Search

In the clinical practice a noteworthy proportion of severe symptomatic aortic stenosis patients presents with low-flow low-gradients features, these having reported a less favorable prognosis even when surgically or transcatheter treated.We retrospectively analyzed the prospectively collected data on 1051 consecutive patients undergone balloon-expandable transcatheter aortic valve replacement at our Institution from January 2008 to January 2020. We divided the population according with a mean aortic gradient (MAG) or ≥40 mmHg and we performed a propensity-matched analysis based on the Society of Thoracic Surgery Score and age, obtaining two homogeneous groups of 314 patients each (Groups A and B, respectively). We then analyzed the outcomes of the two groups by implementing adjusted Cox models adjusted for significant clinical differences between the two groups, such as sex, ejection fraction, comorbidities and other variables not included in the propensity-matched analysis. The only variable associated with both cardiovascular and all-cause events was an ejection fraction ≤35%. Finally, a sensitivity analysis found that an ejection fraction ≤35% was associated with an increase cardiovascular and all-cause mortality only in patients with an indexed end-diastolic volume97 ml/mIn our series a MAG40 mmHg was not found to be per se an independent risk factor for cardiac and all-cause mortality after transcatheter aortic valve replacement. The ejection fraction was found to be an independent risk factor only in the context of enlarged left ventricular dimensions.

Introduction In the last years, genetic testing for inherited cardiac conditions (ICCs) is expanded and evolved at an incredible rate. This tool may inform treatment options and lifestyle choices to avoid arrhythmia triggers. Furthermore, identifying the genetic underpinning of the disorder improves risk assessment for asymptomatic or pre-symptomatic family members. However, despite the large numbers of disease-causative genes identified in the last years, only 60% of the patients with a clinical diagnosis of ICCs carry a pathogenic or likely pathogenic variant. The remaining 40% of the cases have an inconclusive or ambiguous test caused by negative results or mainly by the identification of one or more variants of unknown significance (VUS). In this case, the test results are uninformative and clinically irrelevant, increasing uncertainty about medical management. Purpose We investigated whether a periodic re-evaluation of the detected VUS, using the American College of Medical Genetics and Genomics (ACMG) criteria, may impact the clinical setting of patients with suspected ICC and their family members. Methods We reevaluated 306 consecutive probands with suspected ICC undergoing genetic testing by next-generation sequencing using the Illumina TruSight Cardio Sequencing panel, from 2017 to 2021. Results Thirty-five percent of patients carried at least one variant in a gene associated with the phenotype. Of these, 94 had been previously classified as VUS and were not considered clinically actionable. After an average time of 36 months, they were reevaluated and 26.6% of the VUS were reclassified. In particular, 1 was downgraded to Benign and 24 were upgraded to Likely Pathogenic (16) or Pathogenic (8). According to the different phenotypes, the reclassification rate was 45.8% in Hypertrophic cardiomyopathy, 33.3% in Dilated cardiomyopathy, 27.3% in Arrhythmogenic cardiomyopathy, 12.5% in Brugada syndrome, and 50% in Long QT syndrome patients. This reclassification process allowed to recategorize 24 probands as clinically and molecularly diagnosed and to extend the genetic screening to their at-risk family members. Conclusions Given the extent of the clinical impact that genetic testing can have, these findings suggest that a periodic reevaluation of genetic test results, particularly VUS, should be a mandatory step in the ICC diagnostic workflow.

Mitral regurgitation (MR) is frequently associated with severe aortic stenosis, but its influence on outcomes after transcatheter aortic valve implantation (TAVI) remains controversial. This study sought to assess the baseline etiology and degree of MR in TAVI population, identify the predictors of MR changes and investigate the clinical and prognostic impact of baseline MR at mid and long-term follow-up.We enrolled 572 consecutive patients who underwent TAVI. MR degree and etiology were evaluated by echocardiography at baseline and 1-year follow-up. Clinical outcomes were obtained up to 3-year follow-up.At baseline, 168 patients (29%) had moderate-to-severe MR (MR ≥ 2). Organic MR was more frequently associated with MR ≥ 2 (MR 2: 20%, MR ≥ 2: 43%, p 0.001). Relevant MR had improved more in functional MR (79%) compared to organic MR (50%, p = 0.001). At the multivariate analysis, the coexistence of coronary artery disease (p = 0.026), absence of atrial fibrillation (p = 0.038) and functional etiology (p = 0.025) were predictors of MR improvement after TAVI. Patients with baseline MR ≥ 2 had a higher mortality rate than those with MR 2 at 1-year and 3-year follow-up. Moreover, a landmark analysis starting from 1-year to 3-year follow-up, demonstrated that organic MR was associated with an increased risk of mortality throughout 3-year follow-up compared with functional MR, irrespective of MR severity.Baseline MR ≥ 2 in TAVI patients was associated with early and late mortality rate. At 1-year, significant improvement in MR severity was observed mainly in patients with functional MR ≥ 2. Organic MR ≥ 2 had a negative impact on 3-year, but not 1-year, mortality rate.

