Potential Benefits of Antioxidant Phytochemicals on Endogenous Antioxidants Defences in Chronic Diseases.

Chronic diseases and cancer are worldwide health problems which result in death and disability for millions of people [...].

New Insights into the Role of Ferroptosis in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the principal cause of disease burden and death worldwide. Ferroptosis is a new form of regulated cell death mainly characterized by altered iron metabolism, increased polyunsaturated fatty acid peroxidation by reactive oxygen species, depletion of glutathione and inactivation of glutathione peroxidase 4. Recently, a series of studies have indicated that ferroptosis is involved in the death of cardiac and vascular cells and has a key impact on the mechanisms leading to CVDs such as ischemic heart disease, ischemia/reperfusion injury, cardiomyopathies, and heart failure. In this article, we reviewed the molecular mechanism of ferroptosis and the current understanding of the pathophysiological role of ferroptosis in ischemic heart disease and in some cardiomyopathies. Moreover, the comprehension of the machinery governing ferroptosis in vascular cells and cardiomyocytes may provide new insights into preventive and therapeutic strategies in CVDs.

Intracellular Polyphenol Wine Metabolites Oppose Oxidative Stress and Upregulate Nrf2/ARE Pathway.

Moderate wine consumption has been associated with several benefits to human health due to its high polyphenol content. In this study, we investigated whether polyphenols contained in a particular red wine, rich in polyphenols, can pass the cell membrane and switch the oxidant/antioxidant balance toward an antioxidant pattern of THP-1 cells and human cardiomyocytes through a gene regulatory system. First, we identified which metabolite polyphenols present in red wine extract cross cell membranes and may be responsible for antioxidant effects. The results showed that the wine metabolites in treated cells belonged mainly to stilbenes, flavan-3-ols derivatives, and flavonoids. Other metabolites present in cells were not typical wine metabolites. Then, we found that red wine extract dose-dependently lowered reactive oxygen species (ROS) induced by tert-butyl hydroperoxide (TBHP) up to 50 ± 7% in both cell lines (p < 0.01). Furthermore, wine extract increased nuclear Nrf2 of about 35 ± 5% in both cell lines (p < 0.01) and counteracted its reduction induced by TBHP (p < 0.01). The rise in Nrf2 was paralleled by the increase in hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit gene expression (both mRNA and protein) (p < 0.01). These results could help explain the healthful activity of wine polyphenols within cells.

Effect of Antioxidant Therapy on Oxidative Stress In Vivo 2021.

Oxidative stress (OS) is an imbalance between the formation of reactive oxygen and nitrogen species and antioxidant defenses [...].

Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?

Even though COVID-19 is mostly well-known for affecting respiratory pathology, it can also result in several extrapulmonary manifestations, leading to multiorgan damage. A recent reported case of SARS-CoV-2 myocarditis with cardiogenic shock showed a signature of myocardial and kidney ferroptosis, a novel, iron-dependent programmed cell death. The term ferroptosis was coined in the last decade to describe the form of cell death induced by the small molecule erastin. As a specific inducer of ferroptosis, erastin inhibits cystine-glutamate antiporter system Xc-, blocking transportation into the cytoplasm of cystine, a precursor of glutathione (GSH) in exchange with glutamate and the consequent malfunction of GPX4. Ferroptosis is also promoted by intracellular iron overload and by the iron-dependent accumulation of polyunsaturated fatty acids (PUFA)-derived lipid peroxides. Since depletion of GSH, inactivation of GPX4, altered iron metabolism, and upregulation of PUFA peroxidation by reactive oxygen species are peculiar signs of COVID-19, there is the possibility that SARS-CoV-2 may trigger ferroptosis in the cells of multiple organs, thus contributing to multiorgan damage. Here, we review the molecular mechanisms of ferroptosis and its possible relationship with SARS-CoV-2 infection and multiorgan damage. Finally, we analyze the potential interventions that may combat ferroptosis and, therefore, reduce multiorgan damage.

