Frantz, Robert P.

Background: Pulmonary hypertension (PH) is a life-threatening disease affecting up to 1% of the global population. Diagnosis can be challenging and is often delayed due to the need for advanced imaging and invasive procedures. The use of artificial intelligence applied to ECGs (ECG-AI) has been shown to detect subtle patterns in voltage-time data and may be a valuable tool for the early detection of PH. Hypothesis and Purpose: To evaluate the performance of a previously trained, ECG-AI algorithm to detect PH (ECG-AI PH) using real-world data (RWD) collected in a multicenter, validation study. A joint primary hypothesis required sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) to exceed the null values of 76%, 70%, 10% and 90%. Study Design and Methods: This retrospective validation study was conducted at 5 geographically diverse U.S. health systems. Adult subjects were eligible for inclusion if they had a 12-lead ECG paired with an echocardiogram (Echo) in which tricuspid regurgitation velocity (TRV) was recorded, following presentation with dyspnea. Patients were classified according to echocardiographic criteria as either PH (PH+, TRV >3.4 m/s) or controls (PH-, TRV ≤2.8 m/s) to simulate the real-world use of ECG-AI, where a positive result could lead to a follow-up Echo. The study database was locked before processing the digital ECGs with ECG-AI PH. Performance was also estimated in a subset of subjects that later had a right heart catheterization using mPAP ≥ 20mmHg as the definition of PH. Results: A total of 14281 subjects (53% female, 63% aged 50+ years) met the inclusion criteria, including 3019 PH+ cases and 11262 PH- controls (Figure). Sn and Sp were 84.0% (95% CI: 82.6%, 85.3%) and 71.7% (95% CI: 70.9%, 72.6%), respectively. The positive and negative predictive values were 18.9% (95% CI: 18.4%, 19.4%) and 98.3% (95% CI: 98.1%, 98.4%), respectively, at 7.3% prevalence. Each endpoint met pre-defined performance criteria. In the subset of 1683 subjects with a follow up RHC, performance remained robust (Sn 85% (1155/1358); Sp 46% (151/325)). Conclusion: While ECG-AI PH was first developed as an investigational tool to detect PH, continued development as software as a medical device for clinical use demonstrated that the algorithm retained strong performance to detect PH in diverse, non-overlapping clinical settings and patient populations.

Introduction: Pulmonary hypertension (PH) is a life-threatening, progressive disease with non-specific symptoms, often leading to delayed diagnosis. Early identification of World Health Organization Group 1 (Pulmonary Arterial Hypertension, PAH) and Group 4 (Chronic Thromboembolic Pulmonary Hypertension, CTEPH) is essential, as effective therapies can improve outcomes. Hypothesis: An electrocardiogram-based AI algorithm for PH detection (ECG-AI PH) may enable earlier diagnosis and reduce healthcare utilization, including hospitalizations and procedures. Methods: Retrospective analysis used a de-identified data platform of >7M clinical records from a multistate integrated health system. Adult precapillary PH patients (mPAP >20 mmHg, PVR >2 WU, PCWP ≤15 mmHg) were identified as PAH or CTEPH based on ICD codes, use of approved therapies, or surgical interventions (for CTEPH) between 2002 and 2024. ECG-AI PH was applied to ECGs within 30 days of diagnostic right heart catheterization, using a 5:1 randomly sampled PH-negative control cohort. Training set patients were excluded. Clinical event frequency was compared between two intervals: from first possible PH symptom (dyspnea, syncope, chest pain, fatigue, lower limb swelling) to diagnosis, and from symptom onset to first positive ECG-AI PH prediction. Results: A total of 1882 PAH and 359 CTEPH patients met inclusion criteria. Of these, 1340 PAH and 258 CTEPH patients had symptom codes prior to diagnosis. Both groups showed prolonged intervals from symptom onset to diagnosis, with multiple diagnostic procedures and hospitalizations (Figure). ECG-AI PH performance evaluation on the test set included 647 PAH and 152 CTEPH patients. ECG-AI PH achieved AUCs of 0.90 and 0.89 for PAH and CTEPH, sensitivities of 80.3% and 76.8%, and specificities of 83.4% and 82.4%. Among those tested, 576 PAH and 95 CTEPH patients had a positive ECG-AI PH prediction after symptom onset but before diagnosis. Compared to the current patient journey, the interval between initial symptoms and a positive output from ECG-AI PH was shorter and had fewer diagnostic tests/visits. Conclusion: ECG-AI PH demonstrated strong performance in detecting PAH and CTEPH. It may reduce diagnostic delays, support earlier PH-focused screening (e.g., echocardiograms evaluating the right heart), enable earlier intervention, and reduce pre-diagnosis healthcare burden, benefitting both patient outcomes and healthcare system efficiency.

