Publications by authors named "Fabrizio Montecucco"

342 Publications

The impossible quest to make cardiac amyloidosis diagnosis easy.

Eur J Clin Invest 2021 Feb 11:e13512. Epub 2021 Feb 11.

IRCCS Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1111/eci.13512DOI Listing
February 2021

Ficolin-2 serum levels predict the occurrence of acute coronary syndrome in patients with severe carotid artery stenosis.

Pharmacol Res 2021 Jan 26;166:105462. Epub 2021 Jan 26.

Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. Electronic address:

Background And Purpose: erosion of vulnerable atherosclerotic plaques may cause life-threatening thromboembolic complications. There is indeed an urgent need to recognize a clear-cut biomarker able to identify vulnerable plaques. Here, we focused on circulating proteins belonging to the lectin pathway (LP) of complement activation.

Methods: we analyzed mannose-binding lectin (MBL), ficolin-1, -2 and -3 (LP initiators) levels by ELISA in sera from n = 240 of an already published cohort of patients undergoing endarterectomy for severe carotid stenosis and followed-up until 18 months after surgery. Immunofluorescence followed by confocal and polarized light microscopy was used to detect LP initiator intraplaque localization. Spearman's rank test was drawn to investigate correlation between serum LP levels and circulating inflammatory proteins or intraplaque components. Survival analyses were then performed to test the predictive role of LP on long-term adverse outcome.

Results: ficolins, but not MBL, correlated positively with 1) high circulating levels of inflammatory markers, including MPO, MMP-8, MMP-9, ICAM-1, osteopontin, neutrophil elastase, and; 2) immune cell intraplaque recruitment. Immunofluorescence showed ficolins in calcified plaques and ficolin-2 in cholesterol-enriched plaque regions in association with macrophages. In the multivariate survival analysis, ficolin-2 serum levels predicted a major adverse cardiovascular event during the follow-up, independently of symptomatic status and inflammatory markers (hazard ratio 38.6 [95 % CI 3.9-385.2]).

Conclusions: ficolins support intraplaque immune cell recruitment and inflammatory processes ultimately leading to plaque vulnerability. Especially for ficolin-2 a strong predictive value toward adverse cardiovascular events was demonstrated. This evidence offers potentially new pharmacological target to dampen the inflammatory mechanisms leading to plaque vulnerability.
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http://dx.doi.org/10.1016/j.phrs.2021.105462DOI Listing
January 2021

Diabetic cardiomyopathy and inflammation: development of hostile microenvironment resulting in cardiac damage.

Minerva Cardioangiol 2021 Jan 11. Epub 2021 Jan 11.

IRCCS Ospedale Policlinico San Martino Genoa, Italian Cardiovascular Network, Genoa, Italy -

Diabetes mellitus is emerging as a major risk factor for heart failure. Diabetic cardiomyopathy is defined as a myocardial dysfunction that is not caused by underlying hypertension or coronary artery disease. Studies about clinical features, natural history and outcomes of the disease are few and often conflicting, because a universally accepted operative definition of diabetic cardiomyopathy is still lacking. Hyperglycemia and related metabolic and endocrine disorders are the triggering factors of myocardial damage in diabetic cardiomyopathy through multiple mechanisms. Among these mechanisms, inflammation has a relevant role, similar to other chronic myocardial disease, such as hypertensive or ischemic heart disease. A balance between inflammatory damage and healing processes is fundamental for homeostasis of myocardial tissue, whereas diabetes mellitus produces an imbalance, promoting inflammation and delaying healing. Therefore, diabetes-related chronic inflammatory state can produce a progressive qualitative deterioration of myocardial tissue, which reflects on progressive left ventricular functional impairment, which can be either diastolic, with prevalent myocardial hypertrophy, or systolic, with prevalent myocardial fibrosis. The aim of this narrative review is to summarize the existing evidence about the role of inflammation in diabetic cardiomyopathy onset and development. Ultimately, potential pharmacological strategies targeting inflammatory response will be reviewed and discussed.
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http://dx.doi.org/10.23736/S0026-4725.20.05454-7DOI Listing
January 2021

Prognostic and therapeutic considerations of antibodies against c-ter apolipoprotein A-1 in the general population.

