Researchers Find Potential Biomarkers of ACE Inhibitor-induced Angioedema

Factors involved in blood vessel permeability — called VEGF-A, VEGF-C, and sPLA2 — may predispose people who take ACE inhibitor medications for high blood pressure to develop non-allergic angioedema, a study reports.

Moreover, the findings indicate that switching to sartans, another class of antihypertensive medicines, can be a safe alternative to ACEIs.

The study, “Angiotensin-converting enzyme inhibitor-associated angioedema in a cohort of Caucasian patients: from bed to bench,” was published in the Journal Investigational Allergology and Clinical Immunology.

Angioedema, swelling in the deep layers of the skin or mucus membranes, can be triggered by a variety of factors, such as food and medications, and may also be the result of a hereditary condition.

A type of medication used to treat high blood pressure, called angiotensin-converting enzyme inhibitors (ACEI), is a well-known cause of angioedema (ACEI-AAE). Angioedema is believed to occur as a side effect of ACEIs because they block the breakdown of certain chemicals in the body (e.g. bradykinin and substance P), which cause blood vessels to widen and get more permeable.

Yet, it’s rare that patients on these medications develop angioedema (0.1%–0.7%). While the mechanisms behind ACEI-AEE are not fully understood, some scientists believe that certain risk factors may predispose some people to the disease. If so, these factors could serve as biomarkers to help identify those at greater risk.

Angioedema is a rare but potentially life-threatening side effect of ACEI, so identifying those potentially more vulnerable is an important but challenging task, the researchers wrote.

Therefore, these researchers, from the University of Naples Federico II, in Italy, studied the clinical, genetic, and laboratory features of patients with ACEI-AAE.

They specifically focused on the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secreted phospholipases A2 (sPLA2) — factors naturally found in the body which are involved in the development and permeability of blood vessels.

The same team recently found that these molecules were elevated in the blood of patients with hereditary angioedema due to C1-inhibitor deficiency which, like ACEI-AAE, is a form of angioedema mediated by bradykinin.

A total of 51 Caucasian patients with ACEI-AAE were included in the study, along with 86 healthy subjects and 20 ACEI-treated subjects without angioedema to serve as controls.

The average time for symptom onset was three years after ACEI therapy. Symptom onset ranged widely from 30 days to 20 years. The sites most commonly affected by acute angioedema attacks were the lips (74.5%), tongue (51.9%), and face (41.2%).

After discontinuing ACEIs, 68% of patients no longer experienced angioedema attacks, while the remaining 32% still had angioedema recurrences. This suggests that discontinuation from ACEI may not be sufficient to prevent symptom recurrence in a significant number of patients.

When switching away from ACEI therapy, 44% of the patients changed to sartans, a different class of medicines to treat high blood pressure, also known as angiotensin II receptor blockers (ARBs).

Examples of sartans include losartan (sold as Cozaar, also available as generics) and valsartan (sold as Diovan).

The remaining 56% of patients started other types of treatment for high blood pressure or stopped taking these medications. About 36% of patients switched to calcium antagonists, 14% to no therapy, and 8% to beta-blockers, alpha-blockers, or diuretics.

The researchers found that seven of the 22 patients (31.8%) treated with sartans developed angioedema related to the medication. Two of these patients had angioedema not related to the medicines as it either self-resolved during treatment or it persisted after discontinuation.

In patients who switched to other antihypertensive therapies, the prevalence of angioedema was 28.6%.

Therefore, because switching to sartans was not associated with an increased risk of disease, “sartans can be a safe therapeutic alternative in ACEI-AAE patients,” the researchers wrote.

They also found that VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in healthy controls or ACEI-treated subjects without angioedema. This suggests a “basal predisposition to vasopermeability in ACEI-AAE patients that could play a role in the development of an [angioedema] attack,” the researchers noted.

However, no associations were found between VEGF-A and VEGF-C levels, sPLA2 activity, and clinical features such as age at symptom onset, duration of attacks, or the number of sites involved.