Publications by authors named "Michele Ciccarelli"

143 Publications

Sacubitril/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCOVER-ARNI, a multicenter Italian register.

Eur Heart J Open 2022 Jan 21;2(1):oeab046. Epub 2021 Dec 21.

Department of Medical and Surgical Sciences, University of Foggia, Via Antonio Gramsci, 89, 71122 Foggia, Italy.

Aims: This sub-study deriving from a multicentre Italian register [Deformation Imaging by Strain in Chronic Heart Failure Over Sacubitril-Valsartan: A Multicenter Echocardiographic Registry (DISCOVER)-ARNI] investigated whether sacubitril/valsartan in addition to optimal medical therapy (OMT) could reduce the rate of implantable cardioverter-defibrillator (ICD) indications for primary prevention in heart failure with reduced ejection fraction (HFrEF) according to European guidelines indications, and its potential predictors.

Methods And Results: In this observational study, consecutive patients with HFrEF eligible for sacubitril/valsartan from 13 Italian centres were included. Lack of follow-up or speckle tracking data represented exclusion criteria. Demographic, clinical, biochemical, and echocardiographic data were collected at baseline and after 6 months from sacubitril/valsartan initiation. Of 351 patients, 225 (64%) were ICD carriers and 126 (36%) were not ICD carriers (of whom 13 had no indication) at baseline. After 6 months of sacubitril/valsartan, among 113 non-ICD carriers despite having baseline left ventricular (LV) ejection fraction (EF) ≤ 35% and New York Heart Association (NYHA) class = II-III, 69 (60%) did not show ICD indications; 44 (40%) still fulfilled ICD criteria. Age, atrial fibrillation, mitral regurgitation > moderate, left atrial volume index (LAVi), and LV global longitudinal strain (GLS) significantly varied between the groups. With receiver operating characteristic curves, age ≥ 75 years, LAVi ≥ 42 mL/m and LV GLS ≥-8.3% were associated with ICD indications persistence (area under the curve = 0.65, 0.68, 0.68, respectively). With univariate and multivariate analysis, only LV GLS emerged as significant predictor of ICD indications at follow-up in different predictive models.

Conclusions: Sacubitril/valsartan may provide early improvement of NYHA class and LVEF, reducing the possible number of implanted ICD for primary prevention in HFrEF. Baseline reduced LV GLS was a strong marker of ICD indication despite OMT. Early therapy with sacubitril/valsartan may save infective/haemorrhagic risks and unnecessary costs deriving from ICDs.
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http://dx.doi.org/10.1093/ehjopen/oeab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242049PMC
January 2022

Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Hum Mol Genet 2022 Jul 15. Epub 2022 Jul 15.

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~ 0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
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http://dx.doi.org/10.1093/hmg/ddac158DOI Listing
July 2022

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency.

Cell Mol Life Sci 2022 Jul 11;79(8):410. Epub 2022 Jul 11.

Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Via S. Allende, 84081, Baronissi, Italy.

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.
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http://dx.doi.org/10.1007/s00018-022-04429-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276577PMC
July 2022

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in V600E-Mutated Metastatic Melanoma.

Case Rep Oncol 2022 May-Aug;15(2):560-565. Epub 2022 May 30.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.
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http://dx.doi.org/10.1159/000524185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210023PMC
May 2022

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J Pharmacol Exp Ther 2022 Jul 2. Epub 2022 Jul 2.

Department of Medicine, Surgery and Dentistry, University of Salerno, Italy

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in COVID-19, and no strategies are available to prevent or specifically address CV events in COVID patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors and new therapeutic targets. The current report will focus on the role of miRNAs in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. It is essential to identify the molecular mediators of COVID-19 cardiovascular (CV) complications. This report focused on the role of miRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
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http://dx.doi.org/10.1124/jpet.122.001210DOI Listing
July 2022

Extraction-Free Absolute Quantification of Circulating miRNAs by Chip-Based Digital PCR.

Biomedicines 2022 Jun 8;10(6). Epub 2022 Jun 8.

Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

Circulating microRNAs (miRNA) have been proposed as specific biomarkers for several diseases. Quantitative Real-Time PCR (RT-qPCR) is the gold standard technique currently used to evaluate miRNAs expression from different sources. In the last few years, digital PCR (dPCR) emerged as a complementary and accurate detection method. When dealing with gene expression, the first and most delicate step is nucleic-acid isolation. However, all currently available protocols for RNA extraction suffer from the variable loss of RNA species due to the chemicals and number of steps involved, from sample lysis to nucleic acid elution. Here, we evaluated a new process for the detection of circulating miRNAs, consisting of sample lysis followed by direct evaluation by dPCR in plasma from healthy donors and in the cardiovascular setting. Our results showed that dPCR is able to detect, with high accuracy, low-copy-number as well as highly expressed miRNAs in human plasma samples without the need for RNA extraction. Moreover, we assessed a known myocardial infarction-related miR-133a in acute myocardial infarct patients vs. healthy subjects. In conclusion, our results show the suitability of the extraction-free quantification of circulating miRNAs as disease markers by direct dPCR.
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http://dx.doi.org/10.3390/biomedicines10061354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220272PMC
June 2022

Predictors of sacubitril/valsartan high dose tolerability in a real world population with HFrEF.

