Publications by authors named "Aldo Bonaventura"

91 Publications

What is new about the burning pericardium?

Authors:
Aldo Bonaventura

Panminerva Med 2021 Jan 25. Epub 2021 Jan 25.

Department of Internal Medicine, ASST Sette Laghi, Varese, Italy -

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http://dx.doi.org/10.23736/S0031-0808.21.04283-XDOI Listing
January 2021

An update on the pathophysiology of acute and recurrent pericarditis.

Panminerva Med 2020 Dec 18. Epub 2020 Dec 18.

Virginia Commonwealth University, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Richmond, VA, USA.

Pericarditis is an inflammatory disease of the pericardium. Progress has been done in recent years in the understanding of its pathophysiology. In particular, pre-clinical and clinical studies have contributed to increasing our knowledge on the role of interleukin (IL)-1 and NLRP3 (NACHT, leucine- rich repeat, and pyrin domain- containing protein 3) inflammasome. Based on current evidence, pericarditis should be considered as an inflammatory reaction to various stimuli, including chemical/physical, infectious, or ischemic ones, with a viral infection being a common etiology. Interaction of pathogens or irritants with toll-like receptor (TLRs) and stimulation of IL-1 receptor by IL-1α and IL-1β lead to an increased transcription of pro-inflammatory genes, including those needed for NLRP3 inflammasome assembly. This pathway is confirmed indirectly by the beneficial effect of colchicine (an indirect NLRP3 inflammasome inhibitor) and IL-1 blockers in patients with recurrent pericarditis. More recently, a direct evidence of the NLRP3 inflammasome within the inflamed pericardium has been provided as well. It may, however, occur that selfantigens on the surface of mesothelial cells or microbial peptides may stimulate autoreactive T cells along with B cells producing anti-heart antibodies, although less evidence is available on this. Some uncertainties still remain about the role of neutrophils, neutrophil extracellular traps (NETs), and pericardial interstitial cells in recurrent and constrictive pericarditis. Unraveling these aspects might have a direct impact on the development of novel targeted therapies, especially considering the increasing number of drugs targeting NETs.
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http://dx.doi.org/10.23736/S0031-0808.20.04205-6DOI Listing
December 2020

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

J Cardiovasc Pharmacol 2020 Oct 24;77(1):49-60. Epub 2020 Oct 24.

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA.

Abstract: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.
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http://dx.doi.org/10.1097/FJC.0000000000000931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774821PMC
October 2020

Inflammasome formation in the lungs of patients with fatal COVID-19.

Inflamm Res 2021 Jan 20;70(1):7-10. Epub 2020 Oct 20.

VCU Pauley Heart Center, Virginia Commonwealth University, 1220 E Broad St, Richmond, VA, 23298, USA.

Objective: The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS).

Methods: Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1.

Results: Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064).

Conclusions: These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.
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http://dx.doi.org/10.1007/s00011-020-01413-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572246PMC
January 2021

Cardiology on the cutting edge: updates from the European Society of Cardiology (ESC) Congress 2020.

BMC Cardiovasc Disord 2020 10 19;20(1):448. Epub 2020 Oct 19.

BMC Series, Springer Nature, 4 Crinan Street, London, N1 9XW, UK.

The 2020 annual Congress of the European Society of Cardiology (ESC) was the first ever to be held virtually. Under the spotlight of 'the cutting edge of cardiology', exciting and ground-breaking cardiovascular (CV) science was presented both in basic and clinical research. This commentary summarizes essential updates from ESC 2020-The Digital Experience. Despite the challenges that coronavirus disease 2019 (COVID-19) has posed on the conduct of clinical trials, the ESC Congress launched the results of major studies bringing innovation to the field of general cardiology, cardiac surgery, heart failure, interventional cardiology, and atrial fibrillation. In addition to three new ESC guidelines updates, the first ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease were presented. As former ESC president, Professor Casadei undoubtedly pointed out the ESC Congress 2020 was a great success. During the ESC 2020 Congress, BMC Cardiovascular Disorders updated to seven journal sections including Arrhythmias and Electrophysiology, CV Surgery, Coronary Artery Disease, Epidemiology and Digital health, Hypertension and Vascular biology, Primary prevention and CV Risk, and Structural Diseases, Heart Failure, and Congenital Disorders. To conclude, an important take-home message for all CV health care professionals engaged in the COVID-19 pandemic is that we must foresee and be prepared to tackle the dramatic, long-term CV complications of COVID-19 patients.
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http://dx.doi.org/10.1186/s12872-020-01734-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568944PMC
October 2020

