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Abstract Aims This study aims to investigate the role of echocardiographically determined left ventricular output indices on sacubitril/valsartan titration in a cohort of outpatients with heart failure and reduced ejection fraction (HFrEF). Methods and results We analysed 106 HFrEF patients who underwent echocardiography examination up to 1 week before starting treatment with sacubitril/valsartan. For each patient, a comprehensive list of clinical and laboratory parameters was collected, and stroke volume index (SVi), cardiac index, and flow rate were calculated. The primary endpoint was the occurrence of complete titration of sacubitril/valsartan. The secondary endpoint was the incidence of adverse events (hypotension and renal adverse events). Univariate and multivariate logistic regression were used to identify variables associated with the primary and secondary endpoints. Mean age of patients was 73.7 ± 10.4 years, 72 patients (71.7%) had ischaemic aetiology of HF, and mean ejection fraction was 29.4 ± 5.9%. At multivariate analysis, SVi [odds ratio (OR) 1.43 per 5 mL/m2 increase, 95% confidence interval (CI) 1.03–1.97; P = 0.028], serum sodium (OR 1.18, 95% CI 1.02–1.37; P = 0.022), and haemoglobin (OR 1.73, 95% CI 1.25–2.40; P = 0.001) were found to be independent predictors of titration during follow‐up. Multivariate analysis for the secondary endpoint showed SVi (OR 0.63 per 5 mL/m2 increase, 95% CI 0.44–0.90; P = 0.012) and New York Heart Association Class III (OR 2.65, 95% CI 1.07–6.5; P = 0.034) to be associated with hypotension. Conclusions Stroke volume index is positively associated with complete titration of sacubitril/valsartan. Patients with low SVi are more prone to experience hypotension during titration

Abstract Background Sex influences outcome of patients with acute coronary syndrome (ACS). If there is a relationship between sex and physical performance is unknown. Methods The analysis is based on older (≥70 years) ACS patients included in the FRASER, HULK, and LONGEVO SCA prospective studies. Physical performance was assessed by Short Physical Performance Battery (SPPB). The primary outcome was all-cause mortality. Results The study included 1388 patients, and 441 (32%) were women. At presentation, women were older and more compromised than men. After a median follow-up of 998 [730–1168] days, all-cause death occurred in 334 (24.1%) patients. At univariate analysis, female sex was related to increased risk of death. After adjustments for confounding factors, female sex was no longer associated with mortality. Women showed poor physical performance compared with men (p < 0.001). SPPB values emerged as an independent predictor of death. Including clinical features and SPPB in the multivariable model, we observed a paradigm shift in the prognostic role of female sex that becomes a protective factor (HR 0.73, 95% CI 0.56–0.96). Sex and physical performance showed a significant interaction (p = 0.03). For lower SPPB values (poor physical performance), sex-related changes in mortality were not recorded, while in patients with higher SPPB values (preserved physical performance), female sex was associated with better survival. Conclusions Two key findings emerged from the present real-life cohort of older ACS patients: (i) physical performance strongly influences long-term mortality; (ii) women with preserved physical performance have a better outcome compared to men. Trial registration www.clinicaltrials.gov NCT02386124 and NCT03021044

ObjectivesIn the last decade, percutaneous treatment of valve disease has changed the approach toward the treatment of aortic stenosis (AS) and mitral regurgitation (MR). The clinical usefulness of stress echocardiography (SE) in the candidates for transcatheter aortic valve implantation (TAVI) and transcatheter edge-to-edge repair (TEER) of MR remains to be established. Therefore, the key aim of this review is to assess the main applications of SE in patients undergoing TAVI or TEER.MethodsWe searched for relevant studies to be included in the systematic review on PubMed (Medline), Cochrane library, Google Scholar, and Biomed Central databases. The literature search was conducted in February 2022. The inclusion criteria of the studies were: observational and clinical trials or meta-analysis involving patients with AS or MR evaluated with SE (excluding those in which SE was used only for screening of pseudo-severe stenosis) and treated with percutaneous procedures.ResultsThirteen studies published between 2013 and 2021 were included in the review: five regarding candidates for TEER and eight for TAVI. In TEER candidates, seeing an increase in MR grade, and stroke volume of >40% during SE performed before treatment was, respectively, related to clinical benefits (p = 0.008) and an increased quality of life. Moreover, overall, 25% of patients with moderate secondary MR at rest before TEER had the worsening of MR during SE. At the same time, in SE performed after TEER, an increase in mean transvalvular diastolic gradient and in systolic pulmonary pressure is expected, but without sign and symptoms of heart failure. Regarding TAVI, several studies showed that contractile reserve (CR) is not predictive of post-TAVI ejection fraction recovery and mortality in low-flow low-gradient AS either at 30 days or at long-term.ConclusionThis systematic review shows in TEER candidates, SE has proved useful in the optimization of patient selection and treatment response, while its role in TAVI candidates is less defined. Therefore, larger trials are needed to test and confirm the utility of SE in candidates for percutaneous procedures of valve diseases.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p

