There has been recent interest in the role that exercise plays in right ventricular (RV) remodeling. In patients with pulmonary vascular and RV pathology, experimental data suggest that strenuous exercise may be associated with accelerated RV dysfunction (14,21). However, exercise may also be an important determinant of RV function in healthy populations. In elite endurance athletes, complex ventricular arrhythmias are commonly associated with structural and functional abnormalities of the RV but not the left ventricle (LV) (15). This syndrome occurs primarily in those performing the highest volume of strenuous exercise and is not explained by familial predisposition, thereby suggesting that exercise may have a direct role in RV remodeling (26). However, previous descriptions of athletic cardiac remodeling, termed athlete's heart, have predominantly focused on the LV (27).
In a large nonathletic cohort, Aaron et al. (1) demonstrated that RV mass and RV end-diastolic volumes increased with the level of physical activity, independent of LV measures. This is consistent with some animal studies in which intense exercise resulted in a disproportionate increase in RV mass when compared with the LV (2,3). In endurance athletes, acute changes in RV structure and function are more prevalent and more profound than for the LV when assessed immediately after intense prolonged exercise, (24,30,31,40). In contrast, the few studies that have assessed chronic RV structural remodeling in athletes have demonstrated increases in volume and mass, which are proportional to those of the LV (37,38).
The mechanism by which exercise may exert a disproportionate effect on RV structure and function has not been studied. During intense exercise, the relative pressure increases in the pulmonary circulation exceed those of the systemic circulation (4,8,22,25), and this, combined with a simultaneous demand for greater output, provides a theoretical basis by which greater RV stress may be appreciated. However, according to the principles of Laplace, wall stress may be moderated by increases in wall thickness and/or reductions in cavity size (41). The balance among pressure, ventricular structure, and the resulting wall stress during exercise has not been detailed for the RV.
We devised a minimally invasive method combining cardiac magnetic resonance (CMR) imaging and echocardiography to estimate end-systolic wall stress (ES-σ) to examine whether wall stress changes in the RV and LV during exercise are different and whether a difference in RVES-σ may result in greater relative RV remodeling in athletes.
A total of 39 endurance-trained athletes (EA) and 14 age- and sex-matched nonathletes (NA) volunteered to participate in the study. EA were defined as subjects actively engaged in endurance sports competition, whereas NA were defined as: 1) currently performing <3 h of mild recreational exercise per week and 2) having no previous involvement in regular sports competition. Any subject with a risk factor for, or history of, cardiovascular disease was excluded. Activity levels were assessed by questionnaire, and subjects were asked to describe and quantify exercise during a typical week within the preceding month. Training and recreational exercise were defined as exercise performed with and without intent for improvement in performance, respectively.
EA were performing 16 ± 5 h·wk−1 of exercise training, and testing was performed in the 3-6 wk before one of the following endurance sporting races: a marathon run (7 athletes), a 207-km alpine cycling race (9 athletes), an endurance triathlon (1.9-km swim, 90-km ride, and 21.1-km run; 10 athletes), or an ultraendurance triathlon (3.8-km swim, 180-km ride, and 42.2-km run; 13 athletes). The athletes had been competing in endurance sport events for 10 ± 9 yr (range = 1-45 yr). Well-trained amateur (90%) and professional (10%) athletes were enrolled, and all athletes completed the endurance event in a time less than the median participant's completion time. The recruited NA subjects all performed some leisure time exercise activity (mean = 1.7 ± 0.4 h·wk−1) but no exercise for training effect. Written informed consent was obtained, and the protocol was approved by the St. Vincent's Hospital ethics committee.
