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Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB-MYH11 , belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with CBFB-MYH11 AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low-level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize post-remission monitoring and to define effective MRD-based therapeutic strategies.

Advanced heart failure (HF) represents a public health priority due to the increase of affected patients and the meaningful mortality. Durable mechanical circulatory support (MCS) and heart transplantation (HTx) are unique therapies for end-stage HF (ESHF), with positive early and long-term outcomes. The patients who underwent HTx have a 1-y survival of 91% and a median survival of 12-13 y, whereas the median survival of ESHF is <12 mo. Short-term MCS with veno-arterial extracorporeal membrane oxygenation (VA ECMO) can be used as a bridge to transplantation strategy. Patients bridged with VA ECMO have significantly lower survival in comparison with non-MCS bridged and left ventricular assist device-bridged patients. VA ECMO represents an effective, and sometimes unique, system to obtain rapid hemodynamic stabilization, but possible negative effects on patients' outcomes after HTx must be considered. Here, we discuss the use of VA ECMO as bridge to transplantation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Trans-catheter valve-in-valve (ViV) is a treatment option for patients affected by bioprosthetic heart valve (BHV) failure. Both aortic and mitral ViV procedures present several challenges compared to native valve replacement. To date, no data concerning the balloon-expandable MyVal (Meril, Vapi, India) trans-catheter heart valve (THV) use in ViV procedure have been provided. In this case series, we described for the first time its use in five different BHV failures., Competing Interests: Declaration of competing interest Authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Napoli et al.)

Purpose of Review: Cardiovascular diseases (CVDs) are typically caused by multifactorial events including mutations in a large number of genes. Epigenetic-derived modifications in the cells are normal but can be amended by aging, lifestyle, and exposure to toxic substances. Major epigenetic modifications are DNA methylation, histone modification, chromatin remodeling as well as the noncoding RNAs. These pivotal players are involved in the epigenetic-induced modifications observed during CVDs. Nevertheless, despite impressive efforts capitalized in epigenetic research in the last 50 years, clinical applications are still not satisfactory., Recent Findings: Briefly, we present some of the recent steps forward in the epigenetic studies of CVDs. There is an increased appreciation for the contribution of epigenetic alterations in the development of CVDs. Now, we have novel epigenetic biomarkers and therapeutic trials with the use of statins, metformin, and some compounds affecting epigenetic pathways including a BET inhibitor apabetalone. The new knowledge of epigenetic regulation is also discussed in the light of precision medicine of CVDs., Summary: Epigenetic studies of CVDs have the promise to yield both mechanistic insights as well as adjunct treatments (repurposed drugs and apabetalone). The overall concept of precision medicine is not widely recognized in routine medical practice and the so-called reductionist approach remains the most used way to treat CVD patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

An increased need of extracorporeal membrane oxygenation (ECMO) support is going to become evident as treatment of SARS-CoV-2 respiratory distress syndrome. This is the first report of the Italian Society for Cardiac Surgery (SICCH) on preliminary experience with COVID-19 patients receiving ECMO support. Data from 12 Italian hospitals participating in SICCH were retrospectively analyzed. Between March 1 and September 15, 2020, a veno-venous (VV) ECMO system was installed in 67 patients (94%) and a veno-arterio-venous ECMO in four (6%). Five patients required VA ECMO after initial weaning from VV ECMO. Thirty (42.2%) patients were weaned from ECMO, while 39 (54.9%) died on ECMO, and six (8.5%) died after ECMO removal. Overall hospital survival was 36.6% (n = 26). Main causes of death were multiple organ failure (n = 14, 31.1%) and sepsis (n = 11, 24.4%). On multivariable analysis, predictors of death while on ECMO support were older age (p = 0.048), elevated pre-ECMO C-reactive protein level (p = 0.048), higher positive end-expiratory pressure on ventilator (p = 0.036) and lower lung compliance (p = 0.032). If the conservative treatment is not effective, ECMO support might be considered as life-saving rescue therapy for COVID-19 refractory respiratory failure. However warm caution and thoughtful approaches for timely detection and treatment should be taken for such a delicate patients population., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Competing Interests: Conflict of interestF. Donatelli. A. Miceli, S. Cirri, E. Coscioni, and C. Napoli decalre that they have no no competing interests.