Clin Transl Immunology 2020 14;9(12):e1220. Epub 2020 Dec 14.

Department of Internal Medicine Lausanne University Hospital Lausanne Switzerland.

Objectives: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgGs) and its C-terminal region (cter apoA1) have emerged as an independent biomarker for cardiovascular disease. Cter apoA1 mimetic peptides were shown to reverse the deleterious anti-apoA1 IgG effects . We evaluated the association of anti-cter apoA1 IgGs with overall mortality in the general population and tested the ability of a cter apoA1 mimetic peptide to reverse the anti-apoA1 IgG-induced inflammatory response and mortality and , respectively.

Methods: Anti-cter apoA1 IgGs were measured in serum samples of 6386 participants of the CoLaus study of which 5220 were followed for a median duration of 5.6 years. The primary outcome was overall mortality. The peptide inhibitory concentration 50% (IC) was determined on HEK-Blue-4 and RAW cells. ApoE mice were exposed to 16 weeks of anti-apoA1IgG passive immunisation with and without peptide co-incubation.

Results: Anti-cter apoA1 IgGs were associated with higher interleukin 6 levels and independently predicted overall mortality; an increase of one standard deviation of anti-cter apoA1 IgG level was associated with an 18% increase in mortality risk (hazard ratio: 1.18, 95% confidence interval: 1.04-1.33;  = 0.009). The cterApoA1 analogue reversed the antibody-mediated inflammatory response with an IC of 1 µm but did not rescue the significant anti-apoA1 IgG-induced mortality rate (69% vs. 23%, LogRank  = 0.02).

Conclusion: Anti-cter apoA1 IgG independently predicts overall mortality in the general population. Despite being effective , our cter apoA1 analogue did not reverse the anti-apoA1 IgG-induced mortality in mice. Our data suggest that these autoantibodies are not readily treatable through cognate peptide immunomodulation.
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http://dx.doi.org/10.1002/cti2.1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734471PMC
December 2020

Updating concepts on atherosclerotic inflammation: From pathophysiology to treatment.

Eur J Clin Invest 2020 Dec 1:e13467. Epub 2020 Dec 1.

Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, Genoa, Italy.

Background: Atherosclerosis is recognized as a systemic low-grade inflammatory disease. Furthermore, the dysregulation of the inflammatory response and its timely resolution is a pivotal process in determining the clinical manifestations of cardiac and cerebral acute ischaemia following atherothrombosis.

Methods: This narrative review is based on the material searched on PubMed up to October 2020. The search terms we used were as follows: "atherosclerosis, inflammation, acute myocardial infarction and ischemic stroke" in combination with "biomarker, inflammatory cells and molecules, treatment."

Results: The expected goal of addressing inflammation for the treatment of atherosclerosis and its acute ischaemic complications is reducing mortality and morbidity related to atherosclerotic cardiovascular disease, which are currently the first cause of death and disability worldwide. In this narrative review, we summarize the evidence about the main cellular and molecular mechanisms of inflammation in atherogenesis, atherothrombosis and acute ischaemic complications, with particular focus on the potential molecular targets for novel pharmacological treatments.

Conclusion: Although a large amount of evidence from animal models of atherothrombotic disease, and promising results of clinical trials, anti-inflammatory treatments against atherosclerosis are not yet recommended. A deepest understanding of pathophysiological mechanisms underlying the mechanisms driving resolution of the acute inflammation will probably allow to identify the optimal molecular target.
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http://dx.doi.org/10.1111/eci.13467DOI Listing
December 2020

The role of potassium in atherosclerosis.

Eur J Clin Invest 2021 Mar 27;51(3):e13454. Epub 2020 Nov 27.