The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1) Background: BrS has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. Some authors have recently hypothesized the presence of structural and functional abnormalities. Therefore, several studies investigated the presence of pathological features in echocardiography and cardiac magnetic resonance imaging (MRI) in patients with BrS, but results were controversial. (2) Methods: We performed a systematic review of the literature on the spectrum of features detected by echocardiography and cardiac MRI. Articles were searched in Pubmed, Cochrane Library, and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2021 were selected. After an initial evaluation, 596 records were screened; the literature search identified 19 relevant articles. (3) Results: The imaging findings associated with BrS were as follows: right ventricular dilation, right ventricular wall motion abnormalities, delayed right ventricular contraction, speckle and feature tracking abnormalities, late gadolinium enhancement, and fat infiltration in the right ventricle. Furthermore, these features emerged more frequently in patients carrying the genetic mutation on the sodium voltage-gated channel α-subunit 5 (SCN5A) gene. (4) Conclusions: Specific imaging features detected by echocardiography and cardiac magnetic resonance are associated with BrS. However, this population appears to be heterogeneous and imaging anomalies emerged to be more frequent in patients carrying genetic mutations of SCN5A. Future studies with an evaluation of BrS patients are needed to identify the specific association linking the Brugada pattern, imaging abnormalities and their possible correlation with prognosis.

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p

Cardiac ventricular outpouchings and invaginations are rare structural abnormalities and usually incidental findings during cardiac imaging. A definitive diagnosis is possible through the use of multimodality imaging. A systematic review of the literature was carried out in November 2022 to identify studies regarding ventricular outpouchings and invaginations. The main aim of the review is to summarize knowledge regarding epidemiology, etiology, diagnosis and prognosis of patients with ventricular outpouchings (aneurisms or diverticula) and invaginations (crypts and recesses). Overall, 26 studies published between 2000 and 2020 were included in the review. Diverticula and congenital aneurysms incidence ranges between 0.6 and 4.1%. Myocardial recesses and crypts range between 9% in the general population and up to 25% in patients with hypertrophic cardiomyopathy. The combined use of echocardiography, cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) is useful to establish tissue contractility, fibrosis, extension and relationship with adjacent structures for differential diagnosis of both invaginations and outpouchings. In conclusion, both outpouchings and invaginations are rare entities: a definitive diagnosis may be aided by the use of combining multiple imaging techniques, and the treatment depends both on the lesion-specific risk of complications and on the potential association of some lesions with cardiomyopathy.

Background: Recently, questions around the efficacy and effectiveness of Fractional Flow Reserve (FFR) have arisen in various clinical settings. Methods: The Clinical Outcome of FFR-guided Revascularization Strategy of Coronary Lesions (HALE-BOPP) study is an investigator-initiated, multicentre, international prospective study enrolling patients who underwent FFR measurement on at least one vessel. In accordance with the decision-making workflow and treatment, the vessels were classified in three subgroups: (i) angio-revascularized, (ii) FFR-revascularized, (iii) FFR-deferred. The primary endpoint was the occurrence of target vessel failure (TVF, cardiac death, target vessel myocardial infarction and ischemia-driven target vessel revascularization). The analysis was carried out at vessel- and patient-level. Results: 1305 patients with 2422 diseased vessels fulfilled the criteria for the present analysis. Wire-related pitfalls and transient adenosine-related side effects occurred in 0.8% (95% CI: 0.4%–1.4%) and 3.3% (95% CI: 2.5%–4.3%) of cases, respectively. In FFR-deferred vessels, the overall incidence rate of TVF was 0.024 (95% CI: 0.019–0.031) lesion/year. After a median follow-up of 3.6 years, the occurrence of TVF was 6%, 7% and 11.7% in FFR-deferred, FFR-revascularized and angio-revascularized vessels, respectively. Compared to angio-revascularized vessels, FFR-guided vessels (both FFR-revascularized and FFR-deferred vessels) showed a lower TVF incidence rate lesion/year (0.029, 95% CI: 0.024–0.034 vs. 0.049, 95% CI: 0.040–0.061 respectively, p = 0.0001). The result was consistent after correction for confounding factors and across subgroups of clinical interest. The patient-level analysis confirmed the lower occurrence of TVF in negative-FFR vs. positive-FFR subgroups. Conclusions: In a large prospective observational study, an FFR-based strategy for the deferral of coronary lesions is a reliable and safe tool, associated with good outcomes. Clinical Trial Registration: NCT03079739.

