Publications by authors named "Betti Giusti"

136 Publications

Effects of vegetarian versus Mediterranean diet on kidney function: Findings from the CARDIVEG study.

Eur J Clin Invest 2021 May 6:e13576. Epub 2021 May 6.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Background: The aim of the present study was to assess the effects of a lacto-ovo-vegetarian diet (VD), compared to a Mediterranean diet (MD), on kidney function in a group of subjects with medium-to-low cardiovascular risk profile.

Methods: We analysed 107 subjects (82 women, 25 men; median age 52) who followed a VD (n = 54) and a MD (n = 53) for 3 months in the CARDIVEG study, a randomized, open, crossover trial that compared the effects of these 2 diets on cardiovascular disease risk.

Results: The effect of the two diets on kidney function markers was evaluated by conducting a general linear model for repeated measurements adjusted for possible confounding factors such as age, sex, physical activity, alcohol, smoking, hypertension, LDL cholesterol, glucose and body weight change. A significant reduction in creatinine (-5.3%; P < .001), urea nitrogen levels (-9%; P = .001), blood urea nitrogen (BUN) (-8.7%; P = .001) and BUN/creatinine ratio (-5.8%; P < .001), and an increase in estimated glomerular filtration rate (eGFR) (+3.5%; P = .001) was observed during the VD period. On the contrary, no significant changes were noted in the MD group. Variations obtained in the two dietary interventions were significantly different (P < .0001) for creatinine levels, BUN/creatinine and eGFR, for which opposite trends were observed in the VD and MD groups.

Conclusions: In a selected group of subjects with medium-to-low cardiovascular risk profile, a 3 month VD period determined significant improvements in kidney function markers. Further trials are needed to confirm these results.
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http://dx.doi.org/10.1111/eci.13576DOI Listing
May 2021

Two-Dimensional Aortic Size Normalcy: A Novelty Detection Approach.

Diagnostics (Basel) 2021 Feb 2;11(2). Epub 2021 Feb 2.

Cardiology Service, CMSR Veneto Medica, 36077 Altavilla Vicentina, Italy.

To develop a tool for assessing normalcy of the thoracic aorta (TA) by echocardiography, based on either a linear regression model (Z-score), or a machine learning technique, namely one-class support vector machine (OC-SVM) (Q-score). TA diameters were measured in 1112 prospectively enrolled healthy subjects, aging 5 to 89 years. Considering sex, age and body surface area we developed two calculators based on the traditional Z-score and the novel Q-score. The calculators were compared in 198 adults with TA > 40 mm, and in 466 patients affected by either Marfan syndrome or bicuspid aortic valve (BAV). Q-score attained a better Area Under the Curve (0.989; 95% CI 0.984-0.993, sensitivity = 97.5%, specificity = 95.4%) than Z-score (0.955; 95% CI 0.942-0.967, sensitivity = 81.3%, specificity = 93.3%; < 0.0001) in patients with TA > 40 mm. The prevalence of TA dilatation in Marfan and BAV patients was higher as Z-score > 2 than as Q-score < 4% (73.4% vs. 50.09%, < 0.00001). Q-score is a novel tool for assessing TA normalcy based on a model requiring less assumptions about the distribution of the relevant variables. Notably, diameters do not need to depend linearly on anthropometric measurements. Additionally, Q-score can capture the joint distribution of these variables with all four diameters simultaneously, thus accounting for the overall aortic shape. This approach results in a lower rate of predicted TA abnormalcy in patients at risk of TA aneurysm. Further prognostic studies will be necessary for assessing the relative effectiveness of Q-score versus Z-score.
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http://dx.doi.org/10.3390/diagnostics11020220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912952PMC
February 2021

Heparin induced thrombocytopenia: position paper from the Italian Society on Thrombosis and Haemostasis (SISET).

Blood Transfus 2021 Jan 28;19(1):14-23. Epub 2020 Dec 28.

IRCCS "Ca' Granda Maggiore" Hospital Foundation, "Angelo Bianchi Bonomi" Haemophilia and Thrombosis Center and "Fondazione Luigi Villa", Milan, Italy.

Heparin induced thrombocytopenia (HIT) is a rare immune mediated adverse drug reaction occurring after exposure to heparin. It is a serious and potentially fatal condition, which may be associated with the development of arterial or venous thrombotic events. Although known for many years, HIT is still often misdiagnosed. Pre- test clinical probability, screening for anti-PF4/heparin antibodies and documentation of their platelet activating capacity are the cornerstones of diagnosis. However, both clinical algorithms and test modalities have limited predictive values and limited diffusion so that the diagnosis and management is challenging in the clinical practice. For this reason, there is an unmet need for novel rational non-anticoagulant therapies based on the pathogenesis of HIT.The present paper reports the position of the Italian Society on Haemostasis and Thrombosis (SISET) in order to increase awareness of HIT among clinicians and other health care professionals and to provide information on the most appropriate management.
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http://dx.doi.org/10.2450/2020.0248-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850929PMC
January 2021

Sanger Validation of High-Throughput Sequencing in Genetic Diagnosis: Still the Best Practice?

