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1.
Circ Res ; 132(3): 290-305, 2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36636919

RESUMEN

BACKGROUND: SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. METHODS: We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. RESULTS: Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. CONCLUSIONS: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.


Asunto(s)
COVID-19 , Trombosis , Humanos , Anticuerpos Monoclonales/farmacología , Plaquetas/metabolismo , COVID-19/metabolismo , Estudios Transversales , SARS-CoV-2 , Trombosis/etiología , Trombosis/metabolismo , Tromboxanos/metabolismo , Tromboxanos/farmacología , Receptor Toll-Like 4/metabolismo
2.
Stroke ; 55(3): 604-612, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38323429

RESUMEN

BACKGROUND: No studies have investigated the association between albumin levels and the risk of early cardiovascular complications in patients with ischemic stroke. METHODS: Retrospective analysis with a federated research network (TriNetX) based on electronic medical records (International Classification of Diseases-Tenth Revision-Clinical Modification and logical observation identifiers names and codes) mainly reported between 2000 and 2023, from 80 health care organizations in the United States. Based on albumin levels measured at admission to the hospital, patients with ischemic stroke were categorized into 2 groups: (1) reduced (≤3.4 g/dL) and (2) normal (≥3.5 g/dL) albumin levels. The primary outcome was a composite of all-cause death, heart failure, atrial fibrillation, ventricular arrhythmias, myocardial infarction, and Takotsubo cardiomyopathy 30 days from the stroke. Secondary outcomes were the risk for each component of the primary outcome. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching. RESULTS: Overall, 320 111 patients with stroke had normal albumin levels (70.9±14.7 years; 48.9% females) and 183 729 (57.4%) had reduced albumin levels (72.9±14.3 years; 50.3% females). After propensity score matching, the primary outcomes occurred in 36.0% of patients with reduced and 26.1% with normal albumin levels (HR, 1.48 [95% CI, 1.46-1.50]). The higher risk in patients with reduced albumin levels was consistent also for all-cause death (HR, 2.77 [95% CI, 2.70-2.84]), heart failure (HR, 1.31 [95% CI, 1.29-1.34]), atrial fibrillation (HR, 1.11 [95% CI, 1.09-1.13]), ventricular arrhythmias (HR, 1.38 [95% CI, 1.30-1.46]), myocardial infarction (HR, 1.60 [95% CI, 1.54-1.65]), and Takotsubo cardiomyopathy (HR, 1.51 [95% CI, 1.26-1.82]). The association between albumin levels and the risk of cardiovascular events was independent of advanced age, sex, multimorbidity, and other causes of hypoalbuminemia. A progressively increased risk of adverse events was found in patients with mild and severe reduced compared to normal albumin levels. CONCLUSIONS: Albumin levels are associated with the risk of early cardiovascular events and death in patients with ischemic stroke. The potential pathophysiological or therapeutic roles of albumin in patients with stroke warrant further investigation.


Asunto(s)
Fibrilación Atrial , Insuficiencia Cardíaca , Accidente Cerebrovascular Isquémico , Infarto del Miocardio , Cardiomiopatía de Takotsubo , Femenino , Humanos , Masculino , Albúminas , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Infarto del Miocardio/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Cardiomiopatía de Takotsubo/complicaciones , Estados Unidos/epidemiología , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años
3.
Eur J Clin Invest ; 54(11): e14293, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39072756

