Role of Echocardiography for Assessment of Cardiac Remodeling in Congenitally Corrected Transposition of Great Arteries

Abstract

Background:

The purpose of this study was to assess the role of echocardiography for a comprehensive assessment of cardiac remodeling, and the relationship between indices of cardiac remodeling and cardiovascular events (defined as the composite endpoint of heart failure hospitalization, heart transplant or cardiovascular death) in adults with congenitally corrected transposition of great arteries (cc-TGA).

Methods:

Retrospective study of adults with cc-TGA that underwent echocardiogram (2003–2020). Offline image analysis was performed in all patients. Chamber (atrial and ventricular) function and size were assessed by strain imaging and 2-dimensional echocardiography.

Results:

Of 233 patients with cc-TGA (40±15 years), 123 (55%) had at least one cardiac procedure prior to baseline echocardiogram. Of 233 patients, 76% and 61% had left atrial (LA) dysfunction and systemic right ventricular (RV) dysfunction, respectively; while 43% and 11% had right atrial (RA) dysfunction and left ventricular (LV) dysfunction, respectively. During a median follow-up of 8.9 years, 114 (49%) underwent additional cardiac procedures, and 66 (28%) had cardiovascular events. LA reservoir strain, RV global longitudinal strain (RVGLS), RA reservoir strain, LV systolic pressure, and LVGLS were independently associated with cardiovascular events.

Conclusions:

In addition to the clinical importance of RV systolic dysfunction in cc-TGA that is already well described, the current study demonstrated, for the first time, that biatrial dysfunction was common and was associated with clinical outcomes. Since there are currently no effective therapies for atrial and ventricular dysfunction in patients with cc-TGA, there is a need for research to identify novel strategies to prevent atrial and ventricular dysfunction in this population.

INTRODUCTION

Congenitally corrected transposition of great arteries (cc-TGA) is a rare congenital heart disorder, and it accounts for less than 1% of all congenital heart lesions.^{1, 2} It is characterized by atrioventricular and ventriculoarterial discordance, and as a result the right ventricle (RV) receives pulmonary venous blood, and in turn, pumps the oxygenated blood into the systemic arterial circulation.^{3, 4} More than 80% of patients with cc-TGA have associated structural heart lesions such as tricuspid valve dysplasia (Ebstein-like anomaly), ventricular septal defect and left ventricle (LV) outflow tract obstruction.^{3, 4} These lesions lead to volume and pressure overload of the different cardiac chambers, and over time result in remodeling of all cardiac chambers.^{2, 5, 6} Since the different parts of the cardiovascular system are intricately connected, with abnormalities of one chamber affecting the others because of in-series connections, and also because they are located within a common pericardial space, a comprehensive assessment of cardiac remodeling is important for determining the optimal management plan for each patient.

Two-dimensional, Doppler, and speckle tracking echocardiography is a robust imaging modality for a comprehensive assessment of cardiac remodeling.^7–9 Although cardiac remodeling affects all cardiac chambers, the application of echocardiography in the evaluation and management of patients with cc-TGA has primarily focused on the systemic tricuspid valve and RV systolic function.^{2, 5, 6, 10–12} The purpose of this study was to assess the role of echocardiography for a compressive assessment of cardiac structure, function and hemodynamics, and to evaluate the relationship between echocardiographic indices obtained at the time of baseline assessment and clinical outcomes (functional status and cardiovascular events) during follow-up in adults with cc-TGA.

METHODS

Study Population

The authors declare that all supporting data are available within the article. We conducted a retrospective study of adults (≥18 years of age) with cc-TGA that underwent transthoracic echocardiogram at the Mayo Clinic Rochester from January 1, 2003 to December 31, 2020. The patients were identified through the MACHD (Mayo Adult Congenital Heart Disease) registry. The Mayo Clinic Institutional Review Board approved the study, and informed consent was waived for patients that provided research authorization. The patients were classified either as simple cc-TGA or complex cc-TGA, and complex cc-TGA was defined as having associated ventricular septal defect and/or LV outflow tract obstruction (subvalvular or valvular pulmonic stenosis, and pulmonary atresia).

