NT-proBNP and hs-CRP may be useful biomarkers for identifying and stratifying repaired TOF patients at increased risk of RV systolic dysfunction

ABSTRACT

Introduction:

Repaired TOF (rTOF) is a common condition in adult congenital heart disease care. The aim of this article is to investigate how inflammatory markers and volume overload affect rTOF, and how these factors correlate with echocardiographic findings in the right heart cavities.

Methods:

This study included 32 adult patients (mean age, 27.44 ± 6.22 years) who had undergone surgical correction of TOF during infancy. All participants underwent transthoracic echocardiography, and laboratory assessments included measurements of N-terminal pro-B-type natriuretic peptide (NT-proBNP; reference range ≤125 pg/mL) and high-sensitivity C-reactive protein (hs-CRP; reference range ≤2.0 mg/L).

Results:

Significant correlations were found between NT-proBNP levels and right ventricular (RV) fractional area change (FAC) (r = −0.55, P = 0.001), tricuspid annular plane systolic excursion (TAPSE) (r = −0.35, P = 0.04), RV basal diameter (r = 0.47, P = 0.006), and right atrium (RA) area (r = 0.50, P = 0.003). Similarly, hs-CRP levels showed strong associations with RV FAC (r = −0.58, P < 0.001), TAPSE (r = −0.45, P = 0.009), RV basal diameter (r = 0.43, P = 0.01), and RA area (r = 0.43, P = 0.01). NT-proBNP had a significant impact (P = 0.017; EXP B = 0.982) on RV FAC. A decrease of 10 units in NT-proBNP was associated with a 17% reduction likelihood of having RV FAC <35%.

Conclusion:

The proinflammatory response (hs-CRP) and volume load (NT-proBNP) are directly correlated with echocardiographic parameters of the right heart cavities in patients with rTOF, suggesting that patients may benefit from treatment with anti-inflammatory drugs, as well as medications targeting diastolic dysfunction.

Introduction

Advances in the diagnosis, medical treatment, and surgical correction of Tetralogy of Fallot (TOF) have markedly improved patient outcomes and long-term survival. TOF is the most common cyanotic congenital heart defect, accounting for 5–7% of all congenital anomalies, and repaired TOF (rTOF) is now among the most frequent entities in adult congenital heart disease care.[1,2] Many patients have undergone palliative procedures before complete repair, and long-term follow-up is required to detect complications such as pulmonary valve dysfunction, right ventricular (RV) dilation, arrhythmias, and QRS prolongation.[3] Diastolic dysfunction is closely linked to volume overload and systemic inflammation.[4,5] Inflammatory pathways, including IL-6–JAK–STAT, and NF-κB, have been implicated in myocardial remodeling in congenital heart disease.[6] These findings highlight ongoing uncertainty about optimal monitoring and interpretation of right heart echocardiographic parameters in rTOF patients.[7,8,9] This study investigates the association between inflammatory biomarkers and right ventricular function in adults after TOF repair, aiming to provide clinically relevant information that may support risk stratification, guide follow-up intensity and diagnostic decision-making for practitioners, and enable earlier identification and optimized management of patients at increased risk of right ventricular dysfunction.

Materials and Methods

Study design

This was a cross-sectional observational study including 32 adult patients (mean age, 27.44 ± 6.22 years) with rTOF who underwent surgical correction during infancy. Participants were recruited from routine follow-up examinations at the Department of Cardiology.

Inclusion criteria were as follows: adults (>18 years) with complete surgical repair of TOF, preserved left ventricular systolic function (LVEF ≥50%), and hemodynamic stability at the time of examination. Exclusion criteria included the presence of other congenital or acquired cardiac diseases, systemic inflammatory or autoimmune disorders, renal or hepatic dysfunction, pregnancy, and any evidence of acute infection at the time of blood sampling.

All participants underwent transthoracic echocardiography, focusing on the evaluation of right heart cavities: RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV basal diameter, and right atrium (RA) area. Additionally, laboratory assessments included measurements of N-terminal pro-B-type natriuretic peptide (NT-proBNP; reference range, ≤125 pg/mL) and high-sensitivity C-reactive protein (hs-CRP; reference range, ≤2.0 mg/L).

Echocardiographic examinations were performed using a Vivid E95 ultrasound system (GE Healthcare, Chicago, IL, USA). Measurements of RV FAC, TAPSE, RV basal diameter, and RA area were obtained from RV-focused apical four-chamber view. Serum NT-proBNP concentrations were determined using an electrochemiluminescence immunoassay, and hs-CRP was measured by immunoturbidimetric assay. No drugs, radiopharmaceuticals, or contrast agents were administered as part of the study.

Ethics

Informed consent was obtained from each patient, and the research was approved by the Institutional Ethics Committee. This study was conducted in accordance with the principles of the Helsinki Declaration. No personally identifiable data or images of patients have been included in this manuscript.

