Vanessa Bianconi

Lipoprotein(a) [Lp(a)] is a major, independent determinant of atherosclerotic cardiovascular disease and calcific aortic valve disease, yet its integration into routine clinical practice remains fragmented. Persistent uncertainties regarding when to measure Lp(a), how to interpret assay results, and how to manage elevated Lp(a) levels in the absence of approved Lp(a)-lowering therapies continue to hinder its adoption. Meanwhile, targeted therapies, including antisense oligonucleotides, siRNA agents, and small molecules, are advancing through phase 3 trials and may soon provide evidence regarding the clinical impact of pharmacological reduction of Lp(a). This evolving landscape demands a transition from passive awareness to active implementation. Early identification of individuals with elevated Lp(a), transparent communication of its clinical implications, and structured referral pathways between general practitioners and lipid clinics for the optimization of cardiovascular prevention and preparation for future therapeutic options are crucial steps for bridging the existing Lp(a) gap. This perspective proposes a pragmatic framework for integrating Lp(a) into cardiovascular risk assessment and management across primary and specialist care, addressing operational challenges in measurement, interpretation, and treatment to support an actionable and coordinated Lp(a) clinical pathway. To this end, it formulates practical advice to orient Lp(a) management in primary care.

Cardiovascular–kidney–metabolic (CKM) syndrome is driven by the interplay of visceral adiposity, insulin resistance, chronic inflammation, oxidative stress, and progressive kidney dysfunction. These mechanisms generate a distinct atherogenic dyslipidaemic phenotype characterised by elevated triglycerides (TG), reduced high-density lipoprotein-cholesterol (HDL-C), increased apolipoprotein B (apoB)-containing lipoproteins, remnant cholesterol (RC) accumulation, small dense low-density lipoprotein (LDL) particles, and frequently elevated lipoprotein(a) [Lp(a)]. Such lipid abnormalities contribute to accelerated atherosclerosis and early renal deterioration. In turn, kidney dysfunction further amplifies lipid abnormalities. These pathways underscore the need for a timely and comprehensive lipid assessment using apoB, non-HDL-C, RC, and Lp(a) within the CKM framework. Effective lipid management is crucial for CKM syndrome treatment, with the potential to reduce residual cardiovascular and renal risk and improve long-term clinical outcomes. In this narrative review, we examine current evidence on the pathophysiological mechanisms underlying CKM-related dyslipidaemia and provide a practical framework for its assessment and management. Management requires a multimodal approach tailored to the patient’s lipid phenotype and overall cardiovascular risk, incorporating a range of lipid-lowering strategies including statins, ezetimibe, PCSK9 inhibitors, bempedoic acid, fibrates, icosapent ethyl, and emerging therapies targeting apoC-III, ANGPTL3, and Lp(a). Beyond lipid lowering, lifestyle interventions and cardiometabolic therapies such as glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and finerenone may provide complementary cardiometabolic and renal protection.

Background: Awareness, diagnosis, and treatment of familial hypercholesterolemia (FH) starting from childhood are a cornerstone of cardiovascular disease prevention. The LIPIGEN Paediatric Group, a network of specialised centres for the diagnosis and management of familial genetic dyslipidemia, is an active part of this mission. Materials and Methods: This is the second exploratory survey organised within the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) paediatric centres. A digital questionnaire consisting of 16 questions was proposed to the principal investigators of 35 LIPIGEN centres in September 2023. We analysed the main FH screening strategies implemented in Italy, which are the referral characteristics to the lipid clinics and clinical and biochemical criteria considered to diagnose FH in paediatric patients. Results: Centres frequently reported conducting cascade screening (88.6%) and reverse screening (57.1%), whereas 28.6% of respondents indicated using selective screening and only 5.7% reported employing child–parent screening. We documented a detailed biochemical characterisation of paediatric patients (62.9% of respondents usually perform full lipoprotein profile and 80% determine lipoprotein(a) for each patient) and a high percentage of genetic analysis (82.9%). We have also highlighted a quite low awareness of FH as a genetic condition involving paediatric patients among primary care paediatricians and general practitioners. Conclusions: The results of our survey show that specialised lipid centres usually have good diagnostic competence when dealing with paediatric patients with hypercholesterolemia. However, FH awareness and the importance of early diagnosis and treatment initiation in childhood still need to be further improved.