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Atherosclerosis (AS) is a chronic progressive inflammatory condition with a leading prevalence worldwide. Endothelial dysfunction leads to low-density lipoprotein trafficking into subendothelial space and the subsequent form of oxidized LDL (ox-LDL) within intimal layer, perpetuating the vicious cycle of endothelial dysfunction. K+ exerts beneficial effects in vascular wall by reducing LDL oxidization, vascular smooth muscle cells (VSMCs) proliferation, and free radical generation. K+ also modulates vascular tone through a regulatory effect on cell membrane potential.

Materials And Methods: The most relevant papers on the association between 'potassium channels' and 'atherosclerosis' were selected among those deposited on PubMed from 1990 to 2020.

Results: Here, we provide a short narrative review that elaborates on the role of K+ in atherosclerosis. This review also update the current knowledge about potential pharmacological agents targeting K+ channels with a special focus on pleiotropic activities of agents such as statins, sulfonylureas and dihydropyridines.

Conclusion: In this review, the mechanism of different K+ channels on vascular endothelium will be summarized, mainly focusing on their pathophysiological role in atherosclerosis and potential therapeutic application.
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http://dx.doi.org/10.1111/eci.13454DOI Listing
March 2021

Frailty assessment, hip fracture and long-term clinical outcomes in older adults.

Eur J Clin Invest 2020 Nov 1:e13445. Epub 2020 Nov 1.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background: The primary aim of the study was determining the validation of the modified 19-item Frailty Index (mFI-19), based on the standard procedure for creating a frailty index scoring in the accumulation deficit theory of Rockwood and comparing it with the gold standard comprehensive geriatric assessment (CGA) in old age patients with hip fracture. As a secondary aim, we compared prognostic accuracies of mFI-19 and CGA in predicting long-term mortality after surgery.

Materials And Methods: A total of 364 older patients with hip fractures, each a candidate for surgery, were consecutively enrolled. All were subjected to CGA and mFI-19 at baseline and time to death (years from hip surgery) were collected prospectively.

Results: Mean patient age was 86.5 (SD: 5.65) years. The most common clinical phenotype (77%) was frail. Both CGA and mFI-19 performed similarly in predicting long-term mortality (Harrell's C-index: 0.66 and 0.68, respectively).

Conclusions: The mFI-19 was validated, compared to the gold standard CGA, based on a systematic process for creating a frailty index in relation to the accumulation deficit. This is one of few prospective studies addressing long-term mortality in older adults with hip fractures, invoking a methodologically robust frailty screening assessment.
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http://dx.doi.org/10.1111/eci.13445DOI Listing
November 2020

Atherosclerotic plaque vulnerability is increased in mouse model of lupus.

Sci Rep 2020 10 27;10(1):18324. Epub 2020 Oct 27.

Division of Cardiology, Foundation for Medical Researches, Department of Medicine Specialties, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211, Geneva 4, Switzerland.

Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe mice resulting in ApoeNba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although ApoeNba2.Yaa and Apoe mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in ApoeNba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though ApoeNba2.Yaa mice and Apoe mice had similar lipid levels, ApoeNba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. ApoeNba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of ApoeNba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone ApoeNba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.
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http://dx.doi.org/10.1038/s41598-020-74579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591560PMC
October 2020

Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques.

Int J Mol Sci 2020 10 19;21(20). Epub 2020 Oct 19.

Division of Cardiology, Foundation for Medical Researches, Department of Medicine Specialties, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211 Geneva, Switzerland.

Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated.

Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients.

Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients.

Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.
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http://dx.doi.org/10.3390/ijms21207721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588926PMC
October 2020

Emerging role for the inflammatory biomarker osteopontin in adverse cardiac remodeling.

Biomark Med 2020 10 15;14(14):1303-1306. Epub 2020 Oct 15.

First Clinic of internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.

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http://dx.doi.org/10.2217/bmm-2020-0455DOI Listing
October 2020

Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1).

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.

Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden chamber migration assay and checkerboard analysis we showed a dose-dependent chemotactic effect of r-TPA with a maximum effect reached by 0.03 mg/mL (0.003-1 mg/mL). Pre-incubation with MAP kinases inhibitors allowed the identification of PI3K/Akt, but not ERK1/2 as the intracellular pathway mediating the observed effects. Furthermore, by means of real-time PCR, immunocytochemistry and cytofluorimetry we demonstrated that the r-tPA receptor low density lipoprotein receptor-related protein 1 (LRP-1) is synthetized and expressed by neutrophils in response to r-tPA and TNF-α. Inhibition of LRP-1 by receptor-associated protein (RAP), prevented r-tPA-mediated F-actin polymerization, migration and signal through Akt but not ERK1/2. Lastly, also neutrophil degranulation in response to r-tPA seems to be mediated by LRP-1 under adhesion conditions. In conclusion, we show that r-tPA induces neutrophil chemotaxis through LRP-1/Akt pathway. Blunting r-tPA-mediated neutrophil activation might be beneficial as an adjuvant therapy to thrombolysis in this setting.
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http://dx.doi.org/10.3390/ijms21197014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582901PMC
September 2020

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system.

Cardiovasc Res 2020 Sep 15. Epub 2020 Sep 15.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren, Switzerland.

Aims: Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation.

Methods And Results: Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5.

Conclusions: SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events.

Translational Perspectives: This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting.
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http://dx.doi.org/10.1093/cvr/cvaa268DOI Listing
September 2020

Anti-ApoA-1 IgGs predict resistance to waist circumference reduction after Mediterranean diet.

Eur J Clin Invest 2021 Mar 27;51(3):e13410. Epub 2020 Sep 27.

Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy.

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http://dx.doi.org/10.1111/eci.13410DOI Listing
March 2021

Serum osteopontin predicts glycaemic profile improvement in metabolic syndrome: A pilot study.

Eur J Clin Invest 2021 Mar 25;51(3):e13403. Epub 2020 Sep 25.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.

Prediabetes is often observed in patients with Metabolic Syndrome (MetS) and might be associated with metabolic and inflammatory alterations. Here, we investigated whether the inflammatory molecule osteopontin (OPN) might have a prognostic impact in a cohort of MetS patients (n = 85) with baseline normal glycaemia or impaired fasting glucose (IFG) over one year of recommended pharmacological treatments and Mediterranean diet. Patients were then followed up for 12 months with intermediate evaluation after 6 months. At all time points, anthropometric and clinical data were recorded, alongside with haematological and biochemical profiles, including serum concentrations of OPN. As expected, Mediterranean diet improves glycaemic profile in patients with IFG. Baseline serum OPN failed to be associated with baseline anthropometric or biochemical variables. At baseline, higher levels of OPN were shown in patients with IFG as compared to normal glycaemia. Two distinct subgroups of patients in whom OPN decreased or remained stable/increased at follow-up were identified. When higher serum OPN levels were observed at baseline, greater reduction was observed at 1-year follow-up. Reduction in circulating OPN levels was associated with metabolic improvement in terms of blood pressure, LDL-c, HDL-c, and glycaemia. At both univariate and adjusted logistic regression analyses, serum OPN emerged as an independent predictor of glycaemic profile improvement at 1-year follow-up (adjOR 1.05 [1.00-1.10]; P = .041). In conclusion, pharmacological and dietetic interventions improved glycaemic profile in patients with MetS. In particular, glycaemic improvement was demonstrated in patients who also reduce circulating OPN levels. Higher OPN levels at baseline predict normalization of glycaemic profile.
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http://dx.doi.org/10.1111/eci.13403DOI Listing
March 2021

Statins: Epidrugs with effects on endothelial health?

Eur J Clin Invest 2020 Dec 13;50(12):e13388. Epub 2020 Sep 13.

Halal Research Center of IRI, FDA, Tehran, Iran.