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

IL-18 and infections: Is there a role for targeted therapies?

J Cell Physiol 2021 03 13;236(3):1638-1657. Epub 2020 Aug 13.

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

Interleukin (IL)-18 is a pro-inflammatory cytokine belonging to the IL-1 family, first identified for its interferon-γ-inducing properties. IL-18 regulates both T helper (Th) 1 and Th2 responses. It acts synergistically with IL-12 in the Th1 paradigm, whereas with IL-2 and without IL-12 it can induce Th2 cytokine production from cluster of differentation (CD)4 T cells, natural killer (NK cells, NKT cells, as well as from Th1 cells. IL-18 also plays a role in the hemophagocytic lymphohistiocytosis, a life-threatening condition characterized by a cytokine storm that can be secondary to infections. IL-18-mediated inflammation was largely studied in animal models of bacterial, viral, parasitic, and fungal infections. These studies highlight the contribution of either IL-18 overproduction by the host or overresponsiveness of the host to IL-18 causing an exaggerated inflammatory burden and leading to tissue injury. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19). The damage in the later phase of the disease appears to be driven by a cytokine storm, including interleukin IL-1 family members and secondary cytokines like IL-6. IL-18 may participate in this hyperinflammation, as it was previously found to be able to cause injury in the lung tissue of infected animals. IL-18 blockade has become an appealing therapeutic target and has been tested in some IL-18-mediated rheumatic diseases and infantile-onset macrophage activation syndrome. Given its role in regulating the immune response to infections, IL-18 blockade might represent a therapeutic option for COVID-19, although further studies are warranted to investigate more in detail the exact role of IL-18 in SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/jcp.30008DOI Listing
March 2021

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.

Front Immunol 2020 3;11:1625. Epub 2020 Jul 3.

Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States.

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.
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http://dx.doi.org/10.3389/fimmu.2020.01625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348297PMC
August 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

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

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

Reducing cardiovascular risk in type 2 diabetes: Let's use all we have!

Authors:
Aldo Bonaventura

Int J Cardiol 2020 07 13;310:155-156. Epub 2020 Apr 13.

Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1200 E Marshall St, Richmond, VA, 23298, USA; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2020.04.014DOI Listing
July 2020

Plaque vulnerability and adverse outcomes: The long road to fight atherosclerosis.

Eur J Clin Invest 2020 Jun 15;50(6):e13253. Epub 2020 May 15.

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

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http://dx.doi.org/10.1111/eci.13253DOI Listing
June 2020

Cardiovascular Considerations in Treating Patients With Coronavirus Disease 2019 (COVID-19).

J Cardiovasc Pharmacol 2020 05;75(5):359-367

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA.

A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly across the globe since December 2019. Coronavirus disease 2019 (COVID-19) has a significantly higher mortality rate than seasonal influenza and has disproportionately affected older adults, especially those with cardiovascular disease and related risk factors. Adverse cardiovascular sequelae, such as myocarditis, acute myocardial infarction, and heart failure, have been reported in patients with COVID-19. No established treatment is currently available; however, several therapies, including remdesivir, hydroxychloroquine and chloroquine, and interleukin (IL)-6 inhibitors, are being used off-label and evaluated in ongoing clinical trials. Considering these therapies are not familiar to cardiovascular clinicians managing these patients, this review describes the pharmacology of these therapies in the context of their use in patients with cardiovascular-related conditions.
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http://dx.doi.org/10.1097/FJC.0000000000000836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219860PMC
May 2020

Antiapolipoprotein A-1 Autoantibody Positivity Is Associated with Threatened Abortion.

