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Heart failure (HF) with preserved left ventricular (LV) ejection fraction (HFpEF) represent today the largest ‘unmet medical need’, because none of the drugs presently available improved survival in this consistent proportion of patients with HF, ∼50% of the total, who have an LV ejection fraction ≥50%. Heart failure with preserved left ventricular ejection fraction is a clinical syndrome that in its classical form, is associated to typical risk factors and comorbidities. The comorbidities represent one of the element contributing to the extreme heterogeneity which characterizes HFpEF. The pathophysiological mechanisms, as well as the clinical presentation, are multifaceted. These factors explain, by and large, the failure of a generalized therapeutic strategy, while build the argument for personalized medicine, designed to address the specific phenotypes, with therapies proven in specific subgroups of patients with HFpEF to reduce mortality and improve ‘surrogate’ outcomes, such as quality of life.

The remarkable scientific progress in the treatment of patients with heart failure (HF) and reduced ejection fraction (HFrEF) has more than halved the risk of sudden cardiac death (SCD) in this setting. However, SCD remains one of the major causes of death in this patient population. Beyond the acknowledged role of beta blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS), a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNI), proved to reduce the overall cardiovascular mortality and, more specifically, the risk of SCD in HFrEF patients. The mechanism by which ARNI may reduce the mortality connected with harmful ventricular arrhythmias is not utterly clear. A variety of direct and indirect mechanisms have been suggested, but a favorable left ventricular reverse remodeling seems to play a key role in this setting. Furthermore, the well-known protective effect of implantable cardioverter-defibrillator (ICD) has been debated in HFrEF patients with non-ischemic cardiomyopathy (NICM) arguing against the role of primary prevention ICD in this setting, particularly when ARNI therapy is considered. The purpose of this review was to provide insights into the SCD mechanisms involved in HFrEF patients together with the current role of electrical therapies and new drug agents in this setting. [Figure not available: see fulltext.].

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide determining dramatic impacts on healthcare systems. Early identification of high-risk parameters is required in order to provide the best therapeutic approach. Coronary, thoracic aorta and aortic valve calcium can be measured from a non-gated chest computer tomography (CT) and are validated predictors of cardiovascular events and all-cause mortality. However, their prognostic role in acute systemic inflammatory diseases, such as COVID-19, has not been investigated. OBJECTIVES: The aim was to evaluate the association of coronary artery calcium and total thoracic calcium on in-hospital mortality in COVID-19 patients. METHODS: 1093 consecutive patients from 16 Italian hospitals with a positive swab for COVID-19 and an admission chest CT for pneumonia severity assessment were included. At CT, coronary, aortic valve and thoracic aorta calcium were qualitatively and quantitatively evaluated separately and combined together (total thoracic calcium) by a central Core-lab blinded to patients' outcomes. RESULTS: Non-survivors compared to survivors had higher coronary artery [Agatston (467.76 ​± ​570.92 vs 206.80 ​± ​424.13 ​mm2, p ​

Heart failure (HF) is a pandemic syndrome characterised by raised morbidity and mortality. An acute HF event requiring hospitalisation is associated with a poor prognosis, in both the short and the long term. Moreover, early rehospitalisation after discharge negatively affects HF management and survival rates. Cardiovascular and non-cardiovascular conditions combine to increase rates of HF hospital readmission at 30 days. A tailored approach for HF pharmacotherapy while the patient is in hospital and immediately after discharge could be useful in reducing early adverse events that cause rehospitalisation and, consequently, prevent worsening HF and readmission during the vulnerable phase after discharge.

Aims Limited data are available on the pathophysiological role of the right ventricle (RV) in patients with acute heart failure with preserved ejection fraction (AHF-PEF) and its impact on the main clinical manifestation such as pulmonary oedema or peripheral congestion. Mainly through right-to-left stroke volume mismatch and ventricular-arterial decoupling, right chambers size and function may play a key role leading to fluid overload or maldistributed phenotypes. Methods and results In this monocenter, prospective, observational study 80 consecutive patients with AHF-PEF were enrolled. A complete echocardiographic examination was performed within 6 hours from emergency department admission; multiparametric RV function was carefully evaluated in the very acute phase. Focusing on hypertensive pulmonary oedema (H-AHF) and decompensated AHF without pulmonary oedema (D-AHF) phenotypes, the study aims to analyze the echocardiographic peculiarities of these clinical entities in the early phase of admission and its modification at discharge (D-AHF n = 58, H-AHF n = 22). Baseline clinical characteristics were comparable in both groups, except for coronary artery disease more prevalent in H-AHF and atrial fibrillation more prevalent in D-AHF. D-AHF patients showed dilated and dysfunctional right chambers compared to H-AHF. Regarding systolic function, normal values of fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) were registered in H-AHF at admission and at discharge. D-AHF showed greater systolic pulmonary artery pressure (sPAP) and lower TAPSE/sPAP ratio. Left ventricular dimensions and function were comparable in both groups. Conversely, E/e’ ratio was significantly higher in H-AHF at admission. Data are summarized in the tables and figures below. Conclusion D-AHF and H-AHF represent different phenotypes of AHF-PEF. Right heart structure and function and ventricular-arterial coupling could play a crucial role in their pathophysiology. Non dilated RV with preserved systolic function seems to be crucial to develop pulmonary oedema without signs of peripheral congestion. Further investigations are needed to corroborate the hypothesis of interventricular stroke volume mismatch in the complex AHF-PEF clinical scenario.

