Publications by authors named "Elena Tremoli"

327 Publications

Stereotactic radioablation for the treatment of ventricular tachycardia: preliminary data and insights from the STRA-MI-VT phase Ib/II study.

J Interv Card Electrophysiol 2021 Nov 5;62(2):427-439. Epub 2021 Oct 5.

Division of Radiotherapy, IEO European Institute of Oncology IRCCS, Milan, Italy.

Purpose: We present the preliminary results of the STRA-MI-VT Study (NCT04066517), a spontaneous, phase Ib/II study, designed to prospectively test the safety and efficacy of stereotactic body radiotherapy (SBRT) in patientswith advanced cardiac disease and intractable ventricular tachycardia (VT).

Methods: Cardiac computed tomography (CT) integrated by electroanatomical mapping was used for substrate identification and merged with dedicated CT scans for treatment plan preparation. A single 25-Gy radioablation dose was delivered by a LINAC-based volumetric modulated arc therapy technique in a non-invasive matter. The primary safety endpoint was treatment-related adverse effects during acute and long-term follow-up (FU), obtained by regular in-hospital controls and implantable cardioverter defibrillator (ICD) remote monitoring. The primary efficacy endpoint was the reduction at 3 and 6 months of VT episodes and ICD shocks.

Results: Seven out of eight patients (men; age, 70 ± 7 years; ejection fraction, 27 ± 11%; 3 ischemic, 4 non-ischemic cardiomyopathies) underwent SBRT. At a median 8-month FU, no treatment-related serious adverse event occurred. Three patients died from non-SBRT-related causes. Four patients completed the 6-month FU: the number of VT decreased from 29 ± 33 to 11 ± 9 (p = .05) and 2 ± 2 (p = .08), at 3 and 6 months, respectively; shocks decreased from 11 to 0 and 2, respectively. At 6 months, all patients. showed a significant reduction of VT episodes and no electrical storm recurrence, with the complete regression of iterative VTs in 2/2 patients.

Conclusion: The STRA-MI-VT Study suggests that SBRT can be considered an alternative option for the treatment of VT in patients with structural heart disease and highlights the need for further clinical investigation addressing safety and efficacy.
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http://dx.doi.org/10.1007/s10840-021-01060-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490832PMC
November 2021

Biological Characterization of Human Autologous Pericardium Treated with the Ozaki Procedure for Aortic Valve Reconstruction.

J Clin Med 2021 Aug 31;10(17). Epub 2021 Aug 31.

Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.

Background: The Ozaki procedure is an innovative surgical technique aiming at reconstructing aortic valves with human autologous pericardium. Even if this procedure is widely used, a comprehensive biological characterization of the glutaraldehyde (GA)-fixed pericardial tissue is still missing.

Methods: Morphological analysis was performed to assess the general organization of pericardium subjected to the Ozaki procedure (post-Ozaki) in comparison to native tissue (pre-Ozaki). The effect of GA treatment on cell viability and nuclear morphology was then investigated in whole biopsies and a cytotoxicity assay was executed to assess the biocompatibility of pericardium. Finally, human umbilical vein endothelial cells were seeded on post-Ozaki samples to evaluate the influence of GA in modulating the endothelialization ability in vitro and the production of pro-inflammatory mediators.

Results: The Ozaki procedure alters the arrangement of collagen and elastic fibers in the extracellular matrix and results in a significant reduction in cell viability compared to native tissue. GA treatment, however, is not cytotoxic to murine fibroblasts as compared to a commercially available bovine pericardium membrane. In addition, in in vitro experiments of endothelial cell adhesion, no difference in the inflammatory mediators with respect to the commercial patch was found.

Conclusions: The Ozaki procedure, despite alteration of ECM organization and cell devitalization, allows for the establishment of a noncytotoxic environment in which endothelial cell repopulation occurs.
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http://dx.doi.org/10.3390/jcm10173954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432048PMC
August 2021

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach.

Biomedicines 2021 Aug 23;9(8). Epub 2021 Aug 23.

Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", 80131 Napoli, Italy.

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, < 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 (-value = 0.041), indole (-value = 0.045), and indoleacrylic acid (-value= 0.045) concentrations. Conversely, significant decreases in choline (-value = 0.045) and phosphatidylcholine (-value < 0.01) together with a reduction in platelet activating factor (-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.
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http://dx.doi.org/10.3390/biomedicines9081073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391636PMC
August 2021

Alterations in platelets during SARS-CoV-2 infection.

Platelets 2021 Aug 13:1-9. Epub 2021 Aug 13.

Unit of Cell and Molecular Biology in Cardiovascular Diseases, Centro Cardiologico Monzino IRCCS, Milan, Italy.

