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Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9-12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich.Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing.Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1-4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib.We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.

Funding Acknowledgements Type of funding sources: None. Background Late gadolinium enhancement (LGE) has been proposed as an independent predictor of ventricular arrhythmias. Purpose The purpose of this study was to assess if myocardial scar characterization could enhance the risk stratification for life-threatening arrhythmias and sudden cardiac death (SCD). Methods We included patients with an indication for ICD or CRT-D implantation who underwent cardiac magnetic resonance for clinical proposes since February/2018 and in whom a 3D-LGE dataset was obtained. Patients with channelopathies (n=2) or inappropriate imaging quality (imaging artifacts; n=7) were excluded. Scar characterization using ADAS software was performed in 3D-LGE datasets in all but 5 patients, where 2D datasets were used. The primary endpoint was the composite of appropriate ICD therapy (classified as ATP or shock) or SCD. Results A total of 75 patients were analysed (mean age 63 ± 13 years; 83% male; mean LVEF 31 ± 13%; 50 patients with ischemic and 25 with non-ischemic cardiomyopathy; 14 patients received a device in the setting of secondary prevention). During a median follow-up of 1.4 years (IQR 0.7 – 2.4 years) there were 15 events (12 appropriate ICD therapies [8 shocks and 4 ATP] and 3 SCD). No statistically significant differences were found between patients with or without events in terms of scar mass, border zone (BZ) mass, BZ channels (BZC), BZC mass, number of channels detected, and scar heterogeneity (BZ mass / scar mass ratio) - all p values > 0.2 – Figure. Restricting the analysis to only primary prevention cases yielded similar results. Overall, 11 patients did not show any channel. Two of these experienced an arrhythmic event, yielding a negative predictive value of 80% (95% CI 75-83%) for the absence of channels. Conclusion In this cohort with still relatively limited follow-up duration, no single parameter reflecting scar tissue characterization was able to predict appropriate device therapies or sudden cardiac death.

Funding Acknowledgements Type of funding sources: None. Background Although cardiac magnetic resonance (CMR) is the gold standard for planning ventricular tachycardia (VT) ablation, its accuracy is hindered in patients with implanted cardiac defibrillators (ICD) and resynchronization therapy (CRT). Cardiac computed tomography (CT) has emerged as an alternative for ablation planning in these patients. This pilot study aimed to evaluate the relationship between wall thickness (WT) on CT and voltage of electrical potentials on endocardial electroanatomic mapping (EAM) in patients with ischemic cardiomyopathy. Methods Single centre retrospective study enrolling consecutive patients with ischemic cardiomyopathy referred for endocardial VT ablation that underwent cardiac CT for procedure planning since 2021. Patients were excluded if EAM had < 1000 data points. ADAS 3D® software was used to analyse CT images, automatically segmenting the left ventricle (LV) into the 17 American Heart Association segments and calculating end-diastolic WT for each one. Four standardized views (anterior-posterior, posterior-anterior, superior, and inferior) of the segmented LV on ADAS 3D® were used to aid in manual segmentation of the EAM. The endocardial voltage maps were created using CARTO3® software (Figure 1). For each patient, EAM was interpreted to create 2 different bulls’ eye maps, according to the presence or absence of bipolar potentials < 0.5 (dense scar) or < 1.5mV (low voltage). Only segments with >20% extension of low bipolar voltage were considered as altered. Results We included a cohort of 8 patients (mean age 67±12 years, 87.5% male, median LVEF of 32% [IQR 25-49]). All but one patient had implanted cardiac device (6 ICD, 1 CRT-D). Cardiac CT was performed 1 day (IQR 0-2) before the ablation. Overall, 136 segments were analysed, 8 of which did not have voltage information. Of the remaining 128, 51 (39.8%) had dense scar and 57 (41.9%) had low voltage. There was a good correlation between mean WT and the presence or absence of both dense scar (area under de curve (AUC) 0.799, p Conclusion WT measured by CT appears to have a strong correlation with dense scar and low voltage in EAM in patients with ischemic cardiomyopathy undergoing VT ablation. This technique may be useful to plan interventions in patients in whom CMR is not feasible.

