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 for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study.

BACKGROUND: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO2peak), and prevent cardiac dysfunction. METHODS: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO2peak and functional disability (VO2peak ≤18.0 mL·kg-1·min-1); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide]). RESULTS: Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11-0.94]; P=0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06-1.12]; P=0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P=0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg-1·min-1 improvement in VO2peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve (P<0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P=0.002). There were no changes in BNP in either group. CONCLUSIONS: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO2peak and cardiac reserve. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.

Characterizing the influence of cardiorespiratory fitness on left atrial size and function in the general population.

Increased left atrial (LA) size and reduced LA function have been associated with heart failure and atrial fibrillation (AF) in at-risk populations. However, atrial remodeling has also been associated with exercise training and the relationship between fitness, LA size, and function has not been defined across the fitness spectrum. In a cross-sectional study of 559 ostensibly healthy participants, comprising 304 males (mean age, 46 ± 20 yr) and 255 females (mean age, 47 ± 15 yr), we sought to define the relationship between cardiorespiratory fitness (CRF), LA size, and function. We also aimed to interrogate sex differences in atrial factors influencing CRF. Echocardiographic measures included biplane measures of LA volumes indexed to body surface area (LAVi) and atrial deformation using two-dimensional speckle tracking. CRF was measured as peak oxygen consumption (V̇o2peak) during cardiopulmonary exercise testing (CPET). Using multivariable regression, age, sex, weight, and LAVi (P < 0.001 for all) predicted V̇o2peak (P < 0.001, R2 = 0.66 for combined model). After accounting for these variables, heart rate reserve added strength to the model (P < 0.001, R2 = 0.74) but LA strain parameters did not predict V̇o2peak. These findings add important nuance to the perception that LA size is a marker of cardiac pathology. LA size should be considered in the context of fitness, and it is likely that the adverse prognostic associations of increased LA size may be confined to those with LA enlargement and low fitness.NEW & NOTEWORTHY Left atrial (LA) structure better predicts cardiorespiratory fitness (CRF) than LA function. LA function adds little statistical value to predictive models of peak oxygen uptake (V̇o2peak) in healthy individuals, suggesting limited discriminatory for CRF once LA size is factored. In the wider population of ostensibly healthy individuals, the association between increased LA volume and higher CRF provides an important counter to the association between atrial enlargement and heart failure symptoms in those with cardiac pathology.

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.

Measurement of Stroke Volume With Echocardiography Compared to Gold Standard Cardiac Magnetic Resonance Imaging: An Observational Study.

OBJECTIVES: The authors aimed to compare the assessment of left ventricular (LV) stroke volume with transthoracic echocardiography (TTE) using 2- and 3-dimensional (2D and 3D) Doppler and volumetric techniques with gold standard cardiac magnetic resonance imaging (CMR). DESIGN: An observational study. SETTING: A medical research institute. PARTICIPANTS: A total of 187 volunteer participants free of known structural heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: LV stroke volume was measured with TTE using the following 4 techniques: LV outflow tract (LVOT) pulsed wave Doppler with 2D LVOT area, LVOT pulsed wave Doppler with 3D LVOT area, 2D volumetric (Simpson's biplane), and 3D volumetric techniques. This was compared with gold standard CMR. Stroke volume measured with echocardiography underestimated stroke volume compared to CMR by all techniques (p < 0.001 for all values compared to CMR). The LVOT Doppler stroke volume with a 3D area most closely agreed with CMR, with a bias of 6.35%. This bias progressively increased with 3D volumetric (13.4%), LVOT Doppler with a 2D area (15.1%), and 2D volumetric (18.3%) stroke volume techniques, with wider limits of agreement. CONCLUSION: Of the 4 echocardiographic LV stroke volume measurement methods the authors assessed, stroke volume with LVOT Doppler using 3D measurement of LVOT area most closely approximates gold standard CMR.

Aerosol Generation During High Intensity Exercise-Implications for COVID-19 Transmission.

