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Objective: Venous thromboembolism (VTE) recurrence is a major concern after a first symptomatic episode, potentially impacting survival and healthcare needs in community, hospital and rehabilitation settings. We evaluated the association of D-Dimer positivity after oral anticoagulant therapy (OAT) discontinuation with VTE recurrence. Methods: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched. Differences were expressed as Odds Ratio (OR) with 95% confidence intervals (95%CI). Pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and summary ROC (sROC) curve were calculated. Results: Twenty-six articles on 10,725 VTE patients showed that the absolute risk of recurrence was 16.1% (95%CI: 13.2%-19.5%) among 4,049 patients with a positive D-Dimer and 7.4% (95%CI: 6.0%-9.0%) in 6,676 controls (OR: 2.1, 95%CI: 1.7-2.8, P

Introduction: Dyslipidemias are common clinical conditions associated to cardiovascular diseases. Among these, Familial Hypercholesterolemia (FH) and severe Hypertriglyceridemia (sHTG) are the most frequent ones. The aim of this study is to evaluate the possible use of a wide next-generation-sequencing (NGS) panel of 28 genes involved in lipid metabolism, to improve the molecular diagnosis of dyslipidemias. Methods: A reanalysis of 25 patients (21 FH and 4 sHTG) previously analyzed for a few causative genes has been carried on. Patients bearing different types of variants [single nucleotide variants (SNVs) and copy number variations (CNVs)] in different genes, previously analyzed with Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) have been selected. DNA libraries have been prepared using Agilent SureSelect target enrichment protocol; the sequencing has been performed using Illumina MiSeq (V2 150x2 Micro). The results of the sequencing have been evaluated by Agilent SureCall and Agilent Alissa Align & Call and Intrepret pipelines. Results: All previously identified SNVs and CNVs have been confirmed by NGS. Additional rare variants, not always associated with dyslipidemias, were found in 23/25 patients. An additional pathogenic variant in the APOB gene has been identified in a sHTG patient carrying only 1 pathogenic variant in the APOA5 gene (causative of sHTG). Conclusions: The NGS-method confirmed all the results obtained with direct sequencing and MLPA methodologies. Additional rare variants were detected, even if most of them turned out to be variant of uncertain significance (VUS). In conclusion, this NGS approach may enhance the molecular diagnosis of different types of dyslipidemias, thereby leading to a better understanding and detection of complex phenotypes.

Objective: Limited and conflicting data are available about the association between shortterm blood pressure (BP) variability and urinary albumin excretion rate (uAER). The objective of our study was to analyze the relationships between microalbuminuria, defined as an uAER between 20 and 200mg/ min, and shortterm BP variability, assessed as average real variability (ARV), weighted standard deviation (SD) of 24h BP, and as SD of daytime and nighttime BP. Design and method: The study population consisted of 315 untreated essential hypertensives with normal estimated glomerular filtration rate (> 60ml/min/1.73 m2), which underwent 24h ambulatory BP monitoring and 24h uAER determination. Results: Microalbuminuriawas detected in 82 (26%) patients.ARVof 24h systolic BP (SBP)was significantly higher in patients with mcroalbuminuria [9.8 (8.5–11.1) mmHg] when compared to those without it [9.1 (8–10.2) mmHg; p = 0.007]. This difference held (p = 0.026) after adjustment for age, mean levels of BP and other potential confounders by ANCOVA. The correlation analysis disclosed that, among the indices of shortterm BPV, only ARV of 24h SBP (r = 0.169; p = 0.003) and ARV of 24h DBP (r = 0.125; p = 0.026) were significantly related to (Log) uAER, whereas the relationships of uAER with SD of daytime SBP and with weighted SD of 24h SBP did not reach the statistical significance (respectively, r = 0.095 and r = 0.085). The correlation of uAER with ARV of 24h SBP, but not that with ARV of 24h DBP, remained significant even after adjustment for average 24 –h SBP (figure). This association remained significant (b = 0.15; p = 0.01), also taking into account the effect of age, gender, diabetes, serum uric acid, triglycerides, eGFR in multiple regression analyses. All the other indices of shortterm BP variability tested were not independently associated with microalbuminuria. Conclusions: Our results seem to suggest that in essential hypertension, short-term BP variability, only when estimated by ARV of 24h SBP, is independently associated with microalbuminuria.

