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ObjectivesAge is the strongest risk factor of Giant Cell Arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multi-marker algorithm in tissue artery biopsies (TABs) of GCA patients.MethodsSeventy five positive TABs from GCA patients and 22 negative from patients with Polymyalgia Rheumatica (PMR) were retrospectively retrieved and analyzed. Senescent cells and their histologic origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype (SASP) by triple co-staining. GCA or PMR artery culture supernatants were applied to primary skin fibroblasts with or without IL-6 blocking agent to explore the induction of IL-6 associated cellular senescence.ResultsSenescent cells were mainly present in GCA arteries at higher proportion compared to PMR (9.50% vs 2.66% respectively, pConclusionsSenescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk. These findings might suggest a potential implication in disease pathogenesis by perpetuating inflammation and affecting vascular remodeling via IL-6 dependent mechanisms.

Objectives The implementation of nucleic acid testing in laboratory medicine has revolutionized clinical diagnosis. Unfortunately, incorporation of these technologies in less developed countries remains a challenge. Despite Romania’s recent economic growth, the country is in dire need of medical and laboratory staff trained in modern technologies. The aim of the study was to develop a curriculum that could easily be delivered to laboratory professionals in Romania and to pilot test the effectiveness of the training in increasing their understanding of molecular tests. Methods The program was developed in accordance with the US Centers for Disease Control and Prevention’s (CDC’s) quality training standards. It was offered to 50 laboratory professionals and consisted of online, asynchronous lectures and optional synchronous review sessions. Training effectiveness was evaluated using CDC guidelines based on pre- and postassessment questions answered anonymously. Results Forty-two people participated in the program, and 32 (81%) completed the training successfully. Based on 16 participants’ self-assessment, the course was successful in improving learners’ overall knowledge of molecular diagnostics—specifically, their understanding of molecular techniques and how to interpret results. Those participants were highly satisfied with the overall training. Conclusions The piloted platform presented here is promising and can be a foundation for future larger-scale studies in countries with developing health systems.

Background The non-invasive assessment of myocardial work allows to evaluate LV performance by taking into account the effect of LV load. Aim of this study was to evaluate the acute and chronic impact of percutaneous mitral valve repair (PMVR) on LV performance, in patients with severe primary mitral regurgitation (PMR). Methods 71 patients (age: 77±9 years, females: 44%) with severe PMR (effective regurgitant orifice: 0.57±0.31 cm2, regurgitant volume: 80±34 ml) and preserved LV ejection fraction (LVEF: 60±10%) underwent PMVR according to current recommendations. Myocardial work indices were evaluated before the procedure, 2 days after the procedure and at 1-year follow-up. Results PMVR was associated with an acute reduction in LVEF, global longitudinal strain (GLS), myocardial work index (MWI), and work efficiency (MWE), and a significant increase in myocardial wasted work (MWW) and mechanical dispersion (MD). 1-year after the procedure, LV size significantly decreased, GLS, MWI, MWE and MD improved, whereas GWW remained significantly reduced. LVEF improved but remained significantly altered compared with baseline values (Table 1). Conclusions In patients severe PMR undergoing PMVR, the acute reduction in LV preload causes a significant impairment of all parameters of LV performance. After 1-year, progressive LV remodeling is associated a significant improvement in MCW, counterbalanced by a persistently high MWW, which can explain the partial recovery of LVEF. Funding Acknowledgement Type of funding sources: None.

Background Left atrial reservoir strain (LARS) is a well known prognostic predictor in several cardiac disease. Aim of the study was to assess the value of LARS in predicting the occurrence of major adverse cardiovascular events in patients undergoing percutaneous mitral valve repair (PMVR) Methods and results 112 patients (62 males, mean age 74 years) undergoing PMVR for severe primary (n=71, 63%) or secondary MR were retrospectively included in the study. All patients underwent a comprehensive echocardiography before the procedure. Thirty-eight MACES occurred during a median follow up of 18 months. At multivariable Cox regression analysis, ischemic cardiomyopathy (CAD) [HR: 2.41 (1.11–5.24) p=0.02], indexed left atrial volume (LAVi) [HR: 1.01 (1.00–1.01) p=0 03] and LARS [HR: 0.93, (0.88–0.99) p=0.03] were all significant predictors of MACEs (Table 1). A cut-off of 13 for LARS (AUC 0 66 p=0.008 was able to predict MACEs with a 71% sensitivity and 41% specificity (Figure 1A). At Kaplan Meier analysis a PLAS Conclusions LARS is an independent predictor of MACEs in patients undergoing percutaneous mitral valve repair, independently of the etiology of mitral regurgitation. Funding Acknowledgement Type of funding sources: None.

Introduction Left atrial (LA) dyssynchrony is a predictor of response to cardiac resynchronization therapy (CRT). It is unknown, however, if LA resynchronization contributes to response to CRT. We hypothesize that there is a relationship between correction of LA dyssynchrony and response to CRT. Purpose To investigate the association between LA resynchronization and response to CRT. Methods In a prospective study of 171 heart failure patients with LBBB, myocardial strain was measured by speckle-tracking echocardiography, before and 6 months after CRT. As indicated by the white arrows in Figure 1, LA dyssynchrony was measured as the time delay between onset systolic stretch of the interatrial septum and the LA lateral wall. Response to CRT was defined as at least 15% reduction in left ventricular (LV) end systolic volume at 6 months follow up. Results 119 (70%) patients responded to CRT. The panels in Figure 1 shows LA strain traces in a representative LBBB patient that did respond (upper panels), and a patient that did not respond (lower panels). The white arrows in the left panels indicate that both the responder and the non-responder had marked LA dyssynchrony before CRT (198 and 171 ms, respectively). However, after 6 months with CRT, there was recovery of LA synchrony only in the responder (time delay −40 ms), and still marked LA dyssynchrony of 191 ms in the non-responder (right panels). Figure 2 confirms similar results for the whole study population: CRT response was associated with marked reduction of LA dyssynchrony (p=0.0001). In the CRT non-responders there was, however, only a modest, non-significant reduction of LA dyssynchrony. Conclusions Positive CRT response was associated with resynchronization of the left atrium. These findings suggest LA resynchronization as a potential additional target for CRT. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Institute for Surgical Research, Oslo University HospitalThe Intervention Centre, Oslo University Hospital

