Photo Credit: Surendra Sharma

Elevated levels of the cytokine resistin may be linked to increased disease severity and greater risk for death for adults with PAH.

Elevated levels of the cytokine resistin appear to be linked with increased disease severity and greater risk for death for adults with pulmonary arterial hypertension (PAH), a biobank-based study suggests.

“Resistin, a member of the resistin-like molecule (RELM) family of pleiotropic cytokines, … is predictive of poor clinical outcomes in patients with cardiovascular disease and heart failure,” Li Gao, MD, PhD, and coauthors wrote in Respiratory Research. “Serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. Our study provides evidence to support the use of circulating biomarkers as objective and accessible tools for noninvasive PAH risk stratification.”

The authors explained that human resistin, expressed by myeloid cells, especially macrophages, induces pulmonary vascular remodeling and PAH development by mediating endothelial and smooth muscle cell crosstalk and macrophage activation. In PAH, abnormal remodeling of distal pulmonary arteries leads to increased pulmonary vascular resistance over time, followed by right ventricular hypertrophy and failure, with poor prognosis.

Resistin As Marker for PAH Severity and Survival

To evaluate the potential for using resistin as a genetic and biological marker for PAH severity and survival, Dr. Gao and colleagues analyzed biospecimens and clinical and genetic data from 808 adults with idiopathic PAH and 313 adults with scleroderma-associated PAH who had samples and data in the National Biological Sample and Data Repository for PAH. They also analyzed samples and data from 50 healthy controls obtained from a biotechnology company.

The researchers measured serum resistin levels by ELISA and used multivariable regression to analyze the associations between resistin levels, clinical variables, and single nucleotide polymorphism (SNP) genotypes. They applied machine-learning algorithms to develop and compare risk models for mortality prediction.

Among their findings:

• Resistin levels were significantly higher in all PAH samples and subtype (idiopathic PAH and scleroderma-associated PAH) samples than were present in controls (P<0.001). When area under the curve (AUC) values of the receiver operating characteristic (ROC) curve were used to evaluate how well resistin levels detected PAH, all three tests had excellent discriminative ability (AUCs, 0.84, 0.82, and 0.91, respectively; P<0.001).
• High resistin levels (above 4.54 ng/mL) in patients with PAH tended to occur with older age (P=0.001), shorter 6-minute walk distance results (P=0.001), and decreased cardiac performance (cardiac index, P=0.016).
• Higher resistant levels were found in mutant carriers of RETN gene SNPs rs3219175 or rs3745367 (adjusted P<0.01).
• High resistin levels in patients with PAH were associated with a greater risk of death (hazard ratio: 2.6; 95% CI, 1.27-5.33; P<0.0087).
• Comparisons of machine-learning–derived survival models confirmed the random forest model’s satisfactory prognostic value (AUC=0.70; 95% CI, 0.62–0.79) for PAH.

“To our knowledge, this study is among the very few to attempt machine learning–based risk stratification in patients with PAH,” the researchers wrote. Our findings will facilitate the development of precision prognostication tools and resistin-targeted therapy.”

Although the large sample size and complex clinical features enabled important feature selection and extensive modeling, the study contained limitations, including missing data on 6-minute walk tests and the New York Heart Association functional class. Most patients received PAH-specific therapy during biomarker assessment, which may have affected circulating biomarker levels.

Further Research and Broader Applications

“Circulating resistin levels have an emerging role as biomarkers for a variety of diseases, including glucose metabolism and obesity, diabetes, cancer, inflammatory diseases such as inflammatory bowel disease, and cardiovascular diseases,” Dr. Gao and her colleagues noted. “Because lung is the primary location of most RELM isoforms, research into the association between RELMs and the pathogenesis of cardiothoracic and respiratory diseases is now beginning to expand rapidly.”