The first echocardiogram and cardiac outpatient evaluation performed within the study period were considered as the baseline echocardiogram and clinical assessment respectively. The baseline clinical characteristics of the study group were derived from indices retrieved from the baseline echocardiograms and clinical notes.

Since cardiac implantable electronic devises (CIED) are common in patients with cc-TGA, we classified all CIEDs that were present at the time of baseline echocardiogram into 3 mutually exclusive groups: (1) dual chamber pacemaker defined as having right atrial (RA) and LV leads only; (2) biventricular pacemaker or cardiac resynchronization therapy defined as having a both RV and LV leads; (3) defibrillator defined as having a defibrillator with or without pacing capabilities.

Echocardiography

Comprehensive transthoracic echocardiogram was performed according to contemporary guidelines,^7–9 and offline image analyses and measurements were performed by experienced research sonographers (J.W and K.T). Cardiac structure, function, and hemodynamics were assessed by 2-dimensional, Doppler, and speckle tracking echocardiography. The procedural details for the assessment of RA, RV, left atrial (LA) and LV strain in our laboratory have been described.^{13, 14} In brief, strain imaging was performed using Vivid E9 and E95 (General Electric Co, Fairfield, Connecticut) with M5S and M5Sc-D transducers (1.5–4.6 MHz) at frame rate of 40 to 80 Hz. Three-beat cine-loop clips were obtained from apical 4-chamber view, and these images were exported (DICOM) and then analyzed offline using TomTec (TomTec Imaging Systems, Unterschleissheim, Germany). Adequate tracking by the software was visually verified and retraced if necessary, until adequate tracking was achieved. The ventricular septum was included in the assessment of RV global longitudinal strain (RVGLS). Supplementary Table S1 shows the different echocardiographic indices of cardiac structure, function, and hemodynamics that were assessed in this study. The cut-off points used for defining normal versus abnormal indices were based on published data.^{7, 8, 15–20}

In addition to strain imaging, RV fractional area change (RVFAC) and LV ejection fraction (LVEF) were calculated from end-diastolic and end-systolic images derived from the apical 4-chamber view and were used as secondary indices of RV and LV systolic function respectively. Exploratory analyses were performed to compare the prognostic performance of RVGLS versus RVFAC.

Clinical Outcomes

The New York Heart Association (NYHA) functional classification was used to assess functional status, and patients were considered symptomatic if they were in NYHA II-IV functional class at the time of baseline clinical evaluation. Cardiovascular event was defined as composite endpoint of heart failure hospitalization, heart transplant and cardiovascular death during follow-up, and was ascertained from the electronic health records and Accurint mortality database.

Statistical Analysis

Data were summarized as mean ± standard deviation for continuous variables with normal distribution, median (interquartile range) for continuous variables with skewed distribution, and count (%) for categorical variables. Between-group comparisons were performed using unpaired t-test for continuous variables with normal distribution, Wilcoxon rank sum test for continuous variables with skewed distribution, and Fisher’s exact test for categorical variables. The correlation between chamber function (RVGLS, LVGLS, RA reservoir strain and LA reservoir strain) and pertinent clinical indices (Table 1 and 2) were assessed using linear regression analysis with chamber function as the outcome variable. The strength of association was expressed as beta coefficient± standard error (β±SE). For ease of interpretation, we modeled RVGLS and LVGLS as positive integers (i.e., ignoring the negative sign).

Table 1:

