Prevalence and location of coronary artery disease in anomalous aortic origin of coronary arteries.

BACKGROUND: The prevalence and location of coronary artery disease (CAD) in anomalous aortic origin of a coronary artery (AAOCA) remain poorly documented in adults. We sought to assess the presence of CAD in proximal (or ectopic) and distal (or nonectopic) segments of AAOCA. We hypothesized that the representation of CAD may differ among the different courses of AAOCA. METHODS: The presence of CAD was analyzed on coronary angiography and/or coronary computed tomography angiography in 390 patients (median age 64 years; 73% male) with AAOCA included in the anomalous coronary arteries multicentric registry. RESULTS: AAOCA mainly involved circumflex artery (54.4%) and right coronary artery (RCA) (31.3%). All circumflex arteries had a retroaortic course; RCA mostly an interarterial course (98.4%). No CAD was found in the proximal segment of interarterial AAOCA, whereas 43.8% of retroaortic AAOCA, 28% of prepulmonic AAOCA and 20.8% subpulmonic AAOCA had CAD in their proximal segments (P < 0.001). CAD was more prevalent in proximal than in distal segments of retroaortic AAOCA (OR: 3.1, 95% CI: 1.8-5.4, P < 0.001). On multivariate analysis, a retroaortic course was associated with an increased prevalence of CAD in the proximal segment (adjusted OR 3.4, 95% CI: 1.3-10.7, P = 0.022). CONCLUSION: Increased prevalence of CAD was found in the proximal segment of retroaortic AAOCA compared to the proximal segments of other AAOCA, whereas no CAD was observed in the proximal segment of interarterial AAOCA. The mechanisms underlying these differences are not yet clearly identified.

Cathepsin D stimulates the activities of secreted plasminogen activators in the breast cancer acidic environment.

Two proteases cathepsin D (cath D) and urokinase plasminogen activator (uPA) are tissue markers associated with an increased risk of metastasis in breast cancer. We investigated whether cath D, the major aspartyl protease overexpressed by breast cancer cells can trigger a proteolytic cascade via activation of plasminogens at the extracellular pH measured in hypoxic tumors. The effects of the aspartyl protease inhibitor pepstatin on the plasminogen activator (PA) system were analysed by conditioning media of human MDA-MB231 breast cancer cells at pH 6.6 and pH 7.4. Zymography analysis of culture media showed that pepstatin inhibited the secreted activity of tissue-type plasminogen activator (tPA) but not that of uPA. tPA was identified on the basis of the molecular weight, the immunoreactivity with relevant antibodies and the resistance to amiloride, a specific uPA inhibitor. The secreted tPA activity measured by a chromogenic assay in the presence of amiloride was also inhibited by pepstatin at pH 6.6. Surprisingly, pepstatin did not affect secreted tPA protein concentration but markedly increased the amount of the secreted plasminogen activator inhibitor-1 (PAI-1). We conclude that cath D overexpressed by these cells, stimulates at pH 6.6, but not at neutral pH, the extracellular PA proteolytic activity indirectly via PAI-1 proteolysis. This suggests that cath D at acidic pH close to the hypoxic regions of solid tumors, contributes to trigger a proteolytic cascade facilitating cancer cell invasion and metastasis.