Effect of Antioxidant Therapy on Oxidative Stress In Vivo.

Over the last few decades, many efforts have been put into fields that explore the potential benefits of antioxidants, especially with regards to aging, cancer, cardiovascular diseases, and neurodegenerative diseases. [...].

Potential Role of Antioxidant and Anti-Inflammatory Therapies to Prevent Severe SARS-Cov-2 Complications.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2). Here, we review the molecular pathogenesis of SARS-CoV-2 and its relationship with oxidative stress (OS) and inflammation. Furthermore, we analyze the potential role of antioxidant and anti-inflammatory therapies to prevent severe complications. OS has a potential key role in the COVID-19 pathogenesis by triggering the NOD-like receptor family pyrin domain containing 3 inflammasome and nuclear factor-kB (NF-kB). While exposure to many pro-oxidants usually induces nuclear factor erythroid 2 p45-related factor2 (NRF2) activation and upregulation of antioxidant related elements expression, respiratory viral infections often inhibit NRF2 and/or activate NF-kB pathways, resulting in inflammation and oxidative injury. Hence, the use of radical scavengers like N-acetylcysteine and vitamin C, as well as of steroids and inflammasome inhibitors, has been proposed. The NRF2 pathway has been shown to be suppressed in severe SARS-CoV-2 patients. Pharmacological NRF2 inducers have been reported to inhibit SARS-CoV-2 replication, the inflammatory response, and transmembrane protease serine 2 activation, which for the entry of SARS-CoV-2 into the host cells through the angiotensin converting enzyme 2 receptor. Thus, NRF2 activation may represent a potential path out of the woods in COVID-19 pandemic.

An Exploratory Look at Bicuspid Aortic Valve (Bav) Aortopathy: Focus on Molecular and Cellular Mechanisms.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation. BAV patients are at increased risk for aortic valve disease (stenosis/regurgitation), infective endocarditis, thrombi formation and, in particular, aortic dilatation, aneurysm and dissection. This review aims at exploring the possible interplay among genetics, extracellular matrix remodeling, abnormal signaling pathways, oxidative stress and inflammation in contributing to BAV-associated aortopathy (BAV-A-A). Novel circulating biomarkers have been proposed as diagnostic tools able to improve risk stratification in BAV-A-A. However, to date, the precise molecular and cellular mechanisms that lead to BAV-A-A remain unknown. Genetic, hemodynamic and cardiovascular risk factors have been implicated in the development and progression of BAV-A-A. Oxidative stress may also play a role, similarly to what observed in atherosclerosis and vulnerable plaque formation. The identification of common pathways between these 2 conditions may provide a platform for future therapeutic solutions.

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.

Ultrasonography in Heart Failure: A Story that Matters.

Heart failure (HF) is a clinical syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. It is the leading cause of hospitalization in Internal Medicine departments. This article aims at reviewing evidence of the importance of ultrasound in HF both for hospitalized patients and in the follow-up. Ultrasound may be used as a recovery monitoring instrument at the bedside and also as a global cardiovascular assessment tool for these patients. HF represents an exciting opportunity to create an integrative ultrasound approach in Internal Medicine and/or Geriatric departments. The authors plan a five-step ultrasound examination to evaluate and monitor HF patients during hospitalization and follow-up. They call this examination: the "ABCDE" score. It includes the evaluations of A, the ankle-brachial index, B, the B-lines, C, the carotid intima media thickness, D, the diameter of the abdominal aorta and of the inferior cava vein and E, the echocardiographic assessment of the ejection fraction. This score may represent an integrative ultrasound approach in Internal Medicine and/or Geriatric departments.

Nuclear factor kappa B in patients with a history of unstable angina: case re-opened.

