Showing papers by "Paul M. Hassoun published in 2023"

Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative ‐ Group 3 Pulmonary Hypertension

Abstract: Abstract Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

Insulin‐like growth factor binding Protein‐4: A novel indicator of pulmonary arterial hypertension severity and survival

Abstract: Abstract Proteomic analysis of patients with pulmonary arterial hypertension (PAH) has demonstrated significant abnormalities in the insulin‐like growth factor axis (IGF). This study proposed to establish associations between a specific binding protein, insulin‐like growth factor binding protein 4 (IGFBP4), and PAH severity as well as survival across varying study cohorts. In all cohorts studied, serum IGFBP4 levels were significantly elevated in PAH compared to controls (p < 0.0001). IGFBP4 concentration was also highest in the connective tissue‐associated PAH (CTD‐PAH) and idiopathic PAH subtypes (876 and 784 ng/mL, median, respectively). After adjustment for age and sex, IGFBP4 was significantly associated with worse PAH severity as defined by a decreased 6‐min walk distance (6MWD), New York heart association functional class (NYHA‐FC), REVEAL 2.0 score and higher right atrial pressures. In longitudinal analysis provided by one of the study cohorts, IGFBP4 was prospectively significantly associated with a shorter 6MWD, worse NYHA‐FC classification, and decreased survival. Cox multivariable analysis demonstrated higher serum IGFBP4 as an independent predictor of survival in the overall PAHB cohort. Therefore, this study established that higher circulating IGFBP4 levels were significantly associated with worse PAH severity, decreased survival and disease progression. Dysregulation of IGF metabolism/growth axis may play a significant role in PAH cardio‐pulmonary pathobiology.

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension

Abstract: Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RVFnRec). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. Methods: We evaluated 63 incident patients with PAH by right heart catheterization and cardiac MRI (CMR) at diagnosis and CMR and invasive cardiopulmonary exercise (CPET) following treatment (~11 months). Sex, age, race/ethnicity matched healthy control subjects (n=62) with one-time CMR and non-invasive CPET were recruited from the PVDOMICS project. We examined therapeutic CMR changes relative to the evidence-based peak oxygen consumption (VO2peak)>15mL/kg/min to define RVFnRec by receiver operating curve analysis. Afterload was measured in the as mean pulmonary artery pressure, resistance, compliance, and elastance. Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (AUC 0.87, P=0.0001) and neared upper 95% CI RVEDV of controls. 22/63 (35%) of subjects met this cutoff which was reinforced by freedom from clinical worsening, RVFnRec 1/21 (5%) versus no RVFnRec 17/42, 40%, (log rank P=0.006). A therapy-associated increase of 0.8 mL/mmHg in compliance had the best predictive value of RVFnRec (AUC 0.76, CI 0.64-0.88, P=0.001). RVFnRec subjects had greater increases in stroke volume, and cardiac output at exercise. Conclusions: RVFnRec defined by RVEDV therapeutic decrease of -15mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.

Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure

Abstract: Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis.We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets.Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (Padjusted<0.0005 and 0.0006, respectively), suggesting a role in increased risk of renal dysfunction. In contrast, among EA ARDS patients, the missense variant rs17011368 (I703V) was associated with enhanced mortality at 60-days (P < 0.038). We found higher serum XOR activity in 143 sepsis patients (54.5 ± 57.1 mU/mL) compared to 31 controls (20.9 ± 12.4 mU/mL, P = 1.96 × 10- 13). XOR activity was associated with the lead variant rs185925 among AA sepsis patients with ARDS (P < 0.005 and Padjusted<0.01). Multifaceted functions of prioritized XDH variants, as suggested by various functional annotation tools, support their potential causality in sepsis.Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Spatial and temporal resolution of metabolic dysregulation in the Sugen hypoxia model of pulmonary hypertension

Abstract: Abstract Although PAH is partially attributed to disordered metabolism, previous human studies have mostly examined circulating metabolites at a single time point, potentially overlooking crucial disease biology. Current knowledge gaps include an understanding of temporal changes that occur within and across relevant tissues, and whether observed metabolic changes might contribute to disease pathobiology. We utilized targeted tissue metabolomics in the Sugen hypoxia (SuHx) rodent model to investigate tissue‐specific metabolic relationships with pulmonary hypertensive features over time using regression modeling and time‐series analysis. Our hypotheses were that some metabolic changes would precede phenotypic changes, and that examining metabolic interactions across heart, lung, and liver tissues would yield insight into interconnected metabolic mechanisms. To support the relevance of our findings, we sought to establish links between SuHx tissue metabolomics and human PAH ‐omics data using bioinformatic predictions. Metabolic differences between and within tissue types were evident by Day 7 postinduction, demonstrating distinct tissue‐specific metabolism in experimental pulmonary hypertension. Various metabolites demonstrated significant tissue‐specific associations with hemodynamics and RV remodeling. Individual metabolite profiles were dynamic, and some metabolic shifts temporally preceded the emergence of overt pulmonary hypertension and RV remodeling. Metabolic interactions were observed such that abundance of several liver metabolites modulated lung and RV metabolite‐phenotype relationships. Taken all together, regression analyses, pathway analyses and time‐series analyses implicated aspartate and glutamate signaling and transport, glycine homeostasis, lung nucleotide abundance, and oxidative stress as relevant to early PAH pathobiology. These findings offer valuable insights into potential targets for early intervention in PAH.

When more is more: the role of additional upfront therapy in pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and related increased pulmonary vascular resistance. This disease, if left untreated, will ultimately lead to death from right ventricular failure [1]. Currently available therapies target one of three known pathogenic pathways: the endothelin, prostacyclin or nitric oxide pathway [2, 3]. The current treatment paradigm emphasises the role of upfront combination therapy, although the permutation and timing of which remain unclear [4]. Despite advances in the understanding and treatment of this disease, mortality from PAH remains unacceptably high [5]. Ongoing investigation into drug combination strategies and timing of therapy initiation provides clinicians and patients with the opportunity to maximise benefit from currently available therapies, as novel drug discovery can take decades. Early combination therapy targeting several relevant pathogenic pathways, including the prostacyclin pathway, is likely to be of benefit to most patients with PAH https://bit.ly/3GisHnA

Metabolic profiling of in vivo right ventricular function and exercise performance in pulmonary arterial hypertension

Abstract: BACKGROUND Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. METHODS Consecutive subjects with PAH (n=23) underwent rest and exercise right heart catheterization with multi-beat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared to pro-BNP measurements for accuracy in modeling ventriculo-arterial parameters. RESULTS Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed pro-BNP in modeling RV contractility, diastolic function, and exercise performance. CONCLUSIONS Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.

Metabolomic differences in connective tissue disease-associated versus idiopathic pulmonary arterial hypertension in the PVDOMICS cohort.

Abstract: OBJECTIVE Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in CTD-PAH versus IPAH patients that might underlie these observed clinical differences. METHODS Adult subjects with CTD-PAH (n=141) and IPAH (n=165) from the PVDOMICS (Pulmonary Vascular Disease Phenomics) Study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Subjects were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 subjects. RESULTS Metabolomic profiles distinguished CTD-PAH from IPAH, with CTD-PAH patients demonstrating aberrant lipid metabolism, with lower circulating levels of sex steroid hormones and higher free fatty acids (FA) and FA intermediates in CTD-PAH. Acylcholines were taken up by the right ventricular-pulmonary vascular circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and right ventricular measurements and with transplant-free survival. CONCLUSIONS CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-pulmonary vascular FA metabolism may imply reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.