Publications by authors named "Roberto Latini"

302 Publications

Ventilation with the noble gas argon in an model of idiopathic pulmonary arterial hypertension in rats.

Med Gas Res 2021 Jul-Sep;11(3):124-125

Department of Pathophysiology and Transplantation, University of Milan; Department of Anesthesiology, Intensive Care and Emergency Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.4103/2045-9912.314333DOI Listing
May 2021

Effects of linagliptin on left ventricular DYsfunction in patients with type 2 DiAbetes and concentric left ventricular geometry: results of the DYDA 2 trial.

Eur J Prev Cardiol 2021 03 28;28(1):8-17. Epub 2020 Jul 28.

ANMCO Research Center, Heart Care Foundation, Italy.

Aims: To evaluate the effect of linagliptin on left ventricular systolic function beyond glycaemic control in type 2 diabetes mellitus.

Methods And Results: A multicentre, randomised, double-blind, placebo controlled, parallel-group study, was performed (the DYDA 2 trial). Individuals with type 2 diabetes mellitus and asymptomatic impaired left ventricular systolic function were randomly allocated in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their diabetes therapy. Eligibility criteria were age 40 years and older, haemoglobin A1c 8.0% or less (≤64 mmol/mol), no history of cardiac disease, concentric left ventricular geometry (relative wall thickness ≥0.42), impaired left ventricular systolic function defined as midwall fractional shortening 15% or less at baseline echocardiography. The primary end point was the modification of midwall fractional shortening over time. The main secondary objectives were changes in diastolic and/or in longitudinal left ventricular systolic function as measured by tissue Doppler echocardiography. One hundred and eighty-eight patients were enrolled, predominantly men with typical insulin-resistance comorbidities. At baseline, mean midwall fractional shortening was 13.3%±2.5. At final evaluation, 88 linagliptin patients and 86 placebo patients were compared: midwall fractional shortening increased from 13.29 to 13.82 (+4.1%) in the linagliptin group, from 13.58 to 13.84 in the placebo group (+1.8%, analysis of covariance P = 0.86), corresponding to a 2.3-fold higher increase in linagliptin than the placebo group, although non-statistically significant. Also, changes in diastolic and longitudinal left ventricular systolic function did not differ between the groups. Serious adverse events or linagliptin/placebo permanent discontinuation occurred in very few cases and in the same percentage between the groups.

Conclusions: In the DYDA 2 patients the addition of linagliptin to stable diabetes therapy was safe and provided a modest non-significant increase in left ventricular systolic function measured as midwall fractional shortening.

Trial Registration Number: ClinicalTrial.gov (ID NCT02851745).
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http://dx.doi.org/10.1177/2047487320939217DOI Listing
March 2021

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

Crit Care 2021 03 19;25(1):113. Epub 2021 Mar 19.

Department of Cardiovascular Medicine, Mario Negri Institute for Pharmacological Research IRCCS, Via Mario Negri 2, 20156, Milan, Italy.

Background: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock.

Methods: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization.

Results: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points.

Conclusion: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time.

Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.
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http://dx.doi.org/10.1186/s13054-021-03545-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980645PMC
March 2021

Re-appraisal of the obesity paradox in heart failure: a meta-analysis of individual data.

Clin Res Cardiol 2021 Mar 11. Epub 2021 Mar 11.

Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, 6202AZ, Maastricht, The Netherlands.

Background: Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population.

Methods: In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m, 18.5-25.0 kg/m; 25.0-30.0 kg/m; 30.0 kg/m). Primary endpoints included all-cause mortality and HF hospitalization-free survival.

Results: Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity.

Conclusions: The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF).
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http://dx.doi.org/10.1007/s00392-021-01822-1DOI Listing
March 2021

Semaglutide and effective weight control.

Lancet 2021 Mar 2;397(10278):942-943. Epub 2021 Mar 2.

Department of Cardiovascular Medicine, Mario Negri Institute of Pharmacological Research IRCCS, 20156 Milan, Italy.

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http://dx.doi.org/10.1016/S0140-6736(21)00377-9DOI Listing
March 2021

Circulating pentraxin 3 in severe COVID-19 or other pulmonary sepsis.