ESC Heart Fail 2022 Jun 15. Epub 2022 Jun 15.

Chair of Cardiology, Department of Medicine, Surgery and Dentistry, Schola Medica Salernitana, University of Salerno, Salerno, Italy.

Aims: The angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Sac/Val) demonstrated to be superior to enalapril in reducing hospitalizations, cardiovascular and all-cause mortality in patients with ambulatory heart failure and reduced ejection fraction (HFrEF), in particular when it is maximally up-titrated. Unfortunately, the target dose is achieved in less than 50% of HFrEF patients, thus undermining the beneficial effects on the outcomes. In this study, we aimed to evaluate the role of Sac/Val and its titration dose on reverse cardiac remodelling and determine which echocardiographic index best predicts the up-titration success.

Methods And Results: From January 2020 to June 2021, we retrospectively identified 95 patients (65.6 [59.1-72.8] years; 15.8% females) with chronic HFrEF who were prescribed Sac/Val from the HF Clinics of 5 Italian University Hospitals and evaluated the tolerability of Sac/Val high dose (the ability of the patient to achieve and stably tolerate the maximum dose) as the primary endpoint in the cohort. We used a multivariable logistic regression analysis, with a stepwise backward selection method, to determine the independent predictors of Sac/Val maximum dose tolerability, using, as candidate predictors, only variables with a P-value < 0.1 in the univariate analyses. Candidate predictors identified for the multivariable backward logistic regression analysis were age, sex, body mass index (BMI), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), dyslipidaemia, atrial fibrillation, systolic blood pressure (SBP), baseline tolerability of ACEi/ARBs maximum dose, left ventricle global longitudinal strain (LVgLS), LV ejection fraction (EF), tricuspid annulus plane systolic excursion (TAPSE), right ventricle (RV) fractional area change (FAC), RV global and free wall longitudinal strain (RVgLS and RV-FW-LS). After the multivariable analysis, only one categorical (ACEi/ARBs maximum dose at baseline) and three continuous (younger age, higher SBP, and higher TAPSE), resulted significantly associated with the study outcome variable with a strong discriminatory capacity (area under the curve 0.874, 95% confidence interval (CI) (0.794-0.954) to predict maximum Sac/Val dose tolerability.

Conclusions: Our study is the first to analyse the potential role of echocardiography and, in particular, of RV dysfunction, measured by TAPSE, in predicting Sac/Val maximum dose tolerability. Therefore, patients with RV dysfunction (baseline TAPSE <16 mm, in our cohort) might benefit from a different strategy to titrate Sac/Val, such as starting from the lowest dose and/or waiting for a more extended period of observation before attempting with the higher doses.
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http://dx.doi.org/10.1002/ehf2.13982DOI Listing
June 2022

New Onset of Eosinophilic Granulomatosis with Polyangiitis Following mRNA-Based COVID-19 Vaccine.

Vaccines (Basel) 2022 May 3;10(5). Epub 2022 May 3.

Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy.

Anti-SARS-CoV-2 vaccines are safe and effective, also in individuals with allergic and immune-mediated diseases (IMDs). There are reports suggesting that vaccines may be able to trigger de-novo or exacerbate pre-existing IMDs in predisposed individuals. Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel vasculitis characterized by asthma, eosinophilia, and eosinophil-rich granulomatous inflammation in various tissues. We describe the case of a 63-year-old man who experienced cardiac, pulmonary, and neurological involvement one day after the administration of the booster dose of anti-SARS-CoV-2 vaccine (mRNA-1273). A diagnosis of EGPA was made and the patient was treated with high-dose steroids and cyclophosphamide, with a good clinical response. Interestingly, our patient had experienced a significant worsening of his pre-existing asthma six months earlier, just after the first two vaccine shots with the ChAdOx1 anti-SARS-CoV-2 vaccine. It is impossible to know whether our patient would have had developed EGPA following natural SARS-CoV-2 infection or at some point in his life regardless of infectious stimuli. Nevertheless, our report may suggest that caution should be paid during the administration of additional vaccine doses in individuals who experienced an increase in IMD severity that persisted over time following previous vaccine shots.
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http://dx.doi.org/10.3390/vaccines10050716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144767PMC
May 2022

A Novel Combination of High-Load Omega-3 Lysine Complex (AvailOm) and Anthocyanins Exerts Beneficial Cardiovascular Effects.

