Lidia Staszewsky

There is little information from experimental studies regarding the evolution of post-resuscitation cardiac arrest [post-return of spontaneous circulation (post-ROSC)] myocardial dysfunction during mid-term follow-up. For this purpose, we assessed left ventricular (LV) function and circulating cardiac biomarkers at different time points in a rat model of cardiac arrest (CA). Rats were divided into two groups: control and post-ROSC rats. Eight minutes of untreated ventricular fibrillation were followed by 8 min of cardiopulmonary resuscitation. Conventional and speckle-tracking echocardiographic (STE) parameters and cardiac circulating biomarkers concentrations were assessed, at 3, 4, 72, and 96 h post-ROSC. At 3 and 4 h post-ROSC, LV systolic function was severely impaired, and high-sensitivity cardiac troponin T and N-terminal pro-atrial natriuretic peptide (NT-proANP) plasma concentrations were significantly increased, compared with control rats (P < 0.0001 for all). At 72 and 96 h post-ROSC, LV ejection fraction (LVEF) normalized. At 96 h, the following variables were significantly different from control rats: early trans-mitral peak velocity, 56.8 ± 3.1 vs. 87.8 ± 3.8 cm/s, P < 0.0001; late trans-mitral peak velocity, 50.6 ± 4.7 vs. 73.7 ± 4.2 cm/s, P < 0.0001; mean s′ wave velocity, 4.6 ± 0.3 vs. 5.9 ± 0.3 cm/s, P < 0.0001, global longitudinal strain (GLS) −7.5 ± 0.5 and vs. −11 ± 1.2%, P < 0.01; GLS rate (GLSR) −0.9 ± 0.4 and −2.3 ± 0.2 1/s, P < 0.01; and NT-proANP concentration, 2.5 (0.2; 6.0) vs. 0.4 (0.01; 1.0) nmol/L, P < 0.01. s′ velocity, GLS, and GLSR indicated that LV systolic function was still impaired 96 h post-ROSC. These findings agree with NT-proANP concentrations, which continue to be high. Normalization of LVEF supports the use of STE for its greater sensitivity for monitoring post-CA cardiac function. Further investigations are needed to provide evidence of the post-ROSC LV diastolic function pattern.

Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmd^mdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16–17 up to 24–25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16–17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24–25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.

The role of beta blockers (BB) post–myocardial infarction (MI) in patients without reduced ejection fraction in the era of invasive management is controversial results from observational studies have led to opposite results. REBOOT is an independent multinational pragmatic, controlled, randomized, open–label, with blinded endpoint adjudication clinical trial. The study is testing the benefits of BB maintenance therapy in post–MI patients (either with or without ST segment elevation) discharged with LVEF >40%. Patients ≥18 years old undergoing invasive management during admission and without history of heart failure (HF) are eligible to participate. At discharge, they are 1:1 randomized to either receive BB (agent and dose chosen by the treating physician) or no BB therapy. The primary endpoint is a composite of all–cause death, nonfatal re–MI, or heart failure hospitalization over a minimum follow–up period of 2.75 years (minimum 2 years, maximum 3 years). Events are adjudicated by a blinded committee. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is the sponsor of the trial and the coordinator of Spanish Centers while Istituto di Ricerche Farmacologiche Mario Negri IRCCS coordinates the Italian participating network. Hospital admission for COVID–19 were also recorded since June 2020. The study is currently ongoing and 29 Italian centers are still actively recruiting. A sample size of 8468 pts (728 events) was estimated to provide a power of 85% to detect a RRR of 20% (incidence of primary endpoint in control 10%) and assuming 5% withdrawals. More than 75 Spanish and 35 Italian centers recruited patients. The first patients have been included in Spain in October 2018, in Italy in January 2019. On December 31st 2022, the number of enrolled patients by Italian centers was 1685. The top three Italian enrollers at the moment are: Ospedale G. da Saliceto –Piacenza (483 pts), Ospedale S. Luigi Gonzaga – Orbassano (183 pts) and A.O San’Anna and San Sebastiano – Caserta (170 pts). The patient enrollment rate was almost stable during all the study periods with a slight decrease during COVID pandemic outbreaks. The Italian REBOOT Network goal is to include 1800 patients by April 2023. The first results will become available by the end of 2025. The REBOOT, with other ongoing trials, will provide robust evidence to guide the prescription of BB to patients discharged after MI without reduced LVEF.

