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Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by ventricular dysfunction and ventricular arrhythmias (VA). Adequate arrhythmic risk assessment is important to prevent sudden cardiac death. We aimed to study the incremental value of strain by feature-tracking cardiac magnetic resonance imaging (FT-CMR) in predicting sustained VA in ARVC patients. Methods and results CMR images of 132 ARVC patients (43% male, 40.6 ± 16.0 years) without prior VA were analysed for global and regional right and left ventricular (RV, LV) strain. Primary outcome was sustained VA during follow-up. We performed multivariable regression assessing strain, in combination with (i) RV ejection fraction (EF); (ii) LVEF; and (iii) the ARVC risk calculator. False discovery rate adjusted P-values were given to correct for multiple comparisons and c-statistics were calculated for each model. During 4.3 (2.0–7.9) years of follow-up, 19% of patients experienced sustained VA. Compared to patients without VA, those with VA had significantly reduced RV longitudinal (P ≤ 0.03) and LV circumferential (P ≤ 0.04) strain. In addition, patients with VA had significantly reduced biventricular EF (P ≤ 0.02). After correcting for RVEF, LVEF, and the ARVC risk calculator separately in multivariable analysis, both RV and LV strain lost their significance [hazard ratio 1.03–1.18, P > 0.05]. Likewise, while strain improved the c-statistic in combination with RVEF, LVEF, and the ARVC risk calculator separately, this did not reach statistical significance (P ≥ 0.18). Conclusion Both RV longitudinal and LV circumferential strain are reduced in ARVC patients with sustained VA during follow-up. However, strain does not have incremental value over RVEF, LVEF, and the ARVC VA risk calculator.

Background Cardiac CT acquired during the acute stroke imaging protocol is an emerging alternative to transthoracic echocardiography (TTE) to screen for sources of cardioembolism. Currently, its diagnostic accuracy to detect patent foramen ovale (PFO) is unclear. Methods This was a substudy of Mind the Heart, a prospective cohort in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during the initial stroke imaging protocol. Patients also underwent TTE. We included patients Results Of 452 patients in Mind the Heart, 92 were younger than 60 years. Of these, 59 (64%) patients underwent both cardiac CT and cTTE and were included. Median age was 54 (IQR 49–57) years and 41/59 (70%) were male. Cardiac CT detected a PFO in 5/59 (8%) patients, 3 of which were confirmed on cTTE. cTTE detected a PFO in 12/59 (20%) patients. Sensitivity and specificity of cardiac CT were 25% (95% CI 5–57%) and 96% (95% CI 85–99%), respectively. Positive and negative predictive values were 59% (95% CI 14–95) and 84% (95% CI 71–92). Conclusion Prospective ECG-gated cardiac CT acquired during the acute stroke imaging protocol does not appear to be a suitable screening method for PFO due to its low sensitivity. Our data suggest that if cardiac CT is used as a first-line screening method for cardioembolism, additional echocardiography remains indicated in young patients with cryptogenic stroke, in whom PFO detection would have therapeutic consequences. These results need to be confirmed in larger cohorts.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Amsterdam Movement Sciences and the Dutch Olympic Committee. Background Cardiac magnetic resonance imaging (CMR) T1 mapping is an established tool for tissue characterisation. This is of particular interest in athletes as differentiation of the ‘grey zone’ between physiological adaptation to sports and pathology can be highly challenging. To correctly interpret individual T1 times, T1 times are conventionally compared to normal values derived from healthy controls. However, whether these values can be applied to elite athletes with different types of cardiac adaptation is unknown. Purpose To determine differences in native T1 times between elite athletes and healthy non-athletic controls and to determine differences in athletes with different types of cardiac remodelling. Methods This is a cross-sectional analysis of elite athletes included in the ELITE cohort. ELITE collects the preparticipation cardiovascular screenings data from all athletes that perform at the highest national, international and/or Olympic level in the Netherlands. All athletes were sixteen years or older. The screening includes cardiovascular magnetic resonance imaging on a Siemens Avanto fit 1.5T machine with cine-imaging, delayed hyperenhancement and a three-pulse shortened modified look-locker inversion recovery 5(3)3 sequence. For this analysis, all athletes with a history of cardiovascular disease or pathological late gadolinium enhancement were excluded. Athletes were classified according to the Mitchell Sports Classification based on the intensity (low (L) / moderate (M) / high (H)) of the dynamic (D) and static components (S). Native- and post-contrast T1 mapping times were calculated by manually tracing the endocardial- and epicardial contours. Results A total of 117 elite athletes (44% women; mean age 26±6.5; Mitchell sports classification: 47 HS/HD, 8 HS/LD, 5 HS/MD, 36 LS/HD, 16 MS/HD, 3 MS/MD, 3 missing) and 48 healthy non-athletic controls (54% women; mean age 39±15.1). Men had lower t1 times compared to women, both in athletes (949ms vs 964ms, p Conclusion Men demonstrate markedly shorter T1 times compared to women in both athletes and controls. Moreover, native T1 times were associated with markers for cardiac remodelling. Sex- and athlete-specific characteristics should be taken into account when interpreting T1 times in athletes.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Amsterdam Movement Sciences (AMS); Dutch National Olympic Committee & National Sports Federation (NOC*NSF); Heart To Handle. Background Differentiating between exercise-induced cardiac remodelling (EICR) and pathology constitutes a central challenge in sports cardiology. To facilitate this differentiation, reference ranges for cardiovascular magnetic resonance imaging (CMR) are needed. However, female athletes, and especially, female elite athletes with potentially the most outspoken adaptation, are severely underrepresented. Moreover, no large studies including CMR data in female, elite athletes are currently available. Purpose To quantify EICR on CMR in a large cohort of female, elite athletes, compared with currently available reference values of the general female, and female athlete population. Methods We performed a cross-sectional CMR analysis in female elite athletes aged ≥16 years, included in the ELITE cohort. We excluded athletes with known cardiovascular disease. The primary outcome was EICR quantification as BSA indexed RV and LV end-diastolic volume (EDVi), LV wall mass (LVMi), LV remodelling index (LVMi/LVEDVi), and LV/RV ratio (LVEDi/RVEDVi). Second, we compared our parameters with reference ranges (1,2). CMR was performed according to a uniform protocol, and included cine-imaging and delayed hyperenhancement, preferentially on 1.5T. A dedicated core-lab analysed all CMRs in Circle Cardiovascular Imaging. Results We included 102 female elite athletes, 97% caucasian, mean age of 26.3 ±5.0, BSA 1.79 ±0.14 m2, and mean professional athlete years of 10.3 ±5. Main athlete disciplines (≥10 hours/week) were field hockey (15%), rowing (13%), road cycling (12%), and European style football (10%). Female elite athletes had marked EICR as compared with general population reference values, with higher LVEDVi (108 ±13.9 vs 69 ±12 ml/m2, p Conclusion EICR on CMR in female, elite athletes is mainly characterised by isolated increased volumes, with a considerable proportion (11%) demonstrating no EICR. Compared with the general population, female athletes have larger cardiac ventricular volumes and wall mass; compared with available elite athlete reference ranges comparable ventricular volumes, but a larger spread in cardiac wall mass. Our results constitute a first step towards sex-specific CMR reference ranges for female athletes.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC Norfolk was supported by the Medical Research Council UK (programme grants numbers MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (programme grant number CRUK 8257). Introduction The Systematic COronary Risk Evaluation 2 – Older Persons (SCORE2-OP) algorithm is developed to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in apparently healthy individuals aged ≥70 years. We evaluated the performance of SCORE2-OP in the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. Purpose To validate the SCORE2-OP model in men and women aged 70-80 years without prior myocardial infarction or stroke. Methods We included individuals aged 70-80 without prior myocardial infarction or stroke. We compared SCORE2-OP (low-risk algorithm) calculated 10-year risk with 10-year observed event rates in the EPIC-Norfolk cohort. SCORE2-OP was calculated using baseline EPIC-Norfolk data (1993-1997). Cardiovascular events were defined as a composite outcome of (i) death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, (ii) non-fatal myocardial infarction or (iii) non-fatal stroke. Observed rates were adjusted for competing fatal events. We evaluated discriminative power using C-statistic and calibration by plotting predicted versus observed event rates and calculating the observed/predicted ratios. Results SCORE2-OP was evaluated in 3,712 individuals (54% women) with a median (IQR) age of 73 (72-75) years. Ten-year SCORE2-OP was 10.3% (95% confidence interval (CI) 10.2-10.4) versus observed CVD of 16.8% (95% CI 15.6-18.0), yielding a ratio of 1.6 (95% CI 1.5-1.7). Observed events consisted of 9.4% (95% CI 8.4-10.3) fatal CVD events, 10.6% (95% CI 9.6-11.5) non-fatal myocardial infarctions, 10.5% (95% CI 9.5-11.5) non-fatal strokes, adjusted for 68.9% (95% CI 67.4-70.4) competing mortality events. C-statistic was 0.60 (95% CI 0.58-0.63), with a calibration plot demonstrating underestimation of risk across sex and risk groups.(Figure). Conclusion SCORE2-OP underestimates risk in individuals aged 70-80 years, and demonstrates suboptimal discriminative ability. However some underestimation of risk is to be expected given the EPIC-Norfolk baseline between 1993-1997, a low SCORE2-OP calculated risk should not be used as a standalone argument to withhold preventive efforts in older individuals.