Background: Epigenetic events involving the methylation of CpG cites in DNA, histone modifications and noncoding RNAs correlated with many essential processes in human cells and diseases, such as cancer and cardiovascular diseases. HMG-CoA reductase inhibitors (statins)-the LDL cholesterol-lowering drugs-are broadly used in cardio- and cerebro-vascular diseases. It is well established that statins exert pleiotropic functions, but how they exert effects on epigenetic modifications independently of HMG-CoA reductase inhibition is not yet clear. Thereby, understanding these mechanisms may pave the way for further clinical application of statin therapy.

Design: Following and electronic database search, studies reporting substantial effects of statins on epigenetic reprogramming in both cultured cells and in vivo models were retrieved and reviewed.

Results: Epigenetic mechanisms play an essential role in cellular development and function, and data collected in the past few years have revealed that many of the pleiotropic properties of statins are mediated by epigenetic mechanisms. Furthermore, those 'nonclassical' effects are not limited to CV field but they would extend to other conditions such as malignancies.

Conclusion: This review suggests that the epigenetic effects of statins mediate, at least in part, the pleiotropic actions of these drugs but further validation of such effects in clinical studies is yet to be provided.
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http://dx.doi.org/10.1111/eci.13388DOI Listing
December 2020

Clinical Presentation and Outcomes of Acute Pericarditis in a Large Urban Hospital in the United States of America.

Chest 2020 Dec 24;158(6):2556-2567. Epub 2020 Jul 24.

Pauley Heart Center, Virginia Commonwealth University, Richmond, VA. Electronic address:

Background: Acute pericarditis is the most common presentation of pericardial diseases. Although generally benign, complications such as constrictive pericarditis, cardiac tamponade, and recurrence can occur.

Research Question: What are the clinical factors associated with adverse outcomes in acute pericarditis?

Study Design And Methods: We used an informatics-based search engine to search for International Classification of Diseases codes related to pericardial disease between January 1, 2009 and November 14, 2018 and then extracted clinical information, including only patients meeting the European Society of Cardiology criteria for acute pericarditis. We then evaluated the predictive value of clinical characteristics for adverse outcomes (cardiac tamponade, constrictive pericarditis, failure of therapy, recurrences, or death).

Results: We identified 240 patients with a first episode of pericarditis (51 [34-62] years, 56% males and 50% white). Pericarditis was determined to be idiopathic in 126 (53%) cases and related to cardiac injury in 79 (33%). During a median follow-up time of 179 (20-450) days, 82 (34%) patients experienced at least one adverse outcome. Subacute presentation was an independent predictor of adverse outcomes. Patients with postcardiac injury pericarditis had a lower incidence in the composite of failure of treatment and recurrence (13% vs 26%; P = .022) compared with patients with idiopathic pericarditis. Troponin I measurements were obtained in 167 patients (70%). Elevated troponin I levels were associated with lower incidence of recurrences (4% vs 17%; P = .024) and of the composite outcome (13% vs 36%; P = .004).

Interpretation: Acute pericarditis is associated with at least one adverse outcome in 34% of patients. Subacute presentation and idiopathic etiology are associated with higher incidence of adverse outcomes, whereas elevated troponin I levels identify a group with reduced risk of recurrences.
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http://dx.doi.org/10.1016/j.chest.2020.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768931PMC
December 2020

Supremacy of echocardiography in the diagnostic workup of systemic AL amyloidosis.

Eur Heart J 2020 Sep;41(36):3487

Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa535DOI Listing
September 2020

Inflammatory Biomarkers for Cardiovascular Risk Stratification in Familial Hypercholesterolemia.

Rev Physiol Biochem Pharmacol 2020 ;177:25-52

Halal Research Center of IRI, FDA, Tehran, Iran.