The idea of using ultrashort X-ray pulses to obtain images of single proteins frozen in time has fascinated and inspired many. It was one of the arguments for building X-ray free-electron lasers. According to theory1, the extremely intense pulses provide sufficient signal to dispense with using crystals as an amplifier, and the ultrashort pulse duration permits capturing the diffraction data before the sample inevitably explodes2. This was first demonstrated on biological samples a decade ago on the giant mimivirus3. Since then a large collaboration4has been pushing the limit of the smallest sample that can be imaged5,6. The ability to capture snapshots on the timescale of atomic vibrations, while keeping the sample at room temperature, may allow probing the entire conformational phase space of macromolecules. Here we show the first observation of an X-ray diffraction pattern from a single protein, that ofEscherichia coliGroEL which at 14 nm in diameter7is the smallest biological sample ever imaged by X-rays, and demonstrate that the concept of diffraction before destruction extends to single proteins. From the pattern, it is possible to determine the approximate orientation of the protein. Our experiment demonstrates the feasibility of ultrafast imaging of single proteins, opening the way to single-molecule time-resolved studies on the femtosecond timescale.

Funding Acknowledgements Type of funding sources: None. Background The non-invasive assessment of myocardial work allows to evaluate left ventricular (LV) performance by considering the effect of LV load on LV deformation. Aim of this study is to evaluate the acute and chronic impact of percutaneous mitral valve repair (PMVR) on LV function, in patients with severe secondary mitral regurgitation (SMR). Methods and Results 41 patients (age: 69 ± 10 years, females: 29%) with severe SMR (effective regurgitant orifice: 0.42 ± 0.16 cm2, regurgitant volume: 65 ± 325 ml) underwent PMVR according to current recommendations. Myocardial work indices were evaluated before the procedure, 2 days after the procedure and at 1-year follow-up. PMVR was associated with an acute reduction in LV ejection fraction (LVEF), global longitudinal strain (GLS), and myocardial constructive work (MCW) and with a significant increase in myocardial wasted work (MWW). 1-year after the procedure, we did not observe significant LV reverse remodeling. GWE remained significantly impaired despite the small improvement in GCW, which can explain the absence of improvement in MWE and GLS. Interestingly, LVEF modestly increased compared with the post-procedural values, but remained significantly reduced compared to baseline values (Table1). Conclusions In patients severe SMR undergoing PMVR, the acute reduction in LV preload causes a significant impairment of all parameters of LV performance. After 1-year, the absence of LV reverse remodelling is associated a significant impairment in GWW, without substantial improvement in the remaining parameters of LV function. Abstract Figure.

Funding Acknowledgements Type of funding sources: None. OnBehalf TRAP Introduction. Secondary Tricuspid Regurgitation (TR) is a turning point in cardiac diseases. Symptoms occurred too late according to the right heart reverse remodelling capabilities. The ideal timing for proposing a valve repair remains a challenge. We sought to analyse characteristics of patients with significant secondary TR, seeking for changes in parameters over time that could be related to the risk of clinical event. Material and method. We designed a prospective observational French multicentre study of 160 patients with significant secondary TR (effective regurgitant orifice area > 30 mm²) and LVEF > 40%; we collected clinical, echocardiographic, and EKG data at baseline, 1- and 2-year follow-up. All echocardiographies were centrally analyzed. The primary outcome was death or hospitalization for heart failure Results. At 2-year 95 patients (59.3%) presented the primary outcome. They had significant morphological and functional alteration of the right heart parameters. Right Atrial Volume Index (RAVI) and right ventricular free wall Strain were respectively 73mL/m² and -19.8% versus 64.7mL/m² and 22.3% in the event-free group. None of them had significant group*time interaction. In the multivariable analysis, TAPSE/sPAP ratio > 0.4 (OR = 0.41 95%CL 0.2 to 0.82) associated to RAVI > 60mL/m² (OR = 2.13 95%CL 0.96 to 4.75) were the two independent parameters that enable the fairest and parsimonious evaluation. Conclusion. We demonstrated that short analysis using RAVI and TAPSE/sPAP almost reached us to an easier patient assessment by limiting the number of involved parameters. These parameters are now to be for defining the best timing and response to interventions. Abstract Figure. LAVI and TAPSE/sPAP according to events

