Biomarkers in Young Adults May Predict Origins of Preserved-EF Heart Failure

March 26, 2020

Two biomarkers linked to endothelial activation, measured in young adulthood, may predict subclinical myocardial changes in middle age that herald later heart failure with preserved ejection fraction (HFpEF), say researchers who conducted an observational study.

Elevations in the two inflammatory biomarkers — cellular adhesion molecules E-selectin and ICAM-1 — are considered signs of endothelial activation and markers of existing HFpEF, Ravi B. Patel, MD, Northwestern University Feinberg School of Medicine, Chicago, observed for | Medscape Cardiology.

"But we didn't know before this study whether they are elevated and predictive among those who have not yet developed the disease." The current findings, he said, substantiate a role for the two biomarkers in the pathophysiologic process that drives the development of HFpEF.

Patel is lead author on the study published March 16 in the Journal of the American College of Cardiology and scheduled for online presentation March 30 during the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology virtual meeting.

It was based on 2285 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study, which entered white and African Americans 18 to 30 years of age from four urban areas in the United States starting in 1985.

Early serum levels of the two biomarkers, as well as change in levels of ICAM-1, were independently associated with subclinical adverse left ventricular (LV) remodeling, as indicated by reduction in echocardiographic LV global longitudinal strain (GLS) years later.

"The biomarkers E-selectin and ICAM-1 were drawn at year 7 of the study, so the participants were, on average, quite young in their adulthood. And we saw the associations with echocardiographic outcomes as late as 23 years later in the case of E-selectin," Patel said.

"That shows that these biomarkers were strongly associated at a very young age," he said, "independent of clinical morbidities that accumulate over time, like obesity, high blood pressure, and diabetes."

Interestingly, the biomarkers in young adulthood were not independently associated with later echo measures of diastolic dysfunction.

Patel said the kind of LV dysfunction observed in CARDIA is interpreted as a predictor of later HFpEF, rather than heart failure with reduced ejection fraction (HFrEF), because of previous evidence for GLS "as a prevalent marker of systolic dysfunction and as a marker of prognosis" specifically in patients with HFpEF.

"Over the past 2 decades, we've noticed that HFpEF is very heterogeneous," he said. "We do tend to view it now as a disease of both systolic and diastolic dysfunction."

In CARDIA, levels of the two biomarkers were measured at years 7 and 15, and echocardiography was performed at year 30.

Increased E-selectin levels were significantly correlated with worse echocardiographic LV GLS at both year 7 (P < .001) and year 15 (P = .002).

Increased ICAM-1 was also correlated with the echo finding at year 15 (P = .004). The change in ICAM-1 from years 7 to 15 (P = .03) was also predictive.

The analyses controlled for age, race, sex, cigarettes per day, body mass index, systolic blood pressure, antihypertensive drug use, diabetes, total cholesterol, serum creatinine, CARDIA field center, and image-quality scores, the report notes.

The current study "paves the road for personalized prevention of HFpEF," writes Walter J. Paulus, MD, PhD, Amsterdam University Medical Centers, the Netherlands, in an accompanying editorial.

The study "supports a personalized strategy of early risk assessment with determination of circulating adhesion molecules to prevent later development of HFpEF, a condition for which an effective therapy is unfortunately still lacking."

Potentially, Paulus speculates, "in a young patient with cardiovascular risks such as obesity, diabetes mellitus or arterial hypertension, elevated circulating endothelial adhesion molecules should prompt vigorous efforts to correct the risk factor profile in order to prevent HFpEF development at older age."

Patel agrees with the potential, but cautions that this more mechanistic study is a long way from showing that such early intervention based on the biomarkers can improve HFpEF risk later on.

"It would be great if we could intervene on modifiable risk factors, have folks avoid progression to obesity, adherence to strict, healthy lifestyles to prevent hypertension and diabetes," he said. But whether that would modify endothelial activation in a way that prevents worsening LV function and progression to HFpEF is entirely unknown.

And although it's possible that interventions aimed at reducing levels of the biomarkers might also suppress endothelial activation, Patel said, the cellular adhesion molecules may instead be a product of the disease, not a cause.

Patel had no disclosures, nor did Paulus. Disclosures for the other study authors are in the report.

J Am Coll Cardiol. Published online March 16, 2020. Abstract, Editorial

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology: Abstract 1459-155. To be presented March 30, 2020.

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