Serum Parathyroid Hormone as a Potential Novel Biomarker of Coronary Heart Disease

Abstract

Objective: This study aimed to evaluate the relationships between serum parathyroid hormone (PTH) and coronary heart disease (CHD). Methods: From July 2011 to February 2013, a total of 79 CHD patients and 94 normal control patients with ages ranging from 25 to 79 years were included in this study. Serum PTH level and common risk factors of CHD (age, gender, cholesterol, glycosylated hemoglobin [HbA1c], blood pressure [BP], history of diabetes, smoking, and body mass index) were investigated. Pearson's correlation and multiple regression analyses were used to evaluate the relationships between serum PTH level and CHD risk factors. All statistical analyses were performed using the SPSS 18.0 software. Results: Results from Pearson's correlation analysis indicated that age, systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), HbA1c, history of smoking, and serum PTH level were risk factors for CHD (all p<0.05). Serum PTH levels were positively correlated with DBP (r=0.256, p=0.010) and HbA1c (r=0.223, p=0.003), while not being related to other risk factors of CHD (all p>0.05). Multiple linear regression analysis showed that SBP, DBP, LDL-c, and HDL-c may be important determinants of CHD (all p<0.05). Further, serum PTH level is also an independent risk factor for CHD (p<0.001). Conclusion: Our results provide evidence that serum PTH level may be involved in the pathogenesis of CHD. Thus, PTH could be used as an important biomarker in the diagnosis of CHD.

Introduction

Coronary heart disease (CHD) is the most common form of cardiovascular disease, which develops from progressive narrowing or blockage of coronary arteries induced by increasing plaque burden (Teramoto et al., 2014). As a major global public health problem, CHD is the leading cause of disability and death in the developed countries and the largest contributor of deaths in low- and middle-income countries with an estimated 7.3 million deaths worldwide in 2008, which represents ∼30-40% of all deaths (Kanhai et al., 2013; Odegaard, 2013). A wide range of well-documented fixed risk factors have been implicated in CHD, such as age, sex, family history, as well as various modifiable risks, including smoking, hypertension, diabetes mellitus, obesity, and so on (Holme and Tonstad, 2013; Kivimaki et al., 2013). Further, a body of epidemiological studies revealed that parathyroid hormone (PTH) was broadly correlated with cardiovascular disease and was proposed as an emerging biomarker in plasma and an independent predictor of the development of CHD (Grandi et al., 2011; Taylor et al., 2011).

Serum PTH is secreted by the chief cells of parathyroid glands in response to hypocalcaemia, which is crucial in the maintenance of serum calcium and phosphate balance, as well as in the promotion of vitamin D synthesis (Bergwitz and Juppner, 2010; Cusano et al., 2013). Although PTH was suggested to affect bone and the kidney, which are of great importance in maintaining calcium homeostasis, PTH receptors were also shown to be expressed in the myocardium and the vessel walls, suggesting that it may also directly affect the cardiovascular system (Schierbeck et al., 2011; van Ballegooijen et al., 2013a). Dysfunctions of the parathyroid gland could cause primary hyperparathyroidism, and, in particular, the excessive secretion of PTH was significantly associated with known cardiovascular risk factors, including hypertension, dyslipidemia, left ventricular hypertrophy, and insulin resistance (Pilz et al., 2010; Poss et al., 2011; Schulz et al., 2011; Li et al., 2012). Increased serum PTH was associated with endothelial dysfunction of the heart that leads to heart failure progression, and was suggested to be independently associated with endothelial dysfunction in elderly patients with chronic heart failure (Loncar et al., 2011). Since endothelial dysfunction is the first step toward coronary arteriosclerosis, the reduction in the bioavailability of endothelium-derived nitric oxide also serves as a key link between metabolic disorders and cardiovascular risks (Huang, 2009; Vanhoutte, 2009). The vasodilating properties of PTH showed that impaired vasomotor function may result in increasing platelet adhesion to endothelial cells, which eventually leads to the formation of thrombosis, all of which may contribute to the progression of CHD (van Gils et al., 2009; Rubinshtein et al., 2010). In summary, these connections suggest plausible mechanisms whereby elevated serum PTH level may be in some way associated with acute thrombus formation and occlusion of the coronary vessel, thus promoting the pathological processes of CHD (Taylor et al., 2011; van Ballegooijen et al., 2013b). In this study, we evaluated the relationships between serum PTH and CHD in order to further clarify the potential pathogenesis of CHD.

Materials and Methods

Ethics statement

The study was approved by the ethics committee of the First Affiliated Hospital of Harbin Medical University. Informed consent was obtained in written from all participants using the approved procedures by institutional review boards.

