Ultrasound as first line step in anaemia diagnostics

This review covers the role of ultrasonography as an essential non-invasive diagnostic approach when facing patients with anaemia, a common clinical problem. Abdomen ultrasound is well recognised as a first-line examination in the setting of blood loss, both acute and chronic. Less is clear about the additional opportunities, given by ultrasound in anaemia, due to the many other possible causes. Here we provide information on the utility of ultrasound in different contexts and a practical guide for clinicians facing anaemic patients

PROTOCOLLO ECOGRAFICO DEL PAZIENTE CON SCOMPENSO CARDIACO: RISULTATI AGGIORNATI DELLO STUDIO MULTICENTRICO SIUMB ABCDE 2018-2022

Lo scompenso cardiaco è una sindrome clinica caratterizzata da specifici segni e sintomi causati da anomalie cardiache di tipo strutturale e/o funzionale. La prevalenza dello scompenso cardiaco è di circa 1-2% nella popolazione adulta dei paesi industrializzati, aumenta fin oltre il 10% oltre i 70 anni ed è la maggiore causa di ospedalizzazione oltre che di disabilità. L’approccio ecografico al paziente con scompenso cardiaco è ad oggi pratica comune, sia per la valutazione della funzionalità cardiaca, sia per il monitoraggio dello stato di volemia che per la quantificazione del liquido interstiziale. Dal 2018 è in corso uno studio multicentrico italiano (“ABCDE”) patrocinato dalla SIUMB che ha come centro promotore il reparto di Medicina Generale e Malattie Aterotrombotiche e Degenerative dell’Università di Verona. L’ approccio ecografico proposto comprende le valutazioni di: A: ABI (Ankle Brachial Index), indice caviglia-braccio; B: linee B all’ecografia polmonare; C: CIMT (Carotid Intima Media Thickness), spessore intima-media carotideo; D: Diametro dell’aorta addominale e della vena cava inferiore; E: stima ecocardiografica della frazione di eiezione ventricolare sinistra. Questa presentazione riporta i risultati aggiornati a poco più di un anno dall’avvio dello studio riportando i dati provenienti dal centro promotore (Verona) e dai centri partecipanti. Dai primi risultati dello studio "ABCDE", la metodica ecografica nel paziente con scompenso cardiaco, intesa sia come “bedside” che come approccio ecografico integrato appare essere uno strumento essenziale di valutazione cardiovascolare globale, e di accorciamento della durata della degenza nei reparti medici

Spotlight on Cardiovascular Scoring Systems in Covid-19: Severity Correlations in Real-world Setting

Objectives and Methods: the current understanding of the interplay between cardiovascular (CV) risk and Covid-19 is grossly inadequate. CV risk-prediction models are used to identify and treat high risk populations and to communicate risk effectively. These tools are unexplored in Covid-19. The main objective is to evaluate the association between CV scoring systems and chest X ray (CXR) examination (in terms of severity of lung involvement) in 50 Italian Covid-19 patients. Results only the Framingham Risk Score (FRS) was applicable to all patients. The Atherosclerotic Cardiovascular Disease Score (ASCVD) was applicable to half. 62% of patients were classified as high risk according to FRS and 41% according to ASCVD. Patients who died had all a higher FRS compared to survivors. They were all hypertensive. FRS≥30 patients had a 9.7 higher probability of dying compared to patients with a lower FRS. We found a strong correlation between CXR severity and FRS and ASCVD (P < 0.001). High CV risk patients had consolidations more frequently. CXR severity was significantly associated with hypertension and diabetes. 71% of hypertensive patients’ CXR and 88% of diabetic patients’ CXR had consolidations. Patients with diabetes or hypertension had 8 times greater risk of having consolidations. Conclusions: High CV risk correlates with more severe CXR pattern and death. Diabetes and hypertension are associated with more severe CXR. FRS offers more predictive utility and fits best to our cohort. These findings may have implications for clinical practice and for the identification of high-risk groups to be targeted for the vaccine precedence

Ezetimibe prevents ischemia/reperfusion-induced oxidative stress and up-regulates Nrf2/ARE and UPR signaling pathways

BACKGROUND: While reperfusion is crucial for survival after an episode of ischemia, it also causes oxidative stress. Nuclear factor-E2-related factor 2 (Nrf2) and unfolded protein response (UPR) are protective against oxidative stress and endoplasmic reticulum (ER) stress. Ezetimibe, a cholesterol absorption inhibitor, has been shown to activate the AMP-activated protein kinase (AMPK)/Nrf2 pathway. In this study we evaluated whether Ezetimibe affects oxidative stress and Nrf2 and UPR gene expression in cellular models of ischemia-reperfusion (IR). METHODS: Cultured cells were subjected to simulated IR with or without Ezetimibe. RESULTS: IR significantly increased reactive oxygen species (ROS) production and the percentage of apoptotic cells without the up-regulation of Nrf2, of the related antioxidant response element (ARE) gene expression or of the pro-survival UPR activating transcription factor 6 (ATF6) gene, whereas it significantly increased the pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). Ezetimibe significantly decreased the cellular ROS formation and apoptosis induced by IR. These effects were paralleled by the up-regulation of Nrf2/ARE and ATF6 gene expression and by a down-regulation of CHOP. We also found that Nrf2 activation was dependent on AMPK, since Compound C, a pan inhibitor of p-AMPK, blunted the activation of Nrf2. CONCLUSIONS: Ezetimibe counteracts IR-induced oxidative stress and induces Nrf2 and UPR pathway activation

Increased endoplasmic reticulum stress and Nrf2 repression in peripheral blood mononuclear cells of patients with stable coronary artery disease.

Endoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with ER function lead to the accumulation of unfolded and misfolded proteins in the ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced. We evaluated: (1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMCs) of stable coronary artery disease (CAD) patients; (2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); (3) the possible origin of oxPAPC in PBMCs; and (4) the expression of nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE), a cellular defense mechanism. Twenty-nine CAD patients and 28 matched controls were enrolled. Expression of glucose-regulated protein 78kDa (GRP78/BiP), as a representative of the UPR, and of C/EBP homologous protein (CHOP), as a representative of ER apoptosis, was significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMCs, in plasma, and in low-density lipoprotein (LDL) were significantly higher in CAD compared to controls (p<0.01). The oxPAPC in PBMCs may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione were significantly lower in CAD compared to controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase in CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease in Nrf2/ARE gene expression (p<0.01). In PBMCs of CAD patients there is an activation of the UPR and ER-initiated apoptotic signaling, possibly related to an abnormal concentration of oxPAPC in PBMCs

Endoplasmic reticulum stress and Nrf2 repression in circulating cells of type 2 diabetic patients without the recommended glycemic goals

Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of type 2 diabetes mellitus (T2DM), with activation of the unfolded protein response (UPR) and ER apoptosis in \u3b2-cells. The aim of the study is investigating the role of the prolonged glycemic, inflammatory, and oxidative impairment as possible UPR and ER apoptosis inductors in triggering the ER stress response and the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) activation in peripheral blood mononuclear cells (PBMC) of T2DM patients without glycemic target. Oxidative stress markers (oxidation product of phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine [oxPAPC], and malondialdehyde [MDA]), the UPR and ER apoptosis, the activation of the pro-inflammatory nuclear factor-kappa B (NF-kB) with its inhibitory protein inhibitor-kB\u3b1, and the expression of the protective Nrf2 and heme oxygenase-1 (HO-1) were evaluated in PBMC of 15 T2DM patients and 15 healthy controls (C). OxPAPC concentrations (in PBMC and plasma), MDA levels (in plasma), the expressions of the glucose-regulated protein 78 kDa (or BiP) as representative of UPR, and of the CCAAT/enhancer-binding protein homologous protein as representative of ER apoptosis were significantly higher (p < 0.01) in T2DM with respect to C. IkB\u3b1 expression was significantly lower (p < 0.01) in T2DM as well as Nrf2 and HO-1. In vitro experiments demonstrated that hyperglycemic conditions, if prolonged, were NF-kB inductors, without a corresponding Nrf2/ARE response. In PBMC of T2DM without glycemic target achievement, there is an activation of the UPR and of the ER apoptosis, which may be related to the chronic exposure to hyperglycemia, to the augmented inflammation, and to the augmented oxidative stress, without a corresponding Nrf2/ARE defense activation

Serum oxidative stress-induced repression of Nrf2 and GSH depletion: a mechanism potentially involved in endothelial dysfunction of young smokers

AbstractBackground: Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), ofnuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSHconcentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs).Methods and Results: 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokerswe demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidationproducts of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and inperipheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showedimpairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECsexposed to smokers\u2019 serum but not to non-smokers\u2019 serum we found that oxidative stress increased, whereas nitric oxideand GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamatecysteineligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesisthat the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposedHUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found insmokers\u2019 serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significantreduction of HO-1 and GCLC expression induced by oxPAPC in ECs.Conclusions: In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ARE pathway leading to GSH depletion

Relationship between low Ankle-Brachial Index and rapid renal function decline in patients with atrial fibrillation: A prospective multicentre cohort study

OBJECTIVE: To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF). DESIGN: Observational prospective multicentre cohort study. SETTING:Atherothrombosis Center of I Clinica Medica of 'Sapienza' University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study. PARTICIPANTS: 897 AF patients on treatment with vitamin K antagonists. MAIN OUTCOME MEASURES: The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m(2)/year, and incident eGFR<60 mL/min/1.73 m(2) were primary and secondary end points, respectively. RESULTS: Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m(2), and 28.7% patients had an eGFR60 mL/min/1.73 m(2), 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m(2). ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m(2) (HR 1.851, 95% CI 1.205 to 2.845, p=0.005). CONCLUSIONS: In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m(2). ABI measurement may help identify patients with AF at risk of renal function deterioration

Frequency of left ventricular hypertrophy in non-valvular atrial fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p &lt;0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p &lt;0.0001), age (OR 1.03 per year, p &lt;0.001), hypertension (OR 2.30, p &lt;0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention

CIGARETTE SMOKING BLOCKS THE PROTECTIVE EXPRESSION OF Nrf2/ARE PATHWAY IN BLOOD CELLS OF YOUNG HEAVY SMOKERS FAVOURING INFLAMMATION: RELATION WITH ENDOTHELIAL FUNCTION AND CAROTID INTIMA MEDIA THICKNESS

Background: Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs). Methods and Results: 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers\u2019 serum but not to non-smokers\u2019 serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamatecysteine ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers\u2019 serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs. Conclusions: In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ ARE pathway leading to GSH depletion