Correlation of Biomarkers of Endothelial Dysfunction, Inflammation, and Fibrosis and Preserved and Reduced Right Heart Function without Pulmonary Hypertension

Objectives: A number of biomarkers associated with the diagnosis, disease severity and progression of cardiovascular diseases have recently been identified. Regarding right heart dysfunction without pulmonary hypertension, the predictive value of established biomarkers associated with endothelial dysfunction, inflammation and fibrosis remains unstudied. We hypothesized that decreased RV function, assessed by TAPSE, could be associated with elevated serum biomarker levels as measured by ELISA.

Methods: From August 2016 to July 2018, a total of 271 patients scheduled for coronary artery bypass grafting were studied. Patients were divided into two groups according to preoperative TAPSE (TAPSE > 20 mm, n = 180; TAPSE < 20 mm, n = 91). Right auricular (RA) tissue was harvested and ELISAs were performed for biomarkers of fibrosis (MMP9, galectin-3, GDF-15, TGF-β1, TIMP-1, pentraxin-3), inflammation (hsCRP, hs-IL-6) and endothelial dysfunction (n-acyl-SDMA, ADMA, arginine).

Results: Demographic data revealed that patients with TAPSE < 20 mm exhibited higher rates of atrial fibrillation (43.9 vs. 7.8%, p = 0.001), larger left atrial area (22.51 ± 6.12 vs. 19.85 ± 5.15 cm², p = 0.007), decreased LVEF (48 ± 13 vs. 54 ± 9%, p = 0.003), lower preoperative GFR (66.34 ± 17.6 vs. 76.67 ± 23.7 mL/min//1.73 m², p = 0.005) and increased HbA1c (6.5 ± 1.2 vs. 6.1 ± 0.9%, p = 0.016). GDF-15 (1,311 ± 981 vs. 1,034 ± 1,282 pg/mL, p = 0.01) and pentraxin-3 (3,431 ± 1,025 vs. 2,711 ± 1,409 pg/mL, p = 0.0001), markers of fibrosis, and n-acyl-SDMA (0.74 ± 0.21 vs. 0.69 ± 0.35 µmol/L, p = 0.015) as a signifier of endothelial dysfunction were significantly increased in patients with TAPSE < 20 mm. The remaining biomarkers did not differ significantly. Additionally, binary regression analysis showed that HbA1c was an independent predictor for TAPSE< 20 mm.

Conclusions: Our preliminary results show that biomarkers for endothelial dysfunction (n-acyl-SDMA) and fibrosis (pentraxin-3, GDF-15) are increased in patients with TAPSE< 20mm in coronary heart disease and in the absence of pulmonary hypertension. Increased HbA1c values could reflect recent findings that endothelial activation and impaired endothelial vasodilatation may predict new-onset type 2 diabetes and atherosclerotic progression. Furthermore, HbA1c appears to be an independent predictor of right heart dysfunction and may contribute to the complex interplay of endothelial dysfunction and heart failure.