Introduction and objectives. Secondary bacterial infections (SBIs) contribute to worse in-hospital outcomes in patients with Coronavirus disease 2019 (COVID-19). Treatment with proton pump inhibitors (PPIs) is associated with an increased risk of bacterial infections in different clinical settings. However, the association between PPI treatment prior to hospital admission and the occurrence of either SBIs or secondary bacterial sepsis (SBS) as well as their joint impact on clinical outcomes of patients hospitalized for COVID-19 are not clarified. Patients and methods. We retrospectively analyzed preadmission PPI use, in-hospital occurrence of SBIs and SBS, and in-hospital outcomes of a cohort of patients hospitalized for COVID-19. Results. Among 1087 patients, 447 (41%) were on PPI treatment prior to hospital admission. During the hospital stay, 197 (18%) and 223 (20%) patients were diagnosed with SBIs and SBS, respectively. The composite endpoint of intensive care unit (ICU) admission/in-hospital death was met by 214 (20%) patients. Preadmission PPI treatment was independently associated with up to a 2.1-fold and 1.7-fold increased risk of SBIs and SBS, respectively. The occurrence of SBS was independently associated with up to a 2.2-fold increased risk of ICU admission/in-hospital death. A significant preadmission PPI treatment x SBS interaction emerged in predicting ICU admission/in-hospital death (F = 5.221, p_interaction = 0.023). Conclusions. PPI treatment prior to hospital admission for COVID-19 is associated with an increased risk of SBIs and SBS. In addition, it interacts with SBS in predicting in-hospital prognosis. An appropriate use of PPIs may attenuate the risk of adverse clinical outcomes during hospitalization for COVID-19.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism contributing to cardiovascular (CV) risk in the general population. The relationship between PCSK9 and CV risk in systemic autoimmune diseases has been poorly explored. We investigated the association between plasma PCSK9, measures of immune–inflammatory status and markers of atherosclerosis in 52 consecutive patients with primary Sjögren’s syndrome (pSS) in comparison to healthy controls (HCs). Median plasma PCSK9 levels were significantly higher in pSS patients versus HCs (162 (79–255) vs. 53 (39–99) ng/mL). Significantly higher prevalence of subclinical atherosclerosis and lower of dyslipidaemia (61% vs. 85%, p = 0.042) characterized pSS patients versus HCs. In pSS, no significant correlation emerged between PCSK9 and disease activity, atherosclerosis and lipid levels. In HCs, PCSK9 significantly correlated with lipid levels and atherosclerosis. Interestingly, significantly higher PCSK9 levels were found in HCs with high-to-very-high as compared to low-to-moderate CV risk (p = 0.018) while a non-significant trend towards higher PCSK9 levels was detected in pSS patients with low-to-moderate as compared to high-to-very-high CV risk (p = 0.060). This is the first demonstration that pSS patients, despite lower prevalence of dyslipidaemia and higher CV risk profile, are characterized by a 3-fold increase in PCSK9 levels in comparison to HCs. As PCSK9 does not correlate with measures of CV risk, its role in CV morbidity in pSS needs further investigation.

The prothrombotic and proinflammatory properties of lipoprotein(a) (Lp(a)) have been hypothesized to play a role in the pathogenesis of severe COVID-19; however, the prognostic impact of Lp(a) on the clinical course of COVID-19 remains controversial. This study aimed to investigate whether Lp(a) may be associated with biomarkers of thrombo-inflammation and the occurrence of thrombotic events or adverse clinical outcomes in patients hospitalized for COVID-19. We consecutively enrolled a cohort of patients hospitalized for COVID-19 and collected blood samples for Lp(a) assessment at hospital admission. A prothrombotic state was evaluated through D-dimer levels, whereas a proinflammatory state was evaluated through C-reactive protein (CRP), procalcitonin, and white blood cell (WBC) levels. Thrombotic events were marked by the diagnosis of deep or superficial vein thrombosis (DVT or SVT), pulmonary embolism (PE), stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), and critical limb ischemia (CLI). The composite clinical end point of intensive care unit (ICU) admission/in-hospital death was used to evaluate adverse clinical outcomes. Among 564 patients (290 (51%) men, mean age of 74 ± 17 years) the median Lp(a) value at hospital admission was 13 (10–27) mg/dL. During hospitalization, 64 (11%) patients were diagnosed with at least one thrombotic event and 83 (15%) patients met the composite clinical end point. Lp(a), as either a continuous or categorical variable, was not associated with D-dimer, CRP, procalcitonin, and WBC levels (p > 0.05 for all correlation analyses). In addition, Lp(a) was not associated with a risk of thrombotic events (p > 0.05 for multi-adjusted odds ratios) nor with a risk of adverse clinical outcomes (p > 0.05 for multi-adjusted hazard ratios). In conclusion, Lp(a) does not influence biomarkers of plasma thrombotic activity and systemic inflammation nor has any impact on thrombotic events and adverse clinical outcomes in patients hospitalized for COVID-19.

