Abstract
Background
The purpose of this study was to determine the clinical implications of progressive systemic ventricular (SV) systolic dysfunction in adults with Fontan palliation.
Methods
Retrospective study of Fontan patients with ≥2 echocardiograms at Mayo Clinic. SV systolic function was assessed using echo-derived ejection fraction (Echo_EF) at baseline, and annually for 3 years. Temporal decline in SV systolic function was estimated as relative change (relative Δ_Echo_EF)/year. Exploratory analysis was performed to assess the effect of guideline-directed medical therapy (GDMT) on Echo_EF.
Results
Of 414 patients (age 27 ± 9 years; males 228 [55 %]), 287 (69 %) and 127 (31 %) had dominant morphologic left ventricle (LV) and right ventricle (RV), respectively. Assessment of Echo_EF was feasible in 1464 of 1603 echocardiograms (91 %). The baseline Echo_EF was 54 % (48–58), and the relative Δ_Echo_EF was −3.9 % (95 %CI -6.3 to −2.5 %)/year. The predictors of progressive SV systolic dysfunction were older age, morphologic RV, ≥moderate atrioventricular valve regurgitation, cardiac implantable electronic devices, and atrial fibrillation. Progressive SV systolic dysfunction was associated with an approximately 2-fold increase in death/transplant (hazard ratio 1.92, p = 0.009), independent of baseline Echo_EF and comorbidities. GDMT was associated with improvement in Echo_EF in patients with morphologic LV.
Conclusions
The current study underscores the importance of longitudinal echocardiographic monitoring of SV systolic function, and the potential clinical benefits of GDMT in patients with morphologic LV. Further studies are required to determine whether interventions such as valve surgery, rhythm control strategy, and physiologic pacing would prevent or reverse SV systolic dysfunction.
Keywords: Echocardiography, Systolic dysfunction, Mortality, Prognostication
CONDENSED ABSTRACT: Among 414 patients who underwent 1603 echocardiograms, we observed a temporal decline in SV systolic function over time (relative Δ_Echo_EF −3.9 % [95 % CI -6.3 to −2.5 %]/year). The predictors of progressive SV systolic dysfunction were older age, morphologic RV, ≥moderate atrioventricular valve regurgitation, cardiac implantable electronic devices, and atrial fibrillation. Progressive SV systolic dysfunction was associated with a 2-fold increase in the risk of death/transplant (hazard ratio 1.92, p = 0.009) independent of baseline Echo_EF and comorbidities. GDMT was associated with improvement in Echo_EF in patients with morphologic LV. This suggests that echocardiographic surveillance and GDMT may improve outcomes in this population.
1. Introduction
Adults with Fontan palliation often develop systemic ventricular (SV) systolic dysfunction [1,2]. The etiology of SV systolic dysfunction in the Fontan population has been attributed to several factors such as ventricular morphology, myocardial ischemic injury from prior cardiovascular surgery, rhythm abnormalities related to atrial arrhythmias and ventricular pacing, and ventricular volume overload from atrioventricular valve regurgitation (AVVR) [[1], [2], [3], [4]]. Previous studies have shown that patients presenting with SV systolic dysfunction had increased risk of mortality during follow-up [1,2]. However, there are limited data about the risk of temporal deterioration in SV systolic function and its potential clinical implications in the Fontan population [[1], [2], [3], [4], [5]]. The purpose of this study was to assess the clinical implications of progressive SV systolic dysfunction in adults with Fontan palliation.
2. Methods
2.1. Study population
This is a retrospective cohort study of adults (age ≥18 years) with Fontan palliation who had serial echocardiograms at Mayo Clinic between January 1, 2003 and December 31, 2023. From this cohort, we identified consecutive patients with adequate echocardiographic images for offline assessment of SV volumes and ejection fraction (EF). The patients were classified as having left ventricular (LV) versus right ventricular (RV) morphology, and the patients with indeterminate SV morphology were excluded. Supplementary Fig. S1 shows the flow chart for patient selection. The first clinical encounter after January 1, 2003, was considered the baseline encounter, and clinical indices obtained within 6 months from the baseline encounter were used to define the baseline characteristics of the cohort. The Mayo Clinic Institutional Review Board approved this study.
2.2. Study Objectives
-
(1)
Determine the prevalence of SV systolic dysfunction at baseline echocardiogram and define the clinical characteristics of patients with SV systolic dysfunction [2]. Determine the predictors and prognostic implications of progressive SV systolic dysfunction. Progressive SV systolic dysfunction was defined as temporal decline in SV systolic function during follow-up.
2.3. Assessment of systemic ventricular systolic function
2.3.1. Procedural Details
Comprehensive transthoracic echocardiogram was performed according to contemporary guidelines [6,7]. Offline image analysis was performed in all patients by research sonographers using the standardized protocol for image analysis in the Mayo Adult Congenital Heart Disease (MACHD) Registry Imaging Core Laboratory [[10], [8], [9]]. For this study, SV systolic function was assessed using echocardiography-derived EF (Echo_EF) calculated by monoplane volumetric analysis of SV end-diastolic and end-systolic volumes of the dominant ventricle obtained from the apical 4-chamber view. Echocardiography-derived fractional area change (Echo_FAC) was also calculated from the apical 4-chamber view and used as secondary measure of SV systolic function. Fig. 1 shows representative echocardiographic images of SV end-diastolic volume and end-systolic area from a patient with systemic LV versus RV.
Fig. 1.
Top: Representative echocardiographic images from a patient with tricuspid atresia showing left ventricular end-diastolic volume (left) and end-diastolic area (right). Bottom: Representative echocardiographic images from a patient with hypoplastic left heart syndrome showing right ventricular end-diastolic volume (left) and end-diastolic area (right).
