Nils Nickel

The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension

Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy. A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3–12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease. Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan–Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (Sv,O2) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, Sv,O2 and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline. Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension

RATIONALE Growth-differentiation factor (GDF)-15 is a stress-responsive, transforming growth factor-beta-related cytokine. Circulating levels of GDF-15 provide independent prognostic information in patients with acute pulmonary embolism and chronic left-sided heart failure. OBJECTIVES To assess the prognostic value of GDF-15 in idiopathic pulmonary arterial hypertension. METHODS GDF-15 levels were determined in 76 treatment-naive patients at the time of baseline right heart catheterization. Patients were monitored for a median (range) of 48 (0-101) months (first cohort). Twenty-two additional patients were studied at baseline and 3 to 6 months after initiation of therapy (second cohort). MEASUREMENTS AND MAIN RESULTS Fifty-five percent of the patients in the first cohort presented with GDF-15 levels above 1,200 ng/L, the previously defined upper reference limit. The risk of death or transplantation at 3 years was 15 and 44% in patients with GDF-15 levels below or above 1,200 ng/L, respectively (P = 0.006). Elevated levels of GDF-15 were associated with increased mean right atrial and pulmonary capillary wedge pressures, a lower mixed venous oxygen saturation (Sv(O(2))), and higher levels of uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP). After adjustment for hemodynamic and biochemical variables, GDF-15 remained an independent predictor of adverse outcomes (P = 0.002). GDF-15 provided prognostic information in clinically relevant patient subgroups, and added prognostic information to hemodynamic variables and NT-proBNP. Changes in GDF-15 over time in the second cohort were related to changes in NT-proBNP (P = 0.031) and inversely related to changes in Sv(O(2)) (P < 0.001). CONCLUSIONS GDF-15 is a promising new biomarker in idiopathic pulmonary arterial hypertension.

Plexiform Lesions in Pulmonary Arterial Hypertension: Composition, Architecture, and Microenvironment

Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three-dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling-associated genes, such as HIF1a, TGF-β1, VEGF-α, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy.

Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

RATIONALE Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. OBJECTIVES We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. METHODS Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. MEASUREMENTS AND MAIN RESULTS The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. CONCLUSIONS Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

Circulating angiopoietins in idiopathic pulmonary arterial hypertension

AIMS To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH. METHODS AND RESULTS Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples. CONCLUSION Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn·s·cm−5 at the time of diagnosis and of 1,858 dyn·s·cm−5 at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey

We conducted an international, prospective, 3-year questionnaire-based survey among 11 pulmonary hypertension centres to assemble data from patients with pulmonary arterial hypertension (PAH) undergoing noncardiac and nonobstetric surgery. Data were collected between July 2007 and June 2010 from 114 patients with PAH (70% female, mean age 57 years) who underwent major surgery. At the time of surgery, 43% were in functional class III/IV. 82% of the interventions were performed under general anaesthesia and 18% under spinal anaesthesia. Major complications occurred in seven (6.1%) of the patients, of whom four died, resulting in an overall perioperative mortality rate of 3.5%. The mortality rate was 15% (two out of 13) in emergency procedures, compared with 2% (two out of 101) in nonemergency procedures (p=0.01). Risk factors for major complications were an elevated right atrial pressure (OR 1.1, 95% CI 1.0–1.3; p=0.01), a 6-min walking distance <399 m at the last preoperative assessment (OR 2.2, 95% CI 1.1–3.7; p=0.04), the perioperative use of vasopressors (OR 1.5, 95% CI 1.2–2.7; p=0.03) and the need for emergency surgery (OR 2.4, 95% CI 1.4–3.6; p=0.01). Major surgery in patients with PAH continues to be a high-risk procedure, particularly when emergency interventions are needed.

Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression

BACKGROUND Recent studies have revealed that microRNAs (miRNAs) play a key role in the control of angiogenesis and vascular remodeling. Specific miRNAs in plexiform vasculopathy of severe pulmonary arterial hypertension (PAH) in humans have not yet been investigated. METHODS We analyzed expression of miR-143/145 (vascular smooth muscle-specific), miR-126 (endothelial-specific) and related mRNAs in plexiform (PLs) and concentric lesions (CLs), which had been laser-microdissected from specimens of formalin-fixed, paraffin-embedded, explanted lungs of PAH patients (n = 12) and unaffected controls (n = 8). Samples were analyzed by real-time polymerase chain reaction, and protein expression was determined by immunohistochemistry. RESULTS Expression levels of miR-143/145 and its target proteins (e.g., myocardin, smooth muscle myosin heavy chain) were found to be significantly higher in CLs than in PLs, whereas miR-126 and VEGF-A were significantly up-regulated in PLs when compared with CLs, indicating a more prominent angiogenic phenotype of PL. This correlates with a down-regulation of miR-204 as well as an up-regulation of miR-21 in PLs, which in turn corresponds to enhanced cell proliferation. CONCLUSIONS Our findings show that morphologic changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level.

Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension

Reduced expression of bone morphogenetic protein receptor 2 subverts a stress granule response, heightens GM-CSF mRNA translation, and increases inflammatory cell recruitment to exacerbate pulmonary arterial hypertension.

Atrial flutter and fibrillation in patients with pulmonary hypertension

BACKGROUND Atrial flutter and fibrillation are being increasingly reported in patients with pulmonary hypertension but little is known about their clinical implications. We sought to determine the incidence and clinical impact of these arrhythmias in patients with pulmonary hypertension. METHODS In a 5-year, prospective study, we assessed the incidence of new-onset atrial flutter and fibrillation as well as risk factors, clinical consequences, management, and impact on survival in patients with pulmonary arterial hypertension (PAH, n=157) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH, n=82). RESULTS The cumulative 5-year incidence of new-onset atrial flutter and fibrillation was 25.1% (95% confidence interval, 13.8-35.4%). The development of these arrhythmias was frequently accompanied by clinical worsening (80%) and signs of right heart failure (30%). Stable sinus rhythm was successfully re-established in 21/24 (88%) of patients initially presenting with atrial flutter and in 16/24 (67%) of patients initially presenting with atrial fibrillation. New-onset atrial flutter and fibrillation were an independent risk factor of death (p=0.04, simple Cox regression analysis) with a higher mortality in patients with persistent atrial fibrillation when compared to patients in whom sinus rhythm was restored (estimated survival at 1, 2 and 3 years 64%, 55%, and 27% versus 97%, 80%, and 57%, respectively; p=0.01, log rank analysis). CONCLUSIONS Atrial flutter and fibrillation develop in a sizable number of patients with PAH or inoperable CTEPH and often lead to clinical deterioration and right heart failure. Mortality is high when sinus rhythm cannot be restored.