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Institute for Chirurgical Research - Oslo University Hospital Introduction Left bundle branch block (LBBB) leads to left ventricular (LV) mechanical dyssynchrony. Since the left atrium (LA) and the left ventricle (LV) are anatomically connected, dyssynchronous LV contractions may be transmitted to the LA causing LA dyssynchrony and disturbed LA function. Purpose To investigate if LA dyssynchrony induced by LBBB predicts LV reverse remodelling after cardiac resynchronization therapy (CRT). Methods In a prospective study, myocardial strain was measured by speckle-tracking echocardiography in 171 heart failure patients with LBBB, before and 6 months after CRT. LA dyssynchrony was measured as the time delay between onset systolic stretch of the interatrial septum and the LA lateral wall (white arrows in Figure), and LV dyssynchrony as the time from onset septal shortening to onset lateral wall shortening. Septal flash was assessed visually. Response to CRT was defined as at least 15 % reduction in LV end systolic volume at 6 months follow up. Results The figure shows a representative LBBB patient with LA and LV dyssynchrony which was abolished by CRT. For the whole study population, LA dyssynchrony was 104 ± 77 ms (mean ± SD) before CRT, and decreased to 43 ± 70 ms (p LA dyssynchrony correlated with LV reverse remodelling after CRT (p = 0.009), and multivariable analysis revealed that LA dyssynchrony was an independent predictor of CRT response (β=-0.046, p = 0.04) when combined with septal flash, QRS duration and QRS morphology (Table). Conclusions Patients with LBBB had marked LA dyssynchrony which was attributed to direct LV-LA mechanical interaction. Furthermore, LA dyssynchrony was an independent predictor of LV reverse remodelling after CRT. These findings suggest that assessment of LA dyssynchrony should be part of the echocardiographic evaluation in patients with dyssynchronous heart failure. Abstract Figure.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority. Research grants of the University of Leuven. Background Left ventricular (LV) scar, particularly in the lateral wall and septum, reduces response rate to cardiac resynchronization therapy (CRT), whereas a dyssynchronous LV contraction pattern (septal flash) suggests good response. Lateral wall scar abolishes septal flash. Therefore, a combined approach of septal scar and septal flash may characterize the myocardial substrate responsive to CRT. Cardiac magnetic resonance (CMR) may assess both scar and contraction pattern. Purpose The present study aimed to determine if combined assessment of septal scar and septal flash by CMR as single image modality identifies responders to CRT. Methods We investigated all CRT recipients with available CMR from a prospective, multicenter study (n = 136), with both ischemic and non-ischemic heart failure. Septal scar was assessed by late gadolinium enhancement (LGE) from a stack of short axis slices (n = 128) and septal flash determined visually on ordinary cine sequences (n = 136). CRT response was defined as ≥15% reduction in LV end-systolic volume by echocardiography at 6 months follow-up. We also assessed heart transplantation or death of any cause 39 ± 13 months after device implantation. Results In multivariate analysis including percentage septal scar (LGE), septal flash, QRS-duration and QRS-morphology, septal LGE and septal flash were the only independent predictors of CRT response (both p A practical approach to selection of CRT candidates by septal LGE and septal flash is illustrated in the present figure. As shown, absence of septal LGE indicated excellent response rate (93%) to CRT independent of other parameters. When septal LGE was present, however, overall response rate was substantially lower (58%), but presence or absence of septal flash separated responders from non-responders with high accuracy. This sequential approach correctly classified 86% of patients. Importantly, the approach was equally accurate in patients with intermediate QRS duration (130-150ms), where 93% of patients were correctly classified. Conclusions Combined assessment of septal LGE and septal flash by CMR as single image modality identifies CRT responders with high accuracy and predicts long-term survival. Abstract Figure.

Funding Acknowledgements Type of funding sources: None. Background Functional tricuspid regurgitation (FTR) ≥ moderate is an independent risk factor of morbidity and mortality. FTR could be classified into 2 categories: "atrial functional-TR" (AF-TR) and "ventricular functional-TR" (VF-TR). Percutaneous procedures increase interest in best understanding and selecting patients eligible for intervention. We aim to study echocardiographic criteria associated with the prognosis in patients with severe TR, using a clustering method on a retrospective monocentric cohort that we applied to an external validation prospective multicentric cohort. Methods and results: Ninety-two patients with severe TR (mean age 77.9 ± 13 years, 48.9% female, atrial fibrillation in 68.5%) were enrolled. A hierarchical clustering analysis was conducted. Four parameters explained the clustering categorization (right ventricular (RV) end-diastolic mid-cavity diameter, RV free-wall Strain, right atrial (RA) volume index, RA Strain; p = 0,0039). Three clusters were identified: Cluster 1 with better right ventricular, left ventricular, and right atrial function (related to AF-TR) compared with Cluster 2 (related to VF-TR). Cluster 3 includes patients with severely dilated heart chambers, and RV and RA dysfunction. When applying the 3 clusters in the validation cohort (149 patients), the primary endpoint (hospitalization for Heart failure and/or death from any cause) was significantly better in cluster 1 in 30.8% versus 48% and 58.8% in clusters 2 and 3 respectively (p < 0.05). Conclusion Three phenotypes of FTR were built. Significant TR assessment should include RV and RA characteristics. AF-TR seems to have a better prognosis than VF-TR (under non interventional management). Abstract Figure. survival according to clusters

Funding Acknowledgements Type of funding sources: None. Background There is a need to better predict the risk of atrial arrhythmia (AA) and stroke in patients with hypertrophic cardiomyopathy (HCM). Purpose We sought to look at atrial remodeling and atrial function by echocardiography in a HCM-cohort to assess the association with occurrence of AA and stroke. Methods We retrospectively studied 216 patients diagnosed for HCM (mean age 52 ± 16 years) from 2015 to 2020. All patients underwent transthoracic echocardiography with the assessment of left atrial volume (LAV) and peak left atrial strain (PLAS). Patients were followed-up for 2,9 years for the development of a composite endpoint comprising occurrence of atrial arrhythmias and/or stroke. Results 78 patients had an event (24 stroke and 54 documented atrial arrhythmia). Univariate comparison analysis showed that LAV (37.2 ± 15.7 vs. 47 ± 20 ml/m², p = 0.0001) and anteroposterior LA diameter (41.7 ±7.58 vs. 45.8 ± 8.9 mm; p = 0.0006) were significantly higher in patients who met the composite endpoint, whereas PLAS was significantly impaired (27.1 ± 9.77 vs. 20.4 ± 10.5%; p < 0.0001). Other echographic parameters associated with the composite endpoint were mean E/e" ratio (0.65 [0.55-0.85] vs. 0.60 [0.45-0.75]; p = 0.0204) and tricuspid annular peak systolic velocity (S") (cm/s) (13.3 ± 2.92 vs. 12.2 ± 3.26; p = 0.0148). NTproBNP level (216 vs. 818 ; p < 0.0001), history of hypertension (42.3% vs. 62.3%; p = 0.005) and age at diagnosis (50.3 ± 16.7 vs. 57.1 ± 14.4; p = 0.0035) were the clinical parameters different between groups. In a multivariable analysis, PLAS was the only independent maker associated with the occurrence of AA and stroke, particularly for stroke with an odd ratio of 0.53 ([0.32-0.86]; p = 0.00097). Interestingly, 19 of 28 stroke patients (67%) did not experience any documented AA. Conclusion The decrease of PLAS is strongly associated with the risk of stroke, even in patients without documented atrial arrhythmia. Its use to guide the indication for an implantable holter monitoring and perhaps a prophylactic oral anticoagulation in HCM requires further investigation. Abstract Figure. Impaired PLAS in an HCM patient