2.3.2. SV systolic dysfunction at baseline
The first echocardiogram performed after January 1, 2003 was used to determine the baseline SV systolic function, and the prevalence of SV systolic dysfunction. Regardless of ventricular morphology, we defined normal SV systolic function as Echo_EF >50 %, mild SV systolic dysfunction as Echo_EF 41–50 %, moderate/severe SV systolic dysfunction as Echo_EF ≤ 40 %.
2.3.3. Progressive SV systolic dysfunction (temporal decline in Echo_EF) during follow-up
Using the baseline echocardiogram as ‘time 0’, we reviewed all subsequent echocardiograms performed during annual clinical evaluations (±3 months) within 3 years from the baseline echocardiogram. The annual temporal change in Echo_EF was calculated as absolute Δ (Echo_EF from most recent echocardiogram – Echo_EF from previous echocardiogram), and relative Δ ([Echo_EF from most recent echocardiogram – Echo_EF from previous echocardiogram] ÷ Echo_EF from previous echocardiogram) x100) [10].
2.3.4. Cardiac magnetic resonance imaging (CMRI)
The routine clinical protocol for ventricular volumetric assessment using CMR was performed according to Society for Cardiovascular Magnetic Resonance guidelines [11,12]. CMR studies were performed with 1.5-T scanners (450w, GE Medical Systems, Milwaukee, Wisconsin; and Sola, Siemens Healthineers, Erlangen, Germany). The assessment of ventricular size and function was performed using an electrocardiographically gated steady-state free precession acquisition in the trans-axial and ventricular short-axis planes that spanned from the cardiac apex to the atria, reconstructed into 20 to 30 phases per cardiac cycle. Ventricular volumes were determined by manually tracing the endocardial borders at end-diastole to determine the end-diastolic volume, representing the maximal volume, and at end-systole to determine the end-systolic volume, representing the minimal volume. Contours were generated by a dedicated CMR 3D post-processing lab under supervision from the interpreting CMR reader. Ventricular stroke volume was calculated from the difference between end-diastolic volume and end systolic volume. In cases where patients had two identifiable ventricles contributing to systemic circulation (N = 22, 5 %), the volumes of both ventricles were summed. These ventricular volumes were then indexed to the patient's body surface area CMR-derived volumes and EF were retrieved from clinical reports.
2.3.5. Outcome
The study outcome was a composite endpoint of death from all-cause and/or heart transplant (death/transplant), ascertained from review of electronic health records and the Accurint mortality database. The incidence of death/transplant were assessed from the baseline encounter to the occurrence of composite outcome, last clinical encounter, or December 31, 2023.
2.3.6. Exploratory analysis
Exploratory analysis was performed to assess the effect of guideline directed medical therapy (GDMT) for heart failure on SV systolic function. This analysis was restricted to patients not on GDMT at baseline and were subsequently placed on GDMT following diagnoses of SV systolic dysfunction, and patients on GDMT at baseline but had intensification of GDMT following the diagnosis of SV systolic dysfunction [13,14]. GDMT was defined as being on any two of the following medications: beta blocker, angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker/angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, or sodium-glucose cotransporter-2 inhibitors. Intensification of GDMT was defined as increase in dose and/or addition of a new agent [13,14].
For the exploratory analysis, we compared Echo_EF from pre-intervention echocardiogram (last echocardiogram prior to initiation or intensification of GDMT) to post-intervention echocardiogram (first echocardiogram performed >12 months after initiation or intensification of GDMT). The difference in Echo_EF was expressed as mean difference and 95 % confidence interval (CI) [13].
2.3.7. Statistical analysis
Data were presented as mean ± standard deviation, median (interquartile range, IQR), and count ( %). Between-group comparisons were performed using analysis of variance test, unpaired t-test, Wilcoxon rank sum test, or Fisher exact test, as appropriate. Reproducibility analysis was assessed by 2 dedicated research sonographers using intraobserver and interobserver agreement in 20 randomly selected sample of patients with systemic LV, and 20 randomly selected patients with systemic RV morphology, and expressed as intraclass correlation (ICC) and 95 %CI. Pearson correlation was used to assess the correlation between echocardiographic indices of systolic function (Echo_EF and Echo_FAC) versus CMRI_EF.
As described above, patients with relative Δ_Echo_EF above the median for the group were considered to have progressive SV systolic dysfunction in contrast to patients with relative Δ_Echo_EF below the median for the group. Using the median relative Δ_Echo_EF of 3.9 % as the cutoff, we dichotomized the cohort into patients with progressive SV systolic dysfunction (relative Δ_Echo_EF >3.9 %) versus patients without progressive SV systolic dysfunction (relative Δ_Echo_EF ≤ 3.9 %).
Multivariable logistic regression was used to identify the predictors of progressive SV systolic dysfunction. First, we created univariable models using the following variables: demographic indices (age, sex), anatomic/surgical indices (type of Fontan connection, age at Fontan operation, SV morphology, atrioventricular valve regurgitation, cardiac implantable electronic devices [CIED]), comorbidities (atrial fibrillation, hypertension, coronary artery disease), and use of GDMT at baseline encounter. These variables were chosen based on clinical relevance. The variables with p < 0.1 in the univariable model were used to create the multivariable model. Final covariate selection in the multivariable model was based on stepwise backwards selection with p < 0.1 required for a covariate to remain in the model.
The prognostic implication of progressive SV systolic dysfunction (i.e., relationship between progressive SV systolic dysfunction and death/transplant) was assessed using time-dependent Cox regression. The model was adjusted for Echo_EF at baseline echocardiogram, demographic indices, anatomic/surgical indices, comorbidities, and laboratory indices. The criteria for final covariate selection were similar to that used for the logistic regression model. The cumulative incidence of death/transplant was assessed using Kaplan-Meier analysis and compared using log rank tests.