The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected all health care professionals. The outbreak required a thorough reorganization of the Italian regional local health care system to preserve resources such as ventilators, beds in intensive care units and surgical and anaesthesiological staff. Levels of priority were created, together with a rigorous triage procedure for patients with COVID-19, which led to postponement of all elective procedures. Urgent cases were discussed with the local heart team and percutaneous approaches were selected as the first treatment option to reduce hospital stay. COVID-19 and COVID-19-free pathways were created, including adequate preparation of the operating room, management of anaesthesiological procedures, transportation of patients and disinfection. It was determined that patients with chronic diseases were at increased risk of adverse outcomes. Systemic inflammation, cytokine storm and hypercoagulability associated with COVID-19 increased the risk of heart failure and cardiac death. In this regard, the early use of extracorporeal membrane oxygenation could be life-saving in patients with severe forms of acute respiratory distress syndrome or refractory heart failure. The goal of this paper was to report the Italian experience during the COVID-19 pandemic in the setting of cardiovascular surgery., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Rationale: Although there have been several studies describing clinical and radiographic features about the novel coronavirus (COVID-19) infection, there is a lack of pathologic data conducted on biopsies or autopsies., Patient Concerns: A 56-year-old and a 70-year-old men with fever, cough, and respiratory fatigue were admitted to the intensive care unit and intubated for respiratory distress., Diagnosis: The nasopharyngeal swab was positive for COVID-19 and the chest Computed Tomography (CT) scan showed the presence of peripheral and bilateral ground-glass opacities., Interventions: Both patients developed pneumothoraces after intubation and was managed with chest tube. Due to persistent air leak, thoracoscopies with blebs resection and pleurectomies were performed on 23rd and 16th days from symptoms onset., Outcomes: The procedures were successful with no evidence of postoperative air-leak, with respiratory improvement. Pathological specimens were analyzed with evidence of diffuse alveolar septum disruption, interstitium thickness, and infiltration of inflammatory cells with diffuse endothelial dysfunction and hemorrhagic thrombosis., Lessons: Despite well-known pulmonary damages induced by the COVID-19, the late-phase histological changes include diffused peripheral vessels endothelial hyperplasia, in toto muscular wall thickening, and intravascular hemorrhagic thrombosis.

Heart failure (HF) management is challenging due to high clinical heterogeneity of this disease which makes patients responding differently to evidence-based standard therapy established by the current reductionist approach. Better understanding of the genetic and epigenetic interactions may clarify molecular signatures underlying maladaptive responses in HF, including metabolic shift, myocardial injury, fibrosis, and mitochondrial dysfunction. DNA methylation, histone modifications and micro-RNA (miRNAs) may be major epigenetic players in the pathogenesis of HF. DNA hypermethylation of the kruppel-like factor 15 (KLF15) gene plays a key role in switching the failing heart from oxidative to glycolytic metabolism. Moreover, hypomethylation at H3K9 promoter level of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) genes also leads to reactivation of fetal genes in man. The role of miRNAs has been investigated in HF patients undergoing heart transplantation, for whom miR-10a, miR-155, miR-31, and miR-92 may be putative useful prognostic biomarkers. Recently, higher RNA methylation levels have been observed in ischemic human hearts, opening the era of "epitranscriptome" in the pathogenesis of HF. Currently, hydralazine, statins, apabetalone, and omega-3 polyunsatured fatty acids (PUFA) are being tested in clinical trials to provide epigenetic-driven therapeutic interventions. Moreover, network-oriented analysis could advance current medical practice by focusing on protein-protein interactions (PPIs) perturbing the "cardiac" interactome. In this review, we provide an epigenetic map of maladaptive responses in HF patients. Furthermore, we propose the "EPi-transgeneratIonal network mOdeling for STratificatiOn of heaRt Morbidity" (EPIKO-STORM), a clinical research strategy offering novel opportunities to stratify the natural history of HF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste. However, there is growing concern for their impact on metabolic health., Methods: Human endothelial cells were treated with Glucose, Fructose, Aspartame, Rebaudioside A, Stevioside, or Steviol. Morphological characteristics, in vitro angiogenesis and array gene expression were analyzed., Results: High-glucose and fructose concentrations significantly decreased cell features such as angiogenic capability. Interestingly, non-caloric sweeteners did not significantly modified all cell characteristics and they did not compromised cell angiogenic ability. Array gene expression analysis revealed that the chemokine fractalkine (CX3CL1) and the enzyme transferase (HPRT1) were always significantly upregulated and downregulated respectively, after glucose and fructose treatments (P > .05), whereas they were non-differentially expressed with all the other sweeteners. Interestingly, both genes are considered as cardiovascular disease risk biomarkers. Specifically, upregulation of CX3CL1/CX3CR1 occurs in the human placenta and serum levels of the ligand are associated with markers of insulin resistance in GDM., Conclusions: Differently from glucose and fructose, steviol glycosides do not damage endothelial cells. Prospective preclinical studies and clinical trials are warranted to confirm the long-term safety of such compounds., (Copyright © 2019. Published by Elsevier Ltd.)

