scholarly journals Model of Chronic Thromboembolic Pulmonary Hypertension in Rats Caused by Repeated Intravenous Administration of Partially Biodegradable Sodium Alginate Microspheres

2021 ◽  
Vol 22 (3) ◽  
pp. 1149
Author(s):  
Andrei A. Karpov ◽  
Nikita A. Anikin ◽  
Aleksandra M. Mihailova ◽  
Sergey S. Smirnov ◽  
Dariya D. Vaulina ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Exercise Tolerance ◽  
Complex Disease ◽  
Histopathological Examination ◽  
Main Pulmonary Artery ◽  
Systolic Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Control Group ◽  
Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening complication of pulmonary embolism. As existing animal models of CTEPH do not fully recapitulate complex disease pathophysiology, we report a new rat model for CTEPH evoked by repetitive embolization of the distal pulmonary artery branches with partially biodegradable alginate microspheres (MSs). MSs (180 ± 28 μm) were intravenously administered eight times at 4-day intervals; control animals received saline. The validity of the model was confirmed using transthoracic echocardiography, exercise testing, catheterization of the right ventricle, and histological examination of the lung and heart. The animals in the CTEPH group demonstrated a stable increase in right ventricular systolic pressure (RVSP) and decreased exercise tolerance. Histopathological examination revealed advanced medial hypertrophy in the small pulmonary arteries associated with fibrosis. The diameter of the main pulmonary artery was significantly larger in the CTEPH group than in the control group. Marinobufagenin and endothelin-1 serum levels were significantly elevated in rats with CTEPH. In conclusion, repetitive administration of alginate MSs in rats resulted in CTEPH development characterized by specific lung vasculature remodeling, reduced exercise tolerance, and a persistent rise in RVSP. The developed model can be used for pre-clinical testing of promising drug candidates.

P2774Galectin-3, GDF-15, and ST2 in noninvasive assessment of myocardial remodelling in chronic thromboembolic pulmonary hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S D Kriechbaum ◽  
K Peters ◽  
R Ajnwojner ◽  
J S Wolter ◽  
M Haas ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Disease Severity ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Control Group ◽  
Right Heart ◽  
Non Invasive ◽  
Galectin 3 ◽  
Myocardial Remodelling ◽  
Thromboembolic Pulmonary Hypertension

Abstract Background In chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary artery obstruction leads to impaired pulmonary hemodynamics and secondary right heart failure, which is highly predictive of outcome. Thus, the extent of myocardial -especially right heart- remodelling is an indicator of disease severity. Purpose The aim of the present study was to assess growth differentiation factor-15 (GDF-15), galectin-3, and suppression of tumorigenicity 2 (ST2) as non-invasive biomarkers of myocardial remodelling in patients suffering from CTEPH. Methods We analysed the serum levels of GDF-15, galectin-3 and ST2 in a cohort of 64 CTEPH patients and in a control group of 25 patients without cardiovascular disease. The biomarker levels were further correlated with clinical, laboratory, and hemodynamic data, including 6-minute walking distance (6-MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), mean pulmonary artery pressure (meanPAP), pulmonary vascular resistance (PVR), and right atrial pressure (RAP). Results The biomarker levels in the control group were: galectin-3: 3.5 ng/l (IQR 2.7–4.0), GDF-15: 92.6 pg/ml (IQR 78.5–129.1), and ST2: 48.65 ng/l (IQR 35.5–57.0). CTEPH patients had higher levels of GDF-15 (196.7 pg/ml; IQR 128.4–302.8; p<0.001) and ST2 (52.6 ng/l; IQR 44.5–71.9; p=0.05) but not galectin-3 (3.4 ng/l; IQR 2.7–4.3; p=0.84). In the CTEPH cohort, patients with a meanPAP >35 mmHg (GDF-15: p=0.01; ST2: p=0.04) and patients with a PVR >500 dyn sec cm–5 (GDF-15: p=0.004; ST2: p=0.002) had significantly increased biomarker levels. For the detection of a meanPAP >35mmHg, ROC analysis revealed an AUC of 0.71 for GDF-15 and 0.67 for ST2. The level of GDF-15 correlated with the level of NT-proBNP (rrs=0.69; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=−0.47; p≤0.001). The level of ST2 correlated with the level of NT-proBNP (rrs=0.67; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=-0.31; p=0.02). Conclusion Our results demonstrate that GDF-15 and ST2, non-invasive biomarkers of myocardial remodelling, are significantly elevated in patients suffering from CTEPH. The correlation of biomarker levels with established outcome predictors suggests a use as indicators of disease severity.