Familial hypercholesterolemia (FH) is a frequent autosomal genetic disease characterized by elevated concentrations of low-density lipoprotein cholesterol (LDL) from birth with increased risk of premature atherosclerotic complications. Accumulating evidence has shown enhanced inflammation in patients with FH. In vessels, the deposition of modified cholesterol lipoproteins triggers local inflammation. Then, inflammation facilitates fatty streak formation by activating the endothelium to produce chemokines and adhesion molecules. This process eventually results in the uptake of vascular oxidized LDL (OxLDL) by scavenger receptors in monocyte-derived macrophages and formation of foam cells. Further leukocyte recruitment into the sub-endothelial space leads to plaque progression and activation of smooth muscle cells proliferation. Several inflammatory biomarkers have been reported in this setting which can be directly synthetized by activated inflammatory/vascular cells or can be indirectly produced by organs other than vessels, e.g., liver. Of note, inflammation is boosted in FH patients. Inflammatory biomarkers might improve the risk stratification for coronary heart disease and predict atherosclerotic events in FH patients. This review aims at summarizing the current knowledge about the role of inflammation in FH and the potential application of inflammatory biomarkers for cardiovascular risk estimation in these patients.
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http://dx.doi.org/10.1007/112_2020_26DOI Listing
January 2021

Dysfunctional high-density lipoprotein: the role of myeloperoxidase and paraoxonase-1.

Curr Med Chem 2020 Jul 15. Epub 2020 Jul 15.

Halal Research Center of IRI, FDA, Tehran. Iran.

Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.
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http://dx.doi.org/10.2174/0929867327999200716112353DOI Listing
July 2020

Inflammation and cardiovascular diseases: lessons from seminal clinical trials.

Cardiovasc Res 2021 Jan;117(2):411-422

Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland.

Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials-including the Cardiovascular Inflammation Reduction Trial one using methotrexate-were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory Phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.
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http://dx.doi.org/10.1093/cvr/cvaa211DOI Listing
January 2021

Postischemic Administration of IL-1α Neutralizing Antibody Reduces Brain Damage and Neurological Deficit in Experimental Stroke.

Circulation 2020 Jul 13;142(2):187-189. Epub 2020 Jul 13.

Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland (L.L, N.R.B., Y.M.P., L.S., A.A., J.H.B., T.F.L., G.G.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046301DOI Listing
July 2020

The role of resistin and myeloperoxidase in severe sepsis and septic shock: Results from the ALBIOS trial.

Eur J Clin Invest 2020 Oct 13;50(10):e13333. Epub 2020 Jul 13.

IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Genoa, Italy.

Background: Inflammatory biomarkers are useful in detecting patients with sepsis. The prognostic role of resistin and myeloperoxidase (MPO) has been investigated in sepsis.

Materials And Methods: Plasma resistin and MPO were measured on days 1, 2 and 7 in 957 patients enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. The association between resistin and MPO levels on day 1, 2 and 7 and 90-day mortality was assessed.

Results: Plasma resistin and MPO concentrations were higher at day 1 and decreased until day 7. Both biomarkers were positively correlated with each other and with physiological parameters. Higher levels of resistin and MPO on day 1 were associated with the development of new organ failures. Patients experiencing death at 90 days showed higher levels of resistin and MPO compared with survivors. At day 1, only MPO in the 4th quartile (Q4), but not resistin, was found to predict 90-day death (adjusted hazard ratio [aHR] 1.55 vs Q1). At day 2, resistin in the Q3 and Q4 predicted a > 40% increase in mortality as also did MPO in the Q4. On day 7, Q4 resistin was able to predict 90-day mortality, while all quartiles of MPO were not.

Conclusions: High levels of MPO, but not of resistin, on day 1 were able to predict 90-day mortality. These findings may either suggest that early hyper-activation of neutrophils is detrimental in patients with sepsis or reflect the burden of the inflammatory process caused by sepsis. Further studies are warranted to deepen these aspects (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).
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http://dx.doi.org/10.1111/eci.13333DOI Listing
October 2020

Adipocytokines and cardiovascular diseases: Putative role of Neuregulin 4.

Eur J Clin Invest 2020 Jun 8:e13306. Epub 2020 Jun 8.

First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.

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http://dx.doi.org/10.1111/eci.13306DOI Listing
June 2020

SARS-CoV-2: What is known and what there is to know-Focus on coagulation and lipids.

Eur J Clin Invest 2020 Jul 25;50(7):e13311. Epub 2020 Jun 25.