This study aims at assessing NF-kB activity in unstable angina (UA) patients free of symptoms after a 1 year follow-up (1YFU). Plasma oxidized low-density lipoproteins (oxLDL), circulating NF-kB, Interleukin 6 (IL-6) and Interleukin 1ß (IL-1ß), high-sensitivity C-reactive protein (hs-CRP), as markers of oxidative stress and inflammation and plasma double-stranded DNA (ds-DNA), as marker of Neutrophil Extracellular Traps (NETs), were measured in 23 of the previously enrolled 27 UA patients. These measurements were compared to the UA data at baseline, and then compared to the data derived from the stable angina (SA) and controls (C) enrolled in our previous study (we demonstrated that UA had higher levels of NF-kB compared to SA and C). After a 1YFU, UA patients show a significant decrease in NF-kB, IL-6, hs-CRP, oxLDL, and ds-DNA plasma levels (p < 0.001) and in IL-1ß and White Blood Cells (WBC) (p < 0.005), without differences in lipid and glucose assessment. If compared to SA and C, UA after a 1YFU have higher levels of NF-kB, IL-6, ds-DNA, WBC, and oxLDL compared to C (p < 0.001), but only IL-6 is higher than SA (p < 0.001). No differences are found in lipid and glucose assessment. After a 1YFU, patients with a history of UA improve their oxidative and inflammatory status, such as the levels of circulating ds-DNA, without achieving the status of C. They become comparable to SA subjects. This study provides new insight on the multiple and apparently contradictory facets of NF-kB in UA and on its possible role as mediator in NETs' formation.

Physical Exercise Reduces Cytotoxicity and Up-Regulates Nrf2 and UPR Expression in Circulating Cells of Peripheral Artery Disease Patients: An Hypoxic Adaptation?

AIM: Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression. METHODS: 24 PAD patients underwent 21 sessions of treadmill training and a treadmill test as indicator of acute response to I-R. RESULTS: Maximal and pain free walking distance improved (p＜0.01), whereas LDH leakage and apoptosis of PBMCs decreased (p＜0.01); plasma malondialdehyde and ROS generation in PBMCs declined, while plasma glutathione augmented (p＜0.01). Moreover we demonstrated an up-regulation of UPR and Nrf2 expression in PBMCs (p＜0.01). To understand whether treadmill training may act as a trigger of ischemic conditioning, we examined the effect of repeated episodes of I-R on adaptative response in PBMCs derived from the patients. We showed an up-regulation of UPR and Nrf2 gene expression (p＜0.01), while oxidative stress and cytotoxicity, after an initial increase, declined (p＜0.01). This positive effect on cytotoxicity was reduced after inhibition of UPR and Nrf2 pathways. CONCLUSIONS: Treadmill training in PAD patients through UPR and Nrf2 up-regulation may trigger hypoxic adaptation similar to conditioning, thus modifying cell survival.

Lung ultrasound in internal medicine efficiently drives the management of patients with heart failure and speeds up the discharge time.

Lung ultrasound (LUS) is a valid tool for the assessment of heart failure (HF) through the quantification of the B-lines. This study in HF patients aims to evaluate if LUS: (1) can accelerate the discharge time; (2) can efficiently drive diuretic therapy dosage; and (3) may have better performance compared to the amino-terminal portion of B type natriuretic peptide (NT-proBNP) levels in monitoring HF recovery. A consecutive sample of 120 HF patients was admitted from the Emergency Department (ED) to the Internal Medicine Department (Verona University Hospital). The Chest X-ray (CXR) group underwent standard CXR examination on admission and discharge. The LUS group underwent LUS on admission, 24, 48 and 72 h later, and on discharge. The Inferior Cava Vein Collapsibility Index, ICVCI, and the NT-proBNP were assessed. LUS discharge time was significantly shorter if compared to CXR group (p < 0.01). During hospitalization, the LUS group underwent an increased number of diuretic dosage modulations compared to the CXR group (p < 0.001). There was a stronger association between partial pressure of oxygen in arterial blood (PaO2) and B-lines compared to the association between PaO2 and NT-proBNP both on admission and on discharge (p < 0.001). The B-lines numbers were significantly higher on admission in patients with more severe HF, and the ICVCI was inversely associated with B-lines number (p < 0.001). The potential of LUS in tailoring diuretic therapy and accelerating the discharge time in HF patients is confirmed. Until the technique comes into common use in different departments, it is plausible that LUS will evolve with different facets.

