Publications by authors named "Roberto Ferrari"

469 Publications

Retrotransposons as Drivers of Mammalian Brain Evolution.

Life (Basel) 2021 Apr 22;11(5). Epub 2021 Apr 22.

Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy.

Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocortex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function.
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http://dx.doi.org/10.3390/life11050376DOI Listing
April 2021

Serum uric acid and outcomes in patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes: Analysis of the ESC-EORP Heart Failure Long-Term (HF LT) Registry.

Eur J Intern Med 2021 Apr 22. Epub 2021 Apr 22.

EURObservational Research Programme, European Society of Cardiology, Biot, France; Maria Cecilia Hospital, GVM Care&Research, Cotignola, Italy.

Background: Retrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown.

Objectives: We investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF.

Methods: Through the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HF-LT), 4,438 outpatients were identified and classified into: reduced (<40% HFrEF), mid-range (40-49% HFmrEF), and preserved (≥50% HFpEF) LVEF. Endpoints were the composite of cardiovascular death/HF hospitalization, and individual components.

Results: Median sUA was 6.72 (IQ:5.48-8.20) mg/dl in HFrEF, 6.41 (5.02-7.77) in HFmrEF, and 6.30 (5.20-7.70) in HFpEF. At a median 372-day follow-up, the composite endpoint occurred in 648 (13.1%) patients, with 176 (3.6%) deaths and 538 (10.9%) HF hospitalizations. Compared with lowest sUA quartile (Q), Q-III and Q-IV were significantly associated with the composite endpoint (adjusted HR 1.68: 95% CI 1.11-2.54; 2.46: 95% CI 1.66-3.64, respectively). By univariable analyses, HFrEF and HFmrEF patients in Q-III and Q-IV, and HFpEF patients in Q-IV, showed increased risk for the composite endpoint (P<0.05 for all); after model-adjustment, significant association of sUA with outcome persisted among HFrEF in Q-IV, and HFpEF in Q-III-IV.

Conclusions: In a large, contemporary-treated cohort of HF outpatients, sUA is an independent prognosticator of adverse outcome, which can be appreciated in HErEF and HFpEF patients.
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http://dx.doi.org/10.1016/j.ejim.2021.04.001DOI Listing
April 2021

Inequality between men and women: a very old problem, not only in politics but also in chronic coronary artery disease.

Authors:
Roberto Ferrari

Kardiol Pol 2021 04 23;79(4):376-377. Epub 2021 Apr 23.

Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy; Centro Cardiologico Universitario di Ferrara, University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.33963/KP.15949DOI Listing
April 2021

Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.

Atherosclerosis 2021 Apr 7. Epub 2021 Apr 7.

San Giovanni Bosco Hospital, ASL Città di Torino, Turin, Italy.

Background And Aims: The potential impact of coronary atherosclerosis, as detected by coronary artery calcium, on clinical outcomes in COVID-19 patients remains unsettled. We aimed to evaluate the prognostic impact of clinical and subclinical coronary artery disease (CAD), as assessed by coronary artery calcium score (CAC), in a large, unselected population of hospitalized COVID-19 patients undergoing non-gated chest computed tomography (CT) for clinical practice.

Methods: SARS-CoV 2 positive patients from the multicenter (16 Italian hospitals), retrospective observational SCORE COVID-19 (calcium score for COVID-19 Risk Evaluation) registry were stratified in three groups: (a) "clinical CAD" (prior revascularization history), (b) "subclinical CAD" (CAC >0), (c) "No CAD" (CAC = 0). Primary endpoint was in-hospital mortality and the secondary endpoint was a composite of myocardial infarction and cerebrovascular accident (MI/CVA).