Eur J Clin Invest 2021 May 13;51(5):e13530. Epub 2021 Mar 13.

Department of Anaesthesia and Critical Care, Azienda Ospedaliero-Universitaria S. Luigi Gonzaga, Orbassano, Italy.

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http://dx.doi.org/10.1111/eci.13530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995110PMC
May 2021

Sex differences in factors associated with heart failure and diastolic left ventricular dysfunction: a cross-sectional population-based study.

BMC Public Health 2021 Feb 27;21(1):415. Epub 2021 Feb 27.

Quisisana Clinic, Rome, Italy.

Background: Although sex differences in cardiovascular diseases are recognised, including differences in incidence, clinical presentation, response to treatments, and outcomes, most of the practice guidelines are not sex-specific. Heart failure (HF) is a major public health challenge, with high health care expenditures, high prevalence, and poor clinical outcomes. The objective was to analyse the sex-specific association of socio-demographics, life-style factors and health characteristics with the prevalence of HF and diastolic left ventricular dysfunction (DLVD) in a cross-sectional population-based study.

Methods: A random sample of 2001 65-84 year-olds underwent physical examination, laboratory measurements, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiography, and echocardiography. We selected the subjects with no missing values in covariates and echocardiographic parameters and performed a complete case analysis. Sex-specific multivariable logistic regression models were used to identify the factors associated with the prevalence of the diseases, multinomial logistic regression was used to investigate the factors associated to asymptomatic and symptomatic LVD, and spline curves to display the relationship between the conditions and both age and NT-proBNP.

Results: In 857 men included, there were 66 cases of HF and 408 cases of DLVD (77% not reporting symptoms). In 819 women, there were 51 cases of HF and 382 of DLVD (79% not reporting symptoms). In men, the factors associated with prevalence of HF were age, ischemic heart disease (IHD), and suffering from three or more comorbid conditions. In women, the factors associated with HF were age, lifestyles (smoking and alcohol), BMI, hypertension, and atrial fibrillation. Age and diabetes were associated to asymptomatic DLVD in both genders. NT-proBNP levels were more strongly associated with HF in men than in women.

Conclusions: There were sex differences in the factors associated with HF. The results suggest that prevention policies should consider the sex-specific impact on cardiac function of modifiable cardiovascular risk factors.
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http://dx.doi.org/10.1186/s12889-021-10442-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912519PMC
February 2021

Albumin replacement therapy in immunocompromised patients with sepsis - Secondary analysis of the ALBIOS trial.

J Crit Care 2021 Jun 9;63:83-91. Epub 2021 Feb 9.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Anesthesia and Critical Care, Azienda-Ospedaliero Universitaria S. Luigi Gonzaga, Orbassano, Italy.

Background: The best fluid replacement strategy and the role of albumin in immunocompromised patients with sepsis is unclear.

Methods: We performed a secondary analysis of immunocompromised patients enrolled in the ALBIOS trial which randomized patients with severe sepsis or septic shock to receive either 20% albumin (target 30 g per liter or more) and crystalloid or crystalloid alone during ICU stay.

Results: Of 1818 patients originally enrolled, 304 (16.4%) were immunocompromised. One-hundred-thirty-nine (45.7%) patients were randomized in the albumin while 165 (54.2%) in the crystalloid group. At 90 days, 69 (49.6%) in the albumin group and 89 (53.9%) in the crystalloids group died (hazard ratio - HR - 0.94; 95% CI 0.69-1.29). No differences were observed with regards to 28-day mortality, SOFA score (and sub-scores), length of stay in the ICU and in the hospital, proportion of patients who had developed acute kidney injury or received renal replacement therapy, duration of mechanical ventilation. Albumin was not independently associated with a higher or lower 90-day mortality (HR 0.979, 95% CI 0.709-1.352) as compared to crystalloid.

