Cardiac MRI Derived Inferior Vena Cava Cross-Sectional Area Correlates with Measures of Fontan Associated Liver Disease

doi:10.21203/rs.3.rs-2102272/v1

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Research Article

Cardiac MRI Derived Inferior Vena Cava Cross-Sectional Area Correlates with Measures of Fontan Associated Liver Disease

https://doi.org/10.21203/rs.3.rs-2102272/v1

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Journal Publication

published 01 Dec, 2022

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Background

There is currently no clear consensus on screening techniques to evaluate the presence or severity of Fontan-associated liver disease (FALD). Cardiac MRI (CMR) is used routinely for post-Fontan surveillance, but CMR-derived measures that relate to the severity of FALD are not yet defined.

Methods

This was a cross-sectional single-center study of post-Fontan patients who underwent a CMR. CMR exams were re-analyzed by a single pediatric cardiologist. Surrogates of FALD included Gamma-Glutamyl Transferase (GGT), Fibrosis-4 laboratory score (FIB-4), and imaging findings. Findings consistent with cirrhosis on liver ultrasound included increased liver echogenicity and/or nodularity. Statistical analyses were performed to investigate potential relationships between CMR parameters and markers of FALD.

Results

Sixty-one patients were included. A larger inferior vena cava cross-sectional area (IVC-CSA) indexed to height was significantly associated with a higher FIB-4 score (Spearman’s ρ = 0.28, P = 0.04), a higher GGT level (Spearman’s ρ = 0.40, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04). None of the other CMR parameters were associated with markers of FALD. A larger indexed IVC-CSA was associated with higher systemic ventricle end-diastolic pressure (EDP) on cardiac catheterization (Spearman’s ρ = 0.39, p = 0.018) as well as older age (Spearman’s ρ = 0.46, p = < 0.001).

Conclusions

Indexed IVC-CSA was the only CMR parameter that was associated with markers of FALD. This measure has the potential to serve as an additional non-invasive tool to improve screening strategies for FALD.

Fontan Associated Liver Disease

Cardiac MRI

Inferior Vena Cava

Single Ventricle Physiology

Congenital Heart Disease

The Fontan procedure offers successful palliation for patients with single ventricle congenital heart disease. Prior to the development of the Fontan procedure in 1971, this cardiac diagnosis was largely considered a fatal condition[1]. As surgical techniques and post-operative care improved, excellent short-term outcomes were achieved. There are now an estimated 70,000 patients living with Fontan physiology worldwide[2]. As this cohort of survivors has grown, there has been a shift in focus to reducing long-term morbidity and improving quality of life[3]. One of the primary morbidities associated with this physiology is Fontan-associated liver disease (FALD), which typically manifests as hepatic fibrosis, nodular liver disease, and/or portal hypertension[4, 5]. This chronic liver injury results in an increased risk for cirrhosis and hepatocellular carcinoma[6, 7].

The progression of FALD is thought to be a result of several different factors, including genetic, biochemical, and hemodynamic features[8]. Passive pulmonary blood flow results in chronically elevated central venous pressures and diminished cardiac output[9]. These hemodynamic properties and associated hepatic congestion are thought to be the primary drivers of liver injury in Fontan patients. Additionally, these patients often have discrete liver insults in the pre- and peri-operative time periods. Nearly all patients with Fontan physiology develop some degree of liver injury, which progressively increases with age. A previous study demonstrated that cirrhosis is present in 43% of Fontan patients 30 years after completion of the Fontan procedure[10]. However, it is difficult to predict which patients are at risk for clinically significant advanced liver disease[11].

Detection of FALD is limited by lack of associated physical exam findings, non-specific hepatic laboratory results, and absence of clearly defined imaging features[12]. Liver biopsy is the most accepted method to establish the severity of FALD, but this is an invasive procedure with associated risks[13, 14]. To date, there is no clear consensus on appropriate screening techniques to evaluate the progression and severity of FALD[15–17].