Results: Amongst 1625 patients (male 67.2%, median age 69 [interquartile range 58-77] years), 31%, 57.8% and 11.1% had no, subclinical and clinical CAD, respectively. Increasing rates of in-hospital mortality (11.3% vs. 27.3% vs. 39.8%, p < 0.001) and MI/CVA events (2.3% vs. 3.8% vs. 11.9%, p < 0.001) were observed for patients with no CAD vs. subclinical CAD vs clinical CAD, respectively. The association with in-hospital mortality was independent of in-study outcome predictors (age, peripheral artery disease, active cancer, hemoglobin, C-reactive protein, LDH, aerated lung volume): subclinical CAD vs. No CAD: adjusted hazard ratio (adj-HR) 2.86 (95% confidence interval [CI] 1.14-7.17, p=0.025); clinical CAD vs. No CAD: adj-HR 3.74 (95% CI 1.21-11.60, p=0.022). Among patients with subclinical CAD, increasing CAC burden was associated with higher rates of in-hospital mortality (20.5% vs. 27.9% vs. 38.7% for patients with CAC score thresholds≤100, 101-400 and > 400, respectively, p < 0.001). The adj-HR per 50 points increase in CAC score 1.007 (95%CI 1.001-1.013, p=0.016). Cardiovascular risk factors were not independent predictors of in-hospital mortality when CAD presence and extent were taken into account.

Conclusions: The presence and extent of CAD are associated with in-hospital mortality and MI/CVA among hospitalized patients with COVID-19 disease and they appear to be a better prognostic gauge as compared to a clinical cardiovascular risk assessment.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025539PMC
April 2021

A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients.

Cell Rep 2021 Apr;35(2):108983

Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy; Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy. Electronic address:

Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1 and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.
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http://dx.doi.org/10.1016/j.celrep.2021.108983DOI Listing
April 2021

The impossible interviews-Sherlock Holmes interviews David Sackett: 'how much can we trust the guidelines?'

Eur Heart J 2021 Apr 2. Epub 2021 Apr 2.

Centro Cardiologico Universitario di Ferrara, Department of Translational Medicine, University of Ferrara, Azienda Ospedaliero Universitaria, via Aldo Moro 8, 44124 Cona (Ferrara), Italy.

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http://dx.doi.org/10.1093/eurheartj/ehab187DOI Listing
April 2021

Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.

J Cardiovasc Comput Tomogr 2021 Mar 11. Epub 2021 Mar 11.

San Gerardo Hospital, Monza, Italy.

Background: Coronavirus disease 2019 (COVID-19) has spread worldwide determining dramatic impacts on healthcare systems. Early identification of high-risk parameters is required in order to provide the best therapeutic approach. Coronary, thoracic aorta and aortic valve calcium can be measured from a non-gated chest computer tomography (CT) and are validated predictors of cardiovascular events and all-cause mortality. However, their prognostic role in acute systemic inflammatory diseases, such as COVID-19, has not been investigated.

Objectives: The aim was to evaluate the association of coronary artery calcium and total thoracic calcium on in-hospital mortality in COVID-19 patients.

Methods: 1093 consecutive patients from 16 Italian hospitals with a positive swab for COVID-19 and an admission chest CT for pneumonia severity assessment were included. At CT, coronary, aortic valve and thoracic aorta calcium were qualitatively and quantitatively evaluated separately and combined together (total thoracic calcium) by a central Core-lab blinded to patients' outcomes.

Results: Non-survivors compared to survivors had higher coronary artery [Agatston (467.76 ​± ​570.92 vs 206.80 ​± ​424.13 ​mm, p ​< ​0.001); Volume (487.79 ​± ​565.34 vs 207.77 ​± ​406.81, p ​< ​0.001)], aortic valve [Volume (322.45 ​± ​390.90 vs 98.27 ​± ​250.74 mm, p ​< ​0.001; Agatston 337.38 ​± ​414.97 vs 111.70 ​± ​282.15, p ​< ​0.001)] and thoracic aorta [Volume (3786.71 ​± ​4225.57 vs 1487.63 ​± ​2973.19 mm, p ​< ​0.001); Agatston (4688.82 ​± ​5363.72 vs 1834.90 ​± ​3761.25, p ​< ​0.001)] calcium values. Coronary artery calcium (HR 1.308; 95% CI, 1.046-1.637, p ​= ​0.019) and total thoracic calcium (HR 1.975; 95% CI, 1.200-3.251, p ​= ​0.007) resulted to be independent predictors of in-hospital mortality.

Conclusion: Coronary, aortic valve and thoracic aortic calcium assessment on admission non-gated CT permits to stratify the COVID-19 patients in-hospital mortality risk.
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http://dx.doi.org/10.1016/j.jcct.2021.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946543PMC
March 2021

Cardiovascular risk of chronic coronary syndrome patients according to vascular phenotype, diabetes, and smoking.

Eur J Prev Cardiol 2020 Dec 16. Epub 2020 Dec 16.

