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Background The pathophysiological mechanisms linking tricuspid regurgitation (TR) and chronic kidney disease (CKD) remain unknown. This study aimed to determine which pathophysiological mechanisms related to TR are independently associated with renal dysfunction and to evaluate the impact of renal impairment on long‐term prognosis in patients with significant (≥ moderate) secondary TR. Methods A total of 1234 individuals (72 [IQR 63–78] years, 50% male) with significant secondary TR were followed up for the occurrence of all‐cause mortality and the presence of significant renal impairment (eGFR of

Het is belangrijk om te achterhalen welke ST-elevatiemyocardinfarctpatienten tot de laagrisicogroep behoren, zodat ze naar de huisarts terugverwezen kunnen worden. Wij onderzochten wat de prognose is van patienten met een ST-elevatiemyocardinfarct die na 1 jaar behandeling volgens een specifiek protocol naar de huisarts zijn terugverwezen.

Background Timing of mitral valve surgery for primary mitral regurgitation (MR) remains challenging. Since MR has a significant hemodynamic impact on the left atrium (LA), assessment of LA function may have prognostic value in these patients which is incremental to LA volume and left ventricular (LV) remodeling parameters. Purpose This study sought to investigate whether preoperative assessment of LA reservoir strain (LASr) by speckle tracking echocardiography is associated with long-term outcome in patients undergoing mitral valve repair for severe primary MR. Methods Echocardiography was performed prior to mitral valve surgery in 566 patients (age 64±12 years, 66% men) with severe primary MR. Complete clinical information was collected and the endpoint was all-cause mortality after operation. The study population was divided based on a cut-off value of LASr (22%) derived from a spline curve analysis (hazard ratio for all-cause mortality >1). Results Patients with LASr ≤22% (n=277) were significantly older, had more impaired renal function and were more symptomatic (NYHA functional class III to IV) compared to patients with LASr >22% (n=289). In terms of echocardiographic data, patients with LASr ≤22% had significantly lower LV ejection fraction and LV global longitudinal strain (LV-GLS) and significantly higher systolic pulmonary artery pressures and LA volume index compared with patients with LASr >22%. During a median follow-up of 95 (56 – 147) months, 129 patients (22.8%) died. Patients with LASr ≤22% experienced significantly higher mortality rates compared to patients with LASr >22% (log rank chi-square 35.1; p Conclusions Preoperative LASr is independently associated with all-cause mortality in patients undergoing mitral valve repair for primary MR, has incremental prognostic value over LA volume and LVEF and might therefore be helpful to guide surgical timing. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Jan Stassen has received an ESC training grant (Appehab724.011364741) Association of LASr and outcome

Background Catheter ablation is an established therapy for rhythm control in patients with drug-refractory atrial fibrillation (AF), however, recurrence is frequent particularly in persistent AF. There are no consistently confirmed predictors of AF recurrence after catheter ablation. The left atrial appendage (LAA) potentially plays an important role in AF recurrence, although the exact mechanism and pathophysiology are still unclear. Purpose We aimed to study whether LAA volume (LAAV) and function influence the long-term recurrence of AF after point-by-point radiofrequency catheter ablation, depending on AF type. Methods AF patients who underwent point-by-point radiofrequency catheter ablation after preprocedural cardiac computed tomography (CT) and transthoracic and transesophageal echocardiography (TEE) were included in this retrospective analysis. LAAV and LAA orifice area were measured by CT and LAA flow velocity assessed by TEE and was used as a surrogate marker of LAA function. Uni- and multivariable Cox proportional hazard regression models were performed to determine the predictors of AF recurrence. Results In total, 561 AF patients (61.9±10.2 years, 34.9% females) were included in the study. Recurrence of AF was detected in 40.8% of the cases (34.6% in patients with paroxysmal and 53.5% in those with persistent AF) with a median recurrence-free time of 22.7 [9.3–43.1] months. Patients with AF recurrence had significantly higher body surface area-indexed left atrial volume (iLAV), LAAV and LAA orifice area, as compared to those without recurrence. Moreover, patients with persistent AF had significantly higher iLAV, LAAV, LAA orifice area and lower LAA flow velocity, than those with paroxysmal AF. After adjustment for the main cardiovascular risk factors and comorbidities left ventricular ejection fraction (LVEF) Conclusions The current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is associated with higher rate of AF recurrence after catheter ablation in persistent AF, but not in patients with paroxysmal AF. Our results suggest that preprocedural assessment of LVEF and LAAV might contribute to optimal patient selection and aid to improve long-term results of ablation procedures in patients with persistent AF. Funding Acknowledgement Type of funding sources: None.

Background ST-segment elevation myocardial infarction (STEMI) often involves changes in right ventricular (RV) function and size over time. However, the prognostic implications of RV remodeling after STEMI are unknown. The aim of current study was to characterize RV remodeling in post-STEMI patients and to investigate it's prognostic relevance. Methods RV remodeling in post-STEMI patients who underwent primary percutaneous coronary intervention (PCI) was defined by RV end-systolic area (RV ESA) change at 6 months after STEMI, compared to baseline. The optimal threshold of RV ESA change (≥40%) to define RV remodeling was derived from spline curve analysis (Figure 1A). The primary endpoint was the composite of all-cause mortality and heart failure (HF) hospitalization. Long term outcomes were compared between patients with and without RV remodeling by means of a log rank test. Results A total of 2280 patients were analyzed (mean age 60±11 years, 76% male) and RV remodeling was present in 320 patients (14%). After a median follow-up of 75 months (interquartile range 50–106 months), the composite endpoint of all-cause mortality and HF hospitalization occurred in 292 patients (13%). After adjustment for various risk factors, including tricuspid annular plane systolic excursion (TAPSE), post-STEMI RV remodeling was independently associated with a higher risk of all-cause mortality and HF hospitalization (HR=1.37, 95% CI 1.00–1.87, p=0.049. Finally, patients with RV remodeling were had a significantly lower event-free survival rate compared with patients without RV remodeling during follow-up (log-rank test p=0.009) (Figure 1B). Conclusion RV post-infarct remodeling is associated with mortality and HF hospitalization, independent of RV systolic function. Funding Acknowledgement Type of funding sources: None. Figure 1. A) Spline and B) Kaplan-Meier curve

Background Although preoperative left atrial (LA) dilation is a well-known predictor of adverse cardiovascular events in patients with severe, primary mitral regurgitation (MR), little is known about LA reverse remodeling after mitral valve (MV) surgery and its prognostic value. Purpose This study sought to systematically investigate the changes in LA volume in patients undergoing MV repair for severe, primary MR and the association between LA volume after surgery and long-term outcome. Methods In patients undergoing MV repair for severe, primary MR, echocardiography was evaluated at three different time points: pre-operatively, immediate postoperatively (5 [4–6] days) and within 1–3 years (19 [14–24] months) follow-up. Outcome was all-cause mortality happening after the third echocardiographic evaluation. Results A total of 226 patients (mean age 62±13 years, 66% male) were included. Mean pre-operative LA volume index (LAVi) was 56±28 ml/m2 and significantly decreased immediately after surgery (to 38±21 ml/m2; p Conclusions In patients with severe primary MR, LA reverse remodeling occurs immediately after MV repair, with a further reduction in LAVi during follow-up. Patients in whom LAVi does not remodel to normal values present worse long-term prognosis as compared to patients who achieve normal LAVi values. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): ESC Training Grant (Appehab724.011664741). Changes in LA volume over timeKM curve for all-cause mortality

Background Significant (≥ moderate) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular disease in patients with bicuspid aortic valve (BAV), imposing a greater hemodynamic burden on left ventricle and atrium, possibly culminating in a faster onset of left ventricular (LV) dilation and/or symptoms. Purpose To determine the prevalence and prognostic implications of significant MR in patients with BAV. Methods In this large, multicenter, international registry, a total of 2,932 patients (48±18 years, 71% male) with BAV were identified. All patients were evaluated for the presence of significant primary or secondary MR by transthoracic echocardiography and were followed-up for the endpoint of all-cause mortality and a combined endpoint of all-cause mortality or aortic valve surgery. Results Overall, 147 patients (5.0%) had significant primary (1.5%) or secondary (3.5%) MR. Significant MR was associated with all-cause mortality (HR 2.80, 95% CI 1.91 to 4.11, p Conclusions Significant MR is uncommon in patients with BAV. Following adjustment for confounding variables, significant MR was not associated with event-free or overall survival. Funding Acknowledgement Type of funding sources: None. Survival curves for all-cause mortality