Conclusion: Albumin replacement during the ICU stay, as compared with crystalloids alone, did not affect clinical outcomes in a cohort of immunocompromised patients with sepsis.
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http://dx.doi.org/10.1016/j.jcrc.2021.01.016DOI Listing
June 2021

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

JACC Heart Fail 2021 Apr 3;9(4):268-277. Epub 2021 Feb 3.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.

Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.

Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.

Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).

Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
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http://dx.doi.org/10.1016/j.jchf.2020.11.010DOI Listing
April 2021

PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia.

Sci Rep 2021 Jan 15;11(1):1518. Epub 2021 Jan 15.

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

Ischaemic heart disease is the world's leading cause of mortality. Survival rates from acute myocardial infarction (MI) have improved in recent years; however, this has led to an increase in the prevalence of heart failure (HF) due to chronic remodelling of the infarcted myocardium, for which treatment options remain poor. We have previously shown that inhibition of isoform 4 of the plasma membrane calcium ATPase (PMCA4) prevents chronic remodelling and HF development during pressure overload, through fibroblast mediated Wnt signalling modulation. Given that Wnt signalling also plays a prominent role during remodelling of the infarcted heart, this study investigated the effect of genetic and functional loss of PMCA4 on cardiac outcomes following MI. Neither genetic deletion nor pharmacological inhibition of PMCA4 affected chronic remodelling of the post-MI myocardium. This was the case when PMCA4 was deleted globally, or specifically from cardiomyocytes or fibroblasts. PMCA4-ablated hearts were however less prone to acute arrhythmic events, which may offer a slight survival benefit. Overall, this study demonstrates that PMCA4 inhibition does not affect chronic outcomes following MI.
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http://dx.doi.org/10.1038/s41598-021-81170-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810749PMC
January 2021

Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs.

J Am Heart Assoc 2020 12 8;9(24):e016494. Epub 2020 Dec 8.

Department of Anesthesiology, Intensive Care and Emergency Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (<0.0001). Histology showed less neuronal degeneration in the cortex (<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (<0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (<0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.
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http://dx.doi.org/10.1161/JAHA.120.016494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955395PMC
December 2020

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.

Eur Heart J 2021 Feb;42(6):684-696

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, U1116, France.

Aims : To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.

Methods And Results : Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.

Conclusions : Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.
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http://dx.doi.org/10.1093/eurheartj/ehaa758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878013PMC
February 2021

Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model.

Cardiovasc Drugs Ther 2020 Oct 24. Epub 2020 Oct 24.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milan, Italy.

Purpose: Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented.

Methods: Myocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology.

Results: During ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO and high PCO; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality.

Conclusion: This new model, resulting from a combination of chronic and acute MI, and volume and pressure overload, was able to reproduce all the typical clinical signs occurring during ADHF in a consistent and reproducible manner.
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http://dx.doi.org/10.1007/s10557-020-07096-5DOI Listing
October 2020

Usefulness of Coronary Sinus Reducer Implantation for the Treatment of Chronic Refractory Angina Pectoris.

Am J Cardiol 2021 01 28;139:22-27. Epub 2020 Sep 28.

Department of Cardiology Thoracic and Vascular Sciences and Public Health, University of Padua, Italy. Electronic address:

The coronary sinus (CS) Reducer is a novel device designed for the management of patients with severe angina symptoms refractory to optimal medical therapy and not amenable to further revascularization. Aim of this study was to investigate the efficacy and the safety of the CS Reducer device in a real-world, multicenter, and country-level cohort of patients presenting with refractory angina pectoris. The study included patients affected by refractory angina pectoris who underwent CS Reducer implantation in 16 centers. Clinical follow-up was carried as per each center's protocol. One hundred eighty-seven patients were included. Technical and procedural success were achieved in 98% and 95%, respectively. Minor peri-procedural complications were recorded in 8 patients. During a median follow-up of 18.4 months, 135 (82.8%) patients demonstrated at least 1 CCS class reduction after Reducer implantation, and 80 (49%) patients at least 2 CCS class reduction. Mean CCS class improved from 3.05 ± 0.53 at baseline to 1.63 ± 0.98 at follow-up (p < 0.001). Treatment benefit was also reflected in a significant improvement in quality of life scores and in a reduction of the mean number of anti-ischemic drugs prescribed for patient. In conclusion, in this multicenter, country-level study, the implantation of CS Reducer in patients with refractory angina pectoris resulted to be safe and effective in reducing of angina pectoris and improving quality of life.
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http://dx.doi.org/10.1016/j.amjcard.2020.09.045DOI Listing
January 2021

Efficacy of acute administration of inhaled argon on traumatic brain injury in mice.

