V体育官网入口 - Evolving biomarkers in evaluating the reversibility of pulmonary arterial hypertension associated with congenital heart disease: a literature review

Introduction

Background

Pulmonary hypertension (PH), defined by the American Heart Association as a resting mean pulmonary artery pressure (mPAP) greater than 20 mmHg at rest (1) V体育官网入口. Right heart catheterization (RHC) is the definitive method for diagnosing PH, allowing for accurate disease classification and severity assessment. It plays a vital role in measuring key hemodynamic parameters, including mPAP, pulmonary vascular resistance (PVR), and pulmonary artery wedge pressure (PAWP). RHC is crucial when echocardiographic results are unclear, and it is essential in detecting early PH. Additionally, vasoreactivity testing during RHC can guide therapy in selected patients with pulmonary arterial hypertension (PAH) (2).

PAH is rare in children; however, when it occurs, it is most commonly associated with congenital heart disease (CHD). In a large U. S. claims-based study [2010–2013], 75% of pediatric PAH cases were linked to congenital heart defects VSports在线直播. The annual incidence of PAH in children ranged from 4. 8 to 8. 1 per million, with prevalence reaching up to 32. 6 per million with rates being the highest in children under 2 years of age. These findings underscore the rarity of PAH associated with CHD (PAH-CHD) in the pediatric population and the importance of early recognition (3).

Rationale and gap

Pediatric PH remains an underexplored field, with significant gaps in understanding its natural history, underlying mechanisms, and optimal management strategies. Most biomarkers studied in pediatric PAH associated with CHD have not been validated against RHC, which remains the diagnostic gold standard V体育2025版. Moreover, longstanding PH is known to be associated with poor long-term outcomes in children with severe disease, even following corrective surgical intervention (4).

PH encompasses a range of subtypes, each defined by distinct pathophysiologic mechanisms, hemodynamic profiles, and clinical trajectories. PAH, a distinct subset of PH, is a progressive vasculopathy characterized by obstructive arteriolar remodeling and elevated PVR, ultimately leading to right ventricular (RV) failure (5). In pediatric patients with CHD, where cardiovascular anatomy is often complex and does not conform neatly to a single PH classification, PAH remains a central concern, particularly given its potential for reversibility in selected cases. This review focuses on evaluating biomarkers that may aid in distinguishing between reversible and irreversible PAH VSports. We explore mechanistic pathways such as apoptosis resistance, smooth muscle proliferation and neointimal formation, and vascular remodeling, while also examining tissue-based, genetic, and blood-based biomarkers that hold promise for non-invasive risk stratification and surgical decision-making.

Surgical candidacy and long-term prognosis for pediatric patients with PAH remain key areas of investigation. Clinical, laboratory-based, and hemodynamic assessments have all been historically used as surrogates in aiding to identify surgical candidates with predicted good outcomes. Age at the time of surgical correction has been considered a major contributor to long-term survival and avoidance of pulmonary vascular disease (PVD) (6). From a laboratory perspective, since the 1950s when Heath and Edwards introduced their histological classification system of changes in the pulmonary arteries and arterioles in patients with PAH (7), it has been often used as a qualitative reference for reversibility. Despite having the opportunity of gathering objective data through lung tissue biopsy that can lead to informative decision making for patients with PAH, pre-operative histopathological assessment has been largely abandoned in clinical practice since the 1980s, partly due to the significant risks associated with open lung biopsy, which include morbidity rates of 13% and mortality rates of 20% in children with PAH-CHD (8) VSports app下载. More recent biomarkers used in prognostication include brain natriuretic peptide (BNP) and its more stable byproduct, N-terminal pro B-type natriuretic peptide (NT-proBNP). While increased levels have been related to worsening prognosis in PH patients, these measures lack specificity as markers of PVD or RV remodeling (9). Hemodynamically, acute vasoreactivity testing (AVT) as a predictor for short and long-term outcomes (10,11) has been used often to evaluate if the PVR decline will be sufficient for effective surgical repair. However, AVT represents only one component in determining operability; comprehensive evaluation must also account for the overall clinical context, patient age, and the specific type of congenital lesion (12-15).