Background Moderate aortic stenosis (MAS) is associated with an increased risk of adverse events. Risk assessment in these patients, however, has not been thoroughly investigated. Purpose To investigate the independent determinants of survival in patients with MAS, stratified by left ventricular ejection fraction (LVEF) and severity of symptoms at the time of first diagnosis. Methods Patients with an echocardiographic diagnosis of tricuspid MAS (aortic valve area >1.0 and ≤1.5cm2) were identified. Patients were stratified by LVEF (LVEF ≥60%, LVEF 50–59%, or LVEF Results Of 2003 patients with MAS (mean age 73±10 years, 51% men, AVA 1.22±0.15 cm2), 1063 (53%), had LVEF≥60%, 550 (27%) LVEF 50–59% and 390 (20%) LVEF Conclusions Baseline LVEF and symptom severity are associated with worse outcomes in patients with MAS. Although current guidelines recommend conservative management for MAS, randomized trials appear warranted to determine whether AVR at an earlier stage would be beneficial in these patients. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): ESC Training Grant Appehab724.157064741 Figure 1. Kaplan-Meier outcome curvesFigure 2. Cox regression analysis

Background Women with severe aortic valve stenosis (AS) have better long-term outcomes after transcatheter aortic valve implantation (TAVI) but worse survival after surgical aortic valve replacement compared to men. Whether this is related to sex differences in left ventricular (LV) remodeling is unknown. Purpose To examine sex differences in LV remodeling and outcomes in patients with severe AS undergoing TAVI. Methods Patients with severe AS who underwent TAVI between 2007 and 2018 with a pre-procedural multidetector row computed tomography (MDCT) scan were included. LV volumes, mass and function were analyzed with MDCT. Patients were classified into 4 LV remodeling patterns based on LV mass index and LV mass-to-volume ratio: 1) normal geometry, 2) concentric remodeling, 3) concentric hypertrophy and 4) eccentric hypertrophy. The primary endpoint was all-cause mortality after TAVI. Results A total of 289 patients (age 80±6 years, 54% male) were included. Women showed smaller LV volumes and mass compared to men. Concentric hypertrophy (50%) was the most frequent pattern of LV remodeling followed by eccentric hypertrophy (33%), normal geometry (13%) and concentric remodeling (4%). Concentric remodeling was more frequently observed in men compared to women (91% vs. 9% respectively, p=0.011). However, no sex differences were observed in the remaining LV remodeling patterns (Figure 1). During a median follow-up of 3.8 (IQR 2.2–5.1) years after TAVI, 87 patients died. Women demonstrated better outcome after TAVI compared to men (log-rank χ2=4.29, p=0.038). The survival benefit of women over men was mainly present among patients with concentric hypertrophy (log-rank χ2=4.91, p=0.027, Figure 2). Conclusion LV concentric and eccentric hypertrophy are similarly observed in men and women with severe AS. Women demonstrated better outcome after TAVI as compared to men, particularly among those with LV concentric hypertrophy. However, the outcome benefit of females after TAVI seems not to be related to sex-differences in LV remodeling. Funding Acknowledgement Type of funding sources: None. Distribution of sex in LV remodelingAll-cause mortality after TAVI

Background Cardiac involvement is an important cause of hospitalization and mortality in patients with systemic sclerosis (SSc) and advanced echocardiographic measures such as left ventricular (LV) global longitudinal strain (GLS) have already demonstrated to improve risk-stratification. However, possible sex differences in echocardiographic parameters including LV GLS have not been explored so far. Purpose To compare standard and advanced echocardiographic parameters between men and women with SSc and evaluate their association with cardiovascular outcomes. Methods A total of 746 SSc patients from four different centers were included of which 628 (84%, 54±13 years) women and 118 (16%, 55±15 years) men. Baseline transthoracic echocardiographic (TTE) data with standard and advanced (LV GLS) measurements as well as clinical characteristics were analysed. The study endpoint was the composite of all-cause mortality and cardiovascular hospitalisations. Results Men and women showed several differences in terms of disease characteristics: greater modified Rodnan skin score, higher prevalence of diffuse cutaneous SSc, lung fibrosis and myositis, more impaired pulmonary function (DLCO) and higher creatine phosphokinase were observed in men, while women were characterized by longer disease duration, higher NT-proBNP and lower glomerular filtration rate. By TTE, men showed larger LV indexed volumes, lower LV ejection fraction and more impaired LV GLS [−19% (IQR −20% to −17%) vs. −21% (IQR: −22% to −19%, p Conclusions Among patients with SSc, LV GLS is more impaired in men as compared to women even after matching for clinical characteristics, and its impairment is associated with higher prevalence of death and cardiovascular hospitalization. Funding Acknowledgement Type of funding sources: None.

Background Mismatches between the severity of coronary stenosis and the presence of ischemia by invasive fractional flow reserve (FFR) are frequently reported. Purpose To investigate whether plaque characteristics as evaluated with coronary computed tomography angiography (CCTA) may explain this discordance in nonobstructive versus obstructive coronary artery disease (CAD). Methods From the CREDENCE trial, 612 patients with suspected CAD at 13 sites (64±10 years, 70% men) underwent CCTA with semi-automated whole heart quantification and invasive coronary angiography with 3-vessel FFR measurements. Obstructive CAD was visually defined as ≥50% stenosis. The primary endpoint of coronary vessel-specific ischemia was defined as FFR ≤0.80. Generalized estimating equations were calculated to evaluate the effect of plaque characteristics on coronary vessel-specific ischemia. Interactions were tested by obstructive CAD, adjusted for age. Results Among 1,686 vessels, ischemia was present in 436 (26%) vessels. In both nonobstructive and obstructive CAD, the majority of plaque characteristics were associated with coronary vessel-specific ischemia (p≤0.005, Figure 1). In nonobstructive CAD, odds for ischemia were significantly higher for total percent atheroma volume (PAV, p Conclusion Our findings reveal that ischemia by FFR is documented in the setting of both nonobstructive and obstructive CAD on CCTA. Detection of atherosclerotic plaque characteristics associated with ischemia can potentially improve diagnostic certainty and guide management of symptomatic patients with nonobstructive CAD. Figure 1. Odds ratios for ischemia. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health - National Heart, Lung, and Blood Institute

Background The prognostic significance of speckle tracking echocardiography derived right ventricular (RV) strain has been repeatedly demonstrated in the heart failure with reduced ejection fraction (HFrEF) patient group. Nevertheless, assessing RV systolic function in the context of afterload is vital as even minimal increases in pulmonary pressures may result in a substantial reduction in RV stroke volume. The novel assessment of Right Ventricular Myocardial Work (RVMW) through the evaluation of pressure-strain loops derived by echocardiography, provides a comprehensive evaluation of RV systolic function, integrating both RV strain and afterload. Purpose To explore the relationship between the non-invasive estimation of RVMW with invasive indices of right heart catherization (RHC) in a cohort of patients with HFrEF. Methods Noninvasive analysis of RVMW was performed in 23 HFrEF patients (median age 60.4 [58.0 to 66.0] years, 74% male) who underwent echocardiography and invasive RHC within 48 hours. The novel indices of RV global constructive work (RVGCW), RV global work index (RVGWI), RV wasted work (RVWW) and RV global work efficiency (RVGWE) were analysed utilizing proprietary software originally developed for the assessment of left ventricular myocardial work by speckle tracking echocardiography. These indices and other standard measurements of RV systolic function were then compared with invasively measured cardiac index (CI), derived by thermodilution during RHC. Results Mean left ventricular ejection fraction was 18.7% (±6.7), with a mean cardiac index of 2.2 L/min/m2(±0.7) and a mean pulmonary arterial pressure of 32 mm Hg (±13). None of the standard echocardiographic parameters of RV systolic function, including fractional area change, RV global longitudinal strain, RV free wall strain and TAPSE were significantly correlated with cardiac index in this cohort of HFrEF patients. In contrast, two of the novel indices derived non-invasively by pressure-strain loops, RVGCW and RVGWI, demonstrated a moderate correlation with invasively measured CI (r=0.55, p=0.006 and r=0.49, p=0.018). Conclusion RVGCW and RVGWI are novel parameters that provide integrative analysis of RV systolic function and correlate more closely with invasively measured CI than other standard echocardiographic parameters. Their potential role in aiding clinical decision-making merits further investigation. Funding Acknowledgement Type of funding source: None