Br J Anaesth 2021 01 22;126(1):256-264. Epub 2020 Sep 22.

Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. Electronic address:

Background: Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI.

Methods: Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry.

Results: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1.

Conclusions: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue.
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http://dx.doi.org/10.1016/j.bja.2020.08.027DOI Listing
January 2021

Pentraxin-3, Troponin T, N-Terminal Pro-B-Type Natriuretic Peptide in Septic Patients.

Shock 2020 Nov;54(5):675-680

Department of Anaesthesiology, Emergency, and Intensive Care Medicine, University of Göttingen, Göttingen, Germany.

Objective: To investigate the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their relationships with sepsis severity and oxygen transport/utilization impairment.

Design: Retrospective analysis of PTX3, hsTnT, NT-proBNP levels at day 1, 2, and 7 after admission in the intensive care unit in a subset of the Albumin Italian Outcome Sepsis database.

Setting: Forty Italian intensive care units.

Patients: Nine hundred fifty-eight septic patients enrolled in the randomized clinical trial comparing albumin replacement plus crystalloids and crystalloids alone.

Interventions: The patients were divided into sextiles of lactate (marker of severity), ScvO2 (marker of oxygen transport), and fluid balance (marker of therapeutic strategy).

Measurements And Main Results: PTX3 and hsTnT were remarkably similar in the two treatment arms, while NT-proBNP was almost double in the albumin treatment group. However, as the distribution of all these biomarkers was similar between control and treatment arms, for the sake of clarity, we analyzed the patients as a single cohort. PTX3 (71.8 [32.9-186.3] ng/mL), hsTnT (50.4 [21.6-133.6] ng/L), and NT-proBNP (4,393 [1,313-13,837] ng/L) were abnormally elevated in 100%, 84.5%, 93.4% of the 953 patients and all decreased from day 1 to day 7. PTX3 monotonically increased with increasing lactate levels. The hsTnT levels were significantly higher when ScvO2 levels were abnormally low (< 70%), suggesting impaired oxygen transport compared with higher ScvO2 levels, suggesting impaired oxygen utilization. NT-proBNP was higher with higher lactate and fluid balance. At ScvO2 levels < 70%, the NT-proBNP was higher than at higher ScvO2 levels. However, even with higher ScvO2, the NT-proBNP was remarkably elevated, suggesting volume expansion. Increased level of NT-proBNP showed the strongest association with 90-day mortality.

Conclusions: The selected biomarkers seem related to different mechanisms during sepsis: PTX3 to sepsis severity, hsTnT to impaired oxygen transport, NT-proBNP to sepsis severity, oxygen transport, and aggressive fluid strategy.
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http://dx.doi.org/10.1097/SHK.0000000000001543DOI Listing
November 2020

Cardiopulmonary Resuscitation-associated Lung Edema (CRALE). A Translational Study.

Am J Respir Crit Care Med 2021 02;203(4):447-457

Department of Medical Physiopathology and Transplants, University of Milan, Milano, Italy; and.