Introduction: PH increases RV afterload, often leading to RV systolic and diastolic failure. The metabolic mechanisms underlying RV dysfunction remain poorly understood and are largely unexplored across non-PAH forms of PH. Aims: We aimed to identify which metabolites and metabolic pathways associated with imaging measures of RV systolic function. Methods: We analyzed data from the multi-center PVDOMICS cohort, which includes echo, CMR, invasive hemodynamics, clinical phenotyping, and untargeted plasma metabolomics (via Metabolon). RV systolic function metrics selected as the outcome measures for this study were fractional area change (echo), global longitudinal strain (echo), and RVEF (CMR). Associations between non-xenobiotic, named metabolites and RV function measures were assessed using linear regression adjusted for age, sex, BMI, and PH group, with significance defined by FDR <0.05. Metabolite set enrichment analysis (MSEA) was performed to identify significantly enriched pathways (FDR <0.20). To complement MSEA, we conducted mean-aggregation analysis: we averaged metabolite concentrations within each pathway and tested associations with RV function using the same covariate adjustments (FDR <0.05). Results: We identified 979 participants with plasma metabolomics and at least one available outcome measure (317 Group 1 PH; 106 Group 2 PH; 140 Group 3 PH; 51 Group 4 PH; 26 Group 5 PH; 81 Healthy Controls; 258 Disease Comparators). Linear regression identified 170 metabolites from the 647 named metabolites significantly associated with all 3 RV metrics (Top 10 by average ranked p-value displayed in Image 1 ). MSEA revealed seven enriched pathways across all RV metrics: Androgenic Steroids, Pregnenolone Steroids, Progestin Steroids, Fatty Acid Metabolism (Acyl Choline), Histidine metabolism, Vitamin A metabolism, Gamma-glutamyl Amino Acid ( Image 2) . Mean aggregation analysis showed that higher concentrations of Androgenic/Pregnenolone Steroids and Vitamin A metabolites strongly associated with improved RV function, while higher levels of Fatty Acid Metabolism (Acyl Carnitine) and Acetylated Peptides associated with worse function ( Image 3 ). Conclusions: Using data from the multi-institutional PVDOMICS cohort, we provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Steroid hormones as well as Vitamin A and fatty acid metabolites emerged as central to RV systolic function.

Abstract Rationale Pulmonary artery (PA) dilation on computed tomography (CT) has been associated with moderate-to-severe ­pulmonary hypertension (PH) using outdated diagnostic criteria. The association between PA size and mean PA pressure (mPAP) in mild PH and the prognostic implications of PA dilation remain unclear. Objectives To investigate associations between PA size, mPAP, and survival in subjects without significant lung disease aside from PH. Methods PA size on CT was measured for individuals with group 1 or 2 PH and matched controls in the Pulmonary Vascular Disease Phenomics cohort. Outcomes included mPAP on right heart catheterization (RHC) and time to heart and/or lung ­transplantation or death. Measurements and Main Results A total of 691 subjects were included, with 595 undergoing RHC. PA diameter and PA:aorta ratio demonstrated significant association with mPAP (ρ = 0.557 and 0.564, respectively). Size increased incrementally from no PH to mild PH to moderate-severe PH for PA diameter (27.64 [95% CI, 17.64-37.64] mm to 30.65 [95% CI, 18.99-42.31] mm to 36.00 [95% CI, 22.46-49.54] mm) and PA:aorta (0.89 [95% CI, 0.53-1.24] to 0.99 [95% CI, 0.63-1.35] to 1.19 [95% CI, 0.60-1.78]). PA diameter and PA:aorta demonstrated good discrimination of mPAP &gt;20 mm Hg (area under the curve: 0.834 and 0.816, respectively). Transplant-free survival decreased across the continuum of PA diameter and PA:aorta (P &lt;.001). Adjusted hazard ratio of third versus first quartile values was 2.36 (95% CI, 1.58-3.54) for PA diameter and 2.24 (95% CI, 1.52-3.30) for PA:aorta. Conclusions In subjects without significant lung disease outside of PH, PA size on CT was associated with increased mPAP and decreased transplant-free survival across the spectrum of PH severity and demonstrated modest diagnostic discriminatory ability using updated hemodynamic criteria.

