pyrophosphate and Arteriosclerosis

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A growing body of data points to nontraditional risk factors, including disturbances in mineral metabolism, as important determinants of the extremely high cardiovascular morbidity and mortality rates in these patients. Disturbances in mineral metabolism, especially elevated calcium and phosphate levels, have been linked to vascular and valvular calcification, both of which are associated with poor prognosis in chronic kidney disease patients. This review highlights important recent findings regarding the etiology of vascular calcification, with special emphasis on pathways that may be particularly relevant in chronic kidney disease patients.. New studies indicate that not only vascular intimal calcification (associated with atherosclerosis) but also vascular medial calcification are correlated with decreased survival in chronic kidney disease patients. With the relatively recent recognition of vascular calcification as an actively regulated process, a growing list of inducers (calcium, phosphate, inflammatory cytokines) and inhibitors (matrix Gla protein, fetuin, pyrophosphate, osteopontin) have been discovered. Interesting recent evidence suggests that they may contribute to the prevalence of this pathology in chronic kidney disease patients.. Vascular calcification is associated with decreased survival in chronic kidney disease patients. Understanding the causes and regulatory factors controlling vascular calcification will help refine therapeutic modalities currently in use, as well as develop novel therapeutics to abate and potentially reverse this deleterious process.

Topics: alpha-2-HS-Glycoprotein; Animals; Arteriosclerosis; Blood Proteins; Calcinosis; Calcium Phosphates; Diphosphates; Humans; Osteopontin; Sialoglycoproteins; Uremia; Vascular Diseases

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Topics: Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Arteriosclerosis; Biomarkers; Calcinosis; Calcium Phosphates; Cardiovascular Diseases; Causality; Comorbidity; Diabetes Mellitus; Diphosphates; Disease Susceptibility; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Mortality; Osteoclasts; Phosphates; Prospective Studies; Pulse Wave Analysis; Renal Dialysis; Renal Insufficiency, Chronic; Risk; Serum Albumin; Smoking; Vascular Resistance

Topics: Arteriosclerosis; Carotid Arteries; Coronary Thrombosis; Diphosphates; Endarterectomy, Carotid; Glycerol; Humans; Lipoproteins, LDL; Lysophospholipids; Phospholipids; Platelet Activation; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid

Inogranic pyrophosphate (PPi) inhibits hydroxyapatite deposition, and mice deficient in the PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) Plasma cell membrane glycoprotein-1 (PC-1) develop peri-articular and arterial calcification in early life. In idiopathic infantile arterial calcification (IIAC), hydroxyapatite deposition and smooth muscle cell (SMC) proliferation occur, sometimes associated with peri-articular calcification. Thus, we assessed PC-1 expression and PPi metabolism in a 25-month-old boy with IIAC and peri-articular calcifications. Plasma PC-1 was <1 ng/ml by enzyme-linked immunosorbent assay in the proband, but 10 to 30 ng/ml in unaffected family members and controls. PC-1 functioned to raise extracellular PPi in cultured aortic SMCs. However, PC-1 was sparse in temporal artery lesion SMCs in the proband, unlike the case for SMCs in atherosclerotic carotid artery lesions of unrelated adults. Proband plasma and explant-cultured dermal fibroblast NTPPPH and PPi were markedly decreased. The proband was heterozygous at the PC-1 locus, and sizes of PC-1 mRNA and polypeptide, and the PC-1 mRNA-coding region sequence were normal in proband fibroblasts. However, immunoreactive PC-1 protein was relatively sparse in proband fibroblasts. In conclusion, deficient extracellular PPi and a deficiency of PC-1 NTPPPH activity can be associated with human infantile arterial and peri-articular calcification, and may help explain the sharing of certain phenotypic features between some IIAC patients and PC-1-deficient mice.

Topics: Arteriosclerosis; Blotting, Northern; Calcinosis; Cells, Cultured; Child; Child, Preschool; Diphosphates; DNA; Extracellular Space; Family Health; Female; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; Infant; Male; Membrane Glycoproteins; Microscopy, Confocal; Muscle, Smooth, Vascular; Pedigree; Phosphoric Diester Hydrolases; Pyrophosphatases; RNA; Sequence Analysis, DNA; Skin

Topics: Angina Pectoris; Arteriosclerosis; Coronary Disease; Diagnosis, Differential; Diphosphates; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Alkenes; Animals; Arteriosclerosis; Brain; Cholesterol; Diphosphates; Fatty Acids; Humans; Ligases; Liver Extracts; Mevalonic Acid; Saccharomyces; Squalene; Terpenes; Tissue Extracts

Topics: Adenosine Triphosphate; Aging; Arteriosclerosis; Blood Coagulation; Coagulants; Diphosphates; Fibrinogen; Geriatrics; Humans; Thrombin; Thromboplastin; Thrombosis