Systemic inflammation as a driver of vascular calcification: a proof of concept

Vascular calcification is increasingly recognized as a clinically important manifestation of atherosclerosis with unfavourable prognosis. The presence of vascular calcification may be associated with a substantial increase of adverse events such as sudden death, myocardial infarction, stroke, gangrene and even total mortality [1, 2]. Deposition of calcium occurs in arteries of different calibres and may be disease specific. Coronary artery calcification has attracted the closest attention and is predictive of future coronary events [2–5]. In one multicenter study of 491 patients, for example, the presence of calcium deposits in coronary arteries attributed to a dramatic 10-fold increase of risk of coronary events [Odds ratio 10.8 (95% CI 1.4–85.6)] during the 30-month follow-up, whilst even atherosclerotic plaque burden and coronary stenosis severity failed to show a higher predictive power [2]. Kennedy et al. have also demonstrated that coronary calcification was a strong independent predictor of future cardiovascular complications [3]. In another study, high coronary calcification scores were 13.2 times more likely to suffer a cardiac event than those with low or zero scores, on a multivariate analysis [5]. Of note, vascular calcification is not an uncommon phenomenon. Analysis of computed tomography data reveals that at least one-third of Americans over age 45 have arterial calcification [6]. Risk factors for the development of coronary calcification (e.g. hypertension, lipid abnormalities, diabetes and obesity) appear to be similar to those for classical occlusive atherosclerosis [6, 7]. Indeed, the sensitivity of coronary calcification as a marker of coronary atherosclerosis has been acknowledged in guidelines of the American Heart Association and American College of Cardiology. The detection of coronary calcium has even been suggested as an approach to identify asymptomatic patients at low to intermediate risk who may benefit from more aggressive risk factor management [8]. Whilst most studies have addressed the risks associated with coronary atherosclerosis, less attention has been directed to arterial calcification in noncoronary areas, and similar association with adverse cardiovascular events could well be present [9]. In this issue of the Journal of Internal Medicine, Wang et al. highlight that pathological vascular calcification may even be a systemic phenomenon with tendency of diffuse arterial calcification in different arteries (especially in older patients) [10]. For a long time, vascular calcification was considered a passive, mainly age-related degenerative process but it is increasingly recognized that this is a complexly regulated process involving phenotypic transformation in the arterial wall. Also, all the pathways triggering pathological calcification appear to be inflammation-related and the degree of coronary calcification closely correlates with local vascular inflammation [11]. Exposing to high levels of autoantibodies and inflammatory cytokines [for example, as seen in rheumatoid arthritis (RA)] vascular cellular characteristics significantly change, associated with substantial biological modifications ranging from genetic alterations to a metamorphosis of both resident (within the vascular wall) and circulation-derived cells. Indeed, the expression of bone-related genes in atherosclerotic lesions was described over two decades ago [12]. Vascular smooth muscle cells in the areas of calcification may change their phenotype and acquire some osteogenic or chondrogenic markers (such as transcription factors Cbfa1, Msx2, and Sox9) and further differentiate into osteoblast-like cells [13, 14]. In vitro studies also confirm that vascular smooth muscle cells include populations of so-called ‘calcifying vascular cells’ that are able to undergo calcification, although the in vivo origin of osteoblastic cells still remains uncertain [15]. In addition to arterial wall resident cells, circulating inflammatory cells, monocytes and their tissue descendants – the macrophages – are critical for promoting local inflammation and calcification. Macrophages enhance calcification through the release of tumour necrosis factor-α (TNF-α) and accumulate in the artery, and basic calcium phosphate (BCP) particles being internalized by macrophages further increase their inflammatory cytokine-generating capacity [16, 17]. Also, internalization of BCP crystals into vacuoles of human monocyte-derived macrophages trigger the secretion of TNF-α, interleukin (IL)-1 and IL-8 [16]. Importantly, this serial in vivo study confirms a real-time association of macrophage ‘burden’ with vascular osteogenic activity [18]. Of note, bone osteoclasts originate from the monocytic line of hematopoietic cells, and macrophages activated by chronic inflammation and the expose to BCP may undergo osteoclastic differentiation in the vascular