Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Long-Term Effects of COVID-19 on the Cardiopulmonary System in Adults and Children: Current Status and Questions to be Resolved by the National Institutes of Health Researching COVID to Enhance Recovery Initiative.

TOPIC IMPORTANCE: Long COVID may occur in at least 10% of patients recovering from SARS-CoV-2 infection and often is associated with debilitating symptoms. Among the organ systems that might be involved in its pathogenesis, the respiratory and cardiovascular systems may be central to common symptoms seen in survivors of COVID-19, including fatigue, dyspnea, chest pain, cough, and exercise intolerance. Understand the exact symptomatology, causes, and effects of long COVID on the heart and lungs may help us to discover new therapies. To that end, the National Institutes of Health is sponsoring a national study population of diverse volunteers to support large-scale studies on the long-term effects of COVID-19. REVIEW FINDINGS: The National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) initiative currently is recruiting participants in the United States to answer critical questions about long COVID. The study comprises adult and pediatric cohorts as well as an electronic health record cohort. Based on symptoms, individuals undergo prespecified medical testing to understand whether abnormalities can be detected and are followed up longitudinally. Herein, we outline current understanding of the clinical symptoms and pathophysiologic features of long COVID with respect to the cardiopulmonary system in adults and children and then determine how the clinical, electronic health record, and autopsy cohorts of the RECOVER initiative will attempt to answer the most pressing questions surrounding the long-term effects of COVID-19. SUMMARY: Data generated from the RECOVER initiative will provide guidance about missing gaps in our knowledge about long COVID and how they might be filled by data gathered through the RECOVER initiative.

Pulmonary hypertension across the spectrum of left heart and lung disease.

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.

Correlation Between Right Ventricular Echocardiography Measurements and Functional Capacity in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Accelerometry is an emerging option for real-time evaluation of functional capacity in patients with pulmonary arterial hypertension (PAH). This prospective pilot study assesses the relationship between functional capacity by accelerometry and right ventricular measurements on echocardiography for this high-risk cohort. METHODS: Patients with PAH were prospectively enrolled and underwent 6-Minute Walk Test and cardiopulmonary exercise testing. They were given a Fitbit, which collected steps and sedentary time per day. Echocardiographic data included right ventricular global longitudinal, free wall, and septal strain; tricuspid regurgitant peak velocity; tricuspid annular plane systolic excursion; tricuspid annular plane systolic velocity; right ventricular myocardial performance index; and pulmonary artery acceleration time. Pairwise correlations were performed. RESULTS: The final analysis included 22 patients aged 13 to 59 years. Tricuspid regurgitant peak velocity had a negative correlation with 6-Minute Walk Test (r = -0.58, P = .02), peak oxygen consumption on exercise testing (r = -0.56, P = .03), and average daily steps on accelerometry (r = -0.59, P = .03), but a positive correlation with median sedentary time on accelerometry (r = 0.64, P = .02). Pulmonary artery acceleration time positively correlated with peak oxygen consumption on exercise testing (r = 0.64, P = .002). There was no correlation between right ventricular strain measurements and functional capacity testing. CONCLUSION: In this pilot study, tricuspid regurgitant jet and pulmonary artery acceleration time were the echocardiographic variables that correlated most with accelerometry data. With further echocardiographic validation, accelerometry can be a useful, noninvasive, and cost-effective tool to monitor disease progression in patients with PAH.

The "Lollipop" During Catheter-Directed Thrombectomy: 2 Case Examples.

Intraprocedural embolization has been described as a potential complication of catheter thrombectomy for acute pulmonary embolism and may be under-recognized. We describe 2 case examples of "Lollipopping" during thrombectomy, which may be a mechanism of intraprocedural embolization and describe our treatment approach. (Level of Difficulty: Advanced.).

Hispanic Ethnicity and Social Determinants of Health in Pulmonary Arterial Hypertension: The Pulmonary Hypertension Association Registry.

Rationale: There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objectives: To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods: This was a prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter U.S.-based registry of patients treated at pulmonary hypertension care centers. Participants were classified as Hispanics and non-Hispanic White individuals, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic White individuals. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level, and health insurance. Results: A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD, 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD, 0.60), and lower annual income (32.0% vs. 17.4% with income <20,000 U.S. dollars; ASD, 0.47), compared with non-Hispanic White individuals. Hispanic patients had a higher frequency of emergency room visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio, 1.452; 95% confidence interval [CI], 1.326-1.590; and 1.428; 95% CI, 1.292-1.577, respectively). Although the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (hazard ratio, 0.47; 95% CI, 0.24-0.94; P = 0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR, 0.76; 95% CI, 0.35-1.62; P = 0.474). Conclusions: Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

Obesity in Pulmonary Arterial Hypertension (PAH): The Pulmonary Hypertension Association Registry (PHAR).

