Incremental prognostic value of hepatic tissue alterations derived from cardiac magnetic resonance imaging for arrhythmogenic right ventricular cardiomyopathy: a case-control study

Abstract

Background

Hepatic injury occurs in patients with cardiovascular disease and is associated with adverse clinical outcomes. The prognostic value of hepatic tissue alterations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains unclear. We aimed to evaluate the incremental prognostic value of hepatic native T1 in predicting sustained ventricular arrhythmia (VA) in patients with ARVC.

Methods

This retrospective study included patients with definite ARVC who underwent cardiac magnetic resonance (CMR) examinations between August 2014 and October 2024. Hepatic native T1 values were derived from standard cardiac T1 maps. The clinical outcome was the first occurrence of sustained VA. Cox regression analysis was used to determine the association of variables with sustained VA. Incremental prognostic value was evaluated according to the concordance statistic (C-statistic), likelihood ratio test, and the continuous net reclassification index.

Results

A total of 94 patients with definite ARVC (mean age 37.3±14.2 years; 67% male) were included. At a median follow-up of 39 months, sustained VA occurred in 34 (36%) patients. In multivariable Cox analysis, hepatic native T1 was an independent predictor of sustained VA [hazard ratio (HR) =1.02, 95% confidence interval (CI): 1.00–1.03; P=0.025]. A model combining hepatic native T1 with the ARVC risk score and CMR-derived right ventricular global longitudinal strain (RV GLS) showed improved discrimination and calibration for sustained VA (C-statistic =0.760; likelihood ratio =20.14) compared with models composed of ARVC risk score alone (C-statistic =0.680; likelihood ratio =9.20; P<0.001) or the ARVC risk score and RV GLS (C-statistic =0.735; likelihood ratio =15.30; P=0.028).

Conclusions

Hepatic native T1 derived from cardiac T1 maps was an independent predictor of sustained VA in patients with ARVC, providing incremental prognostic value when incorporated into a model with ARVC risk score and RV GLS.

Introduction

Arrhythmogenic cardiomyopathy (ACM), a genetically determined cardiomyopathy, is pathologically characterized by myocyte necrosis and fibrofatty replacement that lead to myocardial remodeling, ventricular dysfunction, and eventually heart failure (HF) (1,2). Right-dominant ACM, also known as “arrhythmogenic right ventricular cardiomyopathy” (ARVC), is characterized by predominant involvement of the right ventricle and no or minimal left ventricular (LV) involvement (3). The occurrence of life-threatening ventricular arrhythmia (VA) and sudden cardiac death (SCD) represents a critical clinical event and may be the first clinical manifestation of ARVC (4). Therefore, accurate prognostic stratification is critical to effective patient management.

Liver injury frequently occurs in patients with cardiovascular disease and is associated with adverse clinical outcomes, underscoring the complex interplay between the cardiac and hepatic systems (5). Prolonged right ventricular (RV) dysfunction can impair liver perfusion and cause venous congestion, triggering chronic hepatic remodeling and ultimately hepatic fibrosis (6,7). Hepatic tissue alterations may serve as a biomarker of cardiac dysfunction (8,9). In one study, a novel 2019 ARVC risk model exhibited moderate performance for sustained VA risk stratification in patients with ARVC [concordance statistic (C-statistic) =0.77] (10), and it was validated in external independent cohorts (11). However, the model incorporates only a single conventional cardiac functional parameter, RV ejection fraction (RVEF), and thus fails to comprehensively characterize myocardial tissue characteristics and microstructure (myocardial strain or fibrosis). Furthermore, due to cardiohepatic interactions, characterization of hepatic tissue characteristics may provide incremental value for predicting sustained VA in patients with ARVC.

Cardiac magnetic resonance (CMR) imaging, which enables quantitative assessment of cardiac function and tissue characteristics, has become the preferred imaging technique for examining ARVC (1). In particular, modified Look-Locker inversion recovery (MOLLI) T1-mapping indicators, including native T1 value and extracellular volume (ECV) fraction, are extensively used to characterize diffuse myocardial fibrosis and predict outcomes in patients with ARVC (12). Due to the anatomical proximity between the liver and heart, hepatic tissue is frequently captured in standard CMR T1 mapping images (13). Previous studies have demonstrated that liver T1 values obtained from abdominal magnetic resonance imaging (MRI) strongly correlate with the degree of hepatic fibrosis and congestion in patients with liver disease (14). Furthermore, hepatic native T1 values derived from CMR have been reported to be reliable indicators for predicting adverse cardiovascular events in patients with right-sided HF (15,16). However, the prognostic value of CMR-derived hepatic T1 values in patients with ARVC remains unclear.

Therefore, the aim of this study was to (I) evaluate the relationship between hepatic T1 values derived from CMR and cardiac characteristics, (II) assess the ability of hepatic T1 values to predict sustained VA, and (III) investigate its incremental predictive value relative to known predictors, such as the 2019 ARVC risk model and RV global longitudinal strain (GLS). We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1125/rc).