"V体育平台登录" Objective

Although detailed knowledge of patients’ abnormal intracardiac anatomy and physiology can be characterized in the modern era, clearly understanding the pathogenic mechanisms for irreversibility and defining clear cut-off clinical or non-clinical criteria remains one of the major gaps in that field due to the lack of validated, child-specific biomarkers that are benchmarked against the gold standard which is RHC. This highlights the need for exploring alternative reliable tools that have the potential to offer better understanding of the disease spectrum while avoiding the complications and the risks of open lung biopsies. Biomarkers, which are biochemical, cellular, or molecular changes that can be objectively measured in biological media such as human tissues, cells or fluids present may offer a promising alternative (16). While earlier literature has reviewed biomarkers in PAH associated with CHD, this review places a specific emphasis on markers explored in relation to clinical or hemodynamic reversibility, particularly in patients who demonstrated improved outcomes after follow-up V体育官网. We organize the discussion around key mechanistic pathways including apoptosis resistance, smooth muscle proliferation, vascular remodeling, and genetic regulation, highlighting experimental and clinical studies in each area. This perspective aims to enhance clinical relevance by linking molecular findings to operability decisions. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm. amegroups. com/article/view/10. 21037/pm-24-93/rc).

Methods

The review encompassed both recent and historical English language publications indexed in PubMed, Scopus, and Google Scholar, spanning the period from January 2000 to November 2024. The search focused on studies investigating biomarkers of reversibility in PAH-CHD in pediatric populations VSports手机版. More details about the methods, search terms and summary of the search results, including the number of articles retrieved by search term and the number of eligible articles per source are provided in Tables 1,2. A total of 20 articles were initially identified through the structured database search. After removal of duplicates, 9 unique articles met the inclusion criteria and were reviewed. Additionally, 4 relevant articles were identified through manual searching, based on their relevance and frequent citation in the literature. These were evaluated using the same eligibility criteria as the database-identified articles. Inclusion criteria were original research or review articles published in English. Articles were excluded if they were duplicates, abstracts, case reports, or not directly related to the reversibility of PAH in children with CHD. In total, 13 articles were included in the final review.

Markers of apoptosis (VSports)

Apoptosis, or programmed cell death, plays a crucial role in maintaining normal cell turnover and facilitating vascular remodeling (17). Experimental and cell culture studies have showed that resistance to programmed cell death has been implicated in the pathogenesis of abnormal vascular proliferation (18,19). Daunorubicin, an apoptosis-inducing anti-tumor agent, has been shown to reduce pulmonary arterial wall thickness by promoting programmed cell death in cultured human pulmonary artery smooth muscle cells (PASMCs) (20). Apoptosis resistance is a described characteristic in the progression of malignant tumor, programmed cell death related markers have been used as prognostic indicators. Given the cancer-like behavior of pulmonary vascular cells in PAH which is characterized by excessive proliferation and resistance to programmed cell death, apoptosis-associated biomarkers may have the potential to be of use in evaluating reversibility in patients with PAH-CHD (21).

Apoptosis resistance, growth arrest, DNA repair deficiency while being still metabolically active with losing the ability to divide is a state known as senescence, a state of permanent cell cycle arrest as a response to various stressors such as DNA damage. Senescence is the shift toward the pro-inflammatory senescence-associated secretory phenotype (SASP). Markers for senescence and SASP could be investigated as potential markers for irreversibility of PH (22). Senescence in endothelial cells hinders the production of nitric oxide and prostacyclin, thereby promoting vascular dysfunction, constriction, and sclerosis (23).