Non-Exertional Heatstroke: A Case Report and Review of the Literature.

BACKGROUND Heatstroke (HS) is a life-threatening condition characterized by an elevation of the core body temperature above 40°C, central nervous system dysfunction, and possible multi-organ failure. HS can trigger systemic inflammation, disseminated intravascular coagulation (DIC), rhabdomyolysis, cerebral edema and seizures, pulmonary edema, heart dysfunctions, and renal and hepatic failure. CASE REPORT We report the case of a 41-year-old Romanian woman with a history of alcoholism who developed HS after arriving by bus in Verona, Italy in June 2016. The patient developed consecutive multi-organ dysfunction, including liver and renal failure, rhabdomyolysis, DIC, and arrhythmia. The patient was successfully treated with conservative measures. After 17 days, she recovered completely. CONCLUSIONS The exact mechanism of HS-related multiple organ dysfunction is not completely understood and its pathogenesis is complex. It involves inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Development of a model in which chronic alcohol abuse alters oxidative, inflammatory, and ER stress response could also be a conceivable solution to the positive prognosis of severe HS patients, in which liver failure has a prominent role.

Endoplasmic Reticulum Stress, NRF2 Signalling and Cardiovascular Diseases in a Nutshell.

PURPOSE OF REVIEW: This short review is intended primarily to summarize the understanding of the interrelated roles of endoplasmic reticulum (ER) stress, oxidative stress and inflammation in cardiovascular diseases. RECENT FINDINGS: Insults interfering with ER function lead to the accumulation of unfolded and misfolded proteins in the ER. An excess of proteins folding in the ER is known as ER stress. This condition initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signalling is induced. Moreover, the role of the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) and the activation of the pro-inflammatory nuclear factor-kappa B (NF-kB) are analysed. Authors summarize evidence that oxidative stress, inflammation and ER stress are closely entwined phenomena. They are involved in the pathogenesis of different cardiovascular diseases. Current literature data are presented, focusing on three topics of related pathologies: atherosclerotic plaque, coronary artery disease and diabetes. This review will provide a basic platform for study and application to several other conditions in which oxidative stress, ER stress and inflammation are key features. Future studies in this area may identify the most promising molecules to be investigated as common targets for cardiovascular diseases.

An exploratory look at NETosis in atherosclerosis.

Current evidence suggests the likelihood of a link between venous thromboembolism (VTE) and atherosclerosis, although they have been traditionally considered as different pathological entities. The contribution of neutrophils to human atherogenesis has been underestimated, if compared to their contribution established in VTE. This is due to the major importance attributed to macrophages in plaque destabilization. Nevertheless, the role of neutrophils in atherogenesis deserves increasing attention. In particular, neutrophil extracellular traps (NETs) are net-like chromatin fibres that are released from dying neutrophils. The death of neutrophils with NETs formation is called NETosis. During activation, neutrophils produce reactive oxygen species (ROS), through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The main function of NETs is trapping and killing pathogens. Nevertheless, NETs formation has been observed in various chronic inflammatory diseases, autoimmune diseases, vasculitis, lung diseases, cancer and VTE. Recent studies suggest that NETs formation might contribute also to atherosclerosis progression. New data report the presence of NETs in the luminal portion of human atherosclerotic vessels and coronary specimens obtained from patients after acute myocardial infarction. Programmed death mechanisms in atherosclerosis such as apoptosis, efferocytosis and also NETosis, share common features and triggers. If defective, they can lead the cells to a switch from programmed death to necrosis, resulting in the release of pro-atherogenic factors, accumulation of cell debris and progression of the disease. This review provides evidence on the emerging role of neutrophils focusing on NETosis and oxidative stress burden in orchestrating common mechanisms in atherosclerosis and thrombosis.