Aims Haemodynamic classifications of severe aortic stenosis (AS) have important prognostic implications, with low flow state (defined on the basis of a stroke volume index, SVi Methods In this single centre study, 1078 patients (mean age 81±7 years) with severe symptomatic AS (AVA40 mmHg), 94 (9%) with paradoxical low flow LG (pLF-LG: DP mean 50%, and SVi Results TAVR was feasible in all AS subtypes with similar rate of unsuccessful procedure (1.3% NF-HG, 1.1% pLF-LG, 0% LF-LG P=470). Valvular function after TAVR was excellent over time with respect to aortic pressure gradient (mean and peak) and aortic valve area regardless of flow state group (Figure A). Overall, intraoperative (P=957) and 30-day mortality (P=817) did not differ significantly among the 3 groups. Longer follow-up showed that, compared to NF-HG patients, pLF-LG had similar all-cause mortality rate [HR 1.35(0.95–1.90), P=0.094] up to 5 years and LF-LG had a significant higher mortality rate [HR 1.89(1.43–2.49), P Conclusions We provided evidence that TAVR is an effective procedure in all patients with severe AS regardless of transvalvular flow-gradient patterns. A careful haemodynamic classifications of severe AS is of utmost importance for identifying patients who benefits the most from TAVR procedure.

Graphical abstract

Background Nowadays, transvenous lead extraction (TLE) is considered an essential technique in lead management strategy. Since 2011, a multidisciplinary approach was undertaken in our centre involving electrophysiologists, cardiac surgeons and anaesthesiologists to improve cross- unit cooperation and minimize complications and mortality. The present paper reports procedural outcomes and complications of our lead extraction experience. Methods We retrospectively collected and analysed data from all consecutive patients undergoing cardiac implantable electronic device leads TLE at the IRCCS Centro Cardiologico Monzino between January 2011 and November 2017. Results One-hundred fifty patients (111 males, 68 ± 13 years) underwent extraction procedures. The most common extraction indication were infections (86.7%) and TLE was carried out by laser-based approach in 88 (58.6%) patients, by mechanical dilating sheaths in 58 (38.7%) patients and by a combined approach (TLE + open surgical intervention) in 4 (2.7%) patients. Procedural success was obtained in 146 (97.3%) cases with only 3 (2.0%) major complications with 2 cases of structural injury with tamponade requiring emergent median sternotomy. Open surgery extraction was required in 4 patients, after an attempt to TLE, due to leads strict adhesion to cardiac or vascular structures, whereas in 5 (3.3%) cases, the treatment of choice was a combined approach consisting in transvenous leads extraction followed by planned surgery. Conclusions TLE is a complex procedure that sometimes leads to fatal complications. In our single center experience, a multidisciplinary approach involving electrophysiologist, cardiac surgeon, anaesthesiologist in an operating room allows a safer approach and major complications treatment.

Funding Acknowledgements Type of funding sources: None. Background. Transcatheter aortic valve-in-valve (TAVI ViV) implantation is an appealing treatment option for patients with degenerated bioprostheses. However, elevated residual gradients after TAVI ViV procedure are very common. These are an unwanted effects of prosthesis-patient mismatch (PPM). Currently, the actual incidenceof PPM, its predictors and its clinical outcomes have not been completely investigated. Purpose. The aims of this study was to investigate the incidence, predictors and clinical outcome of PPM and therefore of elevated gradients after TAVI ViV. Methods. 75 patients (age 78 ± 9 years, 36 male), who underwent TAVI-ViV due to failed aortic biological valve (60 stented, 15 stentless), were enrolled. Mechanism of bioprosthetic valve failure was stenosis (34 cases, 45%), regurgitation (24 cases, 32%) or combination (17 cases, 23%). Elevated residual gradients were defined as a mean DP> 20 mmHg. PPM was identified by the indexed effective orifice area (EOAi) measured by echocardiography (moderate PPM if 0.65 < EOAi < 0.85 cm²/m²; severe PPM if EOAi < 0.6 cm²/m²). Results. ViV TAVI was feasible in all patients, 33 patients (44%) were implanted with a balloon-expandable valve and 42 (56%) with a self-expandable valve. Post-procedural post-ballooning was performed in 16 out of 42 patients (38%) receiving a self-expandable valve. Post-operative mean DP> 20 mmHg was found in 35 patients (48%). Moderate PPM was found in 24 cases (33%) and severe PPM in 15 (20%). A logistic regression analyses identified small size of surgical prosthesis (size < 23 mm) [OR: 6.061(2.127-17.267), p = 0.001] and failed stented valve [OR: 20.727(2.522-170.364), p = 0.005] as independent predictors for the occurrence PPM. Interestingly PPM did not affect early and 1 years mortality (1 years mortality 1.3 %), while mortality was higher in pts with stentless prostheses (9%) Conclusions. PPM is a frequent finding after ViV procedures. Despite elevated residual gradients, TAVI ViV resolved prosthetic dysfunction and PPM did not affect mortality. Therefore, this procedure represents a promising new option for patients with failed biological prosthetic valves.