"VSports最新版本" P16ink4A and p21cip1: cellular senescence

van der Feen et al. using monocrotaline (MCT), which is a plant-derived toxin that causes injury to the pulmonary arterioles and induces regional inflammation, ultimately leading to pulmonary vascular remodeling and hypertension; investigated the role of cellular senescence in the progression and irreversibility of PAH using MCT plus aorto-cava shunt (MCT-AV) rat models, aiming to create a model with severe, flow-induced PAH mimicking neointimal-type vascular remodeling seen in human PAH (24). Hemodynamic unloading (HU) was achieved by performing a left lung transplant of PAH rat models into recipient rats with normal pulmonary vasculature. HU has demonstrated the ability to reverse PAH in its early stages, but not in advanced disease (point of irreversibility in the study was identified at 28 days after MCT injection). To elucidate the molecular basis behind this they used RNA sequencing on lung tissues from rats and human PAH tissues. They reported that developing irreversibility was associated with cell transition from a hyperproliferative, proapoptotic phenotype to a growth-arrested, apoptosis-resistant, and proinflammatory senescent vascular phenotype. Immunohistochemical analysis showed that in the endothelium of the reversible PAH group, there was increased expression of Ki67, a proliferation marker, and cleaved caspase-3, an apoptosis marker. In contrast, key senescence biomarkers such as p16^INK4a, and p21^Cip1, along with SASP-associated markers like matrix metalloproteinase-2 (MMP2), were elevated in the irreversible group compared to the reversible group.

Reinforcing their theory, they conducted in vitro experiments targeting senescence using the senolytic ABT263, showing reversibility in MCT-AV PAH rat models that were refractory to HU. ABT263 reduced luminal occlusion and neointima formation, as well as decreased mPAP, systolic RV pressure (sRVP), and PVR (P<0.05). Their findings concluded that cellular senescence plays a critical role in the transition from reversible to irreversible PAH, suggesting that targeting senescent cells could be a novel therapeutic approach for advanced PAH (25).

Bcl-2 anti-apoptosis marker: a key player in irreversible PAH (V体育2025版)

Lévy et al. hypothesized that apoptosis resistance in endothelial cells may characterize irreversibility of PAH. They studied 18 patients with PAH-CHD, including patients with single ventricle (SV) physiology, ventricular septal defect (VSD), atrial septal defect (ASD), and transposition of great arteries (TGA) with VSD. Immunohistochemistry of lung tissues obtained in the operating room during surgical repair demonstrated that patients with irreversible PH (persistent elevated PAP >25 mmHg at one year follow up post-surgery) have increased levels of Bcl-2 in their endothelial cells. On the other hand, none of the reversible cases expressed Bcl-2 (P<0.001). Their work highlights the role of dysregulated endothelial cell apoptosis in the pathogenesis of irreversibility of PH (26).

Survivin

An inhibitor of apoptosis protein (IAP) family member, survivin is found abundantly in most human tumors and has been a valuable marker for prognostication (27) but not found in normal adult differentiated tissues (28).

McMurtry et al. although not specifically investigating the reversibility of PAH, reported in their study that PASMCs collected from patients with severe PAH were resistant to apoptosis and expressed survivin compared to patients with no PAH. Furthermore, through implementing survivin-targeted gene therapy, they selectively induced pulmonary vascular programmed cell death and reversed PAH (29).

Li et al. at the Beijing Anzhen Hospital between January 2015 and December 2017, measured preoperative serum survivin level and mPAP 3 days postoperative in 60 CHD patients (non-restrictive VSD >1 cm and ASD >2 cm) with preoperative PVR index (PVRi) greater than 4 Wood units·m² (WU·m²) and mPAP >25 mmHg, who underwent shunt closure. They reported that preoperative serum survivin showed significantly higher levels in the irreversible PAH group compared to the reversible group (mPAP <25 mmHg 3 days post op) with a P value <0.05. Additionally, serum survivin levels positively correlated with preoperative PVRi (r=0.282, P=0.029) (30).

"V体育2025版" Smooth muscle proliferation, neoangiogenesis & neointimal formation

VSports - Endothelin-1 (ET-1) and its receptors

ET-1 was described in 1988 as a potent vasoconstrictor that participates in vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation (31). It is predominantly released from the basal surface of endothelial cells and, to a lesser extent, synthesized and secreted by smooth muscle cells (SMCs), contributing to the regulation of basal vascular tone (32,33). Two endothelin receptors have been described in literature: endothelin type A receptor (ETAR) which is predominantly found on the surface of SMCs, and endothelin type B receptor (ETBR) which is found on the surface of both endothelium and SMCs. Those receptors act as mediators of vasoconstriction and proliferation of the vascular SMCs (34). Furthermore, endothelial dysfunction has been documented as a contributing factor to PH in patients with CHD (35,36).

