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%.

Figure 1

Soluble HLA-G in peripheral blood in relation to left ventricular ejection fraction (box and whiskers plot, min. to max., all points shown; p < 0.001, Kruskal-Wallis test; Dunn's multiple comparisons test, ^∗ p < 0.05, ^∗∗ p < 0.01) (one NT-proBNP test failed in the group with ejection fraction >50% reducing the number to 153).

Figure 2

(a) Receiver Operating Characteristic (ROC) curve of soluble HLA-G with heart failure defined as ejection fraction <50%. Area under the curve is 0.676, p < 0.001. (b) Receiver Operating Characteristic (ROC) curve of soluble HLA-G with heart failure defined as ejection fraction <40%. Area under the curve is 0.639, p = 0.001.

Figure 3

(a) Receiver Operating Characteristic (ROC) curve of NT-proBNP with heart failure defined as ejection fraction <50%. Area under the curve is 0.811, p < 0.001. (b) Receiver Operating Characteristic (ROC) curve of NT-proBNP with heart failure defined as ejection fraction <40%. Area under the curve is 0.902, p < 0.001.

Figure 4

(a) Receiver Operating Characteristic (ROC) curve of uric acid with heart failure defined as ejection fraction <50%. Area under the curve is 0.721, p < 0.001. (b) Receiver Operating Characteristic (ROC) curve of uric acid with heart failure defined as ejection fraction <40%. Area under the curve is 0.788, p < 0.001.

Figure 5

(a) Soluble HLA-G in peripheral blood in relation to significant valvular heart disease (box and whiskers plot, min. to max., all points shown; p = 0.002, Mann–Whitney test). (b) Soluble HLA-G in peripheral blood in relation to significant valvular heart disease in patients without heart failure (EF > 50%) (box and whiskers plot, min. to max., all points shown; p = 0.067, Mann–Whitney test).