All statistical analyses were performed with BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC, Chicago, IL, USA), and JMP statistical software (version 17.1.0, JMP Statistical Discovery LLC, NC). P value < 0.05 was considered to be statistically significant for all analyses.
3. Results
3.1. Baseline characteristics
The study cohort comprised of 414 patients. The mean age at baseline encounter was 27 ± 9 years, 228 (55 %) were males, and 98 (24 %) had CIED. Of the 414 patients 287 (69 %) had morphologic LV while 127 (31 %) had morphologic RV. The median age at initial Fontan operation was 5 (IQR 3–8) years.
The baseline echocardiogram showed normal SV systolic function in 301 (73 %) patients, mild SV systolic dysfunction in 70 (17 %) patients, and moderate/severe SV systolic dysfunction in 43 (10 %) patients. Table 1 shows the baseline clinical and imaging data of the cohort. The patients with SV systolic dysfunction were more like to have morphologic RV dominance, as well as higher N-terminal pro hormone brain natriuretic peptide, and SV volumes (Table 1).
Table 1.
Baseline characteristics.
| All (N = 414) | Normal (301, 73 %) | Mild Dysfn (N = 70, 17 %) | Mod/sev Dysfn (N = 43, 10 %) | p | |
|---|---|---|---|---|---|
| Age, years | 27 ± 9 | 27 ± 8 | 27 ± 10 | 26 ± 8 | 0.9 |
| Body surface area, m2 | 1.78 ± 0.23 | 1.78 ± 0.22 | 1.79 ± 0.21 | 1.78 ± 0.28 | 0.9 |
| Body mass index, kg/m2 | 23.9 ± 4.6 | 24.2 ± 5.1 | 23.4 ± 3.4 | 23.1 ± 4.8 | 0.7 |
| Systemic oxygen saturation, % | 92 (89–94) | 92 (89–94) | 93 (90–94) | 91 (87–94) | 0.2 |
| CIED | 98 (24 %) | 65 (22 %) | 19 (27 %) | 14 (33 %) | 0.2 |
| Ventricular morphology | 0.001 | ||||
| LV | 287 (69 %) | 222 (74 %) | 44 (63 %) | 21 (49 %) | |
| RV | 127 (31 %) | 79 (26 %) | 26 (37 %) | 22 (51 %) | |
| Surgical history | |||||
| Type of initial Fontan connection | 0.2 | ||||
| Atriopulmonary Fontan | 254 (61 %) | 192 (64 %) | 41 (59 %) | 21 (49 %) | |
| Lateral tunnel/IAC Fontan | 92 (22 %) | 60 (20 %) | 14 (20 %) | 18 (42 %) | |
| Extracardiac conduit Fontan | 68 (16 %) | 49 (16 %) | 15 (21 %) | 4 (9 %) | |
| Age at Fontan operation, years | 5 (3–8) | 5 (3–8) | 5 (3–8) | 5 (3–8) | 0.9 |
| Subsequent Fontan conversion | 115 (28 %) | 89 (30 %) | 20 (29 %) | 6 (14 %) | 0.1 |
| Comorbidities | |||||
| Atrial arrhythmias | 186 (44 %) | 131 (44 %) | 36 (51 %) | 19 (44 %) | 0.5 |
| Atrial flutter/tachycardia | 129 (31 %) | 91 (30 %) | 26 (37 %) | 12 (28 %) | 0.5 |
| Atrial fibrillation | 83 (20 %) | 57 (19 %) | 16 (23 %) | 10 (23 %) | 0.7 |
| CKD III-V | 10 (3 %) | 7 (2 %) | 1 (1 %) | 2 (5 %) | 0.6 |
| Cirrhosis | 96 (23 %) | 65 (22 %) | 16 (23 %) | 15 (35 %) | 0.2 |
| Protein losing enteropathy | 47 (11 %) | 37 (12 %) | 6 (9 %) | 4 (9 %) | 0.6 |
| Laboratory data | |||||
| NTproBNP, pg/ml | 205 (71–517) | 167 (60–419) | 211 (82–578) | 458 (192-1144) | <0.001 |
| Estimated GFR, ml/min/1.73 m2 | 102 ± 26 | 103 ± 25 | 104 ± 27 | 98 ± 29 | 0.4 |
| Hemoglobin, g/dl | 14.9 ± 2.3 | 14.8 ± 2.2 | 15.3 ± 2.3 | 15.3 ± 2.7 | 0.2 |
| Medications | |||||
| Diuretics | 167(40 %) | 117 (38 %) | 29 (41 %) | 21 (49 %) | 0.5 |
| Beta blockers | 152 (37 %) | 112 (37 %) | 24 (34 %) | 16 (37 %) | 0.9 |
| ACEI/ARB | 249 (60 %) | 176 (57 %) | 44 (63 %) | 29 (67 %) | 0.5 |
| MRA | 99 (24 %) | 71 (24 %) | 14 (20 %) | 14 (33 %) | 0.3 |
| Echocardiographic indices | |||||
| Ventricular EDV index, ml/m2 | 93 (71–124) | 88 (70–117) | 99 (74–134) | 125 (85–165) | <0.001 |
| Ventricular ESV index, ml/m2 | 44 (33–60) | 38 (30–52) | 52 (40–73) | 84 (60–115) | <0.001 |
| Echo_EF, % | 54 (48–58) | 56 (53–60) | 47 (44–48) | 30 (24–36) | <0.001 |
| Ventricular EDA index, cm2/m2 | 21 (18–25) | 21 (18–24) | 22 (19–26) | 28 (21–32) | <0.001 |
| Ventricular ESA index, cm2/m2 | 14 (11–17) | 13 (11–15) | 16 (13–18) | 19 (16–25) | <0.001 |
| Echo_FAC, % | 35 (31–39) | 38 (35–41) | 30 (28–32) | 23 (18–27) | <0.001 |
| Stroke volume index, ml/m2 | 43 (33–54) | 44 (36–54) | 43 (33–52) | 40 (28–49) | 0.1 |
| Cardiac MRI | |||||
| Ventricular EDV index, ml/m2 | 79 (58–108) | 73 (53–98) | 91 (67–127) | 101 (81–124) | 0.01 |
| Ventricular ESV index, ml/m2 | 37 (26–56) | 34 (24–49) | 51 (35–64) | 57 (46–78) | 0.001 |
| Stroke volume index, ml/m2 | 41 (30–53) | 42 (27–52) | 39 (30–55) | 44 (32–51) | 0.9 |
| CMRI_EF, % | 51 (44–58) | 53 (47–60) | 47 (42–53) | 44 (35–48) | <0.001 |
Abbreviations: ACEI/ARB: Angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker; CKD: Chronic kidney disease; CIED: Cardiac implantable electronic device; EF: Ejection fraction; EDV: End-diastolic volume; ESV: End systolic volume; EDA: End-diastolic area; ESA: End-systolic area; FAC: Fractional area change; GFR: Glomerular filtration rate; IAC: Intra-atrial conduit; LV: Left ventricle; MRI: Magnetic resonance imaging; MRA: Mineralocorticoid receptor antagonist; NTproBNP: N terminal pro hormone brain natriuretic peptide.