In their work on predicting reversibility of PH, Huang et al. reported that the traditional hemodynamic measurements were inconsistent in deciding reversibility for patients with PAH-CHD. AVT, using 100% oxygen, nitric oxide, and/or other vasodilators, showed limited predictability. To address this, the researchers investigated other markers for reversibility beyond AVT, using immunohistochemistry on lung biopsy specimens collected during corrective surgeries in patients with PAH-CHD. Immunohistochemical analysis revealed that the expression of ET-1, ETAR, and ETBR was significantly higher in the irreversible group, with P values of <0.01, <0.05, and <0.01, respectively. PAH was diagnosed using transthoracic Doppler echocardiography (DEC) and RHC, with inclusion criteria of systolic pulmonary artery pressure (sPAP) >65 mmHg and mPAP >50 mmHg. The severity of PAH was categorized based on sPAP values into three groups, severe (sPAP of >65 mmHg), moderate (sPAP of 55–64 mmHg), or mild (sPAP of 40–54 mmHg). Over a median follow-up period of 1.5 years after surgery, reversibility was determined by a decrease in PAH severity, transitioning from the severe to the mild category. The findings suggest that increased expression of ET-1, ETAR, and ETBR, along with activation of their downstream signaling pathways, contributes to irreversible pulmonary vascular abnormalities. This study emphasizes the importance of molecular markers in the assessment and management of PAH-CHD patients, providing insights into improving predictive methods and therapeutic strategies (37).

Transgelin protein

Transgelin, also known as SM22α, is a protein belonging to the calponin family. It is abundantly found in the cytoskeleton of vascular SMCs and is one of the earliest markers of smooth muscle differentiation (38-41). Huang et al. speculated that transgelin may influence the PASMCs function, thus promoting pulmonary vascular remodeling in irreversible PAH-CHD patients. In order to prove their hypothesis, lung biopsies were obtained from CHD patients with PAH undergoing complete surgical repair to investigate the association between transgelin and reversibility of PAH. At 1-year post-surgery, RHC measuring of mPAP was performed to differentiate between reversible PAH (<25 mmHg) and irreversible PAH (≥25 mmHg). Immunohistochemical analysis reported that lung tissue from the irreversible PAH group exhibited transgelin expression, in contrast to the reversible PAH group (P<0.05). They also recognized that increased expression of transgelin has promoted PASMCs proliferation and migration, as well as strengthening the cytoskeleton. Moreover, transgelin has increased the synthetic phenotype markers expression and anti-apoptotic proteins promoting pulmonary arterioles remodeling, leading to irreversible pulmonary vasculopathy (42).

Nestin

Nestin originally identified in neural progenitor and stem cells of the central nervous system, is a cytoplasmic protein currently regarded as a marker for this cell type (43). Also, during reparative angiogenesis, nestin is upregulated in vascular cells, and its expression is also observed in ventricular cardiomyocytes in the setting of human myocardial infarction (44-46). In a study conducted by Saboor et al. they reported increase Nestin expression in MCT-AV induced PAH rat models and patients (47).

Zhou et al. hypothesized that nestin may play a critical role in the proliferation of PASMCs and serve as a key driver of pulmonary vascular remodeling in PAH-CHD patients. To evaluate this hypothesis, the researchers examined lung tissues from PAH-CHD patients and rat models. Their findings revealed that nestin expression was significantly higher in the irreversible patient group with PAH-CHD compared to both the reversible group and normal controls. Proteomic analyses showed a 1.65-fold increase in nestin expression in the irreversible PAH-CHD patient group with PAH-CHD compared to the reversible group, and a 3.05-fold increase compared to normal controls.

These findings were further supported by immunohistochemistry staining, which showed higher average optical density (AOD) of nestin in pulmonary arterioles from the irreversible PAH-CHD group. Moreover, a significant correlation was shown between nestin expression and pathological grading in PAH-CHD patients, with a correlation coefficient I of 0.51 (P<0.05).

