Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease

Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute PE (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were also elevated in patients with PE and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and TGF-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from PE to CTEPH.

Balloon Pulmonary Angioplasty: State of the Art

Balloon pulmonary angioplasty (BPA) is a novel technique for the treatment of chronic thromboembolic pulmonary hypertension. While cardiologists need no introduction to the concept of balloon angioplasty, BPA has its own particular challenges. This article aims to provide the reader with an overview of BPA, starting with an introduction to chronic thromboembolic disease (CTED), the standard management of chronic thromboembolic pulmonary hypertension (CTEPH), technical challenges faced when performing BPA and the evidence base supporting its use. The second part of the article will focus on the future of BPA, in particular the areas where research is required to establish an evidence base to justify the role of BPA in CTEPH and CTED treatment.

Computed tomography appearances of the lung parenchyma in pulmonary hypertension

Computed tomography (CT) is a valuable tool in the workup of patients under investigation for pulmonary hypertension (PH) and may be the first test to suggest the diagnosis. CT parenchymal lung changes can help to differentiate the aetiology of PH. CT can demonstrate interstitial lung disease, emphysema associated with chronic obstructive pulmonary disease, features of left heart failure (including interstitial oedema), and changes secondary to miscellaneous conditions such as sarcoidosis. CT also demonstrates parenchymal changes secondary to chronic thromboembolic disease and venous diseases such as pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). It is important for the radiologist to be aware of the various manifestations of PH in the lung, to help facilitate an accurate and timely diagnosis. This pictorial review illustrates the parenchymal lung changes that can be seen in the various conditions causing PH.

Recurrent chronic thromboembolic disease despite optimal anticoagulation in setting of recent COVID-19 infection

We present a case of a 38-year-old man with a history of chronic thromboembolic pulmonary hypertension on therapeutic anticoagulation and recent hospitalisation for COVID-19 disease who was hospitalised for recurrent acute pulmonary embolism despite therapeutic anticoagulation with warfarin (International Normalized Ratio (INR) of 3.0). Our case highlights the hypercoagulable state associated with COVID-19 disease and the absence of standardised approaches to anticoagulation treatment for this population.

Impact of higher detection rate of residual pulmonary thromboemboli one-year after acute pulmonary embolism: modified CT scan imaging method with modified CT obstruction index

Background Recently, post pulmonary embolism (PE) syndrome or chronic thromboembolic disease after acute PE, has been recognized as important long-term complications. Furthermore, patients may develop with chronic thromboembolic pulmonary hypertension. Purpose We aimed to evaluate the frequency of residual pulmonary thromboemboli after acute PE by using our “higher”-resolution CT scan imaging method to detect residual thromboemboli down to sub-segmental pulmonary arteries. Methods This study was a prospective multi-center observational study. We enrolled consecutive 34 patients with acute symptomatic PE whose informed consent was obtained, and followed up for one year. One year after the onset of acute PE, patients were referred to our hospital and multiple examination including CT scan, 6-minute walk test (6MWT), questionnaire of SF-36, echocardiography and laboratory testing were performed. Additionally, we have modified the CT obstruction index (CTOI) to quantitatively evaluate the thromboemboli down to sub-segmental pulmonary arteries. Results Mean age was 60.5±15.8 years, and 56% were male. No patient was categorized as low recurrent VTE risk which was caused by transient factors, one patient was associated with active cancer, and 12% had known thrombophilia. In 85% of the patients, this onset was the first obvious episode of PE. At diagnosis, elevated B-type natriuretic peptide (BNP) (≥100 pg/ml) or N-terminal (NT)-proBNP (≥500 pg/ml) was observed in 45% of the patients. Median tricuspid regurgitation peak gradient (TRPG) by echocardiography was 30.9 (19.3–50.1) mmHg. Among all, 35% of the patients received single-drug approach with DOACs. At discharge, all of the patients except two were treated with DOACs. One year after the onset, 21% of the patient were in NYHA II and others were in NYHA I. It was notable that pulmonary thromboemboli was detected by our CT scan in 76% of the patients. Modified CTOI was median 11.9 (1.8–24.4) % as shown in the figure. In multiple regression analysis, TRPG at diagnosis and BNP at one month were significantly associated with mCTOI (β=0.536, p=0.002 and β=−0.482, p=0.003, respectively). Additionally, lowest SpO2 during 6MWT after one year from the onset, tended to inversely associate with mCTOI (β=−0.341, p=0.052). Conclusions Using our modified CT scan imaging method and modified CTOI, residual pulmonary thromboemboli was able to be detected more frequently than the previous studies. Residual pulmonary thromboemboli could be one of the cause of the post PE syndrome and lead to exercise-induced desaturation. Figures Funding Acknowledgement Type of funding source: None