Showing papers by "Paul M. Hassoun published in 2016"
TL;DR: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling during exercise, and RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.
Abstract: Background—Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. Methods and Results—RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH...
153 citations
TL;DR: It is suggested that HRQOL may be an important predictor of outcomes in pulmonary arterial hypertension and therefore a target for future therapeutic interventions.
Abstract: Rationale: Pulmonary arterial hypertension is a progressive disease with high morbidity and mortality despite advances in medical therapy. The relationship between patient-related outcomes, such as health-related quality of life (HRQOL), and survival is not well described.Objective: To assess the relationship between HRQOL and outcomes in patients with pulmonary arterial hypertension.Methods: Consecutive patients with right heart catheterization–proven pulmonary arterial hypertension who completed the Medical Outcomes Survey Short Form-36 survey (SF-36) were included. Demographic, clinical, physiological, and hemodynamic data were collected at baseline. Survival was assessed from the time of diagnosis of pulmonary arterial hypertension. Cox proportional hazard models were constructed to assess the relationship between HRQOL and transplant-free survival.Measurements and Main Results: Eighty-seven patients with pulmonary arterial hypertension were enrolled and followed prospectively for a median of 3.8 year...
57 citations
TL;DR: In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation.
Abstract: Rationale: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction.Objectives: The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH.Methods: We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, β-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and ...
50 citations
TL;DR: It is the first miRNA profiling study in lung tissue from end-stage idiopathic PAH and identified dysregulated miRNAs and major pathways (e.g., Wnt signaling) in IPAH.
Abstract: MicroRNAs (miRNAs) play important roles in the pathogenesis of pulmonary arterial hypertension (PAH). However, the pathways targeted by miRNAs in PAH have not been systematically investigated. We aim to identify dysregulated miRNAs for patients with idiopathic PAH (IPAH). miRNA profiling was performed on lung tissue total RNA from eight IPAH patients and eight control subjects. Real-time quantitative RT-PCR (qRT-PCR) was used for validation of miRNA and mRNA expression levels in 14 IPAH patients and 14 control subjects. Pathway enrichment analysis showed that Wnt/β-catenin signaling is among the top PAH-related pathways enriched in target genes of dysregulated miRNAs. We confirmed the significant increased expression levels of five miRNAs (let-7a-5p, miR-26b-5p, miR-27b-3p, miR-199a-3p and miR-656) targeting major PAH-related pathways. Moreover, qRT-PCR validation of Wnt/β-catenin pathway activation indicated multiple genes including receptors (FZD4, FZD5), core molecule (CTNNB1), and downstream targets (CCND1, VEGFA, and AXIN2) were significantly upregulated. The expression level of miR-199b-5p was positively correlated with patients’ hemodynamics (PVR: r = 0.522, p = 0.038) and pulmonary vascular remodeling (muscularization: r = 0.540, p = 0.021). We confirmed overexpression of miR-199b-5p in hypoxic pulmonary arterial endothelial cells that negatively regulates GSK3B expression. In summary, miRNAs influence the pathogenesis of PAH by regulating major PAH-related pathways including Wnt/β-catenin in end-stage IPAH.
42 citations
TL;DR: To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc), a large number of these variants have been found to have a positive effect on expressivity and penetrance.
Abstract: Objective
To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc).
Methods
We performed whole-exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case–control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls.
Results
The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 2.77 × 10−7). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence of association (P = 9.35 × 10−10, odds ratio [OR] 6.11), which was confirmed in the replication cohort (P = 0.012, OR 1.86) and meta-analysis (P = 1.92 × 10−7, OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA–DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10−5). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005).
Conclusion
ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications.
34 citations
TL;DR: Heart rate and BSA are associated with pulmonary RC time and this relationship supports a hemodynamic mechanism for adverse effects of tachycardia on the RV.
Abstract: Background The effect of heart rate (HR) and body surface area (BSA) on pulmonary RC time and right ventricular (RV) load is unknown. Methods To determine the association of HR and BSA with the pulmonary RC time and measures of RV load, we studied three large patient cohorts including subjects with 1) known or suspected pulmonary arterial hypertension (PAH) (n = 1008), 2) pulmonary hypertension due to left heart disease (n = 468), and 3) end-stage heart failure with reduced ejection fraction (n = 150). To corroborate these associations on an individual patient level, we performed an additional analysis using high-fidelity catheters in 22 patients with PAH undergoing right atrial pacing. Results A faster HR inversely correlated with RC time (p<0.01 for all), suggesting augmented RV pulsatile loading. Lower BSA directly correlated with RC time (p<0.05) although the magnitude of this effect was smaller than for HR. With incremental atrial pacing, cardiac output increased and total pulmonary resistance (TPR) fell. However, effective arterial elastance, its mean resistive component (TPR/heart period; 0.60±0.27 vs. 0.79±0.45;p = 0.048), and its pulsatile component (0.27±0.18 vs 0.39±0.28;p = 0.03) all increased at faster HR. Conclusion Heart rate and BSA are associated with pulmonary RC time. As heart rate increases, the pulsatile and total load on the RV also increase. This relationship supports a hemodynamic mechanism for adverse effects of tachycardia on the RV.
33 citations
TL;DR: The minimum important difference for Borg dyspnea scale in pulmonary arterial hypertension is around 1 unit, and further studies are needed to determine the clinical utility of these scores in patients with pulmonary arterials hypertension.