Biomed Res Int 2020 7;2020:9309121. Epub 2020 Mar 7.

Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.

Background: Autoantibodies against apolipoprotein A-1 (anti-ApoA-1 IgG) were demonstrated to be associated with cardiovascular outcomes in several inflammatory diseases. As balanced inflammation is critical for uncomplicated pregnancy, we aimed to investigate the prevalence of anti-ApoA-1 IgG and anti-c-terminal ApoA-1 autoantibodies (Ac-terAA1 IgG) in a cohort of pregnant women and their potential relationship with threatened abortion (TA).

Methods: Between 2012 and 2014, 371 consecutive outpatient pregnant women were included in this study and followed until delivery. Anti-ApoA-1 and anti-Ac-terAA1 IgG were measured by ELISA technique on serum samples collected between the 24 and 26 week of pregnancy. Associations with TA were tested using linear regression analysis and C-statistics.

Results: Median age was 34 with a prevalence of the Caucasian ethnicity (90.5%). TA occurred in 10 women (2.7%). C-statistics indicated that anti-ApoA-1 and anti-Ac-terAA1 IgG levels upon study inclusion were predictive of TA (0.73, 95% confidence interval [CI] 0.69-0.78, < 0.001 and 0.76, 95% CI 0.71-0.80, < 0.001 and 0.76, 95% CI 0.71-0.80, < 0.001 and 0.76, 95% CI 0.71-0.80, < 0.001 and 0.76, 95% CI 0.71-0.80.

Conclusion: Anti-ApoA-1 and anti-Ac-terAA1 IgG are independently associated with TA during pregnancy with an appealing NPV. The causal biological mechanisms underlying this association as well as the possible clinical relevance of these findings require further investigations.
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http://dx.doi.org/10.1155/2020/9309121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081016PMC
December 2020

Neutrophil-Related Oxidants Drive Heart and Brain Remodeling After Ischemia/Reperfusion Injury.

Front Physiol 2019 4;10:1587. Epub 2020 Feb 4.

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

The inflammatory response associated with myocardial and brain ischemia/reperfusion injury (IRI) is a critical determinant of tissue necrosis, functional organ recovery, and long-term clinical outcomes. In the post-ischemic period, reactive oxygen species (ROS) are involved in tissue repair through the clearance of dead cells and cellular debris. Neutrophils play a critical role in redox signaling due to their early recruitment and the large variety of released ROS. Noteworthy, ROS generated during IRI have a relevant role in both myocardial healing and activation of neuroprotective pathways. Anatomical and functional differences contribute to the responses in the myocardial and brain tissue despite a significant gene overlap. The exaggerated activation of this signaling system can result in adverse consequences, such as cell apoptosis and extracellular matrix degradation. In light of that, blocking the ROS cascade might have a therapeutic implication for cardiomyocyte and neuronal loss after acute ischemic events. The translation of these findings from preclinical models to clinical trials has so far failed because of differences between humans and animals, difficulty of agents to penetrate into specific cellular organs, and specifically unravel oxidant and antioxidant pathways. Here, we update knowledge on ROS cascade in IRI, focusing on the role of neutrophils. We discuss evidence of ROS blockade as a therapeutic approach for myocardial infarction and ischemic stroke.
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http://dx.doi.org/10.3389/fphys.2019.01587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010855PMC
February 2020

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update.

Cells 2020 01 17;9(1). Epub 2020 Jan 17.

First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, viale Benedetto XV 6, 16132 Genoa, Italy.

Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases.
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http://dx.doi.org/10.3390/cells9010231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016588PMC
January 2020

PCSK9 is a promising prognostic marker in patients with advanced NSCLC.

Cancer Immunol Immunother 2020 Mar 14;69(3):491-492. Epub 2020 Jan 14.