Department of Endocrinology, Diabetology and Metabolic Diseases, Faculty of Medicine and Health Sciences, Deurne/Antwerp University of Antwerp, Antwerp, Belgium.

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http://dx.doi.org/10.1111/eci.13311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300477PMC
July 2020

SARS-CoV-2 outbreak and lockdown in a Northern Italy hospital. Comparison with Scandinavian no-lockdown country.

Eur J Clin Invest 2020 Jun 7:e13302. Epub 2020 Jun 7.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1111/eci.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300436PMC
June 2020

Serum adiponectin levels are associated with presence of carotid plaque in women with systemic lupus erythematosus.

Nutr Metab Cardiovasc Dis 2020 06 27;30(7):1147-1151. Epub 2020 Mar 27.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy.

Background And Aim: Systemic lupus erythematosus (SLE) is associated with accelerated atherogenesis. Traditional risk factors do not seem to fully explain this process in patients with SLE and no other imaging/serum biomarkers have so far improved risk stratification. Here, we focused on the role of adiponectin in women with SLE.

Methods And Results: This is a sub-analysis of a validated cohort enrolling eighty females (age 18-65 years) affected by SLE. Patient underwent a single blood sampling and carotid echography. Serum adipocytokines (i.e. leptin, resistin and adiponectin) were assessed by enzyme-linked immunosorbent assay (ELISA). Patients with a carotid plaque (n = 23) were older, with longer duration of the disease, chronic use of corticosteroids, and immunosuppressive therapies. As expected, patients with a carotid plaque had increased vascular risk and high serum levels of inflammatory biomarkers, total and LDL cholesterol and adiponectin. Significant positive correlation between serum adiponectin and presence of a carotid plaque was found independently of patient age, SCORE Risk Charts, duration of disease, and SLE treatments.

Conclusions: These results indicate that high serum adiponectin is associated with accelerated carotid atherosclerosis in SLE young women and it might be useful to improve vascular risk stratification in this patient setting.
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http://dx.doi.org/10.1016/j.numecd.2020.03.020DOI Listing
June 2020

Early osteopontin levels predict mortality in patients with septic shock.

Eur J Intern Med 2020 08 11;78:113-120. Epub 2020 May 11.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy; First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.

Background: Inflammatory biomarkers could be useful to stratify the risk of sepsis adverse outcome and potentially improving the clinical management. Here, we investigated the prognostic role of the inflammatory molecule osteopontin (OPN) in patients with severe sepsis with and without septic shock.

Material And Methods: This is a sub-analysis of 957 patients with sepsis/septic shock from the Albumin Italian Outcome Sepsis (ALBIOS) study. Alongside demographic, clinical, and laboratory data, we assessed plasmatic values of OPN at day 1, 2 and 7 after enrolment. The primary outcome was the predictive role of OPN values at day 1on death for any cause at 28 days after enrolment.

Results: Plasma OPN values at day 1 were higher in patients with septic shock and correlated with the severity of multi-organ dysfunction. Once categorized for 28-day mortality, survivors were characterized by lower OPN levels at each time point and statistically significant drop overtime (p<0.001 for all). Similarly, OPN reduction during the first 7 days was associated with reduced hospitalization and mortality overtime. Multivariate logistic and Cox regression models confirmed plasma OPN at day 1 as predictor of both 28- and 90-day mortality and infection resolution as well, independently of demographic, clinical and therapeutic variables. However, this prognostic value was limited to septic shock patients.

Conclusions: In patients with septic shock, OPN plasma levels at day 1 predict a poor clinical outcome. These results provide the rationale for future pathophysiological studies aimed at clarifying the mechanisms triggered by OPN in septic shock (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).
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http://dx.doi.org/10.1016/j.ejim.2020.04.035DOI Listing
August 2020

Statins and the COVID-19 main protease: evidence on direct interaction.

Arch Med Sci 2020 25;16(3):490-496. Epub 2020 Apr 25.

Halal Research Center of IRI, FDA, Tehran, Iran.

