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  • 1
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    Online Resource
    Autocrine Bradykinin Release Promotes Ischemic Preconditioning-Induced Cytoprotection in Bovine Aortic Endothelial Cells
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 8 ( 2020-04-23), p. 2965-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 8 ( 2020-04-23), p. 2965-
    Abstract: The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing bAECs to three cycles of 15 min of hypoxia followed by 15 min of reoxygenation. Bk synthesis peaked in correspondence to the early and late phases of PC (10−12 M and 10−11 M, respectively) and was abolished by a selective tissue kallikrein inhibitor, aprotinin. Stimulation with exogenous Bk at concentrations of 10−12 M and 10−11 M reduced the cell death induced by 12 h of hypoxia by 50%. Pretreatment with HOE−140, a Bk receptor 2 (BKR2) inhibitor, in bAECs exposed to 12 h of hypoxia, abrogated the cytoprotective effect of early and late PC, whereas des-Arg-HOE-140, a Bk receptor 1 (BKR1) inhibitor, affected only the late PC. In addition, we found that PC evoked endocytosis and the recycling of BKR2 during both the early and late phases, and that inhibition of these pathways affected PC-mediated cytoprotection. Finally, we evaluated the activation of PKA and Akt in the presence or absence of BKR2 inhibitor. HOE-140 abrogated PKA and Akt activation during both early and late PC. Consistently, BKR2 inhibition abolished cross-talk between PKA and Akt in PC. In bAECs, Bk-synthesis evoked by PC mediates the protection against both apoptotic and necrotic hypoxia-induced cell death in an autocrine manner, by both BKR2- and BKR1-dependent mechanisms.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21082965
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
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    Validation of Coronary Angiography-Derived Vessel Fractional Flow Reserve in Heart Transplant Patients with Suspected Graft Vasculopathy
    MDPI AG ; 2021
    In:  Diagnostics Vol. 11, No. 10 ( 2021-09-24), p. 1750-
    Details
    In: Diagnostics, MDPI AG, Vol. 11, No. 10 ( 2021-09-24), p. 1750-
    Abstract: Cardiac transplant-related vasculopathy remains a leading cause of morbidity and mortality in heart transplant (HTx) recipients. Recently, coronary angiography-derived vessel fractional flow reserve (vFFR) has emerged as a new diagnostic computational tool to functionally evaluate the severity of coronary artery disease. Although vFFR estimates have been shown to perform well against invasive FFR in atherosclerotic coronary artery disease, data on the use of vFFR in heart transplant recipients suffering from cardiac transplant-related arteriopathy are lacking. The aim of the presented study was to validate coronary angiography-derived vessel fractional flow reserve to calculate fractional flow reserve in HTx patients with and without cardiac transplant-related vasculopathy. A prospective, single center study of HTx patients referred for annual check-up, undergoing surveillance coronarography was conducted. Invasive FFR was measured using a motorized device at the speed of 1.0 mm/s in all three major coronary arteries. Angiography-derived pullback FFR was derived from the angiogram and compared with invasive FFR pullback curve. Overall, 18,059 FFR values were extracted from the FFR pullback curves from 23 HTx patients. The mean age was 59.3 ± 9.7 years, the mean time after transplantation was 5.24 years [IQR 1.20, 11.25]. A total of 39 vessels from 23 patients (24 LAD, 11 LCX, 4 RCA) were analyzed. Mean distal vFFR was 0.87 ± 0.14 whereas invasive distal FFR was 0.88 ± 0.17. An excellent correlation was found between invasive distal FFR and vFFR (r = 0.92; p 〈 0.001). The correlation of the pullback tracing was high, with a correlation coefficient between vFFR and invasive FFR pullback values of 0.72 (95% CI 0.71 to 0.73, p 〈 0.001). The mean difference between vFFR and invasive FFR pullback values was −0.01 with 0.06 of SD (limits of agreements −0.12 to 0.13). In HTx patients, coronary angiography-derived FFR correlates excellently with invasively measured wire-derived FFR. Therefore, angiography derived FFR could be used as a novel diagnostic tool to quantify the functional severity of graft vasculopathy.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics11101750
