Citations

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).

Background Tricuspid valve surgery is recommended for severe isolated tricuspid regurgitation (TR) if symptoms persist despite optimal medical therapy. The definition of optimal therapy for TR is unclear beyond managing underlying conditions. Diuretics are the primary treatment for volume retention in TR, but it is unknown whether a “safe diuretic dose” exists for conservative management. We sought to evaluate the association between diuretic dose and outcomes. Methods Adult patients with ≥moderate–severe isolated TR were retrospectively identified from echocardiographic reports. Clinical and echocardiographic data were extracted from electronic medical records and manually reviewed. The primary end point was all‐cause mortality. Loop diuretic doses were converted to furosemide equivalent and categorized into 4 groups: <40 mg, 40 to 79 mg, 80 to 159 mg, and ≥160 mg daily. Results Of 1302 patients (age 72±13 years, 60% female), 565 (43%) had moderate–severe TR and 737 (57%) had severe TR. Median follow‐up was 8.7 (1.4, 14.0) years. Comorbidities increased with higher diuretic doses. A linear relationship between diuretic dose and mortality was observed in spline‐curve analysis. Hazard ratios (and CIs) for mortality adjusted for age, sex, coronary disease, chronic kidney disease, mild pulmonary hypertension, and New York Heart Association III/IV symptoms were 1.21 (0.96–1.53) ( P =0.12) for <40 mg, 1.50 (1.23–1.82) ( P <0.001) for 40 to 79 mg, 1.86 (1.46–2.37) ( P <0.001) for 80 to 159 mg, and 2.90 (2.18–3.88) ( P <0.001) for ≥160 mg furosemide equivalent. Any diuretic dose was associated with significant symptoms (New York Heart Association III–IV), with more patients experiencing symptoms at higher doses. Conclusion A daily loop diuretic dose ≥40 mg furosemide equivalent is associated with increased mortality and greater symptom severity in patients with TR.

Subjective and objective limitations to exercise and activity are hallmarks of heart failure (HF), regardless of underlying ejection fraction (EF). These limitations relate to cardiovascular abnormalities involving the systolic and diastolic properties of the heart, venous, and arterial vasculature, as well as noncardiovascular abnormalities, including impairments in pulmonary function, autonomic regulation, anemia, metabolism, and changes in mitochondria and skeletal muscle. The contribution of these abnormalities varies between patients with HF with preserved EF and those with HF with reduced EF, but, even within each HF subtype, there is substantial individual patient pathophysiologic variability, which suggests a potentially important role for phenotyping based on exercise reserve responses to individualize treatment. In this article, we review the current understanding of exercise reserve limitation with a focus on specific organ systems involved, both in patients with HF with preserved EF and HF with reduced EF, and how these interact to lead to symptoms of exercise intolerance and objective limitations in submaximal and peak aerobic capacity across the spectrum of HF.

Abstract Aims While intentional weight loss achieved through cardiometabolic medications has been associated with robust salutary effects in heart failure (HF) with preserved ejection fraction (HFpEF), the clinical significance of unintentional weight loss in this setting remains unclear. Methods and results This retrospective cohort study included 434 overweight or obese patients with invasively proven HFpEF (67 ± 11 years, 236 female), without weight-reducing therapies or known malignancy, who underwent invasive hemodynamic cardiopulmonary testing and long-term clinical follow-up. The annualized weight change from index to final evaluation for the tertiles was: −21.1 to −1.8 kg/year (tertile 1); −1.8 to 0 kg/year (tertile 2); and 0 to +17.0 kg/year (tertile 3). Patients in tertile 1 had subtle abnormalities in ventilatory control at baseline, but there were no other significant differences between groups across a vast array of haemodynamic and metabolic parameters, both at rest and during exercise. Baseline weight was directly correlated with right and left heart filling pressures (r = 0.23–0.34, p &lt; 0.001), but annualized weight change showed no correlation with any baseline haemodynamic measurements (all p &gt; 0.05). Over a median follow-up of 4.7 years (interquartile range 2.3–6.5), patients in tertile 1 had higher risk of all-cause death (hazard ratio [HR] 3.36, 95% confidence interval [CI] 1.77–6.39, p &lt; 0.001), all-cause death or HF hospitalization (HR 2.49, 95% CI 1.53–4.04, p &lt; 0.001) and cardiac death or HF hospitalization (HR 2.28, 95% CI 1.28–4.07, p = 0.005) compared with those in tertile 2 or 3. These findings were consistent after multivariable adjustment. Conclusions Unintentional weight loss is associated with worse prognosis in patients with HFpEF and overweight or obesity, even as haemodynamics, exercise capacity, and gas exchange are not different from patients with stable or increasing weight. These data underline important and fundamental differences between therapeutic and unintended weight loss in HFpEF.

Abstract Aims Oxygen consumption at peak exercise is widely used to assess functional impairment in heart failure with preserved ejection fraction (HFpEF), but few patients exercise to this intensity in daily living. Alternative metrics that quantify submaximal fitness may provide more patient-centred evaluations, but the pathophysiology of submaximal exercise intolerance in HFpEF is unexplored. Methods and results Patients with HFpEF underwent invasive haemodynamic cardiopulmonary exercise testing with blood lactate measurement during exercise to volitional fatigue. Lactate threshold (LT) was defined as the exercise workload at which arterial lactate exceeded &gt;2.0 mmol/L, taken as a measure of submaximal fitness. Of patients with HFpEF (n = 286), 194 (68%) reached LT at a workload of 40 W or less (LT ≤40 W), while 92 (32%) reached a workload exceeding 40 W at LT (LT &gt;40 W). As compared to LT &gt;40 W, patients with LT ≤40 W were more likely to be female, anaemic, and had greater pulmonary vascular disease (all p &lt; 0.01). During 20 W exercise, participants with LT ≤40 W had higher pulmonary artery pressure, biventricular filling pressures, minute ventilation and respiratory drive, higher perceived dyspnoea and fatigue ratings, greater arterial–venous oxygen content difference, despite similar cardiac output and oxygen delivery. At peak exercise, most of these differences were no longer apparent. Findings were replicated using non-invasively-measured workload at ventilatory threshold. Conclusions Two-thirds of patients with HFpEF reach LT at workloads typical of activities of daily living. Patients with HFpEF and impaired submaximal fitness are more likely to be female, have greater pulmonary vascular disease and anaemia severity, and display greater haemodynamic, symptomatic, and ventilatory control abnormalities during low-level exercise, which are not apparent at maximal exertion. These findings have therapeutic implications and suggest a potentially important role for wider evaluation of submaximal fitness in addition to peak aerobic capacity.

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.

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.