Background Recent studies have suggested that current grading of tricuspid regurgitation (TR) has significant limitations and specifically cannot identify the various grades of severe TR (such as torrential). New cut-off values for the recommended measures of vena contracta (VC) width and effective regurgitant orifice area (EROA) have been proposed but not yet validated. Purpose To test the prognostic utility of new cut-offs for VC width and EROA in a large registry of patients with functional TR (FTR) and to integrate them into a novel comprehensive grading system. Methods FTR severity was evaluated in 1148 patients (mean age: 69±13 years, 50% male) with significant FTR (≥ moderate). Patients with congenital heart disease or who underwent tricuspid valve repair during follow-up were excluded. The primary endpoint was all-cause mortality. Based on Kaplan-Meier survival analyses, VC width significantly differentiated the prognosis of patients with moderate FTR vs severe FTR (with a cut-off value of 7 mm), whereas EROA was able to further stratify patients with more than severe (torrential) FTR. Therefore these two parameters were combined into a novel grading system (Figure: Upper Panel) to define: moderate FTR (VC Results According to our novel grading system a total of 146 patients (13%) showed moderate FTR, 547 patients (48%) had severe FTR and 454 patients (39%) presented with torrential FTR. Patients with torrential FTR had greater right ventricular (RV) dimensions, lower RV systolic function and were more likely to receive diuretics. The cumulative 10-year survival rates were significantly different among the groups: 54% for moderate FTR, 43% for severe FTR and 32% for torrential FTR (P=0.004 Figure – Lower Panel). After adjusting for potential confounders, torrential FTR retained its association with worse prognosis compared with other FTR grades (HR 1.28; 95% CI 1.07–1.54; P=0.007) together with age, coronary artery disease, diabetes, severe renal impairment, lower RV or left ventricular systolic function, higher pulmonary artery pressures, and dilated tricuspid annulus. Differently, severe FTR graded according to current guidelines did not show any association with the primary outcome (HR for severe FTR vs moderate FTR 1.17; 95% CI 0.96–1.42; P=0.128). Conclusion The proposed novel grading system combining measures of VC width and EROA is able to further risk stratify patients with FTR and specifically to identify patients with torrential FTR, a new clinical condition associated with even worse mortality than severe FTR. Figure 1 Funding Acknowledgement Type of funding source: None

Background Evolving evidence suggests unique sex-specific mechanisms underlying coronary artery disease (CAD). However, it remains unknown if certain coronary atherosclerotic features confer a higher risk for ischemia in women versus men. Purpose To determine the association between coronary atherosclerotic features on coronary computed tomography angiography (CCTA) and ischemia by invasive fractional flow reserve (FFR) in women versus men. Methods Secondary analysis of the CREDENCE trial, including patients referred for nonemergent invasive coronary angiography (ICA). All patients underwent CCTA with semi-automatic quantification of coronary atherosclerosis, as well as ICA with FFR interrogation of all major epicardial arteries ≥2 mm. Generalized estimating equations were calculated to assess the association between coronary atherosclerotic features and invasive vessel-specific ischemia (FFR ≤0.80). Sex interactions were tested, adjusted for age. Results From 612 patients (mean age 64±10 years, 30% women) with 1,686 analyzed vessels, a total of 436 (26%) vessels were ischemic. Women were significantly older than men (p30% stenosis (p=0.030), noncalcified PAV Conclusion Our results support a prominent influence of coronary atherosclerotic features that uniquely impact ischemic risk among women more so than men. These data support the role of CCTA for providing valuable information to guide management of symptomatic women. Figure 1. Ischemic risk in women vs. men Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health - National Heart, Lung, and Blood Institute

Background Assessment of left ventricular (LV) function in patients with secondary mitral regurgitation (SMR) remains challenging because LV ejection fraction (LVEF) reflects changes in LV volume without taking into account the direction of the blood flow. LV global longitudinal strain better reflects active LV myocardial deformation but does not incorporate afterload. LV myocardial work derived from pressure-strain loops integrates speckle tracking echocardiography with non-invasive blood pressure measurement. Purpose To evaluate LV myocardial work components to better characterize LV function in patients with SMR. Methods 378 patients (72% men, median age 68 [range 60 to 74 years]) with various grades of SMR were retrospectively analysed. LV myocardial constructive work, wasted work and work efficiency were measured with speckle tracking echocardiography. Results 145 patients had mild SMR, 130 moderate SMR and 103 severe SMR. Patients with severe SMR had larger LV volumes, lower LVEF and more impaired LV GLS (Table 1). While LV constructive work was more impaired in patients with severe SMR, wasted work was lower as compared to mild SMR (Table 1). Consequently, patients with severe SMR had better myocardial work efficiency than patients with mild MR. This could reflect, the regurgitant volume which is pumped into a low pressure chamber (the left atrium) resulting in less myocardial wasted work and preservation of myocardial efficiency. Conclusion In patients with severe SMR, LVEF, LV GLS and myocardial constructive work are more impaired when compared to mild SMR. However, myocardial wasted work is lower, resulting in higher better LV myocardial work efficiency. Funding Acknowledgement Type of funding source: None

Background Late gadolinium contrast enhanced cardiac magnetic resonance (LGE CMR) imaging accurately quantifies the extent of fibrosis and transmurality in chronically infarcted left ventricular (LV) segments, and identifies viability. Moreover, CMR characterizes the remote, non-infarcted zone, which is an emerging region of interest following ST-segment elevation myocardial infarction (STEMI). Non-invasive myocardial work is a novel LV function parameter - calculated from speckle-tracking strain echocardiography and sphygmomanometrically-determined blood pressure, which has shown excellent correlation with invasively measured myocardial work. Purpose To explore the relation of non-invasively estimated parameters of LV myocardial work to post-infarct scar on LGE CMR, and to compare myocardial work indices between the infarct core and remote zone in STEMI patients who were treated with primary percutaneous coronary intervention (PCI). Methods Patients with a STEMI who underwent primary PCI and LGE CMR, in addition to echocardiographic studies where non-invasive myocardial work analysis was feasible, were included. The LV was subdivided into non-infarcted, non-transmural and transmurally infarcted segments. The remote zone was defined as the non-infarcted myocardial segment diametrically opposed to the infarct core, without any evidence of LGE. Myocardial work indices were compared with linear mixed models, ANOVA and Wilcoxon signed rank tests. Results 53 patients (89% male, age 58±9 years) and 689 segments were analysed. The mean scar burden comprised 14±7% of the total LV mass and 76 (11%) segments showed transmural LGE. The following non-invasive myocardial work indices: myocardial work index (MWI), constructive work (CW) and myocardial work efficiency (MWE) showed a significant inverse relationship with infarct transmurality (p Conclusions In STEMI patients who underwent primary PCI, MWI, CW and MWE were significantly related to the extent of transmural infarction, while WW demonstrated a trend. MWI, CW and MWE were significantly lower, and WW higher, in the core zone compared to the remote zone. Non-invasive myocardial work indices may provide an echocardiographic method for determining post-infarct viability, as well as characterization of the remote zone. MW and scar transmurality on LGE CMR Funding Acknowledgement Type of funding source: None

Background Functional tricuspid regurgitation (FTR) can be caused by right ventricular (RV) and/or right atrial (RA) dilation, and it leads in turn to further RV and RA remodeling. While it is known that in these patients RV dilation is associated with worse prognosis, there are no data on the prognostic value of RA enlargement. Purpose To assess the prognostic impact of RA dilation in patients with significant (≥ moderate) FTR taking into account the presence of atrial fibrillation (AF). Methods 1382 patients (mean age: 69±13 year; 50% male) with moderate or severe FTR were included. Patients with congenital heart disease were excluded. Significant RA enlargement was identified by the value of RA area associated with excess of mortality according to spline curve analysis in the overall population (30 cm2 – Figure: Left Panel). The prognostic value of RA enlargement was investigated separately in patients with sinus rhythm (SR) and AF. The primary endpoint was all-cause mortality. Results A total of 987 (71%) patients were in SR while the remaining 395 (29%) had AF at the time of significant FTR diagnosis. Patients in SR with RA enlargement were more likely to present with RV failure symptoms and to receive diuretics compared with patients in SR with non-enlarged RA, whereas these differences were not detected in patients with AF. During a median follow-up of 53 (interquartile range, 20–89) months, 698 (51%) patients died. The survival rates of patients in SR with RA enlargement were significantly worse compared to the ones of patients in SR with normal RA size (Figure: Right Panel). In contrast, RA enlargement did not affect the prognosis of patients in AF (Log-rank χ2: 0.41; P=0.522). RA enlargement was associated with 33% increase risk of all-cause mortality in patients with SR and this association was retained on a multivariable Cox regression analysis (HR 1.27; 95% CI 1.04–1.56; P=0.022) together with older age, coronary artery disease, diabetes, severe renal impairment, reduced left ventricular or RV systolic function, and increased pulmonary artery pressures. Conclusion RA enlargement has an independent prognostic value for all-cause mortality in patients with FTR and SR, and therefore its evaluation might be useful to further improve their risk stratification. Funding Acknowledgement Type of funding source: None