One of the main causes of out-of-hospital cardiac arrest is acute myocardial infarction (AMI). After successful resuscitation from cardiac arrest, approximately 70% of patients die before hospital discharge due to post-resuscitation myocardial and cerebral dysfunction. In experimental models, myocardial dysfunction after cardiac arrest, characterized by an impairment in both left ventricular (LV) systolic and diastolic function, has been described as reversible but very little data are available in cardiac arrest models associated with AMI in pigs. Transthoracic echocardiography is the first-line diagnostic test for the assessment of myocardial dysfunction, structural changes and/or AMI extension. In this pig model of ischemic cardiac arrest, echocardiography was done at baseline and 2-4 and 96 hours after resuscitation. In the acute phase, the examinations are done in anesthetized, mechanically ventilated pigs (weight 39.8 ± 0.6 kg) and ECG is recorded continuously. Mono- and bi-dimensional, Doppler and tissue Doppler recordings are acquired. Aortic and left atrium diameter, end-systolic and end-diastolic left ventricular wall thicknesses, end-diastolic and end-systolic diameters and shortening fraction (SF) are measured. Apical 2-, 3-, 4-, and 5-chamber views are acquired, LV volumes and ejection fraction are calculated. Segmental wall motion analysis is done to detect the localization and estimate the extent of myocardial infarction. Pulsed Wave Doppler echocardiography is used to record trans-mitral flow velocities from a 4-apical chamber view and trans-aortic flow from a 5-chamber view to calculate LV cardiac output (CO) and stroke volume (SV). Tissue Doppler Imaging (TDI) of LV lateral and septal mitral anulus is recorded (TDI septal and lateral s', e', a' velocities). All the recordings and measurements are done according to the recommendations of the American and European Societies of Echocardiography Guidelines.

Background Coexistent heart failure (HF) and diabetes mellitus (DM) are associated with marked morbidity and mortality. Optimizing treatment strategies can reduce the number and severity of events. Insulin is frequently used in these patients, but its benefit/risk ratio is still not clear, particularly since new antidiabetic drugs that reduce major adverse cardiac events (MACEs) and renal failure have recently come into use. Our aim is to compare the clinical effects of insulin in a real-world setting of first-time users, with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1RA) and the other antihyperglycemic agents (other-AHAs). Methods We used the administrative databases of two Italian regions, during the years 2010–2018. Outcomes in whole and propensity-matched cohorts were examined using Cox models. A meta-analysis was also conducted combining the data from both regions. Results We identified 34 376 individuals ≥50 years old with DM and HF; 42.0% were aged >80 years and 46.7% were women. SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin and particularly death from any cause (SGLT-2i, hazard ratio (95% CI) 0.29 (0.23 to 0.36); GLP-1RA, 0.482 (0.51 to 0.42)) and first hospitalization for HF (0.57 (0.40 to 0.81) and 0.67 (0.59 to 0.76)). Conclusions In patients with DM and HF, SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin, and particularly any cause of death and first hospitalization for HF. These groups of medications had high safety profiles compared with other-AHAs and particularly with insulin. The inadequate optimization of HF and DM cotreatment in the insulin cohort is noteworthy.