It is unknown whether impaired brain structure after congenital blindness is reversible if sight is restored later in life. Using structural magnetic resonance imaging, visual cortical surface area and cortical thickness were assessed in a large group of 21 sight-recovery individuals who had been born blind and who months or years later gained sight through cataract removal surgery. As control groups, we included 27 normally sighted individuals, 10 individuals with permanent congenital blindness, and 11 sight-recovery individuals with a late onset of cataracts. Congenital cataract-reversal individuals had a lower visual cortical surface area and a higher visual cortical thickness than normally sighted controls. These results corresponded to those of congenitally permanently blind individuals suggesting that impaired brain structure did not recover. Crucially, structural brain alterations in congenital-cataract reversal individuals were associated with a lower post-surgery visual acuity. No significant changes in visual cortex structure were observed in sight-recovery individuals with late onset cataracts. The results demonstrate that impaired structural brain development due to visual deprivation from birth is not fully reversible and limits functional recovery. Additionally, they highlight the crucial importance of prevention measures in the context of other types of aberrant childhood environments including low socioeconomic status and adversity.

Supplementary Figure 2 from A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Supplementary Figure 1 from A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Supplementary Figure 3 from A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Supplementary Table 1 from A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Supplementary Figure 4 from A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Legends of Supplementary Tables, and Supplementary References

Documentation of model components, interactions and regulatory rules.

Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes. Simulations showed that hybrid phenotypes may arise through independent molecular paths involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: (i) stiffening of the extracellular matrix was a prerequisite for cells overactivating FAK_SRC to upregulate SNAIL and acquire a mesenchymal phenotype and (ii) FAK_SRC inhibition of cell–cell contacts through the receptor-type tyrosine-protein phosphatases kappa led to acquisition of a full mesenchymal, rather than a hybrid, phenotype. Altogether, these computational and experimental approaches allow assessment of critical microenvironmental signals controlling hybrid EMT phenotypes and indicate that EMT involves multiple molecular programs.Significance:A multidisciplinary study sheds light on microenvironmental signals controlling cancer cell plasticity along EMT and suggests that hybrid and mesenchymal phenotypes arise through independent molecular paths.

Supplementary Methods

Supplementary Figures S1-S8

Clinical overt cardiac cachexia is a late ominous sign in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The main goal of this study was to assess the feasibility and prognostic significance of muscle mass quantification by cardiac magnetic resonance (CMR) in HF with reduced LVEF. HF patients with LVEF

To assess whether a simplified cardiac magnetic resonance (CMR)–derived lung water density (LWD) quantification predicted major events in Heart Failure (HF). Single-centre retrospective study of consecutive HF patients with left ventricular ejection fraction (LVEF) p = 0.017) and had higher NT-proBNP levels [1973 (IQR: 809–3766) vs. 802 (IQR: 355–2157 pg/mL); p p = 0.005), LVEF (HR per 1%: 0.97; 95%-CI: 0.94–0.99; p = 0.031), serum creatinine (HR per 1 mg/dL: 2.51; 95%-CI: 1.36–4.61; p = 0.003) and LWD (HR per 1%: 1.07; 95%-CI: 1.02–1.12; p = 0.007) were independent predictors of the primary endpoint. These findings were mainly driven by an association between LWD and HF hospitalization (p = 0.026). A CMR-derived LWD quantification was independently associated with an increased HF hospitalization risk in HF patients with LVEF

Introduction: Direct oral anticoagulants (DOACs) changed the landscape of atrial fibrillation (AF) treatment, but also brought with them new challenges in terms of accessibility and compliance. The purpose of this study was to assess adherence to DOACs, and its determinants in a population of AF patients. Methods: Single-center retrospective study including all patients with non-valvular AF treated with a DOAC from the outpatient general cardiology list at a tertiary center, whose first DOAC prescription was between 1 April 2016 and August 2018. The number of pharmacy refills from the day of first prescription to 31 August 2018 was counted (by means of an electronic prescription platform). Medication refill adherence (MRA) was calculated by dividing the total days' supply by the number of days under therapy. Non-compliance was defined as MRA

