Association between serum calcium,serum phosphate and aortic stenosis with implications for prevention

Aortic stenosis (AS) is a potentially fatal condition that is commonly recognised as an increasing public health burden. There are no medical therapies able to stop or delay disease progression, and the gold standard for the treatment of severe and symptomatic AS is aortic valve replacement or, recently, transcatheter aortic valve implantation.

There is a growing body of evidence that the development of AS is part of a highly complex and regulated process, ¹ that recognises two distinct phases. The early ‘atherosclerotic’ phase is characterised by lipid deposition and inflammation, and a late phase is characterised by the action of procalcific and pro-osteogenic factors causing disease progression. ²

The ‘atherosclerotic’ pattern typical of the early stage of AS persuaded the researchers that statins might be beneficial in those patients, particularly after the encouraging results of non-randomised studies ³ showing that the conversion of valvular interstitial cells to an osteoblastic phenotype was inhibited by atorvastatin. ⁴ However, these results have not been confirmed by independent randomised controlled trials. ⁵ The later stages of AS are characterised by a self-powered cycle of calcium formation and valvular injury, ² characterised by the initial deposition of collagen matrix, which takes the role of a scaffold promoting progressive calcification, mediated by reduced nitric oxide expression following endothelial injury, ⁶ and the role of the renin–angiotensin system. ⁷

In its most severe form, calcified AS presents with advanced osteogenic metaplasia with osteoblast-like cells, chondrocytes, as well as bone marrow. ⁸ Galli et al. ⁹ demontrated that valves affected by AS cusps showed structural remodeling in severe fibrosis, calcific nodules, neoangiogenesis, inflammation, bone metaplasia with or without haematopoiesis, adipose metaplasia and cartilaginous metaplasia. The authors found that all the tested metalloproteinases and cytokines were expressed in aortic cusps. Inflammation mainly consisted of B and T lymphocytes and plasma cells. Moreover, they found that cultured mesenchymal cusp stem cells could differentiate into osteoblasts/adipocytes, and concluded that aortic valve changes were mostly different from typical atherosclerosis. ⁹ Finally, it was demonstrated that osteopontin, osteoprotegerin and osteocalcin, factors responsible for bone formation, are active in the aortic valve in patients who develop calcified AS. ¹⁰

In a previous issue of European Journal of Preventive Cardiology, Wald and Bestwick ¹¹ have presented an interesting paper showing that the serum levels of calcium, but not phosphate, are altered in subjects affected by AS compared to healthy control subjects. This case–control study was conducted on 132 individuals (63 with aortic stenosis and 69 without) and the results were combined with three other comparable studies (914 individuals overall). The relationship between calcium and phosphate and the severity of AS, according to peak transaortic velocity (V_max), was also examined in the case–control study using linear regression. The authors adjusted the analysis taking into account risk factors, including a history of coronary artery disease, renal failure and medication use that may potentially influence serum calcium or phosphate levels. Both calcium and phosphate were positively associated with AS. The authors concluded that, if the associations are causal and reversible, a small reduction in calcium or phosphate levels, within the physiological range, would translate into a clinically significant reduction in the risk of AS.

The results of the paper published in this issue are consistent with previous reports, ¹² although a very recently published meta-analysis of several randomised trials and observational studies concluded that no consistent dose–response relationship between total, dietary or supplemental calcium intake levels and cardiovascular mortality has been demonstrated. ¹³ Thus, the conflicting research results do not at present allow the recommendation of this therapy to every patient affected by AS. However, the results reported by Wald and Bestwick ¹¹ in the meantime provide new insight into the research on the role of calcium metabolism in AS, while we wait for the results of the ongoing SALTIRE 2 trial ¹⁴ and the Prevention of Aortic Stenosis Pilot trial. ¹⁵

The scientific community of cardiologists and cardiac surgeons is well aware of the ‘clinical’ importance of calcification in AS in the prediction of disease progression and in its repercussions on adverse and suboptimal cardiovascular outcomes, also after aortic valve replacement or implantation. In fact, in a study published by Kalique et al., ¹⁶ the quantity and location of aortic valve calcifications were significantly related to the severity and location of paravalvular regurgitation and the need for post-dilation after balloon-expandable transcatheter aortic valve replacement.

Hopefully, the paper by Wald and Bestwick ¹¹ will stimulate researchers to conduct randomised controlled trials in the near future, in order to confirm further the validity of this therapeutic approach.