In the Search for Biomarkers of Pulmonary Arterial Hypertension, Are Cytokines IL-2, IL-4, IL-6, IL-10, and IFN-Gamma the Right Indicators to Use?

Pulmonary arterial hypertension (PAH) is a complex disorder characterized by increased pressure in the pulmonary arteries, leading to right heart failure. While the exact mechanisms underlying PAH are not fully understood, cytokines have been implicated in the pathogenesis of the disease. Cytokines play a crucial role in regulating immune responses and inflammation. These small proteins also play a key role in shaping the immunophenotype, which refers to the specific characteristics and functional properties of immune cells, which can have a significant impact on the development of PAH. The aim of this study was to determine the immunophenotype and the concentration of selected cytokines, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, in patients diagnosed with PAH (with particular emphasis on subtypes) in relation to healthy volunteers. Based on the obtained results, we can conclude that in patients with PAH, the functioning of the immune system is deregulated as a result of a decrease in the percentage of selected subpopulations of immune cells in peripheral blood and changes in the concentration of tested cytokines in relation to healthy volunteers. In addition, a detailed analysis showed that there are statistically significant differences between the PAH subtypes and the tested immunological parameters. This may indicate a significant role of the immune system in the pathogenesis of PAH.

Impact of diabetes mellitus on disease severity and patient survival in idiopathic pulmonary arterial hypertension: data from the Polish multicentre registry (BNP-PL).

BACKGROUND: Recent studies revealed that alterations in glucose and lipid metabolism in idiopathic pulmonary arterial hypertension (IPAH) are associated with disease severity and poor survival. However, data regarding the impact of diabetes mellitus (DM) on the prognosis of patients with IPAH remain scarce. The aim of our study was to determine that impact using data from a national multicentre prospective pulmonary hypertension registry. METHODS: We analysed data of adult patients with IPAH from the Database of Pulmonary Hypertension in the Polish population (BNP­PL) between March 1, 2018 and August 31, 2020. Upon admission, clinical, echocardiographic, and haemodynamic data were collected at 21 Polish IPAH reference centres. The all-cause mortality was assessed during a 30-month follow-up period. To adjust for differences in age, body mass index (BMI), and comorbidities between patients with and without DM, a 2-group propensity score matching was performed using a 1:1 pairing algorithm. RESULTS: A total of 532 patients with IPAH were included in the study and 25.6% were diagnosed with DM. Further matched analysis was performed in 136 patients with DM and 136 without DM. DM was associated with older age, higher BMI, more advanced exertional dyspnea, increased levels of N-terminal pro-brain natriuretic peptide, larger right atrial area, increased mean right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and all-cause mortality compared with no DM. CONCLUSIONS: Patients with IPAH and DM present with more advanced pulmonary vascular disease and worse survival than counterparts without DM independently of age, BMI, and cardiovascular comorbidities.

Hemodynamic effects of balloon pulmonary angioplasty for the treatment of total and subtotal pulmonary artery occlusions in inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) has become a therapeutic option for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Despite significant improvement in the technique, treatment of subtotal (STO) and total (TO) pulmonary artery occlusions with BPA may pose risk, but the efficacy is less known. AIM: We aimed to evaluate the safety and efficacy of BPA in STO/TO. METHODS: We included consecutive patients with inoperable CTEPH, who underwent BPA treatment. To evaluate the efficacy and safety we grouped all BPA sessions into these in which recanalization of at least one STO or TO was performed and into those without. The primary efficacy outcome was a decrease of pulmonary vascular resistance (PVR) after BPA sessions with STO/TO recanalization as compared to those without. RESULTS: We analysed 169 BPA sessions in 50 CTEPH patients. Out of a total number of 831 lesions subjected for BPA, 169 were classified as STOs or TOs [123 (15,6%) and 39 (4,7%) respectively]. At least one STO/TO recanalization was successfully performed during 90 BPA sessions. Three (2,3%) STOs and 8 (20,5%) TOs were not recanalized despite repeated attempts. Recanalization of at least one STO/TO at the level of segmental pulmonary artery was associated with a significant PVR improvement as compared to subsegmental-only STO/TO recanalizations or no recanalizations (-126 ± 192 vs -38 ± 135 dyn·s·cm - 5, p = 0.007). The rate of complications was similar in STO/TO and non-STO/TO lesions (4.1% vs 2.4%, p = 0.22). CONCLUSIONS: The use of BPA for the recanalization of subtotal and total PA occlusions is safe and feasible. Recanalization of segmental occlusive lesions leads to a significant improvement in PVR as compared to dilatation of nonocclusive ones.

