Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension.

Institute of Cardiology, University of Bologna, Bologna, Italy; and Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California, USA.
Proceedings of the American Thoracic Society 10/2006; 3(7):571-6. 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.

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    ABSTRACT: Objective Chronic thromboembolic pulmonary hypertension (CTEPH) can be cured by pulmonary endarterectomy (PEA). Operability assessment remains a major concern, as there are no well-defined criteria to discriminate proximal from distal obstructions, and surgical candidacy depends mostly on the surgeon’s experience. The intraoperative classification of CTEPH describes 4 types of lesions, based on anatomy and location. We describe our recent experience with the more distal (type-3) disease. Methods More than 500 PEAs were performed at our center. Because of recent changes in the patient population, 331 PEAs performed from January 2008 to December 2013 were analyzed. Two groups of patients were identified, according to the intraoperative classification: proximal (type-1 and type-2 lesions, 221 patients) and distal (type-3 lesions, 110 patients). Results The number of PEAs for distal CTEPH increased significantly over time (currently about 37%). Deep venous thrombosis was confirmed as a risk factor for proximal disease, whereas distal patients had a higher prevalence of indwelling intravascular devices. Overall hospital mortality was 6.9%, with no difference in the 2 groups. Postoperative survival was excellent as well. In all patients, surgery was followed by a significant and sustained improvement in hemodynamic, echocardiographic, and functional parameters, with no difference between proximal and distal patients. Conclusions Despite distal CTEPH represents the most challenging situation, postoperative outcomes of both proximal and distal patients are excellent. The diagnosis of inoperable CTEPH should be achieved only in experienced centers, as many patients who have been deemed inoperable might indeed benefit from favorable surgical outcomes.
    Journal of Thoracic and Cardiovascular Surgery 09/2014; · 3.53 Impact Factor
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    ABSTRACT: Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.
    European Respiratory Journal 08/2014; · 6.36 Impact Factor
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    ABSTRACT: None of the animal models have been able to reproduce all aspects of CTEPH because of the rapid resolution of the thrombi in the pulmonary vasculature. The aim of this study was to develop an easily reproducible large-animal model of chronic pulmonary hypertension (PH) related to the development of a postobstructive and overflow vasculopathy. Chronic PH was induced in 5 piglets by ligation of the left pulmonary artery (PA) through a midline sternotomy followed by weekly transcatheter embolization of the right lower-lobe arteries. Sham-operated piglets (n = 5) served as controls. Hemodynamics, RV function, lung morphometry, and endothelin-1 (ET-1) pathway gene expression (ET-1 and its receptors ETA and ETB) were assessed after 5 weeks in the obstructed (left lung and right lower lobe) and unobstructed (right upper lobe) territories. All animals developed chronic PH within 5 weeks. Compared to controls, chronic-PH animals had higher mean PA pressure (28.5 ± 1.7 vs. 11.6 ± 1.8 mmHg, P = 0.0001) and total pulmonary resistance (784 ± 160 vs. 378 ± 51 dyn s(-1) cm(-5), P = 0.05). Echocardiography showed RV enlargement, RV wall thickening (56 ± 5 vs. 30 ± 4 mm, P = 0.0003), decreased tricuspid annular plane systolic excursion (11.3 ± 0.9 vs. 14.4 ± 0.4 mm, P = 0.01), and paradoxical septal motion. In obstructed territories, morphometry demonstrated increases in the number of bronchial arteries per bronchus (8.7 ± 0.9 vs. 2 ± 0.17, P < 0.0001) and in distal PA media thickness (60% ± 2.8% vs. 29% ± 0.9%, P < 0.0001), consistent with postobstructive vasculopathy. Distal PA media thickness was increased in unobstructed territories (70% ± 2.4% vs. 29% ± 0.9%, P < 0.0001). ET-1 was overexpressed in unobstructed territories, compared to controls and obstructed territories. In conclusion, the large-animal model described here is reproducible and led to the development of PH in a relatively short time frame.
    Pulmonary circulation. 12/2013; 3(4):908-15.