Background Severe aortic stenosis (AS) is associated with adverse clinical outcomes. Little is known about the rate of progression in patients with moderate AS. Purpose Risk factors affecting the rate of progression from moderate to severe AS, and their impact on all-cause mortality were studied in this multicentre registry. Methods Based on the echocardiographic diagnosis of moderate AS (valve area >1.0 and ≤1.5 cm2) at the time of first echocardiogram, 962 patients with follow-up were included. Follow-up echocardiograms were reviewed to identify those who developed severe AS (based on the current guidelines). Patients were divided into 2 groups: AS Progressors (progressed to severe AS) and Non-progressors (remained in moderate AS). Among those with AS progression, patients were subdivided into Slow versus Fast Progressors, according to the median time interval between the two echocardiograms. The clinical correlates of fast AS Progressors were analysed using the binary logistic regression. The association between rate of progression (slow versus fast) and all-cause mortality was assessed by the Kaplan-Meier method using log-rank test. A multivariate Cox proportional analysis was used to identify the independent associates of all-cause mortality, with interval of AS progression between the two echocardiograms (in years) included as a continuous variable. Results Of the 962 patients with moderate AS, AS progressed to severe in 62% (n=595), while 38% (n=367) remained in moderate AS, over a mean follow-up of 6.8 [IQR 4.2–9.3] years. Older age, renal impairment (eGFR Conclusion In a large real-world registry of patients with moderate AS, fast progression to severe AS is associated with worse survival. Close surveillance should be given to those patients who are at higher risk of AS progression. AS progression and all-cause mortality Funding Acknowledgement Type of funding source: None

Background Hypo-attenuated leaflet thickening (HALT) of transcatheter aortic valves can be observed on multidetector computed tomography (MDCT) and is considered as an early marker of leaflet thrombosis. Preliminary data has suggested that HALT will prevent or delay reverse left ventricular (LV) remodeling after transcatheter aortic valve implantation (TAVI). Purpose The purpose of the present study was to assess the association of HALT to reverse LV remodeling after TAVI. Methods In this multicenter study, patients who underwent MDCT after TAVI were evaluated. The presence of HALT was assessed with MDCT. Transthoracic echocardiograms were performed to assess LV dimensions and function before and 12 months after TAVI; transcatheter valve hemodynamics were assessed immediately after TAVI and at 12 months follow-up. Results A total of 169 patients (mean age 81±7 years, 53% male) who underwent MDCT performed 35 days [IQR 32–52] after TAVI were analyzed. HALT was observed in 42 (33%) patients. Before TAVI, LV mass (LVM) and LV mass index (LVMi) did not differ between patients with or without HALT: 227±80 vs. 234±62 g (p=0.568) and 121±37 vs. 126±32 g/m2 (p=0.35), respectively. Also LV ejection fraction (LVEF) was comparable between groups, 51±10 vs. 50±12%, p=0.64. LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were lower in patients with HALT: 75 (67–115) vs. 99 (77–127) ml (p=0.030) and 39 (30–53) vs. 46 (33–65) ml (p=0.050), respectively. At 12 months follow-up, we found no differences in LVM or LVMi regression, decrease of LV volumes or transprosthetic gradients between groups (Figure 1). Conclusion Patients who presented with HALT had significantly lower LV volumes before TAVI. LV mass and volumes regressed significantly at 12 months after TAVI, however LV remodeling was not associated to the presence of HALT. Funding Acknowledgement Type of funding source: None

Background It is unclear whether the annual progression of aortic valve calcification (AVC) is associated with the progression of coronary atherosclerosis. Purpose We explored the association between AVC and the total and compositional plaque volume (PV) progression. Methods We performed a prospective multinational registry of consecutive patients who underwent serial coronary computed tomography angiography (CTA) at ≥2-year intervals. AVC, and total and compositional PV at baseline and follow-up were quantitatively analyzed. Multivariate linear regression models were constructed. Results Overall, 594 patients (56% male, 61.5±9.7 years old) were included (mean coronary CTA interval, 3.9±1.5 years). At baseline, AVC was 30.9±117.3. Normalized total PV at baseline was 122.3±219.4mm3, encompassing 41.9±116.8mm3 of calcified PV and 80.4±131.5mm3 of non-calcified PV. After adjustment of age, sex, clinical risk factors, and drug use, AVC at baseline was independently associated with total and all compositional PVs (all p0.05) (Table, Figure). Conclusion The overall burden of coronary atherosclerosis is associated with AVC at baseline. However, the progression of AVC is associated only with the progression of calcified PV but not with that of total and non-calcified PV. Representative case Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT)

Background Left ventricular (LV) myocardial contractility evaluation is of crucial importance in patients with secondary mitral regurgitation (SMR). The most widespread echocardiographic tool, left ventricular ejection fraction (LVEF), might overestimate LV function, since it calculates the volume changes regardless of the flow direction. Global myocardial constructive work (GMCW) might be a more suitable tool, as LV myocardial work derived from pressure-strain loops obtained with speckle tracking echocardiography incorporates non-invasive blood pressure measurements. Purpose To evaluate the prognostic value of LV GMCW in patients with SMR. Methods 378 patients (72% men, median age 68 [range 60 to 74 years]) with various grades of SMR were retrospectively analysed. LV global myocardial constructive work, wasted work and work efficiency were measured with speckle tracking echocardiography. Results There were 145 patients with mild SMR, 130 with moderate SMR and 103 with severe SMR. Patients with severe SMR had larger LV volumes, lower LVEF and more impaired LV GLS. GMCW was more impaired in patients with severe SMR, compared with mild MR (678 mmHg% vs. 845 mmHg% p Conclusion Global myocardial constructive work ≤700 mmHg% is associated with worse long-term survival in patients with SMR. Kaplan-Meier survival curves Funding Acknowledgement Type of funding source: None

Background Left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) is a complex pathological process which has been associated with long-term cardiovascular adverse events. The current definition of LV remodelling is usually based on the change in LV end-diastolic volume (LVEDV). An increase in LVEDV, however, may also be considered an adaptive response to maintain effective LV ejection fraction (LVEF) in LV remodelling. Purpose To reclassify post-infarct LV remodelling according to the change in LVEDV and LVEF from baseline and to determine the prognostic relevance of integrated LV remodelling and systolic function groups. Methods A total of 1859 patients with STEMI who received primary percutaneous coronary intervention (PCI) and guideline-directed medical treatment, were retrospectively evaluated. Four LV remodelling subgroups were identified, based on the change in LVEDV and LVEF from baseline to 6 months post-infarct. ≥20% increase in LVEDV, compared to baseline, was defined as LV dilatation, while any increase or decrease in LVEF compared to baseline was used to categorise remodelling further according to systolic function. Study endpoints were all-cause mortality and the composite of all-cause mortality and heart failure (HF) hospitalisation. Results The mean age of the study population was 60±11 years and the majority were men (76.4%). 402 patients showed LVEDV≥20% and LVEF increase (Group 1), 952 patients LVEDV≤20% and LVEF increase (Group 2), 325 patients LVEDV≤20% and LVEF decrease (Group 3) and 180 patients LVEDV≥20% and LVEF decrease (Group 4). During a median follow-up of 89 (IQR 64; 113) months, all-cause mortality occurred in 256 patients (13.8%), HF hospitalisation in 40 patients (2.2%) and the composite endpoint in 279 patients (15.0%). All-cause mortality was significantly higher in Group 4 (21.7%, chi-square p=0.002) compared to other groups (15.4% in Group, 12.9% in Group 2 and 9.8% in Group 3). The composite endpoint was also significantly more frequent in Group 4 (25.6%, chi-square p Conclusion Patients with LVEDV≥20% and a LVEF decrease at 6 months after STEMI experienced all-cause mortality and the composite endpoint of all-cause mortality and HF hospitalisation more frequently compared to other LV remodelling groups. Patients with an increase in LVEDV and a decrease in LVEF 6 months after STEMI, may benefit from careful surveillance and preventative strategies. KM comparison for study endpoints. Funding Acknowledgement Type of funding source: None