Objectives: Postoperative hemorrhage in cardiac surgery is a significant cause of morbidity and mortality. Standard laboratory tests fail as predictors for bleeding in the surgical setting. The use of viscoelastic (VE) hemostatic assays thromboelastography (TEG) and rotational thromboelastometry (ROTEM) could be an advantage in patients undergoing cardiac surgery. The objective of this meta-analysis was to analyze the effects (benefits and harms) of VE-guided transfusion practice in cardiac surgery patients., Design: A meta-analysis of randomized trials., Setting: For this study, PubMed, EMBASE, Scopus, and the Cochrane Collaboration database were searched, and only randomized controlled trials were included. A systematic review and meta-analysis were performed in accordance with the standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using a random-effects model., Participants: The study comprised adult cardiac surgery patients., Interventions: VE-hemostatic assays transfusion algorithm compared with transfusion algorithms based on clinicians' discretion., Measurements and Main Results: Seven comparative randomized controlled trials were considered, including a total of 1,035 patients (522 patients in whom a TEG- or ROTEM-based transfusion algorithm was used). In patients treated according to VE-guided algorithms, red blood cell (odds ratio 0.61; 95% confidence interval [CI]: 0.37-0.99; p: 0.04; I 2 : 66%) and fresh frozen plasma transfusions (risk difference 0.22; 95% CI: 0.11-0.33; p < 0.0001; I 2 : 79%) use was reduced; platelets transfusion was not reduced (odds ratio 0.61; 95% CI: 0.32-1.15; p: 0.12; I 2 74%)., Conclusions: This study demonstrated that the use of VE assays in cardiac surgical patients is effective in reducing allogenic blood products exposure, postoperative bleeding at 12 and 24 hours after surgery, and the need for redo surgery unrelated to surgical bleeding., (Copyright © 2019 Elsevier Inc. All rights reserved.)

TAVR has become the standard treatment in patients at increased surgical risk (STS or EuroSCORE II ≥4% or logistic EuroSCORE I  ≥ 10% or other risk factors not included in these scores such as frailty, porcelain aorta, sequelae of chest radiation) and it is increasingly being performed in patients at intermediate to low (STS or EuroSCORE II <4% or logistic EuroSCORE I  < 10%) surgical risk. Although non-inferiority has been demonstrated in intermediate and low-risk patients, several challenges need to be addressed before expansion to younger patients. Current trends, trials results, and remaining challenges are summarized and discussed in this review.