Front Genet 2020 2;11:592588. Epub 2020 Dec 2.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Next-generation sequencing (NGS)'s crucial role in supporting genetic diagnosis and personalized medicine leads to the definition of Guidelines for Diagnostic NGS by the European Society of Human Genetics. Factors of different nature producing false-positive/negative NGS data together with the paucity of internationally accepted guidelines providing specified NGS quality metrics to be followed for diagnostics purpose made the Sanger validation of NGS variants still mandatory. We reported the analysis of three cases of discrepancy between NGS and Sanger sequencing in a cohort of 218 patients. NGS was performed by Illumina MiSeq and Haloplex/SureSelect protocols targeting 97 or 57 or 10 gene panels usually applied for diagnostics. Variants called following guidelines suggested by the Broad Institute and identified according to MAF <0.01 and allele balance >0.2 were Sanger validated. Three out of 945 validated variants showed a discrepancy between NGS and Sanger. In all three cases, a deep evaluation of the discrepant gene variant results and methodological approach allowed to confirm the NGS datum. Allelic dropout (ADO) occurrence during polymerase chain or sequencing reaction was observed, mainly related to incorrect variant zygosity. Our study extends literature data in which almost 100% "high quality" NGS variants are confirmed by Sanger; moreover, it demonstrates that in case of discrepancy between a high-quality NGS variant and Sanger validation, NGS call should not be assumed to represent the source of the error. Actually, difficulties (i.e., ADO, unpredictable presence of private variants on primer-binding regions) of the so-called gold standard direct sequencing should be considered especially in light of the constantly implemented and accurate high-throughput technologies. Our data along with literature raise a discussion on the opportunity to establish a standardized quality threshold by International Guidelines for clinical NGS in order to limit Sanger confirmation to borderline conditions of variant quality parameters and verification of correct gene variant call/patient coupling on a different blood sample aliquot.
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http://dx.doi.org/10.3389/fgene.2020.592588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738558PMC
December 2020

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Hum Genet 2021 Apr 18;140(4):625-647. Epub 2020 Dec 18.

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.
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http://dx.doi.org/10.1007/s00439-020-02231-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981314PMC
April 2021

Association Between Motor and Cognitive Performances in Elderly With Atrial Fibrillation: Strat-AF Study.

Front Neurol 2020 13;11:571978. Epub 2020 Nov 13.

IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Growing evidence suggests a close relationship between motor and cognitive abilities, but possible common underlying mechanisms are not well-established. Atrial fibrillation (AF) is associated with reduced physical performance and increased risk of cognitive decline. The study aimed to assess in a cohort of elderly AF patients: (1) the association between motor and cognitive performances, and (2) the influence and potential mediating role of cerebral lesions burden. Strat-AF is a prospective, observational study investigating biological markers for cerebral bleeding risk stratification in AF patients on oral anticoagulants. Baseline cross-sectional data are presented here. Thrombosis outpatient clinic (Careggi University Hospital). One-hundred and seventy patients (mean age 77.7 ± 6.8; females 35%). Baseline protocol included: neuropsychological battery, motor assessment [Short Physical Performance Battery (SPPB), and walking speed], and brain magnetic resonance imaging (MRI) used for the visual assessment of white matter hyperintensities, lacunar and non-lacunar infarcts, cerebral microbleeds, and global cortical and medial temporal atrophies. Mean Montreal Cognitive Assessment (MoCA) total score was 21.9 ± 3.9, SPPB total score 9.5 ± 2.2, and walking speed 0.9 ± 0.2. In univariate analyses, both SPPB and walking speed were significantly associated with MoCA ( = 0.359, = 0.372, respectively), visual search ( = 0.361, = 0.322), Stroop ( = -0.272, = -0.263), short story ( = 0.263, = 0.310), and semantic fluency ( = 0.311, = 0.360). In multivariate models adjusted for demographics, heart failure, physical activity, and either stroke history (Model 1) or neuroimaging markers (Model 2), both SPPB and walking speed were confirmed significantly associated with MoCA (Model 1: β = 0.256, β = 0.236; Model 2: β = 0.276, β = 0.272, respectively), visual search (Model 1: β = 0.350, β = 0.313; Model 2: β = 0.344, β = 0.307), semantic fluency (Model 1: β = 0.223, β = 0.261), and short story (Model 2: β = 0.245, β = 0.273). In our cohort of elderly AF patients, a direct association between motor and cognitive functions consistently recurred using different evaluation of the performances, without an evident mediating role of cerebral lesions burden.
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http://dx.doi.org/10.3389/fneur.2020.571978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691488PMC
November 2020

Torque teno virus microRNA detection in cerebrospinal fluids of patients with neurological pathologies.

J Clin Virol 2020 12 6;133:104687. Epub 2020 Nov 6.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. Electronic address:

Background: Torque teno virus (TTV) is a widespread anellovirus that establishes persistent infections in humans and represents the most abundant component of the human virome. TTV encodes microRNAs (miRNA) which are found both in viremic and not viremic subjects being potentially ideal tools for the virus to evade the immune system response and to maintain chronic infection in the host.

Objective: To investigate TTV-DNA loads and TTV-miRNAs expression in cerebrospinal fluids (CSF) from subjects under analysis for the assessment of neurological diseases.

Study Design: Detection of TTV-DNA and TTV-miRNAs (e. g. miRNA t1a, t3b, and tth8) were carried out from CSF samples of 93 subjects with neurological diseases by using universal real-time PCR, real-time RT-PCR, and next-generation sequencing (NGS) analyses.

Results: TTV-DNA was detected in 11 of 93 (12 %) CSFs with a mean TTV load of 155 copies/mL. Conversely, 29 CSF samples (31 %) were positive for at least one TTV-miRNA, while 15 (16 %) CSFs contained all the TTV-miRNAs examined. Overall, TTV-miRNA tth8 was detected in 62 % of samples, followed by TTV miRNA t3b (56 %), and t1a (29 %). Interestingly, TTV-miRNAs were found in CSF samples that were negative for the presence of TTV-DNA. Next-generation sequencing analysis carried out from 4 TTV-DNA negative CSF samples detected reads mapped in TTV-miRNA sequences region.