Coronavirus disease 2019 (COVID-19) is a pandemic syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection induces a process of inflammation and thrombosis supported by an altered platelet activation state. This platelet activation is peculiar being characterized by the formation of platelet-leukocytes rather than platelet-platelet aggregates and by an increased procoagulant potential supported by elevated levels of TF positive platelets and microvesicles.Therapeutic strategies targeting, beyond systemic inflammation (i.e. with tocilizumab, an anti interleukin-6 receptor), this state of platelet activation might therefore be beneficial. Among the antithrombotic drugs proposed as candidates to treat patients with SARS-CoV-2 infection, antiplatelet drugs, such as aspirin are showing promising results.
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http://dx.doi.org/10.1080/09537104.2021.1962519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425443PMC
August 2021

Effects of Mediterranean Diet or Low-Fat Diet on Blood Fatty Acids in Patients with Coronary Heart Disease. A Randomized Intervention Study.

Nutrients 2021 Jul 13;13(7). Epub 2021 Jul 13.

Centro Cardiologico Monzino, IRCCS, Via Parea, 4, 20138 Milan, Italy.

The Mediterranean diet (MD) prevents cardiovascular disease by different putative mechanisms, including modifications in the blood fatty acid (FA) profile. Polytherapy for secondary cardiovascular prevention might mask the effect of MD on the FA profile. This study was aimed to assess whether MD, in comparison with a low-fat diet (LFD), favorably modifies the blood FA profile in patients with coronary heart disease (CHD) on polytherapy. One hundred and twenty patients with a recent history of coronary stenting, randomized to MD or to LFD, completed 3 months of this open-label dietary intervention study. Diet Mediterranean-ness was evaluated using the Mediterranean Diet Adherence Screener (MeDAS) score. Both diets significantly reduced saturated FA ( < 0.01). Putative favorable changes in total -3 FA ( = 0.03) and eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA; = 0.04) were significantly larger with MD than with LFD. At 3 months, in the whole cohort, the MeDAS score correlated inversely with palmitic acid (R = -0.21, = 0.02), and with palmitoleic acid (R = -0.32, = 0.007), and positively with total -3 FA (R = 0.19, = 0.03), EPA (R = 0.28, = 0.002), and EPA + DHA (R = 0.21, = 0.02). In CHD patients on polytherapy, both MD and LFD shift FA blood composition towards a healthier profile, with a more favorable effect of MD on omega-3 levels.
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http://dx.doi.org/10.3390/nu13072389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308706PMC
July 2021

Plasma Exosome Profile in ST-Elevation Myocardial Infarction Patients with and without Out-of-Hospital Cardiac Arrest.

Int J Mol Sci 2021 Jul 28;22(15). Epub 2021 Jul 28.

Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

The identification of new biomarkers allowing an early and more accurate characterization of patients with ST-segment elevation myocardial infarction (STEMI) is still needed, and exosomes represent an attractive diagnostic tool in this context. However, the characterization of their protein cargo in relation to cardiovascular clinical manifestation is still lacking. To this end, 35 STEMI patients (17 experiencing resuscitated out-of-hospital cardiac arrest (OHCA-STEMI) and 18 uncomplicated) and 32 patients with chronic coronary syndrome (CCS) were enrolled. Plasma exosomes were characterized by the nanoparticle tracking analysis and Western blotting. Exosomes from STEMI patients displayed a higher concentration and size and a greater expression of platelet (GPIIb) and vascular endothelial (VE-cadherin) markers, but a similar amount of cardiac troponin compared to CCS. In addition, a difference in exosome expression of acute-phase proteins (ceruloplasmin, transthyretin and fibronectin) between STEMI and CCS patients was found. GPIIb and brain-associated marker PLP1 accurately discriminated between OHCA and uncomplicated STEMI. In conclusion, the exosome profile of STEMI patients has peculiar features that differentiate it from that of CCS patients, reflecting the pathophysiological mechanisms involved in STEMI. Additionally, the exosome expression of brain- and platelet-specific markers might allow the identification of patients experiencing ischemic brain injury in STEMI.
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http://dx.doi.org/10.3390/ijms22158065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347807PMC
July 2021

Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis-The IMPROVE Study.

Biomedicines 2021 Jul 19;9(7). Epub 2021 Jul 19.

Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy.

(1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54-79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) ( = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) ( < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.
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http://dx.doi.org/10.3390/biomedicines9070841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301759PMC
July 2021

Psychological and work-related factors associated with emotional exhaustion among healthcare professionals during the COVID-19 outbreak in Italian hospitals.