RESUMEN

BACKGROUND: The incidence of new-onset atrial fibrillation (NOAF) is increasing in the last decades. NOAF is associated with worse long-term prognosis. The C2HEST score has been recently proposed to stratify the risk of NOAF. Pooled data on the performance of the C2HEST score are lacking. METHODS: Systematic review and meta-analysis of observational studies reporting data on NOAF according to the C2HEST score. We searched PubMed, Web of Science and Google scholar databases without time restrictions until June 2023 according to PRISMA guidelines. Meta-analysis of the area under the curve (AUC) with 95% confidence interval (95% CI) and a sensitivity analysis according to setting of care and countries were performed. RESULTS: Of 360 studies, 17 were included in the analysis accounting for 11,067,496 subjects/patients with 307,869 NOAF cases. Mean age ranged from 41.3 to 71.2 years. The prevalence of women ranged from 10.6 to 54.75%. The pooled analysis gave an AUC of .70 (95% CI .66-.74). A subgroup analysis on studies from general population/primary care yielded an AUC of 0.69 (95% CI 0.64-0.75). In the subgroup of patients with cardiovascular disease, the AUC was .71 (.69-.79). The C2HEST score performed similarly in Asian (AUC .72, 95% CI .68-.77), and in Western patients (AUC .68, 95% CI .62-.75). The best performance was observed in studies with a mean age <50 years (n = 3,144,704 with 25,538 NOAF, AUC .78, 95% CI .76-.79). CONCLUSION: The C2HEST score may be used to predict NOAF in primary and secondary prevention patients, and in patients across different countries. Early detection of NOAF may aid prompt initiation of management and follow-up, potentially leading to a reduction of AF-related complications.


Asunto(s)
Fibrilación Atrial , Humanos , Fibrilación Atrial/epidemiología , Medición de Riesgo/métodos , Estudios Observacionales como Asunto , Área Bajo la Curva , Persona de Mediana Edad , Anciano , Femenino , Enfermedades Cardiovasculares/epidemiología , Masculino
4.
Eur J Clin Invest ; 54(9): e14225, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38632681

RESUMEN

BACKGROUND: Midregional-proAdrenomedullin (MR-proADM) has been recently proposed as a tool in patients with sepsis and septic shock. Our aim was to evaluate the prognostic role of MR-proADM in hospitalized patients with sepsis and septic shock. METHODS: PRISMA guideline was followed. MEDLINE and EMBASE were searched up to June 2023. Primary outcome was mean difference in MR-proADM among survivors and nonsurvivors, secondary outcome mean difference in MR-proADM according to infection severity and type. Risk of bias was evaluated using Newcastle-Ottawa scale for observational studies and Cochrane tool for randomized trials. Pooled mean differences (MD) with corresponding 95% confidence intervals (CIs) were calculated in a random-effects model. RESULTS: Twenty-four studies included 6730 adult patients (1208 nonsurvivors and 5522 survivors) and three studies included 195 paediatric patients (30 nonsurvivors and 165 survivors). A total of 10, 4 and 13 studies included, respectively, patients with sepsis (3602 patients), septic shock (386 patients) and a mixed population (2937 patients). Twenty-one studies included patients with different source of infection, three with pneumonia and one with a catheter-related infection. Most studies (n = 12) had a follow-up of 28 days. In adult cohort, pooled mean difference between nonsurvivors and survivors of MR-proADM was 2.55 mmol/L (95% CI: 1.95-3.15) with higher values in patients with septic shock (4.25 mmol/L; 95% CI, 2.23-6.26 mmol/L) than in patients with sepsis (1.77 mmol/L; 95% CI: 1.11-2.44 mmol/L). In paediatric cohort, pooled mean difference was 3.11 mmol/L (95% CI: -0.02-6.24 mmol/L). CONCLUSIONS: Higher values of MR-proADM are detectable in nonsurvivors adult and paediatric-hospitalized patients with sepsis or septic shock.


Asunto(s)
Adrenomedulina , Precursores de Proteínas , Sepsis , Choque Séptico , Adulto , Humanos , Adrenomedulina/sangre , Biomarcadores/sangre , Pronóstico , Precursores de Proteínas/sangre , Sepsis/sangre , Sepsis/mortalidad , Sepsis/diagnóstico , Choque Séptico/sangre , Choque Séptico/diagnóstico , Choque Séptico/mortalidad , Niño
5.
Eur J Clin Invest ; : e14321, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39311651