Antioxidants (Basel) 2022 Apr 30;11(5). Epub 2022 Apr 30.

Department of Medicine, Surgery and Dentistry ''Scuola Medica Salernitana'', University of Salerno, 84081 Baronissi, Italy.

Omega-3 fatty acids have been shown to exert several beneficial effects in the prevention of cardiovascular and cerebrovascular diseases. The objective of the present study was to analyze the effects of a novel high-load omega-3 lysine complex, AvailOm, its related constituents and a novel mixture of AvailOm with specific vasoactive anthocyanins on vascular function in mice resistance artery. Pressure myograph was used to perform vascular reactivity studies. Nitric oxide and oxidative stress were assessed by difluorofluorescein diacetate and dihydroethidium, respectively. Increasing doses of AvailOm exerted a dose-response vasorelaxation via AMPK-eNOS-mediated signaling. Omega-3 Ethyl Ester was identified as the main bioactive derivative of AvailOm, being capable of inducing vasorelaxant action to the same extent of entire product. The combination of AvailOm with a mix of potent vasoactive anthocyanins (C3-glu + DP3-glu + Mal3-glu + Mal3-gal + PEO3-gal), strongly protected mesenteric arteries from vascular dysfunction and oxidative stress evoked by oxidized-LDL. These data demonstrate for the first time the direct effects of AvailOm on resistance arteries. The evidence that the combination of specific vasoactive anthocyanins and AvailOm further enhanced the vasculoprotective properties of these compounds, may offer new promising perspectives for preventing the onset of cardiovascular and cerebrovascular events.
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http://dx.doi.org/10.3390/antiox11050896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137587PMC
April 2022

Untargeted lipidomics reveals specific lipid profiles in COVID-19 patients with different severity from Campania region (Italy).

J Pharm Biomed Anal 2022 Aug 10;217:114827. Epub 2022 May 10.

Department of Pharmacy, University of Salerno, Fisciano, SA, Italy. Electronic address:

COVID-19 infection evokes various systemic alterations that push patients not only towards severe acute respiratory syndrome but causes an important metabolic dysregulation with following multi-organ alteration and potentially poor outcome. To discover novel potential biomarkers able to predict disease's severity and patient's outcome, in this study we applied untargeted lipidomics, by a reversed phase ultra-high performance liquid chromatography-trapped ion mobility mass spectrometry platform (RP-UHPLC-TIMS-MS), on blood samples collected at hospital admission in an Italian cohort of COVID-19 patients (45 mild, 54 severe, 21 controls). In a subset of patients, we also collected a second blood sample in correspondence of clinical phenotype modification (longitudinal population). Plasma lipid profiles revealed several lipids significantly modified in COVID-19 patients with respect to controls and able to discern between mild and severe clinical phenotype. Severe patients were characterized by a progressive decrease in the levels of LPCs, LPC-Os, PC-Os, and, on the contrary, an increase in overall TGs, PEs, and Ceramides. A machine learning model was built by using both the entire dataset and with a restricted lipid panel dataset, delivering comparable results in predicting severity (AUC= 0.777, CI: 0.639-0.904) and outcome (AUC= 0.789, CI: 0.658-0.910). Finally, re-building the model with 25 longitudinal (t1) samples, this resulted in 21 patients correctly classified. In conclusion, this study highlights specific lipid profiles that could be used monitor the possible trajectory of COVID-19 patients at hospital admission, which could be used in targeted approaches.
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http://dx.doi.org/10.1016/j.jpba.2022.114827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085356PMC
August 2022

Importance of Echocardiography and Clinical "Red Flags" in Guiding Genetic Screening for Fabry Disease.

Front Cardiovasc Med 2022 25;9:838200. Epub 2022 Apr 25.

Heart Department, University Hospital San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy.

Introduction: Aim of this study was to evaluate, in a metropolitan area not already explored, the prevalence of Anderson-Fabry disease, by genetic screening, in patients with echocardiographic evidence of left ventricular hypertrophy (LVH) of unknown origin and "clinical red flags".

Methods: From August 2016 to October 2017, all consecutive patients referring to our echo-lab for daily hospital practices with echocardiographic evidence of LVH of unknown origin in association with history of at least one of the classical signs and symptoms related to Fabry disease (FD) (neuropathic pain, anhidrosis/hypohidrosis, angiokeratomas, gastrointestinal problems, chronic kidney disease, or cerebrovascular complications) were considered eligible for the FD genetic screening program. Through dried blood spot testing, α-Galactosidase A (α-Gal A) activity and analysis of the gene were performed.