BACKGROUND AND AIM: COVID-19 can be transmitted through aerosolised respiratory particles. The degree to which exercise enhances aerosol production has not been previously assessed. We aimed to quantify the size and concentration of aerosol particles and evaluate the impact of physical distance and surgical mask wearing during high intensity exercise (HIE). METHODS: Using a prospective observational crossover study, three healthy volunteers performed high intensity cardiopulmonary exercise testing at 80% of peak capacity in repeated 5-minute bouts on a cycle ergometer. Aerosol size and concentration was measured at 35, 150 and 300 cm from the participants in an anterior and lateral direction, with and without a surgical face mask, using an Aerodynamic Particle Sizer (APS) and a Mini Wide Range Aerosol Spectrometer (MiniWRAS), with over 10,000 sample points. RESULTS: High intensity exercise generates aerosol in the 0.2-1 micrometre range. Increasing distance from the rider reduces aerosol concentrations measured by both MiniWRAS (p=0.003 for interaction) and APS (p=0.041). However, aerosol concentrations remained significantly increased above baseline measures at 300 cm from the rider. A surgical face mask reduced submicron aerosol concentrations measured anteriorly to the rider (p=0.031 for interaction) but not when measured laterally (p=0.64 for interaction). CONCLUSIONS: High intensity exercise is an aerosol generating activity. Significant concentrations of aerosol particles are measurable well beyond the commonly recommended 150 cm of physical distancing. A surgical face mask reduces aerosol concentration anteriorly but not laterally to an exercising individual. Measures for safer exercise should emphasise distance and airflow and not rely solely on mask wearing.

Prescribing Exercise in Early-Stage Breast Cancer During Chemotherapy: A Simple Periodized Approach to Align With the Cyclic Phases of Chemotherapy.

ABSTRACT: Bigaran, A, Howden, EJ, Foulkes, S, Janssens, K, Beaudry, R, Haykowsky, MJ, La Gerche, A, Fraser, SF, and Selig, SE. Prescribing exercise in early-stage breast cancer during chemotherapy: a simple periodized approach to align with the cyclic phases of chemotherapy. J Strength Cond Res 36(10): 2934-2941, 2022-To evaluate whether a periodized aerobic and resistance training plan aligned to the anthracycline chemotherapy (AC) cycles would be well tolerated, feasible, and attenuate the decline in peak oxygen uptake (V̇o2peak) in breast cancer (BC) patients. Twenty-eight women with early-stage BC treated with AC self-selected to undertake exercise training (EX 47 ± 9 years, n = 14) or usual care (53 ± 9 years, n = 14) for 12 weeks as part of a nonrandomized controlled trial. The periodized EX was aligned to the cyclic phases of AC, including AC taper and nontaper weeks. Outcome measures included cardiopulmonary exercise testing. Attendance and adherence variables (relative dose intensity [RDI] and volume load) were calculated to quantify the dose of EX completed relative to the amount of EX prescribed. The mean session attendance was 76% (range 46-88%). The mean ± SD prescribed and completed dose of aerobic training was 332.3 ± 48.7 MET h·wk-1 and 380.6 ± 53.2 MET h·wk-1 (p = 0.02), equating to a mean RDI of 89 ± 17%. For resistance training, the prescribed and completed cumulative dose was 128,264 ± 54,578 and 77,487 ± 26,108 kg (p < 0.001), equating to an RDI of 60 ± 11%. Adherence to the AC taper week RDI (52 ± 14%) for resistance training was significantly lower than the non-AC taper week (72 ± 8%, p = 0.02). The most frequent cause for EX interruption was hospitalization (35%), whereas AC-related illness was the most common cause for missed (57%) or modified EX sessions (64%). This periodized approach was mostly well tolerated for patients with BC. We speculate that a periodized approach may be both more palatable and useful, although this requires further investigation in a randomized controlled trial.

Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness.