RESUMEN

BACKGROUND: Atrial fibrillation is associated with several comorbidities, particularly cognitive impairment and dementia, especially in older patients. Non-vitamin K oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) were used to prevent thromboembolic events. However, data on the real benefit of these drugs on cognitive function decline remains controversial. In this study we evaluated the effect of NOACs compared to VKAs on the absolute and relative decline in cognitive function over time. METHODS: Nine hundred and eighty-three older patients with nonvalvular AF were enrolled (76 ± 6 years; 291 on VKAs and 692 on NOACs). The cognitive function was assessed with Mini Mental State examination (MMSE) score. The between-arms difference of cognitive evolution over time was investigated by Linear Mixed Models and group-based trajectory model analyses. RESULTS: In the whole multicenter observational study, after a long follow-up of 7.2 ± 3.4 years, the patients of the NOACs versus VKAs group had lowest absolute reduction of the MMSE score between baseline and follow-up (-0.3 ± 0.03 vs.-1.7 ± 0.1, p < 0.001). After stratification into five subgroups according to trajectories of MMSE score over time, the probability to belong to trajectories with lower decline in cognitive functions was higher in patients on NOACs than in those on VKAs (3.93-13.88 times). CONCLUSION: In older patients with atrial fibrillation, the use of NOACs was associated with a smaller decline of cognitive function over time compared to the VKAs, regardless that patients in the NOACs group were older and with a higher burden of comorbidities.

6.
Arterioscler Thromb Vasc Biol ; 43(10): e396-e403, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37586040

RESUMEN

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)-related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. METHODS: The study included 10 patients with VITT after ChAdOx1 (chimpanzee adenovirus Oxford 1) nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. RESULTS: Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 (P<0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P=0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P<0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa (Fc receptor for IgG class IIa), and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. CONCLUSIONS: Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G-mediated platelet/neutrophil interaction.


Asunto(s)
Trombocitopenia , Trombosis , Vacunas , Humanos , Neutrófilos , Catepsina G , Trombina , Trombosis/prevención & control
7.
Infection ; 52(4): 1539-1546, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38700657

RESUMEN

PURPOSE: Patients hospitalized for community-acquired pneumonia (CAP) may have a higher risk of new-onset atrial fibrillation (NOAF). The C2HEST score was developed to evaluate the NOAF risk in the general population. Data on the value of the C2HEST score in acute patients admitted with CAP are lacking. We want to establish the predictive value of C2HEST score for NOAF in patients with CAP. METHODS: Patients with CAP enrolled in the SIXTUS cohort were enrolled. C2HEST score was calculated at baseline. In-hospital NOAF was recorded. Receiver-operating Characteristic (ROC) curve and multivariable Cox proportional hazard regression analysis were performed. RESULTS: We enrolled 473 patients (36% women, mean age 70.6 ± 16.5 years), and 54 NOAF occurred. Patients with NOAF were elderly, more frequently affected by hypertension, heart failure, previous stroke/transient ischemic attack, peripheral artery disease and hyperthyroidism. NOAF patients had also higher CURB-65, PSI class and CHA2DS2-VASc score. The C-index of C2HEST score for NOAF was 0.747 (95% confidence interval [95%CI] 0.705-0.786), higher compared to CURB-65 (0.611, 95%CI 0.566-0.655, p = 0.0016), PSI (0.665, 95%CI 0.621-0.708, p = 0.0199) and CHA2DS2-VASc score (0.696, 95%CI 0.652-0.737, p = 0.0762). The best combination of sensitivity (67%) and specificity (70%) was observed with a C2HEST score ≥ 4. This result was confirmed by the multivariable Cox analysis (Hazard Ratio [HR] for C2HEST score ≥ 4 was 10.7, 95%CI 2.0-57.9; p = 0.006), independently from the severity of pneumonia. CONCLUSION: The C2HEST score was a useful predictive tool to identify patients at higher risk for NOAF during hospitalization for CAP. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT01773863).