In practice at our institution, liver ultrasounds are frequently used to evaluate for hepatic changes consistent with hepatocellular carcinoma. Screening laboratory tests typically include aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), total bilirubin, and platelet count. Using these laboratory results, several previously established liver disease scores from the adult hepatitis and chronic liver disease population have been applied to the Fontan cohort, including the Fibrosis-4 score (FIB-4)[18]. In a recent study, FIB-4 score was found to be associated with bridging fibrosis on liver biopsy in Fontan patients[15].

Cardiac MRI (CMR) is frequently used for post-Fontan surveillance. It offers a comprehensive and noninvasive method for detecting post-operative anatomic and physiologic changes[19]. Despite the frequent use of CMR in patients with Fontan physiology, CMR derived measures that relate to the severity of FALD are not yet defined. CMR allows accurate visualization and measurements of the Fontan pathway and the inferior vena cava[20]. Supra-hepatic inferior vena cava cross-sectional area (IVC-CSA) is a simple measure that has previously been associated with advanced liver disease in patients with congestive hepatopathy without congenital heart disease[21].The current study aims to determine which CMR parameters are associated with laboratory and imaging markers of FALD. We hypothesize that CMR derived measures, particularly the simple measurement of IVC-CSA, will reflect liver congestion and thus will be associated with markers of FALD.

Patients

A database search identified all post-Fontan individuals who had a CMR study at the Children’s Hospital of Pittsburgh or UPMC Presbyterian Hospital between June 2011 and November 2021. Patients were included if their anatomy was consistent with either an extracardiac or lateral tunnel Fontan. Patients were excluded if they had atrio-pulmonary Fontan anatomy or poor CMR image quality that prevented accurate measurements of the IVC and Fontan pathway. Four patients were excluded from analysis for these reasons resulting in a total of 61 patients. The data dictionary and definitions from the FORCE registry (Fontan Outcome Registry using CMR Examinations) were used[22]. Research Electronic Data Capture (REDCap) was used to store the data for this study. This study was approved by the University of Pittsburgh Institutional Review Board and was conducted in compliance with the Health Insurance Portability and Accountability Act. The requirement for informed consent was waived due to the retrospective nature of the study.

Clinical parameters and cardiac studies

Demographic and clinical data were obtained from the electronic medical records. The dominant ventricle was considered balanced/mixed if the smaller ventricle contributed to the systemic circulation and was \(\ge\) 25% of the combined ventricular end-diastolic volume (EDV), per the FORCE registry definition. Echocardiography and cardiac catheterization reports were obtained from the medical records, and relevant information was recorded. If there were multiple echocardiography or catheterization studies, the study closest to the time of CMR was chosen. If a CMR preceded an interventional catheterization, the pre-intervention hemodynamic data was recorded; if a CMR followed an interventional catheterization, post-intervention hemodynamics were recorded in order to best match the anatomy at the time of CMR.

CMR

CMR studies were performed using 1.5 Tesla scanners (GE Medical Systems, Milwaukee, Wisconsin or Siemens AG, Munich, Germany). Briefly, ventricular assessment was performed by an electrocardiographically-gated, balanced steady-state free precession (bSSFP) cine CMR in vertical and horizontal ventricular long-axis planes and a stack of slices in a ventricular short-axis plane encompassing the atrioventricular junction through the cardiac apex. Retrospectively cardiac gated, through-plane phase-contrast flow measurements were obtained in the branch pulmonary arteries and vena cavae. An ECG-gated respiratory-navigated bSSFP magnetic resonance CMR angiography acquisition was used to measure the Fontan pathway.

