Publications by authors named "Valentina Mercurio"

65 Publications

The multifaceted mechanisms of nitroxyl in heart failure: inodilator or 'only' vasodilator?

Eur J Heart Fail 2021 May 2. Epub 2021 May 2.

Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.1002/ejhf.2204DOI Listing
May 2021

Oxidative stress in anticancer therapies-related cardiac dysfunction.

Free Radic Biol Med 2021 Apr 28;169:410-415. Epub 2021 Apr 28.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Redox abnormalities are at the crossroad of cardiovascular diseases, cancer and cardiotoxicity from anticancer treatments. Indeed, disturbances of the redox equilibrium are common drivers of these conditions. Not only is an increase in oxidative stress a fundamental mechanism of action of anthracyclines (which have historically been the most studied anticancer treatments) but also this is at the basis of the toxic cardiovascular effects of antineoplastic targeted drugs and radiotherapy. Here we examine the oxidative mechanisms involved in the different cardiotoxicities induced by the main redox-based antineoplastic treatments, and discuss novel approaches for the treatment of such toxicities.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.04.021DOI Listing
April 2021

Noncardiovascular comorbidities in patients with heart failure and their impact on prognosis.

Kardiol Pol 2021 Apr 13. Epub 2021 Apr 13.

With the aging of the population and improvement of life expectancy of patients with heart disease, there is an increase in non-CV comorbidities affecting chronic heart failure (HF) patients. The increased prevalence of different cardiovascular (CV) and non-CV comorbidities is a rising problem in the management of patients with HF, mostly because these comorbilities may lead to poor prognosis, increase of hospitalization and mortality rate. Recently, important data from multicenter randomized studies points to diabetes mellitus or iron deficiency as new pharmacological targets, highlighting the need of multiple expertises for the 21st century cardiologist. The management of HF should take into account non-cardiovascular comorbidities. In this review we discuss on the novelty of non-CV comorbidities in HF patients and emphasizing the impact on prognosis.
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http://dx.doi.org/10.33963/KP.15934DOI Listing
April 2021

Assessment of right ventricular reserve utilizing exercise provocation in systemic sclerosis.

Int J Cardiovasc Imaging 2021 Apr 16. Epub 2021 Apr 16.

Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.

Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension, a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. Our pooled cohort analysis revealed reduced global RVLSS at rest (-16.2 ± 3.9%) with normal basal contractility (-25.6 ± 7.7%) and relative hypokinesis of the midventricular (-14.1 ± 6.0%) and apical (-8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p = 0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥ 35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone.
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http://dx.doi.org/10.1007/s10554-021-02237-9DOI Listing
April 2021

Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension: Recent Advances.

Compr Physiol 2021 Apr 1;11(2):1805-1829. Epub 2021 Apr 1.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Inflammatory processes are increasingly recognized in the pathogenesis of the vascular remodeling that characterizes pulmonary arterial hypertension (PAH). Chronic inflammation may contribute to disease progression or serve as a biomarker of PAH severity. Furthermore, inflammatory pathways may represent possible therapeutic targets for novel PAH-specific drugs beyond the currently approved therapies targeting the endothelin, nitric oxide/cyclic GMP, and prostacyclin biological pathways. The main focus of this article is to provide recent advances in the understanding of the role of inflammatory pathways in the pathogenesis of PAH from preclinical studies and current clinical data supporting chronic inflammation in PAH patients and to discuss emerging therapeutic implications. © 2021 American Physiological Society. Compr Physiol 11:1805-1829, 2021.
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http://dx.doi.org/10.1002/cphy.c200025DOI Listing
April 2021

How can we manage the cardiac toxicity of immune checkpoint inhibitors?

