Coronary microvascular disease (CMD) may have an underlying genetic basis, according to findings from a genome-wide association study (GWAS) published in Nature Cardiovascular Research. The study found that inflammatory signaling, particularly the nuclear factor kappa B (NF kappa B) pathway, is involved in the disease process, providing new insights into its underlying biology.

Speaking with El Médico Interactivo, part of the Medscape Professional Network, Javier Martín Moreiras, MD, cardiologist specializing in interventional cardiology at the University Hospital of Salamanca, Salamanca, Spain, and president of the Spanish Working Group of Interventional Cardiology, said, “The study suggests that several genetic markers may be associated with coronary microvascular disease and reduced coronary flow reserve (CFR), which could serve as a useful measure of the condition.” He noted that the study provides the first evidence suggesting a detectable genetic contribution to CMD.

The researchers also found that PET with quantitative assessment of CFR provided a robust approach for phenotyping patients with CMD. Several genetic loci were associated with reduced CFR, with the strongest association involving the NF kappa B inflammatory signaling pathway.

According to Martín Moreiras, these findings could support future genetic studies aimed at improving the understanding of CMD and identifying new therapeutic targets. He noted that CMD is increasingly being recognized as a condition associated with poorer clinical outcomes than previously appreciated.

Higher Cardiovascular Risk

“Patients with a reduced CFR are at greater risk for cardiovascular events, persistent symptoms, repeated hospitalizations, and poorer quality of life. These patients require appropriate treatment,” Martín Moreiras said.

Although men and women were represented in nearly equal proportions, CMD is particularly relevant in women presenting with angina or myocardial ischemia despite nonobstructive coronary artery disease.

Researchers have also observed sex-related heterogeneity, suggesting that the underlying genetic and molecular mechanisms may differ between women and men.

Role of the NF Kappa B Pathway

One of the principal findings of this study was the identification of genetic variants converging on the NF kappa B pathway, which regulates inflammation, angiogenesis, and vascular remodeling.

According to Martín Moreiras, these findings support the hypothesis that dysregulation of the NF kappa B pathway may contribute to endothelial dysfunction by promoting microvascular inflammation, impairing angiogenesis, and ultimately reducing CFR.

Potential Therapeutic Implications

Martín Moreiras noted that this is the first study to identify a genetic alteration that may underlie this condition. However, he emphasized that the findings do not establish a causal relationship. “The results suggest that inhibition or modulation of NF kappa B could eventually become a therapeutic strategy for selected groups of patients with inflammatory disease or an inflammatory phenotype, as well as for patients with coronary microvascular disease who have impaired coronary flow reserve and ventricular dysfunction. Although the evidence is not definitive, these findings point to a potential biological pathway that could improve our understanding of the disease and help identify future therapeutic targets. However, the results do not establish causality and instead provide a specific direction for future research.”

Martín Moreiras added that the findings should be interpreted with caution because the study used a GWAS, which examines the entire human genome to identify genetic variants associated with a particular disease. “This is the first GWAS to link coronary flow reserve measured by PET with phenotypes of coronary microvascular disease, and the findings suggest that genetic factors may play an important role.”

Martín Moreiras reported no relevant financial conflicts of interest.

This article was translated from El Médico Interactivo.