Although venous thromboembolism (VTE) shows a polygenic nature, the crossroad between genome and environment is not fully understood. Genetics explains only a part of VTE hereditability and not defined molecular causes are found in approximately 50% of thrombotic patients. Thus, a major understanding of molecular mechanisms may clarify the missing hereditability. Concerning epigenetics, a particular histone modification (citrullination) plays a key role in increasing the rate of venous occlusive events by inducing neutrophil apoptosis and expulsion of neutrophil extra-cellular traps (NETs), which may be useful biomarkers of active disease. Moreover, an over-expression of miR-320a/b, miR-582, miR-195, miR-424-5p, and miR-532, or a down-regulation of miR495, miR-136-5p and miR-26a may improve the accuracy of VTE diagnosis. No clinical studies have focused on DNA methylation in VTE. Nowadays, no validated epigenetics biomarkers are routinely used for diagnosis and prevention of VTE. In the era of personalized therapy, several clinical trials are investigating the putative role of statins, a class of lipid-lowering epigenetic-based drugs, as additional therapeutic agents in VTE. Furthermore, single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and MIR133 genes can help physicians to predict individual warfarin dose requirement. Consequently, a comprehensive understanding of the mechanisms involved in the control of blood clot development is crucial to design novel therapeutic strategies. This review summarizes the current clinical concepts both in genetic and epigenetic VTE framework. Furthermore, we discuss the contribution of the innovative network medicine paradigm into advancing our knowledge about molecular underpinnings needed to support novel VTE diagnostic and therapeutic options., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Postoperative hyperglycemia is associated with increased rate of surgical site infection, renal failure, and cardiovascular events. The study of insulin sensitivity state before surgery could help in treating postoperative hyperglycemia and preventing iatrogenic hypoglycemia. We studied the postoperative insulin secretion in patients who have a low insulin sensitivity (IR) before surgery compared to patients with normal preoperative insulin sensitivity (IS)., Materials and Methods: Forty-two consecutive patients, undergoing abdominal surgery, underwent preoperative sequential hyperglycemic-euglycemic clamp (SHEC) in order to measure insulin secretion and to screen patients with low insulin sensitivity (IR) or with normal insulin sensitivity (IS). Patients had been randomized to receive either general anesthesia with epidural or PCA., Results: Postoperative insulin secretion in IR patients is decreased compared to IS (P = 0.059) and to IR before surgery regardless to the type of analgesia (P < 0.001). In the IS group, postoperative insulin secretion depends on type of analgesia. It is increased when using PCA and decreased when using epidural (P < 0.05). Blood glucose increased after surgery in both IS an IR (P < 0.001). Patients with preoperative insulin resistance had a higher glycemia before and after surgery (P < 0.001). Blood glucose levels were comparable between PCA and epidural patients (P = 0.450)., Conclusion: Insulin secretion is reduced in IR regardless the type of anesthesia. PCA increases insulin secretion, whereas epidural decreases it in patients with normal insulin sensitivity. These findings implicate that after surgery insulin administration is advisable in patients with preoperative insulin resistance while it should be given cautiously in those with normal preoperative insulin sensitivity., (© 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1 -mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1 -mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1 -mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1 -mutated AML patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Cell therapy is a central issue of regenerative medicine and is raising a growing interest in the scientific community, but its full therapeutic potential in coronary heart disease (CHD) has not been reached yet. Several different methods, cell types, delivery routes, and supporting techniques have been attempted and improved to elicit cardiac regeneration in CHD, but only some of them showed a really convincing potential for the use in clinical practice. Here we provide an update on approaches and clinical trials of cell therapy applied to CHD, which are ongoing or that have been realized in the last 5 years. Moreover, we discuss the evidence collected so far in favor or against the validity of stem cell therapy for CHD. In particular, we review and comment the recent advances in cell therapy applied to CHD, the most promising cell types, delivery strategies, biochemical and engineering techniques that have been adopted in this context., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Aortic stenosis is the most common valvular disease and has a dismal prognosis without surgical treatment. The aim of this meta-analysis was to quantitatively assess the comparative effectiveness of the Perceval (LivaNova) valve versus conventional aortic bioprostheses., Methods and Results: A total of 6 comparative studies were identified, including 639 and 760 patients who underwent, respectively, aortic valve replacement with the Perceval sutureless valve (P group) and with a conventional bioprosthesis (C group). Aortic cross-clamping and cardiopulmonary bypass duration were significantly lower in the P group. No difference in postoperative mortality was shown for the P and C groups (2.8% versus 2.7%, respectively; odds ratio [OR]: 0.99 [95% confidence interval (CI), 0.52-1.88]; P =0.98). Incidence of postoperative renal failure was lower in the P group compared with the C group (2.7% versus 5.5%; OR: 0.45 [95% CI, 0.25-0.80]; P =0.007). Incidence of stroke (2.3% versus 1.7%; OR: 1.34 [95% CI, 0.56-3.21]; P =0.51) and paravalvular leak (3.1% versus 1.6%; OR: 2.52 [95% CI, 0.60-1.06]; P =0.21) was similar, whereas P group patients received fewer blood transfusions than C group patients (1.16±1.2 versus 2.13±2.2; mean difference: 0.99 [95% CI, -1.22 to -0.75]; P =0.001). The incidence of pacemaker implantation was higher in the P than the C group (7.9% versus 3.1%; OR: 2.45 [95% CI, 1.44-4.17]; P =0.001), whereas hemodynamic Perceval performance was better (transvalvular gradient 23.42±1.73 versus 22.8±1.86; mean difference: 0.90 [95% CI, 0.62-1.18]; P =0.001), even during follow-up (10.98±5.7 versus 13.06±6.2; mean difference: -2.08 [95% CI, -3.96 to -0.21]; P =0.030). We found no difference in 1-year mortality., Conclusions: The Perceval bioprosthesis improves the postoperative course compared with conventional bioprostheses and is an option for high-risk patients., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: The aim of this meta-analysis was to compare outcomes of patients undergoing transcatheter aortic valve implantation (TAVI) with those undergoing surgical aortic valve replacement using sutureless valves., Methods: A systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was performed., Results: No randomized controlled trials were identified. Six comparative studies using propensity score matching met the inclusion criteria. This meta-analysis identified 1462 patients in that 731 patients underwent surgical aortic valve replacement using sutureless valves (SU) and 731 patients underwent a TAVI. The 30-day or in-hospital mortality was lower in the SU group [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.36-0.80; P = 0.003]. In the TAVI group, the incidence of postoperative stroke was higher (OR 0.36, 95% CI 0.17-0.79; P = 0.01). The incidence of moderate or severe paravalvular regurgitation was higher in the TAVI group (OR 0.22, 95% CI 0.14-0.35; P = 0.001). There were neither differences in the postoperative renal failure (OR 1.44, 95% CI 0.46-4.58; P = 0.53) nor in the number of patients requiring postoperative pacemaker implantation (OR 1.06, 95% CI 0.54-2.08; P = 0.86). Patients in the SU group required more transfusions (OR 4.47, 95% CI 2.77-7.21; P = 0.0001), whereas those in the TAVI group had higher major vascular complications (OR 0.06, 95% CI 0.01-0.25; P = 0.0001). Intensive care unit stay was not different (mean difference 0.99, 95% CI - 1.22 to 1.40; P = 0.53). One-year survival was better in the SU group (Peto OR 0.35, 95% CI 0.18-0.67; P = 0.001), as was the 2-year survival (Peto OR 0.38, 95% CI 0.17-0.86; P = 0.001)., Conclusions: Surgical aortic valve replacement using sutureless valves is associated with better early and mid-term outcomes compared with TAVI in high- or intermediate-risk patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Type 1 diabetes (T1D) is an irreversible degenerative disease with severe complications such as heart disease, nephropathy, neuropathy, and retinopathy. Although exogenous insulin administration is a life-saving therapy, it does not cure the disease. This review addresses the epigenetic mechanisms responsible for the development of T1D and discusses epigenetic-based strategies for prevention and treatment of the disease. We describe novel epigenetic biomarkers for the identification of susceptible individuals and the establishment of innovative therapies with epidrugs and cell therapy to regenerate the lost β-cells. Despite the wealth of promising data regarding the potential benefits of epigenetic tools to reduce the burden of T1D, clinical trials are still very few, and this issue needs to be resolved in the near future., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Despite left ventricular (LV) dysfunction contributing to mortality in chronic heart failure (HF), the molecular mechanisms of LV failure continues to remain poorly understood and myocardial biomarkers have yet to be identified. The aim of this pilot study was to investigate specific transcriptome changes occurring in cardiac tissues of patients with HF compared to healthy condition patients to improve diagnosis and possible treatment of affected subjects., Methods: Unlike other studies, only dilated cardiomyopathy (DCM) (n = 2) and restrictive cardiomyopathy (RCM) (n = 2) patients who did not report family history of the disease were selected with the aim of obtaining a homogeneous population for the study. The transcriptome of all patients were studied by RNA-sequencing (RNA-Seq) and the read counts were adequately filtered and normalized using a recently developed user-friendly tool for RNA-Seq data analysis, based on a new graphical user interface (RNA-SeqGUI)., Results: By using this approach in a pairwise comparison with healthy donors, we were able to identify DCM- and RCM-specific expression signatures for protein-coding genes as well as for long noncoding RNAs (lncRNAs). Differential expression of 5 genes encoding different members of the mediator complex was disclosed in this analysis. Interestingly, a significant alteration was found for genes which had never been associated with HF until now, and 27 lncRNA/mRNA pairs that were significantly altered in HF patients., Conclusions: The present findings revealed specific expression pattern of both protein-coding and lncRNAs in HF patients, confirming that new LV myocardial biomarkers could be reliably identified using Next-Generation Sequencing-based approaches.