Abstract Rationale Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. Objectives The Pulmonary Vascular Research Institute GoDeep metaregistry collects real-world data of patients with PH from international PH referral centers. Methods Patients with ILD-PH and relevant subgroups (idiopathic interstitial pneumonia [IIP], idiopathic pulmonary fibrosis [IPF]) were stratified by pulmonary vascular resistance (PVR). Kaplan-Meier survival analyses and adjusted Cox proportional hazards models were employed, additionally accounting for immortal time bias, sensitivity analyses, Heller explained relative risk statistics, and target trial emulation framework analysis. Measurements and Main Results Among 34,482 patients, 940 with hemodynamically fully characterized incident ILD-PH (median age, 67 [IQR, 59–74] yr) were identified. A total of 62% had severe ILD-PH with PVR &gt;5 Wood units (WU) and poor survival rates (29% and 18% at 3 and 5 yr), significantly worse than patients with ILD-PH with PVR ≤5 WU and patients with pulmonary arterial hypertension. Survival was poorest in severe IPF-PH. A total of 59% of all patients ILD-PH received PH-targeted therapy, predominantly phosphodiesterase-5 inhibitors (PDE5is). PDE5i treatment was consistently associated with significantly improved survival in patients with severe PH (hazard ratios of 0.537 [0.370–0.781], 0.461 [0.233–0.913], and 0.435 [0.215–0.8] for IIP-PH, IPF-PH, and IIP-PH with nintedanib/pirfenidone background therapy), but not in patients with less severe hemodynamic impairment, supported by sensitivity analyses, Heller statistics, and target trial emulation framework analysis. The survival statistics of patients with PDE5i-treated IIP-PH or IPF-PH were validated in the independent COMPERA registry. Combination therapy with PDE5is and inhaled prostacyclin analogues was superior to monotherapy using PDE5is (hazard ratio, 0.341; 0.205–0.566). Conclusions Prognosis in ILD-PH was generally very poor and was related to PH severity. PDE5i treatment in severe IIP-PH and IPF-PH was associated with improved survival, which is to be further verified in controlled trials.

Abstract Rationale Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Ground-glass opacities (GGOs) are common in Group 1 PH, but their clinical significance is unclear. Objectives We sought to characterize the clinical features and outcomes of patients with Group 1 PH with and without GGOs in the PVDOMICS study, a prospective multicenter cohort study aimed at deep phenotyping PH. Methods Patients with incident and prevalent PH were enrolled across seven U.S. centers. We included patients with Group 1 PH and excluded those with parenchymal lung disease or without chest imaging, resulting in a cohort of 242 patients. Results GGOs were common among patients with Group 1 PH (43% prevalence), associated with female sex, younger age, prostanoid use, and longer disease duration. GGOs were more common among patients with familial pulmonary arterial hypertension and pulmonary veno-occlusive disease. GGOs were associated with established markers of disease severity, including echocardiographic (right ventricular systolic pressure and tricuspid annular plane systolic excursion), biomarkers (N-terminal pro B-type natriuretic peptide), and worse hemodynamics (higher mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary artery wedge pressure). GGOs were associated with worse transplant-free survival (hazard ratio, 2.49; 95% confidence interval = 1.43–4.32; P = 0.001) and had independent prognostic value for predicting transplant-free survival after adjusting for European Society of Cardiology and European Respiratory Society risk stratification (hazard ratio, 2.19; 95% confidence interval = 1.20–3.99; P = 0.01). Conclusions Overall, GGOs were associated with specific clinical characteristics and disease phenotypes, as well as worse hemodynamics, longer disease duration, prostanoid use, and worse survival. Future studies evaluating the pathophysiology and “omic” correlates of GGOs are warranted. Clinical trial registered with www.clinicaltrials.gov (NCT02980887).

ABSTRACTPortopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta‐registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5‐year survival rates (46% vs. 68% vs. 65%, log‐rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5‐year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m2. Treatment of the PoPH patients with PAH‐targeted therapies was associated with significantly higher 5‐year survival rates compared to those not receiving such treatments, as shown by Kaplan–Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log‐rank p = 0.029), ERA (58% vs. 34%, log‐rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log‐rank p < 0.001), as well as any PAH‐targeting treatment (50% vs. 26%, log‐rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long‐term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high‐risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

Abstract Rationale A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. Objectives To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. Methods Patients with group 1 PH were stratified into low (&lt;25%) and high (⩾75%) HFpEF-ABA (age, body mass index, and atrial fibrillation) probability, with healthy control subjects and subjects with clinical HFpEF used for comparison of venous and transpulmonary metabolomics. Measurements and Main Results Group 1 PH + high HFpEF probability (n = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] P &lt; 0.05 and fold change &gt;1) (n = 193, t test) and a significant decrease in 231 metabolites (FDR P &lt; 0.05 and fold change &lt;1) (n = 193, t test) compared with group 1 PH + low HFpEF probability (n = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR P &lt; 0.002 for all, n = 193, t test). Linoleate (precursor to arachidonic acid and prostaglandins) and arginine and homoarginine (precursors to nitric oxide) were all lower in group 1 PH + high HFpEF probability (FDR P &lt; 0.03 for all, n = 193, t test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF (n = 240) but were abnormal relative to control subjects (n = 85) (P &lt; 0.0001 for all, n = 456, t test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction P = 0.04; and kynurenine, interaction P = 0.03; n = 433, mixed model). Conclusions Patients with group 1 PH + high HFpEF probability have a unique metabolome characterized by enhanced tryptophan-kynurenine pathway breakdown, deficiency of amino acids (such as glycine and serine), lower serotonin, and decreased prostaglandin and nitric oxide precursors. Despite fulfilling clinical criteria for group 1 PH, these metabolome changes were comparable with clinical HFpEF, supporting biological overlap between these two forms of PH.

BACKGROUND: Patients with lung disease, sleep apnea, and chronic thromboemboli can develop pulmonary hypertension, currently classified as group 3 or 4. Many of these patients also have risk factors for heart failure with preserved ejection fraction (HFpEF), but the optimal approach to identify the disease overlap remains unclear. METHODS: Pretest probability for HFpEF was determined using the HFpEF-ABA (age, body mass index, atrial fibrillation) algorithm among adjudicated group 3 or 4 patients at risk for pulmonary hypertension in the PVDOMICS study (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Patients were stratified by current resting right heart catheterization criteria, and in a separate analysis, stratified only by HFpEF-ABA probability into low (<25%), intermediate, and high (≥75%) HFpEF probability groups. RESULTS: Among 598 patients with group 3 disease, 27% (n=161) had elevated pulmonary capillary wedge pressure (PCWP) with postcapillary pulmonary hypertension even at rest, which was associated with the highest exercise PCWP. However, regardless of this resting PCWP-based classification, a larger subset had intermediate-to-high HFpEF-ABA probabilities (32% [n=197] high and 57% [n=358] intermediate HFpEF probability). High HFpEF probability in group 3 disease was associated with higher resting and dynamic PCWP response to NO, fluid, and exercise ( P <0.0001 for all). These changes were comparable with more traditionally defined HFpEF without pulmonary vascular disease (n=61) but less severe than those with combined precapillary and postcapillary pulmonary hypertension HFpEF (n=31; interaction P =0.006). Increasing HFpEF probability in group 3 disease was associated with worse left heart remodeling, quality of life, 6-minute walk distance, and peak VO 2 ( P <0.0001 for all). Findings were replicated in group 4 disease (n=102). CONCLUSIONS: Quantifying pretest probability for HFpEF in patients with sleep apnea, lung disease, or chronic thromboemboli identifies a progressive gradient for dynamic PCWP abnormalities with worse functional status and quality of life. These subclinical left heart abnormalities are not universally detectable by resting right heart catheterization alone and call for further study of whether strategies to prevent or treat HFpEF might improve functional status in these patients with high risk of occult HFpEF.