BACKGROUND: Pediatric cancer survivors are at increased risk of cardiac dysfunction and heart failure. Reduced peak oxygen consumption (peak VO2) is associated with impaired cardiac reserve (defined as the increase in cardiac function from rest to peak exercise) and heart failure risk, but it is unclear whether this relationship exists in pediatric cancer survivors. This study sought to investigate the presence of reduced peak VO2 in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac haemodynamics and systolic function during exercise. METHODS: Twenty pediatric cancer survivors (8-24 years; 10 male) treated with anthracycline chemotherapy ± radiation underwent cardiopulmonary exercise testing to quantify peak VO2, with a value < 85% of predicted defined as impaired peak VO2. Resting cardiac function was assessed using 2- and 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate, stroke volume index (SVI) and cardiac index (CI) using exercise cardiovascular magnetic resonance (CMR). RESULTS: Twelve of 20 survivors (60%) had reduced peak VO2 (70 ± 16% vs. 97 ± 14% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired peak VO2. However, those with reduced peak VO2 had diminished cardiac reserve, with a lesser increase in CI and SVI during exercise (Interaction P < 0.01 for both), whilst the heart rate response was similar (P = 0.71). CONCLUSIONS: Whilst exercise intolerance is common among pediatric cancer survivors, it is poorly explained by resting measures of cardiac function. In contrast, impaired exercise capacity is associated with impaired haemodynamics and systolic functional reserve measured during exercise. Consequently, measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure.

Too Little of a Good Thing: Strong Associations Between Cardiac Size and Fitness Among Women.

BACKGROUND: Cardiorespiratory fitness (CRF) is associated with functional impairment and cardiac events, particularly heart failure (HF). However, the factors predisposing women to low CRF and HF remain unclear. OBJECTIVES: This study sought to evaluate the association between CRF and measures of ventricular size and function and to examine the potential mechanism linking these factors. METHODS: A total of 185 healthy women aged >30 years (51 ± 9 years) underwent assessment of CRF (peak volume of oxygen uptake [Vo2peak]) and biventricular volumes at rest and during exercise by using cardiac magnetic resonance (CMR). The relationships among Vo2peak, cardiac volumes, and echocardiographic measures of systolic and diastolic function were assessed using linear regression. The effect of cardiac size on cardiac reserve (change in cardiac function during exercise) was assessed by comparing quartiles of resting left ventricular end-diastolic volume (LVEDV). RESULTS: Vo2peak was strongly associated with resting measures of LVEDV and right ventricular end-diastolic volume (R2 = 0.58-0.63; P < 0.0001), but weakly associated with measures of resting left ventricular (LV) systolic and diastolic function (R2 = 0.01-0.06; P < 0.05). Increasing LVEDV quartiles were positively associated with cardiac reserve, with the smallest quartile showing the smallest reduction in LV end-systolic volume (quartile [Q]1: -4 mL vs Q4: -12 mL), smallest augmentation in LV stroke volume (Q1: +11 mL vs Q4: +20 mL) and cardiac output (Q1: +6.6 L/min vs Q4: +10.3 L/min) during exercise (interaction P < 0.001 for all). CONCLUSIONS: A small ventricle is strongly associated with low CRF because of the combined effect of a smaller resting stroke volume and an attenuated capacity to increase with exercise. The prognostic implications of low CRF in midlife highlight the need for further longitudinal studies to determine whether women with small ventricles are predisposed to functional impairment, exertional intolerance, and HF later in life.

Understanding Exercise Capacity: From Elite Athlete to HFpEF.

Exercise capacity is a spectrum that reflects an individual's functional capacity and the dynamic nature of cardiac remodelling along with respiratory and skeletal muscle systems. The relationship of increasing physical activity, increased cardiac mass and volumes, and improved cardiorespiratory fitness (CRF) is well established in the endurance athlete. However, less emphasis has been placed on the other end of the spectrum, which includes individuals with a more sedentary lifestyle and small hearts who are at increased risk of functional disability and poor clinical outcomes. Reduced CRF is an independent predictor of all-cause mortality and cardiovascular events determined by multiple inter-related exogenous and endogenous factors. In this review, we explore the relationship of physical activity, cardiac remodelling, and CRF across the exercise spectrum, emphasising the critical role of cardiac size in determining exercise capacity. In contrast to the large compliant left ventricle of the endurance athlete, an individual with a lifetime of physical inactivity is likely to have a small, stiff heart with reduced cardiac reserve. We propose that this might contribute to the development of heart failure with preserved ejection fraction in certain individuals, and is key to understanding the link between low CRF and increased risk of heart failure.

Effects of training adaption in endurance athletes with atrial fibrillation: protocol for a multicentre randomised controlled trial.