Footnote: Between-group comparisons were based on analysis of variance test and Wilcoxon rank sum test for continuous variables, and Fisher exact test and goodness of fit test for categorical variables.
3.2. Echo and CMRI-derived EF
The median Echo_EF and Echo_FAC for the overall cohort were 54 % (IQR 48–58) and 35 % (IQR 31–39 %), respectively. There was good intraobserver and interobserver agreement for Echo_EF for morphologic LV (ICC 0.91, 95 %CI 0.87-0.85 and 0.87, 95 %CI 0.82–0.90, respectively) and morphologic RV (ICC 0.89, 95 %CI 0.84–0.93 and 0.85, 95 %CI 0.80–0.91, respectively). Similarly, there was good intraobserver and interobserver agreement for Echo_FAC morphologic LV (ICC 0.88, 95 %CI 0.84–0.92 and 0.86, 95 %CI 0.82–0.90, respectively) and morphologic RV (ICC 0.86, 95 %CI 0.81–0.91 and 0.84, 85 %CI 0.78–0.90, respectively).
Of 414 patients, 148 (36 %) had CMRI data and the median CMRI_EF was 51 % (IQR 44–58 %). There was a modest correlation between CMRI_EF and Echo_EF (r = 0.63, p < 0.001), and between CMRI_EF and Echo_FAC (r = 0.59, p < 0.001) (Fig. 2).
Fig. 2.
Pearson correlation showing correlations between cardiac magnetic resonance imaging-derived ejection fraction (CMRI_EF) versus echocardiography-derived ejection fraction (Echo_EF) (A), and CMRI_EF versus echocardiography-derived fractional area change (Echo_FAC) (B).
3.3. Serial echocardiograms
The 414 patients had 1603 echocardiograms, of which the assessment of Echo_EF was feasible in 1464 (91 %) studies. Table 2 shows echocardiographic indices at baseline echocardiogram, 1 year, 2 years, and 3 years. The mean interval between each echocardiogram was 13 ± 2 months. The absolute Δ_Echo_EF was −2.1 % (95 %CI -3.8 to −1.3 %), and the relative Δ_Echo_EF was −3.9 % (95 %CI -6.3 to −2.5 %). Similarly, the absolute Δ_Echo_FAC was −1.3 % (95 %CI -2.4 to −0.2 %), and the relative Δ_Echo_FAC was −3.7 % (95 %CI -5.6 to −1.1 %).
Table 2.
Serial echocardiograms.
| Baseline (N = 414) | Year 1 (N = 414) | Year 2 (N = 349) | Year 3 (N = 287) | |
|---|---|---|---|---|
| Volumetric indices | ||||
| Ventricular EDV index, ml/m2 | 93 (71–124) | 91 (68–127) | 95 (71–129) | 92 (74–114) |
| Ventricular ESV index, ml/m2 | 44 (33–60) | 47(34–62) | 48 (35–64) | 51 (39–62) |
| Echo_EF, % | 54 (48–58) | 51 (45–57) | 53 (46–59) | 49 (42–56) |
| Area change indices | ||||
| Ventricular EDA index, cm2/m2 | 21 (18–25) | 23 (19–27) | 21 (19–25) | 22 (17–27) |
| Ventricular ESA index, cm2/m2 | 14 (11–17) | 16 (13–20) | 15 (11–19) | 16 (14–21) |
| Echo_FAC, % | 35 (31–39) | 33 (29–36) | 32 (27–36) | 32 (28–36) |
| Doppler-derived indices | ||||
| Stroke volume index, ml/m2 | 43 (33–54) | 46 (37–56) | 44 (35–52) | 41 (32–51) |
Abbreviations: EF: Ejection fraction; EDV: End-diastolic volume; ESV: End systolic volume; EDA: End-diastolic area; ESA: End-systolic area; FAC: Fractional area change.
Table 3 shows serial Echo_EF and Echo_FAC stratified by SV morphology, and in the subgroup of patients who did not undergo any interventions (surgical, transcatheter, or electrophysiologic interventions) between baseline and final echocardiograms. Compared to the patients with morphologic LV, those with morphologic RV had greater relative Δ_Echo_EF (−4.9 % [95 %CI -7.8 to −2.0 %] versus −2.6 % [95 %CI -4.8 to −0.2 %], p < 0.001), as well as greater relative Δ_Echo_FAC (−5.4 % [95 %CI -8.2 to −2.5 %] versus −2.2 % [95 %CI -4.5 - 0.1 %], p < 0.001).