La lipoproteina(a) [Lp(a)] è una lipoproteina plasmatica a bassa densità strutturalmente simile ad una particella LDL, ma legata ad una molecola di apolipoproteina(a) tramite un ponte disolfuro. Da studi epidemiologici e genetici è emersa un’associazione diretta lineare tra i livelli circolanti di Lp(a) ed il rischio di malattia cardiovascolare su base aterosclerotica (ASCVD). Pertanto, la misurazione di Lp(a) è considerata rilevante ai fini della stratificazione del rischio cardiovascolare (CV). Più incerte sono invece le evidenze circa il possibile ruolo di Lp(a) come determinante di eventi trombotici venosi. Sulla base di queste premesse, la riduzione dei livelli circolanti di Lp(a) potrebbe rappresentare un elemento cruciale nell’ambito delle strategie di prevenzione CV. Tuttavia, sebbene varie strategie farmacologiche e non siano state proposte a tal fine, nessuna di esse ha mostrato un buon profilo di efficacia, sicurezza, e tollerabilità tale da giustificarne l’esteso impiego nella comune pratica clinica. Inoltre, non vi sono ad oggi studi clinici randomizzati controllati di fase 3 che abbiano dimostrato l’efficacia della riduzione dei livelli circolanti di Lp(a) in termini di riduzione del rischio CV. Lo sviluppo di terapie mirate per la riduzione dei livelli circolanti di Lp(a) rappresenta quindi una sfida attuale nell’ambito delle strategie di prevenzione CV.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated.Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation.Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity.Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

Introduction: The aim of this meta-analysis was to assess the effect of ongoing statin treatment on susceptibility to influenza virus infection and on influenza-associated mortality.Material and methods: Studies investigating the impact of statin treatment on influenza prevalence and mortality were searched in PubMed-Medline, Scopus, ISI Web of Knowledge, Embase, Proquest, OVID, EBSCO and CINAHLdatabases (up to June 30, 2020). Fixed- and random-effects model and generic inverse variance method were used for quantitative data synthesis.Results: In the meta-analysis of 15 arms of 3 eligible studies including flu-vaccinated and unvaccinated patients, treatment with statins was associated with a reduction of influenza virus prevalence [Odds Ratio (OR) 0.85, 95% Confidence Interval (CI) 0.73-0.99; p 0.040]. No significant effect of statins on the susceptibility to influenza infection was observed in the distinct communities of either vaccinated or unvaccinated subjects. Among 9 arms of 6 eligible studies, the use of statins among patients with influenza was associated with a reduced mortality [OR (95% CI), 0.68 (0.56, 0.82); p<0.001]. This result was confirmed for both 30-day mortality since influenza infection diagnosis [OR (95% CI), 0.61 (0.47, 0.80); p<0.001] and for up to 90-day mortality [OR (95% CI), 0.74 (0.55, 1.00); p=0.042].Conclusions: A reduced influenza prevalence and anincreased survivalfrom influenza infection was observed in patients on ongoing statin treatment. Further research is needed to define the possible role of statins as adjunctive therapy in patients with influenza infection.

Non-invasive respiratory support (NIRS) is widely used in COVID-19 patients, although high rates of NIRS failure are reported. Early detection of NIRS failure and promptly defining the need for intubation are crucial for the management of patients with acute respiratory failure (ARF). We tested the ability of the HACOR score¸ a scale based on clinical and laboratory parameters, to predict adverse outcomes in hospitalized COVID-19 patients with ARF. Four hundred patients were categorized according to high (>5) or low (≤5) HACOR scores measured at baseline and 1 h after the start of NIRS treatment. The association between a high HACOR score and either in-hospital death or the need for intubation was evaluated. NIRS was employed in 161 patients. Forty patients (10%) underwent intubation and 98 (25%) patients died. A baseline HACOR score > 5 was associated with the need for intubation or in-hospital death in the whole population (HR 4.3; p < 0.001), in the subgroup of patients who underwent NIRS (HR 5.2; p < 0.001) and in no-NIRS subgroup (HR 7.9; p < 0.001). In the NIRS subgroup, along with the baseline HACOR score, also 1-h HACOR score predicted NIRS failure (HR 2.6; p = 0.039). In conclusion, the HACOR score is a significant predictor of adverse clinical outcomes in patients with COVID-19-related ARF.