Highlight
- Latent class analysis (LCA) stratified adult PAH-CHD patients into distinct phenogroups with varied clinical and hemodynamic profiles.
- Post-tricuspid shunt phenogroups identified groups with differing right ventricular adaptation, mortality, and response to PAH-targeted combination therapy.
- Pre-tricuspid shunt phenogroups revealed survival differences influenced by comorbidities and inflammation, highlighting attenuated treatment responses in older males.
- Data-driven phenotyping offers a promising tool for personalized risk stratification and clinical management in PAH-CHD.
Study Background
Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a complex clinical condition characterized by elevated pulmonary arterial pressures due to structural cardiovascular anomalies. It presents a diverse clinical spectrum, ranging from patients with well-compensated right heart function to those with severe right ventricular failure and poor prognosis. Conventional classification, largely based on anatomical shunt type and pathophysiology, inadequately captures this heterogeneity, limiting precise risk stratification and personalization of treatment strategies. Given the significant morbidity and mortality associated with PAH-CHD, there is a pressing need for refined phenotyping methods to better understand disease mechanisms and guide therapy.
Study Design and Methods
This study utilized a large, multicenter prospective national registry including 889 adult patients diagnosed with PAH-CHD. Patients were stratified into subgroups based on shunt location: post-tricuspid shunts and pre-tricuspid shunts. Within each group, latent class analysis (LCA), an unsupervised clustering technique, was applied to 28 candidate variables encompassing clinical data, laboratory values, and invasive hemodynamic parameters. The goal of LCA was to identify phenotypically homogeneous subgroups (phenogroups) to enable refined prognostication and evaluation of response to pulmonary arterial hypertension–targeted therapies over a 10-year follow-up period. Outcomes analyzed included survival and the effect modification of PAH-directed medication regimens.
Key Findings
Post-Tricuspid Shunt Subset
LCA revealed four distinct phenogroups:
- Group 1 “Adaptation with Open Shunt”: This group demonstrated preserved right ventricular (RV) function despite high pulmonary afterload, resulting in the most favorable survival outcomes. An open shunt possibly facilitates right heart adaptation and effective decompression.
- Group 2 “Hyperkinetic State”: Characterized by a hyperdynamic circulation, this phenotype uniquely exhibited significant survival benefit from combination PAH-targeted therapies (interaction P=0.026), highlighting potential for tailored therapeutics in this subgroup.
- Group 3 “Maladaptation and Failure” and Group 4 “Closed Shunt and Failure”: Both groups showed marked maladaptive right ventricular remodeling, with two- to threefold increase in mortality compared to Group 1. Group 4 additionally had closed shunts reflective of advanced disease pathophysiology and the poorest prognosis.
Pre-Tricuspid Shunt Subset
Four phenogroups also exhibited heterogeneity:
- Group 1 “High Shunt and Mild Resistance” and Group 3 “Young Female and Low Inflammation”: Both groups showed preserved survival despite different degrees of pulmonary vascular resistance, with young females showing lower systemic inflammation suggestive of better systemic adaptation.
- Group 2 “Old Male and Comorbidities”: This subgroup carried significantly higher mortality and attenuated treatment response (interaction P=0.037) despite relatively mild hemodynamics, emphasizing the impact of age and comorbidity on outcomes beyond traditional hemodynamic criteria.
- Group 4 “High Resistance and Failure”: Marked by severe hypoxemia and the worst prognosis, linked to advanced pulmonary vascular disease and right heart failure.
The findings underscore that survival and therapeutic efficacy in PAH-CHD are influenced not only by anatomic and hemodynamic variables but also by patient-specific factors such as age, sex, inflammation status, and right heart adaptation.
Expert Commentary
This study represents a significant advancement in the nuanced understanding of PAH-CHD phenotypes. The application of latent class analysis demonstrates how complex, multidimensional clinical data can be leveraged to redefine disease subgroups beyond classic classifications. Specifically, the identification of phenogroups with differential mortality risk and distinct responses to combination PAH therapies offers a framework for personalized medicine.
Importantly, the data suggest that residual shunting and right ventricular adaptation mechanisms critically influence clinical trajectory. The attenuated responses seen in older males with comorbidity challenges the notion that mild hemodynamics alone predict favorable outcomes, bringing attention to systemic factors and inflammation. This aligns with emerging pathobiological paradigms in pulmonary hypertension emphasizing the multifaceted disease process.
Limitations include the observational nature and reliance on registry data, which could introduce selection biases and limit causal inference. Additionally, external validation in independent cohorts and integration with molecular biomarkers would strengthen the phenotyping utility. Nevertheless, the prospective design and large sample size confer robustness.
This paradigm may also spark reevaluation of guideline-based risk stratification and treatment algorithms in PAH-CHD, advocating for phenogroup-informed clinical trials and therapeutic decisions.
Conclusion
Latent class analysis applied to a large adult cohort with PAH-CHD successfully delineated distinct phenotypic clusters with divergent survival profiles and treatment responses. This novel phenotyping approach transcends traditional clinical and anatomical classifications, providing a powerful tool for refined risk stratification and individualized therapy selection. Incorporating data-driven phenogrouping into routine clinical assessment and research may enhance prognostication and optimize PAH management in congenital heart disease populations. Future studies should focus on prospective validation and exploration of underlying biological mechanisms to further personalize patient care.
Funding and ClinicalTrials.gov
The original study was conducted under multicenter national registry funding; specific financial disclosures or clinical trial registry numbers were not provided in the abstract.
References
1. Li Q, Yu Q, Zhang G, et al. Phenotyping of pulmonary arterial hypertension associated with congenital heart disease using latent class analysis: insights from a national prospective registry. Chest. 2026 Jun 20; [PMID: 42323108].
2. Humbert M, et al. Pulmonary arterial hypertension in congenital heart disease: clinical features, survival, and treatment approaches. Eur Respir J. 2010.
3. Simonneau G, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019.
4. Hoeper MM, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2015.