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Aims: Uncertainty exists about defining true iron deficiency (ID) in heart failure (HF) patients. We assessed the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in HF outpatients., Methods and Results: Iron deficiency was defined according to guidelines (G-ID: ferritin <100 ng/ml or ferritin 100-299 ng/ml with transferrin saturation [TSAT] <20%). Alternative ID definitions based on TSAT (<20%), iron (≤13 μmol/L), and ferritin (<100 or < 300 ng/ml) were explored. Relationships with rest/exercise measures of cardiac function and congestion using ultrasound, effort intolerance and adverse outcome (HF hospitalizations or all-cause mortality) were assessed. Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G-ID. Patients with TSAT <20% or G-ID had greater left atrial volume but similar LVEF. Lower TSAT, iron and haemoglobin, but not ferritin, were associated with more signs of congestion by ultrasound. After correcting for multiple clinical variables, including haemoglobin, TSAT was directly associated with peak oxygen uptake (standardized coefficient 0.069, p = 0.041), while ferritin was not. There was no interaction with HF phenotype (HF with preserved vs. reduced LVEF). During a median follow-up of 18 months, TSAT <20% and iron ≤13 μmol/L were associated with worse outcomes in models adjusted for clinical variables, including LVEF and N-terminal pro-B-type natriuretic peptide (hazard ratio 2.48, 95% confidence interval 1.88-3.17 and 1.93, 1.48-2.52, respectively), while G-ID or ferritin <100 or <300 ng/ml were not., Conclusion: In HF outpatients, TSAT <20% is more consistently associated with congestion by ultrasound and poorer functional capacity than other ID definitions, irrespective of LVEF. TSAT <20% and iron ≤13 μmol/L, but not G-ID or ferritin-based ID, predict a worse prognosis in HF outpatients with preserved and reduced LVEF., (© 2024 European Society of Cardiology.)

Background: Both left ventricular (LV) mechanical dyssynchrony and filling pressure have been shown to be associated with outcome in heart failure patient treated with cardiac resynchronization therapy (CRT)., Objectives: To investigate the mechanistic link between mechanical dyssynchrony and filling pressure and to assess their combined prognostic value in CRT candidates., Methods: Left atrial pressure (LAP) estimation and quantification of mechanical dyssynchrony were retrospectively performed in 219 CRT patients using echocardiography. LAP was elevated (eLAP) in 49% of the population, normal (nLAP) in 40%, and indeterminate (iLAP) in 11%. CRT response was defined as %-decrease in LV end-systolic volume after 12±6 months CRT. Clinical endpoint was all-cause mortality during 4.8 years (interquartile range: 2.7-6.0 years). To investigate the mechanistic link between mechanical dyssynchrony and filling pressure, the CircAdapt computer model was used to simulate cardiac mechanics and hemodynamics in virtual hearts with LBBB and various causes of increased filling pressure., Results: Patients with nLAP had more significant mechanical dyssynchrony than those with eLAP. The combined assessment of both parameters before CRT was significantly associated with reverse LV remodeling and post-CRT survival. Simulations revealed that mechanical dyssynchrony is attenuated by increased LV operational chamber stiffness, regardless of whether it is caused by passive or active factors, explaining the link between mechanical dyssynchrony and filling pressure., Conclusion: Our combined clinical-computational data demonstrate that in patients with LBBB, the presence of mechanical dyssynchrony indicates relatively normal LV compliance and low filling pressure, which may explain their strong association with positive outcomes after CRT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Low cardiorespiratory fitness (CRF) is associated with functional disability, heart failure and mortality. Left ventricular (LV) end-diastolic volume (LVEDV) has been linked with CRF, but its utility as a diagnostic marker of low CRF has not been tested., Methods: This multi-center international cohort examined the relationship between LV size on echocardiography and CRF (peak oxygen uptake [peak VO2] from cardiopulmonary exercise testing) in individuals with LV ejection fraction ≥50%. Absolute and BSA-indexed LVEDV (LVEDVi) were tested as predictors of low CRF and functional disability (peak VO2 <1100ml/min or <18 ml/kg/min) and compared against candidate measures of cardiac structure and function., Results: 2876 individuals (309 endurance athletes, 251 healthy non-athletes, 1969 individuals with unexplained dyspnea, 347 individuals with heart failure with preserved ejection fraction) were included. For the entire cohort, LVEDV had the strongest univariable association with peak VO2 (R2 =0.45, standardized [std]β 0.67, p<0.001) and remained the strongest independent predictor of peak VO2 after adjusting for age, sex and BMI (stdβ 0.30, p<0.001). LVEDV was better at identifying low CRF than most established echocardiographic measures (LVEDV AUC 0.72; LVEDVi AUC 0.71), but equivalent to the E/e' ratio. The probability of achieving a peak VO2 below the functional independence threshold was highest for smaller ventricular volumes, with LVEDV and LVEDVi of 88ml and 57ml/m2 providing the optimal cut-points, respectively., Conclusions: Small resting ventricular size is associated with a higher probability of low CRF and functional disability. LV size is the strongest independent echocardiographic predictor of CRF across the health-disease continuum., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF., Methods and Results: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e ' (exE/ e ') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/ e '<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/ e '≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/ e '<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/ e '<15 but a high slope had NT-proBNP levels and H 2 FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope., Conclusions: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF)., Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood., Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO 2 ) and its determinants. HFpEF was considered likely when the H 2 FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t -test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression., Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO 2 and its determinants. Overall, women had lower peak VO 2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O 2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O 2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m 2 [95% CI: -8 to -11 mL/m 2 ]) and mass (-12 g/m 2 [95% CI: -9 to -14 g/m 2 ]) and more often iron deficiency (55% vs 33%;  P < 0.001)., Conclusions: Women with unexplained dyspnea had significantly lower peak VO 2 , regardless of HFpEF likelihood, attributed to both lower peak exercise O 2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness., Competing Interests: Dr Bekhuis has received funding through the Flanders Research Foundation (FWO-T004420N). Dr Haykowsky is funded by a Research Chair in Ageing and Quality of life in the faculty of Nursing, 10.13039/501100000190University of Alberta. Dr Falter has received funding through the Flanders Research Foundation FWO, file number 1SE1222N. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes., Methods: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years., Results: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P =0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P <0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P =0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile ( P =0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%., Conclusions: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate., Registration: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268., Competing Interests: Disclosures None.