Department of Cardiology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, French Alliance for Cardiovascular Trials, INSERM U1148, Laboratory for Vascular Translational Science, 46 rue Henri Huchard, 75018, Paris, France.

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http://dx.doi.org/10.1093/eurjpc/zwaa137DOI Listing
December 2020

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients.

Crit Care 2021 02 19;25(1):74. Epub 2021 Feb 19.

Respiratory Section, Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, Italy.

Background: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.

Methods: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.

Results: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).

Conclusions: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.
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http://dx.doi.org/10.1186/s13054-021-03499-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894238PMC
February 2021

Myocarditis in COVID-19 patients: current problems.

Intern Emerg Med 2021 Jan 23. Epub 2021 Jan 23.

Cardiology Center, University of Ferrara, Viale Aldo Moro 8, 44024, Cona, Ferrara, Italy.

Myocarditis has been reported as a possible clinical presentation or complication in patients with coronavirus disease (COVID)-19 due to SARS-CoV-2. Despite the alarm that this possibility generated among physicians, there is paucity of information about mechanisms, prevalence, prognosis, diagnosis and therapy of myocarditis in the context of COVID-19. This brief review has the goal to revise and summarize current knowledge on myocarditis in COVID-19 patients and underline problems especially related to diagnosis and treatment.
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http://dx.doi.org/10.1007/s11739-021-02635-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823176PMC
January 2021

Differential Role of Circulating microRNAs to Track Progression and Pre-Symptomatic Stage of Chronic Heart Failure: A Pilot Study.

Biomedicines 2020 Dec 11;8(12). Epub 2020 Dec 11.

Immunology and Functional Genomics Unit, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy.

(1)Background: Chronic heart failure (CHF) contributes to the overall burden of cardiovascular disease. Early identification of at-risk individuals may facilitate the targeting of precision therapies. Plasma microRNAs are promising circulating biomarkers for their implications with cardiac pathologies. In this pilot study, we investigate the possible exploitability of circulating micro-RNAs (miRNAs) to track chronic heart failure (CHF) occurrence, and progression from NYHA class I to IV. (2)Methods: We screened 367 microRNAs using TaqMan microRNA Arrays in plasma samples from healthy controls (HC) and CHF NYHA-class I-to-IV patients (5/group). Validation was performed by singleplex assays on 10 HC and 61 CHF subjects. Differences in the expression of validated microRNAs were evaluated through analysis of covariance (ANCOVA). Associations between N-terminal pro-BNP (NT-proBNP), left ventricular end-diastolic volume (LVEDV) or peak oxygen uptake (VO2 peak) and plasma microRNA were assessed by multivariable linear regression analysis. (3)Results: Twelve microRNAs showed higher expression in CHF patients vs. HC. Seven microRNAs were associated with NT-proBNP concentration; of these, miR-423-5p was also an independent predictor of LVEDV. Moreover, miR-499-5p was a predictor of the VO2 peak. Finally, a cluster of 5 miRNAs discriminated New York Heart Association (NYHA) class-I from HC subjects. (4)Conclusions: Our data suggest that circulating miRNAs have the potential to serve as pathophysiology-based markers of HF status and progression, and as indicators of pre-symptomatic individuals.
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http://dx.doi.org/10.3390/biomedicines8120597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764340PMC
December 2020

Beta-blockers and COPD: how can harmony be restored in a marriage in crisis?

Eur Heart J 2020 12;41(46):4423-4424

Centro Cardiologico Universitario di Ferrara, University of Ferrara, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa873DOI Listing
December 2020

Use of risk scores to identify lower and higher risk subsets among COMPASS-eligible patients with chronic coronary syndromes. Insights from the CLARIFY registry.

Clin Cardiol 2021 Jan 4;44(1):58-65. Epub 2020 Dec 4.

Université de Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: The COMPASS trial showed a reduction of ischemic events with low-dose rivaroxaban and aspirin in chronic coronary syndromes (CCS) compared with aspirin alone, at the expense of increased bleeding.

Hypothesis: The CHA DS VaSc Score, REACH Recurrent Ischemic (RIS), and REACH Bleeding Risk Score (BRS) could identify patients with a favorable trade-off between ischemic and bleeding events, among COMPASS-eligible patients.