Endurance athletes have a high prevalence of atrial fibrillation (AF), probably caused by exercise-induced cardiac remodelling. Athletes diagnosed with AF are often advised to reduce the intensity and amount of training but the efficacy of this intervention has not been investigated in endurance athletes with AF. Effects of detraining in endurance athletes with atrial fibrillation is a two-arm international multicentre randomised (1:1) controlled trial on the effects of a period of training adaption on AF burden in endurance athletes with paroxysmal AF. One-hundred-and-twenty endurance athletes diagnosed with paroxysmal AF are randomised to a 16-week period of intervention (training adaption) or a control group. We define training adaption as training with a heart rate (HR) not exceeding 75% of the individual maximum HR (HRmax), and total duration of weekly training not exceeding 80% of the self-reported average before the study. The control group is instructed to uphold training intensity including sessions with HR ≥85% of HRmax. AF burden is monitored with insertable cardiac monitors, and training intensity with HR chest-straps and connected sports watches. The primary endpoint, AF burden, will be calculated as the cumulative duration of all AF episodes lasting ≥30sec divided by total duration of monitoring. Secondary endpoints include number of AF episodes, adherence to training adaption, exercise capacity, AF symptoms and health-related quality of life, echocardiographic signs of cardiac remodelling and risk of cardiac arrhythmias related to upholding training intensity. Trial registration number: NCT04991337. Study protocol version: 4.7 (Date 9 March 2023).

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.

Diastolic flow in the left ventricular outflow tract - A normal physiological and underappreciated echocardiographic finding.

Purpose: Diastolic waveforms in the left ventricular outflow tract (LVOT) are commonly observed with Doppler echocardiography. The incidence and mechanism are not well described. Methods: This was a retrospective observational study of 186 adult patients, athletes and non-athletes, free of known cardiac disease, presenting for comprehensive transthoracic echocardiography at a research institute. We aimed to evaluate the incidence and echocardiographic associations between LVOT diastolic waveforms. Results: Left ventricular outflow tract early to mid-diastolic waveforms were present in 100% of athletes and 95% of non-athletes. The LVOT diastolic velocity time integral was larger in athletes than non-athletes with a mean 8.3 cm (95% CI (7.6-8.9)) vs. 5.1 cm (4.4-5.9) (P < 0.0001). Multivariate predictors of this diastolic waveform were age (P = 0.002), slower heart rate (P = 0.035), higher stroke volume (P = 0.003), large mitral E (P = 0.019) and higher E/e' (P = 0.015). Discussion: An LVOT early diastolic wave is a normal physiological finding. It is related to a flow vortex redirecting diastolic mitral inflow around anterior mitral valve leaflet into the LVOT. Conclusions: Early to mid-diastolic LVOT waves are present in almost all patients but more prominent in young athletes than non-athletes. Diastolic LVOT waves increase with younger age, slower heart rate, larger stroke volume and enhanced diastolic function.

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.

Traditional markers of cardiac toxicity fail to detect marked reductions in cardiorespiratory fitness among cancer patients undergoing anti-cancer treatment.

AIMS: Left ventricular ejection fraction (LVEF) is standard of care for evaluating chemotherapy-associated cardiotoxicity, although global longitudinal strain (GLS) offers advantages. However, neither change in LVEF or GLS has been associated with short-term symptoms, functional capacity, or long-term heart failure (HF) risk. We sought to determine whether an integrative measure of cardiovascular function (VO2peak) that is strongly associated with HF risk would be more sensitive to cardiac damage induced by cancer treatment than LVEF, GLS, or cardiac biomarkers. METHODS AND RESULTS: Patients (n = 206, 53 ± 13 years, 35% male) scheduled to commence anti-cancer treatment completed assessment prior to, and within 6 months after therapy. Changes in echocardiographic measures of LV function (LVEF, GLS), cardiac biomarkers (troponin and BNP), and cardiorespiratory fitness (VO2peak) were measured. LV function was normal prior to treatment (LVEF 61 ± 5%; GLS -19.4 ± 2.1), but VO2peak was only 88 ± 26% of age-predicted. After treatment, VO2peak was reduced by 7 ± 15% (equivalent of 7 years normal ageing, P < 0.0001) and the rates of functional disability (defined as VO2peak ≤ 18 mL/min/kg) almost doubled (15% vs. 26%, P = 0.016). In contrast, small, reductions in LVEF (59 ± 5% vs. 58 ± 5%, P = 0.03) and GLS (-19.4 ± 2.1 vs. -18.9 ± 2.2, P = 0.002) and an increase in troponin levels (4.0 ± 6.9 vs. 26.4 ± 26.2 ng/mL, P < 0.0001) were observed. CONCLUSION: Anti-cancer treatment is associated with marked reductions in functional capacity that occur independent of reductions in LVEF and GLS. The assessment of VO2peak prior to, and following treatment may be a more sensitive means of identifying patients at increased risk of HF.

