Pulmonary Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension

ArticleinProceedings of the American Thoracic Society 3(7):571-6 · October 2006with84 Reads
DOI: 10.1513/pats.200605-113LR · Source: PubMed
Abstract
Distal, small-vessel vasculopathy is generally considered a major contributor to the progression of pulmonary hypertension (PH) as chronic thromboembolic pulmonary hypertension (CTEPH) develops over time and is a major determinant of postoperative outcome after pulmonary endarterectomy (PEA). The pathogenesis and natural history of microvascular disease in CTEPH remain uncharacterized. Mechanisms for significant distal disease may involve the following processes: (1) predominant obstructions of "small" subsegmental elastic pulmonary arteries, (2) classical pulmonary arteriopathy of small muscular arteries and arterioles distal to nonobstructed vessels, (3) pulmonary arteriopathy of small muscular arteries and arterioles distal to totally or partially obstructed vessels. Patients in whom obstructed vessels are mainly subsegmental are considered poor surgical candidates. Distal pulmonary vasculopathy in both the occluded and nonoccluded pulmonary vascular bed is characterized by lesions considered typical for idiopathic pulmonary arterial hypertension, including plexiform lesions. The pathogenesis and time course of these vascular lesions remain unclear, but may involve endothelial and/or platelet production and release of mediators and/or altered pulmonary blood flow. The reciprocal contribution of large-vessel (operable) and small-vessel lesions in CTEPH is crucial for the indication and results of PEA. A combination of investigations is used to identify the extent of small-vessel disease, including right-heart catheterization, perfusion lung scan, multidetector spiral computed tomography, pulmonary angiography, and pulmonary arterial occlusion wave-form analysis. Preliminary evidence suggests that medical therapy may provide hemodynamic and clinical benefits for patients in whom PEA cannot be applied, in those who have persistent postoperative PH, or in selected patients with advanced preoperative hemodynamic changes.
    • Wykazano, że proliferacja błony wewnętrznej i tworzenie zmian splotowatych w dystalnych naczyniach płucnych są zbliżone histopatologicznie do występujących u osób chorujących na PAH [8, 11]. Autorzy innej teorii sugerują istnienie zjawiska nazywanego zakrzepicą in situ, która rozwija się w tętnicach płucnych jako skutek zwiększonej ekspresji czynnika VIII krzepnięcia i inhibitora aktywatora plazminogenu I [8, 11]. Jest kilka zaproponowanych skal prawdopodobieństwa wystąpienia CTEPH po epizodzie PE (tab. 1) [12][13][14][15].
    [Show abstract] [Hide abstract] ABSTRACT: Streszczenie Przewlekłe zakrzepowo-zatorowe nadciśnienie płucne (CTEPH) to poważne schorzenie, najczęściej wywołane niepełną rekanalizacją naczyń płucnych po przebytej ostrej zatorowości płucnej prowadzącą do znacznej przebudowy pozostałego łożyska płucnego i w efekcie — do niewydolności prawokomorowej serca. Rokowanie zależy od szybkiego rozpoznania CTEPH i odpowiedniego leczenia. Mimo dostępności skutecznej metody, tj. endarterektomii płucnej (PEA), ponad 1/3 chorych nie kwalifikuje się do tego typu operacji ze względu na lokalizację i charakter zmian. W ich przypadku, oraz przy przetrwałym CTEPH po PEA, należałoby zastosować leczenie swoiste riociguatem. U pewnej grupy pacjentów można rozważyć nowoczesną metodę balonowej angioplastyki tętnic płucnych.
    Full-text · Article · Nov 2016
    • In CTEPH patients, the areas of concern in lung PBV images correspond well to such areas evident on pulmonary perfusion scintigraphs [18]. Because persistent macrovascular obstruction, vasoconstriction, and arteriopathy are considered to be fundamental in terms of the development of pulmonary hypertension in CTEPH patients [4,19], we hypothesized that the extent of hypoperfusion of the pulmonary arterial system, as reflected in color-coded lung PBV images, might indicate the clinical severity of CTEPH . However, few studies have tested the potential correlations between lung PBV findings and the clinical severity of disease [27,28].