scholarly journals Model of chronic thromboembolic pulmonary hypertension in rats, caused by repeated intravenous administration of biodegradable microspheres from sodium alginate

2019 ◽  
Vol 18 (1) ◽  
pp. 86-95
Author(s):  
A. A. Karpov ◽  
N. A. Anikin ◽  
D. E. Cherepanov ◽  
A. M. Mikhailova ◽  
M. V. Krasnova ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Sodium Alginate ◽  
Autologous Blood ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Control Group ◽  
Biodegradable Microspheres ◽  
Treadmill Test ◽  
Thromboembolic Pulmonary Hypertension

Introduction. Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the most severe complications of pulmonary embolism (PE), characterized by poor prognosis and insuffcient effectiveness of standard treatment approaches. A small number of representative models of CTEPH make it diffcult to conduct preclinical studies of promising pharmacological substances.Objective – development and validation of the experimental model of CTEPH in rats by embolization of the distal branches of the pulmonary artery with biodegradable microspheres.Material and methods. Male Wistar rats were used for the experiments. Biodegradable microspheres (MS) based on sodium alginate and autologous blood clots (AT) were used as embolizing particles. The animals were divided into groups: control: saline solution was injected 4 times with an interval of 8 days into the tail vein; AT: according to the above protocol, 50 μL of AT was injected; MS was administered intravenously in a volume of 50 μl of MS according to two protocols: MS4: 4 times with an interval of 8 days; MS8: 8 times with an interval of 4 days. After 2 and 6 weeks after the last injection, a histological examination of the lungs was performed; after 6 weeks: echocardiographic study (TTE), right ventricular catheterization (RV) with measurement of right ventricular systolic pressure (RVSP), treadmill test, assessment of serum endothelin­1 levels by the immunoassay method.Results. During the experiments, the survival rate in the MS8 group was 50 %. In the other groups, there were no animal losses. According to the treadmill test 6 weeks after the modeling of PE, exercise tolerance was signifcantly reduced in the MC4 and MC8 groups compared with the control group. TTE data indicate a signifcant increase in the diameter of the pulmonary trunk and the right ventricular outflow tract in the MC8 compared with the control and AT. There were signifcant increase in RVSP and the level of endothelin­1 compared with the control only in the MS8. After 6 weeks, the index of hypertrophy of vessel wall of the pulmonary artery in the MC4 and MC8 was signifcantly higher compared with the control and AT groups.Conclusion. Based on the use of MS, administered under the MS 8 protocol, a new representative model of CTEPH has been created, which can be used to test promising pharmacological substances.

Experience with pulmonary endarterectomy: Lessons learned across 17 years

2021 ◽  
pp. 021849232110440
Author(s):  
Varun Shetty ◽  
Julius Punnen ◽  
Pooja Natarajan ◽  
Sanjay Orathi ◽  
Basha Khan ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Systolic Pressure ◽  
Significant Risk ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Artery Systolic Pressure ◽  
Pulmonary Endarterectomy ◽  
Female Ratio ◽  
Thromboembolic Pulmonary Hypertension