Table 3.
Serial echocardiograms stratified by subgroups.
| Systemic LV morphology | Baseline (N = 287) | Year 1 (N = 287) | Year 2 (N = 241) | Year 3 (N = 194) |
|---|---|---|---|---|
| Echo_EF, % | 55 (50–59) | 53 (49–58) | 54 (47–60) | 53 (47–59) |
| Echo_FAC, % | 36 (32–40) | 34 (30–38) | 32 (28–36) | 34 (29–38) |
| Systemic RV morphology | Baseline (N=127) | Year 1 (N=127) | Year 2 (N=108) | Year 3 (N=93) |
| Echo_EF, % | 51 (43–55) | 48 (42–56) | 46 (41–51) | 46 (40–52) |
| Echo_FAC, % | 33 (29–37) | 30 (27–35) | 31 (27–36) | 29 (25–32) |
| Patients without CV interventions | Baseline (N=362) | Year 1 (N=362) | Year 2 (N=301) | Year 3 (N=246) |
| Echo_EF, % | 56 (51–62) | 53 (49–57) | 54 (49–59) | 52 (46–57) |
| Echo_FAC, % | 35 (32–39) | 36 (31–40) | 33 (28–39) | 32 (27–35) |
Abbreviations: EF: Ejection fraction; FAC: Fractional area change; LV: Left ventricle; RV right ventricle.
Footnote: Patients without cardiovascular interventions were defined as patients that did not undergo any surgical, transcatheter, or electrophysiologic interventions between baseline and follow-up echocardiogram.
Of the 414 patients, 363 (87 %) did not undergo any interventions between baseline and follow up echocardiograms. The relative Δ_Echo_EF in the patients without intervention was −3.5 % (95 % CI -6.1 to −2.1 %), and was similar to the relative Δ_Echo_EF for the entire cohort (−3.5 % [95 % CI -6.1 to −2.1 %] versus −3.9 % [95 % CI -6.3 to −2.5], p = 0.4).
3.4. Predictors of progressive SV systolic dysfunction
Using the median relative Δ_Echo_EF of 3.9 % as the cutoff, we dichotomized the cohort into patients with progressive SV systolic dysfunction (relative Δ_Echo_EF >3.9 %) versus patients without progressive SV systolic dysfunction (relative Δ_Echo_EF ≤ 3.9 %). Compared to patients without progressive SV systolic dysfunction, those with progressive SV systolic dysfunction were older, more likely to have morphologic RV and CIED, and had higher prevalence of atrial fibrillation and use of cardiac medications (Table 4). The patients with progressive SV systolic dysfunction also had larger SV volumes, lower Echo_EF at baseline echocardiogram, and were more likely to have SV systolic dysfunction at baseline echocardiogram (Table 4).
Table 4.
Comparison of baseline characteristics between patients with versus without progressive systemic ventricular systolic dysfunction.
| All (N = 414) | (+)Progressive dysfn (N = 207) |
(−)Progressive dysfn (N = 207) |
p | |
|---|---|---|---|---|
| Age, years | 27 ± 9 | 28 ± 9 | 25 ± 8 | 0.001 |
| Male sex | 228 (55 %) | 122 (59 %) | 106 (51 %) | 0.1 |
| CIED | 98 (24 %) | 61 (30 %) | 37 (18 %) | 0.006 |
| Morphologic LV | 287 (69 %) | 118 (57 %) | 169 (82 %) | <0.001 |
| Surgical history | ||||
| Type of initial Fontan connection | 0.8 | |||
| Atriopulmonary Fontan | 254 (61 %) | 126 (61 %) | 128 (62 %) | |
| Lateral tunnel/IAC Fontan | 92 (22 %) | 47 (23 %) | 45 (22 %) | |
| Extracardiac conduit Fontan | 68 (16 %) | 34 (16 %) | 34 (16 %) | |
| Age at Fontan operation, years | 5 (3–8) | 5 (3–9) | 4 (3–6) | 0.02 |
| Subsequent Fontan conversion | 115 (28 %) | 57 (28 %) | 58 (28 %) | 0.9 |
| Comorbidities | ||||
| Atrial flutter/tachycardia | 129 (31 %) | 69 (33 %) | 60 (29 %) | 0.3 |
| Atrial fibrillation | 83 (20 %) | 60 (29 %) | 23 (11 %) | <0.001 |
| Medications | ||||
| Diuretics | 167(40 %) | 97 (47 %) | 70 (34 %) | 0.007 |
| Beta blockers | 152 (37 %) | 81 (39 %) | 71 (34 %) | 0.3 |
| ACEI/ARB | 249 (60 %) | 124 (60 %) | 125 (60 %) | 0.9 |
| MRA | 99 (24 %) | 61 (30 %) | 38 (18 %) | 0.008 |
| Echocardiographic indices | ||||
| Ventricular EDV index, ml/m2 | 93 (71–124) | 99 (71–134) | 89 (70–114) | <0.001 |
| Ventricular ESV index, ml/m2 | 44 (33–60) | 51 (37–74) | 38 (29–50) | <0.001 |
| Echo_EF, % | 54 (48–58) | 49 (42–54) | 57 (54–60) | <0.001 |
| Baseline SV systolic function | ||||
| Normal function | 301 (73 %) | 124 (60 %) | 177 (86 %) | <0.001 |
| Mild systolic dysfunction | 70 (17 %) | 53 (27 %) | 17 (8 %) | |
| Mod/severe systolic dysfunction | 43 (10 %) | 30 (15 %) | 13 (6 %) | |
Abbreviations: ACEI/ARB: Angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker; CIED: Cardiac implantable electronic device; EF: Ejection fraction; EDV: End-diastolic volume; ESV: End systolic volume; IAC: Intra-atrial conduit; LV: Left ventricle; MRA: Mineralocorticoid receptor antagonist; SV: Systemic ventricle.