CMR imaging was performed on a 1.5-T scanner (Signa Excite; GE Healthcare, Waukesha, WI) using a dedicated cardiac coil and electrocardiographic gating. Cine imaging was used to obtain a contiguous short-axis stack (slice thickness of 8 mm; no gaps) covering the LV and RV from the apex to a level well above the atrioventricular groove. Twenty images per cardiac cycle were obtained at the end-tidal breath hold. Endocardial and epicardial borders were manually traced using a standard system software analysis tool (Cinetool; Global Applied Science Laboratory, GE Healthcare) at end-diastole and end-systole to quantify volume (EDV and ESV, respectively) by a summation of disks method (Fig. 1). Stroke volume (SVCMR) was measured as the average of EDV minus ESV for both ventricles. Myocardial mass was determined from myocardial volumes (epicardial minus endocardial volume) after multiplication by the specific density of myocardium (1.05 g·cm−3). Papillary muscles were included in the ventricular mass and excluded from volumes, and the interventricular septum was treated as LV mass. All analyses were performed by one observer blinded to subject identity (A.L.G.), with a subset of seven randomly selected studies analyzed by a second blinded observer (H.B.P.) for the assessment of interobserver variability.
Cardiopulmonary exercise testing for V˙O2max quantification was undertaken on an upright cycle ergometer using an automated gas exchange measuring system (ER900 and Oxycon Alpha, Jaeger, Germany). Incremental exercise (12.5 W·min−1) was performed until exhaustion.
Real-time echocardiography was performed separately (between 2 and 7 d after cardiopulmonary exercise testing on a semisupine cycle ergometer (Lode, Groningen, The Netherlands) with the same exercise protocol.
Echocardiographic measures were obtained using a Vivid 7 Dimension echocardiograph (GE, Horten, Norway) and stored for offline analysis (Echopac v.108; GE, Norway). During exercise, pulmonary artery systolic pressure (PASP), stroke volume (SVDopp), and RV fractional area change (RVFAC) were obtained every 2 min. PASP was calculated from maximal tricuspid regurgitant velocities with colloid-contrast enhancement (agitated solution of succinylated gelatin (Gelofusine; Braun Intl., Melsungen, Germany) mixed with room air (95:5 ratio)) using the modified Bernoulli equation without the addition of a right atrial pressure estimate, as has been validated against invasive measures at rest and with exercise (17,20,23). SVDopp was calculated from the velocity-time integral from pulse wave Doppler interrogation of the RV outflow tract, as previously described (25). Using resting measures, SVDopp was validated against SVCMR. RVFAC was obtained from endocardial tracings of specific echocardiographic views of the RV at end-diastole (RVA-d) and end-systole (RVA-s) according to the following formula: RVFAC = (RVA-d − RVA-s)/RVA-d.
Invasive blood pressure monitoring was performed throughout exercise via a 22-gauge radial artery catheter (Arrow Intl., Durham, NC) with continuous pressure transduction monitoring (SpaceLabs, Inc., Redmond, WA). The monitor was carefully referenced such that zero pressure was set with the transducer level with the subject's midaxillary line. Dynamic response testing of the system was performed to determine the natural frequency of the fluid-filled circuit and ensure that the arterial pressure wave was free of significant damping effects (12). The analog pressure wave was recorded continuously while systolic and diastolic values were recorded every minute during exercise.
For the end-systolic wall stress (ES-σ), Laplace's law was used to calculate σ according to the formula
where P (pressure) was quantified as PASP and arterial systolic blood pressure (SBP) for the RV and LV, respectively; r (radius) was calculated from the ESV assuming spherical geometry, as previously described (28), by the formula r = 0.620(ESV)1/3 (for measures during exercise, SVDopp was subtracted from EDV, which was assumed to remain constant throughout exercise); and h (wall thickness) was calculated by subtracting r from the radius of the epicardial volume, again assuming spherical geometry (thus, because myocardial mass is preserved, h increases with exercise-induced decreases in r).
Baseline and peak values were compared using an independent t-test or χ2 for categorical data. The effect of exercise was assessed using a mixed-factorial ANOVA design, with exercise considered as a within-subjects variable and EA versus NA and/or LV versus RV as between-subjects factors. Analysis of group effects with repeated exercise measures was performed by comparing mean slope coefficients from individual linear regressions.
Agreement of measures between tests and observers was assessed according to the methods described by Bland and Altman (7). The mean difference between measures, limits of agreement, and Pearson correlation coefficient are quoted.
All values are expressed as mean ± SD, and P < 0.05 was considered significant. Statistical analysis was performed using SPSS v.16.0 software (Chicago, IL).