If a patient had multiple CMR studies, the most recent study was used for analysis. Ventricular volumes and function were measured by manually tracing the endocardial and epicardial borders on each short-axis bSSFP cine slice at end-diastole (maximal volume) and end-systole (minimal volume). Analysis was performed using commercially available software (Cvi⁴², Circle Cardiovascular Imaging Inc., Calgary, Canada). Ascending aorta flow was measured by manually tracing the ascending aorta, as previously described[23]. All CMR exams were reanalyzed by a single pediatric cardiologist with clinical experience interpreting CMR studies in the single ventricle population. Ventricular contours were redrawn, and vascular measurements were performed using double oblique techniques. IVC-CSA was calculated by measuring two orthogonal dimensions at the largest segment and indexing this to height. Fontan and pulmonary artery cross-sectional area were also calculated using this method. CSA was calculated by incorporating the orthogonal diameters into the equation to estimate the area of an ellipse (CSA= 𝜋r₁r₂). The previously defined Nakata index was calculated by adding the right pulmonary artery (RPA) CSA with the left pulmonary artery (LPA) CSA and dividing this number by the body surface area (BSA)[24].

Hepatic data

The most recent laboratory data at the time of data collection was obtained from the medical record. An abnormal result was defined as an AST level > 55 IU/L, ALT level > 31 IU/L, GGT level > 45 IU/L, and platelet count > 369 x10⁹/L. The FIB-4 index for liver fibrosis score was calculated according to the previously established equation: (Age in years x AST) / (Platelet count x \(\surd\)ALT)[25]. A normal FIB-4 score was defined as \(\le\)1.45, which has been shown to have a negative predictive value of 90% for the exclusion of extended fibrosis[26]. The most recent liver ultrasound report was also obtained from the medical record. Liver cirrhosis was defined as findings consistent with cirrhosis on ultrasound, as documented by an attending radiologist. These findings included nodular liver surface and hypoechoic nodules in the liver parenchyma[27].

Statistical analysis

Continuous data were summarized as median (25th percentile, 75th percentile), and categorical data were summarized as N (%). The Kruskal Wallis and Mann-Whitney U tests were used for comparison between independent categorical variables and dependent continuous variables. The Chi-Square test and Fisher’s Exact test were used for comparison between categorical variables. Univariable associations between continuous variables were determined using the Spearman correlation. Odds ratios with 95% confidence intervals were also calculated. Statistical analyses were performed using commercially available software (JMP, version 14 [SAS Institute] and IBM SPSS Statistics for Windows, Version 24.0. Armok, NY: IBM Corp.). Two-tailed P < 0.05 was considered statistically significant.

Baseline characteristics

Sixty-one patients were included in the analysis. The median age at the time of Fontan operation was 2.7 years, and the median age at the time of CMR was 17.0 years. Forty-two patients (69%) had an extracardiac Fontan and 19 patients (31%) had a lateral tunnel Fontan. Although 48 patients (79%) had a fenestration at the time of Fontan surgery, only eleven patients (18%) had a fenestration at the time of CMR due to spontaneous or catheterization closure (Table 1).

Table 1. Characteristics of the study population (N=61)^*

Age at Fontan (years)	2.7 (1.8, 4.6)
Age at CMR (years)	17.0 (13.5, 22.5)
Sex
Male	38 (62%)
Female	23 (38%)
Known Genetic Disorder
Yes	10 (16%)
No	51 (84%)
Diagnosis^†
HLHS	17 (28%)
DILV	15 (25%)
Tricuspid Atresia	12 (20%)
CC-TGA	8 (13%)
DORV	6 (10%)
Unbalanced AVSD	3 (5%)
PA/IVS	3 (5%)
Ebstein's disease	3 (5%)
TOF	2 (3%)
Heterotaxy	1 (2%)
Other	2 (3%)
Dominant ventricle^‡
Right	19 (31%)
Left	32 (52%)
Balanced/mixed	9 (15%)
Indeterminant/unknown	1 (2%)
Type of Fontan at CMR
Extracardiac	42 (69%)
Lateral Tunnel	19 (31%)
Fenestration at time of Fontan
Yes	48 (79%)
No	8 (13%)
Unknown	5 (8%)
Fenestration at time of CMR
Yes	11 (18%)
No	46 (75%)
Unknown	4 (7%)
^*Data is Represented as Median (25th%ile, 75th%ile) or n (%)
^†If patient had more than one diagnosis, they were placed into each applicable category and counted more than once
^‡The dominant ventricle was considered Balanced/mixed if the smaller ventricle contributed to the systemic circulation and was ≥ 25% of combined ventricular EDV and EDV z-score≥-4 (if available)
CMR = cardiac magnetic resonance imaging; HLHS = hypoplastic left heart syndrome; DILV = double inlet left ventricle; CC-TGA = congenitally corrected transposition of the great arteries; DORV = double outlet right ventricle; AVSD = atrioventricular septal defect; PA/IVS = pulmonary atresia with intact ventricular septum; TOF = tetralogy of Fallot

