Elevated parathyroid hormone predicts high asymmetric dimethylarginine (ADMA) concentrations; independent of vitamin D status

Abstract

Background: Vitamin D deficiency and secondary hyperparathyroidism, either in combination or independently, have been associated with increased cardiovascular (CV) events. We have demonstrated that low 25-hydroxyvitamin D3 (25(OH)D3) concentrations are associated with increased concentrations of asymmetric dimethylarginine (ADMA), an eNOS inhibitor and biomarker of increased CV morbidity and mortality. It remains unclear if this relationship is independent of parathyroid hormone (PTH). Obese diabetic subjects frequently have low vitamin D and high parathyroid hormone (PTH) concentrations. We have currently sought to evaluate the PTH:ADMA relationship in normal subjects and compare this relationship with obese diabetics (a group characterized by vitamin D deficiency and high PTH levels). Methods: Non-diabetic subjects (n=159) were recruited randomly from community. Age-matched subjects (n=160) with diabetes and obesity (BMI >30 kg/m2) were recruited from outpatient clinics. Subjects with stage IV renal failure were excluded. Patient's CV risk factors were recorded. Body mass index (BMI), high-sensitive C-reactive protein (hs-CRP), 25(OH)D3, PTH, HbA1c and routine plasma electrolyte concentrations were measured and creatinine clearance (CrCL) calculated for all subjects. Plasma ADMA concentrations were determined by HPLC. Results: Obese diabetic subjects had significantly lower 25(OH)D3 but unchanged PTH concentrations compared to non-diabetic subjects. On univariate analyses, there was a direct correlation between ADMA and PTH concentrations in both non-diabetic (R=0.2, p=0.02) and obese diabetic subjects (R=0.25, p=0.002), but not between ADMA and 25(OH)D3 concentrations. On multivariate analysis, the correlation of PTH with ADMA resulted in non-diabetic subjects (R=0.23, p=0.005), obese diabetic subjects (R=0.21, p=0.03) and entire cohort (R=0.22, p<0.0001), independent of 25(OH)D3, calcium, phosphate, age, BMI, and CrCL. Other significant correlates of elevated ADMA were HbA1c concentrations (R=0.24, p<0.0001), and female gender (R=0.14, p=0.027) independent of obesity and diabetes. Conclusions: Increased PTH is a predictor of high ADMA concentration, independent of vitamin D status and may explain potential mechanisms for incremental coronary risk associated with raised PTH concentrations in epidemiological studies. This relationship is robust, and exists in both obese diabetic and non-diabetic individuals. It is possible that PTH concentrations may be useful as an additional biomarker of increased CV risk or as a window on endothelial function.