Katarzyna Ptaszyńska-Kopczyńska

Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage.

BACKGROUND The role of IL-6 in pulmonary arterial hypertension (PAH) has been reported but the prevalence of soluble receptors for IL-6: sIL-6R and sgp130 and its potential role in PAH have not been studied.Our aim was to examine the IL-6 together with the soluble receptors and to assess its relationship with clinical status of PAH patients as well as to assess its potential prognostic significance. METHODS Serum concentrations of IL-6, sIL-6R and sgp130 were quantified by ELISA in 26 patients with PAH and 27 healthy controls and related to functional and biochemical parameters and clinical outcome in PAH group. The PAH patients were followed up for 1 year, noting the end point of clinical deterioration (WHO class change, the need for escalation of therapy) or death. RESULTS The PAH group was characterized by higher median serum IL-6 [2.38 (IQR 1.56-3.75) vs 0.87 (0.63-1.3) pg/ml, p=0.000003] and sIL-6R concentrations [69.7 (IQR 60.4-84.4 vs 45.7 (34.6-70.3) ng/ml, p=0.0036] compared to control subjects. Both groups did not differ in sgp130 concentrations. There were significant correlations in PAH group between IL-6 levels and uric acid, parameters of ventilatory efficiency in cardiopulmonary exercise testing: VE/VO2, VE/VCO2, VE/VCO2 slope and peak PetCO2. sIL-6R levels inversely correlated with LDL cholesterol. After 1 year the clinical deterioration occurred in 11 patients, 15 remained stable. Patients in whom the clinical deterioration occurred showed significantly higher baseline concentrations of IL-6 [3.25 (IQR 2.46-5.4) pg/ml vs 1.68 (1.38-2.78) pg/ml, p=0.004], but not sIL-6R. Median IL-6 ⩾ 2.3 pg/ml (91% sensitivity, 73% specificity) identified subjects with worse clinical course. In the univariate analysis, higher IL-6 level at baseline was associated with increased risk and earlier occurrence of clinical deterioration (HR 1.42, 95%CI 1.08-1.85, p=0.015). CONCLUSIONS IL-6 trans-signaling is enhanced in PAH. Elevated concentration of sIL-6R suggests its potential unfavorable role in systemic amplification of IL-6 signaling in PAH. Levels of IL-6 are associated with clinical indicators of disease severity as well as indirectly with systemic metabolic alterations. IL-6 shows prognostic value regarding predicting clinical deterioration.

The significance of diminished sTWEAK and P-selectin content in platelets of patients with pulmonary arterial hypertension

HighlightsPatients with PAH present comparable serum sTWEAK concentrations as controls.Platelet content of TWEAK and P‐selectin is diminished in patients with PAH.Lower platelet TWEAK is associated with clinical indices of more advanced disease.Patients with lowest platelet TWEAK more frequently develop detoriation of PAH.sTWEAK secreted by platelets may affect PAH progression and prognosis. &NA; Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative changes in pulmonary arteries. There is growing evidence suggesting that soluble tumor necrosis factor‐like weak inducer of apoptosis (sTWEAK) and P‐selectin could be involved in PAH development and progression. Here we investigate whether circulating platelets may be a source of sTWEAK and contribute to diminished availability of sTWEAK and P‐selectin in PAH patients. We have prospectively enrolled two independent study groups of stable patients with confirmed PAH and age matched controls: derivation (10 PAH; 15 controls) and validation (20 PAH; 12 controls). P‐selectin and sTWEAK concentrations were measured in platelet‐poor plasma and platelet lysate. To avoid procedural bias, in each group we employed different protocols for platelet isolation. Consistently, both in derivation and validation groups PAH patients presented significantly lower sTWEAK content in platelets than control group with no significant differences in plasma levels. Similarly, patients presented comparable to controls plasma P‐selectin concentrations and lower concentration in platelet lysate. Kaplan‐Meier analysis revealed that patients with low platelet sTWEAK/total protein concentration ratio had more frequently detoriation of PAH in the follow‐up (16.51 ± 3.32 months), log‐rank test, p = .03. Patients diagnosed with pulmonary arterial hypertension present diminished sTWEAK and P‐selectin storage capacity in platelets. Thrombocytes appear to be a major source of sTWEAK that could be released upon local injury and its decreased availability could have an impact on pathophysiology and prognosis in PAH.