Resumo Introducao e objetivos Os anticoagulantes diretos (direct anticoagulants, DOACs) mudaram o panorama do tratamento da fibrilhacao auricular (FA), trazendo novos desafios de acessibilidade e adesao terapeutica. O objetivo deste estudo foi avaliar a adesao terapeutica com DOACs, e os seus fatores determinantes, numa populacao de doentes com FA. Metodos Estudo retrospetivo de centro unico incluindo doentes com FA nao valvular sob terapeutica com DOAC seguidos em consulta de Cardiologia, cuja primeira prescricao de DOAC foi realizada entre 1 de abril de 2016 e agosto de 2018. Foram contabilizadas as embalagens de DOAC levantadas desde a primeira prescricao ate 31 de agosto de 2018, utilizando a Prescricao Eletronica Medica. Foi calculada a adesao a terapeutica atraves da divisao entre o numero de dias cobertos pela dispensa efetiva na farmacia e os dias sob terapeutica. Definiu‐se “nao adesao” como uma adesao inferior a 90%. Resultados Foram incluidos 264 doentes (120 homens, idade media 74 ± 12 anos). O score CHA2DS2VASC mediano foi 3 (IIQ 2‐5) e o score HAS‐BLED mediano foi 1 (IIQ 1‐2). Os DOAC rivaroxabano, apixabano, dabigatrano e edoxabano foram prescritos em 45%, 41%, 24% e 13% dos doentes, respetivamente. Ao longo do periodo avaliado, 51 doentes (19%) tomaram pelo menos dois DOACs diferentes. Os doentes estiveram sob DOAC durante uma mediana de 439 dias (IIQ 269‐638), durante os quais aderiram a terapeutica em mediana 90% (IIQ 75‐100%) do tempo. Cerca de metade (51%) dos doentes foi considerada nao aderente; a maior duracao da terapeutica (OR ajustado de 1,06/mes, IC95% 1,03‐1,08, p Conclusao Metade dos doentes (51%) com FA sob DOAC foram classificados como nao aderentes (adesao

Background Functional mitral regurgitation (fMR) severity grading by 2D transthoracic echocardiography (TTE) can be a complex task, especially in patients where PISA assumptions are not met (eg. non-circular orifice or multiple jets). Cardiac magnetic resonance (CMR) can provide further insight on the hemodynamic burden of fMR by accurately determining mitral regurgitant fraction (RegFrac). Our goal was to investigate the concordance and disagreement between the two modalities in assessing fMR. Methodology Single-center prospective study of fMR patients performing same-day TTE and CMR from Feb to Dec 2021. MR severity was classified according to 2020 ACC consensus: grade I (mild; EROA Results A total of 36 patients were included (age 65±14y; 74% male; left ventricle [LV] ejection fraction by TTE and CMR 35±13% and 34±11%, respectively). Mean RVol and EROA by TTE were 28±11mL and 0.18±0.8 cm2. Mean RVol and Regfrac by CMR were 20±13 mL and 25±12%, respectively. A moderate correlation between RVol by TTE and CMR was found (Pearson's R 0.58, p=0.001). According to TTE, there were 20 patients (56%) with grade I fMR, 12 patients (33%) with grade II fMR and 4 patients (11%) with grade III fMR. All patients considered to have mild (grade I) fMR by TTE had a RegFrac Conclusion Using the criterion of RegFrac ≥35%, CMR re-classifies (half for each side) the patients with moderate and moderate-to-severe regurgitations by TTE. Recognizing, overcoming and resolving the disagreements between the techniques is the way forward to reach excellence. Funding Acknowledgement Type of funding sources: None.

Background The 2021 Guideline for the Evaluation of Chest Pain supports the use of coronary artery calcium (CAC) score as a reasonable first-line test to identify patients with a low likelihood of obstructive coronary artery disease (CAD) who may not require additional testing (class IIa, LOE B). However, a recent study from a large cohort of Northern European patients raised concerns about the added diagnostic value of CAC=0 in younger patients. The aim of this study was to assess the influence of age on the value of CAC=0 in symptomatic patients undergoing coronary computed tomography angiography (CCTA). Methods We conducted a two-center cross-sectional study assessing symptomatic patients with suspected CAD who underwent CAC score and CCTA. Key exclusion criteria were age Results A total of 2043 patients (mean age 60±11 years, 60% women) of whom 990 (48.5%) had a CAC score of 0 were included in the analysis. Symptom characteristics were: 38% non-anginal chest pain, 30% atypical angina, 19% dyspnea, and 13% typical chest pain. Overall, the prevalence of obstructive CAD was 12.8% (n=262). Pretest probability of obstructive CAD increased progressively with age, from 6.0% in patients young than 50 years to 20.7% in those 70 years or older. Contrariwise, the prevalence of patients with a CAC score = 0 decreased from 77% in patients younger than 50 years, to 26% in those who where 70 years or older. The added diagnostic value of a CAC score = 0 was lower in younger patients, with negative likelihood ratios ranging from 0.36 (64% decrease in the likelihood of CAD) in patients younger than 50 years, to 0.09 and 0.10 (∼90% decrease in the likelihood of CAD) in those aged 60–69 years and 70 years or older, respectively – Figure 1. Despite this, the prevalence of obstructive CAD among patients with a CAC score = 0 was low across all age groups: 2.4% (i.e., NPV = 97.6%) in those younger than 50 years, 3.0% (NPV = 97.0%) among those aged 50–59 years, 1.5% (NPV = 98.5%) in patients between 60 and 69 years, and 2.0% (NPV = 98.0%) among those 70 years or older. Conclusions In a cohort of symptomatic patients undergoing CCTA for suspected CAD, the added diagnostic value of a CAC score of zero decreases significantly at younger ages. However, this “diminishing return” of CAC in younger patients if offset by their lower pretest probabilities, yielding high negative predictive values independently of age. Funding Acknowledgement Type of funding sources: None.