Results: Among 3,360 patients who underwent transthoracic echocardiography in our echo-lab during the study period, 30 patients (0.89%; 19 men, mean age 58 ± 18.2 years) were selected. FD was diagnosed in 3 (10%) unrelated patients. Three different gene mutations were detected, one of them [mutation c.388A > G (p.Lys130Glu) in exon 3] never described before. Moreover, probands' familiar genetic screening allowed the identification of 5 other subjects affected by FD.

Conclusion: In a metropolitan area not previously investigated, among patients with LVH of unknown origin associated with other "red flags," undergoing genetic screening, the prevalence of FD was very high (10%). Our results highlight the importance of an echocardiographic- and clinical-oriented genetic screening for FD in patients with uncommon cause of LVH.
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http://dx.doi.org/10.3389/fcvm.2022.838200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081601PMC
April 2022

Enduring Reactive Oxygen Species Emission Causes Aberrant Protein S-Glutathionylation Transitioning Human Aortic Valve Cells from a Sclerotic to a Stenotic Phenotype.

Antioxid Redox Signal 2022 Aug 2. Epub 2022 Aug 2.

Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy.

During calcific aortic valve stenosis (CAVS) progression, oxidative stress and endothelial dysfunction mark the initial pathogenic steps with a parallel dysregulation of the antioxidant systems. Here, we tested whether oxidation-induced protein S-glutathionylation (P-SSG) accounts for a phenotypic switch in human aortic valvular tissue, eventually leading to calcium deposition. Next, we tested whether countering this reactive oxygen species (ROS) surge would prevent these perturbations. We employed state-of-the-art technologies, such as electron paramagnetic resonance (EPR), liquid chromatography-tandem mass spectrometry, imaging flow-cytometry, and live-cell imaging on human excised aortic valves and primary valve endothelial cells (VECs). We observed that a net rise in EPR-detected ROS emission marked the transition from fibrotic to calcific in human CAVS specimens, coupled to a progressive increment in P-SSG deposition. In human VECs (hVECs), treatment with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid triggered highly oxidizing conditions prompting P-SSG accumulation, damaging mitochondria, and inducing endothelial nitric oxide synthase uncoupling. All the events conjured up in morphing these cells from their native endothelial phenotype into a damaged calcification-inducing one. As proof of principle, the use of the antioxidant N-acetyl-L-cysteine prevented these alterations. Borne as a compensatory system to face excessive oxidative burden, with time, P-SSG contributes to the morphing of hVECs from their innate phenotype into a damaged one, paving the way to calcium deposition. Our data suggest that, in the human aortic valve, unremitted ROS emission along with a P-SSG build-up occurs and accounts, at least in part, for the morphological/functional changes leading to CAVS.
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http://dx.doi.org/10.1089/ars.2021.0133DOI Listing
August 2022

A Multistep Approach to Deal With Advanced Heart Failure: A Case Report on the Positive Effect of Cardiac Contractility Modulation Therapy on Pulmonary Pressure Measured by CardioMEMS.

Front Cardiovasc Med 2022 4;9:874433. Epub 2022 Apr 4.

Department of Medicine, Surgery and Dentistry, University of Salerno, Fisciano, Italy.

During the last years, the management of heart failure (HF) made substantial progress, focusing on device-based therapies to meet the demands of this complex syndrome. In this case report, we present a multistep approach to deal with HF. Specifically, we report the first patient subjected to the implantation of both Optimizer Smart (Impulse Dynamics Inc., Marlton, NJ, USA) and CardioMEMS devices. A 72-year-old male patient with HF and reduced ejection fraction (HFrEF) was admitted to our cardiology department in January 2021, following a progressive shortening of the time between hospitalizations for levosimendan infusions. Specifically, the patient was monitored daily by CardioMEMS, and a strategy of levosimendan infusions guided by the device had been adopted. He was also a carrier of MitraClips and cardiac resynchronization therapy defibrillator (CRT-D) and had optimized HF medical therapy. In January 2021, the patient implanted Optimizer Smart device for cardiac contractility modulation (CCM) therapy because of poor response to therapy and elevated pulmonary artery pressure (PAP). CCM significantly reduced PAP values following discharge (systolic PAP 33.67 ± 2.92 vs. 40.6 ± 3.37 mmHg, diastolic PAP 14.5 ± 2.01 vs. 22.5 ± 2.53 mmHg, mean PAP 22.87 ± 2.20 vs. 30.9 ± 2.99 mmHg, HR 60.93 ± 1.53 vs. 80.83 ± 3.66 bpm; < 0.0001), with persisting effect at 9 months. The usefulness of CCM is objectively demonstrated for the first time by continuous invasive monitoring of PAP by CardioMEMS, which can suggest the correct timing for CCM implantation.
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http://dx.doi.org/10.3389/fcvm.2022.874433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013826PMC
April 2022

[Cardiovascular management of patients with chronic myeloid leukemia treated with BCR-ABL tyrosine kinase inhibitors: it is time for a shared management].