Nurs Health Sci 2021 Sep 19;23(3):670-675. Epub 2021 Aug 19.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

The coronavirus disease 2019 (COVID-19) pandemic has induced considerable psychological distress in healthcare workers, increasing the risk of burnout. This research aimed to investigate sociodemographic, work-related, COVID-19-related, and psychological factors associated with emotional exhaustion (the core component of burnout) among healthcare professionals during the first wave of the COVID-19 pandemic in Italy. A cross-sectional study was conducted to assess risk (e.g. perceived risk and fear of contagion, stress) and protective factors (e.g. job satisfaction, resilience) for emotional exhaustion among 616 hospital staff. Women, nurses, shift workers, those with a permanent contract, and frontline workers reported significantly higher levels of emotional exhaustion compared to others. Significant risk factors predicting emotional exhaustion were prolonged use of personal protective equipment, increased work pressure, lack of support, and prolonged working hours; psychologically protective factors were resilience and job satisfaction, while perceived stress was found to be a significant psychological risk factor. Organizational interventions should focus on these factors to prevent the onset of burnout.
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http://dx.doi.org/10.1111/nhs.12871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447372PMC
September 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Association Between Uric Acid, Carotid Intima-Media Thickness, and Cardiovascular Events: Prospective Results From the IMPROVE Study.

J Am Heart Assoc 2021 06 17;10(11):e020419. Epub 2021 May 17.

Centro Cardiologico MonzinoIstituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Milan Italy.

Background The association between elevated serum uric acid (SUA), cardiovascular disease (CVD) risk, and carotid atherosclerosis has long been explored, and contrasting results have been reported. Therefore, the role of SUA as an independent risk factor for vascular events (VEs) and carotid atherosclerosis deserves further attention. We investigated the relationship between SUA, incident VEs, carotid intima-media thickness (cIMT), and cIMT progression in subjects at moderate-to-high CVD risk. Methods and Results In the IMPROVE (IMT-Progression as Predictors of VEs) study, 3686 participants (median age 64 years; 48% men) with ≥ 3 vascular risk factors, free from VEs at baseline, were grouped according to SUA quartiles (division points: 244-284-328 µmol/L in women, 295-336-385 µmol/L in men). Carotid-IMT and its 15-month progression, along with incident VEs, were recorded. A U-shaped association between SUA and VEs was observed in men, with 2.4-fold ( = 0.004) and 2.5-fold ( = 0.002) increased CVD risk in the first and fourth SUA quartiles as compared with the second. Adjusted hazard ratios (HRs) for cerebro-VEs in men were the highest (first and fourth quartile versus second: HR, 5.3, = 0.010 and HR, 4.4, = 0.023, respectively). SUA level was independently associated with cIMT progression in men (β = 0.068, = 0.014). No significant association between SUA levels, CVD end points, and cIMT progression were found in women. Conclusions Both low and high SUA levels are associated with an increased risk of VEs in men at moderate-to-high CVD risk but not in women. Only elevated SUA levels predict cIMT progression and at a lesser but not significant extent in women.
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http://dx.doi.org/10.1161/JAHA.120.020419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483552PMC
June 2021

Lipidomics analysis of monocytes from patients with acute myocardial infarction reveals lactosylceramide as a new player in monocyte migration.

FASEB J 2021 05;35(5):e21494

Centro Cardiologico Monzino I.R.C.C.S, Milan, Italy.

Monocyte recruitment after vascular injury and their migration through the vessel wall represent crucial events in the initiation, progression, and destabilization of atherosclerotic plaque. Circulating monocytes are exposed to stimuli that alter their physiological state, and among them, lipids play a key role. Several studies investigated the mechanisms by which lipids affect monocyte functions promoting coronary atherosclerotic plaque initiation, but information on the relationship between lipid composition and function of monocyte is scant. We aimed at studying the migration of circulating monocytes isolated from patients with acute myocardial infarction (AMI) at hospital presentation and investigating its correlation with cellular lipid profile. The migration of monocytes was tested using both fetal bovine serum (FBS) and autologous serum as chemoattractant stimuli. Monocyte lipid profile was evaluated through an untargeted lipidomics approach, using a liquid chromatography/time-of-flight mass spectrometry platform. We observed that AMI patients' monocytes showed a significant increase in FBS and autologous serum-mediated migration compared to controls. Moreover, a different monocyte lipidomic profile between the two study groups was detected. In particular, AMI patients' monocytes showed an altered composition in ceramides, with an increase in lactosylceramide and in phospholipids (ie, phosphatidylethanolamine and lisophosphatidylethanolamine). Of note, a positive correlation between lactosylceramide levels and monocyte migration was observed. Furthermore, the lactosylceramide synthase inhibition significantly reduced FBS-induced monocyte migration. Our results highlight the influence of lactosylceramide on the monocyte migration capacity, pointing out a new possible mechanism of lipids in the onset of atherothrombosis and, hence, in AMI.
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http://dx.doi.org/10.1096/fj.202001872RRRDOI Listing
May 2021

Intake of food rich in saturated fat in relation to subclinical atherosclerosis and potential modulating effects from single genetic variants.