Hepatic Testing

Fifty-eight patients (95%) had documented AST and ALT levels, and 36 patients (59%) had a GGT level obtained a median of 2.8 years from CMR. Of those who had a GGT level documented, 29 patients (81%) had an abnormal result. Five patients (9%) had an abnormal FIB-4 score. A total of 44 patients (72%) had a previous liver ultrasound. Of those who had an ultrasound, 17 (39%) had findings consistent with cirrhosis (Table 2). The median time between CMR and liver ultrasound was 1.9 years; most of the ultrasounds were performed after CMR.

Table 2. Baseline CMR, liver, cardiac catheterization, and echo data*

Liver Data
FIB-4 Score^†	0.4 (0.3, 0.8)	55
Liver lab Data
AST (IU/L)	24.0 (19.0, 29.8)	58
ALT (IU/L)	29.5 (24.0, 41.3)	58
GGT (IU/L)	67.0 (45.3, 109.0)	36
Tbili (mg/dL)	0.8 (0.5, 1.2)	56
Platelet Count (x10⁹/L)	184.0 (144.8, 229.3)	56
Cirrhosis on ultrasound
Yes	17 (28%)
No	27 (44%)
Unknown	17 (28%)
CMR Data
Dominant ventricle end diastolic volume/BSA (mL/m²)	83.5 (69.1, 106.5)	59
Dominant ventricle end systolic volume/BSA (mL/m²)	42.3 (32.7, 53.3)	59
Dominant ventricle ejection fraction (%)	52.3 (44.3, 60.0)	59
Ascending aorta flow volume/BSA (L/min/m²)	2.9 (2.3, 3.7)	54
Fontan CSA (mm²)	852.5 (650.0, 1045.6)	60
Indexed by height (mm²/cm)	5.5 (4.2, 6.8)	60
IVC CSA (mm²)	1949.9 (1441.3, 2637.6)	61
Indexed by height (mm²/cm)	12.0 (9.9, 15.9)	61
Nakata Index (mm²/m²) ^‡	634.0 (490.4, 795.5)	60
Cardiac Catheterization Data
Mean Fontan Pressure (mmHg)	13.0 (11.0, 15.0)	46
Dominant Ventricle End Diastolic Pressure (mmHg)	8.5 (6.0, 11.0)	37
PVR (WU/m²)	1.4 (1.0, 1.9)	33
Cardiac Index (L/min/m²)	3.0 (2.2, 3.7)	44
Echocardiography Data (N = 61)
Normal or low normal ventricular function	47 (77%)
Mildly depressed ventricular function	6 (10%)
Moderate/severely depressed ventricular function	8 (13%)
Mild or less atrioventricular valve regurgitation	55 (90%)
Moderate to severe atrioventricular valve regurgitation	6 (10%)
Mild or less semi-lunar valve regurgitation	54 (89%)
Moderate to severe semi-lunar valve regurgitation	7 (11%)
^*Data is Represented as Median (25th%ile, 75th%ile) or N (%)
^†FIB-4 Score = Fibrosis-4 index for liver fibrosis = (Age (years) x AST (IU/L)) / (Thrombocytes (x10⁹/L) x √ALT (IU/L))
^‡Nakata Index = (cross sectional areas of the right pulmonary artery (mm²) + cross sectional area of the left pulmonary artery (mm²)) / body surface area (m²)
AST = aspartate transferase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase; Tbili = total bilirubin; BSA = body surface area; CSA = cross-sectional area; IVC = inferior vena cava; PVR = pulmonary vascular resistance