Methods

Study population

This retrospective study was approved by the Institutional Review Board of Guangdong Provincial People’s Hospital (Approval No. GDREC2019338H [R2]), and the requirement for informed consent was waived due to the retrospective nature of the analysis. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Based on the recent Padua Prediction Score (3), ACM is classified into three phenotypic variants: right-dominant ACM (ARVC), left-dominant ACM [arrhythmogenic LV cardiomyopathy (ALVC)], and biventricular ACM (BIV). In this study, ARVC was diagnosed based on predominant RV involvement with preserved or mildly reduced LV systolic function (3). Furthermore, only patients with definitive ARVC were enrolled, while those with ALVC or BIV were excluded.

A total of 262 patients were diagnosed with ACM at Guangdong Provincial People’s Hospital between August 2014 and October 2024. The exclusion criteria were as follows: (I) patients who did not undergo CMR; (II) absence of the MOLLI sequence in CMR examinations; (III) incomplete clinical data; (IV) history of sustained VA prior to CMR examination; (V) ALVC or BIV; (VI) history of hepatic diseases (e.g., symptomatic or asymptomatic hepatitis B infection and fatty liver disease); (VII) CMR imaging quality insufficient for analysis; and (VIII) loss to follow-up. Ultimately, 94 patients with definite ARVC were included in the study (Figure 1). Demographic data, medical history, CMR characteristics, and prognostic data were collected for each study participant. Additionally, to characterize alterations in hepatic tissue features in patients with ARVC, 30 age- and sex-matched healthy volunteers (with no significant age or sex differences between the two groups) were included as controls. These healthy controls had no cardiovascular risk factors, clinical symptoms, cardiovascular disease, or hepatic diseases.

Figure 1.

Flowchart of patient inclusion and exclusion. This study exclusively enrolled patients with definitive ARVC and excluded those patients with ALVC or BIV. ACM, arrhythmogenic cardiomyopathy; ALVC, arrhythmogenic left ventricular cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; BIV, biventricular arrhythmogenic cardiomyopathy; CMR, cardiac magnetic resonance; MOLLI, modified Look-Locker inversion recovery; VA, ventricular arrhythmia.

CMR image acquisition

All CMR images were acquired with a 3.0-T scanner (Ingenia, Philips Healthcare, Best, the Netherlands) with 32 coil elements in accordance with the recommended CMR protocol for ACM (17,18). The imaging protocol included (I) cine imaging; (II) T1 mapping; and (III) late gadolinium enhancement (LGE) imaging. The details of the protocols and sequence parameters are provided in the Appendix 1.

Cardiac and hepatic image analysis

All CMR analyses, including cine images, T1 mapping, strain images, and LGE images, were performed through use of a dedicated post-processing workstation (cvi42 version 5.13, Circle Cardiovascular Imaging, Calgary, AB, Canada). All post-processing analyses were conducted by experienced CMR readers blinded to all clinical data. The details of protocols and parameters for cardiac structural and functional evaluation are presented in Appendix 1.

Hepatic T1 values were derived from standard cardiac T1 maps with a single-breath-hold MOLLI sequence. On midventricular short-axis cine images, three regions of interest (ROIs), each approximately 120 mm² in area, were delineated within the hepatic parenchyma with the cvi42 post-processing workstation. ROIs were placed in both the right and left hepatic lobes, with the lumen of hepatic vessels, biliary ducts, liver capsule, and areas with visible artifacts being carefully avoided (Figure S1). The average of these three ROIs was recorded as the hepatic T1 value.

ECV measurements were performed using three ROIs in the hepatic parenchyma, and the values were averaged for both native and post-contrast T1 mapping. For blood pool T1 value quantification in both native and post-contrast T1 mapping, an ROI was placed in the LV cavity, with the papillary muscle being excluded. Hematocrit levels were measured within 1 week prior to the CMR scan. The hepatic ECV was calculated as follows (19):

$$\mathrm{H}\mathrm{e}\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{c}\mathrm{E}\mathrm{C}\mathrm{V}=(1-\mathrm{hematocrit})\times \frac{\frac{1}{\mathrm{T}{1}_{\mathrm{h}\mathrm{e}\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{c}-\mathrm{p}\mathrm{o}\mathrm{s}\mathrm{t}}}-\frac{1}{\mathrm{T}{1}_{\mathrm{h}\mathrm{e}\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{c}-\mathrm{p}\mathrm{r}\mathrm{e}}}}{\frac{1}{\mathrm{T}{1}_{\mathrm{L}\mathrm{V}\mathrm{b}\mathrm{l}\mathrm{o}\mathrm{o}\mathrm{d}-\mathrm{p}\mathrm{o}\mathrm{s}\mathrm{t}}}-\frac{1}{\mathrm{T}{1}_{\mathrm{L}\mathrm{V}\mathrm{b}\mathrm{l}\mathrm{o}\mathrm{o}\mathrm{d}-\mathrm{p}\mathrm{r}\mathrm{e}}}}$$ [1]

In this equation, hepatic ECV represents liver ECV fraction; hematocrit denotes peripheral venous hematocrit (fraction); T1_hepatic-pre and T1_hepatic-post are the pre-contrast and post-contrast T1 relaxation times of the liver tissue, respectively; and T1_{LV blood-pre} and T1_{LV blood-post} are the pre-contrast and post-contrast T1 relaxation times of the blood pool in the LV cavity. All T1 values are measured in milliseconds (ms).

