Finet, J. Emanuel

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 (<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 < 0.05 and fold change >1) (n = 193, t test) and a significant decrease in 231 metabolites (FDR P < 0.05 and fold change <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 < 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 < 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 < 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.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Aims We recently demonstrated the combined prognostic value of the following two simple non-invasive parameters obtained from treadmill exercise testing in patients with heart failure (HF) with reduced ejection fraction: the Haemodynamic Gain Index (HGI) and peak rate-pressure product (RPP). However, their prognostic value is yet to be validated in patients with undifferentiated HF syndrome. Methods and results We identified consecutive HF patients undergoing treadmill exercise testing for symptom evaluation between January 1991 and February 2015. The HGI was calculated from [(SBPpeak × heart ratepeak) – (SBPrest × heart raterest)]/(SBPrest × heart raterest), and the peak RPP was calculated from SBPpeak × heart ratepeak. Hazard ratios per standard deviation increase of the HGI and peak RPP for all-cause mortality were estimated using multivariable Cox regression models with adjustment for traditional cardiovascular risk factors and exercise-testing parameters (Chronotropic Reserve Index, estimated metabolic equivalents, abnormal heart rate recovery, and total exercise time). In our cohort of 5940 patients with symptomatic HF diagnosis with a median follow-up of 7.1 years, 2222 (37.4%) patients died. Higher values of both HGI and peak RPP were associated with a lower risk of mortality [adjusted hazard ratio per standard deviation increase 0.80 (0.73–0.88) and 0.85 (0.78–0.91), respectively, all P &lt; 0.001]. Optimal cut-off values for HGI and peak RPP for discriminating all-cause mortality were 1.06 and 180 966, respectively. Conclusion Both HGI and peak RPP are predictors of mortality in patients with chronic HF and may be tools to signal the need for advanced HF therapy evaluation.

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 42, 361–377.

Abstract Aims Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2–3), but this group is not well-characterized. Methods and results Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2–3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2–3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2–3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2–3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2–3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30–0.86), and patients with G2–3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38–0.86). Conclusions Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2–3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. Clinical Trial Registration: ClinicalTrials.gov NCT02980887.

AbstractThe prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease‐associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O2 and O2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O2‐only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O2 + iNO. IPAH AVR prevalence (4.1%–18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD‐PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVR responders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log‐rank test p = 0.04 and p = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non‐IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation.

Abstract Aims Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. Methods and results Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P &gt; 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) &lt;21% did. Compared to those with TSAT ≥21%, patients with TSAT &lt;21% demonstrated lower peakVO2 [absolute difference: −1.89 (−2.73 to −1.04) mL/kg/min], 6-min walk test distance [absolute difference: −34 (−51 to −17) m], and SF-36 physical component score [absolute difference: −2.5 (−1.3 to −3.8)] after adjusting for age, sex, and hemoglobin (all P &lt; 0.001). Patients with a TSAT &lt;21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation &lt;21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13–2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. Conclusion The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT &lt;21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.