Introduction: Studies investigating the prognostic implications of short-term blood pressure (BP) variability (STBPV), expressed as standard deviation (SD) and assessed by noninvasive 24-h ambulatory BP monitoring (ABPM), yielded conflicting results. In last years further indices of STBPV have been proposed. Among these, the 24-h BP average real variability (ARV) seems to be associated with an increased cardiovascular risk more closely than the SD. Little is known about the association between mild renal dysfunction (MRD) and STBPV, and particularly between 24-h BP ARV and MRD. Aim: To analyse, in a group of essential hypertensives, the relationships between MRD and STBPV, expressed as SD of day and night-time BP and as 24-h BP ARV and between these latter, 24-h albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR). Methods: We enrolled 178 untreated essential hypertensives, with and eGFR > 60 ml/min/1.73 m2. All the patients underwent 24-h ABPM. BP readings were performed automatically at 15 min intervals during the day and at 20 min intervals during night-time resting. Moreover, 24-h AER was determined and eGFR calculated using the CKDEPI equation. Subjects belonging to the I and II stages of the KDIGO classification of chronic kidney diseases (CKD) were considered as having MRD. Results: No significant difference was found between subjects with MRD (n = 43) and those without it, regarding all the indices of STBPV examined, except for SD of daytime diastolic BP that was higher (p 0.02) in patients with MRD. However, this difference lost statistical significance after adjustment for age, average daytime diastolic BP, waist circumference and triglycerides. Among the STBPV indices studied, only SD of daytime systolic BP showed a weak (p = 0.03) inverse correlation with eGFR, that disappeared after adjustment for age, gender and average systolic daytime BP in multiple regression analysis. Both 24-h systolic and diastolic ARV did not show significant correlations neither with 24-h AER nor with eGFR. Conclusions: Our results seem to suggest that in essential hypertensive patients, STBPV, even when expressed by 24-h ARV, does not influence early renal abnormalities.

RAZIONALE. Il significato prognostico della variabilità pressoria (VP) a breve termine, espressa come deviazione standard (SD), è controverso. Recentemente sono stati proposti altri indici di VP a breve termine, tra i quali l’Average Real Variability (ARV), sembra essere maggiormente associato al rischio cardiovascolare (CV). Non indagata, finora è la relazione tra ARV e disfunzione renale lieve. Scopo del nostro studio è stato quello di analizzare le relazioni dell’ ARV delle 24 h e di altri indici di VP a breve termine con l’ albuminuria (AER) ed il filtrato glomerulare (eGFR) in un gruppo di ipertesi essenziali, non trattati. CASISTICA E METODI. Sono stati arruolati 248 pazienti (età media 48 ± 14 anni, donne 44 %), con ipertensione arteriosa essenziale e con eGFR > 60 ml/min/1.73 m2. Di essi 73 sono stati considerati affetti da disfunzione renale lieve (DRL), in relazione alla appartenenza ai primi due stadi di CKD, secondo le linee guida KDIGO del 2012. RISULTATI. Nessuno degli indici di VP a breve termine studiati [ARV delle pressioni arteriose (PA) delle 24 h, SD ponderata delle PA delle 24 h, SD delle PA del giorno e della notte] sono risultati diversi nei soggetti con DRL, rispetto agli ipertesi con normale funzione renale. Deboli correlazioni sono state osservate tra logaritmo dell’ARV della PA sistolica e logaritmo dell’ AER (r = 0.130; p = 0.04) e tra il primo e l’eGFR (- 0.131; p = 0.04). Tali correlazioni hanno perduto significatività statistica in modelli di regressione lineare multipla, dopo correzione per potenziali fattori confondenti. Analogamente all’analisi di regressione logistica multipla, nessuno degli indici di VP a breve termine esaminati, è risultato associato in maniera indipendente alla DRL. CONCLUSIONI. I nostri risultati, suggeriscono che nell’iperteso essenziale nessuno degli indici di VP a breve termine, ottenibile mediante monitoraggio discontinuo della PA delle 24 ore, sia associato con la DRL.