Background. His bundle pacing (HBP) has emerged as an alternative site to right ventricular pacing (RVP) with encouraging outcomes. To date, no study has investigated the systematic approach of three-dimensional electroanatomic mapping (3D-EAM) to guide HBP implantation and to evaluate myocardial activation timing. Furthermore, studies reporting a comprehensive assessment of the ventricular function, using myocardial work (MW) evaluation are lacking. Objectives. (1) To evaluate the systematic use of the 3D-EAM as a guide to HBP; (2) to assess the electrical and mechanical activations with high-density mapping, comparing spontaneous ventricular activation (SVA), HBP and RVP; (3) to assess the myocardial function through speckle-tracking echocardiography (STE) and MW analysis in SVA, HBP and RVP. Methods. 3D-EAM was performed in consecutive patients undergoing HBP implantation with a low use of fluoroscopy. All patients were systematically evaluated with high-density mapping, MW and STE. Results. Fifteen patients were enrolled, of whom three had an implant failure (20%). RV activation time was not statistically different between SVA and HBP (103 vs. 104 ms, p = 0.969) but was significantly higher in RVP (133 ms, p = 0.011 vs. SVA and p = 0.001 vs HBP). Global constructive work was significantly lower during RVP (1191 mmHg%) than during SVA and HBP (1648 and 1505 mmHg%, p = 0.011 and p = 0.008, respectively) and did not differ between SVA and HBP (p = 0.075). Conclusions. 3D-EAM and MW evaluation showed that HBP was comparable to the physiological SVA in terms of activation time and cardiac performance. Compared to both SVA and HBP, RVP was associated with a worse activation timing and ventricular efficiency.

Background: In cardiology, the global phenomenon of population ageing poses new major challenges, ranging from more comorbid and frail patients to the presence of complex, calcified and multiple coronary lesions. Considering that elderly patients are under-represented in randomized clinical trials (RCT), the aim of this systematic review is to summarize the current knowledge on the revascularization of the elderly patient with myocardial infarction and multivessel coronary artery disease. Methods: A systematic review following PRISMA guidelines has been performed. The search was conducted on Pubmed (Medline), Cochrane library, Google Scholar and Biomed Central databases between January and February 2022. We selected the articles focusing on patients hospitalized for myocardial infarction (MI) with multivessel disease and aged 75 years or older. A total of 36 studies have been included. Results: Multivessel coronary artery disease is present in around 50–60% of older patients with MI. The in-hospital mortality rate of patients older than 75 years is double compared to their younger counterpart, and the most prevalent complications after revascularization are bleeding and renal failure. In the treatment of patients with ST elevation MI (STEMI), primary percutaneous coronary intervention should be the first choice over fibrinolysis. However, it is not clear whether this population would benefit from complete revascularization or not. In patients with non-ST elevation MI (NSTEMI), an invasive approach with either percutaneous coronary intervention or coronary artery bypass graft may be chosen, but a conservative strategy is also accepted. There are no data from large trials about the comparison of possible revascularization strategies in NSTEMI patients. Conclusions: This systematic review shows that this field of research lacks randomized clinical trials to guide revascularization strategy in older STEMI or NSTEMI patients with MI. New results are expected from ongoing trials.