    [Show abstract] [Hide abstract] ABSTRACT: To evaluate whether the extent of perfusion defects assessed by examining lung perfused blood volume (PBV) images is a stronger estimator of the clinical severity of chronic thromboembolic pulmonary hypertension (CTEPH) compared with other computed tomography (CT) findings and noninvasive parameters. We analyzed 46 consecutive patients (10 men, 36 women) with CTEPH who underwent both dual-energy CT and right-heart catheter (RHC) examinations. Lung PBV images were acquired using a second-generation dual-source CT scanner. Two radiologists independently scored the extent of perfusion defects in each lung segment employing the following criteria: 0, no defect, 1, defect in < 50% of a segment, 2, defect in ≥ 50% of a segment. Each lung PBV score was defined as the sum of the scores of 18 segments. In addition, all of the following were recorded: 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, and RHC hemodynamic parameters including pulmonary artery pressure (PAP), right ventricular pressure (RVP), cardiac output (CO), the cardiac index (CI), and pulmonary vascular resistance (PVR). Bootstrapped weighted kappa values with 95% confidence intervals (CIs) were calculated to evaluate the level of interobserver agreement. Correlations between lung PBV scores and other parameters were evaluated by calculating Spearman’s rho correlation coefficients. Multivariable linear regression analyses (using a stepwise method) were employed to identify useful estimators of mean PAP and PVR among CT, BNP, and 6MWD parameters. A _p_ value < 0.05 was considered to reflect statistical significance. Interobserver agreement in terms of the scoring of perfusion defects was excellent (κ = 0.88, 95% CIs: 0.85, 0.91). The lung PBV score was significantly correlated with the PAP (mean, rho = 0.48; systolic, rho = 0.47; diastolic, rho = 0.39), PVR (rho = 0.47), and RVP (rho = 0.48) (all _p_ values < 0.01). Multivariable linear regression analyses showed that only the lung PBV score was significantly associated with both the mean PAP (coefficient, 0.84, _p_ < 0.01) and the PVR (coefficient, 28.83, _p_ < 0.01). The lung PBV score is a useful and noninvasive estimator of clinical CTEPH severity, especially in comparison with the mean PAP and PVR, which currently serve as the gold standards for the management of CTEPH.
    Full-text · Article · Jun 2016
    • W materiale pobranym od chorych po endarterektomii płucnej u zdecydowanej ich większości stwierdza się obecność w naczyniach płucnych świeżego lub zorganizowanego materiału zakrzepowo-zatorowego, a u stosunkowo nielicznych zmiany o charakterze arteriopatii [6]. Te ostatnie zmiany, widoczne w badaniu histopatologicznym pod postacią zmian splotowatych, pogrubienia błony wewnętrznej i środkowej, związane są z przebudową naczyń płucnych i zapoczątkowane są przez dysfunkcję sródbłonka [17]. W podobnych zmianach arteriopatycznych w PAH w materiale autopsyjnym i pooperacyjnym pobranym przy przeszczepie płuc zaobserwowano zwiększoną ekspresję TF [18], co sugeruje, że w rozwoju CTEPH również mogą brać udział czynniki zewnątrzpochodnego toru krzepnięcia: TF i TFPI.
    [Show abstract] [Hide abstract] ABSTRACT: Background: The etiology of CTEPH is not exactly known. The disease is sometimes preceded by acute pulmonary embolism (APE). There are intravascular thrombosis, vasoconstriction, inflammatory and remodeling processes involved in pulmonary arteries. Pulmonary hypertension develops and leads to potentially fatal chronic right heart ventricle failure. Hemostatic disorders are not fully discovered. It is not known, whether extrinsic coagulation pathway disorders play role in the etiology of CTEPH. Aim: Our objective was to determine the role of TF (tissue factor) and TFPI (tissue factor pathway inhibitor) in the etiology of CTEPH. Methods: Plasma concentrations of TF and TFPI were measured and compared in 21 CTEPH patients, in 12 patients suffering from pulmonary arterial hypertension (PAH), in 55 APE survivors, who have not developed chronic pulmonary hypertension after at least six months from the acute episode, and in 53 healthy volunteers (control group C). Most of the patients had vitamin K antagonists (VKA) administered and some of the patients had unfractionated or low molecular weight heparin administered. Exclusion criteria were: malignancy, inflammation and recent operation. Results: In CTEPH and "after APE" patients, not divided according to anticoagulation, TF concentration was similarly lower than in group C (p=0,042; p=0,011) and also lower than in PAH group (p=0,024, p=0,014). Efficiently VKA-anticoagulated CTEPH and "after APE" patients had TF concentration comparable to group C. In CTEPH, "after APE" and PAH patients, not divided according to anticoagulation, TFPI concentration was similar and significantly higher than in group C (p=0,012; p=0,024; p=0,004). Efficiently VKA-anticoagulated CTEPH and "after APE" patients had TFPI concentration comparable to group C. TFPI concentration in efficiently anticoagulated "after APE" patients was not significantly lower than in not anticoagulated "after APE" patients. Group C was significantly (p=0,000) younger than any other group. There was found a correlation (r=0,31) between age and TFPI concentration in this group. Conclusions: In CTEPH there is a high expenditure of TF, leading to reduction of its plasma concentration and increase of TFPI plasma concentration. Efficient VKA-anticoagulation normalizes TF and TFPI plasma concentrations. The situation is similar in APE survivors.
    Article · May 2016
    • It is thus possible that factors in this unique niche have an impact on cell state. Secondly, it has also been suggested that the thrombotic emboli persist secondary to the development of small vessel disease (Tanabe et al. 2013 ; Dorfmuller et al. 2014 ; Galie and Kim 2006 ). As mentioned above, it has been shown that development of persistent thromboemboli is associated to a resistance of the fi brin to plasmin-mediated lysis (Morris et al. 2006Morris et al. , 2007).