Background: Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L -1 ·min -1 . A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown., Methods: In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm 2 underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141)., Results: One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; P =0.036), indexed left atrial volume (OR per SD, 2.15; P =0.001), E/e' at rest (OR per SD, 1.61; P =0.012), mPAP/CO slope (OR per SD, 2.01; P =0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; P =0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; P =0.219). Peak Vo 2 (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area ( P <0.001). These results were confirmed in the validation cohort., Conclusions: In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo 2 were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo 2 and mPAP/CO slope cumulatively improved risk stratification., Competing Interests: Disclosures None.

Introduction: High rates of cardiac involvement were reported in the beginning of the coronavirus disease 2019 (COVID-19) pandemic. This led to anxiety in the athletic population. The current study was set up to assess the prevalence of myocardial fibrosis and ventricular arrhythmias in recreational athletes with the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Methods: Consecutive adult recreational athletes (≥18 years old, ≥4 h of mixed type or endurance sports/week) underwent systematic cardiac evaluation after a prior confirmed COVID-19 infection. Evaluation included clinical history, electrocardiogram (ECG), 5-day Holter monitoring, and cardiac magnetic resonance (CMR) imaging with simultaneous measurement of high-sensitive cardiac Troponin I. Data from asymptomatic or mildly symptomatic athletes (Group 1) were compared with those with moderate to severe symptoms (Groups 2-3). Furthermore, a comparison with a historical control group of athletes without COVID-19 (Master@Heart) was made., Results: In total, 35 athletes (18 Group 1, 10 female, 36.9 ± 2.2 years, mean 143 ± 20 days following diagnosis) were evaluated. The baseline characteristics for the Group 1 and Groups 2-3 athletes were similar. None of the athletes showed overt myocarditis on CMR based on the updated Lake Louise criteria for diagnosis of myocarditis. The prevalence of non-ischemic late gadolinium enhancement [1 (6%) Group 1 vs. 2 (12%) Groups 2-3; p  = 0.603] or ventricular arrhythmias [1 Group 1 athlete showed non-sustained ventricular tachycardia (vs. 0 in Groups 2-3: p  = 1.000)] were not statistically different between the groups. When the male athletes were compared with the Master@Heart athletes, again no differences regarding these criteria were found., Conclusion: In our series of recreational athletes with prior confirmed COVID-19, we found no evidence of ongoing myocarditis, and no more detection of fibrosis or ventricular arrhythmias than in a comparable athletic pre-COVID cohort. This points to a much lower cardiac involvement of COVID-19 in athletes than originally suggested., Competing Interests: HH received personal lecture and consultancy fees from Bayer, Biotronik, Bristol-Myers Squibb, Centrix Healthcare Ltd, Daiichi-Sankyo, Downtown Europe, Pfizer-BMS, European Society of Cardiology, Medscape, Springer Healthcare Ltd, and Viatris Pharmaceuticals Inc. He received unconditional research grants through the University of Antwerp and/or the University of Hasselt from Abbott, Bayer, Biosense-Webster, Boston-Scientific, Daicchi-Sankyo, Fibricheck/Qompium, Medtronic, and Pfizer-BMS, all outside the scope of this work. HM received personal lecture and consultance fees from Bristol-Myers Squibb, Pfizer and Abbott, all outside the scope of this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Miljoen, Favere, Van De Heyning, Corteville, Dausin, Herbots, Teulingkx, Bekhuis, Lyssens, Bogaert, Heidbuchel and Claessen.)

Aims: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms., Methods and Results: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2., Conclusion: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To study the impact of heart failure with preserved ejection fraction (HFpEF) vs. aortic stenosis (AS) lesion severity on left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, haemodynamics, and exercise capacity., Methods and Results: Patients (n = 206) with at least moderate AS (aortic valve area ≤0.85 cm/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the heavy, hypertension, atrial fibrillation, pulmonary hypertension, elder, filling pressure (H2FPEF) score [0-5 (AS/HFpEF-) vs. 6-9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Mean age was 73 ± 10 years with 40% women. Twenty-eight patients had Severe AS/HFpEF+ (14%), 111 Severe AS/HFpEF- (54%), 13 Moderate AS/HFpEF+ (6%), and 54 Moderate AS/HFpEF- (26%). AS/HFpEF+ vs. AS/HFpEF- patients, irrespective of AS severity, had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction. The pulmonary arterial pressure-cardiac output slope was significantly higher in AS/HFpEF+ vs. AS/HFpEF- (5.4 ± 3.1 vs. 3.9 ± 2.2 mmHg/L/min, respectively; P = 0.003), mainly driven by impaired cardiac output and chronotropic reserve, with signs of right ventricular pulmonary arterial uncoupling. AS/HFpEF+ vs. AS/HFpEF- was associated with a lower peak aerobic capacity (11.5 ± 3.7 vs. 15.9 ± 5.9 mL/min/kg, respectively; P < 0.0001) but did not differ between Moderate and Severe AS (14.7 ± 5.5 vs. 15.2 ± 5.9 mL/min/kg, respectively; P = 0.6)., Conclusion: A high H2FPEF score is associated with a reduced exercise capacity and adverse haemodynamics in patients with moderate to severe AS. Both exercise performance and haemodynamics correspond better with intrinsic cardiac dysfunction than AS severity., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We aimed to identify risk factors associated with ICU mortality in critically ill patients with COVID-19 pneumonia treated with Extracorporeal membrane oxygenation (ECMO). We also aimed to assess protocol violations of the local eligibility criteria of ECMO initiation., Methods: All 31 consecutive adult patients with confirmed COVID-19 pneumonia admitted to ICU and treated with ECMO from March 13th 2020 to 8 December 2021 were enrolled. Eligibility criteria for ECMO initiation were: P/F-ratio<50 mmHg >3 hours, P/F-ratio<80 mmHg >6 hours or pH<7.25 + PaCO2>60 mmHg >6 hours, despite maximal protective invasive ventilation. Primary outcome was ICU mortality. Univariate logistic regression analyses were performed to identify predictors of ICU mortality., Results: 12 out of 31 patients (38.7%) did not survive ECMO treatment in ICU. Half of the non-survivors suffered from acute kidney failure compared to 3 out of 19 survivors (15.79%) ( p = .04). Half of the non-survivors required CRRT treatment versus 1 patient in the survivor group (5.3%) ( p < .01). Higher age (2.45 (0.97-6.18), p = .05), the development of AKI (5.33 (1.00-28.43), p = .05), need of CRRT during ICU stay (18.00 (1.79-181.31), p = .01) and major bleeding during ECMO therapy (0.51 (0.19-0.89), p < .01) were identified to be predictors of ICU mortality., Conclusion: Almost 60% of patients could be treated successfully with ECMO with sustained results at 3 months. Predictors for ICU mortality were development of AKI and need of CRRT during ICU stay, higher age category and major bleeding. Inadvertent ECMO allocation was noted in almost one in five patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