G Ital Cardiol (Rome) 2022 Apr;23(4):268-277

Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi, Salerno - Dipartimento Cardio-Toraco-Vascolare, A.O.U. San Giovanni di Dio e Ruggi d'Aragona, Salerno.

Chronic myeloid leukemia is a rare myeloproliferative disease, characterized by a chromosomal translocation detected in 95% of cases, defined as "Philadelphia chromosome", encoding for the BCR-ABL fusion protein with continuous activation of the tyrosine kinase domain. Over the last 20 years, treatment has been revolutionized by the use of BCR-ABL tyrosine kinase inhibitors (TKI). Imatinib is the first TKI approved with a good cardiovascular safety profile, while some second-generation (nilotinib and dasatinib) and third-generation (ponatinib) drugs, developed to overcame drug resistance, can be associated with cardiovascular adverse events. The major adverse effect of dasatinib is pulmonary hypertension, reversible after treatment discontinuation. Conversely, nilotinib or ponatinib assumption is associated with a higher incidence of ischemic events, including coronary artery disease, cerebral stroke and peripheral arterial disease. Therefore, the management of patients receiving TKI therapy should include an integrated multidisciplinary evaluation and follow-up, involving highly specialized figures such as a cardiologist, hematologist and/or oncologist and the application of dedicated pathways, in order to prevent the onset or manage cardiovascular complications associated with these drugs.
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http://dx.doi.org/10.1714/3766.37536DOI Listing
April 2022

Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems.

J Clin Med 2022 Jan 20;11(3). Epub 2022 Jan 20.

Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Salerno, Italy.

Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.
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http://dx.doi.org/10.3390/jcm11030524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836767PMC
January 2022

Echocardiographically defined haemodynamic categorization predicts prognosis in ambulatory heart failure patients treated with sacubitril/valsartan.

ESC Heart Fail 2022 04 5;9(2):1107-1117. Epub 2022 Feb 5.

Cardiology and Cardiovascular Pathophysiology, University of Perugia, Perugia, Italy.

Aim: Echo-derived haemodynamic classification, based on forward-flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan.

Methods And Results: In our multicentre, open-label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m ) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e': ≥ or <15): Profile-A: normal-flow, normal-pressure; Profile-B: low-flow, normal-pressure; Profile-C: normal-flow, high-pressure; Profile-D: low-flow, high-pressure. Patients were started on sacubitril/valsartan and followed-up for 12.3 months (median). Rates of the composite of death/HF-hospitalization were assessed by multivariable Cox proportional-hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile-D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile-A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event-rate (per 100 patients per year) progressively increased from Profile-A to Profile-D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate-adjusted Cox model, profiles with low forward-flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC-score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high-dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile.

Conclusions: Echocardiographically-derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real-world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles.
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http://dx.doi.org/10.1002/ehf2.13779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934975PMC
April 2022

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.

J Clin Invest 2022 02;132(3)

Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Baronissi, Italy.

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.
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http://dx.doi.org/10.1172/JCI146343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803332PMC
February 2022

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC working group on myocardial function and the ESC Working Group on Cellular Biology of the Heart.

Cardiovasc Res 2022 Jan 6. Epub 2022 Jan 6.

Université de Paris, INSERM, PARCC, Paris, F-75015 France.

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept.
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http://dx.doi.org/10.1093/cvr/cvab370DOI Listing
January 2022

Benefit from sacubitril/valsartan is associated with hemodynamic improvement in heart failure with reduced ejection fraction: An echocardiographic study.

Int J Cardiol 2022 Mar 5;350:62-68. Epub 2022 Jan 5.

Cardiology and Cardiovascular Pathophysiology, University of Perugia, Italy; CERICLET-Centro Ricerca Clinica e Traslazionale, University of Perugia, Italy.

Background: Sacubitril/valsartan improves outcome in patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF, HFrEF). However, little is known about possible mechanisms underlying this favourable effect.

Purpose: To assess changes in echocardiographically-derived hemodynamic profiles induced by sacubitril/valsartan and their impact on outcome.

Methods: In this multicenter, open-label study, 727 HFrEF outpatients underwent comprehensive echocardiography at baseline (before starting sacubitril/valsartan) and after 12 months. Estimated LV filling pressure (E/e') and cardiac index (CI, l/min/m) were combined to determine 4 hemodynamic profiles: profile-A (normal-flow/normal-pressure); profile-B (low-flow/normal-pressure); profile-C: (normal-flow/high-pressure); profile-D: (low-flow/high-pressure). Changes among categories were recorded, and their associations with rates of the composite of death/HF-hospitalization were assessed by multivariable Cox analysis.