Introduction Type A aortic dissection (AAD) is a life-threatening disease with very high mortality. The gold standard treatment is surgical, as medical treatment has been proven to be ineffective. It is still unclear the role of pre-operative neurological dysfunction in the prognosis of the patient. Therefore, the choice of performing surgery in patients with neurological symptoms is still left to the surgeon at the time of the diagnosis. The aim of this study is to make a narrative review of the current literature about the management of patients with neurological symptoms in AAD patients. Evidence acquisition A bibliographical research was performed on PubMed, looking for papers containing the words: "(preoperative neurological symptoms in type a aortic dissection) OR brain injury type A aortic dissection) AND ("2010"[Date - Publication] : "3000"[Date - Publication])". A total of 35 papers were found. Evidence synthesis A total of 6 papers were chosen to be reviewed. All of them concluded that even patients with severe neurological symptoms (up to comatose state) had a good chance to recover neurological functions after surgery if treated in the first hours from the onset of symptoms. Interestingly, a hemorrhagic stroke was rarely found. Conclusions Pre-operative neurological dysfunction have been long considered a contro-indication to surgery. Nevertheless, several authors show neurological and survival good results in patients with pre-operative neurological dysfunction. They also stress the importance of surgical timing finding in 5 to 10 hours the surgical time limit to improve neurological dysfunction. A pre-operative neurological dysfunction could be considered a strong advise to surgical intervention. It is time to change and consider prompt surgery not only for survival but also for cerebral protection.

OBJECTIVES During the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic, Northern Italy had to completely reorganize its hospital activity. In Lombardy, the hub-and-spoke system was introduced to guarantee emergency and urgent cardiovascular surgery, whereas most hospitals were dedicated to patients with coronavirus disease 2019 (COVID-19). The aim of this study was to analyse the results of the hub-and-spoke organization system. METHODS Centro Cardiologico Monzino (Monzino) became one of the four hubs for cardiovascular surgery, with a total of eight spokes. SARS-CoV-2 screening became mandatory for all patients. New flow charts were designed to allow separated pathways based on infection status. A reorganization of spaces guaranteed COVID-19-free and COVID-19-dedicated areas. Patients were also classified into groups according to their pathological and clinical status: emergency, urgent and non-deferrable (ND). RESULTS A total of 70 patients were referred to the Monzino hub-and-spoke network. We performed 41 operations, 28 (68.3%) of which were emergency/urgent and 13 of which were ND. The screening allowed the identification of COVID-19 (three patients, 7.3%) and non-COVID-19 patients (38 patients, 92.7%). The newly designed and shared protocols guaranteed that the cardiac patients would be divided into emergency, urgent and ND groups. The involvement of the telematic management heart team allowed constant updates and clinical discussions. CONCLUSIONS The hub-and-spoke organization system efficiently safeguards access to heart and vascular surgical services for patients who require ND, urgent and emergency treatment. Further reorganization will be needed at the end of this pandemic when elective cases will again be scheduled, with a daily increase in the number of operations.

Aims Patients with coronary heart disease (CHD) are at very high risk of recurrent events. A strategy to reduce excess risk might be to deliver structured secondary prevention programmes, but their efficacy has been mostly evaluated in the short term and in experimental settings. This is a retrospective case–control study aimed at assessing, in the real world, the efficacy of a secondary prevention programme in reducing long-term coronary event recurrences after coronary artery bypass surgery (CABG). Methods and results Programme participants (henceforth ‘cases’) were men and women aged Conclusion In a real-world setting, taking part in a structured longstanding secondary prevention programme, in addition to usual cardiology care, meaningfully lowers the risk of coronary recurrences.

Aortic valve stenosis (AS) is a pathological condition that affects about 3% of the population, representing the most common valve disease. The main clinical feature of AS is represented by the impaired leaflet motility, due to calcification, which leads to the left ventricular outflow tract obstruction during systole. The formation and accumulation of calcium nodules are driven by valve interstitial cells (VICs). Unfortunately, to date, the in vitro and in vivo studies were not sufficient to fully recapitulate all the pathological pathways involved in AS development, as well as to define a specific and effective pharmacological treatment for AS patients. Cyclophilin A (CyPA), the most important immunophilin and endogenous ligand of cyclosporine A (CsA), is strongly involved in several detrimental cardiovascular processes, such as calcification. To date, there are no data on the CyPA role in VIC-mediated calcification process of AS. Here, we aimed to identify the role of CyPA in AS by studying VIC calcification, in vitro. In this study, we found that (i) CyPA is up-regulated in stenotic valves of AS patients, (ii) pro-calcifying medium promotes CyPA secretion by VICs, (iii) in vitro treatment of VICs with exogenous CyPA strongly stimulates calcium deposition, and (iv) exogenous CyPA inhibition mediated by CsA analogue MM284 abolished in vitro calcium potential. Thus, CyPA represents a biological target that may act as a novel candidate in the detrimental AS development and its inhibition may provide a novel pharmacological approach for AS treatment.