(1) Background: The development of totally endoscopic aortic valve replacement has the potential to enhance clinical results compared to mini-sternotomy. To our knowledge, no comparison between these two techniques has been conducted before. Therefore, the objective of this retrospective study is to examine the results after both totally endoscopic and mini-sternotomy approaches. (2) Methods: This study covered all elective patients who underwent isolated aortic valve replacement, either totally endoscopically (n = 392) or through a mini-sternotomy (n = 323), between 2013 and 2021. Multivariable analysis was used to account for baseline variations between the two groups. All data were retrospectively gathered and analysed. The primary objective of this study was the one-year mortality rate. (3) Results: The mean aortic cross-clamping and cardiopulmonary bypass times were significantly longer in the totally endoscopic approach (cross-clamping: 43.73 ± 13.71 min and 61.93 ± 16.76 min, p -value < 0.001; CPB time: 64.86 ± 23.02 min and 93.23 ± 23.67 min, p -value < 0.001). However, perioperative bleeding was lower (706.40 ± 542.77 mL and 444.50 ± 515.84 mL, p -value < 0.001). The primary objective, one-year survival, did not significantly differ between both groups (Mini-AVR: 94.5% vs TEAVR: 93.3%, p -value = 0.520). (4) Conclusions: Our results show that totally endoscopic aortic valve replacement has comparable clinical results compared to aortic valve replacement through mini-sternotomy.

Purpose: Although cardiac troponin I (cTnI) increase following strenuous exercise has been observed, the development of exercise-induced myocardial edema remains unclear. Cardiac magnetic resonance (CMR) native T1/T2 mapping is sensitive to the pathological increase of myocardial water content. Therefore, we evaluated exercise-induced acute myocardial changes in recreational cyclists by incorporating biomarkers, echocardiography and CMR., Methods: Nineteen male recreational participants (age: 48 ± 5 years) cycled the 'L'étape du tour de France" (EDT) 2021' (175 km, 3600 altimeters). One week before the race, a maximal graded cycling test was conducted to determine individual heart rate (HR) training zones. One day before and 3-6 h post-exercise 3 T CMR and echocardiography were performed to assess myocardial native T1/T2 relaxation times and cardiac function, and blood samples were collected. All participants were asked to cycle 2 h around their anaerobic gas exchange threshold (HR zone 4)., Results: Eighteen participants completed the EDT stage in 537 ± 58 min, including 154 ± 61 min of cycling time in HR zone 4. Post-race right ventricular (RV) dysfunction with reduced strain and increased volumes (p < 0.05) and borderline significant left ventricular global longitudinal strain reduction (p = 0.05) were observed. Post-exercise cTnI (0.75 ± 5.1 ng/l to 69.9 ± 41.6 ng/l; p < 0.001) and T1 relaxation times (1133 ± 48 ms to 1182 ± 46 ms, p < 0.001) increased significantly with no significant change in T2 (p = 0.474). cTnI release correlated with increase in T1 relaxation time (p = 0.002; r = 0.703), post-race RV dysfunction (p < 0.05; r = 0.562) and longer cycling in HR zone 4 (p < 0.05; r = 0.607)., Conclusion: Strenuous exercise causes early post-race cTnI increase, increased T1 relaxation time and RV dysfunction in recreational cyclists, which showed interdependent correlation. The long-term clinical significance of these changes needs further investigation., Trial Registration Numbers and Date: NCT04940650 06/18/2021. NCT05138003 06/18/2021., (© 2023. The Author(s).)

Background: We investigated the impact of baseline left atrial (LA) strain data and estimated left atrial pressure (LAP) by applying the 2016 American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) guidelines on cardiac resynchronization therapy (CRT) outcomes., Methods: Datasets of 219 CRT patients were retrospectively analysed. All patients had full echocardiographic diastolic function assessment before CRT and were classified based on the guideline algorithm into normal LAP (nLAP = 40%), elevated LAP (eLAP = 49%) and indeterminate LAP (iLAP = 11%). All relevant baseline characteristics were analysed. CRT-induced left ventricular (LV) reverse remodeling was measured as the relative change of LV end-systolic volume (LVESV) at 12 ± 6 months after CRT compared to baseline. Patients were followed up for all-cause mortality for a mean of 4.8 years [interquartile range (IQR): 2.7-6.0 years]., Results: At follow-up, CRT resulted in more pronounced reduction of LVESV in patients with nLAP than in patients with eLAP. In univariate analysis, nLAP was associated with LV reverse remodelling ( p < 0.001), as well as long-term survival after CRT ( p < 0.01). However, multivariable analysis showed that only the association between nLAP and LV reverse remodelling after CRT is independent ( p < 0.01). Adding LA strain analysis to the guideline algorithm improved the feasibility of LAP estimation without affecting the association between estimated LAP and CRT outcome., Conclusion: Normal LAP before CRT, estimated using the 2016 ASE/EACVI guideline algorithm, is associated with LV reverse remodelling and long-term survival after CRT. Albeit non-independent, it can serve as a non-invasive imaging-based predictor of effective therapy. Furthermore, the inclusion of LA reservoir strain in the guideline algorithm can enhance the feasibility of LAP estimation without affecting the association between LAP and CRT outcome.