Results: At baseline, 29% had profile-A, 15% had profile-B, 32% profile-C, and 24% profile-D. After 12 months, the hemodynamic profile improved in 53% of patients (all profile-A achievers, or profile-D patients achieving either C or B profile), while it remained unchanged in 39% patients and worsened in 9%. Prevalence of improved profile progressively increased with increasing dose of sacubitril/valsartan (P < 0.0001). After the second echocardiography, patients were followed up 12.6 ± 7.6 months: event-rate was lower in patients with improved profile (12.3%, 95%CI: 9.4-16.1) compared to patients in whom hemodynamic profile remained unchanged (29.9%, 24.0-37.3) or worsened (31.2%, 20.7-46.9, P < 0.0001). Improved hemodynamic profile was associated with favourable outcome independent of LVEF and other covariates (HR 0.65, 95%CI: 0.45-0.95, P < 0.05).

Conclusion: In HFrEF patients, the beneficial prognostic effects of sacubitril/valsartan are associated with improvement in hemodynamic conditions.
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http://dx.doi.org/10.1016/j.ijcard.2022.01.004DOI Listing
March 2022

Biomarkers Predict In-Hospital Major Adverse Cardiac Events in COVID-19 Patients: A Multicenter International Study.

J Clin Med 2021 Dec 14;10(24). Epub 2021 Dec 14.

Department of Cardiology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Background: The COVID-19 pandemic carries a high burden of morbidity and mortality worldwide. We aimed to identify possible predictors of in-hospital major cardiovascular (CV) events in COVID-19.

Methods: We retrospectively included patients hospitalized for COVID-19 from 10 centers. Clinical, biochemical, electrocardiographic, and imaging data at admission and medications were collected. Primary endpoint was a composite of in-hospital CV death, acute heart failure (AHF), acute myocarditis, arrhythmias, acute coronary syndromes (ACS), cardiocirculatory arrest, and pulmonary embolism (PE).

Results: Of the 748 patients included, 141(19%) reached the set endpoint: 49 (7%) CV death, 15 (2%) acute myocarditis, 32 (4%) sustained-supraventricular or ventricular arrhythmias, 14 (2%) cardiocirculatory arrest, 8 (1%) ACS, 41 (5%) AHF, and 39 (5%) PE. Patients with CV events had higher age, body temperature, creatinine, high-sensitivity troponin, white blood cells, and platelet counts at admission and were more likely to have systemic hypertension, renal failure (creatinine ≥ 1.25 mg/dL), chronic obstructive pulmonary disease, atrial fibrillation, and cardiomyopathy. On univariate and multivariate analysis, troponin and renal failure were associated with the composite endpoint. Kaplan-Meier analysis showed a clear divergence of in-hospital composite event-free survival stratified according to median troponin value and the presence of renal failure (Log rank < 0.001).

Conclusions: Our findings, derived from a multicenter data collection study, suggest the routine use of biomarkers, such as cardiac troponin and serum creatinine, for in-hospital prediction of CV events in patients with COVID-19.
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http://dx.doi.org/10.3390/jcm10245863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703972PMC
December 2021

The association of uric acid with mortality modifies at old age: data from the uric acid right for heart health (URRAH) study.

J Hypertens 2022 04;40(4):704-711

Department of Internal Medicine, University of Genoa and Policlinico San Martino, Genoa.

Objectives: In older individuals, the role of serum uric acid (SUA) as risk factor for mortality is debated. This study investigated the association of SUA with all-cause and cardiovascular (CV) mortality in older adults participating in the large multicentre observational uric acid right for heart health (URRAH) study.

Methods: Eight thousand URRAH participants aged 65+ were included in the analysis. The predictive role of SUA was assessed using Cox regression models stratified according to the cut-off age of 75. SUA was tested as continuous and categorical variable (age-specific quartiles). The prognostic threshold of SUA for mortality was analysed using receiver operating characteristic curves.

Results: Among participants aged 65-74, multivariate Cox regression analysis adjusted for CV risk factors and comorbidities identified an independent association of SUA with both all-cause mortality (hazard ratio [HR] 1.169, 95% confidence interval [CI] 1.107-1.235) and CV mortality (HR 1.146, 95% CI 1.064-1.235). The cut-off value of 4.8 mg/dl discriminated mortality status. In participants aged 75+, we observed a J-shaped relationship of SUA with all-cause and CV mortality, with risk increasing at extreme SUA levels.

Conclusions: These results confirmed the predictive role of SUA for all-cause and CV mortality in older adults, while revealing considerable age-related differences. Mortality risk increased at higher SUA levels in participants aged 65-74, with a prognostic threshold of 4.8 mg/dl. The relationship between SUA and mortality was J-shaped in oldest participants. Large interventional studies are needed to clarify the benefits and possible risks of urate-lowering treatments in older adults.
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http://dx.doi.org/10.1097/HJH.0000000000003068DOI Listing
April 2022

Pathophysiology of Takotsubo syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 1: overview and the central role for catecholamines and sympathetic nervous system.