Background Blood platelets are anucleate cell fragments that prevent bleeding and minimize blood vessel injury. They are formed from the cytoplasm of megakaryocytes located in the bone marrow. For successful platelet production, megakaryocyte fragments must pass through the sinusoid endothelial barrier by a cell biology process unique to these giant cells as compared with erythrocytes and leukocytes. Currently, the mechanisms by which megakaryocytes interact and progress through the endothelial cells are not understood, resulting in a significant gap in our knowledge of platelet production. Objective The aim of this study was to investigate how megakaryocytes interact and progress through the endothelial cells of mouse bone marrow sinusoids. Methods We used a combination of fluorescence, electron, and three-dimensional microscopy to characterize the cellular events between megakaryocytes and endothelial cells. Results We identified protrusive, F-actin-based podosome-like structures, called in vivo-MK podosomes, which initiate the formation of pores through endothelial cells. These structures present a collective and spatial organization through their interconnection via a contractile network of actomyosin, essential to regulate the endothelial openings. This ensures proper passage of megakaryocyte-derived processes into the blood circulation to promote thrombopoiesis. Conclusion This study provides novel insight into the in vivo function of podosomes of megakaryocytes with critical importance to platelet production.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic cardiac condition whose prevalence continues to rise, with high social and economic burden, but with no specific approved treatment. Patients diagnosed with HFpEF have a high prevalence of comorbidities and exhibit a high misdiagnosis rate. True HFpEF is likely to have multiple pathophysiological causes - with these causes being clinically ill-defined due to limitations of current measurement techniques. Myocyte, interstitium, microvascular, and metabolic abnormalities have been regarded as key components of the pathophysiology and potential therapeutic targets. Cardiac magnetic resonance (CMR) has the capability to look deeper with a number of tissue characterization techniques which are closer to the underlying specific abnormalities and which could be linked to personalized medicine for HFpEF. This review aims to discuss the potential role of CMR to better define HFpEF phenotypes and to infer measurable therapeutic targets.

Hypertension is associated with more severe disease and adverse outcomes in COVID-19 patients. Recent investigations have indicated that hypertension might be an independent predictor of outcomes in COVID-19 patients regardless of other cardiovascular and noncardiovascular comorbidities. We explored the significance of coronary calcifications in 694 hypertensive patients in the Score-COVID registry, an Italian multicenter study conducted during the first pandemic wave in the Western world (March-April 2020). A total of 1565 patients admitted with RNA-PCR-positive nasopharyngeal swabs and chest computed tomography (CT) at hospital admission were included in the study. Clinical outcomes and cardiovascular calcifications were analyzed independently by a research core lab. Hypertensive patients had a different risk profile than nonhypertensive patients, with more cardiovascular comorbidities. The deceased hypertensive patients had a greater coronary calcification burden at the level of the anterior descending coronary artery. Hypertension status and the severity cutoffs of coronary calcifications were used to stratify the clinical outcomes. For every 100-mm3 increase in coronary calcium volume, hospital mortality in hypertensive patients increased by 8%, regardless of sex, age, diabetes, creatinine, and lung interstitial involvement. The coronary calcium score contributes to stratifying the risk of complications in COVID-19 patients. Cardiovascular calcifications appear to be a promising imaging marker for providing pathophysiological insight into cardiovascular risk factors and COVID-19 outcomes.

Background: subclinical pulmonary and peripheral congestion is an emerging concept in heart failure, correlated with a worse prognosis. Very few studies have evaluated its prognostic impact in an outpatient setting and its relationship with right-ventricular dysfunction. The study aims to investigate subclinical congestion in chronic heart failure outpatients, exploring the close relationship between the right heart-pulmonary unit and peripheral congestion. Materials and methods: in this observational study, 104 chronic HF outpatients were enrolled. The degree of congestion and signs of elevated filling pressures of the right ventricle were evaluated by physical examination and a transthoracic ultrasound to define multiparametric right ventricular dysfunction, estimate the right atrial pressure and the pulmonary artery systolic pressure. Outcome data were obtained by scheduled visits and phone calls. Results: ultrasound signs of congestion were found in 26% of patients and, among this cohort, half of them presented as subclinical, affecting their prognosis, revealing a linear correlation between right ventricular/arterial coupling, the right-chambers size and ultrasound congestion. Right ventricular dysfunction, TAPSE/PAPS ratio, clinical and ultrasound signs of congestion have been confirmed to be useful predictors of outcome. Conclusions: subclinical congestion is widespread in the heart failure outpatient population, significantly affecting prognosis, especially when right ventricular dysfunction also occurs, suggesting a strict correlation between the heart-pulmonary unit and volume overload.

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.

Since the beginning of the SARS-CoV-2 outbreak, few cases of COVID-19 pneumonia in patients with pulmonary arterial hypertension have been reported. We present four patients with known history of PAH admitted to our hospital with SARS-CoV-2 pneumonia to analyze the impact of this disease on their clinical outcome.