Aims: The impact of long-term endurance sport participation (on top of a healthy lifestyle) on coronary atherosclerosis and acute cardiac events remains controversial., Methods and Results: The Master@Heart study is a well-balanced prospective observational cohort study. Overall, 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after 30 years of age), and 176 healthy non-athletes, all male with a low cardiovascular risk profile, were included. Peak oxygen uptake quantified fitness. The primary endpoint was the prevalence of coronary plaques (calcified, mixed, and non-calcified) on computed tomography coronary angiography. Analyses were corrected for multiple cardiovascular risk factors. The median age was 55 (50-60) years in all groups. Lifelong and late-onset athletes had higher peak oxygen uptake than non-athletes [159 (143-177) vs. 155 (138-169) vs. 122 (108-138) % predicted]. Lifelong endurance sports was associated with having ≥1 coronary plaque [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.17-2.94], ≥ 1 proximal plaque (OR 1.96, 95% CI 1.24-3.11), ≥ 1 calcified plaques (OR 1.58, 95% CI 1.01-2.49), ≥ 1 calcified proximal plaque (OR 2.07, 95% CI 1.28-3.35), ≥ 1 non-calcified plaque (OR 1.95, 95% CI 1.12-3.40), ≥ 1 non-calcified proximal plaque (OR 2.80, 95% CI 1.39-5.65), and ≥1 mixed plaque (OR 1.78, 95% CI 1.06-2.99) as compared to a healthy non-athletic lifestyle., Conclusion: Lifelong endurance sport participation is not associated with a more favourable coronary plaque composition compared to a healthy lifestyle. Lifelong endurance athletes had more coronary plaques, including more non-calcified plaques in proximal segments, than fit and healthy individuals with a similarly low cardiovascular risk profile. Longitudinal research is needed to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum., Competing Interests: Conflict of interest: All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. This study provides an in-;depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic., Methods and Results: Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H2FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation-perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were performed (median of 3 modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure., Conclusion: Holistic workup of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases., Competing Interests: Conflict of interest All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Three-dimensional echocardiography (3DE) is the most accurate cardiac ultrasound technique to assess cardiac structure. 3DE has shown close correlation with cardiac magnetic resonance imaging (CMR) in various populations. There is limited data on the accuracy of 3DE in athletes and its value in detecting alterations during follow-up. Indexed left and right ventricular end-diastolic volume (LVEDVi, RVEDVi), end-systolic volume, ejection fraction (LVEF, RVEF) and left ventricular mass (LVMi) were assessed by 3DE and CMR in two-hundred and one competitive endurance athletes (79% male) from the Pro@Heart trial. Sixty-four athletes were assessed at 2 year follow-up. Linear regression and Bland-Altman analyses compared 3DE and CMR at baseline and follow-up. Interquartile analysis evaluated the agreement as cardiac volumes and mass increase. 3DE showed strong correlation with CMR (LVEDVi r = 0.91, LVEF r = 0.85, LVMi r = 0.84, RVEDVi r = 0.84, RVEF r = 0.86 p < 0.001). At follow up, the percentage change by 3DE and CMR were similar (∆LVEDVi r = 0.96 bias - 0.3%, ∆LVEF r = 0.94, bias 0.7%, ∆LVMi r = 0.94 bias 0.8%, ∆RVESVi r = 0.93, bias 1.2%, ∆RVEF r = 0.87 bias 0.4%). 3DE underestimated volumes (LVEDVi bias - 18.5 mL/m 2 , RVEDVi bias - 25.5 mL/m 2 ) and the degree of underestimation increased with larger dimensions (Q1vsQ4 LVEDVi relative bias - 14.5 versus - 17.4%, p = 0.016; Q1vsQ4 RVEDVi relative bias - 17 versus - 21.9%, p = 0.005). Measurements of cardiac volumes, mass and function by 3DE correlate well with CMR and 3DE accurately detects changes over time. 3DE underestimates volumes and the relative bias increases with larger cardiac size., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims: To compare the cardiac function and pulmonary vascular function during exercise between dyspnoeic and non-dyspnoeic patients with Type 2 diabetes mellitus (T2DM)., Methods and Results: Forty-seven T2DM patients with unexplained dyspnoea and 50 asymptomatic T2DM patients underwent exercise echocardiography combined with ergospirometry. Left ventricular (LV) function [stroke volume, cardiac output (CO), LV ejection fraction, systolic annular velocity (s')], estimated LV filling pressures (E/e'), mean pulmonary arterial pressures (mPAPs) and mPAP/COslope were assessed at rest, low- and high-intensity exercise with colloid contrast. Groups had similar patient characteristics, glycemic control, stroke volume, CO, LV ejection fraction, and E/e' (P > 0.05). The dyspnoeic group had significantly lower systolic LV reserve at peak exercise (s') (P = 0.021) with a significant interaction effect (P < 0.001). The dyspnoeic group also had significantly higher mPAP and mPAP/CO at rest and exercise (P < 0.001) with significant interaction for mPAP (P < 0.009) and insignificant for mPAP/CO (P = 0.385). There was no significant difference in mPAP/COslope between groups (P = 0.706). However, about 61% of dyspnoeic vs. 30% of non-dyspnoeic group had mPAP/COslope > 3 (P = 0.009). The mPAP/COslope negatively predicted V̇O2peak in dyspneic group (β = -1.86, 95% CI: -2.75, -0.98; multivariate model R2:0.54)., Conclusion: Pulmonary hypertension and less LV systolic reserve detected by exercise echocardiography with colloid contrast underlie unexplained exertional dyspnoea and reduced exercise capacity in T2DM., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Mitral regurgitation (MR) has a significant haemodynamic impact on the left atrium. Assessment of left atrial reservoir strain (LARS) may have important prognostic implications, incremental to left atrial (LA) volume, and conventional parameters of left ventricular (LV) structure and function. This study investigated whether preoperative assessment of LARS by speckle tracking echocardiography is associated with long-term outcomes in patients undergoing mitral valve repair for severe primary MR., Methods and Results: Echocardiography was performed prior to mitral valve surgery in 566 patients (age 64 ± 12years, 66% men) with severe primary MR. The study population was subdivided based on a LARS value of 22%, using a spline curve analysis. The primary endpoint was all-cause mortality. During a median follow-up of 7 (4-12) years, 129 (22.8%) patients died. Patients with LARS ≤22% showed significantly higher mortality rates at 1-, 3-, and 5-year follow-up (6%, 12%, and 15%, respectively) when compared with patients with LARS >22% (2%, 3% and 5%, respectively, P < 0.001). Age [hazard ratio (HR): 1.06; 95% confidence interval (CI): 1.03-1.09; P < 0.001], LV global longitudinal strain (HR: 0.92; 95% CI: 0.87-0.98; P = 0.014), and LARS (HR: 0.96; 95% CI: 0.93-0.99; P = 0.014) were independently associated with all-cause mortality., Conclusion: Preoperative LARS is independently associated with all-cause mortality in patients undergoing mitral valve repair for primary MR and provides incremental prognostic value over LA volume. LARS might be helpful to guide timing of mitral valve surgery in patients with severe primary MR., Competing Interests: Conflict of interest: The Department of Cardiology of the Leiden University Medical Centre received unrestricted research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionnis, and Medtronic. J.J.B. received speaker fees from Abbott Vascular. N.A.M. received speaker fees from Abbott Vascular and GE Healthcare. V.D. received speaker fees from Abbott Vascular, Edwards Lifesciences, MSD, Novartis, and GE Healthcare. The remaining authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Cardiac output limitation is a fundamental feature of heart failure with preserved ejection fraction (HFpEF) but the relative contribution of its determinants in symptomatic vs. asymptomatic stages are not well characterized. We aimed to gain insight into disease mechanisms by performing comprehensive comparative non-invasive exercise imaging in patients across the disease spectrum., Methods and Results: We performed bicycle stress echocardiography in 10 healthy controls, 13 patients with hypertensive left ventricular (LV) concentric remodelling and asymptomatic diastolic dysfunction (HTDD), 15 HFpEF patients, and 15 subjects with isolated right ventricular (RV) dysfunction secondary to chronic thromboembolic pulmonary hypertension (CTEPH). During exercise, ventricular performance differed across the groups (all P ≤ 0.01 for interaction). Notably in controls, LV and RV function significantly increased (all P < 0.05) while both LV systolic and diastolic reserve were significantly reduced in HFpEF patients. Likewise, RV systolic reserve was also impaired in HFpEF but not to the extent of CTEPH patients (P < 0.001 between groups). HTDD patients behaved as an intermediary group with borderline LV systolic and diastolic reserve and reduced RV systolic reserve. The increased pulmonary vascular (PV) load in HFpEF and CTEPH patients in combination with impaired RV reserve resulted in RV-pulmonary artery uncoupling during exercise., Conclusion: The multifaceted decline of cardiac and PV function accompanying disease progression in HFpEF is unmasked by exercise and already emerges in preclinical disease. The revelation of these subtle abnormalities during exercise illustrates the benefit of exercise imaging and creates new prospects for early diagnosis and management., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Exercise-induced cardiac remodelling (EICR) results from the structural, functional and electrical adaptations to exercise. Despite similar sports participation, EICR varies and some athletes develop phenotypic features that overlap with cardiomyopathies. Training load and genotype may explain some of the variation; however, exercise 'dose' has lacked rigorous quantification. Few have investigated the association between EICR and genotype., Objectives: (1) To identify the impact of training load and genotype on the variance of EICR in elite endurance athletes and (2) determine how EICR and its determinants are associated with physical performance, health benefits and cardiac pathology., Methods: The Pro@Heart study is a multicentre prospective cohort trial. Three hundred elite endurance athletes aged 14-23 years will have comprehensive cardiovascular phenotyping using echocardiography, cardiac MRI, 12-lead ECG, exercise-ECG and 24-hour-Holter monitoring. Genotype will be determined using a custom cardiomyopathy gene panel and high-density single-nucleotide polymorphism arrays. Follow-up will include online tracking of training load. Cardiac phenotyping will be repeated at 2, 5, 10 and 20 years., Results: The primary endpoint of the Pro@Heart study is the association of EICR with both training load and genotype. The latter will include rare variants in cardiomyopathy-associated genes and polygenic risk scores for cardiovascular traits. Secondary endpoints are the incidence of atrial and ventricular arrhythmias, physical performance and health benefits and their association with training load and genotype., Conclusion: The Pro@Heart study is the first long-term cohort study to assess the impact of training load and genotype on EICR., Trial Registration Number: NCT05164328; ACTRN12618000716268., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Diastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but current algorithms do not detect all patients. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST., Methods and Results: We identified candidate parameters in 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. Elevated exPAWP (≥25 mmHg) was present in 14 patients, and was best identified by peak septal systolic annular velocity <9.5 cm/s [ exS' , area under the receiver operating characteristic curve (AUC) 0.97, 95% confidence interval 0.92-1.0] and mean pulmonary artery pressure/cardiac output slope ≥3.2 mmHg/L [mPAP/CO, AUC 0.88 (0.72-1.0)]. We propose a decision tree to identify patients with elevated exPAWP. Applying this decision tree to 326 patients in an independent non-invasive DST cohort showed that patients labeled as "high probability of HFpEF" ( n = 85) had reduced peak oxygen uptake [13.0 (10.7-15.1) mL/kg/min, p < 0.001 vs. intermediate/low probability], high H2FPEF score [53 (40-72) %, p < 0.001 vs. intermediate/low probability], and typical clinical characteristics. The diagnostic yield of DST increased from 11% using exercise E/e', to 62% using the decision tree., Conclusion: In DST for suspected HFpEF, exS' was the most accurate echocardiographic parameter to identify elevated PAWP. We propose a decision tree including exS' and mPAP/CO for interpretation of DST. Application of this decision tree revealed typical HFpEF characteristics in patients labeled as high probability of HFpEF, and substantially reduced the number of inconclusive results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Verwerft, Verbrugge, Claessen, Herbots, Dendale and Gevaert.)