Cardiopulmonary resuscitation is the cornerstone of cardiac arrest (CA) treatment. However, lung injuries associated with it have been reported. To assess ) the presence and characteristics of lung abnormalities induced by cardiopulmonary resuscitation and ) the role of mechanical and manual chest compression (CC) in its development. This translational study included ) a porcine model of CA and cardiopulmonary resuscitation ( = 12) and ) a multicenter cohort of patients with out-of-hospital CA undergoing mechanical or manual CC ( = 52). Lung computed tomography performed after resuscitation was assessed qualitatively and quantitatively along with respiratory mechanics and gas exchanges. The lung weight in the mechanical CC group was higher compared with the manual CC group in the experimental (431 ± 127 vs. 273 ± 66,  = 0.022) and clinical study (1,208 ± 630 vs. 837 ± 306,  = 0.006). The mechanical CC group showed significantly lower oxygenation ( = 0.043) and respiratory system compliance ( < 0.001) compared with the manual CC group in the experimental study. The variation of right atrial pressure was significantly higher in the mechanical compared with the manual CC group (54 ± 11 vs. 31 ± 6 mm Hg,  = 0.001) and significantly correlated with lung weight ( = 0.686,  = 0.026) and respiratory system compliance ( = -0.634,  = 0.027). Incidence of abnormal lung density was higher in patients treated with mechanical compared with manual CC (37% vs. 8%,  = 0.018). This study demonstrated the presence of cardiopulmonary resuscitation-associated lung edema in animals and in patients with out-of-hospital CA, which is more pronounced after mechanical as opposed to manual CC and correlates with higher swings of right atrial pressure during CC.
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http://dx.doi.org/10.1164/rccm.201912-2454OCDOI Listing
February 2021

Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy.

Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory cytokines and subsequent splenomegaly. We tested whether such drugs protected these mice from cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg ET743 or 0.07 mg/kg PM01183, three times a week for three weeks. ET743 or PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from cachexia. Since PM01183 extended the animal survival more than ET743, we analyzed PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes, PM01183 restrained the NF-κB/PAX7/myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBP/atrogin-1 axis. Inflammation-mediated splenomegaly of C26-mice was inhibited by PM01183 for as long as the treatment lasted, without reducing IL-6, M-CSF or IL-1β in plasma. ET743 and PM01183 extend the survival of C26-bearing mice unchanging tumor growth or cachexia but possibly restrain muscle-related inflammation and C26-induced splenomegaly.
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http://dx.doi.org/10.3390/cancers12082312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463843PMC
August 2020

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

Circ Arrhythm Electrophysiol 2020 08 12;13(8):e008382. Epub 2020 Jul 12.

Brigham and Women's Hospital, Boston, MA (D.M.).

Background: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication.

Methods: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10.

Results: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers.

Conclusions: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCEP.120.008382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457312PMC
August 2020

Relation between plasma ceramides and cardiovascular death in chronic heart failure: A subset analysis of the GISSI-HF trial.

ESC Heart Fail 2020 Jul 6. Epub 2020 Jul 6.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Aims: Ceramides exert several biological activities that may contribute to the pathophysiology of cardiovascular disease and heart failure (HF). The association between plasma levels of distinct ceramides (that have been previously associated with increased cardiovascular risk) and cardiovascular mortality in patients with chronic HF has received little attention.

Methods And Results: In a post hoc ancillary analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure (GISSI-HF; NCT00336336) trial, we randomly selected a sample of 200 ambulatory patients with chronic HF who died due to cardiovascular causes and 200 patients who were alive at the end of the trial (after a median follow-up period of 3.9 years). We measured baseline plasma concentrations of six previously identified high-risk ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) and their individual plasma ratios with Cer(d18:1/24:0)]. Patients who died due to cardiovascular causes had significantly (P < 0.05 or less) higher levels of plasma Cer(d18:1/16:0) and Cer(d18:1/24:1), but lower levels of plasma Cer(d18:1/22:0) and Cer(d18:1/24:0) than had those who did not. All plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly higher in patients who died due to cardiovascular causes. In Cox regression analyses, all five plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly associated with a greater risk of cardiovascular mortality (with unadjusted hazard ratios ranging from 1.23 to 1.59; P < 0.001 or less). These significant associations were attenuated after adjustment for multiple established risk factors, New York Heart Association functional class, left ventricular ejection fraction, use of medications, plasma pentraxin-3 levels, and, especially, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. When we applied a Bonferroni correction for multiple comparisons (using a P-threshold 0.05/5 ceramide ratios = 0.01), none of the five plasma ratios of each ceramide with Cer(d18:1/24:0) remained statistically associated with the risk of cardiovascular mortality (with adjusted hazard ratios ranging from 1.10 to 1.23).