Quantum simulations of the hydroxide anion and hydroxyl radical are reported, employing variational quantum algorithms for near-term quantum devices. The energy of each species is calculated along the dissociation curve, to obtain information about the stability of the molecular species being investigated. It is shown that simulations restricted to valence spaces incorrectly predict the hydroxyl radical to be more stable than the hydroxide anion. Inclusion of dynamical electron correlation from non-valence orbitals is demonstrated, through the integration of the variational quantum eigensolver and quantum subspace expansion methods in the workflow of N-electron valence perturbation theory, and shown to correctly predict the hydroxide anion to be more stable than the hydroxyl radical, provided that basis sets with diffuse orbitals are also employed. Finally, we calculate the electron affinity of the hydroxyl radical using an aug-cc-pVQZ basis on IBM's quantum devices., Comment: 12 pages, 6 figures

Objective: To assess the accuracy of noninvasive parameters, fecal calprotectin (FC), increased bowel wall thickening (BWT) at intestinal ultrasound (IUS) and blood inflammatory indexes (BII), alone or in combination, as diagnostic tools for inflammatory bowel disease (IBD) in pediatric patients. Methods: Retrospective data were collected on consecutive children (age 2–18 years) referred to our pediatric gastroenterology clinic, for recurrent abdominal pain and/or altered bowel habit from 2007 to 2013. Subjects who had diagnostic workup: laboratory tests (FC, BII, white blood cell (WBC), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and IUS as initial assessment were eligible. Subjects with known gastrointestinal (GI) diseases, or signs or symptoms highly suggestive for organic diseases necessitating prompt endoscopy (e.g., perianal disease or rectal bleeding), or who had recently performed endoscopy were excluded. The accuracy of noninvasive tests for detecting IBD was assessed using endoscopic and/or radiological investigations, performed in subsequent clinical follow up, as reference gold standard. Results: Seventy-seven patients (mean age 11.3, 44 males) were included, 23 (29.9%) with a final diagnosis of IBD. As single tests, FC gave the highest sensitivity (96%) but lower specificity (72%) and IUS highest specificity (96%) with lower sensitivity (70%). The combination of FC + IUS showed excellent accuracy for detecting children with IBD with positive predictive value: 100%; negative predictive value: 88.5%. The probability of IBD in children with normal FC, BII and IUS was 0.09%. Conclusions: FC and increased BWT at IUS are accurate to guide reassurance or proceeding with further invasive procedures for detecting IBD in children with mild GI symptoms.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Hospital university of Rennes INSERM - LTSI Background Non-invasive estimation of myocardial work by trans-thoracic echocardiography is a novel tool to analyze myocardial contraction efficiency during systole. Two methods are described, on using Left ventricular (LV) strain and a LV pressure estimation, and another with only LV strain integrals. The present study analyzes their utility in prediction of CRT-response. Methods and results: 243 patients implanted by a CRT according to current recommendations were retrospectively included in hospital university of Rennes. All patients had a complete trans-thoracic echocardiography at implantation and at 6-moths follow-up. Responders were defined as having a 15% decrease in indexed LV end-systolic volume at follow-up compared to baseline. Baseline characteristics are described in table 1. 25.1% were non-responders. In this group, there were more men, more ischemic cardiomyopathies with more dilated LV. Strain signals ware analyzed only in the most informative loop, the apical 4 cavities. Myocardial work estimation with LV pressure estimation was previously described. The 3 different integral of strain signal were represented in figure 1. According to ROC curves, myocardial work (particularly wasted work in septal wall with AUC = 0.718 ± 0.04) estimated with LV pressure estimation is better than strain integrals to predict LV positive remodeling (best AUC 0.631 ± 0.040) after CRT-implantation. Conclusion Left ventricular pressure estimation give useful information on top of strain curves for prediction for CRT-response. Table 1 Responders n = 182 Non-responders n = 61 Men (%) 109 (59.9%) 52 (85%) Ischemic cardiomyopathy (%) 42 (23.1%) 34 (55.7%) LVEF (%) 28 ± 6 28 ± 7 GLS (%) -9 ± 3 -7 ± 3 LVEDD (mm) 62 ± 8 67 ± 7 LVEDVi (ml/m2) 85 ± 34 88 ± 30 LVEF Left ventricular ejection fraction; GLS: global longitudinal strain; LVEDD: left ventricular end-diastolic diameter; LVEDVi: left ventricular end diastolic volume index Abstract Figure 1