Little data is available about the pathophysiological mechanisms of unexplained dyspnea and their clinical meaning. Consecutive patients with unexplained dyspnea underwent prospective standardized cardiopulmonary exercise testing with echocardiography (CPETecho). Patients were grouped as having normal exercise capacity (peak VO 2 > 80% with respiratory exchange [RER] > 1.05), reduced exercise capacity (peak VO 2 ≤ 80% with RER > 1.05), or a submaximal exercise test (RER ≤ 1.05). From 307 patients, 144 (47%) had normal and 116 (38%) reduced exercise capacity, and 47 (15%) had a submaximal exercise test. Patients with reduced versus normal exercise capacity had significantly more mechanisms for unexplained dyspnea (2.3±1.0 vs 1.5±1.0, respectively; p<0.001). Exercise PH (42%), low heart rate reserve (51%), low stroke volume reserve (38%), low diastolic reserve (18%), and peripheral muscle limitation (17%) were most common. Patients with more mechanisms for dyspnea displayed poorer peak VO 2 and had an increased risk for cardiovascular hospitalization (p=0.002). Patients with unexplained dyspnea display multiple coexisting mechanisms for exercise intolerance, which relate to the severity of exercise limitation and risk of subsequent cardiovascular hospitalizations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF., Methods and Results: Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM., Conclusions: Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The benefit of de novo cardiac resynchronisation therapy (CRT) implantation in selected patients with heart failure is well known. The number of upgrade procedures is increasing but data on clinical response and outcome are less well documented as compared to de novo implantation., Objectives: To investigate the efficacy and outcome of CRT upgrade procedures in patients with existing cardiac implantable electronic devices (CIEDs)., Methods: Baseline characteristics, change in New York Heart Association (NYHA) functional class, echocardiographic parameters, life-threatening ventricular tachyarrhythmias, all-cause mortality and mode of death were evaluated in CRT patients with the comparison between de novo and upgrade CRT procedures., Results: About 410 patients (CRT upgrade/ de novo CRT, n  = 97/313) were followed for 63.5 ± 38.1 months. Upgrade patients were older (75.5 ± 8.1 vs 69.9 ± 10.7 years; p  < 0.001), had more often an ischaemic cause of heart failure (58.8% vs 45.4%; p  = 0.021), a higher NYHA functional class ( p  = 0.004) and a higher comorbidity burden. Improvement in left ventricular ejection fraction (LVEF) was higher in the de novo CRT group (8.4 ± 9.9 vs 11.0 ± 10.3%; p  = 0.035). Clinical response was similar between both groups (60.5 vs 62.5%; p  = 0.793), as was mortality at 1 year (8.2 vs 5.8%; p  = 0.351) and at last follow-up (33.0 vs 28.8%; p  = 0.447). The proportion of cardiovascular related deaths was similar between both groups (46.9% vs 38.9%; p  = 0.531)., Conclusions: Patients with CRT upgrade procedures have similar symptomatic improvements, as well as 1 year and long-term outcome as compared to patients with de novo CRT implantation.