wall. Thus, the monocytes and macrophages which are abundant in atherosclerotic lesions may serve as a rich source of preosteoclasts. Additionally, the transformation of monocytes into osteoclasts is a cytokine-dependant process with two major factors involved – macrophage colony-stimulating factor and the ligand for receptor activator of NF-kappaB) – both of which are present in atherosclerotic plaques [19]. Rheumatoid arthritis is a chronic inflammatory disorder that affects about 1% of the population of developed countries, and is associated with an increased mortality which is largely attributable to cardiovascular events [20]. Additionally, RA patients have significantly higher risk of myocardial infarction (nearly three-fold) and more than five-fold higher probability to have unrecognized myocardial infarction. The risk of sudden death in RA is also markedly increased (nearly two-fold) [21]. The pathophysiological substrate for vascular morbidity in RA appears different from that seen in non-RA patients. Despite the higher risk of RA-associated complications, the extent of coronary artery stenosis and the number of acute lesions are similar in patient with or without RA [22]. However, a characteristic feature of RA lesions is the presence of active inflammation, which has been related to the high risk of vascular events in rheumatoid disease [20]. Given the relationship between inflammation and vascular calcification, this may provide a plausible link between RA and the increase cardiovascular risk seen in this condition. Indeed, high levels of chemokines mediating mobilization of inflammatory cells in the arterial wall such as monocyte chemoattractant protein (MCP-1) and fractalkine is a common feature of RA and these levels are associated with inflammatory disease activity [23, 24]. On the other hand, MCP-1 and fractalkine may also be involved in atherosclerosis and monocyte recruitment within the atherosclerotic plaque per se. Whilst the role of inflammation in cardiovascular disease [for example, represented by increased levels of C-reactive protein (CRP)] is now commonly recognized, levels of this inflammatory mediator is very high in those suffering active RA [25]. A chronic increase in CRP levels activates immune cells, triggers secretion of the wide range of other inflammatory molecules and accelerates the progression of atherosclerosis [25]. Circulating amounts of CRP also correlate with coronary calcification score in subjects free of clinically apparent cardiovascular disease, even after adjustment for age and Framingham risk score [26]. In their paper, Wang et al. confirm this, by providing evidence of a significant association of total arterial calcium score with plasma CRP levels amongst their patients with RA [10]. High concentrations of another inflammatory cytokine, TNF-α, is a hallmark of RA and the role of TNF-α in RA pathogenesis is further confirmed by therapeutic success of anti-TNF-α treatments [27]. Moreover, TNF-α promotes osteogenic differentiation and calcification of vascular cells [28]. In response to TNF, peroxides and shear stress, the endothelial cell also produces aortic bone morphogenetic protein-2 and -4 [29]. Additionally, arteries from patients with medial calcification have increased expression of another member of TNF family involved in regulation of osteogenesis, that is, osteoprotegrin [30]. However, the effects of anti-TNF-α treatment on vascular calcification, as well as the risk of acute cardiovascular events have not been addressed by existing studies and the potential cardiovascular benefits of this approach are still to be investigated. Nonetheless, increasing disease severity of RA has been associated with a higher prevalence and extent of coronary calcification; however, the higher prevalence of coronary calcification in RA patients was attenuated after adjustment for IL-6 levels [31]. The study by Wang et al. also provide additional justification that chronic inflammation is a crucial factor of vascular calcification given the high odds ratio (19.5) for the developing aorta calcification, when compared to RA-free controls [10]. The work by Wang et al illustrates that we also need to look for calcification in other parts of the arterial tree, and not just the coronary arteries per se. The link between local plaque inflammation and calcification has not been confirmed in all carotid artery studies and fibrous cap inflammation is more likely to occur in noncalcified than in calcified carotid plaques [32]. Also, drugs may potentially poise additional confounders, given that statins prevent the progression of aortic valve calcification but we still have scarce information on statins for the possible management of vascular calcification. Further studies are clearly needed to test whether the reduction of inflammatory burden would ‘switch off’ ostegenic transformation in the vascular wall. Time will tell. No conflict of interest was declared.