Coronary artery calcification (CAC) is associated with the incidence of congestive heart failure. We evaluated the association between CAC and left ventricular diastolic dysfunction (LVDD) in elderly patients without coronary artery disease. Coronary computed tomography was performed in 1,021 consecutive patients >55 years of age who were suspected of having coronary artery disease. A total of 530 patients (age, 70 ± 8 years; 56 % men) with a LV ejection fraction >50 % and without obstructive coronary artery disease and a history of coronary artery disease were included in the analysis. LVDD was defined according to a standard algorithm by echocardiography (septal e' <8, lateral e' <10, and left atrial volume index ≥34 mL/m(2)). A total of 224 of 530 patients had LVDD. CAC scores in patients with LVDD were higher than those in patients without LVDD (p < 0.01). The prevalence of LVDD in patients with CAC scores ≥400 was greater than that in patients with CAC scores of 0-9 (58 vs. 34 %, p < 0.01). After adjustment for confounding factors, the CAC score was associated with LVDD, with an odds ratio of 1.96 (95 % confidence interval: 1.11-3.43, p = 0.02) for a CAC score ≥400 compared with a CAC score of 0-9. A CAC score ≥400 was associated with LVDD in elderly patients without CAD in this population. Further prospective studies are needed to evaluate the clinical relevance of CAC as a risk of heart failure with preserved ejection fraction.
We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.
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