The right ventricle provides systemic circulation in individuals with congenitally corrected transposition of the great arteries (CCTGA) and in those with complete transposition who have had an atrial switch repair (DTGA). The aim of this study was to evaluate how the systemic right ventricle adapts to increased workload and oxygen demand during exercise.

From November 2005 through December 2015, 3,358 adult patients with congenital heart disease were treated at our institution; we identified 48 (26 females, 22 males; median age, 25.4 ± 8.1 yr) who met the study criteria; 37 had DTGA and atrial switch repair, and 11 had CCTGA. We studied their echocardiographic and cardiopulmonary exercise test results. A control group consisted of 29 healthy sex- and age-matched volunteers.

On exercise testing, oxygen uptake at anaerobic threshold, peak oxygen uptake, peak heart rate, and percentage of maximal heart rate were significantly lower in the group with systemic right ventricle than in the control group (all P <0.001); in contrast, the peak ventilatory equivalent for carbon dioxide was higher in the study group (P=0.013). Impaired systemic right ventricular function reduced peak oxygen uptake. The peak heart rate was lower in the CCTGA group than in the DTGA group.

Our results indicate that reduced exercise capacity is related to impaired systemic right ventricular function, severe tricuspid valve regurgitation, and chronotropic incompetence. There was no correlation between cardiopulmonary exercise test results and time after surgery. Chronotropic efficiency is lower in individuals with CCTGA than in those with DTGA.

The right ventricle (RV) is a thin-walled, crescent-shaped structure designed to support low-pressure pulmonary circulation. However, in individuals with congenitally corrected transposition of the great arteries (CCTGA) or in those with dextro-type transposition of the great arteries (DTGA) after atrial switch repair (a Senning or Mustard procedure), the RV must support high-pressure systemic circulation. In CCTGA, a double atrioventricular (AV) and ventriculoarterial mismatch exists. In DTGA, the anatomic correction in atrial switch repair leaves the aorta connected to the RV. These physiologic adaptations lead to increased RV end-diastolic volume, decreased ejection fraction at rest, and loss of contractile reserve during exercise, which cause marked tricuspid valve (TV) regurgitation. Patients with reduced systemic RV (SRV) function have a low exercise capacity. Increases in cardiac output depend on increases in stroke volume and heart rate. Winter and associates1  found that the adaptive mechanisms to achieve this differed between a group of patients with CCTGA and one with DTGA. The CCTGA group had increased stroke volume and heart rate; in contrast, only heart rate increased in the DTGA group. Augmented cardiac output during exercise is related to an increase in peak oxygen uptake (peak Vo2), and this is an important prognostic factor for determining life expectancy and quality of life in patients with SRV. Therefore, we analyzed cardiopulmonary exercise test (CPET) results from adults who had CCTGA or DGTA, to further identify which factors affect exercise capacity in these populations.

Patients and Methods

To determine how effectively the RV adapts to systemic circulation, we performed a retrospective study of adults with transposition of the great arteries (CCTGA or atrially switched DTGA) who had been treated at the Cardiological Outpatient Clinic of the John Paul II Hospital in Krakow. The study was performed in accordance with the Helsinki Declaration and with the guidelines set by our institutional ethics committee.

Study Design

We conducted a chart review of 3,358 adult patients with congenital heart disease who were treated at our institution from November 2005 through December 2015. Patients were included in the study if they had DTGA or CTGA, were ≥18 years of age, and had been clinically stable for at least 3 months before undergoing CPET. Patients were excluded if they had severe valvular heart disease, a prior acute vascular event, acute inflammatory illness, neoplastic disease, or diabetes mellitus, or were pregnant. Finally, patients were excluded if they had single-ventricle circulation after Fontan operation.

A total of 3,292 patients were excluded on initial review; 28 of them had single-ventricle circulation after Fontan operation. Of the 66 remaining candidates who had SRV, 18 were excluded for these reasons: 2 had severe pulmonary stenosis, 1 had a substantial ventricular septal defect, 5 had severe left ventricular outflow tract obstruction, and 10 had no CPET results.

