Pentraxin 3 as A Cardiovascular Marker in Primary Hyperparathyroidism

Aim: Pentraxin 3 (PTX3) is an acute-phase glycoprotein, which is increased in patients with cardiovascular disease (CVD) and considered as a predictor of CVD in the general population. Accumulating evidence suggests that even mild primary hyperparathyroidism (PHPT) has an elevated risk for CVD. We aimed to investigate plasma PTX3 levels before and after parathyroidectomy in patients with primary hyperparathyroidism and determine its relationship with cardiovascular risk factors Material and Method: Twenty-nine patients with PHPT and 26 healthy controls were enrolled in the study. Anthropometric and laboratory parameters were recorded both before and 6 months after parathyroidectomy. Serum PTX3 levels were measured using a human PTX3 enzyme-linked immunosorbent assay. Results: Plasma PTX3 concentrations were similar between before and after parathyroidectomy and control group (10.97 ± 16.0, 11.97 ± 11.49, 7.88 ± 9.48, respectively, p>0.05). Systolic blood pressure, diastolic blood pressure, carotid intima-media thickness (CIMT) and calcium, parathormone, fasting plasma glucose, alkaline phosphatase concentrations were higher in the PHPT group (p<0.05). Creatinine and phosphorus concentrations were higher in the control group (p<0.05). PTX3 was not correlated with cardi-metabolic risk factors except body mass index (BMI) (r2:0.414, p:0.0253). Conclusion: Plasma PTX3 was not increased as well was not changed after parathyroidectomy in patients with PHPT. The PTX3 was correlated with BMI; however, it was not associated with other cardio-metabolic risk factors including DBP, CIMT, and CRP. These findings might support PTX3 cannot be used as a cardio-metabolic risk marker in patients with PHPT.


Introduction
As an acute-phase glycoprotein, pentraxin 3 (PTX3) has a key role in innate immunity.Additionally, it assists in the removal of degenerated and apoptotic cells.PTX3 plays a role in inflammatory processes, modulates angiogenesis as well as involved in the extracellular matrix formation.Two short pentraxins, C-reactive protein (CRP) and serum amyloid P component, and the long pentraxin, PTX3 are members of the pentraxin family [1,2].PTX3 is synthesized locally in the vascular system by leukocytes, myeloid dendritic cells, fibroblasts, mononuclear macrophages/ phagocytes, and the vascular endothelium in response to stimulation by inflammatory cytokines, however, CRP is mainly produced in the liver upon stimulation by systemic inflammation [3,4].Increased PTX3 concentrations are associated with several disorders including systemic inflammatory response syndrome, sepsis, chronic renal failure, myocardial infarction, cardiac failure, atherosclerosis, vasculitis, lung infections, acute pulmonary damage, lung cancer, eclampsia, rheumatoid arthritis, ankylosing spondylitis and psoriasis [5].PTX3 concentrations are elevated in heart failure [6], coronary artery disease [7], and acute coronary syndrome [8].PTX3 levels are increased as well associated with cardiovascular risk factors in both functional and nonfunctional adrenal tumors [9].Accumulating evidence suggests that even mild PHPT has an elevated risk for CVD [10][11][12][13][14].
We aimed to investigate plasma PTX3 levels before and after parathyroidectomy in patients with primary hyperparathyroidism and determine its relationship with cardiovascular risk factors.

Material and Method
Twenty-nine patients with PHPT and 26 healthy controls were enrolled in the study.Anthropometric and laboratory parameters were recorded both before and 6 months after parathyroidectomy.Local ethics committee approval from Diskapi Training and Research Hospital was obtained and all participants provided written informed consent before the study began.Patients with multiple endocrine neoplasias, parathyroid cancer, thyroid cancer, hyperparathyroidism-jaw tumor syndrome, and patients on drugs that counteract with calcium and vitamin D metabolism were excluded from the study.The diagnosis of PHPT was defined as persistent hypercalcemia with normal or non-suppressed PTH concentrations [15].

