New insights into the risk factors for coronary calcifications

Abstract

The arterial calcification process was recognized as soon as 1812 to be a common feature of atherosclerosis [1]. The common belief is that calcification results from the passive deposit of calcium in vascular tissues. This view is not correct. By contrast, many lines of evidence demonstrate that calcification is an active and regulated process involving a change of phenotype of vascular smooth muscle cells into osteoblast-like cell, leading to focal ossification points. This phenomenon may be associated with atherosclerotic plaques and has a focal intimal expression, or it may be a systemic, generalized process, interesting the media, corresponding to the classical Monckeberg disease. It remains to be discussed whether the intimal and medial calcifications share the same pathophysiology [2]. The presence of calcification has been used as a screening tool for early detection of atherosclerosis. Non-invasive (albeit implying exposure to radiation) techniques are available for detection of large artery calcifications. Standard X-rays of the abdomen may detect aortic calcifications in a specific, but not sensitive way. Despite that, the presence of aortic calcifications is associated with excess mortality in the general population [3], and in patients with end-stage renal disease [4]. London [4] has also clearly shown that, in addition to being a prognostic marker of all-cause and cardiovascular mortality in haemodialysis patients, independently of classical atherogenic factors, the principal effect of arterial medial calcifications on arterial function is increased arterial stiffness. More quantitative techniques have been developed to assess calcification. Coronary calcifications may be detected by electron beam computed tomography. This technique has been widely tested in epidemiological studies, and was proven to have an independent prognostic value for cardiovascular disease [5]. This screening tool has proven to be useful, especially when the cardiovascular risk is medium to high. Calcifications are often detected during coronary angiography. In the current issue of the Journal, Mayer et al.[6] took advantage of a cohort of patients with coronary heart disease, in whom coronary angiography was clinically indicated, to assess the risk factors for coronary calcifications. They show that age, systolic blood pressure and family history are positively correlated with coronary calcifications. On the other hand, coronary calcifications are positively correlated with the extent and severity of coronary artery disease. The demonstration that systolic blood pressure is a risk factor or an expression of coronary calcifications was not totally unexpected. Indeed, arterial calcification was shown to be associated with large artery stiffness [7], the major determinant of systolic hypertension and pulse pressure. Unfortunately, because of the multicentric character of their study, Mayer et al.[6] could not record the central pressures measured during coronary angiography. It is likely that central pressure would have been even more closely correlated with coronary calcification than brachial pressure. The study by Mayer et al.[6] also raises questions about the role of drugs in the development and/or prevention of calcification. Indeed, several of the identified risk factors for coronary calcifications, such as age and family history, are not modifiable. However, the fact that systolic blood pressure has been found to be a potent risk factor for coronary calcification is important. We know that systolic blood pressure is under-controlled, and targeting treatment on either systolic blood pressure or preferably central systolic blood pressure may better prevent calcification of the coronary arteries over the long term. Recently, London et al. showed that nutritional vitamin D deficiency in patients with end-stage renal disease had a profound effect on large artery stiffness and endothelial function [8]. Among the drugs involved in vascular calcification, vitamin K antagonists play a central role. Warfarin inhibits the synthesis of GLA residues, which in turn have an inhibitory effect on two key enzymes for calcification of the extracellular matrix, the matrix GLA protein and osteocalcin. Murine models treated with warfarin [8] or invalidated for matrix GLA protein [9] or GLA [10] show extensive vascular calcifications. Unfortunately, the study by Mayer et al.[6] does not provide information about warfarin therapy or vitamin D status in their patients. The study by Mayer et al.[6] raises the important issue of risk markers among patients with coronary stenosis. The number, extent and degree of stenosis, together with left ventricular dysfunction, are essential risk factors for secondary cardiovascular mortality, but they represent only one part of the story. Indeed, patients with diffuse coronary heart disease are at an even higher risk than patients with focal stenosis. In this context, the presence of calcification may represent a useful marker of risk, either related to the procedure (stenting complications, restenosis), or consisting of the recurrence of coronary heart disease or other cardiovascular disease. This excellently-phenotyped cohort may represent a unique opportunity to address this important question. This would allow application to an ‘orphan’ screening test.