Nrf2 expression is increased in peripheral blood mononuclear cells derived from mild-moderate ex-smoker COPD patients with persistent oxidative stress.

Inadequacy of antioxidant nuclear factor-E2-related factor 2 (Nrf2) and endoplasmic reticulum stress-mediated unfolded protein response has been implicated in severe chronic obstructive pulmonary disease (COPD) and cigarette smoking-induced emphysema. As evidence suggests that the ability to upregulate Nrf2 expression may influence the progression of COPD and no data exist up to now in ex-smokers with mild-moderate COPD, this study was first aimed to evaluate Nrf2 and unfolded protein response expression in peripheral blood mononuclear cells (PBMC) of mild-moderate ex-smokers with COPD compared to smoking habit-matched non-COPD subjects. Then, we tested whether oxidative stress persists after cigarette smoking cessation and whether the concentrations of oxidized phospholipids (oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine [oxPAPC]) in the PBMC of the same subjects may have a causative role in determining the upregulation of Nrf2. The expression (mRNA and protein) of Nrf2 and of its related gene heme oxygenase-1 was significantly increased in COPD group without differences in the unfolded protein response. Plasma malondialdehyde, the circulating marker of oxidative stress, and oxPAPC in PBMC were significantly higher in COPD than in non-COPD subjects. The fact that the expression of p47phox, a subunit of NADPH oxidase, was increased in PBMC of COPD patients and that it was directly correlated with oxPAPC may indicate that oxPAPC may be one of the determinants of oxidative stress-induced Nrf2 upregulation. Finally, we also demonstrated that lung function inversely correlated with plasma malondialdehyde and with Nrf2 and heme oxygenase-1 mRNA expression in all subjects. Our results indicate that mild-moderate ex-smokers with COPD may be able to counteract oxidative stress by increasing the expression of Nrf2/antioxidant-response elements. Because Nrf2 failure significantly contributes to the development of COPD, our findings suggest that the possibility to prevent Nrf2 reduction may open a new scenario in helping to prevent the oxidative stress-associated lung function decline.

Lung ultrasound in internal medicine: training and clinical practice.

BACKGROUND: Lung ultrasound (LUS) represents an emerging technique for bedside chest imaging in different clinical settings. A standardized approach allows the diagnosis, the quantification, and the follow-up of different conditions for which acute respiratory failure is the main clinical presentation. The aim of this study was to test what skill targets could be achieved in LUS, with a short-training course offered to 19 Medical Doctors attending the certification board school in Internal Medicine at the University of Verona, Italy. METHODS: The training course (theoretical and practical) consisted of 9 h subdivided in 4 days. Each trainee examined three healthy volunteers during the first day that was also the day of the theoretical lessons. Moreover, they examined nine patients per day (a total of 27 patients). Trainees were tested in the recognition of the basic signs in LUS, the managing of the Bedside Lung Ultrasound Evaluation (the BLUE protocol), and the recognition of the broad clinical scenarios recognized by the LUS. Kappa statistic was used to calculate the inter-observer agreement (trainees/tutor). RESULTS: Twenty-seven patients were examined by the 19 trainees (ten trainees had previous limited experience in general ultrasound). The agreement among the trainees and the tutor in the recognition of the LUS basic signs and in the recognition of the BLUE protocol profiles ranged from "fair" to "excellent". In particular, the agreement among the trainees and the tutor in the final LUS diagnosis was "excellent" for the recognition of the interstitial syndrome and the pleural effusion, "substantial" for the recognition of the normal lung, and "moderate" for the recognition of consolidation and pneumothorax. LUS outcome gave useful information and drove change in therapy in 16 patients. It affected immediate management in nine patients. The concordance between the previous X chest ray and LUS was observed in 21 patients. CONCLUSIONS: A short training in LUS provided good proficiency in the recognition only of the main signs of the BLUE protocol, but allowed a correct LUS diagnosis in the Internal Medicine most frequent clinical settings of acute respiratory failure. This study supports incorporating LUS into Internal Medicine fellowship training programs.

