Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

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.

Exercise-induced myocardial T1 increase and right ventricular dysfunction in recreational cyclists: a CMR study.

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.

Lifelong endurance exercise and its relation with coronary atherosclerosis.

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.

Relating QRS voltages to left ventricular mass and body composition in elite endurance athletes.

PURPOSE: Electrocardiogram (ECG) QRS voltages correlate poorly with left ventricular mass (LVM). Body composition explains some of the QRS voltage variability. The relation between QRS voltages, LVM and body composition in endurance athletes is unknown. METHODS: Elite endurance athletes from the Pro@Heart trial were evaluated with 12-lead ECG for Cornell and Sokolow-Lyon voltage and product. Cardiac magnetic resonance imaging assessed LVM. Dual energy x-ray absorptiometry assessed fat mass (FM) and lean mass of the trunk and whole body (LBM). The determinants of QRS voltages and LVM were identified by multivariable linear regression. Models combining ECG, demographics, DEXA and exercise capacity to predict LVM were developed. RESULTS: In 122 athletes (19 years, 71.3% male) LVM was a determinant of the Sokolow-Lyon voltage and product (ß = 0.334 and 0.477, p < 0.001) but not of the Cornell criteria. FM of the trunk (ß = - 0.186 and - 0.180, p < 0.05) negatively influenced the Cornell voltage and product but not the Sokolow-Lyon criteria. DEXA marginally improved the prediction of LVM by ECG (r = 0.773 vs 0.510, p < 0.001; RMSE = 18.9 ± 13.8 vs 25.5 ± 18.7 g, p > 0.05) with LBM as the strongest predictor (ß = 0.664, p < 0.001). DEXA did not improve the prediction of LVM by ECG and demographics combined and LVM was best predicted by including VO2max (r = 0.845, RMSE = 15.9 ± 11.6 g). CONCLUSION: LVM correlates poorly with QRS voltages with adipose tissue as a minor determinant in elite endurance athletes. LBM is the strongest single predictor of LVM but only marginally improves LVM prediction beyond ECG variables. In endurance athletes, LVM is best predicted by combining ECG, demographics and VO2max.

Three-dimensional echocardiography of the athlete's heart: a comparison with cardiac magnetic resonance imaging.

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/m2, RVEDVi bias - 25.5 mL/m2) 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.

Rationale and design of the PROspective ATHletic Heart (Pro@Heart) study: long-term assessment of the determinants of cardiac remodelling and its clinical consequences in endurance athletes.

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.

Impaired biventricular contractile reserve in patients with diastolic dysfunction: insights from exercise stress echocardiography.

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.

Endurance exercise and the risk of cardiovascular pathology in men: a comparison between lifelong and late-onset endurance training and a non-athletic lifestyle - rationale and design of the Master@Heart study, a prospective cohort trial.

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.

Oxygen Pathway Limitations in Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis has been attributed to central factors, including ventilation/perfusion mismatch, increased pulmonary vascular resistance, and right heart dysfunction and uncoupling. Pulmonary endarterectomy and balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention. METHODS: Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2 transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (n=10). Furthermore, we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10). RESULTS: Peak Vo2 (oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted; P<0.0001). The difference was attributable to impairments in multiple steps of the O2 cascade, including O2 delivery (product of cardiac output and arterial O2 content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O2 extracted in the periphery (ie, ΔAVo2 [arteriovenous O2 content difference]) was not different. After pulmonary vascular intervention, peak Vo2 increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min]; P=0.036) but remained below age-predicted levels (70±11%). The O2 delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo2 was unchanged, as was skeletal muscle diffusion capacity. CONCLUSIONS: We demonstrated that patients with CTEPH have significant impairment of all steps in the O2 use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo2 by partly correcting O2 delivery but had no effect on abnormalities in peripheral O2 extraction. This suggests that current interventions only partially address patients' limitations and that additional therapies may improve functional capacity.

Exercise cardiac magnetic resonance imaging to assess dynamic right ventricular outflow tract obstruction in congenital heart disease: a case report.

BACKGROUND: Right ventricular outflow tract obstruction in patients with congenital heart disease is usually assessed using echocardiographic peak instantaneous gradient at rest. Since right ventricular outflow tract obstruction may change during exercise (dynamic right ventricular outflow tract obstruction), we present a case emphasizing the potential use of exercise cardiac magnetic resonance imaging (CMR). CASE SUMMARY: We discuss a 15-year-old patient with repaired mid-ventricular sub-pulmonary stenosis type double-chambered right ventricle causing right ventricular outflow tract obstruction and symptoms on exertion. In this case, exercise CMR imaging provided additional information, allowing adequate surgical planning. DISCUSSION: The additional value of exercise CMR imaging in a case of right ventricular outflow tract obstruction was described. Although exercise cardiac magnetic resonance imaging did not show a significant increase in peak gradient across the right ventricular outflow tract obstruction, shifting and D-shaping of the interventricular septum with subsequent insufficient left ventricular filling (preload) was observed in the patient with recurrent double-chambered right ventricle. This case demonstrates how exercise CMR imaging can be helpful in the clinical decision beyond standard echocardiographic evaluation by providing additional evidence of adverse haemodynamics during exercise.

Right ventricular strain rate during exercise accurately identifies male athletes with right ventricular arrhythmias.

AIMS: Athletes with right ventricular (RV) arrhythmias, even in the absence of desmosomal mutations, may have subtle RV abnormalities which can be unmasked by deformation imaging. As exercise places a disproportionate stress on the right ventricle, evaluation of cardiac function and deformation during exercise might improve diagnostic performance. METHODS AND RESULTS: We performed bicycle stress echocardiography in 17 apparently healthy endurance athletes (EAs), 12 non-athletic controls (NAs), and 17 athletes with RV arrhythmias without desmosomal mutations (EI-ARVCs) and compared biventricular function at rest and during low (25% of upright peak power) and moderate intensity (60%). At rest, we observed no differences in left ventricular (LV) or RV function between groups. During exercise, however, the increase in RV fractional area change (RVFAC), RV free wall strain (RVFWSL), and strain rate (RVFWSRL) were significantly attenuated in EI-ARVCs as compared to EAs and NAs. At moderate exercise intensity, EI-ARVCs had a lower RVFAC, RVFWSL, and RVFWSRL (all P < 0.01) compared to the control groups. Exercise-related increases in LV ejection fraction, strain, and strain rate were also attenuated in EI-ARVCs (P < 0.05 for interaction). Exercise but not resting parameters identified EI-ARVCs and RVFWSRL with a cut-off value of >-2.35 at moderate exercise intensity had the greatest accuracy to detect EI-ARVCs (area under the curve 0.95). CONCLUSION: Exercise deformation imaging holds promise as a non-invasive diagnostic tool to identify intrinsic RV dysfunction concealed at rest. Strain rate appears to be the most accurate parameter and should be incorporated in future, prospective studies to identify subclinical disease in an early stage.