The prognostic significance of short–term blood pressure (BP) variability (STBPV), expressed as standard deviation (SD) of blood pressures (BP) intermittently recorded over 24 hours, is debated. Recently, indices of STBPV other than SD have been proposed. Among these, the 24-h BP Average Real Variability (ARV) seems to be associated more consistently than SD with an enhanced cardiovascular risk. The relationship between mild-to-moderate renal dysfunction (MMRD) and ARV was not investigated. Our study was aimed to analyse, in a large group of untreated essential hypertensives, the relationships between ARV, and other STBV indices, with MMRD. We enrolled 329 essential hypertensive patients, with an eGFR > 30 ml/min/1.73 m2. All the subjects were untreated for hypertension and underwent a 24-h ambulatory blood pressure monitoring. Ninety-six of the participants belonged to the first III stages of 2012 KDIGO classification of chronic kidney diseases (CKD) and were considered to have MMRD. Among the STBV indices evaluated [ARV of 24 h BP; Weighted SD of 24 h BP, SD of daytime and nightime BP] only ARV of 24 h systolic BP differed in subjects with MMRD [9.93 (8.57-11.18) mmHg] compared to the hypertensives with normal renal function [9.1 (8-10.2) mmHg; p = 0.001]. This association held (p < 0.03) in multiple logistic regression analysis after adjustment for 24 h average systolic BP, age, gender and other confounding factors. Our results seem to suggest that in essential hypertensive patients, ARV of 24 h systolic BP, but not other STBPV indices, is significantly associated with MMRD.

Blood pressure variability

RAZIONALE. La malattia renale cronica (CKD) è associata ad un’incrementata massa ventricolare sinistra (LVM), che può predisporre ad un aumentato rischio di eventi cardiovascolari. Le concentrazioni plasmatiche di aldosterone (PAC) sono spesso incrementate negli stadi avanzati di CKD. Poco è noto sui livelli di aldosterone e la loro relazione con la LVM nei soggetti con CKD lieve-moderataL’obiettivo del nostro studio è stato quello di analizzare PAC e LVM e la loro relazione in un gruppo di pazienti ipertesi con CKD agli stadi I-III National Kidney Foundation (NKF). CASISTICA E METODI. Abbiamo arruolato 195 pazienti ipertesi con CKD agli stadi I-III NKF e li abbiamo comparati ad un gruppo di controllo, costituito da 82 ipertesi senza disfunzione renale, omogeneo per età e sesso. I pazienti, in wash-out da farmaci anti-ipertensivi, sono stati sottoposti a dosaggio di attività reninica plasmatica e aldosterone, monitoraggio della pressione arteriosa delle 24 ore ed ecocardiogramma. RISULTATI. LVM era più alta nei soggetti con CKD rispetto ai controlli e aumentava progressivamente con l’avanzare degli stadi di CKD (ANOVA: p = 0,004). Abbiamo osservato un simile trend per la PAC (ANOVA: p < 0,0001). Abbiamo inoltre riscontrato una correlazione diretta altamente significativa tra PAC e LVM nei soggetti con CKD (r = 0.29; p < 0.0001). Tale associazione rimaneva significativa all’analisi di regressione multipla anche dopo aggiustamento per vari fattori confondenti (p < 0.0001). CONCLUSIONI. I nostri risultati mostrano come, nei pazienti ipertesi con CKD, LVM e PAC siano incrementate e correlate tra loro, sin dai primi stadi di disfunzione renale. Sembra biologicamente plausibile speculare che l’aldosterone possa contribuire ad incrementare la LVM nei pazienti ipertesi con precoce CKD. Il

Background and Aims Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. Methods and Results We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54±13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygotes (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p=1.00) and T36w (p=0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p=0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. Conclusions After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.

Familial Hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients - 342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased. This article is protected by copyright. All rights reserved.

