GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 18, Number 10, 2014 ª Mary Ann Liebert, Inc. Pp. 670–674 DOI: 10.1089/gtmb.2014.0074
Serum Parathyroid Hormone as a Potential Novel Biomarker of Coronary Heart Disease Fa-Li Zhao, Ying-Zhong Zhang, Guo-Xia Tai, Yu Wang, Qiu-Hui Tong, and Lu Fu
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
C
oronary 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 endotheliumderived 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
Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China.
670
PARATHYROID HORMONE AND CHD
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.
671
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 v2 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, lowdensity lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) levels and lower HDL-c levels
Table 1. Baseline Characteristics of the Subjects CHD patients (n = 79)
Healthy controls (n = 94)
Measurements
Characteristics
All major risk factors were assessed during recruitment. Serum cholesterol, triglycerides, and very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and highdensity 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 - 70C until analysis. Serum lipid concentrations, glycosylated hemoglobin (HbA1c), and ionized calcium were derived from
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 7.2 – 0.8 6.9 – 0.6 0.512 ( · 10 - 3/mm3) 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
p-Value
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.
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ZHAO ET AL.
Table 2. Multiple Linear Regression Analysis of Risk Factors for Coronary Heart Disease Risk factors SBP DBP LDL-c HDL-c PTH
B
SE
b
t
p
0.059 0.184 0.225 - 0.097 0.235
0.009 0.130 0.261 0.023 0.007
0.513 0.427 0.139 - 0.193 0.620
7.134 2.323 2.975 2.467 3.810
< 0.001 0.024 0.007 0.017 < 0.001
B, regression coefficient; b, beta coefficient; SE, standard error.
(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). 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). 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 b-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 medi-
ation 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 shortterm 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.
PARATHYROID HORMONE AND 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. 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. References
Akmal M, Kasim SE, Soliman AR, et al. (1990) Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure. Kidney Int 37:854–858. Bergwitz C, Juppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104. Chiu KC, Chuang LM, Lee NP, et al. (2000) Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism 49:1501–1505. Cusano NE, Anderson L, Rubin MR, et al. (2013) Recovery of parathyroid hormone secretion and function in postoperative hypoparathyroidism: a case series. J Clin Endocrinol Metab 98:4285–4290. Evenepoel P, Claes K, Kuypers D, et al. (2005) Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study. Nephrol Dial Transplant 20:1714–1720. Franklin SS, Larson MG, Khan SA, et al. (2001) Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 103:1245–1249. Frost M, Abrahamsen B, Nielsen TL, et al. (2010) Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism. Clin Endocrinol (Oxf) 73:573–580. Gerstein HC (2004) Glycosylated hemoglobin: finally ready for prime time as a cardiovascular risk factor. Ann Intern Med 141:475–476. Grandi NC, Breitling LP, Hahmann H, et al. (2011) Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease. Heart 97:1215–1221. Hagstrom E, Hellman P, Larsson TE, et al. (2009) Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation 119:2765–2771. He JL, Scragg RK (2011) Vitamin D, parathyroid hormone, and blood pressure in the National Health and Nutrition Examination Surveys. Am J Hypertens 24:911–917. Hjelmesaeth J, Hofso D, Aasheim ET, et al. (2009) Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a crosssectional study. Cardiovasc Diabetol 8:7. Holme I, Tonstad S (2013) Association of coronary heart disease mortality with risk factors according to length of followup and serum cholesterol level in men: the Oslo Study cohort. Eur J Prev Cardiol 20:168–175. Hsia J, Langer RD, Manson JE, et al. (2006) Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 166:357–365.