Asunto(s)
Fibrilación Atrial , Infecciones Comunitarias Adquiridas , Neumonía , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibrilación Atrial/epidemiología , Estudios de Cohortes , Hospitalización/estadística & datos numéricos , Neumonía/epidemiología , Medición de Riesgo , Factores de Riesgo , Curva ROC , Valor Predictivo de las Pruebas
8.
Int J Mol Sci ; 25(11)2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38892108

RESUMEN

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.


Asunto(s)
Linfohistiocitosis Hemofagocítica , Síndrome de Activación Macrofágica , Humanos , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/diagnóstico , Masculino , Adulto , Síndrome de Activación Macrofágica/etiología , Síndrome de Activación Macrofágica/diagnóstico
9.
Int J Mol Sci ; 25(11)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38891768

RESUMEN

Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.


Asunto(s)
Glucósidos Iridoides , Iridoides , Lipopolisacáridos , Enfermedad del Hígado Graso no Alcohólico , Aceite de Oliva , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Glucósidos Iridoides/farmacología , Ratones , Aceite de Oliva/farmacología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Masculino , Iridoides/farmacología , Regulación hacia Abajo/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratones Endogámicos C57BL , Inflamación/metabolismo , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/patología
10.
Am Heart J ; 264: 40-48, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37301317

RESUMEN

Heart failure (HF) is a leading cause of death worldwide despite recent advances in pharmacological treatments. Gut microbiota dysbiosis and gut barrier dysfunction with consequent bacterial translocation and increased blood endotoxemia has gained much attention as one of the key pathogenetic mechanisms contributing to increased mortality of patients at risk or with cardiovascular disease. Indeed, increased blood levels of lipopolysaccharide (LPS), a glycolipid of outer membrane of gut gram-negative bacteria, have been detected in patients with diabetes, obesity and nonalcoholic fatty liver disease or in patients with established coronary disease such as myocardial infarction or atrial fibrillation, suggesting endotoxemia as aggravating factor via systemic inflammation and eventually vascular damage. Upon interaction with its receptor Toll-like receptor 4 (TLR4) LPS may, in fact, act at different cellular levels so eliciting formation of proinflammatory cytokines or exerting a procoagulant activity. Increasing body of evidence pointed to endotoxemia as factor potentially deteriorating the clinical course of patients with HF, that, in fact, is associated with gut dysbiosis-derived changes of gut barrier functionality and eventually bacteria or bacterial product translocation into systemic circulation. The aim of this review is to summarize current experimental and clinical evidence on the mechanisms linking gut dysbiosis-related endotoxemia with HF, its potential negative impact with HF progression, and the therapeutic strategies that can counteract endotoxemia.


Asunto(s)
Endotoxemia , Insuficiencia Cardíaca , Humanos , Endotoxemia/complicaciones , Endotoxemia/microbiología , Lipopolisacáridos/uso terapéutico , Disbiosis/complicaciones , Obesidad/complicaciones , Insuficiencia Cardíaca/complicaciones
11.
Microvasc Res ; 149: 104557, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37268038

RESUMEN

BACKGROUND: Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS: We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS: Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION: This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.


Asunto(s)
COVID-19 , Endotoxemia , Neumonía , Enfermedades Vasculares , Humanos , Endotoxemia/diagnóstico , Lipopolisacáridos , Peróxido de Hidrógeno , Interleucina-6 , Factor de Necrosis Tumoral alfa , COVID-19/diagnóstico , Estrés Oxidativo
12.
Eur J Clin Invest ; 53(2): e13887, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36203411