Background: Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out‐of‐hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA‐induced neurological deficit. Methods and Results: Early KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3‐hydroxy‐anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1‐methyl‐DL‐tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA‐induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle‐treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1‐Methyl‐DL‐tryptophan reduced the CA‐induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus. Conclusions: These data demonstrate the CA‐induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

Background: Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. Objectives: To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. Methods: A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. Results: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04–1.36], p = 0.026; NT-proBNP: HR:1.19[1.06–1.35], p = 0.016; Ang2: HR:1.07[0.95–1.20], p = 0.283; BMP10: HR:1.09[0.96–1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29–1.90], p < 0.001 1.63], p = 0.097). Conclusions: The association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

Objective: (1) to test the association with prevalent and incident atrial fibrillation (AF), and prognosis of total N-terminal pro-B type natriuretic peptide (total NT-proBNP) and of a panel of biomarkers; (2) to assess iwhether the extent of glycosylation affects the relation of NT-proBNP with AF. Methods: In a sub-study of the GISSI-AF trial on 382 patients in sinus rhythm with a history of AF, echocardiographic variables and eight circulating biomarkers were serially assayed over one year. The relations between circulating baseline biomarkers and AF and the risk of CV events, were assessed by Cox-analysis models adjusting the first by clinical variables, the second by clinical variables and the echocardiographic left-atrial-minimum-volume-index (LAVI _min ). Results: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for cardiovascular (CV) reasons. Total NT-proBNP, NT-proBNP, angiopoietin 2 (Ang2), myosin binding protein (MyBPC3) and bone morphogenic protein-10 (BMP-10) were strongly associated to ongoing AF. Natriuretic peptides and MyBPC3 predicted recurrent AF but this lost significance after adjustment for LAVI _min . NT-proBNP and Ang2 predicted CV hospitalization even after adjustment for LAVI _min , HR95%CI: 2.20 [1.02-4.80] and 5.26 [1.16-23.79]. Conclusions: The association of AF recurrence with the novel biomarker total NT-proBNP, is similar to that of NT-proBNP, suggesting no influence of glycosylation. Ang2, MyBPC3 and BMP10 were strongly associated with AF, indicating a possible role of extracellular matrix and myocardial injury. Abstract-words=233 Key messages: What is already known on this subject?: It is still complicated to predict the recurrence of AF in patients in sinus rhythm with a recent history of AF . Though several biomarkers have been associated with AF, few of them have proved to be independent predictors for recurrent AF or cardiovascular (CV) events. Their predictive sensitivity and specificity is modest at best. Previous studies showed that NT-proBNP was possibly the strongest predictor of recurrent AF and CV hospitalization. Natriuretic peptides circulate to a large extent as glycosylated molecules and a novel assay is now available to measure the glycosylated and non-glycosylated NT-proBNP in plasma, the total NT-proBNP. The extent of glycosylation varies in different diseases. What might this study add?: No studies have assessed (a) the extent of NT-proBNP glycosylation in AF, or (b) the association and predictive value in patients with AF of total NT-proBNP. A multimarker approach, ratter than one based on a single biomarker, might predict AF better. The relation with AF of the novel biomarker, total NT-proBNP, is as strong as that of NT-proBNP, suggesting no-influence of glycosylation. Two biomarkers, MyBPC3, secreted few minutes after myocardial injury and Ang-2, involved in inflammation and coagulation, were strongly associated to AF. How might this impact on clinical practice?: The identification of novel circulating biomarkers could have a direct impact on clinical practice when predicting the occurrence of AF, but unfortunately current data do not allow predictions based on biomarkers. The associations of different biomarkers with ongoing AF may cast light on the mechanisms of triggering and maintenance of AF. Strengths and limitations of this study: The data came from to a multicenter randomized clinical trial with available concomitant serial echocardiographic and circulating biomarkers recorded and evaluated centrally, hence with minimal bias; AF recurrence during a 12-month follow up was checked weekly by trans-telephonic electrocardiographic monitoring, and with 12-lead ECG every six months. A comparative analysis of total NT-proBNP with other novel biomarkers and echocardiographic variables has never been done so far. The possible added value of total NT-proBNP to the benchmark biomarker NT-proBNP was assessed on the basis of different dimensions of performance, as recently proposed for new biomarkers. The main limitations are (1) the relatively small numbers of patients with AF during follow-up visits, (2) the very low prevalence of patients with other cardiac diseases such as coronary artery disease and heart failure, and (3) consequently, the low incidence of clinical events in one-year follow-up.

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/EBPβ/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.