Baseline Characteristics

	All (n=233)	Simple cc-TGA (n=128)	Complex cc-TGA (n=105)	p
Age, years	40±15	43±15	34±12	<0.001
Male sex	117 (50%)	61 (48%)	56 (53%)	0.3
Body mass index, kg/m2	27±6	26±5	25±6	0.4
Prior cardiac procedures	123 (55%)	46 (36%)	77 (73%)	<0.001
Tricuspid valve repair	14 (6%)	7 (6%)	7 (7%)	0.6
Tricuspid valve replacement	37 (15%)	13 (10%)	24 (23%)	0.008
Ventricular septal defect closure	57 (26%)	---	57 (54%)	---
Infundibular stenosis resection	2 (2%)	---	2 (1%)	---
PVR/RV-PA conduct placement	26 (12%)	---	26 (25%)	---
Palliative shunts	8 (4%)	---	8 (8%)	---
Pulmonary artery band	6 (3%)	---	6 (6%)	---
CIED	88 (38%)	46 (36%)	42 (40%)	0.6
Dual chamber pacemaker	61 (26%)	31 (24%)	30 (29%)	0.4
Biventricular pacemaker	8 (3%)	5 (4%)	3 (3%)	0.8
Defibrillators	19 (8%)	10 (8%)	9 (9%)	0.8
Comorbidities
Hypertension	21 (9%)	14 (11%)	7 (7%)	0.3
Diabetes	5 (2%)	4 (3%)	1 (1%)	0.2
Coronary artery disease	6 (3%)	4 (3%)	2 (2%)	0.6
Atrial fibrillation	45 (19%)	23 (18%)	22 (21%)	0.5
Medications
Beta blockers	73 (40%)	45 (45%)	28 (34%)	0.1
ACEI/ARB	124 (60%)	65 (60%)	59 (61%)	0.9
Spironolactone	28 (15%)	17 (17%)	11 (13%)	0.5
Loop diuretics	76 (33%)	37 (30%)	39 (37%)	0.3
Digoxin	61 (31%)	28 (27%)	33 (34%)	0.3
Laboratory data
Estimated GFR	91±31	93±27	90±22	0.8
NT-proBNP	328 (48–1055)	428 (43–1316)	116 (51–891)	0.5

cc-TGA: congenitally corrected transposition of great arteries; PVR: pulmonary valve replacement; RV-PA: right ventricular to pulmonary artery; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; GFR: glomerular filtration rate; NT proBNP: N-terminal pro hormone brain natriuretic peptide; CIED: cardiac implantable electronic devices

Table 2:

Echocardiographic Indices of Cardiac Remodeling

	All (n=233)	Simple cc-TGA (n=128)	Complex cc-TGA (n=105)	p
Systemic indices
LA indices
LA volume index, ml/m2	46 (35–64)	46 (34–63)	45 (36–68)	0.5
LA reservoir strain, %	23±10	24±5	21±4	0.02
Systemic RV indices
RV global longitudinal strain, %	−17±4	−18±4	−16±3	0.03
RV end-diastolic area, cm2	37±10	35±9	38±11	0.2
RV end-systolic area, cm2	27±9	25±7	28±8	0.4
RV fractional area change, %	31±10	31±8	28±8	0.2
RV cardiac index, ml/m2	2.6 (2.2–2.7)	2.5 (2.3–2.7)	2.7 (2.4–3.2)	0.3
≥Moderate tricuspid regurgitation*	88 (38%)	54 (43%)	34 (34%)	0.07
≥Moderate aortic regurgitation*	12 (5%)	5 (4%)	7 (7%)	0.3
Non-systemic indices
RA indices
RA volume index, ml/m2	22 (16–29)	19 (15–25)	26 (17–39)	<0.001
RA reservoir strain, %	32±12	37±12	26±11	<0.00
RA pressure, mmHg	9±4	8±4	10±5	0.008
Non-systemic LV indices
LV longitudinal strain, %	−23±7	−24±6	−21±7	0.007
LV end-diastolic volume, ml/m2	43±18	36±15	54±10	<0.001
LV end-systolic volume, ml/m2	16±9	14±8	20±10	0.002
LV ejection fraction, %	62±10	61±11	62±11	0.5
LV systolic pressure, mmHg	37 (30–54)	36±9	48±11	<0.001
≥Moderate mitral regurgitation*	26 (11%)	8 (6%)	18 (917%)	0.005
≥Moderate pulmonary regurgitation*	15 (6%)	1 (1%)	14 (13%)	<0.001
Pulmonary valve mean gradient, mmHg	5 (3–13)	3 (2–3)	13 (6–26)	<0.001

cc-TGA: congenitally corrected transposition of great arteries; LA: left atrium; RV: right ventricle; RA: right atrium; LV: left ventricle;

^*denotes indices obtained from qualitative assessment

The relationships between echocardiographic indices (Table 2) and outcome variables (NYHA II-IV and cardiovascular event) were assessed using univariable and multivariable logistic regression and Cox regression as appropriate. First, we created a univariable model using the different echocardiographic indices of cardiac structure, function, and hemodynamics (Table 2). The variables with p value less than 0.25 in the univariable model were used to create a multivariable model using stepwise backwards selection, and the threshold for a variable to remain in the multivariable model was set at a p value less than 0.1. The multivariable models were also adjusted for age and sex. The prognostic power of RVGLS was compared to that of RVFAC by substituting RVFAC for RVGLS in the multivariable Cox model, and the difference in prognostic power of the models was determined using c-statistic.