Thus, 48 patients met the inclusion criteria: 37 patients with DTGA who had undergone a Senning operation and 11 with CCTGA.

To determine how well SRV function compares with normal left ventricular function, we compared CPET results from the 48 patients who had SRV with those of 29 healthy sex- and age-matched volunteers. Then, to evaluate differences in RV function and exercise capacity in the presence of natural correction of transposition of the great arteries and atrial switch anatomy, we compared CPET results in the CCTGA patients with those in the DTGA patients.

Clinical Analysis

Clinical data gathered included age, body mass index, body surface area, exercise capacity in relation to New York Heart Association (NYHA) functional class, time since surgery (for the DTGA patients), and the presence of a pacemaker.

Transthoracic Echocardiographic Evaluation

Right systolic function was evaluated in the patients with SRV by measuring fractional area change (FAC), tissue-Doppler–derived tricuspid lateral annular systolic velocity (S' wave), and tricuspid annular plane systolic excursion (TAPSE). All calculations were made with use of a Vivid® 7 cardiovascular ultrasound system (GE Healthcare). Fractional area change—the difference in RV area from end-diastole to end-systole—was calculated by manually tracing the contour of the RV in the apical 4-chamber view at each point. The TAPSE was estimated by measuring the extent of systolic motion of the TV ring toward the apex on M-mode echocardiography.

Using the American Society of Echocardiography guidelines,2,3  we defined RV dysfunction as FAC <35%, tissue-Doppler S' wave velocity <9.5 cm/s, and TAPSE <17 mm.

Tricuspid valve regurgitation, evaluated by color-Doppler echocardiography, was classified as mild-to-moderate or severe. We did not evaluate magnetic resonance images, but previous research has shown that the results are comparable to those of echocardiography for evaluating RV function.4 

Cardiopulmonary Exercise Testing

Exercise tolerance was evaluated by CPET. Oxygen uptake (Vo2), carbon dioxide production (Vco2), and minute ventilation (VE) were measured at rest and at peak exercise with use of a computerized analyzer. Peak Vo2/kg (determined by the highest value of workload), peak heart rate, and percentage of maximal heart rate were also measured. The ventilatory anaerobic threshold was calculated by means of the V-slope method.5  The ventilatory equivalent for carbon dioxide (VE/Vco2) was calculated as the amount of ventilation needed to eliminate a given amount of CO2. The respiratory exchange ratio (RER) was calculated by dividing Vo2 by Vco2.6 

Statistical Analysis

Continuous data were presented as mean ± SD when the data distributions were symmetric. Discrete data were presented as number and percentage. Continuous data in 2 different populations were compared by t test when the distributions of characteristics were consistent with the normal distribution and when there was homogeneity of variance. The Mann-Whitney test was used when there was no normality, and the Welch t test was used when there was no homogeneity of variance. The Shapiro-Wilk test was used to evaluate the compliance of the distribution with the normal distribution, and the Levene test was used to determine the equality of variances. Correlation between 2 continuous characteristics was determined by using the Pearson correlation coefficient or the nonparametric Spearman rank correlation coefficient. The correlation of 2 categorized characteristics was determined by means of the χ2 or Fisher exact test when the expected values were too low (<5 in at least one cell of a contingency table). The age difference between the DTGA and CCTGA groups was leveled in statistical analysis. A P value ≤0.05 was considered statistically significant. Statistica version 10.0.1011.7 (Tibco Software Inc.) was used to analyze the data.