Aims Lower limb peripheral artery disease (PAD) is a leading cause of atherosclerotic cardiovascular disease (ASCVD). Discordant data are available on the association between apolipoprotein and PAD. We performed a meta-analyses on the association between apolipoprotein (apo)B, apoA-I, and apoB/apoA-I ratio with PAD. Methods and results PubMed, Web of Science, Scopus databases were systematically searched. Studies providing data about apoB, apoA-I, apoB/apoA-I ratio in PAD subjects and non-PAD controls were included. Differences between PAD and non-PAD subjects were expressed as mean difference (MD) with pertinent 95% confidence intervals (95%CI). Twenty-two studies were included. Peripheral artery disease subjects showed higher apoB (MD: 12.5 mg/dL, 95%CI: 2.14, 22.87) and lower apoA-I levels (MD: −7.11 mg/dL, 95%CI: −11.94, −2.28) than non-PAD controls. Accordingly, ApoB/ApoA-I ratio resulted higher in PAD subjects than non-PAD controls (MD: 0.11, 95% CI: 0.00, 0.21). Non-HDL-C showed a direct association with the difference in apoB (z-value: 4.72, P Conclusions Our meta-analysis suggests that PAD subjects exhibit increased apoB and reduced apoA-I levels, accompanied by an increased apoB/apoA-I ratio as compared with non-PAD controls.

Rationale: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. Objective: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, the plasma lipidome of FH subjects before and at different time intervals during treatment with the PCSK-9 inhibitor Evolocumab was explored. Methods and Results: In 25 FH subjects, heterozygotes or compound heterozygotes for different LDL receptor mutations, untargeted lipidomic revealed significant reductions in 26 lipid classes belonging to phosphatidylcholine (PC), sphingomyelin (SM), ceramide (CER), cholesteryl ester (CE), triacylglycerol (TG) and phosphatidylinositol (PI). Lipid changes were graded between baseline and 4- and 12-week treatment. At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2% of total PC at baseline; two ether/vinyl ether forms; seven SM; five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl—CER (LAC-CER). Although non quantitative modifications were observed in phosphatidylethanolamine (PE) during treatment with Evolocumab, shorter and more saturated fatty acyl chains were documented. Conclusions: Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK-9 inhibitor Evolocumab. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK-9 inhibitors.

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p &lt, 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p &lt, 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p &lt, 0.001), forced vital capacity (rho = 0.406, p &lt, 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p &lt, 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p &lt, 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value &lt, 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

BACKGROUND Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P

Background: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). Methods: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. Results: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p &lt, 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV1%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV1% (≥80% predicted) during the overall study period or those normalizing FEV1% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV1% (&lt, 80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. Conclusions: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients.

Carotid artery plaques are considered a measure of atherosclerosis and are associated with an increased risk of atherosclerotic cardiovascular disease, particularly ischemic strokes. Monitoring of patients with an elevated risk of stroke is critical in developing better prevention strategies. Non-invasive imaging allows us to directly see atherosclerosis in vessels and many features that are related to plaque vulnerability. A large body of evidence has demonstrated a strong correlation between some lipid parameters and carotid atherosclerosis. In this article, we review the relationship between lipids and atherosclerosis with a focus on carotid ultrasound, the most common method to estimate atherosclerotic load.

A number of epidemiologic studies have demonstrated a strong association between increasing lipoprotein a [Lp(a)] and cardiovascular disease. This correlation was demonstrated independent of other known cardiovascular (CV) risk factors. Screening for Lp(a) in the general population is not recommended, although Lp(a) levels are predominantly genetically determined so a single assessment is needed to identify patients at risk. In 2019 ESC/EAS guidelines recommend Lp(a) measurement at least once a lifetime, fo subjects at very high and high CV risk and those with a family history of premature cardiovascular disease, to reclassify patients with borderline risk. As concerning medications, statins play a key role in lipid lowering therapy, but present poor efficacy on Lp(a) levels. Actually, treatment options for elevated serum levels of Lp(a) are very limited. Apheresis is the most effective and well tolerated treatment in patients with high levels of Lp(a). However, promising new therapies, in particular antisense oligonucleotides have showed to be able to significantly reduce Lp(a) in phase II RCT. This review provides an overview of the biology and epidemiology of Lp(a), with a view to future therapies.