Expert Opin Drug Saf 2021 Apr 1:1-10. Epub 2021 Apr 1.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

: Cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints (i.e. CTLA-4 and PD-1/PD-L1) have revolutionized antineoplastic treatments. Immune checkpoint inhibitors (ICIs) approved for cancer immunotherapy are mAbs anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab, and cemiplimab), and anti-PD-L1 (atezolizumab, avelumab, and durvalumab). Treatment with ICIs can be associated with immune-related adverse events (irAEs), including an increased risk of developing myocarditis. These findings are compatible with the observation that, CTLA-4, PD-1, and PD-L1 pathways play a central role in the modulation of autoimmunity.: In this paper, we start from examining the pathogenesis of cardiovascular adverse events from ICIs, and then we focus on risk factors and strategies to prevent and manage this cardiotoxicity.: There is a growing need for a multidisciplinary approach of ICI-associated cardiotoxicity, involving oncologists, cardiologists, and immunologists. Prevention and effective management of ICIs cardiotoxicity starts with an in-depth screening and surveillance strategies of high-risk patients, in order to improve early detection and appropriate management in a personalized approach.
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http://dx.doi.org/10.1080/14740338.2021.1906860DOI Listing
April 2021

Cardiovascular safety of the tyrosine kinase inhibitor nintedanib.

Br J Clin Pharmacol 2021 Feb 23. Epub 2021 Feb 23.

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

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.
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http://dx.doi.org/10.1111/bcp.14793DOI Listing
February 2021

Essential hypertension worsens left ventricular contractility in systemic sclerosis.

J Rheumatol 2021 Jan 15. Epub 2021 Jan 15.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN; Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Division of Cardiology, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. VM: ERS Research Fellowship; AMH: National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (T32AR048522); FMW: Scleroderma Research Foundation and Martha McCoory Professorship; AAS: Staurulakis Family Discovery Fund, Donald B. and Dorothy L. Stabler Foundation; MM: Scleroderma Foundation, Staurulakis Family Discovery Fund, Donald B. and Dorothy L. Stabler Foundation, CHEST Foundation, Johns Hopkins University Clinician Scientist Award. Corresponding Author. Monica Mukherjee, MD, MPH; 301 Mason Lord Drive, Suite 2400, Baltimore, MD 21224. E-mail:

Objective: Primary cardiac involvement in systemic sclerosis (SSc) is prevalent and morbid, however the influence of traditional cardiovascular risk factors such as essential hypertension (HTN) are unclear. In the present study, we sought to understand the effects of HTN on left ventricular (LV) contractility in SSc patients using echocardiographic speckle-derived global longitudinal strain (GLS).

Methods: 56 SSc patients with HTN (SSc+HTN+) and 82 SSc patients without HTN (SSc+ HTN-) were compared with 40 non-SSc controls with HTN (SSc-HTN+) and 40 non-SSc controls without HTN (SSc-HTN-), matched by age and sex. All HTN patients were on stable antihypertensive therapies. Echocardiographic measures included LV ejection fraction (LVEF), left atrial volume index (LAVi), and LV diastolic function. LV contractility was assessed by GLS, averaged across the 18 LV segments.

Results: SSc patients had diminished GLS regardless of HTN status when compared to both control groups despite normal LVEF, p<0.001. SSc+HTN+ had the highest prevalence of diastolic dysfunction with significantly higher septal E/e', a marker of LV filling pressures (p<0.05), as well as the largest reduction in GLS compared to SSc+HTN- and both control groups.

Conclusion: Speckle-derived strain revealed diminished LV contractility in SSc patients despite normal LVEF. SSc+HTN+ had more prominent reductions in GLS associated with evidence of LV remodeling and worsened diastolic function. Our findings demonstrate the presence of subclinical LV contractile dysfunction in SSc that is further exacerbated by concomitant HTN, thereby identifying HTN as an important modifiable cardiovascular risk factor that should be managed aggressively in this at-risk population.
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http://dx.doi.org/10.3899/jrheum.200873DOI Listing
January 2021

Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC).

Eur Heart J Cardiovasc Imaging 2021 Mar;22(4):406-415

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Aims: In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern.

Methods And Results: In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P < 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex.

Conclusions: The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.
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http://dx.doi.org/10.1093/ehjci/jeaa339DOI Listing
March 2021

The use of chest ultrasonography in suspected cases of COVID-19 in the emergency department.

Future Sci OA 2020 Nov 30;7(1):FSO635. Epub 2020 Nov 30.

Department of Emergency Medicine "Santa Maria delle Grazie" Hospital, 80078 Pozzuoli, Italy.