Background Right ventricular myocardial work (RVMW) is a novel method of non-invasively quantifying right ventricular (RV) systolic function. Through the use of speckle tracking echocardiography-derived RV pressure-strain loops, RVMW provides a quantitative evaluation of afterload-dependent RV systolic function. Purpose To investigate RVMW in patients with heart failure and reduced ejection fraction (HFrEF) and compare to that of patients without cardiovascular disease (CVD) and a structurally and functionally normal heart. Methods Noninvasive analysis of RVMW was performed in 23 HFrEF patients and 23 patients without cardiovascular or structural heart disease. The novel indices of RV global constructive work (RVGCW), RV global work index (RVGWI), RV wasted work (RVWW) and RV global work efficiency (RVGWE) were analysed utilizing proprietary software originally developed for the assessment of left ventricular myocardial work by speckle tracking echocardiography. Parameters of RVMW were then compared between the two patient groups. Results The HFrEF group had lower left ventricular (LV) ejection fraction (18.7% [±6.7] vs 60.1% [±4.6], p Conclusion The novel parameters of RVGWI, RVGWW and RVGWE were significantly reduced in patients with HFrEF when compared to those without CVD. Further exploration of the clinical role and prognostic value of these afterload dependent parameters of RV systolic function is warranted. Funding Acknowledgement Type of funding source: None

Background Machine learning allows classifying diseases based only on raw echocardiographic imaging data and is therefore a landmark in the development of computer-assisted decision support systems in echocardiography. Purpose The present study sought to determine the value of deep (machine) learning systems for automatic discrimination of takotsubo syndrome and acute myocardial infarction. Methods Apical 2- and 4-chamber echocardiographic views of 110 patients with takotsubo syndrome and 110 patients with acute myocardial infarction were used in the development, training and validation of a deep learning approach, i.e. a convolutional autoencoder (CAE) for feature extraction followed by classical machine learning models for classification of the diseases. Results The deep learning model achieved an area under the receiver operating curve (AUC) of 0.801 with an overall accuracy of 74.5% for 5-fold cross validation evaluated on a clinically relevant dataset. In comparison, experienced cardiologists achieved AUCs in the range 0.678–0.740 and an average accuracy of 64.5% on the same dataset. Conclusions A real-time system for fully automated interpretation of echocardiographic videos was established and trained to differentiate takotsubo syndrome from acute myocardial infarction. The framework provides insight into the algorithms' decision process for physicians and yields new and valuable information on the manifestation of disease patterns in echocardiographic data. While our system was superior to cardiologists in echocardiography-based disease classification, further studies should be conducted in a larger patient population to prove its clinical application. Funding Acknowledgement Type of funding source: None

Contains fulltext : 182860.pdf (Publisher’s version ) (Open Access) Fractional flow reserve (FFR) guided percutaneous coronary intervention (PCI) is associated with favourable outcome compared with revascularization based on angiographic stenosis severity alone. The feasibility of the new image-based quantitative flow ratio (QFR) assessed from 3D quantitative coronary angiography (QCA) and thrombolysis in myocardial infarction (TIMI) frame count using three different flow models has been reported recently. The aim of the current study was to assess the accuracy, and in particular, the reproducibility of these three QFR techniques when compared with invasive FFR. QFR was derived (1) from adenosine induced hyperaemic coronary angiography images (adenosine-flow QFR [aQFR]), (2) from non-hyperemic images (contrast-flow QFR [cQFR]) and (3) using a fixed empiric hyperaemic flow [fixed-flow QFR (fQFR)]. The three QFR values were calculated in 17 patients who prospectively underwent invasive FFR measurement in 20 vessels. Two independent observers performed the QFR analyses. Mean difference, standard deviation and 95% limits of agreement (LOA) between invasive FFR and aQFR, cQFR and fQFR for observer 1 were: 0.01 +/- 0.04 (95% LOA: -0.07; 0.10), 0.01 +/- 0.05 (95% LOA: -0.08; 0.10), 0.01 +/- 0.04 (95% LOA: -0.06; 0.08) and for observer 2: 0.00 +/- 0.03 (95% LOA: -0.06; 0.07), -0.01 +/- 0.03 (95% LOA: -0.07; 0.05), 0.00 +/- 0.03 (95% LOA: -0.06; 0.05). Values between the 2 observers were (to assess reproducibility) for aQFR: 0.01 +/- 0.04 (95% LOA: -0.07; 0.09), for cQFR: 0.02 +/- 0.04 (95% LOA: -0.06; 0.09) and for fQFR: 0.01 +/- 0.05 (95% LOA: -0.07; 0.10). In a small number of patients we showed good accuracy of three QFR techniques (aQFR, cQFR and fQFR) to predict invasive FFR. Furthermore, good inter-observer agreement of the QFR values was observed between two independent observers.

Introduction Identifying ST-elevation myocardial infarction (STEMI) patients who can be referred back to the general practitioner (GP) can improve patient-tailored care. However, the long-term prognosis of patients who are returned to the care of their GP is unknown. Therefore, the aim of this study was to assess the long-term prognosis of patients referred back to the GP after treatment in accordance with a 1-year institutional guideline-based protocol. Methods All consecutive patients treated between February 2004 up to May 2013 who completed the 1‑year institutional MISSION! Myocardial Infarction (MI) follow-up and who were referred to the GP were evaluated. After 1 year of protocolised monitoring, asymptomatic patients with a left ventricular ejection fraction >45% on echocardiography were referred to the GP. Long-term prognosis was assessed with Kaplan-Meier curves and Cox proportional hazards analysis was used to identify independent predictors for 5‑year all-cause mortality and major adverse cardiovascular events (MACE). Results In total, 922 STEMI patients were included in this study. Mean age was 61.6 ± 11.7 years and 74.4% were male. Median follow-up duration after the 1‑year MISSION! MI follow-up was 4.55 years (interquartile range [IQR] 2.28–5.00). The event-free survival was 93.2%. After multivariable analysis, age, not using an angiotensin-converting enzyme (ACE) inhibitor/angiotensin-II (AT2) antagonist and impaired left ventricular function remained statistically significant predictors for 5‑year all-cause mortality. Kaplan-Meier curves revealed that 80.3% remained event-free for MACE after 5 years. Multivariable predictors for MACE were current smoking and a mitral regurgitation grade ≥2. Conclusion STEMI patients who are referred back to their GP have an excellent prognosis after being treated according to the 1‑year institutional MISSION! MI protocol.

Background Global work efficiency (GWE) is an index of left ventricular function derived from echocardiographic speckle tracking derived strain-pressure loops. GWE is calculated as constructive work divided by the sum of constructive and wasted work and expressed as a percentage. The prevalence of reduced GWE after ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is unknown. Aims To assess GWE in STEMI patients 3 months after the index admission and report on the prevalence and characteristics of patients with impaired GWE. Methods and results This retrospective study included 150 patients (111 men, mean age: 60±10 years) with STEMI. They were divided into GWE normal and GWE reduced groups, based on reference values from the EACVI NORRE study. Reduced GWE was observed in 23% of patients. Those with reduced GWE had significantly higher values of CK [3033.62 U/L (±2003.47) vs. 1308.47 U/L (±1309.07); P Table 1. Patient characteristics GWE normal (N=116) GWE reduced (N=34) P value Age (years) 60 (±10) 58 (±11) 0.224 HR (bpm) 69 (±13) 74 (± 13) 0.063 SBP (mmHg) 138 (±17) 138 (±21) 0.920 DBP (mmHg) 81 (±12) 84 (±15) 0.214 Maximum CK value at baseline (U/L) 1308.47 (±1309.07) 3033.62 (±2003.47) Conclusions Almost one fourth of STEMI patients treated with primary PCI have impaired GWE at 3 months follow-up. Patients with reduced GWE had larger myocardial damage than those with preserved GWE at 3 months.