Methods: We identified the COMPASS-eligible population within the CLARIFY registry (>30.000 patients with CCS). High-bleeding risk patients (REACH BRS > 10) were excluded, as in the COMPASS trial. Patients were categorized as low (0-1) or high (≥ 2) CHA DS VaSc; low (0-12) or intermediate (13-19) REACH RIS, and low (0-6) or intermediate (7-10) REACH BRS. Ischemic outcome was the composite of cardiovascular death, myocardial infarction or stroke. Bleeding was defined as serious bleeding (haemorrhagic stroke, hospitalization for bleeding, transfusion).

Results: The COMPASS-eligible population comprised 5.142 patients with ischemic and bleeding outcome of 2.3 (2.1-2.5) and 0.5 (0.4-0.6) per 100 patient-years, respectively. Patients with intermediate REACH RIS (n = 1934 [37.6%]) had the higher ischemic risk (3.0 [2.6-3.4]) with similar bleeding risk (0.5 [0.4-0.7]) as the overall population. Patients with low CHA DS VaSc (n = 229 [4.4%]) had a very low ischemic risk (0.6 [0.3-1.3]) with similar bleeding risk (0.5 [0.2-1.1]).

Conclusions: Intermediate REACH RIS identified potential optimal candidates for adjunction of low-dose rivaroxaban while patients with low CHA DS VaSc score .appears unlikely to benefit from the COMPASS regimen. None of the three risk scores predicted the occurrence of serious bleeding.
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http://dx.doi.org/10.1002/clc.23505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803362PMC
January 2021

Diastolic dysfunction, frailty and prognosis in elderly patients with acute coronary syndromes.

Int J Cardiol 2021 Mar 30;327:31-35. Epub 2020 Nov 30.

UO Cardiologia, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy.

Background To investigate the relationship between 1-year outcome and diastolic dysfunction (DD) and frailty and/or physical performance (PP) in older adults admitted to hospital for acute coronary syndrome (ACS). Methods and results Older (age ≥ 70 years) hospitalized for ACS and receiving coronary artery angiography ± percutaneous coronary intervention were included. Before discharge a complete transthoracic echocardiogram (TTE) was performed with the assessment of DD, following the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging algorithm. Seven different scales of frailty and PP were assessed. The relationship between DD and tests of frailty and PP was investigated, as well as the association with the 1-year occurrence of all-cause death or re-hospitalization. Overall, 329 patients were included in the analysis. Patients were stratified in two groups: DD grade 0-1 versus 2-3. Those with undetermined degree of DD have been excluded by the analysis (n = 106). Mean age of the groups was 77 ± 5 vs 79 ± 6 years, respectively. Scales of frailty and/or PP were significantly poor in patients with DD grade 2-3 compared to the others. After multivariate Cox regression (considering age, female sex, haemoglobin, albumin, clinical presentation, LVEF and SPPB) DD (degree 2-3 vs. 0-1) emerged as an independent predictor of the composite endpoint (HR 1.69, 95%CI 1.04-2.75, p = 0.033). This was mainly driven by 1-year re-hospitalization (HR 2.01, 95%CI 1.22-3.27, p < 0.001). Conclusions In older ACS patients the assessment of DD is related to parameters of frailty and PP and it is an independent predictor of 1-year outcome.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.056DOI Listing
March 2021

Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure.

Platelets 2020 Dec 3:1-8. Epub 2020 Dec 3.

Department of Morphology, Surgery and Experimental Medicine, Intensive Care Section, University of Ferrara , Ferrara, Italy.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and -selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients ( = .003). In COVID-19 patients, -selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit ( = .004 and = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation ( < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality. ClinicalTrials.gov number: NCT04343053.
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http://dx.doi.org/10.1080/09537104.2020.1852543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754923PMC
December 2020

COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification.

Int J Mol Sci 2020 Nov 24;21(23). Epub 2020 Nov 24.

Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy.

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.
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http://dx.doi.org/10.3390/ijms21238917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727817PMC
November 2020

'Corona' versus 'coronary'.

Eur Heart J 2021 Feb;42(6):555-557

Maria Cecilia Hospital, Cotignola (RA), Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717209PMC
February 2021

Adapting to survive.

Eur Heart J 2020 11;41(41):3981-3983

Maria Cecilia Hospital, GVM Care&Research, Cotignola, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa675DOI Listing
November 2020

[Role of cardiac imaging in the diagnosis of infective endocarditis].

