The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies

Abstract

Cardiovascular calcification is the ectopic deposition of calcium-phosphate crystals within the arterial wall and the aortic valve leaflets. This pathological process leads to increased vascular stiffness, reduced arterial elasticity, and aortic valve stenosis, increasing the risk of cardiovascular diseases. Although cardiovascular calcification is an increasing health care burden, to date no medical therapies have been approved for treating or preventing it. Considering the current lack of therapeutic strategies and the increasing prevalence of cardiovascular calcification, the investigation of some nutraceuticals to prevent this pathological condition has become prevalent in recent years. Recent preclinical and clinical studies evaluated the potential anti-calcific role of nutraceuticals (including magnesium, zinc, iron, vitamin K, and phytate) in the progression of vascular calcification, providing evidence for their dietary supplementation, especially in high-risk populations. The present review summarizes the current knowledge and latest advances for nutraceuticals with the most relevant preclinical and clinical data, including magnesium, zinc, iron, vitamin K, and phytate. Their supplementation might be recommended as a cost-effective strategy to avoid nutritional deficiency and to prevent or treat cardiovascular calcification. However, the optimal dose of nutraceuticals has not been identified and large interventional trials are warranted to support their protective effects on cardiovascular disease.

Keywords: nutraceuticals; nutrition; vascular calcification.

Figure 1

A simplified schematic representation of the processes under investigation leading to the osteogenic differentiation of VSMCs in vascular calcification. Magnesium (Mg) acts at the extracellular level by preventing the maturation of calciprotein particles (CPPs) and by forming whitlockite crystals with phosphate ions (Pi). At the intracellular level, Mg decreases the expression of osteogenic genes (such as Osterix, Smad1, and Runx2) and inhibits pro-calcific pathways (including Wnt/β-catenin). Zinc (Zn) induces the suppression of NF-κB through the activation of the GPR39/TNFAIP3 signaling pathway. Vitamin K promotes the carboxylation and activation of the matrix Gla protein (MGP), which avoids the formation of hydroxyapatite (HA) crystals and prevents the pro-calcific action of BMP-2. Phytate acts as crystallization inhibitor by binding to HA crystals. The regular arrow denote “activation”, and the T-shaped arrow stands for “inhibition”.

Figure 2

A simplified schematic representation of the processes under investigation leading to the osteogenic differentiation of VICs in vascular calcification. Iron (Fe) acts at the intracellular level via ferritin, which prevents phosphate uptake and inhibits VICs osteogenic differentiation. Moreover, ferritin promotes the production of anti-calcific pyrophosphate (PPi) from ATP by activating the enzyme ENPP2. Zinc (Zn) induces VICs apoptosis through the activation of the GPR39-ERK1/2 signaling pathway. Vitamin K promotes the carboxylation and activation of matrix Gla protein (MGP), which avoids the formation of hydroxyapatite (HA) crystals and prevents the pro-calcific action of BMP-2. Phytate acts as crystallization inhibitor by binding to HA crystals. The regular arrow denotes “activation”, and the T-shaped arrow stands for “inhibition”.