Aim: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-specific reverse transcriptase-polymerase chain reaction (RT-PCR) represents the diagnostic gold standard. We explored the value of chest ultrasonography to predict positivity to SARS-CoV-2 on RT-PCR in suspected COVID-19 cases.

Patients & Methods: Consecutive patients with suspect COVID-19 were included if they had fever and/or history of cough and/or dyspnea. Lung ultrasound score (LUSS) was computed according to published methods.

Results: A total of 76 patients were included. A 3-variable model based on aspartate transaminase (AST) > upper limit of normal, LUSS >12 and body temperature >37.5°C yielded an overall accuracy of 91%.

Conclusion: A simple LUSS-based model may represent a powerful tool for initial assessment in suspected cases of COVID-19.
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http://dx.doi.org/10.2144/fsoa-2020-0127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745656PMC
November 2020

Cardiovascular Toxicity of Immune Checkpoint Inhibitors: Clinical Risk Factors.

Curr Oncol Rep 2021 Jan 7;23(2):13. Epub 2021 Jan 7.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Purpose Of Review: Immune checkpoint inhibitors, such as monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1, have improved the outcome of many malignancies, but serious immune-related cardiovascular adverse events have been observed. Patients' risk factors for these toxicities are currently being investigated.

Recent Findings: Interfering with the CTLA-4 and PD-1 axes can bring to several immune-related adverse events, including cardiotoxic events such as autoimmune myocarditis, pericarditis, and vasculitis, suggesting that these molecules play an important role in preventing autoimmunity. Risk factors (such as pre-existing cardiovascular conditions, previous and concomitant cardiotoxic treatments, underlying autoimmune diseases, tumor-related factors, simultaneous immune-related toxic effects, and genetic factors) should be always recognized for the correct management of these toxicities.
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http://dx.doi.org/10.1007/s11912-020-01002-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790474PMC
January 2021

Prevention of cancer therapy-related heart failure, is it really possible?

J Cardiovasc Med (Hagerstown) 2021 Jun;22(6):441-443

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

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http://dx.doi.org/10.2459/JCM.0000000000001140DOI Listing
June 2021

Cancer Risk in the Heart Failure Population: Epidemiology, Mechanisms, and Clinical Implications.

Curr Oncol Rep 2020 12 2;23(1). Epub 2020 Dec 2.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Purpose Of Review: Along with population aging, the incidence of both heart failure (HF) and cancer is increasing. However, little is known about new-onset cancer in HF patients. This review aims at showing recent discoveries concerning this subset of patients.

Recent Findings: Not only cancer and HF share similar risk factors but also HF itself can stimulate cancer development. Some cytokines produced by the failing heart induce mild inflammation promoting carcinogenesis, as it has been recently suggested by an experimental model of HF in mice. The incidence of new-onset cancer is higher in HF patients compared to the general population, and it significantly worsens their prognosis. Moreover, the management of HF patients developing new-onset cancer is challenging, especially due to the limited therapeutic options for patients affected by both cancer and HF and the higher risk of cardiotoxicity from anticancer drugs.
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http://dx.doi.org/10.1007/s11912-020-00990-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716920PMC
December 2020

Time-weighted lactate as a predictor of adverse outcome in acute heart failure.

ESC Heart Fail 2021 Feb 24;8(1):539-545. Epub 2020 Nov 24.

Emergency Department of San Paolo Hospital, Naples, Italy.

Aims: The role of dynamic changes in lactate concentrations on prognosis in acute heart failure has been poorly investigated. The aim of this study was to explore the predictive value of 24 h time-weighted lactate (LAC ) in patients with acute heart failure.

Methods And Results: Ninety-six consecutive acute heart failure patients presenting to the Emergency Department of San Paolo Hospital, Naples, Italy, were prospectively enrolled. Arterial blood lactate was measured at admission and during the following 24 h at random time intervals. LAC was obtained by the sum of the average lactate values among consecutive time points multiplied by the intervals between consecutive time points and dividing the sum by the total time (24 h). The outcome was a composite of need of admission to the intensive care unit, hospitalization duration >7 days, or intra-hospital death. Admission lactate, maximum measured lactate, and LAC were collected. Univariate and multivariate Cox regression analysis was applied to determine the hazard ratio (HR) of developing the outcome. Forty-three patients experienced the pre-specified outcome. In sex-adjusted and age-adjusted multivariable analysis, LAC predicted the outcome occurrence (HR: 1.51, 95% confidence interval: 1.24, 1.84, P < 0.001). Risk stratification analysis based on LAC tertiles demonstrated a gradual increase in risk of developing the outcome (HR: 17.32, 95% confidence interval: 2.30, 130.23, P = 0.006) for the highest LAC tertile.

