Upregulation of Soluble HLA-G in Chronic Left Ventricular Systolic Dysfunction

Abstract

Left ventricular systolic dysfunction (LVSD) defined by ejection fraction (EF) <40% is common, serious but treatable, and correct diagnosis is the cornerstone of effective treatment. Biomarkers may help to diagnose LVSD and give insight into the pathophysiology. The immune system is activated in LVSD, and the immunomodulatory molecule human leukocyte antigen-G (HLA-G) may be involved. The primary aim was to measure soluble HLA-G (sHLA-G) in the blood in different stages of LVSD (<30% and 30–40%), in the midrange EF 40–50%, and in preserved EF ≥ 50% and to validate sHLA-G as a LVSD biomarker. The secondary aim was to examine associations between HLA-G gene polymorphisms influencing expression levels and LVSD. The 260 study participants were ≥75 years old, many with risk factors for heart disease or with known heart disease. Soluble HLA-G was significantly and uniformly higher in the groups with EF < 50% (<30, 30–40, and 40–50%) compared to EF > 50% (p < 0.0001). N-terminal fragment-pro-B-type natriuretic peptide (NT-proBNP) and uric acid values were inversely related to EF. According to Receiver Operating Characteristic (ROC) curves NT-proBNP outperformed both sHLA-G and uric acid as biomarkers of LVSD. Soluble HLA-G in blood plasma was elevated in LVSD regardless of EF. A novel finding was that a combined 14 bp ins-del/+3142 SNP HLA-G haplotype was associated with EF < 40%.

Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia

“…Moreover, diseases in which RAS is activated (i.e. heart failure with reduced ejection fraction and hypertension) present with increased soluble HLA-G (27,28).…”

Integrated analysis of DNA methylation profile of HLA-G gene and imaging in coronary heart disease: Pilot study

“…showed a higher secretion of sHLA-G in CD patients [ 48 ]; no significant difference was detected between plasma levels of SLE patients and control group, although a reduced plasma concentration of sHLA-G was observed when the patients were stratified according to clinical manifestations [ 49 ]. Regarding CVDs, higher levels of circulating sHLA-G were observed in heart transplantation [ 50 ], whereas there are no data about sHLA-G concentrations in CHD patients. In our study, for all subjects, plasma levels of sHLA-G were evaluated, but a not statistically significant difference of sHLA-G level was detected into CS group compared to NCS individuals (p = 0.09).…”

The histone demethylase PHF8 facilitates alternative splicing of the histocompatibility antigen HLA‐G

“…Furthermore, it has been demonstrated that PHF8 is reduced in human failing hearts and required to attenuate cardiac hypertrophy upon pressure overload . Accordingly, soluble HLA‐G was found to be upregulated in the blood of patients with heart failure or with chronic left ventricular systolic dysfunction : It is therefore tempting to speculate that PHF8 might also regulate HLA‐G alternative splicing during heart failure.…”