Sci Rep 2021 04 12;11(1):7866. Epub 2021 Apr 12.

Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, Box 210, 17177, Stockholm, Sweden.

The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54-79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMT, C-IMT), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMT (OR:1.27;1.06-1.47), CC-IMT (OR:1.22;1.04-1.44) and ICA-IMT (OR:1.26;1.07-1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.
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http://dx.doi.org/10.1038/s41598-021-86324-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042105PMC
April 2021

Associations of Preoperative Self-rated Symptoms of Anxiety and Depression on Length of Hospital Stay and Long-term Quality of Life in Patients Undergoing Cardiac Surgery.

J Cardiovasc Nurs 2021 Mar 31. Epub 2021 Mar 31.

Alessandra Gorini, PhD Associate Professor in Psychology, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. Mattia Giuliani, PsyD Research Fellow in Psychology, Centro Cardiologico Monzino (IRCCS), Milan, Italy. Camilla L'Acqua, MD Centro Cardiologico Monzino (IRCCS), Milan, Italy. Simone Barbieri, MSC Research Fellow in Statistics, Centro Cardiologico Monzino (IRCCS), Milan, Italy. Erminio Sisillo, MD Centro Cardiologico Monzino (IRCCS), Milan, Italy. Fabrizio Veglia, PhD Head of the Biostatistics Unit, Centro Cardiologico Monzino (IRCCS), Milan, Italy. Elena Tremoli, PhD Full Professor in Pharmacology, Centro Cardiologico Monzino (IRCCS), Milan, Italy.

Background: Anxiety and depression are often associated with cardiovascular diseases. Nevertheless, few study authors have investigated psychological effects on immediate and long-term cardiac surgery-related outcomes, such as surgical complications, length of hospital stay (LOS), and long-term health-related quality of life (HRQoL).

Objectives: The aims of this study were to (a) investigate the role of preoperative symptoms of anxiety and depression in predicting LOS in a sample of surgical patients and (b) evaluate the impact of preoperative symptoms of anxiety and depression on the patients' HRQoL 3 months after surgery.

Methods: One hundred fifty-one patients waiting for surgery were included. To evaluate symptoms of anxiety and depression, the Hospital Anxiety and Depression Scale was used. Multiple regression analyses were conducted to evaluate the impact of both clinical and psychological factors on LOS, whereas quantile regression was performed to assess their effect on the patients' HRQoL 3 months after surgery.

Results: The multiple regression shows that EuroSCORE, length of endotracheal intubation, and anxiety symptoms predict LOS. The multiple quantile regression analyses also show that both symptoms of anxiety and depression predict a negative HRQoL up to 3 months after surgery.

Conclusion: Preoperative symptoms of anxiety predict the patients' LOS, and both symptoms of anxiety and depression predict a scarce HRQoL 3 months after cardiac surgery. These results suggest the need for implementing presurgical in-hospital screening procedures for both symptoms of anxiety and depression. Finally, focused psychological interventions should be implemented for reducing inpatients' hospital LOS and improving their future quality of life.
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http://dx.doi.org/10.1097/JCN.0000000000000792DOI Listing
March 2021

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

Biomedicines 2021 Mar 11;9(3). Epub 2021 Mar 11.

Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMT; cIMT of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMT) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMT and cIMT, but not with PF CC-IMT, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMT or cIMT were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMT and cIMT when the CETP concentration was below the median (HDL-C × CETP interaction, = 0.001 and = 0.003 for cIMT and cIMT, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMT. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMT. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMT. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.
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http://dx.doi.org/10.3390/biomedicines9030286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999018PMC
March 2021

Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients.

JACC Basic Transl Sci 2021 Mar 24;6(3):202-218. Epub 2021 Feb 24.

Centro Cardiologico Monzino IRCCS, Milan, Italy.

The authors hypothesized that the cytokine storm described in COVID-19 patients may lead to consistent cell-based tissue factor (TF)-mediated activation of coagulation, procoagulant microvesicles (MVs) release, and massive platelet activation. COVID-19 patients have higher levels of TF platelets, TF granulocytes, and TF MVs than healthy subjects and coronary artery disease patients. Plasma MV-associated thrombin generation is present in prophylactic anticoagulated patients. A sustained platelet activation in terms of P-selectin expression and platelet-leukocyte aggregate formation, and altered nitric oxide/prostacyclin synthesis are also observed. COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to that observed in vivo. This effect was blunted by pre-incubation with tocilizumab, aspirin, or a P2Y inhibitor.
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http://dx.doi.org/10.1016/j.jacbts.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904280PMC
March 2021

Letter by Brambilla et al Regarding Article, "Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia".

