Proteomic signatures reveal early signs of cardiovascular-kidney-metabolic disease in children

Researchers at Vanderbilt Health, UTHealth Houston and the University of North Carolina at Chapel Hill have identified early signs of cardiovascular-kidney-metabolic disease (CKMD) in children as young as 8 years old that potentially can be reversed with a new class of weight loss drugs used widely by adults. 

Using cutting-edge analytic techniques, the researchers defined a "signature" of circulating proteins in children and adolescents that mirrored the molecular biomarkers associated with irreversible cardiovascular disease in adults.

Their findings, published Sept. 11 in the journal Nature Metabolism, suggest there may be "a critical opportunity" to improve the health and longevity of young people, free of cardiovascular disease, through precision medicine.

The study, which was supported by the National Institutes of Health, included 273 children and adolescents who participate in the Border Health Research Cohort in Cameron County, Texas, on the U.S.-Mexico border. 

More than a third of them had phenotypes (physical characteristics) of cardiovascular, kidney and metabolic disease including obesity, higher-than-normal blood pressure, prediabetic insulin resistance, and levels of lipids (fats) in the blood associated with increased risk of heart disease. 

From blood samples and other physical measures, the researchers estimated the associations between levels of circulating proteins and disease-associated phenotypes. They used machine learning approaches to identify proteomic "signatures" of CKMD.

Similar protein patterns were identified in 685 adults from the same Cameron County community and in more than 28,000 adults whose blood samples are stored in the UK Biobank in England, one of the world's largest repositories of genetic and other biological samples.

Interestingly, levels of these disease-associated proteins in adults have been found to decline in response to therapy with semaglutide, a GLP-1 receptor agonist developed for type 2 diabetes, and which has become a popular treatment for obesity and weight management - in children as well as adults.

Between 2020 and 2023, pediatric prescriptions for GLP-1 receptor agonists increased by nearly 600%. Yet it is important to balance the benefit of such therapy with potential risk, the researchers cautioned. 

Attempts to combat the rising tide of childhood obesity by promoting cardiovascular health through exercise, a healthy diet and, increasingly, weight loss drugs and surgery, have had limited success. "Yet our data suggest that we can and must redouble these efforts," they noted.

While additional research is needed to validate these results, the study suggests that proteomic signatures, by "opening a window into the earliest roots of cardiovascular disease at its most interruptible phase," may help identify children most at risk, and therefore most likely to benefit from targeted therapy, the paper concluded.

The paper's co-corresponding authors are Ravi Shah, MD, the Gottlieb C. Friesinger II Professor of Cardiovascular Medicine at Vanderbilt Health and Co-Director of the Vanderbilt Diabetes Center, and Kari North, PhD, Professor at UTHealth Houston School of Public Health and Director of the Border Health Research Center.

Childhood is not simply a precursor to adult health. It is where the biology of adult cardiovascular disease is already taking place."

Kari North, PhD, Professor, UTHealth Houston School of Public Health

"Because many of the protein patterns we identified are potentially modifiable," Shah noted, "these findings suggest that the greatest opportunity to prevent heart disease may come decades before the first symptoms appear."

This study was funded in part by the NIH National Center for Advancing Translational Sciences (grant UL1TR000371). The Border Health Research Cohort is supported by the following NIH grants: U54AG089326, R01DK139598, R01HL142302, R01HL163262, R01DK127084 and U01CA288325.