Cardiac testing

CMR data is summarized in table 2. The median ejection fraction was 52.3%, and the median cardiac index by ascending aorta flow was 2.9 L/min/m². Cardiac catheterization data was available for 46 patients. The median mean Fontan pressure was 13.0 mmHg, and the median dominant end diastolic pressure (EDP) was 8.5 mmHg. The median time between cardiac catheterization and CMR was 1 month. By echocardiography, 8 patients (13%) had moderate or severe ventricular dysfunction (Table 2). The median time between echocardiography and CMR was also 1 month.

Association between cardiac measures and markers of FALD

Dominant ventricular morphology, Fontan type, and the presence of a fenestration were not associated with GGT level or findings consistent with cirrhosis on liver ultrasound (Table 3). A larger indexed IVC-CSA was found to be significantly associated with a higher FIB-4 score (Spearman’s ρ = 0.28, p = 0.04), a higher GGT level (Spearman’s ρ = 0.4, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04) (Figs. 2–4). Indexed IVC-CSA was the only CMR parameter to correlate with markers of FALD.

Table 3

Association of patient characteristics and echocardiography data with markers of liver disease
	FIB-4 Score			GGT (IU/L)			Cirrhosis on Liver Ultrasound
	Median (25th%ile, 75th%ile)	p-value	N	Median (25th%ile, 75th%ile)	p-value	N	Cirrhosis Present, N (%)	No Cirrhosis Present, N (%)	p-value
Characteristics of study population
Dominant Ventricle Morphology^†		0.22			0.76				0.88
Left	0.42 (0.32, 0.71)		30	87.0 (36.0, 118.8)		18	7 (35%)	13 (65%)
Right	0.38 (0.27, 0.97)		17	68.5 (34.3, 97.8)		10	6 (40%)	9 (60%)
Balanced/Mixed	0.70 (0.55, 1.46)		8	55.0 (48.5, 98.3)		8	4 (44.4%)	5 (55.6%)
Type of Fontan at CMR		N/A^‡			0.81				0.29
Extracardiac	0.39 (0.27, 0.67)		36	60.0 (36.5, 115.0)		25	10 (33.3%)	20 (66.7%)
Lateral Tunnel	0.75 (0.42, 0.99)		19	69.0 (50.0, 93.0)		11	7 (50%)	7 (50%)
Fontan fenestration at time of CMR		0.01^*			0.85				0.22
Yes	0.31 (0.25, 0.42)		11	71.0 (50.0, 121.3)		4	1 (12.5%)	7 (87.5%)
No	0.55 (0.38, 0.87)		40	68.5 (36.3, 109.0)		28	13 (40.6%)	19 (59.4%)
Echocardiography Data
Atrioventricular valve insufficiency		0.93			0.86				1.00
Mild or less atrioventricular valve regurgitation	0.42 (0.32, 0.82)		49	69.0 (37.0, 109.0)		31	15 (39.5%)	23 (60.5%)
Moderate to severe atrioventricular valve regurgitation	0.53 (0.33, 0.74)		6	66.0 (42.0, 117.5)		5	2 (33%)	4 (67%)
Semi-lunar valve insufficiency		0.01^*			0.53				1.00
Mild or less semi-lunar valve regurgitation	0.41 (0.30, 0.74)		50	68.0 (48.0, 118.0)		31	15 (39.5%)	23 (60.5%)
Moderate to severe semi-lunar valve regurgitation	1.02 (0.66, 1.78)		5	56.0 (36.0, 89.0)		5	2 (33%)	4 (67%)
Qualitative systolic function		0.60			0.82				1.00
Normal or low normal ventricular function	0.42 (0.29, 0.77)		41	64.0 (36.3, 115.8)		28	13 (39.4%)	20 (60.6%)
Mildly depressed ventricular function	0.65 (0.27, 0.87)		6	56.0 (48.0, 86.0)		3	2 (33%)	4 (67%)
Moderate/Severely depressed ventricular function	0.56 (0.39, 0.82)		8	83.0 (50.5, 138.0)		5	2 (40%)	3 (60%)
^*p-value < 0.05 is considered statistically significant
^†The patient with unknown dominant ventricle morphology was excluded from this portion of analysis ^‡Not applicable. Patients with lateral tunnel Fontan anatomy are older at our institution; given that age is included in the FIB-4 equation, a comparison cannot be performed between the two types of Fontan anatomy as they relate to FIB-4 score.

