Right heart exercise-training-adaptation and remodelling in endurance athletes

Long-term sports training leads to myocardial adaptations, with remodelling of the heart chambers. However, while myocardial adaptations of the left heart are well described, remodelling of the right heart and its impact on the development of arrhythmias is still debated. To conduct a systematic review on right ventricle (RV) and right atrium (RA) structural and functional changes in athletes who participate in long-term endurance training. Systematic review. A systematic literature search was conducted. All the articles reporting right heart echocardiographic (ECHO) and cardiac magnetic resonance (CMR) parameters evaluated in endurance athletes and sedentary subjects were considered eligible. A multivariate analysis was conducted to investigate whether age, sex, body surface area (BSA), intensity of training are associated with RV ECHO, CMR parameters and RA ECHO parameters. A positive association between age and right atrium area (RAA) (P = 0.01) was found. This is a negative association to RV E/A (P = 0.004), and RV end diastolic diameter (RVED) longitudinal (P = 0.01). A positive association between BSA and RVED middle (P = 0.001), as well between BSA and RAA (P = 0.05) was found, along with a negative association with RV E/A (P = 0.002). A positive association between intensity of training and RV end systolic area (RVESA) (P = 0.03), RV end diastolic volume indexed (RVEDVI) (P = 0.01), RV end systolic volume indexed (RVESVI) (P = 0.01) was found, along with a negative association with ejection fraction (EF %) (P = 0.01). Endurance athletes demonstrated an association between RV remodelling and age, BSA and intensity of training.

Literature search and selection. Two authors (MP; VC) independently performed the literature search in May 2021. The following databases were used for the search: Medline, Scopus and Cochrane. To conduct a comprehensive systematic literature search, we used both controlled vocabulary and free text terms. For our research, the following MESH terms were used: right ventricle, right atrium, right heart, heart chambers, endurance, athletes, echocardiography, cardiac magnetic resonance, sport, players, remodelling, adaptation, training, work out. Only studies published from 2000 up to May 2021 were accessed. Resulting titles and abstracts of interests were screened by the two authors independently. The full text of the articles of interest were examined. Disagreements about the eligibility of a study were resolved were solved by a third author (FM).
Eligibility criteria. According to the authors' language capabilities, articles in English, Italian, French, German, Portuguese and Spanish were considered. Studies with level of evidence I to III, according to the Oxford Centre for Evidence-Based Medicine (OCEBM), were considered 26 . Data from national registries were excluded, as well as reviews, letters, expert opinions, case reports, editorials, animal, computational and cadaveric studies. As the aim was to investigate the remodelling of the right heart in endurance athletes, only study which investigated athletes who regularly played sports listed on the Mitchel Category class C 27 were examined. Only studies reporting right heart ECHO and/or CMR parameters of endurance athletes and a sedentary group as controls were eligible. To evaluate chronic adaptations, only CMR or an ECHO evaluation performed at rest were considered. The exclusions criteria were represented by all the variables which could alter the physiological parameters: the presence of diseases, a family history of pulmonary or cardiac diseases, chronic use of drugs. Data extraction. Data were extracted by two different authors (MP; VC). Data from the following endpoints were collected: • generalities displayed author and publication year and general characteristics of our population: number of athletes, number of sedentary individuals, sex, age, body mass index (BMI), body surface area (BSA), heart rate (HR), training hours and years of training. • ECHO data to assess the morphological and functional parameters of the right heart: basal, middle, longitu- Outcomes of interest. The primary outcome of interest was to investigate the association between right heart remodelling and age, sex, BSA and intensity of training. The second outcome of interest was to compare the mean values of endurance athletes morphological and functional parameters. To underline the different adaptation of RV in male and female among CMR studies, five studies were selected, in which parameters referred to male athletes, male sedentary, female athletes, female sedentary were reported separately. In these studies, the difference of the means between male athletes-male sedentary subjects and female athletes-female sedentary subjects were compared.
Methodological quality assessment. The same two reviewers who extracted data (MP; VC) assessed the risk of bias of the included studies using the Newcastle Ottawa Scale (NOS) 28 . The NOS evaluates three parameters, namely selection, comparability and exposure. The parameter selection domain includes 4 items useful to check definition and representativeness of cases and controls; the comparability domain includes 1 item to compare cases and controls based on the study design or analysis; the exposure domain includes 3 items to evaluate methods adopted in the study to ascertain exposure for cases and controls 28 . The maximum score for each study is nine points, and a study with lesser than five points is considered at high risk of bias. The NOS has been described as a reliable tool to assess the quality of case control studies and cohort studies 29 .
Statistical analysis. For   Methodological quality assessment. The NOS scale evidenced an overall high quality of the included studies. Studies eligibility criteria and sports category were well described, as were the selection criteria of control groups. The intensity of training was seldom reported. Demographic characteristics were often exhaustively described. The procedure to assess outcomes was overall clearly described.