Antiphospholipid antibodies (aPL) are a cluster of autoantibodies directed against plasma proteins with affinity for membrane phospholipids. The most frequently tested aPL are lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), and anti-β2-glycoprotein I antibodies (anti-β2GPI). aPL play a key pathogenic role in the development of the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by recurrent thrombotic and/or pregnancy complications in patients with persistent aPL. However, aPL positivity is occasionally documented in patients with no previous history of thrombotic or pregnancy morbidity. LA activity, multiple aPL positivity, high-titer aPL, and a concomitant systemic autoimmune disease are recognized risk factors for future thrombotic events in asymptomatic carriers. Moreover, an accelerated atherosclerosis with increased cardiovascular (CV) risk has also been associated with aPL positivity, thus exposing aPL carriers to fatal complications and chronic disability requiring cardiac rehabilitation. Overall, an accurate risk stratification is recommended for aPL-positive subjects in order to prevent both venous and arterial thrombotic complications. In this review, we provide an overview of the main antithrombotic and risk assessment strategies in aPL carriers.

The development of enhanced half-life recombinant factor VIII (EHL-rFVIII) concentrates has improved the management of hemophilia. Furthermore, the chance of maintaining higher trough levels has allowed higher protection from bleeding and, in turn, improved safely performance for certain types of physical activity. The first technology used to improve the pharmacokinetic profile of factor VIII (FVIII) was fusion with the Fc domain of immunoglobulin G. More recently, conjugation to hydrophilic polymers of polyethylene glycol (PEG) has been demonstrated to prolong plasma half-life of FVIII by means of a reduction in clearance of the molecule due to steric hindrance by PEG covering the protein. Here we report results of a systematic review of pivotal studies on EHL-rFVIII concentrates. Significant heterogeneity is observed among different studies on EHL-rFVIII concentrates, and direct comparisons should be avoided. The annualized bleeding rate has ranged between 1.2 and 1.9 in different EHL-rFVIII concentrates, with a progressive further decrease during extension phases of pivotal studies. Zero bleeding was reported by 40 to 45% of patients. Overall, the emerging treatment options seem to be highly effective and safe, associated with a decreased dosing interval to twice weekly or less, which reduces, but does not entirely eliminate, the burden of treatment. Overall, further information is needed from real-life settings to permit differentiation between EHL-FVIII concentrates and for individualizing treatment.

Coronavirus disease 2019 (COVID-19) may have a wide spectrum of clinical presentations, leading in some cases to a critical condition with poor long-term outcomes and residual disability requiring post-acute rehabilitation. A major concern in severe COVID-19 is represented by a concomitant prothrombotic state. However, contrasting data are available about the prevalence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE). A detailed search on the association of COVID-19 with thromboembolic complications was conducted in the main electronic databases (PubMed, Web of Science, and Scopus) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The weighted mean prevalence (WMP) with 95% confidence interval (95% CI) was calculated with the random-effects model. Twenty studies enrolling 1,988 COVID-19 patients were included. The WMP of VTE was 31.3% (95% CI: 24.3–39.2%). The WMP of DVT was 19.8% (95% CI: 10.5–34.0%), whereas the WMP of PE was 18.9% (95% CI: 14.4–24.3%). Similar results were obtained when specifically analyzing studies on patients admitted to intensive care units and those on patients under antithrombotic prophylaxis. Regression models showed that an increasing age was associated with a higher prevalence of VTE (Z-score: 3.11, p = 0.001), DVT (Z-score: 2.33, p = 0.002), and PE (Z-score: 3.03, p = 0.002), while an increasing body mass index was associated with an increasing prevalence of PE (Z-score = 2.01, p = 0.04). Male sex did not impact the evaluated outcomes. The rate of thromboembolic complications in COVID-19 patients is definitely high. Considering the risk of fatal and disabling complications, adequate screening procedures and antithrombotic strategies should be implemented.