Thermonuclear fusion is a potentially clean and limitless energy source that can substantially change the current global electricity generation mix, which is highly dependent on limited fossil fuels. This thesis contributes to the development of fusion energy with experiments on the TCV tokamak, addressing power exhaust in the divertor, which remains a major issue for a fusion tokamak reactor. A large fraction of the heating power needed to keep the plasma at the parameters required for fusion reactions, is continuously transported by the plasma across closed magnetic surfaces into a thin layer with open field lines surrounding the plasma, the Scrape-Off Layer (SOL), where it follows magnetic field lines towards the divertor targets. Unmitigated target peak heat fluxes in a fusion reactor are projected to greatly exceed available material limits. While acceptable target conditions may be possible by operating the divertor in a detached regime, a degradation of core plasma performance may ensue. A unification of a performant core and a detached divertor may be possible using alternative magnetic configurations to the standard Single-Null (SN). This thesis assesses the power exhaust properties over an unprecedented range of alternative magnetic configurations with the goals of both reducing the power exhaust challenge through divertor geometry modifications and improving the current understanding of SOL transport physics. TCV's infrared thermography systems are extensively used to measure divertor target heat fluxes, fitted to extract the SOL heat power width $\lambda_{q,u}$ and the spreading factor $S_u$. Power sharing between divertor targets significantly varies with the plasma and/or divertor geometry, mostly interpreted as the effect of parallel electron heat conduction. The $\lambda_{q,u}$ is found sensitive to properties of the plasma core, shape of the plasma and the divertor, and is consistent with empirical cross-machine scalings. The dependence on plasma current can be mostly understood with a model based on the competition between parallel and perpendicular diffusive transport. Poloidal asymmetries and field direction effects indicate that more physics is needed. The $S_u$ scales with the inverse of the target flux expansion. In the Low-Field-Side Snowflake Minus configuration, the secondary x-point enhances cross-field transport in the divertor, consistently with turbulence simulations. At the L- to H-mode transition, cross-field transport reduces in the main and divertor-SOL, suggesting that the edge transport barrier propagates into the SOL. The upstream $\lambda_{q,u}$ between Type-I ELMs agrees with cross-machine scaling predictions only with the toroidal magnetic field as regression parameter, revealing that this field dependence is vital. A comparison of the ELM power deposition duration in TCV and JET supports the hypothesis of it increasing with the parallel connection length, and the ELM peak parallel energy fluence is consistent with a cross-machine scaling, supporting current extrapolations to ITER. Divertor geometry variations reveal that the ELM power width scales with the inverse of the target flux expansion. These results provide unique input for testing models required to reliably extrapolate to the divertor of a fusion reactor, and may have significant implications in the optimization of its magnetic configuration.

Background Clinical outcomes of patients with paradoxical low-flow, low-gradient aortic stenosis (PLF-LG) undergoing valve replacement are controversial. PLF-LG is a combination of a small aortic valve area (AVA Purpose The aim of this study is to determine the clinical outcomes in patients with PLF-LG AS undergoing transcatheter aortic valve implantation (TAVI) compare to NF-HG patients. Methods A total of 624 patients (age 81 ± 7 years) with symptomatic severe AS and preserved LVEF who underwent TAVI, was enrolled and divided in 2 groups: group NF-HG included 554 patients (89%) and group PLF-LG including 70 patients (11%). At 1-year follow-up, death and clinical events were reported. Results TAVI was feasible in all patients. A significant reduction in mean aortic pressure gradient was observed after TAVI both in PLF-LG (baseline, 30 ± 6 mmHg; 1-year, 12 ± 4 mmHg; p Conclusions Differently from surgical series, TAVI in PLF-LG AS is a useful procedure showing similar mortality and rehospitalization rates compared to NF-HG AS patients. Abstract 624 Figure. Survival curve

Background: Fractional flow reserve (FFR) is a reliable tool for the functional assessment of coronary stenoses. FFR computed tomography (CT) derived (FFR CT ) has shown to be accurate, but its clinical usefulness in patients with complex coronary artery disease remains to be investigated. The present study sought to determine the impact of FFR CT on heart team’s treatment decision-making and selection of vessels for revascularization in patients with 3-vessel coronary artery disease. Methods: The trial was an international, multicenter study randomizing 2 heart teams to make a treatment decision between percutaneous coronary interventions and coronary artery bypass grafting using either coronary computed tomography angiography or conventional angiography. The heart teams received the FFR CT and had to make a treatment decision and planning integrating the functional component of the stenoses. Each heart team calculated the anatomic SYNTAX score, the noninvasive functional SYNTAX score and subsequently integrated the clinical information to compute the SYNTAX score III providing a treatment recommendation, that is, coronary artery bypass grafting, percutaneous coronary intervention, or equipoise coronary artery bypass grafting-percutaneous coronary intervention. The primary objective was to determine the proportion of patients in whom FFR CT changed the treatment decision and planning. Results: Overall, 223 patients were included. Coronary computed tomography angiography assessment was feasible in 99% of the patients and FFR CT analysis in 88%. FFR CT was available for 1030 lesions (mean FFR CT value 0.64±13). A treatment recommendation of coronary artery bypass grafting was made in 24% of the patients with coronary computed tomography angiography with FFR CT . The addition of FFR CT changed the treatment decision in 7% of the patients and modified selection of vessels for revascularization in 12%. With conventional angiography as reference, FFR CT assessment resulted in reclassification of 14% of patients from intermediate and high to low SYNTAX score tertile. Conclusions: In patients with 3-vessel coronary artery disease, a noninvasive physiology assessment using FFR CT changed heart team’s treatment decision-making and procedural planning in one-fifth of the patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02813473.