Introduction We present a case of dual drainage of the right upper lobe of the lung into the left atrium and via partial anomalous venous pulmonary return (PAPVR) into a persistent left superior vena cava (SVC). Discussion It is only in the minority of PAPVR cases where the anomalous pulmonary veins cross the midline. We provide a review of current literature on this topic and an explanatory embryological model. Knowledge of embryonic development and possible anatomic variations, including the concept of dual venous drainage of the lung, leads to better interpretation of imaging, with more accurate description of the morphology at hand. High-resolution multidetector computed tomography (MDCT) helps to delineate the exact vascular anatomy. This will enhance a better understanding of and anticipation on the patient’s disease status, with more accurate planning of intervention, and possibly less complications.

Background/Introduction Specific athlete reference values for cardiac volumes and function using cardiac magnetic resonance (CMR) parameters have been reported and are used in clinical practice. Elite athletes are conventionally thought to demonstrate the highest levels of physiological adaptation to sports and therefore dictate the upper limit of normal for biventricular size and function in the athlete population. Purpose To compare volumetric parameters in a cohort of both male and female elite-level athletes to previously published reference values. Methods We used data from the prospective ELITE-cohort, which collects pre-participation data of elite athletes (national-, international-, Olympic-, Paralympic-level), including CMR imaging. Athletes suspected of pathology based on comprehensively investigated electrocardiograph, exercise test, echocardiogram and late gadolinium enhancement were excluded. Biventricular volumes were derived from short-axis cine images using Cvi42 (v5.1.2.) and indexed for body surface area (BSA). Volumetric parameters were compared to the previously reported gender- and Mitchell sports classification specific cardiac 95th percentile (95%tile) reference values, as reported by Luijkx et al.: left-ventricle (LV) end-diastolic volume (EDV) / BSA for high-static and high-dynamic sports (HS/HD; ♀ 142 ♂ 158); low-static and high-dynamic (LS/HD; ♀ 127 ♂ 149); high-static and low-dynamic (HS/LD; ♀ 114 ♂ 140); right ventricle (RV) EDV / BSA HS/HD (♀ 154 ♂ 184), LS/HD (♀ 136 ♂ 163), and HS/LD (♀ 120 ♂ 157). Results We analysed a total of 221 athletes (38% female), with a median age (IQR) of 26.0 (22.5–29.8) years, and mean ±SD BSA of 1.96±0.22 m2. Athletes were classified according to the Mitchell sports classification: HS/HD 116 (54%); LS/HD 61 (29%); moderate-static and high-dynamic (MS/HD) 20 (9.4%); HS/LD 16 (7.5%) (Table). We found smaller mean ±SD (95%tile) RV EDV/BSA in athletes participating in HS/HD sports (♀: 117±20 (148) and ♂: 133±20 (160)) and LS/HD sports (♀: 109±11 (129) and ♂: 119±15 (142)) and smaller LV EDV/BSA in male athletes in LS/HD sports (116±15 (138)) compared to reference values, (Figure). When using conventional cut-offs in our population we found 10 (4.5%) and 2 (0.9%) athletes above 95%tile for LVEDV/BSA and RVEDV/BSA, respectively (Figure). Conclusion In a cohort consisting of healthy, elite athletes, volumetric adaptations were less outspoken as compared with current reference ranges, specifically in the RV. Only 1 percent of our athletes exceeded conventional 95%tile references for the RV. Potentially, current athlete reference values could overestimate healthy upper limits of cardiac volumes in elite athletes. Our study could indicate that a stricter definition of volumetric reference values, including 95%tile, might be of added value in the specific group of elite athletes to help differentiate between pathology and sports adaptation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Amsterdam Movement Sciences (P1A210AMC2018)

Introduction Current primary prevention strategies in cardiovascular (CV) disease focus on initiating preventive interventions in people at high 10-year risk of CV mortality. However, initiating such strategies should be beneficial not only in the first 10 years, but throughout life. Established risk algorithms estimate the risk of 10-year CV mortality, but limited evidence is available about the relationship between 10-year and longer-term CV mortality. Purpose To compare cumulative incidence of CV mortality in a population cohort at 10- and 20-years follow-up, stratified by sex. Methods We analysed CV mortality at 10-years and 20-years follow-up using Kaplan-Meier estimates among men and women aged 39–70 years without baseline CV disease or diabetes mellitus in the large, prospective population-based EPIC-Norfolk cohort. CV mortality included death with as underlying or contributing cause ischaemic heart disease, heart failure, cerebrovascular disease or peripheral artery disease. Results We analysed data from 20,453 participants (56% women), with a mean age of 56±8 years, and median (IQR) follow-up of 22 (21–23) years. At baseline, there were no clinically relevant differences in CV risk factors between men and women. Overall cumulative CV mortality rate was 1.9% (384 deaths) in the first 10 years, and 7.3% (995 deaths) at 20 years follow-up (ratio 3.8). Among men, 10-year CV mortality was 2.9% (249 deaths), and 9.6% (785 deaths) at 20 years follow-up (ratio 3.3). Among women, CV mortality was 1.2% (135 deaths) at 10 year and 5.5% (594 deaths) at 20 years follow-up (ratio 4.6). Conclusion We observed an incremental increase in CV mortality beyond the 10-year scope of current established CV risk algorithms. At 20 years follow-up, CV mortality rates were 3–5 times higher compared with the first decade, indicating that 20-year CV mortality risk for both men and women cannot simply be estimated based on extrapolation of 10-year risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257).

Background Cardiac radioablation for ventricular tachycardia (VT) appears to be highly effective and safe in patients with recurrent VT despite anti-arrhythmic therapy and catheter ablation(s), although global experience is currently very limited. Detailed echocardiographic strain analysis could provide important insights in (subclinical) functional safety. Importantly, current stereotactic cardiac radioablation techniques includes irradiation of the VT substrate but, inherently, also includes irradiation of the VT border zone and some healthy cardiac tissue. The latter particularly may result in detoriation of cardiac function after cardiac radioablation. Purpose To evaluate functional echocardiographic safety of cardiac radioablation. Methods The STARNL-1 trial is a prospective, monocenter, single-arm, pre-post intervention study. Six patients with recurrent VT despite high dose anti-arrhythmic drugs, after (single or multiple) conventional catheter ablation and deemed unsuited for repeat catheter ablation, were treated with a single fraction 25 Gy radiotherapy dose. Per protocol, patients underwent echocardiograms at baseline, 24 hours after treatment, and 3 months after treatment. Echocardiograms were analysed using 2D-speckle tracking. Mean radiotherapy dose per segment was calculated according to the AHA 17-segment model. Echocardiographic parameters were compared between baseline, 24 hours and 3 months, and correlated to radiotherapy dose. Results Patients were all male (age 55–83 years), all suffered from ischaemic cardiomyopathy, and all completed 3 month follow-up. At baseline, median left ventricle ejection fraction (LVEF) was 38% [30; 47] and median global longitudinal strain (GLS) −8% [−12; −5]. Interestingly, LVEF significantly improved 24 hours after treatment (42% [36; 49], p=0.046) but GLS did not change (−7% [−12; −5], p=0.833). At 3 months, both LVEF and GLS were unchanged compared to baseline (LVEF 39% [33; 49%], p=0.463; GLS −6% [−12; −5], p=0.893). The difference in longitudinal strain per segment before and after treatment did not correlate with the mean radiotherapy dose per segment, both 24 hours after treatment (Pearson coefficient −0.082, p=0.410) and 3 months after treatment (Pearson coefficient −0.005, p=0.957). In Figure 1 an illustrative case is presented. Conclusion(s) Cardiac radioablation for VT does not worsen (subclinical) cardiac function within the first 3 months after treatment. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation

Background/Introduction SARS-CoV-2 (subclinical) myocarditis has been demonstrated in up to 5% in athletes, and is currently a topic being intensively investigated. However, more subtle changes in function and volumetric parameters have been less well documented, especially in elite athletes, who perform at the highest levels of sports, with potentially the most outspoken adaptation. Purpose To determine differences in cardiac function and volumetric parameters using cardiac magnetic resonance imaging (CMR) in elite athletes recovered from a SARS-CoV-2 infection as compared to non-infected elite athletes (controls). Methods We included elite athletes from the ELITE (Evaluation of Lifetime Intensive Top-level sports and Exercise) cohort, who voluntary undergo cardiovascular pre-participation screenings, which includes cardiac magnetic resonance imaging (CMR). SARS-CoV-2 infection was diagnosed with a positive-PCR or antibody test (if unvaccinated). The primary outcome was the incidence of structural cardiac changes on CMR, defined as LV/RV BSA indexed-EDV (EDVi), LV/RV BSA indexed-ESV (ESVi), LV/RV EF, presence of pathological late gadolinium enhancement (LGE) (excluding hinge point fibrosis), and T1 times. Results We included 234 elite athletes, mean age 27 (±7), 39% female, with main athletic disciplines (≥10 hours/week) of cycling (24%), field hockey (13%), and water polo (12%). In total 69 elite athletes had documented SARS-CoV-2 infection, and 165 were documented as not exposed to SARS-CoV-2. The majority reported mild symptoms 61/69 (88%), 1/69 (1%) severe symptoms, and 7/69 (11%) no symptoms. Mean time between infection and CMR was 2.8 (±2) months. CMR showed no significant difference between elite athletes with SARS-CoV-2 and without (Table) in mean LVEDVi (117±19 vs 120±19 ml/m2, p=0.29), LVESVi (50.6±11 vs 53.2±11 ml/m2, p=0.12), LVEF (56.9% ±5 vs 55.8% ±5, p=0.14), RVEDVi (120±20 vs 122±19 ml/m2, p=0.56), RVESVi (54.5±11 vs 56.2±11 ml/m2, p=0.29), and RVEF (54.6% ±4 vs 53.9% ±5, p=0.23). In 4/69 (4.7%) vs 1/165 (1.3%) pathological non-ischemic pattern of myocardial LGE was present (≤20% of total LV mass), of which one athlete (1.2%) showed increased T1 time, all with no deterioration in right and left ventricle function and volumetric parameters (Figure) after SARS-CoV-2 infection. All athletes made a full recovery and returned to elite competitive sports. Conclusion(s) This cross-sectional study of elite athletes demonstrates that infection with SARS-CoV-2 is not associated with deterioration in cardiac function and volumetric parameters on CMR compared with non-infected athletes, also in the small subset of athletes with pathological LGE patterns after SARS-CoV-2 infection. Prospective studies with long-term follow-up are needed to establish whether intensive sports is associated with long-term cardiac deleterious effects in elite athletes exposed to SARS-CoV-2. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart FoundationDutch National Olympic Committee & National Sports Federation (NOC*NSF)

Background Anomalous coronary artery from the pulmonary artery is a rare congenital disorder with high mortality rates in infancy. Adult cases can present with life-threatening arrhythmias and sudden cardiac death. Case summary We report three cases of adults with anomalous pulmonary origin of each of the main coronary branches. The first patient with an anomalous left coronary artery from the pulmonary artery presented with an out-of-hospital cardiac arrest. The second patient with an anomalous circumflex artery from the pulmonary artery was evaluated for a bicuspid aortic valve and a suspected coronary fistula but was otherwise asymptomatic. The third patient with an anomalous right coronary artery from the pulmonary artery presented with anginal symptoms. In all cases, the diagnosis was made by cardiac computed tomography or coronary angiography. Cardiac magnetic resonance imaging was performed in all patients to guide clinical decision making on surgical or non-invasive management. All patients underwent surgical repair. In two patients, a dual coronary artery system was restored by aortic reimplantation of the anomalous coronary artery. In one patient, aortic reimplantation was unsuccessful due to poor vessel quality and the anomalous coronary artery was ligated. Clinical follow-up during 1.8–9.7 years did not show any cardiovascular complications and all patients are currently alive and asymptomatic. Discussion Anomalous coronary artery from the pulmonary artery can have various clinical presentations in adulthood. Cardiac magnetic resonance imaging is a useful modality to guide selection of patients who might have symptomatic or prognostic benefit from surgical repair.

Background/Introduction Transthoracic echocardiography (TTE) is often the first diagnostic imaging modality of choice in athlete care to differentiate between physiological adaptation to sports and pathology. Mechanical strain as outcome measure, i.e. left ventricular (LV) global longitudinal strain (GLS), has been suggested as a tool to detect early signs of myocardial diseases in athletes. However, low or very low rates of myocardial deformation can also be associated with cardiac adaptation to sports. We hypothesize that observing decreased cardiac deformation in elite athletes may be a sign of an outspoken relaxed cardiac state, rather than pathology. Therefore, we investigated whether a short exercise bout can normalize strain values in elite athletes with abnormal resting GLS. Methods We prospectively enrolled elite athletes who participated in the ELITE (Evaluation of Lifetime Participation in Intensive Top-level Sports and Exercise) cohort. In short, ELITE is a prospective athlete cohort, which collects medical history, ECG, TTE and cardiac magnetic resonance (CMR) data in elite athletes (Olympic/Paralympic level or comparable). For this analysis, we analysed TTEs of asymptomatic athletes without cardiovascular disease and with a structurally normal heart on CMR. TTE (Vivid, GE) was performed in each athlete according to guidelines at rest. After a short exercise bout, consisting of 20 squats, additional measurements were performed when heart-rate (HR) was comparable to HR during pre-exercise measurements. TTE data was assessed using EchoPAC (GE). Paired t-tests were calculated for functional parameters; boxplots for pre- and post-exercise measurements; and GLS delta (pre- to post-exercise) for each athlete was calculated were plotted; using R. GLS ≥−16% was considered decreased and −16% ≥ GLS >−18% borderline. Results Our population comprised 51 athletes (35% women), with a mean age (±SD) of 26.4±5.2 years, and mean BSA of 2±0.3m2. Athletic disciplines consisted of road cycling (n=25), hockey (n=7), swimming (n=5), and 7 miscellaneous sports (n=14). We observed an increase of myocardial deformation after a short bout of exercise: mean GLS delta of 2.6±2% (pre- vs post-exercise GLS: −18.2±2.1% vs −20.8±1.9%; P≤0.001; Figure, A). Furthermore, mean LV stroke volumes were 94±19ml vs 103±23ml (P=0.020), ejection fractions (EF) 57±4% vs 60±4% (P≤0.001), and HR 55±10bpm vs 54±13bpm (P=0.8). Finally, we found a decreased strain in 8 athletes (16%), in 7 of which increased to normal values. Mean delta GLS was 4.5±2.2 (pre- vs post-exercise GLS: −14.9±1.1% vs −19.4±2.7%, P=0.002, Figure, B). The athlete who did not show an increase to normal GLS levels had a decreased LV EF (42%), but showed no other signs of cardiac pathology (MRI, biomarkers, complaints). Conclusion In athletes with abnormal GLS at rest, performing a short exercise bout may provide a pragmatic method to separate decreased GLS due to true pathology from sports adaptation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Amsterdam Movement Sciences