Differences of psychological features in patients with heart failure with regard to gender and aetiology — Results of a CAPS-LOCK-HF (Complex Assessment of Psychological Status Located in Heart Failure) study

OBJECTIVE Objective of the study was to assess the psychological state of HF patients with reduced ejection fraction (HFrEF) with regard to gender and aetiology. METHODS 758 patients with HFrEF (mean age - 64±11years, men - 79%, NYHA class III-IV - 40%, ischemic aetiology - 61%) in a prospective Polish multicenter Caps-Lock-HF study. Scores on five different self-report inventories: CISS, MHLC, GSES, BDI and modified Mini-MAC were compared between the sexes taking into account the aetiology of HFrEF. RESULTS There were differences in the CISS and BDI score between the genders - women had higher CISS (emotion- and avoidance-oriented) and BDI (general score - 14.2±8.7 vs 12.3±8.6, P<0.05; subscale - somatic score - 7.3±3.7 vs 6.1±3.7, P<0.05). In the ischemic subpopulation, women had higher BDI (general and subscales) than men. In the non-ischemic subpopulation the differences between genders were limited to CISS scale. In a multivariable analysis with demographic and clinical data female sex, NYHA class, atrial fibrillation and diabetes mellitus determined BDI score. Similarly, in the ischemic subpopulation, the female sex, NYHA class and atrial fibrillation determined the BDI, while in the non-ischemic population NYHA class was the only factor that influenced the BDI score. Adding the psychological data made a significant additional contribution to the prediction of depression status. CONCLUSIONS There are distinct differences in psychological features with regard to gender in patients with HFrEF. Women demonstrate less favourable psychological characteristics. Gender-related differences in BDI score are especially explicit in patients with ischemic aetiology of HF. The BDI score is related to psychological predisposition.

Increased Platelet Content of SDF-1alpha is Associated with Worse Prognosis in Patients with Pulmonary Arterial Hypertension

Abstract Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10–10 [0.29 – 1.37] vs. 0.45*10–10 [0.19–0.65], sIL-6R 1.54*10–7 [1.32–2.21] vs. 1.14*10–7 [1.01–1.28] and SDF-1 (2.72*10–7 [1.85–3.23] vs. 1.70*10–7 [1.43–2.60], all p < 0.05). Patients with disease progression (death, WHO class worsening, or therapy escalation, n = 10) had a significantly higher platelet SDF-1/total platelet protein ratio (3.68*10–7 [2.45–4.62] vs. 1.69*10–7 [1.04–2.28], p = 0.001), with no significant differences between plasma levels. Kaplan–Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 ± 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF-1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation.

Correlations between electrocardiogram and biomarkers in acute pulmonary embolism: Analysis of ZATPOL-2 Registry

Electrocardiography (ECG) is still one of the first tests performed at admission, mostly in patients (pts) with chest pain or dyspnea. The aim of this study was to assess the correlation between electrocardiographic abnormalities and cardiac biomarkers as well as echocardiographic parameter in patients with acute pulmonary embolism.

LC–MS-based serum fingerprinting reveals significant dysregulation of phospholipids in chronic heart failure

HIGHLIGHTSChronic HF patients presented significant disturbances in phospholipids metabolism.Intensities of PCs, lyso‐PCs, lyso‐PEs were significantly decreased in HF patients.Greater reduction of phospholipids was associated with more advanced disease. ABSTRACT Cardiac and extracardiac lipid metabolism is known to be significantly altered in the course of the heart failure with reduced ejection fraction (HF‐REF), however the precise mechanisms are not fully elucidated. The aim of the study was to use of untargeted metabolomics to identify and validate changes in the blood metabolites profile, occurring as a result of HF‐REF development. The analyses were performed first in the derivation set (36 chronic HF‐REF patients and 19 controls without the disease) and repeated in validation cohort (31 chronic HF‐REF patients and 20 controls). Independent analyses of both sets revealed statistically significant decline in intensities of phosphatidylcholine (PC): 34:4 and 36:5, lysophosphatidylcholine (lyso‐PC): 14:0, 15:0, 18:0, 18:2, 20:3, lysophosphatidylethanolamine (lyso‐PE): 18:1 and 18:2 in chronic HF‐REF patients. More symptomatic patients and those with ischaemic etiology of HF‐REF presented greater deficit in phospholipids (PLs) intensities. The decrease of identified PLs intensities (as compared to controls) correlated with decreased serum cholesterol level, impaired renal function, reduced exercise capacity, enhanced ventilatory response and metabolic parameters associated with altered fatty acids oxidation. In multiple regression analysis PLs deficit was significantly associated with age, carnitines serum intensity, renal function, uric acid, cholesterol level. In conclusion, HF‐REF is associated with significant disturbances in phospholipids metabolism. Greater reduction in serum intensities of particular identified PLs is associated with older age, worse clinical condition, impaired oxidative muscle metabolism and enhanced catabolic status.