Mean Fontan pressure on cardiac catheterization was significantly associated with a higher FIB-4 score (Spearman’s ρ = 0.32, p = 0.04) and findings consistent with cirrhosis on liver ultrasound (OR 1.63, CI: (1.12, 2.38), p = 0.01). Dominant ventricle EDP on cardiac catheterization was also significantly associated with a higher FIB-4 score (Spearman’s ρ = 0.35, p = 0.03) and findings consistent with cirrhosis on liver ultrasound (OR 2.71 per 1 mmHg increase, CI: (1.27, 5.78), p = 0.01). Additionally, older age was associated with evidence of cirrhosis on liver ultrasound (Table 4). On echo, moderate to severe semi-lunar valve regurgitation was associated with a higher FIB-4 score. Aside from this result, there were no other associations between the echo data and markers of FALD (Table 3).

Table 4

Association of CMR parameters, cardiac catheterization data, and age with markers of liver disease
	FIB-4 Score			GGT (IU/L)			Cirrhosis on Liver Ultrasound
	Spearman ρ Coefficient	p-value	N	Spearman ρ Coefficient	p-value	N	Odds Ratio	95% CI	p-value	N
Cardiac MRI Parameters
Dominant ventricle end diastolic volume/BSA (mL/m²)	0.16	0.26	53	0.08	0.67	34	1.00	(0.98, 1.02)	0.64	42
Dominant ventricle end systolic volume/BSA (mL/m²)	0.16	0.25	53	0.18	0.3	34	1.00	(0.98, 1.0)	0.73	42
Dominant ventricle ejection fraction (%)	0.01	0.95	53	-0.24	0.17	34	0.99	(0.96, 1.01)	0.50	42
Ascending aorta flow volume/BSA (mL/beat/m²)	-0.16	0.27	48	0.07	0.72	30	0.72	(0.36, 1.46)	0.36	37
Fontan CSA indexed to height (mm²/cm)	0.09	0.51	54	-0.04	0.81	35	1.25	(0.96, 1.63)	0.09	44
IVC CSA indexed to height (mm²/cm)	0.28	0.04^*	55	0.4	0.02^*	36	1.17	(1.01, 1.35)	0.04^*	44
Nakata Index (mm²/m²)	-0.12	0.39	54	0.12	0.51	35	1.00	(0.999, 1.00)	0.16	43
Cardiac Catheterization Data
Mean Fontan Pressure (mmHg)	0.32	0.04^*	43	-0.04	0.83	25	1.63	(1.12, 2.38)	0.01^*	34
Dominant Ventricle End Diastolic Pressure (mmHg)	0.35	0.03^*	36	0.01	0.98	19	2.71	(1.27, 5.78)	0.01^*	30
PVR (WU/m²)	-0.12	0.5	32	-0.12	0.64	18	1.32	(0.30, 5.80)	0.71	26
Cardiac Index (L/min/m²)	-0.17	0.28	41	0.14	0.52	24	0.62	(0.30, 1.28)	0.19	32
Characteristics of study population
Age at time of CMR	0.7	N/A^†	53	0.3	0.08	36	1.14	(1.0, 1.25)	0.007^*	44
^*p-value < 0.05 is considered statistically significant
^†Not applicable. Age is part of the equation for the FIB-4 Score, so analysis was not performed