Background Left ventricular (LV) remodeling in patients with severe aortic valve stenosis (AS) is a complex process that goes beyond hypertrophic response and may involve reparative/replacement fibrosis. Currently, cardiac magnetic resonance (CMR) is the gold-standard imaging technique for detecting focal myocardial fibrosis through late gadolinium enhancement (LGE). However, myocardial fibrosis prevalence and distribution is quite variable among series. Our goal was to assess LGE prevalence and distribution pattern in severe symptomatic high-gradient AS. Methodology Single-center prospective cohort of 132 patients with severe symptomatic high-gradient AS (mean age 73±11 years; 48% male, mean valvular transaortic gradient 60±20 mmHg; mean aortic valve area 0.7±0.2 cm2/m2; mean LV ejection fraction by 2D echocardiogram 58±9%), all with normal flow (except one) undergoing surgical aortic valve replacement. Those with previous history of acute myocardial infarction, ischemic cardiomyopathy or other cardiomyopathy were excluded. All patients performed 1.5T CMR assessment with LV myocardium tissue characterization prior to surgery. Segmental LGE presence was assessed by two independent operators and classified according to the AHA 16 segment model, using 5-standard deviations from remote myocardium as the signal intensity cut-off for LGE identification and quantification. Results Overall, 96 patients (74%) had non-ischemic LGE (median LGE mass 3.2 g [IQR 0.2–8.3] g; median percentage of LGE myocardial mass 2.5% [IQR 0.1–6.1]%); 22 patients [17%] with exclusively junctional LGE); in one patient an incidental ischemic scar (subendocardial distribution) was identified. No cases of subepicardial distribution were found. Intramyocardial LGE was most frequently observed in basal and mid-anterior and inferior interventricular septum – see Figure 1. In these segments, LGE was most often junctional at right-ventricular insertion points (54%), followed by mid-wall LGE (32%) or both sites involvement (14%). Conclusion LGE is frequent in symptomatic high-gradient AS patients with preserved left ventricular ejection fraction, most often presenting as junctional enhancement in basal/mid-anterior and inferior interventricular septum. Future studies may address whether distinct LGE patterns may impact patient prognosis. Funding Acknowledgement Type of funding sources: None.

Background Exercise capacity is usually reduced in Fontan patients, however there is a subset of patients who have normal exercise capacity and better outcomes, the “Super-Fontans”. The aim of this study was to characterize a cohort of Fontan patients undergoing cardiopulmonary exercise testing (CPET) and identify predictors of better functional capacity. Methods Single center retrospective analysis of consecutive Fontan patients aged >10 years old who underwent CPET, between March 2018 and May 2021. Peak respiratory exchange ratio1.05 defined maximal CPET. Peak VO2 (pVO2) as a percentage of its predicted value was used as reference value to stratify patients in tertiles. Patients in 3rd tertile, with a percentage predicted pVO2 superior to 75%, were considered good-performers. Blood tests and transthoracic echocardiogram (TTE) were performed on the same day. Additional data were collected from electronic charts. Results In total, 49 patients were included (mean age 19±7 years old, 67% male) with intra or extracardiac conduit implanted in mean 12±7 years prior to the CPET. The most common primary diagnoses were tricuspid/pulmonary atresia (43%), followed by unbalanced complete AV septal defect (14%) and double inlet left ventricle (14%). 12 patients had a systemic right ventricle. All, except 5 patients, had preserved systolic ventricular function and 37% had moderate to severe AV regurgitation. The majority had normal hemoglobin levels (median 15.6 g/dL), hepatic enzymes (median total bilirubin 0.8 mg/dL), renal function (median creatinine 0.8 mg/dL) and low NT-proBNP (median 122 pg/mL). All patients had maximal CPET, median %VO2 at VT1 was 57% of peak and mean pVO2 was 66±14% of the predicted. Most patients (69%) showed exercise limitation due to cardiovascular cause, followed by O2 desaturation, present in 22% of CPETs. The age of Fontan completion was not associated with functional capacity (p=0.6). The good-performer group comprised 13 patients (27%), all in sinus rhythm, of which 10 were physically active. Compared with the remainder, this group had higher VO2 at VT1 (18.7 vs. 14.6, p=0.01) and VO2 at VT2 (25.9 vs. 22.1, p=0.02), both in mL/kg/min. Also, peak heart rate (% predicted) (90 vs. 81, p=0.03) was higher in this subgroup – fig.1. Conversely, differences on TTE parameters (GLS and AV valve regurgitation) and blood biomarkers were not statistically significant. On multivariable analysis, no single variable predicted better functional capacity. Conclusion In our Fontan cohort, most patients had reduced exercise capacity, largely due to cardiovascular dysfunction. However, “Super-Fontans” stood out as they had a higher anaerobic threshold illustrating their better physical condition. These findings highlight the role of regular physical activity in Fontan patients as a cornerstone for better functional capacity. Funding Acknowledgement Type of funding sources: None.

