Abstract
Background Anthracycline-based cancer chemotherapy (ACC) has been related to myocardial interstitial fibrosis (MIF), a lesion contributing to left ventricular dysfunction (LVD). We investigated whether biomarker-assessed MIF was associated with LVD in patients with breast cancer receiving ACC and in patients with ACC-induced heart failure (ACC-HF). Moreover, chemotherapy agent’s pro-fibrotic activity was evaluated in human cardiac fibroblasts (HCFs). Methods Echocardiography, serum biomarkers of collagen deposition (procollagen type-I C-terminal-propeptide [PICP]) and crosslinking (collagen type-I C-terminal-telopeptide/matrix metalloproteinase-1 ratio), and biomarkers of myocardial and vascular stress (galectin-3, sST2, amino-terminal pro-brain natriuretic peptide [NT-proBNP], hs-troponin-T and vascular cell adhesion molecule-1 [VCAM-1]) were assessed in 70 breast cancer patients at baseline, and during ACC at 3 and 6 months. Subclinical cardiotoxicity was defined as a global longitudinal strain (GLS) relative reduction>15%. In addition, PICP and NT-proBNP were determined in 347 patients with different HF etiologies, 37 with ACC-HF of whom 33 had 12-month-follow-up LVEF assessment. HCF activation was examined after incubation with chemotherapy agents for 24 hours. Results In breast cancer patients, six-months-ACC reduced GLS and upregulated PICP, hs-troponin-T, NT-proBNP and VCAM-1 (P<0.01) versus baseline. At 6 months, elevation of PICP was higher in patients with subclinical cardiotoxicity versus the remaining patients (P for interaction<0.001). PICP levels were directly associated with a relative reduction in GLS (P<0.001). In ACC-HF patients, baseline LVEF was inversely associated with PICP and NT-proBNP (P<0.01). After 12 months, LVEF did not change in patients with higher basal PICP (3rd tertile) but improved in the remaining patients (P<0.001). Doxorubicin, cyclophosphamide and trastuzumab stimulated collagen synthesis in HCFs, including PICP extracellular cleavage. Conclusion These results indicate that increased levels of PICP, a biomarker related to MIF, are associated with early LVD in ACC-treated patients with breast cancer and with established LVD in ACC-HF patients, hindering LV functional improvement after 12 months. Chemotherapy can directly activate collagen metabolism and increase PICP extracellular presence in HCFs. Therefore, PICP emerges as a promising biomarker of ACC-induced cardiotoxicity.
Increased Serum Procollagen type I C-terminal Propeptide Levels are Associated with Left Ventricular Dysfunction in Patients Treated with Anthracycline-based Cancer Chemotherapy