Implications of Elevated Fibrosis-4 Index in Patients Receiving Trans-Catheter Aortic Valve Replacement

Background: The prognostic implication of the fibrosis-4 index, which represents the degree of hepatic injury, on patients receiving trans-catheter aortic valve replacement (TAVR) remains unknown. Methods: Patients who underwent TAVR to treat severe aortic stenosis at our institute between 2015 and 2020 were included in this retrospective study and followed for 2 years from the index discharge. The impact of the fibrosis-4 index, which was calculated using age, hepatic enzymes, and platelet count, on 2-year heart failure readmissions was investigated. Results: A total of 272 patients (median age 85 (82, 88) years old, 76 (28%) men) were included. The median baseline fibrosis-4 index was 2.8 (2.2, 3.7). A high fibrosis-4 index (>3.79) was associated with higher cumulative incidence of the primary endpoint (18% versus 4%, p < 0.001) and higher event rates (0.1041 versus 0.0222 events/year, p < 0.001), with an adjusted hazard ratio of 1.27 (95% confidence interval 1.04–1.54, p = 0.019). Conclusion: an elevated fibrosis-4 index at baseline, indicating the existence of persistent hepatic congestion, was associated with incidences of heart failure following TAVR. Calculating the fibrosis-4 index before TAVR is highly encouraged for risk stratification and shared decision making.


Background
Survival following trans-catheter aortic valve replacement (TAVR) has improved considerably partly due to improvements in peri-procedural management and patient selection optimization [1,2]. Nevertheless, adverse events after TAVR can occur, including decompensated heart failure [3,4]. It is clinically challenging to ascertain predictive factors that are associated with heart failure recurrence following TAVR given the complex interplay of valvular and intrinsic myocardial dysfunction.
This study aimed to investigate the association between the fibrosis-4 index and risk of heart failure recurrence following TAVR.

Patient Selection
Patients who underwent TAVR at our institute between 2015 and 2020 were included in this retrospective study. All patients were followed from index discharge for 2 years or until Jun 2021. Written informed consent was obtained from all participants on admission. The institutional review board approved the study protocol.

TAVR Procedure
Patients with severe aortic stenosis with max velocity > 4.0 m/s, mean pressure gradient > 40 mmHg, or aortic valve area < 1.0 cm 2 were considered for TAVR in a multidisciplinary heart-valve team conference.

Clinical Variables
Demographic, laboratory, echocardiographic, hemodynamics, and medication data within one week before TAVR were collected. Laboratory, echocardiographic, and medication data following TAVR were also collected.

Clinical Outcomes
All patients were followed up at our institute or affiliated institutes. Heart failure readmissions that required IV diuretics or any other intensive therapies under in-hospital observation were defined as the primary endpoint. All-cause death was also counted. The plasma B-type natriuretic peptide level at one-year follow-up was collected.

Statistical Analysis
Continuous variables were presented as a median and an interquartile range and compared using the Mann-Whitney U test. Categorical variables were presented as numbers and percentages and compared using Fisher's exact test. A two-tailed p < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics 22 (SPSS Inc, Armonk, IL, USA) and ESR (Ver 1.54; Saitama Medical Center Jichi Medical University, Saitama, JPN).
The primary endpoint was two-year heart failure readmissions. A time-dependent receiver operating characteristics analysis was conducted to calculate the cutoff for the baseline fibrosis-4 index at the primary endpoint using a Youden index. The patient cohort was stratified into two groups using this cutoff.
Cumulative incidence comparisons with a Gray test between the two groups were performed by accounting for death as a competing risk. Negative binomial regression analyses were performed to compare event rates between the two groups. Fine-Gray proportional hazard ratio regression analyses were performed to investigate the impact of the baseline fibrosis-4 index on the primary endpoint by adjusting for potential baseline characteristics that were significantly different in the comparison study (age, body surface area, hemoglobin, plasma B-type natriuretic peptide, and peak velocity at aortic valve).