Results

We identified 48 patients with SRV who met the study criteria: 37 (77%) had DTGA and had undergone an atrial switch operation, and 11 (23%) had CCTGA. The patients' median age was 25.4 ± 8.1 years; body mass index, 22.6 ± 3.4 kg/m2; and body surface area, 1.75 ± 0.19 m2. The CCTGA patients were older than the DTGA patients (P <0.001) (Table I). Other findings included a hemodynamically insignificant VSD in 6 patients (10.4%), and 3 (6.2%) had left ventricular outflow tract obstruction with maximal gradients below 35 mmHg. All but one of the DTGA patients had undergone a Rashkind procedure before the Senning operation; the median age at the time of the atrial switch operation was 7 months (range, 1–48 mo). One patient had undergone percutaneous angioplasty of a narrowed pulmonary baffle at 5 years of age. No baffle leaks were seen on the patients' echocardiograms.

TABLE I.

Characteristics of the 48 Patients with Systemic Right Ventricle

Characteristics of the 48 Patients with Systemic Right Ventricle
Characteristics of the 48 Patients with Systemic Right Ventricle

Of the 37 DTGA patients, 4 (10.8%) had a permanent cardiac pacemaker to treat total AV block, and 2 (5.4%) had an implantable cardioverter-defibrillator for secondary prevention of sudden cardiac death. Of the 11 CCTGA patients, 5 (45.5%) had total AV block, and 4 (36.4%) had an implanted cardiac pacemaker; none had undergone cardiac surgery.

Echocardiographic Findings

The echocardiographic results showed that severe TV regurgitation was more frequent in the CCTGA patients than in the DTGA patients (P=0.004) (Table II). There were no significant differences between the groups in regard to RV dimensions or function (that is, FAC, S' velocity, and TAPSE), tricuspid ring diameter, or left ventricular dimensions or ejection fraction.

TABLE II.

Comparison of Echocardiographic Results between Patients with DTGA and CCTGA

Comparison of Echocardiographic Results between Patients with DTGA and CCTGA
Comparison of Echocardiographic Results between Patients with DTGA and CCTGA

Cardiopulmonary Exercise Testing

The results of CPET in all 48 patients with SRV were compared with those in a control group of 29 patients (Table III). In the SRV group, the Vo2/kg at anaerobic threshold (19.66 ± 5.8 vs 34.24 ± 11.14 mL/kg/min; P <0.001) and peak Vo2/kg (26.43 ± 6.27 vs 48.01 ± 7.67 mL/kg/min; P <0.001) were significantly lower than that in the control group; in contrast, the SRV group had a significantly higher peak VE/Vco2 (29.31 ± 4.69 vs 26.77 ± 3.21 mL/kg/min; P=0.013). The peak heart rate and the percentage of maximal heart rate were significantly reduced in the study group (both P <0.001).

TABLE III.

Comparison of Exercise Test Results between All Patients with Systemic Right Ventricle and the Control Group

Comparison of Exercise Test Results between All Patients with Systemic Right Ventricle and the Control Group
Comparison of Exercise Test Results between All Patients with Systemic Right Ventricle and the Control Group

Because reduced RV function and severe TV regurgitation negatively affect exercise capacity, we compared CPET results from a subgroup of SRV patients with preserved RV function and trivial regurgitation (n=25) with those of the control group. The SRV patients had a significantly reduced Vo2/kg at anaerobic threshold (20.03 ± 4.64 vs 34.24 ± 11.14 mL/kg/min; P <0.001) and peak Vo2/kg (27.14 ± 4.36 vs 48.01 ± 7.67 mL/kg/min; P <0.001). The study group also had a significantly lower peak heart rate (158.76 ± 24.07 vs 185.97 ± 8.05 beats/min; P <0.001) and percentage of maximal heart rate (82.56% ± 12.05% vs 97.76% ± 6.4%, P <0.001) (Table IV).

TABLE IV.