Background: The use of transcatheter aortic valve implantation (TAVI) following the introduction of Nitinol autoexpandable devices has spread rapidly during recent years. In addition, cardiac surgery has been revolutionized due to the use of Nitinol-based sutureless prostheses for aortic valve replacement (AVR). During the same period, however, permanent pacemaker (PPM) implantation has emerged as a frequent complication. The study aim was to identify the risk factors of PPM following the implantation of a Nitinol self-expanding prosthesis (for AVR or TAVI)., Methods: A study group was created between two institutions experienced in the use of nitinol devices, and a pool of 336 patients (56.6% CoreValve - Medtronic; 43.4% Perceval - Sorin) was available for a retrospective analysis. Pre-procedural clinical and electrocardiography (ECG) variables and postprocedural ECG variables were compared between the PPM group and control patients who had not received a PPM during their index hospitalization., Results: A PPM was required in 12.8% of patients (TAVI 17.5% versus AVR 6.8%, p = 0.007). PPM patients had a higher logistical EuroSCORE (median 20.77% versus 15.59%, p = 0.015), a lower use of statins (18.6% versus 34.2%, p = 0.04), a pre-procedural longer QRS interval (median 117 ms versus 98 ms, p = 0.002), and a higher incidence of conduction disturbances (29.3% versus 16.8%, p = 0.034), with a prevalence of right bundle branch block. At the first postprocedural ECG, non-stimulated PPM patients had a longer QRS interval (median 150 ms versus 113 ms, p<0.001) and a longer QTc interval (487.3 ± 46 ms versus 510.8 ± 53.8 ms, p = 0.005). Prevalent intra-ventricular conduction disorders in both groups included left bundle branch block. AVR patients received a PPM later than the TAVI group (median 6 days versus 3 days, p = 0.01). TAVI was an independent predictor of PPM at logistic regression analysis (OR 3.18; 95% CI 1.19-8.48, p = 0.021), but the significance disappeared after incorporating post-procedural ECG variables., Conclusions: Nitinol technology is a ground-breaking option for aortic valve procedures. However, the radial forces of the self-expandable mechanism may be implicated in the increased need for PPM, mostly in cases of TAVI compared to AVR, that most likely are due to displacement of the stent provoked by in situ calcium clusters. Given the clinical and economic impact of PPM, new parameters are required to understand the stent/tissue interaction and to help with device selection.

