Data suggest a link of aortic stenosis (AS) with calcium and bone metabolism. To further investigate this, the following parameters were analyzed in 38 patients with severe AS and in 38 age- and gender-matched controls, without obstructive coronary artery disease and with preserved renal function: calcium, phosphate, 1,25(OH 2 )-vitamin D 3 , intact parathyroid hormone (iPTH), and osteoprotegerin. Patients with AS had significantly higher serum levels of calcium (2.63 ± 0.28 vs 2.48 ± 0.23 mmol/L, p <0.01) and phosphate (1.56 ± 0.33 vs 1.38 ± 0.26 mmol/L, p <0.01) and increased calcium-phosphorus products (4.16 ± 1.13 vs 3.44 ± 0.89 mmol/L 2 , p = 0.003). Notably, the iPTH concentration in the AS group was lower, and significantly more patients in the AS group had levels less than the study median of 60 ng/L. Osteoprotegerin was elevated in patients with AS, confirming reports in other populations (9.94 ± 5.96 vs 6.73 ± 4.28 pmol/L, p = 0.009). The relations of several parameters to iPTH were also altered (AS vs controls): calcium and iPTH, 0.071 ± 0.034 versus 0.046 ± 0.023, p <0.0001; phosphate and iPTH, 0.042 ± 0.020 versus 0.025 ± 0.013, p <0.0001; vitamin D and iPTH, 0.99 ± 0.61 versus 0.63 ± 0.46, p = 0.006; and osteoprotegerin and iPTH, 0.24 ± 0.15 versus 0.12 ± 0.09, p <0.0001. In conclusion, these data support a hypothesis connecting (severe) AS to altered calcium and bone homeostasis.
The view on the pathogenesis of aortic stenosis (AS) has changed radically in the past 15 years, but many aspects of it are still insufficiently understood. There has been recent interest in the contribution of calcium homeostasis. To further investigate this, we conducted a prospective pair-matched case-control study comparing a well-defined population of patients with AS, with normal renal function, and without coronary artery disease (CAD) to healthy controls. We determined the serum levels of calcium, phosphate, 1,25-(OH 2 )-vitamin D 3 , intact parathyroid hormone (iPTH), and osteoprotegerin (OPG).
Methods
This study complied with the Declaration of Helsinki and was approved by local ethics committees. After written informed consent was obtained, consecutive patients referred for left-sided cardiac catheterization were recruited from the Department of Cardiology at the university clinic of Aachen, Germany. All subjects were Caucasian.
Thirty-eight consecutive patients (AS without obstructive CAD) were recruited before valve surgery and were pair matched with 38 controls for gender and age from a control population of 85 subjects referred for first diagnostic coronary angiography (including cine ventriculography). The control population had no evidence of valve disease, valve calcification, or obstructive CAD and had normal left ventricular function and trileaflet aortic valves as assessed by echocardiography. The stenotic valves were evaluated by the cardiac surgeon at heart valve replacement surgery, and all were classified as being trileaflet. Serum probes of patients and controls were taken after a fasting period of ≥8 hours from 8 to 10 am and were stored at −35°C to −80°C until measurements. Repeating freeze-thaw cycles were avoided.
Cardiovascular risk factors were defined as follows: hypercholesterolemia: serum cholesterol >5.2 mmol/L (200 mg/dL) or medically treated; arterial hypertension: blood pressure >140/90 mm Hg or medically treated; diabetes mellitus: overnight fasting serum glucose >7.0 mmol/L (126 mg/dL) on ≥2 occasions or medically treated; smoking: regular smoking habit; positive family history of CAD: a first-degree relative with known CAD at any age.
Coronary angiography was performed on all patients and controls, and in addition, the gradient across the aortic valve was measured by pullback of the catheter from the left ventricle to the ascending aorta. The mean gradient and the average valve area were calculated using software (METEK GmbH, Elmshorn, Germany).
Serum calcium, serum phosphate, and creatinine were measured using well-established methods used in routine clinical practice. Kidney function was determined using the modified Modification of Diet in Renal Disease (MDRD) formula. The measurement of serum levels of vitamin D (IDS Vitamin D EIA Kit; Immunodiagnostic Systems GmbH, Frankfurt, Germany), iPTH (REF 7022; Biomerica, Immundiagnostik AG, Bensheim, Germany), and OPG (product KB1011; Immundiagnostik AG) were performed using the indicated commercial kits according to the manufacturers’ manuals. All assays were done blinded to the individual performing the tests and were performed in duplicate measurements.
Statistical analysis was performed using SPSS for Windows version 15.0 (SPSS, Inc., Chicago, Illinois). Continuous variables were analyzed using analysis of variance and categorical variables using chi-square analysis with Yates’ correction for continuity. A p value <0.05 was considered statistically significant. All data are expressed as mean ± SD.