Introduction Calcium score of the aortic valve (CaScAoV) is recommended as a supporting tool to assist in the grading of aortic stenosis (AS) severity when echocardiographic assessment is inconclusive. However, a significant proportion of patients have CaScAoV values within a “grey zone” between the “unlikely” and “likely” thresholds. The purpose of this study was to assess the potential usefulness of indexing CaScAoV to the area of the aortic annulus, in order to improve the discriminative power of CaScAoV in this subset of patients. Methods Consecutive patients evaluated at a single center TAVI program were retrospectively identified and included in the analysis if cardiac CT and echocardiography were performed within a 6-month timeframe. Those with LVEF Results A total of 655 patients were included (282 men (43.1%), median age 83 years [IQR 79–86]). AS was considered severe by echocardiographic criteria in 587 patients (89.6%), and moderate in the remainder. Median transvalvular gradient was 49 mmHg (IQR 43–59), and median CaScAoV values were 3329 (IQR 2356–4500) for men, and 1995 (IQR 1462–2781) for women. Overall, 77 patients (11.7%) had CaScAoV values in the “grey zone”, of which 24 (31.2%) had moderate AS (Figure 1). Patients within this region of uncertainty were no different form the others in terms of age, sex, annulus size and body surface area. In this subset of patients, indexing CaScAoV to aortic annulus area showed good discriminative power to identify severe AS (AUC 0.69, 95% CI 0.56–0.81, p=0.008). Using previously established thresholds (>300 AU/cm2 for women and >500 AU/cm2 for men), 48 patients (62.3%) were correctly reclassified (net reclassification index of 0.45, p=0.03). These findings were similar for both sexes. Conclusion In patients undergoing cardiac CT for known or suspected severe AS with CaScAoV values within the “grey zone”, indexing CaScAoV to the area of the aortic annulus improves the classification of AS severity and may decrease diagnostic uncertainty. Funding Acknowledgement Type of funding sources: None.

Background Recently, the European Society of Cardiology issued new algorithms to estimate the 10-year risk of atherosclerotic cardiovascular disease (ASCVD), along with new age-specific thresholds to classify individuals as low-to-moderate, high, or very-high risk. The aim of this study was to compare the latest SCORE-2 model with the older SCORE (Systematic COronary Risk Evaluation) in their ability to identify individuals with high coronary artery calcium score (CACS), and assess the relationship between potential eligibility for statin therapy and CACS. Methods Individuals 40–69 years old without diabetes or known ASCVD were identified in a single center registry of patients undergoing CACS and coronary CT angiography for suspected coronary artery disease. SCORE and SCORE-2 were calculated and used with each patient's untreated LDL-C values to assess eligibility for statin therapy. High CACS was defined as an Agatston score ≥100. Results A total of 389 pts (46% men, mean age 58±8 years) were included, of which 15% (n=60) were active smokers. The mean systolic blood pressure and untreated LDL-C values were 136±17 mmHg and 155±65 mg/dL, respectively. The proportion of patients classified as low-to-moderate risk, high risk, and very high risk was 93%, 6% and 1% using the SCORE algorithm, and 42%, 44%, and 14% using SCORE-2, respectively. Overall, 218 patients (56%) would have their risk category revised upwards, while no patients would be downgraded. The median CACS was 5 (IQR 0–71 AU), with 166 patients (43%) having CACS = 0, and 81 (21%) presenting CACS values ≥100. SCORE and SCORE-2 showed similar discriminative power to identify patients with CACS ≥100 (C-statistic 0.77, 95% CI 0.71–0.82, vs. 0.75, 95% CI 0.69–0.80, P=0.109 for comparison]. The up-reclassification of risk conveyed by SCORE-2 affected patients across all categories of CACS (Fig. 1). The proportion of patients in whom statin therapy would generally be indicated was higher with the SCORE-2 criteria vs. the SCORE algorithm (61% vs. 29%, respectively, p Conclusion Even though the discriminative power of SCORE-2 is similar to the older SCORE, the introduction of age-specific thresholds results in the up-reclassification of risk in roughly half of the patients. The application of SCORE-2 will broaden statin eligibility overall, not only in patients with high atherosclerotic burden, but also in those with CACS = 0. These findings support the use of risk modifiers in selected patients to improve the effectiveness of statin therapy. Funding Acknowledgement Type of funding sources: None.