Background Pulmonary endarterectomy is potential curative therapy for chronic thromboembolic pulmonary hypertension patients. Here, we present our experience with pulmonary endarterectomy spanning 17 years and detail our management strategy. Methods This is a single-centre retrospective study conducted on chronic thromboembolic pulmonary hypertension patients who underwent pulmonary endarterectomy at our centre across 17 years. Results Between 2004 and 2020, 591 patients underwent pulmonary endarterectomy. Amongst them 429 (72.4%) were males with a male to female ratio of 2.6:1, the median age was 38 (range, 14–73) years. The median length of hospital stay was 11 days (IQR, 8–16). Extra corporeal membranous oxygenation was used in 82 (13.9%) patients during/after surgery, out of whom 28 (34.1%) survived. There were 70 (11.8%) in-hospital deaths. Female gender ( p < 0.01), pulmonary artery systolic pressure >100 mmHg ( p < 0.05) and use of extra corporeal membrane oxygenation ( p < 0.001) were significant risk factors for in-hospital mortality. The mortality in the first period (2004–2012) was 15.7% which reduced to 9.1% in the later period (2013–2020). The reduction in mortality rate was 42% ( p < 0.05). Following pulmonary endarterectomy, there was a significant reduction in pulmonary artery systolic pressure (86.68 ± 24.38 vs. 39.71 ± 13.13 mmHg; p < 0.001) and improvement in median walk distance as measured by 6-min walk test on follow-up (300 vs. 450 meters; p < 0.001). The median duration of follow-up was 8 months (inter-quartile range: 2–24). Conclusions pulmonary endarterectomy has a learning curve, high pulmonary vascular resistance alone is not a contraindication for surgery. Patients following surgery have improved survival and quality of life.

Proposition of quantitative parameters for pre- and early post-operative assessment in pulmonary thromboendarterectomy – An Indian prospective study

2021 ◽  
pp. 021849232110421
Author(s):  
Krishnarao N Bhosle ◽  
Saptarshi Paul ◽  
Suraj W Nagre
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Systolic Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Artery Systolic Pressure ◽  
Walk Test ◽  
Pulmonary Thromboendarterectomy ◽  
Thromboembolic Pulmonary Hypertension

Introduction Chronic thromboembolic pulmonary hypertension results from the incomplete resolution of the vascular obstruction associated with pulmonary embolism. Symptoms are exertional dyspnoea and fatigue, and over a period of time, right ventricular dysfunction sets in. Pulmonary thromboendarterectomy is an effective surgical remedy for this condition. Our study is an initial post-operative experience of pulmonary thromboendarterectomy and we have also tried to formulate quantitative parameters for the prediction of the post-operative course in patients who are undergoing surgery. Methods Twenty patients with chronic thromboembolic pulmonary hypertension underwent pulmonary thromboendarterectomy between July 2017 and January 2020. Pre-operatively, each patient was subjected to the (i) 6-min walk test, (ii) pre-operative brain natriuretic peptide values and (iii) pulmonary artery systolic pressure. Following the surgery and subsequent discharge, the patients were followed up at intervals of 15 days, 1, 3, 6, 9 months and at 1 year. At one year post-operatively, the same three quantitative tests were performed on each subject. Results Post-operatively, the mean 6-min walk distance was 499.75 m as against 341.35 m pre-operatively ( p < 0.0001). Mean brain natriuretic peptide was 8.69 pm/l as against 47.58 pm/l pre-operatively ( p < 0.0001). Mean pulmonary artery systolic pressure was 22.25 as against 67.1 pre-operatively ( p < 0.0001). Conclusion 6-Min walk test, brain natriuretic peptide and pulmonary artery systolic pressure could be considered as useful predictors of the haemodynamic severity of disease and predict the post-operative outcome.

