Study: Ang-2 Blood Test May Predict Treatment Outcomes in CTEPH

Angiopoietin-2 protein levels high in patients with rare PH type

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

Share this article:

Share article via email
Ang-2 blood test for CTEPH treatment | Pulmonary Hypertension News | illustration of blood in vials and syringe

A blood test for angiopoietin-2 (Ang-2), a protein associated with forming new blood vessels, may predict treatment outcomes in people with chronic thromboembolic pulmonary hypertension (CTEPH), a study showed.

Researchers found that the protein’s level was significantly higher in the bloodstream of patients with this rare form of pulmonary hypertension, which “suggests Ang2 maybe critical to CTEPH disease pathogenesis [development].”

Pulmonary endarterectomy (PEA) is a surgical treatment for CTEPH patients to remove blood clots that cause abnormally high blood pressure in the lungs’ arteries. The level of Ang-2, as measured before surgery, was the only blood test that predicted blood pressure outcomes afterward.

Additionally, the inflammatory marker C-reactive protein (CRP) was the only predictor of survival following surgery.

Recommended Reading
pulmonary hypertension and Covid-19 | Pulmonary Hypertension News | risk dashboard illustration

Pre-surgery Risk Assessments in CTEPH Did Not Foresee Outcomes

The study, “Angiopoietin 2 and hsCRP are associated with pulmonary haemodynamics and long-term mortality respectively in CTEPH – results from a prospective discovery and validation biomarker study,” was published in The Journal of Heart and Lung Transplantation.

Although the underlying cause of CTEPH is still unclear, emerging evidence suggests that mediators of blood clotting, inflammation, and the formation of new blood vessels — a process called angiogenesis — all play a role.

Ang-2 is a protein that is part of a family of blood vessel growth factors that support angiogenesis. This particular family member has been linked to blood vessel disease and slowing the clearance of blood clots.

Investigating Ang-2 in CTEPH treatment

Researchers at the Cambridge Biomedical Campus, in the U.K., suggested that mediators of angiogenesis, such as Ang-2 and inflammation, may be clinical markers of CTEPH severity and outcomes.

To test this hypothesis, the team collected blood samples from 100 people. These sample came from 71 people with CTEPH before and after PEA surgery, nine patients with chronic pulmonary arterial blood clots but without pulmonary hypertension (CTEPD), and 20 healthy individuals, who served as controls. Levels of Ang-2 and various inflammatory markers were assessed.

Before PEA surgery, Ang-2 levels — along with the inflammatory protein markers CRP, TNF-alpha, and interleukin-8 —found to be significantly elevated in CTEPH patients compared with controls. VEGFc, a protein that promotes the growth of lymphatic vessels, was lower in CTEPH patients. In individuals with CTEPD pre-PEA, the anti-inflammatory protein interleukin-10 was higher than in controls.

After PEA surgery, as assessed in 47 CTEPH patients, significant improvements in blood parameters and physical function were seen.

PEA lowered mean pulmonary artery pressure (mPAP), reduced pulmonary vascular resistance (PVR) — a resistance against blood flow — and increased the distance walked in six minutes (6MWT).

At the same time, Ang2, interleukin-8, interleukin-10, and VEGFc all were found to be significantly lower in CTEPH patients after PEA surgery. Vessel growth factors VEGFd and endoglin also were significantly less following the surgery.

Compared with controls, CTEPH patients had significantly higher Ang2 and TNF-alpha levels after PEA, and significantly reduced VEGFc and VEGFd.

Statistical analysis revealed only Ang-2, before PEA, was significantly associated with clinical assessments at the study’s start, or baseline. Before surgery, elevated Ang-2 was linked to higher mPAP, PVR, NT-ProBNP, a marker for heart dysfunction, functional class reflecting disease severity, and a lower cardiac index, a measure of heart function.

Notably, Ang-2 was the only protein in the blood of CTEPH patients sampled before PEA that predicted clinical outcomes up to six months after PEA. The researchers found that Ang-2 before PEA was significantly associated with PVR after PEA.

Recommended Reading

Balloon Pulmonary Angioplasty and Adempas Both Effective for Inoperable CTEPH, Analysis Shows

Validating the findings

To validate these findings, Ang-2 was measured in a further 277 people with CTEPH and 26 with CTEPD without PH. Among these, 72% of CTEPH and 27% of CTEPD patients underwent PEA. CRP also was tested as an indicator of inflammation.

Ang2 levels were significantly higher in CTEPH patients than in controls after adjusting for age and sex (8197 vs. 4094 picograms per mL of blood). Importantly, Ang2 was significantly lower in those with CTEPD without PH relative to CTEPH with PH (4554 vs. 8197 picograms/mL). CRP also was significantly higher in CTEPH patients.

Again, pre-PEA Ang-2 levels correlated with baseline mPAP, PVR, cardiac index, and 6MWT distance, and Ang2 measured before PEA was significantly associated with PVR after PEA, adjusting for age and sex.

Clinical assessments were done for 166 CTEPH patients, of whom 42 had residual PH after surgery, three to six months after PEA. The results showed that Ang2 measured before surgery was a significant predictor of residual PH post-PEA. Ang2 was no longer an independent predictor of residual PH after adjusting for PVR.

Before adjustments that may influence the data, age, 6MWT distance, and CRP levels were associated with all-cause mortality. Blood parameters and Ang-2 levels before surgery were not significantly linked to survival. After adjustments, the CPR test was the only factor associated with all-cause mortality in people with CTEPH undergoing PEA.

“By targeted screening of key proteins related to inflammation, vascular homeostasis [steady state], and angiogenesis, we provide useful insights into CTEPH pathobiology,” the research team wrote. “This study adds to an increasing body of evidence that the interplay between inflammatory cell signalling (a key trigger event in many forms of PH) and the subsequent angiogenic response to insult may play a key role in disease development.”

A Conversation With Rare Disease Advocates