Changes in Inflammatory Markers in Patients with Chronic Thromboembolic Pulmonary Hypertension Treated with Balloon Pulmonary Angioplasty.

Background: Inflammatory response and endothelial dysfunction contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess changes in biomarkers involved in those processes in inoperable CTEPH patients treated with balloon pulmonary angioplasty (BPA). Methods: We enrolled 20 patients with inoperable CTEPH qualified for BPA and a control group. Interleukin 6, 8, 10 (IL-6, IL-8, IL-10), monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (hsCRP) constituted the markers of systemic inflammation. Endothelin 1 (ET-1) served as a marker of endothelial dysfunction. Selected markers were assessed before the BPA treatment, 24 h after the first BPA, and six months after completion of the BPA treatment. Results: At baseline, the CTEPH patients had increased serum concentrations of IL-6, IL-8 and ET-1. Twenty-four hours after a BPA session, we observed an increase in concentrations of IL-6 (∆ = 3.67 (1.41; 7.16); p < 0.001), of IL-10 (∆ = 0.25 (0; 0.47); p = 0.003), of MCP-1 (∆ = 111 (60.1; 202.8); p = 0.002), and of hsCRP (∆ = 4.81 (3.46; 8.47); p < 0.001). Six months after completion of the BPA treatment, there was a decrease in concentrations of IL-6 (∆ = −1.61 (−3.11; −0.20); p = 0.03), of IL8 (∆ = −3.24 (−7.72; 0.82); p = 0.01), and of ET-1 (∆ = −0.47 (−0.96; 0.05); p = 0.005). Conclusions: Patients with inoperable CTEPH exhibit increased systemic inflammation and endothelial dysfunction, which improves after completion of the BPA treatment. A single BPA session evokes an acute inflammatory response.

Exhaled Air Metabolome Analysis for Pulmonary Arterial Hypertension Fingerprints Identification-The Preliminary Study.

Pulmonary arterial hypertension (PAH) is a rare disease with a serious prognosis. The aim of this study was to identify biomarkers for PAH in the breath phase and to prepare an automatic classification method to determine the changing metabolome trends and molecular mapping. A group of 37 patients (F/M: 8/29 women, mean age 60.4 ± 10.9 years, BMI 27.6 ± 6.0 kg/m2) with diagnosed PAH were enrolled in the study. The breath phase of all the patients was collected on a highly porous septic material using a special patented holder PL230578, OHIM 002890789-0001. The collected air was then examined with gas chromatography coupled with mass spectrometry (GC/MS). The algorithms of Spectral Clustering, KMeans, DBSCAN, and hierarchical clustering methods were used to perform the cluster analysis. The identification of the changes in the ratio of the whole spectra of biomarkers allowed us to obtain a multidimensional pathway for PAH characteristics and showed the metabolome differences in the four subgroups divided by the cluster analysis. The use of GC/MS, supported with novel porous polymeric materials, for the breath phase analysis seems to be a useful tool in selecting bio-fingerprints in patients with PAH. The four metabolome classes which were obtained constitute novel data in the PAH population.

Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: a multicentre registry.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a promising therapy for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are ineligible for pulmonary endarterectomy. AIMS: The present study aimed to evaluate the safety and efficacy of BPA for CTEPH using the first multicentre registry of a single European country. METHODS: Data were obtained from the Database of Pulmonary Hypertension in the Polish Population (NCT03959748), a prospective, multicentre registry of adult and paediatric pulmonary arterial hypertension (PAH) and CTEPH, for a total of 236 patients with confirmed CTEPH (124 women; mean age 67 years) who underwent 1,056 BPA procedures at eight institutions in Poland. RESULTS: In 156 patients who underwent follow-up assessments after a median of 5.9 (IQR: 3.0-8.0) months after final BPA, the mean pulmonary arterial pressure decreased from 45.1±10.7 to 30.2±10.2 mmHg (p<0.001) and pulmonary vascular resistance from 642±341 to 324±183 dynes (p<0.001), and the six-minute walking test (6MWT) improved from 341±129 to 423±136 m (p<0.001). Pulmonary injury related to the BPA procedure occurred in 6.4% of all sessions. Eighteen patients (7.6%) died during follow-up, including 4 (1.7%) who died within 30 days after BPA. Overall survival was 92.4% (95% confidence interval [CI]: 87.6%-94.9%) three years after the initial BPA procedure. CONCLUSIONS: This multicentre registry confirmed significant improvement of haemodynamic, functional, and biochemical parameters after BPA. Complication rates were low and overall survival comparable to the results of another registry. Therefore, BPA may be an important therapeutic option in patients with CTEPH in Poland.

Characteristics and outcomes of patients with chronic thromboembolic pulmonary hypertension in the era of modern therapeutic approaches: data from the Polish multicenter registry (BNP-PL).

BACKGROUND: Significant achievements in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) have provided effective therapeutic options for most patients. However, the true impact of the changed landscape of CTEPH therapies on patients' management and outcomes is poorly known. We aimed to characterize the incidence, clinical characteristics, and outcomes of CTEPH patients in the modern era of CTEPH therapies. METHODS: We analyzed the data of CTEPH adults enrolled in the prospective multicenter registry. RESULTS: We enrolled 516 patients aged 63.8 ± 15.4 years. The incidence rate of CTEPH was 3.96 per million adults per year. The group was burdened with several comorbidities. New oral anticoagulants (n = 301; 58.3%) were preferred over vitamin K antagonists (n = 159; 30.8%). Pulmonary endarterectomy (PEA) was performed in 120 (23.3%) patients and balloon pulmonary angioplasty (BPA) in 258 (50%) patients. PEA was pretreated with targeted pharmacotherapy in 19 (15.8%) patients, and BPA in 124 (48.1%) patients. Persistent CTEPH was present in 46% of PEA patients and in 65% of patients after completion of BPA. Persistent CTEPH after PEA was treated with targeted pharmacotherapy in 72% and with BPA in 27.7% of patients. At a mean time period of 14.3 ± 5.8 months, 26 patients had died. The use of PEA or BPA was associated with better survival than the use of solely medical treatment. CONCLUSIONS: The modern population of CTEPH patients comprises mostly elderly people significantly burdened with comorbid conditions. This calls for treatment decisions that are tailored individually for every patient. The combination of two or three methods is currently a frequent approach in the treatment of CTEPH. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT03959748.

Hemodynamic Effects of Ultrasound-Assisted, Catheter-Directed, Very Low-Dose, Short-Time Duration Thrombolysis in Acute Intermediate-High Risk Pulmonary Embolism (from the EKOS-PL Study).