Background: Critically ill patients often suffer from a protein catabolic state. The aim of this study was to demonstrate that nitrogen balance (NB) in cardiac patients admitted to the intensive care unit (ICU) is related to their insulin sensitivity level and that supraphysiologic doses of insulin can restore anabolism., Materials and Methods: Twenty-eight patients that were admitted to ICU in enteral and/or parenteral nutrition have been enrolled in this study. All patients received a standard nutrition protocol for at least 3 days before starting the study. These patients received either enteral or parenteral nutrition based on 1.4 kcal/kg/h and 1.1 g/kg/24 h of proteins. Participants were studied for three 24 h periods (P1 , P2 , and P3 ). Twenty-four hour NB was calculated from urinary urea nitrogen excretion, fixed protein and energy intake during each of the three periods (P1 , P2 , and P3 ). Simultaneous to P2, a 24 h hyperinsulinemic-euglycemic clamp (HEC) was performed to determine patients' insulin sensitivity (IS) or insulin resistance (IR), as well as the impact of high doses of insulin on NB., Results: Nitrogen balance remained consistently positive in the IS group regardless of the clamp. In IR patients, NB was negative before the clamp and became positive during P2 and P3 . Insulin sensitivity improved during the HEC in IR patients (P < 0.001)., Conclusions: A negative NB was found only in insulin resistant patients admitted to the ICU for more than 7 days. A 24-h period HEC improved NB in these patients., (© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: The use of cardiac resynchronization therapy (CRT) and implantable cardioverter- defibrillator (ICD) for advanced heart failure (HF) is increasing. Renal dysfunction is a common condition in HF which is associated with a worse survival. The study aims at identifying in patients with advanced HF treated with CRT the effect of baseline glomerular filtration rate (GFR), GFR improvement and left ventricular ejection fraction (LVEF) change, after 6-months of CRT implant, on survival., Methods: The study population consisted of 375 advanced HF patients who received a CRT between 1999 and 2009, of these 277 received also an ICD implant. Clinical characteristics (New York Heart Association [NYHA] functional class, ischemic vs. non-ischemic etiology, atrial fibrillation, diabetes, hypertension, LVEF, QRS duration and GFR were recorded. The use of common used drugs was evaluated. Cox proportional hazards analysis was calculated in order to evaluate variables associated to mortality., Results: During a median follow-up of 43.0 months, 93 (24.8%) patients died. Patients deceased during the study had at baseline higher NYHA class and lower LVEF and GFR. In Cox regression analysis, GFR predicts long-term mortality (hazard ratio [HR] 0.983; 95% confidence interval [CI] 0.969-0.998; p = 0.023) independently from the effect of others covariates. In addition, a positive GFR improvement 6 months after CRT implant is significantly associated with a lower hazard of mortality (for each 10 mL/min of GFR improvement HR 0.86; 95% CI 0.75-0.99; p = 0.038)., Conclusions: GFR is a significant predictor of mortality in advanced HF patients who received CRT. A GFR improvement 6 months after CRT implant is significantly associated with a lower hazard of mortality.

Aims: Cryoballoon ablation (CBA; Arctic Front, Medtronic) has proven very effective in achieving pulmonary vein isolation. Real-time three-dimensional transoesophageal echocardiography (RT 3D TEE) is a novel technology, which permits detailed visualization of cardiac structures in a 3D perspective. The aim of the present study was to assess the feasibility, advantages, and safety of RT 3D TEE in guiding CBA in a series of patients affected by paroxysmal atrial fibrillation., Methods and Results: Forty-five patients (34 males, mean age: 63 ± 12 years) underwent CBA guided by 3D TEE. A total of 190 veins could be documented by TEE. Real-time three-dimensional transoesophageal echocardiography successfully guided the operator to position the CB in the pulmonary vein (PV) ostium and obtain complete occlusion in all 190 (100%) veins. Transoesophageal echocardiography identified leakages in 25 (13%) veins led to successful elimination of PV-left atrium (LA) backflow by guiding correct balloon repositioning. In four (2%) veins, this imaging tool led to perform successful pull-down manoeuvres. After a mean 2.6 ± 1.4 applications, isolation could be documented in 190 (100%) PVs. Median procedural and fluoroscopy times were 145 and 24 min. During a median follow-up of 278 days, 37 (82%) patients did not experience atrial fibrillation recurrence following a 3-month blanking period., Conclusion: Cryoballoon ablation is safe and feasible under RT 3D TEE guidance. This imaging tool permits perfect visualization of all PV ostia and neighbouring LA structures. Most importantly, it proved very efficient in guiding the operator to achieve complete occlusion and successful isolation in all veins.

Despite a decline in the last three decades, postinfarction ventricular free wall rupture still complicates more than 3% of acute ST-elevation myocardial infarctions and remains a surgical challenge. TachoSil (Nycomed, Zurich, Switzerland) is an equine collagen patch coated with human fibrinogen and human thrombin, which has recently been used for haemostasis in cardiovascular surgery, but its potential usefulness in free wall rupture has not been reported. Initial clinical experience with an on-pump sutureless technique without cardioplegia, using wide TachoSil patching to achieve free wall rupture repair, has been described.

Loss of body protein and hyperglycaemia represent typical features of the stress response to surgery and anaesthesia. This appears to be particularly pronounced in patients with diabetes mellitus type 2. The aim of the present study was to highlight the greater benefit of amino acids (AA) as represented by positive protein balance and maintenance of blood glucose homoeostasis compared with dextrose (DEX) in diabetic patients after colorectal surgery. A total of thirteen patients underwent a 5 h stable isotope infusion study (2 h fasted, 3 h fed with an infusion of AA (n 6) or DEX (n 7)) on the second post-operative day. Glucose and protein kinetics were assessed by using the stable isotopes l-[1-¹³C]leucine and [6,6-²H₂]glucose. The transition from fasted to fed state decreased endogenous glucose production (P < 0·001) in both groups, with a more profound effect in the DEX group (P = 0·031). In contrast, total glucose production was increased by the provision of DEX while being lowered by AA (P = 0·021). Feeding decreased protein oxidation (P = 0·009) and protein synthesis in the AA group, whereas DEX infusion did not affect oxidation and even decreased protein synthesis. Therefore, only AA shifted protein balance to a positive value, while patients in the DEX group remained in a catabolic state (P < 0·001). Parenteral nutritional support with AA rather than with DEX is an effective strategy to achieve a positive protein balance while maintaining normoglycaemia in diabetic patients after colorectal surgery.

Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases share many common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponential manner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer can impair the structural and functional integrity of the cardiovascular system, giving rise to an interdisciplinary field: cardio-oncology. However, tumors and cardiovascular diseases also share common protective factors: they can be prevented either by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and by modulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great variety of dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinical models, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that some phytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and even anticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a low level cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancer chemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity to preconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach.

Context: Major surgery induces a catabolic state resulting in a net loss of body protein., Objectives: Our objective was to compare protein metabolism before and after surgery in nondiabetic patients with and without preoperative insulin resistance (IR). It was hypothesized that the anabolic response to feeding would be significantly impaired in those patients with preoperative insulin resistance., Design: A hyperinsulinemic-euglycemic clamp has been used to identify two groups of patients: IR and insulin sensitive (IS). A tracer kinetics technique has been used to evaluate the metabolic response to food intake in both groups., Setting: Patients undergoing cardiopulmonary bypass participated., Patients or Other Participants: Ten IS patients and 10 IR patients were enrolled in the study., Intervention: After an overnight fasting, a 3-h infusion of a solution composed of 20% glucose and of amino acids at a rate of 0.67 and 0.44 kcal/kg · h, respectively, was started in each group. Phenylalanine kinetics were studied at the end of fasting and feeding., Main Outcome Measure: Effect of feeding on protein balance before and after surgery was evaluated. Protein balance has been measured as the net difference of protein breakdown minus protein synthesis., Results: Protein balance increase after postoperative feeding was blunted only in the IR group. In contrast, in the IS group, the postoperative anabolic effect of feeding was the same as before surgery., Conclusions: These findings propose a link between insulin resistance and protein metabolism. When non-IR patients are fed, a significant anabolic effect in the postoperative period is demonstrated. In contrast, IR patients are less able to use feeding for synthetic purposes.

The HER family of tyrosine kinase receptors includes several members that are clinically important targets in cancer therapies, in particular HER1 (the EGF receptor) and HER2, other members include HER3 and HER4. Trastuzumab, a humanized monoclonal antibody and lapatinib, a tyrosine kinase inhibitor, are drugs that target HER2, which is highly expressed in 20-30% of breast cancers. Trastuzumab is recommended as an adjuvant therapy for lymph node positive, HER2-positive breast cancers, or node-negative cancer with high-risk of recurrence, as well as in stage IV cancers. One serious side effect of trastuzumab is cardiomyocyte dysfunction, resulting in reduced heart contractile efficiency. The incidence of collateral effects on the heart with trastuzumab therapy increases in people with cardiovascular risk factors, heart disease and when combined with other chemotherapeutics. When cardiotoxicity was observed with trastuzumab, several studies have addressed potential cardiac damage of trastuzumab itself and lapatinib. The differences in cardiovascular effects of these two compounds are somewhat unexpected and suggest distinct mechanisms of action, which have clear implications in clinical application and prevention of cardiotoxicity in cardio-oncological approaches.

Purpose: The pathogenic role of angiotensin-converting enzyme (ACE) inhibition in hypertensive patients regarding endothelial progenitor-cell (EPC) function is still poorly understood. The aim of the study was to evaluate EPC number, function, and relationship to carotid intima media thickness (IMT) progression., Methods: We studied 36 newly diagnosed mildly hypertensive patients free of cardiovascular disease and related risk factors without prior or concurrent therapy with ACE inhibitors. Patients were randomized to receive enalapril 20 mg/day (n = 18) or zofenopril 30 mg/day (n = 18). EPC number and migrating capacity, plasma nitrite and nitrate (NOx), and isoprostane concentrations were evaluated. Carotid IMT was determined by ultrasonography at baseline and after 1 and 5 years of follow-up., Results: EPC number increased during the follow-up, with no statistical differences between treatment groups. There was an inverse correlation between circulating EPCs and IMT increase over time. Plasma NOx decreased during the study without evident differences between treatment groups. Isoprostanes decreased more markedly in zofenopril-treated patients. Multiple linear regression model demonstrated that carotid IMT was significantly inversely correlated with EPC but not with migratory cells after adjusting for confounders., Conclusions: The study demonstrated that EPC levels increased during the follow-up in both groups of newly diagnosed hypertensive patients treated with ACE inhibitors. These drugs prevented progression of vascular damage, with an inverse correlation between circulating EPC levels and IMT values.

