Plasma ACE2 concentration associated with increased risk of major cardiovascular events

By Angela Betsaida B. Laguipo, BSNOct 6 2020

Early in the coronavirus disease (COVID-19) pandemic, scientists have found a cellular gateway the virus uses to enter and invade cells. The angiotensin-converting enzyme 2 (ACE2) receptors act as the entrance of the virus into the cells by binding with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins.

A team of scientists at the Population Health Research Institute, Hamilton Health Sciences, and McMaster University, Hamilton, in Ontario, Canada, revealed that increased plasma ACE2 levels in the blood could indicate a higher risk of major cardiovascular events. The study is published in the journal The Lancet.

There is an ongoing global effort to better understand ACE2, the receptor where the SARS-CoV-2 enter cells. ACE2 is a known regulator of cardiac function, and once the system becomes dysregulated, it could lead to health consequences. It is essential to know more about the role of ACE2 and how it can affect the cardiac health of patients infected with the coronavirus.

Small clinical studies have suggested that elevated levels of circulating ACE2 activity and concentration may serve as a marker of poor prognosis in people with a multitude of cardiovascular diseases. So far, no study has provided evidence in a large cohort in the general population.

Human ACE2 receptor, 3D illustration. Angiotensin Converting Enzyme-Related Carboxypeptidase, a membrane protein which is used by SARS-CoV-2 virus to enter the human cells. Image Credit: Kateryna Kon / Shutterstock

The study

The study, called the Prospective Urban Rural Epidemiology (PURE) study, opens the door to explore the link between ACE2 levels with future cardiovascular disease events and deaths in a global community-based cohort.

The team aims to see the role of demographic and clinical characteristics as possible determinants of the concentration of ACE2 in the plasma, describe the link between plasma ACE2 levels and cardiovascular events and mortality, and explore the importance of ACE2 in the plasma as a risk marker.

To arrive at the study findings, the PURE study involved participants in 27 low-income, middle-income, and high-income countries. The team developed a biobanking initiative for the participants to assess genomic and proteomic markers of chronic disease risk. Further, they collected blood samples from the countries, and 14 countries even shipped samples, including Bangladesh, Brazil, Argentina, Canada, Colombia, Chile, India, Philippines, Pakistan, Iran, South Africa, Tanzania, Sweden, the United Arab Emirates, and Zimbabwe.

The researchers included cardiovascular events, such as stroke, heart failure, diabetes, myocardial infarction, and death.

Measuring proteins

After collecting blood samples from all over the globe, the team measures proteins and plasma concentration using an immunoassay based on proximity extension assay technology. Further, genotyping and genetic analysis were also conducted by the study researchers.

They found that sex accounted for the most variation in plasma ACE2 levels, followed by geographic ancestry, body mass index (BMI), diabetes, age, systolic blood pressure, smoking status, and low-density lipoprotein (LDL) cholesterol levels.

This study adds to the previous one noting that men are at a higher risk of developing severe COVID-19. The study shows that men had higher plasma ACE2 levels than women, while concentrations varied broadly by geographic ancestry.

Moreover, a higher BMI, older age, diabetes, higher blood pressure, higher LDL cholesterol levels, and smoking were all tied to elevated levels of circulating plasma ACE2.

When compared with clinical risk factors, such as diabetes, smoking, blood pressure, BMI, and lipid levels, ACE2 was the highest-ranked predictor of death.

“The ACE2 receptor facilitates viral entry for SARS-CoV-2. In patients with COVID-19, the ACE2 receptors might play a role in leading to cardiovascular complications such as thrombosis, cardiac injury, and heart failure. ACE2 is a possible link between SARS-CoV-2 and the cardiac presentations described in findings that have emerged from global data during the COVID-19 pandemic,” the researchers wrote in the paper.

The researchers noted that the plasma concentration of ACE2 exhibits an independent link with cardiovascular disease, including death.

“Compared with established clinical risk factors, ACE2 consistently emerges as a strong predictor of cardiovascular disease or death,” they added.