Inverse association between coronary artery calcification and plasma pyrophosphate: systemic deficiency and local compensation

Plasma inorganic pyrophosphate (PPi) is a potent endogenous inhibitor of vascular calcification, yet its relevance to coronary artery calcification (CAC) remains unclear, largely due to technical challenges in measurement that have limited clinical investigation. Here, we examined associations between circulating PPi and CAC in a prospective cohort of 150 cardiovascular patients. PPi levels were positively associated with serum phosphate, body mass index, and self-reported vitamin D intake, and inversely associated with alkaline phosphatase (ALP) activity and left circumflex artery calcification (LCx CAC) across the entire cohort. In patients with established calcification, LCx CAC showed an inverse association with both PPi and ALP activity, consistent with a potential local compensatory modulation of the PPi-ALP-phosphate axis. Ex vivo and in vitro analyses further supported this concept, demonstrating increased PPi release from atherosclerotic coronary arteries and calcifying vascular smooth muscle cells. These findings provide the first clinical evidence linking reduced circulating PPi with increased CAC and support the possibility of a dual mechanism, whereby systemic PPi deficiency may promote coronary calcification, while diseased vessels may locally upregulate PPi to limit further mineral deposition. Together, these results position PPi as a potential biomarker and therapeutic target in coronary artery disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/25334157v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@286fe6org.highwire.dtl.DTLVardef@ca9a76org.highwire.dtl.DTLVardef@162d514org.highwire.dtl.DTLVardef@1932c5a_HPS_FORMAT_FIGEXP M_FIG C_FIG