Serum markers of cardiac complications in a systemic sclerosis cohort

Abstract

Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21-0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52-7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08-3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11-2.50, p = 0.014, OR 1.86, 95% CI 1.25-2.77, p = 0.002, OR 0.32, 95% CI 0.15-0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22-2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.

Figure 1

Heat map on circulating serum markers in SSc, diffuse SSc subset and SSc specific autoantibodies (Color print necessary). Mean serum marker values of the SSc group compared to healthy controls and reported as color ratios. Subsets are compared within the SSc cohort; dcSSc is compared to lcSSc, while ACA and ATA positive subsets are compared to ACA and ATA negative subsets, respectively. Colors reflect upregulated serum marker ratios, white squares indicate downregulation, and black squares indicate no significant alteration. ACA anti-centromere antibodies, ATA anti-topoisomerase-I antibodies, CCL C–C motif ligand, CD cluster of differentiation, CXCL C-X-C motif ligand, dcSSc diffuse cutaneous systemic sclerosis, DKK1 Dickkopf-related protein 1, HGF hepatocyte growth factor, IL interleukin, PLGF placental growth factor, SSc systemic sclerosis, TRAIL tumor necrosis factor-related apoptosis-inducing ligand, TSLP thymic stromal lymphopoietin, VEGF vascular endothelial growth factor.

Figure 2

Flow chart on cardiac function and vital status of the SSc cohort. GLS global longitudinal strain, LV left ventricular, RV right ventricular, SSc systemic sclerosis, TAPSE tricuspid annular plane systolic excursion.