Background Natriuretic peptides and diastolic dysfunction have prognostic value in asymptomatic subjects at risk for heart failure. Their integration might further refine the risk stratification process in this setting. Aim of this paper was to explore the possibility to predict heart failure and death combining diastolic dysfunction and natriuretic peptides in an asymptomatic population at risk for heart failure. Methods Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for heart failure. Baseline evaluation included electrocardiogram, echocardiogram, and natriuretic peptides collection. Based on diastolic dysfunction and natriuretic peptides, subjects were classified in four groups: control group (no diastolic dysfunction/normal natriuretic peptides, 57%), no diastolic dysfunction/high natriuretic peptides (9%), diastolic dysfunction/normal natriuretic peptides (24%), and diastolic dysfunction/high natriuretic peptides (11%). We applied Cox multivariable and Classification and Regression Tree analyses. Results The mean age of the population was 69 ± 7 years, 44% were women, mean left ventricular ejection fraction was 61%, and 35% had diastolic dysfunction. During a median follow-up of 5.7 years, 95 heart failure/death events occurred. Overall, diastolic dysfunction and natriuretic peptides were predictive of adverse events (respectively, hazard ratio 1.91, confidence interval 1.19–3.05, padjusted = 0.007, and hazard ratio 2.25, confidence interval 1.35–3.74, padjusted = 0.002) with Cox analysis. However, considering the four study subgroups, only the group with diastolic dysfunction/high natriuretic peptides had a significantly worse prognosis compared to the control group (hazard ratio 4.48, confidence interval 2.31–8.70, padjusted Conclusions The DAVID-Berg data suggest that we look for the quite common combination of diastolic dysfunction/high natriuretic peptides to correctly identify asymptomatic subjects at greater risk for incident heart failure/death, thus more suitable for preventive interventions.

International audience; Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b-/- ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b-/- cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b-/- cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b-/- cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1β. HNF-1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.

Background: Identifying candidates for left ventricular assist device surgery at risk of right ventricular failure remains difficult. The aim was to identify the most accurate predictors of right ventricular failure among clinical, biological, and imaging markers, assessed by agreement of different supervised machine learning algorithms. Methods: Seventy-four patients, referred to HeartWare left ventricular assist device since 2010 in two Italian centers, were recruited. Biomarkers, right ventricular standard, and strain echocardiography, as well as cath-lab measures, were compared among patients who did not develop right ventricular failure (N = 56), those with acute–right ventricular failure (N = 8, 11%) or chronic–right ventricular failure (N = 10, 14%). Logistic regression, penalized logistic regression, linear support vector machines, and naïve Bayes algorithms with leave-one-out validation were used to evaluate the efficiency of any combination of three collected variables in an “all-subsets” approach. Results: Michigan risk score combined with central venous pressure assessed invasively and apical longitudinal systolic strain of the right ventricular–free wall were the most significant predictors of acute–right ventricular failure (maximum receiver operating characteristic–area under the curve = 0.95, 95% confidence interval = 0.91–1.00, by the naïve Bayes), while the right ventricular–free wall systolic strain of the middle segment, right atrial strain (QRS-synced), and tricuspid annular plane systolic excursion were the most significant predictors of Chronic-RVF (receiver operating characteristic–area under the curve = 0.97, 95% confidence interval = 0.91–1.00, according to naïve Bayes). Conclusion: Apical right ventricular strain as well as right atrial strain provides complementary information, both critical to predict acute–right ventricular failure and chronic–right ventricular failure, respectively.

Treatment of chronic diseases, such as heart failure, requires complex protocols based on early diagnosis; self-monitoring of symptoms, vital signs and physical activity; regular medication intake; and education of patients and caregivers about relevant aspects of the disease. Smartphones and mobile health applications could be very helpful in improving the efficacy of such protocols, but several barriers make it difficult to fully exploit their technological potential and produce clear clinical evidence of their effectiveness. App suppliers do not help users distinguish between useless/dangerous apps and valid solutions. The latter are few and often characterised by rapid obsolescence, lack of interactivity and lack of authoritative information. Systematic reviews can help physicians and researchers find and assess the ‘best candidate solutions’ in a repeatable manner and pave the way for well-grounded and fruitful discussion on their clinical effectiveness. To this purpose, the authors assess 10 apps for heart failure self-care using the Intercontinental Marketing Statistics score and other criteria, discuss the clinical effectiveness of existing solutions and identify barriers to their use in practice and drivers for change.

Objectives The aim of this study was to assess the clinical course and outcomes of all heart transplant recipients affected by coronavirus disease-2019 (COVID-19) who were followed at the leading heart transplant centers of Northern Italy. Background The worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Heart transplant patients represent a unique cohort of chronically immunosuppressed subjects in which SARS-CoV-2 may stimulate an unpredictable clinical course of infection. Methods Since February 2020, we enrolled all 47 cases (79% male) in a first cohort of patients, with a mean age of 61.8 ± 14.5 years, who tested positive for SARS-CoV-2, out of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at 7 heart transplant centers in Northern Italy. Results To date, 38 patients required hospitalization while 9 remained self-home quarantined and 14 died. Compared to the general population, prevalence (18 vs. 7 cases per 1,000) and related case fatality rate (29.7% vs. 15.4%) in heart transplant recipients were doubled. Univariable analysis showed older age (p = 0.002), diabetes mellitus (p = 0.040), extracardiac arteriopathy (p = 0.040), previous PCI (p = 0.040), CAV score (p = 0.039), lower GFR (p = 0.004), and higher NYHA functional classes (p = 0.023) were all significantly associated with in-hospital mortality. During the follow-up two patients died and a third patient has prolonged viral-shedding alternating positive and negative swabs. Since July 1st, 2020, we had 6 new patients who tested positive for SARS-CoV-2, 5 patients asymptomatic were self-quarantined, while 1 is still hospitalized for pneumonia. A standard therapy was maintained for all, except for the hospitalized patient. Conclusions The prevalence and mortality of SARS-CoV-2 should spur clinicians to immediately refer heart transplant recipients suspected as having SARS-CoV2 infection to centers specializing in the care of this vulnerable population.