Conclusions: In acute heart failure patients, 24 h LAC had a significant independent predictive value for adverse intra-hospital outcome. LAC could be a useful index at identifying high-risk patients who may require a more aggressive treatment during hospitalization.
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http://dx.doi.org/10.1002/ehf2.13112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835560PMC
February 2021

Lung ultrasound as diagnostic tool for SARS-CoV-2 infection.

Intern Emerg Med 2021 Mar 3;16(2):471-476. Epub 2020 Oct 3.

Department of Emergency Medicine, COVID Care Unit, Santa Maria Delle Grazie Hospital, Via Domitiana, 5, 80078, Pozzuoli, Naples, Italy.

The aim of this study was to explore the role of lung ultrasound (LUS) in the diagnosis of SARS-CoV-2 infection and to verify its utility in the prediction of lung disease's severity and outcome. Fifty-three consecutive patients presenting to the Emergency Department of Santa Maria delle Grazie Hospital with high suspicion of SARS-CoV-2 infection underwent diagnostic test for SARS-CoV-2 on samples obtained from nasopharyngeal swab as well as complete proper diagnostic work-up that included clinical evaluation, laboratory tests, blood gas analyses, chest CT and LUS. A semiquantitative analysis of B-lines distribution was performed to calculate the LUS score. Patients were divided into two groups according to the results of both SARS-CoV-2 diagnostic test and other exams (Group A = pneumonia due to SARS-CoV2 infection vs Group B = no SARS-CoV2 infection and another definite diagnosis). LUS showed an excellent accuracy in predicting the diagnosis of SARS-CoV-2 infection (area under the ROC curve of 0.92 with a sensibility of 73% and a specificity of 89% a the cut-off of 12.5). LUS score was more impaired in SARS-CoV-2 patients (18.1 ± 6.0 vs 7.6 ± 5.9, p < 0.00001) and it is significantly negatively correlated with PF ratio values (r = - 0.719, p < 0.0001). An intrahospital mortality rate of 46% was found; patients with adverse outcome had significant higher value of LUS, PF, LDH, and APACHE II score. None of these parameters was predictive of mortality. LUS is a useful tool for the early detection of SARS-CoV-2 infection and for the evaluation of the disease severity, but does not predict mortality. Further studies with repeated evaluations of LUS score are needed to further explore the role of LUS in the assessment of severity in SARS-CoV-2 disease and in the monitoring of the response to treatments.
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http://dx.doi.org/10.1007/s11739-020-02512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532928PMC
March 2021

Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension.

J Heart Lung Transplant 2020 12 28;39(12):1389-1397. Epub 2020 Aug 28.

Department of Pathophysiology, Free University of Brussels, Brussels, Belgium.

Background: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores.

Methods: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy.

Results: At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7-8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal.

Conclusions: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.
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http://dx.doi.org/10.1016/j.healun.2020.08.016DOI Listing
December 2020

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2021 02;203(4):484-492

Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, Rome, Italy.

An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known. To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs. The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores. Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status. A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
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http://dx.doi.org/10.1164/rccm.202004-1006OCDOI Listing
February 2021

Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades.

Oxid Med Cell Longev 2020 3;2020:9219825. Epub 2020 Aug 3.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 M) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 M) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49 ± 3% of area at risk, AAR) when compared to control IR group (69 ± 2% of AAR). Similarly, administration of INF before the IR injury resulted in significant IS reduction (38 ± 3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment , or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3.
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http://dx.doi.org/10.1155/2020/9219825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424511PMC
August 2020

Redox Imbalances in Ageing and Metabolic Alterations: Implications in Cancer and Cardiac Diseases. An Overview from the Working Group of Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology (SIC).

Antioxidants (Basel) 2020 Jul 21;9(7). Epub 2020 Jul 21.