Background/Introduction The prognosis of peri- and myocarditis can be negatively influenced by intensive exercise and sports. Therefore sustained cardiac involvement after recovery from COVID-19 in athletes is of particular relevance for the prevention of sudden cardiac arrest/sudden cardiac death (SCA/SCD). To date, only small sample-size studies are available, or studies predominantly focusing on hospitalized and severely ill patients. We aimed to address this knowledge gap in a comprehensive, systematic review of peri-/myocardial involvement after SARS-CoV-2 infection in athletes versus healthy non-athletes. Purpose Quantification of peri-/myocardial involvement and risks of SCA/SCD after SARS-CoV-2 infection in athletes as compared with healthy non-athletes. Methods We performed a systematic search with a combination of key terms in Medline (Ovid), Embase (Ovid) and Scopus (through March 8th 2021). To capture potential non- peer-reviewed COVID-19 SCA/SCD reports we performed monthly scoping internet searches. Inclusion criteria: athletes/non-athletes, with cardiovascular magnetic resonance (CMR) or echocardiography after recovery from SARS-CoV-2 infection, including arrhythmia outcomes. Exclusion criteria: study population ≥1 individual comorbidity and mean age 64 years. Results We included 16 manuscripts (933 papers reviewed) comprising 1129 athletes (284 college/student-, 807 professional- and 38 elite athletes) and 382 healthy non-athletes. Athletes vs non-athletes reported myocarditis on echocardiography and/or CMR in 0–15% vs 45–60%, LGE in 0–46% vs 0–74% (Figure 1), and pericardial effusion in 8–58% vs 0–47% (Figure 2). Weighted means of diagnosed myocarditis were 3% in athletes (3.5% college/student-, and 0% elite athletes) and 56.6% in non-athletes. No important arrhythmias were reported. Systematic internet query identified 2 collapsed post-COVID-19 athletes during exercise, 1 lethal. Ten studies (n=1301) reporting post-recovery troponin T/I found no clear relationship with cardiac abnormalities. Summary/Conclusions Rates of peri-/myocardial abnormalities in athletes/healthy non-athletes after SARS-CoV-2 infection are variable, ranging from 0–74%, and predominantly seen on CMR. Athletes have a lower risk of peri-/myocardial involvement, and myocarditis (0–3.5% vs 56.5%) than non-athletes after SARS-CoV-2 infection. Risks of SCA/SCD appear low, but data are lacking. Troponin screenings seems unreliable to identify athletes at risk for myocardial involvement. Prospective studies, with pre-COVID-19 imaging (CMR), in athletes, including follow-up and arrhythmia monitoring, are urgently needed. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Dutch Olympic Committee*Dutch Sports Federation (NOC*NSF)Amsterdam Movement Sciences (AMS) Figure 1. Total peri-/myocardial LGE (%)Figure 2. Total pericardial effusion (%)

Background Various devices are available for electrocardiogram (ECG) based home monitoring and could facilitate early detection of arrhythmias in adult congenital heart disease (ACHD). However, the diagnostic accuracy of these devices in ACHD is unknown. Purpose We aimed to determine the accuracy of different ECG-based devices compared to the standard 12-lead ECG in ACHD. Methods We performed a single-center, prospective, cross-sectional study in consecutive ACHD patients. We determined diagnostic accuracy of the Withings Scanwatch (lead I), Eko DUO (precordial ECG) and Kardia 6L (six leads) compared to the 12-lead ECG on several parameters: 1) automatic atrial fibrillation (AF) detection, 2) QRS-morphology assessment (simplified into normal (120ms) or other wide complexes (>120ms)), and 3) conduction times (PR, QRS, QTc time). All 12-lead and device ECGs were evaluated by a single observer. Results A total of 176 patients (54% male, age 40±16.6 years, 24% severe ACHD, 84% previous correction, six patients with AF) enrolled in the study. The Withings algorithm classified only 5% of ECGs as inconclusive compared to 31% of Kardia 6L (p Conclusions This is the first study to examine diagnostic accuracy of different ECG-based devices in ACHD. Overall, Withings Scanwatch may be the most practical choice for continuous AF screening while Kardia 6L could be preferred to accurately capture symptomatic palpitations. These findings can inform both patients and caregivers for optimal choice of home monitoring. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Multidisciplinary teams (MDT) are an integral part of cardiology. In sports cardiology wide area of expertise is required to differentiate between extraordinary pathophysiological adaption and pathology. In Addition, expertise-based sports advice should be prescribed with great care considering the great impact on (professional) sports careers. Specific guidelines for the composition of MDT's for sports cardiology are currently lacking. We established a sports cardiology MDT in April 2020 (Amsterdam UMC), consisting of experts in the fields of sports medicine, cardiogenetics and paediatric cardiology, cardiovascular imaging and electrophysiology, with bi-monthly meetings. Cases were contributed from cardiologists or referred nationally for expertise with patients/athletes varying from recreational to elite-level sports. Purpose To describe our infrastructure and utilization of a sports cardiology MDT, and to justify the need for a sports cardiology MDT. Methods We retrospectively analysed all MDT reviewed cases (from April 2020 to April 2021), and collected follow-up data 1 year after initial MDT review. Data were classified according to type/level of sports. We compared diagnosis and/or reason for referral and sports advice at initial MDT application and after panel review. In addition we abstracted data on occurrence of cardiac symptoms and/or cardiac events, and adherence to sports advice. Results 112 cases underwent MDT review, with a mean age of 32 (SD 16.0) years. In total 12% were women, 38% professional athletes, and 30% engaged in high dynamic/low static sports. Reasons for referral were personalised sports advice in 48%, expert opinion in 28%, and abnormal ECG/CMR/CPX in 24%. The diagnosis was revised in 55% (n=61), main groups; 1) suspicion of (non-specified) cardiomyopathy (CMP) to no cardiac pathology in 20% (n=12), and 2) “cardiac abnormalities with no clear diagnosis” to “no cardiac pathology” in 36% (n=22) (Figure 1). Sports advice was revised to more personalized sports advice in 30% (n=34) (Figure 2), main groups; no restriction to no peak load/specific maximum load in 38% (n=13), and no restrictions to no competitive sports in 26% (n=9). At 1 year follow-up, the (sports) advice was adhered in 99,98% (n=111), and cases with no sports restrictions reported no cardiac symptoms in 99% (n=72/73), and no major acute cardiovascular events in 100% (73/73). No further revisions of diagnoses were found to have taken place. Conclusion Our experience with a comprehensive, sports cardiology MDT demonstrates that such an approach is feasible, and leads to more personalised treatment- and sports advice in athletes. Medium-term adherence to sports advice given is high. A team-based approach also leads to a higher percentage definitive diagnoses. Our findings serve as a proof-of-concept of the added value of the sports cardiology team in care for athletes and patients who wish to engage in sports and exercise. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Dutch Olympic Committee*Dutch Sports Federation (NOC*NSF)Amsterdam Movement Sciences (AMS) Figure 1. Revised diagnosis before and after panel review (N=61)Figure 2. Revised sports advice before and after panel review (N=34)

Background Transcatheter mitral valve repair (TMVR) is increasingly used to treat mitral regurgitation (MR) in high risk patients. Optimal transseptal access and guiding catheter position are essential to perform adequate repair. Anatomy of the inter-atrial septum (IAS) and mitral annulus (MA) are often complex and difficult to determine from echocardiography. Purpose The aim of the current study was to evaluate whether pre-TMVR cardiac CT and 3D reconstruction of the IAS and MA could discriminate for complexity and hemodynamic effect of TMVR. Methods Patients planned for TMVR, underwent cardiac CT scan (if eligible). Post-processing software was used to segment and reconstruct the aortic root, IAS, fossa ovalis (FO) and MA, resulting in a 3D model. The following parameters were measured in each model: (1) IAS angle (°) (2) Posterior-FO angle (°) (3) FO-perpendicularity angle (°) (4) MA area (cm2). Patient specific anatomy was categorized in 4 groups as either (1) Posterior-perpendicular (PP) FO + limited IAS angle, (2) PP FO + wide IAS angle, (3) non-PP FO + limited IAS angle or (4) non-PP FO + wide IAS angle. PP FO was defined as posterior-FO angle >65° and FO-perpendicularity angle >135°. IAS angle was considered limited if Results 46 patients (mean age 75 years, 41% male) were included. Anatomy was classified (1) PP FO + limited IAS angle in 13, (2) PP FO + wide IAS angle in 13, (3) Non-PP FO + limited IAS angle in 8 and (4) Non-PP FO + wide IAS angle in 12. Median device implantation time was 20 min in group 1, compared to 39 min in group 2 (p=0.02), 33 min in group 3 (p=0.03) and 29 min in group 4 (p=0.08). In patients with MA area Conclusion The current study showed that TMVR seemed less complex in patients with an optimal anatomy. In patients with limited mitral annulus area a more favorable hemodynamic effect was achieved. Cardiac CT and 3D reconstruction could therefore be of strong aid for procedural planning of TMVR. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Abbott Vascular Anatomy and device implantation timeHemodynamic effect of annulus area