Background and Objective: Surgical treatment of severe secondary ischemic mitral regurgitation (IMR) may improve symptoms and functional capacity, however there are few data on its effect on long-on the evolution of heart failure. Time-course changes in brain natriuretic peptide (BNP) are a good marker of the heart failure status and outcomes. We investigated the association between the exercise stress echocardiographic (ESE) parameters and the changes in brain natriuretic peptide (BNP) following surgery for secondary IMR. Methods: We prospectively analyzed data on 50 patients (median age: 67, 61-64 y; EF: 35, 34-40%), undergoing mitral valve annuloplasty or replacement and coronary artery bypass graft (CABG). A valve annuloplasty with undersized ring was performed in 20 patients (40%) and a replacement in 30 (60%). A six minute walking test (6-MWT), BNP levels and ESE were performed at 1 year and at median follow-up (FU) of 6 years (4-7). Results: BNP level was: 388 (329-441) pg/ml before surgery, 175 (142-743) pg/ml at 1 y, and 123 (100-979) pg/ml at last FU (p=0.2). The relative changes of BNP from baseline to last FU significantly correlated with exercise tricuspid annulus plane systolic excursion (TAPSE) at last FU (r= -0.7, p Conclusions: Despite surgical treatment of severe secondary IMR, BNP levels progressively increased over time in nearly 50% of the patients. Lower preoperative and 1-year FU exercise-stress EF was associated with increased levels of BNP during FU..

Cardiomyopathies (CMPs) are primary disorders of myocardial structure and function in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease. Knowledge of the incidence and prevalence of CMPs may help clinicians to compare their observations in clinical practice with expected cases per person-year and to avoid under-reporting in clinical context. Currently, available estimates of prevalence and incidence of CMPs are based on clinical data, collected with a wide variability in population-source, and before the genetic testing evolved as a standard diagnostic tool. This review focuses on the epidemiology of CMPs in subjects aged between 18 and 55 years. A structured up-to-date diagnostic flow-chart for CMPs diagnosis and assessment is proposed to avoid misdiagnosis of CMPs in the young population and in subjects with unexplained cardiac disorders.

Highlights • The paper “Intra-Aortic Balloon Counterpulsation Timing: A New Numerical Model for Programming and Training in the Clinical Environment.”, is original research from our ongoing program on numerical simulation applied to the clinical environment. • In this work we present a new numerical model of the intraaortic balloon pump (IABP). The new model also allows us to simulate patient weaning from IABP assistance. • Furthermore, the cardiovascular network model in which the IABP is inserted, allows us to simulate also a mechanical ventilatory assistance that is very important in patients affected by COVID-19., Background and Objective : The intra-aortic balloon pump (IABP) is the most widely available device for short-term mechanical circulatory support, often used to wean off cardiopulmonary bypass or combined with extra-corporeal membrane oxygenation support or as a bridge to a left ventricular assist device. Although based on a relatively simple principle, its complex interaction with the cardiovascular system remains challenging and open to debate. The aim of this work was focused on the development of a new numerical model of IABP. Methods : The new module was implemented in CARDIOSIM©, which is a modular software simulator of the cardiovascular system used in research and e-learning environment. The IABP is inserted into the systemic bed divided in aortic, thoracic and two abdominal tracts modelled with resistances inertances and compliances. The effect induced by the balloon is reproduced in each tract of the aorta by the presence of compliances connected to PIABP generator and resistances. PIABP generator reproduces the balloon pressure with the option to change IABP timing.We have used literature data to validate the potential of this new numerical model. Results : The results have shown that our simulation reproduced the typical effects induced during IABP assistance. We have also simulated the effects induced by the device on the hemodynamic variables when the IABP ratio was set to 1:1, 1:2, 1:4 and 1:8. The outcome of these simulations is in accordance with literature data measured in the clinical environment. Conclusions : The new IABP module is easy to manage and can be used as a training tool in a clinical setting. Although based on literature data, the outcome of the simulations is encouraging. Additional work is ongoing with a view to further validate its features. The configuration of CARDIOSIM© presented in this work allows to simulate the effects induced by mechanical ventilatory assistance. This facility may have significant importance in the management of patients affected by COVID-19 when they require mechanical circulatory support devices.