Eur J Heart Fail 2022 02 16;24(2):257-273. Epub 2022 Feb 16.

National Heart and Lung Institute, Imperial College, London, UK.

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model.
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http://dx.doi.org/10.1002/ejhf.2400DOI Listing
February 2022

Use of 3D Planning and Patient-specific Guides for Proximal Humerus Corrective Osteotomy Associated With Shoulder Prosthesis Implantation in Proximal Humeral Varus Malunion.

Tech Hand Up Extrem Surg 2022 Jun 1;26(2):131-138. Epub 2022 Jun 1.

E-LISA s.r.l., Naples, Italy.

Humeral stem prosthesis implantation in case of proximal humerus varus malunion (type 1D fracture sequelae) is often complicated by greater tuberosity fracture and by posterosuperior rotator cuff iatrogenic damage. Moreover, the varus malunited humeral head could lead to scapular impingement and reduce the range of motion. To address this problem, we introduced a new surgical procedure consisting in a proximal humerus osteotomy, planned with three-dimensional (3D) preoperative virtual surgery, and performed with patient-specific surgical guides, to correct humerus deformity before the implantation of the prosthetic humeral stem. A 3D evaluation of the deformity, based on the comparison to the healthy contralateral side or to anatomical standard values, is firstly performed. The metaphyseal osteotomy is then planned and virtually performed. To faithfully reproduce the planned correction, 3D printed surgical guides are prepared. Before the surgery, it is advisable to perform a simulation of the planned osteotomies to verify their real feasibility and to find any critical issues. Preliminary outcomes of this surgical technique are encouraging, but formal studies are warranted to validate its clinical utility and longevity of results.
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http://dx.doi.org/10.1097/BTH.0000000000000372DOI Listing
June 2022

Pathophysiology of Takotsubo syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications.

Eur J Heart Fail 2022 02 3;24(2):274-286. Epub 2021 Nov 3.

National Heart and Lung Institute, Imperial College, London, UK.

While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research.
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http://dx.doi.org/10.1002/ejhf.2368DOI Listing
February 2022

Osteochondral allograft transplantation for complex distal humeral fractures assisted by 3D computer planning and printing technology: technical note.

Eur J Orthop Surg Traumatol 2021 Sep 15. Epub 2021 Sep 15.

IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.

Purpose: The surgical treatment of comminuted distal humeral articular fractures (DHF) is challenging and is jeopardized by the high rate of complications. The study aims to describe the application of osteochondral allograft (OCA) transplantation for the treatment of complex DHF assisted with a 3D printed specific instrumentation.

Methods: Retrospective study. Inclusion criteria were the presence of an articular multi-fragmented DHF treated with frozen OCA. Clinical, self-reported and radiographic outcomes were collected every 6 months. CT were performed at 2 years FU.

Results: Four patients were included. At a mean follow-up of 37.3 months (24-49) MEPS, DASH and VAS were 90 (80-100), 11.8 (0-25) and 1 (0-3) points, respectively. Not significant complication or reoperation was recorded. Graft healing was observed in 3 cases. In all cases, we observed arthritic progression after 2 years of follow-up.

Conclusion: OCA transplantation can be considered a reliable and safe procedure in patients affected by a complex DHF.

Level Of Evidence: Level V. Technical Notes.
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http://dx.doi.org/10.1007/s00590-021-03118-6DOI Listing
September 2021

The Role of Glycemic Variability in Cardiovascular Disorders.

Int J Mol Sci 2021 Aug 4;22(16). Epub 2021 Aug 4.

Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

Diabetes mellitus (DM) is one of the most common and costly disorders that affect humans around the world. Recently, clinicians and scientists have focused their studies on the effects of glycemic variability (GV), which is especially associated with cardiovascular diseases. In healthy subjects, glycemia is a very stable parameter, while in poorly controlled DM patients, it oscillates greatly throughout the day and between days. Clinically, GV could be measured by different parameters, but there are no guidelines on standardized assessment. Nonetheless, DM patients with high GV experience worse cardiovascular disease outcomes. In vitro and in vivo studies showed that high GV causes several detrimental effects, such as increased oxidative stress, inflammation, and apoptosis linked to endothelial dysfunction. However, the evidence that treating GV is beneficial is still scanty. Clinical trials aiming to improve the diagnostic and prognostic accuracy of GV measurements correlated with cardiovascular outcomes are needed. The present review aims to evaluate the clinical link between high GV and cardiovascular diseases, taking into account the underlined biological mechanisms. A clear view of this challenge may be useful to standardize the clinical evaluation and to better identify treatments and strategies to counteract this DM aspect.
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http://dx.doi.org/10.3390/ijms22168393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395057PMC
August 2021

Healthberry 865 and Its Related, Specific, Single Anthocyanins Exert a Direct Vascular Action, Modulating Both Endothelial Function and Oxidative Stress.