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority Norwegian Health Association Background Scar in the left ventricular (LV) posterolateral wall is associated with poor response to cardiac resynchronization therapy (CRT). The impact of septal scar, however, has been less thoroughly investigated. As recovery of septal function seems to be an important effect of CRT, we hypothesized that CRT response depends on septal viability. Aim The aim of the present study was to investigate the association between septal scar and volumetric response to CRT, and to compare the impact of scar located in septum to scar located in the posterolateral wall. Methods 128 patients with symptomatic heart failure undergoing CRT implantation based on current guidelines (ejection fraction 30 ± 8%, QRS-width 164 ± 17 ms) were included in the study. Volumes and ejection fraction were measured by echocardiography using the biplane Simpson’s method at baseline and six months follow up. Non-response was defined as less than 15% reduction in end-systolic volume. Scar was assessed by late gadolinium enhancement cardiac magnetic resonance, and reported as percentage scar per regional myocardial volume. Numbers are given in [median ;10-90% percentile]. Results Scar was present in 62 patients (48%). Scar burden was equal in septum [0% ;0-34%] and the posterolateral wall [0% ;0-36%], p = 0.10. 31 patients (24%) did not respond to CRT. The non-responders had higher scar burden than the responders in both septum [16% ;0-57% vs 0% ;0-23%, p In univariate regression analysis both septal and posterolateral scars correlated with non-response to CRT (r = 0.51 and r = 0.33, respectively). However, combined in a multivariate model only septal scar remained a significant marker of non-response (p Septal scar ≥ 7.1% predicted non-response with a specificity of 81% and a sensitivity of 70% by receiver operating characteristic curve analyses. The area under the curve was 0.79 (95% confidence interval 0.70 – 0.89) (Figure). Conclusions Septal scar is more closely associated with volumetric non-response to CRT than posterolateral scar. Future studies should explore the correlation between regional scar burden and different functional parameters, and how they relate to CRT response. Abstract Figure. Septal scar predicts non-response to CRT

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): ANR - Maestro project Background Stratification of aortic stenosis patients remains challenging and robust indices are required. Myocardial work assessment is a new afterload independent alternative to evaluate left ventricular function. Although, this method was developed in patients with normal aortic valve. We previously developed an integrated cardiovascular system simulated by a computational model to estimate non-invasively myocardial work in aortic stenosis patients* (figure 1A). In the present study, we tested our model in a prospective population of AS patients. Method and results 9 patients with severe AS (aortic valve area < 1cm2) were included. A complete trans-thoracic echocardiography with a non-invasive blood pressure by brachial artery cuff were realized immediately before a left heart catheterization to have an invasive left ventricular pressure. Myocardial work is then calculated with non-invasive and invasive LV pressure combined to LV strain curves. For constructive and wasted work, root mean squared between invasive and estimated measures were respectively r2 = 0.92 and r2 = 0.94 (figure 1B) Conclusion The proposed model is efficient to estimate non-invasively myocardial work indices in AS-patients. These afterload independent indices could permit in future to better stratify this population. *Owashi KP, Hubert A and al. Model-based estimation of left ventricular pressure and myocardial work in aortic stenosis. PlosOne 2020. Mar 3;15(3):e0229609 Abstract Figure 1

Funding Acknowledgements Type of funding sources: None. Objective The best modality to assess diastolic function in CRT-candidates is an object of debate and the relationship between diastolic function, CRT-response and survival are not clearly understood. Purpose of the study: to assess diastolic patterns in patients undergoing CRT according to the 2016 recommendations of the American Society of Echocardiography/European Association of Cardiovascular Imaging and to evaluate the prognostic value of diastolic dysfunction (DD) in CRT candidates. Methods 193 patients (age: 67 ± 11 years, QRS width: 167 ± 21 ms) were included in this multicentre prospective study. Patients were stratified according to DD grades (grade I to III). CRT-response was defined as a reduction of left ventricular (LV) end-systolic volume >15% at 6-month follow-up (FU). The primary endpoint was defined as a composite of heart transplantation, LV assisted device implantation or all-cause death during FU. Results During FU, 132 (68%) patients were CRT-responders. CRT delivery was associated with diastolic function degradation in non-responders. Grade I DD was able to predict CRT-response with a sensitivity, specificity and accuracy of 70%, 65%, and 63%, respectively. After a median period of 35 months, the primary endpoint occurred in 29 (15%) patients. Grade I DD was associated with a better outcome [HR 0.26 95% CI: (0.10-0.66)], independently from ischemic cardiomyopathy, LV dyssynchrony and CRT-response (Table 1). Non-responders with grade II or grade III DD had the worse prognosis (HR 4.36, 95%CI: 2.10-9.06) Figure 1. Conclusions Grade I DD is associated with LV remodelling after CRT and is an independent predictor of prognosis in CRT candidates. Abstract Figure.

Aims. We hypothesized that a multiparametric evaluation, based on the combination of electrocardiographic and echocardiographic parameters, could enhance the appraisal of the likelihood of reverse remodeling and prognosis of favorable clinical evolution after cardiac resynchronization therapy (CRT). Also, we sought to test the respective value of automatically extracted parameters from left ventricular (LV) strain curves recorded in apical 4-chamber view as compared to the other echocardiographic views. Methods and results; This is a machine learning study based on a dataset of 161 patients who were treated by CRT according to current ESC-guidelines. The longitudinal strain curves of the 6 LV-segments of the left ventricle were plot for the three different apical views. Several features as times or integrals were extracted as previously published. These features were classified by importance using the out-of-bag method(fig1). Half of the most important features come from the 4-chamber view and a third from the 2-chamber view. The correlation between the most important features was studied to determine the relationship between them. Almost all the features from the 2-chamber and apical long-axis views are correlated with others and generally with one acquired from the 4-chamber view. Conclusion The high number of important features indicate the relevance of the 4-chamber as unique view for applying machine learning approaches on strain curves. Optimizing selection of patients for CRT should be possible just on the dataset coming from one apical 4-chamber view. Abstract 539 Figure. fig1