The protective effects of radiofrequency pulmonary artery denervation on the progression of chronic thromboembolic pulmonary hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B Rudenko ◽  
D Feshchenko
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Control Group ◽  
Artery Pressure ◽  
Mean Pulmonary Artery Pressure ◽  
Thromboembolic Pulmonary Hypertension ◽  
The Mean

Abstract   This study aimed to assess the safety and efficacy of radiofrequency pulmonary artery denervation with the Simplicity system in patients with distal chronic thromboembolic pulmonary hypertension. Methods and results 60 chronic thromboembolic pulmonary hypertension patients with mean pulmonary artery pressure &gt;25 mm Hg and absence of proximal artery lesion defined by pulmonary angiography were randomized into 2 groups. Group 1 included 30 patients who underwent pulmonary artery denervation procedure. The other 30 patients were assigned to the control group (only angio plus right heart catheterization). The procedure of pulmonary artery denervation was performed at the lateral wall of main pulmonary artery and ostium of the left and right pulmonary arteries using the electrode from Simplicity denervation system. The programmed ablation parameters were temperature &gt;50°C and time = 120 s. Using the coronary guiding technique, the tip of electrode was applied at each spot rotating the tip with pace of 2 mm. The success was defined by decrease of mean pulmonary artery pressure &gt;10%, absence of complications. The primary end point was comparison of mean pulmonary artery pressure change from baseline to 12 months in pulmonary artery denervation group compared with change from baseline to 12 months in control group. The secondary point was change in 6-min walk distance and pulmonary vascular resistance at the 12-month follow-up. There were no complications after pulmonary artery denervation. The hemodynamic success was achieved in 93% of all cases. The mean number of radiofrequency applications to achieve success was 10.3 per patient. During follow-up period 3 patients died in pulmonary artery denervation group: (1 died of gastro-intestinal bleeding, 2 – of right ventricular failure) and 3 patients in control group. The mean decreases in the mean pulmonary artery pressure were 8.7 mm Hg in the pulmonary artery denervation group and 3.1 mm Hg in control group (p&lt;0.05). After pulmonary artery denervation in comparison with the control group was observed significant decrease in pulmonary vascular resistance (8.3±2.8 WU vs. 11.2±3.7). 6-min walk distance significantly increased by 81 m after pulmonary artery denervation and 29 m in control group (p&lt;0.05). This improvement was associated with significant improvements in the WHO functional class. Conclusions The usage of the Simplicity denervation system in pulmonary artery denervation procedure is safe and effective. Further studies are required to determine the role of pulmonary artery denervation in the treatment of chronic thromboembolic pulmonary hypertension. The next step of pulmonary artery denervation development will be the use of this method combined with recommended treatment (medical therapy, pulmonary endarterectomy and balloon pulmonary angioplasty) as additional option, that may sufficiently improve outcomes in some patients Funding Acknowledgement Type of funding source: None

3311A new rat model of chronic thromboembolic pulmonary hypertension induced by repeated intravenous administration of biodegradable alginate microspheres

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Karpov ◽  
N Anikin ◽  
D Cherepanov ◽  
A Mihailova ◽  
M Krasnova ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Intravenous Administration ◽  
Exercise Tolerance ◽  
Autologous Blood ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Vasculature ◽  
Endothelin 1 ◽  
Thromboembolic Pulmonary Hypertension

