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.

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.

Diastolic dyssynchrony and its exercise-induced changes affect exercise capacity in patients with heart failure with reduced ejection fraction.

BACKGROUND: Left ventricular diastolic dyssynchrony is common in patients with heart failure with reduced ejection fraction (HFREF). Little is known however, about its pathophysiology and clinical effects. Herein is hypothesized that presence of diastolic dyssynchrony at rest or at exercise may importantly contribute to HF symptoms. The aim was to investigate the influence of diastolic dyssynchrony and its exercise-induced changes on exercise capacity in HFREF patients. METHODS: Patients with stable, chronic HF, left ventricular ejection fraction < 35%, sinus rhythm and QRS ≥ 120 ms were eligible for the study. Rest and cyclo-ergometer exercise echocardiography were performed. Diastolic dyssynchrony was defined as opposing-wall-diastolic-delay ≥ 55 ms measured in tissue-Doppler imaging. Exercise capacity was assessed by peak oxygen consumption (VO2peak). Association between diastolic dyssynchrony and VO2peak was assessed in univariate regression analysis and further adjusted for possible confounders. RESULTS: Fourty eight patients were included (aged 63.7 ± 12.2). Twenty-seven (56.25%) had diastolic dyssynchrony at rest and 13 (27%) at exercise. Twenty-two (46%) experienced a change in diastolic dyssynchrony status during exercise. In univariate models diastolic dyssynchrony at rest or at exercise were associated with lower VO2peak (beta coefficient = -3.8, p = 0.004; beta coefficient = -3.6, p = 0.02, respectively). However, the ability to restore diastolic synchronicity during exercise was associated with higher VO2peak (beta coefficient = 3.4, p = 0.04) and remained an important predictor of exercise capacity after adjustment for age and HF etiology. CONCLUSIONS: The ability to restore diastolic synchronicity at exercise predicts exercise capacity in patients with HFREF.

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.

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.

Triglyceride-to-High-Density Lipoprotein Cholesterol Ratio and Systemic Inflammation in Patients with Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND Idiopathic pulmonary arterial hypertension (IPAH) patients are characterized by elevated triglyceride (TG)-to-HDL cholesterol (HDL-C) ratio, which has been proposed to be an important prognostic factor in this population. The mechanism of this phenomenon remains unknown. We therefore investigated the potential determinants of increased TG/HDL-C ratio in IPAH patients. MATERIAL AND METHODS We prospectively recruited consecutive clinically stable IPAH patients between January 2016 and February 2017. Patients with diabetes or using statins were excluded. Anthropometric measurements included body mass index (BMI) and skinfold thickness; body fat mass was calculated using age and sex-specific equations. We assessed lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR), serum adipokine levels (adiponectin, resistin, leptin, and visfatin), and circulating cytokines (IL-1ß, IL-6, MCP-1, and TNF-α). RESULTS We assessed 47 IPAH patients: 9 of them had been diagnosed with diabetes and 10 were treated with statins; therefore, were excluded them from further analysis. Age, sex distribution, and BMI were similar irrespectively of TG/HDL-C ratio. Patients with increased TG/HDL-C ratio (>3) as compared to patients with TG/HDL-C ≤3 were characterized by higher levels of IL-1ß, MCP-1, and IL-6. TG level was correlated with IL-1ß (R=0.76, p<0.001), IL-6 (R=0.52, p=0.005), TNF-α (R=0.62, p<0.001), and MCP-1 (R=0.63, p<0.001). IL-1ß was also inversely correlated with HDL-C (R=-0.44, p=0.02). We found no differences in concentration of fasting glucose, insulin, HOMA-IR, body fat content, or adipokine levels between patients with higher and lower TG/HDL-C ratios. CONCLUSIONS In IPAH patients, elevated TG/HDL-C ratio is a marker of systemic inflammation.

Ischaemic aetiology predicts exercise dyssynchrony in patients with heart failure with reduced ejection fraction.

BACKGROUND: Left ventricular (LV) dyssynchrony is common in patients with heart failure with reduced ejection fraction (HFREF). However, various conditions including exercise may alter its presence. LV dyssynchrony at exercise (ExDYS) has been associated with lower cardiac performance and exercise capacity but with higher cardiac resynchronization therapy (CRT) response. Therefore, understanding mechanisms underlying ExDYS may improve patient selection for CRT. AIMS: To investigate for predictors of ExDYS among patients with HFREF and prolonged QRS duration. METHODS: Consecutive patients with stable, chronic HF, LVEF<35%, sinus rhythm and QRS≥120ms were eligible. 2D echocardiography and tissue-Doppler were performed at rest and peak cyclo-ergometer exercise to assess LV systolic (LVEF) and diastolic function [mitral E-to-e'-wave velocities (E/e')] and dyssynchrony. Dyssynchrony was defined as a maximal difference between time-to-peak systolic velocities of≥65ms from opposing basal segments. RESULTS: We included 48 patients (aged 63.7±12.2, 81.3% male). Ischaemic aetiology (ICM) was present in 23 (47.9%). Dyssynchrony at rest (rDYS) was present in 32 (66.6%) patients, while ExDYS in 23 (47.9%). ExDYS correlated with ICM, lower LVEF and higher E/e' ratio. ICM remained significant predictor of ExDYS in multiple regression model (OR:4.3, 95%CI:1.2-15.7, p=003). On exercise, 19 (39.5%) patients changed the rDYS status. While, exercise-induced dyssynchronization was observed only in ICM patients, exercise-induced resynchronization was more likely in patients with lower rest E/e' ratio (OR:0.85, 95%CI:0.75-0.97, p=0.02). CONCLUSIONS: Ischaemic aetiology of HFREF is an important predictor of ExDYS. Restoration of LV synchronicity during exercise is more likely in patients with less advanced LV diastolic dysfunction.