A pilot observational study on magnesium and calcium imbalance in elderly patients with acute aortic dissection

Magnesium (Mg) and calcium (Ca) are involved in the most essential processes regulating cardiovascular function and their imbalance is a factor in the development of numerous disorders of the cardiovascular system, mostly linked to endothelial dysfunction and inflammation, mainly affecting vascular smooth muscle cells (VSMCs) [1]. In humans and animals extracellular Mg has cardioprotective properties because it attenuates all the agonist-induced vasoconstriction molecules, including endothelin-1 (EN-1), helping preserve vascular tone and preventing coronary vasospasm [1‐5]. These cardioprotective effects are reinforced by the fact that Mg assists the coagulation reactions, binding specific coagulation proteins in case of endothelial damage [6].

In the cardiovascular system, one of the main mechanisms that regulates VSMC activity during pressure load is the Ca channel block mediated by Mg [7‐14]. This implies that Mg depletion is associated with a high risk of cardiovascular disease (CVD) [2] but little is known about the Mg/Ca concentrations in acute aortic dissection (AAD), a dramatic cardiovascular disorder that is often fatal because of late diagnosis [15]. The etiology of AAD involves either genetic disorders affecting connective tissue, such as Marfan syndrome, or is a consequence of primary disorders, generally called non-Marfan AAD, both of which involve aortic stiffening, reduced coronary vessel flow, increased pulse pressure and left ventricular dysfunction [1, 15, 16].

Aging is one of the main risk factors leading to AAD: these include atherosclerosis, hypertension and calcification of the endothelial tunica [17‐19]. In particular, patients younger than 65 years old with AAD, undergoing coronary bypass surgery, showed active formation of calcification in atherosclerotic plaques [16, 18, 19].

A discrete and temporary intracellular Ca increase, due to Na/K pump inhibition or blocking a natural Ca antagonist like Mg, may alter cell contraction and transcription and cause cell death [20]. This pathophysiological effect may evolve, at endothelial level, in pro-inflammatory mechanisms characteristic of AAD, including the release of pro-inflammatory mediators, pro-coagulant and endothelial factors from damaged vascular cells [1, 21, 22].

Our aim was to record total circulating Mg and Ca levels in AAD, looking for their possible implication in the severity of the disorder, which is also characterized by the release of mediators involved in endothelial dysfunction, including endothelial, pro-inflammatory and pro-coagulant factors.

Circulating Mg and Ca levels were significantly lower in AAD patients than in the control group (p < 0.0001) (Fig. 1a–b) but no significant correlation was found between the two parameters (data not shown). Using a clinical cut-off for Ca of 8.4–10.2 mg/dL, 90% of AAD patients with low total Ca (<8.4 mg/dL) were classified as type A (Fig. 1c). Dividing the patients using the 8.4 mg/dL Ca cut-off, total circulating Mg was significantly lower in patients with low total calcium (p < 0.01) (Fig. 1d).

Compared to controls, types A and B AAD patients all had higher levels of all pro-coagulant mediators including CFIII, s-Psel, and D-dimer (p < 0.0001 for all) (Fig. 2). Human TNF-α, IL-6, and CRP, as pro-inflammatory mediators, were higher in the overall AAD group than controls (p < 0.05, p < 0.05 and p < 0.0001 respectively) (Fig. 2). Dividing type A and B using the Stanford classification, no significant differences were seen in either group.

The endothelial mediators analyzed, including ICAM-1 and EN-1, were lower in AAD patients than controls (p < 0.0001 and p < 0.05 respectively) (Fig. 2). No significant differences were found between type A and B patients (p > 0.05).

No significant correlations were found between Mg and Ca circulating levels and the levels of any of the pro-inflammatory, pro-coagulator and endothelial parameters (data not shown).

This study focusing on AAD found low total magnesemia and calcemia. Mg total circulating levels were markedly lower in AAD patients than controls (Fig. 1a) and the pattern was similar for total Ca (Fig. 1b). Because Mg is the natural antagonist of Ca and both these elements have a primary role in VSM tone [14], we also compared the Mg concentration with total Ca. On stratifying AAD patients on the basis of the lower total Ca cut-off (clinically established as less than 8.4 mg/dL), 90% were type A, which is recognized as having a worse prognosis and higher risk of death than type B (Fig. 1c) [17]. These outcomes suggest that in AAD patients the extracellular Mg deficiency, known as an indicator of severe intracellular Mg depletion, directly influences total Ca. Therefore we assume that the lower extracellular Mg levels in AAD patients were too low to balance Ca entry into the cells, resulting in a total circulating Ca deficiency.

On the basis of this preliminary data we can only suggest that during the acute phase of AAD, within 24 h, the molecular mechanism may be driven by Mg/Ca deficiency promoting an imbalance among the concentrations of several mediators involved in inflammation and vasoconstriction of the endothelium. We therefore measured the circulating levels of the main pro-inflammatory mediators that can be directly affected by Mg/Ca and by endothelial dysfunction, including TNF-α, IL-6 and CRP [25‐27]: they were all substantially higher in AAD patients than controls. The systemic inflammation highlighted in AAD patients was also associated with an imbalance of pro-coagulant and vasoconstrictor factors including D-dimer, CFIII, s-Psel and EN-1, which are deregulated compared to controls, although we found no real differences between type A and B patients. Our findings with ICAM-1 agree with previous studies [28, 29], which reported that during the early phase of AAD deregulation of the production of soluble and intracellular forms of adhesion molecule could result in lower levels of the intracellular form, such as ICAM-1, to compensate the release of circulating mediators, as illustrated in Fig. 2.

The main limitation of this study is the small number of patients and further investigations are obviously needed to increase the power of our results.

Our findings suggest that hypomagnesemia may be one of the principal causes of AAD onset and development, which can result in different sub-events related to Mg depletion including first of all hypocalcemia and subsequently hypertension, then inflammation and vasoconstriction of the endothelium. Therefore it is plausible that besides the systemic Ca level intra-cellular calcium may increase too in AAD patients during Mg depletion, but this assumption needs to be verified by future analysis to better understand the pathophysiology of AAD and its direct relationship with Mg depletion.