Background Bempedoic acid ( BA ) is a novel lipid‐lowering drug. We performed a systematic review and meta‐analysis on efficacy and safety of BA compared with standard treatment in patients with hypercholesterolemia. Methods and Results Studies were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Efficacy outcome was represented by percentage changes (mean difference [ MD ] with pertinent 95% CIs ) in total cholesterol, low‐density lipoprotein cholesterol, triglycerides, high‐density lipoprotein cholesterol, apolipoprotein B, non– high‐density lipoprotein cholesterol , and hs‐CRP (high‐sensitivity C‐reactive protein) in BA patients and controls. Seven studies were included (2767 BA ‐treated patients and 1469 controls), showing a more significant reduction in low‐density lipoprotein cholesterol ( MD , −17.5%; 95% CI , −22.9% to −12.0%), total cholesterol ( MD , −10.9%; 95% CI , −13.3% to −8.5%), non– high‐density lipoprotein cholesterol ( MD, −12.3%; 95% CI , −15.3% to −9.20%), apolipoprotein B ( MD , −10.6%; 95% CI , −13.2% to −8.02%), and hs‐CRP ( MD , −13.2%; 95% CI , −16.7% to −9.79%) in BA ‐treated patients compared with controls. Results were confirmed when separately analyzing studies on patients with high cardiovascular risk, studies on statin‐intolerant patients, and studies on patients with hypercholesterolemia on maximally tolerated lipid‐lowering therapy. BA ‐treated subjects reported a higher rate of treatment discontinuation caused by adverse effects, of gout flare, and of increase in uric acid compared with controls. On the other hand, BA ‐treated patients showed a lower incidence of new‐onset diabetes mellitus than controls. Conclusions BA is associated with a significant reduction in low‐density lipoprotein cholesterol , total cholesterol , non– high‐density lipoprotein cholesterol , apolipoprotein B, and hs‐CRP compared with standard treatment. Documented efficacy is accompanied by an acceptable safety profile.

Despite an increasing access to prophylaxis with clotting factor concentrates, arthropathy still represents the main chronic complication of hemophilia. Whereas previous studies described hemophilic arthropathy (HA) as a degenerative arthropathy, somehow resembling osteoarthritis (OA), most recent evidence suggests that complex inflammatory and immunologic mechanisms are also involved in the pathophysiology of HA. In the present review, we described available data on major mechanisms leading to arthropathic changes in patients with hemophilia, with a specific focus on the role of synovium. The presence of hemosiderin in the joint space induces synovium proliferation, thus leading to formation of several lytic enzymes determining chondrocytes apoptosis and proteoglycans levels reduction. This leads to a direct joint “chemical” damage representing early damages in the pathogenesis of HA (first hit). In parallel, synovial membrane and synovial endothelial cells become a dynamic reservoir of inflammatory cells and mediators, and propagate the inflammatory response (second hit), switching the process from a chemical damage to an inflammatory damage. Overall, consistent data pointed out synovitis as the keystone in HA pathophysiology. This opens novel potential therapeutic targets in this clinical setting.

Objective SLE patients have an increased cardiovascular morbidity and mortality. Contrasting data are available about the association between peripheral arterial disease (PAD) and SLE. We aimed to perform a meta-analysis of studies evaluating the association between SLE and PAD. Methods Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases according to preferred reporting items for systematic reviews and meta-analyses guidelines. Results Eight studies reporting on 263 258 SLE patients and 768 487 controls showed that the prevalence of PAD was 15.8% (95% CI: 10.5%, 23.2%) in SLE patients and 3.9% (95% CI: 1.8%, 7.9%) in controls with a corresponding odds ratio of 4.1 (95% CI: 1.5, 11.6; P Conclusion SLE patients exhibit an increased prevalence of PAD and lower ankle-brachial index values as compared with non-SLE controls. This should be considered when planning prevention, interventional and rehabilitation strategies for these chronic patients with functional disability and poor long-term outcomes.