EA and NA participants were well matched for age, gender, and height. Measures of body habitus, exercise capacity, and cardiac morphology were consistent with those expected for athletic trained and untrained cohorts (Table 1). The body surface area of athletes was no different from NA (1.94 ± 0.16 vs 1.94 ± 0.14 m2, P = 0.45) and had no influence on group comparisons.
Mean cardiac volumes were greater, and RV ejection fraction (EF) was lower in athletes compared with NA (P < 0.001 for each measure), although LVEF was similar in both groups. To address the hypothesis that athletic training may result in disproportionate RV remodeling, the ratio of RV to LV measures was compared between groups. Figure 2 illustrates that the difference between RV and LV volumes was greater in EA relative to that in NA (with the exception of EDV), although the difference in ventricular masses was relatively less.
There was good agreement between two observers for the assessment of ventricular volumes. For the LV and RV, respectively, there was a strong correlation between measures (r = 0.99 and r = 0.97, P < 0.001). As illustrated in the Bland-Altman plots (Supplementary Figure 1, http://links.lww.com/MSS/A68), minimal bias between observers was evident, with mean differences of 3.9 ± 14.3 and 9.5 ± 20.4 mL. Agreement remained acceptable for the determination of ventricular mass (mean difference = 5.0 ± 16.6 and 9.1 ± 12.2 g), but values were less well correlated, possibly reflecting the very small range of values, particularly for RV mass (r = 0.77, P = 0.001 for LV and r = 0.19, P = 0.53 for RV mass).
Changes in volumes, pressures, and wall stress during exercise.
To ensure the accurate assessment of flow during exercise, resting SVDopp was compared with SVCMR. A large bias, with consistently larger volumes by CMR, was found (SVCMR − SVDopp = 50.37 ± 16.7 mL, 95% limits of agreement = 17.6-83.1 mL). The equation, SVCMR = 0.97SVDopp + 52.7, was determined by linear regression, with good correlation between measures (r = 0.72, P < 0.0001; Fig. 1). Given the significant bias but otherwise good correlation of values, this equation was subsequently used to calculate SV from SVDopp during exercise.
Baseline and peak exercise hemodynamic and cardiac measures are shown in Table 2. CO increased to a greater extent in athletes (P < 0.001) because of greater SV, which was maintained through exercise. SV augmentation was due to greater reductions in systolic volumes (as shown by the significant decrease in RVA-s), whereas end-diastolic dimensions were unchanged (RVA-d).
The variables used to calculate ES-σ according to the Laplace relation ES-σ = Pr/(2h) are detailed in Table 2. PASP was able to be measured using contrast enhancement in all subjects during exercise (median = 7 times, range = 2-11). It increased to a greater extent with exercise than SBP (166% vs 36%, P < 0.001) and to a greater extent in EA than in NA (182% vs 118%, P < 0.001). At rest and at peak exercise, r was greater in the RV than in the LV (P < 0.0001), and lastly, exercise-induced increases in h were significantly greater in the LV than in the RV (P < 0.001). Thus, each measure changed in a manner that would augment ES-σ more in the RV than in the LV during exercise. Figure 3 illustrates the exercise-induced changes that were greater in RVES-σ relative to LVES-σ (125.2% vs 13.6%, P < 0.001) and were greater in EA than NA for RVES-σ but not LVES-σ.
The relationship between exercise intensity and RVES-σ response in EA versus NA during strenuous exercise is detailed in Figure 4. The mean regression line for EA (derived as the mean of each subject's individual regression) is represented by the equation RVES-σ = 0.739 × watts + 145 which was not significantly different from that for NA, RVES-σ = 0.776 × watts + 144, P = 0.78 and P = 0.94 for variables and constants, respectively. These regressions were obtained from strongly correlated data, with a mean correlation coefficient of r = 0.85 and r = 0.81 for athletes and NA, respectively. Therefore, the increase in RVES-σ is similar between EA and NA at equivalent absolute exercise intensity, but the peak exercise values differ because of a greater maximal workload in the EA group.