Follow-up analysis

Follow-up data were collected through medical and hospital records, clinical evaluations, and patient interviews. The primary outcome was the first sustained VA after a definite ARVC diagnosis. According to previous studies (10), sustained VA was defined as a composite endpoint including sustained ventricular tachycardia (VT), SCD, sudden cardiac arrest, ventricular fibrillation, or appropriate implantable cardioverter-defibrillator (ICD) intervention. Sustained VT was defined as spontaneous VT lasting ≥30 seconds at a rate of ≥100 beats per minute (bpm) or hemodynamic compromise requiring cardioversion. Follow-up duration was defined as the time interval between baseline CMR and the first sustained VA or censoring, with censoring defined as survival without sustained VA at the latest follow-up date (February 21, 2025).

Statistical analysis

The normality of continuous variables were assessed via the Shapiro-Wilk test. Continuous variables are presented as the mean ± standard deviation (SD) for normally distributed data or as the median and interquartile range (IQR) for nonnormally distributed data. Continuous variables were compared with the independent Student t-test or the Mann-Whitney U test. Categorical variables are presented as frequencies (percentages) and were compared with the χ² test or Fisher exact test, as appropriate. The correlation between hepatic native T1 and CMR imaging (MRI)-derived parameters were assessed via Pearson and Spearman correlation coefficients. Determinants of hepatic tissue changes were assessed through univariate and multivariate stepwise linear regression analyses, and the results are reported as standardized β coefficients.

Univariable and multivariable Cox regression analyses were performed to identify the potential predictors of sustained VA. The independent variables with P<0.05 in the univariable analysis were considered for inclusion in the multivariable Cox regression model, and the variables with the lowest P values were prioritized for inclusion. The number of independent variables included in the multivariable model was constrained to ensure approximately 10 events per variable and thus avoid model overfitting (20). The ARVC risk score (model 1) served as the baseline model due to having the lowest P value among the clinical parameters. The ARVC risk score was calculated via an online calculator (http://www.arvcrisk.com), with variables such as male sex, age, recent cardiac syncope, previous nonsustained VT, 24-hour premature ventricular contraction count, number of leads with T-wave inversion, and RVEF being incorporated (10). To evaluate the incremental role of hepatic native T1 value in predicting sustained VA, the CMR feature tracking (FT) marker of RV GLS (model 2; i.e., ARVC risk score + RV GLS) was first added, followed sequentially by hepatic native T1 value (model 3; i.e., ARVC risk score + RV GLS + hepatic native T1). We formally tested the proportional hazards (PH) assumption using Schoenfeld residuals. In the supplemental analysis, the number of RV LGE segments was added to the baseline model (model 1; i.e., ARVC risk score) instead of RV GLS. Additionally, to investigate the incremental role of hepatic ECV in predicting sustained VA, these steps were repeated only with hepatic native T1 being replaced with hepatic ECV in the supplemental information. The C-statistic for each multivariable model in the prediction of sustained VA was recorded. To assess the incremental predictive value of each subsequent parameter, we performed a likelihood ratio test and supplemented it with a continuous net reclassification improvement (NRI) assessment.

Kaplan-Meier plots were generated for ARVC risk score, cardiac characterization, and hepatic tissue characterization, which were stratified by cutoff values determined by the receiver operating characteristic (ROC) curve and the Youden index. Event-free survival for sustained VA was analyzed via log-rank tests.

Inter- and intraobserver reliability were assessed by two blinded observers who evaluated MRI hepatic T1 mapping images from 20 random patients with ARVC. Reliability was quantified according to the intraclass correlation coefficient (ICC) with the corresponding 95% confidence interval (CI). Agreement was further evaluated with Bland-Altman analysis for the mean bias.

Statistical significance was defined as a two-sided P<0.05. SPSS version 25.0 (IBM Corporation, Armonk, NY, USA), GraphPad Prism version 9.0 (Dotmatics, Boston, MA, USA), and R software version 4.3.3 (The R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses.

Results

Population characteristics

A total of 94 patients with definite ARVC were included in the analysis. The mean age at CMR was 37.3±14.2 years, and 63 (67%) patients were male. The baseline clinical characteristics based on the primary endpoint of the study population are shown in Table 1. Among the patients, 33 (35%) had a New York Heart Association (NYHA) functional class ≥Ⅲ. The major clinical manifestations included 24-hour premature ventricular complex (PVC) count of 1,000 or greater (n=59, 63%) and nonsustained VT (n=57, 61%). Patients with the primary endpoint of sustained VA had a higher ARVC risk score compared to those without it.

Table 1. Baseline clinical characteristics of patients with and without sustained VA during follow-up.