Background: Iron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear., Methods and Results: Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO 2 ), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO 2 (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV-pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm 2 vs 2.58 ± 1.14 mm Hg/cm 2 ; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO 2 /peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea., Conclusions: In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Low and moderate endurance exercise is associated with better control of cardiovascular risk factors, a decreased risk of coronary artery disease and atrial fibrillation (AF). There is, however, a growing proportion of individuals regularly performing strenuous and prolonged endurance exercise in which the health benefits have been challenged. Higher doses of endurance exercise have been associated with a greater coronary atherosclerotic plaque burden, risk of AF and myocardial fibrosis (MF)., Methods and Analysis: Master@Heart is a multicentre prospective cohort study aiming to assess the incidence of coronary atherosclerosis, AF and MF in lifelong endurance athletes compared to late-onset endurance athletes (initiation of regular endurance exercise after the age of 30 years) and healthy non-athletes.The primary endpoint is the incidence of mixed coronary plaques. Secondary endpoints include coronary calcium scores, coronary stenosis >50%, the prevalence of calcified and soft plaques and AF and MF presence. Tertiary endpoints include ventricular arrhythmias, left and right ventricular function at rest and during exercise, arterial stiffness and carotid artery intima media thickness.Two hundred male lifelong athletes, 200 late-onset athletes and 200 healthy non-athletes aged 45-70 will undergo comprehensive cardiovascular phenotyping using CT, coronary angiography, echocardiography, cardiac MRI, 12-lead ECG, exercise ECG and 24-hour Holter monitoring at baseline. Follow-up will include online tracking of sports activities, telephone calls to assess clinical events and a 7-day ECG recording after 1 year., Ethics and Dissemination: Local ethics committees approved the Master@Heart study. The trial was launched on 18 October 2018, recruitment is complete and inclusions are ongoing., Trial Registration Number: NCT03711539., Competing Interests: Competing interests: RW is supported as a postdoctoral clinical researcher by the Fund for Scientific Research Flanders (FWO Vlaanderen)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: An individualised thromboprophylaxis was implemented in critically ill patients suffering from coronavirus disease 2019 (COVID-19) pneumonia to reduce mortality and improve clinical outcome. The aim of this study was to evaluate the effect of this intervention on clinical outcome., Methods: In this mono-centric, controlled, before-after study, all consecutive adult patients with confirmed COVID-19 pneumonia admitted to ICU from March 13th to April 20th 2020 were included. A thromboprophylaxis protocol, including augmented LMWH dosing, individually tailored with anti-Xa measurements and twice-weekly ultrasonography screening for DVT, was implemented on March 31th 2020. Primary endpoint is one-month mortality. Secondary outcomes include two-week and three-week mortality, the incidence of VTE, acute kidney injury and continuous renal replacement therapy (CRRT). Multiple regression modelling was used to correct for differences between the two groups., Results: 46 patients were included in the before group, 26 patients in the after group. One month mortality decreased from 39.13% to 3.85% (p < 0.001). After correction for confounding variables, one-month mortality was significantly higher in the before group (p = 0.02, OR 8.86 (1.46, 53.75)). The cumulative incidence of VTE and CRRT was respectively 41% and 30.4% in the before group and dropped to 15% (p = 0.03) and 3.8% (p = 0.01), respectively. After correction for confounding variables, risk of VTE (p = 0.03, 6.01 (1.13, 32.12)) and CRRT (p = 0.02, OR 19.21 (1.44, 255.86)) remained significantly higher in the before group., Conclusion: Mortality, cumulative risk of VTE and need for CRRT may be significantly reduced in COVID-19 patients by implementation of a more aggressive thromboprophylaxis protocol. Future research should focus on confirmation of these results in a randomized design and on uncovering the mechanisms underlying these observations., Registration Number: NCT04394000., Competing Interests: Declaration of competing interest The authors declare that they have no conflicting interests. The authors affirm that this study has not received any funding/assistance from a commercial organization, and we do not keep any commercial relationships that may lead to a conflict of interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF). In patients with cardiac resynchronization therapy (CRT), it is associated with a diminished reverse remodelling response and poor functional improvement. The latter is partially related to a loss in contractile force at higher heart rates (negative force-frequency relationship)., Methods and Results: The effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy (IRON-CRT) trial is a multicentre, prospective, randomized, double-blind controlled trial in HFrEF patients who experienced incomplete reverse remodelling (defined as a left ventricular ejection fraction below <45%) at least 6 months after CRT. Additionally, patients need to have iron deficiency defined as a ferritin below 100 μg/L irrespective of transferrin saturation or a ferritin between 100 and 300 μg/L with a transferrin saturation <20%. Patients will be randomized to either intravenous ferric carboxymaltose (dose based according to Summary of Product Characteristics) or intravenous placebo. The primary objective is to evaluate the effect of ferric carboxymaltose on metrics of cardiac reverse remodelling and contractility, measured by the primary endpoint, change in left ventricular ejection fraction assessed by three-dimensional (3D) echo from baseline to 3 month follow-up and the secondary endpoints change in left ventricular end-systolic and end-diastolic volume. The secondary objective is to determine if ferric carboxymaltose is capable of improving cardiac contractility in vivo, by assessing the force-frequency relationship through incremental biventricular pacing. A total of 100 patients will be randomized in a 1:1 fashion., Conclusions: The IRON-CRT trial will determine the effect of ferric carboxymaltose on cardiac reverse remodelling and rate-dependent cardiac contractility in HFrEF patients., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The aim of this study was to analyze the whole temporal profiles of the segmental deformation curves of the left ventricle (LV) and describe their interrelations to obtain more detailed information concerning global LV function in order to be able to identify abnormal changes in LV mechanics. The temporal characteristics of the segmental LV deformation curves were compactly described using an efficient decomposition into major patterns of variation through a statistical method, called Principal Component Analysis (PCA). In order to describe the spatial relations between the segmental traces, the PCA-derived temporal features of all LV segments were concatenated. The obtained set of features was then used to build an automatic classification system. The proposed methodology was applied to a group of 60 MRI-delayed enhancement confirmed infarct patients and 60 controls in order to detect myocardial infarction. An average classification accuracy of 87% with corresponding sensitivity and specificity rates of 89% and 85%, respectively was obtained by the proposed methodology applied on the strain rate curves. This classification performance was better than that obtained with the same methodology applied on the strain curves, reading of two expert cardiologists as well as comparative classification systems using only the spatial distribution of the end-systolic strain and peak-systolic strain rate values. This study shows the potential of machine learning in the field of cardiac deformation imaging where an efficient representation of the spatio-temporal characteristics of the segmental deformation curves allowed automatic classification of infarcted from control hearts with high accuracy.