Conclusions: These results shed novel light on the relationship between TTV and the central nervous system and make compelling furthered studies for investigating the potential role of TTV-miRNAs in neurological disorders.
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http://dx.doi.org/10.1016/j.jcv.2020.104687DOI Listing
December 2020

When should a rare inherited connective tissue disorder be suspected in bicuspid aortic valve by primary-care internists and cardiologists? Proposal of a score.

Intern Emerg Med 2021 Apr 19;16(3):609-615. Epub 2020 Sep 19.

Cardiology Service, CMSR Veneto Medica, Altavilla Vicentina, Italy.

Size threshold for aortic surgery in bicuspid aortic valve (BAV) is debated. Connective tissue disorders (CTDs) are claimed as a clinical turning point, suggesting early surgery in BAV patients with CTD. Thus, we aimed at developing a score to detect high risk of carrying CTDs in consecutive BAVs from primary care. Ninety-eight BAVs without ectopia lentis or personal/family history of aortic dissection were studied at the Marfan syndrome Tuscany Referral Center. Findings were compared with those detected in 84 Marfan patients matched for sex and age. We selected traits with high statistical difference between MFS and BAV easily obtainable by cardiologists and primary-care internists: mitral valve prolapse, myopia ≥ 3DO, pectus carenatum, pes planus, wrist and thumb signs, and difference between aortic size at root and ascending aorta ≥ 4 mm. Clustering of ≥ 3 of these manifestations were more frequent in Marfan patients than in BAVs (71.4% vs 6.1%, p < 0.0001) resulting into an Odds Ratio to be affected by MFS of 38.3 (95% confidence intervals 14.8-99.3, p < 0.0001). We propose a score assembling simple clinical and echocardiographic variables resulting in an appropriate referral pattern of BAVs from a primary-care setting to a tertiary center to evaluate the presence of a potential, major CTD.
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http://dx.doi.org/10.1007/s11739-020-02458-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049921PMC
April 2021

Platelet Reactivity in Hepatitis C Virus-Infected Patients on Dual Antiplatelet Therapy for Acute Coronary Syndrome.

J Am Heart Assoc 2020 09 4;9(18):e016441. Epub 2020 Sep 4.

Cardiology Clinic Sassari University Hospital Sassari Italy.

Background Coronary artery disease (CAD) has been recognized as a serious and potentially life-threatening complication of Hepatitis C Virus (HCV) infection. High on-treatment platelet reactivity has been associated with high risk of ischemic events in patients with CAD, but data regarding the association with HCV infection are still lacking. This post hoc analysis aims to assess high on-treatment platelet reactivity, severity of CAD, and long-term outcomes of patients with acute coronary syndrome (ACS) who were infected with HCV. Methods and Results Patients with ACS who were infected with HCV (n=47) were matched to patients with ACS and without HCV (n=137) for age, sex, diabetes mellitus, hypertension, and renal function. HCV-infected patients with ACS had higher levels of platelet reactivity (ADP-light transmittance aggregometry, 56±18% versus 44±22% [=0.002]; arachidonic acid-light transmittance aggregometry, 25±21% versus 16±15% [=0.011]) and higher rates of high on-treatment platelet reactivity on clopidogrel and aspirin compared with patients without HCV. Moreover, HCV-infected patients with ACS had higher rates of multivessel disease (53% versus 30%; =0.004) and 3-vessel disease (32% versus 7%; <0.001) compared with patients without HCV. At long-term follow-up, estimated rates of major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, and ischemia-driven revascularization) were 57% versus 34% (=0.005) in HCV- and non-HCV-infected patients with ACS, respectively. In addition, thrombolysis In Myocardial Infarction (TIMI) major bleeding rates were higher in HCV-infected patients (11% versus 3%; =0.043) compared with noninfected patients. Multivariable analysis demonstrated that HCV infection was an independent predictor of high on-treatment platelet reactivity, severity of CAD, and long-term outcome. Conclusions In this hypothesis-generating study, patients with ACS and HCV infection showed increased on-treatment platelet reactivity, more severe CAD, and worse prognosis compared with patients without HCV.
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http://dx.doi.org/10.1161/JAHA.120.016441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726996PMC
September 2020

Plasma PCSK9 levels and sepsis severity: an early assessment in the emergency department.

Clin Exp Med 2021 Feb 31;21(1):101-107. Epub 2020 Aug 31.

High-Dependency Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, Lg. Brambilla 3, 50134, Florence, Italy.

The aim of the study is to evaluate the prognostic value of early PCSK9 levels in non-intubated septic patients admitted to the emergency department. This report utilized a portion of the data collected in a prospective study, with the aim of identifying reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit from the emergency department with a diagnosis of sepsis. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24). The primary endpoint was in-hospital mortality rate. PCSK9 circulating levels were higher than the normal value (≤ 313 ng/mL): at T0 661 ± 405 ng/mL, at T6 687 ± 417 ng/mL, at T24 718 ± 430 ng/mL. We divided the study population based on T0 quartiles distribution (≤ 370, 370-600, 600-900 and > 900 ng/ml). At T0, patients with normal PCSK9 showed the highest mortality compared to those in higher quartiles (T0: 39%, 20%, 23% and 18%, p = 0.036). By T6, the mortality curve tended to become U-shaped, with the lowest mortality among patients in the intermediate subgroups and an adverse prognosis in the presence of normal or very high levels of PCSK9 (35%, 26%, 18% and 23%, p = 0.235). A Kaplan-Meier analysis showed an increased mortality in patients with T0 and T6 PCSK9 ≤ 313 ng/ml (T0: 55 vs. 80%, p = 0.001; T6: 62 vs. 78%, p = 0.034). In subgroups with increasing levels of PCSK9, we found the best prognosis in the intermediate subgroups and an increased mortality among patients with normal and high values.
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http://dx.doi.org/10.1007/s10238-020-00658-9DOI Listing
February 2021

Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D'D3 and D4 domains.

