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In my recent interview with Dr. Mercola, we discussed measuring vascular calcification with coronary CT scans. This technique offers valuable information, but also a large dose of radiation, so we agreed that we should be cautious about using them. Recent research suggests, in any case, that current imaging techniques are incapable of detecting the vast majority of calcification, including the most dangerous type. In this post, I’ll consider the possibility that in the future blood levels of a specific form of matrix Gla protein (MGP), a vitamin K-dependent protein I’ve discussed often in the past, could be used as a better and less invasive measure of cardiovascular calcification.

The conventional understanding is that arterial plaques accumulate calcium only in advanced stages as arterial tissue begins to develop features of bone tissue, that calcification plays no major role in the rupture of a plaque’s fibrous cap, and that erosion of a calcified nodule contributes to only a small minority of heart attacks (1).

Recent evidence, however, suggests that the conventional view has overlooked the role of small bits of calcium phosphate called “microcalcifications.” Consistent with experiments in mice, a recent human autopsy study showed that microcalcifications begin accumulating in the earliest lesions, and in large amounts by the time fatty streaks develop (2). All this takes place long before the arterial tissue begins developing into bone-like tissue. Another recent study estimated that 97 percent of total calcifications are microcalcifications that are invisible to current imaging techniques, and that a small portion of these microcalcifications are present in the fibrous cap, where they increase the local stress five-fold, which makes plaques far more likely to rupture and cause a heart attack (3).

As I discussed in a previous post, “An Upcoming Plasma Marker of Vitamin K Status,” our cells make two modifications to MGP to help it fulfill its primary function, directing calcium and phosphate away from soft tissues and into bones and teeth: the addition of carbon dioxide (carboxylation) and the addition of phosphate (phosphorylation). Thus, there are four forms of MGP: it can have one or the other modification, none, or both. Although only fully modified MGP is thought to be functional, the other forms may act as useful markers of physiological processes.

One of the papers I referenced above found that uncarboxylated MGP (MGP without the addition of carbon dioxide) sticks to arterial plaque, and that as the plaque increases in severity, it contains more microcalcifications and more uncarboxylated MGP (2):

The authors didn’t report a correlation analysis of the individual data, but it looks from the figure that the correlation between uncarboxylated MGP and microcalcifications is probably strong. We can at least say that they both increase in parallel with one another as plaques become more severe.

As I described in my previous post, phosphorylation is thought to give uncarboxylated MGP enough negative charge to stick to calcium deposits, while unmodified MGP fails to stick. The authors of the above study didn’t differentiate between uncarboxylated MGP that had and had not been phosphorylated, but current theory would suggest that most or all of it had been phosphorylated.

It would seem, then, that phosphorylated but uncarboxylated MGP might act as an inverse marker for microcalcifications: the more calcification, the more that sticks, and the less that is released in the blood.

There are two problems with this. First (4), on the downside, there are no assays available for MGP that has been phosphorylated but not carboxylated. On the upside, however, when investigators measure total uncarboxylated MGP in human blood, they see levels that are a thousand times greater than those they see for MGP lacking both modifications. Presumably, then, 99.9% of uncarboxylated MGP in human blood is phosphorylated, and the total amount of uncarboxylated MGP can act as an excellent proxy for MGP that is phosphorylated but not carboxylated.

This brings us to our second problem: a number of studies have compared the level of cardiovascular calcification to the amount of total uncarboxylated MGP in the blood, which I’ll call t-ucMGP from hereon out, and have obtained mixed results:

• Among 200 apparently healthy postmenopausal women from The Netherlands, high t-ucMGP predicted low calcification of the coronary arteries as determined by CT scan, but the results were not statistically significant (P<0.09) until women without any coronary calcification were excluded from the analysis (5).
• Complementary to that finding, the Heart and Soul Study found that among over 800 heart disease patients in the San Francisco area, high t-ucMGP predicted a lower risk of cardiovascular events and mortality (6). The same study, however, found that high t-ucMGP only predicted lower heart valve calcification as measured with Doppler images in patients without diabetes. In patients with diabetes, high t-ucMGP predicted greater heart valve calcification (7).
• On the other hand, t-ucMGP had no relation to cardiovascular calcifications as measured at many sites with X-ray and ultrasound among just under two hundred non-diabetic, Serbian hemodialysis patients (8).
• Among just over 450 apparently healthy participants in a randomized, controlled trial of vitamin K1 supplementation, there was no relation between t-ucMGP and calcification of the coronary arteries as judged by a CT scan. Three years of vitamin K1 supplementation (500 mg/day) decreased ucMGP and slowed the progression of coronary calcification, but the change in one had no relation to the change in the other (9).
• Among over 100 children with and without kidney disease, t-ucMGP levels were lower in children on dialysis but had no relation to coronary artery or heart valve calcification as judged by a CT scan (10).