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

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http://dx.doi.org/10.1007/s00262-020-02485-zDOI Listing
March 2020

Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 01;75(1):76-92

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

Pericarditis refers to the inflammation of the pericardial layers, resulting from a variety of stimuli triggering a stereotyped immune response, and characterized by chest pain associated often with peculiar electrocardiographic changes and, at times, accompanied by pericardial effusion. Acute pericarditis is generally self-limited and not life-threatening; yet, it may cause significant short-term disability, be complicated by either a large pericardial effusion or tamponade, and carry a significant risk of recurrence. The mainstay of treatment of pericarditis is represented by anti-inflammatory drugs. Anti-inflammatory treatments vary, however, in both effectiveness and side-effect profile. The objective of this review is to summarize the up-to-date management of acute and recurrent pericarditis.
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http://dx.doi.org/10.1016/j.jacc.2019.11.021DOI Listing
January 2020

MicroRNA-122 in heart failure with reduced ejection fraction: Epiphenomenon or causal?

Int J Cardiol 2020 03 18;303:66-67. Epub 2019 Dec 18.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, 8952 Schlieren, Switzerland; Department of Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland; Department of Research and Education, University Hospital Zurich, 8001 Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2019.12.038DOI Listing
March 2020

Sacubitril-Valsartan for the Treatment of Heart Failure: Time for a Paragon?

J Cardiovasc Pharmacol 2020 02;75(2):105-107

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA.

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http://dx.doi.org/10.1097/FJC.0000000000000782DOI Listing
February 2020

Platelet-to-lymphocyte ratio at the time of carotid endarterectomy is associated with acute coronary syndrome occurrence.

J Cardiovasc Med (Hagerstown) 2020 01;21(1):80-82

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

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http://dx.doi.org/10.2459/JCM.0000000000000869DOI Listing
January 2020

Inflammasome Formation in Granulomas in Cardiac Sarcoidosis.

Circ Arrhythm Electrophysiol 2019 09 16;12(9):e007582. Epub 2019 Sep 16.

Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond (J.K., A.G.M., A.B., S.T., F.N.S., K.A.E., A.A.).

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http://dx.doi.org/10.1161/CIRCEP.119.007582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092927PMC
September 2019

Diabetes and Vascular Disease: Is It All About Glycemia?

Curr Pharm Des 2019 ;25(29):3112-3127

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

Background: Diabetes is increasing over time, mainly driven by obesity, aging, and urbanization. Classical macro- and microvascular complications represent the final result of a complex interplay involving atherosclerosis at all stages.

Methods: In this review, we aim at focusing on current updates in the pathophysiology of vascular disease in diabetes and discussing how new therapies might influence the management of these patients at high cardiovascular risk. Diabetes shows accelerated atherosclerosis with a larger inflammatory cell infiltrate, thus favoring the development of heart failure. 'Diabetic cardiomyopathy' perfectly describes a specific ischemia- and hypertension- independent entity due to diabetes-related metabolic alterations on myocardial function. Moreover, platelets from subjects with diabetes display a typical hyperreactivity explaining the stronger adhesion, activation, and aggregation. Additionally, diabetes provokes an exaggerated stimulation of the endothelium, with an increased release of reactive oxygen species and a reduced release of nitric oxide, both key elements of the endothelial dysfunction. Also, the coagulation cascade and leukocytes activate contributing to this pro-thrombotic environment. Neutrophils have been recently recognized to play a pivotal role by releasing neutrophil extracellular traps. Finally, microparticles from platelets, neutrophils or monocytes are detrimental effectors on the vessel wall and are involved both in vascular dysfunction and in thrombotic complications.

Conclusion: In light of these findings, the therapeutic management of diabetes needs to be mostly focused on limiting the progression of complications by targeting precise pathophysiological mechanisms rather than the mere glycemic control, which failed to markedly reduce the risk for macrovascular complications and mortality.
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http://dx.doi.org/10.2174/1381612825666190830181944DOI Listing
June 2020

Drugs to Inhibit the NLRP3 Inflammasome: Not Always On Target.