Blood Adv 2020 07;4(14):3405-3415

Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia Agostino Gemelli, Università Cattolica S. Cuore, Rome, Italy.

We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G>A and (2) c.6532G>T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D'D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient's daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C>T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q/2178S promote conformational transitions in the VWF molecule, causing a type 2B-like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.
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http://dx.doi.org/10.1182/bloodadvances.2020002334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391138PMC
July 2020

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Clin Pharmacol Ther 2020 Nov 9;108(5):1067-1077. Epub 2020 Jul 9.

Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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http://dx.doi.org/10.1002/cpt.1911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689744PMC
November 2020

Clinical Implications of "Tailored" Antiplatelet Therapy in Patients With Chronic Total Occlusion.

J Am Heart Assoc 2020 02 11;9(4):e014676. Epub 2020 Feb 11.

Cardiovascular Department Azienda Ospedaliero-Universitaria Careggi Florence Italy.

Background Clopidogrel nonresponsiveness is a prognostic marker after percutaneous coronary intervention. Prasugrel and ticagrelor provide a better platelet inhibition and represent the first-line antiplatelet treatment in acute coronary syndrome. We sought to assess the prognostic impact of high platelet reactivity (HPR) and the potential clinical benefit of a "tailored" escalated or changed antiplatelet therapy in patients with chronic total occlusion. Methods and Results From Florence CTO-PCI (chronic total occlusion-percutaneous coronary intervention) registry, platelet function assessed by light transmission aggregometry, was available for 1101 patients. HPR was defined by adenosine diphosphate test ≥70% and optimal platelet reactivity by adenosine diphosphate test <70%. The endpoint of the study was long-term cardiac survival. Patients were stratified according to light transmission aggregometry results: optimal platelet reactivity (82%) and HPR (18%). Means for the adenosine diphosphate test were 44±16% versus 77±6%, respectively. Three-year survival was significantly higher in the optimal platelet reactivity group compared with HPR patients (95.3±0.8% versus 86.2±2.8%; <0.001). With the availability of new P2Y inhibitors, a deeper platelet inhibition (46±17%) and similar survival to the optimal platelet reactivity group were achieved in patients with HPR on clopidogrel therapy after escalation. Conversely, HPR on clopidogrel therapy "not switched" was associated with cardiac mortality (hazard ratio 2.37; =0.003) after multivariable adjustment. Conclusions HPR on treatment could be a modifiable prognostic marker by new antiaggregants providing a deeper platelet inhibition associated with clinical outcome improvement in complex chronic total occlusion patients. A "tailored" antiplatelet therapy, also driven by the entity of platelet inhibition, could be useful in these high risk setting patients.
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http://dx.doi.org/10.1161/JAHA.119.014676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070214PMC
February 2020

Genetic and nutritional factors determining circulating levels of lipoprotein(a): results of the "Montignoso Study".

Intern Emerg Med 2020 10 28;15(7):1239-1245. Epub 2020 Jan 28.

Department of Experimental and Clinical Medicine, University of Florence, Atherothrombotic Diseases Center, Careggi Hospital, Largo Brambilla 3, 50134, Florence, Italy.

Increasing evidence shows an association between high lipoprotein(a) [Lp(a)] levels and atherothrombotic diseases. Lp(a) trait is largely controlled by kringle-IV type 2 (KIV-2) size polymorphism in LPA gene, encoding for apo(a). Environmental factors are considered to determinate minor phenotypic variability in Lp(a) levels. In the present study, we investigated the possible gene-environment interaction between KIV-2 polymorphism and Mediterranean diet adherence or fish weekly intake in determining Lp(a) levels. We evaluated Lp(a), KIV-2 polymorphism, fish intake and Mediterranean diet adherence in 452 subjects [median age (range) 66 (46-80)years] from Montignoso Heart and Lung Project (MEHLP) population. In subjects with high KIV-2 repeats number, influence of Mediterranean diet adherence in reducing Lp(a) levels was observed (p = 0.049). No significant difference in subjects with low KIV-2 repeats according to diet was found. Moreover, in high-KIV-2-repeat subjects, we observed a trend towards influence of fish intake on reducing Lp(a) levels (p = 0.186). At multivariate linear regression analysis, high adherence to Mediterranean diet remains a significant and independent determinant of lower Lp(a) levels (β = - 64.97, standard error = 26.55, p = 0.015). In conclusion, this study showed that only subjects with high KIV-2 repeats can take advantage to lower Lp(a) levels from correct nutritional habits and, in particular, from Mediterranean diet.
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http://dx.doi.org/10.1007/s11739-020-02276-5DOI Listing
October 2020

Differential Network Analysis Reveals Metabolic Determinants Associated with Mortality in Acute Myocardial Infarction Patients and Suggests Potential Mechanisms Underlying Different Clinical Scores Used To Predict Death.

J Proteome Res 2020 02 17;19(2):949-961. Epub 2020 Jan 17.

Laboratory of Systems and Synthetic Biology , Wageningen University & Research , Wageningen 6708 WE , the Netherlands.