RESUMEN

BACKGROUND: Lung hyperinflation and systemic inflammation are currently believed to be the most important causes of right heart alterations in chronic obstructive pulmonary disease (COPD) patients. A multicentre observational study was performed to assess the morphological and functional parameters of right ventricle (RV) in COPD subjects, as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs). METHODS: For this retrospective study, from 1 January 2010 to 31 December 2021, we enrolled COPD patients on the basis of their airflow limitation. In particular, we selected subjects spanning across GOLD 1 and 2 functional stages. Clinical, laboratory and functional parameters were collected at baseline. Echocardiography was routinely performed in all COPD patients. RV dysfunction was defined on the basis of tricuspid annular plane systolic excursion (TAPSE) values. MACE occurrence (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery and cardiovascular death) was evaluated during a median follow-up of 55 (36-72) months. RESULTS: Among the 749 enrolled patients, 408 subjects had a TAPSE value ≥20 mm, while the remaining 341 had a TAPSE value <20 mm. In patients with TAPSE ≥20 mm the observed MACEs were 1.9 events/100 patient-year, while in the group with a worse right heart function there were 4.2 events/100 patient-year (p < .0001). The multivariate analysis model confirmed the association between RV dysfunction and MACE. Indeed, a 1-mm increase in TAPSE value and the intake of long-acting ß2 -receptor agonists (LABA)/long-acting muscarinic antagonist (LAMA) inhaled therapy were protective factors for the onset of MACE, while the presence of diabetes mellitus and high values of both uric acid (UA) and systolic pulmonary arterial pressure (S-PAP) enhanced the risk of MACE in study participants. CONCLUSIONS: The results of this study showed that in patients with mild COPD there is an association between right heart dysfunction and the risk of MACE during follow-up.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Disfunción Ventricular Derecha , Humanos , Estudios Retrospectivos , Pronóstico , Ecocardiografía/métodos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Función Ventricular Derecha/fisiología , Volumen Sistólico/fisiología
13.
Nutr Metab Cardiovasc Dis ; 33(11): 2261-2268, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37580234

RESUMEN

BACKGROUND AND AIMS: Statins are mainstream drugs for cardiovascular (CV) prevention, but under-prescription is an important clinical challenge. Data on the use of single statins and on the rate of under-prescription in atrial fibrillation (AF) are lacking. We evaluated the association of statin underuse with mortality risk in a large AF cohort. METHODS AND RESULTS: As many as 5477 patients from the Italian nationwide START registry were included. The prevalence of different statins was reported and the association of under prescription with all-cause and CV mortality investigated. Mean age was 80.2 years, and 46.4% were women. Among 2899 patients with a clinical indication to statin, only 1578 (54.4%) were on treatment. In a mean follow-up of 22.5 ± 17.1 months, 491 (4.7%/year) deaths occurred (106 CV deaths, 1.0%/year). Atorvastatin and Simvastatin were inversely associated with all-cause (HR 0.692, 95% CI 0.519-0.923, p = 0.012 and HR 0.598, 95% CI 0.428-0.836, p = 0.003, respectively) and CV death (HR 0.372, 95% CI 0.178-0.776, p = 0.008 and HR 0.306, 95% CI 0.123-0.758, p = 0.010, respectively). The 1321 untreated patients were older, more frequently women and with a higher prevalence of diabetes, previous cerebrovascular disease, peripheral artery disease compared to those on treatment. Statin undertreatment was associated with higher risk of all-cause (HR 1.400, 95% CI 1.078-1.819, p = 0.012) and CV death (HR 2.057, 95% CI 1.188-3.561, p = 0.010). CONCLUSIONS: AF patients with an indication to statins but left untreated show a high risk of all-cause and CV mortality. Implementation of statin prescription in the AF population can help reducing the residual mortality risk.

14.
J Thromb Thrombolysis ; 55(2): 211-221, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36566304

RESUMEN

The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.


Asunto(s)
COVID-19 , Tromboembolia Venosa , Trombosis de la Vena , Humanos , COVID-19/complicaciones , Enoxaparina/uso terapéutico , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/inducido químicamente , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/inducido químicamente , Medición de Riesgo , Anticoagulantes/uso terapéutico , Factores de Riesgo
15.
Int J Mol Sci ; 24(4)2023 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-36834580

RESUMEN

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE.