Some patients underwent medical, surgical, and electrophysiologic interventions (tricuspid valve replacement, cardiac resynchronization therapy, and medical therapy for heart failure) between the baseline echocardiogram and ascertainment of outcomes. We controlled for the confounding effects of these interventions on outcomes by modeling these interventions as time-dependent covariates. Intraobserver and interobserver correlation was assessed using intraclass correlation coefficient. A p<0.05 was considered statistically significant. All statistical analyses were performed with JMP software (version 14.1.0; SAS Institute Inc, Cary NC) and GraphPad software (version 9.0.1; San Diego, CA).

RESULTS

Baseline Characteristics

Of 233 patients that underwent clinical and echocardiographic assessment within the study period, 128 (55%) had simple cc-TGA while 105 (45%) had complex cc-TGA. A total of 123 (55%) patients had at least 1 cardiac procedure prior to the baseline clinical and echocardiographic evaluation (Table 1). None of the patients had a double-switch operation. Compared to the simple cc-TGA group, the complex cc-TGA were younger and more likely to have had cardiac procedures prior to baseline evaluation (Table 1). However, both groups had similar prevalence of CIED. Of the 88 patients with CIED, 82 (93%) had endocardial pacemakers while 6 (7%) had epicardial pacemakers, and these 6 epicardial pacemakers were dual chamber pacemakers. There was an association between a prior history of cardiac procedures and a history of pacemaker implantation at the time of baseline assessment (odds ratio 3.88, 95% confidence interval 2.13–7.07, p<0.001).

Cardiac Structure, Function, and Hemodynamics

The quantitative assessment of cardiac structure, function, and hemodynamics was feasible in >86% of the patients for all indices except LV systolic pressure which was feasible in only 72% of cases because of insufficient mitral regurgitation signal. There was good intraobserver and interobserver agreement for all indices (Supplementary Table S2).

Table 2 shows echocardiographic indices of cardiac structure, function, and hemodynamics. Compared to the simple cc-TGA group, the complex cc-TGA group had worse cardiac remodeling and hemodynamics across multiple domains (Table 2).

Of the patients with available data, 76% (168/221) and 71% (144/203) had LA enlargement and LA dysfunction respectively, while 91% (207/228), 61% (127/209) and 48% (103/48) had RV enlargement, RV dysfunction, and low cardiac output respectively (Figure 1). LA reservoir strain was associated with tricuspid regurgitation (β±SE = −3.43±1.05, p=0.008), RVGLS (β±SE = 1.17±0.14, p<0.001), RA pressure (β±SE = −0.61±0.17, p<0.001), and history of atrial fibrillation (β±SE = −6.14±1.83, p<0.001), while RVGLS was associated with hypertension (β±SE = −4.18±1.66, p<0.001), LVGLS (β±SE = 0.16±0.04, p<0.001), and dual chamber pacemaker implantation (β±SE = −2.18±1.08, p=0.01).

Figure 1.

Top: Bar chart showing the prevalence of chamber dysfunction. N (%) signifies number (proportion) of patients of normal or abnormal function. LA: left atrium; RV: right ventricle; RA: right atrium; LV: left ventricle

Bottom: Forest plot showing a multivariable Cox model for risk factors associated with cardiovascular events. HR (95%CI): hazard ratio (95% confidence interval). Note that strain indices were modeled as absolute numbers (i.e. ignoring the negative signs for RV and LV strain)

Similarly, 20% (44/219), 43% (95/206) and 52% (114/219) had RA enlargement, RA dysfunction and RA hypertension respectively, while 12% (26/211), 11% (23/204) and 40% (67/168) had LV enlargement, LV dysfunction, and LV hypertension respectively (Figure 1). RA reservoir strain was associated with mitral regurgitation (β±SE = −3.91±1.22, p<0.001), pulmonary regurgitation (β±SE = −1.97±0.74, p=0.006), history of atrial fibrillation (β±SE = −3.72±1.16, p=0.004), and pacemaker implantation (β±SE = −2.97±0.83, p<0.001). Of the 26 patients with moderate or greater mitral regurgitation, 25 (96%) had transvenous CIED leads across the mitral valve, and 23 (89%) of these patients had RA dysfunction.