Differing mechanisms of atrial fibrillation in athletes and non-athletes: alterations in atrial structure and function.

AIMS: Atrial fibrillation (AF) is more common in athletes and may be associated with adverse left atrial (LA) remodelling. We compared LA structure and function in athletes and non-athletes with and without AF. METHODS AND RESULTS: Individuals (144) were recruited from four groups (each n = 36): (i) endurance athletes with paroxysmal AF, (ii) endurance athletes without AF, (iii) non-athletes with paroxysmal AF, and (iv) non-athletic healthy controls. Detailed echocardiograms were performed. Athletes had 35% larger LA volumes and 51% larger left ventricular (LV) volumes vs. non-athletes. Non-athletes with AF had increased LA size compared with controls. LA/LV volume ratios were similar in both athlete groups and non-athlete controls, but LA volumes were differentially increased in non-athletes with AF. Diastolic function was impaired in non-athletes with AF vs. non-athletes without, while athletes with and without AF had normal diastolic function. Compared with non-AF athletes, athletes with AF had increased LA minimum volumes (22.6 ± 5.6 vs. 19.2 ± 6.7 mL/m2, P = 0.033), with reduced LA emptying fraction (0.49 ± 0.06 vs. 0.55 ± 0.12, P = 0.02), and LA expansion index (1.0 ± 0.3 vs. 1.2 ± 0.5, P = 0.03). LA reservoir and contractile strain were decreased in athletes and similar to non-athletes with AF. CONCLUSION: Functional associations differed between athletes and non-athletes with AF, suggesting different pathophysiological mechanisms. Diastolic dysfunction and reduced strain defined non-athletes with AF. Athletes had low atrial strain and those with AF had enlarged LA volumes and reduced atrial emptying, but preserved LV diastolic parameters. Thus, AF in athletes may be triggered by an atrial myopathy from exercise-induced haemodynamic stretch consequent to increased cardiac output.

Persistent Impairment in Cardiopulmonary Fitness after Breast Cancer Chemotherapy.

PURPOSE: Anthracycline chemotherapy (AC) is associated with acute reductions in cardiopulmonary fitness (V˙O2peak). We sought to determine whether changes in V˙O2peak and cardiac function persisted at 12 months post-AC completion, and whether changes in cardiac function explain the heightened long-term heart failure risk. METHODS: Women with breast cancer scheduled for AC (n = 28) who participated in a nonrandomized trial of exercise training (ET; n = 14) or usual care (UC; n = 14) during AC completed a follow-up evaluation 12 months post-AC completion (16 months from baseline). At baseline, 4 months, and 16 months, participants underwent a resting echocardiogram (left ventricular ejection fraction; global longitudinal strain), a blood sample (troponin; B-type natriuretic peptide), a cardiopulmonary exercise test, and cardiac MRI measures of stroke volume (SV), heart rate, and cardiac output (Qc) at rest and during intense exercise. RESULTS: Seventeen women (UC, n = 8; ET, n = 9) completed evaluation at baseline, 4 months, and 16 months. At 4 months, AC was associated with 18% and 6% reductions in V˙O2peak in the UC and ET groups, respectively, which persisted at 16 months (UC, -16%; ET, -7%) and was not attenuated by ET (interaction, P = 0.10). Exercise Qc was lower at 16 months compared with baseline and 4 months (P < 0.001), which was due to a blunted augmentation of SV during exercise (P = 0.032; a 14% reduction in peak SV), with no changes in heart rate response. There was a small reduction in resting left ventricular ejection fraction (baseline to 4 months) and global longitudinal strain (between 4 and 16 months) and an increase in troponin (baseline to 4 months), but only exercise Qc was associated with V˙O2peak (R = 0.47, P < 0.01). CONCLUSION: Marked reductions in V˙O2peak persisted 12 months after anthracycline-based chemotherapy, which was associated with impaired exercise cardiac function. CLINICAL TRIAL REGISTRATION: ACTRN12616001602415.