Determinants of indexed IVC-CSA

A higher systemic ventricle EDP on cardiac catheterization was significantly associated with a larger indexed IVC-CSA on CMR (Spearman’s ρ = 0.39, p = 0.018). Indexed IVC-CSA was not significantly associated with any of the other cardiac catheterization or CMR parameters. It was also not associated with Fontan type or the presence of a Fontan fenestration at the time of CMR. There was a positive association between age at CMR and indexed IVC-CSA (Table 5).

Table 5

Determinants of Indexed IVC-CSA: CMR parameters, cardiac catheterization data, and characteristics of the study population
	Spearman ρ Coefficient or Median (25th%ile, 75th%ile)	p-value	N
Cardiac MRI Parameters
Dominant ventricle end diastolic volume/BSA (mL/m²)	0.12	0.37	59
Dominant ventricle end systolic volume/BSA (mL/m²)	0.17	0.20	59
Dominant ventricle ejection fraction (%)	-0.05	0.74	59
Ascending aorta flow volume/BSA (mL/beat/m²)	0.03	0.85	54
Extracardiac Fontan CSA indexed to height (mm²/cm)	0.29	0.06	42
Lateral Tunnel Fontan CSA indexed to height (mm²/cm)	0.29	0.24	18
Nakata Index (mm²/m²)	0.23	0.07	60
Cardiac Catheterization Data
Mean Fontan Pressure (mmHg)	0.15	0.34	45
Dominant Ventricle End Diastolic Pressure (mmHg)	0.39	0.02^*	36
PVR (WU/m²)	-0.07	0.70	32
Cardiac Index (L/min/m²)	-0.03	0.87	43
Characteristics of study population
Type of Fontan at CMR		0.13
Extracardiac	11.5 (8.4, 16.1)		42
Lateral Tunnel	12.9 (10.8, 16.8)		19
Fontan fenestration at time of CMR		0.18
Yes	9.0 (7.0, 14.4)		11
No	12.2 (10.1, 16.1)		46
Age at time of CMR	0.46	0.0003^*	59
^*p-value < 0.05 is considered statistically significant

Our study evaluated the association of CMR parameters with markers of FALD. The primary finding was that a larger indexed IVC-CSA was the only CMR parameter associated with markers of FALD. We also evaluated the association of other cardiac and clinical measures with FALD. This revealed that Fontan pressure and EDP on cardiac catheterization were also associated with markers of FALD. As expected, older age was associated with evidence of cirrhosis on liver ultrasound. With regards to determinants of indexed IVC-CSA size, we found that a higher EDP and older age were associated with a larger indexed IVC-CSA.

This study demonstrates that Fontan hemodynamics and anatomy, particularly the non-invasive measure of indexed IVC-CSA on CMR, are associated with markers of FALD. This may potentiate opportunities to better predict and mitigate this complication. As already demonstrated in previous studies, a significant percentage of Fontan patients have evidence of advanced liver disease[14, 28]. Nearly 40% of liver ultrasounds revealed findings consistent with liver cirrhosis in our study. This highlights the significant prevalence of FALD and the imperative need to better address this problem.

FALD remains a challenging complication of Fontan physiology, and further understanding of the predictors of FALD are needed to improve the management of these patients. Furthermore, as this Fontan population ages, there is an increased need to consider heart transplant versus combined heart and liver transplant; additional predictors of FALD are necessary to help make this difficult decision[12]. Currently, liver biopsy is the gold standard for assessing the severity of FALD; this is an invasive procedure that carries potential complications[13, 29]. Our study offers insight into alternative, non-invasive methods to aid in the prediction of severe FALD. We highlight the importance of CMR as an imaging tool in patients with Fontan physiology, which is now routinely used for surveillance purposes in this population. Indexed IVC-CSA is easily measured on CMR and can potentially be implemented in clinical practice to aid in the evaluation of FALD. A dilated IVC on CMR may alert the primary cardiologist to pursue further screening for FALD.