Young smoker "ABCD" vascular assessment: a four-step ultrasound examination for detecting peripheral, extra and intra-cranial early arterial damage.

BACKGROUND: Cigarette smoking is known as a major risk factor in the pathogenic mechanisms of stroke, coronary and peripheral artery disease (CAD and PAD), even in young subjects. The aim of this study is the creation of a four-step ultrasound examination to evaluate and monitor the peripheral, the extra and the intra-cranial assessment of the arterial early damage in smokers. The evaluations of A, the Ankle-brachial index, ABI, B, the Breath holding index, BHI, C, the Carotid intima media thickness, CIMT, and D, the Diameter of the abdominal aorta represent the "ABCD" assessment. METHODS: Thirty-eight healthy smokers and 43 controls underwent A, calculated for each leg. B was calculated after determination of subjects' flow velocity of middle cerebral artery (MCA) by trans-cranial colour Doppler (TCCD) before and after 30 s of apnoea at baseline and just after smoking a cigarette, to simulate the chronic and acute effects of smoking. Finally, C and D evaluation were assessed using a high-resolution B-mode ultrasound. RESULTS: Smokers presented higher values of CIMT (mean and maximal), and lower BHI both at baseline and just after smoking (p < 0.01), though in the normal range. No significant differences were found for A and D between smokers and non- smokers. CONCLUSIONS: Our results underline the importance of the assessment of B and C, that, though in the normal range, present significant differences between smokers and non-smokers. These data could drive the screening between smokers in age-related manner. Moreover, the "ABCD" examination could represent a valid method to detect and then monitor smokers' vascular damage. Although it is far to be considered a screening and routine tool, it should be contemplated in a wider context of possible not-invasive practical screening and follow-up modalities. This would be designed to implement preventive strategies and tools aimed at discouraging tobacco addiction and monitoring cardiovascular risk patients.

Searching the perfect ultrasonic classification in assessing carotid artery stenosis: comparison and remarks upon the existing ultrasound criteria.

Doppler ultrasound scanning is the first line investigation for quantifying the internal carotid artery stenosis. Nevertheless, the lack of internationally accepted ultrasound criteria for describing the degree of stenosis has contributed to the different and confusing measurements ranges. The use of two different angiographic methods, the North American Symptomatic Carotid Endoarterectomy Study and the European Carotid Surgery Trial was probably the major initial source of confusion in deriving valid and reliable duplex ultrasound criteria worldwide. The consensus proposed in 2003 by the Society of Radiologists in Ultrasound has been a great attempt to create a conformity document, establishing grey scale and Doppler criteria in considering the different degrees of stenosis. According to this attempt, in 2010, the multi-parametric Deutsche Gesellschaft für Ultraschall in der Medizin ultrasound criteria have been proposed with a precise differentiation between main and additional criteria and depicted a different peak systolic velocity (PSV) threshold. In 2012, these criteria have been implemented, focusing on the multi-parametric approach, re-defining the PSV values and clearly introducing the concept of PSV average. Despite these attempts, a wide range of practice patterns still exists, with consistent disparities in patients' care. This paper collects these previous experiences and summarizes their strengths and weaknesses, to give a contribution in the carotid artery stenosis grading standardization using ultrasonic methods. Carotid ultrasound as the only diagnostic tool for the selection of patients for carotid surgery or stenting will be possible only with internationally accepted criteria.