Background While symptomatic severe aortic stenosis (AS) carries a worse prognosis and early intervention is favoured, it is always assumed that patients with moderate AS are more stable and their disease progression can be monitored yearly. However, it is known that patients with moderate AS have a higher risk of cardiovascular events but is unclear if other factors may also affect the overall prognosis. Purpose In this multicentre registry of patients with moderate AS, the prognostic value of a new staging classification on the extent of cardiac damage was examined. Methods Based on the echocardiographic findings at the time of diagnosis of moderate AS (valve area >1.0 and ≤1.5 cm2), they were re-classified into five stages depending on the extra-aortic valvular cardiac damage: no signs of cardiac damage (Stage 0), left ventricular (LV) damage [LV ejection fraction 95 g/m2 for women or >115 g/m2 for men or E/e' >14] (Stage 1), mitral valve or left atrial (LA) damage [LA volume index >34 ml/m2 or mitral regurgitation ≥grade 3 or presence of atrial fibrillation] (Stage 2), tricuspid valve or pulmonary artery vasculature damage [systolic pulmonary arterial pressure ≥60 mmHg or tricuspid regurgitation ≥grade 3] (Stage 3), or right ventricular damage [tricuspid annular plane systolic excursion Results Of the included 522 patients with moderate AS (age 71±11 years, 54% males), 12% (63) of patients were re-classified as Stage 0, 30% (157) in Stage 1, 47% (245) in Stage 2, 6% (31) in Stage 3 and 5% (26) in Stage 4. During follow-up, 43% (226) of patients underwent surgical or transcatheter aortic valve replacement. Over a median follow-up of 6.2 [interquartile range 3.2–9.0] years, 254 (49%) patients died. The cumulative event rates for all-cause mortality increased with increasing stage, particularly for Stages ≥2: 39% for Stage 0, 55% for Stage 1, 67% for Stage 2, 68% for Stage 3 and 57% for Stage 4, respectively (Figure, log-rank test p=0.001). Cumulative death rates after re-staging Conclusion In a real-world registry of patients with moderate AS patients, worsening extra-aortic valvular cardiac damage portends a worse long-term prognosis.

Introduction Cardiac involvement in Systemic Lupus Erythematosus (SLE) may lead to left ventricular (LV) hypertrophy with possible impairment of LV diastolic function and left atrial (LA) function, particularly in patients with severe forms of SLE with neuropsychiatric manifestations (NPSLE) and can also be associated with cardiovascular outcome. Purpose We evaluated the prevalence of LV diastolic dysfunction and LA dysfunction in a large cohort of SLE patients including also NPSLE patients, and their association with the occurrence of cardiovascular events (cerebrovascular accidents, lung-embolism, coronary revascularisation, heart failure hospitalisations and development of supraventricular arrhythmias). Methods A total of 102 SLE patients (87% female, 42±15 years) were included, of which 43 (42%) with NPSLE according to a multidisciplinary team assessment. All patients fulfilled the American College of Rheumatology (ACR 1997) and Systemic Lupus Erythematosus International Collaborating Clinics (SLICC 2012) classification criteria for SLE. Echocardiography was performed at the first visit: LV diastolic function was assessed according to current recommendations and including Tissue Doppler Imaging measures; LA volume (LAVI) was also measured and LA function was assessed by LA reservoir strain using 2D speckle tracking imaging. Results In the SLE patients, mean LV mass index was 82±32 g/m2, 29% of patients showed an e'septal 14, 16% a LAVI>34 ml/m2 and 5% a tricuspid velocity >2.8m/s. When applying the currently recommended multiparametric approach, only 4% of SLE patients showed LV diastolic dysfunction. In NPSLE patients, the prevalence of LV diastolic dysfunction was not significantly higher (5%). However, an impaired LA reservoir strain (based on the median value of 25%) was observed in 54% of the total SLE population and in 77% of NPSLE patients suggesting higher sensitivity of this parameter to detect impaired LA function and LV diastolic function. During a median follow up of 11 years (Interquartile range: 4–19 years), 43 (42%) patients developed a cardiovascular event. Kaplan-Meier curve analysis showed that SLE patients with impaired LA strain LA reservoir strain Conclusions LA dysfunction as assessed by LA reservoir strain is significantly impaired in SLE and particularly in NPSLE patients and improve detection of myocardial involvement in these patients. Furthermore, LA reservoir strain is independently associated with the development of cardiovascular events.

Background Mitral valve prolapse (MVP) is known to be associated with ventricular arrhythmias (VA), from symptomatic premature ventricular contractions (PVCs) to malignant ventricular tachycardia (VT) and sudden cardiac death (SCD). Previous studies identified risk factors for VA in these patients such as young woman, bileaflet prolapse and inverted T-waves, but they included only specific cohort of patients who experienced SCD or who had only trivial or mild mitral regurgitation (MR). The prevalence of VA and their potential risk factors in a population of MVP patients with severe MR are unknown. Purpose The aim of our study was to describe the prevalence of VA in patients who underwent mitral valve surgery for moderate to severe MR due to MVP and to identify clinical, electrocardiographic and echocardiographic parameters associated with VA. Methods 797 patients (65±12 years, 65% male) who underwent surgery for MVP were included from 2000 until 2018. The presence of VA was defined as symptomatic and frequent PVCs (Lown grade ≥2), non-sustained ventricular tachycardia (nsVT), VT or ventricular fibrillation (VF) documented before surgery and without an ischemic cause. The echocardiogram and electrocardiogram (ECG) prior to operation were used for the specific analysis. ECGs were checked for rhythm, conduction times, QRS morphology and inferior T-wave inversion. The origin of the PVCs was derived from a 12-lead ECG when available and divided in 5 groups; mitral annulus, papillary muscle (PM), left ventricle (LV, including outflow tract), right ventricle (including outflow tract) and other. By echocardiography, several parameters such as LV thickness and volumes, LV ejection fraction (EF), global longitudinal strain (GLS) and MR grade were obtained. Results A total of 99 (12%) patients showed VA; 70% (69/99) of the patients had symptomatic PVCs, 36% (36/99) had nsVT, 12% (12/99) VT and 3% (3/99) VF. 21 patients had more than one type of VA, of which the combination PVCs and nsVT was the most common (19/99, 19%). In addition, 6 patients experienced an out of hospital cardiac arrest of a non-ischemic cause. When comparing the clinical characteristics (Table), patients with VA were significantly younger (and with better renal function), more frequently diagnosed with Barlow's disease and experienced more palpitations as compared to patients without VA. The ECG analysis showed that patients with VA more often had inferior T-wave inversions and that the PVCs predominantly originated from the PM whereas in patients without VA the PVCs originated from different regions. Echocardiography showed that patients with VA had a thinner posterior wall, reduced LV EF and worse GLS; more severe MR was not associated with VA. Conclusion In MVP patients with moderate to severe MR undergoing surgery, Barlow's disease, inferior T-wave inversions, thinner posterior wall and LV systolic dysfunction are associated with the presence and development of VA.

Background Several studies have suggested a familial clustering of mitral valve prolapse (MVP), especially for Barlow disease (BD), which is regarded as the effect of genetic or developmental errors. However, the genetic etiology of MVP, in particular BD, is largely unknown. So far only three genes have been identified: FLNA, DCHS1 and PLD1. Purpose The aim of this study was to identify genes associated with MVP using whole exome sequencing (WES). Methods Patients with MVP, who were classified as BD and/or had a positive family history for MVP, were referred for genetic counseling and WES. In total, 106 unrelated probands were included to identify potentially pathogenic variants in a set of 551 genes associated with cardiovascular development and/or diseases. The population databases Genome Aggregation and WES data from 110 parents of children with mental retardation were used as controls. Variants were analyzed using prediction programs, frequency in the population database and literature search. Variants were divided into the following categories: likely benign, variant of unknown significance or likely pathogenic. Results Thirteen percent (14/106) of the probands had a likely pathogenic variant in seven different genes: DCHS1 (1x), DSP (1x), HCN4 (2x), MYH6 (1x), TMEM67 (1x), TRPS1 (1x) and TTN (7x); the DSP, MYH6 and HCN4 variants cosegregated in affected relatives. None of the 110 parents of children with mental retardation had a likely pathogenic variant in these seven genes. In addition, 31% (33/106) of the probands harbored a variant of unknown significance in 23 different genes, including the genes DSP, FLNA, MYH6 and TTN (Fig). Remarkable, one variant of unknown significance in the FBN2 gene was shared among three unrelated probands and did not occur in population databases. Conclusion WES analysis conducted in probands with MVP using a large panel of genes associated with cardiac development and/or disease confirmed previously known causative genes (DCHS1) and expanded the cardiac phenotype of genes originally associated with cardiomyopathy (DSP, HCN4, MYH6 and TTN). This study is the first study that described the association between MVP and the genes DSP, MYH6 and TTN although the pathogenesis is still unknown. This high yield of likely pathogenic variants emphasizes the importance of genetic screening in MVP patients.

