In congenitally corrected transposition of the great arteries (cc-TGA), the morphologic right ventricle acts as the subaortic (systemic) ventricle, and deterioration of the ventricle over time is a well-known complication. The objective of this study was to characterize the right ventricle and explore factors that may be contributing to ventricular dilation and dysfunction and the relationship with exercise capacity.
This was a prospective study of adults with cc-TGA. All patients underwent cardiopulmonary stress testing, ventricular volume and fibrosis assessment by cardiac magnetic resonance imaging, and Velocity Vector Imaging strain echocardiography.
Twenty-six patients were included (mean age, 38 ± 16 years; 54% women). Exercise capacity was significantly reduced in patients with cc-TGA compared with normal subjects (20.9 ± 6.0 vs 30.8 ± 9.2 mL/kg/min, P = .001). The majority of patients (61%) had right ventricular (RV) ejection fractions ≤ 40%. There was no evidence of fibrosis on cardiac magnetic resonance imaging. There was a significant difference in diastolic volumes among those with RV ejection fractions > 40% versus ≤ 40% (173 ± 29mL vs 233 ± 65 mL, P = .02) and moderate or severe versus no or mild tricuspid regurgitation (240 ± 80mL vs 190 ± 38mL, P = .04). RV apical longitudinal and mid free wall circumferential strain was decreased compared with these values in controls.
In this relatively “well” cc-TGA population, subaortic RV dilation, dysfunction, and exercise intolerance are a common problem. Significant systemic tricuspid atrioventricular valvular regurgitation is an important contributor to the problem. In this study, subaortic RV myocardial deformation parameters were found to be abnormal, suggesting that there is a failure of the ventricle to adapt to systemic pressures, and therapies to reduce afterload should be explored. Recurrent ischemia resulting in fibrosis likely does not contribute to RV dilation or dysfunction as demonstrated by the magnetic resonance imaging findings in this study.
In congenitally corrected transposition of the great arteries (cc-TGA), the morphologic right ventricle acts as the subaortic (systemic) ventricle, and its deterioration over time is well documented. There are a number of factors that may potentially contribute to systolic ventricular dysfunction : the morphologic right ventricle may be poorly equipped to deal with aortic pressures, it may have an inadequate coronary supply with resultant ischemia and/or fibrosis, and the regurgitant systemic atrioventricular valve may impose a volume load on the ventricle and/or dyssynchronous ventricular contraction may negatively affect ventricular function. To date, only a few of these factors have been evaluated in the cc-TGA population.
Subaortic right ventricular (RV) systolic dysfunction is a major cause of morbidity and mortality in this group of patients. However, in contrast to patients with acquired heart disease and left ventricular (LV) dysfunction, there are no proven therapies for systemic ventricular dysfunction in cc-TGA. Thus, it is important to improve our understanding of the disease process to guide future study and selection of therapeutic strategies. Moreover, it is critical that we understand its impact on symptom status and/or exercise capacity.
The objectives of this study were twofold: (1) to explore the factors contributing to systemic RV dysfunction in a cohort of adults with cc-TGA, specifically assessing RV mechanics, synchrony, and fibrosis, and (2) to determine the relations of these factors to exercise capacity.
This was a prospective study of adults with cc-TGA. Seventy-five adults with cc-TGA were identified from the Toronto Adult Congenital Heart Disease database. Patients with permanent pacemakers with or without mechanical valves ( n = 35) were excluded because they could not undergo cardiac magnetic resonance imaging (CMR). Another 11 patients with artificial mechanical valves only (all were systemic atrioventricular valve replacements) were excluded, because it was felt that the accuracy of strain analysis and fibrosis assessment would be adversely affected. Three eligible patients declined participation. The remaining 26 patients agreed to participate, and written consent was obtained. All patients underwent clinical assessments, 12-lead electrocardiography, cardiopulmonary stress testing, transthoracic echocardiography, and CMR. All investigations were performed over a 2-week period. Twenty healthy volunteers (controls) were also included as a comparison group for the echocardiographic assessment, as outlined below. These healthy controls were recruited from the echocardiography laboratory and had no histories of medical illness or medication use and were matched by age and sex to the patient population. The institutional research ethics board approved the study.
All patients underwent complete histories and physical examinations. Functional status was categorized on the basis of the New York Heart Association functional classification. Details pertaining to associated cardiac abnormalities, age at and type of surgical repair, history of cardiac events (acute coronary syndrome, heart failure requiring additional therapy or hospitalization, syncope, arrhythmias, cerebrovascular event, and aortic dissection) and current cardiac medications were recorded. A standard 12-lead electrocardiogram was obtained.
Image acquisition was undertaken on a 1.5-T magnetic resonance scanner (Avanto; Siemens Medical Solutions, Erlangen, Germany) with a 32-channel phased-array cardiac coil. Axial steady-state free precession (SSFP) imaging was used to acquire a stack of slices from the level of the aortic arch to the diaphragm. Further contiguous SSFP images were acquired in the short-axis plane from the atrioventricular groove to the LV apex. Imaging parameters were as follows: repetition time, 2.9 msec; echo time, 1.3 msec; slice thickness, 6 mm; slice gap, 2 mm; matrix size individually optimized according to patient breath-holding ability but a minimum of 192 × 192; field of view optimized according to patient size (35 × 35 cm to 39 × 39 cm).