    [Show abstract] [Hide abstract] ABSTRACT: Chronic thromboembolic pulmonary hypertension or CTEPH is a serious complication of a venous embolism that fails to resolve. Its persistence leads to a complete blockade of the pulmonary artery and development of severe pulmonary hypertension. Mutations in fibrinogen that lead to a resistance to fibrinolysis are one explanation for the prolonged existence of the clot. It is thought that the fibrotic clot provides a unique micro-environmental niche that attracts stem and progenitor cells exacerbating the associated pulmonary vascular remodeling. This chapter focuses on what is currently known about the presence and role of such stem and progenitor cells in the pathogenesis of CTEPH.
    Full-text · Chapter · Jan 2015 · Computational and Mathematical Methods in Medicine
    • These may completely occlude the lumen or form areas of stenosis, webs, or bands. Interestingly, histological changes in the non-occluded pulmonary arteries are similar to those seen in pulmonary artery hypertension (PAH), such as medial hypertrophy and the intimal proliferative and fibrotic changes that include plexiform lesions (Galiè and Kim, 2006). As the pathological changes in the pulmonary vasculature appear similar, new pulmonary vasodilating drugs used to treat PAH have also been used in CTEPH: prostanoids (Ono et al., 2003; Cabrol et al., 2007; Skoro-Sajer et al., 2007), endothelin-receptor antagonists (ERAs) (Becattini et al., 2010), and phosphodiesterase type-5 (PDE5) inhibitors (Suntharalingam et al., 2008) are reported to have hemodynamic and clinical benefits, although these have not been established in randomized , placebo-controlled trials.
    [Show abstract] [Hide abstract] ABSTRACT: Aims Chronic thromboembolic pulmonary hypertension (CTEPH) is a devastating disease, and treating patients with CTEPH who are not eligible for pulmonary endarterectomy is particularly challenging. Short-term bosentan or phosphodiesterase type-5-inhibitor treatment can greatly improve symptoms and hemodynamics in these patients; however, the long-term benefits of advanced pulmonary vasodilators are not known. We retrospectively investigated the long-term effects of advanced pharmacological therapy in Japanese patients with inoperable CTEPH. Main methods Seven consecutive patients with inoperable CTEPH (five women; mean age, 62.6 ± 6.9 years) treated with bosentan were included. World Health Organization functional class (WHO-FC), hemodynamics, exercise capacity, and plasma B-type natriuretic peptide (BNP) concentration were evaluated at baseline and for more than 2 years. Time to clinical worsening was also examined during long-term follow-up. Key findings WHO-FC improved significantly, from 3.1 ± 0.4 to 2.1 ± 0.4 (p = 0.005). Significant improvement was also seen in pulmonary vascular resistance, which decreased from 786.9 ± 300.0 to 352.2 ± 210.7 dynes.s.cm- 5 (p < 0.05). Plasma BNP concentration decreased significantly from 1,160.0 ± 971.4 to 305.1 ± 285.9 pg/mL (p < 0.05). No patient required hospitalization during the follow-up period (mean, 896 ± 564 days). Significance Long-term advanced therapy with bosentan significantly improves symptoms, pulmonary vascular resistance, plasma BNP concentration, and time to clinical worsening in Japanese patients with inoperable CTEPH. We consider bosentan to be an essential treatment for these patients.
    Full-text · Article · Mar 2014
    • These pathologies are currently treated clinically with vasodilators, and further identify the traditional association between distal geometry, PVR and RV afterload, and RV failure in PH progression. Although vascular distal remodeling and distal vessel vasculopathy are generally considered the only major contributors to PH progression12131415, recent clinical [2, 16, 17] and basic science [1, 18, 19] research have respectively found that proximal vascular stiffness is more predictive of disease outcomes than PVR and that significant remodeling occurs in the proximal vessels of animal models of the disease. Remodeling chronically alters the stiffness of the proximal arteries through combined changes in their extracellular matrix composition and thickness [1].
    [Show abstract] [Hide abstract] ABSTRACT: We develop a simple computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH) to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Model parameters were obtained directly from in vivo and ex vivo measurements of neonatal calves. Seventeen sets of model-predicted impedance and mean pulmonary arterial pressure (mPAP) show good agreement with the animal measurements, thereby validating the model. Next, we considered a predictive model in which three parameters, PVR, elastic modulus (EM), and arterial thickness, were varied singly from one simulation to the next to study their individual roles in PH progression. Finally, we used the model to predict the individual impacts of clinical (vasodilatory) and theoretical (compliance increasing) PH treatments on improving pulmonary hemodynamics. Our model (1) displayed excellent patient-specific agreement with measured global pulmonary parameters; (2) quantified relationships between PVR and mean pressure and PVS and pulse pressure, as well as studiying the right ventricular (RV) afterload, which could be measured as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves; (3) qualitatively confirmed the derangement of vascular wall shear stress in progressive PH; and (4) established that decreasing proximal vascular stiffness through a theoretical treatment of reversing proximal vascular remodeling could decrease RV afterload.
    Full-text · Article · Nov 2013
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