Background the assessment of myocardial work (MW) by pressure-strain loops is a recently introduced tool for the assessment of myocardial performance. Aim of the present study is to evaluate the relationship between myocardial work and exercise tolerance in patients with dilated cardiomyopathy (DCM) Methods 51 patients with DCM (mean age 57 ± 13 years, left entricular ejection fraction : 32 ± 9%) underwent cardiopulmonary exercise test (CPET) to assess exercise performance. Trans-thoracic echocardiography (TTE) was performed CPET. The following indices of myocardial work (MW) were measured regionally and globally: constructive work (CW), wasted work (WW), and work efficiency (WE). Left ventricular (LV) dyssynchrony (DYS) was defined by the presence of septal flash or apical rocking at TTE. Results LV-DYS was observed in 16 (31%) patients and associated with lower LV ejection fraction (LVEF), GLS, global and septal WE, and higher global and septal WW (Table 1). In patients with LV-DYS, septal WE was the only predictor of exercise peak VO2max at multivariable analysis (Figure 1), whereas LVEF (β=0.47, p = 0.05) and age (β=-0.42, 47, p= 0.04) were predictors of exercise capacity in patients without LV-DYS. Conclusions In patients with DCM, LV-DYS is associated with an heterogeneous distribution of myocardial work. Septal WE is the best predictor of exercise performance in these patients. Table 1 All n = 51 No-dyssynchrony n = 35 (69%) LV-Dyssynchrony n = 16 (31%) p-value LVEF, % 32 ± 9 34 ± 10 28 ± 7 0.04 GLS, % -12 ± 3 -13 ± 3 -10 ± 3 0.001 GCW, mmHg% 1325 ± 398 1342 ± 354 1287 ± 491 0.65 GWW, mmHg% 201 ± 147 154 ± 95 304 ±191 Abstract P1779 Figure.

Funding Acknowledgements The study was supported by Center for Cardiological Innovation. Introduction Septal dysfunction is the dominant mechanism of left ventricular (LV) failure in left bundle branch block (LBBB). We hypothesize that, provided septum is viable, septal function can recover and hence LV function improve after cardiac resynchronization therapy (CRT). Purpose To determine if combined assessment of septal function and viability identifies responders to CRT. Methods In a prospective multicenter study of 200 unselected patients referred for CRT, we measured myocardial strain by speckle-tracking echocardiography and regional work by pressure-strain analysis before and 7 ± 1 months after CRT. Viability was assessed by late gadolinium enhancement cardiac magnetic resonance imaging (n = 123). CRT response was defined as ≥15% reduction in LV end-systolic volume. Results Before CRT, septal work was 258 ± 463 and LV lateral wall work 1469 ± 674 mmHg·% (p 150 ms. Conclusions The proposed combined approach with assessment of septal work and viability identified CRT responders with high precision. Abstract 561 Figure.

Aims : Secondary mitral regurgitation (MR) is associated with poor outcome in systolic heart failure (HF-)patients. Percutaneous edge-to-edge mitral valve repair (PMVR) recently failed to prove any beneficial effect over optimal medical treatment (OMT). Nevertheless, little is known about the effect of PMVR on LV performance and mechanics in HF-patients with severe secondary MR. Method and results Thirty-seven patients with severe secondary MR treated by PMVR were included and compared (according to indices of LV myocardial function) to nineteen patients with treated by OMT. Both groups were clinically comparable. At 6-month follow-up, only LV constructive work improve significantly in both groups (977 vs 1101 mmHg.%, p =0,003, 967 vs 1110 mmHg.%, p = 0,002 for PMVR and OMT groups, respectively) whereas left ventricular (LV) end-systolic volume index, LV ejection fraction and global longitudinal strain were not different. Compared to MITRA-FR and COAPT studies, our population had a proportionate MR (blue point in Figure 1, panel A). Figure 1-panel B demonstrate that only five patients of PMVR group had disproportionate MR (red points). Interestingly, these patients hadn’t any major event during 6 months FU. Conclusion Echocardiographic characteristics at 6-month follow-up are not different when compare PMVR and OMT for HF- patients with a severe proportionate secondary MR. Main echocardiographic characteristics PMVR OMT Inclusion 6-month p Inclusion 6-month p NYHA 2.6 ± 0.6* 1.8 ± 0.7* Abstract 424 Figure.

Background In patients with dilated cardiomyopathy and left bundle branch block (LBBB), different regions of the left ventricle (LV) have been shown to perform different amounts of work. In this study, we investigate the acute impact of cardiac resynchronization therapy (CRT) on regional LV work distribution and its relation to long-term reverse-remodelling. Methods We recruited 140 heart failure patients, referred for CRT. Regional myocardial work was calculated from non-invasive echocardiographic segmental stress-strain-loop-area before and immediately after CRT. The magnitude of volumetric reverse-remodelling was determined from the change in LV end-systolic volume (ESV), 11 ± 3 months after implantation. Characteristics of patients with the lowest and highest quartile of LV ESV reverse remodelling (LV ESV reduction of less than 10% and LV ESV reduction of more than -48%) were compared. Results Before CRT, myocardial work showed significant differences among the walls of the LV (Figure A). CRT caused an acute re-distribution of myocardial work, on average with most increase in the septum and most decrease laterally (all walls p Conclusions The acute re-distribution of regional myocardial work between the septal and lateral wall of the left ventricle is an important determinant of long term reverse-remodelling after CRT-implantation. Our data suggest that modification of regional loading is the mode of action of CRT treatment. Abstract 553 Figure.