Vasospastic angina (VSA) is considered a broad diagnostic category including documented spontaneous episodes of angina pectoris produced by coronary epicardial vasospasm as well as those induced during provocative coronary vasospasm testing and coronary microvascular dysfunction due to microvascular spasm. The hallmark feature of VSA is rest angina, which promptly responds to short-acting nitrates; however, VSA can present with a great variety of symptoms, ranging from stable angina to acute coronary syndrome and even ventricular arrhythmia. VSA is more prevalent in females, who can present with symptoms different from those among male patients. This may lead to an underestimation of cardiac causes of chest-related symptoms in female patients, in particular if the coronary angiogram (CAG) is normal. Evaluation for the diagnosis of VSA includes standard 12-lead ECG during the attack, Holter monitoring, exercise testing, and echocardiography. Patients suspected of having VSA with a normal CAG without a clear myocardial or non-cardiac cause are candidates for provocative coronary vasospasm testing. The gold standard method for provocative coronary vasospasm testing involves the administration of a provocative drug during CAG while monitoring patient symptoms, ECG and documentation of the coronary artery. Treatment of VSA consists of lifestyle adaptations and pharmacotherapy with calcium channel blockers and nitrates.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Dutch Olympic Committee*Dutch Sports Federation (NOC*NSF) Amsterdam Movement Sciences (AMS) Most studies investigating the cardiotropic effects of SARS-CoV-2 focus on cardiac complications in severely ill patients. Little is known about eventual sustained cardiac involvement after recovery from COVID-19, especially in patients with a moderate or mild course of illness. Furthermore, as physical exercise can potentially worsen the prognosis of patients with COVID-19 peri- or myocarditis, cardiac involvement in athletes or in the physically active population warrants investigation. Finally, the risk of arrhythmias in such individuals remains largely unknown. We aim to provide a comprehensive overview of myocardial and pericardial involvement after SARS-CoV-2 infection, long-term cardiac sequelae after infection, and risks of SCD/SCD in a predominantly healthy/physical active population, including athletes. We performed a systematic PubMed and MedRxiv search through December 19th, 2020, with the combined terms or synonyms for: COVID-19, SARS-CoV-2, cardiovascular imaging, cardiac MRI, athletes. Exclusion criteria were: no CMR investigations reported, ≥1 comorbidities, age ≤16 years, and reviews. Two investigators independently screened and assessed all identified manuscripts, and additionally searched for reported arrhythmia outcomes. The initial search yielded 127 papers; after extensive review, we included a total of nine papers comprising 607 recovered post-COVID patients/athletes. The table summarises the main CMR findings. No study reported arrhythmias except for Ho et al. who found 18% undefined arrhythmias at baseline. In 5 studies in 201 patients, the weighted mean for the prevalence of elevated T1 was 55%, elevated T2 48%, myocardial LGE 35%, and pericardial LGE 17%. One study (Knight et al.) did not report T1 and T2 measurements. Ho et al. and Ming-Yen et al. found respectively 40% and 19% of patients to meet the Lake Louise Criteria (LLC) for myocarditis; Puntmann et al. reported that 60% had active myocardial inflammation. Second, in 1 study in 139 healthcare workers, the mean for the prevalence of elevated T1 was 42%, T2 4%, LGE 30%, and 5% met LCC for myocarditis. Third, in 3 studies in 96 athletes, the weighted mean for the prevalence of elevated T1 was 21%, T2 24%, myocardial LGE 4%, and pericardial LGE 29%. Brito et al., Clark et al. and Rajpal et al. reported that respectively 0%, 5% and 15% met the LCC for myocarditis. Studies investigating peri- and myocardial sequelae after SARS-CoV-2 infection report varying prevalences of cardiac abnormalities. Such studies are limited in numbers, generally include a low number of individuals, and report no follow-up; only 1 study reported non-specified arrhythmia outcomes. Based on the available studies, the short-term risk for post-COVID-19 SCD due to arrhythmias caused by myocardial inflammation appears to be low. Prospective investigations in larger, well-defined populations, including longer-term follow up and arrhythmia monitoring, are urgently needed. Abstract Figure.

Background/Introduction The grey zone between cardiac adaptation to sports and exercise and (early stages of) cardiac pathology constitutes one of the greatest challenges for clinicians involved in the care for (elite level) athletes. Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) is a central diagnostic tool to help differentiate between physiological adaptation and pathology. LGE as seen in myocardial fibrosis has been shown to be a strong predictor for cardiac events. While general (ie. dynamic, static sports) levels of physiological adaptation in athletes have been described, sports-specific CMR findings are essentially lacking, and a systematic sport-specific investigation of LGE is absent. Purpose To establish a sports-specific baseline for CMR indices in apparently healthy, male elite water polo players. Methods We performed a cross-sectional study in Olympic-level male water polo players. All athletes were asymptomatic and were examined during pre-participation screening. The athletes underwent a comprehensive CMR protocol consisting of long- and short-axis cine imaging, LGE and was performed on two 3 Tesla MRI-scanners (Philips). CMR data were analysed using Circle Cardiovascular Imaging software, and statistical analyses were performed in R. Results We screened 24 athletes with a mean age (±SD) of 24.2±3.6 years and body surface area (BSA) of 2.23±0.2 m2. The athletes had indexed end-diastolic volumes of 101.87±33.01 ml and 104.51±43.24 ml, stroke volumes of 140.70±33.23 and 139.44±29.93 ml, and ejection fractions of 56.68±9.07% and 52.98±8.18%, in the left- and right ventricle, respectively. Thirteen athletes (54.2%) had LGE consistent with hinge point fibrosis (HPF+) (one case example presented in the figure). Another two athletes had other patterns of LGE (LGE+). There was a trend towards having a smaller BSA in the LGE+ and HPF+ groups (2.18±0.17 m2 in LGE+ vs 2.31±0.10 m2 in LGE−, p=0.056, and 2.18±0.18 m2 in HPF+ vs 2.29±0.10 m2 in HPF−, p=0.072). Conclusion Myocardial fibrosis is present in more than 50% of asymptomatic elite water polo players, with a predilection for the inferior hinge point. Our findings in asymptomatic elite athletes suggest that HPF could be a normal finding in athletes instead of an early sign of pathology. Further studies are warranted to investigate if the HPF is associated with long-term cardiac changes or the development of cardiac pathology. Figure 1. Late gadolinium enhanced short axis image (left) combined with a polar map of cardiac segmentation (right) depicting the fibrosis pattern in a case of an elite male water polo player alongside the inferior hinge point - as expressed in the percentage of myocardium exceeding the mean signal intensity of reference myocardium plus six-times standard deviation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Harald Jørstad has received funding from the Amsterdam Movement Sciences and the National Olympic Committee & National Sports Federation

Background Percutaneous mitral valve repair (PMVR) using the MitraClip (Abbott Vascular), has gained popularity to treat mitral regurgitation (MR) in high risk patients. Accurate transseptal puncture (TSP) is a crucial step to achieve optimal guiding catheter position during the procedure. Purpose The aim of this study was to determine whether a planned optimal TSP site, using a novel computed tomography (CT) and echo image fusion methodology, corresponded with the actual TSP site, and if this was related to procedure time and outcome. Methods The mitral annulus and inter atrial septum were segmented in 26 patients (mean age 75 years, 50% female) undergoing PMVR. The optimal transseptal puncture (TSP) site was based on (1) perpendicular distance of 35–45mm from the TSP site to the mitral annulus, and (2) posterior position relative to the aorta. Optimal TSP was planned using a cardiac CT scan and 3Mensio software (Pie Medical imaging). The CT scan was exported to a Vivid E95 ultrasound system (GE Healthcare). After alignment with the three-dimensional echo image, the coordinates of the actual TSP site were determined. The distance between the optimal and actual TSP site was measured as (1) difference in height above the mitral annulus, and (2) absolute distance to the actual TSP site. Comparisons were made on procedure time, which was measured from the TSP to the achievement of optimal MitraClip position. Results The distance between the optimal and actual TSP site showed to be more than 5mm in 85% of the cases. The mean difference in height above the mitral annulus was 6.9mm. The mean procedure time was 21% longer when the absolute distance was more than 10mm. However, this did not reach statistical significance yet (p=0.4), likely due to small sample size. Conclusion CT-echo image fusion is an applicable method to plan TSP. This ongoing study suggests that image fusion based guiding may improve TSP site, reduce PMVR procedure time and potentially lead to more effective reduction of MR. Bar chart of optimal and actual TSP site Funding Acknowledgement Type of funding source: Other. Main funding source(s): Abbott