Asunto(s)
COVID-19 , Trombofilia , Tromboembolia Venosa , Trombosis de la Vena , Femenino , Humanos , Masculino , Tromboembolia Venosa/genética , SARS-CoV-2 , Factores de Riesgo , Trombosis de la Vena/genética , Trombofilia/genética
16.
Int J Mol Sci ; 24(18)2023 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-37762110

RESUMEN

Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented VTE, filtered for MAF < 0.04 in 192 candidate genes, revealed 22 heterozygous (16 missense and six synonymous) variants in patients. Functional prediction by multi-component bioinformatics tools, implemented by a database/literature search, including ClinVar annotation and QTL analysis, prioritized 12 missense variants, three of which (CRP Leu61Pro, F2 Asn514Lys and NQO1 Arg139Trp) were present in all patients, and the frequent functional variants FGB Arg478Lys and IL1A Ala114Ser. Combinations of prioritized variants in each patient were used to infer functional protein interactions. Different interaction patterns, supported by high-quality evidence, included eight proteins intertwined in the "acute phase" (CRP, F2, SERPINA1 and IL1A) and/or in the "fibrinogen complex" (CRP, F2, PLAT, THBS1, VWF and FGB) significantly enriched terms. In a wide group of candidate genes, this approach highlighted six low-frequency variants (CRP Leu61Pro, F2 Asn514Lys, SERPINA1 Arg63Cys, THBS1 Asp901Glu, VWF Arg1399His and PLAT Arg164Trp), five of which were top ranked for predicted deleteriousness, which in different combinations may contribute to disease susceptibility in members of this family.


Asunto(s)
Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Secuenciación del Exoma , Factor de von Willebrand/genética , Genes Reguladores , Biología Computacional
17.
Medicina (Kaunas) ; 59(2)2023 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-36837387

RESUMEN

BACKGROUND AND OBJECTIVES: Pulmonary embolism (PE) has a major burden of morbidity and mortality, consequently the need for a prompt risk stratification for these subjects is crucial. In order to evaluate the risk management and final disposition of patients with PE in the Emergency Department (ED), we conducted a study that was divided in two phases: Phase I retrospective study (RS), Phase II prospective study (PS). MATERIALS AND METHODS: In Phase I, 291 patients were enrolled while in Phase II, 83 subjects were evaluated. In both study phases, the enrolled subjects were analyzed for final disposition in ED using PESI score, right ventricle (RV) imaging, and high-sensitive cardiac troponin I (hs-cTnI) data. The RS patients were divided into low risk and high risk according to the sPESI score, while PS patients were grouped in low, intermediate, and high risk classes according to PESI score. In both study phases, all the studied patients were further divided into negative (hs-cTnI-) or positive (hs-cTnI+) groups according to hs-cTnI levels within normal or above cutoff values, respectively. For all enrolled subjects, CT pulmonary angiography was analyzed to assess the RV/LV diameter and volume ratio as an indicator of RV involvement. RESULTS: In both RS and PS phases, hs-cTnI+ group showed a higher PESI score. Nevertheless, a significant percentage of hs-cTnI+ patients resulted to be in the low-risk PESI class. Patients with a positive RV/LV ratio were more likely to have a hs-cTnI+ (p < 0.01), while among those with a negative ratio, 24 to 32% showed as hs-cTnI+. In the hs-cTnI+ group from both study phases, patients were more likely to be admitted in an ICU (RR 3.7, IC: 2.1-6.5). CONCLUSIONS: In conclusion, in patients with PE in the ED compared PESI score alone, the combination of hs-cTnI and PESI seems to be of greater utility in improving risk stratification and final disposition decision-making.


Asunto(s)
Embolia Pulmonar , Troponina I , Humanos , Pronóstico , Estudios Retrospectivos , Estudios Prospectivos , Medición de Riesgo , Valor Predictivo de las Pruebas , Gestión de Riesgos , Servicio de Urgencia en Hospital , Biomarcadores
18.
J Autoimmun ; 129: 102832, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35512480