Paroxysmal Atrial Fibrillation in the Course of Acute Pulmonary Embolism: Clinical Significance and Impact on Prognosis

The relationship and clinical implications of atrial fibrillation (AF) in acute pulmonary embolism (PE) are poorly investigated. We aimed to analyze clinical characteristics and prognosis in PE patients with paroxysmal AF episode. Methods. From the 391 patients with PE 31 subjects with paroxysmal AF were selected. This group was compared with patients with PE and sinus rhythm (SR) and 32 patients with PE and permanent AF. Results. Paroxysmal AF patients were the oldest. Concomitant DVT varies between groups: paroxysmal AF 32.3%, SR 49.5%, and permanent AF 28.1% (p = 0.02). The stroke history frequency was 4.6% SR, 12.9% paroxysmal AF, and 21.9% permanent AF (p < 0.001). Paroxysmal AF comparing to permanent AF and SR individuals had higher estimated SPAP (56 versus 48 versus 47 mmHg, p = 0.01) and shorter ACT (58 versus 65 versus 70 ms, p = 0.04). Patients with AF were more often classified into high-risk group according to revised Geneva score and sPESI than SR patients. In-hospital mortality was lower in SR (5%) and paroxysmal AF (6.5%) compared to permanent AF group (25%) (p < 0.001). Conclusions. Patients with PE-associated paroxysmal AF constitute a separate population. More severe impairment of the parameters reflecting RV afterload may indicate relation between PE severity and paroxysmal AF episode. Paroxysmal AF has no impact on short-term mortality.

Interleukin-6 signaling in patients with chronic heart failure treated with cardiac resynchronization therapy

Introduction Increased expression of interleukin-6 (IL-6) has been described in left ventricular dysfunction in the course of chronic heart failure. Cardiac resynchronization therapy (CRT) is a unique treatment method that may reverse the course of chronic heart failure (CHF) with reduced ejection fraction (HF-REF). We aimed to evaluate the IL-6 system, including soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130), in HF-REF patients, with particular emphasis on CRT effects. Material and methods The study enrolled 88 stable HF-REF patients (63.6 ±11.1 years, 12 females, EF < 35%) and 35 comorbidity-matched controls (63.5 ±9.8 years, 7 females). Forty-five HF-REF patients underwent CRT device implantation and were followed up after 6 months. Serum concentrations of IL-6, sIL-6R and sgp130 were determined using ELISA kits. Results The HF-REF patients had higher IL-6 (median: 2.6, IQR: 1.6–3.8 vs. 2.1, IQR: 1.4–3.1 pg/ml, p = 0.03) and lower sIL-6R concentrations compared to controls (median: 51, IQR: 36–64 vs. 53. IQR 44–76 ng/ml, p = 0.008). There was no significant difference between sgp130 concentrations. In the HF-REF group IL-6 correlated negatively with EF (r = –0.5, p = 0.001) and positively with BNP (r = 0.5, p = 0.008) and CRP concentrations (r = 0.4, p = 0.02). Patients who presented a positive response after CRT showed a smaller change of sIL-6R concentration compared to nonresponders (ΔsIL-6R: –0.2 ±7.1 vs. 7 ±14 ng/ml; p = 0.04). Conclusions HF-REF patients present higher IL-6 and lower sIL-6R levels. IL-6 concentration reflects their clinical status. CRT-related improvement of patients’ functional status is associated with a smaller change of sIL-6R concentration in time.

The strengths and weaknesses of non-invasive parameters obtained by echocardiography and cardiopulmonary exercise testing in comparison with the hemodynamic assessment by the right heart catheterization in patients with pulmonary hypertension

PURPOSE Pulmonary hypertension (PH) diagnosis requires invasive assessment by right heart catheterization (RHC), but screening and monitoring are performed using non-invasive methods: echocardiography and cardiopulmonary exercise testing (CPET). The aim of the study was to assess correlations between the parameters obtained in non-invasive testing and RHC in patients with PH of different etiologies. MATERIAL/METHODS The study included 53 medical records of PH patients (32 women) aged 29-81 years. We analyzed correlations between RHC (systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP), pulmonary vascular resistance (PVR), cardiac output (CO)) and echocardiographic (tricuspid annular plane systolic excursion (TAPSE), sPAP) and CPET parameters (end-tidal oxygen and carbon dioxide pressures (PetO2, PetCO2), ventilation efficiency (VE/VCO2) slope). RESULTS Echocardiographic estimation correlated well with RHC measurement of sPAP (r=0.65, P<0.001). TAPSE correlated with PVR assessed with thermodilution method (r=-0.5, P=0.005), dPAP (r=-0.53, P=0.002) and CO (r=0.53, P=0.002). PVR assessed with thermodilution and Fick methods showed positive correlation with PetO2 (r=0.74, P<0.001 and r=0.72, P<0.001) and negative correlation with PetCO2 (r=-0.59, P=0.004 and r=-0.64, P=0.002) at the anaerobic threshold. VE/VCO2 slope correlated with dPAP (r=0.43, P=0.04) and PVR calculated with both methods (r=0.52, P=0.01 and r=0.52, P=0.02). CONCLUSIONS Simple cardiac function indicators obtained by commonly used non-invasive methods allow only approximate estimation of the main hemodynamic RHC-derived parameters: sPAP, CO and PVR. Obtained results suggest the relationship between RV dysfunction and ventilation abnormalities in PH patients.