Post-Procedural Data
Following TAVR, the median plasma B-type natriuretic peptide was 127 (86, 271) pg/mL. The median peak velocity at aortic valve was 2.1 (1.8, 2.4) m/s. All other clinical parameters are displayed in Table 2.

Baseline Fibrosis-4 Index and Heart Failure Readmissions
The cutoff of the baseline fibrosis-4 index associated with the primary endpoint was calculated as 3.79 (Figure 2). Patients with a high fibrosis-4 index (>3.79) were older, had lower hemoglobin levels, and had higher plasma B-type natriuretic peptide levels than the low fibrosis-4 index group (p < 0.05 for all; Table 1). Following TAVR, those with a high fibrosis-4 index had a lower estimated glomerular filtration ratio and higher plasma B-type natriuretic peptide (p < 0.05 for both; Table 2). During the observational period following the index discharge for a median of 730 (704, 730) days, there were 11 and 8 heart failure readmissions in the high and low fibrosis-4 index groups, respectively. Most of them (15/19) were preserved ejection fraction, and others were mildly reduced ejection fraction (3/19) or reduced ejection fraction (1/19). A 2-year cumulative incidence of the primary endpoint was higher in the high fibrosis-4 index group (18% versus 4%, p < 0.001; Figure 3A). The event rates of the primary endpoint were higher in the high fibrosis-4 index group (0.1041 versus 0.0222 events/year), with an incidence rate ratio of 5.99 (95% confidence interval 5.65-6.33, p < 0.001; Figure 3B).  The impact of baseline fibrosis-4 index on the incidence of primary endpoint was calculated as a hazard ratio 1.27 (95% confidence interval 1.04-1.54, p = 0.019), which was adjusted for five potential confounders that were significantly different in the comparison analysis (age, body surface area, hemoglobin, plasma B-type natriuretic peptide, and peak velocity at aortic valve) ( Table 3).

Other Clinical Outcomes
At one-year follow-up, median plasma B-type natriuretic peptide did not significantly differ between the two groups (100 (71, 165) pg/mL versus 87 (42, 164) pg/mL, p = 0.15). There were 4 and 16 deaths in the high and low fibrosis-4 index groups, respectively. The 2-year cumulative mortality rate did not significantly differ between the two groups (4% versus 5%, p = 0.66) ( Figure 3A).

Changes in Fibrosis-4 Index Following TAVR
Among the 64 patients with high baseline fibrosis-4 indexes, 58 had fibrosis-4 indexes that were also obtained at index discharge. Of them, 18 patients (31%) achieved decreases in their fibrosis-4 index below the cutoff level (<3.79) at index discharge. There were no significant differences in the baseline characteristics between the two groups (decreased and persistently high groups), except for a higher max velocity at the aortic valve in the group with decreases in their fibrosis-4 index (p = 0.010; Table 4). The group with a decreased fibrosis-4 indexes tended to be associated with a lower cumulative incidence of the primary endpoint (6% versus 26%, p = 0.079; Figure 4). Mortality was not significantly different between the two groups (5% versus 3%, p = 0.55). Abbreviations are the same as in Table 1. Continuous variables are presented as median and interquartile and compared using the Mann-Whitney U test. Categorical variables are presented as numbers and percentages and compared using the Fischer's exact test. * p < 0.05. Among the 64 patients with high baseline fibrosis-4 indexes, 6 were excluded due to a lack of data.

Discussion
In this study, we investigated the impact of the baseline fibrosis-4 index on heart failure readmissions following TAVR. We observed that (1) the baseline fibrosis-4 index was elevated in patients with severe aortic stenosis and was associated with more advanced heart failure; (2) the baseline fibrosis-4 index was associated with an increased incidence of heart failure readmissions following TAVR, even after adjustment for other potential confounders; and 3) the peri-procedural improvement in fibrosis-4 index tended to be associated with a lower incidence of heart failure readmissions.