Introduction Mitral balloon valvuloplasty (MBV) is the guideline recommended treatment for symptomatic severe mitral stenosis (MS) with suitable anatomy, but is often deemed transitory. However, data on very-long term echocardiographic follow-up is scarce. The aim of our study was to describe clinical and echocardiographic outcomes in patients previously submitted to MBV for rheumatic MS. Methods We conducted a single-centre retrospective study enrolling patients previously submitted to MBV for rheumatic MS from 1990 until 2021. Follow-up was considered until last registered echocardiographic re-evaluation. Patients without electronic health records available were excluded. The primary endpoint was a composite of all-cause death or need of surgery. Results A total of 193 patients were included (15.5% male, with a mean age of 52±15 years at the time of MBV, 60.6% with permanent atrial fibrillation). During a mean follow-up of 11±8 years, 87 (45.1%) patients implanted a mitral valve prosthesis, 4 (2.1%) were submitted to surgical mitral valvuloplasty and 30 (15.5%) died without being reinterventioned. Moreover, a total of 23 (11.9%) embolic events were registered – 21 strokes, 1 pulmonary embolism and 1 acute lower limb embolism. Overall, 133 patients (68.9%) survived more than 5 years, 95 (49.2%) more than 10 years and 56 (26.9%) more than 15 years since MBV without meeting the primary endpoint. The maximum follow-up without intervention was 32 years. Concerning patients submitted to surgery, the mean time from MBV until operation was 9.4±7.3 years (minimum 8 days; maximum 29.3 years). In regard to echocardiographic long-term outcomes on alive non-operated patients (mean follow-up of 12±9 years), 52.8% remain with mild MS, 91.6% with mild or no mitral regurgitation and 77.6% with mild or no tricuspid regurgitation. Furthermore, only 20.4% have right ventricle dysfunction (defined as a TAPSE 45 mmHg), and 6.8% have residual interatrial communication. Conclusion MBV is a minimally invasive procedure that has an important benefit in a very significant proportion of patients with rheumatic mitral stenosis, with potential benefit that may last more than three decades without need for another invasive intervention. Funding Acknowledgement Type of funding sources: None.

Background The North American 2021 Chest Pain Guidelines recommend not testing stable patients with low pretest likelihood of obstructive coronary artery disease (CAD), defined as pretest probability The purpose of this study was to assess the results of three different testing strategies for patients with pretest probability 0; C) perform CCTA in all. Methods We conducted a two-center cross-sectional study assessing symptomatic patients with suspected CAD who underwent CAC score and CCTA. Patients with known CAD, suspected acute coronary syndrome, or symptoms other than chest pain or dyspnea were excluded. Pretest probability of obstructive CAD was calculated based on age, sex and symptom typicality. Obstructive CAD was defined as any luminal stenosis ≥50% on CCTA. Results A total of 2259 patients were screened, of which 1385 (61.3%) had pretest probability 0 (n=599), 21.2% (n=127) had obstructive CAD. The results that would be reached with each of the 3 diagnostic strategies are presented in Figure 1. The number of patients needed to scan with strategy B (CAC as gatekeeper) vs. A (no testing) to identify one patient with obstructive CAD was 11, whereas the number needed to scan with strategy C (CCTA for all) vs. strategy B was 91. Conclusions Not testing patients with suspected CAD and pretest likelihood Funding Acknowledgement Type of funding sources: None.