Department of Clinical and Biological Sciences, University of Turin, 10043 Torino, Italy.

Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved in MetS are also cancer risk factors, such as the consumption of high calorie-food or high fat intake, low fibre intake, and sedentary lifestyle. Other common aspects of both cancer and MetS are oxidative stress and inflammation. In addition, some anticancer treatments can induce cardiotoxicity, including, for instance, left ventricular (LV) dysfunction and heart failure (HF), endothelial dysfunction and hypertension. In this review, we analyse several aspects of MetS, cancer and cardiotoxicity from anticancer drugs. In particular, we focus on oxidative stress in ageing, cancer and CV diseases, and we analyse the connections among CV risk factors, cancer and cardiotoxicity from anticancer drugs.
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http://dx.doi.org/10.3390/antiox9070641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402085PMC
July 2020

Sex-related differences in COVID-19 lethality.

Br J Pharmacol 2020 10 5;177(19):4375-4385. Epub 2020 Aug 5.

Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.

Many countries have been affected by the worldwide outbreak of COVID-19. Among Western countries, Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere, women seem to be less affected than men by severe/fatal COVID-19 infection, regardless of their age. Although women and men are affected differently by this infection, very few studies consider different therapeutic approaches for the two sexes. Understanding the mechanisms underlying these differences may help to find appropriate and sex specific therapies. Here, we consider that other mechanisms are involved to explain this difference, in addition to the protection attributable to oestrogens. Several X-linked genes (such as ACE2) and Y-linked genes (SRY and SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex-independent, non-genetic factors that can change susceptibility and mortality is enormous, and many other factors should be considered, including gender and cultural habits in different countries.
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http://dx.doi.org/10.1111/bph.15207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405496PMC
October 2020

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment.

Int J Mol Sci 2020 Jun 22;21(12). Epub 2020 Jun 22.

Department of Translational Medical Sciences. Federico II University, 80131 Naples, Italy.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.
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http://dx.doi.org/10.3390/ijms21124430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352262PMC
June 2020

Peripheral Vascular Function in Dilated Cardiomyopathy of Different Etiology.

Angiology 2020 09 17;71(8):726-733. Epub 2020 Jun 17.

Department of Translational Medical Sciences, Federico II University School of Medicine, Naples, Italy.

Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. Moreover, reference values of flow-mediated dilation (FMD) in chronic heart failure (CHF) need to be updated according to the new standardized protocols. We characterized the vascular impairment in different stages of post-ischemic dilated cardiomyopathy (PI-DC) or idiopathic dilated cardiomyopathy (I-DC). Eighty consecutive outpatients with CHF in different New York Heart Association (NYHA) classes (45 PI-DC, 35 I-DC) and 50 control subjects underwent FMD and brachial distensibility coefficient measurement. Patients with CHF showed a marked impairment in FMD compared with controls that worsened from classes NYHA I-II to III-IV, independently of etiology ( < .05). New York Heart Association I-II PI-DC patients showed a worse FMD compared with NYHA I-II I-DC patients ( < .05). Brachial distensibility coefficient values were significantly lower in patients with CHF compared with controls ( < .001) without differences between PI-DC and I-DC. In conclusion, advanced CHF is characterized by vascular impairment that is independent of etiology. In the early stages of CHF, endothelial dysfunction is more severe in patients with PI-DC compared with I-DC probably due to the high cardiovascular risk profile. In I-DC, vascular function impairment is independent of cardiovascular risk factors and could participate in the pathogenesis of I-DC.
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http://dx.doi.org/10.1177/0003319720932803DOI Listing
September 2020

Adapted recreational football small-sided games improve cardiac capacity, body composition and muscular fitness in patients with type 2 diabetes.

J Sports Med Phys Fitness 2020 Sep 12;60(9):1261-1268. Epub 2020 Jun 12.

Department of Human Movement Sciences and Wellbeing, Parthenope University, Naples, Italy -

Background: The usefulness of adapted small-sided games (SSGs) in improving cardiac function in subjects with T2DM is still debated. Here we evaluated the effects of 18 weeks indoor muscular activation training (6 weeks; IMA) followed by adapted SSGs football training (12 weeks) on cardiac function, muscular fitness, body composition and adiponectin expression in sedentary T2DM volunteers.