Introduction Interventions to reduce lifestyle-related risk factors (LRFs) such as overweight, physical inactivity and smoking are effective in the secondary prevention of cardiovascular events. However, evidence of the effects of lifestyle-related secondary prevention programmes in older patients with coronary artery disease (CAD) is less conclusive than in younger patients. Purpose To compare the treatment effect on lifestyle-related risk factors (LRFs) in older (≥65 years) versus younger ( Methods The RESPONSE-2 trial was a community-based lifestyle intervention trial (N=824) comparing nurse-coordinated referral to a comprehensive set of three lifestyle interventions (physical activity, weight reduction and/or smoking cessation) to care as usual. The primary outcome was the proportion of patients with improvement at 12 months follow-up (N=711) in at least 1 LRF (without deterioration in the other LRFs). In the current analysis, we assessed if the overall beneficial treatment effect of the RESPONSE-2 intervention varied by age. Results At baseline, older patients (n=245, 69.2±3.9) had significantly more serious cardiovascular risk profiles and comorbidities (hypertension, diabetes mellitus and peripheral artery disease) than younger patients (n=579, 53.7±3.9). The overall treatment effect did not vary by age (OR overall 1.67, 95% CI 1.22 - 2.31). However, older patients were more likely to achieve ≥5% weight loss (OR old 5.58, 95% CI 2.77–11.26 vs. OR young 1.57, 95% CI 0.98 - 2.49, P interaction=0.003) and younger patients were more likely to show non-improved individual LRFs (OR old 0.38, 95% CI 0.22–0.67 vs. OR young 0.88, 95% CI 0.61–1.26, P interaction=0.01). Conclusion Despite more serious cardiovascular risk profiles and comorbidities among older patients, nurse-coordinated referral to community-based lifestyle interventions was at least as successful in improving LRFs in older as in younger patients. Higher age alone should not be a reason to withhold lifestyle interventions in patients with CAD. LRFs at 12 months follow-up Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The RESPONSE-2 trial was sponsored by Weight Watchers International, Inc. (New York, New York) and Philips Consumer Lifestyle (the Netherlands). This work was also supported by the Netherlands Organisation for Scientific Research (NWO) to PJ.

Background: High-risk patients with mitral regurgitation (MR) may be treated by a percutaneous mitral valve repair with the MitraClip, but identification of patients who may benefit remains difficult. We aimed to determine whether myocardial fibrosis predicts outcome in MR patients undergoing MitraClip implantation and is beneficial in clinical decision making. Methods: Preprocedural to the MitraClip implantation, myocardial fibrosis was analyzed with cardiovascular magnetic resonance (CMR) through late gadolinium enhancement. The CMR data were core-lab adjudicated measured before the MitraClip implantation. Adverse outcome was defined as New York Heart Association (NYHA) class III or IV after 1 month or death within 1 month after the MitraClip implantation. Results: In total, 23 patients underwent preprocedural CMR, mean age 80 ± 9 years, 45% male, 64% atrial fibrillation and 73% NYHA class III or IV at baseline. Myocardial fibrosis was present in 55% of the patients with degenerative MR and in 64% of the patients with functional MR. An adverse outcome occurred in 69% of the patients with myocardial fibrosis and in 11% of the patients without myocardial fibrosis (P = 0.01). Conclusions: Our hypothesis-generating study showed that the presence of myocardial fibrosis predicts adverse outcome in patients undergoing MitraClip implantation. After confirmation with larger sample size, identification of myocardial fibrosis might contribute to assess prognosis and to clinical decision making.

The aim of the current study was to investigate whether stress echocardiography improves selection of patients who might have clinical benefit from percutaneous mitral valve repair with the MitraClip. In total, 39 patients selected for MitraClip implantation underwent preprocedural low-dose stress (dobutamine or handgrip) echocardiography from which stroke volume, ejection fraction and MR grade were measured. Outcome after MitraClip implantation was determined by New York Heart Association classification and Quality of Life questionnaires. Clinical benefit from MitraClip treatment was defined as survival and NYHA class I–II at 6 months follow-up. In total, 36 patients with a technically successful procedure were included in the analysis (mean age 79 ± 8 years, 47% male, 50% functional MR). Clinical benefit was achieved in 18 patients. All seven patients with MR decreasing during stress remained in NYHA III–IV or died within 6 months, while 62% (18 out of 29) of the patients with stable or increased MR during stress had clinical benefit (p = 0.008). Significant increase in Quality of Life on 4/8 subscales of the RAND Short Form-36 questionnaire was observed: Physical Functioning (p

Transcatheter aortic valve implantation (TAVI) has evolved to standard treatment of severe aortic stenosis in patients with an intermediate to high surgical risk. Computed tomography coronary angiography (CTCA) could partially replace invasive coronary angiography to diagnose significant coronary artery disease in the work-up for TAVI. A literature search was performed in MEDLINE and EMBASE for papers comparing CTCA and coronary angiography in TAVI candidates. The primary endpoint was the diagnostic accuracy of CTCA, compared to coronary angiography, for detection of significant (>50% diameter stenosis) coronary artery disease, measured as sensitivity, specificity, positive—(PPV) and negative predictive value (NPV). Seven studies were included, with a cumulative sample size of 1,275 patients. The patient-based pooled sensitivity, specificity, PPV and NPV were 95, 65, 71 and 94% respectively. Quality assessment revealed excellent and good quality in terms of applicability and risk of bias respectively, with the main concern being patient selection. In conclusion, on the basis of a significance cut-off value of 50% diameter stenosis, CTCA provides acceptable diagnostic accuracy for the exclusion of coronary artery disease in patients referred for TAVI. Using the routinely performed preoperative computed tomography scans as a gatekeeper for coronary angiography could decrease additional coronary angiographies by 37% in this high-risk and fragile population. Electronic supplementary material The online version of this article (10.1007/s12471-018-1149-6) contains supplementary material, which is available to authorized users.

Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF. We searched OVID MEDLINE, OVID EMBASE and the Cochrane Central Register of Controlled Trials from inception to June 10th, 2016 for randomized controlled trials (RCT) and observational studies addressing MRA and providing information on AF occurrence. Two independent reviewers selected and appraised the data. We performed random-effects meta-analyses. Summary odds ratios (OR) with 95% confidence intervals (CI) were calculated. We included 14 studies, 5 RCT and 9 observational cohorts, with a cumulative number of 5332 patients (male: 74.9%, age: 65.3years); 2397 (45.0%) received an MRA (spironolactone or eplerenone). During follow-up, 204 (8.5%) patients treated with MRAs, developed AF, compared to 547 (18.6%) patients, without MRA treatment. Meta-analyses showed a significant overall reduction of AF risk in MRA treated patients (OR: 0.48 CI: 0.38-0.60 p

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of most atherogenic lipoproteins such as low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein concentrations have also been linked with calcific aortic valve stenosis (CAVS). Purpose 1) To determine the association between genetic variants in PCSK9 and lipoprotein-lipid levels, 2) to determine whether loss of function (LOF) in PCSK9 is associated with CAVS and 3) to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification. Methods We built a weighted genetic risk score (wGRS) using 10 single nucleotide polymorphisms at the PCSK9 locus associated with LDL-C in the Global Lipids Genetics Consortium. We determined the association between the wGRS and LDL-C, apoB and Lp(a)] in 9692 participants of the EPIC-Norfolk study using linear regression. We investigated the association between the LOF PCSK9 R46L variant and CAVS risk in a meta-analysis of published (three Copenhagen studies, 1463 cases and 101,620 controls) and unpublished studies (UK Biobank, 1350 cases and 349,043 controls, Malmö Diet and Cancer study, 682 cases and 5963 controls and EPIC-Norfolk, 508 cases and 20,421 controls) prospective, population-based studies using logistic regression adjusted for age and sex. We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. We also assessed VICs calcification potential under oxidative stress condition. Results In EPIC-Norfolk, the wGRS was significantly associated with TC, LDL-C, and apoB (all p Conclusion PCSK9LOF variants are associated with lifelong reductions in non-Lp(a) apoB-containing lipoprotein levels and a lower risk of coronary artery disease and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results support randomized clinical trials of PCSK9 inhibition in the prevention of CAVS.