Subgroup Analysis

In a subset of 186 patients that had ≥2 echocardiograms >12 months apart, there was a decline in RVGLS by −0.8 %-points (95% confidence interval −1.3 - −0.5) and LA reservoir strain by −0.6 %-points (95% confidence interval −1.1 - −0.1). In a subset of 186 patients that had ≥2 echocardiograms >12 months apart, there was a decline in LVGLS by −0.5 %-points (95% confidence interval −0.8 - −0.2) and RA reservoir strain by −0.4 %-points (95% confidence interval −1.0 - +0.1).

In the subset of 53 patients that had tricuspid valve replacement, there was a temporal improvement in RVGLS (−17±3% versus −19±4%, p=0.04) without any significant change in RV FAC (31±6% versus 29±10%, p=0.3).

Cardiac Procedures

Of the 233 patients, 114 (49%) patients underwent at least one additional cardiac procedure during follow-up, and there was 1 (0.4%) surgical mortality. The cardiac procedures were surgical tricuspid valve replacement (n=53), transcatheter tricuspid valve-in-valve replacement (n=1), surgical aortic valve replacement (n=6), surgical mitral valve repair (n=7), surgical pulmonary valve replacement (n=15), transcatheter pulmonary valve-in-valve replacement (n=2), closure of ventricular septal defect (n=4), CIED implantation or revision (n=54). The number of patients with CIED at the time of baseline echocardiogram was 88 (38%), and this number increased to 118 (51%) by the end of study period.

Clinical Outcomes

Of the 233 patients, 133 (57%) had NYHA II-IV symptoms at baseline (NYHA II, n=64; NYHA III, n=46; NYHA IV, n=23). Of the demographic and echocardiographic indices analyzed, LA reservoir strain, RVGLS, RV cardiac index, RA pressure and LV systolic pressure were independently associated with symptomatic status (Table 3 and Supplementary Table S3).

Table 3:

Multivariable Model Showing Echocardiographic Indices Associated with Symptomatic Status

	OR (95%CI)	p
Demographic indices
Age, year	1.03 (1.01–1.05)	0.008
LA indices
LA reservoir strain, %	0.93 (0.89–0.97)	0.01
Systemic RV indices
RV longitudinal strain, %	0.91 (0.87–0.96)	0.04
RV cardiac index, ml/m2	0.93 (9.88–0.99)	0.03
RA indices
RA pressure, mmHg	1.08 (0.99–1.84)	0.09
Non-systemic LV indices
LV systolic pressure, mmHg	1.04 (1.01–1.07)	0.006

OR: odds ratio; CI: confidence interval; LA: left atrium; RV: right ventricle; RA: right atrium; LV: left ventricle. Note that RV longitudinal strain and RV fractional area change were not imputed into the same model because of collinearity.

The median interval between baseline assessment and the end of study period was 8.9 (4.3–12.5) years, and during this period, 43 (19%) were hospitalized for heart failure, 4 (2%) underwent heart transplant for end-stage heart failure, and 35 (15%) patients died from cardiovascular cause (end-stage heart failure n=23, sudden cardiac death n=9, stroke-related death n=2, postoperative death n=1). The composite cardiovascular event endpoint occurred in 66 (28%) patients. Age, LA reservoir strain, RVGLS, RA reservoir strain, LV systolic pressure, and LVGLS were independently associated with cardiovascular events. (Figure 1, Table 4, and Supplementary Table S4).