We present here the differential analysis of metabolite-metabolite association networks constructed from an array of 24 serum metabolites identified and quantified via nuclear magnetic resonance spectroscopy in a cohort of 825 patients of which 123 died within 2 years from acute myocardial infarction (AMI). We investigated differences in metabolite connectivity of patients who survived, at 2 years, the AMI event, and we characterized metabolite-metabolite association networks specific to high and low risks of death according to four different risk parameters, namely, acute coronary syndrome classification, Killip, Global Registry of Acute Coronary Events risk score, and metabolomics NOESY RF risk score. We show significant differences in the connectivity patterns of several low-molecular-weight molecules, implying variations in the regulation of several metabolic pathways regarding branched-chain amino acids, alanine, creatinine, mannose, ketone bodies, and energetic metabolism. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate AMI patients according to their outcomes at a molecular level.
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http://dx.doi.org/10.1021/acs.jproteome.9b00779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011173PMC
February 2020

Role of Biological Markers for Cerebral Bleeding Risk STRATification in Patients with Atrial Fibrillation on Oral Anticoagulants for Primary or Secondary Prevention of Ischemic Stroke (Strat-AF Study): Study Design and Methodology.

Medicina (Kaunas) 2019 Sep 23;55(10). Epub 2019 Sep 23.

Stroke Unit, Careggi University Hospital, 50134 Florence, Italy.

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers-both circulating and imaging-based-and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant. : The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with AF, aged 65 years or older, and with no contraindications to magnetic resonance imaging (MRI), referring to Center of Thrombosis outpatient clinic of our University Hospital for the management of oral anticoagulation therapy. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral MRI, and circulating biomarkers assessment at baseline and after 18 months. The main outcome is SVD progression-particularly microbleeds-as a selective surrogate marker of hemorrhagic complication. Stroke occurrence (ischemic or hemorrhagic) and the progression of functional, cognitive, and motor status will be evaluated as secondary outcomes. Circulating biomarkers may further improve predictive potentials. : Starting from September 2017, 194 patients (mean age 78.1 ± 6.7, range 65-97; 61% males) were enrolled. The type of AF was paroxysmal in 93 patients (48%), and persistent or permanent in the remaining patients. Concerning the type of oral anticoagulant, 57 patients (29%) were on vitamin K antagonists, and 137 (71%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI are ongoing. : The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in AF, and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.
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http://dx.doi.org/10.3390/medicina55100626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843419PMC
September 2019

Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Eur Heart J Cardiovasc Pharmacother 2020 07;6(4):203-210

Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, Florence 50055, Italy.

Aims: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.

Methods And Results: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.

Conclusion: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
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http://dx.doi.org/10.1093/ehjcvp/pvz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363022PMC
July 2020

Effects of a dietary intervention with Mediterranean and vegetarian diets on hormones that influence energy balance: results from the CARDIVEG study.

Int J Food Sci Nutr 2020 May 28;71(3):362-369. Epub 2019 Aug 28.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

A randomised, open, crossover trial with two intervention periods was used to compare the effects of a 3-month dietary intervention with Mediterranean diet (MD) and vegetarian diet (VD) on hormones that influence energy balance, and to investigate the relationship with changes in body composition. After 3 months, no significant differences between the two diets were observed. Both MD and VD resulted in a significant ( < .05) reduction in leptin-to-adiponectin ratio and anthropometric parameters, MD resulted in a significant decrease in leptin levels (-7.4%), while VD determined a significant increase in adiponectin (+6.8%) and a significant decrease in visfatin (-12.7%) levels. In both groups, changes in leptin, insulin and HOMA-IR were significantly and positively correlated with changes in anthropometric parameters. In conclusion, both MD and VD have led to a slight but significant improvement in hormones that influence energy balance. The effect was more evident in participants who lost weight and fat mass.
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http://dx.doi.org/10.1080/09637486.2019.1658723DOI Listing
May 2020

Circulating endothelial and progenitor cells in age-related macular degeneration.

Eur J Ophthalmol 2020 Sep 22;30(5):956-965. Epub 2019 Jul 22.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Purpose: To evaluate circulating endothelial and circulating progenitor cells as biomarkers in age-related macular degeneration patients (both exudative and atrophic forms) in order to establish the possible clinical implication of their assessment.

Methods: We have enrolled 44 age-related macular degeneration patients: 22 patients with a recently diagnosed exudative (neovascular) form (Group A) and 22 patients with an atrophic (dry) form (Group B). The control group consisted of 22 age and sex-matched healthy subjects (Group C). The number of circulating endothelial progenitor cells (CD34+/KDR+, CD133+/KDR+, and CD34+/KDR+/CD133+), circulating progenitor cells (CD34+, CD133+, and CD34+/CD133+), and circulating endothelial cells were determined in the peripheral venous blood samples by flow cytometry. Neovascular age-related macular degeneration patients were evaluated at baseline and 4 weeks after a loading phase of three consequent intravitreal injections of ranibizumab.

Results: Comparing age-related macular degeneration patients with the control group, endothelial progenitor cell and circulating progenitor cell levels were not significantly different, while age-related macular degeneration patients showed significantly higher levels of circulating endothelial cells ( = 0.001). Anti-vascular endothelial growth factor treatment with intravitreal ranibizumab was associated with a significant reduction of endothelial progenitor cell levels, with no significant influence on circulating progenitor cells and circulating endothelial cells.