Alkylethoxysulfate (AES) surfactants are the main component of most commercial products used for soil conditioning in the excavation industry, in particular as lubricants for mechanized tunnelling. Huge amounts of soil debris are produced during the excavation process and their possible re-use as by-products (e.g. land covering) or discharge as waste is a critical question in civil engineering. There can be an environmental impact from the potential ecotoxicity of the residual chemical mixture occurring in the foam-conditioned excavated soil. Chemical analyses are not able on their own to assess the potential hazards for the ecosystem ascribable to inadequate management of this kind of conditioned soil. Ecotoxicological tests, on the other hand, provide useful overall information about the potential effects of conditioned debris on soil and aquatic biota, including synergic ones, whether or not there is a detailed knowledge of the chemical composition of all the components of the commercial foaming products. In this context, the objective of this work was to evaluate the overall ecotoxicity of excavated soil conditioned with two common foaming products containing sodium lauryl ether sulphate (SLES) as the main component, in order to verify their possible re-use as by-products. For this purpose, two soils with different geopedological characteristics were conditioned with the commercial foaming agents at the concentrations utilised for mechanized tunnelling and then used for microcosm laboratory experiments. Soil sub-samples were collected at different times (0, 7, 14, 28 days) of incubation and soil elutriates were produced to assess the effects of the foaming agents on five test species (Pseudokirchneriella subcapitata, Daphnia magna, Danio rerio, Vibrio fischeri and Lepidium sativum). The results of the tests were then compared with SLES residual concentrations in the elutriates, determined with the MBAS (methylene blue active substances) spectrophotometric method. Finally, the data were combined in a battery index, which proved effective at evaluating the overall ecotoxicity in a real-life situation of two different excavated soils conditioned with the two products analysed.

Background The relationship between diastolic dysfunction (DD) and outcome after CRT is debated. The purpose of this study was to evaluate the role of DD in predicting all-cause mortality in heart failure patients undergoing CRT. Methods One-hundred ninety-three patients (age: 67 ± 11 years, QRS width: 167 ± 21 ms, LVEF 28 ± 8%) were included in this multicentre prospective study. Mitral filling pattern, mitral tissue Doppler velocity, tricuspid regurgitation velocity, and indexed left atrial volume were used to classify DD from grade I to III according to the 2016 recommendations of the American Society of Echocardiography/European Association of Cardiovascular Imaging. A reduction of LV end-systolic volume > 15% at 6-month follow-up (FU) identified CRT-responders and was observed in 132 (68%) patients. Results During a median 35 months FU, 29 (15%) patients died. Through multivariable analysis, coronary artery disease [HR 2.21 (1.00–4.89) P = 0.05], NYHA [HR 2.92 (1.45–5.87), P = 0.003] and grade I DD [HR 0.34 (0.13–0.89)] were shown to be independent predictors of prognosis ( Table 1 ). Grade I DD was associated with a longer survival rate in both responders and non-responders ( Fig. 1 ). Non-responders with grade II-III DD had the worse outcome [HR 12.5 (3.56–44.04), P Conclusion Better diastolic function at baseline is associated with improved survival after CRT implantation, independently of CRT-response.

In the last decades the increasing rate of obesity in children and adolescents worldwide has led to the onset in paediatric age of metabolic syndrome, a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA's Adverse Event Reporting System database.

Aims. The Assessment of left ventricular (LV) function remains a clinical challenge especially in patients with preserved LV ejection fraction (EF) and valvular heart diseases (VHD). Mechanical dispersion is supposed to be a strong predictor of events and, to be related to the extent of fibrosis. Regional cardiac work is a new validated and very promising approach to quantify LV-function. We investigated the differences in mechanical dispersions and global LV work (totW) and wasted work fraction (WWF) in normal subjects and in patients with severe primary mitral regurgitation (MR) and severe aortic stenosis (AS). Methods and Results A complete transthoracic echocardiography was performed in 21 normal subject, 97 patients with severe valvulopathy (47 AS, 50 MR) and preserved LV EF. Segmental strain analysis was performed in all patients and the dispersion of regional LV strain curves was computed automatically considering peaks and integrals. The LV-pressure was estimated non-invasively using a standard waveform fitted to valvular events and scaled to systolic blood pressure. Using pressure-strain loops, regional cardiac work indices were computed. LVEF was 66±12 in controls, 65±9 in MR and 65±4% in AS (p=0.125). Global longitudinal strain was -23±2.7 in controls, -24±2.9 in MR and -18±3.2% in AS (p < 0.001). The mechanical dispersion was 38±7.9 in controls, 36±11 in MR, and much higher in the hypertrophied LV of the AS: 60±19ms (p < 0.001). Cardiac work was 2200±260 in controls, 2100±270 in MR, and much lower in AS: 1700±280 mmHg.% (p < 0.001). The wasted work fraction (WWF) was even more describing how different the LV systolic function is in the 3 groups (figure1). Conclusion Longitudinal strain data are robusted and new indices might be calculated based on them. These seem especially promising for a more pathophysiological driven analyzing of LV-functions. Abstract P697 Figure. Abstract P697 Figure.