Outcome of interest.
Age showed evidence of statistically significant moderate negative association to RV E/A in athletes (P = 0.009, r = − 0.63). Age showed also a statistically significant negative and strong association to RVED longitudinal in athletes (P = 0.01, r = − 0.7). Age showed evidence of statistically significant strong positive association with an increased rate of progression to RAA both in the athletes and sedentary controls (P = 0.04, r = 0.77, P = 0.02, r = 0.85, respectively). BSA showed statistically significant strong positive association with an increased rate of progression to RVED middle in athletes (P = 0.001, r = 0.71), while in sedentary subject there was evidence of statistically significant moderate positive association with an increased rate of progression (P = 0.05, r = 0.54). Also, BSA showed statistically significant strong positive association with an increased rate of progression to RAA both in athletes and sedentary controls (P = 0.05, r = 0.82, P = 0.04, r = 0.83, respectively).
Notably, BSA showed statistically significant strong negative association to ratio RV E/A in athletes (P = 0.002, r = − 0.72). With regard to ECHO data, intensity of training showed evidence of statistically significant strong positive association with an increased rate of progression to RVESA (P = 0.03, r = 0.85). Considering CMR data, the intensity of training presented statistically significant positive and, respectively, strong moderate association to RVEDVI and RVESVI (P = 0.01, r = 0.65, P = 0.01, r = 0.70, respectively). Moreover, evidence of a statistically significant moderate negative association was found between the intensity of training and EF % (P = 0.01, r = − 0.60). The multivariate analysis is shown in Table 3 and supplemental Table 1 (ECHO data) and in Table 4 (CMR data). A statistically significant difference was observed between RVEDVI means difference values in male and RVEDVI means difference values in female (P = 0.001), as shown in Table 5.
A statistically significant difference was found between all RV ECHO and CMR means in endurance athletes and RV reference means. Results are shown in Table 6 and in Table 7.