RATIONALE: Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations and survival is not well understood. OBJECTIVES: To assess the effect of obesity on health-related quality of life (HRQoL), hospitalizations and survival in patients with PAH. METHODS: We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 (SF-12) and emPHasis-10 (e10). We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. RESULTS: 767 subjects were included: mean age of 57 years, 74% female, 33% overweight and 40% obese, with median follow-up duration of 527 days. Overweight and obese patients had higher baseline e10 scores (worse HRQoL), which persisted over time (p<0.001). The overweight and obese have a trend towards increased incidence of hospitalizations compared to normal weight (IRR 1.34, 95% confidence interval (95%CI) 0.94-1.92 and 1.33, 95%CI 0.93-1.89, respectively). Overweight and obese patients had lower risk of transplant or death as compared to normal weight patients (HR 0.45, 95%CI 0.25-0.80 and 0.39, 95%CI 0.22-0.70, respectively). CONCLUSIONS: In a large multicenter, prospective cohort of PAH, overweight and obese patients had worse disease-specific HRQoL despite better transplant-free survival compared to normal weight patients. Future interventions should address the specific needs of these patients.

Pulmonary arterial hypertension : a comprehensive review of pharmacological treatment.

The treatment of pediatric pulmonary arterial hypertension (PAH) is challenging due to the serious nature of the disease, its rapid progression, and the limited treatment options available. While oral calcium channel antagonists and continuous intravenous epoprostenol have been used successfully for over a decade, novel treatment options - including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors - may change the course of this disease for many children in the future.Prostacyclin analogs offer the benefit over continuous intravenous epoprostenol of an alternative delivery system. However, the efficacy of these medications compared with intravenous epoprostenol and the risk/benefits of each analog need to be weighed in future trials, which need to include larger numbers of pediatric patients to optimize therapy and outcome for individual children with PAH.For patients who do not have an acute response to vasodilator testing or have failed treatment with oral calcium channel antagonists, endothelin receptor antagonists may offer a viable treatment option. Furthermore, in the future, the addition of endothelin receptor antagonists to long-term therapy with calcium channel antagonists or to epoprostenol or a prostacyclin analog may increase the overall efficacy of treatment of PAH. Large multi-institutional randomized trials to determine whether sildenafil is effective and safe for the long-term treatment of PAH in children are in progress.A comprehensive review of these newer agents with an emphasis on the pathobiology/pathophysiology of PAH provides insight into the future management of pediatric PAH patients.

Challenges and Current Efforts in the Development of Biomarkers for Chronic Inflammatory and Remodeling Conditions of the Lungs.

This review discusses biomarkers that are being researched for their usefulness to phenotype chronic inflammatory lung diseases that cause remodeling of the lung's architecture. The review focuses on asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension. Bio-markers of environmental exposure and specific classes of biomarkers (noncoding RNA, metabolism, vitamin, coagulation, and microbiome related) are also discussed. Examples of biomarkers that are in clinical use, biomarkers that are under development, and biomarkers that are still in the research phase are discussed. We chose to present examples of the research in biomarker development by diseases, because asthma, COPD, and pulmonary hypertension are distinct entities, although they clearly share processes of inflammation and remodeling.

Identical twins with primary pulmonary hypertension: beraprost vs epoprostenol.

BACKGROUND: The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. METHODS: Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. FINDINGS: Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. INTERPRETATION: Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.

Effects of dose and age on adverse events associated with tadalafil in the treatment of pulmonary arterial hypertension.

There are limited data on the management of pulmonary arterial hypertension (PAH) in the elderly; therefore, this analysis compared the safety and efficacy of tadalafil between patients ≥65 and <65 years old. This was a post hoc analysis of the randomized, double-blind, placebo-controlled phase 3 Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST-1) study. Patients who completed the 16-week study or who discontinued because of clinical worsening and were not receiving tadalafil 40 mg were eligible for a long-term, open-label extension study. Adverse events (AEs) and efficacy outcomes were assessed in patients ≥65 versus <65 years old, and the dose dependency of common AEs was determined. Twenty-eight percent (112 of 405) of patients were ≥65 years of age (mean in this subset, 72 ± 5 years). Compared with younger patients, elderly patients were more likely to be World Health Organization functional class III/IV (75% vs. 65%, respectively) and to have lower exercise capacity as assessed by 6-minute walk distance (6MWD; mean, 299 vs. 366 m). Compared with placebo, tadalafil increased 6MWD by a mean of 35 and 43 m in patients ≥65 and <65 years, respectively. Common AEs (including headache, dyspepsia, and myalgia) were similar in both groups and tended to decrease in incidence with longer treatment duration. No differences in AEs were observed between elderly patients who received tadalafil 20 or 40 mg. In conclusion, the safety and efficacy of tadalafil for treatment of PAH are similar between elderly patients and patients <65 years old.

Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom.

BACKGROUND: The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial. METHODS AND RESULTS: We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥ 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥ 25 mm Hg was used. Among 572 subjects, 11.2% had TRV ≥ 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥ 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV ≥ 3.0 m/sec. At 24 months the cumulative survival was 83% with TRV ≥ 3.0 m/sec and 98% with TRV < 3.0 m/sec (p < 0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p < 0.0001) for TRV ≥ 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP ≥ 160 pg/mL, and 14.9 (5.5-39.9; p < 0.0001) for both TRV ≥ 3.0 m/sec and NT-proBNP ≥ 160 pg/mL. Age > 47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death. CONCLUSIONS: A TRV ≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.

Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.

Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.

BACKGROUND: Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes. METHODS AND RESULTS: We used whole exome sequencing to study a 3-generation family with multiple affected family members with PAH, but no identifiable TGF beta mutation. We identified a frameshift mutation in caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries. CONCLUSIONS: Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development.

Two Cases of Pulmonary Hypertension Associated with Type III Glycogen Storage Disease.

Glycogen storage diseases (GSDs) comprise a large, heterogeneous group of disorders characterized by abnormal glycogen deposition. Multiple cases in the literature have demonstrated an association between GSD type I and pulmonary arterial hypertension (PAH). We now also report on two patients with GSD type III and PAH, a novel association. The first patient was a 16-year-old girl of Nicaraguan descent with a history of hepatomegaly and growth retardation. Molecular testing identified a homozygous 17delAG mutation in AGL consistent with GSD type IIIb. At the age of 16, she was found to have PAH and was started on medical therapy. Two years later, she developed acute chest pain and died shortly thereafter. The second patient is a 13-year-old girl of Colombian descent homozygous for the c.3911dupA mutation consistent with GSD IIIa. An echocardiogram at age 2 showed left ventricular hypertrophy, which resolved following the institution of a high protein, moderate carbohydrate diet during the day and continuous gastric-tube feeding overnight. At the age of 12, she was found to have pulmonary hypertension. She was started on sildenafil, and her clinical status has shown marked improvement including normalization of her elevated transaminases. PAH may be a rare association in patients with GSD IIIa and IIIb and should be evaluated with screening echocardiograms for cardiac hypertrophy or if they present with symptoms of right-sided heart failure such as shortness of breath, chest pain, cyanosis, fatigue, dizziness, syncope, or edema. Early diagnosis of PAH is important as increasingly effective treatments are now available.

Determinants of right ventricular ejection fraction in pulmonary arterial hypertension.

BACKGROUND: Right ventricular function is a key determinant of exercise capacity and survival in pulmonary arterial hypertension (PAH). We aimed to study the predictors of right ventricular ejection fraction (RVEF) in patients with newly diagnosed PAH. METHODS: We performed a cross-sectional analysis of a retrospective cohort of consecutive patients with idiopathic, familial, or anorexigen-associated PAH who underwent equilibrium radionuclide angiography for measurement of RVEF at baseline. RESULTS: Of the 84 patients in the cohort, 63 underwent equilibrium radionuclide angiography and right heart catheterization and were included. The mean age was 41 +/- 13 years, and 79% of the patients were female. The mean RVEF was 30 +/- 8%. RVEF was directly associated with right ventricular stroke volume index and cardiac index, and inversely associated with pulmonary vascular resistance index from right heart catheterization (all p < 0.001). Older age and male sex were associated with lower RVEF (p < 0.05) after adjustment for pulmonary vascular resistance index and left ventricular ejection fraction. Higher plasma von Willebrand factor levels were also independently associated with lower RVEF (p = 0.01) (n = 55). Body size and type of PAH were not associated with RVEF. CONCLUSIONS: Older patients and males with PAH had lower RVEF at baseline than younger patients and females, even after controlling for left ventricular function and hemodynamics. Higher plasma von Willebrand factor levels, a marker of endothelial dysfunction, were also associated with lower RVEF.