Study design and subjects

From July 2011 to February 2013, a total of 79 CHD patients (aged 25-79 years) admitted to the Department of Cardiology in the First Affiliated Hospital of Harbin Medical University were included in this study. All patients met the diagnostic criteria of CHD: (1) stenosis >50% diameter reduction in the anterior descending coronary artery, circumflex coronary artery, or right coronary artery based on the test results from coronary angiography; (2) diagnosed with acute myocardial infarction through electrocardiogram (ECG) and enzymology; (3) had typical angina without severe aortic stenosis/insufficiency, aortitis, or evidence of coronary thrombosis and cardiomyopathy. Exclusion criteria for the participants were as follows: (1) renal insufficiency or serum creatinine values >120 mM; (2) abnormal calcium levels (reference range=2.2-2.6 mM) and phosphorus levels (reference range=0.7-1.4 mM); (3) organic heart disease (heart failure/arrhythmias); and (4) use of diuretics within a month before the study. Ninety-four matched healthy subjects were included as controls.

Measurements

All major risk factors were assessed during recruitment. Serum cholesterol, triglycerides, and very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were measured. Hematologic variables, including white-cell count and fibrinogen, were assayed. Body mass and height (weight in kg and height in m) were measured with subjects wearing only light clothing without shoes. Body mass index was calculated as kg/m². Participants were also instructed to measure blood pressure (BP) with an ambulatory BP monitor after 5-min rest. Patients were in the sitting position with the antecubital fossa supported at heart level, along with uncrossed legs and both feet on the floor. BP was measured twice, and averages of the two systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were calculated for the analyses. Venous blood for biochemical analyses was drawn in the morning after an overnight fast and stored at −70°C until analysis. Serum lipid concentrations, glycosylated hemoglobin (HbA1c), and ionized calcium were derived from fasting states. Lipid measurements included total cholesterol, triglycerides, HDL, and LDL calculated by the Friedewald method. Serum PTH level was determined on fasting sera specimens by electrochemiluminescence immunoassay (ECLIA) on an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany), with a normal range of 10-26 pg/mL. ECG and coronary CT angiography images were provided by or acquired from the patients during hospitalization examination.

Statistical analyses

Data were presented as mean±standard deviation (mean±SD), median with interquartile ranges, or frequencies. The χ² test was used to compare frequencies. One-way analysis of variance and Student's t-test were used for normally distributed variables, whereas Mann-Whitney's U-test was used for non-normally distributed variables. Comparisons between the two groups for nominal variables were made by the Fisher exact test. Pearson's correlation and multiple regression analyses were also used to evaluate the relationships between serum PTH level and CHD risk factors. All statistical analyses were performed using the SPSS 18.0 software (SPSS, Inc., Chicago, IL). A probability value of <0.05 was considered statistically significant.

Results

Baseline characteristics

The baseline characteristics of the CHD patients and healthy controls in the current analysis as well as of the patients in the original study group are shown in Table 1. Compared with healthy controls, CHD patients were older and more likely to be smokers and had higher SBP, DBP, low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) levels and lower HDL-c levels (all p<0.05). Further, serum PTH level of CHD patients was higher than that of healthy controls (98±11 vs. 65±13 pg/mL, p<0.001).

Table 1.

Baseline Characteristics of the Subjects

Characteristics	CHD patients (n=79)	Healthy controls (n=94)	p-Value
Age (years)	55.2±6.4	47.3±5.1	0.035
Gender (M/F)	47/32	55/39	0.896
BMI	25.8±2.7	23.6±4.7	0.172
SBP (mmHg)	139±21	117±16	0.026
DBP (mmHg)	103±13	82±15	0.019
Cholesterol (mg/dL)	268±31	253±27	0.369
Triglycerides (mg/dL)	177±42	159±16	0.442
LDL-c (mg/dL)	192±23	143±26	0.028
HDL-c (mg/dl)	24±8	39±7	0.024
HbA1c (mmol/mol)	8.1±1.5	5.1±0.2	0.037
WBC count (×10⁻³/mm³)	7.2±0.8	6.9±0.6	0.512
Smoker (%)	68.4 (54/79)	44.7 (42/94)	0.002
Diabetes (%)	7.6 (6/79)	2.1 (2/94)	0.088
PTH (pg/mL)	98±11	65±13	<0.001

BMI, body mass index; CHD, coronary heart disease; DBP, diastolic blood pressure; F, female; HbA1c, glycosylated hemoglobin; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; M, male; PTH, parathyroid hormone; SBP, systolic blood pressure; WBC, white blood cell.

Relationship between serum PTH level and CHD risk factors

Pearson's correlation analysis indicated that age, SBP, DBP, LDL-c, HDL-c, HbA1c, history of smoking, and serum PTH level were all risk factors for CHD (all p<0.05). Serum PTH level was positively correlated with DBP (r=0.256, p=0.010) and HbA1c (r=0.223, p=0.003), while not related with other risk factors of CHD (all p>0.05). Multiple linear regression analysis showed that SBP, DBP, LDL-c, and HDL-c might be important determinants of CHD (all p<0.05) (Table 2). Further, serum PTH level is also an independent risk factor for CHD (p<0.001).

Table 2.

Multiple Linear Regression Analysis of Risk Factors for Coronary Heart Disease

Risk factors	B	SE	β	t	p
SBP	0.059	0.009	0.513	7.134	<0.001
DBP	0.184	0.130	0.427	2.323	0.024
LDL-c	0.225	0.261	0.139	2.975	0.007
HDL-c	−0.097	0.023	−0.193	2.467	0.017
PTH	0.235	0.007	0.620	3.810	<0.001

B, regression coefficient; β, beta coefficient; SE, standard error.

