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Researchers Find Cardiovascular Marker Linked to Overall Mortality Risk


NEW YORK – Researchers from Quest Diagnostics and collaborators have found that changes in levels of the cardiovascular risk marker free myeloperoxidase (MPO) appear correlated with an individual's overall mortality risk.

The finding, described in a study published last month in PLOS One, indicates that longitudinal measurement of MPO could help physicians assess patients' mortality risk and response to interventions.

It also suggests that MPO could prove useful outside the cardiometabolic context in which it has most commonly been used, including potentially for identifying patients at elevated risk of conditions like cancer and Alzheimer's disease, said Marc Penn, senior adviser and medical director of Quest's cardio metabolic endocrine franchise and first author on the study.

MPO is an enzyme released by white blood cells in response to infection and inflammation. It was originally used primarily to help assess patients presenting with symptoms indicative of a potential heart attack but in whom heart injury markers like troponin were negative.

This application stemmed from the realization that in such cases, patients were often suffering not from a heart condition, but from a vascular problem, Penn said.

"We were looking at heart markers to determine if someone had a vascular problem," he said, noting that this prompted the question of "could we develop a vascular marker for vascular events?"

Today, MPO is most commonly used in the ambulatory setting to help assess the likelihood of cardiovascular events in high-risk individuals, Penn said, noting that the marker provides information on cardiometabolic health not captured by traditional measures.

He cited the example of a patient with LDL cholesterol levels just above optimal and a hemoglobin A1c at the high end of normal.

"The patient doesn't really want to go on a statin, but they measure MPO and it is elevated and maybe then the physician is more adamant about that patient lowering their lipids, lowering weight, [improving] diet and exercise," he said.

While MPO's value as a marker of cardiovascular risk has been established through a number of studies, researchers had not previously shown that longitudinal changes in MPO levels reflected a change in a person's risk of cardiovascular events.

"The most important finding in this study is that we've shown for the first time that if you lower MPO, you lower risk, and if you let MPO go up, you raise risk," Penn said.

To establish that relationship, the researchers collected demographic and lab data (MPO, LDL cholesterol, hemoglobin A1c, and ApoB lipoprotein) from a cohort of 3,658 patients seen between 2011 and 2015 by doctors in the national primary care network MDVIP. They analyzed both the correlation between an individual's baseline MPO level and their risk of adverse events including myocardial infarction, stroke, coronary revascularization, and all-cause death and the correlation between changes in MPO level and risk of adverse events.

Running counter to prior studies, the authors found that at baseline the "risk of cardiovascular death did not differ significantly between patients with high and low MPO" once they had adjusted for age, sex, and other cardiovascular risk factors. Penn said that this was due to the fact that the incidence of cardiovascular death was small in the relatively healthy population looked at in the study.

The researchers did find, however, that patients with high MPO levels were at elevated risk for death due to non-cardiovascular conditions and had higher levels of all-cause mortality.

Additionally, as Penn noted, the study found that decreasing MPO levels were linked to mortality reduction, with, the authors wrote, "a 100 pmol/L decrease in MPO correlated with a 5 percent reduction in mortality over five years."

That finding could allow physicians to better assess whether or not particular interventions are mitigating a patient's mortality risk, Penn said.

"It's a reflection of vascular health," he said. For instance, "we've known for years that there is a link between gum disease and heart disease. In people with periodontal abscesses, gingivitis, things of that nature, MPOs are very high. Sending someone to the dentist and having their mouth cleaned up actually lowers MPO. Getting on top of inflammatory bowel disease, rheumatoid arthritis, things that are known to be associated with heart disease … MPO reflects that."

"The real goal of this study was, we have a population where we lowered MPO. Does that have an impact on health and outcomes?" he said. "And I think this study shows that it does."

The fact that baseline MPO levels and longitudinal changes in levels were correlated with non-cardiovascular health and death from non-cardiovascular conditions suggests the marker could prove useful in other patient populations.

For instance, Penn said that elevated MPO in a patient with no signs of elevated cardiovascular risk could lead doctors to more closely examine them for other potential causes, like cancer or Alzheimer's disease.

He suggested that liquid biopsy-based cancer detection is one area that could benefit from such an approach, given the relatively low sensitivity of such tests. Patients with high MPO but no apparent cardiovascular condition might, for instance, be prioritized for more intensive cancer testing or additional follow-up.

Penn said he and his colleagues have not begun any studies exploring the usefulness of MPO in this context but that they are "thinking about looking at patients who have MPO [test results] who go on to get a liquid biopsy to see if higher MPO patients are more likely to have a true positive liquid biopsy."

He noted that the MDVIP network offers its patients liquid biopsies for cancer detection and that he and his collaborators are in discussions with the network about possibly using their patient data to look at correlations between MPO levels and liquid biopsy results.

MPO tests cost $50.86 under the current Centers for Medicare and Medicaid Services Clinical Laboratory Fee Schedule and is widely available. Penn said the primary challenge in testing MPO levels is with sample collection and the requirement that samples be spun down within 10 to 20 minutes after collection.

"Otherwise, the white blood cells sit in the [collection] tube and leach out their MPO as they die, and so you get a false positive," he said.