In assessing biventricular ES-σ, we provide a comprehensive estimate of left and right ventricular afterloads during strenuous exercise in healthy subjects (32). This provides a novel insight into the differential stress imposed by exercise on the RV and LV and helps explain why prolonged intense exercise results in cardiac fatigue, which disproportionately affects the RV (24,30,31,40). Our data confirm previous findings that, in healthy subjects, strenuous exercise can result in considerable increases in pulmonary artery pressures (4,6,8). However, previous studies have not directly compared simultaneous measures of pulmonary and systemic arterial pressures. In addition, they have not assessed whether pressure excesses are counterbalanced by increases in wall thickness or reductions in cavity radius sufficient to moderate increases in wall stress. In considering all of these factors, we demonstrate that exercise-induced increases in RVES-σ are relatively greater than those in LVES-σ. We also demonstrate that increases in RVES-σ are proportional to exercise intensity and that those who perform more frequent strenuous exercise (athletes) have greater structural RV changes relative to the LV when compared with those doing no training (NA). Thus, there is consistency between the acute hemodynamic stressors during exercise and the chronic structural changes of the heart, both of which affect the RV to a greater extent than the LV.
Direct quantification of ES-σ is impossible, and so estimation is reliant on computational models, all of which share common principles, namely, that ES-σ increases with increasing pressure and cavity radius while being offset by greater wall thickness (18,19,29,41). Most ES-σ studies have focused on the LV and have suggested that differing computational frameworks create modest differences in values but that their relative changes in various pathological states are appropriate (41). Furthermore, the use of simple models, such as the thin-walled sphere approximation of Laplace, may be as reliable as more complex formulas are (18). Quaife et al. (35) used the Laplace relation and CMR measures to measure RVES-σ in pulmonary hypertension in the only other study assessing RVES-σ in humans of which we are aware. They demonstrated that CMR measures of the RV cavity and wall volumes were sufficiently accurate to enable such quantification, an assertion that is supported by the low interobserver variability reported here and previously (13), and used RVES-σ to scrutinize the complex balance between RV load and remodeling. Our finding that the pronounced increases in RVES-σ during strenuous exercise may provide an additional stimulus for ventricular remodeling supports their observations.
Studies of ES-σ response to exercise have been confined to the LV and have produced inconsistent results that may be attributed, at least in part, to the substantive differences in methods (9,10,16). Our use of shared measures and assumptions to compare ES-σ in the RV and LV may be expected to result in some canceling of potential systematic errors. We demonstrate that relative exercise-induced increases in PASP were considerably greater than those in SBP. Confidence may be placed in these findings given that invasive SBP measures are more reliable than sphygmomanometer recordings during exercise (33), and the contrast-enhanced Doppler technique used for PASP estimates has been shown to correlate well with invasive measures at rest and during exercise (17,20,23). Although the magnitude of difference is less pronounced, we also found that peak exercise volumes, and hence ventricular radii, were greater in the RV and that wall thickening was relatively less. Combined, this creates a compelling basis for our finding that exercise-induced increases in ES-σ are greater for the RV than LV.
In the first study to highlight differences in RV load to exercise, Bossone et al. (8) found that athletes had greater exercise-induced increases in PASP than in NA at equivalent workloads. Such a finding implies a different, and seemingly disadvantageous, pulmonary vascular response to exercise in athletes. In contrast, we describe a linear dose-response relationship between RVES-σ and exercise intensity, which does not differ according to athletic training (Fig. 4). Rather, peak RVES-σ is determined by the absolute intensity of exercise-the greater the exercise load, the greater the afterload.
We also contend that the current description of athletes' heart may be incomplete. We found that the RV/LV volume ratio at end-systole was greater and the ratio for EF was lower in EA compared with that in NA. This is consistent with our hypothesis that greater RV loading may be matched by greater RV remodeling. Although there are a number of studies using CMR to describe cardiac morphology in athletes, few have provided a comprehensive description of the RV. Scharhag et al. (38) described symmetrical ventricular enlargement in 21 endurance athletes who were considerably younger than our cohort (27 ± 5 vs 36 ± 8 yr), and this may suggest that the athletes had been involved in competitive sport for a shorter period. Cumulative exposure to the hemodynamic stressors of intense exercise may be an important determinant of structural remodeling, although this hypothesis has not previously been explored. Other investigators used CMR measures to demonstrate chronic RV enlargement (34) or acute RV dilation after prolonged exercise (30,40), which was greater than for the LV. It is difficult to draw firm conclusions from these disparate results especially when one considers that the degree of ventricular asymmetry resulting from exercise is likely to be slight, if present at all. It could be argued that all previous studies in athletic cohorts have been underpowered to assess subtle ventricular differences. This proposition is supported by the results of Aaron et al. (1), who recruited a large cohort of 1867 NA to demonstrate that the amount of strenuous activity predicted RV mass and volumes independent of LV size. Our finding of greater relative RV structural changes in a middle-aged cohort of athletes with an extensive history of competitive sport challenges the notion that athletes develop balanced ventricular hypertrophy, although, once again, the cohort is too small to definitively change conceptions.