Fibrosis-4 Index and Aortic Stenosis
The fibrosis-4 index was originally introduced to predict the progression of hepatic fibrosis in patients with hepatic diseases [5]. The use of this index has recently expanded to assess the degree of right-sided volume overload and to predict prognosis in patients with acute/chronic heart failure [6][7][8], pulmonary hypertension due to left heart disease [9], and atrial fibrillation [10]. The fibrosis-4 index would reflect hepatic injury via systemic congestion, mostly due to hepatic congestion, and hypo-perfusion due to low cardiac output. This is the first study to investigate the fibrosis-4 index in patients with aortic stenosis. The median value was 2.8, which is almost comparable with other previous studies including heart failure cohorts [6,7]. Of note, in a study by Takae and colleagues, a higher fibrosis-4 index was associated with clinical outcomes in patients with diastolic heart failure but not in patients with systolic heart failure [7]. They hypothesized that the underlying mechanisms that explained their findings would be systemic tissue fibrosis with a similar pathophysiology between the heart and the liver. A similar pathophysiology might exist in our cohort with aortic stenosis, which often accompanies diastolic heart failure with myocardial fibrosis.
In our study, those with a higher fibrosis-4 index had incremental plasma levels of Btype natriuretic peptide and dilutional anemia, both of which may suggest greater systemic volume overload and more advanced heart failure. Greater impairment of renal function might reflect glomerular congestion due to cardio-renal syndrome in patients with a higher fibrosis-4 index after TAVR. Given these findings, we strongly encourage clinicians to calculate the fibrosis-4 index in all patients with aortic stenosis to assess the refractory systemic congestion and the degree of heart failure progression.

Prognostic Implication of Fibrosis-4 Index
Recurrent heart failure following TAVR has negative prognostic implications [4]. Elevations in intra-cardiac filling pressures and the existence of refractory pulmonary hypertension are associated with poor outcomes following TAVR [11]. The existence of advanced tricuspid regurgitation is also independently associated with poor outcomes after TAVR [12]. Collectively, it is not surprising that a baseline elevated fibrosis-4 index, probably indicating these clinical conditions, was associated with recurrent heart failure following TAVR. Beyond the assessment of heart failure severity, we highly encourage clinicians to calculate the fibrosis-4 index for risk stratification and appropriate shared decision making for all TAVR candidates, particularly the elderly cohort. Some patients who are older with advanced frail and multiple comorbidities might not select TAVR following repeat shared decision making if their calculated fibrosis-4 index is high.
A post-procedural improvement in fibrosis-4 index tended to be associated with a lower incidence of heart failure recurrence. We also showed this important finding in the shared decision-making process. Although further studies are needed to establish how to improve the fibrosis-4 index, aggressive therapeutic approaches using neuro-hormonal blockers and diuretics might be promising tools.

Limitations
This is a retrospective study consisting of a moderate sample size. We observed the association between baseline fibrosis-4 index levels and heart failure recurrence. Detailed mechanisms that explain the causality remains uncertain. We cannot draw any conclusions between fibrosis-4 index levels and mortality due to the low total number of deaths following TAVR. We performed multivariate analyses but other unadjusted potential confounders may also have impacted the risk of the primary endpoint. Patients with liver cirrhosis did not receive TAVR and were not included in this study. Sarajlic and colleagues demonstrated that the sex-specific gene expression was associated with the valvular phenotypes [13]. The uneven sex proportion in our study might have also biased our findings.

Conclusions
The baseline elevated fibrosis-4 index, which is often associated with systemic congestion, was associated with increased heart failure incidence following TAVR. We highly encourage clinicians to calculate the fibrosis-4 index for all TAVR candidates for risk stratification and shared decision making. An aggressive intervention to decrease the score, including neuro-hormonal blockers and diuretics, might improve the clinical outcomes following TAVR.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data are available from the corresponding author upon reasonable requests.

Conflicts of Interest:
The authors declare no conflict of interest.