Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P < 0.05). Conversely, patients with low serum Lp(a) displayed insulin resistance (P < 0.05), transaminase elevation (P < 0.05), and increased risk of developing severe fibrosis (P = 0.007) and cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting fibrosis increased by combining it with transaminases (area under the curve fibrosis stage 4, 0.87; P < 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of NAFLD (P < 0.05). Hepatic LPA messenger RNA levels correlated with those of genes involved in lipoprotein release, lipid synthesis, and fibrogenesis (P < 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, apolipoprotein E (ApoE) rs445925, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating lipids, may influence serum Lp(a) levels (P < 0.05). Conclusion: Circulating Lp(a) combined with transaminases may represent a novel noninvasive biomarker to predict advanced fibrosis in patients with NAFLD.

Lipoprotein(a): Knowns, unknowns and uncertainties.

Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases - A position paper from the International Lipid Expert Panel (ILEP).

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

Long-term fasting improves lipoprotein-associated atherogenic risk in humans.

PURPOSE: Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition. METHODS: This observational study included 40 volunteers (50% men, aged 32-65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days. RESULTS: The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, - 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (- 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, - 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (- 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (- 0.16 ± 0.05 mmol/L), LDL2-C (- 0.30 ± 0.06 mmol/L) and LDL3-C (- 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (- 5.18 ± 1.26 nmol/L), as well as large (- 244.13 ± 39.45 nmol/L) and small LDL particles (- 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (- 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged. CONCLUSION: Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia. TRIAL REGISTRATION: Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 "retrospectively registered".

Proprotein Convertase Subtilisin/Kexin Type 9: A View beyond the Canonical Cholesterol-Lowering Impact.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly synthetized and released by the liver, represents one of the key regulators of low-density lipoprotein cholesterol. Although genetic and interventional studies have demonstrated that lowering PCSK9 levels corresponds to a cardiovascular benefit, identification of non-cholesterol-related processes has emerged since its discovery. Besides liver, PCSK9 is also expressed in many tissues (eg, intestine, endocrine pancreas, and brain). The aim of the present review is to describe and discuss PCSK9 pathophysiology and possible non-lipid-lowering effects whether already extensively characterized (eg, inflammatory burden of atherosclerosis, triglyceride-rich lipoprotein metabolism, and platelet activation), or to be unraveled (eg, in adipose tissue). The identification of novel transcriptional factors in the promoter region of human PCSK9 (eg, ChREBP) characterizes new mechanisms explaining how controlling intrahepatic glucose may be a therapeutic strategy to reduce cardiovascular risk in type 2 diabetes. Finally, the evidence describing PCSK9 as involved in cell proliferation and apoptosis raises the possibility of this protein being involved in cancer risk.

The effect of transgender hormonal treatment on high density lipoprotein cholesterol efflux capacity.

BACKGROUND AND AIMS: A decrease in high-density lipoprotein (HDL)-cholesterol concentrations during transgender hormone therapy has been shown. However, the ability of HDL to remove cholesterol from arterial wall macrophages, termed cholesterol efflux capacity (CEC), has proven to be a better predictor of cardiovascular disease (CVD) largely independently of HDL-concentrations. In addition, the serum capacity to load macrophages with cholesterol (cholesterol loading capacity, CLC) represents an index of pro-atherogenic potential. As transgender individuals are exposed to lifelong exogenous hormone therapy (HT), it becomes of interest to study whether HDL-CEC and serum CLC are affected by HT. HDL-CEC and serum CLC have been evaluated in 15 trans men treated with testosterone and in 15 trans women treated with estradiol and cyproterone acetate at baseline and after 12 months of HT. METHODS: Total HDL-CEC from macrophages and its major contributors, the ATP-binding cassette transporters (ABC) A1 and ABCG1 HDL-CEC and HDL-CEC by aqueous diffusion were determined by a radioisotopic assay. CLC was evaluated in human THP-1 macrophages. RESULTS: In trans women, total HDL-CEC decreased by 10.8% (95%CI: -14.3;-7.3; p < 0.001), ABCA1 HDL-CEC by 23.8% (-34.7; -12.9; p < 0.001) and aqueous diffusion HDL-CEC by 4.8% (-8.4;-1.1; p < 0.01). In trans men, only aqueous diffusion HDL-CEC decreased significantly, -9.8% (-15.7;-3.9; p < 0.01). ABCG1 HDL-CEC did not change in either group. Serum CLC and HDL subclass distribution were not modified by HT in both groups. CONCLUSIONS: Total HDL-CEC decreased during HT in trans women, with a specific reduction in ABCA1 CEC. This finding might contribute to a higher CVD risk.

Lipid Lowering Drugs: Present Status and Future Developments.

PURPOSE OF REVIEW: Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk. RECENT FINDINGS: For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)LRX) and of triglycerides (ANGPTL3LRX and APOCIII-LRx). Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.