Arterioscler Thromb Vasc Biol 2021 03 24;41(3):e183-e184. Epub 2021 Feb 24.

Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., E.T., M.C.).

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http://dx.doi.org/10.1161/ATVBAHA.120.315867DOI Listing
March 2021

Long-term secondary cardiovascular prevention programme in patients subjected to coronary artery bypass surgery.

Eur J Prev Cardiol 2020 Nov 21. Epub 2020 Nov 21.

Centro Cardiologico Monzino, IRCCS, Via Carlo Parea, 4, 20138 Milan, Italy.

Aims: Patients with coronary heart disease (CHD) are at very high risk of recurrent events. A strategy to reduce excess risk might be to deliver structured secondary prevention programmes, but their efficacy has been mostly evaluated in the short term and in experimental settings. This is a retrospective case-control study aimed at assessing, in the real world, the efficacy of a secondary prevention programme in reducing long-term coronary event recurrences after coronary artery bypass surgery (CABG).

Methods And Results: Programme participants (henceforth 'cases') were men and women aged <75 years subjected to CABG between 2002 and 2014, living within 100 km of the hospital. Key programme actions included optimization of treatments according to the most updated European preventive guidelines, surveillance of therapy adherence, and customized lifestyle counselling. Controls were analogous patients not involved in the programme because living farther than 100 km away, matched 1:1 with cases for gender, age at CABG, and year of CABG. Both groups (n = 1248) underwent usual periodic cardiology follow-up at our centre. Data on symptomatic or silent CHD recurrences were obtained from the hospital electronic health records. Cox analysis (adjusted for baseline differences between groups) shows that programme participation was associated with a significantly lower incidence throughout 5 years post-CABG of symptomatic [hazard ratio (95% confidence interval): 0.59 (0.38-0.94)] and silent [0.53 (0.31-0.89)] coronary recurrences.

Conclusion: In a real-world setting, taking part in a structured longstanding secondary prevention programme, in addition to usual cardiology care, meaningfully lowers the risk of coronary recurrences.
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http://dx.doi.org/10.1093/eurjpc/zwaa060DOI Listing
November 2020

Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology.

Biomedicines 2021 Feb 8;9(2). Epub 2021 Feb 8.

Centro Cardiologico Monzino I.R.C.C.S., 20138 Milan, Italy.

Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process.
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http://dx.doi.org/10.3390/biomedicines9020168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915296PMC
February 2021

Red Blood Cell Morphodynamics: A New Potential Marker in High-Risk Patients.

Front Physiol 2020 13;11:603633. Epub 2021 Jan 13.

Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

In the last years, a substantial contribution of red blood cells (RBCs) in cardiovascular homeostasis has been evidenced, as these cells are able to regulate cardiovascular function by the export of adenosine triphosphate and nitric oxide as well as to maintain redox balance through a well-developed antioxidant system. Recently a link between high-risk plaque (HRP) features and myocardial ischemia, in the absence of severe lumen stenosis, has been evidenced. Nonobstructive coronary artery disease (nonob CAD) has been associated in fact with a greater 1-year risk of myocardial infarction and all-cause mortality compared with no apparent CAD. This new evidence increases interest in searching new triggers to identify these high-risk patients, in the absence/or on top of traditional hazard markers. In this study, we investigated the existence of any association between RBC morphodynamics and HRP features in individuals with different grades of coronary stenosis detected by coronary computed tomography angiography (CCTA). Ninety-one consecutive individuals who underwent CCTA [33 no CAD; 26 nonobstructive (nonob), and 32 obstructive (ob) CAD] were enrolled. RBC morphodynamic features, i.e., RBC aggregability and deformability, were analyzed by means of Laser Assisted Optical Rotation Cell Analyzer (LoRRca MaxSis). The putative global RBC morphodynamic (RMD) score and the related risk chart, associating the extent of HRP (e.g., the non-calcified plaque volume) with both the RMD score and the max % stenosis were computed. In nonob CAD group only positive correlations between RBC rigidity, osmotic fragility or aggregability and HRP features (plaque necrotic core, fibro-fatty and fibro-fatty plus necrotic core plaque volumes) were highlighted. Interestingly, in this patient cohort three of these RBC morphodynamic features result to be independent predictors of the presence of non-calcified plaque volume in this patients group. The risk chart created shows that only in nonob CAD plaque vulnerability increases according to the score quartile. Findings of this work, by evidencing the association between erythrocyte morphodynamic characteristics assessed by LoRRca and plaque instability in a high-risk cohort of nonob CAD, suggest the use of these blood cell features in the identification of high-risk patients, in the absence of severe coronary stenosis.
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http://dx.doi.org/10.3389/fphys.2020.603633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838560PMC
January 2021

Persistent long-term platelet activation and endothelial perturbation in women with Takotsubo syndrome.

