In this prospective case-control study of mild PHPT without any known cardiovascular risk factors or medications affecting the cardiovascular system, we found no indication that circulating levels of vitamin D influenced arterial structure or function. Wall composition (IM-GSM) and aortic stiffness (PWVao) were weakly related to PTH and the latter also to ionized calcium levels in univariate analysis, but not when adjusting for confounders like blood pressure. Furthermore, the PTX did not cause any change in indices of vascular function or arterial wall thickness. Our conclusions were substantiated by adding new variables, such as echogenicity of the carotid artery and intima media thickness of the radial artery to the established measures AIx, PWVao, and IMTcca.
Thus, although vitamin D deficiency is common in patients with PHPT 
, and is associated with cardiovascular disease in the general population 
, we did not observe any relations between 25-OH-D and AIx, PWVao
, or IM-GSM in our study. Neither were these measures related to other biochemical data specifically abnormal in PHPT, such as Ca++
and phosphate, apart from a correlation between PWVao
and PTH and ionized Ca and an inverse correlation between IM-GSM and PTH. Interestingly, Reis et al
. found no association between vitamin D and carotid IMT apart from a weak association of 25-OH-D levels to internal carotid IMT when adjusting for, but not excluding, hypertension. Further, they found no evidence of an association between 1,25(OH)2
D and common carotid IMT or internal carotid IMT, apart from a weak association to internal carotid IMT among patients with hypertension in one of several subgroup analyses 
. The higher blood pressure among PHPT patients is not clearly understood. Despite the fact that we excluded patients with hypertension, we found significantly higher SBP, although within normal range, in patients compared with controls. SBP decreased after PTX in our patients, while it did not in another series of mild PHPT patients 
. We have previously reported a weak but significant correlation between SBP and Ca++ as well as PTH levels when including both patients and controls 
. It has been reported that vitamin D may influence blood pressure through the renin-angiotensin system 
, and a number of possible pathophysiological links to atherosclerosis have been ascribed to vitamin D deficiency, including activation of the renin angiotensin system 
. Our data add strength to the hypothesis that associations between the atherosclerotic process and circulating levels of vitamin D, ionized Ca, and PTH are mediated through blood pressure and other risk factors. With regard to the relation between vitamin D status and cardiovascular risk, many issues still remain to be resolved. Recent comprehensive reviews do not support a strong link between vitamin D status or supplementation and cardiometabolic outcome or cardiovascular events 
, and another systematic review and meta-analysis, based on 51 trials, found no significant correlation between vitamin D status, hypertension, or cardiovascular mortality 
Interestingly, it was recently demonstrated that PHPT causes up- regulation of the matrix metallopeptidase 9 (MMP9) gene and a number of other inflammatory and metabolic genes in fat tissue, with possible impacts on blood pressure and atherosclerosis 
. In our study of normotensive PHPT patients and controls, we found slightly higher blood pressure and PWVao
in patients. However, data are not unanimous. While Rosa et al
. noted PHPT patients to have increased arterial stiffness with and without hypertension 
, Kosch et al
. showed no difference in PWV between PHPT patients and controls, and found no correlations between PWV and increased PTH levels 
Our PHPT patients and healthy controls showed no difference in AIx. This is in contrast to the results of Smith et al.
and Rubin et al.
, who also studied patients with mild PHPT. Smith et al.
reported higher AIx in patients with mild PHPT compared to controls, and Rubin et al.
asserted that PHPT was independently associated with increased AIx. In contrast to Rubin et al.
, we did not find any correlation between AIx and elevated PTH. A plausible explanation for the discrepancy is that Rubin et al.
studied groups containing PHPT patients with hypertension and patients on cardiovascular medication. The association between the severity of PHPT and cardiovascular risk factors, however, is not universal. Similar amount of risk factors was recently reported in hypercalcemic and normocalcemic PHPT patients although cardiovascular and cerebrovascular diseases were more common in hypercalcemic PHPT 
. In the same study, however, vascular stiffness was not higher in this group than in normocalcemic PHPT or controls, and in congruence with our material unrelated to calcium and PTH.
Probably, cardiovascular diseases combined with PHPT are more likely to affect the arterial wall and IMT than PHPT alone. This is supported by Fallo et al.
, who included PHPT patients with and without cardiovascular risk factors. When compared to healthy controls, only PHPT patients with concomitant cardiovascular risk factors were found to have an increased IMT of the carotid artery wall. Similarly Walker et al.
reported increased carotid IMT in PHPT patients, including those with cardiovascular diseases, compared to controls. Nuzzo et al.
excluded subjects with high blood pressure or clinical cardiovascular disease and still found significantly higher carotid IMT values in 20 selected patients compared with controls. However, the authors did not indicate the lipid levels in their study group. Kosch et al.
found no disturbance in brachial and carotid IMT or aortic PWV in PHPT patients compared to controls, and Lumachi et al.
reports no improvement in carotid IMT after 18 months of PTX follow-up; further, no correlations between serum calcium and IMT was found. In our study, with careful exclusion of patients with cardiovascular risk factors, we did not observe any differences between patients and controls at baseline, apart from slightly higher SBP and PWVao
in patients with a significant reduction in blood pressure one year after PTX. All our vascular measurements, apart from IM-GSM, were related to age and blood pressure. Adjusting for age and blood pressure, PWVao
was not related to circulating levels of PTH, Ca++
, phosphate, or 25-OH-D.
In order to investigate the vascular structure more thoroughly, we have used new validated techniques in our study, such as grayscale median for the evaluation of echogenicity of the carotid intima media, and a high- resolution ultrasound for measurement of IMT in the radial artery. We have demonstrated that high- resolution ultrasound allows measurement of very thin structures such as IMT of the rat carotid artery wall 
, and it has also been shown that measurement of the human radial artery IMT is feasible by this technique 
. In the current study, we measured the intima media thickness in the radial artery and found no significant increase in IMTrad
in the PHPT patients compared with controls. By measurement of the grayscale in the intima media images of carotid artery, we tried to obtain information regarding the wall composition, with the assumption that fibrotic infiltration should be more echogenic and lipidous transformation should be more echolucent. Earlier studies have shown that IM-GSM in CCA is closely related to the echogenicity in overt carotid plaques; moreover, the same group further reported a relationship between echolucency in the intima-media complex and cardiovascular risk factors in elderly subjects 
. However, our study did not indicate abnormal composition of the carotid artery wall as evaluated by this technique.
Strengths and Limitations
To our knowledge, this is the first study to describe IMTrad and the echogenicity in the intima media of the CCA in patients with mild PHPT. The strict design, excluding cardiovascular risk factors, is the strength of our study, which should favorably influence the reliability of our results. The material is comparatively large for this type of study; however, it is too small for any prognostic evaluations.
We measured the IMT of the common carotid artery in the far wall only, as we assumed relatively symmetrical wall thickness in our patients and controls. Since most patients with PHPT today do not express typical signs and since calcium- and PTH-levels are not examined routinely, it is rarely possible to estimate the duration of the disease.
We found normal arterial function, despite high PTH and Ca as well as low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors. The cardiovascular risk associated with low vitamin D and/or high PTH and Ca levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on the arterial structure. Our findings support the importance of adequate blood pressure control in PHPT if PTX is not performed, but do not indicate vascular abnormalities motivating extended follow-up after PTX.