Discussion
Endurance athletes demonstrated a statistically significant association between RV remodelling and age, BSA and intensity of training. 2-D ECHO is the easiest way to assess morphological and functional parameters of the right heart, and CMR became fundamental to evaluate the RV morphology 23 30 . Right cardiac chambers remodelling depends on many factors. To analyse the differences between male and female RV adaptation to exercise training, five CMR studies in which data were separated for sex were selected. Changes in morphological and functional parameter both in males (athletes versus sedentary) and in females (athletes versus sedentary) were analysed. There are no differences in the kinetics of trend of adaptation between males and females, with the exception of RVEDV, and all the other parameters showed a similar trend of adaptation both in female and male endurance athletes. Age and increased BSA in athletes are linked to a decrease in diastolic function with a reduction in RV E/A. The intensity of exercise training is associated with heart morphological remodelling. The studies show that 6-8 h/w are sufficient to induce remodelling evident on ECHO and CMR [31][32][33] . Another goal of this systematic review was to discuss whether the normal RV reference values fitted the RV characteristics in endurance athletes. Athletes involved in endurance sport have different ECHO parameters from those of the general population 20 . Comparing the studies' results with the reference values, the mean values of all considered parameters in endurance athletes are higher than those of the general population indicated by the American Society of Echocardiography and the European Association of Cardiovascular Imaging 34 . Furthermore, there is a difference between the reference mean values adopted for CMR parameters and the mean values in endurance athletes 35 . This is in accordance with an earlier systematic review, which underlines how endurance sport induces the most significant modification in the right heart, with eccentric hypertrophy 12 . Such structural changes could lead to incorrectly diagnose ARVC.  www.nature.com/scientificreports/ The ARVC is a group of cardiomyopathies with a similar phenotype and tendency to ventricular arrhythmias. Mutations encoding desmosomal genes are associated to ARVC. In some individuals the phenotypical expression can be triggered by endurance exercise training 15 . The mean values of RVEDVI are 132.25 ± 9.63 mL/m 2 and 109.5 ± 9.35 mL/m 2 respectively for males and females, and they are both over the limit of the major criteria for diagnosis of ARVC (≥ 110 mL/m 2 for males and ≥ 100 mL/m 2 for females) 30 . The value of 30.24 ± 1.11 mm for RVOT1 is below the limit of major criteria (≥ 32 mm) but it is included in the minor criteria limit (≥ 29 to ≤ 32 mm), while the BSA indexed value (20.18 ± 4 mm/m 2 ) is just above the major criteria limit (≥ 19 mm/ m 2 ). The value of 31.83 ± 2.34 mm for RVOT2 is above the limit of the minor criteria (> 32 mm), and the RVOT2/ BSA (22.3 ± 3.15 mm/m 2 ) is beyond the limit of the major criteria (> 21 mm/m 2 ). Functional parameters (FAC % and EF %) are not over the limit for diagnosis of ARVC (> 33% to ≤ 40% and > 40% to ≤ 45%, respectively) 28 . A low value of RV E/A is a sign of diastolic disfunction 36 . As highlighted in previous studies, age affects diastolic function, with proliferation of extracellular matrix and crosslinking of collagen fibres 4 . The present study shows that a negative association is evident among athletes, but not among sedentary subjects. Some chronic cardiac microinjuries can emphasise the physiological mechanisms of extracellular matrix rearrangement and fibrotic alteration that normally occur with aging. This leads to a decrease in right heart wall compliance with a reduction in diastolic function. Low values in EF % are related to ventricular chamber dilatation, as shown in Table 8, with a negative association with EDV and ESV. EF % exhibits a negative association with the intensity of training. The more an athlete trains, the more the EF % decreases. Actually, in the case of ventricle dilatation, a lower EF % is necessary to obtain the same SV 22 .Although EF% decreases, this is not sufficient to justify a systolic disfunction or any other pathological condition, and it should be regarded as a physiological adaptation to the increase in EDV and ESV. To make a correct diagnosis of ARVC, it is important to examine the family history, and to fulfil the other Task Force criteria 30 . Pathology should be suspected when ECHO shows akinesia, dyskinesia, or an aneurysm, because they are not features of athlete's heart 37 . Indeed, the remodelling induced by endurance sport could resemble a cardiomyopathy, but the real impact on future morbidity is still unknown. However, if a subject has a latent ARVC, sport-induced adaptation could deteriorate this condition 15,16 . Cardiac remodelling is evident in both sexes, but the lack of studies investigating separately ECHO parameters in male and female athletes does not allow to thoroughly assess similarity and differences. Also, atrial adaptations should be considered, but there are still few studies which analyse atrial chamber remodelling in athletes. A positive association was shown between RAA and age, and between RAA and BSA, but the data available on RA were fewer than data on RV: other studies should be conducted to assess the impact of RA remodelling in endurance athletes. Similarly, years of training were not taken into account because of the lack of relevant data, and further investigations could be conducted to ascertain how many years of training induce permanent RV modifications. The impact of systolic and diastolic disfunction should be analysed considering a longer follow-up period to estimate the incidence of cardiovascular diseases in endurance athletes. Future studies should overcome these limitations to offer a more complete overview.

Conclusion
Endurance athletes exhibit an association between RV remodelling and age, BSA and intensity of training. In particular, RV E/A is an age-related functional parameter, and it should be carefully evaluated because it is a marker of diastolic dysfunction. The systolic function of the RV is decreased in endurance athletes. This is a normal adaptation to exercise, induced by structural changes, and it is within the normal limits. RV ECHO and CMR values in endurance athletes are slightly different from the reference values established in the general population. This could lead to an incorrect diagnosis of ARVC.