Footnote: Between-group comparisons were based on unpaired t-test and Wilcoxon rank sum test for continuous variables, and Fisher exact test and goodness of fit test for categorical variables. Patients were dichotomized based on the median annual relative Δ_Echo_EF. Progressive SV systolic dysfunction was defined as relative Δ_Echo_EF the median (>3.9 %).
The predictors of progressive SV systolic dysfunction were older age (odds ratio [OR] 1.27, 95 % CI 1.11–1.46 per 5 years, p = 0.005), morphologic RV dominance (OR 3.31, 95 % CI 1.96–5.64, p < 0.001), moderate or greater atrioventricular valve regurgitation (AVVR) (OR 2.38, 95 % CI 1.29–4.06, p < 0.001), CIED (OR 1.61, 95 % CI 1.07–23.52, p = 0.01), and atrial fibrillation (OR 2.05, 95 % CI 1.13–4.02, p = 0.008), (Table 5).
Table 5.
Predictors of progressive systolic dysfunction.
| Variables | Univariate analysis |
Multivariate analysis |
||
|---|---|---|---|---|
| OR (95 %CI) | p | OR (95 %CI) | p | |
| Age, per 5 years | 1.25 (1.12–1.43) | 0.001 | 1.27 (1.11–1.46) | 0.005 |
| Male sex | 1.37 (0.93–2.02) | 0.1 | ||
| Atriopulmonary Fontan | 0.96 (0.65–1.43) | 0.9 | ||
| Age at Fontan op, per year | 1.04 (1.01–1.07) | 0.02 | ||
| Systemic RV morphology | 3.35 (2.16–5.29) | <0.001 | 3.31 (1.96–5.64) | <0.001 |
| ≥Moderate AV valve regurgitation | 2.35 (1.46–3.87) | <0.001 | 2.38 (1.29–4.06) | <0.001 |
| CIED | 1.83 (1.26–3.12) | 0.008 | 1.61 (1.07–3.52) | 0.01 |
| Atrial fibrillation | 3.26 (1.95–5.63) | <0.001 | 2.05 (1.13–4.02) | 0.008 |
| Hypertension | 1.38 (0.59–2.94) | 0.5 | ||
| Cyanosis (saturation <90 %) | 1.26 (0.94, 1.62) | 0.12 | ||
| Coronary artery disease | 1.65 (0.73–3.18) | 0.6 | ||
| GDMT at baseline | 1.51 (0.91–2.59) | 0.1 | ||
Abbreviations: AV: Atrioventricular; CI: Confidence interval; GDMT: Guideline directed medical therapy OR: Odds ratio; RV: Right ventricle.
Footnote: Covariate with <0.1 in the univariable model were used to create the multivariable model. Final covariate selection in the multivariable model was based on stepwise backwards selection with p < 0.1 required for a covariate to remain in the model. See Methods section for definition of GDMT.
3.5. Prognostic implications of progressive SV systolic dysfunction
The 414 patients were followed for 5.2 (2.9–9.6) years yielding a total follow-up of 2157 patient-years. Of 414 patients, 77 (19 %) died and 23 (6 %) underwent heart transplant. The composite endpoint of death/transplant occurred in 94 (23 %) patients. The 15-year cumulative incidence of death/transplant was 36 % in the overall cohort, and was 27 %, 35 %, and 56 % in patients with normal, mildly decreased, and moderate/severely decreased SV systolic function at baseline, respectively (Fig. 3).
Fig. 3.
Kaplan-Meier curves comparing cumulative incidence of death/transplant between patients with normal systolic function (black) versus mild systolic dysfunction (blue) versus moderate/severe systolic dysfunction (red) at baseline echocardiogram.
The 15-year cumulative incidence of death/transplant was significantly higher in patients with progressive SV systolic dysfunction compared with the patients without progressive systolic dysfunction (47 % versus 24 %, p < 0.001) (Fig. 4A). These differences remained significant when stratified based on SV systolic function at baseline echocardiogram. The 15-year cumulative incidence of death/transplant was significantly higher in patients with compared to those without progressive SV systolic dysfunction in the subgroup of patients with normal SV systolic function at baseline (48 % versus 22 %, p < 0.001) (Fig. 4B), as well as in the subgroup of patients with SV systolic dysfunction at baseline (63 % versus 23 %, p = 0.02) (Fig. 4B). Progressive SV systolic dysfunction was associated with an approximately 2-fold increase in the risk of death/transplant (hazard ratio 1.92, 95 % 1.16–3.43, p = 0.009) after adjustment for baseline SV systolic function, demographic/anatomic indices, and comorbidities (Table 6).
Fig. 4.
Kaplan-Meier curves comparing cumulative incidence of death/transplant between patients with progressive systolic dysfunction (red) versus without progressive systolic dysfunction (black) in the entire cohort (A), subgroup of patients with normal systolic function at baseline (B), and subgroup of patients with systolic dysfunction at baseline (C).
Table 6.