Background Currently used models to predict cardiovascular event risk have limited value. It has been shown repetitively that the addition of single biomarkers has modest impact. Recently we observed that a model consisting of a larger array of plasma proteins performed very well in predicting the presence of vulnerable plaques in primary prevention patients. However, the validation of this protein panel in predicting cardiovascular outcomes remains to be established. Purpose This study investigated the ability of a 384 preselected protein biomarkers to predict acute myocardial infarction, using state-of-the-art machine learning techniques. Secondly, we compared the performance of this multi-protein risk model to traditional risk engines. Methods We selected 822 subjects from the EPIC-Norfolk prospective cohort study, of whom 411 suffered a myocardial infarction during follow-up (median 15 years) compared to 411 controls who remained event-free (median follow-up 20 years). The 384 proteins were measured using proximity extension assay technology. Machine learning algorithms (random forests) were used for the prediction of acute myocardial infarction (ICD code I21–22). Performance of the model was tested against and on top of traditional risk factors for cardiovascular disease (refit Framingham). All performance measurements were averaged over several stability selection routines. Results Prediction of myocardial infarction using a machine-learning model consisting of 50 plasma proteins resulted in a ROC AUC of 0.74±0.14, in comparison to 0.69±0.17 using traditional risk factors (refit Framingham. Combining the proteins and refit Framingham resulted in a ROC AUC of 0.74±0.15. Focussing on events occurring within 3 years after baseline blood withdrawal, the ROC AUC increased to 0.80±0.09 using 50 plasma proteins, as opposed to 0.67±0.22 using refit Framingham (figure). Combining the protein model with refit Framingham resulted in a ROC AUC of 0.82±0.11 for these events. Diagnostic performance events Conclusion High-throughput proteomics outperforms traditional risk factors in prediction of acute myocardial infarction. Prediction of myocardial infarction occurring within 3 years after inclusion showed highest performance. Availability of affordable proteomic approaches and developed machine learning pave the path for clinical implementation of these models in cardiovascular risk prediction. Acknowledgement/Funding This study was funded by an ERA-CVD grant (JTC2017) and EU Horizon 2020 grant (REPROGRAM, 667837)

INTRODUCTION: Dutch cardiovascular disease (CVD) prevention guidelines recommend the use of modified SCORE risk charts to estimate 10-year risk of fatal and nonfatal CVD (myocardial infarction, cerebrovascular disease and congestive heart failure). This combined risk is derived from the SCORE mortality risk using multipliers. These multipliers have been shown to underestimate overall CVD risk. We aimed to compare the current Dutch risk charts with charts that estimate a broader range of clinically relevant CVD using updated multipliers. METHODS: We constructed new risk charts for 10-year CVD using updated, recently published multipliers from the EPIC-Norfolk study, based on ratios of fatal CVD to clinically relevant CVD (fatal plus nonfatal CVD requiring hospitalisation for ischaemic heart disease, cardiac failure, cerebrovascular disease, peripheral artery disease, and aortic aneurysm). Our primary outcome was the proportion of the three risk categories, i. e. 'high risk' (>20% 10-year risk), 'intermediate risk' (10-19%) and 'low risk' (

BackgroundCardiovascular disease (CVD) prevention guidelines stress the importance of smoking cessation and recommend intensive follow-up. To guide the development of such cessation support strategies, we analysed the characteristics that are associated with successful smoking cessation after an acute coronary syndrome (ACS).MethodsWe used data from the Randomised Evaluation of Secondary Prevention for ACS patients coordinated by Outpatient Nurse SpEcialists (RESPONSE) trial (n = 754). This was designed to quantify the impact of a nurse-coordinated prevention program, focusing on healthy lifestyles, traditional CVD risk factors and medication adherence. For the current analysis we included all smokers (324/754, 43 %). Successful quitters were defined as those who reported abstinence at 1 year of follow-up.ResultsThe majority of successful quitters quit immediately after the ACS event and remained abstinent through 1 year of follow-up, without extra support (128/156, 82 %). Higher education level (33 vs. 15 %, p p p ConclusionThe majority of successful quitters at 1 year stopped immediately after their ACS. Patients in this group showed that it was within their own ability to quit, and they did not relapse through 1 year of follow-up. Our study indicates that in a large group of patients who quit immediately after a life-threatening event, no relapse prevention program is needed.

Patients with congenital heart disease corrected in early childhood may later in life present with cardiac symptoms caused by other associated congenital anomalies that were initially not diagnosed. Nowadays, several noninvasive imaging modalities are available for the visualisation of cardiac anatomy in great detail. We describe two patients with an unroofed coronary sinus, a rare congenital anomaly which could be diagnosed using a combination of modalities including echocardiography, cardiac CT and cardiac MRI.

Communication between the aortic sinus and a cardiac chamber is a rare anomaly that can be diagnosed in children and young adults. We describe two cases with a tunnel between the aortic sinus and right atrium, discuss diagnostic modalities, and review the literature on this anomaly.

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low ( = 20%) risk. Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A(2) mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A(2) mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. JAMA. 2012; 307(23):2499-2506 www.jama.com

Introduction Adolescents with congenital heart disease transition from a paediatric to an adult setting. This is associated with loss-to-follow-up and suboptimal care. Increasing numbers of patients justify a special program. In this study we evaluated the cooperative program between paediatric and adult cardiology departments in a tertiary referral centre. Methods In this retrospective study, patients with congenital heart disease with at least one appointment scheduled at the transition program between January 2010 and January 2015 were included. They were seen by a paediatric cardiologist at the age of 15 years in the paediatric department and from age 18 to 25 in the adult department. Demographic and medical data were collected from the electronic patient files. Results A total of 193 patients (105 males, 88 females) were identified. Sex distribution was almost equal. Most patients were 18–21 years of age. The largest group, 128 patients (67 %), lived within 50 kilometres of our hospital. Paediatric cardiologists referred 157 (81 %) of patients. General practitioners and cardiologists from outside our centre were important referrers for patients lost to follow-up, together accounting for 9 %. A total of 34 (18 %) patients missed an appointment without notification. Repeat offenders, 16 of 34 patients, formed a significant minority within this group. A total of 114 (59 %) patients were attending school, 46 (24 %) were employed, and 33 (17 %) patients were inactive. Activities are in line with capabilities. A nurse practitioner was involved with the 7 % with complex and psychosocial problems. Moderately severe congenital heart defects formed the largest patient category of 102 (53 %) patients. In 3 % of patients the diagnosis had to be revised or was significantly incomplete. In 30 (16 %) patients, cardiac diagnosis was part of a syndrome. Of the 193 patients, 117 (92 %) were in NYHA class I, with 12 (6 %) and 4 (2 %) patients falling into classes II and III, respectively. Conclusions A viable transition program can be built by collaboration between paediatric and adult cardiology departments with the same treating physician taking care of patients between 15 and 25 years of age. General practitioners are important in returning lost-to-follow-up patients to specialised care. Nurse practitioners are essential in the care for patients with complex congenital heart disease.

Background We aimed to examine the association between chocolate intake and the risk of incident heart failure in a UK general population. We conducted a systematic review and meta-analysis to quantify this association. Methods and results We used data from a prospective population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Chocolate intake was quantified based on a food frequency questionnaire obtained at baseline (1993–1997) and incident heart failure was ascertained up to March 2009. We supplemented the primary data with a systematic review and meta-analysis of studies which evaluated risk of incident heart failure with chocolate consumption. A total of 20,922 participants (53% women; mean age 58 ± 9 years) were included of whom 1101 developed heart failure during the follow up (mean 12.5 ± 2.7 years, total person years 262,291 years). After adjusting for lifestyle and dietary factors, we found 19% relative reduction in heart failure incidence in the top (up to 100 g/d) compared to the bottom quintile of chocolate consumption (HR 0.81 95%CI 0.66–0.98) but the results were no longer significant after controlling for comorbidities (HR 0.87 95%CI 0.71–1.06). Additional adjustment for potential mediators did not attenuate the results further. We identified five relevant studies including the current study (N = 75,408). The pooled results showed non-significant 19% relative risk reduction of heart failure incidence with higher chocolate consumption (HR 0.81 95%CI 0.66–1.01). Conclusions Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure., Highlights • Whether chocolate consumption increases or decreases the risk of heart failure remains controversial. • Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure. • Our meta-analysis found consistent findings across all studies that chocolate consumption does not increase the risk of incident heart failure. • Evidence suggests that chocolate consumption does not increase risk of heart failure at the general population level.