Variable	Total sample (n=94)	Sustained VA in follow-up (n=34)	No sustained VA in follow-up (n=60)	P value
Demographic characteristics
Age, years	37.3±14.2	38.6±17.3	36.6±12.3	0.553
Male sex	63 [67]	23 [68]	40 [67]	0.923
BSA, m2	1.6±0.2	1.7±0.2	1.6±0.1	0.670
BMI, kg/m2	22.3±3.1	22.9±3.7	21.9±2.8	0.149
Clinical characteristics
Systemic hypertension	6 [6]	2 [6]	4 [7]	0.626
Diabetes	3 [3]	2 [6]	1 [2]	0.296
Family history of CAD	1 [1]	1 [3]	0 [0]	0.362
Family history of ARVC	8 [9]	4 [12]	4 [7]	0.454
NYHA class Ⅲ–Ⅳ	33 [35]	18 [53]	15 [25]	0.006**
Clinical presentation
History of syncope	23 [24]	12 [35]	11 [18]	0.066
NSVT	57 [61]	24 [70]	33 [55]	0.137
24-h PVC count (≥1,000)	59 [63]	27 [79]	32 [53]	0.012*
Leads with T-wave inversion	1 [0–5]	2 [0–5]	1 [0–5]	0.718
Therapy
Beta-blockers	48 [51]	22 [65]	26 [43]	0.055
ACE inhibitors	16 [17]	9 [26]	7 [12]	0.066
Antiarrhythmic drug	57 [60]	29 [85]	38 [63]	0.024*
Diuretic agent	11 [12]	5 [15]	6 [10]	0.495
ARVC risk score, %	32.5±21.1	41.7±21.2	26.6±19.4	0.001**

Values are mean ± SD, n [%], or median [IQR]. *, P<0.05; **, P<0.01. ACE, angiotensin-converting enzyme; ARVC, arrhythmogenic right ventricular cardiomyopathy; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; IQR, interquartile range; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; PVC, premature ventricular complex; SD, standard deviation; VA, ventricular arrhythmia.

Study outcomes

Over a median follow-up period of 39 [5–113] months, 34 (36%) patients developed sustained VA, with 29 (85%) receiving appropriate ICD interventions, 4 (12%) experiencing spontaneous sustained VT, and 1 (3%) experiencing SCD.

Cardiac and hepatic MRI characteristics

The hepatic T1 mapping parameters of patients with ARVC and healthy controls are shown in Table S1. Hepatic native T1 values and hepatic ECV were significantly higher in patients with ARVC than in healthy controls (P<0.05). The cardiac and hepatic MRI characteristics of patients with ARVC stratified by the primary endpoint of sustained VA are shown in Table 2. Patients with ARVC and sustained VA, compared to those without sustained VA, had a higher RV end-diastolic volume index (EDVi) and end-systolic volume index (ESVi) (P<0.05) and significantly reduced RVEF (32.4%±11.5% vs. 40.6%±12.3%; P=0.002). No significant differences were observed in LV volume or function. Patients who experienced sustained VA during follow-up had a higher proportion of RV LGE and a higher number of RV LGE segments (P<0.05). Regarding CMR-FT parameters, patients with sustained VA, compared to those free from sustained VA, had significantly impaired RV GLS (−14.5%±5.1% vs. −17.7%±5.2%; P<0.001) and LV GLS (−12.9%±5.1% vs. −15.0%±3.5%; P=0.022).

Table 2. Cardiac and hepatic MRI characteristics of patients with and without sustained VA during follow-up.

Parameter	Total sample (n=94)	Sustained VA in follow-up (n=34)	No sustained VA in follow-up (n=60)	P value
Traditional CMR features
LV EDVi, mL/m2	87.0±16.3	89.0±17.0	85.9±15.9	0.382
LV ESVi, mL/m2	39.8±14.2	42.5±14.9	38.3±13.7	0.169
LVEF, %	55.2±9.4	52.9±10.2	56.5±8.7	0.068
LV RWMA	23 [24]	11 [32]	12 [20]	0.087
RV EDVi, mL/m2	119.4±41.5	130.4±39.8	113.3±41.5	0.048*
RV ESVi, mL/m2	77.8±42.8	90.7±42.5	70.5±41.6	0.027*
RVEF, %	37.6±12.6	32.4±11.5	40.6±12.3	0.002**
RV RWMA	86 [91]	33 [97]	53 [88]	0.145
CMR-FT peak strain, %
LV GLS	−14.2±4.2	−12.9±5.1	−15.0±3.5	0.022*
LV GCS	−17.4±3.4	−17.2±3.6	−17.5±3.3	0.661
LV GRS	30.1±7.7	28.7±8.4	30.9±7.2	0.181
RV GLS	−16.6±5.4	−14.5±5.1	−17.7±5.2	0.005**
Cardiac tissue characterization
LV LGE	39 [41]	16 [47]	23 [38]	0.409
LV LGE extent, %	8.3±11.5	11.3±13.6	6.6±9.7	0.082
LV fat infiltration	19 [20]	8 [24]	11 [18]	0.853
RV LGE	54 [57]	24 [71]	30 [50]	0.008**
Number of RV LGE segments	2 [0–9]	3 [0–8]	2 [0–9]	0.004**
RV fat infiltration	61 [65]	22 [65]	39 [65]	0.977
LV native T1, ms	1,307.9±65.3	1,336.9±76.8	1,295.6±56.2	0.008**
LV post T1, ms	564.7±83.0	561.6±106.3	566.4±67.3	0.788
LV ECV, %	30.4±5.0	32.0±5.5	29.4±4.5	0.017*
Hepatic tissue characterization
Hepatic native T1, ms	734.9±75.8	762.9±62.7	719.0±78.4	0.006**
Hepatic post T1, ms	378.4±47.0	366.9±48.9	385.5±54.2	0.662
Hepatic ECV, %	34.5±4.8	35.9±4.9	33.7±4.6	0.032*