Statistics

Descriptive statistics were used to summarize continuous variables as means ± standard deviations, and categorical variables as frequencies and percentages. Normality of data distribution was assessed using the Shapiro–Wilk test. To evaluate associations between continuous variables, Pearson correlation coefficients were calculated. Comparisons of NT-proBNP values against a reference threshold within subgroups were performed using a one-sample t-test. Univariate logistic regression was used to assess the individual effects of hs-CRP and NT-proBNP on the likelihood of reduced RV FAC <35%. Variables that showed significance in univariate analysis were further included in a multivariate logistic regression model to determine their independent predictive value.

Diagnostic performance of the biomarker-based model in classifying patients according to RV function was evaluated by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy. A P value of <0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics, version 29.0 (IBM Corp., Armonk, NY, USA).

Results

Descriptive statistics are shown in Table 1. All continuous variables showed normal distribution according to the Shapiro–Wilk test.

Table 1.

Descriptive statistics of the data

Parameter	Mean±SD*
Age (years)	27.44±6.22
RV† FAC‡ (%)	36.27±2.45
TAPSE§ (mm)	22.03±1.99
S’ (cm/s)	11.50±.950
RV† basal diameter (mm)	39.12±3.50
RV† subcostal width (mm)	6.94±1.01
RA|| area (cm2)	14.22±1.79
RVSP¶ (mmHg)	46.06±10.54
RV† free wall strain	23.31±2.45
NTproBNP** (pg/mL)	191.16±135.03
hsCRP†† (mg/L)	.72±.39

*Standard deviation; ^†Right ventricular; ^‡Fractional area change; ^§Tricuspid annular plane systolic excursion; ^||Right atrial; ^¶Right ventricular systolic pressure; **N-terminal pro-B-type natriuretic peptide; ^††High-sensitive C-reactive protein

Pearson correlation analysis demonstrated significant correlations between NT-proBNP levels and several echocardiographic parameters, including RV FAC (r = −0.55, P = 0.001), TAPSE (r = −0.35, P = 0.04), RV basal diameter (r = 0.47, P = 0.006), and RA area (r = 0.50, P = 0.003). Similarly, hs-CRP levels showed strong associations with these same parameters: RV FAC (r = −0.58, P = 0.001), TAPSE (r = −0.45, P = 0.009), RV basal diameter (r = 0.43, P = 0.01), and RA area (r = 0.43, P = 0.01). A particularly strong correlation was observed between hs-CRP and NT-proBNP (r = 0.627; P = 0.0001).

NT-proBNP and hs-CRP levels differed according to right ventricular systolic function categories, with higher biomarker levels observed in patients with RV FAC <35% compared with those with preserved RV function [Figures 1 and 2]. A one-sample t-test was used to compare the mean NT-proBNP value in the group with RV FAC <35% (140.2 ± 46.7 pg/mL) against the reference threshold (125 pg/mL), revealing a statistically significant elevation (P = 0.003).

Figure 1.

Distribution of NT-proBNP levels according to right ventricular systolic function. RV, right ventricle; FAC, fractional area change; NTproBNP, N-terminal pro-B-type natriuretic peptide

Figure 2.

Distribution of hs-CRP levels according to right ventricular systolic function. RV, right ventricle; FAC, fractional area change; hs-CRP, high-sensitivity C-reactive protein

In univariate regression analysis, we evaluated the effect of the independent predictors hs-CRP and NT-proBNP on the outcome of RV FAC <35% or ≥35%. Both independent predictors significantly affected RV FAC (P < 0.05). Further, in multivariate regression analysis, we examined the combined effect of hs-CRP and NT-proBNP. While hs-CRP did not show a significant effect (P = 0.750), NT-proBNP had a significant impact (P = 0.017; EXP B = 0.982) on RV FAC. A decrease of 10 units in NT-proBNP was associated with a 17% reduction likelihood of having RV FAC <35%. In our sample, this suggests that the probability of RV FAC <35% ranged from 29% to 4% in the population of such patients.

There are two patient phenotypes based on RV FAC values [Figure 3], ≥35% or <35% (NTproBNP ≥150 pg/mL, hsCRP ≥0.75 mg/L; NTproBNP <150 pg/mL, hsCRP <0.75 mg/L). The model’s sensitivity is 75%, specificity is 90%, positive predictive value is 82%, negative predictive value is 86%, and diagnostic accuracy is 84%.

Figure 3.

Two proposed phenotypes in relation to biomarker values. RV, right ventricle; FAC, fractional area change; NTproBNP, N-terminal pro-B-type natriuretic peptide; hs-CRP, high-sensitivity C-reactive protein

Discussion

Early surgical management of TOF has significantly improved outcomes and reduced early mortality rates.[10,11] However, although patients with rTOF experience better survival and minimal morbidity during the first two decades of life, both morbidity and mortality increase notably in the third decade.[12,13,14] Consequently, recent studies have increasingly focused on understanding the pathophysiology and contributing factors in the development of heart failure among adolescent and adult patients with rTOF.