BACKGROUND Mild asymptomatic left ventricular systolic dysfunction (ALVSD) may be associated with incident heart failure (HF). However, this gray zone group needs incremental risk refinement. We hypothesized that diastolic dysfunction (DD) may refine HF and death risk prediction in mild ALVSD. METHODS AND RESULTS Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, N-terminal pro B-type natriuretic peptide, and echocardiogram. Based on left ventricular ejection fraction (LVEF) and DD, subjects were classified as: control group (normal LVEF, n = 459, 76%), mild ALVSD (LVEF ≥40%/

OBJECTIVES: EUROMACS is a registry of the European Association for Cardio-Thoracic Surgery (EACTS) whose purpose is to gather clinical data related to durable mechanical circulatory support for scientific purposes and to publish annual reports. Because the treatment of children with end-stage heart failure has several significantly different characteristics than the treatment of adults, data and outcomes of interventions are analysed in this dedicated paediatric report. METHODS: Participating hospitals contributed pre-, peri- and long-term postoperative data on mechanical circulatory support implants to the registry. Data for all implants in paediatric patients (≤19 years of age) performed from 1 January 2000 to 31 December 2017 were analysed. This report includes updates of patient characteristics, implant frequency, outcome (including mortality rates, transplants and recovery rates) as well as adverse events. RESULTS: Twenty-five hospitals contributed 237 registered implants in 210 patients (81 ♀, 129 ♂) to the registry. The most frequent diagnosis was any form of cardiomyopathy (71.4%) followed by congenital heart disease (18.6%). Overall mean support time on a device was 11.6 months (±16.5 standard deviation). A total of 173 children (82.4%) survived to transplant, recovery or are ongoing; 37 patients (17.6%) died while on support within the observed follow-up time. At 12 months 38% of patients received transplants, 7% were weaned from their device and 15% died. At 24 months, 51% of patients received transplants, 17% died while on support, 22% were on a device and 9% were explanted due to myocardial recovery. The adverse events rate per 100 patient-months was 11.97 for device malfunction, 2.83 for major bleeding, 2.83 for major infection and 1.52 for neurological events within the first 3 months after implantation. CONCLUSIONS: The first paediatric EUROMACS report reveals a low transplant rate in European countries within the first 2 years of implantation compared to US data. The 1-year survival rate seems to be satisfactory. Device malfunction including pump chamber changes due to thrombosis was the most frequent adverse event.

Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.

Purpose The Multicenter Italian study on RAdial Mechanically Assisted Circulatory Support (MIRAMACS) represent the first national observational registry, gathering continuous-flow (CF) left ventricular (LVAD) and biventricular assist device (BiVAD) implantation performed in adult patients by high-volume, mechanical circulatory support (MCS) dedicated, Italian centres. Methods Seven participating hospitals contributed pre-, peri- and long-term postoperative data on LVAD implants to the registry. Data for all implants in adult patients (>18 years of age) performed between January 2000 to September 2020 were analysed. BiVADs were excluded in this preliminary analysis. This initial report focuses on patient demographics, survival, device types, adverse events and competing outcomes. Results A total of 515 patients received a CF LVAD. The mean age of LVAD recipients was 60±10 years. The majority of patients were male (89.3%). The adopted systems were: HeartWare HVAD (n=213), HeartMate III (n=140), HeartMate II (n=89), Jarvik 2000 (n=50), Berlin Heart Incor (n=19) and other brands (n=4). In 6.6% of patients the LVAD implantation was performed by usage of less invasive surgical approaches. Mortality at 30- and 90-days was 6.1% and 11.1%, respectively. A temporary right ventricular assist device (RVAD) support was necessary in 3.1% of patients. Mean follow-up time was 57±15 months. Heart transplantation was performed in 99 patients (19.2%). Survival at 1-year, 3-years, and 5-years of BTT cohort was 82.1%, 60.4% and 41.8%, respectively. Survival at 1-year, 3-years, and 5-years of DT cohort was 69.8%, 45.6% and 30.1%, respectively. Major bleeding, major infection, neurological events and device malfunction were reported in 40 (7.7%), 143 (27.7%), 97 (18.8%) and 36 (6.9%) patients, respectively. Conclusion This first MIRAMACS report reveals frequencies and results comparable with other registries. Overall success rate of CF LVAD patients seems to be satisfactory. Detailed prospective data collection, additional participating centres and further analyses may provide additional robust scientific contributions.

Genetic cardiomyopathies are complex diseases with heterogeneous clinical presentation and phenotypes. Early descriptions of cardiomyopathies originated from case studies involving individuals with severe, paradigmatic presentation, which provided insight into the worst-case scenarios of these conditions. With time, improved diagnostic sensitivity and awareness of cardiomyopathies has uncovered a more heterogeneous disease spectrum, including mild phenotypes overlapping with physiological variation. This diagnostic 'grey area' poses important dilemmas, particularly in athletes. Current screening policies have the potential to identify affected individuals at very early stages, leading to effective prevention of cardiomyopathy-related complications such as sudden cardiac death. Conversely, however, some physicians actively impose diagnoses on individuals who perceive themselves to be disease-free. In addition, the high sensitivity of contemporary diagnostic techniques carries a serious risk of misinterpreting physiological variation as disease. In this Review, three of the most common and controversial areas are discussed, including left ventricular hypertrophy; left ventricular dilatation, noncompaction, and fibrosis; and arrhythmias originating from the right ventricle. A systematic and cautious approach is necessary in patients with mild phenotypes suggestive of, but not definitely diagnostic for, cardiomyopathies. Preventing the mislabelling of healthy individuals and overdiagnosis should be a priority, with the aim to combine adequate counselling and optimal protection.