The study concludes that nestin may serve as a potential marker for pulmonary vascular remodeling in PAH-CHD patients and could provide insights into mechanisms that distinguish reversible from irreversible PAH. These findings highlight the potential of nestin as a therapeutic target in managing this patient cohort (48).

Thrombospondin-4 (THBS4)

THBS4 is a member of the extracellular matrix (ECM) protein-thrombospondin family. In vitro and in vivo studies showed that THBS4 promotes growth of vascular cells, angiogenesis, and vascular remodeling (49-52).

Zeng et al. conducted a study to investigate the role of THBS4 in PAH-CHD. They used an MCT-AV rat model to induce PAH and measured THBS4 expression in lung tissues. Compared with the reversible PAH group, THBS4 expression was significantly increased in the irreversible PAH group with a P value of <0.0001. In their study, reversibility of PAH in the rat models was diagnosed by the normalization of morphological changes that was observed after HU, achieved by transplanting the left lung of MCT-AV rats into healthy rats. Although they did not investigate reversibility in human patients, they investigated the association between circulating THBS4 levels and the severity of PAH. The cohort was divided into; simple CHD (n=8); mild PAH-CHD (n=5), referring to cases where the shunt remained amenable to surgical repair; and severe PAH-CHD (n=5), encompassing patients with uncorrectable defects, post-repair residual PAH, or Eisenmenger physiology. THBS4 was found to be significantly upregulated in severe PAH-CHD, compared to simple CHD and mild PAH-CHD, P=0.04 and P=0.03, respectively. These results suggest that THBS4 is a potential biomarker for distinguishing between reversible and irreversible stages of PAH (53).

Medial collagen content, medial thickening, and the alveolar-arterial ratio on lung biopsy

The pulmonary vascular histological changes described previously by Heath and Edwards including medial coat thickening, intimal layer proliferation, and intra-acinar artery decreased density are hallmark features of abnormal vascular growth (54,55). When obtained via lung biopsy, these structural changes serve as tissue-based biomarkers, providing quantifiable histological indicators that correlate with disease severity, reversibility, and clinical outcomes. Egito et al. analyzed lung biopsy specimens from 26 children with PAH and found that pronounced medial thickening and increased collagen content were significant markers of irreversibility, reporting that arterial medial collagen content was significantly associated with intensive care unit (ICU) complications (P=0.03) and persistent PAH at follow-up (P=0.004). Additionally, medial thickening greater than twice the normal value was associated with ICU complications (P=0.042) and negatively associated with good clinical performance, normal pulmonary arterial pressure, and survival. The alveolar-arterial ratio greater than twice the normal value was negatively associated with survival (P=0.014) and positively associated with persistent PAH at follow-up (P=0.008). These statistical correlations highlight the importance of these markers in predicting the reversibility of PAH post-surgery (56). The findings suggested that early intracardiac repair before significant medial fibrosis development could improve outcomes.

Caveolin-1, filamin A (FLNA), cathepsin D and glutathione S-transferase mu 1 (GSTM1)

Caveolin-1: a key scaffolding protein constituent of caveolae and heavily present in epithelial, endothelial cells, fibroblasts, and SMCs. It has been reported that the expression of caveolin-1 in PASMCs has promotes proliferation in idiopathic PAH (57).

FLNA: FLNA exists as a protein that helps build the cytoskeleton, the network of protein filaments that gives cells structure and the ability to change shape (58). It has been shown to promote tumor progression and angiogenesis (59). Given the cancer-like behavior of SMCs in PAH marked by excessive proliferation and resistance to apoptosis, it is hypothesized that FLNA may similarly contribute to enhanced SMC proliferation and reduced programmed cell death in this context.

Cathepsin D: a soluble protease that when enzymatically active can free growth factors (such fibroblast growth factor), promoting tumor progression and angiogenesis (60,61).

GSTM1: a member of glutathione-S transferases superfamily, GSTM1 metabolizes a wide array of reactive oxygen species (ROS) and xenobiotic compounds. In vitro studies have shown that GSTM1 knockdown results in enhanced proliferation and migration of vascular SMCs, suggesting that GSTM1 may function as a novel regulator of vascular smooth muscle cell (VSMC) behavior (62).