Methods: Six T2DM patients underwent IMA protocol of 6 weeks, twice a week followed by 12 weeks SSGs (5-a-side, once a week) training. Glucose, lipid profile and serum homocysteine concentration, body composition (BC), bone mineral density (DEXA), were determined at baseline and after 18 weeks (IMA+SSGs). VO2max and muscular fitness were recorded at baseline and after IMA (6 weeks) and SSGs (12 weeks), respectively.

Results: No significant differences were found for VO2max and muscular fitness after 6weeks of IMA. After 18 weeks (6 weeks IMA + 12 weeks SSGs) of training, significant improvements were found in the following parameters: work capacity, VO2peak, Ventilation (VEpeak), breathing reserve consumption and oxygen uptake efficiency slope (P<0.05); leg fitness (P<0.05), BC (P<0.05), vertebral column T-score (P<0.01) and adiponectin (total and high-molecular-weight; P<0.05). Compared to baseline, a reduction in serum homocysteine occurred after 18 weeks of training (P<0.05).

Conclusions: We evidenced that weekly adapted SSGs friendly football matches for 12 weeks improve cardiorespiratory capacity and the expression of independent markers associated with cardiovascular risk in T2DM patients, suggesting an overall reduced CVD-risk in these patients. These preliminary data encourage us to test the efficacy of this type of exercise in a larger population.
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http://dx.doi.org/10.23736/S0022-4707.20.10498-5DOI Listing
September 2020

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

University Hospital Giessen und Marburg GmbH, Pulmonary Hypertension Division, Medical Clinic II, Giessen, Germany.

Question Addressed: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality.

Methods And Main Results: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value.

Answer To The Question: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.
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http://dx.doi.org/10.1183/13993003.00513-2020DOI Listing
September 2020

Commentary on "Functional Improvement After Outpatient Cardiac Rehabilitation in Acute Coronary Syndrome Patients is not Related to Improvement in Left Ventricular Ejection Fraction".

High Blood Press Cardiovasc Prev 2020 06 7;27(3):179-181. Epub 2020 May 7.

Department of Translational Medical Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.

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http://dx.doi.org/10.1007/s40292-020-00386-xDOI Listing
June 2020

Effect of Sacubitril-Valsartan in reducing depression in patients with advanced heart failure.

J Affect Disord 2020 07 30;272:132-137. Epub 2020 Apr 30.

Federico II" University of Naples, Department of Translational Medical Sciences, 80131 Naples, Italy.

Background: Depression is highly prevalent in Heart Failure (HF). Treatment with sacubitril/valsartan improved quality of life and survival in HF patients. Aim of the study was to investigate prospectively the effect of sacubitril/valsartan on depression in advanced HF patients in waiting list for heart transplant (HT).

Methods: 37 consecutive patients with advanced HF in waiting list for HT were treated with sacubitril/valsartan. We analyzed data derived from the assessment performed the year before the beginning of sacubitril/valsartan, at study entry, and at one year of follow-up. Depression was assessed with Beck Depression Inventory II (BDI) scale. Cognitive function were assessed with Mini-Mental State Examination (MMSE). Functioning was evaluated measuring meters at 6 Minute Walking Test (6MWT) and maximum rate of oxygen consumption (VO max).

Results: At baseline, 64.9% of HF patients were in NYHA III and 35.1% NYHA IIIB, BDI was 15.2 ± 5.2 with 59.5% of patients with a score > 13. MMSE was 27.8 ± 2.6. After one year of follow-up NYHA class improved significantly, with 56.8% in NYHA II, 40.5% in NYHA III and 2.7% NYHA in IIIB (p < 0.001). VO max and 6MWT increased. Notably, BDI was 9.5 ± 3.9 with 21.6% of patients with a score > 13. MMSE remain stable (28.2 ± 2.1) (p = 0.104). No statistical differences are observed between data collected in the evaluation 1-year before and soon before treatment with sacubitril/valsartan. Multivariate regression analysis demonstrate a relationship between reduction in BDI-II score and improvement in six-minute walking test independently by the effect of sex, age, selective serotonin reuptake inhibitors, VO max, NT-proBNP, PAPs, NYHA class differences evaluated at follow-up versus baseline.

