Publications by authors named "Carlo G Tocchetti"

101 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

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

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

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

J Immunother Cancer 2021 Mar;9(3)

Department of Dermatology and Allergy, LMU Klinikum, Munich, Germany.

Background: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

Methods: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

Results: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

Conclusions: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
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http://dx.doi.org/10.1136/jitc-2020-002007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929895PMC
March 2021

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

Non-coding RNAs: update on mechanisms and therapeutic targets from the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Cardiovasc Res 2020 09;116(11):1805-1819

Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.
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http://dx.doi.org/10.1093/cvr/cvaa195DOI 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

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.

Eur J Heart Fail 2020 11 6;22(11):1945-1960. Epub 2020 Aug 6.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.
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http://dx.doi.org/10.1002/ejhf.1920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019326PMC
November 2020

Cardiomyocyte ageing and cardioprotection: consensus document from the ESC working groups cell biology of the heart and myocardial function.

Cardiovasc Res 2020 09;116(11):1835-1849

Institute of Cardiology, University of Pisa, Pisa, Italy.

Advanced age is a major predisposing risk factor for the incidence of coronary syndromes and comorbid conditions which impact the heart response to cardioprotective interventions. Advanced age also significantly increases the risk of developing post-ischaemic adverse remodelling and heart failure after ischaemia/reperfusion (IR) injury. Some of the signalling pathways become defective or attenuated during ageing, whereas others with well-known detrimental consequences, such as glycoxidation or proinflammatory pathways, are exacerbated. The causative mechanisms responsible for all these changes are yet to be elucidated and are a matter of active research. Here, we review the current knowledge about the pathophysiology of cardiac ageing that eventually impacts on the increased susceptibility of cells to IR injury and can affect the efficiency of cardioprotective strategies.
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http://dx.doi.org/10.1093/cvr/cvaa132DOI 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

Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function.

Cardiovasc Res 2021 Jan;117(1):43-59

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions.
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http://dx.doi.org/10.1093/cvr/cvaa110DOI Listing
January 2021

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

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

J Am Coll Cardiol 2020 02;75(5):467-478

Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York.

Background: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.

Objectives: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.

Methods: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.

Results: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).

Conclusions: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
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http://dx.doi.org/10.1016/j.jacc.2019.11.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067226PMC
February 2020

Recent advances in cardio-oncology: a report from the 'Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019'.

ESC Heart Fail 2019 12 28;6(6):1140-1148. Epub 2019 Dec 28.

Royal Brompton Hospital and Imperial College London, London, UK.

While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment.
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http://dx.doi.org/10.1002/ehf2.12551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989292PMC
December 2019

Comorbidities in chronic heart failure: An update from Italian Society of Cardiology (SIC) Working Group on Heart Failure.

Eur J Intern Med 2020 01 8;71:23-31. Epub 2019 Nov 8.

Section of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy.

The increasing number of patients with heart failure HF and comorbidities is due to aging population and increase of life expectancy of patients with cardiovascular disease. Encouraging results derived by recent trials may suggest some comorbidities as new targets for new drugs, highlighting the need for a better understanding of the comorbidities' effects in HF patients and the need of a multidisciplinary approach for the management of chronic HF with comorbidities. We report a brief review about main cardiovascular and non-cardiovascular comorbidities in HF patients in order to update physicians and researchers engaged in the HF research or in "fight against heart failure."
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http://dx.doi.org/10.1016/j.ejim.2019.10.008DOI Listing
January 2020

Novel Therapeutic Strategies for the Treatment of Chronic Diseases.

Curr Med Chem 2019 ;26(16):2788-2790

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

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http://dx.doi.org/10.2174/092986732616190816162358DOI Listing
October 2019

Heart Failure and Cancer: Mechanisms of Old and New Cardiotoxic Drugs in Cancer Patients.

Card Fail Rev 2019 May 24;5(2):112-118. Epub 2019 May 24.

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

Although there have been many improvements in prognosis for patients with cancer, anticancer therapies are burdened by the risk of cardiovascular toxicity. Heart failure is one of the most dramatic clinical expressions of cardiotoxicity, and it may occur acutely or appear years after treatment. This article reviews the main mechanisms and clinical presentations of left ventricular dysfunction induced by some old and new cardiotoxic drugs in cancer patients, referring to the most recent advances in the field. The authors describe the mechanisms of cardiotoxicity induced by anthracyclines, which can lead to cardiovascular problems in up to 48% of patients who take them. The authors also describe mechanisms of cardiotoxicity induced by biological drugs that produce left ventricular dysfunction through secondary mechanisms. They outline the recent advances in immunotherapies, which have revolutionised anticancer therapies.
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http://dx.doi.org/10.15420/cfr.2018.32.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545979PMC
May 2019

Modulation of Redox Signaling in Chronic Diseases and Regenerative Medicine.

Oxid Med Cell Longev 2019;2019:6091587. Epub 2019 Apr 23.

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

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http://dx.doi.org/10.1155/2019/6091587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507258PMC
January 2020

Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

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

Background And Aim: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients.

Materials And Methods: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI (AIx@75), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure.

Results: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher AIx@75 and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness.

Conclusions: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD.
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http://dx.doi.org/10.3390/ijms20092154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540240PMC
April 2019

The continuous heart failure spectrum: moving beyond an ejection fraction classification.