Biomed Pharmacother 2021 Apr 12;136:111259. Epub 2021 Jan 12.

Centro Cardiologico Monzino I.R.C.C.S., Milan, Italy.

Background: Takotsubo (TTS) syndrome is an acute cardiac condition characterized by transient and reversible left ventricle dysfunction that mainly affects postmenopausal women. Catecholamine burst is the most accredited mechanism underpinning TTS onset and leading to endothelial dysfunction and platelet activation. Even if the use of low dose acetylsalycilic acid (ASA) in this clinical setting is based on both clinical presentation and unfavorable long-term prognosis, its efficacy has been recently challenged.

Aim: This study was designed to assess endothelial function, residual thromboxane formation and platelet aggregation in TTS women on low-dose ASA treatment at long-term follow-up.

Methods: Twenty-eight females with previously diagnosis of TTS syndrome were enrolled. Data were compared to those obtained from 23 coronary artery disease (CAD) women with a history of acute myocardial infarction, and 26 control subjects with no TTS or clinically evident CAD. Psychological and clinical profile were assessed in all study groups at the enrollment. Main metabolites involved in L-arginine/nitric oxide pathway, urinary prostacyclin, serum and urine thromboxane metabolites were measured by LCMS/MS methods. Thrombomodulin levels were quantified using an ELISA kit, and platelet aggregation, carried out on platelet rich-plasma, was induced by ADP or by epinephrine (EPI), norepinephrine (NORE) and TRAP-6, alone or in association with ADP and evaluated by Born's method.

Results: In TTS women an endothelial derangement, characterized by reduced citrulline production and increased thrombomodulin concentration, with no perturbation in prostacyclin levels, was evidenced. In addition, despite ASA treatment, TTS displayed a higher residual thromboxane formation, in parallel with an enhanced platelet response to compared to CAD.

Conclusions: Our study highlighted the presence of endothelial perturbation in TTS patients even at long-term from the index event. The residual thromboxane production and platelet aggregation still leave open the question about the use of low dose ASA in this clinical setting.
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http://dx.doi.org/10.1016/j.biopha.2021.111259DOI Listing
April 2021

The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals.

Sci Rep 2021 01 12;11(1):632. Epub 2021 Jan 12.

Institute of Health and Wellbeing, University of Glasgow, Room 111, Public Health, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK.

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.
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http://dx.doi.org/10.1038/s41598-020-79964-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804422PMC
January 2021

Mental health and risk perception among Italian healthcare workers during the second month of the Covid-19 pandemic.

Arch Psychiatr Nurs 2020 12 21;34(6):537-544. Epub 2020 Oct 21.

Psychology Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy.

A multicentre cross-sectional study was conducted to assess perceived risk and fear of contagion, as well as mental health outcomes among 650 Italian healthcare workers during the COVID-19 outbreak. A relevant proportion of the sample reported symptoms of anxiety, depression, and distress. Female sex, nursing profession, fear of being infected, as well as the time of exposure to the COVID-19 spread and the fact of directly attending infected patients were the main risk factors for developing mental health disturbances. Tailored interventions need to be implemented to reduce psychological burden in healthcare workers, with a particular attention to nurses.
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http://dx.doi.org/10.1016/j.apnu.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577253PMC
December 2020

Endothelial function improvement in patients with familial hypercholesterolemia receiving PCSK-9 inhibitors on top of maximally tolerated lipid lowering therapy.

Thromb Res 2020 10 31;194:229-236. Epub 2020 Jul 31.

Department of Translational Medical Sciences, Federico II University, Naples, Italy. Electronic address:

Background: Treatment with protein convertase subtilisin kexin type 9 inhibitors (PCSK-9i) reduced cholesterol levels and cardiovascular events in patients with hypercholesterolemia. We assessed changes in lipid profile, oxidation markers and endothelial function in patients with familial hypercholesterolemia (FH) after a 12-week treatment with a PCSK-9i.

Methods: Patients with FH starting a treatment with PCSK-9i were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), small dense LDL (assessed by LDL score), 11-dehydro-thromboxane (11-TXB2), 8-isoprostaglandin-2alpha (8-iso-PGF2α), flow-mediated dilation (FMD) and reactive hyperaemia index (RHI) were evaluated before starting PCSK-9i treatment and after a 12-week treatment.