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Huang PL (2009) eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab 20:295–302. Ishay A, Herer P, Luboshitzky R (2011) Effects of successful parathyroidectomy on metabolic cardiovascular risk factors in patients with severe primary hyperparathyroidism. Endocr Pract 17:584–590. Jorde R, Svartberg J, Sundsfjord J (2005) Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens 23:1639–1644. Jorgensen L, Jenssen T, Joakimsen O, et al. (2004) Glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the Tromso study. Circulation 110:466–470. Kanhai DA, Kranendonk ME, Uiterwaal CS, et al. (2013) Adiponectin and incident coronary heart disease and stroke. A systematic review and meta-analysis of prospective studies. Obes Rev 14:555–567. Kivimaki M, Nyberg ST, Fransson EI, et al. (2013) Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data. CMAJ 185:763–769. Li X, Kramer MC, CM VDL, et al. (2012) Early onset of endothelial cell proliferation in coronary thrombi of patients with an acute myocardial infarction: implications for plaque healing. J Thromb Haemost 10:466–473. Loncar G, Bozic B, Dimkovic S, et al. (2011) Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure. J Endocrinol Invest 34:e78–85. Miller VM, Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–241. Odegaard AO (2013) Coronary heart disease: what hope for the developing world? Heart 99:1227–1229. Pilz S, Tomaschitz A, Drechsler C, et al. (2010) Parathyroid hormone level is associated with mortality and cardiovascular events in patients undergoing coronary angiography. Eur Heart J 31:1591–1598. Polonsky TS, McClelland RL, Jorgensen NW, et al. (2010) Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 303:1610–1616. Poss J, Custodis F, Werner C, et al. (2011) Cardiovascular disease and dyslipidemia: beyond LDL. Curr Pharm Des 17:861–870. Rubinshtein R, Kuvin JT, Soffler M, et al. (2010) Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 31:1142–1148. Schierbeck LL, Jensen TS, Bang U, et al. (2011) Parathyroid hormone and vitamin D—markers for cardiovascular and all cause mortality in heart failure. Eur J Heart Fail 13:626–632. Schulz E, Gori T, Munzel T (2011) Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 34:665– 673. Slinin Y, Foley RN, Collins AJ (2005) Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 16:1788–1793. Taylor EN, Rimm EB, Stampfer MJ, et al. (2011) Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J 161:956–962. Teramoto T, Sasaki J, Ishibashi S, et al. (2014) Coronary artery disease. J Atheroscler Thromb 21:86–92. Thanopoulou A, Karamanos B, Archimandritis A (2010) Glycated hemoglobin, diabetes, and cardiovascular risk in
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nondiabetic adults. N Engl J Med 362:2030–2031; author reply 2031. van Ballegooijen AJ, Reinders I, Visser M, et al. (2013a) Serum parathyroid hormone in relation to all-cause and cardiovascular mortality: the Hoorn study. J Clin Endocrinol Metab 98:E638–45. van Ballegooijen AJ, Visser M, Kestenbaum B, et al. (2013b) Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study). Am J Cardiol 111:418–424. van Gils JM, Zwaginga JJ, Hordijk PL (2009) Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol 85:195–204. Vanhoutte PM (2009) Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J 73:595–601.
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Weaver J (2013) Insights into how calcium forms plaques in arteries pave the way for new treatments for heart disease. PLoS Biol 11:e1001533.
Address correspondence to: Lu Fu, MD Department of Cardiology The First Affiliated Hospital of Harbin Medical University No. 23, Youzheng Street Nangang District Harbin 150001 Heilongjiang Province People’s Republic of China E-mail: [email protected]
Serum Parathyroid Hormone as a Potential Novel Biomarker of Coronary Heart Disease Fa-Li Zhao, Ying-Zhong Zhang, Guo-Xia Tai, Yu Wang, Qiu-Hui Tong, and Lu Fu
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
C
oronary 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 endotheliumderived 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
Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China.
670
PARATHYROID HORMONE AND CHD
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.
671
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 v2 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, lowdensity lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) levels and lower HDL-c levels
Table 1. Baseline Characteristics of the Subjects CHD patients (n = 79)
Healthy controls (n = 94)
Measurements
Characteristics
All major risk factors were assessed during recruitment. Serum cholesterol, triglycerides, and very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and highdensity 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 - 70C until analysis. Serum lipid concentrations, glycosylated hemoglobin (HbA1c), and ionized calcium were derived from
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 7.2 – 0.8 6.9 – 0.6 0.512 ( · 10 - 3/mm3) 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
p-Value
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.
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Table 2. Multiple Linear Regression Analysis of Risk Factors for Coronary Heart Disease Risk factors SBP DBP LDL-c HDL-c PTH
B
SE
b
t
p
0.059 0.184 0.225 - 0.097 0.235
0.009 0.130 0.261 0.023 0.007
0.513 0.427 0.139 - 0.193 0.620
7.134 2.323 2.975 2.467 3.810
< 0.001 0.024 0.007 0.017 < 0.001
B, regression coefficient; b, beta coefficient; SE, standard error.
(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). 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). 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 b-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 medi-
ation 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 shortterm 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.