Table 4:

Multivariable Model Showing Echocardiographic Indices Associated with Cardiovascular events

	HR (95%CI)	p
Demographic indices
Age, year	1.10 (1.04–1.16)	<0.001
Systemic indices
LA reservoir strain, %	0.94 (0.90–0.98)	0.002
RV longitudinal strain, %	0.90 (0.84–0.92)	0.01
Non-systemic indices
RA reservoir strain, %	0.94 (0.89–0.99)	0.03
LV longitudinal strain, %	0.92 (0.87–0.97)	0.02
LV systolic pressure, mmHg	1.02 (1.01–1.04)	0.01

HR: hazard ratio; CI: confidence interval; LA: left atrium; RV: right ventricle; RA: right atrium; LV: left ventricle. Note that LV longitudinal strain and LV ejection fraction were not included in the same model because of collinearity.

There was no significant change in the prognostic power of the models when we substituted RVFAC for RVGLS (c-statistic for model with RVGLS 0.783, 95% confidence interval 0.769–0.796 versus c-statistic for model with RVFAC 0.776, 95% confidence interval 0.761–0.790, c-statistic difference −0.007, 95% confidence interval −0.019 - +0.005).

DISCUSION

In this study, we used 2-dimensional, Doppler, and speckle tracking echocardiography for a comprehensive assessment of cardiac remodeling in 233 adult patients with cc-TGA. The main findings are: (1) LA dysfunction was the most common chamber dysfunction (present in 71% of patients), and was associated with both functional status and cardiovascular events; (2) RV systolic dysfunction was present in more than half of the patients (61%), and both RVGLS and RVFAC had comparable prognostic performance; (3) RA hypertension and dysfunction was present in about half of the patients, and having RA hypertension or dysfunction was associated with functional status and cardiovascular events; (4) Overall there was a significant risk of cardiovascular events (28%) and need for cardiac procedures (49%), and this underscores need for close follow-up in tertiary centers with the expertise to identify and treat these complications and determine optimal timing for intervention.

A novel finding from the current study was the high prevalence of LA dysfunction (more common than RV systolic dysfunction) and its association with both functional status and cardiovascular events. We postulate that this may be related to LA remodeling from systemic tricuspid regurgitation and high filling pressures from RV dysfunction, based on our correlation analyses. There was also a strong correlation between LA dysfunction and atrial fibrillation, although causality cannot be inferred using the current study design.

Systemic RV systolic dysfunction is a well-recognized and expected complication in patients with cc-TGA, and it is a known predictor of adverse events.^{5, 10–12, 21, 22} Diller et al⁶ assessed biventricular function in 42 patients with cc-TGA using speckle tracking echocardiography, and reported that more than half of their cohort had biventricular systolic dysfunction (82% and 44% for RV and LV respectively), and that both LV and RV systolic dysfunction were independently associated with cardiovascular outcomes. They also observed a strong correlation between RVGLS and LVGLS, and postulated ventricular-ventricular interaction as a potential mechanism for ventricular dysfunction.⁶ Consistent with the Diller et al study, we observed a strong correlation between RV and LV systolic function in our cohort. Additionally, we also observed a correlation between RV systolic function and hypertension, and LV pacing (dual chamber pacemaker). We postulated that this may be related to the inability of the RV to tolerate increased afterload due to hypertension, as well as ventricular desynchrony from chronic LV pacing. Both RVGLS and RVFAC had comparable prognostic performance in this study, and both indices are used for monitoring RV systolic function in our institution.

Several strategies such as anatomic repair, tricuspid valve replacement, and cardiac resynchronization therapy have been proposed for the prevention and treatment of RV systolic dysfunction.^{2, 11, 22–24} Our data showed that performing tricuspid valve replacement or cardiac resynchronization therapy after the onset of RV systolic dysfunction was not associated with a reduction in the risk of cardiovascular events, as evidenced by the consistent association between RV function at baseline and cardiovascular events during follow-up after adjustment for cardiac interventions. This is consistent with previous studies showing that preoperative RV systolic function was the strongest predictor of postoperative RV remodeling and cardiovascular outcomes.⁵ Collectively, these data will reinforce the importance of early surgical intervention in patients with significant tricuspid regurgitation. Other strategies for managing RV systolic dysfunction such as anatomical repair (double switch operation) may not be applicable to this cohorts because the mean age at the time of initial presentation to our clinic was 40 years, which is already past the age when LV retraining and anatomical repair can be performed safely. It is also important to highlight that anatomical repair is a complex operation that carries high risk of surgical mortality in children (6–11%) as compared to the surgical risk of 1% of tricuspid valve replacement and other surgical procedures in this population of adult patients.²⁵