Results: Twenty-five subjects were enrolled (52% males, mean age 51.5 years). At the 12-week assessment, we observed a 38% median reduction in TC, 52% in LDL-C, 7% in Lp(a) and 46% in LDL score. In parallel, 11-TXB2 and 8-iso-PGF2α showed a reduction of 18% and 17%, respectively. FMD changed from 4.78% ± 2.27 at baseline to 10.6% ± 5.89 at 12 weeks (p < 0.001), with RHI changing from 2.37 ± 1.23 to 3.76 ± 1.36 (p < 0.001). A multivariate analysis showed that, after adjusting for potential confounders, change in LDL score was an independent predictor of changes in FMD (β = -0.846, p = 0.015) and in 8-iso-PGF2α (β = 0.778, p = 0.012).

Conclusions: Small dense LDL reduction (assessed by LDL score) is related to changes in oxidation markers and endothelial function in patients with FH treated with PCSK-9i.
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http://dx.doi.org/10.1016/j.thromres.2020.07.049DOI Listing
October 2020

Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study.

Genes (Basel) 2020 10 22;11(11). Epub 2020 Oct 22.

Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study ( = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels ( < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMT and c-IMT ( = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.
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http://dx.doi.org/10.3390/genes11111243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690395PMC
October 2020

Human monocyte-derived macrophages: Pathogenetic role in plaque rupture associated to systemic inflammation.

Int J Cardiol 2021 02 6;325:1-8. Epub 2020 Oct 6.

Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Gemelli I.R.C.C.S., Roma, Italy; Università Cattolica del Sacro Cuore, Roma, Italy.

Background: Macrophages play a key role in coronary plaque destabilization. In-vitro human monocyte-derived macrophages (MDMs) are used to study macrophages infiltrating tissue. Optical coherence tomography (OCT) provides an in-vivo insight of the coronary arteries. We compared the MDMs morpho-phenotype and culprit plaque features at OCT in acute coronary syndrome (ACS) patients according to the underlying plaque pathobiology.

Methods: Sixty-six patients undergoing coronary angiography and pre-angioplasty OCT of the culprit vessel were allocated to three groups according to mechanism of ACS at OCT and C-reactive protein levels (cut-off: 2 mg/Ll): 1) plaque rupture with systemic inflammation; 2) plaque rupture without systemic inflammation, 3) plaque with intact fibrous cap. A blood sample was collected to obtain MDMs, categorized as having "round" or "spindle" morphology.

Results: Thirty-two patients (48.5%) were assigned to Group 1, 10 (15.2%) to Group 2 and 24 (36.4%) to Group 3. The "round" MDMs were significantly more frequent in Group 1 (39.25 ± 4.98%) than in Group 2 (23.89 ± 3.10%) and Group 3 (23.02 ± 7.89%), p = 0.008. MDMs in Group 1 as compared to Groups 2 and 3 showed lower efferocytosis (8.74 ± 1.38 vs 9.74 ± 2.15 vs 11.41 ± 2.41; p = 0.012), higher tissue factor levels (369.84 ± 101.13 vs 301.89 ± 59.78 vs 231.74 ± 111.47; p = 0.001) and higher heme oxygenase-1 expression (678.78 ± 145.43 vs 419.12 ± 74.44 vs 409.78 ± 64.33; p = 0.008).

Conclusions: MDMs of ACS patients show morpho-phenotypic heterogeneity with prevalence of pro-thrombotic and pro-oxidative properties in case of plaque rupture and systemic inflammation. Such MDMs subpopulation may take part to the cellular pathways leading to fibrous cap rupture with the subsequent thrombus formation.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.071DOI Listing
February 2021

Examination of the best cut-off points of PHQ-2 and GAD-2 for detecting depression and anxiety in Italian cardiovascular inpatients.

Psychol Health 2021 09 7;36(9):1088-1101. Epub 2020 Oct 7.

Centro Cardiologico Monzino, IRCCS, Milan, Italy.

Objective: Despite the frequent association between anxiety, depression and cardiovascular diseases (CVD), cardiovascular inpatients are not usually screened for these psychopathological conditions. To fill this gap, especially in hospital environments, there is the need of brief screening instruments that provide reliable information in a very short time. According to this need, the aim of this study was to examine the best cut-off points of two brief and easy-to-use questionnaires in a sample of Italian cardiovascular inpatients: the 2-item Patient Health Questionnaire (PHQ-2) and the 2-item Generalized Anxiety Disorder (GAD-2).

Design: 3500 cardiovascular inpatients were recruited and completed both the 9-item Patient Health Questionnaire (PHQ-9) and the 7-item Generalized Anxiety Disorder (GAD-7). PHQ-2 and GAD-2 were then obtained extracting the first two item from PHQ-9 and GAD-7.