Background: Diabetic patients with critical limb ischemia (CLI) and foot lesions show a poor prognosis. Optimal risk stratification to guide tailored intervention is still uncertain. The aim of the present study was to assess the prognostic role of high-sensitivity cardiac troponin T (hs-TnT) in such a high-risk population.Methods and Results: Clinical, laboratory, and interventional data, as well as the SPINACH score, were collected. Hs-TnT was measured at hospital admission. All patients were followed up for at least 1 year. The primary endpoint was the cumulative occurrence of major cardiovascular events (MACEs, all-cause death, myocardial infarction, or stroke). The secondary endpoint was all-cause mortality. Overall, 618 patients were included and followed for a median of 981 (557–1,325) days. Diagnosis of coronary artery disease (CAD) was established in 270 (43.7%) patients. Median hs-TnT at admission was 31 (20–59) ng/L, with 525 (85%) patients over the upper reference limit. Hs-TnT values were significantly higher in patients with established CAD (39 vs. 29 ng/L, p < 0.01). Hs-TnT was an independent predictor of MACE (HR 2.440, 95% CI 1.706–3.489, p < 0.001). The best cut-offs were 40 ng/L (AUC 0.711) for patients with established CAD and 25 ng/L (AUC 0.725) for those without. Hs-TnT emerged also as an independent predictor of all-cause mortality. The addition of hs-TnT improved prognostic value of the SPINACH score.Conclusions: Hs-TnT is a powerful biomarker for prognostic stratification of diabetic CLI patients with foot lesions. This is confirmed independently to CAD diagnosis and permits the identification of higher risk patients requiring tailored intervention.

Background The 12‐lead ECG plays a key role in the diagnosis of Brugada syndrome (BrS). Since the spontaneous type 1 ECG pattern was first described, several other ECG signs have been linked to arrhythmic risk, but results are conflicting. Methods and Results We performed a systematic review to clarify the associations of these specific ECG signs with the risk of syncope, sudden death, or equivalents in patients with BrS. The literature search identified 29 eligible articles comprising overall 5731 patients. The ECG findings associated with an incremental risk of syncope, sudden death, or equivalents (hazard ratio ranging from 1.1–39) were the following: localization of type 1 Brugada pattern (in V2 and peripheral leads), first‐degree atrioventricular block, atrial fibrillation, fragmented QRS, QRS duration >120 ms, R wave in lead aVR, S wave in L1 (≥40 ms, amplitude ≥0.1 mV, area ≥1 mm2), early repolarization pattern in inferolateral leads, ST‐segment depression, T‐wave alternans, dispersion of repolarization, and Tzou criteria. Conclusions At least 12 features of standard ECG are associated with a higher risk of sudden death in BrS. A multiparametric risk assessment approach based on ECG parameters associated with clinical and genetic findings could help improve current risk stratification scores of patients with BrS and warrants further investigation. Registration URL: https://www.crd.york.ac.uk/prospero/. Unique identifier: CRD42019123794.

Summary: Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

Background: Deficient interferon responses have been proposed as one of the relevant mechanisms prompting severe manifestations of COVID-19.Objective: To evaluate the interferon (IFN)-α levels in a cohort of COVID-19 patients in relation to severity, evolution of the clinical manifestations and immune/inflammatory profile.Methods: This is prospective study recruiting consecutive hospitalized patients with respiratory failure associated with SARS-COV-2 infection and matched controls. After enrollment, patients were assessed every 7 ± 2 days for additional 2 consecutive visits, for a total of 21 days. The severity of the clinical condition was ranked based on the level of respiratory support required. At each time-point blood samples were obtained to assess immune cells and mediators by multiplex immunoassay.Results: Fifty-four COVD-19 and 11 control patients matched for severity were enrolled. At recruitment, lower levels of blood IFN-α were found in COVID-19 patients compared to controls (3.8-fold difference, p < 0.01). Improvements in COVID-19 severity were paralleled by a significant increase of blood IFN-α levels. A significant increase in blood IFN-α was found over the study period in survivors (70% of the study population). A similar trend was found for blood IFN-β with IFN-β levels below the threshold of detectability in a substantial proportion of subjects. Significantly higher values of blood lymphocytes and lower levels of IL-10 were found at each time point in patients who survived compared to patients who died. In patients who clinically improved and survived during the study, we found an inverse association between IL-10 and IFN-α levels.Conclusion: The study identifies a blood immune profile defined by deficient IFN-α levels associated with increased IL-10 expression in patients progressing to severe/life threatening COVID-19 conditions, suggesting the involvement of immunological pathways that could be target of pharmacological intervention.Clinical Trial Registration:ClinicalTrials.gov identifier NCT04343053.