Conclusions: Higher levels of specific plasma ceramides [especially when used in ratios with Cer(d18:1/24:0)] are associated with increased cardiovascular mortality in ambulatory patients with chronic HF. However, these associations are weakened after adjustment for established cardiovascular risk factors, medication use, and plasma NT-proBNP concentrations.
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http://dx.doi.org/10.1002/ehf2.12885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754905PMC
July 2020

Cardiovascular mortality and morbidity burden in successive and age pre-stratified case-control cohorts of breast cancer women. A population-based study.

Breast Cancer Res Treat 2020 Aug 25;183(1):177-188. Epub 2020 Jun 25.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.

Aims: To assess the existence, components and clinical relevance of cardiac causes of death and cardiovascular (CV) hospitalizations in a population-wide database of patients with breast cancer (BC).

Methods And Results: A population-wide database of the Puglia Region, Italy was analyzed, with a prospective comparative design. Three successive closely matched case/control cohorts representing current care in the period 2007-2014 were also stratified according to age to focus specifically on the potential interaction of treatment-related cardiac toxicity and the expected different baseline CV risk profiles.

Results: At 3-year follow-up, in the successive cohorts the incidence of BC-related (7.7, 7.0, 6.5%) and cardiac causes of death, specifically attributed to heart failure (HF, 1.3, 0.5, 0.5%), decreased. Significant mortality hazard ratio (HR) for HF was found in the total population (1.47, 95% CI 1.14-1.90), in particular in the 2007-2009 cohort (1.71, 95% CI 1.19-2.46) and in the 50-69 age group (7.96, 95% CI 2.81-22.55). Results at 5 years confirm the mortality findings, and a significant HR for hospitalizations for HF, non-atrial arrhythmias and ischemic heart disease in the younger than 50 subpopulation pointed to a late expression of toxicity in the youngest BC population.

Conclusions: The incidence of CV causes of death 3 and 5 years after BC diagnosis was very low, even if an excess in risk of death for HF as compared with the control cohort was observed. While younger patients seems to tolerate BC and BC therapy better in the short term, HF mortality and morbidity resulted significantly increased at 5-year follow-up. As the risk for hospitalization for CV reasons increased at 5-year follow-up in particular in women aged less than 50 years, CV monitoring in this subgroup of patients seems mandatory.
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http://dx.doi.org/10.1007/s10549-020-05758-4DOI Listing
August 2020

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

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

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

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

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

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

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

Association of high-risk coronary atherosclerosis at CCTA with clinical and circulating biomarkers: Insight from CAPIRE study.

J Cardiovasc Comput Tomogr 2021 Jan-Feb;15(1):73-80. Epub 2020 Jun 11.

Heart Care Foundation Onlus, Florence, Italy.

Background: High-risk coronary atherosclerosis features evaluated coronary CT angiography (CCTA) were suggested to have a prognostic role. The present study aimed to evaluate the association of circulating biomarkers with high-risk plaque features assessed by CCTA.

Methods: A consecutive cohort of subjects who underwent CCTA because of suspected CAD was screened for inclusion in the CAPIRE study. Based on risk factors (RF) burden patients were defined as having a low clinical risk (0-1 RF with the exclusion of patients with diabetes mellitus as single RF) or an high clinical risk (≥3 RFs). In all patients, measurement of inflammatory biomarkers and CCTA analysis focused on high-risk plaque features were performed. Univariate and multivariate logistic regression analysis were used to evaluate the relationship between clinical and biological variables with CCTA advanced plaque features.

Results: 528 patients were enrolled in CAPIRE study. Older age and male sex appeared to be predictors of qualitative high-risk plaque features and associated with the presence of elevated total, non-calcified and low-attenuation plaque volume. Among circulating biomarkers only hs-CRP was found to be associated with qualitative high-risk plaque features (OR 2.02, p = 0.004 and 2.02, p = 0.012 for LAP and RI > 1.1, respectively) with borderline association with LAP-Vol (OR 1.52, p = 0.076); HbA1c and PTX-3 resulted to be significantly associated with quantitative high-risk plaque features (OR 1.71, p = 0.003 and 1.04, p = 0.002 for LAP-Vol, respectively).