Recently, particular attention has been given to the association between systemic inflammation and heart failure. Chronic inflammation promotes myocardial remodeling through increased collagen deposition, altered extracellular matrix turnover, and microvascular dysfunction, ultimately leading to impaired diastolic and systolic function and progressive heart failure.[15,16,17] Our findings are in line with previous work showing that myocardial fibrosis and chronic volume overload are central determinants of RV dysfunction in rTOF.[18,19] Several studies using cardiovascular magnetic resonance have demonstrated that older rTOF patients have increased diffuse myocardial fibrosis in both right and left ventricles, which is associated with ventricular systolic dysfunction and development of heart failure.[18,19]

In the present study, both systemic inflammation and increased myocardial stress were significantly associated with RV dysfunction in patients with rTOF. Higher levels of NT-proBNP and hs-CRP showed strong correlations with key echocardiographic measures of RV systolic function and right-sided chamber remodeling, including RV FAC, TAPSE, and RA size. The observed associations between hs-CRP and echocardiographic indices of RV dysfunction support the concept that chronic inflammation contributes to myocardial remodeling and progression toward heart failure, consistent with previous reports linking inflammatory processes to myocardial fibrosis in rTOF.[15]

Prior studies have extensively investigated natriuretic peptides in rTOF.[20,21] Genuchten et al.[22] reported that changes in RV size parameters were associated with NT-proBNP concentrations. Additionally, Cheung et al.[23] showed that BNP levels correlate with RV volume overload, pulmonary regurgitation and reduced exercise capacity. A systemic review and meta-analysis by Alborikan et al.[24] further confirmed that NT-proBNP is elevated in rTOF and associated with structural RV alternations, more severe pulmonary regurgitation, impaired functional capacity and worse prognosis. Our results extend these observations by demonstrating that NT-proBNP remains an independent predictor of reduced RV FAC even after adjustment for hs-CRP, suggesting that it may be a more robust biomarker for RV systolic dysfunction in this population than previously recognized.

In contrast to the extensive data on natriuretic peptides, only limited research has focused on systemic inflammatory markers specifically in the rTOF population. While inflammation is a known driver of remodeling in general heart failure,[6,15,25] our study adds to the literature by quantifying the association between hs-CRP and right-sided chamber enlargement in rTOF adults. The strong positive correlation between hs-CRP and NT-proBNP suggests an interaction between systemic inflammation and myocardial strain. While hs-CRP showed significant univariate associations with RV dysfunction, it lost statistical significance in multivariate analysis, likely reflecting its close relationship with NT-proBNP and the shared pathophysiological pathway linking inflammation, fibrosis, and ventricular remodeling.[25]

Compared with previous studies that focused predominantly on imaging markers or natriuretic peptides in isolation,[18,19,20,21,22,23,24] the present work is, to our knowledge, among the first to jointly evaluate an inflammatory biomarker (hs-CRP) and a marker of wall stress (NT-proBNP) in relation to detailed right-heart echocardiographic parameters. Furthermore, the most significant distinction of this study is the development of a practical “two-patient phenotype” model. By proposing specific biomarker thresholds (NT-proBNP ≥150 pg/mL and hs-CRP ≥0.75 mg/L), we provide an easily applicable clinical framework that demonstrated high specificity (90%) and diagnostic accuracy (84%) in identifying patients with reduced RV systolic function. This represents a step beyond basic correlation studies and offers a potentially superior strategy for early risk stratification.

Limitations of the study

Several limitations of this study should be acknowledged. The relatively small sample size from a single center may limit the generalizability of the findings. The cross-sectional design precludes establishing causal relationships between inflammation, biomarker levels, and RV functional deterioration. In addition, advanced imaging modalities, such as cardiac MRI were not used to assess myocardial fibrosis, and follow-up data on clinical outcomes, were not available.

Future perspectives

Future research should focus on validating NT-proBNP and hs-CRP–based risk stratification in larger, multicenter rTOF cohorts with longitudinal follow-up for hard outcomes such as heart failure hospitalization, arrhythmias, and mortality.[26,27] Integrating these biomarkers with advanced imaging markers of RV and biventricular remodeling (CMR strain, fibrosis indices, and RV–LV interdependence measures) and with emerging fibrosis- and remodeling-related biomarkers (e.g., galectin-3, matrix metalloproteinases, collagen propeptides) may yield more robust multiparametric scores for disease staging.[6,28,29,30] Prospective interventional studies are also needed to test whether therapies targeting systemic inflammation or diastolic dysfunction slow RV remodeling and improve functional capacity and prognosis in rTOF.[31,32]

Conclusion

In conclusion, the proinflammatory response (hs-CRP) and volume load (NT-proBNP) are directly correlated with echocardiographic parameters of the right heart cavities in patients with TOF, suggesting that patients may benefit therapeutically from treatment with anti-inflammatory drugs, as well as medications targeting diastolic dysfunction.

Therefore, the use of NT-proBNP and hs-CRP may facilitate early identification of high-risk patients. Moreover, a better understanding of the roles of inflammation and heart failure in rTOF patients could be crucial for developing strategies to modify disease progression. Targeting the inflammatory pathology of heart failure in rTOF patients through anti-inflammatory medications, alongside standard of care, may ultimately reduce morbidity and mortality in this population.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.