Main Outcome Measures: The PHQ-2 and GAD-2 psychometric properties were calculated comparing them with PHQ-9 and GAD-7, respectively.

Results: The PHQ-2 threshold of ≥ 2 and the GAD-2 threshold of ≥ 3 are the best solutions in balancing between sensitivity and specificity, also providing acceptable rates of false positives and false negatives.

Conclusions: the PHQ-2 and GAD-2 Italian versions showed good diagnostic features for measuring depression and anxiety in CVD patients.
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http://dx.doi.org/10.1080/08870446.2020.1830093DOI Listing
September 2021

Relationship between Influenza Vaccination Coverage Rate and COVID-19 Outbreak: An Italian Ecological Study.

Vaccines (Basel) 2020 Sep 16;8(3). Epub 2020 Sep 16.

Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy.

The lack of specific vaccines or drugs against coronavirus disease 2019 (COVID-19) warrants studies focusing on alternative clinical approaches to reduce the spread of this pandemic disease. In this study, we investigated whether anti-influenza vaccination plays a role in minimizing the diffusion of COVID-19 in the Italian population aged 65 and over. Four COVID-19 outcomes were used: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence, hospitalizations for COVID-19 symptoms, admissions to intensive care units for reasons related to SARS-CoV-2, and deaths attributable to COVID-19. At univariate analyses, the influenza vaccination coverage rates correlated negatively with all COVID-19 outcomes (Beta ranging from -134 to -0.61; all < 0.01). At multivariable analyses, influenza vaccination coverage rates correlated independently with SARS-CoV-2 seroprevalence (Beta (95% C.I.): -130 (-198, -62); = 0.001), hospitalizations for COVID-19 symptoms (Beta (95% C.I.): -4.16 (-6.27, -2.05); = 0.001), admission to intensive care units for reasons related to SARS-CoV-2 (Beta (95% C.I.): -0.58 (-1.05, -0.12); = 0.017), and number of deaths attributable to COVID-19 (Beta (95% C.I.): -3.29 (-5.66, -0.93); = 0.010). The R observed in the unadjusted analysis increased from 82% to 159% for all the considered outcomes after multivariable analyses. In the Italian population, the coverage rate of the influenza vaccination in people aged 65 and over is associated with a reduced spread and a less severe clinical expression of COVID-19. This finding warrants ad hoc studies to investigate the role of influenza vaccination in preventing the spread of COVID-19.
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http://dx.doi.org/10.3390/vaccines8030535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563271PMC
September 2020

Plasma phospholipid dysregulation in patients with cystathionine-β synthase deficiency.

Nutr Metab Cardiovasc Dis 2020 11 23;30(12):2286-2295. Epub 2020 Jul 23.

Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", 80131 Napoli, Italy.

Background & Aims: Patients with cystathionine β-synthase deficiency (CBSD) exhibit high circulating levels of homocysteine and enhanced lipid peroxidation. We have characterized the plasma lipidome in CBSD patients and related lipid abnormalities with reactions underlying enhanced homocysteine levels.

Methods And Results: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, plasma lipids were determined with an untargeted lipidomics approach in 11 CBSD patients and 11 matched healthy subjects (CTRL). Compared to CTRL, CBSD patients had a higher medium and long-chain polyunsaturated fatty acids (PUFA) content in phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (LPE) species (p < 0.02), and depletion of phosphatidylcholine (PC; p = 0.02) and of lysophosphatidylcholine (LPC; p = 0.003) species containing docosahexaenoic acid (DHA), suggesting impaired phosphatidylethanolamine-N-methyltransferase (PEMT) activity. PEMT converts PE into PC using methyl group by S-adenosylmethionine (SAM) thus converted in S-adenosylhomocysteine (SAH). Whole blood SAM and SAH concentrations by liquid chromatography tandem mass spectrometry were 1.4-fold (p = 0.015) and 5.3-fold (p = 0.003) higher in CBSD patients than in CTRL. A positive correlation between SAM/SAH and PC/PE ratios (r = 0.520; p = 0.019) was found.

Conclusions: A novel biochemical abnormality in CBSD patients consisting in depletion of PC and LPC species containing DHA and accumulation of PUFA in PE and LPE species is revealed by this lipidomic approach. Changes in plasma SAM and SAH concentrations are associated with such phospholipid dysregulation. Given the key role of DHA in thrombosis prevention, depletion of PC species containing DHA in CBSD patients provides a new direction to understand the poor cardiovascular outcome of patients with homocystinuria.
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http://dx.doi.org/10.1016/j.numecd.2020.07.019DOI Listing
November 2020
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