Results
Clinical data are listed in Table 1 . The 2 patient groups were generally well balanced. In contrast to the norm, women were overrepresented in the AS group (63%), because men with AS had more often concomitant CAD and were therefore excluded. Regarding the cardiovascular risk factors, no statistically significant differences were noted apart from serum cholesterol levels. There were significantly fewer patients with hypercholesterolemia in the AS group.
| Variable | Patients With AS (n = 38) | Controls (n = 38) | p Value |
|---|---|---|---|
| Age (years) | 70 ± 5 | 70 ± 5 | — |
| Men | 14 (37%) | 14 (37%) | — |
| Diabetes mellitus | 6 (16%) | 7 (18%) | 0.999 |
| Hypercholesterolemia ⁎ | 12 (32%) | 25 (66%) | 0.006 |
| Arterial hypertension | 28 (74%) | 30 (79%) | 0.788 |
| Active smokers | 11 (29%) | 19 (50%) | 0.100 |
| Body mass index (kg/m 2 ) | 27.0 ± 4.4 | 27.6 ± 5.1 | 0.579 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 62 ± 19 | 57 ± 14 | 0.204 |
| Aortic valve area (cm 2 ) | 0.84 ± 0.30 | — | — |
| Mean gradient (mm Hg) | 44 ± 17 | — | — |
⁎ Total cholesterol >5.2 mmol/L (200 mg/dL) or medically treated.
Patients with AS had significantly higher serum levels of serum calcium (2.63 ± 0.28 vs 2.48 ± 0.23 mmol/L, p = 0.008) and serum phosphate (1.56 ± 0.33 vs 1.38 ± 0.26 mmol/L, p = 0.008) and increased calcium-phosphorus products (4.16 ± 1.13 vs 3.44 ± 0.89 mmol/L 2 , p = 0.003) compared to the group without AS. There was no significant difference in the serum concentration of iPTH when analyzing the continuous data. However, an analysis by a median split revealed that a larger proportion of patients had iPTH values <60 ng/L in the AS groups. No statistically significant variances were seen in the serum levels of vitamin D (35 ± 14 vs 33 ± 14 ng/ml, p = 0.682) or iPTH (53 ± 55 vs 69 ± 35 ng/L, p = 0.142). The ratios of calcium (p <0.0001), phosphate (p <0.0001), and vitamin D (p = 0.006) to iPTH of patients with severe AS were also significantly elevated.
Patients with AS had higher serum OPG concentrations than controls, with a mean of 9.94 ± 5.96 versus 6.73 ± 4.28 pmol/L. This difference reached statistical significance (p = 0.009). When the values were dichotomized by a median split of the total population (9.5 pmol/L), 53% of the patients with AS had serum OPG concentrations higher than that value, compared with 18% of the control group (p = 0.004). The ratio of OPG to iPTH was significantly higher in the cohort with AS than in the control group (p < 0.0001).
There were no statistically significant differences between the genders regarding the measured parameters. The data are listed in Table 2 .
| Serum Parameter | Patients With AS (n = 38) | Controls (n = 38) | p Value |
|---|---|---|---|
| Calcium (mmol/L) | 2.63 ± 0.28 | 2.48 ± 0.23 | 0.008 |
| Phosphate (mmol/L) | 1.56 ± 0.33 | 1.38 ± 0.26 | 0.008 |
| Calcium-phosphorus product (mmol/L 2 ) | 4.16 ± 1.13 | 3.44 ± 0.89 | 0.003 |
| Calcium-phosphorus product >4 mmol/L 2 | 22 (58%) | 5 (13%) | <0.0001 |
| Vitamin D 3 (ng/ml) | 35 ± 14 | 33 ± 14 | 0.682 |
| iPTH (ng/L) | 53 ± 55 | 69 ± 35 | 0.142 |
| iPTH <60 ng/L | 33 (87%) | 18 (47%) | <0.0001 |
| OPG (pmol/L) | 9.94 ± 5.96 | 6.73 ± 4.28 | 0.009 |
| OPG >9.5 pmol/L | 20 (53%) | 7 (18%) | 0.004 |
| Ratio to iPTH | |||
| Calcium | 0.071 ± 0.034 | 0.046 ± 0.023 | <0.0001 |
| Phosphate | 0.042 ± 0.020 | 0.025 ± 0.013 | <0.0001 |
| Vitamin D 3 | 0.99 ± 0.61 | 0.63 ± 0.46 | 0.006 |
| OPG | 0.24 ± 0.15 | 0.12 ± 0.09 | <0.0001 |
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