Background: Techniques of 2-dimensional speckle tracking enable the measurement of myocardial deformation (strain) during systole. Recent clinical studies explored the prognostic role of left ventricular global longitudinal strain (GLS). However, there are few data on the association between cardiovascular outcome and GLS in the community. Therefore, we hypothesized that GLS contains additive prognostic information over and beyond traditional cardiovascular risk factors in a large, population-based cohort., Methods and Results: We measured GLS by 2-dimensional speckle tracking in the apical 4-chamber view in 791 participants (mean age 50.9 years). We calculated multivariable adjusted hazard ratios for midwall, endocardial, and epicardial GLS, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 7.9 years (5th to 95th percentile, 3.7-9.6). In continuous analysis, with adjustments applied for covariables, midwall, endocardial, and epicardial GLS were significant predictors of fatal and nonfatal cardiovascular (n=96; P<0.0001) and cardiac events (n=68; P≤0.001). In the sex-specific low quartile of midwall GLS (<18.8% in women and <17.4% in men), the risk was significantly higher than the average population risk for cardiovascular (128%, P<0.0001) and cardiac (94%, P=0.0007) events. We also noticed that the risk for cardiovascular events increased with increasing number of left ventricular abnormalities, such as low GLS, diastolic dysfunction, and hypertrophy (log-rank P<0.0001)., Conclusions: Low GLS measured by 2-dimensional speckle tracking predicts future cardiovascular events independent of conventional risk factors. Left ventricular midwall strain represents a simple echocardiographic measure, which might be used for assessing cardiovascular risk in a population-based cohort., (© 2016 American Heart Association, Inc.)

Purpose: Chronic heart failure (CHF) patients often present with (pre)diabetes, which negatively influences prognosis. Unlike the proven effect of exercise on glucose regulation in the general population, its effect in CHF is unclear. Therefore, this study aimed at investigating the effect of exercise training on glucose regulation in stable CHF patients., Methods: Twenty-two CHF patients were randomized into training (EX, n = 15) and control (CON, n = 7) groups. Before and after a 12-week training intervention involving endurance and resistance training, glucose tolerance (2-hour oral glucose tolerance test), exercise tolerance (cardiopulmonary exercise test), muscle strength (isokinetic dynamometer), heart function (echocardiography), glycated hemoglobin, body composition (dual-energy x-ray absorptiometry), and quality of life (EQ5D) were assessed., Results: At baseline, glucose levels 2 hours after glucose intake were elevated in both groups. Whereas area under the glucose curve did not change, area under the insulin curve decreased following training (EX, -13 ± 23% vs CON, +22 ± 33%; P < .05). Changes in the ratio of mitral peak velocity of early filling/early diastolic mitral annular velocity and waist-to-hip fat mass ratio were related to changes in the insulin curve. Exercise training resulted in improved oxygen uptake at the second ventilatory threshold (EX, +10 ± 5% vs CON, -8 ± 5%; P < .05) and isokinetic strength endurance of the upper leg (EX, +25 ± 9% vs CON, -6 ± 5%; P < 0.05). Lean body tissue was increased by 2.2 ± 0.5% in EX versus 0.2 ± 0.6% in CON (P < .05)., Conclusion: Our data suggest that exercise training attenuates worsening of glucose regulation typically seen in a stable CHF population.

Background: New techniques of Tissue Doppler Imaging (TDI) enable the measurement of myocardial velocities and provide information about left ventricular (LV) diastolic function. Recent studies explored the prognostic role of TDI-derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population., Methods and Results: We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by TDI in 793 participants (mean age 50.9 years). We calculated multivariable-adjusted hazard ratios for conventional and TDI Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e' velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59; P=0.004) and cardiac events (n=40; P=0.001). TDI e' yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21; P=0.042) and cardiac (4.50; P=0.002) events were significantly elevated in participants with increased LV filling pressure compared with subjects with normal diastolic function., Conclusions: TDI e' velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated LV filling pressure.

The consistency of the normal spatial distribution of segmental passive stretch (PreS) and systolic strain (SS) within the left ventricle was investigated and a recently proposed echocardiographic estimate of left ventricular (LV) contractility was used to detect contractility changes with age. Hereto, in 54 healthy subjects, segmental PreS and SS were measured on tissue Doppler images of six left ventricle walls. For each subject, a linear regression line was estimated through the segmental PreS and SS values. The slopes and intercepts of this PreS-SS relationship did not differ between age groups, suggesting no changes in LV contractility with age. Moreover, a consistent regional distribution of PreS was observed, with the highest values measured in the septum, resulting in a similar distribution of SS as a direct consequence of the Frank-Starling mechanism., (Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objectives: DOPPLER-CIP aims to determine the optimal noninvasive parameters (myocardial function, perfusion, ventricular blood flow, cell integrity) and methodology (ergometry, echocardiography, scintigraphy, MRI) in a given ischemic substrate that best predicts the impact of an intervention (or the lack thereof) on adverse morphological ventricular remodeling and functional recovery. Moreover, the relative predictive value of each of these parameters, in respect to the cost of extracting this information in order to enable optimization of cost-effectiveness for improved health care, will be determined by this project., Design: DOPPLER-CIP is a multi-center registry study. All patients with ischemic heart disease included in this study undergo at least two noninvasive stress imaging examinations at baseline. The presence/or absence of left ventricular (LV) remodeling will be assessed after a follow-up of 2 years, during which all cardiac events will be registered., Results: 676 patients were included. Currently, baseline data analysis is almost finished and the follow-up is ongoing., Conclusions: After completion, DOPPLER-CIP will provide evidence-based guidelines toward the most effective use of cardiac imaging in the chronically ischemic heart disease patient. The study will generate information, knowledge, and insight into the new imaging methodologies and into the pathophysiology of chronic ischemic heart disease.