Another important and novel observation in the current study is the importance (prevalence and prognostic implication) of RA dysfunction and RA hypertension. There was a strong association between RA dysfunction, mitral regurgitation, and pacemaker implantation. Almost all the patients (98%) with significant mitral regurgitation had transvenous LV leads across the mitral valve, suggesting that the mitral regurgitation may be iatrogenic. Typically, it is believed that the LV is a robust pump, and hence can tolerate pressure and volume overload for a long time. In contrast, our data suggest that LV volume overload from valvular regurgitation was associated with RA remodeling and dysfunction, and in turn, associated with adverse clinical outcomes. Perhaps LV volume overload should not be considered benign, and mitral and pulmonary valve interventions should be performed in patients with progressive valvular regurgitation, symptoms and/or LV enlargement/dysfunction Additionally, the strong correlation between transvenous LV leads and mitral regurgitation should prompt more research into alternative methods of ventricular pacing such as leadless pacemakers and coronary sinus leads since more than half of the patients with cc-TGA will required pacing in their lifetime.

An important negative finding was that complex cc-TGA was not associated with functional class or cardiovascular events after adjustment for chamber remodeling. This suggests that if surgical or transcatheter corrections of these associated structural lesions are performed prior to the onset of significant remodeling, patients with complex cc-TGA will likely have similar long-term outcomes as those with simple cc-TGA.

Limitations

We did not have invasive hemodynamic indices and cardiac magnetic resonance imaging indices in our cohort, and the contributions of diastolic dysfunction and atrioventricular valve regurgitation on atrial dysfunction were not characterized in this study. Although we controlled for the effect of cardiac interventions (tricuspid valve surgery, cardiac resynchronization therapy, and medical therapy for heart failure) using multivariable Cox regression models, the current study design did not allow for the assessment of the effect of these interventions on progression or regression of cardiac remodeling.

Conclusions

In addition to the clinical importance of RV systolic dysfunction in cc-TGA that is already well described, the current study demonstrated, for the first time, that biatrial dysfunction was common and had important prognostic implications. Since there are currently no effective therapies for atrial and ventricular dysfunction in patients with cc-TGA, there is a need for research to identify novel strategies to prevent atrial and ventricular dysfunction in this population. Additionally, adult patients with cc-TGA had significant risk of cardiovascular events, and an ongoing need for cardiac procedures, and hence they should be followed at tertiary centers with the expertise for early detection and treatment of complications. Finally, the current study showed that quantitative assessment of cardiac structure, function, and hemodynamics was feasible in >86% of patients, with good reproducibility, thus highlighting the feasibility and clinical importance of echocardiography for comprehensive and integrated assessment in patients with cc-TGA.

Clinical Perspective:

The purpose of this study was to assess the role of echocardiography for a comprehensive assessment of cardiac remodeling, and the relationship between indices of cardiac remodeling and cardiovascular events (defined as the composite endpoint of heart failure hospitalization, heart transplant or cardiovascular death) in adults with congenitally corrected transposition of great arteries (cc-TGA). Of 233 patients, 76% and 61% had left atrial (LA) dysfunction and systemic right ventricular (RV) dysfunction, respectively; while 43% and 11% had right atrial (RA) dysfunction and left ventricular (LV) dysfunction, respectively. LA reservoir strain, RV global longitudinal strain (RVGLS), RA reservoir strain, LV systolic pressure, and LVGLS were independently associated with cardiovascular events. In addition to the clinical importance of RV systolic dysfunction in cc-TGA that is already well described, the current study demonstrated, for the first time, that biatrial dysfunction was common and was associated with clinical outcomes.

Abbreviations:

RA

right atrium

LA

left atrium

LV

left ventricle

RV

right ventricle

FAC

fractional area change

GLS

global longitudinal strain

cc-TGA

congenitally corrected transposition of great arteries

NYHA

New York Heart Association

EF

ejection fraction

CIED

cardiac implantable electronic devises

β±SE

beta coefficient± standard error