Aims Midwall fractional shortening (MWFS) is a measure of left ventricular (LV) systolic function that is more reliable in case of concentric LV geometry compared to LV ejection fraction (LVEF). We hypothesized that MWFS might predict heart failure (HF) and death in a high-risk asymptomatic population, beyond other echocardiographic parameters. Methods and results Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, electrocardiogram, N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiogram. Mean age of the population was 69 ± 7 years, 56% were men, 88% had hypertension, mean LVEF was 61 ± 9%, and mean MWFS 16.2 ± 3.3. During a median follow-up of 5.7 years, 95 subjects experienced HF/death events. At Cox analysis, lower MWFS was the only echocardiographic parameter, among structural/functional ones, associated with higher risk of HF/death [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.84–0.95, Padjusted < 0.001]. The risk of HF/death related to clinical data and NT-proBNP (baseline model) was reclassified by echocardiography only when MWFS was included into the model (baseline C-statistics 0.761; adding conventional structural/functional echocardiographic data 0.776, P = 0.09; adding MWFS 0.791, P = 0.007). Compared to subjects with normal LVEF and MWFS, only subjects with combined systolic dysfunction (11% of the population) were at higher risk (P = 0.001 for both abnormal; P > 0.24 for either LVEF or MWFS abnormal). Conclusion DAVID-Berg data suggest to include MWFS assessment in clinical practice, a simple and reliable echocardiographic parameter able to improve risk stratification in subjects at high risk for HF.

Purpose: Adaptive servo-ventilation (ASV) is a ventilator algorithm able to correct breathing through anticyclic support of breathing in patients with central sleep apnea (CSA). So far, very few data exist regarding the role of ASV on acute heart failure with preserved ejection fraction (HFpEF). Methods: We performed a single-center prospective, randomized, case-control study in consecutive acute HFpEF (left ventricle ejection fraction, LVEF ≥ 45%) patients with sleep-disordered breathing (SDB, apnea–hypopnea index, AHI > 15/h) and prevalence of CSA. Results: We included ten consecutive patients randomized for ASV on top of standard therapy for acute heart failure (group 1) versus standard care alone (group 2). ASV therapy significantly reduced AHI and CSA. An improvement in cardiac diastolic function was seen in group 1 compared to group 2 (E/E’ 17.5 to 9.6, p < 0.02 vs 18.5 to 14.5, p = 0.4). Brain natriuretic peptide (BNP) markedly decreased in cases, but not in controls (298 to 84 pg/ml, p < 0.02 vs 280 to 120 pg/ml, p = 0.06). Right ventricle (RV) function significantly improved in group 1, differently from group 2. Conclusions: An acute use of ASV seems effective in reducing BNP and improving diastolic and RV function in acute HFpEF patients with SDB and CSA, compared to standard treatment.

Aims Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality, but the identification of LVAD candidates at risk for RVF remains challenging. We undertook a systematic review and meta-analysis of observational studies of risk factors associated with RVF after LVAD implant. Thirty-six studies published between 1 January 1995 and 30 April 2015, comprising 995 RVF patients out of a pooled final population of 4428 patients, were identified. Meta-analysed prevalence of post-LVAD RVF was 35%. A need for mechanical ventilation [odds ratio (OR) 2.99], or continuous renal replacement therapy (CRRT; OR 4.61, area under the curve 0.78, specificity 0.91) were the clinical variables with the highest effect size (ES) in predicting RVF. International normalized ratio [INR; standardized mean difference (SMD) 0.49] and N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD 0.52) were the biochemical markers that best discriminated between RVF and No-RVF populations, though NT-proBNP was highly heterogeneous. Right ventricular stroke work index (RVSWI) and central venous pressure (CVP) (SMD -0.58 and 0.47, respectively) were the haemodynamic measures with the highest ES in identifying patients at risk of post-LVAD RVF; CVP was particularly useful in risk stratifying patients undergoing continuous-flow LVAD implant (SMD 0.59, P < 0.001, I2 = 20.9%). Finally, pre-implant moderate to severe right ventricular (RV) dysfunction, as assessed qualitatively (OR 2.82), or a greater RV/LV diameter ratio (SMD 0.51) were the standard echocardiographic measurements with the highest ES in comparing RVF with No-RVF patients. Longitudinal systolic strain of the RV free wall had the highest ES (SMD 0.73) but also the greatest heterogeneity (I2 = 74%) and was thus only marginally significant (P = 0.05). Patients on ventilatory support or CRRT are at high risk for post-LVAD RVF, similarly to patients with slightly increased INR, high NT-proBNP or leukocytosis. High CVP, low RVSWI, an enlarged right ventricle with concomitant low RV strain also identify patients at higher risk.

The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.

Background Little is known about the coronavirus SARS-CoV-2 disease (COVID-19) in solid organ transplanted patients. We here report a series of heart transplanted patients with COVID-19 from two centers of Italy. Methods All heart transplanted patients of Transplant Centers of Bergamo and Torino with a microbiologically confirmed SARS-CoV-2 infection were enrolled. Data collection included clinical presentation, laboratory and radiological findings, treatment and outcome. Follow-up was performed by visit or phone. Results From February to March 2020 twenty-six heart transplanted patients (age 62±12 years; 77% males; time from transplant 10±10 years; 69% with comorbidities) had a microbiologically confirmed COVID-19. The most frequent symptom was fever, followed by cough. Seventeen patients had a pneumonia, 8 of them severe pneumonia. Seven patients died (27%) and 17 (65%) were hospitalized. Discontinuation of immunosuppression was associated with death (71 vs 21%, p=0.02). Conversely, all patients receiving steroids survived (p The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. Conclusions COVID-19 has a significant impact on long term heart transplanted patients. Conversely, SARS-CoV-2 infection seems to have a limited influence on more recent transplants. Our experience may suggest that heart transplantation programs can be maintained even during the pandemic phase if specific and tailored paths to prevent and to limit virus transmission are provided.