G Ital Cardiol (Rome) 2020 Nov;21(11):878-889

Centro Cardiologico Universitario e LTTA Centre, Università degli Studi, Ferrara - Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola (RA).

Infective endocarditis is an increasingly common disease in the hospital setting. Although the 2015 guidelines of the European Society of Cardiology deal extensively with many aspects of infective endocarditis, there are still unsolved problems related to diagnosis, in particular to the appropriate use of cardiac imaging methods, that require further study. The aim of this review is to analyze the advantages and limitations of the echocardiographic, radiological and nuclear imaging methods in order to identify diagnostic pathways applicable in clinical practice.
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http://dx.doi.org/10.1714/3455.34442DOI Listing
November 2020

Heart Failure Association of the European Society of Cardiology update on sodium-glucose co-transporter 2 inhibitors in heart failure.

Eur J Heart Fail 2020 11 27;22(11):1984-1986. Epub 2020 Oct 27.

Centre for Heart Diseases, Faculty of Health Sciences, Wrocław Medical University, Wrocław, Poland.

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: • Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. • Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline-directed medical therapy regardless of the presence of type 2 diabetes mellitus.
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http://dx.doi.org/10.1002/ejhf.2026DOI Listing
November 2020

The journey of omega-3 fatty acids in cardiovascular medicine.

Eur Heart J Suppl 2020 Oct 6;22(Suppl J):J49-J53. Epub 2020 Oct 6.

Cardiology Unit, Maria Cecilia Hospital, GVM Care & Research, via Corriera 1, 48033 Cotignola, Ravenna, Italy.

In subjects with cardiovascular risk factors or in patients in need of secondary prevention, hypertriglyceridemia is a well-defined risk factor for adverse cardiac events. Drugs containing n-3 polyunsaturated fatty acids () are approved for treatment of hypertriglyceridemia. In 1999, a cardioprotective effect in post infarct patients was suggested by a large multicentre study, the GISSI prevention trial. The hypothesized mechanism of action was an antiarrhythmic action leading to reduction of the sudden death. However, such a cardioprotective effect of n-3 PUFAs has not been straightforward like for other cardiovascular drugs such as aspirin, statins or ACE inhibitors. On the contrary, it has been a long journey with several ups and downs. Recently, the European Medicines Agency (EMA) has not confirmed the risk benefit of low dose of n-3 PUFA in preventing outcomes after a myocardial infarction. Since the EMA decision, the use of a high dose () of pure and stable EPA in a multicentre, international trial, the REDUCE-IT study showed a clear cardiovascular event reduction which was not confirmed in another trial, the STRENGTH study, which utilized 4g daily of an EPA+DHA mixture. It follows that the OMEGA-3 fatty acid story seems to be endless and the last word on cardiovascular benefits cannot be pronounced. We report a brief narrative of an entire journey from the beginning to nowadays.
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http://dx.doi.org/10.1093/eurheartj/suaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537797PMC
October 2020

Current Role of Echocardiography in Cardiac Resynchronization Therapy: from Cardiac Mechanics to Flow Dynamics Analysis.

Curr Heart Fail Rep 2020 12;17(6):384-396

Cardiac Unit, Azienda Ospedaliero-Universitaria, Via Aldo Moro 8, 44124, Cona (Ferrara), Italy.

Purpose Of Review: The aim of this review is to summarily explain what LV synchrony, coordination, myocardial work, and flow dynamics are, trying to clarify their advantages and limitations in the treatment of heart failure patients undergoing or with implanted cardiac resynchronization therapy (CRT).

Recent Findings: CRT is an established treatment for patients with heart failure and left ventricular systolic dysfunction. In the current guidelines, CRT implant indications rely only on electrical dyssynchrony, but in the last years, many aspects of cardiac mechanics (including contractile synchrony, coordination, propagation, and myocardial work) and flow dynamics have been studied using echocardiographic techniques to better characterize patients undergoing or with implanted CRT. However, the concepts, limits, and potential applications of all these echocardiographic evaluations are unclear to most clinicians. The use of left ventricular dyssynchrony and discoordination indices may help to identify those significant mechanical alterations whose correction may increase the probability of a favorable CRT response. Assessment of myocardial work and intracardiac flow dynamics may overcome some limitations of the conventional evaluation of cardiac mechanics but more investigations are needed before extensive clinical application.
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http://dx.doi.org/10.1007/s11897-020-00484-wDOI Listing
December 2020

Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement.