Based on our findings, we hypothesize that a higher EDP, a marker of diastolic dysfunction, leads to worsening systemic and hepatic venous congestion and thus results in an increased IVC-CSA. This is supported by our findings that a higher EDP is associated with both increased indexed IVC-CSA on CMR and markers of FALD. However, more research must be done to determine causality. Systolic dysfunction and ejection fraction were not associated with markers of FALD in our study. Our group and others have previously described this association between diastolic dysfunction and markers of FALD[30]. It is thought that diastolic dysfunction leads to higher Fontan pressures and worsening FALD. An alternative hypothesis is that worsening FALD leads to a decline in diastolic function as seen in cirrhotic cardiomyopathy[31].

Similar to previous studies, older age was associated with evidence of cirrhosis on liver ultrasound in our study. Goldberg et al[32] found that hepatic fibrosis on liver biopsy is universal after the Fontan procedure and that older age is the only factor associated with increased severity of hepatic fibrosis. Age was also associated with indexed IVC-CSA in our study. This is not surprising as it is likely that older patients have declining hemodynamics, which is often associated with IVC dilation and liver cirrhosis.

Limitations

Although our study demonstrates important findings related to the association of indexed IVC-CSA with markers of FALD, there are several limitations that must be discussed. First, the cohort size is relatively small and derived from a single center. Larger, multi-center studies will be needed to validate our results. Higher powered studies could also facilitate multivariable analysis and predictive modeling to improve the clinical applicability of these results. We used the data definitions from the FORCE national registry to mitigate some of the limitations of being a single center study by using nationally accepted definitions. Second, although liver disease is very common in Fontan patients, there is no universal definition of FALD. This made it challenging to define our outcomes of liver disease. Evidence of cirrhosis on liver ultrasound is a somewhat non-specific finding and is subject to interpretation by the reading radiologist. We used combined imaging and laboratory findings to mitigate this limitation. Future research evaluating the association of CMR parameters with liver biopsy results would be helpful given that this is the gold-standard method for evaluating the severity of FALD. Furthermore, the time between CMR and liver evaluation is relatively long. However, previous studies showed slow progress of liver fibrosis[10, 33]; this is therefore unlikely to change the study conclusions. We must also consider the potential for surveillance bias; patients who are referred for advanced cardiac imaging may represent a higher risk population. Finally, as this is a CMR study, patients with pacemakers or defibrillators were excluded since CMR is currently not performed in these patients with epicardial leads.

Our study demonstrates that a larger indexed IVC-CSA is the only parameter on CMR associated with markers of FALD. We hypothesize that increased diastolic and Fontan pressures lead to worsening systemic and hepatic congestion and thus results in FALD and an increased IVC-CSA. This is supported by our findings that a higher EDP is associated with both increased indexed IVC-CSA on CMR and markers of FALD. Indexed IVC-CSA on CMR has the potential to serve as a non-invasive tool for predicting the severity FALD. This may aid in providing an individualized approach to screening for FALD as it helps identify patients at high risk for this complication.

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No competing interests reported.

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Cardiac MRI Derived Inferior Vena Cava Cross-Sectional Area Correlates with Measures of Fontan Associated Liver Disease

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Patients

Clinical parameters and cardiac studies

CMR

Hepatic data

Statistical analysis

Results

Baseline characteristics

Hepatic Testing

Cardiac testing

Association between cardiac measures and markers of FALD

Determinants of indexed IVC-CSA

Discussion

Limitations

Conclusions

References

Additional Declarations

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Journal Publication

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