Values are mean ± SD, n [%] or median [IQR]. *, P<0.05; **, P<0.01. CMR, cardiac magnetic resonance; CMR-FT, cardiac magnetic resonance feature tracking; ECV, extracellular volume; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; IQR, interquartile range; LGE, late gadolinium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; RV, right ventricular; RVEF, right ventricular ejection fraction; RWMA, regional wall motion abnormalities; SD, standard deviation; VA, ventricular arrhythmia.

Regarding hepatic T1 mapping parameters, patients who experienced sustained VA during follow-up, compared to those free from sustained VA, had significantly higher hepatic native T1 values (762.9±62.7 vs. 719.0±78.4 ms; P=0.006) and ECV (35.9%±4.9% vs. 33.7%±4.6%; P=0.032). The inter- and intraobserver variability for hepatic T1 mapping parameters is presented in Table S2. The inter- and intra-observer agreement was excellent for all hepatic T1 mapping parameters. Results of Bland-Altman analysis for hepatic native T1, hepatic post-contrast T1, and hepatic ECV are presented in Figure S2.

Association of hepatic T1 values with clinical and cardiac characteristics

The factors associated with hepatic native T1 values in the univariable analyis are presented in Table S3. In multivariable linear regression analysis, the independent predictors of hepatic native T1 values were male sex (β=−0.409; P=0.001), ARVC risk score (β=0.330; P=0.011), and LV native T1 value (β=0.231; P=0.045). We drew a scatter plot to show the correlation of hepatic native T1 values with LV native T1 values, RV EDVi, RV ESVi, and RVEF in patients with ARVC (Figure S3) and healthy controls (Figure S4).

The optimal prognostic cutoff value of hepatic native T1 value for sustained VA according to ROC curve analysis was 716 ms. When categorized by the cutoff value, hepatic native T1 value showed significant correlations with the ARVC risk score, RV EDVi, RV ESVi, and LV native T1 (Figure 2). It should be noted that the hepatic native T1 threshold identified in our study is exploratory in nature, and external validation in independent cohorts is needed before it can be applied in clinic.

Figure 2.

Box plots comparing ARVC risk score and CMR parameters stratified by hepatic native T1 values. When stratified by the cutoff value, hepatic native T1 showed significant correlations with the ARVC risk score (A), RV EDVi (B), RV ESVi (C), and LV native T1 (G), but no significant correlations with RVEF (D), RV GLS (E), LV GLS (F), or LV ECV (H). ARVC, arrhythmogenic right ventricular cardiomyopathy; CMR, cardiac magnetic resonance; ECV, extracellular volume; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; GLS, global longitudinal strain; LV, left ventricular; RV, right ventricular; RVEF, right ventricular ejection fraction.

Univariable association of hepatic T1 values with sustained VA

The univariable predictors of sustained VA are provided in Table 3. The factor significantly associated with sustained VA were hepatic native T1 value [hazard ratio (HR) =1.61, 95% CI: 1.08–2.41; P=0.020] and hepatic ECV (HR =1.04, 95% CI: 1.00–1.14; P=0.048). Additionally, the ARVC risk score, RV GLS, RV LGE, the number of RV LGE segments, LV GLS, LV native T1, and LV ECV were also significantly associated with the risk of sustained VA in the univariable analyses.

Table 3. Univariable Cox regression analysis for the prediction of sustained VA during follow-up.