RESUMEN

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is emerging as a novel cardiovascular risk factor. Levels of PCSK9 in thrombotic primary antiphospholipid syndrome (PAPS) have never been investigated. METHODS: Cross sectional comparison of baseline characteristics of 91 PAPS patients enrolled in the multicenter prospective ATHERO-APS cohort study. PCSK9 levels were categorized into tertiles and the association with arterial and recurrent thrombosis were assessed by univariable and multivariable logistic regression analysis. RESULTS: Median age was 51 years and 71.4% (n = 65) were women. Overall, 33% (n = 30) experienced an arterial event while 31% (n = 28) had recurrent thrombotic events. Median PCSK9 levels were 1243 (1100-1650) pg/ml. Patients in the third PCSK9 tertile (>1458 pg/ml) showed a higher prevalence of dyslipidemia, lupus anticoagulant positivity and a history of previous arterial and recurrent thrombosis than patients in the first and second tertile. PCSK9 levels were higher in arterial than venous thrombosis (1502 vs. 1180 pg/ml, p = 0.002), and in patients with recurrent vs isolated thrombosis (1680 vs. 1150 pg/m, p < 0.001). High plasma PCSK9 levels were associated with a 4-fold increase risk for arterial events and with a 10-fold increase risk for recurrent thrombosis after adjustment for confounding factors. CONCLUSION: These preliminary data suggest that PCSK9 levels are increased in PAPS patients with arterial and recurrent thrombosis. Its role as a possible therapeutic target in PAPS needs further studies.


Asunto(s)
Síndrome Antifosfolípido , Trombosis , Síndrome Antifosfolípido/epidemiología , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9 , Estudios Prospectivos , Trombosis/epidemiología
19.
Circ Res ; 126(10): 1415-1442, 2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32379574

RESUMEN

Previous studies reported an inverse association between healthy dietary patterns (such as Mediterranean diet) and the incidence of cardiovascular events. As the mechanism accounting for cardiovascular disease is prevalently due to the atherothrombosis, where a pivotal role is played by platelet activation, it would be arguable that diets with protective effects against cardiovascular disease exert an anti-atherothrombotic effect via inhibition of platelet activation. There are several and sparse typologies of studies, which investigated if single nutrients by diets recognized as having cardiovascular protection may exert an antithrombotic effect. The most investigated nutrients are key components of the Mediterranean diets such as fruits and vegetables, fish, olive oil, and wine; other diets with protective effects include nuts and cocoa. Here we summarize experimental and human interventional studies which investigated the antithrombotic effects of such nutrients in experimental models of thrombosis or analyzed biomarkers of clotting, platelet, and fibrinolysis activation in human; furthermore in vitro studies explored the underlying mechanism at level of several cell lines such as platelets or endothelial cells. In this context, we analyzed if nutrients affect simultaneously or separately clotting, platelet, and fibrinolysis pathways giving special attention to the relationship between oxidative stress and thrombosis as most nutrients are believed to possess antioxidant properties.


Asunto(s)
Aterosclerosis/prevención & control , Coagulación Sanguínea , Plaquetas/metabolismo , Dieta Saludable , Estado Nutricional , Valor Nutritivo , Conducta de Reducción del Riesgo , Trombosis/prevención & control , Animales , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Aterosclerosis/fisiopatología , Modelos Animales de Enfermedad , Humanos , Activación Plaquetaria , Factores Protectores , Especies Reactivas de Oxígeno/sangre , Medición de Riesgo , Factores de Riesgo , Trombosis/sangre , Trombosis/epidemiología , Trombosis/fisiopatología , Resultado del Tratamiento
20.
Br J Clin Pharmacol ; 88(1): 155-165, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34087003

RESUMEN

BACKGROUND AND PURPOSE: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear. EXPERIMENTAL APPROACH: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up. KEY RESULTS: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 µg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 µg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity. CONCLUSION AND IMPLICATIONS: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.


Asunto(s)
Infecciones Comunitarias Adquiridas , Insuficiencia Cardíaca , Neumonía , Corticoesteroides/efectos adversos , Anciano , Anciano de 80 o más Años , Biomarcadores , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/epidemiología , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Neumonía/tratamiento farmacológico , Neumonía/epidemiología , Pronóstico , Troponina T
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