Objectives: The aim of this study was to test the hypothesis that the noninvasively constructed slope of the relationship between left ventricular (LV) regional systolic strain and stretch during atrial contraction represents LV inotropic state., Background: LV systolic response to a changing preload depends on its inotropic state. Changing the preload has allowed constructing the slope of the end-systolic pressure-volume relationship that is used as an invasive measurement of LV inotropy. We assumed that the slope of the relationship between regional systolic LV strain (total&#95;S) and stretch during atrial contraction (preS) depends on the LV inotropic state as well and can thus be used as a LV inotropy index., Methods: Strain curves (tissue Doppler) were extracted from 27 healthy individuals to determine the normal stretch-strain relationship at rest, during a low-dose dobutamine (LD) challenge and during passive leg-lift (LL). The method was also applied in 7 patients with breast cancer before and after chemotherapy with anthracyclines., Results: PreS and total&#95;S correlated closely in all subjects (r = 0.82). Total&#95;S values increased (p < 0.05) with LD (-20.44 ± 3.89% vs. -24.24 ± 5.55%) and LL (-19.65 ± 3.77% vs. -24.05 ± 3.67%), whereas preS increased only with LL (5.96 ± 1.72% vs. 8.61 ± 2.18%), but not with LD (6.83 ± 2.34% vs. 7.29 ± 2.24%). No changes of total&#95;S or preS were observed after the exposure to chemotherapy (-21.23 ± 2.93% vs. -21.49 ± 2.89% and 8.11 ± 1.03% vs. 8.59 ± 1.73%, respectively). The slope of stretch-strain relationship got steeper with LD (-1.47 ± 0.36 vs. -2.34 ± 0.36, p < 0.05), declined after the chemotherapy (-1.68 ± 0.15 to -0.86 ± 0.23, p < 0.05) and did not change with LL (-1.39 ± 0.57 vs. -1.51 ± 0.38, p = NS)., Conclusions: The slope of the regional stretch-strain relationship can be regarded as a noninvasive index of myocardial inotropic state. It gets steeper with increasing inotropy, does not change with preload induced changes of LV systolic function, and flattens after the exposure to a cardiotoxic drug., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To quantify right ventricular (RV) function in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary endarterectomy (PEA)., Methods: Out of 33 patients, 16 were evaluated clinically and with echocardiography (conventional and myocardial deformation parameters) before PEA (preop) and at 1 week, 1 month, 3 months and 6 months after PEA. RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE) as well as mid-apical and basal peak ejection strain (S) and strain rate (SR) of the RV free wall were measured. Left ventricular (LV) apical lateral wall motion was regarded as indicating changes in overall heart rocking motion (RM). Heart catheterisation was performed before, within 1 week and at 6 months after PEA., Results: Clinical and haemodynamic parameters improved significantly after PEA. This correlated with the improvement in RVFAC, S and SR. TAPSE, on the other hand, showed a biphasic response (14.5 (4) mm preop, 8.5 (2.7) mm at 1 week and 11 (1.5) mm at 6 months). Changes in LV apical motion explain this finding. At baseline, TAPSE was enhanced by rocking motion of the heart as a result of the failing RV. Unloading the RV by PEA normalised the rocking motion and TAPSE decreased., Conclusions: RV function of CTEPH patients improves steadily after PEA. Unlike S, SR and RVFAC, this is not reflected by TAPSE because of postoperative changes in overall heart motion. Motion independent deformation parameters (S, SR) appear superior in the accurate description of regional RV function.

Because life expectancy and the prevalence of risk factors such as hypertension, obesity and diabetes are rising globally, heart failure (HF) is growing into a major health problem. Impairment of left ventricular (LV) diastolic function as well as systolic function appear very early in the course of heart disease. Recent HF guidelines, therefore, place special emphasis on the detection of subclinical LV dysfunction and the timely identification of risk factors for HF. Conventional echocardiography combined with new imaging techniques such as tissue Doppler and tissue tracking are sensitive tools to detect early subclinical deterioration of LV function. Community-based studies revealed a higher prevalence of LV systolic and diastolic dysfunction using the new echocardiographic imaging techniques. Future prospective studies will clarify the hitherto unknown prognosis associated with early symptom-free LV dysfunction.

Aims: To investigate whether intracoronary transfer of bone marrow progenitor cells (BMPCs) early after reperfusion of an acute myocardial infarction improves regional myocardial function in a randomized double-blind, placebo-controlled strain rate imaging study., Methods and Results: Regional myocardial deformation was measured using velocity-derived strain rate imaging in 67 STEMI patients randomized 1:1 to intracoronary infusion of BMPC (n = 33) or placebo (n = 34). Myocardial segments were grouped into infarct (n = 232), border (n = 250), and remote (n = 526) based on MRI-delayed enhancement and the perfusion territory of the infarct-related vessel. Four months after revascularization and progenitor cell/placebo transfer, regional myocardial deformation (rate) improved significantly more in the infarct segments of BMPC patients (treatment effect on end-systolic strain: -3.7 +/- 1.0%, P = 0.0003; peak-systolic strain rate: -0.20 +/- 0.07 s(-1), P = 0.0035). These findings were confirmed by a significantly greater improvement of longitudinal mitral valve ring displacement in the infarct walls of BMPC patients (treatment effect: 0.93 mm, P = 0.034)., Conclusion: Intracoronary infusion of BMPC early after reperfusion of a STEMI improves recuperation of regional myocardial function at 4 months' follow-up. Quantitative assessment of regional systolic function might be more sensitive than global LV ejection fraction for the evaluation of BMPC therapy after STEMI.

Background: Because the process of myocardial remodelling starts before the onset of symptoms, recent heart failure (HF) guidelines place special emphasis on the detection of subclinical left ventricular (LV) systolic and diastolic dysfunction and the timely identification of risk factors for HF. Our goal was to describe the prevalence and determinants (risk factors) of LV diastolic dysfunction in a general population and to compare the amino terminal probrain natriuretic peptide level across groups with and without diastolic dysfunction., Methods and Results: In a randomly recruited population sample (n=539; 50.5% women; mean age, 52.5 years), we measured early and late diastolic peak velocities of mitral inflow (E and A), pulmonary vein flow by pulsed-wave Doppler, and the mitral annular velocities (Ea and Aa) at 4 sites by tissue Doppler imaging. A healthy subsample of 239 subjects (mean age, 43.7 years) provided age-specific cutoff limits for normal E/A and E/Ea ratios and the differences in duration between the mitral A and the reverse pulmonary vein flows during atrial systole (DeltaAd-ARd). The number of subjects in diastolic dysfunction groups 1 (impaired relaxation), 2 (elevated LV end-diastolic filling pressure), and 3 (elevated E/Ea and abnormally low E/A) were 53 (9.8%), 76 (14.1%), and 18 (3.4%), respectively. We used Delta(Ad