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that may involve the cardiovascular system. Diagnosis of cardiac involvement, particularly at an early stage, represents challenge since symptoms in SLE patients are often atypical and current diagnostic tools are characterized by a low sensitivity to detect myocardial dysfunction. Purpose of this study was to assess left ventricular (LV) systolic function in a large cohort of SLE patients in comparison with a control group of healthy subjects and using standard echocardiographic measures and global longitudinal strain (GLS) by 2D speckle tracking analysis. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was tested. Methods A total of 102 patients (87% female, 42±15 years) were analysed including echocardiography at the time of their first visit. All patients fulfilled the American College of Rheumatology (ACR 1997) and The Systemic Lupus Erythematosus International Collaborating Clinics (SLICC 2012) classification criteria for SLE. During follow-up, cardiovascular events included cerebrovascular accident or transient ischemic attack, pulmonary embolism, coronary artery interventions, hospitalisations for heart failure and development of supraventricular arrhythmias. The control group consisted of 50 age- and gender-matched healthy subjects. Results Prevalence of comorbidities, such as hypertension (8%), hypercholesterolemia (4%) and diabetes mellitus (2%) was relatively low in SLE patients. In comparison with the control group, SLE patients were characterized by worse LV systolic function as measured by LV ejection fraction (51±6% vs 62±6%, p LV GLS in SLE patients Conclusions In SLE patients, LV systolic function as measured by GLS is significantly impaired and independently associated with cardiovascular events. Incorporation of LV GLS in the early assessment of these patients may significantly improve risk-stratification for cardiovascular events.

Background The impact of left bundle branch block (LBBB) on left ventricular (LV) myocardial work may vary according to the specific definition of a LBBB. Quantification of the interplay between LV myocardial work and the underlying electrical dyssynchrony may improve our understanding of cardiac resynchronization therapy (CRT) response. Objective To evaluate the impact of LBBB, defined according to Strauss and ESC 2013 ECG criteria, as well as non-LBBB morphologies on different LV myocardial work indices and response to CRT. Methods LBBB was defined according to the Strauss criteria and ESC 2013 guidelines on heart failure. LV myocardial constructive and wasted work (CW and WW) were derived from pressure-strain loop analysis integrating valvular opening and closing times, speckle tracking strain echocardiography and noninvasive blood pressure measurement. LV myocardial work efficiency (WE) was calculated from the ratio of constructive work, divided by the sum of constructive and wasted work. CRT response was defined as a decrease in LV end-diastolic volume (EDV) ≥15% at 6 months' follow-up. Results Patients were divided into 3 groups: 1) LBBB according to Strauss criteria (group 1, n=109, age 64±10 years), 2) LBBB according to ESC 2013 criteria (group 2, n=22, age 64±10 years) and 3) non-LBBB (group 3, n=44, age 69±10 years). Patients from group 1 were 4.2 times more likely to respond to CRT than patients from group 3 (odds ratio [OR] 4.182; 95% confidence interval [CI], 1.999–8.750; p Conclusion Patients with a LBBB according to Strauss criteria had a higher probability of response to CRT, compared to those with a LBBB defined by ESC 2013 guidelines criteria or with non-LBBB morphology. This is reflected in a greater amount of wasted work and more impaired LV myocardial work efficiency at baseline in patients with LBBB satisfying Strauss criteria, compared to the other two groups, representing the substrate for CRT. Acknowledgement/Funding Study was supported by ESC Research grant 2018

Background Myocardial work, assessed by speckle tracking echocardiography, reflects mechanical efficiency of the left ventricle. In heart failure patients, characterization of acute changes in regional (septal and lateral) left ventricular (LV) myocardial walls after cardiac resynchronization therapy (CRT) may enhance understanding of CRT response. Objective To evaluate the interaction between CRT response and components of myocardial work of the lateral wall and septum in patients with heart failure. Methods Regional LV myocardial work was calculated by integrating non-invasive blood pressure measurements, timing of mitral and aortic valve opening and closure and speckle tracking-derived LV longitudinal strain. From pressure-strain loops, constructive work (CW) and wasted work (WW) were calculated. CRT response was defined as a decrease in LV end-systolic volume ≥15% at 6 months follow-up. Changes in CW and WW of the septal and lateral walls prior to (baseline) and within the first 5 days after CRT implantation were compared between CRT responders and non-responders. Results At baseline, measurement of regional CW and WW was performed in 168 patients treated with CRT (71% men, 66±10 years). At 6 months, 59% of patients were CRT responders. CRT responders more frequently had non-ischemic heart failure than non-responders (54% vs 36%; p=0.027). At baseline, CRT responders were characterized by a significantly higher septal WW (270.5 [160.0; 451.5] mmHg% vs. 210.5 [106.3; 336.5] mmHg%; p=0.038) and lateral CW (989.5 [574.0; 1439.0] mmHg% vs. 689.0 [463,3; 1140.0] mmHg%; p=0.005). On multivariable analysis, only CW of the lateral wall at baseline was independently associated with CRT response (HR 1.001; 95% CI, 1.000–1.001; p=0.048). Immediately after CRT implantation, measurement of regional CW and WW was feasible in 115 patients. CRT responders showed improvement in CW (433.0 [254.5; 686.5] mmHg% to 664.5 [424.5; 977.8] mmHg%; p Conclusion CRT responders are characterized by increased WW of the septum and CW of the lateral wall at baseline, which are corrected immediately after CRT implantation. Constructive work of the LV lateral wall at baseline is independently associated with CRT response. Acknowledgement/Funding Study was supported by ESC Research grant 2018

Background It is unclear whether sex impacts the plaque volume (PV) progression in patients with stable coronary artery disease (CAD). Purpose To explore whether the total and compositional PV progression rate differ according to sex. Methods We performed a prospective multinational registry of consecutive patients who underwent serial CCTA at ≥2-year interval. Total and compositional PV at baseline and follow-up were quantitatively analysed and normalized using the analysed total vessel length. Multivariate linear regression models were constructed for each women and men. Results Of the 1,255 patients included (median CT interval 3.8 years), 543 were women and 712 were men. Women were older (62±9 years vs. 59±9 years, p0.05). At baseline, men possessed greater total PV (131.5±230.5mm3 vs. 97.7±193.6mm3, p=0.005) and a higher prevalence of high-risk plaques (HRP) than women (31% vs. 20%, p In multivariate analysis (TABLE), although total PV progression rate was not different, women were associated with greater calcified PV progression (β=2.83, p=0.004) but slower non-calcified PV progression (β=-3.39, p=0.008) and less development of HRP (β=-0.18, p=0.049) than men. CCTA findings according to sex Univariate analysis Female Sex in Multivariable Analysis Women (n=543) Men (n=712) P β SE P Agatston CACS, /year 0.44±0.7 0.4±0.7 0.332 0.106 0.04 0.006 Total PVnormalized, mm3/year 14.7±23.4 17.8±26.2 0.026 -0.56 1.33 0.677 Calcified PVnormalized, mm3/year 10.5±21.5 10.0±19.1 0.670 2.83 0.98 0.004 Non-calcified PVnormalized, mm3/year 4.2±17.3 7.8±21.2 0.001 -3.39 1.28 0.008 Development of high-risk plaque*, n (%) 86 (15.8) 139 (19.5) 0.092 -0.18 0.09 0.049 In linear multivariate regression analysis adjusted with age, race, HTN, DM, family history, smoking, LDL, statin, anti-platelets, beta-blockers, and PV at baseline, women were associated with greater calcified PV progression and slower non-calcified PV progression. (High-risk plaque was defined as ≥2 of low-attenuation plaque, spotty calcification, and positive remodelling.) Conclusion In this large CCTA cohort, we found that the compositional PV progression differs according to sex. These findings, which are hypothesis generating, suggest that comprehensive plaque evaluation may contribute to further refine risk stratification according to sex. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