Introduction: No proven drug and no immunisation are yet available for COVID-19 disease. The SARS-CoV-2 main protease (Mpro), a key coronavirus enzyme, which is a potential drug target, has been successfully crystallised. There is evidence suggesting that statins exert anti-viral activity and may block the infectivity of enveloped viruses. The aim of this study was to assess whether statins are potential COVID-19 Mpro inhibitors, using a molecular docking study.

Material And Methods: Molecular docking was performed using AutoDock/Vina, a computational docking program. SARS-CoV-2 Mpro was docked with all statins, while antiviral and antiretroviral drugs - favipiravir, nelfinavir, and lopinavir - were used as standards for comparison.

Results: The binding energies obtained from the docking of 6LU7 with native ligand favipiravir, nelfinavir, lopinavir, simvastatin, rosuvastatin, pravastatin, pitavastatin, lovastatin, fluvastatin, and atorvastatin were -6.8, -5.8, -7.9, -7.9, -7.0, -7.7, -6.6, -8.2, -7.4, -7.7, and -6.8 kcal/mol, respectively. The number of hydrogen bonds between statins and amino acid residues of Mpro were 7, 4, and 3 for rosuvastatin, pravastatin, and atorvastatin, respectively, while other statins had two hydrogen bonds.

Conclusions: These results indicate, based upon the binding energy of pitavastatin, rosuvastatin, lovastatin, and fluvastatin, that statins could be efficient SARS-CoV-2 Mpro inhibitors. This is supported by the fact that the effects of some statins, especially pitavastatin, have a binding energy that is even greater than that of protease or polymerase inhibitors. However, further research is necessary to investigate their potential use as drugs for COVID-19.
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http://dx.doi.org/10.5114/aoms.2020.94655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212226PMC
April 2020

Anti-DFS70 antibodies detected by specific methods in patients with thrombosis or recurrent pregnancy loss: no evidence of an association.

Sci Rep 2020 05 8;10(1):7748. Epub 2020 May 8.

Dipartimento Biotecnologie Mediche, Università degli Studi di Siena, UOC Laboratorio Patologia Clinica, Policlinico S. Maria alle Scotte, AOU Senese, Siena, Italy.

A dense fine speckled pattern (DFS) caused by antibodies to the DFS70 kDa nuclear protein is a relatively common finding while testing for anti-nuclear antibodies (ANA) by indirect immunofluorescence (IIF) on HEp-2 cells. However, despite many efforts and numerous studies, the clinical significance of anti-DFS70 antibodies is still unknown as they can be found in patients with various disorders and even in healthy subjects. In this study we aimed at verifying whether these antibodies are associated with thrombotic events or with unexplained recurrent pregnancy loss (RPL). We studied 443 patients with venous or arterial thrombosis or RPL and 244 controls by IIF on HEp-2 cells and by a DFS70-specific chemiluminescent immunoassay (CIA). The DFS pattern was observed in IIF in 31/443 (7.0%) patients and in 6/244 (2.5%) controls (p = 0.01) while anti-DFS70 specific antibodies were detected by CIA in 11 (2.5%) patients and in one (0.4%) control (p = 0.06). Positive samples, either by IIF or by CIA, were then assayed by a second DFS70-specific line-immunoassay (LIA) method: 83.3% of the CIA positive samples were confirmed DFS70 positive versus only 29.7% of the IIF positive samples. These findings show that IIF overestimates anti-DFS70 antibody frequency and that results obtained by specific CIA and LIA assays do not indicate that venous or arterial thrombosis or RPL are linked to a higher prevalence of anti-DFS70 antibodies.
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http://dx.doi.org/10.1038/s41598-020-64550-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210276PMC
May 2020

Epigenetics in atherosclerosis: key features and therapeutic implications.

Expert Opin Ther Targets 2020 08 1;24(8):719-721. Epub 2020 Jun 1.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad, Iran.

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http://dx.doi.org/10.1080/14728222.2020.1764535DOI Listing
August 2020