Background Left ventricular (LV) hypertrophy is a common expected finding in aortic stenosis (AS) patients. Cardiac magnetic resonance (CMR) plays an important role as a non-invasive method for determining LV mass and volume, and to characterize the LV remodeling response in AS. Aim To assess the prevalence, to describe the patterns and evolution of LV remodeling (by CMR) in AS patients referred for surgical aortic valve replacement (AVR). Methods Single-center prospective cohort of 132 consecutive patients (73 years [68–77 years], 49% men] with severe AS: mean transaortic pressure gradient (AVmean): 61±1.5 mmHg; aortic valve area (AVA): 0.7±0.1 cm2, referred for surgical AVR, with no previous history of ischemic cardiomyopathy. Before surgery, all patients underwent electrocardiogram, complete transthoracic echocardiogram (TTE) and CMR for LV assessment and tissue characterization (mean LV indexed mass [LVMi]: 80.3±26.5 g/m2; mean end-diastolic LV indexed volume [LVEDVi]: 84.4±24.5 mL/m2 and median geometric remodeling ratio [M/V]: 0.95 g/mL [IQR 0. 81–1.08 g/mL]). Patterns of LV remodeling were investigated before and after AVR by CMR measurements of LVMi, LVEDVi and M/V. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling (Figure 1). Results Overall, 43% (n=58) of the patients had concentric hypertrophy, 30% (n=40) concentric remodeling, 22% (n=29) normal ventricular geometry, 4% (n=5) eccentric hypertrophy and in two patients we observed an adverse remodeling pattern. AVR was performed in 80 patients. At the 3rd to 6th month post-AVR assessment, LV remodeling changed to: normal ventricular geometry in 46%, concentric remodeling in 31%, concentric hypertrophy in 19%, eccentric hypertrophy in 3% and adverse remodeling in only one patient (Figure 1). Conclusions In this group of patients with severe aortic stenosis, concentric hypertrophy was not the sole pattern of LV remodeling and two out of every five still presented a normal ventricular geometry and mass as assessed by CMR. LV response was dynamic after AVR which stands for complex and multifactorial interaction in these group of patients despite similar valvular pathophysiology and therapeutic intervention. Funding Acknowledgement Type of funding sources: None.

Background Left ventricular (LV) hypertrophy is a known compensatory mechanism to pressure overload in aortic stenosis (AS) patients. However, by cardiac magnetic resonance (CMR) different patterns of LV adaptation are seen in this group of patients. Aim To describe the patterns of LV adaptation (by CMR) and to analyze its structure and function indexes in AS patients referred for surgical aortic valve replacement (AVR). Methods We prospectively studied 134 consecutive patients (age: 73y [IQR 68–77y], 49% men) with severe symptomatic AS - mean transaortic pressure gradient (AVmean): 61±1.5 mmHg; mean aortic valve area: AVA): 0.7±0.1 cm2, referred for surgical AVR with no previous history of ischemic cardiomyopathy or other. All patients underwent electrocardiogram, 2D transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) before surgery for LV assessment and tissue characterization. Five patterns of LV structure were considered: normal ventricular structure (normal LV mass/volume ratio [M/V], normal LVMi and normal indexed LV end-diastolic volume (LVEDVi); concentric remodeling: increased M/V, normal LVMi; concentric hypertrophy: increased M/V and LVMi; eccentric hypertrophy: increased LVMi and LVEDVi, normal M/V and ejection fraction; and adverse remodeling: dilated left ventricle, increased LVMi and normal M/V in the context of an impaired ejection fraction. Echocardiogram and CMR structural and functional indexes were compared between these groups. Results At baseline study, at CMR: mean LV indexed mass [LVMi]: 80.3±26.5 g/m2; mean end-diastolic LV indexed volume [LVEDVi]: 84.4±24.5 mL/m2 and median geometric remodeling ratio [M/V]: 0.95 g/mL [IQR 0. 81–1.08 g/mL]. Overall, 22% patients had normal LV structure, 30% concentric remodeling ventricular geometry, and two patients had an adverse remodeling pattern. LV hypertrophy was the most prevalent pattern and occurred in 48% of subjects (concentric 43%; eccentric 4%). In our cohort, the severity of AS (AVmean (p Conclusions In our cohort, AS patients presented several distinct patterns of LV remodeling. Disease severity, functional repercussion and loading conditions are distinct between them. Funding Acknowledgement Type of funding sources: None.