Background Heart failure with mid-range ejection fraction (HFmrEF) has been identified as a multi-faceted phenotype that may encompass both patients with mild disease or those who from previous HFrEF recover EF (HFrecEF) Purpose To describe clinical characteristics and factors associated with phenotype transition at follow-up. Methods From 2009 to 2016, 1194 patients with baseline EF Results When compared to HFrEF patients, those with HFmrEF had less often an ischemic etiology, advanced symptoms and a HF admission in the previous year. No other differences were found in clinical characteristics and drug therapy (Table). At a median follow-up of 6 months, 30% of HFrEF patients improved EF by 14 (9) units: 21% showed partial EF recovery (transition to HFmrEF) and 9% had full EF recovery. Conversely among HFmrEF patients 22% improved EF, by 9 (5) units, to full recovery, and 18% deteriorated by 1.5 (5.5) units sloping to HFrEF. By multivariable logistic regression analysis, variables associated with EF recovery at 6-month follow-up differed between baseline phenotypes. Within HFrEF, ischemic etiology (OR 0.46, 95% CI 0.33–0.64) and NYHA class III-IV symptoms (OR 0.57, 95% CI 0.38–0.68) were associated with a lower likelihood of EF recovery, while a history of HF At a median follow-up of 36+28 months mortality was 4.6% vs 6.9% in HFrecEF vs non-recovered patients (log rank p=0.08). Baseline characteristics HFrEF vs HFmrEF Conclusions HFmrEF patients showed a less severe clinical picture than HFrEF patients, but had EF recovery less often. EF improvement is negatively associated with ischemic etiology in both phenotypes, and positively associated with atrial fibrillation in HFmrEF and a short history of HF in HFrEF.

During energy demanding conditions, white adipocytes store triglycerides and release fatty acids through lipolysis. In contrast, bone marrow adipocytes (BM-Ad) increase in size during caloric restriction, suggesting this fat depot exhibits precise metabolic specificity. We found subcutaneous adipocytes (SC-Ad) and BM-Ad share morphological features, but possess distinct lipid metabolism. BM-Ad show enrichment in cholesterol-oriented metabolism that correlates with increased free cholesterol content, while proteins involved in lipolysis were downregulated. A strong down-regulation in expression of monoacylglycerol (MG) lipase was observed leading to an accumulation of major MG species and accordingly the basal and induced lipolytic responses were absent in BM-Ad. These features are not recapitulatedin vitrousing differentiated bone marrow mesenchymal stem cells. Since our data demonstrate that BM-Ad comprise a distinct class of adipocytes, we propose renaming them yellow adipocytes.

Objective: To identify the exercise echocardiographic determinants of long-term functional capacity, in patients with chronic ischemic mitral regurgitation, after restrictive mitral valve annuloplasty (RMA) or mitral valve replacement (MVR). Methods: We retrospectively analyzed 121 patients with significant chronic ischemic mitral regurgitation, who underwent RMA (n = 62) or MVR (n = 59), between 2005 and 2011. Preoperatively, all patients underwent a resting echocardiographic examination, and a 6-minute walking test (6-MWT) to measure distance. Resting and exercise stress echocardiography, and the 6-MWT were repeated at 41 +/- 16.5 months. Results: After surgery, the 6-MWT distance significantly improved in the MVR group, and decreased in the RMA group (+37 +/- 39 m vs -24 +/- 49 m, respectively; P < .0001). Exercise indexed effective orifice area was significantly higher in the MVR, versus the RMA, group (MVR: change from 1.3 +/- 0.2 cm(2)/m(2) to 1.5 +/- 0.3 cm(2)/m(2); RMA: change from 1.1 +/- 0.3 cm(2)/m(2) to 1.2 +/- 0.3 cm(2)/m(2); P = .001). The mean mitral gradients significantly increased from rest to exercise, in both groups, but to a greater extent in the RMA group (change from 4.4 +/- 1.4 to 11 +/- 3.6 mm Hg; MVR: change from 4.3 +/- 1.8 to 9 +/- 3.5 mm Hg; P = .006). On multivariate analysis, MVR and exercise indexed effective orifice area were the main independent determinants of postoperative 6-MWT. In the RMA group, 25 patients experienced late mitral regurgitation recurrence, severe in 9 (14%) of them. The rate of postoperative cardiovascular events was significantly higher in the RMA group (21% vs MVR: 8%; P = .03). Follow-up survival was 83% in the RMA group and 88% in the MVR group (P = .54). Conclusions: For chronic ischemic mitral regurgitation, MVR versus RMA was associated with better postoperative exercise hemodynamic performance and long-term functional capacity.