SERine Protein INhibitor-A1 (SERPINA1) is an inducible blood cell gene coding for alpha1-antitrypsin (AAT), a plasma protease inhibitor whose circulating levels are raised during inflammation, infection and advanced pregnancy. DNA methylation has been suggested to play a role in SERPINA1 gene expression regulation in peripheral blood mononuclear cells (PBMCs). The methylation status of SERPINA1 in PBMCs is unknown. The aim of this study was to evaluate the methylation profile of the SERPINA1 promoter in PBMC. To this purpose PBMCs and serum were collected from healthy subjects (HS) (n = 75), including blood donors (BD) (n = 25), pregnant women at early pregnancy (EP) (n = 25), i.e., within the first trimester, and pregnant women at late pregnancy (LP) (n = 25), i.e., at the third trimester. DNA from PBMCs was treated with sodium bisulfite and PCR amplified for SERPINA1 gene promoter, followed by sequencing analyses. AAT serum levels were determined by ELISA test. SERPINA1 was found hypermethylated in 58.7% of HS. The prevalence of SERPINA1 hypermethylation was significantly higher in BD (68%) and EP (88%) than in LP (20%) (p < 0.01). The median serum AAT concentration was 1.07, 0.63, and 3.15 mg/ml in BD, EP, and LP, respectively (p < 0.05, BD and EP vs LP). This study indicates, for the first time, that SERPINA1 gene promoter is differentially methylated in PBMCs from HS. Likely, modulation of the methylation may be a novel epigenetic regulator mechanism of AAT expression in the PBMC of HS. Therefore, SERPINA1 gene promoter methylation may represent an epigenetic biomarker of PBMCs in healthy subjects.

Beyond their role in hemostasis, platelets have emerged as key contributors in the immune response; accordingly, the occurrence of thrombocytopenia during sepsis/septic shock is a well-known risk factor of mortality and a marker of disease severity. Recently, some studies elucidated that the response of platelets to infections goes beyond a simple fall in platelets count; indeed, sepsis-induced thrombocytopenia can be associated with—or even anticipated by—several changes, including an altered morphological pattern, receptor expression and aggregation. Of note, alterations in platelet function and morphology can occur even with a normal platelet count and can modify, depending on the nature of the pathogen, the pattern of host response and the severity of the infection. The purpose of this review is to give an overview on the pathophysiological interaction between platelets and pathogens, as well as the clinical consequences of platelet dysregulation. Furthermore, we try to clarify how understanding the nature of platelet dysregulation may help to optimize the therapeutic approach.

Abstract Background Reduced physical performance and impaired mobility are common in elderly patients after acute coronary syndrome (ACS) and they represent independent risk factors for disability, morbidity, hospital readmission and mortality. Regular physical exercise represents a means for improving functional capacity. Nevertheless, its clinical benefit has been less investigated in elderly patients in the early phase after ACS. The HULK trial aims to investigate the clinical benefit of an early, tailored low-cost physical activity intervention in comparison to standard of care in elderly ACS patients with reduced physical performance. Design HULK is an investigator-initiated, prospective multicenter randomized controlled trial (NCT03021044). After successful management of the ACS acute phase and uneventful first 1 month, elderly (≥70 years) patients showing reduced physical performance are randomized (1:1 ratio) to either standard of care or physical activity intervention. Reduced physical performance is defined as a short physical performance battery (SPPB) score of 4–9. The early, tailored, low-cost physical intervention includes 4 sessions of physical activity with a supervisor and an home-based program of physical exercise. The chosen primary endpoint is the 6-month SPPB value. Secondary endpoints briefly include quality of life, on-treatment platelet reactivity, some laboratory data and clinical adverse events. To demonstrate an increase of at least one SPPB point in the experimental arm, a sample size of 226 patients is needed. Conclusions The HULK study will test the hypothesis that an early, tailored low-cost physical activity intervention improves physical performance, quality of life, frailty status and outcome in elderly ACS patients with reduced physical performance. Trial registration Clinicaltrials.gov, identifier NCT03021044, first posted January, 13th 2017.

Mortality and morbidity in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are still high [1]. A huge amount of the myocardial damage is related to the mitochondrial events happening during reperfusion [2]. Several drugs directly and indirectly targeting mitochondria have been administered at the time of the PCI and their effect on fatal (all-cause mortality, cardiovascular (CV) death) and non fatal (hospital readmission for heart failure (HF)) outcomes have been tested showing conflicting results [3–16]. Data from 15 trials have been pooled with the aim to analyze the effect of drug administration versus placebo on outcome [17]. Subgroup analysis are here analyzed: considering only randomized clinical trial (RCT) on cyclosporine or nicorandil [3–5,9–11], excluding a trial on metoprolol [12] and comparing trial with follow-up length

Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.