Abstract: Rationale: Despite therapeutic advances, pulmonary arterial hypertension remains a disease without a cure. Focusing on symptoms, such as dyspnea, is an important part of assessing response to therapy.Objectives: To determine the minimal important differences for the Borg dyspnea score and the Borg fatigue score in adult patients undergoing initial therapy for pulmonary arterial hypertension.Methods: We studied 129 patients enrolled between 2003 and 2013 in the Pulmonary Arterial Hypertension Program registry at Johns Hopkins University Hospital in Baltimore, Maryland. We analyzed baseline demographics, clinical characteristics, 6-minute-walk test distance, and Borg dyspnea and fatigue scores at baseline and at follow up 3 months after initiation of pulmonary arterial hypertension therapy. The minimal important differences for the Borg dyspnea and fatigue scores were determined using distributional and anchor-based methods, using 6-minute-walk test distance as the anchor.Measurements and Main Results: Most...
31 citations
TL;DR: The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and it is recommended that it be used in clinical prognostication and PAH predictive models.
Abstract: Background Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables. Methods We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center. Results Cohort 1 ( n = 847) and Cohort 2 ( n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 ( p = 0.0001) and 1.35, respectively ( p Conclusions The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models.
21 citations
TL;DR: It is demonstrated that both the activity of xanthine oxidoreductase (XOR), a superoxide-generating enzyme obligatory for CS-induced DNA damage and EndoC apoptosis, and superoxide concentrations are increased after CS exposure in the absence of MIF.
Abstract: Cigarette smoke (CS) exposure is the leading cause of emphysema. CS mediates pathologic emphysematous remodeling of the lung via apoptosis of lung parenchymal cells resulting in enlargement of the airspaces, loss of the capillary bed, and diminished surface area for gas exchange. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, is reduced both in a preclinical model of CS-induced emphysema and in patients with chronic obstructive pulmonary disease, particularly those with the most severe disease and emphysematous phenotype. MIF functions to antagonize CS-induced DNA damage, p53-dependent apoptosis of pulmonary endothelial cells (EndoCs) and resultant emphysematous tissue remodeling. Using primary alveolar EndoCs and a mouse model of CS-induced lung damage, we investigated the capacity and molecular mechanism(s) by which MIF modifies oxidant injury. Here, we demonstrate that both the activity of xanthine oxidoreductase (XOR), a superoxide-generating enzyme obligatory for CS-induced DNA damage and EndoC apoptosis, and superoxide concentrations are increased after CS exposure in the absence of MIF. Both XOR hyperactivation and apoptosis in the absence of MIF occurred via a p38 mitogen-activated protein kinase-dependent mechanism. Furthermore, a mitogen-activated protein kinase kinase kinase family member, apoptosis signal-regulating kinase 1 (ASK1), was necessary for CS-induced p38 activation and EndoC apoptosis. MIF was sufficient to directly suppress ASK1 enzymatic activity. Taken together, MIF suppresses CS-mediated cytotoxicity in the lung, in part by antagonizing ASK1-p38-XOR-dependent apoptosis.
16 citations
TL;DR: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH.
Abstract: Rationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival.Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival.Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker.Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and ...
9 citations
TL;DR: It is concluded that FENO is not useful for the diagnosis of PAH in SSc and increased alveolar nitric oxide in S Sc-PAH likely represents impaired diffusion into pulmonary capillary blood.
Abstract: The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J'awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar (P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients (P = 0.9). J'awNO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.
TL;DR: In patients with more advanced disease who have established PH or are at high risk of developing PH, pulmonary vasoactive agents might represent a viable therapeutic option.
Abstract: Sildenafil may be of benefit in IPF with out-of-proportion PH and could be a step toward effective multimodal therapy http://ow.ly/YYYap
TL;DR: It is concluded that combined therapy did not decrease the composite endpoint of mortality, hospital admission for worsening pulmonary arterial hypertension, lung transplantation, or escalation of therapy, and calls for the establishment of more relevant endpoints such as morbidity and mortality.
TL;DR: A major hurdle in designing clinical trials of pharmaceutical therapies for patients with the acute respiratory distress syndrome (ARDS) is the difficulty in translating promising findings from preclinical animal experiments to human clinical trials.
Abstract: To the Editor: We read with great interest the article by Christie et al (1) published in a recent issue of Critical Care Medicine. A major hurdle in designing clinical trials of pharmaceutical therapies for patients with the acute respiratory distress syndrome (ARDS) is the difficulty in translating promising findings from preclinical animal experiments to human clinical trials. This is likely due in part to tremendous heterogeneity in ARDS. Recent work has identified discrete molecular patterns of injury based on the etiology of ARDS, where direct causes of lung injury lead to significantly more epithelial damage, whereas indirect causes lead to more endothelial damage (2). The clinical importance of this distinction was highlighted in the recent clinical trials of β-agonists for the treatment of ARDS. The β-Agonist Lung Injury Trial (BALTI) demonstrated a significant reduction in lung water with salbutamol treatment compared with placebo (3). However, these promising results could not be replicated in the BALTI-2 trial. In fact, patient recruitment was interrupted early due to safety concerns (4). Interestingly, 64% of patients in BALTI-2 trial, compared with only 15.8% in BALTI trial, randomized to the salbutamol group had a direct cause of injury identified as the source of ARDS. As β-agonists rely on functioning epithelial cells to promote adequate clearance of extravascular lung water, it is reasonable to think that when there is a significant epithelial injury, as is the case with direct lung injury, β-agonists may be ineffective. is questionable as many major public hospitals have highly developed intensive care services in the absence of such arrangements. Autonomy and political power are the key words in their letter. It swings back toward the original premise that professional independence and strength are the predominant driving factors in creating ICM as a single, dynamic, committed medical specialty and that training issues follow in their wake (3). The author has disclosed that he does not have any potential conflicts of interest.