Late gadolinium enhancement (LGE) imaging was performed 10 min after an intravenous bolus of 0.2 mmol/kg gadobutrol using a phase-sensitive inversion recovery gradient-echo sequence acquired in a late diastolic phase in both axial and short-axis planes planned to match the slice locations of the SSFP images. The optimum inversion time was individually selected by the supervising radiologist to maximally null signal from normal myocardium (normal range, 200–300 msec).
Images were transferred to a dedicated offline workstation (Advantage Windows; GE Healthcare, Milwaukee, WI). Short-axis SSFP images were manually contoured in end-diastolic and end-systolic phases on a slice-by-slice basis using dedicated software (MASS version 4.2; MEDIS Medical Imaging, Leiden, The Netherlands). Measurements of end-diastolic volume (EDV), end-systolic volume, stroke volume, and ejection fraction (EF) were made. The papillary muscles were considered to be included within the blood pool for the purposes of volume and EF measurements. Resulting volumetric data were normalized to the patients’ body surface areas. A single observer (A.C.) made the ventricular measurements in all patients.
The image set was reviewed by two observers for the presence or absence of LGE. LGE was considered present if there was high signal within the myocardium at the same point in both axial and short-axis planes, in the presence of good myocardial nulling and no significant respiratory or arrhythmia-related image degradation.
Transthoracic echocardiography was performed using Philips iE33 system (Philips Medical Systems, Andover, MA). Echocardiograms were examined by the primary reader (J.G.), who was blinded to CMR data. Complete two-dimensional, Doppler color flow, and spectral Doppler studies were performed in the usual manner according to the guidelines of the American Society of Echocardiography. Severity of systemic tricuspid atrioventricular valvular regurgitation (SAAVR) was graded qualitatively following the American Society of Echocardiography’s guidelines for native valve regurgitation and reported as follows: 1 = mild, 2 = moderate, 3 = moderate to severe, and 4 = severe.
Regional myocardial function and contraction patterns were determined using Velocity Vector Imaging software (Siemens Medical Solutions USA, Inc., Mountain View, CA) from prospectively collected echocardiograms by a single observer (J.G.) ( Figure 1 ). Cine loops of six consecutive beats were acquired, with frame rates > 100 Hz. Strain was defined as the instantaneous local trace lengthening or shortening and strain rate as the rate of lengthening. The longitudinal strain and strain rates of the septal and free walls of the systemic subaortic right ventricle and free wall of the subpulmonic left ventricle were determined. Measurements were obtained from the apical four-chamber view at three levels (base, mid, and apex). Circumferential strain and strain rate were measured at three parasternal short-axis planes (base, mid, and apex) in the septal and free walls of the systemic right ventricle. An average of longitudinal strain was calculated for both the septal and free walls using the basal and midventricular level wall strain values. For intraobserver variability, 15 randomly assigned patients were reanalyzed by the same observer (J.G.) 2 months after the initial analysis.
Time to peak strain from the onset of the QRS complex (Tϵ) was calculated for the RV free wall, LV free wall, and interventricular septum in the four-chamber view. The average time to peak strain for each of the walls was calculated from the basal and mid Tϵ values. Intraventricular mechanical delay was defined as the difference in Tϵ between the RV free wall and the ventricular septum, and interventricular mechanical delay was defined as the difference in Tϵ between the RV and LV free walls.
Cardiopulmonary Exercise Testing
The stage 1 cardiopulmonary tests were performed on an ergometer cycle (Elema, Solna, Sweden). The protocol used at our center has been previously described. Briefly, heart rate, oxygen saturation (finger probe), and ventilation are measured continuously, and measurements are averaged over 30-sec intervals. The maximal oxygen uptake is assumed to reflect the subject’s maximal aerobic capacity. An abnormal normal heart rate reserve was defined as ≥15%. The forced vital capacity and forced expiratory volume at 1 sec are measured before exercise testing (Sensor-Medics, Yorba Linda, CA) and conducted according to American Thoracic Society standards.
Data were analyzed using SPSS version 16.0 (SPSS, Inc., Chicago, IL). The mean and standard deviation and the number and percentage are presented for continuous and categorical variables, respectively. Chi-square and Student’s t tests were used for comparisons between two groups. Pearson’s correlation coefficient was used as appropriate. P values < .05 were considered significant. For intraobserver variability, intraclass correlation coefficients with 95% confidence intervals were calculated.
Twenty-six patients were included (mean age, 38 ± 16 years; 54% women). The baseline characteristics of the 26 patients in the study are summarized in Table 1 . Nine patients (35%) had undergone prior surgical intervention: Blalock-Taussig shunt ( n = 2), pulmonary artery banding ( n = 2), ventricular septal defect closure ( n = 6), atrial septal defect closure ( n = 2), subpulmonic left ventricle–to–pulmonary artery conduit ( n = 2), pulmonary valvotomy ( n = 2), and cryoablation for atrial flutter ( n = 1).