Background Controversial data exist on clinical outcomes of patients with paradoxical low-flow, low-gradient aortic stenosis (PLF-LG) undergoing valve replacement. This entity is a combination of a small aortic valve area (AVA Purpose The aim of this study was to determine the clinical outcomes in patients with PLF-LG AS undergoing transcatheter aortic valve implantation (TAVI) compare to NF-HG patients. Methods A total of 609 patients (age 81±6 years) with symptomatic severe AS and preserved LVEF who underwent TAVI, was enrolled and divided in two groups: group A included patients with NF-HG (542 patients) and group B including those with PLF-LG (66 patients). At 1-year follow-up, death and clinical events were reported. Results TAVI was feasible in all patients. A significant reduction in mean aortic pressure gradient was observed after TAVI both in PLF-LG (baseline, 30±5 mmHg; 1-year, 11±4 mmHg; p Kaplan-Meier analysis Conclusions Differently from surgical series, TAVI patients with PLF-LG AS had showed similar mortality and rehospitalization rates compared to NF-HG.

We describe an approach to address the left ventricular outflow tract obstruction in hypertrophic obstructive cardiomyopathy with concomitant systolic anterior motion of mitral valve. The two main purposes of this approach are to enlarge the left ventricular outflow tract through a "moderate" myectomy and to "discipline" the excessive movement of the mitral valve anterior leaflet through paradoxical chords implantation, and similarly, the papillary muscle too, if necessary, by hanging paradoxical chords between the papillary muscle itself and the posterior mitral annulus.

The Commando procedure is challenging, and aims to replace the mitral valve, the aortic valve and the aortic mitral curtain, when the latter is severely affected by pathological processes (such as infective endocarditis or massive calcification). Given the high complexity, it is seldomly performed. We aim to review the literature on early (hospitalization and up to 30 days) and long-term (at least 3 years of follow-up) results. Bibliographical research was performed on PubMed and Cochrane with a dedicated string. Papers regarding double valve replacement or repair in the context of aortic mitral curtain disease were included. The metaprop function was used to assess early survival and complications (pacemaker implantation, stroke and bleeding). Nine papers (540 patients, median follow-up 41 (IQR 24.5–51.5) months) were included in the study. Pooled proportion of early mortality, stroke, pacemaker implant and REDO for bleeding were, respectively 16.2%, 7.8%, 25.1% and 13.1%. The long-term survival rate ranged from 50% to 92.2%. Freedom from re-intervention was as high as 90.9% when the endocarditis was not the first etiology and 78.6% in case of valvular infection (one author had 100%). Freedom from IE recurrences reached 85% at 10 years. Despite the high mortality, the rates of re-intervention and infective endocarditis recurrences following the Commando procedure are satisfactory and confirm the need for an aggressive strategy to improve long-term outcomes.

Aortic stenosis is the most common primary valve disease needing surgical treatment in Europe and North America. The prevalence of this disease increases over years due to the ageing population. Age and comorbidities often represent an obstacle to surgical aortic valve replacement (AVR) for those patients considered at high and prohibitive risk. In this scenario, transcatheter aortic valve replacement (TAVR) has become an appealing therapeutic option for prohibitive-risk patients with severe symptomatic aortic stenosis who were previously only medically managed and considered unsuitable for AVR. However, the delicate balance between feasibility and appropriateness needs to be accurately defined.

Key Clinical Message Transvenous extraction of Riata lead could be a challenging procedure due to insulation failure and conductor cables’ externalization through the eroded outer insulation. In this case, a complete lead extraction was achieved through a combined LASER and femoral approach because of the massive conductors’ externalization.

Objective In this observational prospective study, we assessed the role of clinical variables and circulating biomarkers in graft occlusion at 18 months to identify a signature for graft occlusion. Methods A total of 330 patients undergoing primary elective coronary artery bypass grafting were enrolled. Blood collection for biomarker assessment was performed before surgery and discharge. Patients were then scheduled to undergo coronary computed tomography angiography at 18 months follow-up, and 179 patients underwent coronary computed tomography angiography 18 ± 2 months postoperatively. Results There were 46 of 503 (9.1%) occluded grafts; of these, 29 (63%) were venous and 17 (37%) were arterial grafts; overall, 43 of 179 patients (24%) had at least 1 occluded graft. Logistic mixed effects model assessing independent factors associated with graft occlusion identified that lower D-dimer levels at baseline (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.36-4.89; P = .00) and total protein content at discharge (OR, 1.09; 95% CI, 1.01-1.19; P = .028) were related to overall graft occlusion at follow-up, along with an arterial graft other than the left internal thoracic artery (OR, 2.92; 95% CI, 1.24-6.9; P = .078); moreover, a venous graft emerged was possibly associated with graft occlusion (OR, 1.51; 95% CI, 0.95-2.39; P = .078). By separately analyzing saphenous vein and arterial grafts, D-dimer levels (OR, 2.67; 95% CI, 1.15-6.2; P = .022 and OR, 2.5; 95% CI, 1.01-7.0; P = .05 for venous and arterial graft, respectively) were still associated with arterial and venous graft occlusion at follow-up. Conclusions We identified D-dimer as a biomarker associated with arterial and venous grafts occlusion. This may help stratify patients at risk of graft failure and identify new molecular targets to prevent this complication.