Based on the earlier literature and preliminary data on caveolin-1, FLNA, cathepsin D and GSTM1, in 2018 Huang et al. investigated these potential biomarkers in relation to the reversibility of PAH-CHD. The study included 14 PAH-CHD patients diagnosed with RHC, primarily with ASD and VSD. The cut off for reversibility was mPAP of ≥25 mmHg at rest at one year post complete surgical repair. Caveolin-1, FLNA, GSTM 1 and cathepsin D expression were measured in lung tissue samples from patients. The study showed that the upregulation of caveolin-1, FLNA, and cathepsin D, accompanied by the increased macrophagocytes presence, and the downregulated GSTM1 were significantly associated with irreversible PAH (P values <0.05). Based on Heath and Edwards classification system, pathological changes in the irreversible PAH group included pulmonary arteriolar lesions graded as III or IV, characterized by medial hypertrophy, intimal fibrosis, early diffuse vascular dilatation (grade III), and advanced vascular remodeling with progressive dilatation and luminal occlusion due to intimal fibrosis and fibroelastosis (grade IV). These biomarkers showed significant correlations with the severity of pulmonary vascular lesions, with the upregulation of caveolin-1, FLNA, and cathepsin D, along with increased macrophagocytes, positively correlated with higher pathological grades, and downregulated GSTM1 negatively correlated. The study concluded that these biomarkers and associated pathological changes in lung biopsies could serve as valuable tools in predicting the irreversibility of PAH-CHD patients (63).

Blood-based biomarkers

Circulating endothelial cells (CEC) are a noninvasive tool for assessing vascular integrity, remodeling, and functional impairment, all key players in the pathophysiology of PAH (64). While present at undetectable levels in healthy individuals, higher levels have been observed in different pathological conditions, such as coronary artery disease (65,66). Wang et al. in their efforts of assessing reversibility of PH related to CHD, investigated CECs, ET-1, and endothelial nitric oxide synthase (eNOS) as markers of pulmonary vascular dysfunction. Patients with suspected and confirmed PAH were stratified based on tricuspid regurgitation (TR) velocity measurements and were further categorized into reversible and irreversible groups based on 6 months postoperative follow up measurements. Patients were considered irreversible if they had TR >3.4 m/s, evidence of clinical deterioration, or death during follow-up. The study reported that CECs and ET-1 levels were significantly elevated in the confirmed group, compared to the normal group. CEC levels were also higher in the irreversible group vs. the reversible group (P=0.004), indicating their potential as a marker of irreversibility. However, no significant intergroup differences were observed for ET-1 and eNOS levels in terms of reversibility. The study highlighted the high diagnostic value of risk stratification combining imaging and CECs in evaluating the reversibility of PH-CHD (67).

Smadja et al. likewise studied the utility of CECs in assessing PAH reversibility associated with CHD, including 26 CHD patients with PAH, who underwent VSD closure, pulmonary artery banding, ASD closure, repair of truncus arteriosus, patent ductus arteriosus (PDA) closure. They stratified patients into reversible and irreversible PAH based on mPAP measured 6 months post-surgery. mPAP >25 mmHg was defined as irreversible PAH. In their analysis they found that CECs counts in patients with irreversible PAH was 13.2 times higher than in patients with reversible PAH (P<0.0001) (68).

Potential biomarkers for PAH reversibility

"V体育ios版" Circulating miRNA

Earlier studies observed miRNA’s key role in apoptosis and SMCs proliferation (69). The miR-17-92 cluster, including miR-19a, was reported to be overexpressed in PH, contributing to SMC proliferation and angiogenesis (70).

Chen and Li, although not investigating reversibility of PH-CHD in their work, hypothesized that circulating microRNAs, particularly miR-19a, could serve as novel biomarkers for PAH-CHD. Their patient cohort included 30 patients with VSD, divided into PAH (n=14), severe PAH (mPAP >45 mmHg) and a control group (n=16) without PAH (mPAP <25 mmHg). In summary, analyzing both lung tissues and blood levels of miR-19a showed that it could be a potential biomarker, finding that miR-19a levels were significantly elevated in the PAH group, with a nearly 17-fold increase compared to the control group (P<0.0001) (71).