Background It is still debatable whether the so-called high-risk plaque (HRP) simply represents a certain phase during the natural history of coronary atherosclerotic plaques or the disease progression would differ according to the presence of HRP. Purpose We determined whether the pattern of non-obstructive lesion progression into obstructive lesions would differ according to the presence of HRP. Methods Patients with non-obstructive coronary artery disease, defined as % diameter stenosis (%DS) ≥50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an inter-scan interval of ≥2 years. HRP was defined as lesions with ≥2 of positive remodelling, spotty calcification, and low-attenuation plaque. The total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions. Results A total of 1,115 non-obstructive lesions were identified from 327 patients (61.1±8.9 years old, 66.0% male). There were 690 non-HRP and 425 HRP lesions. HRP lesions possessed greater PAV and %DS at baseline compared to non-HRP lesions. However, the annualized total and non-calcified PAV change were greater in non-HRP lesions than in HRP lesions. On multivariate analysis, addition of baseline PAV and %DS to clinical risk factors improved the predictive power of the model (Table). When clinical risk factors, PAV, %DS, and HRP were all adjusted on Model 3, only baseline PAV and %DS independently predicted the development of obstructive lesions (hazard ratio (HR) 1.046 [95% confidence interval (CI): 1.026–1.066] and HR 1.087 [95% CI: 1.055–1.119], respectively, all p0.05). Comparison of C-statistics of per-lesion analysis to predict progression to obstructive lesion C-statistics (95% CI) P Model 1: Baseline PAV 0.880 (0.879–0.884) – Model 2: Model 1 + baseline %DS 0.938 (0.937–0.939) vs. Model 1: Conclusion The pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV was the most important predictor for lesions developing into obstructive lesions rather than the presence of HRP features at baseline. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

Background The frequency of discordant mean valve gradient (MG) and aortic valve area (AVA) in patients with moderate aortic stenosis (AS) has not been investigated. Objectives Determine the occurrence of discordant gradient in patients with moderate AS (defined by MG 20 mmHg) in terms of patients' characteristics and the impact on long term prognosis. Methods Based on the echocardiographic findings at the time of diagnosis of moderate AS (valve area >1.0 and ≤1.5 cm2), they were re-classified into discordant or concordant gradients, MG 20 mmHg, respectively. The clinical endpoint was all-cause mortality. Results Of 522 patients with moderate AS, 95 (18.2%) had discordant gradient moderate AS (MG Cox proportional hazard analysis All-cause mortality Univariate analysis Multivariate analysis Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age (per 1 year increase) 1.05 (1.03–1.06) moderate (yes/no) 2.02 (1.29–3.16) 0.002 1.36 (0.73–2.54) 0.337 Discordant moderate AS (yes/no) 1.81 (1.34–2.45) Conclusion Discrepant aortic mean gradient in moderate AS is not uncommon and occurs more often in older patients, with higher LV filling pressure and lower EF and stroke volume index. The lower gradient values lead to underestimation of AS severity, and is associated with greater cardiac extra-valvular damage and higher mortality.

Background Tricuspid regurgitation (TR) can be caused by atrial fibrillation (AF) in the absence of left-sided heart disease or pulmonary hypertension. The prognostic impact of AF-TR has not been investigated. Purpose The aim of this study was to investigate the prognostic significance of TR in AF patients who do not show left-sided heart disease, pulmonary hypertension or primary structural abnormalities. Methods A total of 63 AF patients with moderate and severe TR were identified and matched by age and gender to 116 patients with AF without significant TR, resulting in a total study population of 179 patients (mean age 71±7 years, 59% male). As per design of the study, patients with primary TR, significant (moderate or severe) aortic and/or mitral valve disease, previous valvular surgery, congenital heart disease, left ventricular ejection fraction 40mmHg, pacemaker or implantable cardioverter defibrillator leads in situ were excluded as well as patients with AF de novo. Patients were followed for the combined endpoint of all-cause mortality, hospitalization for heart failure and stroke. Results Patients with AF-TR had more often paroxysmal AF as compared to patients without TR (60% vs. 43%, p=0.028). In addition, right atrial volumes and the tricuspid annulus diameter (TAD) were significantly larger in patients with AF-TR compared to their counterparts (p2, renal function, right ventricular (RV) function and TAD, the presence of significant TR was independently associated with the combined endpoint (HR, 2.495; 95% CI, 1.167–5.335; p=0.018), while RV function was not (HR, 1.026; 95% CI, 0.971–1.085; p=0.364). Figure 1. Kaplan-Meier curves Conclusion In the absence of left-sided heart disease and pulmonary hypertension, significant TR is independently associated with worse event-free survival in patients with AF.

Introduction Known predictors of poor outcome in aortic valve stenosis patients include older age, significant valvular calcification, rapid hemodynamic progression and impaired left ventricular (LV) systolic function. LV global longitudinal strain (GLS) quantifies myocardial deformation and LV function and is associated with prognosis in patients with severe aortic stenosis (AS). Multi-detector row computed tomography (MDCT) data are key in the evaluation of patients undergoing transcatheter aortic valve implantation (TAVI) and when acquired throughout the entire cardiac cycle, LV systolic function can be assessed. Novel software can assess LV GLS from MDCT-data. Purpose The present study aimed at assessing the feasibility of determining novel MDCT-derived LV GLS as well as MDCT-derived LV ejection fraction (EF) and their agreement with echocardiographic LV GLS and LVEF in patients treated with TAVI. Methods LVEF and LV GLS were measured on echocardiography and dynamic MDCT using novel CT-software. Agreement between the measurements of two different modalities was assessed using Bland-Altman analysis. Results A total 214 patients (51% male, mean age: 80±7 years) were analysed retrospectively. Mean value of LV GLS on echocardiography was −14±4% whereas mean MDCT-derived GLS was −12.5±4%. Mean value of LVEF on echocardiography was 47±10% and mean MDCT-derived LVEF was 39±11%. On Bland-Altman analysis, MDCT-derived strain analysis underestimated LV GLS compared to echocardiography with a mean difference of 1.44% (95% limits of agreement −3.8 to 6.7%). LVEF was also underestimated on CT with a mean difference of 7.68% (95% limits of agreement −11.5% to −26%). Correlation of measurements between MDCT-derived LV GLS and echocardiographic LV GLS was significant (r=0.791, p Conclusions Assessment of LV GLS and LVEF on dynamic MDCT data provides similar values to those obtained with echocardiography and could be used in the risk-stratification of severe AS patients undergoing TAVI.

Background Left atrial remodelling in hypertrophic cardiomyopathy (HCM) is recognized as the main contributor to the development of atrial fibrillation (AF). It is well reported that the occurrence of AF in HCM increases both morbidity and mortality. Therefore, early recognition of AF is essential. Due to its often silent and paroxysmal nature, the diagnosis can be missed. Purpose PA-TDI, representing total atrial conduction time, reflects the left atrial structural and electrical remodelling. We sought to evaluate the association between this novel non-invasive echocardiographic parameter and AF in patients with HCM. Methods The electronic charts of patients with HCM and no previous history of AF from 1993 to 2018 were retrospectively analysed. PA-TDI was measured offline using pulsed wave tissue Doppler imaging with the sample volume placed on the lateral wall of the left atrium just above the mitral annulus in an apical 4-chamber view. The time interval was determined from the onset of P wave on surface ECG to the peak of the a' wave of the left atrial tissue Doppler tracing. Results There were 208 patients (64% male) with a mean age of 53±14 years in this study. The incidence of AF was 20% over a median follow-up of 56.3 (IQR 18.4–84.5) months. Patients who developed AF, had higher baseline PA-TDI intervals when in sinus rhythm (134±23 ms vs 111±30 ms, P Conclusion A prolonged PA-TDI was strongly associated with the development of AF in patients with HCM. This parameter may be useful to risk-stratify patients with HCM who are at risk of having AF.

Background It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. Methods and results This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3‑month and P = 0.15 at 12-month follow-up). Conclusion Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. Clinical Trial Registration: NTR2516 Electronic supplementary material The online version of this article (10.1007/s12471-018-1213-2) contains supplementary material, which is available to authorized users.