Keywords: light-chain amyloidosis; T-cell receptor repertoire; regulatory T-cells; flow cytometry; spectratyping; CDR3

Aims Scarce data are available on the long-term structural and functional changes of prosthetic valves after transcatheter aortic valve implantation (TAVI). The objective was to evaluate with echocardiography the long-term structural and functional changes of prosthetic valves after TAVI. Methods and results Structural valve deterioration (SVD) was defined as leaflet thickening ≥3mm, presence of calcification and abnormal leaflet motion. Five-year echocardiographic follow-up was available in 96 out of 318 patients who underwent TAVI with a balloon-expandable device between April 2008 and December 2011. At 1-year follow-up, no patient showed SVD. At 5-year follow-up, SVD were observed in 29 (30%) patients who showed also a significant reduction of aortic valve area (AVA) together with an increase of mean and peak aortic pressure gradients at the latest echocardiography evaluation. Moreover, rate of central aortic valve regurgitation ≥2 was higher in SVD patients as compared to those without SVD, while there was no difference in terms of paravalvular regurgitation. Despite SVD, one patient only reached the criteria for severe stenosis and no reintervention was needed at 5-year follow-up. Variables independently associated with SVD were female sex, small body surface area, use of a 23 mm valve, and small AVA at pre-discharge echocardiogram. Conclusion At 5-year follow-up, 30% of patients who underwent TAVI with a balloon-expandable valve showed initial SVD. However, SVD was not associated with severe stenosis in most of the patients and had no significant impact on and clinical outcome.

Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non-Hodgkin's lymphomas (NHL), the shape of the T-cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T-cell receptor (TCR) repertoire and the distribution of different T-cell subsets - including regulatory T cells (Treg) - in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T-cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T-cell branch of the immune system of patients with B-cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg.

In a previous survey of newly diagnosed haematological malignancies (HMs) in Sardinia from 1974 to 1993, we observed a marked increase in the incidence of many HMs that we chiefly attributed to improvements in case ascertainment. To better define the nature of this increase, we extended the survey by an additional decade (1994-2003), applying the same previously used methods. The incidence of HMs further increased from 1994 to 2003. The incidence rate of total HMs (THMs), standardised to the world population, was 30.15 × 10(5) person-years vs. 21.58 from 1984 to 1993 and 15.26 from 1974 to 1983. The temporal variations in the incidence differed in different HMs and were correlated with the diseases clinical characteristics and the increased availability of diagnostic tools and skills in Sardinia. These observations support the hypothesis that the temporal differences in the incidence rates observed for many HMs in Sardinia over the 30-year survey period were caused by temporal differences in diagnostic efficiency rather than by disease occurrence. An important exception was the increase in non-Hodgkin's lymphoma, which represents a true increase in occurrence, similarly to most Western countries. The incidence rates of HMs already having or reaching stable values in the decade 1994-2003 were similar to those of most Western countries. No significant evidence emerged to suggest that Sardinian particularities influenced the occurrence of HMs. This study demonstrates the extent to which diagnostic efficiency can influence incidence evaluations and emphasises the importance of prolonged observation to determine the validity of incidence rates for both temporal and geographic comparisons.

Using coronary computed tomography angiography (CCTA), severe coronary calcification hampers visual assessment due to the blooming artefact. Calcifications have been associated with discrepancy between non-invasive and invasive luminal evaluation. Moreover, the presence of severe calcification

Over the last few years several studies have addressed the possible influence of different immune mechanisms on the evolution of hematologic malignancies. More specifically, a fundamental role of reactive T-cells has now been demonstrated in the pathogenesis of many of these disorders as well as in the typical immunological milieu observed after stem cell transplantation in patients affected by these malignancies. In this context the study of the T-cell receptor (TCR) repertoire performed by different techniques, such as for instance flow cytometry and spectratyping, has undoubtedly provided a fundamental contribution. More recently, these seminal observations have even opened new potential therapeutic avenues based on the employment of adoptive T-cells somehow engineered toward potential neoplastic targets. This review will run through the most relevant studies which have tried to dissect the TCR repertoire usage in patients with different hematologic malignancies, especially focusing on the possible pathogenetic and therapeutic implications.

Different vascular accesses have been described for the delivery of a transcatheter aortic bioprosthesis. We report the use of the superficial femoral artery (SFA) as the arterial site of puncture with surgical cut-down. It may be a reasonable access alternative to the other classical routes, especially in the setting of either obese patients with elevated body mass index or in the presence of high femoral artery bifurcation. This route seems to be feasible with a low-profile risk.

Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 ( p = 1.16 × 10 −12 ), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10 −6 and 3.34 × 10 −6 , are situated in the methylene tetrahydrofolate reductase ( MTHFR ) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.

La transizione dall’infanzia all’adolescenza è un momento chiave nella vita di una persona. Si affrontano numerose sfide e compiti di sviluppo, che aiutano la persona a potenziare le capacità e a formare la propria identità. Quali fattori favoriscono la crescita positiva e proteggono dai rischi? È la domanda principale dello studio CRESCERE. I risultati mettono in luce i circoli virtuosi che si possono sviluppare nella vita dei ragazzi. Emerge l’importanza dei legami familiari, del dialogo con i genitori, del supporto che percepiscono dalla famiglia e di quanto sia importante per promuovere la fiducia nelle proprie capacità, il sentirsi bene con se stessi e con gli altri. Il benessere scolastico è un altro aspetto fondamentale per la crescita, per lo sviluppo psicologico e sociale dei ragazzi. Fil: Barbero Vignola, G. Fondazione Emanuela Zancan; Italia Fil: Bezze, Maria. Fondazione Emanuela Zancan; Italia Fil: Canali, Cinzia. Fondazione Emanuela Zancan; Italia Fil: Crocetti, Elisabetta. Università di Bologna; Italia Fil: De Leo, Diego. Griffith University; Australia Fil: Eynard, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; Argentina Fil: Maurizio, Roberto. Fondazione Emanuela Zancan; Italia Fil: Milan, Giuseppe. Università di Padova; Italia Fil: Ongaro, Fausta. Università di Padova; Italia Fil: Schiavon, Maurizio. Centro di Medicina dello Sport ; Italia Fil: Vecchiato, Tiziano. Fondazione Emanuela Zancan; Italia

It is widely accepted that a deranged immune system plays a key role in the onset and evolution of classic Kaposi sarcoma (CKS). Nevertheless, the usage of the T-cell receptor (TCR) β-variable (BV) chain repertoire expressed by peripheral blood lymphocytes in patients with CKS is still unknown. With the aim of providing some further insights into the complex role of the immune system in CKS pathogenesis, we performed an extensive analysis of the TCR BV repertoire in both CD4(+) and CD8(+) T cells in 30 human herpesvirus 8-positive Sardinian patients with CKS and an equal number of age-matched healthy controls. We used a panel of monoclonal antibodies covering approximately 70% of human BV subfamilies and third complementarity determining region (CDR3) spectratyping. Patients with CKS showed an increased frequency of BV expansions in both CD4(+) and CD8(+) lymphocytes, with no prevalent clones. On spectratyping analysis, most of the 720 BV CDR3 profiles obtained from both CD4(+) and CD8(+) T cells in patients with CKS were skewed. In particular, the surprising increase of BV skewing observed in CD4(+) lymphocytes mimics the pattern of progressive TCR BV narrowing described in responses to persistent viral antigen stimulations. Our findings support the hypothesis that CKS evolution is associated with inadequate activation rather than impairment of the immune system.

Even though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by an inefficient maturation of haematopoietic precursors, also immune mechanisms seem to play a crucial functional role. In this review, we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the mechanisms of T-cell activation and their implications in the disease history. The potential impact of specific cell subsets, such as regulatory T-cells, Th17 cells and natural killer cells, will be also described. We will finally focus on potential therapeutic approaches based on immunomodulation, ranging from more classical immunosuppressive drugs to vaccination and transplantation strategies.

Unbalanced whole-arm translocations (WATs) of the long arm of chromosome 1, resulting in complete trisomy 1q, are chromosomal abnormalities detectable in both solid tumors and hematologic neoplasms. Among the WATs of 1q to acrocentric chromosomes, a few patients with der(1;15) described as a dicentric chromosome have been reported so far, whereas cases of der(1;14) are much rarer. We report on a case of der(1;14) detected as single anomaly in a patient with myelodysplastic syndrome. The aim of our work was to investigate the breakpoints of the (1;14) translocation leading to the der(1;14). Fluorescence in situ hybridization (FISH) experiments have been performed on chromosome preparations from bone marrow aspirate, using specific centromeric probes of both chromosomes, as well as a probe mapping to 1q11 band. FISH results showed that in our patient the derivative chromosome was monocentric with a unique centromere derived from chromosome 14. The breakpoints of the translocation were located in the short arm of chromosome 14 and in the long arm of chromosome 1, between the alphoid D1Z5 and the satellite II domains. The 1q breakpoint was within the pericentromeric region of chromosome 1, which is notoriously an unstable chromosomal region, involved in different chromosomal rearrangements.

Regulatory T cells (Treg) have often been ascribed a role in the pathophysiology of several neoplastic diseases considering their potential ability to suppress anti-tumor immunity. This is particularly the case in myelodysplastic syndromes (MDS), which are clonal hematologic disorders characterized by marked immune dysregulation. We analyzed Treg frequencies in a cohort of 36 patients with early-stage MDS using a flow-cytometric approach based on the concomitant expression of CD25 and CD127. MDS patients showed a higher frequency of CD4+CD25high+CD127low Treg than healthy controls (1.51 vs. 1.14%), with no specific effect of patient- and disease-related factors. Our data point to impaired anti-tumor immunity in patients with MDS, even in the early stage, which has already been noted in other clonal disorders.

