Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population

Abstract

Objective: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T 50 ) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T 50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T 50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T 50 was 329±58 minutes. A shorter serum T 50 is indicative of a higher calcification propensity. Serum T 50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T 50 ( P <0.001, total multivariable model R 2 =0.281). During median (interquartile range) follow-up for 8.3 (7.8–8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T 50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04–1.36], P =0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. Conclusions: Serum T 50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.

Calciprotein Particles Cause Endothelial Dysfunction under Flow

“…Despite the growing evidence of the CPP importance for the progression of CKD [18,19,[30][31][32][33], coronary artery disease [15][16][17], and arterial hypertension [14] as well as improved understanding of their formation and maturation in the human blood, studies published to date failed to provide a significant insight into the molecular consequences of CPP internalisation. Albeit the detrimental effects of CPPs on ECs have been demonstrated previously [11,12], these studies employed a static culture model, which is canonical but does not fully correspond to the physiological conditions of EC functioning in vivo.…”

“…In addition, increased CPP count was observed in patients with unstable coronary plaque phenotype and large plaque volume [15] while a higher rate of CPP generation correlated with severity and progression of coronary artery calcification [16]. Furthermore, elevated serum propensity to produce CPPs was associated with cardiovascular death and major adverse cardiovascular events in general population [17] as well as in patients with chronic kidney disease (CKD) and ESRD [18] even after the renal transplantation [19]. These studies highlighted the potential importance of CPPs for the development of cardiovascular disease; however, the molecular response of ECs to CPPs remains obscure.…”

Phosphate and fibroblast growth factor 23 in diabetes

“…The T50 test is able to quantify the transformation time from CPP1 to CPP2 in serum, thus reflecting serum calcification propensity. Across many studies, plasma phosphate was consistently the strongest determinant of serum T50, even after multivariable adjustment [ 131 , 132 ]. Recently we performed a study in 932 patients with type 2 diabetes and discovered that glycosylated hemoglobin (HbA1c), reflecting long-term glycemic control, was inversely associated with serum T50 levels upon multivariate analysis [ 133 ].…”

Propensity for Calcification in Serum Associates With 2-Year Cardiovascular Mortality in Ischemic Heart Failure With Reduced Ejection Fraction

“…T 50 strongly associates with death and cardiovascular outcomes in CKD patients and renal transplant recipients (21)(22)(23)(24)(25)(26)(27)(28). It has been recently shown, that T 50 was associated with cardiovascular mortality in the large general-population based Prevention of Renal and Vascular End-Stage Disease (PREVEND-) Study (29). To our knowledge, a potential role of T 50 in patients with chronic heart failure has not been studied so far.…”