Europace 2020 12;22(12):1848-1854

Cardiological Center, University of Ferrara, Italy.

Aims: Our aim was to describe the electrocardiographic features of critical COVID-19 patients.

Methods And Results: We carried out a multicentric, cross-sectional, retrospective analysis of 431 consecutive COVID-19 patients hospitalized between 10 March and 14 April 2020 who died or were treated with invasive mechanical ventilation. This project is registered on ClinicalTrials.gov (identifier: NCT04367129). Standard ECG was recorded at hospital admission. ECG was abnormal in 93% of the patients. Atrial fibrillation/flutter was detected in 22% of the patients. ECG signs suggesting acute right ventricular pressure overload (RVPO) were detected in 30% of the patients. In particular, 43 (10%) patients had the S1Q3T3 pattern, 38 (9%) had incomplete right bundle branch block (RBBB), and 49 (11%) had complete RBBB. ECG signs of acute RVPO were not statistically different between patients with (n = 104) or without (n=327) invasive mechanical ventilation during ECG recording (36% vs. 28%, P = 0.10). Non-specific repolarization abnormalities and low QRS voltage in peripheral leads were present in 176 (41%) and 23 (5%), respectively. In four patients showing ST-segment elevation, acute myocardial infarction was confirmed with coronary angiography. No ST-T abnormalities suggestive of acute myocarditis were detected. In the subgroup of 110 patients where high-sensitivity troponin I was available, ECG features were not statistically different when stratified for above or below the 5 times upper reference limit value.

Conclusions: The ECG is abnormal in almost all critically ill COVID-19 patients and shows a large spectrum of abnormalities, with signs of acute RVPO in 30% of the patients. Rapid and simple identification of these cases with ECG at hospital admission can facilitate classification of the patients and provide pathophysiological insights.
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http://dx.doi.org/10.1093/europace/euaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543398PMC
December 2020

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial.

Lancet 2020 09 30;396(10254):830-838. Epub 2020 Aug 30.

Department of Cardiology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris-Descartes, Paris, France.

Background: Angina might persist or reoccur despite successful revascularisation with percutaneous coronary intervention (PCI) and antianginal therapy. Additionally, PCI in stable patients has not been shown to improve survival compared with optimal medical therapy. Trimetazidine is an antianginal agent that improves energy metabolism of the ischaemic myocardium and might improve outcomes and symptoms of patients who recently had a PCI. In this study, we aimed to assess the long-term potential benefits and safety of trimetazidine added to standard evidence-based medical treatment in patients who had a recent successful PCI.

Methods: We did a randomised, double-blind, placebo-controlled, event-driven trial of trimetazidine added to standard background therapy in patients who had undergone successful PCI at 365 centres in 27 countries across Europe, South America, Asia, and north Africa. Eligible patients were aged 21-85 years and had had either elective PCI for stable angina or urgent PCI for unstable angina or non-ST segment elevation myocardial infarction less than 30 days before randomisation. Patients were randomly assigned by an interactive web response system to oral trimetazidine 35 mg modified-release twice daily or matching placebo. Participants, study investigators, and all study staff were masked to treatment allocation. The primary efficacy endpoint was a composite of cardiac death; hospital admission for a cardiac event; recurrence or persistence of angina requiring an addition, switch, or increase of the dose of at least one antianginal drug; or recurrence or persistence of angina requiring a coronary angiography. Efficacy analyses were done according to the intention-to-treat principle. Safety was assessed in all patients who had at least one dose of study drug. This study is registered with the EU Clinical Trials Register (EudraCT 2010-022134-89).

Findings: From Sept 17, 2014, to June 15, 2016, 6007 patients were enrolled and randomly assigned to receive either trimetazidine (n=2998) or placebo (n=3009). After a median follow-up of 47·5 months (IQR 42·3-53·3), incidence of primary endpoint events was not significantly different between the trimetazidine group (700 [23·3%] patients) and the placebo group (714 [23·7%]; hazard ratio 0·98 [95% CI 0·88-1·09], p=0·73). When analysed individually, there were no significant differences in the incidence of the components of the primary endpoint between the treatment groups. Similar results were obtained when patients were categorised according to whether they had an elective or urgent PCI. 1219 (40·9%) of 2983 patients in the trimetazidine group and 1230 (41·1%) of 2990 patients in the placebo group had serious treatment-emergent adverse events. Frequencies of adverse events of interest were similar between the groups.