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662336-5
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  • 3
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    Online Resource
    Carotid Artery Stenting Using Five-French Distal Radial Vascular Access
    MDPI AG ; 2023
    In:  Diagnostics Vol. 13, No. 7 ( 2023-03-27), p. 1266-
    Details
    In: Diagnostics, MDPI AG, Vol. 13, No. 7 ( 2023-03-27), p. 1266-
    Abstract: Carotid artery stenting (CAS) is usually performed through a femoral vascular access using 6–9 Fr guiding catheters. We investigated whether a systematic distal radial approach using 5 Fr guiding sheaths was a safe and effective alternative to transfemoral approach for CAS. From July 2020 to October 2022, two operators at our center systematically performed CAS using a 5 Fr distal radial approach in consecutive patients. The main endpoints of the study were procedural success via distal radial and via proximal or distal radial access. The learning curve was evaluated by comparing the first half of patients versus the second half of patients enrolled. Procedural data and 30-day clinical outcomes were collected. Fifty-one patients were prospectively enrolled. CAS was effectively performed via distal radial access in 45 patients (88%). Overall radial artery success was 92%. Distal radial CAS was successfully performed in 20 out of the first 25 patients enrolled (80%), and in 25 of the last 26 patients enrolled (96%; p = 0.07). Significantly less contrast was administered in the last 26 patients compared to the first 25 enrolled (110 (70, 140) mL vs. 120 (107, 150) mL; p = 0.045). Radial artery occlusion was reported in 1 patient (2%). Only 1 minor stroke (2%) was reported in-hospital and at 30-day follow-up. In conclusion, distal radial CAS using 5 Fr catheters was a safe procedure with a high success rate. The procedure had a relatively short learning curve in operators familiar with transfemoral CAS.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics13071266
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662336-5
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  • 4
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    Online Resource
    Design of an Antimatter Large Acceptance Detector In Orbit (ALADInO)
    MDPI AG ; 2022
    In:  Instruments Vol. 6, No. 2 ( 2022-05-11), p. 19-
    Details
    In: Instruments, MDPI AG, Vol. 6, No. 2 ( 2022-05-11), p. 19-
    Abstract: A new generation magnetic spectrometer in space will open the opportunity to investigate the frontiers in direct high-energy cosmic ray measurements and to precisely measure the amount of the rare antimatter component in cosmic rays beyond the reach of current missions. We propose the concept for an Antimatter Large Acceptance Detector In Orbit (ALADInO), designed to take over the legacy of direct measurements of cosmic rays in space performed by PAMELA and AMS-02. ALADInO features technological solutions conceived to overcome the current limitations of magnetic spectrometers in space with a layout that provides an acceptance larger than 10 m2 sr. A superconducting magnet coupled to precision tracking and time-of-flight systems can provide the required matter–antimatter separation capabilities and rigidity measurement resolution with a Maximum Detectable Rigidity better than 20 TV. The inner 3D-imaging deep calorimeter, designed to maximize the isotropic acceptance of particles, allows for the measurement of cosmic rays up to PeV energies with accurate energy resolution to precisely measure features in the cosmic ray spectra. The operations of ALADInO in the Sun–Earth L2 Lagrangian point for at least 5 years would enable unique revolutionary observations with groundbreaking discovery potentials in the field of astroparticle physics by precision measurements of electrons, positrons, and antiprotons up to 10 TeV and of nuclear cosmic rays up to PeV energies, and by the possible unambiguous detection and measurement of low-energy antideuteron and antihelium components in cosmic rays.