Background: Recent observational studies show an increase of more complex and critically ill patients referred to Italian cardiac rehabilitation (CR) departments; the exact mechanisms underlying this phenomenon, however, have not been clearly identified. The aim of our study was to evaluate the epidemiological and clinical changes that occurred over the last decade in patients hospitalized in CR departments with high admittance rates., Methods: We have retrospectively evaluated all patients admitted between 2002 and 2009 to our division of CR (n = 3340, 1155 female, mean age 66.4 ± 11 years) after recent cardiac surgery. The study population was divided into two homogeneous groups: the four-year period 2002-2005, group A (n = 1614, 540 female, mean age 66.1 ± 10 years) and the four-year period 2006-2009, group B (n = 1726, 615 female, mean age 67.4 ± 11 years). Data were compared using specific indicators of clinical complexity., Results: Patients aged >75 years were more in group B compared to A (26.3 vs 19.8%, p<0.0001), as well as patients with recent complex surgical interventions, such as combined coronary artery bypass grafting and heart valve surgery (16.4 vs 10.2%, p<0.0001). An increased incidence of cardiovascular death (1.4 vs 0.6%, p=0.02), acute coronary syndrome (1.5 vs 0.7%, p=0.02) and persistent atrial fibrillation/flutter (13.5 vs 7.1%, p<0.0001) was observed in group B, as well as an increased prevalence of systolic heart failure (18.3 vs 9.0%, p<0.0001). Similarly, the incidence of acute respiratory failure episodes (1.0 vs 0.4%, p=0.05), the prevalence of patients admitted with a tracheostomy tube (2.6 vs 0.2%, p<0.0001) and the incidence of acute renal failure (1.1 vs 0.5%, p=0.05) were significantly increased in group B. Postoperative infections and surgical wound complications were 4-fold higher in group B (13.9 vs 3.1%, p<0.0001, and 12.8 vs 2.3%, p<0.0001, respectively). Compared to group A, patients of group B showed a significantly lower physical performance, as expressed by the Rivermead motility index (3.8 ± 1.1 vs 5.2 ± 0.8, p<0.001); moreover, the number of subjects able to perform an incremental training program was significantly lower in group B than group A (14.8 vs 60.6%, p<0.0001). Mean hospital stay was longer in group B than group A (25.4 ± 13 vs 22.1 ± 9 days, p<0.001)., Conclusions: Our study, by collecting data from a CR division in northern Italy with high admittance rates, demonstrates a dramatic increase in clinical complexity over the last few years. This points to the need for new expertise and major resources to be allocated to CR departments.

Surgical revascularization for postinfarction cardiogenic shock carries 20-50% mortality. Beating-heart techniques have been favoured, but their impact on the avoidance of additional myocardial injury is unknown. Ten consecutive patients with postinfarction cardiogenic shock, unsuitable anatomy for percutaneous coronary intervention (Syntax score 34.0±7.5; triple-vessel disease, 10/10; left main stenosis, 5/10), and no associated cardiac procedure, were selected for salvage/emergent on-pump beating-heart coronary bypass surgery. Remote muscle was sequentially substrate-enhanced reperfused through the grafts after construction of distal anastomoses. Early/late mortality, preoperative/peak postoperative enzyme release, and baseline/pre-discharge ventricular function were analysed. One early death occurred. Patients received 2.9±0.6 grafts, always employing the left internal mammary artery. Cardiopulmonary bypass duration was 140±62 min. Left ventricular ejection fraction (29.4±5.8 vs. 37.5±8.3%), wall motion score index (2.10±0.29 vs. 1.86±0.28), and end-systolic volume index (42.1±11.5 vs. 33.1±14.0 ml/m(2)) acutely improved (P≤0.001), whereas functional mitral regurgitation decreased from 1.4±0.8 to 0.8±0.4 (P=0.051). Total creatine kinase levels significantly increased (P=0.017), but myocardial band isoenzyme did not (P=0.18). After 3.1±1.4 years, eight patients are alive and seven are free of recurrent heart failure. Satisfactory functional outcome can be achieved with beating-heart on-pump revascularization for postinfarction cardiogenic shock. Perioperative enzyme releases and ventricular functional variables may suggest reduced perioperative myocardial injury.

Hypermetabolism, abnormal plasma amino acid profiles, increased gluconeogenesis, and changes in liver and muscle protein turnover are well-described undesirable effects in patients with cancer and diabetes mellitus type 2 (DM2) The aim of the present study was to analyze the specific impact and interaction of these 2 disease patterns on patients' preoperative glucose and protein metabolism. Eight nondiabetic and 8 diabetic patients devoid of cachexia underwent a stable isotope infusion study on the day before surgery for colorectal cancer or adenoma with high-grade dysplasia. Protein and glucose kinetics were assessed in a fasted state by L-[1-(13)C]leucine and [6,6(2)H(2)]glucose. In diabetic patients, glucose metabolism was found to be elevated as the plasma glucose level increased (P = 0.013) and endogenous rate of appearance of glucose tended to be higher compared to nondiabetic patients (P = 0.083). Protein metabolism was not affected by the metabolic state of the 2 groups. Resting energy expenditure was higher in diabetic patients (P = 0.028). Under postabsorptive conditions, noncachectic patients with DM2 suffering from colorectal tumors showed an elevated turnover in glucose metabolism whereas the nondiabetic counterparts failed to demonstrate any metabolic changes due solely to malignancy.