Interpretation: Our results show that the routine use of oral trimetazidine 35 mg twice daily over several years in patients receiving optimal medical therapy, after successful PCI, does not influence the recurrence of angina or the outcome; these findings should be taken into account when considering the place of trimetazidine in clinical practice. However, the long-term prescription of this treatment does not appear to be associated with any statistically significant safety concerns in the population studied.

Funding: Servier.
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http://dx.doi.org/10.1016/S0140-6736(20)31790-6DOI Listing
September 2020

Right Atrial Pressure Is Associated with Outcomes in Patients with Heart Failure and Indeterminate Left Ventricular Filling Pressure.

J Am Soc Echocardiogr 2020 11 31;33(11):1345-1356. Epub 2020 Jul 31.

Cardiology Unit and LTTA Centre, University of Ferrara, Cona, Italy; Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy.

Background: In a significant proportion of patients with left-sided heart failure (HF), left ventricular filling pressure (LVFP) may not be estimated using echocardiography, so filling pressure status may remain indeterminate. In these patients, mean right atrial pressure (mRAP) has been suggested as a surrogate of LVFP. The aim of this study was to determine whether high mRAP has prognostic value in patients with HF with indeterminate pressure (IP) and whether mRAP-based reclassification of patients with IP has an impact on outcomes.

Methods: A cohort of 465 patients hospitalized with HF was retrospectively studied and divided into groups with normal pressure (n = 102), high pressure (n = 265), and IP (n = 98). A composite end point of all-cause mortality and HF rehospitalization was evaluated after a median follow-up duration of 2.5 years.

Results: There were 282 events in the entire population (53 in the normal pressure group, 173 in the high pressure group, and 56 in the IP group; P = .047). High mRAP was independently associated with outcome only in patients with IP (hazard ratio, 2.72; 95% CI, 1.25-5.9; P = .012). Evaluation of LVFP after mRAP-based reclassification of patients with IP resulted in higher risk stratification capability than current recommendations alone (log-rank χ = 15.057 vs 8.148).

Conclusions: In patients with inconclusive determination of LVFP, echocardiographic estimation of mRAP is associated with outcomes. This finding corroborates previous observation of mRAP as a surrogate marker of elevated LVFP in left-sided HF and suggests its use in clinical practice.
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http://dx.doi.org/10.1016/j.echo.2020.05.027DOI Listing
November 2020

Left ventricular output indices in hospitalized heart failure: when "simpler" may not mean "better".

Int J Cardiovasc Imaging 2021 Jan 30;37(1):59-68. Epub 2020 Jul 30.

Cardiology Unit and LTTA Centre, University of Ferrara, Ferrara, Italy.

Assessment of left ventricular (LV) output in hospitalized patients with heart failure (HF) is important to determine prognosis. Although echocardiographic LV ejection fraction (EF) is generally used to this purpose, its prognostic value is limited. In this investigation LV-EF was compared with other echocardiographic per-beat measures of LV output, including non-indexed stroke volume (SV), SV index (SVI), stroke distance (SD), ejection time (ET), and flow rate (FR), to determine the best predictor of all-cause mortality in patients hospitalized with HF. A final cohort of 350 consecutive patients hospitalized with HF who underwent echocardiography during hospitalization was studied. At a median follow-up of 2.7 years, 163 patients died. Non-survivors at follow-up had lower SD, SVI and SV, but not ET, FR and LV-EF than survivors. At multivariate analysis, only age, systolic blood pressure, chronic kidney disease, chronic obstructive pulmonary disease, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SVI remained significantly associated with outcome [HR for SVI 1.13 (1.04-1.22), P = 0.003]. In particular, for each 5 ml/m decrease in SVI, a 13% increase in risk of mortality for any cause was observed. SVI is a powerful prognosticator in HF patients, better than other per-beat measures, which may be simpler but partial or incomplete descriptors of LV output. SVI, therefore, should be considered for the routine echocardiographic evaluation of patients hospitalized with HF to predict prognosis.
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http://dx.doi.org/10.1007/s10554-020-01946-xDOI Listing
January 2021