Conclusion: We reported higher levels of circulating endothelial cells in age-related macular degeneration patients in comparison with the control group, thereby supporting the hypothesis of an involvement of endothelial dysregulation in the age-related macular degeneration and a reduction of the endothelial progenitor cell level in neovascular age-related macular degeneration patients after three intravitreal injections of ranibizumab.
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http://dx.doi.org/10.1177/1120672119863306DOI Listing
September 2020

Influence of a 3-month low-calorie Mediterranean diet compared to the vegetarian diet on human gut microbiota and SCFA: the CARDIVEG Study.

Eur J Nutr 2020 Aug 10;59(5):2011-2024. Epub 2019 Jul 10.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Purpose: We evaluated the effect of low-calorie mediterranean (MD) and vegetarian (VD) diets on gut microbiome (GM) composition and short-chain-fatty acids (SCFA) production.

Methods: We performed next generation sequencing (NGS) of 16S rRNA and SCFA analysis on fecal samples of 23 overweight omnivores (16 F; 7 M) with low-to-moderate cardiovascular risk. They were randomly assigned to a VD or MD, each lasting 3 months, with a crossover study design.

Results: Dietary interventions did not produce significant diversity in the GM composition at higher ranks (family and above), neither between nor within MD and VD, but they did it at genus level. MD significantly changed the abundance of Enterorhabdus, Lachnoclostridium and Parabacteroides, while VD significantly affected the abundance of Anaerostipes, Streptococcus, Clostridium sensu stricto, and Odoribacter. Comparison of the mean variation of each SCFA between MD and VD showed an opposite and statistically significant trend for propionic acid (+ 10% vs - 28%, respectively, p = 0.034). In addition, variations of SCFA were negatively correlated with changes of some inflammatory cytokines such as VEGF, MCP-1, IL-17, IP-10 and IL-12, only after MD. Finally, correlation analyses showed a potential relationship-modulated by the two diets-between changes of genera and changes of clinical and biochemical parameters.

Conclusions: A short-term dietary intervention with MD or VD does not induce major change in the GM, suggesting that a diet should last longer than 3 months for scratching the microbial resilience. Changes in SCFA production support their role in modulating the inflammatory response, thus mediating the anti-inflammatory and protective properties of MD.
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http://dx.doi.org/10.1007/s00394-019-02050-0DOI Listing
August 2020

Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke.

Eur Stroke J 2019 Jun 22;4(2):119-126. Epub 2018 Oct 22.

Department of NEUROFARBA, Neuroscience Section, University of Florence, Florence, Italy.

Introduction: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients.

Patients And Methods: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke.

Results: A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (β = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (β = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (β = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (β = 0.26; p = 0.006).

Discussion: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease.

Conclusions: Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.
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http://dx.doi.org/10.1177/2396987318805905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591766PMC
June 2019

CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians - The MUGELLO Study.

Sci Rep 2019 02 6;9(1):1472. Epub 2019 Feb 6.

IRCCS Don Carlo Gnocchi Foundation Italy, Florence, Italy.

A total of 356 elderly subjects [257F; 88-106 years] were genotyped for three polymorphisms of the CLOCK gene by TaqMan real-time PCR approach, in order to find associations with quality of aging. Subjects homozygous for the minor allele of rs1801260 were less frequently overweight (p = 0.046), had higher fasting glucose levels (p = 0.037), better scores at the Clock Drawing Test (CDT) (p = 0.047) and worse scores at the Geriatric Depression Scale (p = 0.032). Subjects homozygous for the minor allele of rs11932595 showed higher fasting glucose levels (p = 0.044) and better scores at CDT (p = 0.030). Conversely, subjects homozygous for the minor allele of rs4580704 showed higher triglyceride (p = 0.012), and LDL-cholesterol levels (p = 0.44), and a greater adherence to the Mediterranean diet (MD) (p = 0.044). In addition, AAC, AAG, GGC and AGC (rs1801260-rs11932595-rs4580704) haplotypes were analyzed: AAG was associated with higher risk of overweight (p = 0.008), hypertriglyceridemia (p = 0.040) and hypercholesterolemia (p = 0.036); GGC with lower risk of hyperglycemia (p = 0.022), better sleep pattern (p = 0.001) and with better score at mini-mental state examination (p = 0.010); AGC with lower risk of depression (p = 0.026) and AAC with lower adherence to the MD (p = 0.028). Therefore, CLOCK gene polymorphisms let us hypothesize an involvement in the quality of aging in a cohort of nonagenarians.
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http://dx.doi.org/10.1038/s41598-018-37992-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365537PMC
February 2019

NMR-based metabolomics identifies patients at high risk of death within two years after acute myocardial infarction in the AMI-Florence II cohort.

BMC Med 2019 01 7;17(1). Epub 2019 Jan 7.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Background: Risk stratification and management of acute myocardial infarction patients continue to be challenging despite considerable efforts made in the last decades by many clinicians and researchers. The aim of this study was to investigate the metabolomic fingerprint of acute myocardial infarction using nuclear magnetic resonance spectroscopy on patient serum samples and to evaluate the possible role of metabolomics in the prognostic stratification of acute myocardial infarction patients.

Methods: In total, 978 acute myocardial infarction patients were enrolled in this study; of these, 146 died and 832 survived during 2 years of follow-up after the acute myocardial infarction. Serum samples were analyzed via high-resolution H-nuclear magnetic resonance spectroscopy and the spectra were used to characterize the metabolic fingerprint of patients. Multivariate statistics were used to create a prognostic model for the prediction of death within 2 years after the cardiovascular event.