Beta1-adrenoceptor expression in rat anterior pituitary gonadotrophs and in mouse alphaT3-1 and LbetaT2 gonadotrophic cell lines.

The rat anterior pituitary expresses beta(2)-adrenoceptors (ARs) on somatotrophs, lactotrophs, and corticotrophs. The present study investigates whether beta(1)-ARs exist in the anterior pituitary, in which cell type(s) they are found, and whether they are regulated by glucocorticoids. As determined by quantitative RT-PCR and Western immunoblotting, the rat anterior pituitary expressed beta(1)-AR mRNA and protein. Unlike the beta(2)-AR, expression decreased to very low levels after 5-d aggregate cell culture but was strongly up-regulated in a dose- and time-dependent manner by dexamethasone (DEX). Glucocorticoids attenuated isoproterenol-induced down-regulation of beta(1)-AR mRNA levels. As examined by immunofluorescence confocal microscopy, beta(1)-AR immunoreactivity was detected in a subpopulation of gonadotrophs, but not in somatotrophs, lactotrophs, corticotrophs, thyrotrophs, or folliculo-stellate cells. beta(1)-AR-immunoreactivity cells were often surrounded by cup-shaped lactotrophs. Consistent with these findings, beta(1)-AR mRNA was considerably more abundant in the gonadotrophic alphaT3-1 and LbetaT2 cell lines than in the GHFT, GH3, and TtT/GF cell lines. DEX did not affect expression level in the cell lines. DEX also failed to up-regulate beta(1)-AR mRNA levels in aggregates from a subpopulation enriched in large gonadotrophs obtained by gradient sedimentation. In contrast, excessive DEX-dependent up-regulation of beta(1)-AR mRNA was found in a subpopulation enriched in small nonhormonal cells. The present data indicate that beta(1)-AR is expressed in a subpopulation of gonadotrophs with a topographical relationship to lactotrophs. However, the glucocorticoid-induced up-regulation does not seem to occur directly in the gonadotrophs but within (an)other unidentified cell type(s), or is transduced by that cell type on gonadotrophs.

Beta1-adrenoceptors in rat anterior pituitary may be constitutively active. Inverse agonism of CGP 20712A on basal 3',5'-cyclic adenosine 5'-monophosphate levels.

Catecholamines directly stimulate GH, ACTH, and prolactin secretion from rat anterior pituitary through the beta(2)-adrenoceptor (AR). We recently showed that gonadotrophs express the beta(1)-AR and that glucocorticoids drastically increase its mRNA expression level. The present investigation explores whether beta(1)-ARs are functionally coupled to adenylate cyclase. In anterior pituitary cell aggregates, the highly selective beta(1)-AR antagonists CGP 20712A and ICI 89,406-8a attenuated isoproterenol-stimulated cAMP accumulation, but no agonist action of norepinephrine could be detected. Remarkably, CGP 20712A inhibited basal cAMP levels by its own for at least 50%, an action that tended to be more effective in dexamethasone-supplemented medium. The latter effect was abolished by the beta-AR antagonist carvedilol, but not by other beta-AR antagonists. Pretreatment with pertussis toxin abolished the action of CGP 20712A on basal cAMP. CGP 20712A also attenuated isoproterenol-induced cAMP accumulation in the gonadotroph cell lines alphaT3-1 and LbetaT2, but not in the somatotroph precursor cell line GHFT and the folliculo-stellate cell line TtT/GF. However, in LbetaT2 cells CGP 20712A did not inhibit basal cAMP levels by its own. The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. CGP 20712A may act as an inverse agonist with approximately 50% negative intrinsic activity, suggesting that the beta(1)-AR significantly contributes to basal adenylate cyclase activity in the pituitary.