Background In patients with severe aortic stenosis (AS), left ventricular (LV) remodeling is believed to be a compensatory adaptive process which should reverse after aortic valve intervention. However, this is not always the rule and remodeling persistence may negatively impact post-procedural outcomes and survival. Aim To assess the prevalence and predictors of morphological LV reverse remodeling in severe symptomatic AS patients after surgical aortic valve replacement (AVR). Methods We prospectively studied 75 patients (72y [68–77y], 45% male) with severe symptomatic AS - mean gradient (AVM): 61±17mmHg; mean indexed aortic valve area (AVAi) 0.41±0.10 cm2/m2 with no previous history of ischemic cardiomyopathy, all with high gradient, 4 with low-flow, 81% with hypertension, 27% with type 2 diabetes mellitus and 35% patients with stage 3 chronic kidney disease: median MDR creat clearance: 70.4mL/min [40–102]. All patients performed pre-operative cardiac magnetic resonance (CMR) at a mean period of 3.4 months (0–17 months) before AVR and at the 3–6th months after AVR, for LV reverse remodeling assessment. It was defined as at least the occurrence of one of the following: >15% reduction in LVEDVi; >15% reduction in LVMi by CMR; >10% reduction in geometric remodeling ratio. Clinical, AV severity data, preoperative functional LV and tissue characterization data were analyzed at multivariate regression to predict the occurrence of LV reverse remodeling. Results Overall, at pre-operative CMR: mean LV indexed mass (LVMi): 82±28.9 g/m2; mean end-diastolic LV indexed volume (LVEDVi): 87.4±26.6 mL/m2; mean geometric remodeling (LV mass/end-diastolic volume): 0.92±0.2 g/mL. After AVR, at echocardiographic evaluation, no patient had prosthetic obstruction or prosthetic patient mismatch: median LV-Ao gradient 12mmHg [9.1–14 mmHg]; 5 of them had mild paravalvular regurgitation. LV reverse remodeling occurred in 65 patients (88%) (Figure 1A) and these were younger, had significantly smaller preoperative AVAi and higher valvular gradients (Figure 1B). At multivariate analysis, only preoperative AVAi remained an independent predictor (odds ratio 0.85, 95% CI 0.735–0.984, p=0.029). Conclusions In this prospective cohort of patients LV reverse remodeling after surgical AVR was highly frequent, occurring in almost nine out of every ten patients. Funding Acknowledgement Type of funding sources: None.

Background The usefulness of implantable cardioverter defibrillators (ICD) for primary prevention of arrhythmic sudden cardiac death (SCD) in patients with non-ischemic dilated cardiomyopathy (DCM) has been questioned. Efforts to improve risk stratification have included scores such as the “MADIT-ICD benefit score”, and the use of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR). The purpose of this study was to evaluate the potential usefulness of these two tools to assess the risk of life-threatening arrhythmias in patients with non-ischemic DCM undergoing ICD implantation for primary prevention of SCD. Methods We conducted a single-center retrospective study of consecutive patients who underwent contrast-enhanced CMR before ICD implantation for primary prevention of SCD. Patients with ischemic cardiomyopathy were used as reference. Patients with non-dilated cardiomyopathies were excluded. The arrhythmic component of the MADIT-ICD benefit score (VT/VF score) was calculated for each patient, and considered high if ≥7, as recommended. The primary endpoint was the occurrence of SCD or life-threatening arrhythmias (VF or VT >200 bpm). Follow-up was performed by device interrogation in all patients except those who suffered SCD. Results A total of 151 patients (93 ischemic, mean age 62±13 years, 75% male) with mean left ventricular ejection fraction (LVEF) of 27±8% were included. Overall, 72% (n=67) ischemic and 45% (n=26) non-ischemic patients had scores ≥7 and were considered high-risk. LGE was present in all patients with ischemic cardiomyopathy, and in 76% (n=44) of patients with non-ischemic DCM. During a median follow-up of 21 (8–38) months, 21 patients (13.9%, 11 ischemic and 10 non-ischemic) met the primary endpoint. Overall, the event-free survival of non-ischemic patients was similar to that of ischemic patients (log rank p=0.269). In patients with non-ischemic DCM, there were 7 arrhythmic events (26.9%) in those with MADIT-ICD VT/VF scores ≥7, and 3 events (9.4%) in those with scores In the same population, there were 10 arrhythmic events (23%) in patients with LGE, but no events in patients without LGE (log rank p=0.036). LVEF was similar in patients with and without arrhythmic events (26±8% vs. 27±7%, p=0.717), and in those with and without LGE (26±7% vs. 28±9%, p=0.342). Conclusion The presence of LGE is a strong predictor of life threatening arrhythmias in patients in non-ischemic DCM undergoing ICD implantation for primary prevention, seemingly outperforming the clinical MADIT-ICD benefit score. Funding Acknowledgement Type of funding sources: None.