Clinical, Biochemical and Hormonal Measurements
Basal demographic data, clinical features, carotid intimamedia thickness (CIMT) measurements were recorded for all participants.Weight, height, waist circumference (WC), body mass index (BMI), systolic blood pressure (SDP) and diastolic blood pressure (DBP) were measured.Fasting state biochemical and hormonal measurements were performed in the morning using colorimetric methods and complete blood counts were obtained from all participants.An intact chemilum inescent immunoassay of PTH (Immulite 2000) was used for measurement of serum PTH levels.25-OH vitamin D concentrations were measured using a radio immune assay.
High-resolution B-mode ultrasound (EUB 7000 HV; Hitachi, Tokyo, Japan) with a 13-mhz linear array transducer was used to image parathyroid glands.Carotid intima-media thickness (CIMT) was measured to assess carotid atherosclerosis.CIMT was measured by a B-mode imaging high-resolution ultrasound (EUB 7000 HV; Hitachi, Tokyo, Japan).CIMT is defined as the distance between the blood-intima and media-adventitia boundaries on B-mode imaging high-resolution ultrasound system.Same investigator (MC) performed all ultrasonographic measurements.

Measurement of PTX3
Serum PTX3 levels were measured using a human PTX3 enzyme-linked immunosorbent assay kit (R&D Systems Inc, Minneapolis, MN).The sensitivity was 0.116 ng/mL, and the assay range was 0.31 to 20 ng/mL.

Statistical Analysis
Statistical analysis was performed using JMP 13.0.0software (SAS Institute, Cary, NC, USA).software.Variables are presented as mean ± standard deviation (SD) or median, percentage (%), odds ratio (OR) and 95 % confidence intervals (CI).Normality was tested by Kolmogorov-Smirnov and Shapiro-Wilk W test. Student t test for normally distributed continuous variables between two groups.Paired sample t-test was used for normally distributed continuous variables before and after the operation.The Chi-square test or Fisher's exact test was used for categorical variables.The correlation was analyzed with the Spearman and Pearson's test.Statistical significance was defined as a p< 0.05.

Discussion
Our aim was to evaluate the PTX3 concentrations in PHPT patients.Plasma PTX3 was not increased as well was not changed after parathyroidectomy in patients with PHPT.The PTX3 was correlated with BMI; however, it was not associated with other cardio-metabolic risk factors including DBP, CIMT, and CRP.We believe that ours is the first to evaluate the concentrations of PTX3 and its relation to cardio-metabolic risk factors in PHPT.
The association between PTX3 and cardiovascular disorders is well documented [6][7][8].The presence of PTX3 in the myocardium and the vasculature with different diseases suggest the elevated concentrations of plasma PTX3 in patients with cardiovascular disorders [16].The high levels of PTX3 in atherosclerotic plaques and serum of patients with increased LDL cholesterol and widespread atherosclerosis support the potential association between PTX3 and vascular diseases [17][18][19].
PTH receptors are present in cardiomyocytes, endothelial cells, and smooth muscle cells [20], and patients with myocardial fibrosis, calcification, and hypertrophy have higher PTH concentrations [21].Many studies have demonstrated PHPT had increased cardiovascular events and mortality which improved after parathyroidectomy [10][11][12][13][14]. Hypertension, hyperlipidemia, CIMT, CRP, and insulin resistance are all well-known risk factors for CVD [22,23].PHPT patients have higher CVD risk and cardiovascular-related mortality [24].Several risk factors for CVD have been reported in patients with PHPT, including hypertension, and elevated CIMT, insulin resistance, and CRP [25][26][27][28].In light of this information, we aimed to investigate whether PTX3 could be higher and related to cardio-metabolic risk factors in PHPT patients.However, PTX3 was not higher as well was not changed after parathyroidectomy in patients with PHPT.Additionally, PTX3 concentrations were not correlated with well-known cardio-metabolic risk factors except BMI.Some studies suggest a positive correlation between PTX3 and BMI [29,30] however, others found a negative correlation [31,32].In our study, we found a positive correlation between PTX3 levels and BMI.
These findings might be explained by many of our patients possibly being in the early stage of the disease, which might explain why PTX3 was not increased and did not represent an association with all cardio-metabolic risk factors; this is a possible limitation of the study.Additional limitations include the fact that it was a single-center study, and the small sample size was small.

Conclusion
In conclusion, the PTX3 did not increase in patients with PHPT as well was not changed by parathyroidectomy.PTX3 was correlated with only BMI; however, it was not associated with other cardio-metabolic risk factors.Our findings do not support the thesis of PTX3 as a potential marker of CVD in patients with PHPT.However, more comprehensive studies are necessary to support our findings.

as A Cardiovascular Marker in Primary Hyperparathyroidism Copyright: © 2018 Kızılgü MD, et al.Table 2 :
Preoperative correlation analysis of Pentraxin 3 with cardio-metabolic risk factors