Ultrasound-assisted, catheter-directed, low-dose thrombolysis (USAT) at an average alteplase dose of 20 mg infused over 12 to 24 hours reversed right ventricular disfunction and improved pulmonary hemodynamics in intermediate-high-risk pulmonary embolism patients. As bleeding risk increases with the thrombolytic dose, establishing a minimal effective USAT dosing regimen is of clinical importance. We aimed to investigate hemodynamic effects and safety of a very low-alteplase-dose USAT of 10 mg administered within 5 hours. We included 12 consecutive intermediate-high-risk pulmonary embolism patients with symptoms duration of <14 days and proximal thrombi location in pulmonary arteries. Pulmonary Embolism Response Team decision-based fixed, bilateral ultrasound-assisted alteplase infusions at the rate of 1mg/hour/catheter for 5 hours through EKOS system catheters were made. The primary efficacy measure was the change in invasive systolic and mean pulmonary arteries pressure, and in cardiac index from USAT start to termination. Safety measures were 180-day all-cause death or cardiopulmonary decompensation and bleeding complications. The systolic pulmonary arteries pressure and mean pulmonary arteries pressure decreased from 53 (45.5 to 59) to 37.5 (27.5 to 40.5) mm Hg (p = 0.02) and from 29.5 (27.5 to 32) to 21.5 (15.5 to 25) mm Hg (p = 0.02), respectively. The cardiac index increased from 1.6 (1.5 to 1.8) to 2.2 (1.9 to 2.4) l/min/m2, (p = 0.02). No deaths, decompensations, or need for therapy intensification occurred. There was 1 episode of access-site bleeding, which subsided after conservative management. No intracranial hemorrhages appeared. In conclusion, reduced dose and duration USAT improved pulmonary hemodynamics and cardiac function leading to cardiopulmonary stabilization in intermediate-high risk pulmonary embolism patients at a low periprocedural risk.

Virtual Histology to Evaluate Mechanisms of Pulmonary Artery Lumen Enlargement in Response to Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) results from an obstruction of pulmonary arteries (PAs) by organized thrombi. The stenosed PAs are targeted during balloon pulmonary angioplasty (BPA). We aimed to evaluate the mechanism of BPA in inoperable patients with CTEPH. We analyzed stenosed PAs with intravascular grey-scale ultrasound (IVUS) to determine the cross-sectional area (CSA) of arterial lumen and of organized thrombi. The composition of organized thrombi was assessed using virtual histology. We distinguished two mechanisms of BPA: Type A with dominant vessel stretching, and type B with dominant thrombus compression. PAs were assessed before (n = 159) and after (n = 98) BPA in 20 consecutive patients. Organized thrombi were composed of dark-green (57.1 (48.0-64.0)%), light-green (34.0 (21.4-46.4)%), red (6.4 (2.9-11.7)%;) and white (0.2 (0.0-0.9)%) components. The mechanism type depended on vessel diameter (OR = 1.09(1.01-1.17); p = 0.03). In type B mechanism, decrease in the amount of light-green component positively correlated with an increase in lumen area after BPA (r = 0.50; p = 0.001). The mechanism of BPA depends on the diameter of the vessel. Dilation of more proximal PAs depends mainly on stretching of the vessel wall while dilation of smaller PAs depends on compression of the organized thrombi. The composition of the organized thrombi contributes to the effect of BPA.

Pregnancy in a Patient With Chronic Thromboembolic Pulmonary Hypertension After Successful Treatment with Balloon Pulmonary Angioplasty.

Pulmonary hypertension has been recognized as a contraindication to pregnancy. Recently, several groups have shown promising results with the use of balloon pulmonary angioplasty (BPA) in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) patients with distally located organized thrombi who were not candidates for pulmonary endarterectomy. We present the case report of a 26-year-old woman who became pregnant after successful treatment of severe CTEPH with the use of BPA. We conclude that patients undergoing effective BPA for CTEPH can consider becoming pregnant if followed closely by a multidisciplinary team, including experts in thrombosis, pulmonary hypertension, and obstetrics.

Prognostic role of traditional cardiovascular risk factors in patients with idiopathic pulmonary arterial hypertension.