Variable	Univariable
	HR (95% CI)	P value
Age, years	1.01 (0.99–1.03)	0.463
Male	0.94 (0.46–1.93)	0.861
BSA, m2	2.29 (0.38–13.74)	0.366
BMI, kg/m2	1.89 (0.78–5.46)	0.257
Systemic hypertension	1.06 (0.25–4.43)	0.935
Diabetes	0.42 (0.10–1.76)	0.236
Family history of CAD	0.25 (0.03–1.83)	0.171
Family history of ARVC	0.71 (0.25–2.01)	0.513
History of syncope	0.53 (0.26–1.07)	0.074
NYHA class Ⅲ–Ⅳ	1.06 (1.01–1.14)	0.019*
NSVT	0.61 (0.29–1.28)	0.194
24 h PVC count (≥1,000)	1.05 (1.01–1.13)	0.039*
Leads with T-wave inversion	1.01 (0.85–1.21)	0.881
Beta-blockers	0.54 (0.27–1.10)	0.090
ACE inhibitors	0.55 (0.26–1.17)	0.120
Antiarrhythmic drug	0.40 (0.16–1.04)	0.059
Diuretic agent	0.80 (0.31–2.06)	0.638
ARVC risk score	1.02 (1.01–1.04)	0.006**
Traditional CMR features
LV EDVi, mL/m2	1.01 (0.99–1.02)	0.498
LV ESVi, mL/m2	1.01 (0.99–1.03)	0.301
LVEF, %	0.97 (0.94–1.01)	0.139
LV RWMA	0.50 (0.26–0.99)	0.055
RV EDVi, mL/m2	1.01 (0.99–1.01)	0.101
RV ESVi, mL/m2	1.00 (1.00–1.01)	0.071
RVEF, %	0.97 (0.94–0.99)	0.020*
RV RWMA	0.32 (0.04–2.35)	0.263
CMR-FT peak strain
LV GLS, %	1.07 (1.01–1.14)	0.033*
LV GCS, %	1.02 (0.92–1.12)	0.762
LV GRS, %	0.97 (0.93–1.02)	0.240
RV GLS, %	1.09 (1.02–1.17)	0.008**
Cardiac tissue characteristics
LV LGE	0.78 (0.40–1.53)	0.465
LV LGE extent, %	1.02 (0.99–1.05)	0.109
LV fat infiltration	0.98 (0.38–2.53)	0.965
RV LGE	1.04 (1.01–1.10)	0.028*
Number of RV LGE segments	1.19 (1.04–1.37)	0.012*
RV fat infiltration	1.03 (0.51–2.09)	0.931
LV native T1, ms (per 100-ms increase)	1.82 (1.15–3.24)	0.024*
LV ECV, %	1.07 (1.01–1.14)	0.025*
Hepatic tissue characterization
Hepatic native T1, ms (per 100-ms increase)	1.61 (1.08–2.41)	0.020*
Hepatic ECV, %	1.04 (1.00–1.14)	0.048*

*, P<0.05; **, P<0.01. ACE, angiotensin-converting enzyme; ARVC, arrhythmogenic right ventricular cardiomyopathy; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; CI, confidence interval; CMR-FT, cardiac magnetic resonance feature tracking; ECV, extracellular volume; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; HR, hazard ratio; LGE, late gadolinium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; PVC, premature ventricular complex; RV, right ventricular; RVEF, right ventricular ejection fraction; RWMA, regional wall motion abnormalities; VA, ventricular arrhythmia.

Incremental value of hepatic T1 values for prognostication

In a multivariable model including the ARVC risk score, RV GLS, and hepatic native T1 value, hepatic native T1 value retained independent significance as a predictor of sustained VA (model 3; HR =1.02; 95% CI: 1.00–1.03; P=0.025; Table 4). The global test for model 3 was nonsignificant (χ²=2.108, degrees of freedom =3; P=0.55; Table S4), and smoothed scatter plots of residuals against time showed no systematic trends (Figure S5), confirming that the PH assumption was reasonable for our models. Similar findings were observed when the number of RV LGE segments was substituted for RV GLS (model 3; P=0.012; Figure S6). However, the significance of the association between hepatic ECV and sustained VA did not persist in the multivariable model (Figures S7,S8).

Table 4. Nested multivariable models for sustained VA.

Variable	Model 1		Model 2		Model 3
	Fit	P value	Fit	P value	Fit	P value
Likelihood ratio	9.20	–	15.30	vs. Model 1: 0.014*	20.14	vs. Model 1: <0.001***
						vs. Model 2: 0.028*
C-statistic	0.680	–	0.735	–	0.760	–
Continuous NRI	–	–	0.19 (0.01–0.37)	vs. Model 1: <0.001***	0.42 (0.22–0.50)	vs. Model 1: <0.001***
					0.24 (0.04–0.38)	vs. Model 2: <0.001***
Covariates†
ARVC risk score	1.02 (1.01–1.04)	0.004**	1.02 (1.00–1.03)	0.045*	1.01 (1.00–1.03)	0.047*
RV GLS			1.09 (1.02–1.17)	0.018*	1.08 (1.01–1.15)	0.034*
Hepatic native T1					1.02 (1.00–1.03)	0.025*

*, P<0.05; **, P<0.01; ***, P<0.001. ^†, for the covariates in the multivariable Cox regression analysis, HR and 95% CI are reported instead of fit statistics. Fit statistics for the prognosis of sustained VA are shown for each model, with P values reported for the likelihood test. The continuous NRI estimates (95% CIs) were calculated to quantify the incremental predictive value between models. Model 1: ARVC risk score. Model 2: model 1 + RV GLS. Model 3: model 2 + hepatic native T1. ARVC, arrhythmogenic right ventricular cardiomyopathy; C-statistic, concordance statistic; CI, confidence interval; GLS, global longitudinal strain; HR, hazard ratio; NRI, net reclassification improvement; RV, right ventricular; VA, ventricular arrhythmia.