Conclusions: Our results support the association between inflammatory biomarkers (hs-CRP, PTX- 3), HbA1c and high-risk atherosclerotic features detected by CCTA. Male sex and older age are significant predictors of high-risk atherosclerosis.
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http://dx.doi.org/10.1016/j.jcct.2020.03.005DOI Listing
April 2021

Early osteopontin levels predict mortality in patients with septic shock.

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

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

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

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

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

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

Cancer in chronic heart failure patients in the GISSI-HF trial.

Eur J Clin Invest 2020 Sep 31;50(9):e13273. Epub 2020 May 31.

ANMCO Research Centre, Florence, Fondazione per il Tuo cuore - HCF onlus, Florence, Italy.

Background: Cancer complicating heart failure (HF) is an emerging issue. We investigated it in the GISSI-HF trial, which uniquely included patients with malignancies if deemed likely to allow follow-up.

Methods And Results: At enrolment, 256 of 6913 participants in GISSI-HF (3.7%) had a tumour diagnosis, which was malignant (cancer) in 145 (2.1%). Patients with cancer were older and more often former smokers, had lower body mass index, lower left ventricular ejection fraction (LVEF), less implanted devices, lower glucose and haemoglobin and higher uric acid levels than those without cancer. During a median 4-year follow-up, cardiovascular (CV), non-CV non-cancer and cancer death occurred in 1477, 272 and 220 subjects (75%, 13.8% and 11.2% of total mortality, respectively). Cancer at trial entry portended an increased risk of all-cause mortality after accounting for age and confounders (HR 1.33, 95%CI 1.02-1.73), which was attributable to cancer-specific mortality. Among the 6657 patients without any tumour at enrolment, 1879 subsequently died. CV, non-CV non-cancer and cancer causes accounted for 1422 (75.7%), 261 (13.9%) and 196 (10.4%) of these deaths, respectively, median time to specific death being 22, 25 and 30 months (P < .0001). Patients facing cancer vs CV death had lower NYHA class, slower heart rate, higher blood pressure, higher LVEF, shorter HF history, less diuretic use, lower creatinine and uric acid and higher haemoglobin and cholesterol.

Conclusions: Even when considered not aggressive, concomitant cancer worsens HF prognosis. The inverse relationship between HF severity and cancer death in the absence of prior tumour warrants further study.
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http://dx.doi.org/10.1111/eci.13273DOI Listing
September 2020

Circulating MicroRNAs as Potential Predictors of Anthracycline-Induced Troponin Elevation in Breast Cancer Patients: Diverging Effects of Doxorubicin and Epirubicin.

J Clin Med 2020 May 11;9(5). Epub 2020 May 11.

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

Anthracyclines are anti-neoplastic drugs presenting cardiotoxicity as a side effect. Cardiac troponins (cTn) and echocardiography are currently used to assess cardiac damage and dysfunction, but early biomarkers identifying patients in need of preventive treatments remain a partially met need. Circulating microRNAs (miRNAs) represent good candidates, so we investigated their possible roles as predictors of troponin elevation upon anthracycline treatment. Eighty-eight female breast cancer patients administered with doxorubicin (DOX) or epirubicin (EPI) were divided into four groups basing on drug type and cTn positive (cTn+) or negative (cTn-) levels: DOX cTn-, DOX cTn+, EPI cTn- and EPI cTn+. Blood was collected at baseline, during treatment, and at follow-up. We identified plasma miRNAs of interest by OpenArray screening and single assay validation. Our results showed miR-122-5p, miR-499a-5p and miR-885-5p dysregulation in DOX patients at T0, identifying a signature separating, with good accuracy, DOX cTn- from DOX cTn+. No miRNAs showed differential expression in EPI subjects. Conversely, an anthracycline-mediated modulation (regardless of cTn) was observed for miR-34a-5p, -122-5p and -885-5p. Our study indicates specific circulating miRNAs as possible prediction markers for cardiac troponin perturbation upon anthracycline treatment. Indeed, our findings hint at the possible future use of plasma miRNAs to predict the cardiac responsiveness of patients to different anticancer agents.
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http://dx.doi.org/10.3390/jcm9051418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290665PMC
May 2020

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial.