PARATHYROID HORMONE AND 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. 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. References
Akmal M, Kasim SE, Soliman AR, et al. (1990) Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure. Kidney Int 37:854–858. Bergwitz C, Juppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104. Chiu KC, Chuang LM, Lee NP, et al. (2000) Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism 49:1501–1505. Cusano NE, Anderson L, Rubin MR, et al. (2013) Recovery of parathyroid hormone secretion and function in postoperative hypoparathyroidism: a case series. J Clin Endocrinol Metab 98:4285–4290. Evenepoel P, Claes K, Kuypers D, et al. (2005) Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study. Nephrol Dial Transplant 20:1714–1720. Franklin SS, Larson MG, Khan SA, et al. (2001) Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 103:1245–1249. Frost M, Abrahamsen B, Nielsen TL, et al. (2010) Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism. Clin Endocrinol (Oxf) 73:573–580. Gerstein HC (2004) Glycosylated hemoglobin: finally ready for prime time as a cardiovascular risk factor. Ann Intern Med 141:475–476. Grandi NC, Breitling LP, Hahmann H, et al. (2011) Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease. Heart 97:1215–1221. Hagstrom E, Hellman P, Larsson TE, et al. (2009) Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation 119:2765–2771. He JL, Scragg RK (2011) Vitamin D, parathyroid hormone, and blood pressure in the National Health and Nutrition Examination Surveys. Am J Hypertens 24:911–917. Hjelmesaeth J, Hofso D, Aasheim ET, et al. (2009) Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a crosssectional study. Cardiovasc Diabetol 8:7. Holme I, Tonstad S (2013) Association of coronary heart disease mortality with risk factors according to length of followup and serum cholesterol level in men: the Oslo Study cohort. Eur J Prev Cardiol 20:168–175. Hsia J, Langer RD, Manson JE, et al. (2006) Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 166:357–365.
673
Huang PL (2009) eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab 20:295–302. Ishay A, Herer P, Luboshitzky R (2011) Effects of successful parathyroidectomy on metabolic cardiovascular risk factors in patients with severe primary hyperparathyroidism. Endocr Pract 17:584–590. Jorde R, Svartberg J, Sundsfjord J (2005) Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens 23:1639–1644. Jorgensen L, Jenssen T, Joakimsen O, et al. (2004) Glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the Tromso study. Circulation 110:466–470. Kanhai DA, Kranendonk ME, Uiterwaal CS, et al. (2013) Adiponectin and incident coronary heart disease and stroke. A systematic review and meta-analysis of prospective studies. Obes Rev 14:555–567. Kivimaki M, Nyberg ST, Fransson EI, et al. (2013) Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data. CMAJ 185:763–769. Li X, Kramer MC, CM VDL, et al. (2012) Early onset of endothelial cell proliferation in coronary thrombi of patients with an acute myocardial infarction: implications for plaque healing. J Thromb Haemost 10:466–473. Loncar G, Bozic B, Dimkovic S, et al. (2011) Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure. J Endocrinol Invest 34:e78–85. Miller VM, Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–241. Odegaard AO (2013) Coronary heart disease: what hope for the developing world? Heart 99:1227–1229. Pilz S, Tomaschitz A, Drechsler C, et al. (2010) Parathyroid hormone level is associated with mortality and cardiovascular events in patients undergoing coronary angiography. Eur Heart J 31:1591–1598. Polonsky TS, McClelland RL, Jorgensen NW, et al. (2010) Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 303:1610–1616. Poss J, Custodis F, Werner C, et al. (2011) Cardiovascular disease and dyslipidemia: beyond LDL. Curr Pharm Des 17:861–870. Rubinshtein R, Kuvin JT, Soffler M, et al. (2010) Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 31:1142–1148. Schierbeck LL, Jensen TS, Bang U, et al. (2011) Parathyroid hormone and vitamin D—markers for cardiovascular and all cause mortality in heart failure. Eur J Heart Fail 13:626–632. Schulz E, Gori T, Munzel T (2011) Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 34:665– 673. Slinin Y, Foley RN, Collins AJ (2005) Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 16:1788–1793. Taylor EN, Rimm EB, Stampfer MJ, et al. (2011) Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J 161:956–962. Teramoto T, Sasaki J, Ishibashi S, et al. (2014) Coronary artery disease. J Atheroscler Thromb 21:86–92. Thanopoulou A, Karamanos B, Archimandritis A (2010) Glycated hemoglobin, diabetes, and cardiovascular risk in
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nondiabetic adults. N Engl J Med 362:2030–2031; author reply 2031. van Ballegooijen AJ, Reinders I, Visser M, et al. (2013a) Serum parathyroid hormone in relation to all-cause and cardiovascular mortality: the Hoorn study. J Clin Endocrinol Metab 98:E638–45. van Ballegooijen AJ, Visser M, Kestenbaum B, et al. (2013b) Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study). Am J Cardiol 111:418–424. van Gils JM, Zwaginga JJ, Hordijk PL (2009) Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol 85:195–204. Vanhoutte PM (2009) Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J 73:595–601.
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Weaver J (2013) Insights into how calcium forms plaques in arteries pave the way for new treatments for heart disease. PLoS Biol 11:e1001533.
Address correspondence to: Lu Fu, MD Department of Cardiology The First Affiliated Hospital of Harbin Medical University No. 23, Youzheng Street Nangang District Harbin 150001 Heilongjiang Province People’s Republic of China E-mail: [email protected]