Results: In the training set, metabolomics showed significant differential clustering of the two outcomes cohorts. A prognostic risk model predicted death with 76.9% sensitivity, 79.5% specificity, and 78.2% accuracy, and an area under the receiver operating characteristics curve of 0.859. These results were reproduced in the validation set, obtaining 72.6% sensitivity, 72.6% specificity, and 72.6% accuracy. Cox models were used to compare the known prognostic factors (for example, Global Registry of Acute Coronary Events score, age, sex, Killip class) with the metabolomic random forest risk score. In the univariate analysis, many prognostic factors were statistically associated with the outcomes; among them, the random forest score calculated from the nuclear magnetic resonance data showed a statistically relevant hazard ratio of 6.45 (p = 2.16×10). Moreover, in the multivariate regression only age, dyslipidemia, previous cerebrovascular disease, Killip class, and random forest score remained statistically significant, demonstrating their independence from the other variables.

Conclusions: For the first time, metabolomic profiling technologies were used to discriminate between patients with different outcomes after an acute myocardial infarction. These technologies seem to be a valid and accurate addition to standard stratification based on clinical and biohumoral parameters.
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http://dx.doi.org/10.1186/s12916-018-1240-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323789PMC
January 2019

Prognostic value of sepsis-induced coagulation abnormalities: an early assessment in the emergency department.

Intern Emerg Med 2019 04 7;14(3):459-466. Epub 2018 Dec 7.

High-Dependency Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, Lg. Brambilla 3, 50134, Florence, Italy.

To evaluate if the assessment of coagulation abnormalities at ED admission could improve prognostic assessment of septic patients. This report utilizes a portion of the data collected in a prospective study, with the aim to identify reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit with a diagnosis severe sepsis/septic shock. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24): D-dimer, thrombin-antithrombin complex (TAT) and prothrombin fragment F1 + 2 levels were analyzed. The primary end-points were day-7 and in-hospital mortality. Day-7 mortality rate was 16%. D-dimer (T0: 4661 ± 4562 µg/ml vs 3190 ± 7188 µg/ml; T6: 4498 ± 4931 µg/ml vs 2822 ± 5623 µg/ml; T24 2905 ± 2823 µg/ml vs 2465 ± 4988 µg/ml, all p < 0.05) and TAT levels (T0 29 ± 45 vs 22 ± 83; T6 21 ± 22 vs 15 ± 35; T24 16 ± 19 vs 13 ± 30, all p < 0.05) were higher among non-survivors compared to survivors. We defined an abnormal coagulation activation (COAG+) as D-dimer > 500 µg/ml and TAT > 8 ng/ml (for both, twice the upper normal value). Compared to COAG-, COAG+ patients showed higher lactate levels at the earliest evaluations (T0: 3.3 ± 2.7 vs 2.5 ± 2.3, p = 0.041; T6: 2.8 ± 3.4 vs 1.8 ± 1.6, p = 0.015); SOFA score was higher after 24 h (T24: 6.7 ± 3.1 vs 5.4 ± 2.9, p = 0.008). At T0, COAG+ patients showed a higher day-7 mortality rate (HR 2.64; 95% CI 1.14-6.11, p = 0.023), after adjustment for SOFA score and lactate level. Presence of abnormal coagulation at ED admission shows an independent association with an increased short-term mortality rate.
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http://dx.doi.org/10.1007/s11739-018-1990-zDOI Listing
April 2019

Bicuspid Aortic Valve: Role of Multiple Gene Variants in Influencing the Clinical Phenotype.

Biomed Res Int 2018 5;2018:8386123. Epub 2018 Sep 5.

Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy.

Bicuspid aortic valve (BAV) is a common congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant pattern of inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with other clinical manifestations in syndromic conditions. Identification of a syndromic condition in a BAV patient is clinically relevant in order to personalize indication to aortic surgery. We aimed to point out how genetic diagnosis by next-generation sequencing (NGS) can improve management of a patient with complex BAV clinical picture. We describe a 45-year-old Caucasian male with BAV, thoracic aortic root and ascending aorta dilatation, and connective features evocative but inconclusive for clinical diagnosis of Marfan syndrome (MFS). Targeted (91 genes) NGS was used. Proband genetic variants were investigated in first-degree relatives. Proband carried 5 rare variants in 4 genes: (p.Asn542Ser and p.Lys2460Arg), (p.Val1739Met), (p.Arg1330Gln), and (p.Arg423Trp). The two FBN1 variants were inherited in cis by the mother, showing systemic features evocative of MFS, but with a milder phenotype than that observed in the proband. Careful clinical observation along with the presence of the variants allowed diagnosis of MFS in the proband and in his mother. variant was found in mother and brother, not exhibiting BAV, thus not definitely supporting/excluding association with BAV. Interestingly, the proband, his brother and father, all showing root dilatation, and his sister, with upper range aortic root dimension, were carriers of a variant. might also modulate the vascular phenotype. Our results underline the usefulness of NGS together with family evaluation in diagnosis of patients with monogenic traits and overlapping clinical manifestations due to contribution of the same genes and/or presence of comorbidities determined by different genes.
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http://dx.doi.org/10.1155/2018/8386123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145047PMC
January 2019

Role of lipoprotein (a) and LPA KIV2 repeat polymorphism in bicuspid aortic valve stenosis and calcification: a proof of concept study.

Intern Emerg Med 2019 Jan 11;14(1):45-50. Epub 2018 Aug 11.

Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

Hemodynamic valvular impairment is a frequent determinant of the natural history of bicuspid aortic valve (BAV). The role of elevated Lp(a) levels and LPA Kringle IV type 2 (KIV-2) size polymorphism in influencing aortic valve calcification and stenosis development in patients with tricuspid aortic valve was recognized. In this study, we investigate the association between Lp(a) and LPA KIV-2 repeat number, and the presence of calcification and stenosis in BAV patients. Sixty-nine patients [79.7% males; median age 45(30-53) yrs], consecutively referred to Center for Cardiovascular Diagnosis or Referral Center for Marfan syndrome or related disorders, AOU Careggi, from June to November 2014, were investigated. For each patient, clinical (ECG and echocardiography) and laboratory [Lp(a) (Immunoturbidimetric assay) and LPA KIV-2 repeat number (real-time PCR)] evaluation were performed. Patients were compared with 69 control subjects. No significant association between Lp(a) circulating levels and LPA KIV-2 repeat number and BAV was evidenced. Among BAV patients, significantly higher Lp(a) levels according to calcification degree were found [no calcifications:78(42-159) mg/L, mild/moderate: 134(69-189) mg/L; severe: 560(286-1511) mg/L, p = 0.008]. Conversely, lower LPA KIV-2 repeat numbers in subjects with more severe calcification degree were observed. Furthermore, higher Lp(a) levels in patients with aortic stenosis [214(67-501) mg/L vs 104(56-169) mg/L, p = 0.043] were also found. In conclusion, present data suggest the potential role for Lp(a) as a possible risk marker useful to stratify, among BAV patients, those with a higher chance to develop valvular calcifications and aortic stenosis.
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http://dx.doi.org/10.1007/s11739-018-1925-8DOI Listing
January 2019

On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty.

Eur J Vasc Endovasc Surg 2018 Oct 17;56(4):545-552. Epub 2018 Jul 17.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Objectives: Few data are available on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischaemic and haemorrhagic adverse events at follow up in PAD patients undergoing percutaneous transluminal angioplasty (PTA).

Methods: In this observational, prospective, single centre study, 177 consecutive patients with PAD undergoing PTA were enrolled, and treated with dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Platelet function was assessed on blood samples obtained within 24 h from PTA by light transmission aggregometry (LTA) using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists of platelet aggregation. High on-treatment platelet reactivity (HPR) was defined by LTA ≥ 20% if induced by AA, and LTA ≥ 70% if induced by ADP. Follow up was performed to record outcomes (death, major amputation, target vessel re-intervention, acute myocardial infarction and/or myocardial revascularisation, stroke/TIA, and bleeding).

Results: HPR by AA and HPR by ADP were found in 45% and 32% of patients, respectively. During follow up (median duration 23 months) 23 deaths (13%) were recorded; 27 patients (17.5%) underwent target limb revascularisation (TLR), two (1.3%) amputation, and six (3.9%) myocardial revascularisation. Twenty-four patients (15.6%) experienced minor bleeding. On multivariable analysis, HPR by AA and HPR by ADP were independent predictors of death [HR 3.8 (1.2-11.7), p = .023 and HR 4.8 (1.6-14.5), p = .006, respectively]. The median value of LTA by ADP was significantly lower in patients with bleeding complications than in those without [26.5% (22-39.2) vs. 62% (44.5-74), p < .001). LTA by ADP ≤ 41% was independently associated with bleeding HR 14.6 (2.6-24.0), p = .001] on multivariable analysis.

Conclusions: In this study a high prevalence of on-clopidogrel and aspirin high platelet reactivity was found, which was significantly associated with the risk of death. Conversely, a low on-clopidogrel platelet reactivity was associated with a higher risk of bleeding. These results document that the entity of platelet inhibition is associated with both thrombotic and bleeding complications in PAD patients.
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http://dx.doi.org/10.1016/j.ejvs.2018.06.032DOI Listing
October 2018

Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study.

BMJ Open 2018 05 24;8(5):e021183. Epub 2018 May 24.

Institute of Neuroscience, Italian National Research Council, Florence, Italy.

Introduction: Treatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a number of factors, ranging from blood-brain barrier (BBB) disruption to circulating biomarkers. Our aim is to evaluate the relative effect of imaging and circulating biomarkers in relation to reperfusion injury.

Methods And Analysis: Observational hospital-based study that will include 140 patients who had ischaemic stroke, treated with systemic thrombolysis, endovascular treatment or both. BBB disruption will be assessed with CT perfusion (CTP) before treatment, and levels of a large panel of biomarkers will be measured before intervention and after 24 hours. Relevant outcomes will include: (1) reperfusion injury, defined as radiologically relevant haemorrhagic transformation at 24 hours and (2) clinical status 3 months after the index stroke. We will investigate the separate and combined effect of pretreatment BBB disruption and circulating biomarkers on reperfusion injury and clinical status at 3 months. Study protocol is registered at http://www.clinicaltrials.gov (ClinicalTrials.gov ID: NCT03041753).

Ethics And Dissemination: The study protocol has been approved by ethics committee of the Azienda Ospedaliero Universitaria Careggi (Università degli Studi di Firenze). Informed consent is obtained by each patient at time of enrolment or deferred when the participant lacks the capacity to provide consent during the acute phase. Researchers interested in testing hypotheses with the data are encouraged to contact the corresponding author. Results from the study will be disseminated at national and international conferences and in medical thesis.

Trial Registration Number: NCT03041753.
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http://dx.doi.org/10.1136/bmjopen-2017-021183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988101PMC
May 2018

Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke.

Transl Stroke Res 2019 02 23;10(1):44-51. Epub 2018 Apr 23.

Institute of Neuroscience, Italian National Research Council, Florence, Italy.

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (β = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (β = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (β = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (β = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.
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http://dx.doi.org/10.1007/s12975-018-0627-xDOI Listing
February 2019