A series of nested multivariable models indicated that the addition of CMR-FT markers of RV GLS (model 2) significantly improved discrimination and calibration for sustained VA (C-statistic =0.735; likelihood ratio =15.30; P=0.014; Table 4) in comparison with the baseline clinical model of ARVC risk score (model 1; C-statistic =0.680; likelihood ratio =9.20; Table 4). Furthermore, the addition of hepatic native T1 to the model (ARVC risk score + RV GLS; model 3) further significantly improved the discrimination and calibration for sustained VA (C-statistic =0.760; likelihood ratio =20.14; P=0.028; Table 4, Figure 3). Similar findings were observed when the number of RV LGE segments was substituted for RV GLS (Figure S6). However, the substitution of hepatic ECV for hepatic native T1 value did not significantly improve the predictive performance of the model (likelihood ratio =18.59 and likelihood ratio =17.86; P=0.070 and P=0.068, respectively; Figures S7,S8).

Figure 3.

Incremental prognostic value of hepatic native T1. Hepatic native T1 provided incremental prognostic value for sustained ventricular arrhythmia when incorporated into a model with ARVC risk score and RV GLS. ARVC, arrhythmogenic right ventricular cardiomyopathy; GLS, global longitudinal strain; RV, right ventricular.

Incidence of sustained VA and hepatic T1 values

In the Kaplan-Meier curve analysis, patients with ARVC were categorized according to a cutoff value for hepatic native T1 of 716 ms. Patients with higher hepatic native T1 values (>716 ms) had a higher probability of sustained VA (Figure 4A). Similar findings were observed when patients were categorized by hepatic ECV, ARVC risk score, and RV GLS, respectively (Figure 4B-4D). Additional groups categorized by cardiac parameters are shown in Figure S9, while example images for the association between different hepatic native T1 values and sustained ventricular VA are shown in Figure 5.

Figure 4.

Kaplan-Meier survival analysis of hepatic tissue characteristics, ARVC risk score, and RV GLS. Patients with higher hepatic native T1 were associated with a higher probability of sustained VA (A). Similar findings were observed when patients were categorized by hepatic ECV (B), ARVC risk score (C), and RV GLS (D). ARVC, arrhythmogenic right ventricular cardiomyopathy; ECV, extracellular volume; GLS, global longitudinal strain; RV, right ventricular; VA, ventricular arrhythmia.

Figure 5.

Image examples of the relationship between hepatic native T1 abnormalities and sustained VA. In the context of similar RVEF and RV GLS, a patient with ARVC and lower hepatic native T1 values (A) did not experience ICD intervention during follow-up; by contrast, a patient with ARVC and higher hepatic native T1 values (B) did experience such an event. ARVC, arrhythmogenic right ventricular cardiomyopathy; GLS, global longitudinal strain; ICD, implantable cardioverter-defibrillator; RV, right ventricular; RVEF, right ventricular ejection fraction; VA, ventricular arrhythmia.

Discussion

To the best of our knowledge, this is the first study to evaluate the association of hepatic T1 tissue characteristics with myocardial tissue damage and their prognostic utility in predicting sustained VA in patients with ARVC. The key findings can be summarized as follows: (I) patients with ARVC who experienced sustained VA during follow-up had poor RV function and hepatic T1 tissue characteristics; (II) hepatic native T1 values were significantly associated with female sex, ARVC risk score, and LV native T1; (III) the elevated hepatic native T1 values were associated with a higher risk of sustained VA in patients with ARVC, and hepatic native T1 value was a significant independent risk predictor of sustained VA; (IV) hepatic native T1 provided incremental prognostic value relative to the ARVC risk score and CMR risk factors (RV GLS) in the prediction of sustained VA, predominantly ICD-treated events.

Association of hepatic T1 values with cardiac characteristics

The results indicated that hepatic tissue alterations are closely associated with myocardial tissue alterations. The evaluation of hepatic tissue alterations has been substantially advanced by the development of advanced CMR techniques, particularly T1 mapping sequences, which provide critical insights into hepatic tissue composition and pathological alterations (16,21,22). In T1 mapping MRI, the native T1 values correspond to intra- and extracellular water content in hydrated fibrotic tissue, whereas the hematocrit-corrected ECV, derived from post-contrast T1 mapping, provides a quantitative measure of the relative extracellular space (23). Specifically, variations in hepatic T1 values and ECV serve as sensitive biomarkers for both liver injury pathological processes, including diffuse fibrosis, and acute hepatic changes, such as those induced by congestion or inflammatory responses (24,25). One study involving 60 patients with liver cirrhosis receiving both liver MRI and CMR examinations, demonstrated that individuals with a greater severity of liver disease exhibited more pronounced myocardial fibrosis, as quantified by T1 relaxation values (21). In our ARVC cohort, hepatic native T1 values were significantly correlated with LV myocardial native T1 values, while this association was absent in the healthy controls, suggesting that our findings may reflect a genuine disease-specific interaction rather than shared acquisition-related or timing-related artifacts. However, residual confounding cannot be entirely excluded, and future multicenter prospective studies are needed to validate these observations. Moreover, the exact nature of pathophysiological mechanisms underlying our observations remain to be fully elucidated, but we speculate that they may involve the following. First, fibrosis is the end result of chronic inflammatory responses triggered by various stimuli. Furthermore, LV myocardial fibrosis may induce systemic inflammatory responses, and inflammatory factors may affect the liver through the circulatory system, leading to hepatic inflammation or fibrosis (26). Additionally, myocardial fibrosis and hepatic fibrosis may share certain pathological mechanisms (e.g., signaling pathways or oxidative stress), leading to their simultaneous occurrence, ultimately resulting in elevated T1 values in both the liver and the ventricular myocardium (27,28).