J Cardiovasc Pharmacol 2019 09;74(3):225-227

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA.

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http://dx.doi.org/10.1097/FJC.0000000000000729DOI Listing
September 2019

Baseline serum levels of osteopontin predict clinical response to treatment with nivolumab in patients with non-small cell lung cancer.

Clin Exp Metastasis 2019 10 2;36(5):449-456. Epub 2019 Aug 2.

First Clinic of Internal Medicine, IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132, Genoa, Italy.

Treatment with nivolumab improves survival and response rate in non-small cell lung cancer (NSCLC). Nevertheless, due to its high financial cost, identifying predictors of response to treatment has become an urgent need. Here, we focused on serum osteopontin (OPN), a pleiotropic protein overexpressed in lung cancer and involved in the immune response. A cohort of NSCLC patients (n = 72) treated with nivolumab was enrolled. Blood samples were collected at the time of first five nivolumab administrations. OPN and high-sensitivity C-reactive protein (hs-CRP) were assayed at each time point. The primary endpoint was to assess the predictive value of baseline serum levels of OPN towards overall survival (OS). Secondary endpoints included the potential association between OPN, hs-CRP and response to nivolumab. OPN and hs-CRP correlate with each other, with neutrophil count and biochemical markers of metastatic disease. At baseline, serum OPN increased with increasing Eastern Cooperative Oncology Group scale of Performance Status (ECOG PS). When Eastern Cooperative Oncology Group scale of Performance Status) (RECIST) criteria were considered, high baseline OPN levels were associated with a worse response to nivolumab. Cox hazard regression further confirmed baseline serum OPN as a predictor of mortality with the best predictive accuracy for serum levels above 37.7 ng/mL. Patients above the cut-off value had a higher mortality rate as compared to low serum OPN levels during follow up. Serum OPN may have a predictive role in NSCLC patients treated with nivolumab. Although larger confirmatory studies are needed, measuring serum OPN levels at baseline can be a clinically useful tool in a near future.
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http://dx.doi.org/10.1007/s10585-019-09984-zDOI Listing
October 2019

NLRP3 Inflammasome in Acute Myocardial Infarction.

J Cardiovasc Pharmacol 2019 09;74(3):175-187

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA.

Acute myocardial infarction (AMI) is associated with the induction of a sterile inflammatory response that leads to further injury. The NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a macromolecular structure responsible for the inflammatory response to injury or infection. NLRP3 can sense intracellular danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is primed and triggered by locally released damage-associated molecular patterns and amplifies the inflammatory response and cell death through caspase-1 activation. Here, we examine the scientific evidence supporting a role for NLRP3 in AMI and the available strategies to inhibit the effects of the inflammasome. Our focus is on the beneficial effects seen in experimental models of AMI in preclinical animal models and the initial results of clinical trials.
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http://dx.doi.org/10.1097/FJC.0000000000000717DOI Listing
September 2019

Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study.

Cancer Immunol Immunother 2019 Aug 20;68(8):1351-1358. Epub 2019 Jul 20.

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

Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.
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http://dx.doi.org/10.1007/s00262-019-02367-zDOI Listing
August 2019

In-Hospital Initiation of Sacubitril/Valsartan: A New PARADIGM for Acute Decompensated Heart Failure?

J Cardiovasc Pharmacol 2019 07;74(1):1-3

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA.

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http://dx.doi.org/10.1097/FJC.0000000000000685DOI Listing
July 2019

Comment on Hypoglycemia and hyperglycemia are risk factors for falls in the hospital population by Berra et al.

Acta Diabetol 2020 01 22;57(1):109-110. Epub 2019 Jun 22.

Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, 1200 East Marshall Street, Richmond, 23298, Virginia, USA.

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http://dx.doi.org/10.1007/s00592-019-01379-6DOI Listing
January 2020