Abstract Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is life-threatening complication of pulmonary embolism (PE) with insufficiently understood mechanisms. Several rodent CTEPH models based on i.v. administration of non-biodegradable microparticles have been validated for preclinical studies. Major limitation of these models is the lack of partial dissolution of emboli following their entrapment in the lung vasculature. Purpose The study was aimed at development and validation of rat CTEPH model based on recurrent embolization of (sub)segmental pulmonary artery branches with biodegradable microspheres. Methods Male Wistar rats were used for the experiments. Pulmonary vasculature was embolized either with sodium alginate microspheres (MS) or with autologous blood clots (AT). The animals were randomized into the following groups: i) controls: saline at a volume of 50 μL was injected 4 times with 8-day interval into the tail vein; the same regimen was used in two next groups; ii) AT; iii) MS4; iv) MS8: MS were administered 8 times with 4-day interval. Histological examination of the lungs was performed after 2 and 6 weeks after the last injection. 6 weeks after the last injection the following analyses were performed: treadmill test, transthoracic echocardiography (TTE), right ventricular catheterization with measurement of right ventricular systolic pressure (RVSP), determination of serum endothelin-1 level. Results The survival rate in the MS8 group was 50%. In the other groups, there were no animal deaths. Multiple emboli were found in the lumen of (sub)segmental pulmonary artery branches 2 weeks after the last injection in MS4 and MS8 groups. Increased diameter and thickening of the bronchial arterial wall were also registered. After 6 weeks, the index of hypertrophy of vessel wall in MS4 and MS8 groups was significantly higher than in controls (p=0.041 and p=0.006, respectively) (Fig. 1). No sign of vascular remodeling was identified in the branches of the pulmonary artery in the AT group. Exercise tolerance was significantly reduced in both MS4 and MS8 groups compared with the controls (p=0.025 and p=0.008, respectively). There were no significant differences in exercise tolerance between the AT and control groups. TTE data indicate a significant increase in the diameter of the pulmonary trunk and the right ventricular outflow tract in the MS8 group compared with controls and AT (p<0.05). Significant increase in RVSP as well as in endothelin-1 level versus controls was found only in the MS8 group. Figure 1. Histological changes in the branches of the pulmonary artery 6 weeks after the last injection of emboli. Conclusion Recurrent (×8) intravenous administration of MS in rats resulted in CTEPH development characterized by specific lung vasculature remodelling, reduced exercise tolerance, and persistent rise in RVSP. The model developed can be used for preclinical testing of promising drug candidates.

scholarly journals Importance of computed tomography in defining segmental disease in chronic thromboembolic pulmonary hypertension

2020 ◽  
Vol 6 (4) ◽  
pp. 00461-2020
Author(s):  
Micheal C. McInnis ◽  
David Wang ◽  
Laura Donahoe ◽  
John Granton ◽  
John Thenganatt ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Main Pulmonary Artery ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
High Quality ◽  
Thromboembolic Pulmonary Hypertension ◽  
Level 3 ◽  
Hypertension Therapy ◽  
Level 1

BackgroundRadiological assessment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is critical to decide whether patients should be treated with pulmonary endarterectomy (PEA). Although computed tomography pulmonary angiography (CTPA) is increasingly used for decision making in CTEPH, the value of CTPA to predict surgical findings and outcome has never been explored.MethodsWe retrospectively reviewed 100 consecutive patients with high-quality CTPA undergoing PEA for CTEPH between May 2015 and December 2017. The most proximal level of disease in the pulmonary artery on CTPA was classified by two blinded radiologists as level 1 (main pulmonary artery), 2a (lobar pulmonary artery), 2b (origin of basal segmental pulmonary artery), 3 (segmental pulmonary artery) or 4 (predominantly subsegmental pulmonary artery).ResultsCTPA demonstrated level 1 in 20%, level 2a in 43%, level 2b in 11%, level 3 in 23% and level 4 in 3%. A majority of males presented with level 1 (55%) and level 2 (57%), and a majority of females (83%) with level 3 (p=0.01). Levels 3 and 4 were associated with longer duration of circulatory arrest (p=0.03) and higher frequency of Jamieson type III disease at surgery (p<0.0001). Requirement for targeted pulmonary hypertension therapy after PEA was 28% at 3 years in level 2b/3/4 compared with 6% in level 2a and 13% in level 1 (p=0.002). Level 2b/3/4 was an independent predictor for targeted pulmonary hypertension therapy after PEA (hazard ratio 4.23, 95% CI 1.24–14.39; p=0.02).ConclusionsHigh-quality CTPA provides accurate evaluation of CTEPH patients. The level of disease on CTPA can help guide peri-operative planning and post-operative monitoring.

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