In patients with suspected or established hypertrophic cardiomyopathy (HCM), cardiovascular magnetic resonance (CMR) is widely employed for clinical management, given its multimodality approach capable of providing unique information on cardiac morphology, function, and tissue characterization. Guidance regarding all aspects of HCM diagnosis and management is provided by the comprehensive 2014 European Society of Cardiology (ESC) guidelines on HCM. CMR should be performed in centres with recognized expertise in heart muscle diseases, by physicians who are familiar with the whole HCM disease spectrum, differential diagnoses, and pitfalls. Because CMR is usually performed and interpreted by physicians not directly involved in patient care, detailed, bidirectional, and standardized communication becomes essential to obtain best results and avoid misinterpretation. In order to maximize the potential of CMR, it is of paramount importance that reporting physicians are provided with the essential clinical information and that, in turn, referring physicians are given a core set of CMR morphological, functional, and tissue characterization results following the test. This article aims to summarize the current knowledge on the role of CMR in managing HCM and, in addition, to review the importance of the clinical context in which the report is provided, in both adult and paediatric population, highlighting implications for clinical research.

Background: Despite the burden of pre-clinical heart failure (HF) among diabetes mellitus (DM) patients, routine screening echocardiography is not currently recommended. We prospectively assessed risk prediction for HF/death of a screening strategy combining clinical data, electrocardiogram, NTproBNP, and echocardiogram, aiming to identify DM patients more suitable for selective echocardiography. Methods: Among 4047 screened subjects aged. ≥. 55/≤80. years, the DAVID-Berg Study prospectively enrolled 623 outpatients with DM, or hypertension, or known cardiovascular disease but with no HF history/symptoms. The present analysis focuses on data obtained during a longitudinal follow-up of the 219 patients with DM. Results: Mean age was 68. years, 61% were men, and median DM duration was 4.9. years. During a median follow-up of 5.2. years, 50 subjects developed HF or died. A predictive model using clinical data demonstrated moderate predictive power, which significantly improved by adding electrocardiogram (C-statistic 0.75 versus 0.70; p

UNLABELLED Essentials Information about the formation of the demarcation membrane system (DMS) is still lacking. We investigated the role of the cytoskeleton in DMS structuration in megakaryocytes. Cdc42/Pak-dependent F-actin remodeling regulates DMS organization for proper megakaryopoiesis. These data highlight the mandatory role of F-actin in platelet biogenesis. SUMMARY Background Blood platelet biogenesis results from the maturation of megakaryocytes (MKs), which involves the development of a complex demarcation membrane system (DMS). Therefore, MK differentiation is an attractive model for studying membrane remodeling. Objectives We sought to investigate the mechanism of DMS structuration in relationship to the cytoskeleton. Results Using three-dimensional (3D) confocal imaging, we have identified consecutive stages of DMS organization that rely on F-actin dynamics to polarize membranes and nuclei territories. Interestingly, microtubules are not involved in this process. We found that the mechanism underlying F-actin-dependent DMS formation required the activation of the guanosine triphosphate hydrolase Cdc42 and its p21-activated kinase effectors (Pak1/2/3). Forster resonance energy transfer demonstrated that active Cdc42 was associated with endomembrane dynamics throughout terminal maturation. Inhibition of Cdc42 or Pak1/2/3 severely destructured the DMS and blocked proplatelet formation. Even though this process does not require containment within the hematopoietic niche, because DMS structuration was observed upon thrombopoietin-treatment in suspension, integrin outside-in signaling was required for Pak activation and probably resulted from secretion of extracellular matrix by MKs. Conclusions These data indicate a functional link, mandatory for MK differentiation, between actin dynamics, regulated by Cdc42/Pak1/2/3, and DMS maturation.

Blood platelets play a pivotal role in haemostasis and are strongly involved in arterial thrombosis, a leading cause of death worldwide. Besides their critical role in pathophysiology, platelets represent a valuable model to investigate, both in vitro and in vivo, the biological roles of different branches of the phosphoinositide metabolism, which is highly active in platelets. While the phospholipase C (PLC) pathway has a crucial role in platelet activation, it is now well established that at least one class I phosphoinositide 3-kinase (PI3K) is also mandatory for proper platelet functions. Except class II PI3Kγ, all other isoforms of PI3Ks (class I α, β, γ, δ; class II α, β and class III) are expressed in platelets. Class I PI3Ks have been extensively studied in different models over the past few decades and several isoforms are promising drug targets to treat cancer and immune diseases. In platelet activation, it has been shown that while class I PI3Kδ plays a minor role, class I PI3Kβ has an important function particularly in thrombus growth and stability under high shear stress conditions found in stenotic arteries. This class I PI3K is a potentially interesting target for antithrombotic strategies. The role of class I PI3Kα remains ill defined in platelets. Herein, we will discuss our recent data showing the potential impact of inhibitors of this kinase on thrombus formation. The role of class II PI3Kα and β as well as class III PI3K (Vps34) in platelet production and function is just emerging. Based on our data and those very recently published in the literature, we will discuss the impact of these three PI3K isoforms in platelet production and functions and in thrombosis.

Chronic ischaemic mitral regurgitation (CIMR) remains a challenge in terms of preop assessment, surgery indications and postop outcome. Aim: to evaluate the impact of exercise stress echocardiography (ESE) and type of surgery in predicting postop functional status in pts with CIMR Surgery was