Cox regression model assessing the relationship between progressive systolic dysfunction and death/transplant.
| Variables | Univariate analysis |
Multivariate analysis |
||
|---|---|---|---|---|
| HR (95 %CI) | p | HR (95 %CI) | p | |
| Echocardiographic indices | ||||
| Echo EF at baseline, per 5 % | 0.84 (0.77–0.93) | 0.003 | 0.91 (0.83–0.99) | 0.04 |
| Progressive systolic dysfunction | 2.64 (1.69–4.09) | <0.001 | 1.92 (1.16–3.43) | 0.009 |
| Demographic/anatomic indices | ||||
| Age, per 5 years | 1.34 (1.21–1.48) | <0.001 | ||
| Male sex | 0.93 (0.62–1.41) | 0.7 | ||
| Atriopulmonary Fontan | 1.65 (1.16–2.85) | 0.01 | ||
| Age at Fontan op, per year | 1.04 (1.02–1.07) | <0.001 | ||
| Systemic RV morphology | 1.86 (1.26–3.03) | 0.01 | ||
| CIED | 2.25 (1.44–3.51) | 0.002 | ||
| Comorbidities | ||||
| Atrial fibrillation | 2.59 (1.71–3.94) | <0.001 | ||
| Atrial flutter | 1.41 (0.92–2.12) | 0.3 | ||
| Cirrhosis | 3.42 (2.09–5.57) | <0.001 | 4.67 (2.43–8.93) | <0.001 |
| Protein losing enteropathy | 2.55 (1.53–4.20) | 0.003 | 2.88 (1.53–5.40) | 0.008 |
| CKD III-V | 4.65 (2.00–10.81) | 0.002 | ||
| Laboratory indices | ||||
| GFR, per 10 ml/min/1.73 m2 | 0.84 (0.78–0.90) | <0.001 | ||
| Log NTproBNP, pg/ml | 1.49 (1.24–1.81) | <0.001 | 1.26 (1.03–1.55) | 0.03 |
| MELD-XI | 1.18 (1.13–1.23) | <0.001 | 1.11 (1.04–1.17) | 0.002 |
Abbreviations: CI: Confidence interval; CKD: Chronic kidney disease; CIED: Cardiac implantable electronic device; EF: Ejection fraction; GFR: Glomerular filtration rate; HR: Hazard ratio; NTproBNP: N terminal pro hormone brain natriuretic peptide; RV: Right ventricle; MELD-XI: Model for end-stage liver disease excluding international normalized ratio.
Footnote: Covariate with <0.1 in the univariable model were used to create the multivariable model. Final covariate selection in the multivariable model was based on stepwise backwards selection with p < 0.1 required for a covariate to remain in the model.
3.6. Exploratory analysis: effect of GDMT on SV function
Of the 113 patients with baseline SV systolic dysfunction, 46 (41 %) had initiation or intensification of GDMT. Following GDMT intensification, the 46 patients were on the following medications: beta blocker (N = 33), angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker (N = 39), angiotensin receptor-neprilysin inhibitor (N = 6), mineralocorticoid receptor antagonist (N = 4), or sodium-glucose cotransporter-2 inhibitors (N = 2).
The average interval between baseline and follow-up echocardiogram was 15 ± 3 months. There was significant improvement in Echo_EF (absolute Δ_Echo_EF 4.2 % [1.8–6.9] and relative Δ_Echo_EF 10.5 % [5.3–16.4]). The improvement in Echo_EF was more robust in patients with morphologic LV (absolute Δ_Echo_EF 5.6 % [2.9–7.8] and relative Δ_Echo_EF 13.9 % [7.1–19.2]) but was not statistically significant in patients with morphologic RV (absolute Δ_Echo_EF 3.2 % [−0.5-6.4] and relative Δ_Echo_EF 10.5 % [−1.4-17.8]) (Table 7).
Table 7.
Effect of GDMT on systemic ventricular function.
| All | Baseline (N = 46) | FU (N = 46) | Absolute Δ (95 % CI) |
|---|---|---|---|
| Echo_EF, % | 38 (29–42) | 42 (36–48) | 4.2 (1.8–6.9) |
| Echo_FAC, % | 26 (22–29) | 29 (25–34) | 3.4 (1.7–6.2) |
| Systemic LV morphology | Baseline (N=29) | FU (N=29) | Absolute Δ (95 % CI) |
| Echo_EF, % | 41 (36–47) | 46 (41–52) | 5.6 (2.9–7.8) |
| Echo_FAC, % | 28 (25–33) | 32 (29–37) | 4.1 (2.3–6.8) |
| Systemic RV morphology | Baseline (N=17) | FU (N=17) | Absolute Δ (95 % CI) |
| Echo_EF, % | 36 (28–42) | 39 (31–46) | 3.2 (−0.5–6.4) |
| Echo_FAC, % | 24 (19–29) | 27 (26–33) | 2.9 (−0.3–5.8) |
Abbreviations: CI: Confidence interval; EF: Ejection fraction; FAC: Fractional area change; GDMT: Guideline directed medical therapy; FU: Follow-up; LV: Left ventricle; RV right ventricle.
4. Discussion
In this study, we assessed the clinical implications of progressive SV systolic dysfunction in adults with Fontan palliation. We observed a temporal decline in Echo_EF (absolute decline of Echo_EF of 2 %-point per year and a relative decline of 4 % per year) suggestive of progressive SV systolic dysfunction. Progressive SV systolic dysfunction was more common in patients with RV morphology, and in patients with SV systolic dysfunction at baseline. Other predictors of progressive SV systolic dysfunction were older age, AVVR, atrial fibrillation, and the presence of CIED. Progressive SV systolic dysfunction was associated with death/transplant, independent of baseline Echo_EF and comorbidities. The use of GDMT was associated with improvement in Echo_EF, especially in the patients with morphologic LV.
