Breast Arterial Calcifications and Heart Disease Risk in women

Imaging of vascular calcification is increasingly used for cardiovascular screening purposes in asymptomatic patients. Coronary and aortic calcium deposits in the vascular wall have been shown to be related to atherosclerotic plaque burden. New imaging techniques with electron beam computed tomography (EBCT) and multi-slice computed tomography (MSCT), to measure the calcium content in the coronary arteries, are promising methods for clinical risk assessment. However, the rising costs of these emerging cardiac imaging techniques and the radiation exposure involved demand a more critical evaluation of already existing and less expensive technology. In this thesis we have investigated whether arterial calcifications that are frequently seen on mammograms may serve as a screening tool for atherosclerotic risk assessment in women. The simultaneous use of mammograms for screening on breast cancer and atherosclerotic disease could be very cost-effective. Based on our findings in two different populations of women we can now conclude that the major determinants of medial calcification in the breast arteries are age, diabetes, previous pregnancies and lactation after pregnancy. The mechanisms of BAC are comparable to the medial calcification that is seen in the peripheral vessels of diabetics and in patients with end stage renal disease (ESRD). In diabetics, hyperglycaemia is an important determinant for medial sclerosis and not the classic CHD risk factors. High glucose can induce proliferation of VSMC into calcifying cells, but other metabolic stimuli in patients with diabetes, like hyperinsulinemia and glycoxidation products, can also promote the calcifying process. In patients with ESRD the uptake of calcium by VSMC is multifactorial and enhanced by elevated extracellular calcium- and phosphate levels, secondary hyperparathyreoidism and uremic toxins. The wide-spread use of calcium containing oral phosphate binders, to prevent uremic dystrophy, further promote the calcifying process. The alterated mineral metabolism during pregnancy and lactation is presumably the most important causative factor in the occurrence of BAC. Pregnancy is associated with major changes in the calcium metabolism to meet the high requirements for foetal growth and for breast-milk production. Some biochemical proteins of bone resorption and formation (e.g. osteocalcin, bone morphogenic protein) are elevated in the first months of lactation and are also found in calcified vascular tissues. We assume that when calcium is more available in the (breast) circulation, like during pregnancy and lactation, vascular smooth muscle cells can become activated and promote mineralization. Another common factor in the enhancement of vascular calcification in pregnant women and patients with ESRD may be caused by elevated levels of parathyroid hormone-related protein (PTHrP). PTHrP is expressed in a variety of bone and vascular tissues and causes hypercalcaemia. The production of PTHrP by the lactating mammary gland may be an explanation for the association of BAC with breastfeeding