Trials 2020 May 12;21(1):401. Epub 2020 May 12.

Laboratory of Cardiovascular Clinical Pharmacology, Mario Negri Institute for Pharmacological Research-IRCCS, Via Mario Negri, 2, 20156, Milan, Italy.

Background: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression.

Methods: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory).

Discussion: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial.

Trial Registration: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.
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http://dx.doi.org/10.1186/s13063-020-4202-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218540PMC
May 2020

Circulating biomarkers and cardiac function over 3 years after chemotherapy with anthracyclines: the ICOS-ONE trial.

ESC Heart Fail 2020 08 1;7(4):1452-1466. Epub 2020 May 1.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Aims: A multicentre trial, ICOS-ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12 months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra-normal cTn (troponin-triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline-based treatment could induce cardiotoxicity over 36 month follow-up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI-Ultra, B-type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36 months.

Methods And Results: Eligible patients were those prescribed first-in-life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin-angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36 months. No differences were observed in biomarker concentration between the two study arms, 'prevention' vs. 'troponin-triggered'. During additional follow-up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non-cardiovascular cause. No new occurrences of LV-dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI-Ultra was reported in the extended follow-up. BNP remained within normal range: at 36 months was 23.4 ng/L, higher (N.S.) than at baseline, 17.6 ng/L. PTX3 peaked at 5.2 ng/mL 1 month after CT and returned to baseline values thereafter. cTnI-Ultra peaked at 26 ng/L 1 month after CT and returned to 3 ng/L until the last measurement at 36 months. All echocardiographic variables remained stable during follow-up with a median LVEF of 63% and left atrial volume index about 24 mL/m .

Conclusions: First-in-life CT with median cumulative dose of anthracyclines of 180 mg/m does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51 years (median), without pre-existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin-triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow-up.
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http://dx.doi.org/10.1002/ehf2.12695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373944PMC
August 2020

Testing longitudinal data for prognostication in ambulatory heart failure patients with reduced ejection fraction. A proof of principle from the GISSI-HF database.

Int J Cardiol 2020 08 30;313:89-96. Epub 2020 Mar 30.

ANMCO Research Centre, Fondazione per il Tuo cuore - HCF onlus, Florence, Italy. Electronic address:

Background: Variability of parameter measurements in heart failure with reduced ejection fraction (HFrEF) may contribute to reducing the prediction accuracy of available prognostic models. We investigated whether the use of longitudinal versus cross-sectional measurements of established predictors of mortality in patients with HFrEF would increase the accuracy of prognostication.

Methods: We used longitudinal measurements of systolic blood pressure (SBP), heart rate, hemoglobin, creatinine and uric acid from HFrEF patients enrolled in the GISSI-HF trial. We performed linear mixed models to investigate the difference in first 6-month trajectories of these parameters between patients alive and dead at 4-year follow-up, and examined the change in prediction accuracy by comparing area under the curve (AUC) and net reclassification index (NRI) values obtained using a traditional cross-sectional survival model versus a longitudinal joint model using information up to 6-month follow-up.

Results: We included 5469 patients with 32,206 repeated visits and measurements. We demonstrated a significant difference in the first 6-month change of each one of the selected parameters between those alive and dead at the end of follow-up (p-value for time∗mortality interaction ≤0.01). The comparison of prediction accuracy of the two models revealed a significant increase of about 2% in the AUCs when using longitudinal values of each parameter of interest up to 6 months, with significant concomitant increase in NRI. The greatest increase in accuracy was noticed when using longitudinal SBP measurements in patients with baseline SBP ≤ 110 mmHg.

Conclusions: Our findings support the use of longitudinal data to improve prognostication in patients with HFrEF, and warrant validation in external cohorts and creation of new prognostic tools.
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http://dx.doi.org/10.1016/j.ijcard.2020.03.064DOI Listing
August 2020