    Type of Medium: Online Resource
    ISSN: 2410-390X
    URL: Article
    DOI: 10.3390/instruments6020019
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2911707-0
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  • 5
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    Online Resource
    Pathophysiology, Diagnosis, and Treatment of Patients with Concomitant Severe Aortic Stenosis and Coronary Artery Disease: A Closer Look to the Unresolved Perplexity
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 8 ( 2021-04-11), p. 1617-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 8 ( 2021-04-11), p. 1617-
    Abstract: Degenerative aortic stenosis (AS) and coronary artery disease (CAD) are the most prevalent cardiovascular diseases in developed countries, and they coexist in up to 50% of patients. The pathophysiological rationale behind concomitant AS and CAD is discussed in detail in this review, together with prognostic implications. Detecting CAD in patients with AS may be challenging, as AS may mask the existence and symptoms of CAD. The safety and reliability of invasive and non-invasive physiological assessment for epicardial coronary disease are also a matter of debate. Finally, the selection and timing of optimal treatment of CAD in patients with severe AS are still unclear. Given the aging of the population, the increase in the prevalence of AS, and the ongoing paradigm shift in its treatment, controversies in the diagnosis and treatment of CAD in the setting of AS are deemed to grow in importance. In this paper, we present contemporary issues in the diagnosis and management of CAD in patients with severe AS who are transcatheter aortic valve implantation (TAVI) candidates and provide perspective on the treatment approach.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10081617
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 6
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    Online Resource
    Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 13 ( 2021-07-01), p. 2968-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 13 ( 2021-07-01), p. 2968-
    Abstract: The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10132968
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 7
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    Severity of Coronary Atherosclerosis and Risk of Diabetes Mellitus
    MDPI AG ; 2019
    In:  Journal of Clinical Medicine Vol. 8, No. 7 ( 2019-07-21), p. 1069-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 8, No. 7 ( 2019-07-21), p. 1069-
    Abstract: Background: Cardio-vascular target organ damage predicts the onset of type 2 diabetes mellitus (DM) in hypertensive patients. Whether an increased incidence of DM is also in relation to the severity of coronary atherosclerosis is unknown. Objective: We evaluated the onset of DM in relation to the extent and severity of coronary atherosclerosis, using the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score (SS), in patients with stable angina or acute coronary syndromes, referred for coronary angiography (CA). Methods: Non-diabetic patients that underwent CA for the first time were included, and the SS was computed. Predictors of DM onset in low, medium, and high SSs were investigated. Results: Five hundred and seventy patients were included, and the mean SS was 6.3 ± 7.6. During a median follow-up of 79 months (interquartile range (IQR): 67–94), 74 patients (13%) developed DM. The risk of DM onset was significantly higher in the patients with a medium or high SS (hazard ratio (HR)—95% confidence interval (CI): 16 (4–61), p 〈 0.0001; and 30 (9–105), p 〈 0.0001, vs low SS, respectively), even after adjustment for obesity, history of hypertension, impaired fasting glucose, and cardiovascular therapy. Conclusions: The severity and extent of the coronary atherosclerosis, evaluated by the SS, is a strong and independent predictor of the development of DM in patients, referred to CA.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm8071069
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2662592-1
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  • 8
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    Online Resource
    The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 9 ( 2020-09-21), p. 2134-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 9 ( 2020-09-21), p. 2134-
    Abstract: During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a “multi-targeted cardioprotective therapy”, defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9092134
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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  • 9
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    Stress-Induced Hyperglycaemia in Non-Diabetic Patients with Acute Coronary Syndrome: From Molecular Mechanisms to New Therapeutic Perspectives
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 2 ( 2021-01-14), p. 775-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 2 ( 2021-01-14), p. 775-
    Abstract: Stress-induced hyperglycaemia (SIH) at hospital admission for acute coronary syndrome is associated with poor outcome, especially in patients without known diabetes. Nevertheless, insulin treatment in these subjects was not correlated with the reduction of mortality. This is likely due to the fact that SIH in the context of an acute coronary syndrome, compared to that in known diabetes, represents an epiphenomenon of other pathological conditions, such as adrenergic and renin-angiotensin system over-activity, hyperglucagonaemia, increase of circulating free fatty acids and pancreatic beta-cell dysfunction, which are not completely reversed by insulin therapy and so worsen the prognosis. Thus, SIH may be considered not only as a biomarker of organ damage, but also as an indicator of a more complex therapeutic strategy in these subjects. The aim of this review is to analyse the molecular mechanisms by which SIH may favour a worse prognosis in non-diabetic patients with acute coronary syndrome and identify new therapeutic strategies, in addition to insulin therapy, for a more appropriate treatment and improved outcomes.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22020775
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
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    The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 22 ( 2020-11-15), p. 8612-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 22 ( 2020-11-15), p. 8612-
    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21228612
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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