There could be several explanations for these conflicting results. As discussed above, vitamin K supplementation decreases t-ucMGP, which is unsurprising since vitamin K is used to carboxylate MGP. Diabetics and non-diabetics with kidney disease have poor vitamin K status. Perhaps t-ucMGP could act as a marker for calcification in the general population, but not in populations with extremes in vitamin K status, whether because of supplementation on the high end or kidney disease (and associated diets) on the low end. More studies in non-supplementing populations free of kidney disease would be needed to address this.

There remain two important unknowns, however, that, once known, could change the game. First, we are presuming that t-ucMGP is a good proxy for phosphorylated ucMGP, but until investigators develop an assay for phosphorylated ucMGP, we don’t know for sure that this is truly the case.

Second, if, as discussed in the beginning of this post, the current imaging techniques miss out on 97 percent of the calcification, including the most dangerous ones — microcalcifications in the fibrous cap — then the present studies may be deceiving. Studies that fail to show a relation between t-ucMGP and cardiovascular calcifications as judged by imaging techniques may be revealing the limitations of the imaging techniques rather than the limitations of t-ucMGP.

The only way I can see this being addressed is to compare blood levels of t-ucMGP to microcalcifications judged by arterial biopsies. Autopsy studies could provide data for subjects without serious heart disease in cases where blood samples had been obtained. I suspect such studies will be a long time coming, but potentially fascinating results could follow.

Read more about the author, Chris Masterjohn, PhD, here.

References

1. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481-8.

2. Roijers RB, Debernardi N, Cleutjens JP, Schurgers LJ, Mutsaers PH, van der Vusse GJ. Microcalcifications in early intimal lesions of atherosclerotic humans coronary arteries. Am J Pathol. 2011; 178(6):2879-87.

3. Maldonado N, Kelly-Arnold A, Vengrenyuk Y, Laudier D, Fallon JT, Virmani R, Cardoso L, Weinbaum S. A mechanistic analysis of the role of micro calcifications in atherosclerotic plaque: stability potential implications for plaque rupture. Am J Physiol Heart Circ Physiol. 2012;303(5):H619-28.

4. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012;3(2):166-73.

5. Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeeyns EJ, Schurgers LJ, Beulens JW. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women.

6. Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M, Shlipak MG, Whooley MA, Ix JH. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med. 2010;152(10):640-8.

7. Parker BD, Schurgers LJ, Vermeer C, Schiller NB, Whooley MA, Ix H. The association of uncarboxylated matrix Gla protein with mitral annular calcification differs by diabetes status: The Heart and Soul study. Atherosclerosis. 2010;210(1):320-5.

8. Schlieper G, Brandenburg V, Djuric Z, Damjanovic T, Markovic N, Schurgers L, Kruger T, Westenfeld R, Ackermann D, Haselhuhn A, Dimkovic S, Ketteler M, Floege J, Dimkovic N. Risk factors for cardiovascular calcifications in non-diabetic Caucasian haemodialysis patients. Kidney Blood Press Res. 2009;32(3):161-8.

9. Shea MK, O’Donnell CJ, Vermeer C, Magdeleyns EJ, Crosier MD< Gundberg CM, Ordovas JM, Krichevsky SB, Booth SL. Circulating uncarboxylated matrix Gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. 2011;141(8):1529-34.

10. Schroff RC, Shah V, Hiorns MP, Schoppet M, Hofbauer LC, Hawa G, Schurgers LJ, Singhal A, Merryweather I, Brogan P, Shanahan C, Deanfield J, Rees L. The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis. Nephrol Dial Transplant. 2008;23(10):3263-71.

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