Eur Heart J 2019 07;40(26):2155-2163

Experimental Cardiology Unit, Department of Cardiovascular Medicine, University of Lausanne Medical School, Lausanne, Switzerland.

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.
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http://dx.doi.org/10.1093/eurheartj/ehz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963129PMC
July 2019

The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity.

Eur J Heart Fail 2019 04 6;21(4):519-528. Epub 2019 Mar 6.

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

Aims: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function.

Methods And Results: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H O , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO.

Conclusions: Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
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http://dx.doi.org/10.1002/ejhf.1439DOI Listing
April 2019

Nitroxyl (HNO) targets phospholamban cysteines 41 and 46 to enhance cardiac function.

J Gen Physiol 2019 06 6;151(6):758-770. Epub 2019 Mar 6.

Department of Chemistry, Johns Hopkins University, Baltimore, MD

Nitroxyl (HNO) positively modulates myocardial function by accelerating Ca reuptake into the sarcoplasmic reticulum (SR). HNO-induced enhancement of myocardial Ca cycling and function is due to the modification of cysteines in the transmembrane domain of phospholamban (PLN), which results in activation of SR Ca-ATPase (SERCA2a) by functionally uncoupling PLN from SERCA2a. However, which cysteines are modified by HNO, and whether HNO induces reversible disulfides or single cysteine sulfinamides (RS(O)NH) that are less easily reversed by reductants, remain to be determined. Using an N-edited NMR method for sulfinamide detection, we first demonstrate that Cys46 and Cys41 are the main targets of HNO reactivity with PLN. Supporting this conclusion, mutation of PLN cysteines 46 and 41 to alanine reduces the HNO-induced enhancement of SERCA2a activity. Treatment of WT-PLN with HNO leads to sulfinamide formation when the HNO donor is in excess, whereas disulfide formation is expected to dominate when the HNO/thiol stoichiometry approaches a 1:1 ratio that is more similar to that anticipated in vivo under normal, physiological conditions. Thus, N-edited NMR spectroscopy detects redox changes on thiols that are unique to HNO, greatly advancing the ability to detect HNO footprints in biological systems, while further differentiating HNO-induced post-translational modifications from those imparted by other reactive nitrogen or oxygen species. The present study confirms the potential of HNO as a signaling molecule in the cardiovascular system.
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http://dx.doi.org/10.1085/jgp.201812208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571998PMC
June 2019

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.

J Immunother Cancer 2019 02 22;7(1):53. Epub 2019 Feb 22.

Cardio-Oncology Program, Division of Cardiology, Hopitaux Universitaires est Paris, Paris, France.

Background: Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.

Methods: Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.

Results: The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002).

Conclusion: The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.
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http://dx.doi.org/10.1186/s40425-019-0535-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387531PMC
February 2019

Cardiovascular toxicities associated with immune checkpoint inhibitors.

Cardiovasc Res 2019 04;115(5):854-868

Division of Cardiology, Cardio-Oncology Program, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, USA.

Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year.
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http://dx.doi.org/10.1093/cvr/cvz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452314PMC
April 2019

Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology.

Eur J Heart Fail 2019 03 4;21(3):272-285. Epub 2019 Feb 4.

Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
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http://dx.doi.org/10.1002/ejhf.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607480PMC
March 2019

Novel Therapeutic Approaches and Targets for the Treatment of Cardiovascular and Immunological Diseases.

Curr Pharm Biotechnol 2018 ;19(9):684-685

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

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http://dx.doi.org/10.2174/138920101909181024112720DOI Listing
February 2019

Modern-day cardio-oncology: a report from the 'Heart Failure and World Congress on Acute Heart Failure 2018'.

ESC Heart Fail 2018 12;5(6):1083-1091

Royal Brompton Hospital and Imperial College London, London, UK.

During the 'Heart Failure and World Congress on Acute Heart Failure 2018', many sessions and lectures focused on cardio-oncology. This important field of research is constantly growing, and therefore, a great amount of time during the congress focused on it. Prevention and early recognition of side effects is very important in cancer patients. One of the most common and potentially severe problems during antineoplastic therapy is cardiotoxicity. Hence, cardio-oncology is vital in managing cancer patients. This paper will summarize the topics discussed in three main sessions and many additional lectures throughout the 'Heart Failure and World Congress on Acute Heart Failure 2018'. The covered topics included pathophysiological mechanisms in the development of heart failure, risk factors, and early signs of cardiotoxicity detectable with different circulating and imaging biomarkers, as well as cardioprotective treatments recommended by different guidelines and position papers.
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http://dx.doi.org/10.1002/ehf2.12386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300814PMC
December 2018

Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.

J Physiol 2020 04 30;598(7):1393-1415. Epub 2018 Dec 30.

Laboratory of Cardiovascular Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Key Points: Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients.

Abstract: Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.
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http://dx.doi.org/10.1113/JP276824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739175PMC
April 2020

Pharmacovigilating cardiotoxicity of immune checkpoint inhibitors.

Lancet Oncol 2018 12 12;19(12):1545-1546. Epub 2018 Nov 12.

Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, World Allergy Organization Center of Excellence, Federico II University, Naples 80131, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(18)30622-3DOI Listing
December 2018