Background and aim: Protein convertase subtilisin kexin type 9 (PCSK-9) inhibitors demonstrated efficacy in cholesterol reduction and in the prevention of cardiovascular events. We evaluated changes in lipid profile and carotid stiffness in patients with familial hypercholesterolemia during 12 weeks of treatment with a PCSK-9 inhibitor, Evolocumab®. Methods and results: Patients with familial hypercholesterolemia starting a treatment with Evolocumab® were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), small dense LDL (assessed by LDL score) and carotid stiffness were evaluated before starting treatment with Evolocumab® and during 12 weeks of treatment. Twenty-five subjects were enrolled (52% males, mean age 51.5 years). TC and LDL-C were reduced of 38% and 52%, respectively during treatment, with LDL score reduced of 46.1%. In parallel, carotid stiffness changed from 8.8 (IQR: 7.0–10.4) m/sec to 6.6 (IQR: 5.4–7.5) m/sec, corresponding to a median change of 21.4% (p < 0.001), with a significant increase in carotid distensibility (from 12.1, IQR: 8.73–19.3 kPA−1 × 10−3 at T0 to 21.8, IQR: 16.6–31.8 kPA−1 × 10−3 at T12w) corresponding to a median change of 62.8% (p < 0.001). A multivariate analysis showed that changes in LDL score were independently associated with changes in carotid stiffness (β = 0.429, p = 0.041). Conclusion: Small dense LDL reduction, as assessed by LDL score, is associated with changes in carotid stiffness in patients with familial hypercholesterolemia treated with Evolocumab®.

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p &lt, 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6, flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.

Aim: The aim of this study was to test small dense LDL changes with Armolipid Plus treatment in patients with familial combined hyperlipidemia (FCHL). Methods: After 4 weeks, 30 patients with FCHL were included in an 8-week, randomized, double-blind study and were taking, in addition to the standard diet, either placebo or Armolipid Plus. Results: The placebo group showed no statistically significant differences in the studied parameters; instead, in the Armolipid Plus group, statistically significant reduction differences were detected in BMI (p = 0.010), LDL score (p = 0.035) and an increase in mean LDL particle diameter (p = 0.040). Conclusion: The combination of a standard diet with Armolipid Plus is able to reduce LDL score and increase LDL particle diameter in a group of FCHL after 8 weeks of treatment.

The authors aimed to analyze the relationship between subclinical renal damage, defined as the presence of microalbuminuria or an estimated glomerular filtration rate (eGFR) between 30mL/min/1.73m(2) and 60mL/min/1.73m(2) and short-term blood pressure (BP) variability, assessed as average real variability (ARV), weighted standard deviation (SD) of 24-hour BP, and SD of daytime and nighttime BP. A total of 328 hypertensive patients underwent 24-hour ambulatory BP monitoring, 24-hour albumin excretion rate determination, and eGFR calculation using the Chronic Kidney Disease Epidemiology Collaboration equation. ARV of 24-hour systolic BP (SBP) was significantly higher in patients with subclinical renal damage (P=.001). This association held (P=.04) after adjustment for potential confounders. In patients with microalbuminuria, ARV of 24-hour SBP, weighted SD of 24-hour SBP, and SD of daytime SBP were also independently and inversely related to eGFR. These results seem to suggest that in essential hypertension, short-term BP variability is independently associated with early renal abnormalities.

Plasma aldosterone concentrations (PACs) are often increased in the advanced stages of chronic kidney disease (CKD); however, PAC has not been fully investigated in early CKD. Moreover, little is known about the relationship between aldosteronemia and left ventricular (LV) mass in subjects with mild-to-moderate CKD. The study objectives were to analyze PAC, LV mass (LVM), LV geometry and their relationships, in a group of hypertensive patients with stage I-III CKD. One hundred ninety-five hypertensive patients with stage I-III CKD were enrolled and compared with a control group of 82 hypertensive patients without renal dysfunction. LVM was higher in subjects with CKD than in the control group and increased progressively with advancing stages of CKD (P=0.004). A similar trend was observed for PAC (P