MILAN — Increases in neutrophil counts appear to be causally associated with incident coronary artery disease (CAD) and myocardial infarction (MI), suggests a novel analysis that combined observational and genetic data.

The study initially confirmed the association between increased neutrophil counts and coronary artery disease, ischemic cerebrovascular disease, ischemic stroke, and vascular dementia in an observational study of more than 100,000 individuals who were followed for over 9 years.

The researchers then used a series of databases to conduct a two-sample Mendelian randomization study, which showed that each unit increase in neutrophil counts was associated with a 14% increased risk of CAD and a 22% increased risk of MI.

“Higher neutrophil counts, either biologically…or genetically determined, are associated with high risk of coronary artery disease,” said study presenter Jiao Luo, PhD, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.

“However, higher neutrophil counts are unlikely to be a causal risk factor for ischemic stroke, and the association with vascular-related dementia needs to be further explored,” she added, noting the lack of genetic databases to explore the association.

The research was presented at European Atherosclerosis Society (EAS) 2022 on May 23.

In the post-presentation discussion, Luo explained that the findings could “absolutely” have implications for patient management.

She highlighted a 2021 study that combined data from five randomized trials to show that the baseline neutrophil-lymphocyte ratio (NLR) predicted incident cardiovascular events and mortality.

It also showed, crucially, that while lipid-lowering agents had no significant effect on the NLR, the ratio was significantly lowered by the anti-inflammatory therapy canakinumab.

“So, if the association between neutrophils and especially cardiovascular disease is causal,” Luo continued, “this might be a very good target for testing new drugs,” which could have a major benefit for patients.

Christoph Binder, MD, PhD, who was not involved in the study, told theheart.org | Medscape Cardiology that the data are “really exciting,” as they demonstrate a causality that was seen previously only in animal models.

“We have learned that neutrophils are not only inflammatory cells that may be involved in the initiation of plaque development, but they are also critically involved in thrombotic events.”

One potential therapeutic target, added Binder, who is a professor of atherosclerosis at the Medical University of Vienna, Vienna, Austria, could be via targeting the secretion of neutrophil extracellular traps (NETs) by the cells.

He noted that experimental studies are being undertaken to try to demonstrate that treating these NETs with DNase enzymes could “reduce the consequences of neutrophil activation.

“Then potentially there is still inflammation, because upstream of the high neutrophil counts there must be some inflammatory triggers that are responsible for this” and “maybe in some individuals they are responsive” to treatment, he said.

However, Binder underlined that the exact cause of neutrophil activation in the context of atherosclerosis remains to be identified.

“Minimally Invasive, Inexpensive, Reliable”

Luo noted in her presentation that neutrophils are the most common myeloid cells in peripheral lymphocytes, and measuring them is “minimally invasive, inexpensive, and very reliable.”

She added that interpretation of the results is “very easy and, most importantly,” neutrophils are measured as part of routine clinical practice.

This makes them “an ideal and easy biomarker for several inflammatory conditions, including atherosclerosis” and other forms of cardiovascular disease.

Luo also noted that the mechanisms by which neutrophils contribute to atherosclerosis have been “widely studied” and include the recruitment and adhesion of monocytes and the secretion of reactive oxygen species and NETs.

While previous studies have shown that higher neutrophil counts are associated with cardiovascular disease and mortality, Luo pointed out that, owing to residual confounding, “the association may not be causal.”

To investigate further, the researchers conducted a two-part study, the first of which examined the associations between neutrophil counts and cardiovascular disease in an observational study.

They examined individual-level data from the Copenhagen General Population Study, which includes 101,582 individuals (median follow-up, 4.5 years).

Multivariate analysis showed that individuals in the ≥95th percentile of neutrophil counts had a significantly increased risk of CAD in comparison with those in the 25th to 75th percentile, at an adjusted hazard ratio of 1.22 (95% CI, 1.10 – 1.36).

People with the highest neutrophil counts also had a significantly increased risk of MI, at an adjusted hazard ratio of 1.22 (95% CI, 1.02 – 1.45), as well as of non-Alzheimer’s dementia, at an adjusted hazard ratio of 1.29 (95% CI, 1.05 – 1.59).

Next, the team conducted a two-sample Mendelian randomization analysis.

Luo reminded the audience that these analyses use genetic data to examine naturally occurring differences in the exposure variable ― in this case, neutrophil counts ― and their relationship with the outcome variable ― in this case, vascular endpoints ― with the aim of minimizing confounding and reverse causality.

The researchers first studied genetic associations with neutrophil counts using data on 563,085 individuals from the Blood Cell Consortium (BCX). They linked those to information from the CARDIoGRAMplusC4D consortium and the UK Biobank to examine their association with CAD.

Data from MEGASTROKE consortium were then used to study associations between variations in neutrophil counts and ischemic stroke.

However, no datasets were available to examine associations between neutrophil counts and ischemic cerebrovascular disease or vascular-related dementia.

The results showed that each one standard deviation increase in genetically determined neutrophil counts was associated with an odds ratio for CAD of 1.14 (95% CI, 1.05 – 1.23).

Each standard deviation increase was also associated with an odds ratio for MI of 1.22 (95% CI, 1.06 – 1.41).

However, there was no significant association between elevations in neutrophil counts and ischemic stroke, at an odds ratio for each standard deviation increase of 0.98 (95% CI, 0.89 – 1.07).

No funding for the study was reported. Luo and Binder have disclosed no relevant financial relationships.

European Atherosclerosis Society (EAS) 2022: Presented May 23, 2022.

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