Comparison of Exercise Test Results between Patients with Preserved Systemic Right Ventricular Function and Trivial Tricuspid Valve Regurgitation and the Control Group

Comparison of Exercise Test Results between Patients with Preserved Systemic Right Ventricular Function and Trivial Tricuspid Valve Regurgitation and the Control Group
Comparison of Exercise Test Results between Patients with Preserved Systemic Right Ventricular Function and Trivial Tricuspid Valve Regurgitation and the Control Group

Among all patients with SRV, our analysis showed no significant correlations between CPET results and age, body mass index, NYHA class, or time since surgery. In a comparison of CPET results between the CCTGA and DTGA groups, however, peak heart rate (124.67 ± 35.04 vs 159.33 ± 21.57 beats/min; P=0.021) and percentage of maximal heart rate (67.56% ± 18.32% vs 83.27% ± 10.91%, P=0.03) were lower in the CCTGA group. In the CCTGA patients with pacemakers, heart rate increased above the stimulation threshold during exercise, and at peak exercise, native sinus rhythm resumed, but it was slower than that in the control group, and it was below 85% of the predicted value for age. A greater percentage of the CCTGA patients also had total AV block and bradyarrhythmia, which have an important negative impact on exercise capacity. Peak Vo2/kg and the percentage of the predicted value for age were similar between the CCTGA and DTGA groups.

In comparison with the 32 patients (67%) who had preserved RV function, the 16 patients (33%) who had reduced RV function (that is, FAC <35%) had a lower peak Vo2/kg (24.64 ± 7.86 vs 27.11 ± 4.76 mL/kg/min; P=0.603), peak heart rate (144.27 ± 32.44 vs 155.65 ± 26.04 beats/min; P=0.949), percentage of maximal heart rate (76.13% ± 15.97% vs 81.77% ± 13.12%; P=0.999), and RER (1.03 ± 0.11 vs 1.07 ± 0.1; P=0.521); in contrast, the peak VE/Vco2 was higher (30.22 ± 4.96 vs 28.79 ± 4.62 mL/kg/min; P=0.677). A similar comparison was made between 13 patients (27%) with severe TV regurgitation and 35 (73%) with trivial TV regurgitation. The patients with severe regurgitation had a significantly lower peak heart rate (122 ± 28.19 vs 162.52 ± 19.95 beats/min; P <0.001) and percentage of maximal heart rate (65.64% ± 14.33% vs 84.97% ± 10.25%; P <0.001). In addition, their peak Vo2/kg (24.55 ± 8.46 vs 27.14 ± 5.22 mL/kg/min; P =0.226) and peak RER (1.02 ± 0.12 vs 1.07 ± 0.1; P=0.137) were lower. Severe TV regurgitation was related to the RV enlargement and the dilation of the tricuspid ring (41.62 ± 1.71 vs 34.29 ± 2.52 mm; P <0.001).

Discussion

The most important finding of our study is that adults with SRV have reduced exercise capacity. Previously, peak Vo2/kg had been positively related to the capability of increasing cardiac output, which is dependent on stroke volume and heart rate.1  Peak heart rate and percentage of maximal heart rate during CPET were significantly lower in our patients with SRV than in healthy control subjects. Further analysis showed that peak heart rate and percentage of maximal heart rate were significantly lower in the patients with CCTGA than in those with DTGA. The inadequate heart response to exercise is an important factor in reduced exercise capacity and peak Vo2/kg in patients with SRV. Fredriksen and colleagues,7  who observed similar results in CCTGA patients, reported a correlation between chronotropic inability and abnormally low peak Vo2 values. Winter and associates1  found that patients with CCTGA were able to increase stroke volume and heart rate, but patients with DTGA had no increase in stroke volume.