Conclusions: Our study showed a reduction in depressive symptomatology in heart transplant waiting list patients treated with sacubitril/valsartan. The improvement in depressive symptomatology was paralleled by 6MWT increase in the follow-up.
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http://dx.doi.org/10.1016/j.jad.2020.03.158DOI Listing
July 2020

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

Eur Heart J 2020 05;41(18):1733-1743

Division of Oncology and Hematology, Department of Medicine, Lehigh Valley Hospital, 1200 S Cedar Crest Blvd, Allentown, PA 18103, USA.

Aims: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.

Methods And Results: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.

Conclusion: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.
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http://dx.doi.org/10.1093/eurheartj/ehaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205467PMC
May 2020

Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty.

ESC Heart Fail 2020 04 19;7(2):757-762. Epub 2020 Feb 19.

Department of Translational Medical Sciences, University of Naples 'Federico II', 80131, Naples, Italy.

Aims: The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF).

Methods And Results: We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow-up visit after 2 years of follow-up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m , and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow-up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E', VE/VCO slope, and NT-pro-BNP decreased. At right heart catheterization performed after 1 year of follow-up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow-up (P < 0.001), with a reduction in all PF domains.

Conclusions: Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO and 6MWT increase and together with an NT-pro-BNP reduction constant over the follow-up.
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http://dx.doi.org/10.1002/ehf2.12610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160499PMC
April 2020

Progress in Understanding, Diagnosing, and Managing Cardiac Complications of Systemic Sclerosis.

Curr Rheumatol Rep 2019 12 7;21(12):68. Epub 2019 Dec 7.

Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.

Purpose Of The Review: Systemic sclerosis (scleroderma) is a complex autoimmune disease that commonly involves the cardiovascular system. Even if often subclinical, cardiac involvement is considered a poor prognostic factor as it is a leading cause of death in scleroderma patients. We review the cardiac manifestations of scleroderma, the diagnostic methods useful in detection, and current advances in therapeutic management.

Recent Findings: Beside the routine exams for the assessment of cardiac status (including EKG, standard echocardiography, provocative tests) novel techniques such as myocardial strain imaging on echocardiography, cardiac magnetic resonance imaging, invasive hemodynamic assessment, and endomyocardial biopsy have been demonstrated to be useful in understanding the cardiac alterations that typically affect scleroderma patients. Recent application of novel cardiac detection strategies is providing increased insight into the breadth and pathogenesis of cardiac complications of scleroderma. Further studies coupling exercise provocation, invasive and imaging assessment, and mechanistic studies in scleroderma cardiac tissue are needed to develop the optimal approach to early detection of cardiac disease in scleroderma and targeted therapies.
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http://dx.doi.org/10.1007/s11926-019-0867-0DOI Listing
December 2019

Long-term follow-up in high risk hypertensive patients with carotid dolicoarteriopathies.

Int Angiol 2020 Feb 25;39(1):24-28. Epub 2019 Nov 25.

Department of Translational Medical Sciences, Federico II University, Naples, Italy -

Background: Carotid dolicoarteriopathies (CDA) are a common finding during the carotid ultrasound or angiography, but their potential role in the development of cerebrovascular diseases is still unclear. Aim of this study is to clarify the possible relationship between CDA and the occurrence of cerebral events.

Methods: We performed a retrospective analysis on 2124 hypertensive patients with high cardiovascular risk that underwent carotid ultrasound from January 2000 to December 2008. Follow-up data on cerebrovascular events (transient ischemic attack and/or stroke occurrence) at 10 years were collected.

Results: The global prevalence of CDA in the study population was 12.9% (274/2124), and carotid kinking was more frequent in females and in the left carotid axis. The percentage of cerebrovascular events among hypertensive patients with CDA was similar to those occurred in the group of patients without CDA (10.94% vs. 10.97%, P=NS), with no differences in the number of strokes (8.39% vs. 8.38% P=NS) and TIA (2.55% vs. 2.59% P=NS).

Conclusions: CDA are not associated with a major occurrence of cerebrovascular events in a high-risk population of hypertensives.
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http://dx.doi.org/10.23736/S0392-9590.19.04229-9DOI Listing
February 2020