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Patients with vascular calcifications are at increased risk of cardiovascular events: implications for risk factor management and further research

2007; Wiley; Volume: 261; Issue: 3 Linguagem: Inglês

10.1111/j.1365-2796.2007.01768.x

1365-2796

Carlos Iribarren,

Cerebrovascular and Carotid Artery Diseases

Mrs Smith is a 67-year-old, mildly obese, Caucasian woman who was referred for X-rays to investigate recent episodes of intense, intermittent, pain in the lower back. She reported no smoking history and that her father died of a heart attack at the age of 64. The radiographs showed generalized osteoporosis and arthritic changes in the lumbar spine, plus extensive calcifications of the abdominal aorta. Hoping to achieve an LDL cholesterol <3.37 mmol L−1 (<130 mg dL−1), her primary care physician had advised a fat-restricted diet and weight reduction. On her best efforts, recent lipid panel results were as follows: total cholesterol = 5.39 mmol L−1 (208 mg dL−1), LDL = 3.49 mmol L−1 (135 mg dL−1), HDL = 1.11 mmol L−1 (43 mg dL−1) and triglycerides = 1.24 mmol L−1 (110 mg dL−1). Her blood pressure and fasting glucose levels were within the normal range. Should the aortic calcification lead the physician to treat with a statin to aim for a target LDL below 2.59 mmol dL−1 (100 mg dL−1)? In the judgement of this commentator, the answer is 'yes'. The study by Rodondi et al. in this issue of The Journal of Internal Medicine adds to the existing evidence that aortic calcifications are helpful in predicting cardiovascular mortality in older women [1] and thus supports more aggressive management of patients with known vascular calcifications who are otherwise in a moderate risk category. Imaging techniques including X-ray, ultrasound, computer tomography (CT), magnetic resonance imaging (MRI) or dual-energy X-ray absorptiometry (DXA) often reveal calcifications of the vascular wall. In current medical practice, these calcifications are considered 'incidental findings' and usually ignored, even though there is mounting evidence that the presence of these calcified deposits confers an increased risk of cardiovascular risk independently of traditional risk factors [2–5]. The Rodondi et al. study included 2056 older, postmenopausal women recruited in 1986–1988 in four clinical centres in the USA as part of the Study of Osteoporotic Fractures, who were followed up for 13 years. The authors found associations of abdominal aortic calcification with advancing age and cardiac risk factors and, more importantly, significant age-adjusted associations with cardiovascular, cancer and noncardiovascular noncancer and all-cause mortality. Multivariable adjustment for risk factors resulted in attenuation of the risk estimate for cardiovascular death, which is consistent with the notion that abdominal aortic calcification (as a marker of atherosclerosis) is in the causal pathway between risk factors and fatal cardiovascular outcomes. This study is important because it focuses on the age group where vascular calcifications are more prevalent. In addition, this study sheds light on the question of whether age influences the relation between vascular calcified deposits and cardiovascular risk. Whilst a prior study found that abdominal aortic calcification may be more strongly related to outcomes at an earlier age [2], another report indicated that aortic arch calcification was more strongly related to coronary heart disease amongst men aged 65 and older compared with younger men and that there was no age interaction in women [3]. Vascular calcification, once viewed as irreversible crystallization of calcium and phosphate into plaque, is now thought to be a dynamic process paralleling that of osteogenesis. It involves a complex, highly regulated process including osteoblast differentiation, bone matrix deposition and bone resorption [6]. Vascular calcification tends to occur in small amounts in earlier stages of atherogenesis [7], and is more extensive in advanced lesions [8]. The presence and extent of calcified areas predicts clinical events, presumably because it is a surrogate measure of the atherosclerotic burden. However, it has been argued that, as calcifications progress, plaques coalesce and become more stable, which would lead to decreased risk of acute coronary events [9]. An aspect that has instigated some debate is the distinction between medial and intimal calcification [10]. Whereas medial (also know as Mönckeberg) calcification is seen as fine and diffuse and is associated with ageing and diabetes, intimal calcification appears as discontinuous, punctuated lesions and is associated with inflammation, lipid deposits and thus atherosclerosis. A limitation of conventional radiology is that it is not possible to differentiate between these two modalities of calcification. Questions that remain unanswered and that warrant further research in this area are: Are there subgroups of patients in whom presence of aortic calcifications conveys a particularly high risk? For example, patients with type 2 diabetes [11] and/or renal insufficiency[12, 13] with arterial calcifications seem to be at strikingly higher risk of cardiovascular disease morbidity and mortality. Furthermore, duration of diabetes is likely to be an important determinant of the presence of medial arterial calcifications [14]. Are there differences in the prevalence of aortic calcifications by race/ethnic background additional to cardiac risk factors? A particularly interesting observation that requires confirmation is that African-Americans and Hispanics with type 2 diabetes tend to have reduced burden of both coronary and aortic calcification compared with non-Hispanic whites, not explained by differences in cardiovascular disease prevalence or measured lifestyle or risk factors [15, 16]. What is the importance of location, severity and progression of aortic calcifications? Although promising severity scores have been proposed [5], there is at the moment no widely adopted, reproducible method of scoring severity of aortic calcification; Are patients who present with aortic calcification ideal candidates for coronary calcium screening? Coronary calcium assessment and CT is clearly a much more sensitive technique than conventional radiography, but is more expensive and less available. What is the contribution of genetic polymorphisms in development of vascular calcification? Expression of critical regulators of inflammation and extracellular matrix remodelling in the vascular wall likely contribute to the initiation and progression of human vascular fibrosis and calcification. Genetic variability in proteins associated with inflammation, transforming growth factor-β (TGF-β) signaling and ossification is though to modulate susceptibility to vascular calcification. The vascular matrix undergoes a number of changes during embryonic development. In the adult, maintaining the appropriate balance of matrix components is a dynamic process that is dependent on new matrix synthesis and on matrix degradation by enzymes, particularly by matrix metalloproteases (MMPs). Imbalance in these processes can lead to vascular diseased states including vascular wall weakening and aneurysm development, vascular stiffness, hypertension and arteriosclerosis. What is the effectiveness and safety of specific therapies to reverse vascular calcifications? Although experiments with animals and human cells in vivo with matrix Gla protein, an inhibitor of calcification, are promising [17], no human trials have yet been conducted. What practical clinical recommendations emerge from this new study? First, the discovery of vascular calcifications should trigger an investigation of risk factor levels and subsequent reduction of those found to be elevated. Second, as the hypothetical case of Mrs Smith illustrates, one scenario where vascular calcifications may be particularly useful is when there is moderate elevation of cardiovascular risk. In this circumstance, a more aggressive approach may be appropriate. The author is grateful to Arthur L. Klatsky, MD, for his insightful comments.