PURPOSE: Vasorelaxation of pulmonary resistance vessels by a NO mediated accumulation of cGMP in the vascular smooth muscle cells is one of the main treatment principles of pulmonary hypertension (PH). The NO and VEGF pathway can be counteracted by the binding of thrombospondin-1 (TSP-1) to its receptors CD47 and CD36. TSP-1 is synthesized from both smooth muscle cells and endothelial cells under conditions of hypoxia or pathologically increased shearstress as found in PH. We examined the clinical relevance of TSP in patients with PH as a new pathophysiological concept and biomarker.
METHODS: After informed consent, blood was drawn in 62 patients with pulmonary hypertension, 15 of these patients underwent right heart catheterization with vasoreactivity testing for diagnostic reasons. Thrombocytes were stabilized by using CTAD tubes and then eliminated by centrifugation. We processed and measured levels of TSP-1, PDGF-BB and big-endothelin by ELISA according to vendor instructions. Twenty-one healthy subjects served as control.
RESULTS: Patients with pulmonary arterial hypertension (n=50) or chronic thromboembolic pulmonary hypertension (n=5) showed a significant elevation of TSP-1 (491±133 resp. 416±119ng/ml), PDGF-ββ (809±166 vs. 652±326pg/ml) and big-Endothelin (4.45±0.69 vs. 2.56±1.80pg/ml) as compared to the control group (n=21, TSP-1: 113±22ng/ml, PDGF-ββ: 279±107pg/ml, big-Endothelin: 1.35±0.37pg/ml). Patient with a PH related to COPD (n=5) showed a normal TSP-1 level (212±54ng/ml). Although the control group was slightly younger, there was no correlation of age and TSP-level. Furthermore, a trend of decreased circulating TSP was observed after ilomedin testing. No relationship between TSP-1 levels and hemodynamic parameters could be found.
CONCLUSION: This data suggest that pathological shearstress and chronic hypoxia lead to an induction of TSP-1 in pulmonary hypertension. While previous biomarkers focus on endothelial function or myocardial strain, we examined TSP-1 as a biomarker of shearstress for the first time.
CLINICAL IMPLICATIONS: Binding of TSP-1 to its receptor CD47 could interfere with therapies using the cGMP or PKG pathways. The predictive value of TSP-1 in pulmonary hypertension remains to be elucidated.
DISCLOSURE: Ralf Kaiser, No Financial Disclosure Information; No Product/Research Disclosure Information