INTRODUCTION: Metabolic alterations have been recently associated with onset and progression of idiopathic pulmonary arterial hypertension (IPAH). We aimed to determine the prevalence and prognostic role of cardiovascular risk factors in patients with IPAH. MATERIAL AND METHODS: Between February 2009 and January 2015 we recruited consecutive IPAH patients. Clinical assessment included medical history, fasting glucose, lipid profile, N-terminal pro-brain natriuretic peptide concentration, 6-minute walk test distance, WHO functional class and hemodynamic evaluation. Patients' risk was estimated based on the Swedish PAH Register grading system. RESULTS: The study group included 61 IPAH patients, and the control group included 2413 Polish residents. When compared to the general population, IPAH patients had lower low-density lipoprotein cholesterol (LDL-C) and a higher triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. Female patients were characterized by elevated glucose level, higher prevalence of diabetes and lower HDL-C than controls. PAH severity grade correlated positively with age and TG/HDL-C ratio (R = 0.29, p = 0.02) and inversely with LDL-C (R = -0.28, p = 0.03) and HDL-C (R = -0.39, p = 0.02) concentrations. After a follow-up of 48 (23-79) months we recorded 28 deaths in the IPAH group. In the regression analysis lower LDL-C (p = 0.002) and HDL-C (p = 0.0002) levels, and higher TG/HDL-C ratio (p = 0.003) and glucose level (p = 0.003) were associated with all-cause mortality after adjustment for age, sex or PAH severity grade. CONCLUSIONS: Patients with IPAH are characterized by an altered profile of lipid and glucose metabolism. Lowered levels of LDL-C and HDL-C and increased TG/HDL-C ratio correlate with disease severity and together with elevated plasma glucose level predict poor survival in IPAH.

HDL Cholesterol as a Marker of Disease Severity and Prognosis in Patients with Pulmonary Arterial Hypertension.

The impact of high-density lipoprotein (HDL) cholesterol on the development of atherosclerosis and diseases of systemic circulation has been well documented both in experimental and registry studies. Recent discoveries in pulmonary arterial hypertension (PAH) revealed a significant impact of HDL on pulmonary artery vasoreactivity and patients' prognosis. The vasoprotective activity of HDL primarily involves vascular endothelium that also plays a central role in pulmonary arterial hypertension (PAH) pathobiology. However, the exact mechanism in which this lipoprotein fraction exerts its effect in pulmonary circulation is still under investigation. This paper reviews potential vasoprotective mechanisms of HDL in pulmonary circulation and presents current clinical reports on the role of HDL in PAH patients.

Pulmonary Artery Elastic Properties After Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: A significant proportion of the right ventricular afterload is determined by the elastic properties of the pulmonary artery (PA). We aimed to assess the effect of balloon pulmonary angioplasty (BPA) on PA elastic properties in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: We enrolled adult patients with CTEPH treated with BPA and controls without PH. Total PA compliance (CPa) was calculated as stroke volume/PA pulse pressure. PA distensibility (DC) and compliance (CC) coefficients were assessed by intravascular ultrasound to denote local elastic properties of the treated PA segments. RESULTS: We performed 103 BPA sessions in 17 patients with CTEPH (5 men [29%], aged 66 [64 to 73] years) who were followed for 6 (5 to 7) months after the last BPA. The median time between BPA sessions was 39 (28 to 52) days. The CPa, CC, and DC were lower in patients with CTEPH than in controls without PH (n = 10). Complete BPA treatment led to increase of CPa from 1.02 (0.70 to 1.39) to 2.08 (1.49 to 2.39) mL/mm Hg (P < 0.001) at the 6-month follow up, and this increase was in proportion to a decrease in pulmonary vascular resistance (PVR) (R2 = 0.74; P = 0.001). CPa increased immediately after BPA session by 0.13 (-0.05; 0.33) mL/mm Hg (P = 0.001) and remained unchanged until the next BPA session. CC and DC exhibited no immediate change after catheter balloon inflation (Δ=0 [-0.03; 0.02] mm2/mm Hg, P = 0.52, and Δ = 0 [-0.13; 0.13] %/mm Hg, P = 0.91, respectively) and remained unchanged at the 6-month follow-up. CONCLUSIONS: BPA improved total CPa in proportion to a decrease in PVR despite no improvement in local elastic properties of the treated PA segments.