Discussion

This meta-analysis study revealed that serum PTH level in the CHD group was significantly higher than that in the control group, suggesting that PTH may potentially be associated with the increased risk of CHD. Although the precise roles of PTH in the development and progression of CHD remain only partially understood, we believe that elevated PTH level might lead to abnormal energy metabolism, reduced cardiac output, and hypertrophy of cardiomyocytes, which are involved in the development of CHD (Slinin et al., 2005). Excess PTH may reduce lipoprotein lipase activity in the plasma, which in turn results in impaired or reduced lipid removal from the circulation and consequently causing hyperlipidemia (Evenepoel et al., 2005). There is evidence that PTH may be a crucial pathogenetic factor in the disturbance of blood glucose metabolism through insulin resistance combined with inability of the β-cells to secrete insulin, which is related to the failure in overcoming the defect in peripheral glucose removal (Chiu et al., 2000). Serum PTH could indirectly cause dysfunctions in lipid and glucose metabolism in vivo by inducing a rise in calcium concentration, which would eventually lead to an increase in serum total cholesterol and triglyceride concentrations, which could finally play important roles in the incidence of CHD (Frost et al., 2010; Ishay et al., 2011). Multiple linear regression analysis showed that PTH was an independent risk factor in CHD, suggesting that PTH may have significant effect on the development and progression of CHD. While the underlying mechanism is still only partially understood, we suggested that a probable explanation may be that estrogen possesses a vital role in protecting vasculature indirectly through mediation of lipoprotein metabolism and directly by affecting the vessel wall itself (Miller and Duckles, 2008). Evidence from a previous epidemiological study also indicated that estrogen replacement therapy in postmenopausal women could decrease their CHD risk (Hsia et al., 2006).

HbA1c is the most abundant minor component of hemoglobin in normal red cells and increases as much as threefold in diabetic red cells (Gerstein, 2004). A previous study evidenced that metabolic changes of blood lipid and blood glucose reflected by HbA1c levels may lead to increased CHD risk (Jorgensen et al., 2004). It has been suggested that HbA1c values in the normal range can identify whether persons are at enhanced risk for CHD and death before the diagnosis of diabetes, implying that HbA1c is a useful marker of cardiovascular risk and tissue death (Thanopoulou et al., 2010). We also found a positive association between serum PTH level and elevated HbA1c level, implying that PTH may have a vital role in the development of CHD by impacting the HbA1c level. Although the exact relationship between PTH and HbA1c levels is still not fully explored, we hypothesized that increased PTH levels may be involved in carbohydrate and lipid metabolism, which may result in elevated HbA1c level and contributes to the development and progression of CHD (Akmal et al., 1990; Hjelmesaeth et al., 2009). In a previous study, metabolic changes in blood lipid and blood glucose reflected by HbA1c levels may lead to increased CHD risk (Jorgensen et al., 2004).

It has been widely acknowledged that hypertension is of significant importance in being an early sign of cardiovascular complications, and SBP and DBP may be robust predictors of CHD events after adjustment for age, sex, and other risk factors (Franklin et al., 2001). The results observed in our study showed that PTH is positively associated with DBP, suggesting that increased PTH levels may lead to hypertension and increase the risk of incident CHD. It was suspected that elevated levels of PTH may result in the increase of calcium in cardiac cells and osteoblast-like cells, and thereby promoting atherosclerotic calcium build-up, an action that, if it occurred in vascular smooth muscle cells, could possibly induce increased vascular constriction and elevated BP, and consequently CHD events (Jorde et al., 2005; Weaver, 2013). PTH was strongly suggested to be related to the variability in BP that is generally attributed to elevation of the PTH receptor promoting the enhancement of myocardial contractility and ejection fraction (He and Scragg, 2011). Consistent with a recent investigation, serum PTH was demonstrated to be associated with the occurrence of CHD through BP regulation in normotensive subjects (Hagstrom et al., 2009).

Apart from the results discussed just now, several limitations of our study should be addressed. First, relatively short-term follow-up limited our ability to properly record the mortality of CHD patients. Second, small sample sizes in our current study may lead to sample selection bias that may have insufficient and noncomprehensive statistical power to adequately study the role of PTH in the pathogenesis of CHD. Moreover, patients with elevated serum calcium levels were excluded, while the abnormal Ca²⁺ modulation might be associated with the development of CHD (Polonsky et al., 2010); thus, more in-depth investigation is required on the role of PTH in cardiovascular system and CHD.

In conclusion, our findings provide evidence that serum PTH levels may be involved in the pathogenesis of CHD. Thus, PTH could be used as an important biomarker in the diagnosis of CHD. However, due to the limitations acknowledged just now, larger sample-size research with more detailed data is necessary in order to acquire a more statistically significant analysis.

Footnotes

Acknowledgment

The authors would like to acknowledge the reviewers for their helpful comments on this article.

Author Disclosure Statement

The authors declare no financial conflicts of interest.

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