Additionally, we observed significant correlations between hepatic native T1 values and RV parameters, including RV EDVi, RV ESVi, and RVEF, in the ARVC cohort—a relationship not present in healthy controls. These results may attest to an interplay between cardiac dysfunction and hepatic tissue alterations. ARVC is predominantly characterized by right-sided hemodynamic alterations, typically manifesting as RV dysfunction or right HF. The associated hepatic tissue alterations in these patients is primarily attributable to backward failure, which has been conceptualized as cardiohepatic syndrome (29). RV volume and pressure overload can increase hepatic venous pressure, which may subsequently contribute to the development of congestive hepatopathy and potentially culminate in hepatocellular injury (8,30). Notably, our findings align with data from a large, all-comer CMR cohort (13), in which elevated hepatic T1 values were significantly associated with reduced ventricular function, further supporting the generalizability of our observations regarding the liver-heart interaction in ARVC patients.

Prognostic utility of hepatic T1 values

Our study confirmed the independent and incremental prognostic value of hepatic native T1 for predicting sustained VA in patients with ARVC, predominantly ICD-treated events. Due to the complex venous drainage system and metabolic pathways, hepatic tissue alterations are often an early indicator of cardiac dysfunction (31). Previous studies have demonstrated that hepatic T1 values are independently associated with adverse cardiovascular outcomes in patients with pulmonary arterial hypertension (32) and dilated (22,33) or infiltrative cardiomyopathy (13). Furthermore, in the UK Biobank imaging substudy, elevated hepatic T1 values were associated with an increased risk of new-onset cardiovascular disease (34). These findings suggest that hepatic T1 values may serve as a promising tool for risk stratification, particularly for identifying individuals at heightened risk of cardiovascular morbidity and mortality. However, these investigations did not focus on patients with ARVC, highlighting the novelty of our study as the first to establish this association.

Nevertheless, the molecular mediators of the association of hepatic native T1 with sustained VA remain to be elucidated. The correlation between hepatic native T1 and LV native T1 in our study might shed light on the mechanisms underlying the relationship of hepatic tissue alterations with sustained VA, as LV diffuse fibrosis may lead to arrhythmia due to alterations in the electrophysiologic substrate (35). Moreover, the activation of the renin-angiotensin-aldosterone system is associated with both myocardial fibrosis and hepatic fibrosis (26,36). The overactivation of the renin-angiotensin-aldosterone system, as one of the key drivers of multiorgan fibrosis, may significantly contribute to the association between hepatic fibrosis and sustained VA. These findings may position hepatic native T1 as an integrative prognostic marker in ARVC, although its actual causal impact remains to be further clarified in mechanistic research. The modest gain in C-statistic over existing scores—which themselves showed suboptimal performance (C-statistic =0.680) in our cohort—suggests incremental rather than replacement value. However, this may be a result of referral bias, differences in endpoint definitions, limited sample size, and population heterogeneity.

Regarding LV parameters, native T1, ECV, and GLS were all associated with sustained VA in the univariable analysis but were excluded from multivariable modeling due to event number constraints and overfitting concerns. Larger prospective studies are needed to determine whether adding LV tissue characterization parameters to existing risk models can improve risk stratification beyond traditional RV-centric markers.

Limitations

Several limitations to this study should be acknowledged. First, our single-center retrospective study had a modest sample size and lacked external validation, which may limit the generalizability of our predictive model. Although we excluded known liver disease, we could not fully exclude residual confounding from subclinical hepatic dysfunction or occult metabolic disease. Furthermore, no direct indicators of venous congestion were available, which limited the pathophysiological interpretation of the association between hepatic native T1 and RV dysfunction. Second, in the absence of liver biopsy, T1 mapping cannot differentiate fibrosis from congestion as the underlying cause of elevated T1 values. Although single-slice measurements may not fully capture the global fibrotic burden, this limitation was partly mitigated by the averaging of T1 values from ROIs placed at three distinct locations. Finally, because appropriate ICD interventions could not be separated into antitachycardia pacing (ATP)—only therapy, appropriate shock, or ATP followed by shock, the clinical severity of the endpoint could not be fully characterized. This limitation might have biased the results in either direction and limits the interpretation of hepatic native T1 as a predictor of clinically severe ventricular arrhythmic events.

Conclusions

Hepatic T1 values can be quantified on standard T1 mapping CMR scans and are associated with female sex, ARVC risk score, and LV myocardial native T1 values in patients with ARVC. Hepatic native T1 provides independent prognostic value for the occurrence of sustained VA in patients with ARVC, predominantly ICD-treated events, and offers incremental predictive value relative to the ARVC risk score and RV GLS. Hepatic native T1 may serve as a novel marker of sustained VA and improve risk stratification in patients with ARVC.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Guangdong Provincial People’s Hospital (Approval No. GDREC2019338H [R2]) and individual consent for this retrospective analysis was waived.

Data Sharing Statement

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DOI: 10.21037/qims-2026-1125