The T-cell receptor (TCR) is the key player within the so called immunological synapse and the analysis of its repertoire offers a picture of both versatility and wideness of the whole immune T-cell compartment. Among the different approaches applied to its study the so-called spectratyping identifies the pattern of the third complementarity determining region (CDR3) length distribution in each one of the beta variable (TRBV) subfamilies encoded by the corresponding genes. This technique consists in a CDR3 fragment analysis through capillary electrophoresis, performed after cell separation, RNA extraction and reverse transcriptase PCR. This review will run through the most relevant studies which have tried to dissect the TCR repertoire usage in patients with different immune-mediated and infective diseases as well as solid or haematologic malignancies.

Objectives This study sought to compare clinical, echocardiographic, and cardiopulmonary exercise testing response to cardiac resynchronization therapy (CRT) in patients with unfavorable anatomy of coronary sinus (CS) veins, randomized to transvenous versus surgical left ventricular (LV) lead implantation. Background CRT efficacy depends on proper positioning of the LV lead over the posterolateral wall. A detailed pre-operative knowledge of CS anatomy might be of pivotal importance to accomplish a proper LV lead placement over this area. Methods Study population included 40 patients (age 66 ± 4 years) with heart failure and indication to CRT, with unsuitable CS branches anatomy documented by pre-operative multislice computed cardiac tomography; 20 patients (Group 1) underwent surgical minithoracotomic LV lead implantation whereas 20 (Group 2) were implanted transvenously. New York Heart Association functional class, echocardiographic, and cardiopulmonary exercise testing data were assessed before and 1 year after CRT-system implant. Results In all Group 1 patients, the LV leads were placed over the middle-basal segments of the posterolateral wall of the LV. This was not possible in Group 2 patients. One year after CRT, in Group 1, a significant improvement of New York Heart Association functional class, LV ejection fraction (from 28.8 ± 9.2% to 33.9 ± 7.2%, p o 2/kg (from 10.4 ± 4.5 ml/kg/min to 13.1 ± 3.1 ml/kg/min, p o 2/kg from 11.2 ± 3.2 ml/kg/min to 11.3 ± 3.4 ml/kg/min (p = 0.9). Changes after CRT between groups were highly significant. Conclusions In the setting of unfavorable CS branches of anatomy, CRT by a surgical minithoracotomic approach is preferable to transvenous lead implantation.

We studied the geographical distribution of all cases of HM that were diagnosed among residents of Sardinia during the 20-year period from 1974 to 1993. Cases, grouped into three categories (lymphoproliferative diseases, myeloproliferative diseases, and total haematological malignancies), were assigned to the 356 municipalities of the island according to the reported residence of each patient. In each municipality, the relative risk (RR) of diagnosis was calculated for the three disease groups, for females, for males, and for the total population. The RR of diagnosis of HM was significantly different from 1 (p

In hematologic malignancies, the microenvironment is often characterized by nonneoplastic cells with peculiar phenotypic and functional features. This is particularly true in Hodgkin's lymphoma (HL), in which T lymphocytes surrounding Hodgkin's Reed-Sternberg cells are essentially polarized towards a memory T-helper type 2 phenotype. In this paper we will first evaluate the main processes modulating T-cell recruitment towards the lymph node microenvironment in HL, especially focusing on the role played by cytokines. We will then consider the most relevant mechanisms of immune escape exerted by neoplastic cells in order to evade antitumor immunity. The potential pathogenetic and prognostic impact of regulatory T cells in such a context will be also described. We will finally overview some of the strategies of cellular immunotherapy applied in patients with HL.

The association between non-Hodgkin lymphomas and autoimmune disorders is a well-known event. Also autoimmune hemolytic anemia (AHA), although much more frequent in patients with chronic lymphocytic leukemia (CLL), has been described in this group of patients. In recent years, among the more traditional therapeutic options, rituximab, an anti-CD20 monoclonal antibody, has shown interesting results in the treatment of primary AHA. Although this drug has been frequently used for AHA in patients with CLL, much less data are available on its use in NHL patients. However, considering that the main pathogenetic mechanism of AHA in course of lymphoproliferative disorders seems to be an antibody production directly or indirectly mediated by the neoplastic clone, this monoclonal antibody represents an ideal therapeutic approach. In this paper we will briefly describe some biological and clinical features of NHL-patients with AHA. We will then analyze some studies focusing on rituximab in primary AHA, finally reviewing the available literature on the use of this drug in NHL related AHA.

Fludarabine and Cytarabine Combination in the Induction of Adult Patients with Acute Myeloid Leukaemia Francesco Longu;Claudio Fozza;Laura Dessi;Maurizio Longinotti;Silvana Bonfigli;Maria Careddu;Lorenzo Coppola;Domenica Giannico;Rosa Nieddu;Luigi Podda;Simonetta Pardini;Fausto Dore;Simone Dore;Giovanni Sotgiu; Acta Haematologica