Cardiovascular disease (CVD) is the leading cause of death worldwide. While there is indisputable evidence that statin treatment reduces the burden of CVD, undertreatment remains a concern for primary and secondary prevention. The aim of this study was to assess the use of lipid-lowering drugs (LLD) among 70,292 individuals in the Netherlands as a proxy of adherence to the national guideline for prevention and treatment of CVD.LifeLines is a population-based prospective cohort study in the three Northern provinces of the Netherlands. At baseline, all participants completed questionnaires, and underwent a physical examination and lab testing. The national guidelines were used to assess how many participants were eligible for LLD prescription and we analysed how many indeed reported LLD use.For primary prevention, 77% (2515 of 3268) of those eligible for LLD treatment did not report using these drugs, while for secondary prevention this was 31% (403 of 1302). Patients with diabetes mellitus were treated best (67%) for primary prevention. Notably, of the patients with stroke, only 47% (182 of 386) reported LLD treatment.Despite clear guidelines and multiple national initiatives to improve CVD risk management, adherence to guidelines for the treatment of CVD in the Netherlands remains a major challenge. This study calls out for improving public awareness of CVD and to improve primary and secondary prevention to prevent unnecessary CVD-related morbidity and mortality.

Solid evidence is available concerning the beneficial effect of atherosclerotic risk factor management both in primary and secondary prevention. However, recent registries have indicated considerable potential for improvement of clinical practice concerning secondary prevention of atherosclerosis. The guideline 'Secondary Prevention of Atherosclerosis' is aimed at the improvement and standardisation of atherosclerotic risk factor assessment in cardiovascular patients hospitalised at the Academic Medical Centre in Amsterdam. The guideline was developed by a task force, consisting of physicians from the Departments of Cardiology, Cardiothoracic Surgery, Internal Medicine, Interventional Radiology, Neurology, Pharmacology and Vascular Surgery. The guideline offers a standardised method for the identification of atherosclerotic risk factors and provides thresholds for treatment, treatment goals and the treatment of choice. A form listing all relevant data is completed before discharge and is mailed with the discharge letter to the referring physician and to the general practitioner.

Cardiac platypnoea-orthodeoxia syndrome (POS) is a position-dependent condition of dyspnoea and hypoxaemia due to right-to-left shunting. It often remains unrecognised in clinical practice, possibly because of its complex underlying pathophysiology. We present four consecutive patients with POS and patent foramen ovale (PFO) who underwent a successful percutaneous PFO closure, describe the mechanism of their POS and provide a review of the literature.

Patent ductus arteriosus (PDA) is a rare diagnosis in adults, since symptoms and signs usually occur in infancy and most cases are treated shortly after diagnosis. We present two patients who were first diagnosed with PDA during adulthood. The first case represents a more severe form of PDA, where the need for closure of the PDA is obvious. In the second case the sequelae of the PDA are less clear. In both patients, closure of the PDA (surgically in one case, percutaneously in the other) was successful.

Background Paraoxonase-1 (PON1) is a potent antioxidant enzyme bound to high-density lipoprotein (HDL). Its activity, but not its concentration, is controlled by the PON1 Q192R polymorphism. PON1 is considered to protect against atherogenesis, but it is unclear whether this relation is independent of its carrier, HDL. Objective To evaluate the predictive value of PON1 for coronary artery disease (CAD) we assessed PON1 activity and genotype (Q192R polymorphism) in a large cohort. Methods and results We performed a case-control study nested in the prospective EPIC-Norfolk cohort. Cases (n = 1138) were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n=2237) were matched by age and sex. Serum PON1 activity was lower in cases vs. controls (59.9 ± 44.6 U/L vs. 63.4 ± 46.7 U/L, p=0.020) and correlated with HDL cholesterol (r= 0.16, p Conclusion In the largest prospective study to date, we show that PON1 activity inversely relates to CAD risk, but not independently of HDL, presumably due to its close association with the HDL particle. Since the Q192R polymorphism profoundly affects lifelong PON1 activity, our inability to demonstrate a relation between the Q192R polymorphism and CAD risk suggests that PON1 activity is not a causal factor in atherogenesis.

Objective: We aimed to assess whether oxidized phospholipids on apoB-100 particles (OxPL/apoB) predict future coronary heart disease (CHD) in the prospective EPIC-Norfolk cohort of apparently healthy men and women aged 45–79 years followed up 1993–2007. Methods and Results: Cases who developed CHD during follow-up were matched to controls who remained free of cardiovascular disease and who matched to cases by sex, age and enrollment time. OxPL/apoB levels were measured with antibody E06 in 905 cases and 1809 controls. Subjects in the highest quartile of OxPL/apoB at entry in the study had significantly higher risk of future CHD events (OR 1.72, 95%CI 1.32–2.24, p2 and Lp-PLA 2 . Subjects in the highest tertiles of both OxPL/apoB and LpPLA2 (OR 2.22 [1.51–3.27]) or OxPL/apoB and sPLA 2 (OR 4.34 [2.84 – 6.64]) had significantly higher risk of future CHD than subjects in the lowest tertiles (p2 to traditional risk factors and the FRS. Strong inverse associations were noted between the OxPL/apoB and VLDL and IDL size, CETP mass and RANK Ligand. Conclusion: Elevated OxPL/apoB levels are a strong, independent predictor of CHD events. The predictive values is further enhanced by elevated activity levels of sPLA 2 and Lp-PLA 2 , which mediate breakdown of OxPL present on lipoproteins and within atherosclerotic lesions. This study links several pathophysiologically related oxidative biomarkers in the prediction of CHD events and suggests novel approaches to predicting CHD risk in apparently health men and women.

Obesity is an important healthcare issue. --Recent research has led to insights into the role of the endocannabinoid system in the regulation of body weight. --Rimonabant is a CB1-endocannabinoid-receptor antagonist. --Four trials were published recently on the efficacy and safety of rimonabant in the treatment of people with obesity. --When combined with a hypocaloric diet, rimonabant 20 mg/day was more effective than placebo in achieving and maintaining weight loss. In addition, treatment with rimonabant had beneficial effects on insulin resistance, HDL-cholesterol and hypertriglyceridaemia. --There is concern regarding the increased incidence of depression during treatment. --Whether the beneficial effects of rimonabant on weight reduction and cardiovascular risk factors translate into a reduction in cardiovascular morbidity and mortality remains to be established in large phase III trials.

We examined the relationship between granulocyte, lymphocyte and monocyte counts and risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in men and women. There is paucity of data on the differential leucocyte count and its relationship with the risk of CHD and CVD.This prospective study comprised 7073 men and 9035 women who were 45-79 years of age and were residents of Norfolk. United Kingdom.During an average of 8 years of follow-up we identified 857 incident CHD events and 2581 CVD incident events. Increased total leucocyte count was associated with increased risk for both CHD and CVD. The highest quartile of granulocyte count was associated with increased risk when compared to lowest quartile for CHD (men HR 1.70 95% CI: 1.30-2.21; women HR 1.24 95% CI: 0.91-1.69) and for CVD (men HR 1.46 95% CI: 1.24-1.71; women HR 1.20 95% CI: 1.02-1.42). The association remained unchanged when the analyses were restricted to nonsmokers and when risk was assessed for every 1000 cells L(-1) increase in cell count. In multivariable models, despite adjusting for C-reactive protein (CRP), the granulocyte count remained an independent predictor of CHD and CVD risk, especially amongst men. Lymphocyte or monocyte counts were not significantly associated with increased risk. In all analyses, additionally adjusting for CRP did not affect the results materially.In conclusion, we found that the higher risk for CHD and CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count.