Antioxidants (Basel) 2021 Jul 26;10(8). Epub 2021 Jul 26.

Cardiovascular Research Unit, Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy.

In recent years, epidemiological studies have identified a relationship between diet and cerebro-cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865 and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865 exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865 significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865 on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.
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http://dx.doi.org/10.3390/antiox10081191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388872PMC
July 2021

Vascular and metabolic effects of SGLT2i and GLP-1 in heart failure patients.

Heart Fail Rev 2021 Aug 11. Epub 2021 Aug 11.

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients.
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http://dx.doi.org/10.1007/s10741-021-10157-yDOI Listing
August 2021

PD-L1 Dysregulation in COVID-19 Patients.

Front Immunol 2021 7;12:695242. Epub 2021 Jun 7.

Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi (SA), Italy.

The COVID-19 pandemic has reached direct and indirect medical and social consequences with a subset of patients who rapidly worsen and die from severe-critical manifestations. As a result, there is still an urgent need to identify prognostic biomarkers and effective therapeutic approaches. Severe-critical manifestations of COVID-19 are caused by a dysregulated immune response. Immune checkpoint molecules such as Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) play an important role in regulating the host immune response and several lines of evidence underly the role of PD-1 modulation in COVID-19. Here, by analyzing blood sample collection from both hospitalized COVID-19 patients and healthy donors, as well as levels of PD-L1 RNA expression in a variety of model systems of SARS-CoV-2, including tissue cultures, ex-vivo infections of primary epithelial cells and biological samples obtained from tissue biopsies and blood sample collection of COVID-19 and healthy individuals, we demonstrate that serum levels of PD-L1 have a prognostic role in COVID-19 patients and that PD-L1 dysregulation is associated to COVID-19 pathogenesis. Specifically, PD-L1 upregulation is induced by SARS-CoV-2 in infected epithelial cells and is dysregulated in several types of immune cells of COVID-19 patients including monocytes, neutrophils, gamma delta T cells and CD4+ T cells. These results have clinical significance since highlighted the potential role of PD-1/PD-L1 axis in COVID-19, suggest a prognostic role of PD-L1 and provide a further rationale to implement novel clinical studies in COVID-19 patients with PD-1/PD-L1 inhibitors.
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http://dx.doi.org/10.3389/fimmu.2021.695242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215357PMC
July 2021

Short-term health-related quality of life, physical function and psychological consequences of severe COVID-19.

Ann Intensive Care 2021 Jun 4;11(1):91. Epub 2021 Jun 4.

Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, 20089, Rozzano, Italy.

Background: Survivors of severe COVID-19 are at risk of impaired health-related quality of life (HRQoL) and persistent physical and psychological disability after ICU and hospital discharge. The subsequent social burden is a major concern. We aimed to assess the short-term HRQoL, physical function and prevalence of post-traumatic stress symptoms of invasively mechanically ventilated COVID-19 patients treated in our ICU.

Methods: Prospective, observational cohort study in a follow-up clinic. Patients completed a 6-min walking test (6MWT) to assess their cardio-pulmonary function around 2 months (early follow-up) from hospital discharge, the EQ-5D-5L questionnaire for quality of life assessment around 2 months and at 6 months from hospital discharge and an anonymous web-based Impact of Event Scale-Revised (IES-R) questionnaire for Post-Traumatic Stress symptoms at 2 months.

Results: 47 patients attended our follow-up program, mean age 59 ± 10 years, median pre-morbid Clinical Frailty Scale (CFS) 2 [2-3]. The median distance walked in 6 min was 470 [406-516] m, 83 [67-99]% of the predicted value. Overall 1 out 3 patients and 4/18 (22%) among those with a good functional baseline prior to COVID-19 (CFS of 1 or 2) had lower (84%) than predicted 6MWT. EQ-5D-5L quality of life VAS was 80 [70-90] out of 100 at early follow-up with a slight improvement to 85 [77.5-90] at 6 months. Mobility, self-care and usual activities improved between the two timepoints, while pain/discomfort and depression/anxiety did not improve or got worse. The IES-R total score was greater than the threshold for concern of 1.6 in 27/41(66%) respondents.

Conclusions: Patients recovering from severe COVID-19 requiring invasive mechanical ventilation surviving hospital discharge present with early mild to moderate functional impairment, mildly reduced quality of life from hospital discharge with an overall improvement of mobility, self-care and the ability of performing usual activities, while a worsening of pain and depression/anxiety symptoms at 6 months and a large proportion of symptoms of post-traumatic distress soon after hospital discharge.
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http://dx.doi.org/10.1186/s13613-021-00881-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177269PMC
June 2021
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