Background. In recent years, pathophysiology of aortic stenosis (AS) has been considered as a possibly active inflammatory process, but its determinants remain unclear. Calcium tissue deposition observed in dilaysis patients have been linked to low level of Fetuin-A, a powerful inhibitor of ectopic calcification. It is thus suspected to play a role in development of aortic stenosis. Purpose. To assess correlation between Fetuin-A level and AS progression in a prospective cohort of AS patients, COFRASA (clinicalTrial.gov_number_NCT00338676) and GENERAC (clinicalTrial.gov_number_NCT00647088). Methods. A comprehensive clinical evaluation and Fetuin-A plasma level measurement was performed at baseline. AS severity was evaluated at baseline and yearly thereafter using echocardiography (mean pressure gradient (MPG)) and computed tomography (degree of aortic valve calcification or AVC). Annual progression was calculated as [(final measurement - baseline measurement)/follow-up duration] for both MPG and AVC measurements. Results. We enrolled 296 patients with at least 1 year of follow-up. Mean age was 74±10 years, 217 (73%) were men. Mean Fetuin-A level was 0.55±0.15 g/L. After a mean follow-up of 3.0±1.7 years, no correlation was found between AS progression and Fetuin-A level, using either MPG (r=0.015, p=0.82) or AVC (r=0.014, p=0.82). This was also true when comparing patients with lower level of Fetuin-A (≤0.53 g/L, the median in our cohort) with patients with higher level(+3±5 mmHg/year (median 2, [0-5] vs +4±4 mmHg/year (median 2, [1-6]) p=0.06, and +205±290 AUC/year (median 122, [32-269]) vs +240±310 AUC/year (median 145, [50-313], p=0.24). This was true also after adjustment for baseline severity and valve antomy. Conclusions. In our prospective cohortot of AS patients we found no impact of Fetuin-A on both hemodynamic and anatomic AS progression. Despite strong capacity to inhibit ectopic calcium deposition, Fetuin-A plasma level seems to have minor influence on AS progression.

Background Mitral valve resistance (MVR) is a hemodynamic consequence of mitral stenosis but it has no clear threshold and it has a shortage of data to be reliable. Purpose is to investigate match and mismatch between opening area and resistance especially in patients with moderate and mild mitral stenosis. Materials This cross section case control study comprised 88 patients with moderate and mild rheumatic mitral stenosis. Transthorathic echocardiographic study estimated: mitral valve area (MVA) both by planimerty (2D) and pressure half time (PHT), mitral valve score (MVS), mean transmitral pressure gradient (MPG), diastolic filling time(DFT), left ventricular out flow tract diameter (LVOTd) and velocity time integral (LVOT vti) , the MVR was calculated as: MPG/aortic flow ratio [(LVOTd) (LVOTvti)/ DFT] in dynes.sec.cm5, NYHA function class of all patients was estimated. We classified our patients into 2 groups, group 1 (51 patients) with matched MVR and group 2 (37 patients) with unmatched MVR (unexpected high MVR in relation to valve area). Methods Patients with moderate mitral stenosis have MVR less than 105 dynes.sec/cm5, while patient with mild mitral stenosis have MVR less than 76 dynes.sec/cm5 this is in the matched group, but there are patients with unmatched higher MVR. Group 2 compared to group 1; had higher NYHA function class (1.4±0.6 vs. 1.2±0.4, P < 0.05), MVS (8.1±1.8 vs 7±0.9, P < 0.05), MPG (11,3±3.7 vs.7.8±2.5 mmHg, P < 0.01) and higher MVR (122.37±29.87 vs. 67.18±20.12 dynes.sec/cm5 , P < 0.01), MVR showed positive correlation with MVS (r=0.5, P < 0.05), Step wise logistic regression analysis showed that MVS is the only independent predictor of the MVR severity in the mismatched (unexpected high) group , so the higher the MVS the higher the expected MVR whatever the MVA is ; (B±SE=6.997±2.826, t=2.476, 95% CI 1.241±12.752 with an odds ratio=0.412, P < 0.05). Conclusion It would make much more sense to investigate match and mismatch between opening area and resistance in rheumatic mitral stenosis, the only independent predictor of mismatch is the mitral valve score.

The effect of untreated olive mill wastewater (OMW) spreading on chemical and biological soil properties of two different fields located in Campania (Italy) was investigated. Fields were irrigated since 2003 with quantities of about 30 m(3) ha(-1) year(-1), a volume lower than the maximum limit of 80 m(3) ha(-1) year(-1) established by Italian law. Results showed that the addition of OMW, even if repeated for many years, had little impact on pH, electrical conductivity, organic matter, concentrations of main cations and polyphenolic content of both soil plots; moreover, microbial respiration was low during the winter time, but an increase was evident in the second sampling carried out in warm season. This study suggests that OMW, without pre-treatments, can be annually used for crops and tree irrigation. As a consequence, OMW should be a readily and inexpensive source of nutrients that could replace chemical fertilizers which are extensively employed in agricultural practices of Mediterranean countries.

Purpose: Deformation analysis from 3D echocardiography results in a considerable amount of parameters, for which the conventional statistical approach is cumbersome. We investigate local motion and deformation patterns to determine the parameters of relevance for the study of LV myocardial deformation in the presence of LAD infarct. Methods: The study included 46 patients acquired at max. 5 days after LAD infarct (37 sequences) and at 1-year follow-up (33 sequences), and 46 controls. Patients were selected if they had a LVEF

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Neisseria meningitidis serogroup B is the main cause for meningococcal invasive disease in many parts of the world. Since 2013, a new multicomponent vaccine against meningococcal serogroup B (4CMenB) has been licensed in Europe, Australia, Canada, Chile, Uruguay, USA and Brazil with different immunization schedules. Clinical trials involving adults, adolescents, children and infants showed 4CMenB has a good immunogenicity and safety profile. Strain coverage estimates are similar to or better than other recently approved vaccines, ranging from 66% in Canada to 91% in Unites States. Some points still remain to be clarified such as the best immunization strategy, the effect of 4CMenB on carriage, the long-term persistence of protective bactericidal antibodies titers, long-term safety outcomes, the possible emergence of N. meningitidis escape mutants and the vaccine cost–effectiveness. In this review, we focus on the vaccine composition, clinical trials and suggested schedules, safety data, potential strain coverage and future challenges.