Highlight
1. Unclassified pulmonary hypertension (PH) affects approximately 7.8% of symptomatic patients undergoing pulmonary vascular assessment and commonly features normal resting pulmonary vascular resistance and wedge pressure.
2. Advanced phenotyping reveals that unclassified PH predominantly represents early, subclinical heart failure with preserved ejection fraction (HFpEF), driven by left heart remodeling and metabolic dysfunction.
3. Dynamic exercise right heart catheterization unmasked elevated pulmonary artery wedge pressure indicating undiagnosed HFpEF in over half of patients with unclassified PH.
4. Metabolomic profiling demonstrated reduced glycine metabolites in unclassified PH, linking metabolic shifts to disease pathophysiology and potential therapeutic targets.
Study Background
Pulmonary hypertension (PH) is a heterogeneous syndrome characterized by elevated pulmonary artery pressures, often secondary to disorders affecting pulmonary vasculature or the left heart. While classical PH definitions rely on elevated resting pulmonary vascular resistance (PVR) and pulmonary artery wedge pressure (PAWP), a subset of symptomatic patients present with elevated pulmonary artery pressures despite normal resting hemodynamics—termed unclassified PH. These patients exhibit neither the hallmark vascular resistance increase seen in pulmonary arterial hypertension (PAH) nor overt left heart disease traditionally linked to PH. Prior hypotheses suggested that increased pulmonary flow, such as in congenital heart disease (CHD), might underlie this condition. However, the broader clinical implications, phenotypic characteristics, and underlying pathophysiology remain incompletely understood, complicating diagnosis and management strategies.
Study Design
This investigation utilized data from the PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort, comprising 1046 participants, including individuals with no PH and those with unclassified PH. The study integrated dynamic right heart catheterization protocols combined with comprehensive transpulmonary metabolomics profiling to characterize disease phenotype. To validate findings, a separate cohort of 1202 individuals underwent exercise right heart catheterization to assess hemodynamic responses under stress conditions. Exploratory analyses examined unclassified PH prevalence in two clinical populations with frequent pulmonary flow alterations: adult congenital heart disease (n=1005) and high output heart failure (n=159). Comparative evaluations included clinical metrics, cardiac remodeling parameters, biomarker profiles, exercise capacity, and quality of life assessments.
Key Findings
Prevalence
The prevalence of unclassified PH was 7.8% (175/2248) across the PVDOMICS and validation cohorts combined, closely matching the 6.6% prevalence observed in adult congenital heart disease, while significantly lower than the 14.5% in high output heart failure (p=0.006), indicating a notable presence of this phenotype in diverse cardiac conditions.
Flow Contributions
Contrary to hypotheses focusing on increased pulmonary flow as a main driver, only a minority of unclassified PH patients demonstrated increased flow: 28% in PVDOMICS and 11% in the validation cohort. This suggests that elevated pulmonary pressure in this group is not predominantly explained by flow dynamics alone.
Phenotypic Characteristics
Compared to subjects without PH, individuals with unclassified PH exhibited significantly greater adiposity and higher risk scores associated with HFpEF, including advanced age and body mass index. Notably, markers of left heart remodeling—such as atrial enlargement and left ventricular structural changes—were more pronounced. Arrhythmia burden, exemplified by increased atrial fibrillation probability scores, was also higher, reinforcing the link between left heart disease and unclassified PH.
Metabolic Profiling
Metabolomic analyses revealed lower levels of glycine-related metabolites in the unclassified PH group, indicating disrupted amino acid metabolism and broader metabolic dysfunction. Glycine is integral to cardiovascular and endothelial function and its deficiency may contribute to pathophysiology through oxidative stress and impaired vascular homeostasis.
Functional and Quality of Life Measures
Unclassified PH patients demonstrated reduced exercise capacity and impaired quality of life compared to healthy controls. These functional deficits align with early signs of heart failure despite normal resting hemodynamics.
Hemodynamic Insights
Resting catheterization in unclassified PH showed subtle abnormalities in PAWP, PVR, and pulmonary artery compliance compared to no PH. Exercise provocation testing identified that 59% of unclassified PH patients developed abnormal elevation of PAWP with exertion, consistent with occult HFpEF. This dynamic assessment was critical in unmasking left heart dysfunction not apparent at rest.
Expert Commentary
These findings underscore that unclassified PH likely represents an early or subclinical stage of HFpEF, with left heart remodeling and metabolic dysregulation as central features. The use of dynamic exercise right heart catheterization is pivotal in revealing latent left-sided filling pressures. This advances current understanding beyond traditional PH classifications by incorporating metabolic and hemodynamic nuances that inform pathophysiology and therapeutic approaches.
Limitations include the observational nature of the cohorts and potential referral biases. The metabolomic findings, while compelling, require further mechanistic exploration and validation in longitudinal studies. Nonetheless, this study provides a robust phenotypic framework guiding clinicians to consider early HFpEF in unexplained pulmonary hypertension presentations.
Conclusion
Unclassified pulmonary hypertension most commonly reflects subclinical left heart and metabolic dysfunction consistent with early HFpEF, rather than isolated pulmonary vascular disease or increased flow states. Dynamic right heart catheterization with exercise testing is a valuable diagnostic tool to unmask occult HFpEF in this population, enabling timely initiation of evidence-based therapies targeting HFpEF pathobiology. Integration of metabolic biomarkers such as glycine metabolites offers potential avenues for improved mechanistic insight and personalized treatment strategies. Collectively, these advances can improve symptom control, exercise tolerance, and quality of life for patients with this complex condition.
Funding and Clinical Trials Registration
This research was conducted within the framework of the PVDOMICS study. The trial is registered at ClinicalTrials.gov under the identifier NCT02980887.
References
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