On CPET, our DTGA and CCTGA groups had similar results for peak Vo2/kg and the percentage of predicted value for age, even though the CCTGA patients had a lower peak heart rate. It may be assumed that the DTGA patients had a lower stroke volume. Stroke volume is related to SRV systolic function. Thus, RV failure is caused by chronic microvascular ischemia and high wall stress, which lead to diffuse myocardial fibrosis and ongoing functional decline.8  Roest and colleagues,9  who used cardiovascular magnetic resonance to analyze ventricular function at rest and during exercise, found that RV ejection fraction did not increase during exercise and that RV functional reserve decreased. This is caused by morphologic changes of the SRV over time. Some investigators1,10  have proposed that myocardial fibrosis results from prolonged hypoxemia during infancy while patients await the atrial switch operation, and others11  have thought that it may be caused by inadequate RV blood supply from the right coronary artery in the presence of hypertrophic SRV myocardium. These conditions are similar to the morphologic and hemodynamic changes of the RV in pulmonary artery hypertension in which afterload is also increased. Naeije and Manes12  observed RV changes in patients with pulmonary artery hypertension. In the presence of high afterload, the RV adapts first by increasing contractility, after which right chamber dimensions increase, leading to hypertrophy and diastolic dysfunction due to myocardial fibrosis, and finally to systolic dysfunction and TV regurgitation.

The results of our study show that exercise capacity is related to SRV function. Exercise capacity during CPET was lower in patients with reduced RV ejection fraction than in those who had preserved RV function; however, these differences were not statistically significant. Myocardial dysfunction is not the only cause of diminished exercise capacity.13  Patients with SRV who have undergone atrial switch surgery also have preload abnormalities, and such factors should be taken into account. After a Senning operation, patients may have hemodynamic abnormalities associated with pulmonary and systemic baffles. In our study, we observed no baffle narrowing. However, the presence of the atrial baffles—even those that are functioning properly—may decrease RV inflow.14 

We also found that TV regurgitation had a negative effect on exercise capacity. During CPET, peak heart rate and percentage of maximal heart rate were significantly lower in patients with severe TV regurgitation than in those with no or trivial TV regurgitation. The patients with severe regurgitation also had lower levels of peak Vo2/kg and peak RER, but these differences were not statistically significant. There are several potential mechanisms for TV regurgitation,15  including congenital abnormalities of the TV, dysfunction of the SRV, right-to-left septal shift, increased retrograde transtricuspid pressure gradient, and iatrogenic causes. In our study, severe TV regurgitation was related to RV enlargement and dilation of the tricuspid ring. It is not clear whether SRV dysfunction or TV regurgitation occurs first. In one study,16  patients who had undergone TV repair with an artificial ring had no significant increases in SRV ejection fraction. On the other hand, the modification to arterial switch and RV to low-pressure circulation reduced TV regurgitation.16 

Study Limitations

Our study had several limitations. The number of patients was small, so the conclusions drawn from the statistical analysis should be read with caution; nevertheless, our patient population was representative of that in clinical practice. Another limitation is the retrospective nature of the study, which meant that we had to rely on the data that had been collected. In addition, the observed population was not uniform; some patients had concomitant heart disease (such as trivial pulmonary stenosis or mild VSD), which may have affected our results. Moreover, we did not account for anemia, respiratory system diseases, or thyroid abnormalities, all of which can affect CPET results. A larger series of patients and longer follow-up times are needed.

Conclusions

Adult patients with SRV have reduced exercise capacity, related to impaired SRV function, severe TV regurgitation, and chronotropic incompetence. Exercise intolerance occurs as a result of a lowered oxygen uptake and increased ventilatory response. Patients with CCTGA have lower chronotropic efficiency than do patients after atrial switch repair. These patients need regular follow-up monitoring at specialist centers for adult patients with congenital heart diseases.

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Author notes

From: Departments of Cardiovascular Diseases, Cardiological Outpatient Clinic (Drs. Okolska and Rog), and Cardiac and Cardiovascular Diseases, Institute of Cardiology, Jagiellonian University Medical College (Drs. Dluzniewska, Podolec, and Tomkiewicz-Pajak), John Paul II Hospital, 31-202 Krakow; Department of Bioinformatics and Telemedicine, Jagiellonian University (Ms Salapa), 31-530 Krakow; and Department of Pediatric Cardiology, Polish-American Children's Hospital (Dr. Werynski), 30-663 Krakow; Poland