Evidence of subclinical atherosclerosis in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES: Patients affected by eosinophilic granulomatosis with polyangiitis (EGPA) display an increased risk of atherothrombotic events compared with the general population. An increased frequency of subclinical markers of atherosclerosis has been observed in other ANCA-associated vasculitis, but no specific study focused on EGPA. We therefore evaluated subclinical atherosclerosis in EGPA patients and in a control population. METHODS: Forty EGPA patients and 80 controls matched by age, sex and traditional cardiovascular risk factors underwent sonographic assessment of common carotid artery (CCA) intima-media thickness (IMT). The presence of plaques of the CCA was also investigated. The correlation between CCA-IMT and clinical and laboratory features was also assessed. RESULTS: Median CCA-IMT was significantly higher in EGPA patients compared with controls (P = 0.002). Also, the proportion of subjects with increased CCA-IMT and with presence of plaques was significantly higher among EGPA patients (P < 0.001 for both). Moreover, within the EGPA cohort, CCA-IMT tended to increase with disease duration (P = 0.034) and corticosteroid cumulative dose (P = 0.004). No significant associations were found between CCA-IMT, ANCA status, other clinical features and therapeutic regimens. Notably, the prevalence of traditional cardiovascular risk factors was comparable in patients with vs without an increased CCA-IMT. CONCLUSION: Ultrasound markers of subclinical atherosclerosis are increased in EGPA patients as compared with controls, independently of traditional cardiovascular risk factors.

Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials.

BACKGROUND: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. METHODS: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. RESULTS: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I2  = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I2  = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I2  = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I2  = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I2  = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I2  = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I2  = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions. CONCLUSIONS: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study.

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 homozygous (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.

Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies.

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.

Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.

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.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

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 < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies.

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.

Association of systemic lupus erythematosus with peripheral arterial disease: a meta-analysis of literature studies.

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 <0.001). In addition, five studies reporting on ankle-brachial index showed significantly lower values in 280 SLE patients as compared with 201 controls (mean difference: -0.018; 95% CI: -0.034, -0.001; P =0.033). Meta-regression models showed that age, hypertension and diabetes were inversely associated with the difference in the prevalence of PAD between SLE patients and non-SLE controls, whereas no effect for all the other clinical and demographic variables on the evaluated outcome was found. 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.

Changes in carotid stiffness in patients with familial hypercholesterolemia treated with Evolocumab®: A prospective cohort study.

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 (ß = 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®.

Efficacy and safety of direct oral anticoagulants in splanchnic vein thrombosis: a pooled analysis of literature studies.

BACKGROUND: Limited evidence is available on management of splanchnic vein thrombosis (SVT). OBJECTIVES: This study aimed to evaluate safety and efficacy of direct oral anticoagulants (DOACs) for SVT treatment. METHODS: Studies were systematically searched in the PubMed, Web of Science, and Scopus databases according to PRISMA guidelines. We assessed any recanalization, full recanalization, recurrence, mortality, and major bleeding as outcomes of interest. Results were reported as weighted mean prevalence (WMP) with 95% CI. Subgroup analyses and meta-regressions have been performed to address heterogeneity and adjust for potential confounders. RESULTS: We included a total of 16 studies (17 datasets) on 648 patients with SVT treated with DOACs. We found any recanalization in 60.3% (95% CI: 41.8%-76.3%; I2 = 84.9%; P < .001) and full recanalization in 51.7% (95% CI: 36.0%-67.0%; I2 = 87.4%; P < .001). Recurrent venous thromboembolism occurred in 2.8% (95% CI: 1.4%-5.9%; I2 = 0%; P = .787) and death in 3.4% (95% CI: 1.6%-7.3%; I2 = 13.2%; P = .318) of patients. Major bleeding was reported by 5.8% (95% CI: 3.7%-8.9%; I2 = 29.2%; P = .125) of patients. Results were consistent when separately analyzing prospective studies, retrospective studies, studies on cirrhotic patients, and studies enrolling patients with portal vein thrombosis. Meta-regression analyses showed that an increasing age and cancer impacted the rate of recanalization. Cirrhosis was associated with a higher rate of major bleeding and mortality. CONCLUSION: The results of the present study, mostly based on observational studies, suggest good safety and efficacy profiles of DOACs in patients with SVT. Randomized studies are needed to corroborate our findings.

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized. METHODS: In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V-/USV-) were considered (n = 162). RESULTS: Higher values of both scores were observed in V+ than in V-. Considering a cut-off leading to 80% of V-/USV- as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ (p = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162-240; p = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children. CONCLUSIONS: The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants.

Post-Bariatric Hypoglycemia Is Associated with Endothelial Dysfunction and Increased Oxidative Stress.