Ticagrelor is one of the most powerful P2Y12 inhibitor. We have recently reported that, in patients with concomitant Stable Coronary Artery Disease (SCAD) and Chronic Obstructive Pulmonary Disease (COPD) undergoing percutaneous coronary intervention (PCI), treatment with ticagrelor, as compared to clopidogrel, is associated with an improvement of the endothelial function (Clinical Trial NCT02519608). In the present study, we showed that, in the same population, after 1 month treatment with ticagrelor, but not with clopidogrel, there is a decrease of the circulating levels of epidermal growth factor (EGF) and that these changes in circulating levels of EGF correlate with on-treatment platelet reactivity. Furthermore, in human umbilical vein endothelial cells (HUVEC) incubated with sera of the patients treated with ticagrelor, but not with clopidogrel there is an increase of p-eNOS levels. Finally, analyzing the changes in EGF and p-eNOS levels after treatment, we observed an inverse correlation between p-eNOS and EGF changes only in the ticagrelor group. Causality between EGF and eNOS activation was assessed in vitro in HUVEC where we showed that EGF decreases eNOS activity in a dose dependent manner. Taken together our data indicate that ticagrelor improves endothelial function by lowering circulating EGF that results in the activation of eNOS in the vascular endothelium.

Nuisance bleeding is a major determinant of quality of life and drug discontinuation in patients on dual antiplatelet therapy (DAPT). However, no randomized trial has been focused on the impact of nuisance bleeding on quality of life.BATMAN is an investigator-driven, randomized, controlled, single-center, open trial (NCT02554006). Four hundred and forty-eight consecutive patients with indication to at least 6 months of DAPT were randomized to: i) multimodal counseling program focused on nuisance bleedings (interventional arm); ii) usual discharge process (control arm). The primary endpoint was the one-month health-related quality of life assessed by the EuroQol-5 Dimension (EQ-5D) visual analog scale (VAS) score. Secondary endpoints were EQ-5D at 1 and 6 months, EQ-5D VAS at 6 months, DAPT withdrawal, need of information regarding DAPT and/or nuisance bleedings, 6-month ischemic and bleeding adverse events.The EQ5D-VAS was significantly higher in the interventional arm compared to the control arm at 1 and 6 months (81[74-88] vs. 73[64-80], p < 0.001 at 1 month; 82[76-88] vs. 74[65-81], p < 0.001 at 6 months). Patients in the interventional arm had also significantly lower pain/discomfort and anxiety/depression at the EQ-5D both at 1 and 6 months. Patients in the control arm withdrew DAPT significantly more (7 (3%) vs. 1 (0.4%), p = 0.03) and looked for information regarding DAPT and/or about nuisance bleeding more frequently than those in the interventional arm (178 (79%) vs.19 (8%), p < 0.001).The systematic utilization of a multimodal counseling program improved quality of life and reduced the DAPT withdrawal rate in patients on DAPT.

Cardiac ventricular outpouchings and invaginations are rare structural abnormalities and usually incidental findings during cardiac imaging. A definitive diagnosis is possible through the use of multimodality imaging. A systematic review of the literature was carried out in November 2022 to identify studies regarding ventricular outpouchings and invaginations. The main aim of the review is to summarize knowledge regarding epidemiology, etiology, diagnosis and prognosis of patients with ventricular outpouchings (aneurisms or diverticula) and invaginations (crypts and recesses). Overall, 26 studies published between 2000 and 2020 were included in the review. Diverticula and congenital aneurysms incidence ranges between 0.6 and 4.1%. Myocardial recesses and crypts range between 9% in the general population and up to 25% in patients with hypertrophic cardiomyopathy. The combined use of echocardiography, cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) is useful to establish tissue contractility, fibrosis, extension and relationship with adjacent structures for differential diagnosis of both invaginations and outpouchings. In conclusion, both outpouchings and invaginations are rare entities: a definitive diagnosis may be aided by the use of combining multiple imaging techniques, and the treatment depends both on the lesion-specific risk of complications and on the potential association of some lesions with cardiomyopathy.