Genetic markers

Zeng et al. performed bioinformatic analysis on RNA sequence. The study cohort consisted of rats with (MCT-AV)-induced PAH, divided into three groups: a control group (n=5), a reversible PAH group (n=12), and an irreversible PAH group (n=6). It was hypothesized that dysregulation of cell cycle control, metabolic pathways, inflammatory responses, and mechanisms of DNA damage and repair may contribute to the loss of reversibility seen in late-stage PAH-CHD. Through their analysis they identified 880 differentially expressed genes (DEGs) between reversible and irreversible PAH-CHD, with 678 down-regulated and 203 up-regulated in the irreversible group. Key pathways significantly elevated in the irreversible PAH-CHD group included complement and coagulation cascades (adjusted P<0.001), ECM-receptor interaction (adjusted P=0.004), and focal adhesion (adjusted P=0.015). Additionally, hub genes such as interleukin 6 (IL-6) and collagen type I alpha 1 chain (Col1a1) were identified as significantly up regulated in the irreversible group. The study also highlighted that the renin-angiotensin system and ferroptosis were up-regulated in the irreversible patient group, while the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was down-regulated. These findings imply that alterations in cell cycle regulation, metabolic processes, inflammatory pathways, and DNA damage and repair mechanisms may underlie the loss of reversibility in advanced stages of PAH-CHD. The comprehensive analysis of DEGs and their biological functions offers new insights into the molecular mechanisms underlying the transition from reversible to irreversible PAH-CHD, potentially guiding future therapeutic strategies (72).

Conclusions

Assessing reversibility remains a challenge in the management of PAH-CHD. Despite the use of informative tools such as histopathological analysis, hemodynamic measurements, and circulating biomarkers, no consensus currently exists on a safe and reliable strategy to predict operability. This has driven the search for novel biomarkers capable of predicting reversibility with greater accuracy. Our review highlights a range of novel tissue and blood-based biomarkers that reflect diverse mechanisms such as apoptosis resistance, senescence, endothelial dysfunction, and smooth muscle proliferation, each offering potential insight into the transition from reversible to irreversible disease. To facilitate clarity, a summary of the reviewed biomarkers, including sample type, association with reversibility, and statistical significance, is provided in Table 3. However, these findings must be interpreted considering several important limitations. The reviewed studies varied in biomarker detection methods, including immunohistochemistry on lung tissue versus serum-based assays, resulting in methodological inconsistencies that limit reproducibility and comparability. In addition, very few studies accounted for age-related physiological variation in pediatric patients or incorporated age-specific thresholds for interpretation. This limits the generalizability of their findings across broader pediatric subgroups. Definitions of reversibility also differed substantially, with some studies using postoperative RHC (mPAP thresholds), while others relied on echocardiographic or clinical improvement criteria. These discrepancies further hinder efforts to validate findings or translate them into clinical protocols.

Despite these limitations, the reviewed biomarkers show early promise in improving perioperative decision-making. Several markers demonstrated potential to stratify operability risk prior to cardiac repair and may also serve as tools for dynamic follow-up to assess response to surgical interventions. In clinical practice, blood-based markers such as survivin could be valuable in risk triage, while histologic markers, though more invasive, may offer critical insights when tissue is already being obtained intraoperatively. Future research should aim to build on these findings by conducting prospective multicenter studies with standardized detection protocols, age-specific reference ranges, and harmonized definitions of reversibility. As a narrative review, a key strength of our work lies in its focus on pediatric PAH-CHD and its synthesis of early evidence linking biomarker expression to reversibility. However, limitations include the exclusion of non-English publications, the reliance on primarily small-scale or single-center studies, and the heterogeneity in study designs. However, our literature review has highlighted the preliminary promise of these multiple biomarkers, hoping to facilitate further, larger scale validation studies that may allow for effective clinical utility of these markers in the quest to better understand and manage risk profiles in this high risk, high morbidity population of patients.

"V体育安卓版" Acknowledgments

None.

VSports注册入口 - Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-93/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-93/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-93/coif). The authors have no conflicts of interest to declare.

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