Post-bariatric hypoglycemia (PBH) is a potentially serious complication that may occur after bariatric surgery. Recurrent hypoglycemia may exert detrimental effects on vascular function. The aim of the present study was to evaluate endothelial function and oxygen reactive compounds in patients who experience PBH compared with controls. We performed a cross-sectional study on subjects with PBH (HYPO) and those without (NO-HYPO), detected by seven-day continuous glucose monitoring (CGM) performed at least twelve months after bariatric surgery. We enrolled 28 post-bariatric subjects (17.9% males, mean age 40.6 ± 10.7 years), with 18 in the HYPO group and 10 in the NO-HYPO group. In the two groups, we measured brachial artery flow-mediated dilation (FMD), oxidized low-density lipoproteins (oxLDL) and reactive oxygen metabolites (D-ROMs). The HYPO group had significantly lower FMD values than the NO-HYPO group (3.8% ± 3.0 vs. 10.5% ± 2.0, p < 0.001). A significant correlation was found between FMD and the time spent in hypoglycemia (rho = −0.648, p < 0.001), the number of hypoglycemic events (rho = −0.664, p < 0.001) and the mean glucose nadir (rho = 0.532, p = 0.004). The HYPO group showed significantly higher levels of D-ROMs (416.2 ± 88.7 UCARR vs. 305.5 ± 56.3 UCARR, p < 0.001) and oxLDLs (770.5 ± 49.7 µEq/L vs. 725.1 ± 51.6 µEq/L, p = 0.035) compared to the NO-HYPO group. In the multiple linear regression analysis, hypoglycemia independently predicted FMD values (ß = −0.781, p < 0.001), D-ROMs (ß = 0.548, p = 0.023) and oxLDL levels (ß = 0.409, p = 0.031). PBH is associated with impaired endothelial function accompanied by increased oxidative stress.

Association of apolipoprotein levels with peripheral arterial disease: a meta-analysis of literature studies.

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 < 0.001) and an inverse association with the difference of apoA-I (z-value: -2.43, P = 0.015) between PAD subjects and non-PAD controls. An increasing BMI was associated with an increasing difference in apoA-I values between PAD subjects and non-PAD controls (z-value: 1.98, P = 0.047). 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.

Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

Cardiovascular disease and antiphospholipid syndrome: how to predict and how to treat?

Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by a hypercoagulable state secondary to the presence of antiphospholipid antibodies and associated with vascular thromboses and / or pregnancy complications. Although venous thrombosis represents approximately 60% of thrombotic manifestations, also cardiovascular events can occur in patients with APS, including coronary and / or noncoronary complications. Moreover, several studies consistently showed a more significant atherosclerosis in patients with APS than controls. Thus, a stratification of thrombotic and cardiovascular risk according to clinical and immunologic features is mandatory in order to prevent APS-related vascular events. The most appropriate antithrombotic treatment of patients with arterial APS still represents an open issue, mainly in primary prevention settings. After a thrombotic event, in the absence of an adequate antithrombotic treatment, a 50% recurrence rate is reported in APS patients over a 5-year follow-up. Vitamin K antagonists still remain the mainstay treatment to prevent a recurrent event in patients with APS. The use of non­vitamin K oral anticoagulants in those with APS is still controversial, and identification of patients who could benefit from this therapy is still an open issue. Low-dose aspirin should be considered in arterial APS in addition to vitamin K antagonists in a high-risk subset, or alone for primary prophylaxis in high-risk antiphospholipid antibodies carriers. Furthermore, statins and immunomodulation therapies have an emerging role in the treatment of APS. Overall, ad hoc designed high-quality studies are needed to definitely determine optimal therapeutic strategies for arterial APS.

An Untargeted Lipidomic Analysis Reveals Depletion of Several Phospholipid Classes in Patients with Familial Hypercholesterolemia on Treatment with Evolocumab.

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.

Diagnostic accuracy of D-Dimer testing for recurrent venous thromboembolism: A systematic review with meta-analysis.: VTE recurrence and D-dimer.

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<0.001), with an attributable risk of 54.0%. sROC curve of the association between positive D-Dimer and recurrence showed a diagnostic AUC of 63.8 (95%CI: 60.3-67.4), with a pooled sensitivity of 54.3% (95%CI: 51.3%-57.3%), specificity of 64.2% (95%CI: 63.2-65.1), PLR of 1.53 (95%CI: 1.37-1.72), and NLR of 0.71 (95%CI: 0.60-0.84). Subgroup and meta-regression analyses suggested that a positive D-Dimer may have a higher discriminatory ability for patients with provoked events, confirmed by better pooled diagnostic indexes for recurrence and a diagnostic AUC of 70.6 (95%CI: 63.8-77.4). Regression models showed that the rate of OAT resumption after the evidence of D-Dimer positivity was inversely associated with VTE recurrence (Z-score: -3.91, P<0.001). CONCLUSIONS: D-Dimer positivity after OAT may identify VTE patients at higher risk of recurrence, with a better diagnostic accuracy for provoked events.

Risk Assessment and Antithrombotic Strategies in Antiphospholipid Antibody Carriers.

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-ß2-glycoprotein I antibodies (anti-ß2GPI). 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.