Despite significant improvements in the outcomes of adults with congenital heart disease (CHD), the long-term survival of adults with Fontan palliation is still significantly reduced relative to other patients [[14], [15], [16], [17], [18], [19]]. The transplant-free survival in adults with Fontan palliation is less than 40 years, and mortality is driven mostly by end-organ dysfunction from chronic systemic venous congestion [17,18,[20], [21], [22], [23]]. Additionally, SV systolic and/or diastolic dysfunction is relatively common in this population, and it is associated with adverse outcomes [1,3]. Our results are consistent with that of Moon et al. showing a higher 20-year cumulative incidence of SV systolic dysfunction in patients with dominant morphologic RV versus LV (18 % versus 6 %, respectively) [1]. Moon et al. also observed a relationship between ventricular morphology, AVVR, SV systolic dysfunction, whereby patients with morphologic RV had higher risk of AVVR and SV systolic dysfunction [1]. This is consistent with our results identifying RV morphology and AVVR as risk factors for progressive SV systolic dysfunction. The limitation of the Moon et al. study was that the assessment of SV systolic function was based on qualitative echocardiographic estimation of EF, rather than quantitative assessment of SV Echo_EF. In contrast, we relied on quantitative assessment of Echo_EF which has better intra- and interobserver reproducibility, making it ideal for longitudinal assessment of temporal changes in the SV systolic function compared to qualitative assessment [3].
In a different study, Ghelani et al. assessed SV remodeling and outcomes in 334 patients with Fontan palliation using CMRI [2]. They observed that patients with morphologic RV had larger SV volumes, lower mass-to-volume ratio, and higher SV wall strain compared to those with morphologic LV [2]. In contrast to our results and Moon et al. study, Ghelani et al. observed similar CMRI_EF and global longitudinal strain in patients with morphologic LV compared to RV. A possible explanation for the different results observed in the Ghelani et al. study may be related to the relatively younger age of their cohort (mean age 16 years) compared to our cohort (mean age 27 years). Since older age (i.e., time) is a risk factor for developing SV systolic dysfunction, perhaps the younger patients may not have had enough time to display significant between-group differences in SV systolic dysfunction (decrease in EF) in patients with morphologic RV versus LV. This postulate is consistent with the more advanced ventricular remodeling (ventricular dilation and increase in wall stress) observed in the patients with morphologic RV compared to those with morphologic LV, despite having similar EF [2].
The higher risk of progressive SV systolic dysfunction observed in patients with morphologic RV may be related to differences in fiber arrangement [2]. The normal RV myofiber architecture and orientation are characterized by more longitudinal and fewer circumferentially oriented fibers compared to the LV [2]. This fiber orientation is not optimal for pressure generation, leading to RV dilation and dysfunction when the RV is coupled to the systemic circulation [2]. RV dilation also leads to tricuspid annular dilation and tricuspid regurgitation, resulting in ventricular volume overload, and further exacerbating RV dilation and dysfunction [2,24].
4.1. Clinical implications
The results of the current study have important clinical implications. First, the temporal deterioration of SV systolic function underscores the need for longitudinal monitoring of SV systolic function, and provides empirical evidence to support the guideline recommendations for surveillance echocardiograms during annual cardiac evaluation [25,26]. Second, the observed improvement in EF following the use of GDMT patients with morphologic LV suggests clinical benefit in this population. This is consistent with improvement in EF and outcomes observed in adults with CHD and biventricular circulation presenting with systemic LV systolic dysfunction [13]. Although we did not observed improvement in EF in patients with morphologic RV, recent studies by Neijenhuis et al. and Maurer et al. suggest that GDMT, including Sodium-glucose cotransporter-2 inhibitor may be beneficial even in patients with morphologic RV end systemic ventricle [27,28].
Risk stratification in adults with Fontan palliation remain challenging. In a recent study, Montanaro et al. proposed the Fontan Adult Bromptom (FAB) score that was derived from clinical indices such as older age, New York heart Association functional, systolic blood pressure, hypoxia, atrial tachyarrhythmia, heart failure [29]. Patients with higher FAB score had higher risk of mortality in that study [29]. It is noteworthy that older age and atrial arrhythmias were also correlates of SV systolic dysfunction in our study, suggesting that these risk factors may be complimentary. Further studies is required to determine whether integration of SV systolic dysfunction (a modifiable risk factor) into the risk modeling would improve the prognostic performance of the FAB score.
4.2. Limitations
This is a retrospective cohort study conducted in a single tertiary referral center, and it is prone to selection and ascertainment bias. The clinical characteristics of the patients in this study may differ from that of other Fontan patients at other centers, this limiting the generalizability of the results. We were unable to verify compliance with GDMT given the constraints of a retrospective study. Furthermore, the definition of GDMT evolved over time to include angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitors in the later part of the study. These confounders could have influenced the results of the study. The strengths of the study include large sample with longitudinal follow-up, standardized image analysis in a central imaging core laboratory, and rigorous statistical methodology to control confounders. Additionally, we relied on 2-dimensional echocardiography for the assessment of SV systolic function, instead of cardiac magnetic resonance imaging volumetric analysis or 3-dimensional echocardiography, which have better reproducibility.
5. Conclusions
The current study demonstrated the risk, predictors, and prognostic implications of progressive SV systolic dysfunction in adults with Fontan palliation. It underscores the importance of longitudinal echocardiographic monitoring of SV systolic function, and the potential clinical benefits of GDMT in patients with morphologic LV. Further studies are required to determine whether interventions such as AVV surgery, catheter ablation for atrial fibrillation, and physiologic pacing strategies would prevent or reverse SV systolic dysfunction.
CRediT authorship contribution statement
Meena Bai: Writing – review & editing, Writing – original draft. Ahmed Bahnasy: Writing – review & editing, Writing – original draft. Sara Aboelmaaty: Writing – review & editing, Writing – original draft. Mohamed Ellabbad: Writing – review & editing, Writing – original draft. Ahmed Ali: Writing – review & editing, Writing – original draft. Alexander C. Egbe: Writing – review & editing, Writing – original draft.
Funding
Dr. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517, R01 HL160761, and R01 HL162830). The MACHD Registry is supported by the Al-Bahar Research grant.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcchd.2025.100620.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
figs1.
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