Several assumptions are required in our approximation of wall stress and its relation to chronic cardiac remodeling. The effect of these assumptions on the overall study conclusion is reduced by the fact that they apply equally to both ventricles and are therefore diminished when considering relative changes. The Laplace equation was used given that it is the simplest construct by which wall stress may be considered, and a more accurate model of load estimates remains elusive. Although our assumption of spherical geometry to determine radii of curvature may be an oversimplification, especially for the complex shape of the RV, Arts et al. (5) have suggested that ES-σ remains related to cavity and wall volumes independent of geometry.
The use of Doppler-derived SV during exercise required adjustment for significant bias to enable integration with CMR measures. We feel that the improved accuracy of CMR measures outweighs the error introduced through this correction. Also, it was necessary to assume that EDV remained constant through exercise, but numerous imaging studies have demonstrated that this reflects reality, as detailed in a review by Rowland (36). This assertion is further supported by our finding that RV end-diastolic area (an RVEDV surrogate) was unchanged throughout exercise.
It is notable that invasive measures of systemic blood pressures were elevated at baseline, particularly in the athletes. This may suggest underlying hypertension and latent LV disease. However, no subject had a history of clinical hypertension, and normal blood pressures were measured by a sphygmomanometer immediately before the insertion of the arterial lines. Also, the "peak exercise" HR and CO were lower than may be expected during maximal upright exercise. This may be explained by the recording of peak values at the maximal intensity at which PASP and SV could be reliably measured. This occurred close to maximal exercise, with no difference between EA and NA groups. The semisupine exercise also contributed to lower maximal HR than would be expected with upright exercise.
Although EA and NA were well matched for age, sex, and body surface area, NA were heavier, and this may have influenced comparisons in ventricular remodeling. Finally, our assertion that acute exercise hemodynamic stressors explain disproportionate RV enlargement and hypertrophy is based on estimates of end-systolic wall stress although end-diastolic wall stress (a measure of preload) is possibly a more direct stimulus for ventricular enlargement. We were unable to directly estimate end-diastolic pulmonary pressures using echocardiographic techniques during exercise. However, invasive measures suggest that systolic and diastolic pulmonary pressures are linearly related and remain so during exercise (39). Therefore, a similar imbalance in relative increases in RV versus LV preload may also be expected, although this remains to be established.
We have demonstrated that exercise-induced increases in RVES-σ are considerably greater than those of LVES-σ and that athletes have relatively greater RV ESV than LV ESV and lower RVEF than LVEF. This has direct application to sports cardiology practice where the distinction between athletes' heart and RV pathology can be difficult (27). Our results suggest that reduced RVEF and relative RV enlargement are expected in athletes and should not necessarily be interpreted as a sign of pathology. Further work is required to define the diagnostic cutoff between the measures of RV function in our healthy athletes compared with the low RVEF described by Ector et al. (11) in the context of athletes with complex ventricular tachyarrhythmias. Perhaps RV evaluation during exercise (when load is greatest) may prove to be the best discriminator.
This project was financed, in part, by a Cardiovascular Lipid Grant (Pfizer, Australia). A. L. G. is supported by a postgraduate scholarship (National Health and Medical Research Council/National Heart Foundation, Australia). A. J. T. is supported by a National Health and Medical Research Council Program Grant, Australia.
All authors had full access to and take full responsibility for the integrity of the data. The authors agree to the article as written. None of the authors have professional relationships with any companies or manufacturers who will benefit from the results of the present study.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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